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Internal Medicine Diagnosis & Treatment & Approaches

Prepared By The Department Of Internal Medicine Aleppo University Hospital

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INTRODUCTION
This topics prepared by the resident doctor in the department of the Internal Medicne of Aleppo University Hospital . We depend in preparing this topics on the last available verision of up to date 17.3 and Current 2010 and MKSAP 15. We centered on the most common disease and most Hard issue . For Any Question : Email Dr. Waseem Zakaria (Dr-house83@hotmail.com) Aleppo July 2010

Authors
1. Dr. Waseem zakaria (4ed Year) 2. Dr. Firas Oraby (3ed Year) 3. Dr . Bian Najem (3ed Year) 4. Dr. Mohammad Hnan (3ed Year) 5. Dr. Mohammad Shikho (3ed Year) 6. Dr. Amir kebbieh (3ed Year) 7. Dr. Mohamad Hassan Al-Taher (3ed Year) 8. Dr. Saad Hadad (3ed Year) 9. Dr. Khaled Hj Nasan (3ed Year) 10. Dr. Shaza AL-Bakar (3ed Year) 11. Dr. Mahmood Draw (3ed Year) 12. Dr. Noura Ajoury (3ed Year) 13. Dr. Khaled Yaseen (2st Year) 14. Dr. Mohammed Abdelmohsen (2st Year) 15. Dr. Abd Al-rahman Ato (2st Year) 16. Dr. Jorg Khwam (2st Year) 17. Dr. Rama Marachi (2st Year) 18. Dr. Nour Kounber(2st Year) 19. Dr. Ahmad Al-yousef (2st Year) 20. Dr. Hasen Al-Abdulla (2st Year) 21. Dr. Iman Alsayd (2st Year) 22. Dr. Naeim Kassar (2st Year) 23. Dr. Mohammad Joid (2st Year) 24. Dr. Bsher Abo Dan (2st Year) 25. Dr. Razmik Behjian (2st Year) 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. Dr. Ahmed Montaser Jazbh (2st Year) Dr. Anas Kizawi (2st Year) Dr. Mohammad Jounid (2st Year) Dr. Amer Al-Mahmoud (2st Year) Dr. Khalil Aiat (2st Year) Dr. Hamed Byoud (2st Year) Dr. Hamza Almoraweh (2st Year) Dr. Alaeldin Addas (2st Year) Dr. Mnal Bader (2st Year) Dr. Sami Hadad (2st Year) Dr. Basel Mtly (2st Year) Dr. Mohamad Ahmad Aisa (2st Year) Dr. Hazem Mnadel (2st Year) Dr. Mustafa Shehade (2st Year) Dr. Muhammad Talal Kayali (2st Year) Dr. Hassan Shaar (2st Year) Dr. Rasha Barkat (2st Year) Dr. Issa Al-farj (2st Year) Dr. Nael Hariri (2st Year) Dr. Khaled Ibesh (2st Year) Dr. Rana Alnaser (2st Year) Dr. Abd Almasih Nwya (2st Year) Dr. Fatema Tabak (2st Year) Dr. Ahmad Alsayed (2st Year) Dr. Abd Alahad Dawood (2st Year)

CONTENTS
CARDIOLOGY Management of ST-Elevation Myocardial Infarction .. Dr. Firas Oraby Management of unstable angina/NonST-Elevation Myocardial Infarction ... Dr. Waseem zakaria Management of heart failure Dr. Saad Hadad Treatment of acute pulmonary embolism Dr. Hamza Almoraweh Evaluation and management of acute pericarditis ... Dr. Fatema Tabak Aortic dissection .. Dr. Mohammad Joid Approach To The Diagnosis And Treatment Of Wide QRS Tachycardias . Dr. Bian Najem Advanced cardiopulmonary life support (ACLS) ... Dr. Alaeldin Addas Acute rheumatic fever .. Dr. Waseem zakaria Therapy of native and prosthetic valve endocarditis ... Dr. Khaled Ibesh Prophylaxis for bacterial endocarditis .. Dr. Muhammad Talal Kayali Treatment of deep vein thrombosis .. Dr. Abd Almasih Nwya Management of a supratherapeutic INR .. Dr. Abd Al-rahman Ato Choice of therapy in essential hypertension Dr. Mustafa Shehade ENDOCRINOLOGY Diagnosis of diabetes mellitus . Dr. Ahmad Alsayed Diagnostic criteria for diabetic ketoacidosis and hyperosmolar hyperglycemic state . Dr. Basel Mtly Protocol for the management of patients with HHS Dr. Basel Mtly Protocol for the management of patients with DKA Dr. Basel Mtly Diagnostic approach to hypoglycemia in adults .. Dr. Hamed Byoud Initial management of blood glucose in type 2 diabetes mellitus Dr. Razmik Behjian Treatment of acute adrenal insufficiency (adrenal crisis) Dr. Mnal Bader Treatment of chronic primary adrenal insufficiency Dr. Mnal Bader Testing to establish the diagnosis of cushing's syndrome Dr. Hamza Almoraweh Diagnostic approach to and treatment of thyroid nodules ... Dr. Alaeldin Addas Polycystic ovary syndrome in adults .. Dr. Hasen Al-Abdulla GASTROENTEROLOGY Approach to the adult with acute diarrhea .. Dr. Bian Najem Approach to the patient with abnormal liver function tests ..... Dr. Mohamad Hassan Al-Taher Diagnosis and treatment of celiac disease Dr. Hamed Byoud Treatment of bleeding peptic ulcers . Dr-Amer al-mahmoud Treatment regimens for helicobacter pylori Dr-Amer Al-Mahmoud Management of variceal hemorrhage ... Dr. Issa Al-farj Treatment of acute pancreatitis Dr. Ahmed Montaser Jazbh Diagnosis and treatment of hepatorenal syndrome .. Dr. Amir kebbieh Gastroesophageal reflux disease in adults ... Dr. Waseem zakaria 8 14 40 49 53 57 62 73 87 89 91 93 96 103

103 105 106 107 108

Treatment and serologic markers of autoimmune hepatitis . Dr. Anas Kizawi Medical management of ulcerative colitis ... Dr. Anas Kizawi Medical management of crohn's disease .. Dr. Anas Kizawi Treatment of hepatic encephalopathy .. Dr. Iman Alsayd Management of spontaneous bacterial peritonitis Dr. Iman Alsayd Management of chronic hepatitis B ..... Dr. Naeim Kassar HEMATOLOGY Use of antimicrobial in neutropenic patients with cancer .... Dr. Mohammad Joid Anemia due to iron deficiency . Dr. Rasha Barkat TTP-HUS syndrome ... Dr. Waseem zakaria Multiple myeloma ... Dr. Khaled Yaseen Disseminated intravascular coagulation .. Dr. Rasha Barkat INFECTIOUS DISEASES Diabetic foot infections Dr. Khaled Yaseen Septic shock . Dr. Waseem zakaria HIV infection .. Dr. Razmik Behjian and Dr. Naeim Kassar Malaria . Dr. Abd Alahad Dawood H1N1 influenza ('swine influenza') .. Dr. Waseem zakaria NEPHROLOGY Radiocontrast media-induced acute renal failure Dr. Shaza AL-Bakar Renal tubular acidosis .. Dr. Firas Oraby Treatment of hypocalcemia .. Dr. Alaeldin Addas Treatment of hyperkalemia Dr. Rana Alnaser Seizures in patients undergoing hemodialysis . Dr. Firas Oraby Management of suspected nephrolithiasis .. Dr. Hamed Byoud Minimal change disease in adults ... Dr. Mohammed Abdelmohsen General management of chronic kidney disease .. Dr. Mohammad Hnan and Dr. Saad Hadad Indications for initiation of dialysis in chronic kidney disease ... Dr. Mohamad Ahmad Aisa NEUROLOGY Guillain-barr syndrome in adults ... Dr. Alaeldin Addas Spontaneous intracerebral hemorrhage .. Dr. Khalil Aiat Subarachnoid hemorrhage Dr. Khalil Aiat Carotid endarterectomy Dr. Sami Hadad Bell's palsy Dr. Mohammad Jounid Treatment of status epilepticus. Dr. Mahmood Draw Viral encephalitis . Dr. Amir kebbieh treatment of Headeach in adults . Dr. Mohammad Jounid

Treatment and prevention of bacterial meningitis in adults. Dr. Mohammad Jounid Treatment of of multiple sclerosis ... Dr. Anas Kizawi PULMONOLOGY Treatment of of acute exacerbations of COPD. Dr. Noura Ajoury Treatment of acute exacerbations of asthma Dr.Hamza Almoraweh Treatment of idiopathic pulmonary fibrosis Dr. Sami Hadad and Dr. Jorg Khwam Treatment of bronchiectasis Dr. Jorg Khwam sarcoidosis .... Dr. Mohammed Jouid Treatment of community-acquired pneumonia Dr. Nour Kounber RHEUMATOLOGY Antiphospholipid syndrome. Dr. Hassan Shaar An Approch to Vasculitis ..... Dr. Waseem zakaria Treatment and Prevention of acute gout .. Dr.Mohammed Abdelmohsen Diagnosis and management of osteoporosis .... Dr. Rama Marachi

CARDIOLOGY

2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of ST-Elevation Myocardial Infarction

ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure

Treatment Of Acute Pulmonary Embolism

Respiratory Support : Supplemental Oxygen Should Be Administered If Hypoxemia Exists. Patients With Significant Hypoxemia Or Hemodynamic Compromise Should Be Admitted To The Intensive Care Unit. Severe Hypoxemia Or Respiratory Failure Should Prompt Intubation And Mechanical Ventilation. Hemodynamic Support : If The Patient Presents With Systemic Hypotension (Sbp <90 Mmhg Or A Drop In Sbp Of 40 Mmhg From Baseline), Prompt Hemodynamic Support Should Be Instituted. Intravenous Fluid Administration Is First-Line Therapy (Usually Normal Saline), It Should Be Administered Cautiously Because Increased Right Ventricular However, Clinicians Should Be Wary Of Administering More Than 500 To 1000 Ml Of Normal Saline During The Initial Resuscitation Period. For Patients Whose Hypotension Does Not Resolve With Intravenous Fluids, We Recommend Prompt Vasopressor Therapy (Dopamine, Epinephrine, Or A Combination Of Dobutamine Plus Norepinephrine) ( Grade 1b). We Suggest Using Norepinephrine As The Initial Agent ( Grade 2c). Combination Of Dobutamine Plus Norepinephrine Increased Myocardial Contractility, While Minimizing Both Vasodilation And The Risk Of Hypotension From Dubotamin. Norepinephrine Dosage : Amp Contain 4 Mg ; Initial: 0.5-1 Mcg/Minute And Titrate To Desired Response; 8-30 Mcg/Minute Is Usual Range Dobutamine Dosage: Amp Contain 250mg ; I.V. Infusion: 2.5-20 Mcg/Kg/Minute; Maximum: 40 Mcg/Kg/Minute, Dopamine Dosage: Amp Contain 200 Mg ; I.V. Infusion: 1-5 Mcg/Kg/Minute Up To 50 Mcg/Kg/Minute, Titrate To Desired Response; Infusion May Be Increased By 1-4 Mcg/Kg/Minute At 10- To 30-Minute Intervals Until Optimal Response Is Obtained Anticoagulation For Patients In Whom There Is A High Clinical Suspicion Of Pe And No Excess Risk Of Bleeding, We Recommend That Empiric Anticoagulation Be Initiated Immediately And Continued During The Diagnostic Evaluation ( Grade 1b). For Patients In Whom There Is A Low Or Moderate Suspicion Of Pe Or An Increased Risk Of Bleeding, Decisions About Empiric Anticoagulation Must Be Made On A Case-By-Case Basis. The Efficacy Of Anticoagulant Therapy Depends Upon Achieving A Therapeutic Level Of Anticoagulation Within The First 24 Hours Of Treatment Therapeutic Options : Sc Lmwh, Iv Ufh, Sc Ufh, And Sc Fondaparinux Fondaparinux o Fondaparinux Is Administered Subcutaneously Once Per Day. o The Dose: 5 Mg For <50 Kg, 7.5 Mg For 50-100 Kg, And 10 Mg For >100 Kg. Low Molecular Weight Heparin : o Enoxaparin, Tinzaparin, Dalteparin, Nadroparin, Ardeparin, And Reviparin. o The Preferred Anticoagulant For Initial Therapy In Most Cases Of Acute Pe o We Recommend Sc Lmwh For Most Hemodynamically Stable Patients With Pe. o Dosing Of Enoxaparin (Clexan):1 Mg/Kg Every 12 Hours Sc . Alternatively, It Can Be Administered Subcutaneously At A Dose Of 1.5 Mg/Kg Of Once Daily. The 1 Mg/Kg Every 12 Hours Regimen Is Preferred For Patients With Cancer, Extensive Clot Burden, An Actual Body Weight Between 101 - 150 Kg, Or Bmi Between 30 - 40 Unfractionated Heparin : o For Patients With Pe And Severe Renal Failure (Creatinine Clearance 30 Ml/Min), We Suggest Ufh Rather Than Sc Lmwh o We Suggest Iv Ufh Rather Than An Alternative Anticoagulantwhen When Any Of The Following Circumstances Exist: 1) Persistent Hypotension Due To Pe 2) Increased Risk Of Bleeding 3) Thrombolysis Is Being Considered For The Shortest Duration When Iv Ufh Is The Anticoagulant Used Prior To Thrombolysis. 4) Subcutaneous Absorption (Eg, Morbid Obesity, Severe Anasarca)

Heparin Vial 5 Ml Contain 25000 Unit Every Ml Contain 5000 Unit Dosing Of Heparin Intravenous : Starting Bolus Of 80 Units/Kg, Followed By An Infusion At 18 Units/Kg Per Hour Or Fixed Dosing (Bolus Of 5000 Units (1 Ml) , Followed By An Infusion At 1000 Units/Hour) Initial Dose 80 Units/Kg Bolus, Then 18 Units/Kg Per Hour Aptt <35 Sec (<1.2 X Control) 80 Units/Kg Bolus, Then Increase Infusion Rate By 4 Units/Kg Per Hour Aptt 35-45 Sec (1.2-1.5 X 40 Units/Kg Bolus, Then Increase Infusion Rate By 2 Units/Kg Per Hour Control) Aptt 46-70 Sec (1.5-2.3 X No Change Control) Aptt 71-90 Sec (2.3-3.0 X Decrease Infusion Rate By 2 Units/Kg Per Hour Control) Aptt >90 Sec (>3.0 X Control) Hold Infusion 1 Hour, Then Decrease Infusion Rate By 3 Units/Kg Per Hour APTT Should Be Drawn Every 6 Hours After Initial Dose Or After Each Dose Change. o Dosing Of Heparin Subcutaneous : Initiated At A Dose Of 17,500 Units ( 3.5 Ml) Or 250 Units/Kg Every 12 Hours. The Dose Should Then Be Titrated To Achieve A Therapeutic Aptt. The First Aptt Is Generally Measured Six Hours After The Second Dose. The Magnitude Of Most Dose Adjustments Should Be An Increase Or Decrease Of 10 To 30 Percent. The Aptt Should Be Measured Six Hours After The Second Injection That Follows Each Dose Adjustment. Once A Stable Dose Is Achieved, The Aptt May Be Measured After Three To Four Days Of Treatment And Then Every Few Weeks . o Sc Ufh May Also Be Administered By Giving An Initial Dose Of 333 Units/Kg, Followed By A Standing Dose Of 250 Units/Kg Every 12 Hours. The Aptt Is Not Monitored With This Protocol. Warfarin o Warfarin Can Be Initiated On The Same Day Or After Heparin Or Fondaparinux Is Begun. o It Should Not Be Initiated Prior To Heparin Or Fondaparinux Because Warfarin Alone Is Associated With A Three-Fold Increase In The Incidence Of Recurrent Pe Or Dvt o Warfarin Should Be Overlapped With Heparin Or Fondaparinux For A Minimum Of 5 Days And Until The Inr Has Been Within The Therapeutic Range (2.0 To 3.0) For At Least 24 Hours o Requires Approximately 36 To 72 Hours To Start Its Effection . o Starting Dose : 5 Mg/Day For Most Patients ,For Patient More Than 80 Kg Starting Dose : 7.5 Mg/Day o Doses Of 5 Mg/Day May Be More Appropriate In The Elderly, Debilitated, Or Malnourished Patient, Or Those With Congestive Failure, Liver Disease, Recent Major Surgery, Or Are Taking Medication Known To Increase Sensitivity To Warfarin (Eg, Amiodarone). o Initial Doses >5 Mg/Day Can Be Employed In Selected Patients Deemed To Be At Low Risk For Bleeding And/Or In Those Previously Treated With Warfarin At Maintenance Doses >5 Mg/Day. o Loading Doses >10 Mg/Day Should Be Avoided. o Initial Monitoring We Suggest That The Patient Have A Baseline Inr Determination Before Initiation Of Treatment, Receive Two Or Three Daily Doses Of Warfarin, And Have The Inr Checked Again On The Following Day. Subsequent Doses Are Modified, Up Or Down, In Order To Achieve A Target Inr Of 2.5 (Target Range: 2.0 To 3.0) o Initially, Inr Measurements Are Required Every One To Two Days. Once The Patient's Warfarin Dose Has Stabilized For At Least One To Two Weeks, Subsequent Inr Monitoring Can Be Performed At Two To Four Week Intervals Duration Of Therapy : o For Patients With A First Episode Of Pe Due To A Temporary Risk Factor (Eg, Surgery, Immobilization, Trauma), We Recommend Warfarin Therapy For Three Months, Rather Than A Shorter Duration. (Grade 1a) o For Patients With A First Episode Of Unprovoked Pe, We Recommend Warfarin Therapy For At Least Three Months, Rather Than A Shorter Duration (Grade 1a). o The Potential Benefits And Risks Of Indefinite Anticoagulant Therapy Should Be Assessed After The Three Months Of Anticoagulant Therapy.

o o

For Patients Who Do Not Have An Increased Risk Of Bleeding, We Suggest Indefinite Warfarin Therapy (Grade 2b). o For Patients With Two Or More Episodes Of Pe, We Recommend Indefinite Warfarin Therapy Thrombolysis Improves Rv Function And Pulmonary Perfusion. However, No Clinical Trial Has Been Large Enough To Conclusively Demonstrate A Mortality Benefit. The Most Widely Accepted Indication For Thrombolytic Therapy Is Persistent Hypotension Due To Pe (Ie, Massive Pe) Some Clinicians Believe That Thrombolysis Should Be Considered On A Case-By-Case Such As: 1) Persistent Hypotension (Sbp <90 Mm Hg Or A Drop In SBP Of 40 mmHg From Baseline) 2) Severe Hypoxemia 3) Large Perfusion Defect On Ventilation-Perfusion Scans 4) Extensive Embolic Burden On Computed Tomography (Ct) 5) Right Ventricular Dysfunction 6) Free-Floating Right Atrial Or Ventricular Thrombus 7) Patent Foramen Ovale 8) Extensive Deep Vein Thrombosis Among These Situations, Only Persistent Hypotension Due To Pe Is A Widely Accepted Indication For Thrombolysis Thrombolysis Should Be Considered Only After Pe Has Been Confirmed (By : High-Probability Ventilation-Perfusion Scan Or Positive Pulmonary Arteriogram ) Because The Adverse Effects Of Thrombolytic Therapy Can Be Severe. For Patients With Pe Who Have Neither Hemodynamic Nor Respiratory Compromise (Eg, Hypotension, Severe Hypoxemia), We Recommend That Thrombolytic Therapy Not Be Administered (Grade 1b). For Patients With Confirmed Pe Who Are Persistently Hypotensive Due To Pe And Do Not Have An Increased Risk Of Bleeding, We Suggest Thrombolytic Therapy Followed By Anticoagulation, Rather Than Anticoagulation Alone (Grade 1b). We Recommend That The Thrombolytic Agent Be Administered By A Peripheral Venous Catheter, Rather Than A Pulmonary Arterial Catheter (Grade 1b). Anticoagulant Therapy Is Generally Discontinued During The Thrombolytic Infusion Common Thrombolytic Regimens Include: o Tpa - Administer 100 Mg Intravenously Over Two Hours. o Streptokinase (Durkinase) Vial Contain 1,500,000 Unit - Administer 250,000 Units Intravenously Over The Initial 30 Minutes, Then 100,000 Units/Hour For 24 Hours. Pump : Vial Dilution To 50 Cc With SD5 Speed 16.6 Ml/H (For 30 Min Or For 8.3 Cc) Then Turn The Speed To 3.2 Ml/H . o Urokinase - Administer 4400 Units/Kg Intravenously Over The Initial 10 Minutes, Then 2200 Units/Kg Per Hour For 12 Hours. We Suggest A Thrombolytic Regimen With A Short Infusion Time (Ie, 2 Hours), Rather Than A Regimen With A More Prolonged Infusion Time (Grade 2b). When There Are Contraindications To Thrombolysis (Or Thrombolysis Fails To Induce Clinical Improvement), Catheter Or Surgical Embolectomy May Be Warranted If The Necessary Resources And Expertise Are Available. Inferior Vena Caval Filters Preventing Large Emboli From Traveling From The Pelvis Or Lower Extremities To The Lung We Suggest Insertion Of Ivc Filter For Patients With Confirmed Pe Who Have : 1) Contraindications To Anticoagulation 2) Complications Of Anticoagulation (Eg, Bleeding) 3) Recurrent Pe Despite Therapeutic Anticoagulation 4) Hemodynamic Or Respiratory Compromise That Is Severe Enough That Another Pe May Be Lethal, Patients Who Have Undergone Embolectomy (Surgical Or Catheter) Frequently Undergo Ivc Filter Insertion. In Addition, Ivc Filters Are Being Used For Pe Prophylaxis In Select Groups Of Patients.

Embolectomy : Embolectomy (Ie, Removal Of The Emboli) Can Be Performed Using Catheters Or Surgically. In Patients With Pe In Whom Thrombolysis Is Indicated(Eg, Persistent Hypotension Due To Pe), But Who Fail Thrombolysis Or Have Contraindications To Thrombolysis, We Suggest Catheter Or Surgical Embolectomy If The Necessary Resources And Expertise Are Available ( Grade 2c). Treatment Algorithm For Patients With Suspected Pulmonary Embolism

Acute Pericarditis
Diagnostic criteria for acute pericarditis (at least 2 criteria of 4 should be present) : 1. 2. 3. 4. Typical chest pain Pericardial friction rub Suggestive ECG changes (typically widespread ST segment elevation) New or worsening pericardial effusion

ECG : Stage 1, seen in the first hours to days, is characterized by diffuse ST elevation (typically concave up), There is also an atrial current of injury, reflected by elevation of the PR segment in lead aVR and depression of the PR segment in other limb leads and in the left chest leads, primarily V5 and V6. Stage 2 is characterized by normalization of the ST and PR segments. Stage 3 is characterized by the development of diffuse T wave inversions, generally after the ST segments have become isoelectric. However, this stage is not seen in some patients. In stage 4, the ECG may become normal or the T wave inversions may persist indefinitely ("chronic" pericarditis (.

Atypical ECG changes : localized ST-elevation and T-wave inversion before ST-segment normalization occur in a minority of patients with acute pericarditis without myocardial involvement. These changes Additional findings indicative of myocardial involvement include arrhythmias (particularly ventricular), new bundle branch block or other intraventricular conduction delay and Q waves. can simulate changes found in acute coronary syndrome

Chest pain: may be absent in TB, neoblastic , uremic pericarditis. Determination of risk and need for hospitalization A patient with simple uncomplicated acute pericarditis can undergo initial evaluation in a same day hospital facility or clinic, although outpatient follow-up is required

Features of high risk for Hospital admission include 1. 2. 3. 4. 5. 6. 7. 8. Fever (>38C ) and leukocytosis Evidence suggesting cardiac tamponade A large pericardial effusion (ie, an echo-free space of more than 20 mm) Immunosuppressed state A history of oral anticoagulant therapy Acute trauma Failure to respond within 7 days to NSAID therapy Elevated cardiac troponin, suggestive of myopericarditis

TREATMENT In acute viral or idiopathic pericarditis, no therapy has been rigorously proven to prevent serious sequelae, such as tamponade and constriction. Fortunately, these complications are rare. NSAID We recommend NSAIDs for all patients without a contraindication ( Grade 1B). In the treatment of idiopathic or viral pericarditis, the goals of therapy are the relief of pain and resolution of inflammation and, if present, effusion. Ibuprofen 400 to 800 mg of ibuprofen every 6-8 hours. o (Profen 600mg /tab 14 or 3) Aspirin 800 mg every 6-8 hours followed by gradual tapering of 800 mg every week o (Ascaltin 500mg /tab 24 or 3 ) or (S-pirin 325mg /tab 24 or 5)

treatment period : 3-4 weeks.

Colchicine : We suggest that colchicine not be used routinely in the management of a first episode of acute pericarditis ( Grade 2B). ome physicians and patients may choose to add colchicine as an adjunct to NSAID therapy. colchicine might prevent recurrence of acute idiopathic or viral pericarditis Dose : 1-2 mg on the first day, followed by 0.5 once or twice daily for three months o COLCHICINE 0.5 mg/tab 2 or 4 1 on the first day, followed by 1 2 We suggest that colchicine should be avoided in patients treated with macrolides, and in patients with hepatobiliary dysfunction, severe renal, gastrointestinal disorders, and blood dyscrasias. It is also prudent to reduce maintenance/prophylactic dose by 50 % in individuals >70 years, and in patients with impaired renal function with glomerular filtration rates below 50 ml/min. every patient should undergo a careful monitoring of possible side effects also including blood analyses (transaminases, serum creatinine, creatine kinase, and blood cell count) before starting the drug, and later at least after one month of treatment.

Glucocorticoids: Glucocorticoids should be considered only if the patient is clearly refractory to NSAIDs and colchicine, and a specific cause for the pericarditis has been excluded . use of high doses of glucocorticoids (eg, Predlon 1 mg/kg/day) when indicated with rapid tapering to reduce the risk of systemic side effects. we favor lower doses and slower taper : moderate initial dosing (eg, Predlon 0.25 to 0.50 mg/kg/day), and slow tapering. Systemic Steroid therapy be restricted to patients with the following conditions: 1. Acute pericarditis due to connective tissue disease 2. Autoreactive (immune-mediated) pericarditis 3. Uremic pericarditis

Pericardiocentesis: generally performed for one of three reasons: 1. If moderate to severe tamponade is present. 2. If tuberculous, or neoplastic pericarditis is suspected. 3. If there is a persistent symptomatic pericardial effusion. Post-MI pericarditis : we recommend that aspirin is preferred, and the use of an NSAID other than aspirin should probably be AVOIDED, since anti inflammatory therapy may impair scar formation . Uremic Pericarditis usually resolves with the institution ofor with more aggressivedialysis. Tamponade is fairly common, and partial pericardiectomy (pericardial window) may be necessary. Whereas antiinflammatory agents may relieve the pain and fever associated with uremic pericarditis, indomethacin and systemic corticosteroids do not affect its natural history Neoplastic Pericarditis The prognosis with is dismal, with only a small minority surviving 1 year. If it is compromising the clinical comfort of the patient, the effusion is initially drained percutaneously. Radiation Pericarditis: Symptomatic therapy is the initial approach to, but recurrent effusions and constriction often require surgery Tuberculous Pericarditis: Standard antituberculous drug therapy is usually successful for , but constrictive pericarditis can occur. Recurrent pericarditis Approximately 15 to 30 percent of patients with idiopathic acute pericarditis who are not treated with colchicine develop either recurrent or incessant disease. The treatment of recurrent pericarditis is similar to that of the initial acute episode

we recommend aspirin or other nonsteroidal antiinflammatory drug plus colchicine for initial therapy of recurrent pericarditis due to idiopathic or viral causes. In patients with another identified cause, specific therapy appropriate to the underlying disorder is indicated. it is recommended that the use of glucocorticoids for recurrent pericarditis be limited

Indications for Pericardiectomy: 1. If more than one recurrence is accompanied by cardiac tamponade, which in uncommon. 2. If a recurrence is principally manifested by persistent pain despite an intensive trial with medical treatment and evidence of serious glucocorticoid toxicity. Evaluation of patients with suspected acute pericarditis : A history and physical examination with particular focus upon evidence of cardiac tamponade, the presence of disorders known to affect the pericardium (eg, uremia, tuberculosis, recent MI, or prior cardiac surgery). Assessment for the presence of risk factors that would necessitate hospitalization. . Echocardiography should be obtained in all patients, to evaluate for the presence of an effusion and evidence of tamponade. In patients with clinical evidence of tamponade, the echocardiogram should be obtained urgently. An ECG and a chest x-ray should be obtained in all patients. In selected patients, additional tests should include : o tuberculin skin testing o interferon-gamma release assay (eg, QuantiFERON TB assay) o ANA o HIV serology. Diagnostic criteria for Myopericarditis: 1. Definite diagnosis of acute pericarditis, PLUS 2. Suggestive symptoms (dyspnea, palpitations, or chest pain) and ECG abnormalities beyond normal variants, not documented previously (ST/T abnormalities, supraventricular or ventricular tachycardia or frequent ectopy, atrioventricular block), OR focal or diffuse depressed LV function` of uncertain age by an imaging study 3. Absence of evidence of any other cause 4. One of the following features: evidence of elevated cardiac enzymes (CK-MB, or troponin I or T), OR new onset of focal or diffuse depressed LV function by an imaging study, OR abnormal imaging consistent with myocarditis (MRI with gadolinium, gallium-67 scanning, antimyosin antibody scanning) Case definitions for myopericarditis include: o Suspected myopericarditis: criteria 1 , 2 , 3 o Probable myopericarditis: criteria 1,2,3, 4 o Confirmed myopericarditis: hystopathologic evidence of myocarditis by endomyocardial biopsy or on autopsy

Aortic Dissection
EPIDEMIOLOGY Incidence : Patients with acute aortic dissection tend to be 60 to 80 year-old men , Women presenting with aortic dissection tend to be older than men (67 versus 60 years) Predisposing factors : o systemic hypertension and history of atherosclerosis.he most important o Preexisting aortic aneurysm o Inflammatory diseases that cause a vasculitis (giant cell arteritis, Takayasu arteritis, rheumatoid arthritis, syphilitic aortitis). o Disorders of collagen (eg, Marfan syndrome, Ehlers-Danlos syndrome, annuloaortic ectasia) o A bicuspid aortic valve. o Aortic coarctation. o Turner syndrome. o Coronary artery bypass graft surgery (CABG). o Previous aortic valve replacement. o Cardiac catheterization with or without coronary intervention o chest Trauma o Crack cocaine,

CLASSIFICATION OF AORTIC DISSECTION AND VARIANTS Class Description Daily or Stanford classification Type A Dissection involving the ascending aorta, regardless of the site of the primary tear Type B Dissection of the descending aorta DeBakey classification Type 1 Dissection of the ascending and descending thoracic aorta Type 2 Dissection of the ascending aorta Type 3 Dissection of the descending aorta Classification of variants Class 1 Classic dissection with separation of intima/media; intimal flap between dual lumens (true and false) Class 2 Medial disruption with intramural hematoma separation of intima/media; no intraluminal tear or flap imaged Class 3 Discrete/subtle dissection; intimal tear without hematoma (limited dissection) and eccentric bulge at tear site Class 4 Atherosclerotic penetrating ulcer; ulcer usually penetrating to adventitia with localized hematoma Class 5 Iatrogenic/traumatic dissection CLINICAL MANIFESTATIONS : Patients with an aortic dissection typically present with severe, sharp or "tearing" posterior chest or back pain (in dissection distal to the left subclavian) or anterior chest pain (in ascending aortic dissection). The pain can radiate anywhere in the thorax or abdomen. It can occur alone or be associated with syncope, a cerebrovascular accident, myocardial infarction (MI), heart failure or other clinical symptoms or signs Presentations of aortic dissection based on artery or structure involvement Clinical findings Aortic insufficiency or heart failure Myocardial infarction Cardiac tamponade Hemothorax Stroke or syncope Artery or structure involved Aortic valve Coronary artery (often right) Pericardium Thorax Brachiocephalic, common carotid, or left subclavian arteries

Upper extremity pulselessness, hypotension pain Paraplegia Lower extremity pain, pulselessness, weakness Abdominal pain; mesenteric ischemia Back or flank pain; renal failure Horner syndrome

Subclavian artery Intercostal arteries (give off spinal and vertebral arteries) Common iliac artery Celiac or mesenteric arteries Renal artery Superior cervical sympathetic ganglion

Involvement of the ascending aorta : o chest pain more often than back or abdominal pain o Acute aortic insufficiency, leading to an diastolic decrescendo murmur most commonly heard along the right sternal border, hypotension, or heart failure, in one-half to two-thirds of ascending dissections. o Acute myocardial ischemia or MI due to coronary occlusion. The right coronary artery is most commonly involved and, in infrequent cases, leads to complete heart block. o Cardiac tamponade and sudden death due to rupture of the aorta into the pericardial space. o Hemothorax and exsanguination if the dissection extends through the adventitia, with hemorrhage into the pleural space. o A considerable variation (>20 mmHg) in systolic blood pressure between the arms. o Neurologic deficits, including stroke or decreased consciousness due to direct extension of the dissection into the carotid arteries or diminished carotid blood flow. o Horner syndrome if there is compression of the superior cervical sympathetic ganglion o Vocal cord paralysis and hoarseness due to compression of the left recurrent laryngeal nerve. Involvement of the descending aorta : o Abrupt onset of Chest pain or back pain or abdominal o Hypertension or Hypotension/shock o Pulse deficit o Spinal cord ischemia o Ischemic peripheral neuropathy o acute renal failure o mesenteric ischemia o limb ischemia o coma or altered consciousness Periaortic hematoma : Periaortic hematoma, which is detected by imaging, hese patients had higher rates of shock, cardiac tamponade, and altered consciousness/coma and had a significantly higher mortality rate compared to those without a periaortic hematoma

DIAGNOSIS acute aortic dissections could be identified based upon some combination of the following three clinical features : 1. Abrupt onset of thoracic or abdominal pain with a sharp, tearing and/or ripping character 2. Mediastinal and/or aortic widening on chest radiograph 3. A variation in pulse (absence of a proximal extremity or carotid pulse) and/or blood pressure (>20 mmHg difference between the right and left arm) The incidence of a dissection related to the presence or absence of these three: o All three absent (4 percent of dissections): 7 percent o Pain: 31 percent o Presence of chest radiographic abnormalities: 39 percent o Variation in pulse or blood pressure differential: 83 percent o Any two out of three variables (77 percent of dissections): 83 percent ECG : ECG was normal in 31 %, showed nonspecific ST and T wave changes in 42 % (commonly, LVH and strain patterns associated with hypertension), showed ischemic changes in 15 %, and, among patients with an ascending aortic dissection, showed evidence of an acute MI in 5 %.

CXR : o show widening of the aorta with aortic dissections , pleural effusion, Other findings, which are less specific for dissection but have been described, include widening of the aortic contour, displaced calcification, aortic kinking, and opacification of the aorticopulmonary window o Because of the limited sensitivity of the chest radiograph, especially in type B dissections, additional imaging studies are obtained in almost all patients Recommendations for the use of imaging in acute and chronic aortic dissection: Thoracic MRI, thoracic CT, and multiplane TEE are the preferred methods for evaluating suspected aortic dissection, if available. We generally perform multiplane TEE at the bedside or in the Emergency Department for patients who present with acute chest pain and/or are clinically unstable. Hemodynamically unstable patients with a very strong suspicion of dissection can be emergently brought to the operating room and undergo TEE after induction of anesthesia as the chest is being prepared. MRI is preferred in patients with chronic chest pain and in those who are hemodynamically stable, or are seen for follow-up of a chronic dissection (Class I) CT scan with contrast is reserved for situations in which both TEE and MRI are unavailable or contraindicated. As such, it is often indicated as an initial screening study in patients with suspected aortic dissection, especially in the emergency department setting where TEE and MRI are less available, especially after hours. If CT is equivocal, or further delineation of the dissection is needed, TEE or MRI are indicated. Aortography is used when ascending aortic dissection is strongly suspected, but noninvasive tests are unavailable or inconclusive. Coronary angiography is generally safe in stable patients, although the delay to surgical invention for ascending dissections should be minimized. Retrospective data suggest no in-hospital benefit to coronary angiography At our institution, coronary angiography is generally attempted in all patients with a prior history or angina or MI, patients older than 60 years of age, and patients with multiple risk factors for coronary disease. Blood tests : o Routine blood tests are generally nondiagnostic in aortic dissection. o The serum LDH concentration may be elevated due to hemolysis of blood in the false lumen, but this is a nonspecific finding. o Newer tests have been developed, which might prove to be more useful. A rapid 30-minute immunoassay for the serum concentration of smooth muscle myosin heavy chain has been evaluated in patients suspected of having an aortic dissection. The sensitivity and specificity of this assay in the first three hours were similar and possibly superior to those of TTE, conventional CT, and aortography, but were lower than those of TEE, helical CT, or MRI. The utility of this test needs further evaluation.

MANAGEMENT OF AORTIC DISSECTION GENERAL PRINCIPLES o Dissections of Ascending aorta are considered surgical emergencies. o Dissections of Descending aorta are treated medically unless the patient demonstrates progression or continued hemorrhage into the pleural or retroperitoneal space. ACUTE MANAGEMENT Transfer to intensive care unit Heart rate and blood pressure (BP) monitoring Pain relief (morphine sulphate) For blood pressure control, initial treatment consists of an intravenous beta blocker to reduce the heart rate below 60 beats/min; . Reduction of systolic blood pressure to 100 to 120 mmHg or the lowest level that is tolerated o IV beta blockers (propranolol, metoprolol, esmolol, or labetalol) In patients with obstructive pulmonary disease (asthma, or heart failure) , blood pressure lowering with calcium channel blockers ( Verapamil or diltiazem )

The patient can be switched to oral therapy after heart rate control has been achieved. If, at this time, the systolic blood pressure remains above 100 mmHg with good mentation and renal function, IV sodium nitroprusside should be added to titrate BP to 100-120 mmHg) o Nitroprusside should NOT be used without beta blockade since vasodilation alone induces reflex activation of the sympathetic nervous system leading to enhanced ventricular contraction and increased aortic shear stress. o While nitroprusside is the preferred agent, angiotensin converting enzyme inhibitors or intravenous nicardipine, verapamil or diltiazem may also be effective in lowering BP o Other direct vasodilators, such as hydralazine, should be avoided, since they increase shear stress and provide less accurate and reversible control of the blood pressure. Hypotensive patients should be evaluated to determine if the cause is blood loss, hemopericardium with tamponade, or cardiac failure before volume is administered. Inotropic agents should be avoided since they will increase aortic shear stress and worsen the dissection. In patients with cardiac tamponade, percutaneous pericardiocentesis can accelerate bleeding and shock . Diagnostic evaluation should be accomplished as promptly as possible. o In patients with severe hemodynamic instability, bedside TEE is the procedure of choice o In more stable patients, chest CT, MRI, TEE, or angiography may be appropriate.

DEFINITIVE THERAPY Descending (type B) aortic dissection : o Medical therapy : Patients with uncomplicated aortic dissections confined to the descending thoracic aorta (Stanford type B or DeBakey type III) are best treated with medical therapy o Surgical aortic replacement : Surgical intervention in descending aortic dissections is reserved for patients who have a complicated course. Indications include occlusion of a major aortic branch, continued aortic expansion or extension of the dissection (as may be manifested by persistent or recurrent pain), and evidence of aortic rupture Acute distal dissections in patients with Marfan syndrome may also be best treated surgically Surgical or endovascular fenestration and stenting if persisting mesenteric, renal or limb ischemia or neurologic deficits Ascending (type A) aortic dissection : o Acute ascending aortic dissections (Stanford type A) should be treated as a surgical emergency since these patients are a high risk for a life-threatening complication such as aortic regurgitation, cardiac tamponade, or myocardial infarction, and the mortality rate is as high as 1 to 2 % per hour early after symptom onset LONG-TERM MANAGEMENT Medical therapy o All patients should receive life-long therapy with an oral beta blocker to reduce systemic blood pressure and the rate of rise in systolic pressure, both of which will minimize aortic wall stress. we suggest a goal blood pressure less than 120/80 mmHg . o Combination antihypertensive drug therapy is usually required. o Avoidance of strenuous physical activity is also recommended . Serial imaging o We generally perform a baseline thoracic MR scan prior to discharge with follow-up examinations at 3, 6, and 12 months, even if the patient remains asymptomatic. o Subsequent screening studies are then performed every 1-2 years if there is no evidence of progression. o MRI is as accurate as TEE and, because it is noninvasive, is more acceptable for serial studies. CT scanning is another alternative, but requires potentially nephrotoxic iodinated contrast. Reoperation Repeat surgery is required in approximately 12 to 30 % of patients, higher in patients with Marfan syndrome .

Approach To The Diagnosis And Treatment Of Wide QRS Tachycardias

Causes Of A Wide QRS Complex Tachycardia 1. Ventricular tachycardia (VT) 2. Any type of SVT with a preexistant bundle branch block or a rate-related (functional) bundle branch block a. Sinus tachycardia b. Atrial tachycardia c. Atrial flutter d. Atrioventricular nodal reentrant tachycardia e. Atrioventricular reentrant tachycardia (orthodromic) 3. Any SVT occurs in a patient receiving an antiarrhythmic drug, primarily class IA or IC 4. Any SVT with antegrade conduction via an accessory pathway (WPW syndrome) a. Sinus tachycardia b. Atrial tachycardia c. Atrial flutter d. Atrioventricular reentrant tachycardia (antidromic) 5. Electronic pacemaker in certain specific settings GENERAL APPROACH Assessment of patient stability Immediate assessment of patient stability takes precedence over any further diagnostic evaluation. o Findings of hemodynamic instability include : hypotension, angina,altered level of consciousness, and heart failure. o A patient who is unresponsive or pulseless should be treated according to standard ACLS algorithms. o In a patient who is unstable but conscious, we recommend immediate synchronized cardioversion ( Grade 1B). o In a stable patient, a focused diagnostic evaluation may proceed to determine the etiology of the arrhythmia and guide specific therapy include the following :

History Physical examination Laboratory testing Diagnostic maneuvers in selected patients

The primary goals of the initial evaluation are to determine the etiology of the WCT and to elucidate any underlying conditions related to the event (eg, heart failure, myocardial ischemia, drug reaction, or electrolyte abnormalities). History History of heart disease The presence of structural heart disease, especially coronary heart disease and a previous MI, strongly suggests VT as an etiology Presence of a pacemaker or ICD The presence of either a pacemaker or an ICD raises the possibility of a device-associated WCT. More importantly, the presence of an ICD implies that the patient is known to have an increased risk of ventricular tachyarrhythmias and suggests strongly (but does not prove) that the patient's WCT is VT.

Symptoms Symptoms are not useful in determining the diagnosis, but they are important as an indicator of the severity of hemodynamic compromise . Age A WCT in a patient over the age of 35 years is likely to be VT . SVT is more likely in younger patients However, VT must be considered in younger patients, particularly those with a family history of ventricular arrhythmias or premature sudden cardiac death.

Duration of the tachycardia SVT is more likely if the tachycardia has recurred over a period of more than three years. The first occurrence of the tachycardia after an MI strongly implies VT .

Medications Many medications have proarrhythmic effects.

QT prolonging drugs The most common drug-induced WCT is a form of polymorphic VT called torsades de pointes (TdP). This arrhythmia is associated with QT interval prolongation when the patient is in sinus rhythm. Frequently implicated agents include antiarrhythmic drugs such as sotalol and quinidine and certain antimicrobial drugs such as erythromycin. Class I antiarrhythmic drugs can cause both aberrancy during an SVT and also VT. These drugs, especially class IC agents, slow conduction and have a property of "use-dependency" (a progressive decrease in impulse conduction velocity at faster heart rates). As a result, these drugs can cause raterelated aberration and a wide QRS complex during any SVT. However, they can also cause VT with a very wide, bizarre QRS, which may be incessant Digoxin Digoxin can cause almost any cardiac arrhythmia, especially at plasma concentrations above 2.0 ng/mL. Digoxin-induced arrhythmias are more frequent at any given plasma concentration if hypokalemia is also present. . Diuretics Diuretics are a common cause of hypokalemia and hypomagnesemia, which may predispose to ventricular tachyarrhythmias, particularly TdP.

Physical examination the initial physical examination should focus upon evidence of underlying cardiovascular disease which can impact the likelihood that the WCT is VT. o Findings suggestive of cardiovascular disease include:
o

Signs of acute or chronic heart failure.. A healed sternal incision as evidence of previous cardiothoracic surgery. The sequelae of peripheral arterial disease or stroke. A pacemaker or ICD.

o In addition, the physical examination can reveal evidence of AV dissociation, which is present in up to 75 % of patients with VT, although it is not always easy to detect . During AV dissociation, the normal coordination of atrial and ventricular contraction is lost, which may produce characteristic physical findings. The presence of AV dissociation strongly suggests VT, although its absence is less helpful. o Although AV dissociation is typically diagnosed on the ECG, characteristic physical examination findings include:

Marked fluctuations in the blood pressure . Variability in the occurrence and intensity of heart sounds (especially S1), which is heard more frequently when the rate of the tachycardia is slower. Cannon "A" waves upon examination of the jugular pulsation in the neck. Cannon waves are intermittent and irregular jugular venous pulsations of greater amplitude than normal waves. Prominent A waves can also be seen during some SVTs.

Maneuvers The response of the arrhythmia to maneuvers may provide insight to the mechanism of the WCT. o Carotid sinus pressure Carotid sinus pressure enhances vagal tone and therefore depresses sinus and AV nodal activity. Examples of how various arrhythmias respond to carotid pressure include:

Sinus tachycardia will gradually slow with carotid sinus pressure and then accelerate upon release. During atrial tachycardia or atrial flutter, the ventricular response will transiently slow (due to increased AV nodal blockade). The arrhythmia itself, which occurs within the atria, is unaffected. A paroxysmal SVT (either AVNRT or AVRT) frequently terminates with carotid sinus pressure.

VT is generally unaffected by carotid sinus pressure, although this maneuver may slow or block retrograde conduction. In some cases, this response exposes AV dissociation. Rarely, VT terminates in response to carotid sinus pressure.

Pharmacologic interventions

The administration of certain drugs can provide diagnostic information. However, some drugs used for the diagnosis or treatment of SVT (eg, verapamil, adenosine, or beta blockers) can cause severe hemodynamic deterioration in patients with a VT that is initially hemodynamically tolerated and can provoke ventricular fibrillation (VF) and cardiac arrest . Thus, these medications are generally reserved for the treatment of patients in whom the diagnosis of SVT is already known; they are rarely used for diagnostic purposes for a WCT. The diagnostic implications of the responses to certain medications include: o Termination of the arrhythmia with lidocaine suggests, but does not prove, that VT is the mechanism. Infrequently an SVT, especially AVRT, terminates with lidocaine. o Termination of the arrhythmia with digoxin, verapamil, diltiazem, or adenosine strongly implies SVT. However, VT can rarely terminate after the administration of these drugs. o Termination of the arrhythmia with procainamide or amiodarone does not distinguish between VT and SVT. Laboratory tests The plasma potassium and magnesium: Hypokalemia and Hypomagnesemia both predispose to the development of ventricular tachyarrhythmias.Hyperkalemia can cause a wide QRS complex rhythm with the loss of a detectable P wave, although this usually has a slow rate (so-called "sinoventricular rhythm"). In patients taking digoxin, quinidine, or procainamide, plasma concentrations of these drugs should be measured to assist in evaluating possible toxicity. Chest x-ray A chest x-ray can provide evidence suggestive of structural heart disease, such as cardiomegaly. Evidence of previous cardiothoracic surgery and the presence of a pacemaker or ICD can also be detected. Electrophysiologic study Electrophysiologic testing allows definitive diagnosis of a WCT, but is rarely feasible in the acute setting. . Diagnostic evaluation In a stable patient, a rapid diagnostic evaluation should focus upon features that help determine the likelihood of VT versus SVT, as well as associated medical conditions or potential arrhythmia triggers. Definitive diagnosis, when possible, usually comes from the ECG . EVALUATION OF THE ECG

Rate The rate of the WCT is of limited use in distinguishing VT from SVT. When the rate is approximately 150 beats per minute, atrial flutter with aberrant conduction should be considered, although this diagnosis should not be accepted without other supporting evidence. Regularity VT is generally regular, although slight variation in the RR intervals is sometimes seen. Slight irregularity suggests VT as opposed to most SVTs, which are characterized by uniformity of the RR intervals. When the onset of the arrhythmia is available for analysis, a period of irregularity ("warm-up phenomenon"), suggests VT. More marked irregularity of RR intervals occurs in polymorphic VT and in atrial fibrillation (AF) with aberrant conduction. Axis The QRS axis in the frontal plane can be useful in distinguishing SVT from VT. o A right superior axis (axis from -90 to 180), sometimes called an indeterminate or "northwest" axis, is rare in SVT and strongly suggests VT . One exception to this rule is an antidromic AVRT seen with the Wolff-Parkinson-White (WPW) syndrome . o Compared to the axis during sinus rhythm, an axis shift during the WCT of more than 40 suggests VT . o In a patient with a RBBB-like WCT, a QRS axis to the left of -30 suggests VT. o In a patient with an LBBB-like WCT, a QRS axis to the right of +90 suggests VT.

QRS duration o In general, a wider QRS favors VT. In a RBBB-like WCT, a QRS duration >140 msec suggests VT In a LBBB-like WCT, a QRS duration >160 msec suggests VT. o A QRS duration <140 msec does not exclude VT.

Concordance Concordance is present when the QRS complexes in all six precordial leads (V1 through V6) are monophasic with the same polarity. They can either all be entirely positive with tall, monophasic R waves, or all be entirely negative with deep monophasic QS complexes. If any of the six leads has a biphasic QRS (qR or RS complexes), concordance is not present. o Negative concordance is strongly suggestive of VT. Rarely, SVT with LBBB aberrancy will demonstrate negative concordance, but there is almost always some evidence of an R wave in the lateral leads. o Positive concordance is most often due to VT but can also occur in the relatively rare case of antidromic AVRT with a left posterior accessory pathway o While the presence of concordance strongly suggests VT, its absence is not helpful diagnostically. AV dissociation AV dissociation is characterized by atrial activity that is independent of ventricular activity .

In a WCT with AV dissociation, an atrial rate slower than the ventricular rate strongly suggests VT. An atrial rate that is faster than the ventricular rate is seen with some SVTs, such as atrial flutter or an atrial tachycardia with 2:1 AV conduction. In these settings, however, there is a consistent relationship between the P waves and the QRS complexes, so there is not true AV dissociation. While the presence of AV dissociation largely establishes VT as the diagnosis, its absence is not as helpful . The following findings are helpful in establishing the presence of AV dissociation.
1.

Dissociated P waves P waves are said to be dissociated if they are not consistently coupled to the QRS complexes, as evidenced by the following: PP and RR intervals are different PR intervals are variable There is no association between P and QRS complexes During a WCT, P waves are often difficult to identify. If P waves are not evident on the surface ECG, direct recordings of atrial activity (eg, with an esophageal lead or an intracardiac catheter) can reveal AV dissociation .

Fusion beats Fusion occurs when one impulse originating from the ventricle and a second supraventricular impulse simultaneously activate the ventricular myocardium. The resulting QRS complex has a morphology intermediate between that of a sinus beat and a purely ventricular complex . Intermittent fusion beats during a WCT are diagnostic of AV dissociation and therefore of VT. 3. Capture beats Capture beats, or Dressler beats, are QRS complexes during a WCT that are identical to the sinus QRS complex . The term "capture beat" implies that the normal conduction system has momentarily "captured" control of ventricular activation from the VT focus. Fusion beats and capture beats are more commonly seen when the tachycardia rate is slower
2.

QRS morphology

Diagnostic criteria Most of these approaches involve classifying the WCTs as having one of two patterns:

An RBBB-like pattern QRS polarity is positive in leads V1 and V2 An LBBB-like pattern QRS polarity is negative in leads V1 and V2

This distinction does not, by itself, make the diagnosis, but additional features favor VT in either RBBB-like or LBBB-like WCTs.

V1 positive (RBBB) pattern In the patient with a WCT and positive QRS polarity in lead V1, the following associations have been made : Findings in lead V1 A monophasic R or biphasic qR (small Q wave followed by a large R wave) in lead V1 favors VT. A triphasic RSR' or RsR' complex (the so-called "rabbit-ear" sign) in lead V1 usually favors SVT. As an exception, if the left peak of the RsR' complex is taller than the right peak, VT is more likely . Findings in lead V6 An rS complex (R wave smaller than S wave) in lead V6 favors VT . In contrast, an Rs complex (R wave larger than S wave) in lead V6 favors SVT.

V1 negative (LBBB) pattern In the patient with a WCT and negative QRS polarity in lead V1, the following associations have been made : Findings in lead V1 or V2 A broad initial R wave of 40 msec duration or longer in lead V1 or V2 favors VT. In contrast, the absence of an initial R wave or a small initial R wave of less than 40 msec in lead V1 or V2 favors SVT. Two other findings that favor VT are a slurred or notched downstroke of the S wave in lead V1 or V2, and a duration from the onset of the QRS complex to the nadir of the QS or S wave of 60 msec in lead V1 or V2. In contrast, a swift, smooth downstroke of the S wave in lead V1 or V2 with a duration of <60 msec favors SVT. Findings in lead V6 The presence of any Q or QS wave in lead V6 favors VT [ 18] . In contrast, the absence of a Q wave in lead V6 favors SVT.

Variation in QRS and ST-T shape Subtle, non-rate-related fluctuations or variations in QRS and ST-T wave configuration suggest VT and may reflect variations in the VT reentrant circuit within the myocardium. AV dissociation can cause variability in the ST segment and T wave morphology. In contrast, SVT, because it follows a fixed conduction pathway, is characterized by uniformity of QRS and ST-T shape unless the rate changes.

Diagnosis of VT The presence of any of these ECG features is adequate for the diagnosis of VT: concordance

Precordial lead concordance AV dissociation QRS morphologic features

Diagnosis of SVT The absence of the historical or ECG features of VT does not confirm a diagnosis of SVT. Similarly, algorithms for the evaluation of WCTs are likely to be less accurate in general practice than in published reports. . In the acute setting, the diagnosis of SVT should be reserved to the following situations:

Patients with a history of SVTs that have presented similarly. Young patients, whose hearts are structurally normal, in whom none of the historical (eg, family history of sudden cardiac death), physical, or ECG criteria supporting VT are present.

Uncertain diagnosis When the diagnosis of a WCT is uncertain, we recommend that the patient be treated as if the rhythm is VT ( Grade 1B). Treatment In stable patients, initial therapy should be directed at the specific arrhythmia.

Ventricular tachycardias In stable patients with known or presumed VT, we recommend the following approach: o We recommend synchronized external cardioversion of 100 to 200 joules (monophasic) or 50 to 100 joules (biphasic), with titration of the energy upward as needed following appropriate conscious sedation, as the initial therapy for most patients with stable VT ( Grade 1C). o In patients with refractory or recurrent WCT, we suggest a class I or III antiarrhythmic drug ( Grade 2C). . o In selected patients known to have one of the syndromes of VT in the setting of a structurally normal heart, we suggest calcium channel blockers or beta blockers be used for arrhythmia termination or suppression ( Grade 2C). Supraventricular tachycardias In stable patients with a WCT that is known to be an SVT, initial management is similar to that of an SVT with a narrow QRS complex. A continuous rhythm strip should be obtained during any intervention that is intended to slow or terminate the arrhythmia. For AVNRT or AVRT, or an SVT in which the specific arrhythmia is unknown, we suggest the following sequence of interventions in order to terminate the arrhythmia or to slow ventricular response and facilitate diagnosis ( Grade 2C) : o Vagotonic maneuvers (eg, valsalva or carotid sinus pressure) o Intravenous Adenosine : 6 mg IV over 1-2 seconds If ineffective, a 12 mg dose may be given and repeated once if necessary. o Intravenous calcium channel blockers or beta blockers : Intravenous verapamil (2.5 to 5 mg IV), or metoprolol 5 to 10 mg IV) may be given if the SVT persists after adenosine administration. o Cardioversion: if AVNRT or AVRT persist after the above interventions, synchronized cardioversion is usually effective in restoring sinus rhythm. Following appropriate conscious sedation, an initial synchronized shock of 100 to 200 joules (monophasic) or 50 to 100 joules (biphasic) is administered. Recurrent or refractory WCT If the WCT recurs or persists following initial attempts at cardioversion, suppression of the arrhythmia by pharmacologic means should be attempted and further evaluation should focus upon the presence of arrhythmia triggers (eg, ischemia, electrolyte abnormalities, and drug toxicity). Cardioversion or defibrillation should be repeated as necessary in patients who are hemodynamically unstable. For patients with recurrent VT or a WCT of uncertain etiology, we recommend the following: o Amiodarone (150 mg IV over 10 minutes followed by an infusion of 1 mg/minute for 6 hours, then 0.5 mg/minute) is recommended in most settings, due to its efficacy in the suppression of both atrial and ventricular arrhythmias. o Procainamide (15 to 18 mg/kg administered as slow infusion over 25-30 minutes, followed by 1-4 mg/minute by continuous infusion) is an alternative to amiodarone that also suppresses both SVTs and VT. In addition, because of its ability to suppress conduction over a bypass tract, procainamide is recommended if antidromic AVRT or an SVT conducting over a bypass tract is suspected. o Intravenous lidocaine (1 to 1.5 mg/kg over 2 to 3 minutes) may be useful, particularly if cardiac ischemia is suspected. In some cases lidocaine may actually slow conduction in the accessory pathway and terminate an antidromic AVRT. o In a patient with a stable blood pressure and recurrent arrhythmias, the cautious use of beta blockers (eg, metoprolol 5 to 10 mg IV) may be initiated. Due to the possibility of precipitating hemodynamic deterioration, beta blockers should be administered in a setting where urgent defibrillation can be performed, if necessary. For patients with a known SVT that recurs or persists, intravenous verapamil, diltiazem, or beta blockers may be used. Multiple recurrences of WCT should raise concern about cardiac ischemia, hypokalemia, digitalis toxicity, and polymorphic VT with or without QT prolongation, all of which have specific appropriate therapy. (See appropriate topic reviews).

ALGORITHMS FOR WCT DIAGNOSIS Brugada criteria The Brugada criteria are a stepwise approach in which four criteria for VT are sequentially assessed (. If any of the criteria is satisfied, the diagnosis of VT is made, and if none are fulfilled, an SVT is diagnosed. An exception is an antidromic AVRT in WPW syndrome. The steps are as follows: 1. Leads V1-V6 are inspected to detect an RS complex. If there are no RS complexes, concordance is present and the diagnosis of VT can be made 2. If an RS complex is present, the interval between the onset of the R wave and the nadir of the S wave (RS interval) is measured. If the longest RS interval in any lead is >100 msec, the diagnosis of VT can be made. 3. If the longest RS interval is <100 msec, the presence or absence of AV dissociation is assessed. If AV dissociation is seen, the diagnosis of VT is made . 4. If the RS interval is <100 msec and AV dissociation cannot clearly be demonstrated, the QRS morphology criteria for V1-positive and V1-negative wide QRS complex tachycardias are considered . o QRS morphology criteria consistent with VT must be present in leads V1 or V2 and in lead V6 to diagnose VT. If either the V1-V2 or the V6 criteria are not consistent with VT, an SVT is assumed . Alternative approaches An alternative algorithm uses a stepwise approach similar to the Brugada criteria, but includes different ECG features . Two unique features of this algorithm include an initial R wave in aVR (diagnostic of VT), and the Vi:Vt ratio. Vi and Vt are the magnitude of voltage change in the initial and terminal 40 msec of a QRS, respectively. A Vi:Vt ratio 1 is diagnostic of VT.

VT versus AVRT Differentiation between VT and an antidromic AVRT is particularly difficult. Because ventricular activation begins outside of the normal conduction system in both tachycardias, many of the standard criteria are not able to discriminate antidromic AVRT from VT. The clinical significance of this problem is often limited, however, because preexcitation is an uncommon cause of WCT . This is particularly true if other factors (eg, age, underlying heart disease) suggest VT. For cases in which preexcitation is thought to be likely (such as a young patient without structural heart disease, or a patient with a known accessory pathway), a separate algorithm was developed by the Brugada group. Their second algorithm consists of the following three steps : o The predominant polarity of the QRS complex in leads V4 through V6 is defined either as positive or negative. If predominantly negative, the diagnosis of VT can be made. o If the polarity of the QRS complex is predominantly positive in V4 through V6, the ECG should be examined for the presence of a qR complex in one or more of precordial leads V2 through V6. If a qR complex can be identified, VT can be diagnosed. o If a qR wave in leads V2 through V6 is absent, the AV relationship is then evaluated (AV dissociation). If a 1:1 AV relationship is not present and there are more QRS complexes present than P waves, VT can be diagnosed. o If the ECG of the arrhythmia does not display any morphologic characteristics diagnostic of VT after using this algorithm, the diagnosis of antidromic AVRT must be considered. When any of these criteria are met, VT is likely. However, it is difficult to make the diagnosis of SVT with confidence, because up to 25 percent of WCTs that meet none of these criteria is actually VT.

Advanced Cardiovascular Life Support

EPIDEMIOLOGY The incidence of sudden cardiac arrest (SCA), both fatal and nonfatal, is difficult to establish in the general population. The United States Centers for Disease Control (CDC) estimate that nearly 250,000 people die annually from SCA in the United States (US), an incidence of approximately 5.6 percent . Of those suffering cardiac arrest, mortality varies depending on the etiology, setting, and available resources. There is ample evidence that survival is maximized when cardiac defibrillation is indicated and provided within five minutes of SCA. Survival improves further if defibrillation is performed immediately. Overall survival of SCA ranges from 5 to 22 percent, with average survival for out of hospital SCA approximately 6 percent. PRINCIPLES OF MANAGEMENT Proper CPR and its importance the key modification is the emphasis on well-performed cardiopulmonary resuscitation (CPR) and its critical role in resuscitative efforts In the past, clinicians frequently interrupted CPR to perform pulse checks, intubate the patient, or initiate venous access. The AHA now recommends that every effort be made not to interrupt CPR. Other less vital interventions are performed either while CPR is performed or with the briefest possible interruption A 30 to 2 compression to ventilation ratio (one cycle) is now recommended in patients without advanced airway interventions. Asynchronous ventilations at 8 to 10 per minute are dministered if an endotracheal tube is in place, while continuous and simultaneous chest compressions are provided. A single biphasic defibrillation is now recommended with immediate resumption of chest compressions, as opposed to the long-established approach of three sequential defibrillations using increasing energy levels in refractory cases of ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT). This new recommendation takes into account both the enhanced first-shock efficacy of biphasic defibrillators and recognition that the three shock method causes an unacceptably long interval without CPR, leading to cardiocerebral hypoperfusion . The AHA now recommends that chest compressions continue until the defibrillator is ready to shock and should cease only when the defibrillator is ready for immediate discharge. We recommend that all defibrillations be delivered at the highest available energy in adults (generally 360 J for a monophasic defibrillator and 200 to 360 J for a biphasic defibrillator). In addition, other interventions such as the administration of vasopressor agents, antiarrhythmics, and advanced airway management should be coordinated in order to minimize or avoid interruptions in CPR . Necessary interruptions in CPR (eg, for repeat attempts at defibrillation) should occur no more frequently than every two minutes, and for the shortest possible duration. Initial management and ECG interpretation As with all medical emergencies, the primary focus is on the airway, breathing, and circulation. Assessment and treatment occur in parallel. Properly performed cardiopulmonary resuscitation (CPR) is begun immediately Initial interventions for ACLS include administering oxygen, establishing intravenous access, placing the patient on a cardiac and oxygen saturation monitor, and obtaining an electrocardiogram (ECG) Unstable patients must receive immediate care, even when data are incomplete or presumptive. Stable patients require an assessment of their electrocardiogram in order to provide appropriate treatment consistent with ACLS guidelines. Although it is best to make a definitive interpretation of the ECG prior to making management decisions, the settings in which ACLS guidelines are commonly employed require a modified, empirical approach. Such an approach involves answering the following questions : 1. Is the rhythm fast or slow? 2. Are the QRS complexes wide or narrow? 3. Is the rhythm regular or irregular?

Basic life support algorithm

Advanced cardiopulmonary life support

MANAGEMENT OF SPECIFIC ARRHYTHMIAS Ventricular fibrillation and pulseless ventricular tachycardia: Ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) are nonperfusing rhythms emanating from the ventricles, for which early rhythm identification, early defibrillation, and cardiopulmonary resuscitation (CPR) are the mainstays of treatment. Early defibrillation is the most critical action in the resuscitation effort, followed by the performance of excellent CPR. Manage potentially treatable underlying causes as appropriate. Defibrillation should take precedence over establishing IV access, intubation,or the administration of any drug! ABCs (always begin with assessing your ABCs!!!). Initiate and continue CPR until defibrillator is attached. Defibrillate (shock), 360J (monophasic) or 150 to 200J (biphasic) Perform five CPR cycles in sequence. Epinephrine 1 mg IV q 35 minutes or vasopressin 40 U IV 1. Amiodarone 300 mg IV for VF/pulseless VT, then infusion. Lidocaine 1 to 1.5 mg/kg IV; can repeat once. Magnesium sulfate 1 to 2 g IV, then infusion. Procainamide 30 mg/min, max total dose 17 mg/kg. Sodium bicarbonate 1 mg/kg IV if prolonged arrest, tricyclic antidepressant (TCA) overdose, or known acidosis. Consider calcium if hyperkalemia suspected There are limited data supporting the use of antiarrhythmics in refractory VF or pulseless VT. Two randomized controlled trials suggest amiodarone may provide short term benefit. The current ACLS guidelines describe antiarrhythmic use as "reasonable." Amiodarone (300 mg IV with a repeat dose of 150 mg IV as indicated) is recommended in the ACLS guidelines in VF or pulseless VT unresponsive to defibrillation. Lidocaine (1 to 1.5 mg/kg IV, then 0.5 to 0.75 mg/kg every 5 to 10 minutes) may be used if amiodarone is unavailable The timing of antiarrhythmics is not specified in the ACLS guidelines. We suggest antiarrhythmics be considered after a second unsuccessful defibrillation attempt in anticipation of a third shock.

Ventricular fibrillation/pulseless ventricular tachycardia algorithm

Pulseless electrical activity Pulseless Electrical Activity (PEA) is defined as any of a heterogeneous group of organized electrocardiographic rhythms without sufficient mechanical contraction of the heart to produce a palpable pulse or measurable blood pressure. By definition, PEA is a non-perfusing rhythm and CPR is initiated immediately. PEA may be caused by reversible conditions including hyperkalemia, hypothermia, hypoxia, tension pneumothorax, drug ingestion, hemorrhage, and cardiac tamponade . Treat these conditions as appropriate. PEA does not respond to defibrillation. Give epinephrine (1 mg IV every three to five minutes). The ACLS guidelines state that a single dose of vasopressin (40 units IV) may also be given, but several trials raise questions concerning the drug's efficacy. Atropine (1 mg IV every three to five minutes for a total of three doses) may be given in bradycardic PEA. Asystole Asystole is defined as a complete absence of demonstrable electrical and mechanical cardiac activity. In the most recent ACLS guidelines, asystole and pulseless electrical activity (PEA) are addressed together because successful management for both depends on excellent CPR, vasopressors, and a search for and reversal of underlying causes. Asystole may be the result of a primary or secondary cardiac conduction abnormality, possibly from endstage tissue hypoxia and metabolic acidosis, or, rarely, the result of excessive vagal stimulation. A flatline rhythm is indicative of the absence of any electrical activity of the heart. The most common cause of a flatline tracing on ECG is a detached lead or malfunctioning equipment, not asystole; therefore, always confirm Asystole in more than one lead! Asystole is always pulseless. Never shock asystole (no matter what you see on TV).

Pulseless electrical activity algorithm

Asystole treatment algorithm

Bradycardia Bradycardia is defined conservatively as a heart rate below 60 beats per minute. The ACLS guidelines recommend that clinicians not intervene unless the patient exhibits evidence of inadequate tissue perfusion thought to result from the slow heart rate . Signs and symptoms of inadequate perfusion include hypotension, altered mental status, evidence of acute pulmonary edema, or ongoing ischemic chest pain. If any such symptoms are present in the setting of bradycardia, immediately prepare for transcutaneous pacing. Preparations for pacing are not delayed to administer medications. Before using transcutaneous pacing, assess whether the patient can perceive the pain associated with this procedure, and if so provide appropriate sedation and analgesia. While preparing for transcutaneous pacing, it is reasonable to administer atropine (0.5 mg IV, which may be repeated every five minutes to a total dose of 3 mg), unless there is evidence of high degree (second degree [Mobitz] type II or third degree) atrioventricular (AV) block. Atropine exerts its antibradycardic effects at the AV node and is unlikely to be effective if this block is at or below the Bundle of His. If transcutaneous pacing fails to capture, prepare for transvenous pacing. While doing so, epinephrine (2 to 10 micrograms/minute) or dopamine (2 to 10 micrograms/kg/minute) infusions, titrated to the patient's response, may be started. Patients requiring transcutaneous or transvenous pacing also require immediate cardiology consultation, and admission for evaluation for permanent pacemaker placement. Glucagon may be given (3 mg IV followed by a 3 mg/hour drip as necessary) if symptomatic bradycardia is thought to result from supratherapeutic levels of beta-blockers or calcium channel blockers .

Tachycardia Tachycardia is defined as a heart rate above 100 beats per minute. Management of tachydysrhythmias is governed by the presence of clinical symptoms and signs caused by the rapid heart rate First determine if the patient is unstable (eg, has ongoing ischemic chest pain, mental status changes, hypotension, or signs of acute pulmonary edema). If the instability appears related to the tachycardia, treat immediately with synchronized cardioversion, unless the rhythm is sinus tachycardia. Some cases of supraventricular tachycardia may respond to immediate treatment with a bolus of adenosine (12 mg IV) without the need of cardioversion. Whenever possible, assess whether the patient can perceive the pain associated with cardioversion, and if so provide appropriate sedation and analgesia. In the stable patient, use the electrocardiogram (ECG) to determine the nature of the arrhythmia. In the urgent settings in which ACLS algorithms are most often employed, specific rhythm identification may not be possible. Nevertheless, by performing an orderly review of the ECG, one can identify the appropriate ACLS management algorithm. Three questions provide the basis for assessing the electrocardiogram in this setting: 1. Is the patient in a sinus rhythm? 2. Is the QRS complex wide or narrow? 3. Is the rhythm regular or irregular? Regular narrow complex Sinus tachycardia is a common response to fever, anemia, shock, sepsis, pain, heart failure, or any other physiologic stress. No medication is needed to treat sinus tachycardia; care is focused on treating the underlying cause. Supraventricular tachycardia (SVT) is a regular tachycardia most often caused by a reentrant mechanism within the conduction system . The QRS interval is usually narrow, but can be longer than 120 ms if a bundle branch block (ie, SVT with aberrancy) is present. Vagal maneuvers, which may block conduction through the AV node and result in interruption of the reentrant circuit, may be employed on appropriate patients while other therapies are prepared. Vagal maneuvers alone, (eg, valsalva, carotid sinus massage) convert up to 25 percent of SVTs to sinus rhythm . SVT refractory to vagal maneuvers may be treated with nucleoside adenosine . Because of its extremely short half-life, adenosine (6 mg IV) is injected as rapidly as possible into a large proximal vein, followed immediately by a 20 cc saline flush and elevation of the extremity to ensure the drug enters the central circulation before its degradation. If the first dose of adenosine does not convert the rhythm, a second and third dose of 12 mg IV may be given. Prior to injection, warn the patient about transient side effects from adenosine, including chest discomfort, dyspnea, and flushing, and give reassurance that these effects are very brief. Perform continuous ECG recording during administration. If adenosine fails to convert the SVT, consider other etiologies for this rhythm, including atrial flutter, which may become apparent on the ECG when AV nodal conduction is slowed, or a nonreentrant SVT. If conversion fails, initiate rate control with either intravenous calciumchannel blockers or beta-blockers. Irregular narrow complex Irregular narrow-complex tachycardias most often represent atrial fibrillation, atrial flutter with variable atrioventricular (AV) nodal conduction, or multifocal atrial tachycardia (MAT). The initial goal of treatment is to control the heart rate using either calcium channel blockers (diltiazem 15 to 20 mg IV over two minutes, repeat at 20 to 25 mg IV after 15 minutes, or verapamil 2.5 to 5 mg IV over two minutes followed by 5 to 10 mg IV every 15 to 30 minutes) or beta-blockers (eg, lopressor 5 mg IV for 3 doses every 2 to 5 minutes; then up to 200 mg PO every 12 hours). Calcium channel blockers and beta-blockers may cause or worsen hypotension. Patients should be closely monitored while the drug is given, and patients at risk of developing severe hypotension may require loading doses that are below the usual range. Diltiazem is suggested in most instances for the management of acute atrial fibrillation with rapid ventricular response (RVR). Beta-blockers may also be used and may be preferred in the setting of an acute coronary syndrome. Beta-blockers are more effective for chronic rate control. For atrial fibrillation associated with hypotension, amiodarone may be used (150 mg IV over 10 minutes, followed by 1 mg/min

drip for six hours, and then 0.5 mg/min). Treatment of MAT includes correction of possible precipitants, such as hypokalemia and hypomagnesemia. Cardioversion of stable patients with irregular narrow complex tachycardias should NOT be undertaken without considering the risk of embolic stroke. If the duration of atrial fibrillation is known to be less than 48 to 72 hours, the risk of embolic stroke is low, and the clinician may consider electrical or chemical cardioversion. Chemical cardioversion may be done with procainamide (50 mg/min IV, up to a dose of 18 to 20 mg/kg or until conversion), ibutilide (0.01 mg/kg IV over 15 minutes), or amiodarone (5 mg/kg IV over 15 minutes). Regular wide complex A regular, wide-complex tachycardia is most often ventricular in etiology. Aberrantly conducted supraventricular tachycardias may also be seen. Because differentiation between ventricular tachycardia (VT) and SVT with aberrancy can be difficult, assume VT is present and treat clinically stable undifferentiated wide-complex tachycardia with amiodarone (150 mg IV given over 10 minutes, repeated as needed to a total of 2.2 g IV over the first 24 hours) or procainamide (20 mg/min IV up to a total of 17 mg/kg) SVT with aberrancy, if DEFINITIVELY identified (eg, old ECG demonstrates bundle branch block), may be treated in the same manner as narrow-complex SVT, with vagal maneuvers, adenosine, or rate control. Irregular wide complex A wide complex, irregular tachycardia may be atrial fibrillation with aberrancy (bundle branch block), atrial fibrillation with preexcitation (eg, Wolf Parkinson White), or polymorphic ventricular tachycardia (VT) . Use of atrioventricular (AV) nodal blockers in wide complex, irregular tachycardia of unclear etiology may precipitate ventricular fibrillation (VF) and patient death, and is contraindicated. If the patient has a history of preexcitation (eg, Wolf-Parkinson White), or there is evidence of preexcitation on the ECG (eg, delta wave), procainamide is the preferred treatment (20 mg/min continuous IV drip until arrhythmia is suppressed, the patient becomes hypotensive, the QRS widens 50 percent beyond baseline, or a maximum dose of 17 mg/kg is administered). The ACLS guidelines state that amiodarone is an alternative treatment, but according to several case reports treatment with amiodarone of an irregular wide complex dysrhythmia due to preexcitation can result in unstable VT or VF. A clinically stable patient with atrial fibrillation and a wide QRS interval KNOWN to stem from a preexisting bundle branch block (ie, old ECG demonstrates preexisting block) may be treated in the same manner as a narrow-complex atrial fibrillation. Polymorphic ventricular tachycardia consistent with Torsades de Pointes is treated with magnesium sulfate (2 gr IV, followed by a maintenance infusion) TERMINATION OF RESUSCITATIVE EFFORTS Determining when to stop resuscitation efforts is difficult, and little data exist to guide decision-making. Physician survey data and clinical practice guidelines suggest that factors influencing the decision to stop resuscitative efforts include : 1. Duration of resuscitative effort >30 minutes without a sustained perfusing rhythm 2. Initial electrocardiographic rhythm of asystole 3. Prolonged interval between estimated time of arrest and initiation of resuscitation 4. Patient age and severity of comorbid disease 5. Absent brainstem reflexes 6. Normothermia

ACLS tachycardia algorithm

ACUTE RHEUMATIC FEVER

DIAGNOSIS Jones criteria 1992 presence of two major manifestations or of one major and two minor manifestations is indicative of a high probability of acute rheumatic fever. Major manifestations Minor manifestations 1. 2. 3. 4. 5. Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules

1. 2. 3. 4.

Arthralgia Fever Elevated ESR, CRP Prolonged PR interval

Laborory testing Any one of the following is considered adequate evidence of infection.: 1. Positive throat culture for group A beta-hemolytic streptococci or 2. positive rapid streptococcal antigen test 3. Elevated or rising streptococcal antibody titer, most often antistreptolysin O Notes Throat cultures are negative in about 75 percent of patients by the time rheumatic fever appears Only 80 percent of patients with documented ARF show a rise in the titer of antistreptolysin. Thus, a negative titer should incite testing for other antistreptococcal antibodies such as anti-DNAse B, streptokinase, and antihyaluronidase. Anti-DNAse titers are generally detectable for 6 to 9 months following infection. the CRP or ESR is useful in monitoring "rebounds" of inflammation; a normal test obtained a few weeks after discontinuing antirheumatic therapy suggests that the illness has ended, unless chorea appears. The CRP is probably more useful for this purpose, since it typically resolves over a matter of days once an episode of acute inflammation has resolved. The ESR, on the other hand, may stay elevated for up to two months after a transient inflammatory stimulus. A mild normochromic normocytic anemia of chronic inflammation may be seen ARF. Suppressing the inflammation usually improves the anemia, and iron therapy generally is not indicated.

TREATMENT Symptomatic Relief antiinflammatory agents, most commonly aspirin ( ASCALTIN 500mg). Dose of Aspirin: 80 to 100 mg/kg per day in children and 4 to 8 g/day in adults ( 34). The duration of antiinflammatory therapy varies. It should be maintained until all symptoms are absent and the erythrocyte sedimentation rate and C-reactive protein concentration are normal.

Carditis Severe carditis : significant cardiomegaly, CHF, or third-degree heart block. Such patients should be treated with conventional therapy for heart failure. Patients with severe carditis are often treated with corticosteroids, but studies of the effects of corticosteroids in the treatment of rheumatic carditis have shown conflicting results . corticosteroids usual dose: 2 mg/kg per day of oral prednisone PREDLON for the first one to two weeks. Depending upon the clinical and laboratory response, the dose is then tapered over the next two weeks. During this time, aspirin may be added in the dose recommended above. Valve surgery may be necessary when heart failure is due to regurgitant lesions that cannot be adequately managed with medical therapy . Surgical outcomes are generally better if valve surgery can be performed when carditis is quiescent . Valve repair, if feasible, is preferred to valve replacement since repair avoids the need for long-term anticoagulation associated with mechanical valves and the long-term risk of deterioration of a bioprosthesis .

ANTIBIOTIC THERAPY Antibiotic therapy with penicillin should be started and maintained for at least 10 days, regardless of the presence or absence of pharyngitis at the time of diagnosis. T dose of oral penicillin V: o OSPENINE 250 mg two to three times daily for children o OSPENINE 500 mg two to three times daily for adults. A depot penicillin, such as benzathine penicillin G, in one single IM dose should be given if compliance is an issue: o DEPOPEN 600,000 units for children who weigh 27 kg o DEPOPEN 1.2 million units for children who weigh >27 kg and adults. Individuals who are allergic to penicillin can be treated with erythromycin 40 mg/kg per day (maximum dose of 1000 mg) divided into two to four doses or Azithromycin 500 mg on first day then 250 mg per day for the next 4 days . A 10-day course of a narrow spectrum oral cephalosporin is also acceptable. In addition, the throats of all family contacts should be cultured; penicillin therapy is initiated if they are positive for beta-hemolytic streptococci.

ANTIBIOTIC PROPHYLAXIS started immediately after resolution of the acute episode. PO: Penicillin V potassium 400,000 units (250 mg) twice per day o Sulfadiazine 500 mg / day for children 27 kg , 1000 mg / day for children >27 kg and adults. IM : benzathine penicillin G 1.2 million units every four weeks. However, injections every three weeks may be more effective in preventing recurrences of acute rheumatic fever . allergic to penicillin and sulfadiazine can be treated with oral erythromycin 250 mg twice daily.

Duration of prophylaxis WHO guidelines 2001 : without proven carditis At least 5 years following diagnosis of ARF or until age 18 with mild mitral regurgitation At least 10 years or until age 25 Patients with severe valve disease and/or after valve surgery Life-long prophylaxis A possible future alternative to long-term prophylaxis in an individual with rheumatic fever may be streptococcal vaccines designed not only to prevent recurrent infections in rheumatic-susceptible individuals, but also to prevent streptococcal disease in general.

Antimicrobial therapy of native valve endocarditis Therapy of native valve endocarditis due viridans streptococci 4 week regimens: Either penicillinG 12-18 million U/24 h IV either continuously or in 4 or 6 divided doses Or Ceftriaxone 2 g/24 h IV/IM in 1 dose Or Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses not to exceed 2 g/24 h unless concentrations in serum are inappropriately low 2 week regimens: Either penicillinG 12-18 million U/24 h IV either continuously or in 6 divided doses Or Ceftriaxone 2 g/24 h IV/IM in 1 dose plus Gentamicin 3 mg/kg per 24 h IV/IM in 1 dose or in 2 to 3 equally divided doses 4 week regimens Preferred in most patients >65 y or with impairment of 8th nerve or renal function. 2 week regimens Not intended for patients with known cardiac or extracardiac abscess or for creatinine clearane <20 mL/min, impaired 8th nerve function. Vancomycin therapy only recommended for patients allergic to penicillin and cephalosporins;

Therapy of native valve endocarditis due to staphylococcus Oxacillin-susceptible strains Nafcillin or oxacillin 12 g/24 h IV in 4 or 6 equally divided doses for 6 wks, plus optional addition of Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses for 3 to 5 days Or Cefazolin 6 g/24 h IV in 3 equally divided doses for 6 wks, plus optional addition of Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses for 3 to 5 days

Oxacillin-resistant strains Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses for 6 wks; not to exceed 2 g/24 h unless concentrations in serum are inappropriately low Penicillin G 24 million U/24 h IV in 4 to 6 equally divided doses may be used in place of nafcillin or oxacillin if strain is penicillin susceptible and does not produce Oxacillin-susceptible Regimen for complicated right-sided and all left-sided IE. Cefazolin For penicillin-allergic, nonanaphylactoid type patients. Therapy of culture-negative native valve endocarditis One of the following: 1. Ampicillin-sulbactam 12 g/24 h IV in 4 divided doses for 4-6 wks plus Gentamicin 3 mg/kg per 24 h IV/IM in 3 divided doses for 4-6 wks OR 2. Vancomycin 30 mg/kg per 24 h IV in 2 divided doses for 4-6 wks; not to exceed 2 g/24 h unless concentrations in serum are inappropriately low Plus Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 3 divided doses for 4-6 wks plus Ciprofloxacin 1000 mg/24 h PO or 800 mg/24 h IV in 2 divided doses for 4 to 6 weeks

Recommendations For Surgery In Patients With Native Valve Endocarditis Surgery should not be delayed to complete antimicrobial therapy in patients with progressive HF or evidence of other complications. 1. valve dysfunction leading to heart failure (Grade 1B). 2. infection with difficult to treat pathogens (Grade 1C). 3. valve destruction resulting in severe regurgitation with hemodynamic evidence of elevated left ventricular end-diastolic or left atrial pressures (Grade 1C). 4. persistent infection, including perivalvular abscess (Grade 1C). 5. embolic events while on an appropriate antibiotic regimen OR associated with a large vegetation (Grade 2C). 6. mobile, large (>10 mm) left sided vegetations with or without emboli if associated with other signs of more severe disease (Grade 2C). Antimicrobial therapy of prosthetic valve endocarditis Treatment of prosthetic valve endocarditis is more difficult than treatment of native valve endocarditis and may require surgical replacement of the prostheses in addition to antibiotic therapy. We recommend the same treatment regimens for a specific pathogen causing PVE as is used for that organism when it causes native valve endocarditis ( Grade 1B). An exception is staphylococcal endocarditis; we recommend treatment with three agents for this microorganism. ( Grade 1B). We recommend treatment of PVE with an agent(s) that is bactericidal for the isolated microorganism for at least six weeks ( Grade 1C).

Therapy of prosthetic valve endocarditis due to staphylococcus Oxacillin-susceptible strains Nafcillin or oxacillin 12 g/24 h IV in 6 divided doses for 6 wks Or Cefazolin 6 g/24 h IV in 3 divided doses for 6 wks Or Vancomycin 30 mg/kg per 24 h IV in 2 divided doses for 6 wks Plus Rifampin 900 mg/24 h IV/PO in 3 divided doses for 6 wks Plus Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 divided doses for 2 wks Oxacillin-resistant strains Vancomycin 30 mg/kg per 24 h IV in 2 divided doses for 6 wks Plus Rifampin 900 mg/24 h IV/PO in 3 divided doses for 6 wks Plus Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 divided doses for 2 wks Penicillin G 24 million U/24 h IV in 4 to 6 equally divided doses may be used in place of nafcillin or oxacillin if strain is penicillin susceptible Cefazolin For penicillin-allergic, nonanaphylactoid type patients. Vancomycin therapy only recommended for patients allergic to penicillin and cephalosporins; If organism is gentamicin resistant, an alternative drug such as another aminoglycoside (eg, amikacin), a fluoroquinolone, or another antimicrobial to which the organism is susceptible may be substituted . If gentamicin susceptible, added for the full course for MRSA but only for 2 wks for coagulase-negative staphylococci. If organism is resistant to all aminoglycosides, a fluoroquinolone may be substituted.

PREVENTION OF INFECTIVE ENDOCARDITIS

Which patients Prophylaxis was recommended only in Patients at highest risk : 1. 2. 3. 4. 5. Prosthetic heart valves, including bioprosthetic and homograft valves. Prosthetic material used for cardiac valve repair A prior history of IE. Unrepaired cyanotic congenital heart disease, including palliative shunts and conduits. Completely repaired congenital heart defects with prosthetic material or device, whether placed by surgery or by catheter, during the first 6 months after the procedure. 6. Repaired congenital heart disease with residual defects at the site or adjacent to the site of the prosthetic device. 7. Cardiac "valvulopathy" in a transplanted heart. Valvulopathy is defined as documentation of substantial leaflet pathology and regurgitation . No longer indicated bicuspid aortic valve, acquired aortic or mitral valve disease (including mitral valve prolapse with regurgitation and those who have undergone prior valve repair), and hypertrophic cardiomyopathy with latent or resting obstruction. The Highest Risk Procedures That May Result In Transient Bacteremia : 1. All dental procedures that involve manipulation of either gingival tissue or the periapical region of teeth or perforation of the oral mucosa. 2. Procedures of the respiratory tract that involve incision or biopsy of the respiratory mucosa (tonsillectomy, adenoidectomy, or bronchoscopy with biopsy). 3. Procedures in patients with ongoing GI or GU tract infection. 4. Procedures on infected skin, skin structure, or musculoskeletal tissue. 5. Surgery to place prosthetic heart valves or prosthetic intravascular or intracardiac materials. . Not Recommend Routine Antimicrobial Prophylaxis in these procedures : Genitorurinary procedures : dilation of strictures, catheters, and prostatectomy . Gastrointestinal procedures: diagnostic colonoscopy or EGD with biopsy or ERCP. Vaginal or cesarean delivery CHOICE OF ANTIMICROBIAL AGENT Dental, oral, or upper respiratory tract procedures The primary antibiotic regimen is amoxicillin, 2 g orally 30 to 60 minutes before the procedure , a second dose is not necessary .

Patients who are allergic to penicillins can be treated with cephalexin (2 g) or azithromycin or clarithromycin (500 mg) or clindamycin (600 mg). Patients who are unable to take oral treated with 2 g of IV or IM ampicillin. Patients allergic to penicillin can be given cefazolin or ceftriaxone (1 g IV) OR 600 mg of IV or IM clindamycin.

Genitourinary or gastrointestinal procedures antibiotic for enterococcal bacteremia : amoxicillin or ampicillin In the patient unable to tolerate these drugs, vancomycin. Skin and musculoskeletal tissue antistaphylococcal penicillin or a cephalosporin. In patient is unable to take a beta-lactam or is known or suspected to have an infection caused by a MRSA:Clindamycin or vancomycin Pregnancy amoxicillin, ampicillin, and vancomycin are appropriate agents and they should be administered at the time of delivery. Patients on antibiotics If patients are receiving antibiotics for other indications at the time that dental or invasive procedures, alternate antibiotic of a different class is chosen.

Surgery for placement of prosthetic valves or intracardiac/intravascular materials Patients undergoing surgery for placement of prosthetic valves or intracardiac or intravascular materials are at risk for the development of bacterial endocarditis . antimicrobial prophylaxis directed against staphylococci is advisable. First generation cephalosporins are often used, but local hospital susceptibility patterns need to be taken into account, and if methicillin-resistant staphylococci are common or prevalent local pathogens, vancomycin should be substituted for cephalosporins. Antibiotic regimens for prophylaxis of bacterial endocarditis : Situation Agent Oral Amoxicillin 500mg Unable to take oral Ampicillin 1gr OR medication Cefazolin 1gr OR Ceftriaxone 1gr Oral But penicillins Allergic to Cephalexin 500 mg OR Clindamycin 300mg OR Azithromycin 250mg OR Clarithromycin 500mg Dose 2g 2 g IM or IV 1 g IM or IV 1 g IM or IV 2g 600 mg 500 mg 500 mg 1 g IM or IV 1 g IM or IV 600 mg IM or IV

Allergic to penicillins or Cefazolin OR ampicillin and unable to Ceftriaxone OR take oral medication Clindamycin

Treatment Of Deep Vein Thrombosis

Initial anticoagulation regimen We recommend that patients with DVT be treated acutely with LMW heparin, unfractionated intravenous heparin, adjusted-dose or fixed dose subcutaneous heparin, or subcutaneous fondaparinux ( Grade 1A). In comparison to unfractionated heparin, LMW heparin and fondaparinux offer the major benefits of convenient dosing, facilitation of outpatient treatment, and a lower incidence of heparin-induced thrombocytopenia. If direct cost to the patient is not an issue, we recommend that clinicians use LMW heparin over unfractionated heparin ( Grade 1A) Dosing of heparins : I.V.: 80 units/kg (or 5000 units) I.V. push followed by continuous infusion of 18 units/kg/hour (or 1300 units/hour). o SubQ: In Monitored dosing: Initial: 17,500 units or 250 units/kg then 250 units/kg every 12 hours. In Unmonitored dosing: Initial: 333 units/kg then 250 units/kg every 12 hours Dosing of Enoxaparin : Inpatient treatment : 1 mg/kg/dose every 12 hours or 1.5 mg/kg once daily. Outpatient treatment (without pulmonary embolism): 1 mg/kg/dose every 12 hours In patients with severe renal failure (eg, creatinine clearance <30 mL/min), we suggest intravenous unfractionated heparin over LMW heparin ( Grade 2C) .

We recommend that treatment with LMW heparin, heparin, or fondaparinux should be continued for at least 5 days and that oral anticoagulation be initiated simultaneously and both agents overlapped for at least five days ( Grade 1A). The heparin or fondaparinux can be discontinued on day 5 or 6 if the INR has been in the therapeutic range for at least 24 hours or two consecutive days. As an integral part of the initial treatment of VTE, we recommend that oral anticoagulation with warfarin should prolong the INR to a target of 2.5 (INR range: 2.0 to 3.0) ( Grade 1A). We recommend against high-intensity therapy (INR range: 3.1 to 4.0) as well as against low-intensity therapy (INR range: 1.5 to 1.9) The use of thrombolytic agents in the treatment of venous thromboembolism must be individualized and requires further investigation. Patients with hemodynamically unstable PE or massive iliofemoral thrombosis, and who are also at low risk to bleed, are the most appropriate candidates. The placement of an inferior vena cava filter is recommended when there is a contraindication to, or a failure of, anticoagulant therapy in an individual with acute proximal vein DVT ( Grade 1C). . All heparin products should be stopped if any one of the following occurs: a precipitous or sustained fall in the platelet count, or a platelet count <100,000/microL. . To monitor for heparin-induced thrombocytopenia : o For patients receiving therapeutic-dose UFH, every other day platelet count monitoring is suggested from day 4 to day 14, or until UFH is stopped, which ever occurs first. o For patients receiving prophylactic dose UFH or LMW heparin, platelet count monitoring is suggested every 2 to 3 days from day 4 to day 14, or until heparin is stopped, which ever occurs first. o For patients who have received UFH in the past 100 days and who are starting treatment with UFH or LMW heparin, who are therefore at risk of developing accelerated thrombocytopenia, a baseline platelet count should be obtained and repeated within 24 hours o For medical/obstetric patients who are only receiving LMW heparin, or medical patients who are receiving only intravascular catheter UFH "flushes", in whom the incidence of HIT is expected to be <0.1 percent, routine platelet count monitoring is not suggested. If oral anticoagulants are contraindicated or inconvenient, long-term therapy can be undertaken with either low molecular weight heparin or adjusted-dose unfractionated heparin. .

General medical management and ambulation : Once warfarin/ heparin have been started and symptoms (eg, pain, swelling) are under control, we recommend early ambulation in preference to bed rest ( Grade 1A). During initial ambulation, and for the first two years following an episode of VTE, we recommend use of an elastic graduated compression stocking with a pressure of 30 to 40 mmHg at the ankle ( Grade 1A) . LENGTH OF TREATMENT patients with a first thromboembolic event in the context of a reversible or time-limited risk factor (eg, surgery, trauma, pregnancy, use of oral contraceptives) should be treated for a minimum of three months, rather than for a shorter period of time ( Grade 1A). Longer-term therapy (ie, longer than 6 months) is not necessary, since the risk of recurrence in such patients is low, being 3 percent in the first year . In those patients with a continuing risk factor that is potentially reversible (eg, prolonged immobilization), long-term therapy should be continued until the risk factor is reversed.

For a patient with a first episode of idiopathic VTE, we recommend anticoagulation for a minimum of 3 months ( Grade 1A). Following this time, and periodically thereafter, all patients should be evaluated for the risk/benefit ratio of long-term anticoagulation. For patients with a first unprovoked proximal VTE, we suggest indefinite treatment (eg, >12 months) over treatment for a lesser period of time ( Grade 2A). Recurrent VTE and antiphospholipid syndrome : we recommend indefinite anticoagulation ( Grade 1A). . Isolated calf vein (distal) thrombosis : we suggest that anticoagulation for 3 months is sufficient, rather than indefinite therapy ( Grade 2B). If anticoagulation is not administered (eg, isolated asymptomatic distal venous thrombosis), serial noninvasive studies of the lower extremity should be performed over the next 10 to 14 days to assess for proximal extension of the thrombus. Malignancy : o we suggest INITIAL treatment with LMW heparin over the use of oral anticoagulants (Grade 2A). o initiate treatment with LMW heparin for the first 3 to 6 months. Because the risk of recurrent VTE is unacceptably high in patients with active cancer who stop anticoagulant therapy, we suggest that subsequent treatment with either LMW heparin or warfarin be given indefinitely or until the cancer is resolved (Grade 2C). o We recommend anticoagulation in all patients with brain tumors and venous thromboembolism (VTE) except those that have a high rate of intracranial hemorrhage (ie, metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma). (Grade 1C). o VTE in low-grade glioma and benign tumors should be treated for 3 to 6 months. Long-term anticoagulation is recommended for malignant gliomas. . o We suggest LMW heparin rather than warfarin for anticoagulation (Grade 2B). o For patients with brain tumors that have an increased risk of hemorrhage (ie, metastases from melanoma, choriocarcinoma, thyroid carcinoma, and renal cell carcinoma), we suggest placement of an IVC filter if there is significant residual metastatic disease in the brain (Grade 2C). o For patients whose metastatic disease has already been surgically removed or treated effectively and for those whose medical condition is too unstable for placement of an IVC filter, we suggest anticoagulation (Grade 2C)

Anticoagulation failure insertion of an inferior vena cava filter or one or more vascular interventions such as thrombolytic therapy or thrombectomy. A vascular surgery consultation should be obtained under such circumstances; the selected intervention(s) will depend upon available expertise . Pregnancy :

Warfarin can produce an embryopathy when given between the sixth and ninth weeks of pregnancy. subcutaneous unfractionated or LMW heparin (which should be switched to unfractionated heparin two weeks prior to the expected delivery) at full doses should be continued until delivery; a four to six week course of warfarin should be completed after delivery.

Management of a supratherapeutic INR after warfarin

INR <5 and no bleeding the dose of warfarin can be reduced or one or more doses of warfarin can be omitted. The INR should then be monitored more frequently, and therapy resumed at an adjusted dose when the INR is again within the desired target range. If the INR elevation is minimal and/or expected to be transient, no dose reduction may be necessary. INR 5 to 9 without bleeding the next one or two doses of warfarin can be omitted, the INR monitored more frequently, and therapy resumed at reduced dose when the INR returns to the therapeutic range. Alternatively, in patients at increased risk for bleeding (eg, history of bleeding, stroke, renal failure, anemia, hypertension), we suggest omitting a dose and administering a low oral dose of vitamin K (eg, 1 to 2.5 mg) rather than a higher oral dose or an intravenous dose (Grade 2A).

INR 9 without bleeding we recommend holding warfarin therapy, administering one or more 2.5 to 5 mg doses of vitamin K ORALLY, monitoring the INR more frequently, and resuming therapy once the INR is again in the therapeutic range, rather than more aggressive treatment (Grade 1B). Serious or life-threatening bleeding and any INR We recommend holding warfarin and giving vitamin K (10 mg) by SLOW IV INFUSION(eg, over 20 to 60 minutes), supplemented with fresh frozen plasma (initial dose: 2 to 3 units; more as clinically indicated), prothrombin complex concentrate , or recombinant factor VIIa (Grade 1C). Vitamin K administration can be repeated every 12 hours for persistantly elevated INR. Temporary Reversal Of Warfarin If more rapid reversal is required because of the need for urgent surgery, we suggest stopping this medication and administering one or more oral doses of vitamin K ( 5 mg/dose) (Grade 2C). Intracerebral hemorrhage Immediate cessation of all anticoagulant and antiplatelet therapy For immediate and short-term reversal of anticoagulation (eg, minutes to hours) we recommend infusion of an agent (ie, prothrombin complex concentrates (PCC), recombinant human factor VIIa, fresh frozen plasma (FFP)) to reverse the anticoagulant effect as rapidly as possible. we suggest PCC over factor VIIa or FFP, In institutions where PCC is not available, we suggest the use of recombinant human factor VIIa rather than FFP (Grade 2C). Fresh frozen plasma is indicated when neither PCC nor recombinant human factor VIIa is available. For longer-term reversal of anticoagulation (ie, hours to days) we recommend administration of vitamin K by slow intravenous infusion, rather than by the oral or subcutaneous route. The usual dose is 10 mg, which can be repeated every 12 hours for persistent INR elevation. Keeping the systolic blood pressure <180 mmHg during the acute phase is advisable. surgical evacuation of the hematoma after reversing anticoagulation can be considered in selected patients. If the INR has been corrected to normal, it is reasonable to begin low-dose prophylactic subcutaneous heparin or LMW heparin 48 hours after ICH onset. For patients who will resume anticoagulation, warfarin can be restarted at 7 to 14 days. Pneumatic compression stockings and early ambulation should be considered if leg paresis is present.

THERAPY IN ESSENTIAL HYPERTENSION

The amount of blood pressure reduction is the major determinant of reduction in cardiovascular risk in patients with hypertension, not the specific antihypertensive drug Among hypertensive patients without an indication for a specific drug, we recommend initial monotherapy with a low dose thiazide-type diuretic, an angiotensin converting enzyme (ACE) inhibitor/angiotensin II receptor blocker (ARBs), or a calcium channel blocker (Grade 1B). Monotherapy is most likely to be successful in those with initial blood pressures within 20/10 mmHg of goal. . If a thiazide-type diuretic is chosen, we suggest chlorthalidone rather than hydrochlorothiazide (Grade 2B). Most clinicians, particularly in the United States, have limited, if any, experience with chlorthalidone, which may be somewhat more likely to induce hypokalemia than hydrochlorothiazide at the same dose. The basic principles of monitoring for hypokalemia with chlorthalidone are identical to those with hydrochlorothiazide. An additional issue is the approach to patients already being treated with low-dose hydrochlorothiazide. Some patients have an indication for a particular class of antihypertensive drugs. . Among patients who do not attain goal blood pressure with adequate monotherapy, the choice of a second drug for combination therapy varies with the drug that was used for initial therapy. . Among patients who have an initial blood pressure more than 20/10 mmHg above goal, we suggest initial therapy with the combination of two long-acting drugs from different classes rather than monotherapy with a single agent (Grade 2C).

Classification and management of blood pressure for adults BP classification SBP DBP Management Lifestyle Initial drug therapy modification Without compelling indication

With compelling indications

Normal Prehypertension Stage hypertension Stage hypertension

<120 120139 1 140159 2 160

and <80 or 8089 or 9099 or

Encourage Yes Yes

No antihypertensive drug indicated

100 Yes

Drug(s) for the compelling Thiazide-type diuretics for most; indications may consider ACE inhibitor, ARB, beta blocker, CCB, or combination 2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or beta blocker or CCB)

Treat patients with chronic kidney disease or diabetes to BP goal of less than 130/80 mmHg. Other compelling indications include disorders such as heart failure, post-myocardial infarction, and atrial fibrillation in which particular antihypertensive drugs are warranted independent of BP.

Considerations for individualizing antihypertensive therapy : Indication Antihypertensive drugs Systolic heart failure Post-myocardial infarction Proteinuric chronic renal failure High coronary disease risk Diabetes mellitus (no proteinuria) Angina pectoris Atrial fibrillation rate control Atrial flutter rate control Benign prostatic hypertrophy Essential tremor Hyperthyroidism Migraine Osteoporosis Perioperative hypertension Raynaud's syndrome Contraindications Angioedema Bronchospastic disease Depression Liver disease Pregnancy Second or third degree heart block ACE inhibitor Beta blocker Reserpine Methyldopa ACE inhibitor, ARB (includes women likely to become pregnant) Beta blocker, nondihydropyridine calcium channel blocker ACE inhibitor or ARB, beta blocker, diuretic, aldosterone antagonist* ACE inhibitor, beta blocker, aldosterone antagonist ACE inhibitor and/or ARB Diuretic (ALLHAT), perhaps ACE inhibitor (HOPE) Diuretic (ALLHAT), perhaps ACE inhibitor (HOPE) Beta blocker, calcium channel blocker Beta blocker, nondihydropyridine calcium channel blocker Beta blocker, nondihydropyridine calcium channel blocker Alpha blocker Beta blocker (noncardioselective) Beta blocker Beta blocker, calcium channel blocker Thiazide diuretic Beta blocker Dihydropyridine calcium channel blocker

May have adverse effect on comorbid conditions Depression Gout Hyperkalemia Hyponatremia Renovascular disease Beta blocker, central alpha agonist Diuretic Aldosterone antagonist, ACE inhibitor, ARB Thiazide diuretic ACE inhibitor or ARB

ENDOCRINOLOGY

DIAGNOSIS OF DIABETES MELLITUS

Criteria 1. Symptoms of diabetes and a casual plasma glucose 200 mg/dl (11.1 mmol/l). Casual : any time of day without regard to time since last meal. classic symptoms of DM : polyuria, polydipsia, unexplained weight loss. OR 2. FPG 126 mg/dl (7.0 mmol/l). Fasting : no caloric intake for at least 8 hours. Impaired fasting glucose (IFG) (pre-diabetes): FPG 100 - 125 mg/dL. OR 3. Oral Glucose Tolerance Test (OGTT) : plasma glucose 200mg/dl (11.1 mmol/l) two hours after glucose load (75 g). Impaired Glucose Tolerance (IGT) : Two-hour plasma glucose value during a 75 gram oral glucose tolerance test between 140 and 199 mg/dl The oral glucose tolerance test OGTT, which is more expensive but more sensitive than fasting plasma glucose, should be performed in patients: 1. with an Impaired Fasting Glucose IFG 2. with a normal fasting plasma glucose but in whom the clinical suspicion for type 2 diabetes remains high. Characteristics of type 1 and Type 2 diabetes mellitus in children and adolescents Type 1 Diabetes Type 2 Diabetes Prevalence Age at presentation Onset Ketosis at onset Affected relative Female:male Inheritance HLA-DR3/4 Ethnicity Insulin secretion Insulin sensitivity Insulin dependence Overweight Acanthosis nigricans Pancreatic antibodies Common Throughout childhood Acute severe Common 5 to 10 percent 1:1 Polygenic Association All, Caucasians Decreased/absent Normal when controlled Permanent No No Yes Increasing Puberty Insidious to severe About one-third 75 to 90 percent 2:1 Polygenic No association All Variable Decreased Episodic >90 percent Common No

Autoantibodies to insulin (IAA), islet cell cytoplasm (ICA), glutamic acid decarboxylase (GAD), or tyrosine phosphatase (insulinoma associated) antibody (IA-2 and IA-2 ) at diagnosis in 85 to 98 %.

Monitoring in patients with diabetes mellitus Intervention Frequency Notes History and physical examination Smoking cessation Blood pressure eye examination Every visit Every visit Annually* For smokers only Goal <130/80 (120/75 in patients with nephropathy) Begin at onset of type 2 diabetes, 3 to 5 years after onset of type 1 diabetes. Examine more than annually if significant retinopathy Every visit if peripheral vascular disease or neuropathy

Foot examination Laboratory studies Fasting lipid profile

Annually

Annually

May obtain every two years if profile is low risk goal LDL less than 100 mg/dL

A1C Microalbuminuria

Every 3 to 6 Goal <7% (may be lower or higher in selected patients) months Annually Begin 3 to 5 years after onset of type 1 diabetes; protein excretion and serum creatinine should also be monitored if persistent albuminuria is present as Begin at age 40, earlier if significant additional CAD risk factors aspirin (75 to 162 mg/day) in patients with or at high risk for cardiovascular disease. .

Serum creatinine Electrocardiogram

Initially, indicated Annually

Vaccinations Pneumococcus Influenza One time Annually Patients over age 65 need a second dose if vaccine was received 5 years previously and age was <65 at time of vaccination

* Less frequent screening (every two to three years) may be appropriate for some patients. GESTATIONAL DIABETES MELLITUS We recommend screening pregnant women for gestational diabetes mellitus (Grade 1B). We suggest screening be performed at 24 to 28 weeks of gestation (Grade 2B) We suggest the 50-g oral glucose challenge test be used for screening (Grade 2B). We use 130 mg/dL as the threshold for an abnormal test. We perform a three-hour 100-g oral glucose tolerance test in women who screen positive, but a 75-g twohour oral glucose tolerance test is also acceptable. Diagnose : if two or more of the following serum glucose values are met or exceeded : o Fasting serum glucose >95 mg/dL (5.3 mmol/L) o One-hour serum glucose >180 mg/dL (10 mmol/L) o Two-hour serum glucose >155 mg/dL (8.6 mmol/L) o Three-hour serum glucose >140 mg/dL (7.8 mmol/L)

Diagnostic Criteria For Diabetic Ketoacidosis (DKA)

Plasma glucose (mg/dL) Arterial pH Serum bicarbonate (mEq/L) Urine ketones Serum ketones Effective serum osmolality (mOsm/kg) Anion gap Alteration in sensoria or mental obtundation DKA Mild >250 7.25-7.30 15-18 Positive Positive Variable >10 Alert Moderate >250 7.00-7.24 10 to <15 Positive Positive Variable >12 Alert/drowsy Severe >250 <7.00 <10 Positive Positive Variable >12 Stupor/coma

Diagnostic criteria for Hyperosmolar Hyperglycemic State (HHS)

Plasma glucose (mg/dL) Arterial pH Serum bicarbonate (mEq/L) Urine ketones Serum ketones Effective serum osmolality (mOsm/kg) Anion gap Alteration in sensoria or mental obtundation >600 >7.30 >15 Small Small >320 Variable Stupor/coma

Protocol for the management of adult patients with HHS

* After history and physical exam, obtain capillary glucose and serum or urine ketones (nitroprusside method). Begin one liter of 0.9 percent NaCl over one hour and draw arterial blood gases, complete blood count with differential, urinalysis, serum glucose, BUN, electrolytes, chemistry profile and creatinine levels STAT. Obtain electrocardiogram, chest X-ray, and specimens for bacterial cultures, as needed. Serum Na+ should be corrected for hyperglycemia (for each 100 mg/dl glucose >100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value.) An alternative IV insulin regimen is to give a continuous intravenous infusion of regular

Protocol For The Management Of DKA

After history and physical exam, obtain capillary glucose and serum or urine ketones (nitroprusside method). Begin one liter of 0.9 percent NaCl over one hour and draw arterial blood gases, complete blood count with differential, urinalysis, serum glucose, BUN, electrolytes, chemistry profile, and creatinine levels STAT. Obtain electrocardiogram, chest X-ray, and specimens for bacterial cultures, as needed. Serum Na+ should be corrected for hyperglycemia (for each 100 mg/dl glucose >100 mg/dl, add 1.6 mEq to sodium value for corrected serum sodium value).An alternative IV insulin regimen is to give a continuous intravenous infusion of regular insulin at 0.14 units/kg/hour; at this dose, an initial intravenous bolus is not necessary.

Diagnostic Approach To Hypoglycemia In Adults

In patients with symptoms of hypoglycemia but normal serum glucose concentrations at the same time, no further evaluation is needed. Although low blood glucose values measured using reflectance meters suggest the presence of hypoglycemia, these methods are not sufficiently reliable in the low range. An oral glucose tolerance test done in an effort to replicate postprandial symptoms should not be performed because misleading results may be obtained. In patients who are fortuitously observed during an episode of symptoms and are found to have simultaneous hypoglycemia (fasting or postprandial), additional measurements that are typically done at the end of a prolonged fast should be performed (plasma insulin, C-peptide, proinsulin, and betahydroxybutyrate) If neither symptoms nor hypoglycemia have been observed and if clinical suspicion remains high, the patient should undergo a 72-hour fast, which is described in detail above. Interpretation of the data obtained at the end of the prolonged fast is the same as that performed during the occurrence of a spontaneous hypoglycemic episode o A lower plasma beta-hydroxybutyrate value and a vigorous plasma glucose response to intravenous glucagon point to hypoglycemia mediated by insulin or an insulin-like factor. o Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinomas and sulfonylurea-induced hypoglycemia; sulfonylurea is present in the plasma only in the latter condition o Plasma insulin values are higher than levels observed in insulinoma in patients with exogenous insulin administration, but plasma C-peptide values are low or undetectable. o Serum insulin may be very high (>100 U mL) in factitious hypoglycemia from insulin o Hypoglycemia that is not mediated by insulin or an insulin-like factor is characterized by low plasma concentrations of beta-cell polypeptides. Serum hydroxyProinsulin butyrate pmol L mmol L 5 2.7 <5 2.7 Serum glucose Sulfonylurea after in serum glucagon 25 No 25 No

Diagnostic interpretation of the results of a 72-hour fast Serum Insulin CDiagnosis Symptom Glucose U peptide mg dL mL pmol L Insulinoma Yes 45 3 200 Factitious hypoglycemia Yes 45 3 <200 from insulin Sulfonylureainduced Yes 45 3 200 hypoglycemia Hypoglycemia mediated by Yes 45 3 <200 insulin-like growth factor Non-insulinmediated Yes 45 <3 <200 hypoglycemia

2.7

25

Yes

<5

2.7

25

No

<5

>2.7

<25

No

Initial Management Of Blood Glucose In Type 2 Diabetes Mellitus

In the absence of specific contraindications, we suggest metformin as initial therapy in most patients (Grade 2B). We suggest initiating metformin at the time of diabetes diagnosis, along with consultation for lifestyle intervention (Grade 2C). The dose of metformin should be titrated to its maximally effective dose (usually 2000 to 2500 mg per day in divided doses) over one to two months, as tolerated. Metformin should not be administered when conditions predisposing to lactic acidosis are present. In the presence of contraindications to metformin, we suggest a shorter-duration sulfonylurea (glipizide) for initial therapy (Grade 2B). We suggest initiating lifestyle intervention first, at the time of diagnosis, since the weight gain that often accompanies a sulfonylurea will presumably be less if lifestyle efforts are underway (Grade 2C). However, if lifestyle intervention has not produced a significant reduction in symptoms of hyperglycemia or in glucose values after one or two weeks, then the sulfonylurea should be added. In patients who are intolerant of or are not candidates for metformin or sulfonylureas, repaglinide is a reasonable alternative, particularly in a patient with chronic kidney disease at risk for hypoglycemia. Another alternative is a thiazolidinedione, which may be considered in patients with lower initial A1C values or if there are specific contraindications to sulfonylureas. If a thiazolidinedione is to be used as initial therapy, pioglitazone is preferred because of the greater concern about atherogenic lipid profiles and a potential increased risk for cardiovascular events with rosiglitazone. Sitagliptin can be considered as monotherapy in patients who are intolerant of or have contraindications to metformin, sulfonylureas, or thiazolidinediones. As an example, sitagliptin might be a good choice as initial therapy in a patient with chronic kidney disease at risk for hypoglycemia. It is however, more expensive and less potent in lowering glycemia than the glinides, such as repaglinide, which can also be used safely in patients with chronic kidney disease. Further adjustments of therapy, which should usually be made no less frequently than every three months, are based upon the A1C result (and the results of home glucose monitoring), aiming for levels as close to the nondiabetic range as possible, and with A1C values >7 percent suggesting need for further adjustments in the diabetic regimen. If inadequate control is achieved (A1C remains >7 percent), another medication should be added within two to three months of initiation of the lifestyle intervention and metformin.

Insulin can be considered a first-line therapy for all patients with type 2 diabetes, particularly patients presenting with : o A1C >10 percent o fasting plasma glucose >250 mg/dL (13.9 mmol/l) o random glucose consistently >300 mg/dL (16.7 mmol/l) o ketonuria. o patients in whom it is difficult to distinguish type 1 from type 2 diabetes

Algorithm for the metabolic management of type 2 diabetes;

* Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7 percent and then at least every 6 months. The interventions should be changed if A1C is 7 percent.

Summary of glucose-lowering interventions Intervention Expected decrease in Advantages A1C with monotherapy, percent Tier 1: well-validated core Step 1: initial therapy Lifestyle to 1.0-2.0 Broad benefits decrease weight and increase activity Metformin 1.0-2.0 Weight neutral Step 2: additional therapy Insulin 1.5-3.5

Disadvantages

Insufficient for most within first year GI side effects, contraindicated with renal insufficiency

Sulfonylurea

1.0-2.0

No dose limit, rapidly One to four injections daily, effective, improved lipid monitoring, weight gain, profile hypoglycemia, analogues are expensive Rapidly effective Weight gain, hypoglycemia (especially with glibenclamide or chlorpropamide) Improved lipid profile Fluid retention, CHF, weight (pioglitazone), potential gain, bone fractures, expensive, decrease in MI potential increase in MI (pioglitazone) (rosiglitazone) Weight loss Two injections daily, frequent GI side effects, long-term safety not established, expensive Weight neutral Rapidly effective Weight loss Frequent GI side effects, three times/day dosing, expensive Weight gain, three times/day dosing, hypoglycemia, expensive Three injections daily, frequent GI side effects, long-term safety not established, expensive Long-term safety not established, expensive

Tier 2: less well validated TZDs 0.5-1.4

GLP-1 agonist

0.5-1.0

Other therapy -Glucosidase 0.5-0.8 inhibitor Glinide 0.5-1.5* Pramlintide 0.5-1.0

DPP-4 inhibitor

0.5-0.8

Weight neutral

CHF: congestive heart failure; GI: gastrointestinal; MI: myocardial infarction. * Repaglinide more effective in lowering A1C than nateglinide.

Treatment of acute adrenal insufficiency (adrenal crisis)

Emergency measures 1. Establish intravenous access with a large-gauge needle. 2. Draw blood for stat serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for lab results. 3. Infuse 2 to 3 liters of isotonic saline or 5 percent dextrose in isotonic saline as quickly as possible. Monitor for signs of fluid overload by measuring central or peripheral venous pressure and listening for pulmonary rles. Reduce infusion rate if indicated. 4. Inject 4 mg of dexamethasone phosphate intravenously. Intravenous hydrocortisone (100 mg immediately and every 6 h thereafter) may also be used, but will interfere with measurement of plasma cortisol during the short ACTH stimulation test. Mineralocorticoids are unnecessary at this time. 5. Use supportive measures as needed. Subacute measures after stabilization of the patient 1. Continue intravenous isotonic saline at a slower rate for next 24 to 48 h. 2. Search for and treat possible infectious precipitating causes of the adrenal crisis. 3. Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency, if patient does not have known adrenal insufficiency. 4. Determine the type of adrenal insufficiency and its cause if not already known. 5. Taper glucocorticoids to maintenance dosage over 1 to 3 d, if precipitating or complicating illness permits. 6. Begin mineralocorticoid replacement with fludrocortisones flurinf (0.1 mg by mouth daily) when saline infusion is stopped.

Treatment of chronic primary adrenal insufficiency

Glucocorticoid replacement 1. 2. 3. 4. Dexamethasone (Dexamin) 0.5mg (0.25-0.75) mg Or prednisone 5mg (2.5-7.5) mg orally at bedtime. Supplement with hydrocortisone (Hydrocort10mg) 5-10 mg orally in mid-afternoon if indicated. Alternative therapy : hydrocortisone 15-20 mg upon awakening and 5-10 mg in early afternoon. 3. Monitor clinical symptoms and morning plasma ACTH.

Mineralocorticoid replacement 1. Fludrocortisone (flurinif ) 0.1mg (0.05-0.2) mg orally. 2. Liberal salt intake. 3. Monitor lying and standing BP and pulse, edema, serum K and plasma renin activity. Androgen replacement 1. We suggest Dehydroepiandrosterone DHEA therapy only in women with impaired mood or sense of wellbeing despite optimal glucocorticoid . 2. Dehydroepiandrosterone 25-50 mg orally in women. Treatment of minor febrile illness or stress 1. 2. 3. 4. 2-3 times the usual maintenance glucocorticoid dosage for 3 days (known as the 3 x 3 rule) Do not change mineralocorticoid dose. Contact physician if illness worsens or persists for more than 3 d. No extra supplementation is needed for uncomplicated, outpatient dental procedures under local anesthesia. General anesthesia or intravenous sedation should not be used in the office.

Treatment of surgical procedures or severe illness 1. For minor procedures such as herniorrhaphy: hydrocortisone 25 mg for the day of operation only, with a return to the usual replacement dose on the second day. 2. For moderate surgical stress (eg, cholecystectomy, joint replacement): hydrocortisone 50 to 75 mg in divided doses on the day of surgery and the first post-operative day, with a return to the usual dose on the second post-operative day (using oral or IV preparation). 3. for major surgical procedures (eg, cardiac bypass) : 100 to 150 mg hydrocortisone in divided doses for two to three days, then returning to the usual dose. Alternatively, the dose used on the day of surgery can be halved on post-operative day one. Emergency treatment of severe stress or trauma Inject contents of prefilled dexamethasone (4 mg in 1 mL saline) syringe intramuscularly. Pregnancy 1. During labor, adequate saline hydration and 25 mg hydrocortisone should be administered intravenously every six hours. 2. At the time of delivery, or if labor is prolonged, hydrocortisone should be administered intravenously in a dose of 100 mg every six hours or as a continuous infusion. 3. After delivery, the dosage can be tapered rapidly to maintenance within three days . 4. An occasional woman in the first trimester with severe nausea and vomiting may require intramuscular dexamethasone at a slightly increased dosage (1 mg daily).

Establishing the diagnosis of Cushing's syndrome

We recommend that at least two first-line tests should be abnormal to establish the diagnosis of Cushing's syndrome We suggest late night salivary cortisol, urinary cortisol, and the low-dose dexamethasone suppression tests as first line tests. Overnight 1 mg test The overnight test consists of administration of 1mg of dexamethasone at 11 PM to 12 AM, and measurement of serum cortisol at 8 AM the next morning Urinary and Late evening salivary cortisol measurements should be obtained at least twice. The urinary cortisol excretion should be unequivocally increased (threefold above the upper limit of normal for the assay), or the diagnosis of Cushing's syndrome is uncertain and other tests should be performed. The diagnosis of Cushing's syndrome is confirmed when two tests are unequivocally abnormal. The patient should undergo additional evaluation if the test results are discordant or only slightly abnormal. If test results are normal, the patient does not have Cushing's syndrome unless it is extremely mild or cyclic. We do not suggest additional evaluation unless symptoms progress or cyclic Cushing's syndrome is suspected.

Establishing the cause of Cushing's syndrome Determine whether the hypercortisolism is ACTH-dependent (ie, due to a pituitary or nonpituitary ACTH-secreting tumor), or ACTH-independent (ie, due to an adrenal source) by measuring plasma ACTH. A low plasma ACTH concentration [<5 pg/mL (1.1 pmol/L)] in a hypercortisolemic patient is evidence of ACTH-independent disease; thin-section CT imaging of the adrenal glands is usually the next diagnostic procedure in these patients. Patients with ACTH-independent disease and bilateral adrenal micronodular or macronodular hyperplasia on imaging require additional testing. Patients with an intermediate plasma ACTH concentration, 5 to 20 pg/mL (1.1 to 4.4 pmol/L), should undergo CRH testing. The presence of an ACTH response indicates Cushing's disease. The remaining majority of patients with ACTH-dependent disease (ACTH >20 pg/mL) should undergo non-invasive tests (a high-dose dexamethasone suppression test and CRH stimulation test) and/or inferior petrosal sinus sampling. high-dose dexamethasone suppression test : 8 mg dexae given PO at 11 PM to midnight Suppression of cortisol during dexamethasone administration as well as increases in ACTH and cortisol after CRH administration are consistent with the diagnosis of a pituitary adenoma (Cushing's disease). A pituitary MRI should be obtained when ACTH-dependent hypercortisolism has been confirmed. If a clear pituitary lesion >6 mm is identified and high dose dexamethasone and CRH tests are consistent with Cushing's disease, no further diagnostic tests are required. Petrosal sinus sampling with CRH stimulation is recommended for patients with unclear MRI (lesions <6mm) or non concordant non invasive tests to distinguish between Cushing's disease and ectopic ACTH secretion.

Diagnostic Approach To And Treatment Of Thyroid Nodules

Risk Factors For The Development Of Thyroid Carcinoma : 1. twice as high in men than women 2. higher in adults over age 60 and under age 30 years 3. A history of radiation treatment to the head and neck region 4. Hematopoietic stem cell transplantation 5. Ultrasonographic features : Hypoechoic Microcalcifications "Twinkling" on B-flow imaging Central vascularity

Irregular margins Incomplete halo Nodule is taller than wide Documented enlargement of a nodule

RECOMMENDATIONS FOR EVALUATION Fine-needle aspiration (FNA) biopsy. This technique is the most accurate method for selecting patients needing thyroid surgery, but is not always the best initial diagnostic test. High-resolution thyroid ultrasonography, which provides anatomic definition superior to thyroid scintigraphy., ultrasonography is not usually cost-effective as an initial test, and scintigraphy remains the only way to determine the functional status of a nodule. Thyroid function should be assessed in all patients with thyroid nodules TSH , anti-thyroid peroxidase antibody An excellent case can be made for evaluating all patients with thyroid nodules initially with FNA, assuming the serum TSH is normal o Patients with benign macrofollicular lesions are followed clinically. o Those with cancer are referred for surgery. o Radionuclide imaging is performed in patients with microfollicular or cellular (indeterminate or suspicious) lesions. Patients with nonautonomous cold lesions are referred for surgery to exclude capsular invasion, while those with autonomous hot lesions are followed, or if the patient is hyperthyroid, radioiodine therapy or surgery is advised. There are two important exceptions to this approach, in which thyroid scintigraphy becomes the best first procedure: o If the serum TSH concentration is low, the possibility that the nodule is autonomous is considerably increased. Scintigraphy should be the initial test to avoid obtaining suspicious cytology from an autonomous nodule. o If Hashimoto's thyroiditis is suspected (A high TSH or a high anti-TPA), scintigraphy may show that the palpable nodule corresponds to an entire functioning thyroid lobe. Biopsy is not indicated in these patients. Furthermore, the cytology may be falsely suspicious due to the presence of Hurthle (oxyphilic) cells. Other potential reasons for beginning with scintigraphy include patient anxiety about the performance of FNA and the potential concern of obtaining a FNA in some patients taking anticoagulants, although many endocrinologists are comfortable doing FNA with a 27 gauge needle in anticoagulated patients, as long as the nodule is anterior and easily compressible. Previously, the response of a nodule to T4 suppressive therapy was used to select nodules that required excision: nodules that shrank were assumed to be benign, and those that failed to shrink were excised to exclude malignancy. However, this approach is not very specific since only 20 to 30 percent of nodules regress when T4 is administered. Furthermore, 13 percent of subsequently proven papillary cancers in one series decreased in size during T4 treatment Repeat FNA o Reaspiration of thyroid nodules that are unchanged clinically is not warranted . o small changes in nodule size on serial ultrasonography do not require a repeat aspiration. o reassessment is warranted when there is substantial growth or change in the texture of a nodule, or new symptoms are attributed to a nodule.

Patients with a history of childhood head or neck irradiation: I recommend ultrasonography based upon an assessment of each patient's risk factors for thyroid cancer.

RECOMMENDATIONS FOR TREATMENT Patients with macrofollicular nodules are usually followed without surgery. There is considerable controversy concerning the efficacy of T4 therapy for these patients. o Patients who have small, asymptomatic, solitary nodules are followed without therapy unless they enlarge. Growing nodules are rebiopsied, and the patient is given a trial of T4 therapy if the nodule is benign. o A trial of T4 therapy is initiated in patients with nodules that are 2.0 to 2.5 cm. in diameter or larger, or in patients with nodules of any size that are causing symptoms, especially if there was abundant colloid in the needle aspirate or if further growth might necessitate surgery. If the nodule does regress, slightly lower doses of T4 are given. o T4 therapy to prevent further goitrogenesis is initiated if the patient has other nodules detected by ultrasonography or if the thyroid gland is diffusely enlarged (and the patient's serum TSH concentration is not low). o I am more reluctant to begin T4 therapy in elderly patients and in postmenopausal women with low bone density who are not taking antiresorptive therapy. o The goal of therapy should be a TSH concentration of approximately 0.1 to 0.4 mU/L. Lower doses of T4 can be tried if there is an initial response. Most patients with nonautonomous (cold) microfollicular adenomas should have surgery. However, T4 therapy may be reasonable in elderly patients with adenomas or even carcinomas in whom surgery is risky or who have limited life expectancy because of nonthyroidal disease. Those with autonomous nodules (hot nodules) causing hyperthyroidism should be treated with radioiodine or surgery, possibly after a period of antithyroid drug therapy. I treat older patients with autonomous nodules and subclinical hyperthyroidism because they are at increased risk for atrial fibrillation and reduced bone density. On the other hand, I simply follow young patients, in whom the risks of subclinical hyperthyroidism are small. Patients with small cystic nodules with nondiagnostic cytology can be followed with the assumption that the nodule is benign. In some patients, however, recurrent bleeding or cyst reformation may be a source of discomfort, anxiety, or rarely obstructive symptoms, mandating excision of the nodule.

Polycystic Ovary Syndrome

EPIDEMIOLOGY Polycystic ovary syndrome (PCOS) is thought to be one of the most common endocrinopathies in women, affecting between 6.5 and 8 percent of women overall. High-risk groups 1. Women with oligoovulatory infertility 2. Obesity and/or insulin resistance , although the impact of obesity appears to be relatively modest Type 1, type 2, or gestational diabetes mellitus 3. A history of premature adrenarche 4. First-degree relatives with PCOS 5. Mexican-American more than Caucasian or African-American women. 6. Women using antiepileptic drugs PATHOGENESIS Inherited factors act to create a susceptible genotype, most commonly identifiable by a positive family history for PCOS or related features. This susceptible genotype, in isolation or in association with environmental or acquired factors, may result in intermediate forms of functional hyperandrogenism. Continued exposure to environmental factors, or an increasing load of genetic variants favoring its occurrence, leads to the development of clinically evident PCOS. AA: adrenal androgen; CNS: central nervous system; FSH: follicle stimulating hormone; HA: hyperandrogenemia; IR: insulin resistance; LH: luteinizing hormone; PCOM: polycystic ovarian morphology.

CLINICAL MANIFESTATIONS The syndrome is characterized clinically by oligomenorrhea and hyperandrogenism, as well as the frequent presence of associated risk factors for cardiovascular disease, including obesity, glucose intolerance, and dyslipidemia. Menstrual dysfunction : Menstrual dysfunction, characterized by infrequent or absent menses. However, some women with PCOS have dysfunctional uterine bleeding as a result of their chronic anovulation. The ovulatory dysfunction typically results in infertility and the need for ovulation induction in those who wish to conceive. Hyperandrogenism : Hyperandrogenism, which may include clinical signs (acne, hirsutism, alopecia) and/or elevated serum androgen concentrations. Ovarian abnormalities : Typical polycystic appearance of the ovaries on transvaginal ultrasound in the majority of women with irregular menses and hyperandrogenism (using the original ultrasound criteria for polycystic ovaries) . However, this ultrasound appearance is non-specific as it may also be seen in normal cycling women. Gonadotropin dynamics : Abnormal gonadotropin dynamics in most women with PCOS, including high serum LH concentrations (due to an increase in LH pulse frequency and amplitude). However, serum LH concentrations are affected by body mass index and timing of the blood sample relative to the last menstrual period. Neither an elevated serum LH concentration nor a high LH:FSH ratio is part of the diagnostic criteria for PCOS. Metabolic issues :

o Obesity and insulin resistance o IGT or type 2 diabetes: 45 % o Dyslipidemia o Metabolic syndrome Risk for CHD : has not yet been demonstrated definitively. Sleep apnea Nonalcoholic steatohepatitis

DIAGNOSTIC CRITERIA NIH consensus criteria Menstrual irregularity due to oligo- or anovulation Evidence of hyperandrogenism, whether clinical (hirsutism, acne, or male pattern balding) or biochemical (high serum androgen concentrations) Therefore, a patient with oligomenorrhea and clinical evidence of hyperandrogenism, but normal serum androgen concentrations is still considered to have PCOS. Exclusion of other causes of hyperandrogenism and menstrual irregularity, such as congenital adrenal hyperplasia, androgen-secreting tumors, and hyperprolactinemia.

Rotterdam criteria two out of three of the following are required to make the diagnosis: Oligo- and/or anovulation Clinical and/or biochemical signs of hyperandrogenism Polycystic ovaries (by ultrasound) other etiologies (congenital adrenal hyperplasias, androgen-secreting tumors, Cushing's syndrome) must be excluded. The ultrasound criteria : o presence of 12 follicles in each ovary measuring 2 - 9 mm in diameter and/or increased ovarian volume (>10 mL; calculated using the formula 0.5 x length x width x thickness). o It was suggested that follicle distribution and an increase in stromal echogenicity and volume be eliminated as diagnostic criteria. o The transvaginal approach should be used. o Women with the ultrasound appearance of PCO in the absence of oligo/amenorrhea or hyperandrogenism should not be considered to have PCOS.

EVALUATION Biochemical tests Biochemical evaluation of the oligomenorrhea and/or hyperandrogenism is the same as in women with these disorders in the absence of PCOS: o measurement of serum HCG to rule out pregnancy o measurements of serum prolactin, TSH, FSH to rule out hyperprolactinemia, thyroid disease, and ovarian failure, respectively. We do not routinely measure serum androgen concentrations in women with mild hirsutism. However, in women with moderate-to-severe hirsutism, we typically measure a total testosterone concentration, and if there are concerns about a possible androgen-secreting tumor causing the hyperandrogenism, we add serum dehydroepiandrosterone sulfate (DHEA-S). A fasting glucose measurement is a less sensitive test for diagnosing IGT and diabetes in women with PCOS. Once the diagnosis of PCOS is made, we perform an OGTT in all patients. When this is not practical, a fasting glucose along with a hemoglobin A1C can be obtained. If either one is abnormal, an OGTT should be performed to distinguish between IGT and diabetes. measuring a fasting lipid profile in all women with the disorder.

TREATMENT Hirsutism : o For hirsutism or other androgenic symptoms, we suggest an oral contraceptive as the treatment of choice (Grade 2B). o We typically start with a preparation containing 30 - 35 mcg of ethinyl estradiol combined with a progestin with minimal androgenicity (such as norethindrone, norgestimate, desogestrel, and drospirenone). o If the patient is not satisfied with the clinical response to the oral contraceptive after 6 months of therapy, we suggest adding spironolactone (Grade 2B). o removal of hair by mechanical means such as shaving, waxing, depilatories, electrolysis or laser treatment. In addition, Vaniqa (eflornithine hydrochloride cream 13.9 percent) is a topical drug that inhibits hair growth. It is not a depilatory, and must be used indefinitely to prevent regrowth. Endometrium : Oral contraceptives provide endometrial protection (preventing dysfunctional uterine bleeding and possibly endometrial cancer) as well as contraception and androgen suppression. Intermittent progestin therapy is effective for endometrial protection, but it provides no contraception or androgen suppression. o For women with PCOS who present with dysfunctional uterine bleeding due to chronic anovulation (and anatomic causes have been ruled out), we recommend oral contraceptives (Grade 1B). o For prevention of endometrial hyperplasia and possibly cancer, we suggest oral contraceptive therapy (Grade 2C). o For women with PCOS who choose not to or cannot take oral contraceptives, we suggest intermittent progestin therapy (Grade 2B). In this setting we typically use medroxyprogesterone acetate (10 mg) for 7 to 10 days every one to two months. o Metformin can also be used, but as noted above, it has not been proven to be endometrial protective. However, if the patient is having regular ovulatory cycles in response to metformin, she presumably has endometrial protection. o Metformin may also be used (particularly in women with contraindications to pill use) Obesity The approach to obesity management is the same as that for patients without PCOS, starting with lifestyle changes (diet and exercise). Modest weight loss in women with PCOS may result in restoration of normal ovulatory cycles. Glucose intolerance For women with PCOS who are found to have type 2 diabetes mellitus or impaired glucose tolerance, the management is the same as other non-PCOS patients with these disorders. o We do not suggest the routine use of metformin except in women with glucose intolerance o We do not suggest the routine use of Thiazolidinediones, as concern has been raised about their cardiovascular safety. Ovulation induction : o For women who desire pregnancy, we first recommend weight loss (Grade 1B). o If they are unable to lose weight, or modest weight loss does not restore ovulatory cycles, we suggest initiating ovulation induction with clomiphene citrate (Grade 2B). If this is unsuccessful, we continue with other ovulation induction strategies outlined elsewhere. Multistep approach to treatment of anovulatory infertility associated with PCO Intervention Risk of multiple gestation pregnancy Weight loss (if baseline weight is elevated) Not increased Clomiphene* Modest increase in risk If DHEAS >2 mcg/mL Clomiphene plus Modest increase in risk glucocorticoid 4 FSH injections Markedly increased 5 Ovarian surgery Not increased 6 In vitro fertilization Potentially increased but controllable (eg, single embryo transfer) The initial steps emphasize interventions that are low cost and associated with a low risk of multiple gestation. * Some clinicians add metformin to clomiphene if clomiphene alone is unsuccessful. Step 1 2 3

GASTROENTROLOGY

Approach to the adult with acute diarrhea

Diarrhea : three or more loose or watery stools per day or a definite decrease in consistency and increase in frequency based upon an individual baseline. o Acute diarrhea 14 days in duration o Persistent diarrhea more than 14 days in duration o Chronic diarrhea more than 30 days in duration Infectious causes of diarrhea include: viral, bacterial, and parasitic pathogens. Most cases of acute infectious gastroenteritis are viral The most common bacterial or protozoal causes in the United States : Salmonella , Campylobacter , Shigella , Cryptosporidium , E. coli O157:H7 . The most common pathogens identified in patients with bloody diarrhea: are Shigella, Campylobacter, Salmonella, and E. coli O157:H7. The most common protozoal pathogens include: Cryptosporidium, Giardia, Cyclospora. important viral causes of gastroenteritis: norovirus (known as Norwalk-like virus), rotavirus, enteric adenoviruses, and astroviruses.

DIAGNOSTIC APPROACH The initial evaluation of patients with acute diarrhea should include looking for evidence of extracellular volume depletion (eg, decreased skin turgor, orthostatic hypotension), a careful history to determine the duration of symptoms, and presence of fever and peritoneal signs, which may be clues to infection with an invasive enteric pathogen , careful history to determine the duration of symptoms and the frequency and characteristics of the stool.

Indications for diagnostic evaluation :

Profuse watery diarrhea with signs of hypovolemia Passage of many small volume stools containing blood and mucus Bloody diarrhea Temperature 38.5C (101.3F) Passage of 6 unformed stools per 24 hours or a duration of illness >48 hours Severe abdominal pain Recent use of antibiotics or hospitalized patients Diarrhea in the elderly ( 70 years of age) or the immunocompromised

Historical clues :

The patient's history can be useful in identifying the pathogens. residence, occupational exposure, recent and remote travel, pets, and hobbies. fever, which suggests infection with invasive bacteria (eg, Salmonella, Shigella, or Campylobacter), enteric viruses, or a cytotoxic organism such as Clostridium difficile or Entamoeba histolytica . A food history : may also provide clues to a diagnosis.
Beef, pork, poultry, eggs Beef, pork, poultry, home-canned foods Beef, pork, fried rice (Chinese), vegetables Beef, pork, fast food restaurants (undercooked hamburger), apple cider, leaf lettuce, milk, cheese, extremes of age

Staphylococcus aureus Clostridium perfringens Bacillus cereus Enterhemorrhagic E. coli

Enteroinvasive E. coli Enterotoxigenic E. coli Salmonella

Milk, cheese Travelers to developing world Beef, pork, poultry, eggs, (eg, Caesar salad), raw milk, ice cream, vegetables (eg, alfalfa sprouts), unpasteurized orange juice, pet ducklings, lizards, rattlesnake meat Poultry (undercooked at barbecues), raw milk and cheeses Daycare centers, vegetables (eg, green onions) Pork (not common), beef, milk, cheeses, hemochromatosis Shellfish from the Gulf of Mexico, inadequately cooked seafood from South America, coconut milk from Thailand, airline outbreaks Ingestion of raw seafood, particularly in East Asia, shellfish, cirrhosis Hospitalization, inpatient or outpatient antibiotic(s) or chemotherapy within the last several weeks, daycare centers Beef, pork, poultry, milk cheese, coleslaw, hot dogs, potato salad, pregnancy, neonates, immunocompromised patients Daycare centers, nurseries, Australia Schools, nursing homes, cruise ships, camps, military barracks, vegetables, waterborne, foodborne, and shellfish-associated outbreaks Overcrowding, lack of clean water, patients and staff of institutions, day care centers, men who have sex with men, IV drug users, travelers, military barracks, shellfish (clams, oysters, mussels) Infantile diarrhea, ?AIDS HIV-infected homosexual men with AIDS, organ transplantation Daycare centers, swimming pools, travel (eg, St. Petersburg, mountainous areas with ingestion of stream water), fruit salad Travelers to endemic areas (eg, Mexico), for more than one month, men who have sex with men, institutions Daycare centers, swimming pools, AIDS, farm animal exposure, city water supply contamination Raspberries (from Guatemala) Haiti, HIV infection AIDS (? travelers, ? fresh water)

Campylobacter Shigella Yersinia Vibrio cholerae Vibrio parahaemolyticus Clostridium difficile Listeria Rotavirus Noroviruses Hepatitis A

Adenovirus Cytomegalovirus Giardia lamblia Entamoeba histolytica Cryptosporidium Cyclospora Isospora Microsporidium

Timing of symptoms with regard to exposure to suspected offending food can be important clues to the diagnosis:
Major symptom Vomiting Likely microbes S. aureus B. cereus Norwalk-like viruses C. perfringens Enterotoxigenic E. coli Enteric viruses C. parvum C. cayetanensis Campylobacter spp Non-typhoidal salmonella Shiga toxin-producing E. coli Shigella spp V. parahemolyticus Incubation period 1 to 6 hours 1 to 6 hours 24 to 48 hours 8 to 16 hours 1 to 3 days 10 to 72 hours 2 to 28 days 1 to 11 days 2 to 5 days 1 to 3 days 1 to 8 days 1 to 3 days 2 to 48 hours

Watery diarrhea

Inflammatory diarrhea

Recent antibiotic use (as a clue to the presence of C. difficile infection, although cases of communityassociated C. difficile infection are occurring in patients without antibiotic exposure), other medications, complete past medical history (eg, to identify an immunocompromised host or the possibility of nosocomial infection). Bloody diarrhea : E. coli O157:H7 , Less common bacterial causes of visibly bloody diarrhea were Shigella, Campylobacter, and Salmonella species.

Fecal leukocytes and occult blood : the presence of occult blood and fecal leukocytes supports the diagnosis of a bacterial cause of diarrhea ,we perform this examination in addition to obtaining a bacterial culture in high risk patients. Fecal leukocyte determination is probably not of value in patients who develop diarrhea while hospitalized, in whom testing for Clostridium difficile is much more likely to be helpful . Fecal lactoferrin Lactoferrin is a marker for fecal leukocytes, sensitivity and specificity ranging from 90 to 100 % in distinguishing inflammatory diarrhea (eg, bacterial colitis or inflammatory bowel disease) from noninflammatory causes (eg, viral colitis, IBS) . When to obtain stool cultures: 1. 2. 3. 4. Immunocompromised patients, including those infected with HIV Patients with comorbidities that increase the risk for complications Patients with more severe, inflammatory diarrhea (including bloody diarrhea) Patients with underlying IBD in whom the distinction between a flare and superimposed infection is critical 5. Some employees, such as food handlers, occasionally require negative stool cultures to return to work Processing stool cultures A routine stool culture will identify Salmonella, Campylobacter, and Shigella, A stool culture that is positive for one of these pathogens in a patient with acute diarrheal symptoms can be interpreted as a true positive. Gastroenteritis due to Listeria should be considered in outbreaks of febrile gastroenteritis with non-bloody diarrhea if routine cultures are negative. Unlike ova and parasites, which are often shed intermittently, these pathogens generally are excreted continuously. Thus, a negative culture is usually not a false negative, and repeat specimens are rarely required. Other organisms which should be considered in selected situations include Enterohemorrhagic Escherichia coli (EHEC), viruses, and vibrios.

When to obtain stool for ova and parasites : 1. Persistent diarrhea (associated with Giardia, Cryptosporidium, and Entamoeba histolytica) 2. Persistent diarrhea following travel to Russia, Nepal, or mountainous regions (associated with Giardia, Cryptosporidium, and Cyclospora) 3. Persistent diarrhea with exposure to infants in daycare centers (associated with Giardia and Cryptosporidium) 4. Diarrhea in a man who has sex with men (MSM) or a patient with AIDS (associated with Giardia and Entamoeba histolytica in the former, and a variety of parasites in the latter 5. A community waterborne outbreak (associated with Giardia and Cryptosporidium) 6. Bloody diarrhea with few or no fecal leukocytes (associated with intestinal amebiasis) Endoscopy : It may be helpful in the following settings: 1. Distinguishing inflammatory bowel disease from infectious diarrhea 2. Diagnosing C. difficile in patients who are toxic while results of culture are pending. 3. immunocompromised patients who are at risk for opportunistic infections such as CMV.

4. In patients in whom ischemic colitis is suspected but the diagnosis remains unclear after clinical and radiologic assessment. . The management of patients with acute diarrhea : Dietary recommendations : NPO 24h Good hydration: 1-2 L NS over 1-2 hours; then D5 NS with 40 mEq KCL/L at 125 cc/h. We recommend no antibiotic therapy in most cases. ( Grade 1A). Empiric antibiotic therapy : We recommend empiric antibiotic therapy for patients with: 1. moderate to severe travelers' diarrhea as characterized by more than 4 unformed stools daily, fever, blood, pus, or mucus in the stool. 2. Those with more than 8 stools per day, volume depletion, symptoms for more than one week, those in whom hospitalization is being considered, immunocompromised patient. 3. signs and symptoms of bacterial diarrhea such as fever, bloody diarrhea (except suspected EHEC or C. difficile infection), and the presence of occult blood or fecal leukocytes in the stool. We recommend empiric therapy with an oral fluoroquinolone for 3-5 days:ciprofloxacin 500 mg twice daily , norfloxacin 400 mg twice daily,levofloxacin 500 mg once daily o alternative agents: Azithromycin (500 mg PO once daily for 3 days) and erythromycin (500 mg PO twice daily for 5 days) are Enterohemorrhagic E. coli Antibiotics should be avoided in patients with suspected or proven infection with enterohemorrhagic E. coli (EHEC) or C. difficile , EHEC infection should be suspected in patients with bloody diarrhea, abdominal pain and tenderness, but little or no fever.

Clostridium difficile discontinuation of antibiotics, and metronidazole or vancomycin for 10 days if the symptoms are more than mild or worsen or persist Salmonella are not treated except for infants, adults over 50, immunocompromised patients, patients with prostheses or valvular heart disease, those with severe diarrhea. Symptomatic therapy : We suggest the antimotility agent loperamide (Idium 2mg) be used for the symptomatic treatment of patients with acute diarrhea in whom fever is absent or low grade and the stools are not bloody. ( Grade 2A) , The dose of loperamide is two tablets (4 mg) initially, then 2 mg after each unformed stool, not to exceed 16 mg/day for 2 days. Specific antibiotic therapy : Specific antibiotic therapy : Pathogen S. aureus B.cereus Salmonella Shigella Campylobacter Yersinia C. difficile E.coli Enterotoxigenic E.coli Enteroinvasive First choice Not required , resolve with hydration only Usually not required Oral quinolone for 5 d Macrolides in severe cases. Second choice Not required , TMP/SMX* can be used only in severe cases Oral quinolone for 3 to 5 days TMP/SMX* or azithromycin Oral quinolone for 5 days

PO quinolone for 7 to 10 d in TMP/SMX* or doxycycline severe cases. Metronidazole 250 mg PO 4 Vancomycin 125mg PO 4 times/d times /d , IV if not tolerate PO PO quinolone for 1 to 3 d TMP/SMX, doxycycline, furazolidone Same as for Shigellosis

E.coli Enterohemorrhagic V. cholera Amebiasis Giardiasis Cryptosporidia Microsporidia Isospora Cyclospora

Should be avoided Doxycycline, single dose

Ciprofloxacin, single Azithromycin, single dose

dose;

Metronidazole 750 mg PO TID Dehydroemetine for 5 day for 10 d Metronidazole 250 mg PO TID Tinidazole, quinacrine, furazolidone for 10 d No therapy proven effective Nitazoxanide, Parmomycin, TMP/SMX, Azithromycin, or Metronidazole

Albendazole 200-400 mg PO BID for 3 m TMP/SMX 1 DS PO BID for Pyrimethamine plus folinic acid 10 d TMP/SMX 1 DS PO BID for 7 - 10 d

Travelers' diarrhea : diarrhea develops within 10 days after the individual returns home. Classic passage of 3 or more unformed stools in a 24 hour period plus at least one of these symptoms: nausea, vomiting, abdominal pain or cramps, fever, blood in stools Mild passage of 1 or 2 unformed stools in 24 hours without other symptoms

Moderate passage of 1 or 2 unformed stools in 24 hours plus at least one of the above symptoms or more than 2 unformed stools in 24 hours without other symptoms Evaluation of acute diarrhea

Approach to the patient with abnormal liver function tests

The most common laboratory measures classified as liver function tests include:

enzyme tests (ALT , AST , ALP, and gamma glutamyl transpeptidase) tests of synthetic function (the serum albumin concentration and prothrombin time) the serum bilirubin, which reflects hepatic transport capability.

HISTORY :

A complete medical history is the single most important part of the evaluation of the patient with elevated LFTs. The use of or exposure to any chemical or medication (including prescription and over-the-counter medications as well as herbal therapies) which may be temporally related to the onset of LFT abnormalities The duration of LFT abnormalities The presence of any accompanying symptoms such as jaundice, arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool A history of arthralgias and myalgias predating jaundice, for example, suggests viral or drug-related hepatitis, while jaundice associated with the sudden onset of severe right upper quadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis. The patient should also be carefully questioned about possible parenteral exposures including transfusions, intravenous and intranasal drug use, tattoos, and sexual activity. Other important questions include recent travel history, exposure to people with jaundice, exposure to possibly contaminated foods, occupational exposure to hepatotoxins, and alcohol consumption.

PHYSICAL EXAMINATION:

The physical examination should focus upon findings suggesting the presence of liver disease. Temporal and proximal muscle wasting suggest longstanding diseases Stigmata of chronic liver disease include spider nevi, palmar erythema, gynecomastia, caput medusae Dupuytren's contractures, parotid gland enlargement, and testicular atrophy are commonly seen in advanced Laennec's cirrhosis and occasionally in other types of cirrhosis An enlarged left supraclavicular node (Virchow's node) or periumbilical nodule (Sister Mary Joseph's nodule) suggest an abdominal malignancy Jugular venous distension, a sign of right sided heart failure, suggests hepatic congestion A right pleural effusion, in the absence of clinically apparent ascites, may be seen in advanced cirrhosis Patients with cirrhosis may have an enlarged left lobe of the liver and an enlarged spleen . A grossly enlarged nodular liver or an obvious abdominal mass suggests malignancy. An enlarged tender liver could be viral or alcoholic hepatitis or, less often, an acutely congested liver secondary to right-sided heart failure . Severe RUQ tenderness with respiratory arrest on inspiration (Murphy's sign) suggests cholecystitis or, occasionally, ascending cholangitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread.

LABORATORY TESTING :

A critical step in guiding the evaluation is determining the overall pattern of the abnormal LFTs, which can be broadly divided into two categories: o 1) patterns predominantly reflecting hepatocellular injury, o 2) patterns predominantly reflecting cholestasis. Patients with a hepatocellular process generally have a disproportionate elevation in the serum aminotransferases compared with the alkaline phosphatase Patients with a cholestatic process have the opposite findings.

The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two. A low albumin suggests a chronic process such as cirrhosis or cancer, while a normal albumin suggests a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunction. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury. he presence of bilirubin in the urine reflects direct hyperbilirubinemia and therefore underlying hepatobiliary disease. Conjugated bilirubin may be found in the urine when the total serum bilirubin concentration is normal because the renal reabsorptive capacity for conjugated bilirubin is low and the methods used can detect urinary bilirubin concentrations as low as 0.05 mg/dL (0.9 mmol/L). Thus, bilirubinuria may be an early sign of liver disease.

COMMON PATTERNS OF LFT ABNORMALITIES : Marked elevation in aminotransferase levels : Striking increases (exceeding 1000 IU/L or 50 times the upper limit of normal) are most commonly seen in acute viral hepatitis, shock liver (ischemic hepatitis) , and acute drug- or toxin-induced liver injury (eg, acetaminophen intoxication). rare occasions, similar values suggesting acute hepatitis can be seen in a other settings: 1. During an acute exacerbation of autoimmune chronic active hepatitis. 2. Spontaneous reactivation of chronic type B hepatitis. 3. Superimposition of delta hepatitis in a chronic carrier of hepatitis B virus infection . 4. Miscellaneous disorders such as acute Budd-Chiari syndrome (especially those with concomitant portal vein thrombosis), veno-occlusive disease, HELLP syndrome, acute fatty liver of pregnancy, and hepatic infarction.. AST-to-ALT ratio : o The AST/ALT ratio is approximately 0.8 in normal subjects. o the AST is greater than the ALT in alcoholic hepatitis and a ratio greater than 2:1 is highly suggestive of this disorder. o ratio >1.0 suggest the presence of cirrhosis in patients with chronic viral hepatitis. Normal aminotransferase levels in the presence of liver disease : 1. Hemochromatosis 2. Methotrexate- or amiodarone-induced hepatic injury 3. Chronic hepatitis C virus infection 4. Post-jejuno-ileal bypass 5. Nonalcoholic fatty liver disease. Elevated aminotransferase levels without liver disease : 1. False positive elevations in the AST in patients receiving erythromycin or para-aminosalicylic acid and during DKA when AST was measured using a calorimetric assay 2. Primary muscle disease in whom liver disease has been excluded by serologic tests and/or normal liver biopsy. A concurrent increase in (CPK), LDH or aldolase levels suggests a primary muscle source. 3. Macro AST in which AST complexes with immunoglobulin, usually IgG 4. Subclinical celiac disease 5. Hypothyroidism and hyperthyroidism 6. Adrenal insufficiency.

Evaluation of isolated mild chronic elevation of serum aminotransferases The laboratory evaluation of patients with chronic (defined as six months or greater), mild elevation (defined approximately as less than four times the upper limit of normal or <250 U/L) of one or both of the aminotransferases is best achieved in a stepwise fashion: Step 1 Review possible link to medications, herbal therapies or recreational drugs Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab) Screen for hemochromatosis (FE/TIBC >45 percent) Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)

Step 2: If the above is unrevealing confirm that source is hepatic and consider proceeding to Step 3 Exclude muscle disorders (obtain creatinine kinase or aldolase) thyroid function tests (TSH if hypothyroidism is suspected otherwise obtain FT4 , FT3) Consider celiac disease (especially in patients with a history of diarrhea or unexplained iron deficiency serum antiendomysial IgA or anti tissue transglutaminase IgA) Consider adrenal insufficiency

Step 3: Consider less common causes of liver disease

autoimmune hepatitis particularly in women and thosewith a history of other autoimmune disorders (serum proteinelectrophoresis, ANA and ASMA if positive) Wilson's disease in those <40 (serum ceruloplasmin, evaluate for Kayser Fleischer rings) alpha-1-antitrypsin deficiency especially in patients with a history of emphysema out of proportion to their age orsmoking history (obtain alpha-1-antitrypsin phenotype)

Step 4: Obtain a liver biopsy or observe Observe if ALT and AST are less than two-fold elevated Otherwise consider a liver biopsy

Medications : o Features suggesting drug toxicity include lack of illness prior to ingesting the drug, clinical illness or biochemical abnormalities developing after beginning the drug, and improvement after the drug is withdrawn. o If the identified medication is essential to the patient's well-being and no suitable substitute is available, the physician needs to make a risk-benefit analysis to determine if a drug should be continued despite the aminotransferase elevation. A liver biopsy is occasionally necessary to determine the nature and severity of liver injury. Alcohol abuse o AST to ALT ratio of 2:1 or greater.

o A twofold elevation of the gamma glutamyltransferase (GGT) in patients whose AST to ALT ratio is greater than 2:1 strongly suggests alcohol abuse. however, an elevated GGT by itself is insufficiently specific to establish the diagnosis o It is rare for the AST to be greater than eightfold elevated and even less common for the ALT to be greater than fivefold elevated. The ALT may even be normal even in patients with severe alcoholic liver disease. Hepatitis B The proper initial testing for patients suspected of having chronic hepatitis B includes: Hepatitis B surface antigen (HBs Ag) Hepatitis B surface antibody (Anti HBS) Hepatitis B core antibody (HBc Ab) A surface antigen and core antibody positive are chronically infected and additional testing (hepatitis B "e" antigen and "e" antibody and a hepatitis B DNA) is indicated. A positive HBsAb and HBcAb indicates immunity and another cause of aminotransferase elevation should be sought. A positive HBV DNA in the presence or absence of the "e" antigen indicates viral replication. A positive HBV DNA and a negative "e" antigen indicates that the patient has a precore mutant of hepatitis B. Both of these situations warrant further evaluation with a liver biopsy and possible treatment. A positive hepatitis B surface antigen with a negative HBV DNA and a negative "e" antigen suggests that the patient is a carrier and in a non-replicative state. And does not explain elevated aminotransferases and another cause needs to be sought.

Hepatitis C The initial test for hepatitis C is the hepatitis C antibody. A positive hepatitis C antibody in a patient with risk factors for the infection is sufficient to make the diagnosis and a quantitative hepatitis C RNA, hepatitis C genotype, and liver biopsy should next be done to assess the patient's need and suitability for treatment. A positive hepatitis C antibody in a low-risk patient should be verified with either a RIBA or a qualitative PCR test. A negative hepatitis C antibody in a patient with risk factors for hepatitis C should be verified with a qualitative PCR test.

Hereditary hemochromatosis Screening should begin with a serum iron and total iron binding capacity (TIBC), which permits the calculation of the iron or transferrin saturation (serum iron/TIBC). An iron saturation of greater than 45 percent warrants obtaining a serum ferritin. Ferritin should not be obtained as an initial test because it is an acute phase reactant and therefore less specific than the iron saturation. A serum ferritin concentration of greater than 400 ng/mL in men and 300 ng/mL in women further supports the diagnosis of HHC. A liver biopsy should be performed if screening tests suggest iron overload to quantify hepatic iron and to assess the severity of liver injury, and genetic testing should be done. A hepatic iron index (hepatic iron concentration in micromoles per gram dry weight divided by the patient's age) greater than 1.9 is consistent with homozygous HHC. A liver biopsy is not necessary for patients less than 40 years of age with genotypically defined hemochromatosis (C282Y homozygous) with normal liver function tests. Genetic testing has not replaced liver biopsy in the diagnosis of HHC.

Hepatic steatosis and steatohepatitis patic steatosis and an associated condition, non-alcoholic steatohepatitis (NASH), may present solely with mild elevations of the serum aminotransferases, which are usually less than fourfold elevated. NASH is a condition more common in women and associated with obesity and type 2 diabetes mellitus. the ratio of AST to ALT is usually less than 1 he initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging including ultrasound, computed tomographic imaging, or magnetic resonance imagin we do not advocate a liver biopsy unless one of the following are present: o Peripheral stigmata of chronic liver disease o Splenomegaly o Cytopenia o Abnormal iron studies o Diabetes and/or significant obesity in an individual over the age of 45

Muscle disorders Serum AST and ALT may both be elevated with muscle injury. Immediately after muscle injury, the AST/ALT ratio is generally greater than three, but approaches one within a few days because of a faster decline in the serum AST. The creatine kinase or aldolase levels should be determined if other more common hepatic conditions have been ruled out

Autoimmune hepatitis The diagnosis is based upon the presence of elevated serum aminotransferases, the absence of other causes of chronic hepatitis, and features (serological and pathological) suggestive of AIH. A useful screening test for AIH is the serum protein electrophoresis (SPEP). More than 80 percent of patients with autoimmune hepatitis will have hypergammaglobulinemia. A greater than twofold polyclonal elevation of the immunoglobulins supports the diagnosis. Additional tests commonly ordered include antinuclear antibodies (ANA), anti-smooth muscle antibodies (SMA), and liver-kidney microsomal antibodies (LKMA). A reasonable approach to diagnosing autoimmune hepatitis is to start with an SPEP. An ANA and SMA should be obtained in patients who have a polyclonal increase in gamma globulin. Elevated gamma globulins and high titer autoantibodies should prompt a liver biopsy to confirm the diagnosis of AIH. Patients (especially young women) with negative viral serologies and persistently elevated aminotransferases greater than 100 u/L should undergo liver biopsy even in the absence of elevated gamma globulins and autoantibodies. If the biopsy is consistent with chronic active hepatitis, patients should receive a trial of corticosteroids since approximately 20 % of patients with steroid responsive hepatitis will not have a positive ANA or SMA at the time of presentation .

Wilson's disease cause elevated aminotransferases in asymptomatic patients. the diagnosis should be considered in patients up to the age of 40. The initial screening test for Wilson's disease is a serum ceruloplasmin, which will be reduced in approximately 85 percent of patients. Patients should also be examined by an ophthalmologist for Kayser-Fleischer rings. If the ceruloplasmin is normal and Kayser-Fleischer rings are absent, but there is still a suspicion of Wilson's disease, the next test is a 24-hour urine collection for quantitative copper excretion. A value of greater than 100 mcg/day is suggestive of the diagnosis. The diagnosis is usually confirmed by a liver biopsy for quantitative copper.Patients with Wilson's disease have liver copper levels of greater than 250 mcg/gm of dry weight.

Alpha-1 antitrypsin deficiency Decreased levels of alpha-1 antitrypsin can be detected either by direct measurement of serum concentrations or by the absence of the alpha-1 peak on a serum protein electrophoresis. However, serum concentrations of alpha-1 antitrypsin can be increased in response to inflammation resulting in a falsely negative test. As a result, obtaining an alpha-1 antitrypsin phenotype is probably the most cost-effective test. In adults, alpha-1 antitrypsin deficiency should be suspected in patients who have a history of emphysema either at a young age or out of proportion to their smoking history.

Who to observe We recommend observation only in patients in whom the ALT and AST are less than twofold elevated and no chronic liver condition has been identified by the above noninvasive testing. Who to biopsy We recommend a liver biopsy in patients in whom the ALT and AST are persistently greater than twofold elevated.

ISOLATED HYPERBILIRUBINEMIA
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The initial step in evaluating a patient with an isolated elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the hyperbilirubinemia is predominantly conjugated or unconjugated. An increase in unconjugated bilirubin in serum results from either overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment.

Classification of jaundice according to type of bile pigment and mechanism

Unconjugated hyperbilirubinemia Increased bilirubin production Extravascular hemolysis Extravasation of blood into tissues Intravascular hemolysis Dyserythropoiesis Impaired hepatic bilirubin uptake Congestive heart failure Portosystemic shunts Some patients with Gilbert's syndrome Certain drugs - rifampin, probenecid flavaspadic acid, bunamiodyl Impaired bilirubin conjugation Crigler-Najjar syndrome type I and II Gilbert's syndrome Neonates Hyperthyroidism Ethinyl estradiol Liver diseases - chronic persistent hepatitis, advanced cirrhosis, Wilson's disease Conjugated hyperbilirubinemia Extrahepatic cholestasis (biliary obstruction) Choledocholithiasis Intrinsic and extrinsic tumors - eg, cholangiocarcinoma Primary sclerosing cholangitis AIDS cholangiopathy Acute and chronic pancreatitis Strictures after invasive procedures Certain parasitic infections - eg, Ascaris lumbricoides, liver flukes Intrahepatic cholestasis Inherited : Rotor , Dubin-Johnson , Alagille syndromes Viral hepatitis Primary sclerosing cholangitis Alcoholic hepatitis Nonalcoholic steatohepatitis Primary biliary cirrhosis Drugs and toxins - eg, alkylated steroids, chlorpromazine, herbal medications (eg, Jamaican bush tea), arsenic Non-hepatobiliary Sepsis and hypoperfusion states Infiltrative diseases - eg, amyloidosis, lymphoma, sarcoidosis, tuberculosis Total parenteral nutrition Benign Postoperative patient Following organ transplantation Hepatic crisis in sickle cell disease Cholestasis of Pregnancy End-stage liver disease Paraneoplastic syndrome (Stauffer's syndrome) Hepatocellular injury Viral hepatitis Hepatitis A, B, C, D, and E EPV CMV Alcohol Drugs Predictable, dose-dependent (eg, acetaminophen) Unpredictable, idosyncratic (many drugs) Environmental toxins Autoimmune hepatitis Wilson's disease

hyperbilirubinemia induced by drugs usually resolves within 48 hours after the drug is discontinued

Unconjugated hyperbilirubinemia : Hemolysis

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Hemolysis :detected by obtaining a reticulocyte count, haptoglobin, and peripheral smear. Hemolytic disorders : may be either inherited or acquired. 1. Inherited disorders : include spherocytosis, sickle cell anemia, and deficiency of red cell enzymes such as pyruvate kinase and G6PD. In these conditions the serum bilirubin rarely exceeds 5 mg/dL. Higher levels may occur when there is co-existent renal or hepatocellular dysfunction or in acute hemolysis such as a sickle cell crisis. 2. Acquired hemolytic disorders : include microangiopathic hemolytic anemia (eg, HUS), paroxysmal nocturnal hemoglobinuria, and immune hemolysis.

Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies.

Impaired hepatic uptake or conjugation

o

This is most commonly caused by certain drugs (including rifampicin and probenecid) or Gilbert's syndrome. Much less commonly Crigler-Najjar syndrome, types I and II. Gilbert's syndrome : affects approximately 3 to 7 percent of the population white males predominating over females by a ratio of 2 to 7:1. Impaired conjugation of bilirubin is due to reduced bilirubin UDP glucuronosyl transferase activity. Affected patients have mild unconjugated hyperbilirubinemia with serum levels almost always less than 6 mg/dL. The serum levels may fluctuate and jaundice is often identified only during periods of illness or fasting. In an otherwise healthy adult with mildly elevated unconjugated hyperbilirubinemia and no evidence of hemolysis, the presumptive diagnosis of Gilbert's syndrome can be made without further testing. Crigler Najjar type I : is an exceptionally rare condition found in neonates and is characterized by severe jaundice (bilirubin >20 mg/dL) and neurologic impairment due to kernicterus. Crigler-Najjar type II : somewhat more common than Type I. Patients live into adulthood with serum bilirubin levels that range from 6 to 25 mg/dL. Bilirubin UDP glucuronosyl transferase activity is typically present, but greatly reduced. Bilirubin UDP glucuronosyl transferase activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients.

Conjugated hyperbilirubinemia

found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. Dubin-Johnson syndrome due to altered excretion of bilirubin into the bile ducts Rotor syndrome : due to defective hepatic storage of bilirubin. present with asymptomatic jaundice typically in the second decade of life. Dubin-Johnson and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 %) in the absence of other abnormalities of standard liver function tests. Normal levels of serum alkaline phosphatase and gamma-glutamyltranspepetidase help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible, but clinically unnecessary, due to their benign nature.

Isolated elevation of Alkaline Phosphatase :

Serum alkaline phosphatase is derived predominantly from the liver and bones. elevated serum alkaline phosphatase :
1. 2. 3.

Women in the third trimester of pregnancy Individuals with blood types O and B can after eating a fatty meal benign familial occurrence of elevated serum alkaline phosphatase due to intestinal alkaline phosphatase.

The first step in the evaluation of an elevated alkaline phosphatase is to identify its source. Although electrophoretic separation on either polyacrylamide gel or sepharose are the most sensitive and specific ways to do this, these tests are not widely available. If gel electrophoresis is not available, either a 5'-nucleotidase or GGT should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders, but are not increased in bone disorders. An elevated serum alkaline phosphatase with a normal 5'-nucleotidase or GGT should prompt an evaluation for bone diseases. Chronic cholestatic or infiltrative liver diseases should be considered in patients in whom the alkaline phosphatase is determined to be of liver origin and persists over time. The most common causes include partial bile duct obstruction, primary biliary cirrhosis (PBC), primary sclerosing cholangitis, adult bile ductopenia, and certain drugs such as androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other granulomatous diseases, and less often unsuspected cancer metastatic to the liver. Initial testing should include a RUQ ultrasound and an antimitochondrial antibody (AMA), which is highly suggestive of PBC .
o

The presence of biliary dilatation suggests obstruction of the biliary tree. In patients with biliary dilatation or choledocholithiasis, an ERCP should be done to identify the cause of obstruction and to allow for an s stone removal or stent placement. Patients with a positive AMA should have a liver biopsy to diagnosis of PBC. if the AMA and ultrasound are both negative and the ALP is persistently more than 50 % above normal for more than 6 months We suggest a liver biopsy and either an ERCP or magnetic resonance cholangiopancreatogram (MRCP). If the ALP is less than 50 % above normal, all of the other liver tests are normal, and the patient is asymptomatic, we suggest observation since further testing is unlikely to influence management .

o o

Isolated elevation of Gamma glutamyl transpeptidase : GGT is found in hepatocytes and biliary epithelial cells. GGT is very sensitive for detecting hepatobiliary disease, but its lack of specificity. Elevated GGT: pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes, alcoholism and in patients taking medications such as phenytoin, barbiturates. . Some authorities use GGT to identify patients with occult alcohol use. GGT is best used to evaluate elevations of other serum enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a suspicion of alcohol abuse in a patient with an elevated AST and an AST:ALT ratio of greater than 2:1). An elevated GGT with otherwise normal liver tests should not lead to an exhaustive work-up for liver disease.

Evaluation of elevated serum alkaline phosphatase

Diagnosis of celiac disease

INTRODUCTION Celiac disease can be defined as a small bowel disorder characterized by mucosal inflammation, villous atrophy, and crypt hyperplasia, which occur upon exposure to dietary gluten and which demonstrate improvement after withdrawal of gluten from the diet.

The classical form, characterized by fully developed villous atrophy and features of intestinal malabsorption. The atypical form, characterized by fully developed villous atrophy in the setting of milder clinical features such as iron deficiency, osteoporosis, short stature, and/or infertility. Despite the historical title of "atypical", this form is the most common. The silent form in which villous atrophy is found after testing asymptomatic patients (eg, because of a family history of celiac disease or during an upper endoscopy performed for another reason). A potential form in those who have never had a biopsy consistent with celiac disease, but show serologic and/or immunologic abnormalities characteristic for the disorder. This is most often detected in patients with a family history of celiac disease. A latent form in patients who had a previous diagnosis of celiac disease that responded to gluten withdrawal but retained normal villous architecture after gluten reintroduction. The latent form also refers to patients with elevated IgA tTG serology but normal intestinal mucosa who may subsequently develop celiac disease.

WHO SHOULD BE TESTED 1. Those with gastrointestinal symptoms including chronic or recurrent diarrhea, malabsorption, weight loss, and abdominal distension or bloating. This includes patients with symptoms suggestive for irritable bowel syndrome or severe lactose intolerance. 2. Individuals without other explanations for signs and symptoms such as iron deficiency anemia, folate or vitamin B12 deficiency, persistent elevation in serum aminotransferases, short stature, delayed puberty, recurrent fetal loss, low birth weight infants, and reduced fertility persistent apthous stomatitis, dental enamel hypoplasia, idiopathic peripheral neuropathy, nonhereditary cerebellar ataxia, or recurrent migraine headaches. 3. Symptomatic individuals at high risk for celiac disease including patients with type 1 diabetes mellitus or other autoimmune disorders, first- and second-degree relatives of individuals with celiac disease, patients with Turner, Down, or Williams syndromes. As will be discussed below, screening of the general population is not recommended. Screening of patients with osteoporosis is also not recommended in the consensus statement

DIAGNOSTIC APPROACH All testing should be performed while patients are on a gluten-rich diet. No single test can confidently establish the diagnosis of celiac disease in every individual. Serologic evaluation As a general rule, testing should begin with serologic evaluation. the most sensitive and specific tests are IgA anti tissue transglutaminase and IgA endomysial antibody, which have equivalent diagnostic accuracy. By contrast, antigliadin antibody tests are no longer used routinely because of their lower sensitivity and specificity. However, a second generation AGA test (Deamidated Gliadin Peptide (DGP)) yielded far higher diagnostic accuracy (sensitivity 94 percent, specificity 99 percent) . The DGP uses synthetic gliadin peptides that mimic tTG-modified gliadin sequences to capture serum IgA or IgG against DGP. If these initial data are reproducible in practice, the combination of anti-tTG and DGP serology may become a powerful non-invasive

pairing for serologic diagnosis of celiac disease. Serologic testing may not be as accurate in children less than age five and is less accurate before age two. Testing on a gluten-rich diet All diagnostic tests should be performed while the patient is on a gluten-rich diet. Some patients may have already begun a low gluten diet before undergoing formal evaluation and thus may have normal results from antibody testing. Such patients should be advised to consider resuming a glutenrich diet for 2 to 12 weeks before antibody titers are drawn. This recommendation was based upon studies in children, which have suggested that approximately 75 percent of patients will have abnormal antibody levels within two to four weeks . At least one study in adults found that three weeks of ingestion of a gluten-containing diet in patients with histologically proven celiac disease in remission was insufficient to achieve an increase in antibody titers, although the patients experienced worsening of symptoms and developed carbohydrate and fat malabsorption. The authors suggested that tests of malabsorption rather than antibody tests are preferred when attempting to diagnose celiac disease in patients already consuming a gluten-free diet. However, the traditional approach of performing a small bowel biopsy after a period of "gluten challenge" remains the gold standard for diagnosis. Antibody levels remain elevated for varying lengths of time (1 to 12 months) after patients with celiac disease begin a gluten free diet. Thus, antibody testing in patients who have only recently begun a gluten free diet is reasonable and may yield a positive result, although testing while on a gluten containing diet is preferable to exclude celiac disease. Small bowel biopsy Patients with a positive IgA endomysial or transglutaminase antibody test should undergo a small bowel biopsy. Exceptions are those who have biopsy-proven dermatitis herpetiformis in whom the diagnosis can be established without a small bowel biopsy. Multiple biopsies should be obtained in the second and third portion of the duodenum. The exact minimal number is uncertain, although some experts believe that at least four should be obtaine. The duodenal mucosa may appear atrophic with loss of folds, contain visible fissures, have a nodular appearance or the folds may be scalloped ( show endoscopy), but such findings are not universally present and may be seen with other disorders Causes of small intestinal villous atrophy other than celiac disease 1. Bacterial overgrowth 2. Crohn's disease 3. Cow's milk protein intolerance (children) 4. Eosinophilic gastroenteritis 5. Giardiasis 6. Lymphoma 7. Peptic duodenitis 8. Post gastroenteritis 9. Tropical sprue 10. Zollinger-Ellison syndrome 11. Common variable immunodeficiency 12. Autoimmune enteropathy 13. Other immunodeficiency states (usually apparent clinically) Staining techniques and high resolution magnification endoscopy can help identify areas of villous atrophy for biopsy. The diagnosis is presumptively established when there is concordance between the serologic results and the biopsy findings. It is confirmed when symptoms resolve subsequently on a gluten-free diet. Demonstration of histologic normalization is not always required. Suggestive clinical features but negative serologic tests There are three main possibilities in those with suggestive clinical features but negative serologic tests:

The individual may have selective IgA deficiency. In such patients, testing for IgG anti tissue transglutaminase antibodies, IgG endomysial antibodies and/or IgG deamidated gliadin peptide antibodies should be performed.

The individual may already be on a low gluten diet. The serologic test could be falsely negative in which case a small bowel biopsy is needed to make a diagnosis. The patient may not have celiac disease in which case other causes of symptoms or villous atrophy should be considered.

There are occasional patients in whom the diagnosis is unclear despite the above. Such patients can undergo testing for HLA haplotypes associated with celiac disease. More than 99 percent of patients with celiac disease have HLA DQ2 and/or DQ8 compared with about 40 percent of the general population. Thus, celiac disease is highly unlikely in patients without these haplotypes Positive serologic tests but negative small bowel biopsies IgA tTG serology may occasionally be positive but the small intestinal biopsy normal. False positive tTG results are rare but do occur and are usually low titer (typically less that twice the upper limit of normal). Repeating the test using an assay that uses human tTG as the capture antigen may resolve the discrepancy since older tTG tests using non-human tTG have more frequently been associated with false positive results. The intestinal biopsy should be reviewed by a pathologist familiar with CD to look for subtle abnormalities of CD such as an increase in IELs. If these two steps do not reconcile the results, the patient can be placed on a high gluten diet and, after 6 to 12 weeks, numerous additional biopsies obtained from multiple sites in the mid and distal duodenum since CD enteropathy can be patchy and missed due to sampling error. As noted above, staining techniques and high resolution magnification endoscopy can help identify areas of villous atrophy for biopsy. Some patients have a positive serologic test and only mild histologic changes supportive of celiac disease. Patients with mild villous atrophy appear to benefit from a gluten free diet. The response to gluten free diet in patients with an increase in intraepithelial lymphocytes but normal villi is less clear . There may be a subset of patients with clinical features resembling IBS who do not have a serologic or histologic profile diagnostic of celiac disease but who may respond symptomatically to a gluten free diet. One study suggested that the presence of serum IgG antigliadin antibodies and expression of HLA-DQ2 may be predictive of such a response in patients with diarrhea-predominant IBS but the strength of the association remains unclear . SERUM ANTIBODY ASSAYS A variety of serologic studies have been described to aid in the diagnosis of celiac disease, including:

IgA endomysial antibody (IgA EMA) IgA tissue transglutaminase antibody (IgA tTG) IgA antigliadin antibody (IgA AGA) IgG antigliadin antibody (IgG AGA)

Serum IgA endomysial and tissue transglutaminase antibody testing have the highest diagnostic accuracy. The IgA and IgG antigliadin antibody tests have lower diagnostic accuracy with frequent false positive results and are therefore no longer recommended for initial diagnostic evaluation or screening . However, the newer antideamidated gliadin peptide assays described above may result in the re-introduction of AGA testing in celiac disease. IgA EMA, IgA tTG, and IgA AGA levels fall with treatment; as a result, these assays can be used as a noninvasive means of monitoring the response to a gluten-free diet. Serologic studies for celiac disease can be divided into two groups based upon their target antigens: antiendomysial and antigliadin antibody tests . IgA endomysial assay Endomysial antibodies bind to connective tissue surrounding smooth muscle cells. Frozen sections of monkey esophagus were initially used for the assay. Currently, many laboratories use sections of human umbilical cord which are more readily available . Serum IgA endomysial antibodies bind to the endomysium, producing a characteristic staining pattern, which is visualized by indirect immunofluorescence. The test result is reported simply as positive or negative since even low titers of serum

IgA endomysial antibodies are specific for celiac disease. The target antigen has been identified as a tissue transglutaminase . IgA endomysial antibody testing is moderately sensitive and highly specific for untreated celiac disease. Serum levels of IgA endomysial antibody fall on a gluten-free diet and the test often becomes negative in treated patients . Anti-tissue transglutaminase antibodies The antigen against which antiendomysial antibodies are directed is a tissue transglutaminase (tTG) . Anti-tTG antibodies were highly sensitive and specific for the diagnosis of celiac disease in most reports . In an illustrative series, anti-tTG antibodies were present in 98 percent of patients with biopsy-proven celiac disease compared to 5 percent of controls . In another study that included 136 patients with celiac disease and 207 controls, the sensitivity and specificity of anti-tTG antibodies was 95 and 94 percent, respectively . ELISA tests for IgA anti-tTG antibodies are now widely available and are easier to perform and less costly than the immunofluorescence assay used to detect IgA endomysial antibodies. The diagnostic accuracy of IgA antitTG immunoassays has been improved further by the use of human tTG in place of the non-human tTG preparations used in earlier immunoassay kits . Antigliadin antibody assays Gliadin is a component of the wheat storage protein gluten. Purified gliadin is readily available and is used as the antigen for enzyme-linked immunosorbent assays (ELISA) to detect serum antigliadin antibodies. Serum antigliadin antibody levels are frequently elevated in untreated celiac disease, and antigliadin assays have been used for some years as a diagnostic aid . Although these tests demonstrate moderate sensitivity and specificity, with the IgA tests being marginally superior, their positive predictive value in a general population is relatively poor. In one series, as an example, the positive predictive value for IgG antigliadin antibodies corrected for the expected prevalence in the general population was <2 percent . Antigliadin antibody test results are reported as a titer or level. A high titer of antigliadin antibody is somewhat more specific for celiac disease than a low titer, but some normal individuals have high serum levels of antigliadin antibody. Antigliadin antibody levels decrease during treatment with a gluten-free diet. Assay sensitivity and specificity A systematic review of the literature estimated that the sensitivity and specificity of IgA endomysial and IgA tissue transglutaminase antibodies were over 95 percent and close to 100 percent, respectively . However, the literature reports wide variations in test sensitivity and specificity among different laboratories . It is therefore important to know the sensitivity and specificity of the assay as performed by the testing laboratory before determining the clinical significance of a particular test result. The following data come from our experience :

IgA endomysial antibodies sensitivity 85 to 98 percent; specificity 97 to 100 percent IgA tissue transglutaminase antibodies sensitivity 90 to 98 percent; specificity 95 to 97 percent IgA antigliadin antibodies sensitivity 80 to 90 percent; specificity 85 to 95 percent IgG antigliadin antibodies sensitivity 75 to 85 percent; specificity 75 to 90 percent

It is also important to consider the likelihood that the patient has the disease since, at a given sensitivity and specificity, the pretest probability of disease determines the positive and negative predictive values of the test. In addition to laboratory variation, the sensitivity of these tests may depend upon the severity of the disease. In one report, as an example, serum antibodies were determined in 101 patients with biopsy proven celiac disease . The sensitivity of IgA endomysial antibodies varied for 100 percent in patients with total villous atrophy to only 31 percent in those with partial villous atrophy. Role of antibodies in disease pathogenesis Antigliadin antibodies do not appear to be essential for the pathogenesis of celiac disease . Furthermore, many normal individuals have increased IgA and/or IgG antigliadin levels . In contrast, IgA endomysial antibodies are rarely found in the absence of gluten-sensitive enteropathy. However, patients with celiac disease who lack these antibodies do not differ in their clinical presentation from those who are antibody positive. Nevertheless, there is some evidence to suggest that, in

addition to cellular immunity, antibodies against tissue transglutaminase, the target autoantigen within the endomysium, are of some pathogenetic importance. Furthermore, tissue transglutaminase enzymatically alters gliadin peptides to increase their propensity to induce helper T-cell activation when presented by DQ2 or DQ8 on antigen presenting cells. Individuals with celiac disease also have increased levels of serum antibodies against other food proteins such as beta-lactoglobulin, casein, and ovalbumin. It is not clear whether this reflects a general aberrant immune responsiveness to food antigens or results from enhanced systemic exposure to these proteins because of increased small intestinal permeability. CLINICAL APPLICATION OF SEROLOGIC TESTS Three different clinical circumstances should be considered when using serologic studies in the diagnosis and management of celiac disease:

Evaluation of individuals with a low pretest probability for celiac disease. Such patients may have undergone testing for celiac disease during evaluation of common disorders such as irritable bowel syndrome, reduced fertility or osteoporosis. Evaluation of individuals with a moderate or high pretest probability for celiac disease Monitoring adherence and response to a gluten-free diet

Individuals with a low risk for celiac disease When the pretest probability of celiac disease is perceived to be low (ie, less than 5 percent), serologic studies are useful in excluding the diagnosis. Asymptomatic patients without a family history of celiac disease or laboratory or clinical evidence for malabsorption can be considered to be low risk. The patient's ethnicity may also help determine baseline risk. While celiac disease affects persons of many ethnic backgrounds, it is rare in those of purely Chinese, Japanese, or Sub-Saharan African descent. In the low-risk setting, the IgA endomysial antibody test has the highest diagnostic accuracy but is a little more costly than the IgA tTG ELISA test. The antigliadin antibody tests have lower diagnostic accuracy. As noted above, the serum IgA antigliadin and IgA endomysial tests have similar sensitivities. A negative result for either test has a high negative predictive value in this situation and may obviate the need for small bowel biopsy. The IgG antigliadin test is less sensitive and therefore less useful. IgG antigliadin is usually positive in the 1 to 2 percent of celiac patients who have IgA deficiency. Many clinicians test simultaneously for both IgA and IgG antigliadin. This approach gives a small incremental increase in sensitivity but increases cost and leads to frequent false positive test results, especially with the IgG antigliadin test. As a result most experts advise against routine AGA testing. The newer DGP tests are more specific and may be used to supplement tTG testing. IgA tTG titers will be very low in patients with celiac disease and IgA deficiency. IgG DGP testing can be used in patients with IgA deficiency. The specificities of the IgA endomysial and IgA tissue transglutaminase tests are high. Thus, their positive predictive values are high even in low-risk populations. In contrast, the specificities of IgA and IgG antigliadin tests are lower, and positive results have a low positive predictive value in low-risk populations . In summary a positive IgA tissue transglutaminase or endomysial antibody test is highly specific. The standard antigliadin antibody tests have lower diagnostic accuracy and are no longer recommended because they yield many false positive results (15 to 20 percent of subjects tested) leading to unnecessary endoscopy with biopsy. Individuals with a moderate or high risk for celiac disease When the pretest probability of celiac disease is perceived to be high (ie, greater than 5 percent), diagnosis is based upon serologic tests and histology. Celiac disease is frequently associated with dermatitis herpetiformis, Down syndrome, selective IgA deficiency, and other conditions that have autoimmune features such as type 1 diabetes mellitus, thyroid disease, and autoimmune liver disease. Patients with these conditions or a family history of celiac disease can be considered as being at increased risk. Patients with suggestive clinical features such as severe diarrhea, weight loss, or persistent anemia can also be considered to be at high risk.

The standard approach has been to obtain a small bowel biopsy for histopathologic examination. However, the very high specificity of the IgA endomysial test has led to debate as to whether a positive result in the appropriate clinical setting can be considered diagnostic and eliminate the need for small bowel biopsy. We recommend performing both IgA endomysial (or TTG) and small bowel biopsy prior to dietary treatment. This approach provides the best means of making a definitive diagnosis of celiac disease from the outset. Antigliadin antibody tests are not helpful when there is a moderate or high probability of celiac disease. A positive or negative result will not alter the need for small bowel biopsy and definitive histologic diagnosis. Since antigliadin antibody tests have a high false positive rate there is no role for a trial of a gluten-free diet for presumed celiac disease based on the finding of an elevated antigliadin antibody level. Monitoring adherence and response to gluten free diet The IgA antigliadin antibody assay was previously the most frequently used test for this indication. However, with increased use of IgA tTG for initial diagnosis this assay is now also increasingly used in monitoring response to gluten free diet. For whichever assay that will be used, a pretreatment antibody level should be determined at the time of diagnosis. Exclusion of gluten from the diet results in a gradual decline in serum IgA antigliadin and IgA tTG levels (half-life of six to eight weeks). A normal baseline value is typically reached within three to twelve months depending upon the pre-treatment concentrations. Normal IgA tTG levels do not reliably indicate recovery from villous atrophy . Conversely, if the levels do not fall as anticipated, the patient is usually continuing to ingest gluten either intentionally or inadvertently. Although the general patterns above can be helpful, the accuracy of these tests in establishing compliance with a gluten free diet is unsettled. The value of these tests in monitoring adherence to a gluten-free diet is particularly limited in three respects:

The test is useless if antibody levels are not elevated prior to therapy. Interassay variations in test results may be substantial and make interpretation difficult. Ideally, sera should be stored and assayed in parallel to avoid variations caused by interassay artifact. However, this approach is seldom practical. Serial samples should certainly be sent to one laboratory for testing to keep interassay variation to a minimum. Minor fluctuations in IgA antigliadin or IgA TTG levels are the norm and their importance should not be overinterpreted. Persistently high antibody levels usually reflect continued exposure to substantial amounts of dietary gluten. However, antibody levels will fall when dietary gluten intake is reduced, and they are not a sensitive indicator of occasional or minor dietary transgressions [ 59] .

Serum IgG antigliadin and IgA endomysial antibody levels also fall when patients with celiac disease adhere to a strict gluten-free diet. However, the decline in IgG antigliadin is more gradual than for IgA antigliadin, making it less useful in monitoring recent dietary adherence. IgA endomysial antibody levels are more costly and results are more difficult to quantify than IgA antigliadin or IgA tTG. Other methods for assessing compliance continue to be developed. One group proposed a short survey that on initial evaluation was a more accurate predictor of compliance with a gluten free diet than serologic testing compared with a formal nutritional assessment as the reference standard. Additional validation studies are needed. SCREENING IN ASYMPTOMATIC INDIVIDUALS Screening studies suggest that the incidence of celiac disease in whites of northern European ancestry may be as high as 1:100 to 1:250. The benefit of population screening for asymptomatic celiac disease, usually using the IgA endomysial or IgG tTG assays , has not yet been demonstrated. The potential advantages of screening for asymptomatic celiac disease include a reduction in risk for enteropathy-associated T-cell lymphoma, a reversal of unrecognized nutritional deficiency states, resolution of mild or ignored intestinal symptoms, avoidance of other autoimmune disorders, and an improvement in general well-being. However, all of these hypothetical benefits depend upon compliance with an exacting, sometimes expensive, dietary regimen. Asymptomatic individuals may not be sufficiently motivated to adhere to a strict gluten-free diet. There may also be adverse psychological

effects when asymptomatic individuals receive a diagnosis of a chronic incurable condition that demands substantial lifestyle changes. For these reasons, widespread screening of asymptomatic individuals is not generally advocated at this time, even in populations in which the prevalence of celiac disease is high. This must be distinguished from testing to diagnose celiac disease in patients with subtle clinical manifestations in which instance the value of serologic tests as diagnostic aids is widely accepted. OTHER NONINVASIVE TESTS FOR THE DIAGNOSIS OF CELIAC DISEASE A variety of hematologic and biochemical abnormalities may be found in individuals with untreated celiac disease including iron deficiency, folic acid deficiency, and vitamin D deficiency. These abnormalities reflect nutritional deficiency states secondary to enteropathy-induced malabsorption. Although relevant to patient evaluation and management, none is sufficiently sensitive or specific to serve as useful screening or diagnostic tools . An oral xylose and/or lactulose absorption test, fecal fat evaluation, small bowel radiographic study, or capsule endoscopy may also be abnormal in untreated celiac disease, but will not provide a specific diagnosis . HLA typing may be useful in patients who are already on a gluten-free diet without having achieved a firm diagnosis. Those without HLA DQ2 or DQ8 are very unlikely to have celiac disease . A systematic review of the literature estimated that testing for these haplotypes had a sensitivity of 90 to 95 percent but specificity was only around 30 percent . Thus, the greatest value lies in its negative predictive value (ie, the disease is unlikely in those with a negative result).

Treatment of bleeding peptic ulcers

INITIAL EVALUATION The initial evaluation involves an assessment of hemodynamic stability and resuscitation if necessary, a history and physical examination, NGT lavage, gastroenterology and surgical consultation. Patients who require hospitalization should be admitted to a monitored bed or intensive care unit depending upon the severity of bleeding. We suggest ruling out a myocardial infarction in elderly patients and those with known cardiovascular disease who have severe bleeding, especially if there has been hemodynamic instability (Grade 2C). We suggest that patients with upper GI bleeding be treated with an intravenous PPI at presentation until confirmation of the cause of bleeding, after which the need for specific therapy can be determined (Grade 2B); We recommend upper endoscopy for evaluation of UGI bleeding (Grade 1A). The majority of patients with UGI bleeding due to peptic ulcer disease will stop bleeding spontaneously and most will not rebleed during hospitalization. However, a subgroup of patients are at high risk for recurrent hemorrhage. Gastroduodenal ulcers can be stratified into high versus low risk for rebleeding by the presence or absence of stigmata of ulcer hemorrhage. The major endoscopic predictors of persistent or recurrent bleeding include : o Active bleeding during endoscopy 90 % recurrence o Visible vessel 50 % recurrence o An adherent clot (in elderly patients particularly with large ulcers) 25 to 30 % recurrence The absence of all of these stigmata identifies a subgroup of patients who are at low risk of rebleeding. We suggest that these patients can be discharged early from the hospital on antiulcer therapy. (Grade 2B). ENDOSCOPIC THERAPY : including thermal coagulation, injection therapy, hemostatic clips, and combination approaches. For patients with active arterial bleeding or a nonbleeding visible vessel, we recommend combination endoscopic therapy (injection of epinephrine followed by thermal coaptive coagulation or endoscopic hemoclips) rather than medical therapy alone (Grade 1A). We also suggest combination endoscopic therapy rather than endoscopic monotherapy (Grade 2B). For patients with a nonbleeding adherent clot, we suggest combination endoscopic therapy rather than medical therapy alone (Grade 2B) or endoscopic monotherapy (Grade 2B). For high risk patients with nonbleeding visible vessels, we recommend endoscopic therapy rather than medical therapy alone (Grade 1B). We suggest thermal coagulation or hemoclips alone in average risk patients with easily accessible lesions rather than combination endoscopic therapy (Grade 2C). Endoscopic DUP scanning may improve risk stratification and endoscopic treatment and can be used in centers with appropriate expertise. For patients with ulcers that have persistent oozing bleeding without other stigmata (such as a clot or a nonbleeding visible vessel), we suggest endoscopic thermal therapy or hemoclipping alone followed by an oral PPI rather than endoscopic combination therapy or an oral PPI alone (Grade 2B). For patients whose ulcers contain flat spots or a clean ulcer base, we recommend medical therapy alone rather than endoscopic therapy (Grade 1B). ACID SUPPRESSION We recommend that patients with actively bleeding peptic ulcers or ulcers with high-risk stigmata (such as a visible vessel or adherent clot) receive an intravenous PPI (Grade 1B). Although omeprazole has been the most extensively studied, other intravenous formulations of proton pump inhibitors given in doses that are known to inhibit gastric acid secretion are probably acceptable alternatives. Pantoprazole (Penta) and lansoprazole (Lansodol) are the only intravenous formulation available in the United States. The suggested IV pantoprazole dose is 80 mg bolus followed by 8 mg/hr infusion.

If there is no rebleeding within 24 hours, the patient may be switched to oral pantoprazole 40 mg/day or omeprazole 20 mg/day or another proton pump inhibitor given in equivalent dosing. We suggest twice daily dosing of an oral proton pump inhibitor when intravenous formulations are not available (Grade 2B). It is unlikely that an intravenous proton pump inhibitor would be of significant benefit in patients who do not have active bleeding, or other high-risk stigmata for recurrent bleeding; in such patients the risk of recurrent bleeding is low. The goal of treatment in these patients (following resuscitation) should be directed at healing the ulcers and eliminating precipitating factors (such as H. pylori and NSAIDs). SOMATOSTATIN AND OCTREOTIDE an be used as adjunctive therapy before endoscopy, or when endoscopy is unsuccessful, contraindicated, or unavailable Octreotide Dose (Sandostatin) : 50 to 100 mcg given as a bolus followed by 25 mcg/h for up to 3 day. REFRACTORY BLEEDING : Indications for angiography for acute nonvariceal upper gastrointestinal bleeding have been suggested in a consensus statement from the American College of Radiology : o Endoscopy is the best initial diagnostic and therapeutic procedure. o Surgery and transcatheter arteriography/intervention (TAI) are equally effective following failed therapeutic endoscopy, but TAI should be considered particularly in patients at high risk for surgery. o TAI is less likely to be successful in patients with impaired coagulation. o TAI is the best technique for treatment of bleeding into the biliary tree or pancreatic duct. Indications For Surgery For Peptic Ulcer Hemorrhage 1. failure of endoscopic therapy 2. Hemodynamic instability despite vigorous resuscitation (more than a 3 unit transfusion) 3. bleeding persists or rebleeding occurs after two therapeutic endoscopies. 4. Shock associated with recurrent hemorrhage 5. Continued slow bleeding with a transfusion requirement exceeding 3 units per day Secondary or relative indications include: 1. rare blood type 2. difficult crossmatch 3. refusal of transfusion 4. shock on presentation 5. advanced age 6. severe comorbid disease 7. chronic gastric ulcer as the origin of hemorrhage 8. These criteria also apply to elderly patients in whom prolonged resuscitation, large volume transfusion, and periods of hypotension are poorly tolerated the risk of recurrent ulceration and bleeding depends upon : o characteristics of the ulcer : gastric ulcers along the lesser curvature and duodenal bulbar ulcers in the posterior wall appeared to be at greater risk for severe bleeding or rebleeding compared with ulcers in other locations because of their proximity to large underlying arteries (left gastric and posterior gastroduodenal arteries, respectively) o patients who presented with active hemorrhage, shock, and the lowest hemoglobin concentrations did less well than those without these risk factors. o use of endoscopic therapy Factors that did not predict outcome of endoscopic therapy were a history of NSAID or aspirin use, coagulopathy, previous peptic ulceration, and concomitant cardiorespiratory disease. severe bleeding, active bleeding, fresh blood in the stomach and large ulcers were independent risk factors for therapeutic failure after injection of epinephrine plus heater probe treatment o the extent to which risk factors such as use of NSAIDs and H. pylori infection. Maintenance therapy with acid suppression may be required for patients at high risk of recurrence.

Treatment Regimens For Helicobacter Pylori

1st line treatment regimen of choice : for 7-14 days o PPI twice daily o amoxicillin 1 gm twice daily substitute metronidazole 500 mg twice daily in penicillin allergic patients o clarithromycin 500 mg twice daily substitute metronidazole 500 mg twice daily in macrolide allergic patients Recommendations for PPI doses in the treatment of gastroduodenal ulcers o duodenal ulcers should be treated for 4 weeks and gastric ulcers for 8 weeks Omeprazole (omepral ) - 20 mg Lansoprazole (lansodol)30 mg Rabeprazole - 20 mg Pantoprazole (PentA) 40 mg Esomeprazole Es-omperal)40 mg o All administered daily before breakfast Alternative 1st line treatment : Bismuth 525 mg, metronidazole 500 mg, tetracycline 500 mg all four times daily with a PPI twice daily for 7-14 days . if failed 1st line treatment retreatment with : o Bismuth 525 mg, metronidazole 500 mg, tetracycline 500 mg all four times daily with a PPI twice daily for 14 days preferably given with meals and an evening snack or o PPI, amoxicillin 1 gm, metronidazole 500 mg all twice daily for 14 days "Rescue" therapy for those failing two course of above treatments : o Culture with antibiotic sensitivity testing o PPI, levofloxacin 250 mg, amoxicillin 1 gm all twice daily for 14 days o PPI, rifabutin 150 mg, amoxicillin 1 gm all twice daily for 14 days o PPI twice daily plus amoxicillin 1 three times daily for 14 days The most common side effect : o metallic taste due to metronidazole or clarithromycin. o Metronidazole can cause a peripheral neuropathy, seizures, and a disulfuram-like reaction when taken with alcohol. o Clarithromycin can cause taste alteration, nausea, vomiting, abdominal pain, and rarely QT prolongation. Tetracycline can induce a photosensitivity reaction in some cases. It should also not be administered to pregnant women or young children. o Amoxicillin can cause diarrhea or an allergic reaction with skin rash. o Side effects due to bismuth, H2 receptor antagonists, and proton pump inhibitors are rare.

Management Of Variceal Hemorrhage

Variceal Hemorrhage Occurs In 25 To 40 Percent Of Patients With Cirrhosis. Only 50 % Of Patients With Variceal Hemorrhage Stop Bleeding Spontaneously; This Is Quite Different From The More Than 90 % Spontaneous Cessation Rate In Patients With Other Forms Of Upper Gastrointestinal Hemorrhage. Following Cessation Of Active Hemorrhage, There Is A Period Of Approximately Six Weeks In Which There Is A High Risk Of Recurrent Hemorrhage. The Greatest Risk Is Within The First 48 To 72 Hours, And Over 50 % Of All Early Rebleeding Episodes Occur Within The First 10 Days. The Risk Of Bleeding And Of Death In Patients Who Survive Six Weeks Is Similar To That In Patients With Cirrhosis Of Equivalent Severity Who Have Never Bled . Prediction Of Patients At Risk Include : The Location, Size And Appearance Of Varices, Their Pressure And Clinical Features Of The Patient. Size Of Varices: o F1: Small Straight Varices o F2: Enlarged Tortuous Varices That Occupy < Of The Lumen o F3: Large Coil-Shaped Varices That Occupy > Of The Lumen

Primary Prophylaxis Against Variceal Hemorrhage

We Suggest That All Patients With Cirrhosis Undergo Diagnostic Endoscopy To Document The Presence Of Varices And To Determine Their Risk For Variceal Hemorrhage (Grade 2b). In Patients With Cirrhosis Who Do Not Have Varices, Nonselective Beta Blockers Cannot Be Recommended To Prevent Their Development. In Patients Who Have Compensated Cirrhosis And Small Varices That Have Not Bled But Have Criteria For Increased Risk Of Hemorrhage (Child B/C Or Presence Of Red Wale Marks On Varices), Beta Blockers Should Be Used For The Prevention Of First Variceal Hemorrhage. In Patients With Cirrhosis And Small Varices That Have Not Bled And Have No Criteria For Increased Risk Of Bleeding, Beta Blockers Can Be Used, In Patients With Medium/Large Varices That Have Not Bled But Have A High Risk Of Hemorrhage (Child B/C Or Variceal Red Wale Markings On Endoscopy), Beta Blockers (Propranolol Or Nadolol) Or Evl May Be Recommended For The Prevention Of First Variceal Hemorrhage. In Patients With Medium/Large Varices That Have Not Bled And Are Not At The Highest Risk Of Hemorrhage (Child A Patients And No Red Signs), Nonselective Beta Blockers Are Preferred And Evl Should Be Considered In Patients With Contraindications Or Intolerance Or Non-Compliance To Beta Blockers.

Child-Pugh Classification Of Severity Of Liver Disease Ascites Bilirubin Albumin Inr Encephalopathy 1 Absent <2 Mg/Dl >3.5 G/Dl <1.7 None 2 Slight 2-3 Mg/Dl 2.8-3.5 G/Dl 1.7-2.3 Grade 1-2 3 Moderate >3 Mg/Dl <2.8 G/Dl >2.3 Grade 3-4

Grade A : 5-6: (Well-Compensated Disease) Grade B :7-9 (Significant Functional Compromise) Grade C : 10-15 (Decompensated Disease)

Patients At High Risk For Development Of Variceal Hemorrhage Should Be Considered For Primary Prophylaxis. This High Risk Group Includes : All Patients With Large (F2 Or F3) Esophageal Varices With Or Without Red Signs And Those With Small (F1) Varices Should Also Be Considered For Primary

Prophylaxis Based Upon A Controlled Trial Showing A Reduction In Bleeding Risk And Progression Of Varices. In Patients In Whom Primary Prophylaxis Is Considered Appropriate As Described Above, We Recommend Propranolol (Inderal) Or Nadolol(Corgard ) (Grade 1a). We Typically Use Nadolol At A Starting Dose Of 40 Mg Per Day In Patients Who Have High Risk Varices And Have Potential Contraindications To Beta Blockers Or Have Been Intolerant To Beta Blockers( Hypotension), We Suggest Endoscopic Variceal Ligation (Evl) (Grade 1b). Monitoring Response:By Measurement Of The Hepatic Venous Pressure Gradient (Hvpg) Considered Additional Agents Such As Nitrates Or Clonidine In Patients Who Do Not Show A Response To Beta Blockers (Ie, A Decline In Hvpg). These Drugs Should Only Be Prescribed By Those With Considerable Experience With Portal Hypertension Since The Use Of Combination Therapy Does Not Constitute "Standard Medical Practice." We Suggest Not Using A Nitrate Alone Even In Patients Who Cannot Tolerate Beta Blockers (Grade 1b). We Suggest That Combination Therapy With A Nitrate Plus A Beta Blocker Not Be Used Routinely For Primary Prophylaxis Of Variceal Hemorrhage (Grade 2b). Follow-Up : o In Patients With Small Varices That Have Not Bled And Who Are Not Receiving Beta Blockers, Egd Should Be Repeated In Two Years. If There Is Evidence Of Hepatic Decompensation, Egd Should Be Done At That Time And Repeated Annually. o If A Patient Is Placed On A Nonselective Beta Blocker, It Should Be Adjusted To The Maximal Tolerated Dose; Follow-Up Surveillance Egd Is Unnecessary. o If A Patients Is Treated With Evl, It Should Be Repeated Every One To Two Weeks Until Obliteration With The First Surveillance Egd Performed One To Three Months After Obliteration And Then Every 6 To 12 Months To Check For Variceal Recurrence.

Supportive Care Of Patients With Active Variceal Hemorrhage Hemodynamic Resuscitation

1. 2. 3.

Packed Red Cell Transfusion To Keep Hemoglobin At About 8 G/Dl Crystalloids To Keep Urine Volume >50 Ml/H Correct Coagulopathy And Thrombocytopenia As Indicated Platelet Counts Often Drop Within The First 48 Hours After A Bleed And May Necessitate Platelet Transfusions If Values Below 50,000/Mm3 Occur In An Actively Bleeding Patient. In Extreme Settings, Correction Of The Coagulopathy Is Necessary But Cannot Be Achieved Adequately With Ffp, Particularly In Patients Who Are Severely Volume Overloaded. Avoid Volume Overload Patients Must Be Monitored Carefully To Avoid Overtransfusion With Volume Overload Because Of The Risk Of Rebound Portal Hypertension And Induction Of Rebleeding . Those Receiving Large Volumes Of Blood Products Should Also Be Monitored For A Reduction In The Serum Ionized Calcium Concentration (Due To Citrate Binding Of Ionized Calcium) And Thrombocytopenia; These Abnormalities Should Be Corrected.

4.

Pulmonary Resuscitation Monitor Airway Integrity And Oxygen Saturation Protect Airway If Mental Status Obtunded Or If Active Hemetemesis Present Antibiotic Prophylaxis Guidelines By Aasld Short-Term (Maximum 7 Days) Antibiotic Prophylaxis Should Be Instituted In Any Patient With Cirrhosis And Gi Hemorrhage. Oral Norfloxacin (Uriflox) (400 Mg Twice Daily) Or Intravenous Ciprofloxacin (Cipref )(In Patients In Whom Oral Administration Is Not Possible) Is The Recommended Antibiotic. In Patients With Advanced Cirrhosis, Intravenous Ceftriaxone(Ross) (1 G/Day) May Be Preferable, Particularly In Centers With A High Prevalence Of Quinolone-Resistant Organisms.

Renal Management Avoid Transfusion Mismatch Avoid Aminoglycosides And Other Nephrotoxic Drugs Maintain Euvolemia Metabolic

Monitor For Alcohol Withdrawal Thiamine Replacement Monitor For Hypokalemia, Hypophosphatemia, And Acid-Base Balance Monitor For Acid-Base Balance And Correct As Necessary Hepatic Encephalopathy Management : Should Be Managed With Lactulose And An Aggressive Search For Potentially Reversible Factors Other Than Gastrointestinal Bleeding That May Contribute To The Encephalopathy. Hypokalemia May Be A Particular Problem Because It Can Promote The Development Of Hepatic Encephalopathy Via Increased Renal Ammonia Production . The Current Metabolic Alkalosis, If The Hypokalemia Is Induced By Diuretics Or Vomiting, May Also Contribute By Promoting The Movement Of Ammonia Across The Blood-Brain Barrier.

Treatment Of Active Variceal Hemorrhage Intravenous Vasopressin And Somatostatin And Its Analogs: o We Suggest Terlipressin In Countries Where It Is Available And Somatostatin Or Octreotide (Sandostatin) Where Terlipressin Is Unavailable (Grade 2c).It Is Probably Only Effective When Used In Conjunction With Endoscopic Therapy. And Continued For 3 To 5 Days After Diagnosis Is Confirmed. o Octreotide Dose :50 Mcg Bolus Followed By 50 Mcg/Hour By Intravenous Infusion (Put 12 Amp 100 Mcg In 250 Cc Sd5% At 24 Houre (Every Amp 100mcg Diluted To 20 Cc Sd) We Recommend That Bleeding Esophageal Varices Be Treated By Esophageal Band Ligation Or Sclerotherapy (Grade 1a). When Bleeding Is Brisk And The Field Of Vision Is Limited, We Prefer Initial Sclerotherapy Because It Is Faster, Provides Better Vision, And Is As Effective As Band Ligation For Achievement Of Hemostasis. We Recommend Pharmacologic Treatment In Addition To Endoscopic Treatment Of Bleeding Esophageal Varices (Grade 1b). What To Do When Endoscopic Treatment Fails : Definitions Failure Of Endoscopic Treatment Is Generally Considered Within Two Time Frames According To Consensus Definitions : o Within Six Hours - When The Following Factors Are Present: 1. Transfusion Of 4 Units Of Blood Or More, 2. Inability To Achieve An Increase In Sbp Of 20 Mmhg Or To 70 Mmhg Or More, 3. A Pulse Reduction To Less Than 100/Min Or A Reduction Of 20/Min From The Baseline Pulse Rate. o After Six Hours - When The Following Factors Are Present: 1. Occurrence Of Hematemesis, 2. Reduction In Blood Pressure Of More Than 20 Mmhg From The Six Hour Point 3. Increase Of Pulse Rate Of More Than 20/Min From The Six Hour Point On Two Readings One Hour Apart, 4. Transfusion Of 2 Units Of Blood Or More (Over And Above The Previous Transfusions) Required To Increase The Hematocrit Above 27 % Or Hb To Above 9g/Dl. Any Bleeding That Occurs More Than 48 Hours After The Initial Admission For Variceal Hemorrhage And Is Separated By At Least A 24 Hour Bleed-Free Period Is Considered To Represent Rebleeding. Rebleeding That Occurs Within 6 Weeks From The Onset Of Active Bleeding Is Considered To Be "Early Rebleeding" , Rebleeding Episodes At Later Time Points Are Referred To As "Late Rebleeding".

The Highest Risk For Failure To Control Bleeding Or Early Rebleeding Is In The First 72 Hours After The Onset Of Bleeding. Balloon Tamponade: Should Be Used As A Temporizing Measure (Maximum 24 Hours) In Patients With Uncontrollable Bleeding For Whom A More Definitive Therapy (Eg, Tips Or Endoscopic Therapy Is Planned. We Recommend Salvage Treatment (Tips Or Surgery) When The Above Measures Fail To Control Bleeding From Esophageal Varices (Grade 1b). The Ideal Patient For Surgery Is One With Well Preserved Liver Function Who Fails Emergent Endoscopic Treatment And Has No Complications From The Bleeding Or Endoscopy. The Choice Of Surgery Usually Depends Upon The Training And Expertise Of The Surgeon. Although A Selective Shunt Has Some Physiologic Advantages, It May Significantly Exacerbate Marked Ascites. Thus, A Portacaval Shunt Would Be Preferable In Patients With Marked Ascites. We Recommend That Patients Who Experience Rebleeding Episodes From Esophageal Varices Following Initial Control Of Bleeding Be Managed With An Additional Session Of Endoscopic Treatment (Grade 1b). We Recommend That Tips Or Surgery Be Performed If Bleeding From Esophageal Varices Continues Or Recurs (Grade 1b). Gastric Varices : We Suggest That Bleeding Intragastric Varices Be Treated With Endoscopic Variceal Obturation Using The Tissue Adhesive Cyanoacrylate Where Available (Grade 2b). In Settings Where It Is Not Available, We Suggest Tips

Prevention Of Recurrent Variceal Hemorrhage In Patients With Cirrhosis We Recommend That All Patients Who Have Bled From Esophageal Varices Receive Band Ligation And Beta Blockers Unless Beta Blockers Are Contraindicated (Grade 1b). We Usually Perform Band Ligation Seven Days After Initial Endoscopic Control Of Variceal Hemorrhage And Every One To Two Weeks Thereafter. Surgical Portal Decompression May Also Be An Option For Patients With Child Class A Cirrhosis Provided That The Appropriate Surgical Expertise Is Available. We Recommend That Patients With Liver Failure Undergo Evaluation For Liver Transplantation (Grade 1b). In Patients With Acute Variceal Bleeding Despite Adequate Band Ligation And Beta Blockers We Recommend Either Tips Or Surgery As A Bridge To Transplantation (Grade 1b). The Choice Of Procedure Should Be Individualized Based Upon The Patient's Condition And Available Expertise. Other Approaches Have Also Been Proposed Based Upon Measurement Of The Hepatic Venous Pressure Gradient And May Be Equally Valid As The Approach Outlined Above

Treatment Of Acute Pancreatitis

Definitions Acute pancreatitis can be divided into two broad categories: Edematous or mild acute pancreatitis and necrotizing or severe acute pancreatitis.

Predicting the severity of acute pancreatitis : During the initial 24 hours, individual clinical, laboratory, and radiologic risk factors (described above), the simple SIRS score, APACHE II system, and CT severity index (if a CT scan has been performed) can be used to predict severe acute pancreatitis. There are a number of risk factors for disease severity that should be noted on admission. These include older age (>55 years), obesity (BMI>30 kg/m2), organ failure at admission, and pleural effusion and/or pulmonary infiltrates. Such patients may require treatment in a highly supervised area, such as a step-down unit or an intensive care unit. The two tests that are most helpful at admission in distinguishing mild from severe acute pancreatitis are the APACHE-II score and the hematocrit. o The APACHE-II score should be generated during the first three days of hospitalization and repeated as needed. o The hematocrit should be measured on admission, 12 hours after admission, and 24 hours after admission to help assess the adequacy of fluid resuscitation. Pancreatic necrosis and organ failure are the two most important markers of severity in acute pancreatitis. Laboratory tests have an adjunctive role in predicting the severity of acute pancreatitis. We agree with the guideline issued by the AGA, which suggests that of the available tests, a C-reactive protein level of >150 mg/L at 48 hours after disease onset is preferred for discriminating patients with severe disease. Prompt transfer to an intensive care unit is warranted in patients with sustained organ failure. Transfer to an intensive care unit or possibly a step-down care unit should also be considered if there are signs that suggest that the pancreatitis is severe or is likely to be severe. Ranson criteria to predict severity of acute pancreatitis 0 hours Age White blood cell count Blood glucose Lactate dehydrogenase Aspartate aminotransferase (AST) 48 hours >55 >16,000/mm3 >200 mg/dL (11.1 mmol/L) >350 U/L >250 U/L

Hematocrit Fall by 10 percent Blood urea nitrogen Increase by 5 mg/dL (1.8 mmol/L) despite fluids Serum calcium <8 mg/dL (2 mmol/L) pO2 <60 mmHg Base deficit >4 MEq/L Fluid sequestation >6000 mL o The presence of 1 to 3 criteria represents mild pancreatitis o the mortality rate rises significantly with 4 or more criteria.

Defining features of systemic inflammatory response syndrome (SIRS) Two or more of the following conditions: Temperature >38.5C or <35.0C Heart rate of >90 beats/minute Respiratory rate of >20 breaths/minute or PaCO 2 of <32 mm Hg WBC count of >12,000 cells/mL, <4000 cells/mL, or >10 percent immature (band) forms CT findings and grading of acute pancreatitis (CT severity index [CTSI]) Grading based upon findings on unenhanced CT Grade Findings Normal pancreas - normal size, sharply defined, smooth contour, homogeneous enhancement, A retroperitoneal peripancreatic fat without enhancement Focal or diffuse enlargement of the pancreas, contour may show irregularity, enhancement B may be inhomogeneous but there is on peripancreatic inflammation C Peripancreatic inflammation with intrinsic pancreatic abnormalities D Intrapancreatic or extrapancreatic fluid collections E Two or more large collections of gas in the pancreas or retroperitoneum Necrosis score based upon contrast enhanced CT Necrosis, percent 0 <33 33-50 50 o CT severity index equals unenhanced CT score plus necrosis score: maximum = 10. 6 = severe Score 0 1 2 3 4 Score 0 2 4 6

BISAP system : during the first 24 hours: BUN >25 mg/dL, impaired mental status, SIRS, age >60 years, or the presence of a pleural effusion (ie, the acronym BISAP) GENERAL PRINCIPLES OF THERAPY : Supportive treatment : o fluid resuscitation : aggressive hydration. approximately 250 to 300 cc of intravenous fluids per hour are typically required for 48 hours if the cardiac status permits. Adequate fluid replacement can be assessed by improvement in vital signs and urine output and reduction in hematocrit over 24 hours o Oxygen saturation needs to be assessed routinely and supplemental oxygen administered to maintain arterial oxygen saturation of greater than 95 %. Blood gas analysis should be done if SaO2 is less than 95 percent or if clinical situation demands. o Prophylaxis against deep vein thrombosis should be considered in bedridden patients. Intermittent pneumatic compression may be the preferred method because of the theoretical risk of precipitating pancreatic hemorrhage with anticoagulation. Pain management : o Meperidine has traditionally been favored over morphine for analgesia in pancreatitis o Repeated doses of meperidine can lead to accumulation of the metabolite normeperidine that causes neuromuscular irritation and, rarely, seizures. An alternative is intravenous fentanyl, which we use in patients who require large doses of meperidine Preventing infection in severe acute pancreatitis : o The use of prophylactic antibiotics to prevent pancreatic infection is not recommended. o we suggest the use of prophylactic imipenem/ meropenem in severe acute pancreatitis, with significant necrosis (defined as >30 percent by CT scan) and/or organ failure

Nutrition AND Initiation of oral feedings :

o In patients with mild pancreatitis, recovery generally occurs quickly, making it generally unnecessary to initiate supplemental nutrition. o We suggest beginning oral feedings by giving 100 to 300 mL of clear liquids every four hours for the first 24 hours ( Grade 2B). If this diet is tolerated, feedings are advanced gradually to a soft diet and finally to solid foods. o Nutritional support should be provided to those likely to remain fasting for more than seven days. Nasojejunal tube feeding is preferred to total parenteral nutrition o In patients with severe pancreatitis, we recommend attempting to provide early enteral nutrition in the first 72 hours through a nasojejunal tube placed endoscopically or radiologically ( Grade 1B). If the target rate is not achieved within a few days and if severe acute pancreatitis is not resolved, supplemental parenteral nutrition should be provided. o Jejunal feeding permits earlier discharge from the hospital and avoidance of TPN. A few weeks of jejunal feeding allows for the inflammation to subside or the fluid collection to mature and be drained, leading to resolution of gastric outlet obstruction and resumption of oral feeding. o We do not feel that the presence of fluid collections or elevated pancreatic enzymes are necessarily contraindications to oral or enteral feeding. However, in a subgroup of patients there is clear correlation of pain, recurrence of pancreatitis, or worsening of fluid collections to feeding, either oral or enteral. These patients often have disrupted pancreatic ducts with fluid collections. Drainage of fluid collections may allow resumption of oral intake. If the fluid collections are not considered suitable for drainage TPN will be needed to maintain nutrition. Recommended approach : o After assessment of the patient, We suggest a contrast-enhanced CT be performed in patients considered to have severe acute pancreatitis based upon clinical criteria and possibly the APACHE II score to determine if necrotizing pancreatitis is present (Grade 2B). o A CT scan is not required on the first day unless there are other possible diagnoses. It takes time for pancreatic necrosis to develop, and thus CT may be normal in the first 48 hours. As noted above, a guideline issued by the American Gastroenterological Association suggests a CT be performed after 72 hours of illness in patients with predicted severe disease and those with evidence of organ failure during the initial 72 hours. Although there are some experimental data that ionic contrast may worsen pancreatitis, the association is probably not strong, and the information obtained from the CT scan justifies the potential risk. o Acute fluid collections do not require therapy in the absence of infection or obstruction of a surrounding hollow viscus. o Patients without severe necrotizing pancreatitis are managed conservatively with the supportive measures noted above. o If there is necrotizing pancreatitis (involving more than approximately 30 % of the pancreas), we initiate antimicrobial therapy with imipenem/ meropenem and continue it for at least one week. o Dose of imipenem (Lastinem) : 500 mg every 6 hours o Dose of meropenem (Ronem): 1 g every 8 hours o We do not routinely recommend prophylactic antifungal therapy with fluconazole. o If at any time the patient becomes unstable from pulmonary, cardiovascular, or renal complications, we perform a minimally invasive necrosectomy, (endoscopic, or percutaneous radiologic) if possible (see below), to remove necrotic debris and pus. o If there has been no improvement after one week of antibiotics, we perform a percutaneous CT-guided aspirationwith Gram's stain and culture : o If there is bacterial infection, we consider performing a necrosectomy (see below) and change the antibiotics according to the culture and sensitivity results .

o If, on the other hand, the aspirated material is sterile, we continue conservative treatment for four to six weeks. After this time, debridement should be considered if the abdominal pain persists and prevents oral intake. Debridement is usually performed surgically, but percutaneous or endoscopic approaches are reasonable in selected cases by physicians with appropriate expertise. Pancreatic duct leaks and fistulas are common and may require endoscopic or surgical therapy. o However, if clinical suspicion for infection is high, a repeat aspiration may be indicated since a negative FNA does not confidently exclude infection o We suggest open surgical debridement for patients with infected necrosis (and rarely for sterile necrosis) who have persistent pain and cannot tolerate oral intake if the minimally invasive methods fail to resolve the fluid collections or if the collections are not amenable for these methods . Managment algorithm for severe acute pancreatitis

Miscellaneous treatments Plasma exchange dramatically reduced triglyceride levels and improved the outcome in patients with necrotizing pancreatitis due to hypertriglyceridemia . Intravenous infusion of heparin reduced triglyceride levels and improved the outcome in a pregnant patient with severe acute pancreatitis due to hypertriglyceridemia and may be an option in such cases . Hypocalcemia (seen in severe cases) can be treated like any other case of low calcium with no special recommendation because of acute pancreatitis. Splenic vein thrombosis 19 %. prophylactic splenectomy or anticoagulation during the acute stage of thrombosis is not recommended Anticoagulation may be needed if there is extension of the clot into the portal or superior mesenteric vein resulting in hepatic decompensation or compromise of bowel perfusion.

Gallstone pancreatitis o In patients with gallstone pancreatitis, we recommend early ERCP and sphincterotomy only for those who have persistently abnormal or deteriorating liver tests or biliary sepsis ( Grade 1B) o Cholecystectomy should be performed prior to discharge in patients with mild pancreatitis. o In patients who have had mild pancreatitis, cholecystectomy can usually be performed safely within seven days after recovery . o On the other hand, in patients who have had severe necrotizing pancreatitis, delaying cholecystectomy for at least three weeks may be reasonable because of an increased risk of infection o a cholangiogram and clearance of the common bile duct of stones either before or during surgery is mandatory to prevent recurrence after cholecystectomy. If the clinical suspicion of common bile duct stones is high (eg, in those with persistent or worsening liver test abnormalities or cholangitis) a preoperative ERCP is the best test as there is a high likelihood that therapeutic intervention (sphincterotomy, stone extraction) will be required. urgent ERCP (within 24 hours) if there is concomitant cholangitis, while early ERCP (within 72 hours) should be performed in those with a high suspicion of persistent bile duct stones if the suspicion of persistent common bile duct stone is low (eg, if liver tests normalize) an intraoperative cholangiogram during cholecystectomy may be preferable to avoid the morbidity associated with ERCP. For patients who remain in the gray zone (eg, if liver test abnormalities are slow to decrease), MRCP or EUS are other imaging options that can exclude common bile duct stones . An ERCP can then be performed only in those with stones or sludge in the common bile duct. An MRCP may miss small stones or sludg , is not tolerated by some due to claustrophobia, and is not possible in patients with metal clips or implants. An endoscopic ultrasound is an invasive procedure requiring expertise that is not widely available.

Diagnosis And Treatment Of Hepatorenal Syndrome

DIAGNOSTIC CRITERIA 1. Chronic or acute hepatic disease with advanced hepatic failure and portal hypertension 2. A plasma creatinine concentration above 1.5 mg/dL (133 mol/L) that progresses over days to weeks. As noted above, the rise in plasma creatinine with reductions in glomerular filtration rate may be minimized by the marked reduction in creatinine production. 3. The absence of any other apparent cause for the renal disease, including shock, ongoing bacterial infection, current or recent treatment with nephrotoxic drugs, and the absence of ultrasonographic evidence of obstruction or parenchymal renal disease. It is particularly important to exclude spontaneous bacterial peritonitis, which is complicated by acute renal failure that may be reversible in 30 to 40 % . 4. Urine red cell excretion of less than 50 cells per high power field (when no urinary catheter is in place) and protein excretion less than 500 mg/day. 5. Lack of improvement in renal function after volume expansion with intravenous albumin (1 g/kg of body weight per day up to 100 g/day) for at least two days and withdrawal of diuretics. TREATMENT combination therapy with midodrine and octreotide or single agent therapy with norepinephrine should be considered in patients with hepatorenal syndrome, given the apparent absence of significant side effects and the dismal prognosis with other available therapies (excluding liver transplantation). We also administer intravenous albumin at approximately 1 g/kg/day (100 g maximum) for two or more days. In the United States, liver transplant candidates who develop end-stage renal disease usually undergo hemodialysis; those who are not transplant candidates commonly receive the combination of midodrine and octreotide when they are not in an intensive care unit (ICU) and norepinephrine when they are in an ICU. Whether terlipressin will be approved for use in the United States has not been determined.

PREVENTION Hepatorenal syndrome regularly develops in patients with systemic bacterial infection (eg, spontaneous bacterial peritonitis) and/or severe alcoholic hepatitis. The following therapies may prevent the development of hepatorenal syndrome in these patients: In patients with spontaneous bacterial peritonitis, the administration of intravenous albumin (1.5 g/kg) at the time of diagnosis of infection and another dose of albumin (1.0 g/kg) on day three of antibiotic treatment may reduce the incidence of both renal impairment that does not reverse during hospitalization and mortality during hospitalization and at three months [25] . Although these findings need to be confirmed in additional controlled studies, it seems appropriate to give intravenous albumin as part of the treatment regimen of spontaneous bacterial peritonitis because of the possible survival advantage. A randomized trial reported significant benefits with the oral administration of norfloxacin at 400 mg/day to 68 patients with cirrhosis and ascitic fluid total protein <1.5 g/dL who fulfilled either of the following two criteria: a Child-Pugh score >9 points and serum bilirubin >3 mg/dL (51.3 micromol/L); or a serum creatinine >1.2 mg/dL [106 micromol/L] or blood urea nitrogen >20 mg/dL or serum sodium <130 meq/L [65] . Norfloxacin was associated with the following significant benets: decreased one-year probability of SBP (7 versus 61 percent) and hepatorenal syndrome (28 versus 41 percent), and improved survival at three months (94 versus 62 percent) and one year (60 percent versus 48 percent). Based upon these findings, we recommend the use of norfloxacin in patients who meet the inclusion criteria in this trial.

Gastroesophageal Reflux GERD

Clinical manifestations and diagnosis GERD is applied to patients with symptoms suggestive of reflux or complications thereof, but not necessarily with esophageal inflammation. A consensus statement (the Montreal Classification) defines GERD as "a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications" . The most common symptoms of GERD are heartburn (or pyrosis), regurgitation, and dysphagia. In addition, a variety of extraesophageal manifestations have been described including bronchospasm, laryngitis, and chronic coughing. Diagnostic Evaluation : It is neither necessary nor practical to initiate a diagnostic evaluation in every patient with heartburn. Endoscopy : Endoscopy with biopsy should be done at presentation for patients with an esophageal GERD syndrome with troublesome dysphagia. Biopsies should target any areas of suspected metaplasia, dysplasia, or, in the absence of visual abnormalities, normal mucosa (at least five samples to evaluate for eosinophilic esophagitis). Endoscopy should also be done to evaluate patients with a suspected esophageal GERD syndrome who have not responded to an empirical trial of twice daily PPI therapy. Los Angeles classification o Grade A one or more mucosal breaks each 5 mm in length o Grade B at least one mucosal break >5 mm long, but not continuous between the tops of adjacent mucosal folds. o Grade C at least one mucosal break that is continuous between the tops of adjacent mucosal folds, but which is not circumferential. o Grade D mucosal break that involves at least three-fourths of the luminal circumference . For patients who require diagnostic evaluation, potentially useful tests are endoscopy and ambulatory pH monitoring, which provide distinct but related information Who should have endoscopy o Some experts advocated an endoscopy in patients who require continuous maintenance medical therapy to rule out Barrett's esophagus. o In patients without Barrett's esophagus on an initial examination, the cancer risk is too low to justify a follow-up endoscopy. Exceptions are patients who develop bleeding, dysphagia, or a significant change in symptoms while on effective therapy. Who should NOT have endoscopy o chronic GERD symptoms. o Endoscopic screening for Barrett's esophagus and dysplasia in adults 50 years or older with >5-10 years of heartburn

Ambulatory esophageal pH monitoring Indications for esophageal pH recording : 1. Esophageal pH recording is indicated to document abnormal esophageal acid exposure in an endoscopynegative patient being considered for surgical antireflux repair (pH study done after withholding antisecretory drug regimen for one week). 2. Esophageal pH recording is indicated to evaluate patients after antireflux surgery who are suspected to have ongoing abnormal reflux (pH study done after withholding antisecretory drug regimen for one week). 3. Esophageal pH recording is indicated to evaluate patients with either normal or equivocal endoscopic findings and reflux symptoms that are refractory to proton pump inhibitor therapy (pH study done after

4.

5.

6.

7. 8.

withholding antisecretory drug regimen for one week if the study is done to confirm excessive acid exposure or while taking the antisecretory drug regimen if symptom reflux correlation is to be scored). Esophageal pH recording is possibly indicated to detect refractory reflux in patients with chest pain after cardiac evaluation using a symptom reflux association scheme, preferably the symptom association probability calculation (pH study done after a trial of proton pump inhibitor therapy for at least four weeks). Esophageal pH recording is possibly indicated to evaluate a patient with suspected otolaryngologic manifestations (laryngitis, pharyngitis, chronic cough) of gastroesophageal reflux disease after symptoms have failed to respond to at least four weeks of proton pump inhibitor therapy (pH study done while the patient continues taking the antisecretory drug regimen to document the adequacy of therapy). Esophageal pH recording is possibly indicated to document concomitant gastroesophageal reflux disease in an adult onset, nonallergic asthmatic suspected of having reflux-induced asthma (pH study done after withholding antisecretory drugs for one week). Note: a positive test does not prove causality! Esophageal pH recording is not indicated to detect or verify reflux esophagitis (this is an endoscopic diagnosis). Esophageal pH recording is not indicated to evaluate for "alkaline reflux." Esophageal manometry Esophageal manometry is of minimal use in the diagnosis of GERD. One possible exception is for the evaluation of peristaltic function before antireflux surgery to exclude major motor disorders. Response To Antisecretory Therapy A symptomatic response to antisecretory therapy with proton pump inhibitors or H2 antagonists is frequently considered to support the presumptive diagnosis of GERD. GERD needs to be distinguished from gastritis, infectious esophagitis, pill esophagitis, eosinophilic esophagitis, peptic ulcer disease, non-ulcer dyspepsia, biliary tract disease, coronary artery disease, and esophageal motor disorders. Unexplained chest pain should be evaluated with an electrocardiogram and exercise stress test prior to a gastrointestinal evaluation. The remaining elements of the differential diagnosis can be evaluated by endoscopy or biliary tract ultrasonography.

Medical management of GERD : We suggest lifestyle changes (eg, head of bed elevation, food avoidance before sleep, avoidance of foods that decrease LES pressures) in patients with GERD (Grade 2C). avoidance of a core group of reflux-inducing foods (fatty foods, chocolate, peppermint, and excessive alcohol, which may reduce lower esophageal sphincter pressure) and then to suggest that the patient selectively avoid foods known to cause symptoms. As an example, a number of beverages have a very acidic pH and can exacerbate symptoms. These include colas, red wine, and orange juice (pH 2.5 to 3.9). Refraining from assuming a supine position after meals and avoidance of meals before bedtime, both of which will minimize reflux. Avoidance of tight fitting garments, which reduces reflux by decreasing the stress on a weak sphincter. Obesity is a risk factor for GERD, erosive esophagitis, and esophageal adenocarcinoma . However, improvement in symptoms following weight loss is not uniform. Nevertheless, because of a possible benefit, and because of its other salutary effects, weight loss should be recommended. Promotion of salivation by either chewing gum or use of oral lozenges may also be helpful in mild heartburn. Salivation neutralizes refluxed acid, thereby increasing the rate of esophageal acid clearance. Restriction of alcohol use and elimination of smoking; smoking is deleterious in part because it diminishes salivation.

ACID-SUPPRESSIVE MEDICATIONS In patients with worse than mild and intermittent GERD symptoms, we recommend acid suppressive therapy (Grade 1A).

In patients with GERD and moderate to severe esophagitis, we recommend acid suppression with a PPI rather than an H2RA (Grade 1A). We suggest the stepwise use of therapies in patients with GERD according to the following algorithm (Grade 2C). We initiate therapy based mainly upon the patient's history including response to previous GERD therapy. We perform an endoscopy if there is significant doubt regarding the diagnosis or in patients with alarm symptoms suggesting alternative diagnoses (eg, dysphagia, bleeding, weight loss, odynophagia). Depending upon the initial therapy used, we adjust the medical regimen using a step-up or step-down approach with the goal of identifying the least potent, but still effective, regimen according to the scale of potency Therapeutic regimens for GERD in order of increasing potency 1. Over-the-counter antacids and/or H2 receptor blockers 2. Prescription H2-blockers (twice daily) 3. Intermittent (2 weeks) use of a PPI 4. Omeprazole (20 mg daily) or equivalent dose of the other PPIs 5. Omeprazole (20 mg twice daily or 40 mg daily) or equivalent doses of the other PPIs We consider the severity of persistent symptoms in guiding the approach. Patient comfort is optimized using a step-down approach, with incremental changes in therapy being made at two- to four-week intervals. Once identified, the optimal acute therapy should be maintained for at least 8 weeks. Further evaluation should be undertaken if the most potent medical therapy still results in a poor symptomatic response A trial off medications should be considered in patients who have a good clinical response. The need for maintenance medical therapy is determined by the rapidity of recurrence. Recurrent symptoms in less than 3 months suggest disease best managed with continuous therapy, while recurrences occurring after more than 3 months can be managed by repeated courses of acute therapy as necessary.

We do NOT recommended uses Once- or twice-daily PPIs (or H2RAs) for acute treatment of patients with potential extraesophageal GERD syndromes (laryngitis, asthma) in the absence of a concomitant esophageal GERD syndrome We do NOT recommended uses of Metoclopramide as monotherapy or adjunctive therapy in patients with esophageal or suspected extraesophageal GERD syndromes

An Approach to patient with "refractory" GERD : Patients with GERD who fail treatment with PPIs fall into two main categories: o Patients who require more aggressive therapy o Patients who have other causes of the symptoms TREATMENT Additional studies In patients in whom the adequacy of acid suppression is in question, a 24-hour pH study while taking medications can help to quantify the effectiveness of acid control. The study can also assist in understanding the relationship between reflux and symptoms. It must be recognized, however, that the likelihood of an abnormal pH study in patients taking twice daily PPI therapy is low, and thus other causes of symptoms may be more likely in such patients A repeat endoscopy may be helpful, particularly in patients who had a limited initial examination (due, for example, to problems with sedation) or severe esophagitis. Persistent ulcerated lesions should be biopsied to exclude esophageal carcinoma. A repeat endoscopy can also be helpful to exclude other causes of esophagitis such as infection or pill esophagitis. Patients in whom a motility disorder is suspected should undergo esophageal manometry. In addition, the appropriate diagnostic tests should be obtained in patients who have symptoms consistent with dyspepsia, irritable bowel syndrome, or delayed gastric emptying. Optimizing therapy Medical therapy can be optimized with several approaches. Increasing the frequency of dosing Patients with continued symptoms or esophagitis despite once daily treatment should be offered twice daily treatment. In particular, a dose of a proton pump inhibitor before dinner may reduce nocturnal acid breakthrough Increasing the dose A stepwise increase in the total dose of a proton pump inhibitor is usually successful in achieving adequate acid suppression, even in patients who initially failed therapy with standard or relatively high-dose therapy. Adding a second drug The addition of a nighttime dose of an H2 antagonist is of theoretic benefit Switching to another drug Another option for patients refractory to a proton pump inhibitor is to switch to another proton pump inhibitor. Although there are limited data that have addressed this option, some individuals may be more responsive to one or the other drug , As a result, a trial of substitution may be reasonable. Surgery Indications for surgery in the patient with GERD: 1. Persistent or recurrent symptoms despite high doses of PPI , particularly young patients who may require lifelong therapy. 2. Severe esophagitis by endoscopy 3. Benign stricture 4. Barrett's columnar-lined epithelium (without severe dysplasia or carcinoma) 5. Recurrent pulmonary symptoms (eg, aspiration, pneumonia) associatied with GERD

Autoimmune Hepatitis
Classification of autoimmune hepatitis : according to the type of autoantibodies Type 1 (classic) : 1. ANA 2. Anti-smooth muscle (ASMA) 3. Anti-actin 4. Anti-soluble liver/ liver pancreas antigen (Anti-SLA/LP) 5. Atypical pANCA 6. Antimitochondrial (AMA) Type 2 : 1. Anti-LKM-1 2. Anti-liver cytosol -1 (Anti-LC1)

Autoimmune hepatitis overlap syndromes 1. Autoimmune hepatitis-primary biliary cirrhosis overlap a. AMA-positive with histological evidence suggesting autoimmune hepatitis but not primary biliary cirrhosis b. ANA and/or SMA-positive with histologic changes suggestive of primary biliary cirrhosis (autoimmune cholangitis) 2. Autoimmune hepatitis-primary sclerosing cholangitis overlap CLINICAL MANIFESTATIONS : variability in its clinical manifestations: asymptomatic patients, those with considerable and sometimes debilitating symptoms, and those with fulminant hepatic failure. The physical findings range from a normal physical examination to the presence of hepatomegaly, splenomegaly, stigmata of chronic liver disease, and/or deep jaundice. Asymptomatic patients may be identified when they undergo routine screening examinations. In this setting, the finding of an elevated aminotransferase level . patients who present with an acute, sometimes fulminant picture characterized by profound jaundice, an elevated prothrombin time, and aminotransferase values in the thousands . Such a presentation is uncommon with autoimmune hepatitis . Many patients with an acute presentation have established cirrhosis when biopsied. Thus, they must have had subclinical disease for some period of time. some patients present with a variety of mild or severe nonspecific symptoms, such as fatiguability, lethargy, malaise, anorexia, nausea, abdominal pain, and itching. Although not specific to autoimmune hepatitis, arthralgia involving the small joints . Diseases commonly seen with autoimmune hepatitis include hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, thyroiditis, celiac sprue, and ulcerative colitis (which is more often associated with primary sclerosing cholangitis). a polyglandular autoimmune syndrome can occur in children with type 2 autoimmune hepatitis.

DIAGNOSIS : Diagnosis is based upon characteristic serologic and histologic findings and exclusion of other forms of chronic liver disease.

Laboratory features As a general rule, aminotransferase elevations are more striking in autoimmune hepatitis than those of bilirubin and alkaline phosphatase. In some cases, however, autoimmune hepatitis has a cholestatic picture marked by high levels of conjugated bilirubin and alkaline phosphatase. One characteristic laboratory is an elevation in serum globulins, particularly gamma globulins and generally IgG . In adults and children with compatible clinical or laboratory features, we obtain a serum ANA, SMA, AMA and either a serum protein electrophoresis or quantitative immunoglobulin analysis. In those who are SMAnegative, we obtain SLA and AAA. In children we also obtain anti-LKM1. The diagnosis is confirmed with positive results on serology and compatible histologic findings after excluding other forms of chronic hepatitis. Scoring system Probable Diagnosis : points 6 , Definite Diagnosis: points 7 o Autoantibodies: 1 point if the ANA or SMA are 1:40 2 points if the ANA or SMA are 180 (OR if the LKM 1:40 OR if the SLA is positive). o IgG: 1 point if the IgG is > the upper limit of normal OR 2 points if the IgG is >1.10 times the upper limit of normal. o Liver histology : 1 point if the histological features are compatible with autoimmune hepatitis 2 points if the histological features are typical of autoimmune hepatitis. o Absence of viral hepatitis: assign 2 points if viral hepatitis has been excluded.

Treatment of autoimmune hepatitis : Indications 1. Patients with serum aminotransferase levels greater than 10-fold the upper limit of normal. 2. Patients with more modest elevations in aminotransferase and/or serum gamma globulin if they are symptomatic and/or have significant interface hepatitis. 3. patients with histologic features of bridging necrosis or multiacinar necrosis. 4. The presence of interface hepatitis without bridging necrosis or multiacinar necrosis on histologic examination may warrant treatment but does not compel it. 5. Treatment is warranted in most children at the time of diagnosis. Treatment may Not be indicated in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances. Choice of initial therapy: We recommend that patients with autoimmune hepatitis who are eligible for treatment based upon the indications above receive treatment with immunosuppressive(Grade 1A). Corticosteroids are the mainstay of therapy However, steroid-sparing with azathioprine or 6-MP is used frequently. We suggest starting therapy with corticosteroids alone unless there are significant contraindications (Grade 2C). Because combination therapy can result in fewer corticosteroid side effects, azathioprine or 6-MP can be added if clinical and biochemical remission is not achieved in the initial 3 months of therapy. We suggest testing for TPMT activity before starting azathioprine or 6-MP (Grade 2C).

Treatment regimens for adults Prednisone only, mg/day Week 1 Week 2 Week 3 Week 4 Maintenance until end point Reasons for preference: 60 40 30 30 20 Cytopenia Thiopurine methyltransferase deficiency Pregnancy Malignancy Short course ( 6 months) Combination mg/day Prednisone, Azathioprine, 30 50 20 50 15 50 15 50 10 50 Postmenopausal state Osteoporosis Brittle diabetes Obesity Acne Emotional lability Hypertension

Treatment endpoints: As a general rule, we suggest treatment should be continued until remission, treatment failure, or the development of drug toxicity (Grade 2B). The optimal endpoint is to achieve sustained remission without the need for drug therapy, an endpoint achievable in 10 to 40 % of patients.

Achieving initial remission We suggest maintaining patients on a fixed daily dose of maintenance medications until remission is achieved which defined as(Grade 2C).: 1. resolution of symptoms 2. reduction in serum aminotransferase to normal levels, or at minimum to less than twice the upper limit of normal 3. normalization of serum bilirubin and gamma globulin levels 4. improvement in liver histology to normal or only mild portal hepatitis or minimal or no activity in patients with cirrhosis Earlier attempts at titrating the dose to clinical response may delay or impede histologic improvement. Daily therapy is recommended since alternate day and pulse steroid regimens have been disappointing. Remission is generally not observed before 12 months. Approximately 65 and 80 % of patients achieve remission by 18 months and 3 years, respectively. The probability of remission decreases after two years.

Liver transplantation: Patients who are refractory to or intolerant of immunosuppressive therapy and develop end stage liver disease require liver transplantation. Immunizations: We suggest vaccinations of patients with autoimmune hepatitis, including hepatitis A and B. Withdrawing Therapy After Remission : We suggest withdrawing corticosteroids gradually over a 6-week period in patients who achieve remission (Grade 2C). Patients should be monitored clinically and with serial laboratory tests. Multiple relapses may occur before achieving sustained remission. Thus, we suggest repeated attempts at drug withdrawal in patients who are otherwise stable (Grade 2C).

Maintenance therapy: Approximately 50 % of patients remain in remission or have only mild activity for months to years when initial treatment is withdrawn. However, most patients eventually require reinstitution of therapy for recurrent disease and long-term maintenance therapy with prednisone and/or azathioprine.

Partial suppression in frequent relapsers: We suggest "partial suppression" in patients who suffer multiple relapses (Grade 2C). Partial suppression can be achieved with low doses of prednisone, with or without azathioprine, rather than the administration of conventional doses of prednisone.

Monitoring While a survival benefit for screening for hepatocellular cancer has not been proven, we suggest that patients with cirrhosis undergo surveillance with a right upper quadrant ultrasound and alfa fetoprotein level every 6 to 12 months (Grade 2C). Patients in whom treatment is not initiated should be monitored carefully, including performance of repeat liver biopsies for evidence of disease progression. We generally re-biopsy such patients no longer than two years after diagnosis.

Medical management of Crohn's disease in adults

DEFINITIONS OF SEVERITY Mild to moderate Crohn's disease Ambulatory patients able to tolerate an oral diet without dehydration, toxicity, abdominal tenderness, mass, or obstruction Moderate to severe Crohn's disease Patients who have failed treatment for mild to moderate disease or patients with prominent symptoms such as fever, weight loss, abdominal pain and tenderness, intermittent nausea or vomiting, or anemia Severe-fulminant disease Patients with persisting symptoms despite treatment with steroids or patients presenting with high fever, persistent vomiting, intestinal obstruction, rebound tenderness, cachexia, or an abscess Remission Patients who are asymptomatic either spontaneously or after medical or surgical intervention. Patients requiring steroids to remain asymptomatic are not considered to be in remissio

GENERAL APPROACH We suggest an approach to therapy based upon the location of disease, its severity, and response to treatment. ORAL LESIONS Aphthous ulcerations are the most common oral manifestation of Crohn's disease. A wide variety of additional lesions have been described including granulomatous masses, cheilitis, and granulomatous sialadenitis. They usually occur with coexistent intestinal disease and respond to treatment directed at the intestinal disease. Topical therapy consisting of hydrocortisone in a carrier of pectin gelatin and carboxymethylcellulose or topical sucralfate may be effective for local symptom relief.

GASTRODUODENAL CROHN'S DISEASE Fewer than 5 % of patients with Crohn's disease have gastroduodenal disease most often in association with concurrent distal intestinal involvement. The distal antrum and varying areas of the duodenum are most commonly affected. The clinical presentation is often confused with that of peptic ulcer disease and symptoms may include epigastric pain, nausea, and postprandial vomiting. Treatment with a proton pump inhibitor, H2 receptor antagonist, or sucralfate may provide partial or complete relief of symptoms. The slow release form of mesalamine (Pentasa): may be of use in duodenal Crohn's disease. There are, however, no clinical trials to confirm its efficacy in this setting. Prednisone is necessary and usually effective for moderate to severe gastroduodenal disease. The response to therapy is usually seen within 2 weeks We usually suggest azathioprine or 6-mercaptopurine in patients who remain symptomatic despite a course of prednisone or who become steroid-dependent to remain in clinical remission.

ACTIVE ILEITIS the ileum is the most common region of the small bowel involved in Crohn's disease. Patients with active ileitis typically present with diarrhea , abdominal pain, weight loss, low-grade fever, and anemia, increased frequency of acquired lactase deficiency and symptomatic lactose intolerance .

Patients with suggestive symptoms should undergo a lactose breath hydrogen test to confirm the diagnosis. Calcium supplementation should be maintained in patients on a limited lactose intake to minimize the risk of bone loss. We usually begin therapy with oral 5-aminosalicylic acid (5-ASA) drugs, and may progress to treatment with antibiotics, corticosteroids, and immunosuppressive agents depending upon the response

5-ASA drugs o Optimal treatment of patients who are asymptomatic or minimally symptomatic . o In patients with mild symptoms, we usually begin treatment with a slow release oral 5-ASA agent (such as Pentasa or Asacol) o the clinical response is typically seen within 4 weeks. o Treatment is usually begun with either Pentasa or Asacol o Dose of mesalamine (Pentasa or Asacol Mesacol) : 2.4 g/day with an increase to a maximum of 4.8 g/day (Mesacol400 mg/tab 23 43 ) o In contrast, sulfasalazine is less useful for ileitis, with response rates in some studies ranging from 0 to 20 %. The diminished response probably reflects the need for colonic bacteria to cleave the drug to release the active 5-ASA moiety. Antibiotics o For patients do not respond to or do not tolerate 5-ASA before beginning corticosteroids. o We suggest use of metronidazole (10 or 20 mg/kg/day) Or the combination of metronidazole and ciprofloxacin 500 mg twice daily: for primary or adjunctive therapy of colonic Crohn's disease, Not for isolated small intestinal disease.

Corticosteroids o Prednisone : mainstay of treatment for : 1. patients with mild disease who are unresponsive to the above measures 2. patients presenting with more severe initial symptoms o Prednisone dose : 40 - 60 mg/day , a gradual tapering by 5 mg/week o 60 - 80 % of patients respond to this dose, usually within 10 to 14 days. o Controlled ileal release (CIR) budesonide: a corticosteroid with a high first-pass hepatic metabolism may be used as an alternative to prednisone. o CIR budesonide dose : 9 mg/day for 8 to 16 weeks and then discontinued over 2 to 4 weeks by tapering in 3 mg increments. Maintenance therapy o We suggest maintenance therapy with a 5-ASA drug once control of active ileitis has been achieved with a 5-ASA drug, antibiotics, or prednisone. o Mesalamine (Pentasa, Asacol) at a dose of 3 g/day should be considered as long-term therapy with the hope of preventing disease relapse (Mesacol400 mg/tab 2.53 ) o CIR budesonide 6 mg/day was found to be effective for prolongation of time to relapse and maintenance of remission at 6 months but not one year in patients with Crohn's disease in medically induced remission. o Budesonide 6 mg/day was more effective than placebo or mesalamine 3 g/day for maintenance of remission in patients with steroid-dependent Crohn's disease. Incomplete responders o Symptomatic treatment with antidiarrheal agents should be considered in patients not responding completely to first line therapy. o We suggest : o loperamide (Iduim ) o Cholestyramine : it is indicated for patients with nonstenosing ileitis who have chronic watery diarrhea and patients with previous ileal resections who have bile salt diarrhea. The initial dose is 4 g/day, which is increased as needed to 12 g/day in three divided doses. For patients intolerant of cholestyramine because of dyspepsia, colestipol, a similar binding resin, is often a suitable alternative. Localized peritonitis o present with fever, chills, and RLQ pain associated with leukocytosis. o Appendicitis in the patient without prior appendectomy is also a consideration in this setting. An abdominal and pelvic CT scan at the time of admission may help to distinguish among the diagnostic possibilities. o The management of localized peritonitis includes : o bowel rest o intravenous broad-spectrum antibiotics ( ciprofloxacin and metronidazole) for 7 to 10 days then 2-4week course of outpatient oral therapy o A response to therapy is usually seen within 3 to 4 days o Intestinal resection should be considered in nonresponders. o For patients already on steroids, a small increase in the dose may be required. o for patients not previously on steroids, we suggest withholding of steroids to avoid masking any further sepsis. Abscesses o medical management with antibiotics and possibly steroids, percutaneous drainage, and surgery with resection of involved intestinal segments.

Small bowel obstruction o Conservative therapy with intravenous hydration, nasogastric suction, and parenteral nutrition is often successful with a response seen within 24 to 48 hours. o Parenteral corticosteroids should be considered in nonresponders. o Surgery is reserved for those patients who do not respond to these noninvasive measures.

ILEOCOLITIS AND COLITIS present with abdominal pain, bloody or nonbloody diarrhea, fever, and weight loss. For the patient with mild to moderate symptoms, we initiate therapy with sulfasalazine or one of the mesalamine agents o Dose of sulfasalazine : 2 - 4g/day (Azopirin 500 mg/tab 22 24 ) o Dose of mesalamine (Pentasa or Asacol Mesacol) : 2.4 g/day with an increase to a maximum of 4.8 g/day (Mesacol400 mg/tab 23 43 ) Antibiotics We suggest antibiotics in the patient who does not tolerate these medications or does not improve within 3 to 4 weeks. Corticosteroids o If a response is not noted to these measures OR o If the patient's initial symptoms are more severe, we suggest prednisone at a dose of 40 to 60 mg/day with 5-ASA agents and antibiotics . combination of sulfasalazine and prednisone was better than either alone. Oral budesonide may also be an option for patients with active ileitis or right-sided Crohn's colitis, particularly in those with prior intolerance or contraindications to systemic corticosteroids. remission : Once achieved and the steroid tapered and stopped, long-term remission therapy with an oral 5ASA agent at a dose of 3 g/day should be considered. Hospitalization o for patients who present with severe symptoms or appear toxic. o Therapy should consist of bowel rest, parenteral nutrition, and parenteral corticosteroids.

REFRACTORY DISEASE patient who, regardless of disease location, remains symptomatic despite adequate doses of steroids (steroid-resistant), 5-ASA agents, and antibiotics or the patient who flares once the prednisone is decreased or stopped (steroid-dependent). Since surgery is accompanied by a high recurrence rate and many of these patients have already had resections with further surgery threatening short bowel syndrome, medical therapy becomes an important consideration. key points : o Azathioprine or 6-MP are associated with a higher overall response rate than placebo, a higher rate of fistula healing, and more frequent reduction in steroid use (in patients with severe Crohn's disease. However, onset of action is slow (>3 months). o Azathioprine and 6-MP are more effective than placebo in maintaining remission in patients who achieved remission with these drugs and in reducing steroid consumption in patients with severe Crohn's disease. o methotrexate for the maintenance of remission in Crohn's disease are less than for AZA or 6-MP. However, methotrexate is more effective than placebo in inducing remission in patients with severe Crohn's disease. o Cyclosporine has little or no role in the management of Crohn's disease except in patients with fistulizing disease, that is non-responsive to 6-MP, AZA, infliximab, and adalimumab.

Tacrolimus should be reserved for patients non-responsive to 6-MP, AZA, methotrexate, infliximab, and adalimumab. Azathioprine and 6-mercaptopurine o For most refractory patients o dose: 50 mg/day; maximum 2 mg/kg/day for 6-MP and 2.5 mg/kg/day for azathioprine o A response will usually be seen within 3 to 6 months. o During this period patients often require concomitant steroid therapy with a gradual reduction in the steroid dose after 1 -2 months of treatment with azathioprine or 6-MP. Methotrexate o Methotrexate is an alternative for the patient who does not tolerate or is unresponsive to azathioprine or 6-MP and may be used in preference to azathioprine or 6-MP in patients with troublesome Crohn's disease-related arthropathy. o Dose: 25 mg per week intramuscularly o response will be seen within 3 months. o For patients on steroid therapy, the drug should be continued during this period with a gradual lowering of the prednisone dose. o Once a response to intramuscular methotrexate is achieved, the patient can be switched to oral methotrexate with an attempt to lower the dose gradually over several months. o Concomitant therapy with folic acid 1 mg/day may diminish adverse effects to methotrexate. Anti-TNF therapies ( infliximab, adalimumab, and certolizumab pegol) Our general approach is to advance to anti-TNF-alpha therapy (including adalimumab or infliximab) in patients who have demonstrated failure or intolerance to a course of corticosteroids and immunosuppressive agents, who are steroid dependent despite immunosuppressants, or who have failed corticosteroids and are too sick to wait for the effects of methotrexate or azathioprine. Adalimumab and certolizumab pegol have an advantage of subcutaneous administration rather than intravenous administration required for infliximab. The former requires administration every two weeks and the latter every four weeks. However, certolizumab's labeling requires it to be reconstituted by a healthcare professional. Adalimumab has been associated with injection site reactions and pain at a higher frequency than certolizumab pegol Certolizumab will be priced 5 percent lower than adalimumab, but the relative prices will be expected to vary at local formularies. Infliximab and adalimumab have an advantage in a broader labeling indication; both are approved for reducing signs and symptoms of Crohn's disease and inducing and maintaining clinical remission while certolizumab pegol does not have an explicit maintenance indication. However, the remission rates in clinical trials have not revealed an important distinction from remission rates with the other two drugs. Experience with adalimumab for patients who have lost response to or had an adverse reaction to infliximab is greater than with certolizumab pegol, although preliminary data suggest that certolizumab can also be effective in such patients. The safety record with infliximab and adalimumab is longer than with certolizumab pegol. Infliximab has demonstrated efficacy in the treatment of fistulizing Crohn's disease while efficacy of adalimumab and certolizumab pegol has not yet been established in placebo-controlled trials. adalimumab have similar efficacy with perianal fistulas as infliximab. There are no data for certolizumab pegol. Neither infliximab nor adalimumab nor certolizumab pegol can be recommended as safe agents for the treatment of Crohn's disease in pregnancy, but in urgent situations, when no reasonable therapeutic

alternative to anti-TNF agents is available, infliximab may be the preferred drug because of a larger body of safety data. Infliximab : o We recommend infliximab for patients with moderate to severe Crohn's disease that is refractory to conventional treatment (Grade 1B). o We recommend retreatment of patients who respond to initial therapy every 4- 8 week interval at 5 mg/kg or 10 mg/kg, depending upon how quickly relapse of the Crohn's disease symptoms occurs (Grade 1B). o Infliximab should not be used as first line therapy until appropriate clinical trials have been performed. Its value as primary therapy and the long-term effects of infliximab have been able to be fully evaluated. Adalimumab : o In patients with moderate to severely active Crohn's disease despite concomitant immunosuppressive therapy, adalimumab induction therapy (160 mg at week zero and 80 mg at week two) is more effective than placebo at achieving clinical remission at four weeks. o In patients who achieved clinical remission, maintenance treatment with adalimumab (40 mg subcutaneously every two weeks) is more effective than placebo in maintaining remission for up to one year. However, between 30 and 50 percent may require escalation of the dose from every two weeks to weekly over the course of one year to sustain a remission or response. o We suggest switch to adalimumab when patients are intolerant or lose response to infliximab. o The efficacy of adalimumab in patients with fistulizing disease has not been well-established. However, subgroup analysis suggests a similar efficacy of adalimumab in perianal fistula as seen with infliximab. certolizumab o We suggest certolizumab pegol be used in patients with moderate to severe Crohn's disease who had an inadequate response to conventional therapy (Grade 2B), although other approaches may be equally effective. There are no clinical trials that have compared certolizumab pegol to other anti-TNF therapies. o Preliminary data suggest that certolizumab pegol can also be effective in patients who responded to infliximab and lost response or became intolerant to it. o In patients who respond, we suggest that certolizumab pegol be used for maintenance therapy (Grade 2B). o The recommended dosing for induction is 400 mg subcutaneously at weeks 0, 2 and 4 and then every four weeks for maintenance of response. o There are no clinical trials that have compared certolizumab pegol to other anti-TNF therapies. o efficacy and safety for long-term maintenance have not been established.

Continued disease resistance There are two medical approaches to patients who continue to have chronic active symptoms of their Crohn's disease despite therapy with 5-ASA agents, antibiotics, immunomodulators, infliximab, or adalimumab: chronic low-dose steroid therapy, and total parenteral nutrition. In addition, surgery should be considered if a limited resection or another conservative procedure is possible. PERINEAL DISEASE In those who present with draining fistulae and small abscesses not amenable to surgical drainage, we initiate therapy with metronidazole at a dose of 10 mg/kg per day. If the drug is tolerated but a response is not seen within 2 -4 weeks, the dose is increased to a maximum of 20 mg/kg per day. One problem with this approach is a high relapse rate following cessation of metronidazole therapy so that Long-term therapy (at least 12 months) at the lowest effective dose may be necessary in such patients. Ciprofloxacin (500 mg BID) can be tried in patients who fail metronidazole or be used as an alternative initial therapy.

surgical management or treatment with azathioprine or 6-MP should be considered for patients who are resistant to the above therapies .

FISTULAE Infliximab should be considered for all Crohn's patients with active draining fistulas. Infliximab 5 mg/kg administered at weeks 0, 2, and 6 and azathioprine 2-2.5 mg/kg or 6-MP 1 to 1.5 mg/kg are the drugs with the best established roles for the medical treatment of active Crohn's fistulous disease. Before initiating infliximab and azathioprine or 6-MP therapy for perianal fistulous disease, it is important to establish a thorough understanding of the anatomic site of the fistula tract(s), to exclude of abscesses, and to evaluate for the presence of inflammation of the rectal mucosa. This may entail endoscopy, and frequently, a combination of magnetic resonance imaging of the pelvis, endorectal ultrasound, and/or examination under anesthesia with appropriate surgical and radiological treatment of abscess cavities and fistula tracts. Azathioprine or 6-MP should be considered in patients with enteroenteric fistulae associated with high output diarrhea and other fistulae. In comparison, steroids and sulfasalazine have not been successful for inducing fistula closure . Enterovesical fistulae present with recurrent urinary tract infections with multiple organisms, pneumaturia, and fecaluria. Antibiotics will usually control the urinary tract infection but azathioprine or 6-MP should be considered to heal the fistula. Most patients with this complication will ultimately come to surgery. However, many can be maintained on courses of antibiotics and continuous immunomodulator therapy without fear of developing irreversible renal complications .

Medical management of ulcerative colitis in adults

The initial therapeutic approach depends upon both the extent of colonic involvement and the severity of the disease process at presentation Medical therapy of active ulcerative colitis according to disease severity Disease severity Medication Mild-to-moderate disease Sulfasalazine Mesalamine Delayed release EC tablet: - Asacol* - Lialda* Extended release capsule: - Apriso* Controlled release capsule: - Pentasa* Olsalazine Balsalazide Mesalamine suppository Hydrocortisone foam 10% (rectal) Daily dose 1 - 1.5 g PO four times daily

800 - 1600 mg PO three times daily 2.4 or 4.8 g PO once daily (2.4 g initially; 4.8 g if no complete response) 1.5 g orally (four Apriso* capsules) in the morning once daily 500 - 1000 mg PO four times daily 1 - 1.5 g PO twice daily 2.25 g PO three times daily 1000 mg at night 90 mg (one applicatorful) at night or twice daily 4 g at night 100 mg at night

Mesalamine enema Hydrocortisone enema Sulfasalazine/oral 5-ASA plus 5-ASA enemas/steroid enema Prednisone 40 - 60 mg PO once daily Severe active disease On steroids recently Methylprednisolone Hydrocortisone

Cyclosporine Infliximab Toxic megacolon Intravenous corticosteroids Broad-spectrum antibiotics Chronic active disease Mercaptopurine (steroid refractory) Azathioprine Infliximab PROCTITIS AND PROCTOSIGMOIDITIS

48 - 60 mg IV once daily 100 mg IV every 6 hours or as continuous infusion See topic review for dosing See topic on "Anti-TNF therapy " See topic on "Toxic megacolon" See topic on "Azathioprine and 6mercaptopurine See topic on "Anti-TNF therapy "

present with bleeding, mucus, tenesmus, mild diarrhea or constipation. Rectal pain . Treatment: o In patients with mildly or moderately active proctitis, we recommend topical, rectal 5-ASA or steroid suppositories for patients with mildly active proctitis (Grade 1B). o In patients with mildly or moderately active ulcerative proctosigmoiditis, we recommend topical, rectal 5-ASA, or steroid enemas or hydrocortisone foam in combination with 5-ASA or steroid suppositories (Grade 1B).

o mesalamine suppository : 1g once at bedtime continued until the patient is in remission. o Steroid foams : nightly or twice daily with gradual tapering once remission is achieved o In patients who cannot tolerate or who will not take rectal, topical therapy, we recommend oral 5-ASA medications at a high dose (Grade 1B). o Maintenance therapy is not recommended in patients with a first episode of proctitis that has responded promptly to treatment. o Maintenance therapy in Proctitis : Mesalamine suppository 1000 mg every night to every third night o Maintenance therapy in proctosigmoiditis : Mesalamine enema 4 g every night to every third night o oral prednisone (40 - 60 mg/day) are rarely required in patients with ulcerative proctitis and should be considered in two settings: those with more severe symptoms and those who fail to respond to oral 5ASA and topical therapy.

LEFT-SIDED COLITIS manifested by bloody diarrhea , mild cramping, fever, weight loss, and anorexia. Treatment : o In patients with mild or moderately active left-sided colitis, we recommend combination therapy with oral 5-ASA medications with topical, rectal 5-ASA or steroid suppositories plus 5-ASA or steroid enemas or hydrocortisone foam (Grade 1B) o As with suppository or foam therapy, the 5-ASA drug is preferred because of its proven efficacy in maintaining remission [2,3] o Therapy can be initiated with a nightly 4 g 5-ASA enema with a response usually seen within four to six weeks. If the patient does not respond within this time, an additional morning 5-ASA or hydrocortisone enema (Cortenema) should be considered. As with the treatment of proctitis, once a response is

obtained, the frequency of treatment can be tapered to an every third night regimen for maintenance purposes o For patients who do not respond to or tolerate topical therapy, oral 5-ASA preparations are an effective alternative. The combination of an oral 5-ASA drug with 5-ASA enemas may be more effective than either alone. o A common error in the management of such patients is accepting a therapeutic failure when sulfasalazine or 5-ASA have not been pushed to a maximum tolerated dosage. o For active disease, sulfasalazine can be gradually increased to a maximum of 4 to 6 g/day , mesalamine to 4.8 g/day, and olsalazine to 3 g/day. These agents are usually given three times daily or four times daily in divided doses. At these doses, the latter two agents are often better tolerated than high-dose sulfasalazine.

o These agents often require 3 to 6 weeks to exert their maximal benefit. Once remission is achieved, the drug dose can be tapered to maintenance levels of sulfasalazine (2 g/day), mesalamine (1.2 to 2.4 g/day), or olsalazine (1 g/day) o Patients whose disease exacerbates on maintenance levels will often require higher doses to prevent recurrence. With sulfasalazine, for example, a daily dose of 4 g is more likely than 2 g to maintain remission. Folic acid supplementation (1 mg/day) is recommended for patients on long-term sulfasalazine since it can inhibit the absorption of dietary forms of folate. o Prednisone should be considered for patients who have a more severe clinical presentation or who do not respond to the above regimen. The starting dose of prednisone is usually 40 to 60 mg/day, depending upon the weight of the patient and the severity of symptoms. This dose is usually effective within 10 to 14 days, after which the dose can be tapered gradually, usually by 5 mg per week. There is no evidence that chronic steroid therapy is effective at maintaining remission; as a result, the goal is to taper and stop the prednisone with the initiation of maintenance therapy

EXTENSIVE COLITIS AND PANCOLITIS o present with symptoms of rectal involvement (ie, urgency and tenesmus) that may predominate the clinical picture, justifying the concomitant use of topical therapy. o Therapy in patients with pancolitis varies according to the severity of symptoms. Initial therapy in those with mild to moderate symptoms includes the combination of oral 5-ASA or sulfasalazine and topical therapy with either 5-ASA or steroid enemas. o The addition of oral prednisone (40 to 60 mg/day) should be considered in two settings: those with more severe symptoms and those who fail to respond to oral 5-ASA and topical therapy.Once a patient has achieved remission, we generally taper the steroids (typically 5 mg every 7 to 10 days unless side effects require a more rapid taper). o long-term maintenance therapy should be considered with a standard maintenance dose of an oral 5ASA agent. At times, the addition of maintenance topical 5-ASA may further decrease the risk of disease exacerbation. o Supplemental iron may be necessary to prevent or treat iron deficiency anemia due to chronic blood loss o Antidiarrheal agents should not be used in the acutely ill patient because of the risk of precipitating toxic megacolon. These drugs are particularly beneficial in patients with persistent diarrhea without systemic symptoms despite therapy directed at the colitis. Loperamide is the preferred drug because of its safety and efficacy SEVERE OR FULMINANT COLITIS o severe ulcerative colitis : frequent bloody stools (up to 10 to 15 per day) associated with weight loss, volume depletion, fever, and often marked anemia. o Fulminant colitis : acute, severe toxic symptoms including fever, anorexia, and abdominal pain in addition to bloody diarrhea. Such patients are at risk of progressing to toxic megacolon and bowel perforation, and require immediate hospitalization. o Treatment : bowel rest, nutrition, and parenteral steroids. o pical starting regimens include hydrocortisone (100 mg IV q8h), prednisolone (30 mg IV q12h), and methylprednisolone (16 to 20 IV q8h). The last two are preferred because they produce less sodiumretention and potassium-wasting. o Antibiotics should be considered before such patients are considered refractory to medical therapy. We typically use a regimen of intravenous ciprofloxacin and metronidazole in this setting.

o In contrast, broad-spectrum antibiotics should be given to all patients who present with fulminant disease with high fever, leukocytosis with extreme numbers of immature neutrophils (bandemia), and peritoneal signs or megacolon. Flat plate supine abdominal films should be obtained at the time of admission. o Patients with intestinal dilation should receive decompression with a nasogastric tube and may benefit from insertion of a rectal tube. Such patients should roll supine to prone every two hours to help redistribute the gas

o Indications for colectomy Patients with toxic megacolon (ie, those with colonic dilation of 6 cm or greater who appear toxic) who do not respond to therapy within 72 hours should be considered candidates for colectomy. Surgical consultation should be obtained early on such patients. Less severely ill patients usually respond to parenteral corticosteroids within 7 to 10 days. o Indications for or cyclosporine : Cyclosporine may be particularly suitable in steroid-resistant patients with new onset ulcerative colitis presenting as severe or fulminant disease, especially those who are not psychologically prepared for colectomy. o Cyclosporine can be given as a continuous infusion to a patient with severe colitis that is steroidresistant after 7 to 10 days of therapy. o cyclosporine at a dose of 4 mg/kg per 24 hours with the goal of achieving a stable trough level of 300 to 400 nanograms/mL during the acute phase [44] . However, a lower dose of cyclosporine (2 mg/kg adjusted to a stable trough level of 150 to 250 nanograms/mL) appears to have similar efficacy and may have less toxicity o For responding patients who have not previously been on AZA or 6-MP, oral cyclosporine (8 mg/kg per day) should be continued for three to four months while 6-MP or azathioprine is introduced (usually started at discharge). o Infliximab : we suggest that infliximab can be considered in patients with acute steroid-refractory disease who are reluctant to undergo colectomy and in whom cyclosporine is contraindicated (Grade 2B). REFRACTORY ULCERATIVE COLITIS

o some patients remain symptomatic despite optimal doses of oral 5-ASA drugs, topical therapy with either 5-ASA or steroids, and systemic corticosteroids. additional medical therapy should be considered : Cyclosporine or Infliximab . o Immunomodulator therapy For patients whose ulcerative colitis remains refractory despite intensive therapy as described above, immunomodulator therapy with either azathioprine or 6mercaptopurine (6-MP), should be considered prior to referral for surgery. o Mercaptopurine :50 mg up to 1.5 mg/kg PO/day o Azathioprine :50 mg up to 2.5 mg/kg PO/day o Because surgery in ulcerative colitis is curative and, in many patients, However, patients who do not desire surgery or those with more limited disease but with persistent or debilitating symptoms are particularly good candidates for long-term therapy with these drugs. Sulfasalazine , 5-ASA dosages (g/day) for active disease and remission maintenance in IBD Ulcerative colitis Crohn's colitis Active Maint Active Maint Sulfasalazine 2-4 2-4 2-4 NR Asacol 2.4 - 4.8 2.4 - 4.8 2.4 - 4.8 2.4 - 4.8 Pentasa 4 3-4 4 3-4 Dipentum 2-3 1 2-3 1 Rowasa (enema) 4 2-4 4 ID Maint: maintenance; ID: insufficient data; NR: Maintenance medical therapy in ulcerative colitis Disease type Proctitis Distal colitis Left-sided colitis pancolitis Medication Mesalamine suppository Crohn's ileitis Active Maint NR 2-4 2.4 - 4.8 2.4 - 4.8 4 3-4 NR NR NR NR not recommended.

Mesalamine enema and Sulfasalazine Mesalamine EC tablet (Asacol*) Olsalazine Sulfasalazine/oral 5-ASA plus 5-ASA enema Steroid-dependent colitis Mercaptopurine 50 mg up to 1.5 mg/kg PO/day Azathioprine 50 mg up to 2.5 mg/kg PO/day Methotrexate 10 to 15 mg PO once per week Indications For Surgery In Inflammatory Bowel Disease

Dose 1000 mg every night to every third night 4 g every night to every third night 500 mg PO four times daily 400 to 800 mg PO three times daily 500 mg PO twice daily

Advances in medical therapy (including use of infliximab) have reduced the need for emergency surgery due to catastrophic complications such as massive hemorrhage, perforation, fulminant colitis, and acute colonic obstruction . most common indication for elective surgery is disease activity that has been intractable to medical therapy. We recommend that surgery should be considered for the following indications: 1. Persistent symptoms despite high-dose corticosteroid therapy 2. Dependence upon steroids to maintain remission 3. Progression of disease with worsening of the symptoms or new onset of complications while on maximal medical therapy 4. Significant treatment-related complications such as severe steroid side effects 5. Detection of unequivocal dysplasia in patients with long-standing colitis during endoscopic surveillance 6. Suspicion of a malignant stricture or fistula in patients with Crohn's disease 7. massive hemorrhage, colonic perforation, unresolving toxic megacolon, and dysplasia or carcinoma.

Colorectal cancer surveillance in inflammatory bowel disease There is consensus that patients with UC should undergo surveillance colonoscopy, although the interval in which this should be done and the optimal number and location that biopsies should be obtained are uncertain. Furthermore, a reduction in mortality due to surveillance has not been clearly established. Patients with Crohn's colitis probably have the same risk of colorectal cancer as those with UC, and should also undergo surveillance. In patients with ulcerative colitis extending proximal to the splenic flexure or Crohn's colitis, we suggest initiating surveillance colonoscopy after eight years of disease followed by annual examinations (Grade 2B). Those with Crohn's colitis may require use of a thin caliber colonoscope to adequately sample the colon including strictured areas [31] . We offer surgical resection to patients with Crohn's colitis who have an impassable stricture since they cannot be surveyed adequately; we suggest a barium enema in those who decline resection. In patients with left-sided UC, we suggest beginning with colonoscopy after 12 years of disease; examinations are then performed every year thereafter (Grade 2C). n patients who have undergone a subtotal colectomy with an ileostomy and have rectum left in place and tied off (ie, a Hartmann's pouch), we suggest surveillance of the remaining rectum every year (Grade 2B). We suggest not performing surveillance for patients with ulcerative colitis limited to the rectum (Grade 2B). In patients with a pouch, we suggest flexible sigmoidoscopy every other year; however, if they have evidence of severe atrophy we increase the surveillance interval to yearly (Grade 2C). Multiple biopsies are required to adequately sample the colon. We recommend colectomy for patients who are found to have high-grade dysplasia (Grade 1B). Although opinions continue to vary, we also suggest colectomy for those with low-grade dysplasia (Grade 2B). We suggest (Grade 2B) that rather than performing a colectomy, an adenomatous polyp can be removed endoscopically with close follow-up for polyps

Antibody for diagnosis IBD and distinguishing Crohn's disease from ulcerative colitis: 1. antineutrophil cytoplasmic antibodies (pANCA) : UC 2. anti-Saccharomyces cerevisiae antibodies (ASCA) : CD Antibody Sensitivity % Specificity % PPV % ASCA +/CD + 60 86 92 pANCA +/UC + 50 94 76 ASCA +/pANCA -/CD + 56 92 95 pANCA +/ASCA -/UC + 44 98 88 Where CD + or UC +, the control group for comparison is the other type of IBD.

Toxic megacolon
Causes : 1. Inflammatory : Ulcerative colitis , Crohn's colitis 2. Infectious a. Bacterial : Clostridium difficile pseudomembranous colitis , Salmonella - typhoid and non-typhoid , Shigella , Campylobacter ,Yersinia b. Parasitic : Entameba histolytica , Cryptosporidium c. Viral : CMV colitis d. Self-limited colitis (culture negative) 3. Pseudomembranous colitis secondary to methotrexate therapy 4. Kaposi's sarcoma CLINICAL MANIFESTATIONS : Signs and symptoms of acute colitis that are frequently resistant to therapy are often present for at least one week prior to the onset of acute dilatation. Severe bloody diarrhea is the most common presenting symptom, while improvement of diarrhea may herald the onset of megacolon. Physical examination invariably reveals a toxic appearing patient with altered sensorium, tachycardia, fever, postural hypotension, lower abdominal distension and tenderness, with or without signs of localized or generalized peritonitis.

DIAGNOSIS The diagnosis should be considered in all patients presenting with abdominal distension and acute or chronic diarrhea. The diagnosis is clinical, based upon the finding of an enlarged dilated colon accompanied by severe systemic toxicity. A thorough history is crucial. Knowledge of prior attacks of IBD, the extent and type of disease, details of prior therapy, extraintestinal manifestations of IBD, recent travel, occupational exposure (eg, day care workers), antibiotic or chemotherapy use, use of antimotility agents, and HIV/AIDS status are very helpful. Plain abdominal films should be obtained immediately. In addition, stool specimens should be sent for culture, microscopic analysis, and C. difficile toxin. The most widely used criteria for the clinical diagnosis of toxic megacolon are: o Radiographic evidence of colonic distension ( transverse or right colon is > 6 cm ) o PLUS at least three of the following: 1. Fever >38C 2. Heart rate >120 beats/min 3. Neutrophilic leukocytosis >10,500/microL 4. Anemia o PLUS at least one of the following: 1. Dehydration 2. Altered sensorium 3. Electrolyte disturbances 4. Hypotension Endoscopy :A full colonoscopy is extremely risky in patients with toxic megacolon; this procedure can easily lead to colonic perforation and we feel that it should generally be avoided.

Laboratory studies Anemia related to blood loss and leukocytosis with a left shift occur frequently, except in patients with AIDS in whom neutropenia may supervene. Electrolyte disturbances Hypoalbuminemia may not be a prominent feature in the early stages of illness, but a serum albumin concentration below 3 g/dL develops eventually in approximately 75 percent of cases due to protein loss and decreased hepatic synthesis due to chronic inflammation and malnutrition. The erythrocyte sedimentation rate and serum C-reactive protein are usually increased.

TREATMENT The initial therapy is medical, which is successful in preventing surgery in up to 50 % of patients. However, a surgical consultation should be obtained upon admission, and the patient should be evaluated daily by both the medical and surgical team. Medical therapy in patients with IBD complete bowel rest and a nasogastric tube (or long intestinal tube) is inserted to decompress the gastrointestinal tract. Enteral feeding is begun as soon as the patient shows signs of improvement to hasten mucosal healing and stimulate normal motility. The patient should be monitored in the intensive care unit with frequent examinations by the nursing and medical staff to assess for signs of deterioration. Complete blood counts, electrolytes, and serial abdominal plain films are reviewed every 12 hours initially, and then daily as the patient improves. Anemia, dehydration, and electrolyte deficits, particularly hypokalemia, may aggravate colonic dysmotility and should be treated aggressively. Total parenteral nutrition (TPN) is of limited value in IBD. It offers no proven benefit in terms of avoiding surgery or decreasing hospital stay in patients with acute colitis due to ulcerative colitis. All antimotility agents, opiates, and anticholinergics should be discontinued. Patients should be given prophylaxis for both gastric stress ulcerations and deep venous thrombosis (pneumatic compression stockings). Broad spectrum antibiotics are recommended to reduce septic complications and in anticipation of peritonitis resulting from perforation. We generally use ampicillin-gentamicin-metronidazole or a thirdgeneration cephalosporin with metronidazole. Intravenous corticosteroids (hydrocortisone 100 mg or equivalent every 6 to 8 hours or by continuous infusion) should be given to all patients for the treatment of underlying ulcerative colitis or Crohn's disease; this does not increase the risk of perforation. Some clinicians prefer to use methylprednisolone because of its lower sodium retaining and potassium wasting properties, while others prefer prednisolone since the parenteral dose is equal to the oral dose. o Steroids are not used in toxic megacolon due to C. difficile colitis or infective colitis if the etiology has been established. o Some authorities recommend adrenocorticotropic hormone (ACTH) in patients who have not received steroids for at least 30 days; there is some evidence that it may be more beneficial than intravenous corticosteroids in the treatment of underlying ulcerative colitis. Although initially popular, ACTH is now infrequently used. Sulfasalazine and 5-ASA compounds have no role in patients with toxic megacolon due to IBD and should be initiated only after the attack begins to resolve. In some instances, a flare may actually coincide with the

initiation of certain 5-ASA compounds. Cyclosporine is useful in the treatment of severe colitis refractory to steroid therapy, but the experience in toxic megacolon is limited. Some authors recommend intermittent rolling maneuvers or the knee-elbow position to help redistribute gas in the colon and thereby promote decompression. These techniques are based upon the observation that when a patient is rolled from the supine to prone position or adopts a knee-elbow position, gas rises to the distal colon/rectum and is more easily expelled. This technique may be particularly useful in patients in whom the "toxicity" is controlled but colonic dilatation persists. Medical therapy is successful when the patient appears to be less toxic, fluid and transfusion requirements decrease, abdominal and colonic dilatation begin to resolve, and laboratory parameters improve. On the other hand, persistent fever after 48 to 72 hours of steroid therapy should raise the possibility of localized perforation or abscess. Free perforation, massive hemorrhage, increasing transfusion requirements, worsening signs of toxicity, and progression of colonic dilatation are absolute indications for surgery. In addition, most surgical studies recommend colectomy if there is persistent colonic distention after 48 to 72 hours. However, we recommend prolongation of medical therapy up to seven days if the patient appears to be clinically improving despite persistent megacolon and there is no perforation .

Medical therapy in patients with other disorders In addition to the general maneuvers for intensive care unit monitoring cited above (including a nasogastric tube for decompression), medical therapy in patients with toxic megacolon due to diseases other than IBD may include the following:

In patients with toxic megacolon due to severe C. difficile colitis: the first step is to stop the offending antibiotic, followed by vancomycin via a nasogastric tube with or without intravenous metronidazole. Oral vancomycin should be started at a dose of 125 mg four times daily; the dose is increased up to 500 mg four times daily if there is no response. Severely ill patients who do not respond to oral vancomycin alone may benefit from the addition of intravenous metronidazole at a dose of 500 mg every eight hours. Fecal concentrations in the therapeutic range are achieved with this regimen because of biliary excretion of the drug [28] . In contrast, intravenous vancomycin has no effect on C. difficile colitis since the antibiotic is not excreted into the colon. Colectomy is reserved for patients who do not improve within 48 to 72 hours, or who show evidence of localized perforation Patients with azotemia, lactic acidosis, or white blood cell counts above 20,000/cu ml are more likely to require emergency colectomy for fulminant C. difficile infection.

In patients with HIV infection who develop toxic megacolon an aggressive search for treatable infectious and noninfectious causes is warranted, including early limited endoscopy and imaging studies. Patients with CMV colitis or C. difficile infection respond poorly to medical therapy and often require emergent laparotomy with subtotal colectomy and ileostomy . Critically ill patients who would not be able to withstand surgery, as well as patients with terminal AIDS, could be managed by careful colonic decompression, antibiotics, and supportive therapy.

Fulminant colitis during pregnancy with or without toxic megacolon: difficult because the gravid uterus impairs a proper abdominal examination, and diagnostic radiation poses hazards to the fetus.

In addition, laboratory tests such as hemoglobin and serum albumin concentrations fall during pregnancy, while the erythrocyte sedimentation rate and serum C-reactive protein levels rise; thus, these tests are not reliable measures of disease activity. High dose intravenous steroid therapy (the equivalent of 60 to 120 mg/day of prednisone) results in resolution of 75 % of cases of fulminant colitis; the remainder requiring urgent colectomy.

Surgery Subtotal colectomy with end-ileostomy is the procedure of choice for urgent or emergent surgery; this technique has a lower morbidity and mortality than single stage proctocolectomy. Early surgery in patients without evidence of perforation results in much lower mortality than colectomy performed after colonic perforation has occurred (2 to 8 versus 40 percent or more)

Treatment Of Hepatic Encephalopathy

Hepatic encephalopathy (HE) describes the spectrum of potentially reversible neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of unrelated neurologic and/or metabolic abnormalities.

Clinical manifestations : o Disturbance in the diurnal sleep pattern (insomnia and hypersomnia) is also common, and typically precedes overt neurologic signs. o More advanced neurologic features include the presence of asterixis (flapping motions of outstretched, dorsiflexed hands), hyperactive deep tendon reflexes, and less commonly, transient decerebrate posturing. Laboratory tests : o evidence of hepatic biochemical and synthetic dysfunction o electrolyte disturbances (such as hyponatremia and hypokalemia) that occur as a result of portal hypertension and use of diuretics. o Ammonia is the best characterized neurotoxin that precipitates HE. However, routine determination of venous or arterial ammonia concentrations are not required to establish the diagnosis. o All other routine laboratory tests are only useful to exclude other causes of brain dysfunction (eg, hypoglycemia, uremia, electrolyte disturbances, and intoxication). Diagnosis : o The diagnosis is usually established based upon the clinical and laboratory features discussed above, and the exclusion of other causes of mental status changes. o A CT scan of the brain should be performed in patients with overt HE if clinical findings suggest that another cause may be implicated (such as a subdural hematoma from trauma) and to detect the presence of generalized or localized cerebral edema. o MRI is superior to CT for the diagnosis of brain edema in liver failure, but is not an established method for diagnosis of HE. Typical changes have been observed on T1 weighted pictures with a strong signal in the basal ganglia in patients with HE, possibly due to manganese accumulation . However, these changes are neither sensitive nor specific indicators of HE o Once the diagnosis has been made, it is useful to grade the severity of HE. The simplest assessment is a grading of the mental status based upon clinical findings. The most commonly used system grades HE into stages I to IV

Acute therapy The initial management of overt hepatic encephalopathy type C (ie, caused by cirrhosis and portal hypertension /or systemic shunts) involves two steps: 1. Measures to lower the blood ammonia concentration 2. Identification and correction of precipitating causes : Drugs : Benzodiazepines , Narcotics ,Alcohol Increased ammonia production, absorption or entry into the brain

Excess dietary intake of protein Gastrointestinal bleeding Infection Electrolyte disturbances such as hypokalemia Constipation Metabolic alkalosis Dehydration : Vomiting , Diarrhea ,Hemorrhage ,Diuretics , Large volume paracentesis Portosystemic shunting Vascular occlusion :Portal vein thrombosis , Hepatic vein thrombosis Primary hepatocellular carcinoma

Correction of precipitating causes The first step is the identification and correction of precipitating causes. Careful evaluation should be performed to determine the presence of any of the following: 1. Hypovolemia 2. Gastrointestinal bleeding 3. Hypokalemia and/or metabolic alkalosis 4. Hypoxia 5. Sedatives or tranquilizers 6. Hypoglycemia 7. Infection (including SBP) 8. Vascular occlusion (hepatic vein or portal vein thrombosis) Approximately 70 to 80 % of patients with hepatic encephalopathy improve after correction of precipitating factors

Lower blood ammonia The second step is initiation of measures to lower the blood ammonia concentrations (whether or not the values are frankly elevated). Correction of hypokalemia is also an essential component of therapy since hypokalemia increases renal ammonia production. We do not recommend dietary protein restriction in patients with acute hepatic encephalopathy.

Our approach to drug therapy is as follows: o We suggest initiating drug therapy with lactulose or lactitol (Grade 2C). o Lactulose bottle (66.67 g / 100 ml ) = every 15 ml = 10 gr = spoon o Lactulose Dose (45- 90 g/day) should be titrated to achieve 2-3 soft stools per day 20-30 g (30-45 mL) every 1-2 hours to induce rapid laxation then reduce 60-100 g (90-150 mL) daily = 23 to 33 o Lactulose enemas can be given if the patient cannot take lactulose orally. 200 g (300 mL= 3 bottle) diluted with 700 mL of H2O or NS; administer rectally via rectal balloon catheter and retain 30-60 minutes every 4-6 hours. o An acceptable alternative is infusion of ornithine-aspartate o 20 g infusion per day given over four hours. o For those who have not improved within 48 hours, we suggest second-line therapy with non-absorbed antibiotics (Grade 2C).

o As a general rule, antibiotics are added to rather than substituted for lactulose. Whether a combination of lactulose with antibiotics provides a benefit for the patient is unknown. o Neomycin : 500 mg orally three times a day or 1 gram twice daily has been used as a second-line therapy in patients who have not responded to disaccharides, but we are concerned about its lack of efficacy in a placebo-controlled trial and its theoretical potential for ototoxicity and nephrotoxicity. o An alternative is rifaximin :400 mg orally three times daily. o Metronidazole: 250 mg orally three times daily, has also shown benefit. o A further alternative is sodium benzoate (5 g twice daily). Chronic therapy In patients with recurrent type C encephalopathy, we suggest continuous administration of lactulose (Grade 2B). Protein restriction is not needed unless encephalopathy is resistant to lactulose. In patients whose symptoms worsen with protein intake, substitution of proteins from fish, milk, or meat with vegetable proteins may improve nitrogen balance. Another alternative for patients intolerant to protein is the addition of branched-chain amino acids to a low protein diet. BCAA supplementation is indicated only in severely protein-intolerant patients.

Minimal hepatic encephalopathy Patients with minimal hepatic encephalopathy may benefit from treatment with lactulose.

Treatment Of Spontaneous Bacterial Peritonitis

The diagnosis is established by a positive ascitic fluid bacterial culture and an elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count 250 cells/mm3. Most cases of SBP are due to gut bacteria, such as Escherichia coli and Klebsiella; however, streptococcal and, infrequently, staphylococcal infections can also occur In patients with fever, abdominal pain or tenderness, or altered mental status, treatment can be started as soon as ascitic fluid, blood, and urine have been obtained for culture and analysis. In patients without these findings, it is reasonable to wait until the results of the PMN count are available. The main indication for empiric therapy : is the otherwise unexplained presence of one or more of the following findings that are characteristically seen in SBP : o Temperature greater than 37.8C o Abdominal pain and/or tenderness o A change in mental status o Ascitic fluid PMN count 250 cells/mm3 we recommend relatively broad-spectrum therapy in patients with suspected ascitic fluid infection until the results of susceptibility testing are available (Grade 1A). o IV third-generation cephalosporin, preferably cefotaxime 2 g every 8 hours. o Oral ofloxacin (400 mg twice per day) can be considered a substitute for cefotaxime Patients with ascitic fluid PMN counts <250 cells/mm3 and signs or symptoms of infection (temperature >37.8C or abdominal pain or tenderness) should also receive empiric antibiotic therapy while awaiting results of cultures. Duration of therapy : We treat for 5 days and then reassess the patient. o Treatment is discontinued if there has been the usual dramatic response. o If fever or pain persists, paracentesis is repeated and the decision to continue or discontinue treatment is determined by the PMN response. If the PMN count is <250 cells/mm3, treatment is stopped. If the PMN count is > the pretreatment value, a search for a surgical source of infection is undertaken. If the PMN count is elevated but < the pretreatment value, antibiotics are continued for another 48 hours and paracentesis is repeated. We also generally repeat a paracentesis after 48 hours of treatment if there is clinical suspicion of secondary peritonitis. We suggest giving intravenous albumin as part of the treatment of SBP who also have a serum creatinine >1 mg/dL, urea >60 mg/dL, or total bilirubin >4 mg/dL o Dose : 1.5 g albumin/kg within 6 hours of detection and 1.0 g/kg on day 3.

Prophylaxis Of Spontaneous Bacterial Peritonitis

long-term prophylaxis Regmine : Norfloxacin (Uriflox) :400 mg/day, or Bactrim Fort : one tablet once daily. Indication : o patients who have had one or more episodes of SBP (Grade 2B). o In patients with cirrhosis and ascites but no gastrointestinal bleeding, if the ascitic fluid protein <1.5 g/dL and at least one of the following is present: (Grade 1B). serum creatinine 1.2 mg/dL urea 50 mg/dL serum sodium 130 mEq/L Child-Pugh 9 points with bilirubin 3 mg/dL. In patients with cirrhosis who are hospitalized for gastrointestinal bleeding, we recommend initial intravenous ceftriaxone 1 g daily (Grade 1A). We transition patients to 400 mg of norfloxacin orally twice daily or Bactrim (one double-strength tablet twice daily) for 7 days of total antibiotic use once bleeding has been controlled, and patients have been stabilized and able to tolerate oral intake. In patients with cirrhosis hospitalized for other reasons who have an ascitic fluid protein concentration <1 g/dL, we use norfloxacin (400 mg/day) or Bactrim with discontinuation of the drug at the time of discharge Intermittent dosing of antibiotics to prevent bacterial infections may be inferior to daily dosing (due to the development of bacterial resistance) and thus daily dosing should preferentially be used.

Management Of Chronic Hepatitis B

HEPATITIS B VIRUS a double-stranded DNA virus , classified into 8 genotypes (A to H) . genotypes may correlate with clinical course and response to interferon. Genotype testing is not necessary in routine clinical practice, but it may be indicated for HBeAg-positive patients who are considering interferon therapy since patients with genotype A have a more favorable response. WHO SHOULD BE TESTED 1. Individuals born in areas of high(8%) or intermediate prevalence rates (2-7%) 2. Household and sexual contacts of HBsAg-positive persons 3. Persons who have ever injected drugs 4. Persons with multiple sexual partners or history of sexually transmitted disease 5. Men who have sex with men 6. Inmates of correctional facilities 7. Individuals with chronically elevated ALT or AST 8. Individuals infected with HCV or HIV 9. Patients undergoing renal dialysis 10. All pregnant women 11. Persons needing immunosuppressive therapy Evaluation of patients with chronic HBV infection Initial evaluation 1. History and physical examination 2. Family History of liver disease, HCC 3. Laboratory tests to assess liver disease - CBC with platelets, hepatic panel (AST, ALT, total bilirubin, alkaline phosphatase, albumin) , and PT 4. Tests for HBV replication - HBeAg/anti-HBe, HBV DNA 5. Testing for immunity to hepatitis A virus (HAV) with HAV IgG antibody should be considered in patients who are not known to be immune. 6. Tests to rule out viral coinfections - anti-HCV, anti-HDV (in persons from countries where HDV infection is common and in those with history of injection drug use), and anti-HIV in those at risk 7. Tests to screen for HCC - AFP at baseline and, in high risk patients, ultrasound 8. Consider liver biopsy to grade and stage liver disease - for patients who meet criteria for chronic hepatitis : ie, HBsAg positive for >6 months, serum HBV DNA >10(5) copies/mL or >20,000 IU/mL, persistent or intermittent elevation in ALT/AST levels). Liver biopsy is most important for patients who do not meet current criteria for treatment but have serum HBV DNA 10(4) to 10(5) copies/mL (2000 to 20,000 IU/mL) and ALT/AST levels that are normal or mildly elevated (<2x upper limit); patients with histologically active or advanced liver disease may benefit from treatment. Suggested follow-up for patients not considered for treatment HBeAg+, HBV DNA >20,000 int. units/mL and normal ALT 1. ALT every 3-6 months, more often if ALT becomes elevated 2. If ALT levels are between 1-2 x ULN, recheck ALT every 1-3 months; consider liver biopsy if age >40, ALT borderline or mildly elevated on serial tests. Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis. 3. If ALT >2 x ULN for 3-6 months and HBeAg+, HBV DNA >20,000 int. units/mL, consider liver biopsy and treatment 4. Consider screening for HCC in relevant population

Inactive HBsAg carrier state 1. ALT every 3 months for 1 year, if persistently normal, ALT every 6-12 months 2. If ALT >1-2 x ULN, check serum HBV DNA level and exclude other causes of liver disease. Consider liver biopsy if ALT borderline or mildly elevated on serial tests or if HBV DNA persistently 2000 int. units/mL. Consider treatment if biopsy shows moderate/severe inflammation or significant fibrosis. 3. Consider screening for HCC in relevant population

WHO SHOULD BE TREATED AND HOW The rationale for treatment is to reduce the risk of progressive chronic liver disease, transmission to others, and other long-term complications from chronic HBV such as hepatocellular carcinoma. 2008 criteria for treatment of HBV : Patients in whom therapy is indicated: 1. acute liver failure 2. clinical complications of cirrhosis 3. cirrhosis or advanced fibrosis with HBV DNA in serum 4. reactivation of chronic HBV after chemotherapy or immunosuppression. Patients for whom therapy may be indicated: patients in the immune-active phase who do not have advanced fibrosis or cirrhosis (HBeAg-positive or HBeAg-negative chronic hepatitis). Patients for whom immediate therapy is not routinely indicated: 1. Patients with chronic HBV in the immune tolerant phase (with high levels of serum HBV DNA but normal serum ALT levels or little activity on liver biopsy) 2. Patients in the inactive carrier or low replicative phase (with low levels of or no detectable HBV DNA in serum and normal serum ALT levels) 3. Patients who have latent HBV infection (HBV DNA without HBsAg). HBeAg-positive patients Treatment is recommended for those with HBV DNA >20,000 IU/mL and ALT >2 x ULN. Treatment should be delayed for 3-6 months in newly diagnosed HBeAg positive patients with compensated liver disease to determine whether spontaneous HBeAg seroconversion will occur. Patients with chronic hepatitis whose serum ALT is persistently below two times the upper limit of normal can be observed, considering treatment if and when the serum ALT becomes higher. Possible exceptions to this rule are those who have recurrent hepatitis flares that fail to clear HBeAg, patients with icteric flares, those with active or advanced histologic findings (such as moderate/severe inflammation or bridging fibrosis/cirrhosis), and patients above the age of 40 with persistently high HBV DNA levels. Treatment may also be indicated in patients with HBV-related polyarteritis nodosa. HBeAg-negative patients Treatment may be initiated immediately once a diagnosis of HBeAg negative chronic hepatitis (ALT >2 x ULN and HBV DNA >2000 IU/mL) serial follow-up is needed to differentiate an inactive carrier state from HBeAg negative chronic hepatitis. Liver biopsy should be considered in HBeAg negative patients who have serum HBV DNA levels >2,000 IU/mL and normal or mildly elevated ALT to determine if treatment is warranted.

Recommendations for treatment of chronic hepatitis B HBeAg HBV DNA ALT Treatment strategy (PCR) + >20,000 int. 2 x Low efficacy with current treatment. units/mL ULN Observe; consider treatment when ALT becomes elevated. Consider biopsy in persons >40 years, ALT persistently high normal-2x ULN, or with family history of HCC. Consider treatment if HBV DNA >20,000 int. units/mL and biopsy shows moderate/severe inflammation or significant fibrosis. + >20,000 int. >2 x Observe for 3-6 months and treat if no spontaneous HBeAg loss. units/mL ULN Consider liver biopsy prior to treatment if compensated. Immediate treatment if icteric or clinical decompensation. IFN /pegIFN , LAM, ADV, ETV, TDF or LdT may be used as initial therapy. ADV not preferred due to weak antiviral activity and high rate of resistance after 1st year. LAM and LdT not preferred due to high rate of drug resistance. End-point of treatment - Seroconversion from HBeAg to anti-HBe. Duration of therapy: IFN- : 16 weeks PegIFN- : 48 weeks LAM/ADV/ETV/LdT/TDF: minimum 1 year, continue for at least 6 months after HBeAg seroconversion IFN non-responders / contraindications to IFN TDF/ETV. >2000 int. >2 x IFN- / peg IFN- , LAM, ADV, ETV, TDF or LdT may be used as units/mL ULN initial therapy. LAM and LdT not preferred due to high rate of drug resistance. ADV not preferred due to weak antiviral activity and high risk of resistance after 1st year. End-point of treatment - not defined. Duration of therapy: IFN- /pegIFN- : 1 year LAM/ADV/ETV/LdT/TDF: >1 year IFN non-responders / contraindications to IFNTDF/ETV. >2000 int. 1->2 x Consider liver biopsy and treat if liver biopsy shows moderate/severe units/mL ULN necroinflammation or significant fibrosis. 2000 int. ULN Observe, treat if HBV DNA or ALT becomes higher. units/mL +/Detectable Cirrhosis Compensated: HBV DNA >2000 int. units/mL - Treat, LAM/ADV/ETV/LdT/TDF may be used as initial therapy. LAM and LdT not preferred due to high rate of drug resistance; ADV not preferred due to weak antiviral activity and high risk of resistance after 1st year. HBV DNA <2000 int. units/mL - Consider treatment if ALT elevated. Decompensated: Coordinate treatment with transplant center, LAM (or LdT) +ADV, TDF or ETV preferred. Refer for liver transplant. +/Undetectable Cirrhosis Compensated: Observe. Decompensated: Refer for liver transplant. ALT: alanine aminotransferase; ULN: upper limit of normal; IFN : interferon alpha; pegIFN- : pegylated IFN-alpha; LAM: lamivudine; ADV: adefovir; ETV: entecavir; LdT: telbivudine; TDF: tenofovir disoproxil fumarate.

Choosing among the available options Treatment strategies for chronic HBV include : interferon (standard and pegylated), lamivudine, adefovir dipivoxil, telbivudine, entecavir, and tenofovir .. Prediction of response HBeAg positive patients For HBeAg positive patients, the likelihood of response to lamivudine, adefovir, telbivudine, entecavir, interferon, and probably tenofovir depends upon the degree of elevation of the serum aminotransferases. As a general rule, treatment with any of these drugs does not result in higher rates of HBeAg seroconversion compared to no treatment in those who have a serum ALT 2 X the upper limit of normal. Prediction of response in HBeAg negative patients For HBeAg negative patients, prediction of response is less precise. Because of the need for long-term treatment, therapy is recommended only for those with persistent or intermittent elevation in ALT and/or substantial histologic abnormalities (moderate/severe inflammation or bridging fibrosis/cirrhosis). Interferon, adefovir, entecavir, or tenofovir are generally preferred because long-term treatment with lamivudine or telbivudine is associated with diminishing response due to selection of drug-resistant mutants. Advantages of entecavir and tenofovir are more potent antiviral activity and lower rate of drug resistance compared with adefovir. Renal insufficiency Entecavir may be a better option than adefovir or tenofovir in patients with renal insufficiency and in those who are at risk for renal insufficiency. Failed prior interferon therapy can be treated with lamivudine, adefovir, telbivudine, entecavir, or tenofovir with the expectation of a similar response as treatment-nave patients. Breakthrough infection Those who develop breakthrough infection due to antiviral drug resistance should be treated with additional antiviral therapy. Salvage therapy should be initiated promptly at the time of virologic breakthrough, prior to biochemical breakthrough, especially those with worsening liver disease, decompensated cirrhosis, recurrent HBV after transplantation, or immunosuppression. The choice of therapy in patients who developed resistance to nucleotide/side analogue depends upon which drug was used for initial treatment. Although data from a small study in patients with compensated liver disease showed that substitution of lamivudine for adefovir was as effective in viral suppression as addition of adefovir, patients who stopped lamivudine were more likely to have hepatitis flares during the first few months. In addition, follow-up data found that adefovir resistance was detected only in patients who stopped lamivudine but not in those who received combination therapy. These data indicate that lamivudine should be continued after the addition of adefovir. For lamivudine / telbivudine resistance, addition of adefovir or tenofovir may be a better option than entecavir since the likelihood of entecavir resistance increases in patients who have preexisting mutations that confer resistance to lamivudine/telbivudine. For adefovir resistance, addition of lamivudine/telbivudine/entecavir is recommended. However, the durability of response is unclear in patients with prior lamivudine resistance. Case series suggest partial cross resistance between adefovir and tenofovir. For patients with entecavir resistance, we suggest the addition of adefovir or tenofovir. Compensated cirrhosis interferon may be used with caution but nucleosides/nucleotides are safer. Because of the need for long-term treatment, entecavir or tenofovir is preferred. Decompensated cirrhosis should be considered for treatment with lamivudine, telbivudine, adefovir, entecavir, or tenofovir. Interferon is contraindicated in these patients. In view of the need for long-term treatment, lamivudine and telbivudine are not optimal treatments unless used in combination with adefovir or tenofovir. If adefovir monotherapy is used, HBV DNA levels and liver function should be monitored closely (monthly or more often) and treatment modified by switching to tenofovir or adding lamivudine, telbivudine, or entecavir if virus suppression is slow or inadequate. Renal function (creatinine every one to three months) should be monitored closely in patients receiving adefovir or tenofovir. Entecavir may be a preferred option if ongoing studies demonstrate its safety in these patients. Treatment of such patients should be coordinated with a transplant center.

DOSES The following are recommended doses of the specific drugs: o Standard interferon alfa (SC) : o 5 MU daily or 10 MU three times a week o Treatment duration for HBeAg positive chronic hepatitis is 16 to 32 weeks o Treatment duration for HBeAg negative hepatitis is 12 to 24 months o Pegylated interferon alfa-2a (SC): o 180 microG once weekly o The manufacturer recommends 48 weeks of treatment for HBeAg positive or negative chronic HBV. o Lamivudine (PO): 100 mg daily. the dose needs to be adjusted in renal impairment. o Adefovir (PO) 10 mg daily. the dose needs to be adjusted in renal impairment o Entecavir (PO) 0.5 mg once daily , 1 mg daily for those who have lamivudine resistance. the dose needs to be adjusted in renal impairment o Telbivudine (PO) 600 mg once daily. o Tenofovir (PO) 300 mg daily; the dose needs to be adjusted in renal impairment. Duration And Treatment Endpoints The optimal duration of therapy for the oral drugs is not wellestablished. Most patients receiving nucleoside/nucleotide analogue therapy will require at least four to five years of treatment, and some may require indefinite treatment. HBeAg-positive chronic hepatitis The endpoint of treatment is HBeAg seroconversion. o Patients in whom HBeAg seroconversion has occurred and serum HBV DNA has become undetectable should be treated for at least 6 more months o All patients should be closely monitored after discontinuation of treatment as viral relapse may lead to hepatitis flares and hepatic decompensation. o Treatment can be continued in patients who have maintained viral suppression but have not seroconverted as HBeAg seroconversion may occur in subsequent years. HBeAg-negative chronic hepatitis Treatment may be discontinued in patients who have confirmed loss of HBsAg (by testing on two occasions at least two months apart). Compensated cirrhosis life-long treatment is generally recommended. It is possible that treatment may be discontinued in those who have lost HBsAg. Decompensated cirrhosis Life-long treatment is recommended.

COUNSELING AND PREVENTION Heavy use of alcohol (>40 g/d), has been associated with worsening liver disease and an increased risk of HCC. The exact amount of alcohol that can be safely consumed is unclear. Thus, advising patients to be completely abstinent is reasonable in those who have substantial liver injury. Patients with chronic HBV should receive appropriate immunizations. Carriers of HBV should be counseled regarding the risk of transmission to others Patients should be advised regarding prevention of sexual transmission (ie, vaccination of spouses and steady sex partners in individuals with monogamous partners, and safe sex practice including use of condoms in subjects with multiple partners), perinatal transmission, and risk of environmental exposure from blood. Household members should be vaccinated if they test negative for HBV serologic markers. HBsAg positive pregnant women should inform their providers so that their infants can receive hepatitis B immune globulin and vaccine immediately after delivery. Healthcare workers who are HBeAg positive should not perform invasive procedures without prior counseling and advice from an expert review panel.

HEMATOLOGY

Treatment Neutropenic Patients With Cancer

o Fever in a neutropenic patient is usually defined as a single temperature of >38.3C (101.3F), or a sustained temperature >38C (100.4F) for more than one hour o neutropenia is usually defined as an absolute neutrophil count (ANC) <500 cells/microL or <1,000 cells/microL with a predicted nadir of <500 cells/microL o ANC can be calculated = WBC percentage of neutrophils /100. o We recommend the use of monotherapy with cefepime or carbapenem as initial therapy (Grade 2A). o In more critically ill patients, we suggest the addition of an aminoglycoside for better gram-negative coverage (Grade 2B) o in critically ill patients with renal insufficiency, we suggest the use of a fluoroquinolone or aztreonam instead (Grade 2C). o Antibiotic therapy should be altered if there is evidence of progressive disease or a new complication. o We do NOT recommend the routine use of gram-positive antibiotic coverage (eg, vancomycin or linezolid) (Grade 1A). o we do recommend the addition of vancomycin or linezolid in the following circumstances: 1. hypotension 2. mucositis 3. skin or catheter site infection 4. history of MRSA colonization 5. recent quinolone prophylaxis 6. clinical deterioration 7. persistent fever despite empiric antibiotics. o Empiric antifungal therapy We recommend the addition of an antifungal agent in neutropenic patients with no obvious source of infection who are persistently febrile for five days despite broad-spectrum antibacterials (Grade 1A). We recommend adding caspofungin as first-line antifungal therapy (Grade 1B). o We do NOT recommend the routine use of prophylactic antibiotics. o Duration of antibiotic therapy If an infectious source of fever is identified, antibiotics should be continued for the standard duration for that particular pathogen and site of infection. In the patient with no known source, the timing of the discontinuation of antibiotics is usually dependent upon resolution of fever and neutropenia. We suggest that antibiotics be stopped if the ANC increases to >500/microL and the patient becomes afebrile. (Grade 2C). In the patient without an identified source who becomes afebrile but remains neutropenic, we suggest treatment for a total of 14 days with careful follow-up on discontinuation of therapy. (Grade 2C) In the patient with an identifiable source who improves on antibiotic therapy, we suggest switching to an appropriate oral agent for completion of the antibiotic course. o we recommend catheter removal for patients with catheter-related candidemia or bacteremia in which one of the following organisms is implicated: S. aureus, Pseudomonas species, fast-growing atypical mycobacteria, Stenotrophomonas species, Bacillus species, or Corynebacterium jeikeium. . o Low risk patients Outpatient or oral antibiotic therapy is a reasonable option for patients with low-risk febrile neutropenia who meet all of the requirements for safe and successful outpatient management .

2002 IDSA guidelines for the use of antimicrobial agents in neutropenic patients with cancer:
Initial antibiotic therapy Monotherapy: Cefepime or ceftazidime or imipenem or meropenem Cefepime 1gr 23 , ceftazidime 1gr 23 , imipenem 500mg 14 , meropenem1gr 13 Dual therapy: Aminoglycoside plus antipseudomonal beta-lactam, cephalosporin (cefepime or ceftazidime), or carbapenem Vancomycin : added to monotherapy or dual therapy only if criteria are met : 1gr 12 Oral therapy (only for low-risk adults): Ciprofloxacin + amoxicillin-clavulanate Afebrile within first 3-5 days of treatment If etiology identified: Adjust to most appropriate treatment If no etiology identified: Low risk: Change after 48 hours to oral antibiotics (ciprofloxacin/amoxicillin-clavulanate [adults], cefixime [children]) High risk: Continue same antibiotics Persistent fever during first three to five days of treatment Reassess on day 3 If no change: Continue antibiotics; stop vancomycin if cultures are negative If progressive disease: Change antibiotics If febrile after day 5: add an antifungal drug with or without antibiotic changes Duration of antibiotic therapy Afebrile on day 3: If ANC 500/L for 48 hours: Stop antibiotics as long as there is no site of infection or positive cultures If ANC <500/L by day seven: o Low risk: Stop when afebrile for five to seven days o High risk: Continue antibiotics Persistent fever: If ANC 500/L: Stop 4-5 days after ANC is >500/L and reassess If ANC <500/L: Continue for two more weeks, reassess and stop if no disease sites Use of antivirals : Not routine Granulocyte transfusions: Not routine Use of colony-stimulating factors: Not routine; consider in certain cases Antibiotic prophylaxis in afebrile neutropenic patients Not routine, except for Pneumocystis carinii pneumonitis prophylaxis Antifungal prophylaxis with fluconazole and antiviral prophylaxis with acyclovir or ganciclovir are warranted for patients undergoing hematopoietic stem cell transplantation.

Treatment of anemia due to iron deficiency

Diagnostic issues Successful overall management of the patient with iron deficiency anemia must include attempts to identify and treat, if possible, the underlying cause(s) of the iron deficiency (eg, blood loss from a tumor or varicosity, iron malabsorption) as well as the ability of the patient to tolerate oral iron preparations. In comparison with oral iron therapy, treatment with parenteral iron is more complex, more expensive, and can be associated with severe adverse drug reactions. It should be reserved for those with severe intolerance to oral iron or when the level of continued bleeding, usually gastrointestinal, exceeds the ability of the gastrointestinal tract to absorb iron.

ORAL IRON THERAPY General principles There are a few simple principles governing the use of oral iron :

Iron is not absorbed in the stomach and is absorbed best from the duodenum and proximal jejunum. Therefore, enteric coated or sustained release capsules, which release iron further down in the intestinal tract, are less efficient sources of iron. Iron salts should not be given with food A number of factors can inhibit the absorption of iron salts, including the use of antacids, certain antibiotics (eg, quinolones, tetracycline), and the ingestion of iron along with cereals, dietary fiber, tea, coffee, eggs, or milk. Iron should be given two hours before, or four hours after, ingestion of antacids. Iron is best absorbed as the ferrous (Fe2+) salt in a mildly acidic medium. As a result, we usually add a 250 mg ascorbic acid (VIFORCIT vitamin C ) tablet at the time of iron administration to enhance the degree of iron absorption. Gastrointestinal tract symptoms (eg, abdominal discomfort, nausea/vomiting, diarrhea/constipation) suffered by some patients seem to be directly related to the amount of elemental iron ingested . Patients with persistent gastric intolerance to oral iron tablets may tolerate ferrous sulfate elixir, which provides 44 mg of elemental iron per 5 mL. Patients can titrate the dose up or down to the level at which the gastrointestinal symptoms become acceptable.

Choice of preparation The most appropriate oral iron therapy is use of a tablet containing ferrous salts, such as: The recommended daily dose for the treatment of iron deficiency in adults is in the range of 150 to 200 mg/day of elemental iron

Ferrous fumarate (FOLI-FERR ,DIMAFER) : 106 mg elemental iron/tab 12 (212mg) Ferrous sulfate (FERROFOL-Z , Adafol Fe+zn ): 65 mg elemental iron/ Cap 13 (195mg) Ferrous gluconate (Glucofer ) : 28 to 36 mg iron/tablet 14

Expected response If pica is present, it will disappear almost as soon as oral iron therapy is begun, well before there are any changes in the peripheral blood. The patient will note an improved feeling of well-being within the first few days of treatment.

In patients with moderate to severe anemia, a modest reticulocytosis will be seen, maximal in approximately 7 to 10 days. Patients with mild anemia may have little or no reticulocytosis. The hemoglobin concentration will rise slowly, usually beginning after about one to two weeks of treatment, and will rise approximately 2 g/dL over the ensuing three weeks. The hemoglobin deficit should be halved by about one month and should return to normal by 6 to 8 weeks.

Side effects Approximately 10 to 20 percent of patients may complain of nausea, constipation, epigastric distress and/or vomiting after taking oral iron preparations. There are a number of treatment options for such patients:

The patient may take an iron preparation containing a smaller dose of elemental iron (eg, switching from ferrous sulfate to ferrous gluconate), or may switch from a tablet to a liquid preparation, the dose of which (44 mg elemental iron per 5 mL) can be easily titrated by the patient The patient may slowly increase the dose from one tablet per day to the recommended three times per day, as tolerated. The iron may be taken with meals, although this will decrease absorption somewhat.

Duration of treatment Some physicians stop treatment with iron when the hemoglobin level becomes normal,Others believe that it is wise to treat for at least six months after the hemoglobin has normalized, in order to replenish iron stores. Pregnancy Treatment of iron deficiency in pregnancy is the same as that in nonpregnant, postpartum, premenopausal, and postmenopausal women; indications for the use of parenteral iron are also the same [ 6] . PARENTERAL IRON THERAPY Indications Parenteral iron, which can be given IM but preferably IV, 1. for the rare patient unable to tolerate even modest doses of oral iron, 2. in iron deficient patients whose level of continued bleeding, usually gastrointestinal, exceeds the ability of the gastrointestinal tract to absorb iron. 3. Patients with inflammatory bowel disease and iron deficiency may give a history of severe intolerance to oral iron preparations, making therapy with parental iron necessary. 4. Parenteral iron is routinely employed in dialysis patients 5. Parenteral iron is the preferred route for iron treatment in anemic cancer patients receiving treatment with erythropoiesis- stimulating agents (eg, erythropoietin, darbepoetin). Patients with severe malabsorption and/or malnutrition may not be candidates for IM treatment if they have a markedly reduced muscle mass into which the iron preparation can be injected. the rise in the hemoglobin concentration is only slightly faster in Intramuscular iron then that which occurs following the use of oral iron preparations.

Available preparations Iron dextran ,Ferric carboxymaltose, Ferric gluconate , Iron sucrose . Iron dextran Iron dextran preparations contain 50 mg of elemental iron/mL, and can be given either IM or IV. Local reactions include pain, muscle necrosis, and phlebitis in adjacent vessels. Anaphylactic reactions occur in about 1 percent of patients with either the "low" or "high" molecular weight products and are thought to be caused by the free iron present in the preparation . Other systemic effects include fever, urticaria, and a flare in arthritis in patients with rheumatoid arthritis. Ferric gluconate complex approved for IV use. Iron sucrose (Venofer, Sucrofer,vial 100 mg iron) is only approved for IV use. Dosing of Iron sucrose :

in chronic renal disease (Hemodialysis-dependent patient) : I.V 100 mg over 2-5 minutes administered 1-3 times/week during dialysis; administer no more than 3 times/week to a cumulative total dose of 1000 mg (10 doses) Nondialysis-dependent patient: 200 mg slow injection (over 2-5 minutes) on 5 different occasions within a 14-day period. Total cumulative dose: 1000 mg in 14-day period. Note: Dosage has also been administered as two infusions of 500 mg in a maximum of 250 mL 0.9% NaCl infused over 3.5-4 hours on day 1 and day 14 (limited experience)

Administration of Iron sucrose Slow I.V. injection : over 2-5 minutes. Can be administered through dialysis line. Infusion: Dilute : 1 vial 100 mg in 100 mL 0.9% NaCl infuse over at least 15 minutes. 3 Vial 300 mg in 250 mL 0.9% NaCl infused over at least 1hours. 4 Vial 400 mg in 250 mL 0.9% NaCl infused over at least 2 hours. 5 Vial 500 mg in 250 mL 0.9% NaCl infused over at least 3 hours. Calculation of parenteral iron dose Hemoglobin iron deficit (mg) = BW x (14 - Hgb) x (2.145) Volume of product required (mL) = BW x (14 - Hgb) x (2.145) C Example: sucrofer: 20 mg/mL amp 5ml=100mg 60 kg woman with a hemoglobin concentration of 8 g/dL. Parenteral iron product is iron sucrose sucrofer (C = 20 mg elemental iron/mL) Hemoglobin iron deficit = 60 x (14 - 8) x (2.145) = 772 mg iron Volume of sucrofer needed = 60 x (14 - 8) x (2.145) 20 = 38.6 mL 7.72 amp 8amp

BLOOD TRANSFUSION For the patient who is hemodynamically unstable because of active bleeding and/or shows evidence for end-organ ischemia secondary to severe iron deficiency anemia, packed red blood cell transfusion can be life-saving. Each unit of packed cells with a volume of 300 mL contains approximately 200 mL of red cells and 200 mg of iron in the form of hemoglobin heme. Transfusion of one such unit to an adult will raise the hematocrit by roughly 3 percentage points (and the hemoglobin by about 1 gm/dl) unless there is continued bleeding. While blood transfusion therapy should be individualized, transfusion is not recommended in hemodynamically stable patients without end-organ ischemia unless the hemoglobin level is less than 7 g/dL

Causes for failure to respond to oral iron therapy 1. Coexisting disease interfering with marrow response Infection Inflammatory disorder (eg, rheumatoid arthritis) Concomitant malignancy Coexisting folic acid and/or vitamin B12 deficiency Bone marrow suppression from another cause 2. Diagnosis is incorrect, possible correct diagnoses include Thalassemia Lead poisoning Anemia of chronic disease (anemia of chronic inflammation) Copper deficiency (zinc toxicity) Myelodysplastic syndrome/refractory sideroblastic anemia 3. Patient is not taking the medication Prescription has not been filled Prescription has been filled but patient is no longer taking the medication 4. Medication is being taken but is not being absorbed Rapid intestinal transport bypasses area of maximum absorption Enteric coated product: coating is not dissolving Patient has malabsorption for iron (eg, sprue, atrophic gastritis) Medication taken in association with an agent interfering with absorption (eg, antacids, tetracycline, tea) 5. Continued blood loss or need in excess of iron dose ingested Cause of blood loss treatable (eg, bleeding peptic ulcer) Initiate appropriate treatment Cause of blood loss not treatable (eg, Osler Weber Rendu disease) or need cannot be met by oral iron preparation (eg, renal failure responding to erythropoietin) Switch patient to parenteral iron product

TREATMENT OF TTP-HUS
Suspecting the diagnosis Idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) should be suspected in a patient who presents with microangiopathic hemolytic anemia and thrombocytopenia without an apparent alternative etiology. The diagnosis of TTP-HUS is supported if neurologic abnormalities, usually fluctuating (eg, confusion, headache, seizures, coma) or renal insufficiency are also present. Fever, although one of the features of TTP-HUS in the era before effective treatment, is rarely present. The only requirement for making an initial diagnosis of idiopathic TTP-HUS and initiating treatment with plasma exchange is the presence of thrombocytopenia and microangiopathic hemolytic anemia without another clinically apparent cause. Initial treatment Idiopathic TTP-HUS is a MEDICAL EMERGENCY which is almost always fatal if appropriate treatment is not initiated promptly. Accordingly, all patients diagnosed with this disorder should be admitted without delay to a medical center capable of performing plasma exchange. We recommend that all such patients be treated on an urgent basis with plasma exchange, rather than with plasma infusion or the use of immunosuppressive agents alone (Grade 1A). Plasma exchange should be initially performed daily until the platelet count has normalized and hemolysis largely ceased, as evidenced by a return of the serum lactate dehydrogenase (LDH) concentration to normal. If plasma exchange is not immediately available, high dose plasma infusion (25 to 30 mL/kg per day 8-10 unit )may serve as TEMPORARY treatment until the patient can be tranferred to a medical center capable of performing plasma exchange. We suggest the use of adjunctive treatment with glucocorticoids in the following settings (Grade 2C): o If there is no evidence for a drug-induced etiology or a bloody diarrheal prodrome, or o In patients whose platelet counts do not increase within several days of treatment with plasma exchange, or o In those in whom thrombocytopenia recurs when plasma exchange treatments are diminished or discontinued The dose : prednisone (1mg/kg/day PO) or methylprednisolone (125 mg IV twice daily) Refractory or recurrent TTP-HUS In patients with a severe course who do not rapidly respond to plasma exchange, worsen with neurologic abnormalities despite plasma exchange plus corticosterois, or have relapsing disease: We suggest increasing plasma exchange frequency to twice daily (Grade 2C). . We recommend the addition of rituximab or cyclosporine (Grade 1B).

Algorithm for Management of patients with TTP-HUS

Diagnosis and initial therapy of multiple myeloma

Neoplastic proliferation of immunoglobulin-producing plasma cells, often resulting in extensive skeletal destruction with focal lytic lesions, bone pain, and hypercalcemia Pallor is seen on examination. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon Spinal cord compression, with severe back pain, weakness or paresthesias of the legs, bladder or bowel dysfunction or incontinence constitutes a medical emergency The incidence of infection is increased, with Streptococcus pneumoniae and gram-negative organisms being the most frequent pathogens.

LABORATORY FINDINGS ESR more than 20mm/h CBC and differential with examination of the peripheral blood smear: o A normocytic, normochromic anemia is common; macrocytosis in less than 10 %. o The peripheral blood smear often shows rouleaux formation o The peripheral blood smear occasional shows plasma cells : with a median absolute peripheral blood plasma cell count of 3 cells/microL; Plasma cell leukemia (plasma cells >2,000/microL) is a rare occurrence and carries an ominous prognosis o Leukopenia and thrombocytopenia calcium, creatinine, albumin, LDH, beta-2 microglobulin, and CRP. o beta-2 microglobulin level is elevated (ie, >2.7 mg/L) in 75 % of patients o creatinine concentration is increased in almost one-half of patients at diagnosis o hypercalcemia in 28% A serum protein electrophoresis with immunofixation and quantitation of immunoglobulins. o A monoclonal protein can be detected in the serum and/or urine in 97 % of patients by immunofixation. o An IgG monoclonal protein was found in 52 %, IgA in 21 percent, light chain (Bence Jones) only in 16 %, IgD in 2 %, biclonal in 2 %, IgM in 0.5 % (IgM myeloma) and no monoclonal protein in 7 % . o Kappa is the predominant light chain isotype seen in myeloma compared to lambda, A 24-hour urine collection for electrophoresis and immunofixation can be done instead of the serum free light chain assay but is more cumbersome. However, urine studies are always indicated if a monoclonal protein is detected on serum based tests. Serum viscosity should be measured if the M-protein concentration is high (ie, >5 g/dL) or there are symptoms of hyperviscosity. Measurement of serum free monoclonal light chains (Bence jones) in 20 % of patients A routine urinalysis : It is important to note that light chains are not detected by the urinary dipstick, which detects mainly albumin so that we use Sulfosalicylic acid test.

Radiographic studies A metastatic bone survey with plain radiographs including the humeri and femoral bones should be performed in all patients. Diagnosis : The diagnosis is typically confirmed by bone marrow examination : The bone marrow of patients with MM usually contains more than 10 % plasma cells.

Infiltration with malignant plasma cells may be focal, requiring aspiration/biopsy at multiple sites so that Imaging with MRI and/or PET scan can be helpful in locating focal disease.

Diagnostic criteria for multiple myeloma (all 3 criteria must be met) 1. Presence of a serum or urinary monoclonal protein 2. Presence of clonal plasma cells in the bone marrow 10 % or a plasmacytoma 3. Presence of end organ damage felt related to the plasma cell dyscrasia, CRAB such as: Calcium concentration is increased Renal failure Anemia, or Lytic Bone lesions Diagnostic criteria for Asymptomatic smoldering multiple myeloma (SMM) : both criteria 1. Serum monoclonal protein 3 g/dL and/or bone marrow plasma cells 10 % 2. No end organ damage related to plasma cell dyscrasia (see list above) Diagnostic criteria for Monoclonal gammopathy of undetermined significance (MGUS) : all 3 criteria 1. Serum monoclonal protein <3 g/dL 2. Bone marrow plasma cells <10 % 3. No end organ damage related to plasma cell dyscrasia or a related B cell lymphoproliferative disorder Durie-Salmon staging system for multiple myeloma Stage I Description Low cell mass - <0.6 x 10(12) cells/m2 All of the following present: o Hgb >10 g/dL o Serum IgG <5 g/dL o Serum IgA <3 g/dL o Normal serum calcium o Urine monoclonal protein excretion <4 g/day o No generalized lytic bone lesions Intermediate cell mass - neither stage I nor stage III II III High cell mass - >1.2 x 10(12) cells/m2 One or more of the following: o Hgb < 8.5 g/dL o Serum IgG >7 g/dL o Serum IgA > 5 g/dL o Serum calcium >12 mg/dL (3 mmol/L) o Urine monoclonal protein excretion >12 g/day o Advanced lytic bone lesions Serum creatinine <2 mg/dL (177 mol/L) A Serum creatinine 2 mg/dL B Determination of appropriate initial therapy in patients with multiple myeloma : Not all patients who fulfill the minimal criteria for the diagnosis of MM should be treated : Among patients with smoldering (asymptomatic) myeloma, we recommend deferral of chemotherapy until disease progression (Grade 1B). Patients who have symptomatic disease at the time of diagnosis require chemotherapy. The following findings are clear indications for treatment: o Anemia (ie, hemoglobin <10 g/dL or 2 g/dL below normal)

o Hypercalcemia (ie, serum calcium >11.5 mg/dL [2.875 mmol/liter]) o Renal insufficiency (ie, serum creatinine >2 mg/dL [176.8 mol/liter]) o Lytic bone lesions or severe osteopenia o Extramedullary plasmacytoma Among patients with symptomatic myeloma as defined above, we recommend the initiation of therapy rather than postponing treatment (Grade 1B).

Risk stratification: Patients are stratified at the time of diagnosis into two main risk categories (standard risk and high risk) which offer prognostic value and guide the selection of initial therapy. We recommend that at least two of the following tests be performed to assess risk in newly diagnosed patients: o FISH for t(4;14), t(14;16), and del17p13 o conventional cytogenetics for del 13 or hypodiploidy o plasma cell labeling index. The presence of an abnormality in any of the above markers defines high risk myeloma. Patients without any high risk markers are treated as standard risk myeloma. The main treatment options for standard risk multiple myeloma are chemotherapy alone or chemotherapy plus hematopoietic cell transplantation (HCT).

Determining transplant eligibility transplantation for myeloma is offered primarily to patients < 65 years of age. Patient are NOT eligible for autologous HCT in myeloma: o Age >77 years o Direct bilirubin >2.0 mg/dL o Serum creatinine >2.5 mg/dL unless on chronic stable dialysis o Eastern Cooperative Oncology Group performance status 3 or 4 unless due to bone pain o New York Heart Association functional status Class III or IV For patients with standard risk multiple myeloma who are candidates for HCT, we recommend the use of induction therapy followed by autologous HCT rather than either conventional chemotherapy alone (Grade 1B) or myeloablative allogeneic HCT (Grade 1A). HCT is performed either early in the disease course or at the time of first relapse. We suggest that patients proceed with their first HCT after recovery from stem cell collection (early transplant) (Grade 2A), Awaiting the results of further trials, we suggest a second (tandem) HCT only for patients who did not have at least a very good partial response (VGPR) to the first transplant (Grade 2B).

Treatment Of Transplant Candidates among patients with symptomatic standard risk multiple myeloma who are candidates for autologous HCT, we recommend avoiding melphalan-containing regimens as induction chemotherapy (Grade 1B). In patients who are candidates for autologous HCT, induction chemotherapy is administered for 2-4 months prior to stem cell collection. we suggest lenalidomide plus low dose dexamethasone dexamethasone (Grade 2C). o Lenalidomide 25 mg by mouth daily for 21 days of a 28 day treatment cycle along o Dexamethasone 40 mg by mouth once per week of each 28 day cycle. an acceptable alternative is thalidomide plus low dose dexamethasone.

o Thalidomide (Thalomid) 200 mg daily and for 28 day cycle o Dexamethasone 40 mg by mouth once per week of 28 day cycle. Treatment Of Patients Who Are Not Transplant Candidates Among patients with symptomatic standard risk multiple myeloma who are NOT candidates for autologous HCT, we recommend a regimen consisting of melphalan, prednisone, and thalidomide (MPT) or bortezomib, melphalan, and prednisone (VMP) (Grade 1A). o Melphalan 0.25 mg/kg by mouth (9 mg/m2) per day o prednisone (20 mg by mouth 3 times daily) for 4 days every 4 to 6 weeks o thalidomide 100 to 200 mg daily we give thromboembolic prophylaxis to patients receiving a thalidomide derivative. o It has been recommended that aspirin (81 to 325 mg once daily) be used only in low-risk patients, such as those with no individual risk factors for thrombosis (eg, obesity, prior VTE, central venous line, cardiac disease) or only one individual/myeloma-related risk factor (eg, diagnosis of multiple myeloma, hyperviscosity) . . Initial chemotherapy should be continued until the patient reaches a plateau phase, which is defined as a stable M-protein in the serum and urine and no evidence of progression of myeloma. We recommend NOT administering maintenance therapy with an alkylating agent after induction chemotherapy (Grade 1B). We suggest that non-alkylating agents NOT be administered as maintenance therapy outside of a clinical trial (Grade 2C).

TREATMENT OF HIGH RISK MYELOMA For patients with high risk multiple myeloma who are candidates for HCT, we suggest the administration of a bortezomib-based regimen early in the disease course, and delaying HCT until first relapse (Grade 2C). For patients with high risk multiple myeloma who are not candidates for HCT, we suggest the administration of a bortezomib-based regimen as initial therapy rather than the use of a other regimens used for standard risk disease (Grade 2C).

PREVENTION OF INFECTION The efficacy of prophylactic antibiotics is unclear at this time so we suggest NOT administering routine prophylaxis outside a clinical trial (Grade 2C). pneumococcal and influenza vaccine should be given to all patients .

RADIATION THERAPY should be limited to localized radiation given to patients with disabling pain who have a well-defined focal process that has not responded to adequate chemotherapy. Patients with impending fractures of weight bearing bones or spinal compression fractures may benefit from therapies offered by orthopedic surgeons and interventional radiologists. Management of patients with acute renal failure associated with multiple myeloma: We recommend dexamethasone-based chemotherapy (eg, thalidomide and dexamethasone, or bortezomib, thalidomide, and dexamethasone) initiated as rapidly as possible to decrease light chain production for patients with multiple myeloma who have acute renal failure with a course and findings consistent with myeloma cast nephropathy (Grade 1B). If volume depletion is present clinically (eg, hypotension, decreased skin turgor), isotonic fluids should be provided for initial volume replacement (Grade 1B). We recommend fluid therapy for the maintenance of euvolemia and high urine output ( 3L/day), in the treatment of acute renal failure related to multiple myeloma (Grade 1B). We suggest isotonic or one-half

isotonic saline at a rate of 100 to 150 mL/hour, which is adjusted to achieve a urine output of approximately 3 L/day. In patients with acute renal failure and oliguria, we still administer the fluid regimen described above. Within 24 hours, reversal of oliguria should become evident. If oliguria persists, fluid administration should to be modified to prevent volume overload. We base treatment of hypercalcemia on the initial serum calcium concentration. For severe or refractory hypercalcemia, we recommend treatment with bisphosphonates (Grade 1B). o if the corrected serum calcium concentration is elevated, but <14 mg/dL (4 mmol/L), we treat initially with the fluid regimen previously mentioned. If hypercalcemia persists despite 6 to 12 hours of fluids, we administer a bisphosphonate : Zoledronic acid (Zometaor Aclasta)4 mg IV over 15 minutes or pamidronate 60-90 mg over 2-3 hours, with the dose adjusted for kidney function). o If the corrected serum calcium concentration is 14 mg/dL (4 mmol/L), we administer bisphosphonates immediately, concurrently with the fluid regimen described above. Hyperuricemia, if present, should be treated. Nephrotoxic agents, such as nonsteroidal antiinflammatory drugs, and ACEi or angiotensin receptor blockers should be stopped, and radiocontrast dye avoided if possible. we suggest plasmapheresis in patients with multiple myeloma who have acute renal failure with a course consistent with myeloma cast nephropathy and monoclonal free light chains in the serum or urine, or who have cast nephropathy on kidney biopsy (Grade 2B). o We use a of 5-7 exchanges within seven to ten days, in conjunction with chemotherapy. o We recommend repeating the relevant monoclonal light chain assay one to two days after completing the initial course of plasmapheresis, as further treatments may be necessary if there is continued excess light chain production. Patients with acute renal failure who progress to requiring dialysis , we suggest hemodialysis in the acute setting for patients undergoing plasmapheresis(Grade 2C). For the prevention of myeloma cast nephropathy: We recommend Intravenous fluids, unless contraindicated, to prevent volume depletion and maintain a high urine output (approximately 3 L/day) (Grade 1B). Dexamethasone-based chemotherapy (eg, thalidomide and dexamethasone, or dexamethasone alone), is indicated. Nephrotoxic agents should also be avoided.

Management of hypercalcemia associated with multiple myeloma: Hydration, preferably with isotonic saline, plus prednisone (25 mg four times daily) is effective in most cases of mild hypercalcemia. In moderate to severe hypercalcemia, a bisphosphonate such as zolendronic acid or pamidronate should be given. Typically, zoledronic acid or pamidronate.

Management of skeletal lesions associated with multiple myeloma: Analgesics in combination with chemotherapy can usually control the bone . Local radiation in a dose of 20 to 30 Gy should be limited to patients with disabling pain who have a well defined focal process that has not responded to adequate chemotherapy and/or kyphoplasty/vertebroplasty. Extensive radiation should be avoided because it can reduce bone marrow reserve, compromise future chemotherapy, and may prevent a future autologous stem cell procedure. Intravenous Bisphosphonates : o recommended for prophylactic treatment of patients with multiple myeloma. o We suggest that therapy be restricted to those with either lytic bone lesions on plain radiographs, or in those with osteopenia or osteoporosis on bone mineral density studies o intravenous pamidronate or zoledronic acid every 3 to 4 weeks is recommended.

o Once initiated, bisphosphonate therapy should be continued for a period of two years, at which time consideration should be given for stopping bisphosphonates in those with responsive or stable disease. For those in whom bisphosphonates were stopped after two years, the drug should be resumed on relapse with new onset of skeletal-related events.

Disseminated Intravascular Coagulation DIC

Major causes of disseminated intravascular coagulation : 1. Septicemia - Gram negative and Gram positive 2. Crush injury or complicated surgery 3. Severe head injury 4. Cancer procoagulant (Trousseau's syndrome) 5. Acute leukemia, especially promyelocytic 6. Complications of pregnancy o Amniotic fluid embolism o Abruptio placentae o HELLP syndrome o Eclampsia and severe preeclampsia o Dead fetus syndrome o Septic abortion 7. Amphetamine overdose 8. Giant hemangioma (Kasabach-Merritt syndrome) 9. Abdominal aortic aneurysm 10. Peritoneovenous shunt 11. Acute hemolytic transfusion reaction (ABO incompatibility) 12. Paroxysmal nocturnal hemoglobinuria 13. Snake and viper venoms 14. Liver disease o Fulminant hepatic failure o Reperfusion after liver transplantation 15. Heat stroke 16. Burns 17. Purpura fulminans 18. Shock 19. Complement pathway activation CLINICAL MANIFESTATIONS The consequences of DIC, which include bleeding and thrombotic manifestations, depend upon its cause and the rapidity with which the initiating event is propagated . Although there is overlap, two clinical forms have been described: acute and chronic DIC. Acute DIC The clinical consequence is a profound systemic bleeding diathesis and tissue ischemic injury, and a microangiopathic hemolytic anemia in addition to bleeding, thromboembolism and dysfunction of the kidney, liver, lungs, and central nervous system. Bleeding Petechiae and ecchymoses are common in conjunction with blood oozing from wound sites, intravenous lines, catheters, and, in some cases, mucosal surfaces. The bleeding can be life-threatening if it involves the gastrointestinal tract, lungs, or central nervous system. In patients who develop DIC after surgical procedures, hemorrhage may develop around indwelling lines, catheters, drains, and tracheostomies, and blood may accumulate in serous cavities. Acute renal failure Acute renal failure occurs in 25 to 40 percent of patients with acute DIC. Hepatic dysfunction Jaundice is common in patients with DIC and may be due both to liver disease and increased bilirubin production secondary to hemolysis. In addition, hepatocellular injury may be produced by sepsis and hypotension.

Pulmonary disease Pulmonary hemorrhage with hemoptysis and dyspnea may result from damage to the pulmonary vascular endothelium. In addition, sepsis, trauma, and amniotic fluid embolism are causes of acute respiratory distress syndrome (ARDS) as well as DIC. Diffuse pulmonary microthrombosis due to DIC can augment the lung injury associated with ARDS. Central nervous system dysfunction A number of neurologic abnormalities can occur in patients with DIC. These include coma, delirium, and transient focal neurologic symptoms. Microthrombi, hemorrhage, and hypoperfusion all may contribute. Malignancy and acute DIC Although malignancy more often causes chronic DIC, it can produce acute DIC, particularly in acute promyelocytic leukemia (APL). Chronic DIC the patient is either asymptomatic with increased levels of fibrin degradation products or has manifestations of venous and/or arterial thrombosis. Patients with chronic DIC may also have minor skin and mucosal bleeding. Malignancy, particularly solid tumors, is the most common cause of chronic DIC. Venous thromboses commonly present as deep venous thrombosis in the extremities or superficial migratory thrombophlebitis (Trousseau's syndrome), while arterial thromboses can produce digital ischemia, renal infarction, or stroke. Arterial ischemia can also be due to embolization from nonbacterial thrombotic (marantic) endocarditis. This subject is discussed in detail separately. DIAGNOSIS Parameter Acute (decompensated) DIC Chronic (compensated) DIC Platelet count Reduced Variable PT Prolonged Normal aPTTK Prolonged Normal Thrombin time Prolonged Normal Plasma fibrinogen Reduced Normal-elevated Plasma factor V Reduced Normal Plasma factor VIII Reduced Normal FDP Elevated Elevated D-dimer Elevated Elevated Acute DIC The diagnosis of acute DIC is suggested by the history (eg, sepsis, trauma, malignancy), clinical presentation, moderate to severe thrombocytopenia (<100,000/microL) and the presence of microangiopathic changes on the peripheral blood smear . The diagnosis is confirmed by a variety of laboratory studies which should demonstrate evidence of both increased thrombin generation (eg, decreased fibrinogen) as well as increased fibrinolysis (eg, elevated FDPs and D-dimer) Chronic DIC The above laboratory studies are variable in chronic DIC because a slower rate of consumption of coagulation factors may be balanced by enhanced synthesis of these proteins. Thus, the platelet count may be only moderately reduced, plasma fibrinogen is often normal or slightly elevated, and the PT and aPTT may be within normal limits. In such patients, the diagnosis may be largely based upon evidence of microangiopathy on the peripheral blood smear and increased levels of FDPs and particularly, D-dimer. Fibrin degradation products (FDP), D-dimer Clinically significant DIC is unlikely if there is no biochemical evidence of accelerated fibrinolysis . Elevated D-dimer levels, reflecting degradation of cross-linked fibrin, are the most common abnormal parameter in patients with DIC . Measurement of D-dimer is more specific although somewhat less sensitive than a latex agglutination test for fibrin degradation products . The method of choice is the enzyme-linked immunosorbent assay (ELISA). is not specific for DIC, as there are multiple other causes for an elevated D-dimer level:

1. Arterial thromboembolic disease ( Myocardial infarction , Stroke , Acute limb ischemia ,Atrial fibrillation , Intracardiac thrombus ) 2. Venous thromboembolic disease ( Deep vein thrombosis , Pulmonary embolism ) 3. Disseminated intravascular coagulation 4. Preeclampsia and eclampsia 5. Abnormal fibrinolysis; use of thrombolytic agents 6. Cardiovascular disease, congestive failure 7. Severe infection/sepsis/inflammation 8. Surgery/trauma (eg, tissue ischemia, necrosis) 9. Systemic inflammatory response syndrome 10. Vasoocclusive episode of sickle cell disease 11. Severe liver disease (decreased clearance) 12. Malignancy 13. Renal disease ( Nephrotic syndrome (eg, renal vein thrombosis) , Acute renal failure , Chronic renal failure and underlying cardiovascular disease ) 14. Normal pregnancy 15. Venous malformations Other testing the thrombin time and reptilase time, which are usually prolonged and the presence of fibrin degradation products. Factors V and VIII, in addition to fibrinogen, are usually significantly depressed. Prothrombin levels may be normal in some patients, particularly those with abruptio placentae . Acute DIC is also characterized by reduced levels of endogenous coagulation inhibitors such as antithrombin (AT), protein C, and protein S . Another potentially useful marker is measurement of soluble fibrin monomers.

DIFFERENTIAL DIAGNOSIS Acute DIC with severe liver disease Severe liver disease results in decreased synthesis of coagulation factors and inhibitors , and thrombocytopenia may be induced by hypersplenism secondary to portal hypertension. In addition, liver disease alone may be associated with chronic or intermittent fibrinolysis, fibrinogenolysis, and elevated levels of FDPs. Accordingly, it may be difficult to distinguish the coagulopathy associated with primary severe liver disease from the liver dysfunction often seen in patients with acute DIC. DIC versus TTP-HUS The pathogenesis of DIC, is different from the pathogenesis of TTP-HUS. Patients with TTP-HUS present with thrombocytopenia and a microangiopathic blood smear, but usually have normal levels of the coagulation components and little or no prolongation of the PT or aPTT , In addition to the different laboratory findings, TTP-HUS is usually not seen in the typical clinical settings that are associated with DIC (eg, sepsis, trauma, malignancy, and obstetrical complications). Establishing the correct diagnosis is important clinically, because TTP-HUS in adults is initially treated with plasma exchange, which may be lifesaving; this is not the modality used to treat DIC. DIC versus fibrinogenolysis Primary fibrinogenolysis occurs when plasmin is generated in the absence of thrombosis. It is rare and may occur in certain conditions, such as direct infusion of thrombolytic agents and in patients with prostate cancer [23-25] . It can be distinguished from DIC by the absence of elevated levels of Ddimers.However, when fibrinolysis is prominent, elevated levels of D-dimer and other fibrin degradation products will be present.

DIC versus heparin-induced thrombocytopenia The appearance of otherwise unexplained thrombocytopenia, thrombosis associated with thrombocytopenia, a platelet count which has fallen 50 percent or more from a prior value, or necrotic skin lesions at heparin injection sites, should raise the possibility of heparin-induced thrombocytopenia (HIT) in any patient begun on heparin therapy within the preceding 5 to 10 days, or in a patient receiving prolonged treatment with low molecular weight heparin. The diagnosis of HIT is initially made on clinical grounds, because the assays with the highest sensitivity and specificity may not be readily available and have a slow turnaround time. Test Primary Hyperfibrinolysis DIC TTP Platelet count Normal Decreased Decreased Fibrinogen Decreased Decreased Normal FDP Increased Increased Normal D-dimer Increased Increased Normal Antithrombin Normal Decreased Normal Schistocytes Absent Present Present Plasma clotting times Prolonged Prolonged Normal Euglobulin lysis time Shortened Shortened Normal Treatment Acute DIC is a serious complication associated with a high mortality rate, determined in part by the underlying disease. The reported mortality rate ranges from 40 to 80 % in patients with severe sepsis, trauma, or burns Treatment of the underlying disease (eg, sepsis) is of central importance in controlling acute or chronic DIC. Hemodynamic support is essential. Many patients do not require specific therapy for the coagulopathy associated with DIC, either because it is of short duration or because it is not severe enough to present a major risk of bleeding or thrombosis . administration of antifibrinolytic agents, such as epsilon-aminocaproic acid (EACA) or aprotinin, is generally CONTRAINDICATED . Supportive modalities There is no evidence to support the administration of platelets and coagulation factors in patients who are not bleeding or who are not at high risk of bleeding. We suggest the use of one or more of the following supportive modalities for the symptomatic patient (Grade 2C): o Treatment with platelets and coagulation factors is justified in patients who have serious bleeding, are at high risk for bleeding (eg, after surgery), or require invasive procedures. o Patients with marked or moderate thrombocytopenia (<50,000/microL) and serious bleeding should be given platelet transfusions (1 to 2 units per 10 kg per day). o Actively bleeding patients with a significantly elevated prothrombin time (INR) and/or a fibrinogen concentration <50 mg/dL, should receive fresh frozen plasma (Initial dose: 15 mL/kg) or cryoprecipitate in order to keep the fibrinogen level >100 mg/dL. o The administration of heparin is generally limited to the subset of patients with chronic, compensated DIC who have predominantly thrombotic manifestations. It is important to be sure that the patient's antithrombin (AT) level is near normal (ie, 80 to 100 %) in order for heparin to be effective . In chronic DIC, a continuous infusion of Heparin at 500 units/hour.

INFECTIOUS DISEASES

Overview of diabetic infections of the lower extremities

Clinical classification of a diabetic foot infection severity Uninfected Mild Clinical manifestations of infection Wound lacking purulence or any manifestations of inflammation. Presence of 2 manifestations of inflammation (purulence, or erythema, pain, tenderness, warmth, or induration), but any cellulitis/erythema extends 2 cm around the ulcer, and infection is limited to the skin or superficial subcutaneous tissues; no other local complications or systemic illness. Infection (as above) in a patient who is systemically well and metabolically stable but which has 1 of the following characteristics: cellulitis extending >2 cm, lymphangitic streaking, spread beneath the superficial fascia, deep-tissue abscess, gangrene, and involvement of muscle, tendon, joint or bone. Infection in a patient with systemic toxicity or metabolic instability (eg, fever, chills, tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia).

Moderate

Severe

factors increase likelihood of osteomyelitis in patients with diabetic foot: 1. Grossly visible bone or ability to probe to bone 2. Ulcer size larger than 2 x 2 cm 3. Ulcer depth >3 mm 4. Ulcer duration longer than 1 to 2 weeks 5. ESR >70 mm/h

MANAGEMENT wound management, good nutrition, antimicrobial, glycemic control, and fluid and electrolyte balance. . Wound management o Superficial diabetic foot : relief of pressure on the ulcer, wound cleansing, and debridement of callus and necrotic tissue . o A wide array of dressing and wound healing products for ulcer management (including enzymes, gels, hydrocolloids, honey and antiseptics containing iodine or silver salts), Avoidance of weight bearing is generally more important than the specific type of wound dressing or ointment applied. o Infections with extensive involvement require surgical intervention. . Surgery Prompt surgical debridement is necessary for cure of infections complicated by abscess, extensive bone or joint involvement, crepitus, necrosis, gangrene or necrotizing fasciitis . In addition to debridement, revascularization (via angioplasty or bypass grafting) and/or amputation may be required. Determination of the extent of surgical intervention required should be guided by vascular evaluation . Duration of therapy o Patients with mild infection should receive oral antibiotic therapy in conjunction with attentive wound care until there is evidence that the infection has resolved (usually about 1 to 2 weeks). o Patients with infection also requiring surgical debridement should receive intravenous antibiotic therapy perioperatively. In the absence of osteomyelitis, antibiotic therapy should be administered in conjunction with attentive wound care until signs of infection appear to have resolved (2 to 4 weeks of therapy is usually

sufficient). If there is a good response to parenteral therapy, oral agents can be used to complete the course of treatment . o Patients requiring amputation of the involved limb should receive intravenous antibiotic therapy perioperatively. If the entire area of infection is fully resected, a brief course of oral antibiotic therapy (about a week) following surgery is usually sufficient. Oral agents for empiric treatment of mild to moderate diabetic foot Regimens against streptococci and MRSA Clindamycin 300 to 450 mg every 6 to 8 hours Linezolid 600 mg every 12 hours Penicillin 500 mg every 6 hours PLUS Bactrim 2 DS every 12 hours or doxycycline 100 mg every 12 hours Regimens against streptococci, MRSA, aerobic gram neg bacilli and anaerobes Bactrim PLUS

Amoxicillin-clavulanate1000 mg every 12 hours Clindamycin PLUS one of the following:

Ciprofloxacin 750 mg every 12 hours or levofloxacin 750 mg every 24 hours or moxifloxacin 400 mg every 24 hours Parenteral agents for empiric treatment of moderate to severe diabetic foot Vancomycin should be combined with one of the following regimens: Beta-lactam/beta-lactamase inhibitors Ampicillin-sulbactam 3 g every 6 hours Piperacillin/tazobactam 4.5 g every 8 hours Ticarcillin-clavulanate 3.1 g every 4 hours Carbapenems Imipenem 500 mg every 6 hours Meropenem 1 g every 8 hours Metronidazole 500 mg IV every 8 hours PLUS one of the following: Ceftazidime 2 g every 8 to 12 hours Cefepime 2 g every 12 hours Ciprofloxacin 400 mg IV every 12 hours Aztreonam 2 g every 6 to 8 hours

Management of severe sepsis and septic shock in adults

DEFINITIONS: Bacteremia: the presence of viable bacteria in the blood Systemic Inflammatory Response Syndrome SIRS: consequences of a dysregulated host inflammatory response when infection is absent. It is clinically recognized by the presence of two or more of the following : Temperature >38.5C or <35C Heart rate >90 beats/min Respiratory rate >20 breaths/min or PaCO2 <32 mmHg WBC >12,000 cells/mm3, <4000 cells/mm3, or >10 % immature (band) forms SIRS can result from a variety of conditions such as autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery.

Sepsis: the clinical signs that define SIRS are present and are due to either a culture-proven infection or an infection identified by visual inspection . Severe sepsis : sepsis plus at least one of the following signs of organ hypoperfusion or dysfunction : Areas of mottled skin Capillary refilling requires three seconds or longer Urine output <0.5 mL/kg for at least one hour, or renal replacement therapy Lactate >2 mmol/L Abrupt change in mental status Abnormal EEG findings Platelet count <100,000 platelets/mL DIC Acute lung injury or ARDS Cardiac dysfunction, by echocardiography or direct measurement of the cardiac index Septic shock : severe sepsis plus one or both of the following : Systemic mean blood pressure is <60 mmHg (or <80 mmHg if the patient has baseline hypertension) despite adequate fluid resuscitation. Maintaining the systemic mean blood pressure >60 mmHg (or >80 mmHg if the patient has baseline hypertension) requires dopamine >5 mcg/kg per min, norepinephrine <0.25 mcg/kg per min, or epinephrine <0.25 mcg/kg per min despite adequate fluid resuscitation. Adequate fluid resuscitation : infusion of 20 to 30 mL/kg of starch or infusion of 40 to 60 mL/kg of saline solution or a measured pulmonary capillary wedge pressure (PCWP) of 12 to 20 mmHg. Refractory septic shock : exists if maintaining the systemic mean blood pressure >60 mmHg (or >80 mmHg if the patient has baseline hypertension) requires dopamine >15 mcg/kg per min, norepinephrine >0.25 mcg/kg per min, or epinephrine >0.25 mcg/kg per min despite adequate fluid resuscitation

Management of Sepsis Resuscitate: ABCs Identify and eradicate source of infection Glucose Control Nutrition Steroids Activated Protein C EARLY MANAGEMENT : The first priority in any patient with severe sepsis or septic shock is stabilization of their airway and breathing. Next, perfusion to the peripheral tissues should be restored

Stabilize respiration : Supplemental oxygen should be supplied to all patients with sepsis oxygenation should be monitored continuously with pulse oximetry. Intubation and mechanical ventilation may be required to support the increased work of breathing that typically accompanies sepsis, or for airway protection since encephalopathy and a depressed level of consciousness frequently complicate sepsis Etomidate (an ultrashort-acting nonbarbiturate hypnotic) should be avoided in septic patients, if possible. Etomidate can cause adrenal insufficiency via inhibition of glucocorticoid synthesis, which may contribute to increased mortality in patients with sepsis CXR and ABG should be obtained following initial stabilization. Assess perfusion Hypotension is the most common indicator that perfusion is inadequate. An arterial catheter may be inserted if blood pressure is labile or restoration of arterial perfusion pressures is expected to be a protracted process, because a sphygmomanometer may be unreliable in hypotensive patients . Critical hypoperfusion can also occur in the absence of hypotension, especially during early sepsis.. Common signs of hypoperfusion include : cool, vasoconstricted skin due to redirection of blood flow to core organs (although warm, flushed skin may be present in the early phases of sepsis) obtundation or restlessness oliguria or anuria and lactic acidosis.

Catheters After initial assessment, a central venous catheter (CVC) should be inserted in most patients with severe sepsis or septic shock. A CVC can be used to : To infuse intravenous fluids, medications, blood products, and draw blood. For hemodynamic monitoring by measuring the central venous pressure (CVP) and the central venous oxyhemoglobin saturation (ScvO2). We believe that pulmonary artery catheters (PACs) should not be used in the routine management of patients with severe sepsis or septic shock.

Restore perfusion : Once it has been established that hypoperfusion exists, early restoration of perfusion is necessary to prevent or limit multiple organ dysfunction, as well as reduce mortality. Tissue perfusion should be promptly restored using intravenous fluids, vasopressors, red blood cell transfusions, and inotropes . We recommend patients be managed with therapy aimed at achieving : ScvO2 or SvO2 70 percent within six hours of presentation . CVP : 8 to 12 mmHg mean arterial pressure (MAP) 65 mmHg urine output 0.5 mL /kg /hour. Intravenous fluids : rapid, large volume infusions of intravenous fluids are indicated as initial therapy for severe sepsis or septic shock, unless there is coexisting clinical or radiographic evidence of heart failure . therapy required a approximately 5 liters within the initial 6hours of therapy Volume status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be assessed before and after each bolus. Careful monitoring is essential in this approach because patients with sepsis typically develop noncardiogenic pulmonary edema (ie, ALI, ARDS). Crystalloid versus colloid : There are no data to support preferential administration of crystalloid or colloid.

Vasopressors : intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema. There is no definitive evidence of the superiority of one vasopressor over another . We suggest norepinephrine, although dopamine is also a reasonable first-choice among vasopressors Phenylephrine, a pure alpha-adrenergic agonist, may be particularly useful when tachycardia or arrhythmias preclude the use of agents with beta-adrenergic activity. Additional therapies : For patients whose ScvO2 remains <70 % after intravenous fluid and vasopressor therapy, it is reasonable to administer additional therapies, including blood transfusions or inotropic therapy.

Inotropic therapy : Dobutamine is the usual inotropic agent. Red blood cell transfusions Early goal-directed therapy aggressively utilizes red blood cell transfusions to raise the ScvO2 until hematocrit 30%. Monitoring organ system function in patients with sepsis : ORGAN SYSTEM PARAMETER PaO2/FiO2 ratio Respiratory system Urine output and serum creatinine Renal system Platelet count Hematologic system Glasgow coma score Central nervous system Serum bilirubin and liver enzymes Hepatobiliary system Blood pressure, arterial lactate Cardiovascular system Gastric intramucosal pH (pHi), ileus, blood in nasogastric aspirate Gastrointestinal system Protocol for early goal-directed therapy

Identification of the septic focus A careful history and physical examination may yield clues to the source of sepsis and help guide subsequent microbiologic evaluation . Sputum and urine should be collected for gram stain and culture. Intra-abdominal fluid collections should be percutaneously sampled. Blood should be taken from two distinct venipuncture sites and from indwelling vascular access devices and cultured aerobically and anaerobically. several laboratory tests, which are still investigational, have been studied as diagnostic markers of active bacterial infection we do not suggest the routine use of either): The plasma concentration of soluble TREM-1 is increased in patients with sepsis . Elevated serum procalcitonin are associated with bacterial infection and sepsis Evaluation of common sources of sepsis :
SUSPECTED SITE Upper respiratory tract Lower respiratory tract Urinary tract SYMPTOMS/SIGNS Pharyngeal inflammation plus exudate swelling and lymphadenopathy Productive cough, pleuritic chest pain, consolidative auscultatory findings Fever, urgency, dysuria, loin pain MICROBIOLOGIC EVALUATION Throat swab for aerobic culture

Wound or burn Skin/soft tissue Central nervous system Gastrointestinal Intraabdominal Peritoneal dialysis (PD) infections Genital tract

Sputum of good quality, quantitative culture of protected brush or bronchoalveolar lavage Urine microscopy >50 WBC/hpf plus: midstream urine >100,000 cfu/mL catheter urine >100,000 cfu/mL Suprapubic aspirate >1000 cfu/mL Inflammation, edema, erythema, Gram stain and culture of draining pus, wound discharge of pus culture not reliable Erythema, edema, lymphangitis Culture blister fluid or draining pus; role of tissue aspirates not proven Signs of meningeal irritation CSF microscopy, protein, glucose, culture, bacterial antigen test Abdominal pain, distension, diarrhea, and Stool culture for Salmonella, Shigella, and vomiting Campylobacter Specific abdominal symptoms/signs Aerobic and anaerobic culture of percutaneously or surgically drained abdominal fluid collections Cloudy PD fluid, abdominal pain, fever Cell count and culture of PD fluid Low abdominal pain, vaginal discharge Endocervical and high vaginal swabs onto selective media

Eradication of infection :
SITE Sinusitis Pneumonia Empyema thoracis Mediastinitis Peritonitis Cholangitis Pancreatic infection Urinary tract Catheter-related bacteremia Endocarditis Septic arthritis Soft tissue infection Prosthetic device infection INTERVENTIONS Surgical decompression of the sinuses Chest physiotherapy, suctioning Drainage, decortication Drainage, debridement, diversion Resection, repair, or diversion of ongoing sources of contamination, drainage of abscesses, debridement of necrotic tissue Bile duct decompression Drainage or debridement Drainage of abscesses,relief of obstruction, remove or change infected catheters Removal of catheter Valve replacement Joint drainage and debridement Debridement of necrotic tissue and drainage of discrete abscesses Device removal

Antimicrobial regimen : Intravenous antibiotic therapy should be initiated immediately after obtaining cultures. The choice of antibiotics can be complex and should consider the patient's history, comorbidities clinical syndrome , Gram's stain data , and local resistance patterns . When the potential pathogen or infection source is not immediately obvious, we favor broad spectrum antibiotic coverage directed against both gram-positive and gram-negative bacteria. If Pseudomonas is an unlikely, we favor combining vancomycin with one of the following: Cephalosporin, 3rd or 4th generation (eg, ceftriaxone or cefotaxime), or Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate, or ampicillin-sulbactam), or Carbapenem (eg, imipenem or meropenem). If Pseudomonas is a possible, we combine vancomycin with two of the following : cephalosporin (eg, ceftazidime, cefepime), or carbapenem (eg, imipenem, meropenem), or beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam,ticarcillin-clavulanate), or Fluoroquinolone (eg, ciprofloxacin), or Aminoglycoside (eg, gentamicin, amikacin), or Monobactam (eg, aztreonam) Selection of two agents from the same class, should be avoided. considering local susceptibility patterns when choosing an empiric antibiotic regimen. The duration of therapy is typically 7 to 10 days, although longer courses may be appropriate in patients who have a slow clinical response, an undrainable focus of infection, or immunologic deficiencies . In patients who are neutropenic, antibiotic treatment should continue until the neutropenia has resolved. If infection is thoroughly excluded, antibiotics should be discontinued to minimize colonization or infection with drug-resistant microorganisms and superinfection with other pathogens. Nutritional support in the critically ill : Enteral nutrition is indicated for patients with an extended duration of actual or anticipated inadequate oral intake. Parenteral nutrition is indicated for patients who fail an enteral feeding trial, or have a contraindication to enteral feeding . Enteral feeding should be initiated at an infusion rate of 15 to 30 mL/hr and incrementally increased. We suggest that the enteral nutrition of critically ill patients NOT be routinely supplemented with glutamine, arginine, or omega-3 fatty acids (Grade 2B). . We suggest that critically ill patients be managed in a semirecumbent position, with the head of the bed elevated approximately 45 degrees (Grade 2B). Intensive insulin therapy : Hyperglycemia and insulin resistance are common in critically ill patients, independent of a history of diabetes mellitus . For most critically ill patients, we suggest a target blood glucose <180 mg/dL. To achieve our target blood glucose, we minimize our use of intravenous fluids that contain glucose and administer insulin only when necessary. Glucocorticoids : we suggest initiation of intravenous corticosteroid therapy within eight hours after the onset of shock For patients with severe septic shock (which we define as a systolic blood pressure <90 mmHg for more than one hour despite both adequate fluid resuscitation and vasopressor administration), (Grade 2B). Dose : 50-100 mg IV every 6 hours for 5-7 days , A tapering course is optional. We suggest that fludrocortisone NOT be added to the corticosteroid regimen (Grade 2C). Recombinant human activated protein C (Drotrecognin alfa): The suggested dosing regimen of drotrecogin alfa is 24 mcg/kg per hour for 96 hours . no dose adjustment for patients with renal failure initiate the infusion within 24 hours from the first-sepsis induced organ dysfunction. we suggest that recombinant human activated protein C be administered if contraindications do not exist In patients with septic shock or severe sepsis with a high risk of death, defined as an APACHE II score >25, multiple organ dysfunction, or sepsis-induced acute respiratory distress syndrome, (Grade 2B).

We suggest not be administered to children or to patients with severe sepsis and a low risk of death (defined as an APACHE II score <25 or single organ dysfunction) and is associated with increasing bleeding. Inclusion criteria for Drotrecognin alfa : o Infection criteria : Patients had to have a known infection or a suspected infection, as evidenced by one or more of the following: 1. white cells in a normally sterile body fluid; 2. perforated viscus 3. radiographic evidence of pneumonia with the production of purulent sputum 4. a syndrome associated with a high risk of infection (eg, ascending cholangitis). o Modified SIRS criteria : Patients with at least three of the following four criteria: 1. a core temperature of 38C or 36C 2. a heart rate of 90 beats/min, except in patients with a medical condition known to increase the heart rate or those receiving treatment that would prevent tachycardia; 3. a respiratory rate of 20 breaths/min or a PaCO2 of 32 mmHg or the use of mechanical ventilation for an acute respiratory process; 4. a white-cell count of 12,000/mm3 or 4,000/mm3 or a differential count showing >10 percent immature neutrophils. o Criteria for dysfunctional organs or systems : The first sepsis-induced organ or system dysfunction had to develop within 24 hours before study enrollment. Patients had to meet at least one of the following five criteria: 1. for cardiovascular system dysfunction, the arterial systolic blood pressure had to be 90 mm Hg or the mean arterial pressure 70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure of 90 mm Hg or a mean arterial pressure of 70 mm Hg; 2. for kidney dysfunction, urine output had to be <0.5 mL/kg of body weight/hr for 1 hour, despite adequate fluid resuscitation; 3. for respiratory-system dysfunction, the ratio of PaO2 to FiO2 had to be 250 in the presence of other dysfunctional organs or systems or 200 if the lung was the only dysfunctional organ; 4. for hematologic dysfunction, the platelet count had to be <80,000/mm3 or to have decreased by 50 percent in the 3 days preceding enrollment; 5. in the case of unexplained metabolic acidosis, the pH had to be 7.30 or the base deficit had to be 5.0 mmol/liter in association with a plasma lactate level that was >1.5 times the upper limit of the normal value for the reporting laboratory. Exclusion criteria for Drotrecognin alfa: 1. 2. 3. 4. Pregnancy or breast-feeding Age <18 yr or weight >135 kg Platelet count <30,000/mm3 Conditions that increased the risk of bleeding: surgery requiring general or spinal anesthesia within 12 hours before the infusion, the potential need for such surgery during the infusion, or evidence of active bleeding postoperatively; a history of severe head trauma requiring hospitalization, intracranial surgery, or stroke within 3 months before the study or any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system; a history of congenital bleeding diatheses; gastrointestinal bleeding within 6 weeks before the study unless corrective surgery had been performed; and trauma considered to increase the risk of bleeding 5. Known hypercoagulable condition, including resistance to activated protein C; hereditary deficiency of protein C, protein S, or antithrombin III; presence of anticardiolipin antibody, antiphospholipid antibody, lupus anticoagulant, or homocysteinemia; or recently documented (within 3 months before the study) or highly suspected deep-vein thrombosis or pulmonary embolism 6. Patient's family, physician, or both not in favor of aggressive treatment of patient or presence of an advance directive to withhold life-sustaining treatment

7. Patient not expected to survive 28 days because of uncorrectable medical condition, such as poorly controlled neoplasm or other end-stage disease 8. Use of any of the following medications or treatment regimens: unfractionated heparin to treat an active thrombotic event within 8 hours before the infusion; low-molecular-weight heparin at a higher dose than recommended for prophylactic use (as specified in the package insert) within 12 hours before the infusion; warfarin (if used within 7 days before study entry and if the prothrombin time exceeded the upper limit of the normal range for the institution); acetylsalicylic acid at a dose of more than 650 mg/day within 3 days before the study; thrombolytic therapy within 3 days before the study; glycoprotein IIb/IIIa antagonists within 7 days before study entry; antithrombin III at a dose of more than 10,000 U within 12 hours before the study; or protein C within 24 hours before the study 9. Moribund state in which death was perceived to be imminent 10. Human immunodeficiency virus infection in association with a last known CD4 count of 50/mm3 11. History of bone marrow, lung, liver, pancreas, or small-bowel transplantation 12. Chronic renal failure requiring hemodialysis or peritoneal dialysis 13. Known or suspected portosystemic hypertension, chronic jaundice, cirrhosis, or chronic ascites 14. Acute pancreatitis with no established source of infection 15. Participation in another investigational study within 30 days before the current study NOTES Prophylactic treatment with a dose of unfractionated heparin of up to 15,000 U per day was permitted. Thrombolytic agents were permitted for the treatment of thromboses within a catheter. Acute renal failure was not an exclusion criterion

HIV/AIDS
EPIDEMIOLOGY major risk categories including homosexual men, injection drug users, blood product recipients, and healthcare workers with a needle-stick exposure . Transmission of HIV during primary infection is correlated with unprotected anal intercourse, the number of sexual contacts, and high rates of acute sexually transmitted diseases in MSM PATHOPHYSIOLOGY : one of three known mechanisms: immunodeficiency, autoimmunity, and allergic and hypersensitivity reactions. AIDS definition : 1. opportunistic infections and malignancies that rarely occur in the absence of severe immunodeficiency (eg, Pneumocystis pneumonia, central nervous system lymphoma) 2. positive HIV serology and certain infections and malignancies that can occur in immunocompetent hosts but that are more common among persons infected with HIV (pulmonary tuberculosis, invasive cervical cancer). 3. positive HIV serology and Several nonspecific conditions, including dementia and wasting (documented weight loss). 4. positive HIV serology + CD4 < 200 cells/mcL or a CD4 lymphocyte percentage < 14%. STAGES OF HIV-1 INFECTION HIV-1 infection is divided into the following stages: 1. 2. 3. 4. 5. 6. Viral transmission Primary HIV infection (also called acute HIV infection or acute seroconversion syndrome) Seroconversion Clinical latent period with or without persistent generalized lymphadenopathy (PGL) Early symptomatic HIV infection recently referred to as Class B according AIDS (AIDS indicator condition according to 1993 CDC criteria that include a CD4 cell count below 200/mm3 regardless of the presence or absence of symptoms) 7. Advanced HIV infection characterized by a CD4 cell count below 50/mm3 Examples of B conditions in early symptomatic HIV infection Thrush Vaginal candidiasis that is persistent, frequent, or difficult to manage Oral hairy leukoplakia Herpes zoster involving two episodes or more than one dermatome Peripheral neuropathy Bacillary angiomatosis Cervical dysplasia , Cervical carcinoma in situ Constitutional symptoms such as fever (38.5C) or diarrhea for more than one month ITP Pelvic inflammatory disease, especially if complicated by a tubo-ovarian abscess Listeriosis

Indicator conditions in case definition of AIDS

Definitive AIDS diagnoses (with or without laboratory evidence of HIV infection) 1. Candidiasis of the esophagus, trachea, bronchi, or lungs. 2. Cryptococcosis, extrapulmonary. 3. Cryptosporidiosis with diarrhea persisting > 1 month. 4. Cytomegalovirus disease of an organ other than liver, spleen, or lymph nodes. 5. Herpes simplex virus infection causing a mucocutaneous ulcer that persists longer than 1 month; or bronchitis, pneumonitis, or esophagitis of any duration. 6. Kaposi sarcoma in a patient < 60 years of age. 7. Lymphoma of the brain (primary) in a patient < 60 years of age. 8. Mycobacterium avium complex or Mycobacterium kansasii disease, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes). 9. Pneumocystis jiroveci pneumonia. 10. Progressive multifocal leukoencephalopathy. 11. Toxoplasmosis of the brain. Definitive AIDS diagnoses (with laboratory evidence of HIV infection) 1. Coccidioidomycosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes). 2. HIV encephalopathy. 3. Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes). 4. Isosporiasis with diarrhea persisting > 1 month. 5. Kaposi sarcoma at any age. 6. Lymphoma of the brain (primary) at any age. 7. Other non-Hodgkin lymphoma of B cell or unknown immunologic phenotype. 8. Any mycobacterial disease caused by mycobacteria other than Mycobacterium tuberculosis, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes). 9. Disease caused by extrapulmonary M tuberculosis. 10. Salmonella (nontyphoid) septicemia, recurrent. 11. HIV wasting syndrome. 12. CD4 lymphocyte count below 200 cells/mcL or a CD4 lymphocyte percentage below 14%. 13. Pulmonary tuberculosis. 14. Recurrent pneumonia. 15. Invasive cervical cancer. Presumptive AIDS diagnoses (with laboratory evidence of HIV infection) 1. Candidiasis of esophagus: (a) recent onset of retrosternal pain on swallowing; (b) oral candidiasis. 2. Cytomegalovirus retinitis. A characteristic appearance on serial ophthalmoscopic examinations. 3. Mycobacteriosis. Specimen from stool or normally sterile body fluids or tissue from a site other than lungs, skin, or cervical or hilar lymph nodes, showing acid-fast bacilli of a species not identified by culture. 4. Kaposi sarcoma. Erythematous or violaceous plaque-like lesion on skin or mucous membrane. 5. Pneumocystis jiroveci pneumonia 6. Toxoplasmosis of the brain 7. Recurrent pneumonia: more than one episode in a 1-year period 8. Pulmonary tuberculosis

LABORATORY FEATURES fall in the total white blood cell count. Atypical lymphocytes uncommonly may be seen during this latter phase but, even when found, are less pronounced than in mononucleosis caused by EBV, Elevation of liver associated enzymes, mild anemia and thrombocytopenia . Diagnostic assays for HIV infection : Serologic tests for HIV infection are based upon detection of IgG antibodies against HIV-1 antigens in serum. HIV-specific IgG antibodies appear 6-12 weeks following HIV infection in the majority of patients and by 6 months in 95 percent of patients. Standard HIV-1 antibody tests : o The standard screening assay for detecting antibodies to HIV is an enzyme immunoassay (EIA). o A confirmatory Western blot is performed if the screening test is positive to exclude a false positive test. o Test results are reported as either positive, negative, or indeterminate. o The most common cause of a false negative HIV antibody test in a high-risk patient is that the assay is being conducted during the "window period" of acute HIV infection prior to seroconversion. o False positive tests are very rare and usually represent labeling errors. o The most important step in evaluating an indeterminate result is assessing the patient's risk factors: Low-risk patients should be reassured that HIV infection is unlikely; repeat serologic testing and HIV RNA quantification can provide absolute assurance. high-risk patients may be in the process of seroconversion; these patients often have a high viral load and should be counseled regarding the risk of HIV transmission. Repeat serologic testing and HIV RNA determination should be assessed within one month. Rapid HIV testing : o Rapid serologic tests offer high diagnostic accuracy with the advantage of providing test results at the point of care. o These tests are particularly advantageous for occupational or nonoccupational HIV exposures, women who present in labor without prior HIV testing, and for patients who are unlikely to return for results. o All positive rapid HIV test results must be confirmed with standard EIA antibody and Western blot testing. Testing is complete if the rapid test is negative, unless there is clinical suspicion of acute HIV infection. In this scenario, HIV RNA testing should be performed. The patient with an indeterminate result should have repeat testing in one to two months with rapid or standard serologies. Combination antibody-antigen testing: o detect both antibody and p24 antigen and perform with high sensitivity and specificity. o advantage : ability to detect HIV p24 antigen during the window period of acute HIV infection. Viral detection assays: o viral isolation or qualitative or quantitative detection of HIV antigens alone through PCR techniques, branched chain DNA testing, or nucleic acid sequence-based amplification. o None of these tests is considered superior to routine serologic tests. o DNA PCR assay : useful in specific situations, such as the diagnosis of neonatal HIV infection, in patients with indeterminate serologic tests, or in those who may be in the "window period" of HIV seroconversion. o Quantitative HIV RNA : this is the preferred test for staging and therapeutic monitoring.

TREATMENT NAIVE HIV-INFECTED PATIENT When to initiate antiretroviral therapy (ART) in HIV-infected patients : We recommend initiating ART in patients with a CD4 <200 cells or a history of an AIDS-defining illness (Grade 1A). We recommend initiation of ART in all pregnant women to prevent perinatal transmission regardless of CD4 (Grade 1A). We suggest initiating ART in a patient with a CD4 range of 200 - 350 cells/microL, even if the patient is asymptomatic (Grade 2B). We also suggest initiating ART in patients with a CD4 range of 350 - 500 cells/microL if the CD4 slope of decline exceeds 100 cells/microL/year or the baseline viral load exceeds 100,000 c/mL (Grade 2C). We suggest initiation of ART in AIDS-related neurocognitive disorders and HIV-associated nephropathy (Grade 2B). We also suggest initiating ART in patients over the age of 50 years (Grade 2C). Patients who need treatment for HBV-related liver disease, but who do not need therapy for HIV, should be considered for early ART initiation with dual-active agents against HBV and a fully suppressive regimen versus HIV. Alternatively, a selective regimen for HBV treatment alone can also be considered. ART initiation may be considered in discordant monogamous couples to reduce transmission to the HIVseronegative partner. Such decisions need to involve discussions with both partners.

Goals of therapy : The goals of ART include viral suppression to a viral load <50 copies/mL; secondary goals are immunologic restoration and prevention of HIV-related complications. General principles General laboratory testing prior to initiation of ART: renal function, hepatic function, lipid profile, blood glucose, presence of HLA-B*5701, anemia, and neutropenia. ART regimens are composed of a "base" and a "backbone". o The base is either an NNRTI OR a PI. o The backbone typically consists of two NRTIs. Two and preferably three active drugs are desired when possible. Four drug regimens are no more effective than three-drug regimens and may be associated with greater toxicity.

Antiretroviral Classifications : 1. Nucleoside (and nucleotide) reverse transcriptase inhibitors (NRTIs) o Abacavir (ABC) o Didanosine (ddI) o Emtricitabine (FTC) o Lamivudine (3TC) o Stavudine (d4T) o Tenofovir (TDF) o Zalcitabine (ddC) o Zidovudine (ZDV, AZT) 2. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) o Delavirdine (DLV) o Efavirenz (EFV) o Nevirapine (NVP) 3. Protease inhibitors (PIs) o Amprenavir (APV) o Atazanavir (ATV) o Darunavir (DRV) o Fosamprenavir (FPV) o Indinavir (IDV) o Lopinavir/ritonavir (LPV/r) o Nelfinavir (NFV) o Ritonavir (RTV) o Saquinavir (SQV) o Tipranavir (TPV) 4. Integrase inhibitors (IIs) o Raltegravir (RAL) 5. CCR5 antagonists o Maraviroc (MVC)

We recommend efavirenz, or raltegravir, or ritonavir-boosted PI-based combination ART as regimens of choice in treatment-naive HIV-infected patients (Grade 1A). Of the PIs that can be pharmacologically boosted with ritonavir, lopinavir, fosamprenavir, darunavir, or atazanavir have good potency and favorable side effect profiles Of the NNRTIs, we recommend efavirenz due to its more favorable toxicity profile and ease of dosing (Grade 1A). However, efavirenz should not be administered to women of child-bearing potential or who are pregnant. Nucleoside analogs are usually given in pairs as coformulations. We recommend tenofovir/emtricitabine (Truvada) or abacavir/lamivudine (Epzicom) as preferred agents to zidovudine/lamivudine (Combivir) due to their lower pill burden, once-daily dosing frequency, and favorable side effect profile (Grade 1A). The 2008 IAS-USA guidelines : either of two basic three-drug regimens : Efavirenz plus two NRTIs OR A ritonavir-boosted protease inhibitor (lopinavir, atazanavir, fosamprenavir, darunavir or saquinavir) plus two NRTIs The IAS-USA guidelines recommend any of the following choices as the NRTI backbone: o Tenofovir and emtricitabine (Truvada) o Abacavir-lamivudine (Epzicom)

Management of healthcare workers exposed to HIV : The risk for a healthcare worker (HCW) of contracting HIV from exposure to body fluids from an HIVinfected patient is very low. The average risk of seroconversion after a needlestick injury is about 3 per 1000 with no prophylaxis; it is estimated that this risk is reduced at least 80 % when postexposure prophylaxis is administered in a timely fashion. The first response to a percutaneous exposure should be to wash the area thoroughly with soap and water; for punctures and small lacerations, cleaning the area with an alcohol-based hand hygiene agent is reasonable. Exposed mucous membranes should be irrigated copiously with water or saline. Timing: o PEP should be started as early as possible after an exposure (ideally within one to two hours, or sooner, if possible) if the decision is made to administer PEP. "Starter packs" with a three day supply may be given if relevant data are pending, such as testing of the source patient or the HCW needs more time to decide, but does not want to reduce potential benefit while making that decision. o For occupational exposures from a source of unknown HIV status who is felt to be low risk, the decision on whether to initiate PEP may be delayed while awaiting rapid HIV testing of the source, provided obtaining the test results will create an additional delay of no more than two hours. Selection of antiretroviral therapy: o Assessment of risk :The choice of a two or three drug regimen for PEP is typically based on the risk of transmission. o Low risk injury defined by the mode of injury and the source. This kind of injury occurs through a solid needle, appears superficial, and occurs from a low risk source, such as a patient with an HIV viral load <1500 copies/mL. o High risk injury include those involving a hollow bore needle with presence of visible blood on the device, or exposure from a needle that was in an artery or vein of the source patient. o Mucocutaneous exposures are considered low risk except large volumes of blood from a source who has an HIV viral load >1500 copies/mL. o Two nucleosides are recommended for low risk exposures o Two nucleosides + boosted protease inhibitor are recommended for high risk exposures o For higher risk exposureswe suggest Truvada (Tenofovir300 mg plus Emtricitabine 200 mg one tablet daily) plus Kaletra (Lopinavir/ritonavir) (two tablets twice daily). o For higher risk exposures in patients who desire a once daily regimen, we suggest Truvada plus atazanavir (150 mg) two capsules daily plus ritonavir (RTV 100 mg) one capsule daily. o Drugs that should NOT be used for PEP are Abacavir (ABC) and Nevirapine (NVP) o Efavirenz should not be used in women who are or might be pregnant.

Duration of therapy : It is recommended that PEP be continued for four weeks, although the duration needed to achieve maximal benefit is not known. PEP should be discontinued if testing shows that the source patient is HIV-negative. Patient monitoring: HIV screening on the exposed individual should be performed at baseline, 6 and 12 weeks, and at 6 months after exposure. The majority of individuals who seroconvert will do so within the first three months.

Recommended HIV Postexposure prophylaxis (PEP) for percutaneous injuries Infection status of source HIV-Positive class 1 HIV-Positive class 2 Source of unknown HIV status Unknown Source Exposure type Less severe Recommend basic 2-drug PEP Recommend expanded 3-drug PEP More severe Recommend expanded 3-drug PEP Recommend expanded 3-drug PEP

Generally, no PEP warranted; however Generally, no PEP warranted; however consider basic 2-drug PEP for source with consider basic 2-drug PEP for source with HIV risk factors HIV risk factors Generally, no PEP warranted; however, Generally, no PEP warranted; however, consider basic 2-drug PEP in settings where consider basic 2-drug PEP in settings where exposure to HIV-infected persons is likely exposure to HIV-infected persons is likely HIV-Negative No PEP warranted No PEP warranted Less severe (eg, solid needle and superficial injury). More severe (eg, large bore hollow needle, deep puncture, visible blood on device, or needle used in patient's artery or vein). HIV-Positive, Class 1: asymptomatic HIV infection or known low viral load (eg, <1500 RNA copies/mL) HIV-Positive, Class 2: symptomatic HIV infection, AIDS, acute seroconversion, or known high viral load Source of unknown HIV-status (eg, deceased source person with no samples available for HIV testing). Unknown source (eg, needle from a sharps disposal container). Recommended HIV postexposure prophylaxis for mucous membrane exposures and nonintact skin exposures Infection status of source HIV-Positive class 1 HIV-Positive class 2 Source of unknown HIV status Unknown Source Exposure type Small volume Consider basic 2-drug PEP Recommend basic 2-drug PEP Generally, no PEP warranted; however consider basic 2-drug PEP for source with HIV risk factors Generally, no PEP warranted; however, consider basic 2-drug PEP in settings where exposure to HIV-infected persons is likely Large volume Recommend basic 2-drug PEP Recommend expanded 3-drug PEP

Generally, no PEP warranted; however consider basic 2-drug PEP for source with HIV risk factors Generally, no PEP warranted; however, consider basic 2-drug PEP in settings where exposure to HIV-infected persons is likely HIV-Negative No PEP warranted No PEP warranted For skin exposures, follow-up is indicated only if there is evidence of compromised skin integrity (eg, dermatitis, abrasion, or open wound). Small volume (ie, a few drops). Large volume (ie, major blood splash)

Primary prevention of opportunistic infections in HIV-infected patients : Preventive measures against opportunistic infections can include avoidance of certain exposures, good hygiene, and the use of prophylactic medications. Specific recommendations are governed by the degree of immunosuppression and the risk of disease, which varies for each pathogen. The need for primary prophylaxis is stratified below by CD4 cell count thresholds. We recommend NOT using primary prophylaxis for : Candida , Cryptococcus ,Cytomegalovirus ,Cryptosporidium . Discontinuation of primary prophylaxis : o We recommend discontinuation of primary prophylaxis for mycobacterium avium complex when the CD4 count is >100 cells/microL for 3 months (Grade 1A). o We recommend discontinuation of primary prophylaxis for pneumocystis and toxoplasmosis when the CD4 count is >200 cells/microL for 3 months (Grade 1A). Preferred drug

Infection

Indications 1. CD4 <200 2. Thrush Pneumocystis carinii Bactrim (double-strength tablet daily) 3. unexplained fever>2 w 4. history of PCP 1. CD4 <100 Toxoplasmosis Bactrim (double-strength tablet daily) 2. Toxoplasma sero-positive 1. CD4 <100 Histoplasmosis Itraconazole (200 mg daily) 2. lives in an endemic area Mycobacterium avium Azithromycin (1250 mg weekly) CD4 <50 CD4 <250 cells/mL, who have fluconazole 400 mg/day or itraconazole 200 mg positive IgG or IgM serology, Coccidioidomycosis bid and who live or work in the endemic area. INH 300 mg PO for 9 months + B6 25-50 mg PPD 5mm TB OR Rifampin 600 mg PO for 4 months Pneumocystis carinii :In patients with severe reactions to TMP-SMX, we recommend dapsone (100 mg given once daily) (Grade 1A). In patients who cannot tolerate TMP-SMX or dapsone, we suggest atovaquone suspension (1500 mg daily with food) rather than aerosolized pentamidine (Grade 2A). Mycobacterium avium: If azithromycin is not tolerated, clarithromycin should be initiated. If neither macrolide is tolerated, then rifabutin can be considered an alternative. Toxoplasmosis : For patients who have contraindications to Bactrim , we recommend dapsone (200 mg orally per week) plus pyrimethamine (75 mg orally per week) plus leucovorin (25 mg orally per week) (Grade 1B). In the patient who is intolerant or allergic to the above two regimens, we suggest atovaquone (1500 mg once daily) with or without pyrimethamine/leucovorin (Grade 2C). SYMPTOMS AND SIGNS Many individuals with HIV infection remain asymptomatic for years even without antiretroviral therapy, with a mean time of approximately 10 years between exposure and development of AIDS. When symptoms occur, they may be remarkably protean and nonspecific. Since virtually all the findings may be seen with other diseases, a combination of complaints is more suggestive of HIV infection than any one symptom. Physical examination may be entirely normal. Abnormal findings range from completely nonspecific to highly specific for HIV infection. Those that are specific for HIV infection include hairy leukoplakia of

the tongue,disseminated Kaposi sarcoma, and cutaneous bacillary angiomatosis. Generalized lymphadenopathy is common early in infection. Systemic complaints Fever, night sweats, and weight loss are common symptoms in HIV-infected patients and may occur without a complicating opportunistic infection.

Fever : Patients with persistent fever and no localizing symptoms should nonetheless be carefully examined, and evaluated with a chest radiograph (Pneumocystis pneumonia can present without respiratory symptoms), bacterial blood cultures if the fever is greater than 38.5 C, serum cryptococcal antigen, and mycobacterial cultures of the blood. Sinus CT scans or sinus radiographs should be considered to evaluate occult sinusitis. If these studies are normal, patients should be observed closely. Antipyretics are useful to prevent dehydration.

Weight loss is a particularly distressing complication of long-standing HIV infection. The mechanism of HIV-related weight loss is not completely understood but appears to be multifactorial. AIDS patients frequently suffer from anorexia, nausea, and vomiting, all of which contribute to weight loss by decreasing caloric intake. Malabsorption also plays a role in decreased caloric intake. Patients may suffer diarrhea from infections with bacterial, viral, or parasitic agents. AIDS patients with secondary infections also have decreased protein synthesis, which makes maintaining muscle mass difficult. Several strategies have been developed to slow AIDS wasting. Effective fever control decreases the metabolic rate and may slow the pace of weight loss, as does treating the underlying opportunistic infection. Food supplementation with high-calorie drinks may enable patients with not much appetite to maintain their intake. Selected patients with otherwise good functional status and weight loss due to unrelenting nausea, vomiting, or diarrhea may benefit from total parenteral nutrition (TPN). It should be noted, however, that TPN is more likely to increase fat stores than to reverse the muscle wasting process. Two pharmacologic approaches for increasing appetite and weight gain are the progestational agent megestrol acetate (80 mg four times a day) and the antiemetic agent dronabinol (2.55 mg three times a day). Two regimens that have resulted in increases in lean body mass are growth hormone and anabolic steroids. Growth hormone at a dose of 0.1 mg/kg/d (up to 6 mg) subcutaneously for 12 weeks has resulted in modest increases in lean body mass. The most commonly used regimens are testosterone enanthate or testosterone cypionate (100200 mg intramuscularly every 24 weeks). Testosterone transdermal system (apply 5 mg system each evening) and testosterone gel (1%; apply a 5-g packet [50 mg testosterone] to clean, dry skin daily) are also available. The anabolic steroidoxandrolone (20 mg orally in two divided doses) has also been found to increase lean body mass. Nausea leading to weight loss is sometimes due to esophageal candidiasis. Patients with oral candidiasis and nausea should be empirically treated with an oral antifungal agent. Patients with weight loss due to nausea of unclear origin may benefit from use of antiemetics prior to meals (prochlorperazine, 10 mg three times daily; metoclopramide, 10 mg three times daily; or ondansetron, 8 mg three times daily). Depression and adrenal insufficiency are two potentially treatable causes of weight loss.

Pulmonary disease

PNEUMOCYSTIS PNEUMONIA Pneumocystis jiroveci pneumonia is the most common opportunistic infection associated with AIDS. Clinical Manifestations : the symptomsfever, cough, and shortness of breathare nonspecific. Furthermore, the severity of symptoms ranges from fever and no respiratory symptoms through mild cough or dyspnea to frank respiratory distress. Hypoxemia may be severe, with a PO 2 less than 60 mm Hg. Radiographic Manifestations CXR : two-thirds of patients with Pneumocystis pneumonia have Diffuse or perihilar infiltrates are most characteristic , Normal chest radiographs are seen in 510% of patients with Pneumocystis pneumonia, while the remainder have atypical infiltrates. Apical infiltrates are commonly seen among patients with Pneumocystis pneumonia who have been receiving aerosolized pentamidine prophylaxis. Other, less common presentations include : Large pleural effusions , Pneumothoraces Other Laboratory Studies : o Gallium-67 citrate scanning is a highly sensitive test, demonstrating intense, diffuse bilateral uptake o Measurement of the diffusing capacity for carbon monoxide (DLCO). PCP is highly unlikely if the DLCO is normal, defined by 70 percent of the predicted value or greater. o ssessment of oxygenation at rest and with exercise . The presence of PCP is highly unlikely if the response to exercise is normal, ie, a decrease in the A-a oxygen gradient or an increase in the oxygen saturation with exercise. o CD4 count below 200 cells/mm3 , In addition, a CD4 count above 250 cells/mcL within 2 months prior to evaluation of respiratory symptoms makes a diagnosis of PCP unlikely; only 15% of cases occur above this CD4 o elevated LDH in 90 % of HIV-infected patients with PCP and has some prognostic significance. DEFINITIVE DIAGNOSIS OF PCP : o Definitive diagnosis can be obtained in 5080% of cases by Wright-Giemsa stain or direct fluorescence antibody (DFA) test of induced sputum. o The next step for patients with negative sputum examinations in whom Pneumocystis pneumonia is still suspected should be bronchoalveolar lavage. This technique establishes the diagnosis in over 95% of cases. o Either a normal diffusing capacity of carbon monoxide (DLCO ) or a high-resolution CT scan of the chest that demonstrates no interstitial lung disease makes the diagnosis of Pneumocystis pneumonia very unlikely. o It is uncommon to require lung tissue to diagnose PCP in HIV-infected patients. PCR-based testing can be considered but is not in widespread use. Recommendations about the use of plasma sadenosylmethionine awaits further confirmatory testing Treatment : Patients with PCP should be treated with a 21-day course of anti-Pneumocystis therapy (TMP-SMX , Pentamidine , Atovaquone , dapsone , clindamycin ) Patients with an arterial blood gas measurement showing a PO2 70 mmHg, or A-a gradient 35 mmHg should also receive prednisone 40 mg twice daily for five days, followed by prednisone 40 mg daily for five days, followed by prednisone 20 mg daily for 11 days (total course 21 days). Patients who have a tenuous respiratory status as evidenced by a wide A-a gradient (above 45 mmHg), poor oxygenation (PO2< 60 mmHg), or potential for fatigue leading to respiratory failure (suggested by a high respiratory rate or a partial pressure of arterial carbon dioxide that is normal or higher than normal in a patient with hypoxia) should receive intravenous therapy.

 TMP-SMX is the preferred regimen for intravenous therapy of PCP. TMP-SMX (two double-strength tablets every eight hours) is also the preferred oral regimen for PCP, treatment with TMP-dapsone is less likely to cause adverse reactions and is a reasonable alternative initial regimen, particularly in patients with mild disease. Patients who experience treatment failure (failure to improve after 5-7 days of therapy) while on an oral regimen should be switched to an intravenous regimen. Patients who experience treatment failure on an intravenous regimen should be switched to an alternate intravenous regimen. This typically involves switching from TMP-SMX to pentamidine or vice-versa. Patients who fail or do not tolerate both regimens should be treated with intravenous clindamycin plus oral primaquine. Based on data demonstrating clinical benefit from prospective and retrospective studies, ART should be initiated if possible within two weeks of starting PCP therapy. OTHER INFECTIOUS PULMONARY DISEASES Other infectious causes of pulmonary disease in AIDS patients include bacterial, mycobacterial, and viral pneumonias. Community-acquired pneumonia is the most common cause of pulmonary disease in HIV-infected persons. An increased incidence of pneumococcal pneumonia with septicemia and Haemophilus influenza pneumonia has been reported. Pseudomonas aeruginosa is an important respiratory pathogen in advanced disease. The incidence of infection with Mycobacterium tuberculosis has markedly increased in metropolitan areas because of HIV infection as well as homelessness. Tuberculosis occurs in an estimated 4% of persons in the United States who have AIDS. Apical infiltrates and disseminated disease occur more commonly than among immunocompetent persons. Although a purified protein derivative (PPD) test should be performed on all HIV-infected persons in whom a diagnosis of tuberculosis is being considered, the lower the CD4 cell count, the greater the likelihood of anergy. Because "anergy" skin test panels do not accurately classify those patients who are infected with tuberculosis but unreactive to the PPD, they are not recommended. Treatment of HIV-infected persons with active tuberculosis is similar to treatment of HIV-uninfected tubercular individuals. However, rifampin should not be given to patients receiving indinavir, nelfinavir, amprenavir, lopinavir, or delavirdine. In these cases, rifabutin may be substituted, but it may require dosing modifications depending on the antiretroviral regimen. Drug therapy should be individualized. Patients with multidrug-resistant M tuberculosis infection should receive at least three drugs to which their organism is sensitive. Atypical mycobacteria can cause pulmonary disease in AIDS patients with or without preexisting lung disease and responds variably to treatment. Making a distinction between M tuberculosis and atypical mycobacteria requires culture of sputum specimens. If culture of the sputum produces acid-fast bacilli, definitive identification may take several weeks using traditional techniques. DNA probes allow for presumptive identification usually within days of a positive culture. While awaiting definitive diagnosis, clinicians should err on the side of treating patients as if they have M tuberculosis infection. In cases in which the risk of atypical mycobacteria is very high (eg, a person without risk for tuberculosis exposure with a CD4 count under 50 cells/mcL, clinicians may wait for definitive diagnosis if the person is smearnegative for acid-fast bacilli, clinically stable, and not living in a communal setting. Isolation of cytomegalovirus from bronchoalveolar lavage fluid occurs commonly in AIDS patients but does not establish a definitive diagnosis.

Diagnosis of CMV pneumonia requires biopsy; response to treatment is poor. Histoplasmosis, coccidioidomycosis, and cryptococcal disease should also be considered in the differential diagnosis of unexplained pulmonaryinfiltrates.

NONINFECTIOUS PULMONARY DISEASES Noninfectious causes of lung disease include Kaposi sarcoma, non-Hodgkin lymphoma, and interstitial pneumonitis. In patients with known Kaposi sarcoma, pulmonary involvement complicates the course in approximately one-third of cases. However, pulmonary involvement is rarely the presenting manifestation of Kaposi sarcoma. Non-Hodgkin lymphoma may involve the lung as the sole site of disease but more commonly involves other organs as well, especially the brain, liver, and gastrointestinal tract. Both of these processes may show nodular or diffuse parenchymal involvement, pleural effusions, and mediastinal adenopathy on chest radiographs. Nonspecific interstitial pneumonitis may mimic Pneumocystis pneumonia. Lymphocytic interstitial pneumonitis seen in lung biopsies has a variable clinical course. Typically, these patients present with several months of mild cough and dyspnea; chest radiographs show interstitial infiltrates. Many patients with this entity undergo transbronchial biopsies in an attempt to diagnose Pneumocystis pneumonia. Instead, the tissue shows interstitial inflammation ranging from an intense lymphocytic infiltration (consistent with lymphoid interstitial pneumonitis) to a mild mononuclear inflammation. Corticosteroids may be helpful in some cases refractory to antiretroviral therapy.

SINUSITIS Chronic sinusitis can be a frustrating problem for HIV-infected patients even in those on adequate antiretroviral therapy. Symptoms include sinus congestion and discharge, headache, and fever. Some patients may have radiographic evidence of sinus disease on sinus CT scan or sinus x-ray in the absence of significant symptoms. Nonsmoking patients with purulent drainage should be treated with amoxicillin (500 mg orally three times a day). Patients who smoke should be treated with amoxicillin-potassium clavulanate (500 mg orally three times a day) to cover H influenzae. Prolonged treatment (36 weeks) with an antibiotic and guaifenesin (600 mg orally twice daily) to decrease sinus congestion may be required. For patients not responding to amoxicillinpotassium clavulanate, levofloxacin should be tried (400 mg orally daily). Some patients may require referral to an otolaryngologist for sinus drainage.

Central Nervous System Disease Central nervous system disease in HIV-infected patients can be divided into intracerebral space-occupying lesions, encephalopathy, meningitis, and spinal cord processes. TOXOPLASMOSIS Toxoplasmosis is the most common space-occupying lesion in HIV-infected patients. Headache, focal neurologic deficits, seizures, or altered mental status may be presenting symptoms. The diagnosis is usually made presumptively based on the characteristic appearance of cerebral imaging studies in an individual known to be seropositive for Toxoplasma. Typically, toxoplasmosis appears as multiple contrast-enhancing lesions on CT scan, Lesions tend to be peripheral, with a predilection for the basal ganglia. Single lesions are atypical of toxoplasmosis.

When a single lesion has been detected by CT scanning, MRI scanning may reveal multiple lesions because of its greater sensitivity. If a patient has a single lesion on MRI and is neurologically stable, clinicians may pursue a 2-week empiric trial of toxoplasmosis therapy. A repeat scan should be performed at 2 weeks. If the lesion has not diminished in size, biopsy of the lesion should be performed. Since many HIV-infected patients will have detectable titers, a positive Toxoplasma serologic test does not confirm the diagnosis. Conversely, less than 3% of patients with toxoplasmosis have negative titers. Therefore, negative Toxoplasma titers in an HIV-infected patient with a space-occupying lesion should be a cause for aggressively pursuing an alternative diagnosis.

CENTRAL NERVOUS SYSTEM LYMPHOMA Primary non-Hodgkin lymphoma is the second most common space-occupying lesion in HIV-infected patients. Symptoms are similar to those with toxoplasmosis. imaging techniques cannot distinguish these two diseases with certainty, lymphoma more often is solitary. Other less common lesions should be suspected if there is preceding bacteremia, positive tuberculin test, fungemia, or injection drug use. These include bacterial abscesses, cryptococcomas, tuberculomas, and Nocardia lesions. Biopsy should be strongly considered if lesions are solitary or do not respond to toxoplasmosis treatment, especially if they are easily accessible. Diagnosis of lymphoma is important because many patients benefit from treatment (radiation therapy). In the future, it may be possible to avoid brain biopsy by utilizing polymerase chain reaction (PCR) assay of cerebrospinal fluid for Epstein-Barr virus DNA, which is present in 90% of CNS lymphoma cases.

AIDS DEMENTIA COMPLEX The diagnosis of AIDS dementia complex (HIV-associated cognitive-motor complex) is one of exclusion based on a brain imaging study and on spinal fluid analysis that excludes other pathogens. Neuropsychiatric testing is helpful in distinguishing patients with dementia from those with depression. Patients with AIDS dementia complex typically have difficulty with cognitive tasks and exhibit diminished motor speed. Patients may first notice a deterioration in their handwriting. The manifestations of dementia may wax and wane, with persons exhibiting periods of lucidity and confusion over the course of a day. Many patients improve with effective antiretroviral treatment.

CRYPTOCOCCAL MENINGITIS Cryptococcal meningitis typically presents with fever and headache. Less than 20% of patients have meningismus. Diagnosis is based on a positive latex agglutination test that detects cryptococcal (or "CRAG") or positive culture of spinal fluid for Cryptococcus . 70 - 90% of patients with cryptococcal meningitis have a positive serum CRAG. Thus, a negative serum CRAG test makes a diagnosis of cryptococcal meningitis unlikely and can be useful in the initial evaluation of a patient with headache, fever, and normal mental status. HIV meningitis, characterized by lymphocytic pleocytosis of the spinal fluid with negative culture, is common early in HIV infection.

HIV MYELOPATHY HIV myelopathy presents with leg weakness and incontinence. Spastic paraparesis and sensory ataxia are seen on neurologic examination.

Myelopathy is usually a late manifestation of HIV disease, and most patients will have concomitant HIV encephalopathy. should be evaluated by lumbar puncture to rule out CMV polyradiculopathy and an MRI or CT scan to exclude epidural lymphoma.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) PML is a viral infection of the white matter of the brain seen in patients with very advanced HIV infection. It typically results in focal neurologic deficits such as aphasia, hemiparesis, and cortical blindness. Imaging studies are show nonenhancing white matter lesions without mass effect. Several patients have stabilized or improved after the institution of combination antiretroviral therapy or cidofovir.

Peripheral Nervous System Peripheral nervous system syndromes include inflammatory polyneuropathies, sensory neuropathies, and mononeuropathies. An inflammatory demyelinating polyneuropathy similar to Guillain-Barr syndrome occurs in HIV-infected patients,usually prior to frank immunodeficiency. The syndrome in many cases improves with plasmapheresis. CMV can cause an ascending polyradiculopathy characterized by lower extremity weakness and a neutrophilic pleocytosis on spinal fluid analysis with a negative bacterial culture. Transverse myelitis can be seen with herpes zoster or CMV. Peripheral neuropathy is common among HIV-infected persons. Patients typically complain of numbness, tingling,and pain in the lower extremities. Symptoms are disproportionate to findings on gross sensory and motor evaluation. Beyond HIV infection itself, the most common cause is prior antiretroviral therapy with stavudine or didanosine. Patients who report these symptoms should be switched to an alternative agent if possible. Caution should be used when administering these agents to patients with a history of peripheral neuropathy. Unfortunately,drug-induced neuropathy is not always reversed when the offending agent is discontinued. Patients with advanced disease may also develop peripheral neuropathy even if they have never taken antiretroviral therapy. Evaluation should rule out other causes of sensory neuropathy such as alcoholism, thyroid disease, vitamin B12 deficiency,and syphilis. Treatment of peripheral neuropathy is aimed at symptomatic relief. Patients should be initially treated with gabapentin (start at 300 mg at bedtime and increase to 300900 mg orally three times a day).

Rheumatologic Manifestations Arthritis, involving single or multiple joints, with or without effusion, has been commonly noted in HIVinfected patients. Involvement of large joints is most common. Although the cause of HIV-related arthritis is unknown, most patients will respond to nonsteroidal antiinflammatory drugs. Patients with a sizable effusion, especially if the joint is warm or erythematous, should have the joint tapped, followed by culture of the fluid to rule out suppurative arthritis as well as fungal and mycobacterial disease. Several rheumatologic syndromes, including reactive arthritis (Reiter syndrome), psoriatic arthritis, sicca syndrome, and systemic lupus erythematosus, have been reported in HIV-infected patients However, it is unclear if the prevalence is greater than in the general population. Cases of avascular necrosis of the femoral

heads have been reported sporadically, generally in the setting of advanced disease with long-standing infection and in patients receiving long-term antiretroviral therapy. Myopathy Myopathies are infrequent in the era of effective antiretroviral therapy but can be related to either HIVinfection or antiretroviral therapy, particularly with use of zidovudine (azidothymidine[AZT]). Proximal muscle weakness is typical, and patients may have varying degrees of muscle tenderness. A muscle biopsy can distinguish HIV myopathy from zidovudine myopathy and should be considered in patients for whom continuation of zidovudine is essential.

Retinitis Complaints of visual changes must be evaluated immediately in HIV-infected patients. CMV retinitis, characterized by perivascular hemorrhages and white fluffy exudates, is the most common retinal infection in AIDS patients and can be rapidly progressive. In contrast, cotton wool spots, which are also common in HIV-infected people, are benign, remit spontaneously, and appear as small indistinct white spots without exudation or hemorrhage. Other rare retinal processes include other herpesvirus infections or toxoplasmosis.

Oral Lesions The presence of oral candidiasis or hairy leukoplakia is significant for several reasons. First, these lesions are highly suggestive of HIV infection in patients who have no other obvious cause of immunodeficiency. Second, several studies have indicated that patients with candidiasis have a high rate of progression to AIDS even with statistical adjustment for CD4 count. Hairy leukoplakia is caused by the Epstein-Barr virus. The lesion is not usually troubling to patients and sometimes regresses spontaneously. Hairy leukoplakia is commonly seen as a white lesion on the lateral aspect of the tongue.It may be flat or slightly raised, is usually corrugated, and has vertical parallel lines with fine or thick ("hairy") rojections. Oral candidiasis can be bothersome to patients, many of whom report an unpleasant taste or mouth dryness. There are two major types of oral candidiasis: pseudomembranous (removable white plaques) and erythematous (red friable plaques). Treatment is with topical agents such as clotrimazole 10-mg troches (one troche four or five times a day). Patients with candidiasis who do not respond to topical antifungals can be treated with fluconazole (50100 mg orally once a day for 37 days). Angular cheilitisfissures at the sides of the mouthis usually due to Candida as well and can be treated topically with ketoconazole cream (2%) twice a day. Gingival disease is common in HIV-infected patients and is thought to be due to an overgrowth of microorganisms.It usually responds to professional dental cleaning and chlorhexidine rinses. A particularly aggressive gingivitis or periodontitis will develop in some HIV-infected patients; these patients should be given antibiotics that cover anaerobic oral flora (eg, metronidazole, 250 mg four times a day for 4 or 5 days) and referred to oral surgeons with experience with these entities. Aphthous ulcers are painful and may interfere with eating. They can be treated with fluocinonide (0.05% ointment mixed 1:1 with plain Orabase and applied six times a day to the ulcer). For lesions that are difficult to reach, patients should use dexamethasone swishes (0.5 mg in 5 mL elixir three times a day). The pain of the ulcers can be relieved with use of an anesthetic spray (10%lidocaine). For patients with refractory ulcers, thalidomide, starting at a dose of 50 mg orally daily and increasing to 100200 mg daily, has proved useful.

Other lesions seen in the mouths of HIV-infected patients include Kaposi sarcoma (usually on the hard palate) and warts.

Gastrointestinal Manifestations

CANDIDAL ESOPHAGITIS Esophageal candidiasis is a common AIDS complication. In a patient with characteristic symptoms, empiric antifungal treatment is begun with fluconazole (200 mg daily for 1014 days). Further evaluation to identify other causes of esophagitis (herpes simplex, CMV) is reserved for patients who do not improve with antifungal treatment.

HEPATIC DISEASE Autopsy studies have demonstrated that the liver is a frequent site of infections and neoplasms in HIVinfected patients. However, many of these infections are not clinically symptomatic. Clinicians may note elevations of alkaline phosphatase and aminotransferases on routine chemistry panels. Mycobacterial disease, CMV, hepatitis B virus, hepatitis C virus, and lymphoma cause liver disease and can present with varying degrees of nausea, vomiting, right upper quadrant abdominal pain, and jaundice. Sulfonamides, imidazole drugs, antituberculous medications, pentamidine, clarithromycin, and didanosine have also been associated with hepatitis. HIV-infected patients with chronic hepatitis may have more rapid progression of liver disease because of the concomitant immunodeficiency or hepatotoxicity of antiretroviral therapy. Percutaneous liver biopsy may be helpful in diagnosing liver disease, but some common causes of liver disease (eg, Mycobacterium avium complex, lymphoma) can be determined by less invasive measures (eg, blood culture, biopsy of a more accessible site). With patients living longer as a result of advances in antiretroviral therapy, advanced liver disease and hepatic failure due to chronic active hepatitis B and or C are increasing causes of morbidity and mortality. HIV-infected individuals who are coinfected with hepatitis B, should be treated with antiretroviral regimens that include drugs with activity against both viruses (eg, lamivudine[3TC], emtricitabine[FTC], tenofovir[TDF]). Treatment of HIV-infected persons with hepatitis C with peginterferon and ribavirin has been shown to be efficacious, although less so than in HIV- uninfected persons. HIV-infected persons are also more likely to have difficulty tolerating treatment with peginterferon than uninfected persons. Liver transplants have been performed successfully in HIV-infected patients. This strategy is most likely to be successful in persons who have CD4 counts above 100 cells/mcL and nondetectable viral loads.

BILIARY DISEASE Cholecystitis presents with manifestations similar to those seen in immunocompetent hosts but is more likely to be acalculous. Sclerosing cholangitis and papillary stenosis have also been increasingly reported in HIV-infected patients. Typically, the syndrome presents with severe nausea, vomiting, and right upper quadrant pain. Liver function tests generally show alkaline phosphatase elevations disproportionate to elevation of the aminotransferases. Although dilated ducts can be seen on ultrasound, the diagnosis is made by ERCP, which reveals intraluminal irregularities of the proximal intrahepatic ducts with "pruning" of the terminal ductal branches. Stenosis of the distal common bile duct at the papilla is commonly seen with this syndrome.

CMV, Cryptosporidium , and microsporidia are thought to play inciting roles in this syndrome.

ENTEROCOLITIS Enterocolitis is a common problem in HIV-infected individuals. Organisms known to cause enterocolitis include bacteria (Campylobacter , Salmonella , Shigella ), viruses (CMV, adenovirus), and protozoans (Cryptosporidium ,Entamoeba histolytica , Giardia , Isospora , microsporidia). HIV itself may cause enterocolitis. HIV-infected patients tend to have more severe and more chronic symptoms, including high fevers and severe abdominal pain that can mimic acute abdominal catastrophes. Bacteremia and concomitant biliary involvement are also more common with enterocolitis in HIV-infected patients. Relapses of enterocolitis following adequate therapy have been reported with both Salmonella and Shigella infections. Because of the wide range of agents known to cause enterocolitis, a stool culture and multiple stool examinations for ova and parasites (including modified acid-fast staining for Cryptosporidium ) should be performed. Those patients who have Cryptosporidium in one stool with improvement in symptoms in less than 1 month should not be considered to have AIDS, as Cryptosporidium is a cause of self-limited diarrhea in HIV-negative persons. More commonly, HIV-infected patients with Cryptosporidium infection have persistent enterocolitis with profuse watery diarrhea. To date, no consistently effective treatments have been developed for Cryptosporidium infection. The most effective treatment of cryptosporidiosis is to improve immune function through the use of effective antiretroviral treatment. The diarrhea can be treated symptomatically with diphenoxylate with atropine (one or two tablets orally three or four times a day). Those who do not respond may be given paregoric with bismuth (510 mL orally three or four times a day). Octreotide in escalating doses (starting at 0.05 mg subcutaneously every 8 hours for 48 hours) has been found to ameliorate symptoms in approximately 40% of patients with cryptosporidia or idiopathic HIV-associated diarrhea. Patients with a negative stool examination and persistent symptoms should be evaluated with colonoscopy and biopsy. Patients whose symptoms last longer than 1 month with no identified cause of diarrhea are considered to have a presumptive diagnosis of AIDS enteropathy. Patients may respond to institution of effective antiretroviral treatment. Upper endoscopy with small bowel biopsy is not recommended as a routine part of the evaluation.

OTHER DISORDERS Two other important gastrointestinal abnormalities in HIV-infected patients are gastropathy and malabsorption There is no evidence that Helicobacter pylori is more common in HIV-infected persons. A malabsorption syndrome occurs commonly in HIV-infected patients. It can be due to infection of the small bowel with M avium complex, Cryptosporidium , or microsporidia.

Endocrinologic Manifestations Hypogonadism is probably the most common endocrinologic abnormality in HIV-infected men. The adrenal gland is also a commonly afflicted endocrine gland in patients with AIDS. Abnormalities demonstrated on autopsy include infection (especially with CMV and M avium complex), infiltration with Kaposi sarcoma, and injury from emorrhage and presumed autoimmunity. Patients with suggestive symptoms should undergo a cosyntropin stimulation test. Although frank deficiency of cortisol is rare, an isolated defect in mineralocorticoid metabolism may lead to salt- wasting and hyperkalemia. Such patients should be treated with fludrocortisone (0.10.2 mg daily).

AIDS patients appear to have abnormalities of thyroid function tests different from those of patients with other chronic diseases. AIDS patients have been shown to have high levels of triiodothyronine (T3 ), thyroxine (T4 ), and thyroid-binding globulin and low levels of reverse triiodothyronine (rT3 ). The causes and clinical significance of these abnormalities are unknown.

Skin Manifestations Herpes simplex infections occur more frequently, tend to be more severe, and are more likely to disseminate in AIDS patients than in immunocompetent persons. Because of the risk of progressive local disease, all herpes simplex attacks should be treated with acyclovir (400 mg orally three times a day until healed, usually 7 days),famciclovir (500 mg orally twice daily until healed), or valacyclovir (500 mg orally twice daily until healed). To avoid the complications of attacks, many clinicians recommend suppressive therapy for HIV-infected patients with a history of recurrent herpes. Options for suppressive therapy include acyclovir (400 mg orally twice daily), famciclovir (250 mg orally twice daily), and valacyclovir (500 mg orally daily). Herpes zoster is a common manifestation of HIV infection. patients with zoster should be treated with acyclovir to prevent dissemination (800 mg orally four or five times per day for 7 days). Alternatively, famciclovir (500 mg orally three times a day) or valacyclovir (500 mg three times a day) may be used. Vesicular lesions should be cultured if there is any question about their origin, since herpes simplex responds to much lower doses of acyclovir. Disseminated zoster and cases with ocular involvement should be treated with intravenous (10 mg/kg every 8 hours for 710 days) rather than oral acyclovir. Molluscum contagiosum caused by a pox virus is seen in HIV-infected patients,The characteristic umbilicated fleshy papular lesions have a propensity for spreading widely over the patient's face and neck and should be treated with topical liquid nitrogen. Staphylococcus is the most common bacterial cause of skin disease in HIV-infected patients; it usually presents as folliculitis, superficial abscesses (furuncles) , or bullous impetigo. Folliculitis is initially treated with topical clindamycin or mupirocin, and patients may benefit from regular washing with an antibacterial soap such as chlorhexidine. Intranasal mupirocin has been used successfully for staphylococcal decolonization in other settings. In HIV-infected patients with recurrent staphylococcal infections, weekly intranasal mupirocin should be considered in addition to topical care and systemic antibiotics. Abscesses often require incision and drainage. Patients may need antistaphylococcal antibiotics as well. Due to high frequency of MRSA skin infections in HIV-infected populations, lesions should be cultured prior to initiating empiric antistaphylococcal therapy. Although there is limited experience treating MRSA with oral antibiotics, current recommendations for empiric treatment are trimethoprim-sulfamethoxazole (one double-strength tablet orally twice daily) or doxycycline (100 mg orally twice daily) with close follow-up. Bacillary angiomatosis is a well-described entity in HIV-infected patients. It is caused by two closely related organisms: Bartonella henselae and Bartonella quintana. The most common manifestation is raised, reddish, highly vascular skin lesions that can mimic the lesions of Kaposi sarcoma. Fever is a common manifestation of this infection; involvement of bone, lymph nodes, and liver has also been reported. The infection responds to doxycycline, 100 mg orally twice daily, or erythromycin, 250 mg orally four times daily. Therapy is continued for at least 14 days, and patients who are seriously ill with visceral involvement may require months of therapy. The majority of fungal rashes afflicting AIDS patients are due to dermatophytes and Candida . These are particularly common in the inguinal region but may occur anywhere on the body. Fungal rashes generally respond well to topical clotrimazole (1% twice a day) or ketoconazole (2% twice a day). Seborrheic dermatitis is more common in HIV-infected patients. Scrapings of seborrhea have revealed Malassezia furfur (Pityrosporum ovale) , implying that the seborrhea is caused by this fungus. Consistent

with the isolation of this fungus is the clinical finding that seborrhea responds well to topical clotrimazole (1% cream) as well as hydrocortisone (1% cream). Xerosis presents in HIV-infected patients with severe pruritus. The patient may have no rash, or nonspecific excoriations from scratching. Treatment is with emollients (eg, absorption base cream) and antipruritic lotions (eg, camphor 9.5% and menthol 0.5%). Psoriasis can be very severe in HIV-infected patients. Phototherapy and etretinate (0.259.75 mg/kg/d orally in divided doses) may be used for recalcitrant cases in consultation with a dermatologist. Because of the underlying immunodeficiency, methotrexate should be avoided.

HIV-Related Malignancies Four cancers are currently included in the CDC classification of AIDS: Kaposi sarcoma, non-Hodgkin lymphoma,primary lymphoma of the brain, and invasive cervical carcinoma. Kaposi sarcoma lesions : o may appear anywhere; careful examination of the eyelids, conjunctiva, pinnae, palate,and toe webs is mandatory to locate potentially occult lesions. In light-skinned individuals, Kaposi lesions usually appear as purplish, nonblanching lesions that can be papular or nodular (Plate 41). In dark-skinned individuals, the lesions may appear more brown. In the mouth, lesions are most often palatal papules, though exophytic lesions of the tongue and gingivae may also be seen. Kaposi lesions may be confused with other vascular lesions such as angiomas and pyogenic granulomas. Visceral disease (eg, gastrointestinal, pulmonary) will develop in about 40% of patients with dermatologic Kaposi sarcoma. o Treatment: Best treated with systemic chemotherapy : doxorubicin given intravenously every 3 weeks . Interferon (10 million units subcutaneously three times a week) Patients with milder forms of Kaposi sarcoma do not require specific treatment as the lesions usually improve and can completely resolve with antiretroviral therapy. Non-Hodgkin lymphoma : o in HIV-infected persons tends to be very aggressive. o The malignancies are usually of Bcell origin and characterized as diffuse large-cell tumors. o Over 70% of the malignancies are extranodal. o Treatment: Patients with primary central nervous system lymphoma are treated with radiation. Systemic disease is treated with chemotherapy. Common regimens are CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and modified M-BACOD (methotrexate,bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone). G-CSF is used to maintain white blood counts with this latter regimen. Intrathecal chemotherapy is administered to prevent or treat meningeal involvement. Hodgkin disease are more likely to have mixed cellularity and lymphocyte depletion subtypes of Hodgkin disease and to seek medical attention at an advanced stage of disease. Anal dysplasia and squamous cell carcinoma have been noted in HIV-infected men and women. These lesions have been strongly correlated with previous infection by human papillomavirus (HPV). Although many of the infected MSM report a history of anal warts or have visible warts, a significant percentage have silent papillomavirus infection. Cytologic (using Papanicolaou smears) and papillomavirus DNA studies can easily be performed on specimens obtained by anal swab. Because of the risk of progression from dysplasia to cancer in immunocompromised patients, some experts suggest that annual anal swabs for cytologic examination should be done in all HIV-infected persons. An anal Papanicolaou smear is

performed by rotating a moistened Dacron swab about 2 cm into the anal canal. The swab is immediately inserted into a cytology bottle. HPV also appears to play a causative role in cervical dysplasia and neoplasia.

Coronary artery disease HIV-infected persons are at higher risk for coronary artery disease than age- and sex-matched controls. Part of this increase in coronary artery disease is due to changes in lipids caused by antiretroviral agents, especially stavudine and most of the protease inhibitors. However, some of the risk appears to be due to HIV infection.

Renal Diseases The primary form of HIV nephropathy : A collapsing form of focal glomerulosclerosis (FGS) Acute and often reversible renal failure, resulting from infection, hypotension, the administration of nephrotoxins used to treat opportunistic infections, and the use of HAART. Postinfectious glomerulonephritis, which also may resolve with treatment of the bacterial infection. Membranous nephropathy, due to concurrent infection with hepatitis B or C virus or syphilis Membranoproliferative glomerulonephritis associated with concurrent HCVor mixed cryoglobulinemia An immune complex glomerulonephritis with IgA deposits Interstitial nephritis, often with nephrocalcinosis, that may reflect CMV or a reaction to a Bactrim Amyloidosis that may be due to chronic infection Thrombotic thrombocytopenic purpura electrolyte disorders also may occur, particularly hyponatremia, metabolic acidosis (possibly distal renal tubular acidosis), and hyperkalemia. Adrenal insufficiency and/or high-dose trimethoprim (acting similar to a potassium-sparing diuretic) are usually responsible for the rise in the plasma potassium concentration.

Inflammatory reactions (immune reconstitution syndromes) With initiation of HAART, some patients experience inflammatory reactions that appear to be associated with immune reconstitution as indicated by a rapid increase in CD4 count. may present with generalized signs of fevers, sweats, and malaise with or without more localized manifestations that usually represent unusual presentations of opportunistic infections. The diagnosis of IRIS is one of exclusion and can be made only after recurrence or new opportunistic infection has been ruled out as the cause of the clinical deterioration. Management of IRIS is conservative and supportive with use of corticosteroids only for severe reactions. Most authorities recommend that antiretroviral therapy be continued unless the reaction is life-threatening.

Evaluation of the HIV-infected patient with diarrhea o INCIDENCE : The use of HAART itself (particularly nelfinavir and ritonavir) can also lead to medicationinduced diarrhea , despite HAART, 40 percent of HIV-infected adults still reported at least one episode of diarrhea o PATHOGENESIS : o Diarrheal disease in HIV-infected individuals is frequently caused by infectious agents but may also be due to infiltrative diseases, such as lymphoma or Kaposi's sarcoma o The infectious pathogens associated with diarrheal disease in HIV infection: the enteroaggregative Escherichia coli (EAEC) , Cryptosporidium parvum , Mycobacterium avium complex (MAC) , HIV infection of the gastrointestinal tract o Regional involvement

o o

o Small bowel involvement : diarrhea is usually watery and of large volume; bloating, gas, cramping, and potentially profound weight loss. malabsorption of D-xylose or vitamin B12. o Large bowel involvement : diarrhea is characterized by frequent, small volume, often painful stools. o Anorectal involvement severe tenesmus, dyschezia and urgency, localizes the process to the anorectum. Exposures : o travel history (Entamoeba, Giardia), sexual exposures, food associations (lactose intolerance) or other significant past medical history (eg, chronic pancreatitis). o A history of unprotected receptive anal intercourse may suggest sexual transmission of Herpes simplex virus (HSV), Neisseria gonorrhea, Chlamydia, or occasionally Entamoebae . o In patients who are taking HAART, medication-induced diarrhea include nelfinavir and ritonavir; other implicated agents include mainly protease inhibitors (ie, lopinavir, fosamprenavir, and atazanavir). o HIV-infected patients are often prescribed antibiotics, so Clostridium difficile or small bowel overgrowth syndrome are also diagnostic considerations. PHYSICAL EXAMINATION o Height and weight will assist in determining nutritional status. o Orthostatic blood pressure will determine the degree of volume depletion, both suggesting infection of the small bowel. o The skin and mucous membranes may reflect underlying micronutrient deficiencies, which could also accompany a small bowel process. o Fever in an immunosuppressed host may indicate the possibility of opportunistic infections such as CMV, MAC, and other pathogens. o Hepatosplenomegaly may suggest a systemic infiltrative process, such as MAC, histoplasmosis, or lymphoma. o Abdominal tenderness may indicate the possibility of an abdominal abscess, colitis, or biliary tract or pancreatic disease. o Perirectal tenderness may suggest anorectal infection from gonorrhea or Chlamydia or lymphogranuloma venereum. o Guaiac positive stools in a patient with advanced immunosuppression may suggest mucosal disease such as CMV or HSV colitis. o A full physical examination, including ophthalmologic evaluation in the patient with advanced immunosuppression, is important since there may be other clues as to the etiology of diarrhea, such as concomitant retinitis and colitis from CMV infection. DIAGNOSTIC STUDIES o Stool examination : Stool examinations should be ordered for culture of bacteria, C. difficile toxin assay, and examination for ova and parasites , n acid-fast smear should also be requested to look for Cryptosporidium, Isospora, and Cyclospora. o Blood cultures : If disseminated MAC infection is a diagnostic consideration, blood should also be obtained in fungal isolator tubes for culture. o Endoscopy: In patients with advanced immunocompromise and either persistent diarrhea or diarrhea with fever, more extensive workup is reasonable, with small bowel biopsies looking for MAC, lymphoma, or microsporidiosis. In patients with colitis and negative stool examinations, colonoscopy and biopsy looking for CMV or other inflammatory enteridites should be considered. o Imaging : Radiographic contrast studies generally are not useful in evaluating diarrhea COMPLICATIONS : Malnutrition , Significant electrolyte disturbances particularly in severe cryptosporidiosis EMPIRIC THERAPY :

 If stool evaluation and flexible sigmoidoscopy are nondiagnostic, some clinicians prefer empiric antibiotic therapy with a quinolone and metronidazole to treat possible small bowel overgrowth, culturenegative Campylobacter, or Giardia. We generally do not recommend this strategy unless the patient has a clinical history strongly suggestive of a possible diagnosis (ie, the sexual partner was recently diagnosed with Giardia). Empiric therapy directed towards amoebic colitis is also not recommended in developed countries. If chronic diarrhea continues unabated without a diagnosis, symptomatic therapy with antimotility drugs can be initiated. If a particular antiretroviral medication is the culprit (ie, nelfinavir, ritonavir), alternative medications should be substituted . Evaluation of the HIV-infected patient with pulmonary symptoms o HIV- patients are at increased risk of both infectious and noninfectious pulmonary diseases. o Careful attention to historical detail and physical examination, combined with a rational approach to noninvasive testing, can provide a definitive diagnosis in many cases. Patients who require rapid diagnostic evaluation, or those who fail to respond to therapy should be considered for invasive diagnostic testing, including FOB and surgical lung biopsy. o A diagnostic algorithm for the evaluation of HIV-infected patients with pulmonary symptoms, including options for empiric therapy and definitive diagnosis, is recommended Treat Empirically if bacterial pneumonia, TB, or PCP are suspected based on clinical presentation. Screening procedures : include chest CT , exercise oximetry, DLCO, or gallium scan. If patient is critically ill, procede with bronchoscopy and/or other invasive procedure. Evaluation of the HIV Patient with odynophagia and dysphagia A history of dysphagia or odynophagia should prompt concerns regarding possible esophagitis. This may be due to Candida, HSV, CMV, or aphthous ulcers. Although oropharyngeal thrush often accompanies esophagitis with a positive predictive value of 90 percent If odynophagia rather than dysphagia is the most prominent symptom, candida esophagitis is less probable. The patient with severe odynophagia, without dysphagia or thrush, is more likely to have ulcerative esophagitis. Rarely, esophageal lymphoma may be diagnosed The only way to establish a specific etiology for dysphagia and/or odynophagia in patients with HIV is by endoscopy with biopsy , barium swallow radiography is not a recommended study

most clinicians treat patients with dysphagia (especially if they also have oral thrush) with an empiric course of fluconazole (100 mg/day PO after a 200 mg loading dose) prior to proceeding with endoscopy since Candida infection is so common . Improvement in symptoms should be expected in 5 to 7 days.

Evaluation of abdominal pain in the HIV-infected patient Symptoms Suspect Dull pain, diarrhea, mild Infectious enteritis nausea, vomiting Acute, severe pain, Perforation, peritoneal irritation peritonitis Diagnostic approach Stool cultures, ova and parasites, sigmoidoscopy infectious Abdominal plain films, surgical consultation, ultrasonography, paracentesis; if ascites is present, laparoscopy cholangitis, Liver function tests, CT/ultrasound, ERCP, liver infiltration, biopsy Contrast study, endoscopy

Right upper quadrant pain, Cholecystitis, abnormal liver function hepatic tests cholangiopathy Subacute pain, severe Obstruction nausea and vomiting Differential diagnosis of abdominal pain in AIDS

Organ Causes Stomach Gastritis CMV*, cryptosporidium, H. pylori Focal ulcer CMV*, acid-peptic disease Outlet Cryptosporidium*, CMV, lymphoma, MAC obstruction Mass Lymphoma, KS, CMV Small bowel Enteritis Cryptosporidium*, CMV, MAC Obstruction Lymphoma*, KS Perforation CMV*, lymphoma Colon Colitis CMV*, HSV, salmonella, Histoplama Obstruction Lymphoma*, KS, intussusception, Perforation CMV*, lymphoma, HSV Appendicitis KS*, cryptosporidium, CMV Anorectum Proctitis Herpes*, bacteria, CMV Tumor KS, lymphoma, condyloma Liver, spleen Infiltration Lymphoma*, CMV, MAC Biliary tract Cholecystitis CMV*, cryptosporidium*, KS Papillary stenosis CMV*, cryptosporidium*, KS, cholangitis, CMV* Pancreas Inflammation CMV*, KS, pentamidine, DDI Tumor Lymphoma, KS Mesentery, peritoneum Infiltration MAC*, cryptococcus, KS, lymphoma, histoplasmosis, tuberculosis, coccidiomycosis, toxoplasmosis * More frequent.

Malaria
INTRODUCTION : Plasmodium species : P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi In areas where malaria is endemic, groups at high risk for severe malaria include : 1. young children (6 to 36 months) 2. pregnant women. 3. Travelers to areas where malaria is endemic generally have no previous exposure to malaria parasites and are at very high risk for severe disease if infected with P. falciparum. . Older children and adults develop partial immunity after repeated infection and are at relatively low risk for severe disease. Although most severe and complicated malaria is usually due to P. falciparum, patients with complicated infection due to P. vivax have also been described.

INCUBATION PERIOD : The incubation period for P. falciparum infection is usually 12 to 14 days. Longer incubation periods are more likely in semi-immune individuals and individuals taking inadequate malaria prophylaxis at the time of infection. The relapsing malarias (P. vivax and P. ovale) can cause clinical illness several weeks or months after the initial infection due to presence of hynozoites in the liver

CLINICAL MANIFESTATIONS Uncomplicated malaria : Malaria should be suspected in patients with any febrile illness after exposure to a region where malaria is endemic. The initial symptoms of malaria are nonspecific and may also include tachycardia, tachypnea, chills, malaise, fatigue, diaphoresis, headache, cough, anorexia, nausea, vomiting, abdominal pain, diarrhea, arthralgias, and myalgias. Complicated malaria : Complicated or severe malaria is generally defined as acute malaria with hyperparasitemia ( 5 to 10 percent of RBCs infected) and/or major signs of organ dysfunction: Altered consciousness with or without seizures Respiratory distress or acute respiratory distress syndrome (ARDS) Circulatory collapse Metabolic acidosis Renal failure, hemoglobinuria ("blackwater fever") Hepatic failure Coagulopathy with or without DIC Severe anemia or massive intravascular hemolysis Hypoglycemia

Features indicating a poor prognosis in severe malaria Clinical features 1. Impaired consciousness 2. Repeated convulsions (3 in 24 hr) 3. Respiratory distress (rapid, deep, labored breathing) 4. Substantial bleeding 5. Shock

Biochemical features 1. Renal impairment (serum creatinine, >3 mg/dl) 2. Acidosis (plasma bicarbonate, <15 mmol/liter) 3. Jaundice (serum total bilirubin, >2.5 mg/dl 4. Hyperlactatemia (venous lactate, >45 mg/dl) 5. Hypoglycemia (blood glucose, <40 mg/dl) 6. Elevated aminotransferase levels (>3 times normal) Hematologic features 1. Parasitemia (>500,000 parasites/mm3 or >10,000 mature trophozoites and schizonts/mm3) 2. 5 % of neutrophils contain malaria pigment The combination of deep jaundice and renal failure is particularly grave

FEVER : Early in the course of malaria infection, febrile paroxysms occur at irregular intervals each day. The temperature of nonimmune individuals may rise above 40C Febrile paroxysms may occur every other day for P. vivax, P. ovale, and P. falciparum and every third day for P. malariae. Paroxysms occurring at regular intervals are more common in the setting of infection due to P. vivax or P. ovale than P. falciparum

CHILDREN VERSUS ADULTS : Common manifestations among children with severe malaria include convulsions, coma, hypoglycemia, metabolic acidosis, severe anemia, and neurodevelopmental sequelae. Findings observed more frequently among adults than children include severe jaundice, acute renal failure, and acute pulmonary edema. DIFFERENTIAL DIAGNOSIS : viral infection, meningitis, pneumonia, bacteremia, leptospirosis, typhus, and enteric fever. Malaria can coexist with these entities, and with HIV, malnutrition, and intestinal geohelminths. DIAGNOSIS OF MALARIA : Malaria diagnostic tools include clinical criteria, light microscopy, rapid diagnostic tests, and molecular diagnostic techniques. There are no pathognomonic clinical signs or symptoms for diagnosis of malaria. Light Microscopy Light microscopy remains the gold standard for diagnosis of malaria; it permits determination of the infecting species as well as quantification of parasitemia, facilitating monitoring the response to therapy. Clues to species diagnosis via thin smear Size of RBCs P. falciparum P. vivax Normal size (sometimes Enlarged distorted and crenated) May be multiple Usually one P. ovale P. malariae Enlarged, and usually Normal size oval in shape (with fimbriated ends) Usually one Usually one

Number of parasites per RBC Typical form of trophozoite Other characteristics

Rings Banana-shaped gametocytes; pigment in

Amoeboid, often fragmented Schuffner's granules; black often see RBCs; gametocytes and

Compact and regular

Compact

Schuffner's granules; Often see often see gametocytes and gametocytes and schizonts

schizonts rare Plasmodium blood smears

schizonts

schizonts

* Identification of a schizont with >12 merozoites in the peripheral circulation is an important diagnostic clue for P. vivax. In general, schizonts of P. falciparum are very rarely seen in blood films; they are generally absent from the peripheral circulation except in cases of severe infection with overwhelming parasitemia. Life cycle of the Plasmodium 1. Plasmodium-infected Anopheles mosquito bites a human and transmits sporozoites into the bloodstream. 2. Sporozoites migrate through the blood to the liver where they invade hepatocytes and divide to form multinucleated schizonts (pre-erythrocytic stage). Atovaquone-proguanil and primaquine have activity against hepatic-stage schizonts. 3. Hypnozoites are a quiescent stage in the liver that exist only in the setting of P. vivax and P. ovale infection. This liver stage does not cause clinical symptoms, but with reactivation and release into the circulation, late-onset or relapsed disease can occur up to many months after initial infection. Primaquine is active against the quiescent hypnozoites of P. vivax and P. ovale. 4. The schizonts rupture and release merozoites into the circulation where they invade red blood cells. Within red cells, merozoites mature from ring forms to trophozoites to multinucleated schizonts (erythrocytic stage). Blood-stage schizonticides such as artemisinins, atovaquone-proguanil, doxycycline, mefloquine and chloroquine interrupt schizogony within red cells.

5. Some merozoites differentiate into male or female gametocytes. These cells are ingested by the Anopheles mosquito and mature in the midgut, where sporozoites develop and migrate to the salivary glands of the mosquito. The mosquito completes the cycle of transmission by biting another host. Primaquine is a blood stage schizonticide with activity against schizonts of P. vivax but not those of P. falciparum. Rapid Diagnostic Tests (Rdts) For Malaria generally employ immunochromatographic lateral flow technology, in which a blood sample migrates across the surface of a nitrocellulose membrane containing stripes of antibodies specific for different epitopes of a target antigen along with a control antibody. Targets conserved across all human malarias include Plasmodium lactate dehydrogenase (PLDH) and aldolase enzymes. Diagnostic targets specific for P. falciparum include P. falciparum lactate dehydrogenase (pfLDH) and histidine-rich protein-2 (HRP-2). Other Diagnostic Approaches Molecular technologies have been developed to improve the diagnosis of malaria, although these methods are limited by a number of factors including specialized equipment, continuing supplies, operator expertise, turnaround time and cost. Comparing the malaria species
RBC preference Infected RBC diameter Ameboid trophozoites Band forms Schizont* P. falciparum RBCs of all ages Normal No No 16 to 20 merozoites; very rare in peripheral circulation Can be very high End organ damage and death can occur Yes No 12 days (8 to 25) P. vivax Young RBCs (reticulocytes) Larger than normal Yes No 20 to 24 merozoites P. ovale Young RBCs (reticulocytes) Larger than normal Yes No 4 to 16 merozoites (8 typical) Usually <2 percent Severe disease uncommon No Yes 15 days (10 to 20) P. malariae Older RBCs Normal or than normal No smaller P. knowlesi RBCs of all ages Normal No Yes 8 to 16 (10 typical) Can be high Severe disease can occur No No Uncertain infected humans Uncertain infected humans Uncertain infected humans in

Yes 6 to 12 merozoites (8 or 10 typical) Usually very low Severe disease rare

Parasitemia Disease severity Chloroquine resistance Relapses from liver Incubation period Prepatent period in liver Cycle in red cell

Usually <2 percent End organ damage and death less common than P. falciparum Yes Yes 14 days (10 to 30) (occasionally months) 12 days

Rare No 18 days (15 to 35) (occasionally months to years) 32 days

11 days

12 days

in

48 hours

48 hours

48 hours

72 hours

in

* Identification of a schizont with >12 merozoites in the peripheral circulation is an important diagnostic clue for P. vivax. In general, schizonts of P. falciparum are very rarely seen in blood films; they occur only in the setting of severe disease with hyperparasitemia. The latency period of vivax is typically longer than falciparum

Treatment of malaria
Antimalarial drugs : Drug Chloroquine Amodiaquine Quinine Quinidine Mefloquine Halofantrine Sulfadoxine-pyrimethamine Atovaquone-progunail Artemether-lumefantrine Clindamycin Tetracycline, Doxycycline Primaquine Indication Uncomplicated X X X X X X X X X X X X X Complicated Prophylaxis X

X X X

X (?)

Guidelines for treatment of uncomplicated P. falciparum malaria : Chloroquine-sensitive (Chloroquine OR Hydroxychloroquine) :Central America west of Panama Canal; Haiti; the Dominican Republic; and most of the Middle East. Infections acquired in Korea and the states of the former Soviet Union have been uniformly caused by P. vivax to date and should therefore be treated as chloroquine-sensitive infections. Chloroquine-resistant or unknown resistance: All malarious regions except those specified as chloroquine-sensitive listed below. Middle Eastern countries with chloroquine-resistant P. falciparum include Iran, Oman, Saudi Arabia, and Yemen. A. Artemisinin combination therapy (first line) Artemether + lumefantrine Artesunate + amodiaquine Artesunate + mefloquine Artesunate + sulfadoxine-pyrimethamine

B. Atovaquone-proguanil C. Quinine PLUS one of the following: Doxycycline, Tetracycline, Clindamycin D. Mefloquine + artesunate OR Mefloquine +/- doxycycline PLUS Doxycycline Therapeutic options for parenteral treatment of severe malaria I. Artesunate II. Quinine or Quinidine PLUS one of the following: Doxycycline, Tetracycline , Clindamycin The total duration of therapy with quinine/quinidine for severe malaria is 7 days. The total duration of therapy with artemisinin based therapy is 3 days. After the acute stage of illness has been treated with parenteral therapy and the patient can swallow, a complete course of oral therapy should be administered

Treatment of non-falciparum species Generally : o We suggest chloroquine (Grade 2B). o We suggest mefloquine for treatment of chloroquine-resistant P. vivax (Grade 2C). o Following treatment of malaria due to P. vivax or P. ovale, we recommend presumptive antirelapse therapy with primaquine to prevent relapse (Grade 1B). P. vivax , P. ovale : o (hloroquine-sensitive : Chloroquine OR Hydroxy-chloroquine PLUS Primaquine o Chloroquine-resistant : A. Mefloquine OR Atovaquone-proguanil PLUS Primaquine B. Quinine PLUS one of the following: Doxycycline , Tetracycline PLUS Primaquine P. malariae , P. knowlesii : Chloroquine OR Hydroxy-chloroquine

Prevention of malaria infection in travelers : We recommend chemoprophylaxis for patients traveling to destinations with risk for malaria transmission (Grade 1A). Areas with chloroquine-resistant Plasmodium falciparum : Atovaquone-proguanil , Mefloquine, Doxycycline Areas with chloroquine-sensitive Plasmodium falciparum : Chloroquine ,Hydroxychloroquine , Atovaquone-proguanil ,Mefloquine ,Doxycycline , Primaquine Areas with P. vivax : Primaquine ,Chloroquine ,Hydroxychloroquine , Atovaquone-proguanil ,Mefloquine , Doxycycline Antirelapse therapy (to prevent relapse due to P. vivax or P. ovale) : Primaquine

Global distribution of Malaria in 2005 A- P. falciparum B- P. vivax

H1N1 influenza ('swine influenza')

EPIDEMIOLOGY In March and April 2009, an outbreak of H1N1 influenza A virus infection was detected in Mexico, with subsequent cases observed in many other countries including the United States. On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents. VIROLOGY Influenza subtypes : Clinical influenza can be caused by several different influenza subtypes, although H1N1 is the most common subtype implicated in both swine and human infections . Human cases of swine H3N2 influenza A virus infection have been reported rarely . Other subtypes that have circulated in pigs include H1N2, H3N1, and H3N2. Genetic and antigenic characterization :The 2009 H1N1 influenza A pandemic was caused by an H1N1 virus that had not been recognized previously in pigs or humans. This strain represents a genetic reassortment of swine, human, and avian strains of influenza. TRANSMISSION Person-to-person transmission : Influenza virus can be transmitted through sneezing and coughing via largeparticle aerosols, as well as by contact with surfaces that have been contaminated with respiratory droplets. Incubation period : Although the incubation period has not been established for pandemic H1N1 influenza A infection, it could range from one to seven days, and most likely from one to four days. Shedding : Immunocompetent patients with pandemic H1N1 influenza A virus infection are likely to be contagious from one day prior to the development of signs and symptoms until resolution of fever. Longer periods of shedding may occur in children (especially young infants), elderly adults, patients with chronic illnesses, and immunocompromised hosts. CLINICAL MANIFESTATIONS : Typical clinical manifestations include fever, headache, cough, sore throat, myalgias, chills, and fatigue; vomiting and diarrhea have also been common, both of which are unusual features of seasonal influenza. During the 2009 pandemic, rapidly progressive pneumonia, respiratory failure, and acute respiratory distress syndrome have been reported in some cases. LABORATORY FINDINGS Elevated alanine aminotransferase (45 percent) Elevated aspartate aminotransferase (44 percent) Anemia (37 percent) Leukopenia (20 percent) Leukocytosis (18 percent) Thrombocytopenia (14 percent) Thrombocytosis (9 percent) Elevated total bilirubin (5 percent)

DIAGNOSIS Whom to test : Most patients with an uncomplicated influenza-like illness who reside in areas where influenza viruses are known to be circulating do not need to be tested for influenza infection. Patients in whom influenza testing should be considered include: 1. Hospitalized patients with suspected influenza infection 2. Patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts. 3. Individuals who died of acute illness in whom influenza was suspected.

Specimens : To establish the diagnosis of pandemic H1N1 influenza A, an upper or lower respiratory sample should be collected. Appropriate swabs must be used and conditions observed for optimal specimen collection. Diagnostic tests : 1. 2. 3. 4. Polymerase chain reaction Rapid antigen tests Immunofluorescent antibody testing Choice of test : Among patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts, it is reasonable to use a rapid antigen or immunofluorescence antibody test. If identification of pandemic H1N1 influenza A is required, then real-time reverse transcriptase polymerase chain reaction testing should be performed.

CASE DEFINITIONS OF PANDEMIC H1N1 INFLUENZA Influenza-like illness (ILI) is defined as fever (temperature of 100F [37.8C] or greater) with cough or sore throat in the absence of a known cause other than influenza. A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratoryconfirmed H1N1 influenza A virus detected by real-time reverse transcriptase (rRT)-PCR or culture. Pandemic H1N1 influenza A may be suspected in an individual who does not meet the definition of confirmed pandemic H1N1 influenza A, but has an ILI and an epidemiologic link.

High risk groups High risk groups for the development of complications of pandemic H1N1 influenza A include: 1. 2. 3. 4. Children younger than 5 years of age, but especially those younger than 2 Individuals 65 years of age or older Pregnant women Individuals younger than 19 years of age who are receiving long-term aspirin therapy and who therefore might be at risk for Reye syndrome after influenza virus infection 5. Individuals of any age with chronic medical conditions requiring ongoing medical care, including: o Chronic pulmonary disease, including asthma (particularly if systemic glucocorticoids have been required during the past year) o Cardiovascular disease, except isolated hypertension o Active malignancy o Chronic renal insufficiency o Chronic liver disease o Diabetes mellitus o Hemoglobinopathies such as sickle cell disease

o Immunosuppression, including HIV infection (particularly if CD4 <200 cells/microL), organ or hematopoietic stem cell transplantation, inflammatory disorders treated with immunosuppressants o Individuals who have any condition that can compromise handling of respiratory secretions (eg, cognitive dysfunction, spinal cord injuries, seizure disorders, neuromuscular disorders, cerebral palsy, metabolic conditions) o Children with an underlying metabolic disorder, such as medium-chain acyl-CoA dehydrogenase deficiency, who are unable to tolerate prolonged fasting ANTIVIRAL THERAPY Resistance patterns : The vast majority of strains of pandemic H1N1 influenza A virus circulating in 2009 appear sensitive in vitro to the neuraminidase inhibitors, oseltamivir and zanamivir, but all strains tested have been resistant to amantadine and rimantadine. Indications : Not all individuals with suspected pandemic H1N1 influenza A infection need to be seen by a health care provider or treated. During the current pandemic, patients with mild illness do not need to be tested or treated unless they have risk factors for complications. Patients with severe illness and those at high risk for complications from influenza should contact their health care provider or seek medical care. We recommend antiviral therapy with zanamivir or oseltamivir for : 1. all patients with confirmed or suspected influenza virus infection (either pandemic or seasonal strains) who are hospitalized (Grade 1B). 2. Patients with confirmed or suspected influenza virus infection who present with clinical findings suggestive of lower respiratory tract infection (eg, dyspnea, tachypnea, unexplained oxygen desaturation) and those who are showing signs of rapid clinical deterioration. 3. Antiviral therapy should be considered for outpatients with confirmed or suspected influenza virus infection who are at increased risk for complications: Individuals with obesity (particularly those with morbid obesity) may be at increased risk of hospitalization and death due to pandemic H1N1 influenza infection; many obese persons have underlying conditions that increase the risk of influenza complications, such as diabetes mellitus, asthma, chronic respiratory illness, or liver disease . Thus, patients with morbid obesity (BMI >40) and possibly those with obesity (BMI 30 - 39) with suspected or confirmed influenza virus infection should be carefully evaluated for the presence of conditions that confer increased risk of influenza complications.If any such conditions are present treatment should be given.

Timing of antiviral initiation : Treatment should be initiated as soon as possible. In patients who are more than mildly ill, we would initiate therapy even past 48 hours of symptoms. Choice of antiviral : As of September 2009, 99 percent of influenza isolates circulating in the United States were pandemic H1N1 influenza A, the vast majority of which are sensitive to oseltamivir. However, if local surveillance data indicate that oseltamivir-resistant seasonal H1N1 influenza A virus is circulating, zanamivir is the preferred antiviral. Patients who are unable to take zanamivir in such a setting can be given the combination of rimantadine and oseltamivir. As the 2009 to 2010 influenza season evolves, clinicians will need to be aware of local surveillance data and updated recommendations from the US Centers for Disease Control and Prevention Dosing : Zanamivir : 10 mg (2 inhalations) twice daily for 5 days

Oseltamivir: 75 mg twice daily for 5 days

Pregnant women : Oseltamivir and zanamivir are Pregnancy Category C drugs, reflecting that clinical studies have not been done to assess the safety of their use during pregnancy . No adverse events have been shown to be caused by oseltamivir or zanamivir among women who received these agents during pregnancy or among infants who were exposed while in utero, although there are limited data . Pregnant women who meet current case definitions for confirmed or suspected pandemic H1N1 influenza A infection should receive antiviral therapy with oseltamivir, since the potential benefit outweighs the theoretical risk to the fetus . Oseltamivir is recommended over zanamivir because only the former agent is systemically absorbed (show table 1). In addition, zanamivir is relatively contraindicated in patients with asthma or chronic obstructive pulmonary disease. Treatment should be initiated as early as possible, and should not be withheld while awaiting results of diagnostic testing or in situations in which testing is not performed [6,10] . Although the benefits of antiviral therapy are expected to be greatest when initiated within the first 48 hours following symptom onset, treatment should be administered even to pregnant women who present >48 hours after illness onset, particularly in those requiring hospitalization. . In addition to antiviral therapy, use of acetaminophen is important when fever is present, since hyperthermia during the first trimester has been associated with neural tube defects and other birth defects . In addition, fever during labor is a risk factor for neonatal seizures, encephalopathy, cerebral palsy, and neonatal death

ANTIBACTERIAL : Patients with pandemic H1N1 influenza A who develop pneumonia should be treated empirically for community-acquired pneumonia (CAP), given the risk of secondary bacterial pneumonia. In hospitalized patients with severe CAP requiring intensive care unit admission who also have either necrotizing/cavitary infiltrates or empyema, methicillin-resistant Staphylococcus aureus (MRSA) infections should be suspected and treated in addition to other potential causes. Prevention of pandemic H1N1 influenza : Indications post-exposure antiviral prophylaxis can be considered for : 1. Individuals who are at high risk for complications of influenza (eg, individuals with certain chronic medical conditions, 65 years of age, pregnant women) who have had close contact with a confirmed or suspected case. 2. Health care workers, public health workers, or first responders who were not using appropriate personal protective equipment during close contact with a confirmed or suspected patient during that person's infectious period. Prophylaxis is generally NOT recommended if >48 hours have elapsed since the last contact with an infectious individual. An alternative to post-exposure prophylaxis for individuals who meet the criteria outlined above is to counsel them about the early signs and symptoms of influenza and to advise them to contact their healthcare provider for evaluation and potential early treatment if they become symptomatic. Post-exposure prophylaxis should NOT be used : o In healthy children or adults based upon potential exposures in the community, school, camp, or other settings. o When contact occurred before or after, but not during, the ill individual's infectious period.

Once a vaccine is available for the prevention of pandemic H1N1 influenza, chemoprophylaxis will probably be unnecessary in immunocompetent individuals who have been vaccinated 2 weeks earlier. Certain individuals who have ongoing occupational risk for exposure (eg, healthcare workers, public health workers, first responders), and who are also at increased risk of influenza complications, should follow guidelines for personal protective equipment stringently or consider temporary reassignment in order to reduce the need for post-exposure prophylaxis .

Choice of agent For patients in whom prophylaxis for pandemic H1N1 influenza A virus infection is indicated, we recommend either oseltamivir or zanamivir (Grade 1B). Zanamivir is relatively contraindicated in individuals with asthma or chronic obstructive pulmonary disease. Duration of prophylaxis : Antiviral prophylaxis should be continued for a total of 10 days following the last known exposure to a confirmed case. Dosing : Zanamivir : 10 mg (2 inhalations) once daily Oseltamivir : 75 mg once daily

Immunization : Recommended for administration of the pandemic H1N1 influenza vaccine, 1. Pregnant women 2. Household contacts and caregivers of children younger than 6 months of age (eg, parents, siblings, and daycare providers) 3. Healthcare and emergency medical services personnel 4. Individuals from 6 months through 24 years of age 5. Individuals from 25 through 64 years of age with health conditions associated with increased risk of influenza complications (High risk groups) Dosing schedule : Children aged 6 months to 9 years should receive two doses of the vaccine, separated by 4 weeks; individuals 10 years of age should receive one dose .

Dosing recommendations for antiviral agents for treatment and prophylaxis of influenza Drug Oseltamivir Zanamivir Amantadine Rimantadine Formulations 75-mg capsule 5 mg per inhalation 100-mg tablet 100-mg tablet Treatment 150 mg/d divided into 2 doses for 5 days 2 inhalations twice daily for 5 days 200 mg/day divided into 2 doses for 5 days 200 mg/day divided into 2 doses for 5 days Prophylaxis 75 mg once daily 2 inhalations once daily for 10 days 200 mg/day divided into 2 doses for 5 days 200 mg/day divided into 2 doses for 5 days

NEPHROLOGY

Radiocontrast Media-Induced Acute Kidney Injury (Acute Renal Failure)

The administration of radiocontrast media can lead to a usually reversible form of acute renal failure that begins soon after the contrast is administered. The various iodinated radiocontrast agents have different levels of nephrotoxicity, with the lowest risk of toxicity associated with low- or iso-osmolal agents. The mechanism of injury are renal vasoconstriction resulting in medullary hypoxemia, and direct cytotoxic effects of the contrast agents. The renal failure typically becomes apparent within the first 12 to 24 hours after the contrast study, is nonoliguric, and in almost all cases, the decline in renal function is mild and transient. The differential diagnosis : ischemic ATN and renal atheroemboli. Risk factors for radiocontrast nephrotoxicity include: 1. underlying renal insufficiency, with progressively increased risk with crea 1.5 mg/dL 2. diabetic nephropathy with renal insufficiency 3. advanced heart failure 4. other cause of reduced renal perfusion (such as hypovolemia) 5. high total dose of and high osmolality contrast agent; 6. multiple myeloma 7. cardiac catheterization or intervention. Low dose has been variably defined as less than 70 mL, less than 125 mL, or less than 5 mL/kg [to a maximum of 300 mL] divided by the plasma creatinine concentration. We recommend the following preventive measures for patients at increased risk of contrast nephropathy: Use, ultrasonography, MRI without gadolinium, or CT without radiocontrast. We recommend NOT using high osmolal agents (1400-1800 mosmol/kg)(Grade 1A). We suggest the use of iso-osmolal agents (approximately 290 mosmol/kg) rather than low osmolal agents (500 to 850 mosmol/kg) (Grade 2B). Use lower doses of contrast and avoid repetitive, closely spaced studies (eg, <48 hours apart). Very small amounts of contrast (<10 mL) have been safely used in patients with advanced kidney disease for examination of poorly maturing arteriovenous fistula Avoid volume depletion and nonsteroidal antiinflammatory drugs. If there are no contraindications to volume expansion, we recommend isotonic intravenous fluids prior to and continued for several hours after contrast administration (Grade 1B). The optimal type of fluid and timing of administration are not well established. We suggest isotonic bicarbonate rather than isotonic saline (Grade 2B).

A suggested regimen is: 1. isotonic bicarbonate : o prepared a solution by adding 150 meq of sodium bicarbonate (15 ampules 10 mmol) to 850 mL of 5 % dextrose in water. o A bolus of 3 mL/kg (200 ml) of isotonic bicarbonate for one hour prior to the procedure, and continued at a rate of 1 mL/kg per hour(400ml) for six hours after the procedure. 2. isotonic saline: o Isotonic saline at a rate of 1 mL/kg per hour(500 ml before and 500 ml after) , begun at least two and preferably 6 to 12 hours prior to the procedure, and continuing for 6 to 12 hours after contrast administration.

o The duration of administration of fluid should be directly proportional to the degree of renal impairment (eg, should be longer for individuals with more severe renal impairment). 3. Acetylcysteine : o at a dose of 600 to 1200 mg orally twice daily, administered the day before and the day of the procedure (Mucolys tab 200 mg 32 or 62) (Grade 2B). o If bicarbonate is used as the hydration solution, we prefer administering acetylcysteine at a dose of 1200 mg orally twice daily the day before and the day of the procedure. o Based upon the lack of convincing evidence of benefit and the potential risk of anaphylactoid reactions, we suggest not routinely using intravenous acetylcysteine for the prevention of contrast nephropathy (Grade 2B). We recommend NOT using mannitol or other diuretics prophylactically (Grade 1B). Among patients with stage 3 and 4 CKD, we recommend NOT performing prophylactic hemofiltration or hemodialysis after contrast exposure (Grade 1B). Among patients with stage 5 CKD, we suggest prophylactic hemodialysis after contrast exposure if there is already a functioning hemodialysis access (Grade 2C). We would not place a temporary access for prophylactic hemodialysis in these patients. Some clinicians would not perform prophylactic hemodialysis in any of these patients, pending further data.

OVERVIEW OF RENAL TUBULAR ACIDOSIS RENAL ROLE IN ACID-BASE BALANCE: Reabsorption of bicarbonate 85 to 90 % of filtered bicarbonate reabsorbed in the proximal tubules primarily by Na-H exchange. By comparison, 10 % is reabsorbed in the distal nephron primarily via (HATPase). Under normal conditions, virtually no bicarbonate is present in the final urine. Acid excretion The excretion of the daily hydrogen ion load is a function of the distal tubule.

Forms of RTA : 1. Distal or type 1 RTA Proximal 2. type 2 RTA 3. Hypoaldosteronism or type 4 RTA Type 3 RTA : o transiently severe form of type 1 RTA in infants o rare autosomal recessive syndrome (resulting from carbonic anhydrase II deficiency) o with features of both type 1 and type 2 RTA o affected patients suffer from osteopetrosis, cerebral calcification, and mental retardation.

Distal (type 1) RTA: Pathogenetic : is characterized by an impaired capacity for hydrogen ion and therefore ammonium secretion in the collecting tubules. Characteristics o urine anion gap is positive o normal anion gap (hyperchloremic) metabolic acidosis. o Plasma bicarbonate : may be <10 meq/L o Urine pH : > than 5.5 o Plasma potassium : Usually reduced but hyperkalemic forms exist; hypokalemia largely corrects with alkali therapy o It is often associated with hypercalciuria contributes to the development of nephrolithiasis and nephrocalcinosis, a not uncommon complication of this syndrome Major causes of type I (distal) renal tubular acidosis o The most common causes in adults are autoimmune disorders and other conditions associated with chronic hyperglobulinemia. o In children, type 1 RTA is most often a primary, hereditary condition. 1. Primary ( Idiopathic, sporadic ) 2. Familial ( Autosomal dominant , Autosomal recessive) 3. Autoimmune Disorders : Sjgren's, Rheumatoid arthritis , SLE (may be hyperkalemic) 4. Hyperglobulinemia 5. Hypercalciuria 6. Drugs : Ifosfamide , Amphotericin B , Lithium carbonate 7. Cirrhosis 8. Sickle cell anemia (may be hyperkalemic) 9. Obstructive uropathy (may be hyperkalemic) 10. Renal transplantation

Incomplete distal RTA persistently high urine pH and hypocitraturia, as in the complete forms, but are able to maintain net acid excretion and the plasma bicarbonate concentration in the normal range The pathogenesis : is not well understood. These patients can develop hypercalciuria and nephrolithiasis; thus, should be considered in any calcium stone former with a urine pH persistently above 5.5.

Treatment : The aim of alkali therapy is to achieve a relatively normal plasma bicarbonate concentration (22 to 24 meq/L). generally treated with 1 to 2 meq/kg of sodium bicarbonate or sodium citrate (Bicitra , which is usually better tolerated). Children, however, may require as much as 4 to 8 meq/kg per day in divided doses because the urine pH and fixed bicarbonate losses may be higher than in adults . Potassium citrate, alone or with sodium citrate (Polycitra ), is indicated for persistent hypokalemia or for calcium stone disease. In hyperkalemic form of type 1 RTA should not be used with Potassium salts and use a high-sodium, lowpotassium diet plus a thiazide or loop diuretic, if necessary .

Proximal (type 2) RTA : Pathogenetic : inability to reabsorb bicarbonate normally in the proximal tubule.. may occasionally present as an isolated defect, but is more commonly associated with generalized proximal tubular dysfunction called the Fanconi syndrome. Fanconi syndrome: bicarbonaturia, generalized proximal dysfunction may be associated with one or more of the following: glucosuria, phosphaturia, uricosuria, aminoaciduria, and tubular proteinuria. Characteristics o urine anion gap is positive o normal anion gap (hyperchloremic) metabolic acidosis. o Plasma bicarbonate : Usually 12 to 20 meq/L o Urine pH : Variable urine pH < 5.3 : In Untreated patients urine pH > 5.3 : if the plasma bicarbonate concentration is above 16 meq/L; this occurs with alkali therapy given for the diagnosis or treatment . o Plasma potassium : Reduced, made worse by bicarbonaturia induced by alkali therapy o The diagnosis of proximal RTA is : made by measurement of the urine pH and fractional bicarbonate excretion during a bicarbonate infusion. The hallmark is a urine pH above 7.5 and the appearance of more than 15 percent of the filtered bicarbonate in the urine when the serum bicarbonate concentration is raised to a normal level. Major causes of type I (distal) renal tubular acidosis o The most common causes of Fanconi syndrome in adults are the excretion of light chains due to multiple myeloma (which may be occult) and the use of a carbonic anhydrase inhibitor (such as acetazolamide) or the anticancer drug ifosfamide . o MM should be excluded in all patients with proximal RTA unless another cause is apparent. o In children, several forms of genetically inherited diseases are responsible for proximal RTA ; cystinosis is the most common.. 1. Primary disorders Idiopathic, sporadic

2. 3. 4. 5. 6. 7. 8. 9.

Familial disorders ( Cystinosis , Tyrosinemia , Hereditary fructose intolerance , Galactosemia , Glycogen storage disease (type I) , Wilson's disease , Lowe's syndrome ) Multiple myeloma Amyloidosis Ifosfamide Carbonic anhydrase inhibitors (acetazolamide) Heavy metals (Lead , Cadmium , Mercury ,Copper ) Vitamin D deficiency Renal transplantation Paroxysmal nocturnal hemoglobinuria

Treatment : phosphate and vitamin D supplementation . Treatment may be difficult since raising the bicarbonate concentration leads to a marked bicarbonate diuresis and excessive potassium losses . Most children require 10 to 15 meq/kg of bicarbonate per day to maintain a normal pH. an empirically determined fraction of the alkali replacement must be given as the potassium salt (usually potassium citrate). Treatment of a mild acidosis may not be necessary in adults who are not growing. The addition of a thiazide diuretic may be beneficial if large doses of alkali are ineffective or not well tolerated.

TYPE 4 RENAL TUBULAR ACIDOSIS : Pathogenetic : aldosterone deficiency or tubular resistance to the action of aldosterone Characteristics o urine anion gap is positive o mild normal anion gap metabolic acidosis. o Plasma bicarbonate : > 17 meq/L o Urine pH : Usually < 5.5. o Plasma potassium : Increased o The diagnosis can be made by measurement of plasma renin and aldosterone levels but many patients are treated empirically.. Major causes of type I (distal) renal tubular acidosis o The most common form of aldosterone deficiency in adults is hyporeninemic hypoaldosteronism which is frequently observed among patients with mild to moderate renal insufficiency, especially if due to diabetic nephropathy o Adrenal insufficiency and, in children, congenital adrenal hyperplasia are other common causes of hypoaldosteronism. o Resistance to the action of aldosterone is observed in patients with chronic tubulointerstitial disease and those treated with potassium-sparing diuretics.. 1. Aldosterone deficiency a. Primary i. Primary adrenal insufficiency ii. Congenital adrenal hyperplasia, particularly 21-hydroxylase deficiency iii. Isolated aldosterone synthase deficiency iv. Heparin and low molecular weight heparin b. Hyporeninemic hypoaldosteronism

i. Renal disease, most often diabetic nephropathy ii. Volume expansion, as in acute glomerulonephritis iii. ACEi iv. NSAIDs v. Cyclosporine HIV infection vi. Some cases of obstructive uropathy 2. Aldosterone resistance a. Drugs :Amiloride ,Spironolactone ,Triamterene ,Trimethoprim (usually in high doses) ,Pentamidine b. Tubulointerstitial disease c. Pseudohypoaldosteronism d. Distal chloride shunt Treatment : Appropriate therapy varies with the cause of hypoaldosteronism. Patients with primary adrenal insufficiency, for example, should receive mineralocorticoid replacement therapy (with fludrocortisone at a dose of 0.05 to 0.2 mg/day) to correct the hyperkalemia and, if present, volume depletion. They are also treated with a glucocorticoid, such as hydrocortisone or prednisone, to correct the cortisol deficiency. Despite its efficacy, fludrocortisone is often not used in hyporeninemic hypoaldosteronism because many patients with this disorder have hypertension and/or edema, problems that can be exacerbated by mineralocorticoid replacement. In this setting, use of a low potassium diet and, if necessary, a loop or thiazide-type diuretic will usually control the hyperkalemia RTA Bicarbonate Urine pH Potassium Nephrocalcinosis Type 1 < 10 > 5.5 + Type 2 12 to 20 < 5.5 Type 4 >17 < 5.5 -

TREATMENT OF HYPOCALCEMIA
Intravenous calcium :

Indication for Intravenous calcium : o Patients with hypocalcemia who are severely symptomatic (carpopedal spasm, tetany, seizures, decreased cardiac function, or prolonged QT interval) o asymptomatic patients with an acute decrease in serum corrected calcium to 7.5 mg/dL o acutely symptomatic patients, as can occur when there is a rapid and progressive reduction in serum calcium (eg, acute hypoparathyroidism following post-radical neck dissection for head and neck cancer). o patients with milder degrees of hypocalcemia or with chronic hypocalcemia (due to hypoparathyroidism) who become unable to take or absorb oral supplements. Initially, intravenous calcium (1 to 2 g of calcium gluconate, equivalent to 90 to 180 mg elemental calcium, in 50 mL of 5 % dextrose) can be infused over 10 to 20 minutes. The calcium should not be given more rapidly, because of the risk of serious cardiac dysfunction, including systolic arrest . followed by a slow infusion of calcium with 10 % calcium gluconate (90 mg of elemental calcium per 10 mL) or 10 % calcium chloride (270 mg of elemental calcium per 10 mL) can be used to prepare the infusion solution. intravenous solution : prepared by adding 100 mL of 10 % calcium gluconate (10 Amp) to 1000 mL of 5 % dextrose in water at an initial infusion rate of 50 mL/h (for 20 hours). Calcium gluconate is usually preferred because it is less likely to cause tissue necrosis if extravasated. the infusion should be prepared with the following considerations: o The calcium should be diluted in dextrose and water or saline, because concentrated calcium solutions are irritating to veins. o The intravenous solution should not contain bicarbonate or phosphate, which can form insoluble calcium salts. If these anions are needed, another intravenous line (in another limb) should be used. Intravenous calcium should be continued until the patient is receiving an effective regimen of oral calcium and vitamin D. Calcitriol, in a dose of 0.25 to 0.5 mcg twice daily, is the preferred preparation of vitamin D for patients with severe acute hypocalcemia because of its rapid onset of action (hours).

Oral calcium :

For those with milder symptoms of neuromuscular irritability (paresthesias) and corrected serum calcium concentrations greater than 7.5 mg/dL initial treatment with oral calcium with 1500 to 2000 mg of elemental calcium given as calcium carbonate or calcium citrate daily, in divided doses. As an example, calcium carbonate is 40 percent elemental calcium, so that 1250 mg of calcium carbonate contains 500 mg of elemental calcium. Calcicar , Calcium D 1250 If symptoms do not improve with oral, intravenous calcium infusion is required.

Concurrent hypomagnesemia

To effectively treat hypocalcemia in patients with concurrent magnesium deficiency , hypomagnesemia should be corrected first. Hypomagnesemia is a common cause of hypocalcemia, both by inducing resistance to parathyroid hormone (PTH) and by diminishing its secretion. In patients with hypomagnesemia, hypocalcemia is difficult to correct without first normalizing the serum magnesium concentration. Thus, if the serum magnesium concentration is low, 2 g of magnesium sulfate should be infused as a 10 % solution over 10 to 20 minutes, followed by 1 gram in 100 mL of fluid per hour. Magnesium repletion should be continued as long as the serum magnesium concentration is less than 0.8 meq/L (1 mg/dL or 0.4 mmol/L).

More careful monitoring is required in patients who have impaired renal function who would be at greater risk of developing hypermagnesemia. Persistent hypomagnesemia, as occurs in some patients with ongoing gastrointestinal (eg, malabsorption) or renal losses, requires supplementation with oral magnesium, typically 300 to 400 mg daily divided into three doses. amp of magnesium sulfate contain 2.5 gr of magnesium multimagnesuim tab

Vitamin D When hypoparathyroidism (transient or permanent) or vitamin D deficiency are the cause of hypocalcemia, administration of intravenous calcium is only transiently effective (as long as the infusion continues), and oral calcium may not be well absorbed. In these cases, successful management requires the addition of vitamin D, which often permits a lower dose of calcium supplementation.

For the initial management of patients with hypoparathyroidism, we recommend vitamin D supplementation in addition to calcium ( Grade 1A). Calcitriol is the vitamin D metabolite of choice because it does not require renal activation, it has a rapid onset of action (hours), and a shorter half-life. Other acceptable options include alfacalcidol, vitamin D (ergocalciferol or cholecalciferol), or dihydrotachysterol . we recommend vitamin D repletion In individuals with hypocalcemia due to vitamin D deficiency, Nutritional deficiency (25OHD <20 ng/ml [50 nmol/L]) requires initial treatment with 50,000 units of vitamin D2 or D3 orally once per week for six to eight weeks, and then 800 to 1000 international units of vitamin D3 daily thereafter.

Treatment of hypoparathyroidism Treatment Calcium Dosage 1.0-1.5 g elemental daily (total diet + supplement) in divided doses Adjust dose as needed to control symptoms and maintain lownormal serum calcium concentration 0.5-1.0 micgrograms daily (in divided doses) 0.5-2.0 micrograms daily (in divided doses) 25,000-100,000 International Units daily 0.2-1.2 mg daily 25-100 mg daily

Vitamin D Calcitriol Alfacalcidol " One-Alpha " Ergocalciferol (D2) "Sterogel " Cholecalciferol (D3) Dihydrotachysterol Thiazide diuretics (if required to control hypercalciuria) Permanent hypoparathyroidism

In patients with permanent hypoparathyroidism, the goals of therapy are to relieve symptoms, to raise and maintain the serum calcium concentration in the low-normal range, eg, 8.0 to 8.5 mg/dL (2.0 to 2.1 mmol/L), and to avoid hypercalciuria (maintain 24-hour urinary calcium below 300 mg). All patients with permanent hypoparathyroidism require adequate calcium intake (1.0 to 1.5 g elemental calcium daily). Along with calcium supplementation, we suggest calcitriol rather than recombinant human parathyroid hormone (PTH) ( Grade 2B). The long-term safety of the relatively higher dose of PTH has not been established. In addition, recombinant PTH is much more expensive than standard therapy with calcitriol. However, in patients with refractory hypercalciuria, PTH is a reasonable option.

The initial treatment of hypercalciuria in patients with hypoparathyroidism is reducing the dose of calcium and vitamin D. Some patients will require the addition of thiazide diuretics.

TREATMENT OF HYPERKALEMIA
Confirm the patient is truly hyperkalemic (ie, exclude pseudohyperkalemia) Obtain electrocardiogram and, if signs of hyperkalemia are seen, place patient on cardiac monitor The specific therapies that follow are listed according to their rapidity of action; the choice among them varies according to the severity of ECG changes and muscle weakness Stabilize cardiac membranes with calcium: Give only for hyperkalemia with significant ECG findings (eg, widening of the QRS complex or loss of P waves, but not peaked T waves alone) or severe arrhythmias thought to be caused by hyperkalemia Give adults calcium chloride 500 to 1000 mg (5 to 10 mL of 10 % solution) by IV infusion slowly over 2 to 3 minutes, preferably via a central line; or give calcium gluconate 1000 mg (amp 10 % contain 10 mL) also infused slowly; may be given peripherally in large vein; time to onset is immediate Calcium treatment may be repeated after 5 minutes if ECG changes persist; patient must be on cardiac monitor when receiving calcium; calcium can exacerbate digoxin toxicity Since the effect of calcium is transient, patients with hyperkalemia also require treatments to shift potassium into cells and to remove potassium Shift potassium into cells: Give insulin and glucose to hyperkalemic patients with serum K 6.5 meq/L, except patients with chronic renal failure and no ECG changes, who are treated with hemodialysis Insulin and glucose: Give IV bolus of regular insulin 10 units with 100 mL of a 50 % glucose solution or 166 cc of SD 30% or or 500 cc of SD 10% or 1 liter of SD5% , monitor fingerstick glucose closely; time to onset is 15 to 30 minutes Beta 2 agonist: May give albuterol 10 to 20 mg in 4 mL saline nebulized over 20 minutes (may use metered dose inhaler) Sodium bicarbonate: Has minimal effect on shifting potassium intracellularly unless patient is acidemic; may promote renal excretion; give 45 meq slow IV infusion over 5 minutes Remove potassium Cation exchange resin (sodium polystyrene sulfonate): Give 15 to 30 grams orally; although less preferable, may also be given as retention enema; do not give enema with sorbitol; time to onset is approximately 1 to 2 hours; may repeat dose after 4 hours based upon repeat serum K Loop diuretic: May give furosemide 20 to 40 mg IV; higher dose may be required with renal insufficiency; the fluid losses must be replaced unless the patient is volume expanded Hemodialysis: Can be used if the conservative measures listed above fail, if hyperkalemia is severe, if the patient has renal failure, or if the patient has marked tissue breakdown and is releasing large amounts of potassium from injured cells

Seizures In Patients Undergoing Hemodialysis

CAUSES 1. 2. 3. 4. 5. 6. 7. 8. 9. Uremic encephalopathy Dialysis disequilibrium syndrome Drugs, such as erythropoietin, carbapenem and ertapenem Hemodynamic instability, whether hypotension or hypertension Cerebrovascular disease( hypertensive encephalopathy, infarction, hemorrhage, subdural hematoma) Dialysis dementia due to aluminum intoxication Electrolyte disorders, ( hyper-hypocalcemia, hypo-hyperglycemia, hypo-hypenatremia) Alcohol withdrawal Air embolism

Uremic encephalopathy Central nervous system dysfunction is universally observed among patients with severe untreated uremia. Depending upon the degree and rapidity of onset of renal failure, symptoms may range from irritability and restlessness to seizures, coma, and death. Seizures, which are most often generalized, and CNS dysfunction should abate shortly (within days to weeks) after the adequate renal replacement therapy. Dialysis Disequilibrium Syndrome (DDS) Central Nervous System disorder that is characterized by neurologic symptoms of varying severity that are thought to be due primarily to cerebral edema. predisposing factors : 1. New patients just being started on hemodialysis, particularly if the BUN is elevated (> 170 mg/dL ) 2. severe metabolic acidosis 3. older age 4. pediatric patients 5. the presence of other central nervous system disease, such as a preexisting seizure disorder. The classic DDS refers to acute symptoms developing during or immediately after hemodialysis. Early findings include headache, nausea, disorientation, restlessness, blurred vision, and asterixis. More severely affected patients progress to confusion, seizures, coma, and even death. It is now recognized, however, that many milder signs and symptoms associated with dialysis, such as muscle cramps, anorexia, and dizziness developing near the end of a dialysis treatment, are also part of this syndrome

Erythropoietin A rapid rise in blood pressure due to the administration of erythropoietin (EPO) may result in hypertensive encephalopathy, which is sometimes accompanied by seizures Drugs or toxins Penicillin and cephalosporin-related antibiotics : particularly when administered at extremely high doses , Meperidine , Metoclopramide: decrease the seizure threshold , Ethanol, Theophylline , L-dopa , Lithium toxicity , Amantadine , Acyclovir , High doses of intravenous contrast material , Carbamazepine overdose , Star fruit ingestion, Ertapenem . Hemodynamic instability Hypotension is a common complication of hemodialysis, occurring most frequently when dialysis is initiated or near its completion . When prolonged or severe, it may predispose to seizure, especially if associated with volume removal, osmotic shifts, abnormal cardiac function, or an underlying lesion of the central nervous system.

Severe intradialytic hypertension due to reactive vasoconstriction also can potentiate seizure activity in predisposed individuals. The acute increase in blood pressure is secondary to a hyperactive response to hypotension induced by ultrafiltration. This blood pressure response is relatively common.

Cerebrovascular disease Patients on dialysis are at an increased risk of cerebrovascular disease because of accelerated atherosclerosis, older age, a high incidence of hypertension, diabetes, malnutrition, hyperlipidemia. Hypertensive encephalopathy Hypertensive encephalopathy refers to the presence of signs of cerebral edema Signs and symptoms of neurologic involvement may include headache, nausea, vomiting, confusion, and mental status abnormalities, including focal or generalized seizures. The initial aim of treatment in the patient with hypertensive encephalopathy is to lower the diastolic pressure with the maximum initial fall in blood pressure not exceeding 25 % of the presenting value; this goal should be achieved within 2 to 6 hours and should not be exceeded in the first 24 hours. With dialysis patients, initial therapy of hypertensive encephalopathy should aim to optimize volume status via fluid removal with dialysis, since volume overload is likely to be causative. If blood pressure remains high despite the attainment of optimal dry weight, parenteral therapy may be necessary, particularly in the setting of clinical cardiac or neurologic involvement. Vasodilators, such as sodium nitroprusside, may be used since the dose of the agent can be titrated easily to the desired blood pressure. The recommended dose of nitroprusside ranges from 0.25 to 10 g/kg per minute, which is titrated to maintain the blood pressure at the desired target. Constant blood pressure monitoring (preferably in an intensive care unit) is required during the infusion. However, patients treated with sodium nitroprusside may require daily dialysis to eliminate the toxic metabolite (thiocyanate, which is normally eliminated by the kidney); the agent should generally not be used for more than 48 hours. An alternative parentally administered drug is labetalol, which can be administered by bolus or intravenous infusion. The usual intravenous dose of labetalol is 20 mg (which is administered over two minutes); an additional 20 to 80 mg may be administered at 10 minute intervals to a maximum total dose of 300 mg. Labetalol may also be administered as an intravenous infusion at a rate of two mg/minute. The drug begins to act within five minutes of administration. Oral antihypertensive medications should be concurrently initiated to shorten the duration of parenteral therapy.

Cerebral infarction and hemorrhage Dialysis patients appear to be at markedly increased risk of stroke large infarcts may be associated with edema or hemorrhage; the latter may be more likely to occur with heparin administration during dialysis or among those with elevated blood pressures. important strategies to avoid worsening of the neurologic deficit include better blood pressure control and the elimination of heparin during dialysis.

Subdural hematoma can occur spontaneously in hemodialysis patients or after routine dialysis treatment or trauma to the head.To avoid recurrence, hemodialysis should be performed without heparin for 7 to 10 days or peritoneal dialysis should be used temporarily PREVENTION Uremic encephalopathy An absolute indication for the initiation of dialysis includes progressive uremic encephalopathy, including confusion, seizures, and asterixis. However, since these findings may be lifethreatening, it is now appreciated that the initiation of dialysis prior to the onset of these findings does not place the patient in unnecessary jeopardy and may prevent the occurrence of CNS dysfunction, including seizures.

Dialysis disequilibrium syndrome therapy can be initiated with 2 hours of dialysis at a relatively low blood flow rate of 150 to 250 mL/min o Patients who also have marked fluid overload can be treated with ultrafiltration with a small surface area dialyzer (0.9 to 1.2 m2 o This regimen, which is repeated daily for three or four days, If the patient shows no signs of DDS, the blood flow rate can be increased by 50 mL/min per treatment (up to 300 to 400 mL/min) and the duration of dialysis can be increased in 30 minute increments (up to 4 or more hours) The patient can be started on peritoneal dialysis in which the low rate of peritoneal blood flow results in a urea clearance per unit time that is much lower than that with hemodialysis. The DDS has not been reported with continuous peritoneal dialysis Some physicians recommend prophylactic phenytoin (1000 mg loading dose followed by 300 mg/day until uremia is controlled) and/or the administration of 12.5 g of hypertonic mannitol intravenously every hour of dialysis in high-risk patients with marked azotemia (BUN above 150 to 200 mg/dL [54 to 71 mmol/L]) or an underlying alteration in mental status. use of bicarbonate dialysate, and a dialysate glucose concentration of 200 mg/dL (11.1 mmol/L) in diabetic patients to prevent hypoglycemia.

dialyzable antiepileptic drugs Certain antiepileptic medications, are removed by dialysis, such as phenobarbital and primidone , Unfortunately, the more commonly used drugs are nondialyzable phenytoin, carbamazepine, and valproic acid Erythropoietin therapy To reduce the frequency of seizures in association with EPO therapy, the following treatment guidelines have been suggested The initial weekly dose of EPO should not exceed 150 units/kg. The subcutaneous route of administration is preferred. High risk patients, such as those with hypertension and/or a history of seizures, should be closely monitored; in addition, the dose of EPO should be slowly increased among such patients. patients with severe or uncontrolled hypertension should initially be excluded from EPO therapy. If seizures have occurred in association with an elevation of blood pressure, EPO therapy can be resumed at a reduced dose of to the previous dose following good blood pressure control.

Dialysis-induced hypotension We suggest the following for the treatment of hemodynamic instability : Exclude causes that are non-dialysis related, such as myocardial ischemia and pericardial effusion Dialysis prescription should be altered based upon individual patient characteristics: o Accurate setting of the dry weight o Fixed sodium concentration greater than 140 meq/L or sodium modeling o Bicarbonate buffer o Avoid low magnesium and low calcium dialysate Ultrafiltration method should be optimized. This include ultrafiltration modeling alone or with sodium modeling, or sequential ultrafiltration and isovolemic dialysis Avoidance of food and antihypertensive medicines on dialysis day The administration of midodrine.

MANAGEMENT OF SEIZURES IN THE DIALYSIS PATIENT : Stopping dialysis Securing a patent airway Stabilizing the circulation Blood should be sampled for serum levels of glucose, calcium, sodium, magnesium and other electrolytes. Intravenous glucose should be administered if hypoglycemia is suspected, particularly in diabetic patients. If seizures persist, a diazepam 5 to 10 mg should be administered given by slow intravenous push. The dose can be repeated at 5 minute intervals to a maximum total dose of 20 to 30 mg. If administered, an antidote for diazepam (flumazenil) should always be available if respiratory depression occurs. followed by a loading dose of phenytoin (10 to 15 mg/kg) given at a rate no greater than 50 mg/min; constant electrocardiographic monitoring should be performed during this infusion. Maintenance therapy o Long-term therapy with antiepileptic medications may not be required if the patient's seizure is due to a reversible cause. If not, maintenance therapy with: phenytoin, carbamazepine, or valproic. o Phenytoin is the most common medication used for the treatment of seizures in dialysis patients. o Seizures resulting from DDS respond best to benzodiazepines, particularly clonazepam. No dose adjustment is necessary for clonazepam in renal failure; the daily recommended oral dose is 1.5 mg .

Diagnosis and acute management of suspected nephrolithiasis in adults

DIAGNOSIS The diagnosis of nephrolithiasis should be suspected in all patients with the acute onset of atraumatic flank pain, particularly if without abdominal tenderness and with hematuria. Possible confirmatory radiologic tests include abdominal plain film, intravenous pyelography (IVP), ultrasonography, and most commonly, non-contrasted helical CT scan, which is the test of choice A negative study should prompt consideration of a different diagnosis. IVP and ultrasonography are alternatives if helical CT is not available. Individual patient factors may influence the work-up in some instances : o Ultrasound is the initial diagnostic test in pregnant women or in patients in whom cholecystitis or a gynecologic process is a prominent consideration. o Abdominal plain film is a reasonable initial test in patients who have a history of radiopaque calculi and acute flank pain that is similar to that in previous episodes. However, a helical CT may be necessary if the abdominal plain film is negative, since the latter test may miss stones in the ureter.

Evaluation of the adult patient with established nephrolithiasis: complete metabolic evaluationis indicated in : 1. all patients with multiple stones at first presentation 2. in patients with a strong family history of stones 3. in patients with active stone disease, which is defined as recurrent stone formation, enlargement of existing stones, or the recurrent passage of gravel. METABOLIC EVALUATION Blood tests serum calcium: should be measured on two occasions, looking for hypercalcemia. serum bicarbonate : Although usually normal, the presence of a low serum bicarbonate concentration raises the possibility of Type I renal tubular acidosis. intact PTH is warranted in patients with plasma calcium in the high-normal range or if the urine calcium is high, since primary hyperparathyroidism is often associated with only intermittent and mild elevations in the plasma calcium concentration.

Urinalysis A careful urinalysis should be performed, since certain findings point toward a specific diagnosis. A urine pH above 7 with phosphate crystals in the urine sediment (coffin lid) is suggestive of calcium phosphate or struvite calculi, while the presence of hexagonal cystine crystals is diagnostic of cystinuria. In comparison, uric acid crystals (rhombic plates or rosettes) and calcium oxalate crystals (dumbbell-shaped calcium oxalate monohydrate and envelope-shaped calcium oxalate dihydrate) may be seen in individuals without stone disease and are therefore of limited diagnostic utility. Similar consideration applies to indinavir crystals, which are much more common in patients taking this drug than indinavir stones

24-hour urine collections At least two 24-hour urine collections should be obtained

The urine volume, pH, and excretion of calcium, uric acid, citrate, oxalate, sodium, and creatinine (to assess the completeness of the collection) should be measured. The urine is screened for cystine using the cyanide-nitroprusside test, which if positive indicates a cystine concentration >75 mg/L. If positive, a 24 hour urine collection should be performed . The frequently used upper limit of normal values for the above parameters (in mg/day) are : Men Women Calcium <300 <250 Uric acid <800 <750 Oxalate <45 <45 citrate <320 <320 cystine <400 <400 The normal of urinary creatinine excretion in patients < age of 50 is 20 to 25 mg/kg in men and 15 to 20 mg/kg in women. Values below this level suggest an incomplete collection, Measurement of sodium excretion is also important. Increased sodium intake can contribute to hypercalciuria, and will affect the response to a thiazide when prescribed to reduce urine calcium.

Urine calcium-creatinine ratio Although not as accurate as measurement from a 24-hour urine collection, calcium excretion (in g/day) can be estimated from 1.1 times the calcium-to-creatinine ratio (in mg/mg) in a random urine specimen , Normal calcium-to-creatinine ratio is below 0.3. As an example, urine calcium and creatinine concentrations of 30 and 100 mg/dL represent a ratio of 0.3 and, therefore, daily calcium excretion of roughly 0.33 g or 330 mg . ACUTE THERAPY Many patients can be managed with pain medication and hydration until the stone passes . Straining urine Patients should be instructed to strain their urine for several days and bring in any stone that passes for analysis. This will enable the clinician to better plan therapy. Pain control Patients can be managed at home if they are able to take oral medications and fluids. Hospitalization is required for those who cannot tolerate oral intake or who have uncontrollable pain or fever.

NSAIDs and opioids Both NSAIDs and opioids have been used for pain control in patients with acute renal colic. NSAIDs and opioids may be superior to either agent alone NSAIDs should be stopped 3 days before shock wave lithotripsy to minimize the risk of bleeding. Standard doses of opiates will relieve pain in those who do not respond to NSAIDs.

Stone passage Stone size and stone location is the major determinant of the likelihood of spontaneous passage Most stones 4 mm in diameter pass spontaneously. For stones > 4 mm in diameter, there is a progressive decrease in the spontaneous passage rate, which is unlikely with stones 10 mm in diameter. Proximal ureteral stones are also less likely to pass spontaneously.

Facilitating stone passage Several different medical interventions increase the passage rate of ureteral stones, including antispasmodic agents, calcium channel blockers, and alpha blockers, which have been used in combination with or without steroids Based upon data suggesting faster stone passage with tamsulosin, we initiate treatment with tamsulosin for four weeks to facilitate spontaneous stone passage in patients with stones 10 mm in diameter. Patients are then re-imaged if spontaneous passage has not occurred. Patients with stones larger than 10 mm in diameter and patients with significant discomfort or who have not passed the stone after four to six weeks should be referred to urology for potential intervention.

UROLOGY CONSULTATION Urgent urologic consultation is warranted in patients with urosepsis, acute renal failure, anuria, and/or unyielding pain, nausea, or vomiting Current options for therapy of stones that do not pass include shock wave lithotripsy (SWL), ureteroscopic lithotripsy with electrohydraulic or laser probes, percutaneous nephrolithotomy and laparoscopic stone removal. Open surgical stone removal is rarely needed. SWL is the treatment of choice in 75 % of patients and works best for stones in the renal pelvis and upper ureter. Both SWL and ureteroscopy are considered first-line management options for ureteral stones that require removal For patients with larger renal calculi (eg, >1.5 cm), renal stones of harder composition (eg, cystine or calcium oxalate monohydrate) or stones in complex renal or ureteral locations (eg, lower pole calyx or midureter), SWL is only successful in approximately 50 percent of cases. In these settings, endoscopic stone fragmentation with a percutaneous or ureteroscopic approach is preferred.

EVALUATION AND SUBSEQUENT TREATMENT Patients with calcium stones : Most patients require increased fluid intake: the best strategy is to recommend how much additional fluid the patient should drink based on his or her 24 hour urine volume. As an example, if the total urine volume is 1.5 liters, then we recommend two additional 8 ounce (240 mL) glasses of fluid each day to reach the goal of at least 2 liters of urine output per day. Limiting animal protein in the diet. Limiting dietary sodium to 100 meq/day. Increasing dietary potassium intake . Limiting dietary sucrose and fructose. Limiting dietary oxalate and vitamin C in patients with calcium oxalate stones. patients should continue to consume a wide variety of fruits and vegetables. Drug therapy is indicated if the stone disease remains active or adequate improvements are not realized in urinary chemistries despite attempted dietary modification over a 3 to 6 month period. Initial drug therapy varies with the metabolic abnormality that is present: o Thiazide diuretics for reducing urinary calcium excretion o Allopurinol for hyperuricosuria o Potassium citrate for hypocitraturia

Patients with uric acid stones : Urinary alkalinization: goal can usually be achieved by raising the urine pH to 6.5 for at least part of the dayby Either potassium bicarbonate or potassium citrate can be given, with the typical dose being 60 to 80 meq/day Allopurinol can be used in patients who excrete more than 1000 mg of uric acid per day and who do not respond to hydration and alkali therapy

Patients with cystine stones: High fluid intake, sufficient to reduce the concentration of cystine to below 243 mg/L (1 mM) in the 24 hour urine Urine alkalinization, using potassium citrate or potassium bicarbonate to achieve a urine pH of approximately 7.0 Restriction of sodium to 100 meq/day and protein to 0.8 to 1.0 g/kg per day If conservative measures are unable to achieve these goals, or stones recur, we recommend adding a cystine-binding drug (Grade 1B). Patients with extremely high cystine excretion rates may require cystinebinding drugs as part of initial therapy. We recommend tiopronin, given a lower incidence of side effects compared with penicillamine, and greater evidence of efficacy compared with captopril (Grade 1C). typical dose of tiopronin : 400 to 1200 mg/day, given in 3 divided doses. typical dose of Penicillamine comes 0.5 to 2 g/day, given in 3 to 4 divided doses. typical dose of captopril 75 to 150 mg/day m its use is typically limited to patients who cannot tolerate other cystine binding agents.

Patients with Struvite stones : o We suggest that percutaneous nephrolithotomy be used as the first line of treatment (Grade 2B). o PNL should be the final procedure in patients with combination therapy with PNL and SWL, o We suggest shock-wave lithotripsy as monotherapy, with placement of adequate drainage of the kidney prior to the procedure, only in selected patients with small stone volumes who have normal collecting system anatomy (Grade 2B). o For patients with small fragments that persist 8 weeks after the procedure, we suggest appropriate antibiotic treatment and administration of 40 to 60 mEq of potassium citrate per day (Grade 2C). o we recommend open surgery (anatrophic nephrolithotomy) only in very selected circumstances, as follows (Grade 1B): Patients with a large stone burden, especially if the collecting system anatomy is very distorted, in whom a reasonable number of less invasive procedures would not be expected to successfully remove the stone. Morbidly obese individuals in whom endoscopic and fluoroscopic techniques are difficult. For patients with a staghorn stone in a non-functioning or poorly functioning kidney, especially if it is chronically infected, a reasonable treatment option is nephrectomy.

Phosphate crystals

Cystine crystals

Uric acid crystals

Calcium oxalate crystals

Minimal Change Disease

INTRODUCTION : Minimal change disease (MCD) is a major cause of nephrotic syndrome in both children and adults and, together with focal and segmental glomerulosclerosis (FSGS), underlies the idiopathic nephrotic syndrome. MCD and FSGS may be variants of the same disease or represent separate pathophysiologic entities. PATHOGENESIS : Although the pathogenesis is unclear, systemic T cell dysfunction appears to produce increasing levels of a glomerular permeability factor in MCD. This circulating factor directly affects the glomerular capillary wall, resulting in foot process fusion. PATHOLOGY : Histologically, MCD is characterized by normal appearing glomeruli by light microscopy and the absence of complement or immunoglobulin deposits by immunofluorescence microscopy. The characteristic histologic lesion in MCD is diffuse effacement of the epithelial foot processes on electron microscopy. ETIOLOGY : Most cases of MCD are idiopathic (or primary) and not clearly associated with an underlying disease or event. With secondary MCD, the onset of nephrotic syndrome occurs concurrently or following an extraglomerular or glomerular disease process. MCD is associated with the following: 1. Drugs NSAIDs and selective COX-2 inhibitors. Antimicrobials (ampicillin, rifampicin, cephalosporins) , Lithium , D-penicillamine and tiopronin , Pamidronate and other bisphosphates , Sulfasalazines (mesalazine and salazopyrine) Trimethadione , Immunizations , Gamma interferon . 2. Neoplasm particularly hematologic malignancies, such as Hodgkin's disease, non-Hodgkin lymphomas, or leukemias. In rare cases solid tumors. 3. Infection MCD has rarely been associated with infections including syphilis, tuberculosis, HIV, mycoplasma, Ehrlichiosis, Hepatitis C virus, and Echinococcus 4. Allergy Atopy is reportedly associated with up to 30 % of cases of MCD 5. Other glomerular diseases MCD may be associated with mesangial IgA MCD occurring in association with the following glomerular or renal diseases: SLE , DM I , PCKD , HIV nephropathy 6. Other chronic graft-versus-host-disease after peripheral blood stem cell transplantation, sclerosing cholangitis, sarcoidosis, Graves' disease, thyroiditis, vasculitis, myasthenia gravis, Guillain-Barre syndrome, dermatitis herpetiformis, primary biliary cirrhosis, antiphospholipid syndrome and stiffperson syndrome

EPIDEMIOLOGY : MCD occurs in adults of all ages and is the cause of 10 to 15 % of all cases of adult nephrotic syndrome. CLINICAL MANIFESTATIONS Nephrotic syndrome is characterized by the constellation of : o Edema o proteinuria (usually greater than 3 g/day) o Hypoalbuminemia o Hyperlipidemia. Microscopic hematuria is common in adults with MCD The plasma creatinine concentration is usually normal, but in adults is often slightly elevated at presentation; in addition, acute renal failure may occur. Increased risk of thrombosis

Susceptibility to infection, particularly with encapsulated organisms, This is perhaps a result of moderate to severe hypogammaglobulinemia.

DIAGNOSIS : Unlike children, a renal biopsy is necessary in adults to diagnose MCD. The diagnosis is made based upon the characteristic findings on histology and the exclusion of histologic features that characterize other disorders with foot process effacement. The response to corticosteroid treatment is the essential prognostic factor in MCD. Steroid resistance should suggest that MCD is not the correct diagnosis.

PROGNOSIS Untreated minimal change disease is associated with potentially fatal complications, including sepsis and thrombosis. Prednisone leads to complete remission of proteinuria in over 90 percent of adults with MCD, and is the treatment of choice (show figure 1). Approximately 50 to 65 percent of adults will have a relapse, and repeated relapses occur in 10 to 25 percent. Remissions are typically abrupt, with the patient being free of proteinuria within one to two weeks from the time of initial response. Partial responses are not characteristic of MCD and, when seen, one should suspect a misdiagnosis, most often focal segmental glomerulosclerosis (FGS) that was missed by sampling error.

NITIAL THERAPY Glucocorticoid therapy : we recommend initial therapy with prednisone in patients with MCD (Grade 1B). We use oral prednisone at an initial daily dose of 1 mg/kg of body weight (maximum dose 60 to 80 mg per day), which is continued for 12 to 16 weeks and is subsequently progressively tapered to discontinuation over the following six months.

TREATMENT OF RELAPSE For the therapy of infrequent relapses in steroid-sensitive patients who do not have significant steroid-related side effects, we suggest repeating an abbreviated course of high dose oral prednisone (Grade 2B). FREQUENTLY RELAPSING OR GLUCOCORTICOID-DEPENDENT MCD Low-dose alternate-day prednisone : For patients with frequent relapses but no significant steroid-related side effects, we suggest a prolonged course of low-dose oral prednisone (approximately 15 mg on alternate days) to maintain a steroid-induced remission (Grade 2B). Cyclophosphamide : For patients with frequent relapses in whom avoidance of continued steroid exposure is desired, we suggest a course of oral cyclophosphamide rather than cyclosporine, given the lower rate of relapse and shorter duration of therapy with cyclophosphamide (Grade 2B). We typically treat with 2 mg/kg per day for 12 weeks, usually beginning after remission has been induced or maintained with prednisone. Calcineurin inhibitors : For patients who continue to relapse after an initial course of cyclophosphamide, who are steroid-resistant or steroid-dependent, or in whom avoidance of the toxicities of cyclophosphamide is important (eg, gonadal toxicity), we suggest therapy with cyclosporine and low-dose prednisone (Grade 2B).

Low-dose prednisone (eg, 15 mg on alternate days) is the preferred therapy for maintaining a prednisoneinduced remission in patients with frequently relapsing disease who do not have significant glucocorticoidrelated toxicity. The higher likelihood of a sustained remission makes a course of cyclophosphamide, rather than cyclosporine, the preferred therapy in most patients with frequently relapsing MCD who cannot tolerate continued glucocorticoid therapy. However, the hazards of cytotoxic therapy, especially that of masculine infertility, must be clearly explained to the patient and/or his guardians before beginning this treatment. Such therapy is typically given after glucocorticoid-induced remission. Once cyclophosphamide is started, prednisone is tapered and then discontinued as described above. Slow tapering to avoid adrenal suppression may be important for the renal disease, since a study in children found that moderate to severe postprednisone adrenal suppression was associated with an increased risk of relapse If relapse recurs following therapy with cyclophosphamide, cyclosporine may be safer than repeated courses of cyclophosphamide. Cyclosporine may be somewhat more effective in glucocorticoid-dependent disease, and can also be used in patients who refuse cyclophosphamide.

PERSISTENT NEPHROTIC SYNDROME : Other therapies, such as blockade of the renin-angiotensinaldosterone system with ACE inhibitors or angiotensin II receptor blockers to reduce proteinuria, or statin therapy for hyperlipidemia, should be instituted in patients who are persistently nephrotic despite adequate courses of immunosuppressive therapy.

General management : Proteinuria administration of an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker. Potentially adverse effects of these agents include acute renal failure and hyperkalemia; serum creatinine and potassium levels should be measured during the initiation of therapy. Although protein restriction also may slow disease progression, the evidence is unclear and this modality is not usually used in nephrotic patients because of the heavy protein losses. Edema should be treated with dietary sodium restriction (to approximately 2 g of sodium per day) and diuretics. Edema should be reversed slowly to prevent acute hypovolemia. Loop diuretics are usually required. There generally is a lesser natriuresis than seen in normal patients because of hypoalbuminemia (causing decreased delivery of protein bound drug to the kidney) and albuminuria (binding the drug within the tubular lumen). For these reasons, the diuretic dose often has to be increased. An important guide for the evaluation of diuretic therapy is serial measurement of body weight. Hyperlipidemia The lipid abnormalities induced by the nephrotic syndrome reverse with resolution of the disease, as with corticosteroid therapy in minimal change disease. The optimal treatment of patients with persistent nephrosis is uncertain. Dietary modification is generally of little benefit. Most patients are initially treated with an HMG CoA reductase inhibitor (statin) . Hypercoagulability There is a relatively high incidence of arterial and venous thromboemboli among patients with the nephrotic syndrome, particularly with membranous nephropathy . At present, however, we do not recommend routine prophylactic anticoagulation. If thrombosis occurs, it is typically treated with heparin followed by warfarin for as long as the patient remains nephrotic.

Overview of the management of chronic kidney disease in adults

Reversible causes of renal dysfunction Decreased renal perfusion : o common causes of potentially reversible declines in renal function. Hypovolemia (such as vomiting, diarrhea, diuretic use, bleeding) hypotension (due to myocardial dysfunction or pericardial disease) infection (such as sepsis) administration of drugs which lower the GFR (such NSAIDs and ACEi) o As a result, hypovolemia in these patients should be diagnosed by the history and physical examination, including the presence of relative hypotension, a low jugular venous pressure, and poor skin turgor. In this setting, a judicious trial of fluid repletion may result in the return of renal function to the previous baseline. Administration of nephrotoxic drugs : o The administration of drugs or diagnostic agents that adversely affect renal function are a frequent cause of worsening renal function. o common offenders include aminoglycoside antibiotics (particularly with unadjusted doses), nonsteroidal antiinflammatory drugs, and radiographic contrast material, particularly in diabetics. o The administration of such drugs should therefore be avoided or used with caution in patients with underlying chronic renal disease. o Certain drugs also interfere with either creatinine secretion or the assay used to measure the serum creatinine. These include cimetidine, trimethoprim, cefoxitin, and flucytosine. In these settings, there will be no change in GFR; the clinical clue that this has occurred is the absence of a concurrent elevation in the blood urea nitrogen (BUN). Urinary tract obstruction o Urinary tract obstruction should always be considered in the patient with unexplained worsening renal function although, in the absence of prostatic disease, it is much less common than decreased renal perfusion. o Patients with slowly developing obstruction typically have no changes in the urinalysis, no symptoms referable to the kidney, and initially maintain their urine output. Given this lack of clinical clues, renal ultrasonography is often performed to exclude urinary tract obstruction in patients with an unexplained elevation in the serum creatinine.

Slowing the rate of progression : that the administration of angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) slows the progression of chronic kidney disease, with the greatest benefit in patients with higher degrees of proteinuria Thus, protective therapy has the greatest impact if it is initiated relatively early in the course, before the serum creatinine concentration exceeds 1.2 and 1.5 mg/dL in women and men, respectively, or the GFR is less than 60 mL/min per 1.73 m2. The following recommendations are consistent with JNC 7 and the K/DOQI Clinical Practice Guidelines on hypertension and antihypertensive agents in chronic kidney disease. Aggressive goals are recommended for both proteinuria and blood pressure. Antihypertensive therapy is given for both renal protection and cardiovascular protection, since chronic kidney disease is associated with a marked increased in cardiovascular risk.

o A reduction in protein excretion to less than 500 to 1000 mg/day; recognizing the difficulty of achieving such a goal in many patients, we recommend a minimum reduction of at least 60 percent of baseline values. o A reduction in blood pressure to less than 130/80 mmHg. Caution is advised about lowering the systolic blood pressure below 110 mmHg. ACE inhibitors and ARBs can cause a decline in renal function and a rise in plasma potassium that typically occur soon after the onset of therapy. An elevation in serum creatinine of as much as 30 to 35 % above baseline that stabilizes within the first 2-4 months of therapy is considered acceptable and not a reason to discontinue therapy with these drugs . However, a repeat plasma creatinine and potassium should be measured within 3-5 days. In patients with nonproteinuric renal disease, most often a tubulointerstitial disease, none of the above drugs has been shown to slow progression of the renal disease and therapy is limited to blood pressure control. Other therapeutic modalities also may offer some renal protection: o The optimal level of protein intake has also not been determined but it may be reasonable to restrict intake to 0.8 to 1.0 g/kg per day of high biologic value protein, with the lower value used in patients with progressive chronic kidney disease. Some recommend even lower levels, such as 0.6 to 0.75 g/kg per day of high value protein, with close supervision and dietary counseling o Both hyperlipidemia and metabolic acidosis should be treated, in part because there is some evidence that they may enhance the rate of progression of the renal disease o Smoking cessation should be encouraged, with smoking stoppage being associated with a reduced rate of progression of chronic kidney disease . In an increasing number of studies, smoking also appears to correlate with an enhanced risk of developing kidney disease (primarily nephrosclerosis) as well as increasing the rate of progression among those with existing CKD.

Treatment of the complications of renal dysfunction Volume overload : Sodium and intravascular volume balance are usually maintained via homeostatic mechanisms until the GFR falls below 10 to 15 mL/min. However, the patient with mild to moderate chronic kidney disease, despite being in relative volume balance, is less able to respond to rapid infusions of sodium and is therefore prone to fluid overload. Patients with chronic kidney disease and volume overload generally respond to the combination of dietary sodium restriction and diuretic therapy, usually with a loop diuretic given daily. dose adjustment of loop diuretic in patients with renal insufficiency : 1. In moderate renal insufficiency 80 mg of furosemide, 2 to 3 mg of bumetanide, or 20 to 50 mg of torsemide. 2. In severe renal insufficiency 200 mg of furosemide, 8 to 10 mg of bumetanide, or 50 to 100 mg of torsemide. Some investigators have also claimed that limiting sodium intake may also help decrease progression of chronic kidney disease by lowering intraglomerular pressure

Hyperkalemia Thus, hyperkalemia generally develops in the patient who is oliguric or who has an additional problem such as a high potassium diet, increased tissue breakdown, or hypoaldosteronism (due in some cases to the administration of an ACE inhibitor or ARB)

Hyperkalemia due to ACE inhibitor or ARB therapy is most likely to occur in patients in whom the serum potassium concentration is elevated or in the high normal range prior to therapy. In this setting, institution of a low-potassium diet or concurrent use of a loop diuretic (to increase urinary potassium losses) often ameliorates the degree of hyperkalemia. In selected patients, low dose Kayexalate (5 grams with each meal) can be used to lower the serum potassium concentration without the side effects associated with larger doses. In addition to treating hyperkalemia, there are several measures that can help prevent hyperkalemia in patients with chronic kidney disease. These include ingestion of a low potassium diet (eg, less than 40 to 70 meq/day [1500 to 2700 mg/day]) and avoiding, if possible, the use of drugs that raise the serum potassium concentration such as nonsteroidal antiinflammatory drugs . Nonselective beta-blockers (propranolol) make the postprandial rise in the serum potassium concentration but do not produce persistent hyperkalemia

Metabolic acidosis : We recommend alkali therapy to maintain the serum bicarbonate concentration above 23 meq/L . sodium bicarbonate (in a daily dose of 0.5 to 1 meq/kg per day) is the agent of choice. Sodium citrate (citrate is rapidly metabolized to bicarbonate) may be used in patients who are unable to tolerate sodium bicarbonate, since it does not produce the bloating associated with bicarbonate therapy . Sodium citrate should be avoided in the rare patient who may be taking aluminum-containing antacids since it markedly enhances intestinal aluminum absorption

Hyperphosphatemia : A tendency toward phosphate retention begins early in renal disease. However, phosphate balance and a normal serum phosphate concentration are generally maintained (at the price of elevated PTH and FGF23 levels) until the GFR falls below 25 to 40 mL/min. Restricting dietary phosphate intake and the administration of phosphate binders are the two principal modalities used to reverse the hyperphosphatemia of CKD. To optimally manage elevated phosphate levels in all patients with CKD, it is important to first assess the presence or absence of other mineral abnormalities, vascular calcifications, and note the administration of concurrent therapies, particularly vitamin D and vitamin D analogs. The K/DOQI guidelines recommend that Goal serum phosphorus levels should be : 1. 2.7 - 4.6 mg/dL in patients with stage 3 and 4 chronic kidney disease 2. 3.5 - 5.5 mg/dL in those with end-stage renal disease (or stage 5 disease) 3. The serum calcium-phosphorus product should also be maintained at <55 mg2/dL2. Treatment Options For Hyperphosphatemia: o We first suggest restricting dietary phosphate to 900 mg per day (Grade 2C). o Among patients with serum phosphate levels greater than target levels despite dietary phosphorus restriction after 4 weeks, we suggest the administration of phosphate binders (Grade 2C). o the major phosphate binders are : o Calcium-containing phosphate binders ( calcium carbonate or calcium acetate) o Non-calcium containing phosphate binders ( sevelamer and lanthanum). o Doses of Phosphate Binder: o Calcium Carbonate (Calcicar) 500mg (=elemental Ca 200 mg) 3-7.5 tab/daily with meals o Lanthanum (Fosbind) 500mg (1500-3000mg) 3- 6 tab/daily with meals o Sevelamer 800mg (2400-4800 mg) 3- 6 tab/daily with meals o Our specific approach varies based upon the serum calcium level:

Calcium >9.5 mg/dl: we recommend the administration of a non-calcium containing phosphate binder (Either sevelamer or lanthanum ). calcium 8.4 - 9.5 mg/dL : management varies based upon the presence of adynamic bone disease, low PTH levels, and/or vascular calcification: - Among those without such comorbidities, we suggest first titrating a calcium-based phosphate binder (up to 1,500 mg of elemental calcium from binders alone). Higher doses of calcium may be tolerated in patients not receive vitamin D analogues or who have hypocalcemia while being treated with calcimimetics. If phosphate remains above 5.5 mg/dL despite this strategy, we then add a non-calcium containing phosphate binder. - Among those with adynamic bone disease, low PTH levels, and/or vascular calcification, a non-calcium based phosphate binder is preferred ( Either sevelamer or lanthanum carbonate ). Calcium <8.4 mg/dL : we recommend a calcium-based phosphate binder. Some patients do not achieve the recommended serum phosphate goals with the above regimen due in part to the use of various agents to help control PTH levels. Vitamin D analogs (calcitriol) may contribute, raising both phosphate and calcium concentrations. A possible alternative is the use of cinacalcet. Among dialysis patients with persistent hyperphosphatemia, we suggest increasing phosphate removal via hemodialysis (Grade 2C). Among patients with refractory hyperphosphatemia, nocturnal hemodialysis is an option among those who are willing to accept this form of dialysis. Among all patients with CKD, we recommend NOT administering aluminum hydroxide except for shortterm therapy (four weeks for one course only) of severe hyperphosphatemia (Grade 1B). Approach to hypercalcemia The combination of hypercalcemia (calcium >10.2 mg/dL corrected for serum albumin) and persistent hyperphosphatemia may be a particular problem with calcium therapy and active vitamin D analog administration, possibly leading to extraskeletal calcium phosphate deposition. In this setting, we suggest that the dose of calcium-based phosphate binders should be decreased or therapy discontinued, and/or therapy should be switched to sevelamer to control phosphate . In addition, the dose of active vitamin D sterols should be lowered or therapy should be discontinued until calcium levels return to 8.4 to 9.5 mg/dL.

Renal osteodystrophy : Four main types of renal bone disease can be seen in patients with chronic kidney disease : 1. Adynamic bone disease (the most common disorder) 2. Osteitis fibrosa cystic 3. Osteomalacia 4. Mixed renal osteodystrophy : mixture of the first three. Adynamic bone disease: 1. bone turnover is markedly reduced and there is a lack of bone cell activity (both osteoblasts and osteoclasts). 2. The principal factor underlying adynamic bone disease appears to be oversuppression of parathyroid hormone (PTH) release, which may be induced by the relatively high doses of vitamin D analogues and possibly of calcium-based phosphate binders. 3. Clinical manifestations: risk of fractures, patients with adynamic bone disease are at increased risk of hypercalcemia, cardiovascular calcification and mortality. determined either by bone biopsy or intact serum PTH <100 pg/mL 4. Treatment : allowing PTH secretion to rise by decreasing the doses of calcium-based phosphate binders and/or vitamin D analogs, a low dialysate calcium concentration, and perhaps by the use of noncalcium-based phosphate binders.

Osteitis fibrosa cystic : 1. Disorder in which bone turnover is increased due to secondary hyperparathyroidism. 2. The three main abnormalities that contribute to the pathogenesis of secondary hyperparathyroidism are phosphate retention, a decreased free calcium level, and a decreased 1,25-dihydroxyvitamin D (Calcitriol) level. 3. Prevention and/or treatment : dietary phosphate restriction, the administration of oral phosphate binders, and the administration of calcitriol (or vitamin D analogs) to directly suppress the secretion of parathyroid hormone. Osteomalacia : is characterized by reductions in bone turnover, the number of bone-forming and boneresorbing cells, and a marked increase in the volume of unmineralized bone. This was largely due to the accumulation of aluminimum in bone. Due to the abandonment of aluminum-based phosphate binders, the incidence of osteomalacia has markedly decreased. The K/DOQI work group suggests the following target serum levels for intact PTH : 35 - 70 pg/mL for stage 3 disease 70 - 110 pg/mL for stage 4 disease 150 - 300 pg/mL for stage 5 disease Management of secondary hyperparathyroidism with stage 3-5 CKD not on dialysis: 1. combination of : dietary phosphate restriction phosphate binders (either calcium or non-calcium containing binders) vitamin D analogues calcium supplementation and/or (possibly) a calcimimetic. 2. we suggest maintaining intact PTH, calcium, phosphorus levels in the normal range (Grade 2C). 3. Among patients with elevated PTH levels, we suggest a stepped approach to the management of hyperparathyroidism and bone mineral abnormalities (Grade 2C). 1. Step 1 : We suggest that the initial focus in managing secondary hyperparathyroidism should be the management of hyperphosphatemia (Grade 2C). Among patients with hyperphosphatemia, we suggest restricting dietary phosphate intake. (Grade 2C) 2. Step 2 : Among patients with hyperphosphatemia despite dietary phosphorus restriction after 2-4 months, we suggest the administration of phosphate binders (Grade 2C). The two principal options are calcium and non-calcium based phosphate binders. We also suggest that treatment with ergocalciferol be initiated if vitamin D deficiency exists ( 25 OH-vitamin D level of < 30 ng/mL) (Grade 2C). 3. Step 3 : If elevated PTH levels remain despite ergocalciferol and phosphate binder therapy over a 6month period, we suggest administering a low dose active oral vitamin D analog (calcitriol, alfacalcidol (Onealpha), doxercalciferol, or paricalcitol) (Grade 2C). we recommend NOT initiating vitamin D analog if : serum calcium level > 9.5 mg/dL serum phosphate is > 5.5 mg/dL Ca X P product is > 55 mg2/dL2. If the serum level of corrected total calcium > 10.2 mg/dL we recommend that ergocalciferol therapy and all forms of vitamin D therapy should be discontinued (Grade 1B).

4. Step 4 : Among predialysis patients with secondary hyperparathyroidism that is refractory to therapy with vitamin D analogues, calcium supplements, and phosphate binders, Calcimimetics may be useful but it is Not approved for patients with CKD not yet on dialysis Calcimimetics are agents that allosterically increase the sensitivity of the calcium-sensing receptor in the parathyroid gland to calcium. Cinacalcet, the only currently available calcimimetic Cinacalcet should not be initiated if the serum calcium level < 8.4 mg/dL . The initial dose of Cinacalcet 30 mg/day should be cautiously titrated upwards every two weeks only if the serum calcium level is greater than 8.4 mg/dL and PTH is higher than the target range. Management of secondary hyperparathyroidism in dialysis patients: For dialysis patients, we suggest maintaining intact PTH (second generation PTH assay) levels between 150 to 300 pg/mL , serum phosphate levels between 3.5 and 5.5 mg/dL, and serum levels of corrected total calcium between 8.4 and 9.5 mg/dL (Grade 2C). Among dialysis patients with elevated intact PTH levels, our general strategy is to reduce serum phosphate levels to the normal range, limit excessive calcium loading, avoid high dose active vitamin D analog administration, reduce vitamin D analog dose in patients with suppressed PTH levels, use a calcimimetic to help lower PTH levels, prevent progression of parathyroid disease, maintain bone health and prevent fractures. Among dialysis patients with elevated PTH levels, we suggest a stepped approach to the management of hyperparathyroidism and bone mineral abnormalities (Grade 2C) : 1. Steps 1 and 2 : We suggest management of hyperphosphatemia with diet and/or phosphate binders (Grade 2C). Specific interventions are based upon serum phosphate and calcium levels: Phosphate <5.5 mg/dL and calcium <9.5 mg/dL Calcium-based phosphate binders should be administered. We suggest keeping daily elemental calcium intake from binders to less than 1,500 mg, and total elemental calcium from diet and binders to less than 2,000 mg (in the presence of concurrent therapy with active vitamin D analogues). Phosphate <5.5 mg/dL and calcium >9.5 mg/dL No phosphate binder is necessary in most patients. Among those with vascular calcifications, we suggest treatment with a non-calcium containing phosphate binder. Phosphate >5.5 mg/dL and calcium >9.5 mg/dL We recommend the administration of a non-calcium containing phosphate binder Phosphate >5.5 mg/dL and calcium <9.5 mg/dL We suggest first titrating a calciumbased phosphate binder (up to 1,500 mg of elemental calcium from binders alone if there is concurrent use of active vitamin D analogues). If phosphate remains above 5.5 mg/dL (>1.78 mmol/L), we then add a non-calcium containing phosphate binder. 2. STEP 3 : decide whether phosphate binder therapy is sufficient or whether a calcimimetic or vitamin D analogue should be added. This is based upon calcium, phosphate, and PTH levels that are measured when administering optimal phosphate binder therapy. If calcium supplementation and phosphate binders are effective in controlling PTH No additional therapy may be needed. If PTH levels remain > 300 pg/mL with optimal binder therapy, the choice is either cinacalcet or vitamin D analogues:

We initiate cinacalcet in patients with PTH >300 pg/mL when administering optimal phosphate binder therapy and the following measured levels : Phosphate >5.5 mg/dL and Calcium >8.4 mg/dL Phosphate <5.5 mg/dL and Calcium >9.5 mg/dL Cinacalcet should NOT be initiated if the serum calcium < 8.4 mg/dL We initiate vitamin D analogue in patients with PTH >300 pg/mL, when administering optimal phosphate binder and the following measured levels : Phosphate <5.5 mg/dL and Calcium <9.5 mg/dL vitamin D analogues NOT be initiated if the serum calcium >9.5 mg/dL, serum phosphate > 5.5 mg/dL, or the Ca X P product > 55 mg2/dL2. 3. Step 4 : adjust the doses of phosphate binders, active vitamin D, and cinacalcet to attempt to attain target values. Indications For Parathyroidectomy: 1. Severe hypercalcemia. 2. Progressive and debilitating hyperparathyroid bone disease as defined by radiographic or histologic evaluation (Renal Osteodystrophy).. 3. Pruritus that does not respond to medical or dialytic therapy. 4. Progressive extraskeletal calcification or calciphylaxis that are usually associated with hyperphosphatemia that is refractory to oral phosphate binders. 5. Otherwise unexplained symptomatic myopathy. many of these problems can develop in dialysis patients without significant hyperparathyroidism. Thus, parathyroidectomy should not be performed unless very high intact PTH levels have been documented.( > 800 pg/mL )

.Hypertension : Treatment of even mild hypertension is important in patients with chronic kidney disease (CKD) to protect against both progressive renal failure and cardiovascular disease, the rate of which is increased with even mild to moderate CKD. Goal blood pressure less than 130/80 mmHg , More aggressive goals may be warranted in patients with a spot urine total protein-to-creatinine ratio 1000 mg/g (which represents protein excretion of greater than 1000 mg/day). Choice of therapy The desired degree of blood pressure control typically requires combination therapy in patients with CKD. The regimen should include an ACE inhibitor or angiotensin II receptor blocker, which are the preferred drugs to prevent progressive kidney disease, and a diuretic for fluid control (a loop diuretic is generally used but thiazide diuretics become less effective as monotherapy when the GFR falls below 20 mL/min.) diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of persistent hypertension, is defined as the weight at which further fluid loss leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration. Calcium channel blockers are also effective in the hypertension of CKD. These agents are relatively unique in that they seem to be more effective in patients who are volume expanded. the reduction in blood pressure tends to be greater in patients on a high-salt diet. This is in comparison to almost all other antihypertensive agents which are more effective when the patient is salt restricted.

Other antihypertensive drugs can also be used as necessary in patients with renal disease. The potent vasodilator minoxidil is generally reserved for refractory hypertension. hypertensive dialysis patients The major therapeutic goal in hypertensive dialysis patients is gradual fluid removal to attain "dry weight.

Anemia : o The anemia of chronic kidney disease is, in most patients, normocytic and normochromic, and is due primarily to reduced production of erythropoietin by the kidney (a presumed reflection of the reduction in functioning renal mass), and to shortened red cell survival o The evaluation of patients should therefore include red blood cell indices, absolute reticulocyte count, serum iron, TIBC , transferrin saturation, serum ferritin, white blood cell count and differential, platelet count, and testing for blood in stool. This work-up should be performed prior to administering epoietin alfa (EPO) or darbepoietin alfa therapy. o Absolute iron deficiency is likely to be present in patients with ESRD when: o transferrin saturation (plasma iron TIBC x 100) <20 % o serum ferritin is < 100 ng/mL among predialysis or < 200 ng/mL among hemodialysis o We suggest targeting Hgb levels in the range of 11 - 12 g/dL in patients with CKD (Grade 2C). We recommend NOT targeting Hgb levels > 13 g/dL (Grade 1B). o Incication of iron use : o Among hemodialysis patients with anemia due to CKD and absolute iron deficiency we recommend the administration of iron therapy prior to the use of erythropoietic stimulating agents for the treatment of anemia (Grade 1B). o Among hemodialysis patients with anemia due to CKD and transferrin saturation 20 % and ferritin between 200 and 500 ng/mL, we suggest the administration of iron therapy prior to the use of erythropoietic stimulating agents only if an underlying infection and/or cause of an inflammatory state have been excluded (Grade 2C). o Among hemodialysis patients, we recommend the use of parenteral iron rather than oral iron therapy (Grade 1B). ' o The parenteral preparations of iron : iron dextran, sodium ferric gluconate and iron sucrose. We recommend either intravenous sodium ferric gluconate complex in sucrose or iron sucrose rather than iron dextran (Grade 1A). o We administer one of the following loading regimens: o 125 mg of sodium ferric gluconate can be given at each consecutive hemodialysis treatment for a total of 8 doses (1000 mg in total). o 100 mg iron sucrose (Fenofer) can be given at each consecutive hemodialysis treatment for a total of 10 doses (1000 mg in total). o We repeat either of these loading regimens if the transferrin saturation remains <20 %, the hemoglobin level does not increase to the target level, or the serum ferritin level remains <200 ng/mL. o We aim to raise the transferrin saturation >20 to 25 %, the serum ferritin level >200 ng/mL, and increase hemoglobin levels o For maintenance iron therapy, we recommend the administration of weekly continuous therapy rather than intermittent therapy (Grade 1B). o Among iron replete patients receiving erythropoietin-stimulating agents, Typical regimens include sodium ferric gluconate complex in sucrose at a dose of 31.25 to 125 mg or iron sucrose at a dose of 25 to 100 mg administered once weekly or every other week.

o If oral iron is given, we recommend that adults should receive a daily dose of approximately 200 mg of elemental iron, usually as ferrous sulfate 325 mg three times daily (65 mg elemental iron per tablet). o Erythropoietic Agents : o Erythropoietin Dose : Predialysis : 10,000 units SC once weekly or 20,000 units every other week. Hemodialysis : 50 to 100 U/kg IV three times weekly o Darbepoietin Alfa Dose : 0.45 mcg/kg IV or SC administered once weekly. Dyslipidemia : o The primary finding in chronic kidney disease is hypertriglyceridemia with the total cholesterol concentration usually being normal o Among patients with CKD, the degree of hypertriglyceridemia that occurs may not be sufficient to significantly increase coronary risk, but other changes have been found that might contribute to the accelerated atherosclerosis commonly seen in end-stage renal disease. o First, dietary modification may be helpful for the hypertriglyceridemia. o Drug therapy in patients without renal failure may be beneficial in selected patients with isolated marked hypertriglyceridemia (serum triglycerides 500 mg/dl) who have proven coronary disease, a strong family history of CHD, or multiple coexisting cardiac risk factors. o In the patient with hypercholesterolemia, a statin can effectively and safely lower the plasma cholesterol concentration to or near acceptable levels. o the goal LDL-cholesterol is similar to that in patients with CHD, which has been less than 100 mg/dL. some experts recommend a lower goal of less than 70 mg/dL. o A similar lipid-lowering goal, beginning with statin therapy, should be administered to patients with chronic kidney disease. Sexual dysfunction : 50 % of uremic men complain of symptoms that include erectile dysfunction, decreased libido, and marked declines in the frequency of intercourse ; in addition, disturbances in menstruation and fertility are commonly encountered in women with chronic kidney disease, usually leading to amenorrhea by the time the patient reaches ESRD. Treatment of complications of ESRD Uremic bleeding : o An increased tendency to bleeding is present in both acute and chronic kidney disease. This appears to correlate most closely with prolongation of the bleeding time, due primarily to impaired platelet function. o No specific therapy is required in asymptomatic patients. o correction of the platelet dysfunction is desirable in patients who are actively bleeding or who are about to undergo a surgical or invasive procedure (such as a renal biopsy). o A number of different modalities can be used in this setting, including : Correction Of Anemia : achieved acutely by red cell transfusions or chronically via the administration of recombinant human erythropoietin Desmopressin (dDAVP) : is the preferred route of treatment, at a dose of 0.3 microg/kg given in 50 mL of saline over 15 to 30 minutes. Alternatively, the same dose can be given subcutaneously or 3 microg/kg can be given intranasally. Cryoprecipitate : 10 units intravenously every 12 to 24 hours Estrogen : 0.6 mg/kg intravenously, daily for five days, 2.5 to 25 mg of Premarin orally, or 50 to 100 microg of transdermal estradiol twice weekly

Dialysis : with minimal or regional heparin, avoidance of all anticoagulants, and/or dialysis using prostacyclin or regional citrate administration as anticoagulants. Pericarditis : o major presentations :Fever, pleuritic chest pain, and a pericardial friction rub . o electrocardiogram does not usually show the typical diffuse ST and T wave elevation, o The development of otherwise unexplained pericarditis in a patient with advanced renal failure is an indication to institute dialysis (providing there is no circulatory compromise or evidence of impending tamponade) o Anticoagulation can increase hemorrhage into the pericardial space, systemic anticoagulation should be avoided when hemodialysis is the chosen modality o drainage of the effusion is the treatment of choice if it gets larger or fails to resolve in 7 to 14 days with intensified dialysis. o Drainage is also often recommended without a trial of intensive hemodialysis in patients presenting with a moderate to large (>250 mL) effusion o Acute cardiac tamponade with circulatory collapse should be treated with pericardiocentesis o he surgical procedures for a large, nonresolving effusion are subxiphoid pericardiotomy (with or without the instillation of intrapericardial corticosteroids) or pericardiectomy. Uremic neuropathy : o Included : encephalopathy (impaired mental status progressing if untreated to seizures and coma), polyneuropathy, and mononeuropathy o These complications are usually absolute indications for the initiation of dialysis. o Sensory dysfunction, characterized by the restless leg or burning feet syndromes, are frequent presentations of uremic neuropathy. o Treatment : correcting anemia, decreasing exposure to agents that may exacerbate the syndrome, and administering levodopa or dopamine agonists . Thyroid dysfunction : The disturbances that can occur include low serum free and total T3 concentrations and normal reverse T3 and free T4 concentrations. The serum thyrotropin (TSH) concentration is normal and most patients are euthyroid. Uremic pruritus : The best therapy for severe pruritus is probably a combination of providing an adequate dialysis dose, effective management of anemia and mineral metabolism, emollients, UVB light, and, if necessary, an antihistamine and perhaps topical capsaicin .

Dialysis in Acute Renal Failure

INDICATIONS FOR AND OPTIMAL TIMING OF DIALYSIS INITIATION 1. Refractory fluid overload 2. Hyperkalemia (plasma potassium concentration >6.5 meq/L) or rapidly rising potassium levels 3. uremic symptoms and signs , such as pericarditis, neuropathy, encephalopathy or an otherwise unexplained decline in mental status 4. Metabolic acidosis (pH less than 7.1) 5. overdose with a dialyzable drug/toxin, Whether there is a benefit to early initiation of RRT for volume management rather than escalating diuretic dose is not known. The optimal timing for initiation of RRT in patients with AKI will require an adequately powered prospective randomized trial. Adequate design of such a trial is limited by the current inability to quickly prospectively identify patients with early AKI who will have protracted renal injury and eventually require RRT. For this reason, it is not possible to provide evidence-based criteria for the initiation of RRT in AKI. It is unproven whether initiation of earlier or prophylactic dialysis offers any clinical or survival benefit. We suggest initiating dialysis prior to the development of symptoms and signs of renal failure due to AKI (Grade 2B). It is not possible to specify a specific duration of renal injury or level of azotemia at which RRT should be optimally initiated. General practice is to initiate RRT when the urea reaches 160 to 200 mg/dL, although there is no consensus and practice patterns vary widely. Current data do not support the superiority of either CRRT or IHD. A paucity of data exists concerning the relative benefits of hybrid therapies and acute peritoneal dialysis. Thus, the selection of modality of RRT should be based upon local expertise and experience in combination with the needs of the individual patient. If CRRT is administered, we recommend the use of venovenous circuits rather than arteriovenous circuits (Grade 1B). We suggest the following strategies for dosage of RRT: o We recommend that intermittent hemodialysis be provided on a three-times per week schedule (alternate days) with monitoring of the delivered dose of dialysis to ensure delivery of a Kt/V of at least 1.2 per treatment (Grade 1B). o We recommend that CRRT be provided with an effluent flow rate (sum of hemofiltration rate and dialysate flow rate) of at least 20 mL/kg per hour (Grade 1B).

Indications for initiation of dialysis in chronic kidney disease

1. Pericarditis or pleuritis (urgent indication) 2. Progressive uremic encephalopathy or neuropathy, with signs such as confusion, asterixis, myoclonus, wrist or foot drop, or, in severe, cases, seizures (urgent indication) 3. A clinically significant bleeding diathesis attributable to uremia (urgent indication) 4. Fluid overload refractory to diuretics 5. Hypertension poorly responsive to antihypertensive medications 6. Persistent metabolic disturbances that are refractory to medical therapy. These include hyperkalemia, metabolic acidosis, hypercalcemia, hypocalcemia, and hyperphosphatemia. 7. Persistent nausea and vomiting 8. Weight loss or signs of malnutrition most nephrologists agree that delaying initiation of dialysis until one or more of these complications is present may put the patient at unnecessary jeopardy.

Relative indications : anemia that is refractory to erythropoietic stimulating agents and iron treatment, decreased attentiveness and cognitive tasking, depression, persistent pruritus or the restless leg syndrome. Unfortunately, the expressions of these signs and symptoms are variable in patients with slowly progressive renal disease. The following are some of the factors that may contribute to this variability. o Some patients accommodate to these symptoms and downgrade their sense of well being as renal failure progresses. o Many of the medications given to patients with CKD have side effects that mimic uremic symptoms. As examples, oral iron therapy often leads to nausea and centrally-acting antihypertensive drugs can induce drowsiness independent of the degree of renal failure. o On the other hand, partial correction of anemia by erythropoietin may improve the patient's sense of well being without affecting the extent of uremia. dialysis should therefore be initiated well before these indications have developed. Patients with CKD or disease should therefore be closely followed and the GFR estimated. We therefore strongly consider initiation of dialysis when the approximate GFR is below 10 to 15 mL/min, especially in elderly patients and diabetics. The 2006 National Kidney Foundation Dialysis Outcomes Quality Initiative (K/DOQI) for peritoneal dialysis and hemodialysis adequacy published guidelines concerning the initiation of dialysis among patients with renal insufficiency . The work group suggested that the benefits and risks of initiating renal replacement therapy should be considered in patients with GFR less than 15 mL/min per 1.73 m2 (stage 5 chronic kidney disease). Initiation of dialysis prior to stage 5 chronic kidney disease may also be required in patients with certain characteristics and/or complications, such as declining health due to the loss of kidney function. The 2005 European Best Practice Guidelines for peritoneal dialysis suggest that dialysis be initiated before the GFR is less than 6 mL/min per 1.73 m2, with consideration of initiation when the GFR is approximately 8 to 10 mL/min per 1.73 m2 .

NEUROLOGY

Guillain-Barr syndrome
CLINICAL FEATURES : The cardinal clinical features of GBS are progressive, mostly symmetric muscle weakness and absent or depressed deep tendon reflexes. The weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles. Severe respiratory muscle weakness necessitating ventilatory support develops in about 30 percent, and dysautonomia occurs in 70 percent of patients. GBS usually progresses over a period of about two weeks. GBS is a heterogeneous syndrome with several variant forms. Acute inflammatory demyelinating polyneuropathy (AIDP) is the most common variant of GBS in North America, Europe, and most of the developed world. The Miller Fisher syndrome (MFS) is a GBS variant characterized by ophthalmoplegia with ataxia and areflexia. Axonal forms of GBS include acute motor axonal neuropathy (AMAN), most common in Japan and China, and acute motor and sensory axonal neuropathy (AMSAN).

DIAGNOSTIC EVALUATION : The initial diagnosis of GBS is based upon the clinical presentation. The diagnosis is confirmed by cerebrospinal fluid (CSF) analysis and clinical neurophysiology studies. Therefore, these studies should be performed in all patients with suspected GBS. Cerebrospinal fluid analysis : The typical finding of increased CSF protein with a normal CSF white blood cell (WBC) count (albuminocytologic dissociation) is found in 80 to 90 percent of patients with GBS at one week after onset of symptoms. An alternative diagnosis, particularly human immunodeficiency virus (HIV), should be considered in patients with a CSF cell count greater than 10 mm3. Clinical neurophysiology studies : Clinical neurophysiology studies show evidence of acute polyneuropathy with either predominantly demyelinating (AIDP) or axonal (AMAN, AMSAN) features. Antibodies : o Testing for serum IgG antibodies to GQ1b is useful for the diagnosis of MFS. o Testing for other glycolipid antibodies has no clinical role.

Diagnostic criteria : Required features include:: o Progressive weakness of more than one limb, ranging from minimal weakness of the legs to total paralysis of all four limbs, the trunk, bulbar and facial muscles, and external ophthalmoplegia o Areflexia. While universal areflexia is typical, distal areflexia with hyporeflexia at the knees and biceps will suffice if other features are consistent. Supportive features include: 1. Progression of symptoms over days to four weeks 2. Relative symmetry 3. Mild sensory symptoms or signs 4. Cranial nerve involvement, especially bilateral facial nerve weakness 5. Recovery starting two to four weeks after progression halts 6. Autonomic dysfunction 7. No fever at the onset 8. Elevated protein in CSF with a cell count <10 mm3 9. Electrodiagnostic abnormalities consistent with GBS

The following features make the diagnosis of GBS doubtful: 1. Sensory level (decrement or loss of sensation below a spinal cord root level as determined by neurologic examination) 2. Marked, persistent asymmetry of weakness 3. Severe and persistent bowel and bladder dysfunction 4. More than 50 white cells in the CSF The differential diagnosis of GBS: includes other acute polyneuropathies, as well as disorders of the spinal cord, neuromuscular junction, and muscle. The differential diagnosis of the MFS variant of GBS includes brainstem stroke, Wernicke's encephalopathy, and brainstem encephalitis.

Treatment : Supportive care is extremely important in Guillain-Barr syndrome (GBS) since about 30 percent of patients develop neuromuscular respiratory failure requiring mechanical ventilation. In addition, severe autonomic dysfunction occurs in about 20 percent and warrants intensive care unit (ICU) monitoring. Close respiratory monitoring with frequent measurement of vital capacity and negative inspiratory force should be instituted in all patients with GBS on admission and continued while weakness is progressing. Patients with a forced vital capacity <20 mL/kg, maximum inspiratory pressure <30 cmH2O, or maximum expiratory pressure <40 cmH2O are at high risk of impending respiratory failure and should undergo urgent intubation and mechanical ventilation. For patients with GBS and progressive weakness, we recommend cardiac and blood pressure monitoring. For patients with GBS and progressive weakness, we recommend daily abdominal auscultation to monitor for bowel silence and the development of adynamic ileus. Neuropathic pain occurs in about 40 to 50 percent of patients during the course of GBS and often requires treatment. In the absence of disease-modifying treatment, most patients with GBS show continued progression for up to two weeks, followed by a plateau phase of about two weeks, and then recovery of function over several weeks to months. The main modalities of disease modifying therapy for GBS are plasma exchange and intravenous immune globulin (IVIG). The treatments are equivalent and improve outcome. Treatment shortens the time to walking independently by 40 to 50 percent. For nonambulatory adult patients with GBS who are within four weeks of neuropathic symptom onset, we recommend treatment with plasma exchange or IVIG (Grade 1A). For ambulatory adult patients with GBS who are not yet recovering within four weeks of neuropathic symptom onset, we suggest treatment with plasma exchange or IVIG (Grade 2B) Combining the two treatments is not beneficial the choice between plasma exchange and IVIG is dependent on local availability and on patient preference, risk factors, and contraindications. When both therapies are equally available and there are no contraindications for either, we suggest treatment with IVIG (Grade 2B). For adult patients with GBS, we recommend NOT treating with glucocorticoids (Grade 1A). Intravenous immune globulin o given for 5 days o Doses 0.4 gram/kg per day. o Side effects include aseptic meningitis, rash, acute renal failure (mostly related to sucrose containing products), and (rarely) hyperviscosity leading to stroke. IgA deficiency can lead to anaphylaxis . Plasma exchange o given for 4 to 6 treatments over 8 to 10 days, for a total of 200 to 250 mL/kg. o The main complications are hypotension, sepsis, and problems with intravenous access.

CLINICAL COURSE Even with treatment, approximately 5 to 10 percent of patients have a prolonged course with very delayed and incomplete recovery, and 5 percent die despite intensive care. In addition, relapses occur in up to 10 percent of patients. Prognostic factors poor prognosis for recovery from GBS include : 1. Older age 2. Rapid onset (less than seven days) prior to presentation 3. Need for ventilatory support 4. An average distal motor response amplitude reduction to <20 percent of normal 5. Preceding diarrheal illness

Treatment of Spontaneous intracerebral hemorrhage

ICH score Glasgow Coma Scale :GCS 3 - 4 (= 2 points); GCS 5 - 12 (= 1 point) and GCS 13 - 15 (= 0 points) ICH volume 30 cm3 (= 1 point), ICH volume <30 cm3 (= 0 points) Intraventricular extension of hemorrhage present (= 1 point); absent (= 0 points) Infratentorial origin yes (= 1 point); no (= 0 points) Age 80 (= 1 point); <80 (= 0 points)

30-day mortality rates increased steadily with ICH score; mortality rates for ICH scores of 1, 2, 3, 4, and 5 were 13, 26, 72, 97, and 100 percent, respectively. No patient with an ICH score of 0 died, and none had a score of 6 in the cohort. General management : Patients with acute ICH should be managed in an intensive care unit. All anticoagulant and antiplatelet drugs should be discontinued acutely, and anticoagulant effect should be reversed immediately with appropriate agents. Sources of fever should be treated. We suggest use of antipyretic medications to lower body temperature to normothermia in febrile patients. We suggest insulin treatment for elevated serum glucose >185 mg/dL . Options for the prevention of venous thromboembolism and deep venous thrombosis in patients with ICH include intermittent pneumatic compression, low-dose subcutaneous low molecular weight heparin, unfractionated heparin, and placement of a vena cava filter In patients with acute ICH and proximal DVT or nonfatal PE, we recommend treatment with heparin, LMW heparin, or heparinoid, followed by the use of reduced dosages of oral anticoagulation (ie, a target INR of 2.0) for a period of three months.

Intracranial pressure control : elevating the head of the bed to 30 degrees use of analgesia and sedation. o Suggested intravenous agents for sedation are propofol, etomidate, or midazolam. o Suggested agents for analgesia and antitussive effect are morphine or fentanil. aggressive therapies : o osmotic diuretics (eg, mannitol It is administered as an initial bolus of 1 g/kg, followed by infusions of 0.25 to 0.5 g/kg every six hours. The goal of therapy is to achieve plasma hyperosmolality (300 to 310 mosmol/kg) while maintaining an adequate plasma volume , Normal saline initially should be used for maintenance and replacement fluids; hypotonic fluids are contraindicated. Mild hypernatremia should be tolerated, but marked hyperosmolality should be avoided to prevent precipitation of acute renal failure o Barbiturate anesthesia can be used if mannitol fails to lower ICP to an acceptable range. Barbiturate coma acts by reducing cerebral metabolism, which results in a lowering of cerebral blood flow and thus decreases ICP o ventricular catheter drainage of cerebrospinal fluid o Neuromuscular blockade is sometimes employed to reduce ICP in patients who are not responsive to analgesia and sedation alone o hyperventilation to a PaCO2 of 25 to 30 mmHg.

We suggest continuous monitoring of ICP and arterial blood pressure when using these aggressive therapies, with the goal of maintaining cerebral perfusion pressure above 70 mmHg.

Blood pressure control : Severe elevations in blood pressure may worsen ICH For patients with SBP >200 mmHg or MAP >150 mmHg, we suggest aggressive reduction of blood pressure with continuous intravenous infusion of medication accompanied by blood pressure monitoring every five minutes For patients with SBP >180 mmHg or MAP >130 mmHg and evidence or suspicion of elevated ICP, we suggest monitoring ICP and reducing blood pressure using intermittent or continuous intravenous medication to keep cerebral perfusion pressure in the range of 61 to 80 mmHg For patients with SBP >180 mmHg or MAP >130 mmHg and no evidence or suspicion of elevated ICP, we suggest a modest reduction of blood pressure to a target MAP of 110 mmHg or target blood pressure of 160/90 mmHg using intermittent or continuous intravenous medication accompanied by reexamination of the patient every 15 minutes Labetalol, nicardipine, esmolol, enalapril, hydralazine, nitroprusside, and nitroglycerin are useful intravenous agents for controlling blood pressure.

Intravenous medications that control of elevated blood pressure in patients with ICH Drug Intravenous bolus dose Labetalol 5 to 20 mg every 15 minutes Nicardipine NA Esmolol 250 mcg/kg IVP loading dose Enalapril 1.25 to 5 mg IVP every 6 hours Hydralazine 5 to 20 mg IVP every 30 min Nitroprusside NA Nitroglycerin NA Seizure prophylaxis and treatment : Continuous infusion rate 2 mg per minute (maximum 300 mg/day) 5 to 15 mg per hour 25 to 300 mcg/kg per minute NA 1.5 to 5 mcg/kg per minute 0.1 to 10 mcg/kg per minute 20 to 400 mcg /minute (2.4ml/h 48ml/h)

Appropriate intravenous antiepileptic treatment should be used to quickly control seizures for patients with ICH and clinical seizures. Current guidelines suggest lorazepam or diazepam followed directly by intravenous fosphenytoin or phenytoin Some experts suggest a brief period of antiepileptic prophylaxis soon after ICH onset as a potential means of reducing the risk for early seizures in patients with lobar hemorrhages . However, this strategy has not been tested prospectively in clinical trials.

Surgery: we recommend surgical removal of hemorrhage For patients with : o cerebellar hemorrhages >3 cm in diameter who are deteriorating o brainstem compression o hydrocephalus due to ventricular obstruction. Surgery for supratentorial ICH is controversial, and current guidelines suggest consideration of standard craniotomy only for those who have lobar clots within 1 cm of the surface. The routine evacuation of supratentorial ICH in the first 96 hours is not recommended.

Hemostatic therapy : Recombinant factor VIIa treatment for acute ICH is investigational and should not be used for the treatment of ICH outside the context of a clinical trial.

Secondary prevention : Treating hypertension is the most important step to reduce the risk of ICH, and probably recurrent ICH. Stopping smoking, heavy alcohol use, and cocaine use are also recommended. Resumption of antiplatelet therapy: we do not recommend aspirin or antiplatelets for those patients with only an "average" risk of recurrent ischemic stroke. What exactly constitutes "average" or "above average" risk is not certain, but we consider hypertension, diabetes, hypercholesterolemia, and the absence of heart disease to be markers of average risk. Atrial fibrillation, cardiomyopathy, large vessel extracranial and intracranial stenoses, and malignancy can be considered as markers for those with "above average" risk who may benefit from long-term antiplatelet therapy after ICH. We do not recommend resumption of aspirin or antiplatelets for primary prevention of cardiovascular disease. The AHA/ASA guidelines of 2006 state that antiplatelets should be discontinued for at least one to two weeks Some experts have argued that aspirin can be used safely as soon as 48 hours after ICH in those who require prophylaxis for venous thromboembolism. We agree, provided neuroimaging has demonstrated a stable ICH. If aspirin is used after ICH, we agree with others that a lower dose (30 to 160 mg daily) is both effective and safer than higher doses.

Resumption of anticoagulation : For patients who require anticoagulation soon after a cerebral hemorrhage, the AHA/ASA guidelines conclude that intravenous heparin may be safer than oral anticoagulation [44] . In addition, the guidelines suggest that oral anticoagulants may be resumed three to four weeks after onset of the hemorrhage with rigorous monitoring and maintenance of INRs in the lower end of the therapeutic range.

Treatment of aneurysmal subarachnoid hemorrhage

GENERAL MANAGEMENT admitted to an ICU for constant hemodynamic monitoring. stool softeners bedrest given analgesia to diminish hemodynamic fluctuations and lower the risk of rebleeding. Transcranial Doppler (TCD) ultrasonography measurements are taken and used as a baseline as the patient progresses through treatment; serial TCD is used to monitor for vasospasm. Deep venous thrombosis (DVT) prophylaxis with pneumatic compression stockings is started prior to aneurysm treatment. Subcutaneous unfractionated heparin 5000 units three times daily can be added for DVT prophylaxis once the aneurysm is treated. We recommend that all anticoagulants and antiplatelet agents should be discontinued after SAH . In addition, the guidelines recommend that any anticoagulant effect should be reversed immediately with appropriate agents such as vitamin K, fresh frozen plasma, or unactivated prothrombin complex concentrate.

Intracranial pressure and blood pressure usually due to acute hydrocephalus and reactive hyperemia after hemorrhage. We generally place a ventriculostomy in appropriate patients; this allows direct measurement of intracranial pressure and often drops systemic blood pressure into the normal range. In the absence of ICP measurement, antihypertensive therapy is often withheld unless there is a severe elevation in blood pressure because of concern about cerebral ischemia and the frequent compensatory nature of acute hypertension . The patients cognitive status may be a useful guide; if the patient is alert, then CPP is adequate, and lowering the blood pressure may decrease the risk of rerupture; we typically keep the systolic blood pressure in such patients below 140 mmHg. In contrast, antihypertensive therapy is generally withheld in those with a severely impaired level of consciousness since the impairment may be due to a reduced CPP. When blood pressure control is necessary, the use of vasodilators such as nitroprusside or nitroglycerin should be avoided because of their propensity to increase cerebral blood volume and therefore intracranial pressure. Labetalol is preferred.

Nimodipine calcium channel blocker was initially used in patients with SAH to prevent vasospasm. Nimodipine is ideally administered within four days of SAH. The typical dose is 60 mg every four hours by mouth or nasogastric tube. Nimodipine must be given orally; inadvertent intravenous administration has been associated with serious adverse events, including death.

Seizure prophylaxis should probably be minimized whenever possible. The decision to treat with antiepileptic agents can be based upon the distribution of blood on axial imaging studies. A lower impetus to start antiepileptic agents is warranted in the setting of perimesencephalic blood without cortical layering, since this pattern of hemorrhage is associated with a particularly good prognosis.

Continuation of AED therapy may not be necessary in most patients after undergoing aneurysmal clipping following a SAH, especially those without acute seizures who present with a good grade

Glucocorticoid therapy Glucocorticoid therapy for cerebral injury remains controversial. There is some justification for using glucocorticoids in the setting of SAH because of their putative effects on cerebral edema, prevention of vasospasm, and delayed hydrocephalus . However, limited evidence from available clinical trials supports neither a beneficial nor adverse effect of glucocorticoids for the treatment of aneurysmal SAH

PREVENTION OF VASOSPASM It typically begins no earlier than day 3 after hemorrhage, reaching a peak at days 7 to 8. Vasospasm is manifested clinically by a decline in neurologic status including the onset of focal neurologic abnormalities. It is the leading cause of death and disability after aneurysm rupture Hyperdynamic therapy "triple-H" therapy : Hemodilution, induced Hypertension (with pressor agents such as phenylephrine or dopamine), Hypervolemia , the results from two studies did suggest some benefit of triple-H therapy on symptomatic vasospasm and mortality. Surgical approaches Other methods to prevent vasospasm may be used at the time of surgery in patients with SAH: nfusion of urokinase after aneurysm clipping , intrathecal urokinase infusion into the cisterna magna , Early cisternal cerebrospinal fluid (CSF) washout Statins we suggest initiating statin treatment within 48 hours of aneurysmal SAH and continuing until discharge from intensive care. In addition, we suggest continuing statin therapy after SAH for patients who were taking statins prior to SAH.

TREATMENT OF ANEURYSMS Surgery Surgical management of cerebral aneurysms is an effective and safe procedure with the evolution of microsurgical techniques in the hands of an experienced surgeon. Placement of a clip across the neck of the aneurysm remains the treatment of choice for most aneurysms Timing and choice of therapy The timing of surgery following intracranial aneurysm rupture is an area of controversy. The potential benefits of early surgery (within 48 to 72 hours of the hemorrhage) include prevention of rebleeding and management of vasospasm. Treatment of vasospasm Nimodipine treatment reduces poor outcome associated with vasospasm in a significant number of patients. However, aggressive therapy is often necessary when symptomatic vasospasm occurs. Aggressive therapy of vasospasm can only be pursued after the aneurysm has been treated with surgery or intraluminal therapy. Following aneurysmal occlusion, hyperdynamic therapy, including modest hemodilution, induced hypertension (with pressor agents such as phenylephrine or dopamine), and hypervolemia (so-called "triple-H" therapy), is instituted in an effort to raise the mean arterial pressure and thereby increase cerebral perfusion. Volume expansion is achieved via crystalloid or colloid solution dependent upon physician preference. Treatment of Refractory vasospasm Vasospasm that persists despite triple-H therapy has been treated successfully in some cases by percutaneous intraarterial angioplasty or by the administration of vasodilators including intraarterial (IA) papaverine, IA nicardipine, IA nimodipine, and intrathecal nitroprusside. Intraarterial papaverine and angioplasty also may be used in combination

Hydrocephalus Ventricular drain placement can improve the clinical grade of patients presenting with SAH. Drainage should be considered for patients who have a deteriorating level of consciousness and for those in whom no improvement in hydrocephalus occurs within 24 hours Antiepileptic drug therapy Antiepileptic drugs are usually continued for approximately six months in patients who have experienced an acute seizure (within seven days) following SAH, although there are no strict guidelines. Agents such as phenytoin, carbamazepine, and phenobarbital are typically used.

Recommendations for Carotid Endarterectomy in asymptomatic patients

CEA Is Beneficial For Patients With Asymptomatic Carotid Stenosis Of 60 To 99 Percent. However, The Number Needed To Treat To Prevent One Stroke At Three Years Is About 33, And The Degree Of Benefit Is Not As Great As It Is For Symptomatic Carotid Stenosis. Therefore, Careful Patient Selection Is Particularly Important And Should Be Guided By Individual Factors. The Evidence Supporting Cea In Asymptomatic Women Is Less Compelling Than In Asymptomatic Men, And A Meta-Analysis Of The Acas And Acst Trial Data Showed No Benefit For Women.. Cea In Asymptomatic Patients Should Be Considered A Long-Term Investment, As The Benefit Of Cea Emerges Only After A Number Of Years. . We Suggest Cea For Medically Stable Men Between The Ages Of 40 And 75 Years With Asymptomatic Carotid Stenosis Of 60 To 99 Percent Who Have A Life Expectancy Of At Least Five Years, Provided The Perioperative Risk Of Stroke And Death For The Surgeon Or Center Is Less Than 3 Percent ( Grade 2a). This Recommendation Places A Relatively High Value On Longer-Term Stroke Prevention And A Relatively Lower Value On Avoidance Of Short-Term Perioperative Stroke And Death. We Suggest Medical Management Rather Than Cea For Women With Asymptomatic Carotid Stenosis ( Grade 2b). A Number Of Additional Factors May Influence The Decision To Perform Cea In Patients With Asymptomatic Carotid Disease. These Include Complete Occlusion Of The Contralateral Carotid Artery, Knowledge Of Stroke Heterogeneity, The Risk Of Unheralded Carotid Stroke, And Evidence That Stroke Risk Is Or Is Not Associated With Progression Of Carotid Stenosis. . We Recommend Low-Dose Aspirin (81 To 325 Mg Daily) Treatment For All Patients Having Cea Prior To Surgery And For At Least Three Months After Surgery ( Grade 1a).

Recommendations for Carotid Endarterectomy in symptomatic patients

CEA is beneficial for patients with 50 to 69 percent symptomatic stenosis, and the NNT over five years in this group is 22. However, women with 50 to 69 percent symptomatic carotid stenosis have not shown clear benefit. We suggest CEA for men with recently symptomatic carotid stenosis of 50 to 69 percent who have a life expectancy of at least five years, provided that the perioperative risk of stroke and death for the surgeon or center is less than 6 percent ( Grade 2A). We suggest medical management rather than CEA for women with recently symptomatic carotid stenosis of 50 to 69 percent ( Grade 2B). . CEA is not beneficial for symptomatic carotid stenosis of 30 to 49 percent, and CEA is harmful for symptomatic patients with less than 30 percent stenosis. We recommend medical management rather than CEA for patients with symptomatic carotid stenosis that is less than 50 percent ( Grade 1A). CEA is likely to be of greatest benefit if performed within two weeks of the last symptomatic event in patients with nondisabling stroke or transient ischemic attack (TIA) who have 70 percent or greater carotid stenosis. However, CEA may not be beneficial if performed two weeks or longer after the last event for patients with 50 to 69 percent stenosis. In addition, CEA may not be beneficial if performed beyond two weeks after the last event for women irrespective of the degree of stenosis. We recommend that CEA be performed without delay, preferably within two weeks of the last symptomatic event, for patients with carotid stenosis and a nondisabling stroke or TIA ( Grade 1B). . A number of additional factors may influence the benefit and risk of CEA for patients with symptomatic carotid stenosis. CEA is not associated with significant benefit for patients with near occlusion of the symptomatic ipsilateral internal carotid artery. Older patients may have a greater benefit than younger patients. Patients with hemispheric TIA appear to have greater benefit than patients with transient retinal ischemia. Coexisting severe contralateral carotid stenosis or occlusion may increase perioperative risk but does not cancel out benefit. . The benefit of CEA for patients with moderate to severe ischemic stroke has not been evaluated in randomized clinical trials, and patients with an ipsilateral stroke who have persistent disabling neurologic deficits are unlikely to benefit from CEA. The risks of CEA for such patients probably vary according to clinical and radiologic features. . We recommend aspirin (81 to 325 mg/day) treatment starting before surgery for all patients having CEA and continuing for at least three months after surgery ( Grade 1A).

Bell's palsy
3 times greater during pregnancy, Diabetes is present in about 5 to 10 % of patients

CAUSE : 1. 2. 3. 4. About 50% unknown Herpes simplex virus activation the likely cause of Bell's palsy in most cases Herpes zoster is probably the second most common Other: CMV, EPV , adenovirus, rubella virus, mumps, influenza B, and coxsackievirus

DIAGNOSIS based upon the following criteria: paralysis of the facial muscles, with or without loss of taste on the anterior two-thirds of the tongue or altered secretion of the lacrimal and salivary glands. Onset is acute, over a day or two; the course is progressive, reaching maximal clinical weakness/paralysis within three weeks or less from the first day of visible weakness; and recovery or some degree of function is present within six months. Associated prodrome, ear pain, dysacusis, is variable.

Diagnostic tests : Electrodiagnostic studies help determine the prognosis, and imaging studies (CT , MRI) can define potential surgical causes of facial palsy. However, these tests are not necessary in all patients. Patients with a typical lesion that is incomplete and recovers do not need further study.

Differential diagnosis : Lyme disease , HIV , Bacterial infection of the middle ear (otitis media) , Cholesteatoma , Melkersson-Rosenthal syndrome ,Sarcoidosis , Sjogren's. MANAGEMENT Eye care : Artificial tears (LARMA ) should be applied every hour while the patient is awake ophthalmic ointments ( GENTAMYCIN ) should be used at night. Protective glasses or goggles should be prescribed. Patches can be used at night, but tape should not be placed directly on the eyelid since the patch could slip and abrade the cornea.

Drug therapy : we recommend early treatment with oral glucocorticoids for all patients with Bell's palsy. Treatment should preferably begin within 3 days of symptom onset. Our suggested regimen is prednisone (60 to 80 mg/day) for one week. we suggest early combined therapy with predlone (60 to 80 mg per day) plus valacyclovir (1000 mg three times daily) for one week for patients with severe facial palsy.

Surgical decompression : it is not a currently recommended treatment. Nerve stimulation : we recommend against its use.

Treatment of status epilepticus

Status epilepticus refers to the occurrence of a single unremitting seizure with a duration longer than 5 to 10 minutes or frequent clinical seizures without an interictal return to the baseline clinical state. Etiologies include :noncompliance with antiepileptic drug (AED) treatment, drug or alcohol withdrawal syndromes, acute brain injury or infection, and metabolic disturbances, among others. The diagnosis of status epilepticus can be difficult. A careful neurologic examination is critical. Electroencephalogram (EEG) studies are especially important in situations where there is a high risk of nonconvulsive status epilepticus or there is any uncertainty in the correct diagnosis.

Assessment and support The initial assessment and treatment of a patient in status epilepticus should proceed relatively simultaneously. Hemodynamic and respiratory monitoring are also required in order to avoid side effects of therapy We recommend lorazepam 0.02 to 0.03 mg/kg IV as the initial treatment for status epilepticus (Grade 1A). This should be repeated, as needed up to 0.1 mg/kg. A loading dose of phenytoin or fosphenytoin should follow in order to maintain anti-seizure effect (Grade 1B). We divide the initial management into three phases: 1. assessment/supportive treatment, 2. initial pharmacologic therapy 3. secondary pharmacotherapy (if required) for the treatment of refractory seizures .

Assessment and support These tasks may require 1-5 minutes and may overlap with the next phase of treatment 1. A rapid neurologic examination should be performed to provide a preliminary classification of the type of status epilepticus and its probable etiology. 2. A rapid general evaluation, with particular attention to respiratory and circulatory status, and supportive therapy (eg, oxygen, mechanical ventilation) should be instituted as needed. 3. intravenous catheters should be placed and blood obtained for electrolyte, glucose, and toxicology studies, a CBC, and a rapid "finger-stick" glucose. Measurement of ABG is often valuable and may suggest a need for intubation and mechanical ventilatory support. 4. Cardiac monitoring, frequent measurement of blood pressure, and pulse oximetry should be instituted. Initial pharmacologic therapy This phase of treatment usually lasts approximately 30 minutes Lorazepam 0.02 to 0.03 mg/kg should be administered intravenously and approximately one minute allowed to assess its effect. Diazepam 0.1 mg/kg IV or midazolam 0.05 mg/kg IV may be substituted if lorazepam is not available. o If seizures continue at this point, additional doses of lorazepam (up to a cumulative dose of 0.1 mg/kg) should be infused at a maximum rate of 2 mg/minute, and a second intravenous catheter placed in order to begin a concomitant phenytoin (or fosphenytoin) loading infusion. o Even if seizures terminate after the initial lorazepam dose, therapy with phenytoin or fosphenytoin is generally indicated to prevent the recurrence of seizures. Phenytoin and any of the benzodiazepines are incompatible and will precipitate if infused through the same intravenous line.

A phenytoin infusion of 20 mg/kg (or 20 mg/kg phenytoin equivalents (PE) for fosphenytoin) should be started at 25 to 50 mg/min (or 100 mg PE/minute for fosphenytoin) and reduced if significant adverse effects of the infusion are seen. (show algorithm 1.)

Treatment of refractory seizures Status epilepticus that is refractory to first line anticonvulsants indicates a grave prognosis and requires management in an intensive care setting. After failure of the first line therapy discussed above, the next step is to consider infusion of another 10 mg/kg of phenytoin (or 10 mg/kg PE of fosphenytoin) and up to another 0.05 mg/kg of lorazepam if the patient is stable. Metabolic derangements from initial laboratory studies should be appropriately treated. Further measures are required if seizures continue, but whereas there is reasonable agreement upon treatment up to this point, the optimal therapy of refractory status epilepticus is less well defined. Regardless of the specifics of pharmacologic therapy, it is critical to provide adequate ventilatory and hemodynamic support. Patients with refractory seizures should be endotracheally intubated, and continuous electroencephalogram (EEG) recordings are desirable The primary drugs used for refractory status epilepticus are phenobarbital, pentobarbital, midazolam, and propofol. There is no consensus about which should be used first. Further pharmacologic therapy at this point is based primarily upon the patient's hemodynamic stability and the risk for prolonged mechanical ventilation .

Hemodynamically stable patients Treatment with high-dose barbiturates (pentobarbital or phenobarbital) remains common in this setting because of the greatest experience with its use . However, propofol is gaining some acceptance in this setting for patients who are already intubated because response to therapy is very rapid, allowing a rapid change to another regimen if propofol infusion is unsuccessful. Continuous EEG monitoring should be instituted, if possible, along with continuous pulse oximetry and blood pressure monitoring via an arterial catheter. Vasopressors should be available at the bedside. An initial dose of 20 mg/kg of phenobarbital should be infused at a maximum rate of 100 mg/minute. If seizure activity continues, a dose of 10 mg/kg of pentobarbital should be infused while careful attention is paid to the EEG and hemodynamic status. Additional doses of pentobarbital at rates up to 100 mg/min should be infused until all seizures stop. Subclinical seizures may still be evident on the EEG after clinical seizures have stopped. As it is important to stop both clinical and electrographic seizures, EEG monitoring is important in the treatment of refractory status epilepticus. However, it can be difficult to be certain if electrographic patterns are ictal or interictal. Thus, it is common practice to titrate therapy until the EEG shows a pattern that is clearly not ictal. A burst suppression pattern is often chosen as an electrographic endpoint because it is clearly not ictal and is easy to recognize .

Almost all patients at this point will require vasopressor support (typically phenylephrine or dopamine), as well as crystalloid infusions. If seizures are terminated with pentobarbital, then an infusion at 1 to 4 mg/kg per hour should be maintained for 24 hours and tapered over the following 24 hours. Some physicians may prolong the duration of highdose therapy if frequent focal epileptiform discharges remain on the EEG after treatment. During this time, high therapeutic phenytoin and/or phenobarbital concentrations must be maintained.

Hemodynamically unstable patients Treatment with barbiturates or propofol may significantly worsen the hemodynamics of unstable patients. Therefore, one option is to proceed with a midazolam infusion because it is the best-tolerated treatment in this setting . Generally, therapy is initiated with a 0.2 mg/kg bolus, followed by a continuous infusion of 0.05 to 0.5 mg/kg per hour. o If this is unsuccessful within 45 to 60 minutes, a propofol or pentobarbital infusion should be started.

Patients at high risk for respiratory failure Patients who are at high risk for prolonged mechanical ventilation (eg, those with severe COPD, severe debilitation, or cancer) should be treated with propofol in an attempt to minimize the duration of sedation . Pressors should be ready at the bedside, and blood pressure and EEG should be monitored closely while propofol infusion is initiated at 1 to 2 mg/kg per hour. This infusion should be titrated over the next 20 to 60 minutes to maintain a seizure-free state and burst suppression on the EEG. Infusion rates up to 10 to 12 mg/kg/hour may be required, but should not be maintained for more than 18 to 48 hours because of the risk of the propofol infusion syndrome. If seizures are controlled with propofol, the effective infusion rate should be maintained for 24 hours and then tapered at a rate of 5 percent per hour. This prevents rebound seizures that commonly occur with abrupt propofol discontinuation. It is critical that high therapeutic levels of at least one anticonvulsant (phenytoin levels >25 mg/L [99 mol/L] or phenobarbital levels >30 mg/L [129 mol/L]) are obtained prior to tapering the propofol in order to reduce the risk of seizure recurrence. Treatment with propofol should generally be considered unsuccessful if it does not terminate seizure activity within 45 to 60 minutes. In this case, a high dose barbiturate infusion should be considered. Propofol infusions for refractory status epilepticus are relatively new in comparison with midazolam or high dose barbiturates.

Malignant status epilepticus The term "malignant" status epilepticus has been introduced to refer to status epilepticus that either fails to respond to the therapies discussed above or recurs quickly on tapering these medications . It has been reported that as many as 20 percent of patients with refractory status epilepticus evolve into malignant status epilepticus, a transition that is associated with a very poor prognosis.

Viral encephalitis in adults

Patients with aseptic meningitis most commonly present with fever and headache with meningismus on examination. Patients may be lethargic but have a normal sensorium. By contrast, patients with encephalitis present with mental status changes. Patients with features of both may be considered to have a meningoencephalitis. Viral encephalitis can be primary or postinfectious, which are difficult to differentiate clinicaly. Elicit a detailed sexual, travel, and exposure history (to both insects and animals).

Clues on physical examination : Parotitis strongly suggests the diagnosis of mumps encephalitis in an unvaccinated patient with mental status changes. Flaccid paralysis that evolves into an encephalitis strongly suggests the possibility of West Nile virus infection . In fact, it has been misdiagnosed as Guillain-Barre syndrome. A maculopapular rash is also seen in approximately half of patients with this infection. Tremors of the eyelids, tongue, lips, and extremities may suggest the possibility of St. Louis encephalitis or WN encephalitis in the appropriate geographic location or travel history. Findings of hydrophobia, aerophobia, pharyngeal spasms, and hyperactivity suggest encephalitic rabies. Atypical presentations of rabies include seizures, cranial nerve palsies, and myoclonus. Grouped vesicles in a dermatomal pattern may suggest varicella-zoster virus.

Neuroimaging : to assess the possibility of a localized process, such as an abscess, and to look for focality, which may suggest a specific etiology of encephalitis : Temporal lobe involvement is strongly suggestive of HSV encephalitis, although other herpes viruses (eg, VZV, EBV, human herpesvirus 6) can also produce this clinical picture The most common areas of involvement in eastern equine encephalitis are basal ganglia , thalami presence of hydrocephalus may suggest nonviral etiologies, as bacteria, fungal, or parasitic agents .

Electroencephalography is often abnormal in acute encephalitis. Focality in the temporal lobe region is suggestive of HSV encephalitis. CSF examination : of patients with suspected meningitis or encephalitis is essential for diagnosis. A lymphocytic predominance is suggestive of a viral etiology. RBC in absence of a traumatic tap is suggestive of HSV or other necrotizing viral encephalitides.

Diagnosis : we recommend diagnostic CSF PCR for HSV-1 and West Nile virus (PCR). Testing for other viral pathogens will depend on travel or exposure history to insects and animals. Serologic testing for West Nile virus, mumps, and Epstein-Barr virus can also be considered in the appropriate clinical setting.

Empiric therapy:In the patient with encephalitis, we recommend rapid initiation of acyclovir 10 mg/kg three times daily intravenously due to the high mortality associated with HSV encephalitis when treatment is delayed (Grade 1A).

Acute treatment of migraine in adults

We typically begin specific migraine therapy with a triptan for outpatients with moderate to severe migraine. There are no efficacy data that definitively support use of one triptan versus another; different pharmacologic properties and delivery routes may help guide the choice. For initial treatment of patients who present to the hospital emergency department with severe migraine, particularly if the migraine is accompanied by severe nausea or vomiting, we suggest treatment with intravenous (IV) metoclopramide (10 mg) or prochlorperazine (10 mg). o A more aggressive alternative option, based upon the results of one clinical trial, is high-dose metoclopramide (20 mg IV every 30 minutes up to four doses) given with diphenhydramine (20 mg IV every hour up to two doses) to prevent akathisia and other dystonic reactions. o IV dihydroergotamine (DHE 45) 1 mg combined with IV metoclopramide 10 mg is also a reasonable alternative for treatment of intractable severe migraine in the emergency department, and it can be used if metoclopramide monotherapy is ineffective. Parenteral DHE 45 should not be used as monotherapy. DHE 45 is contraindicated in patients with ischemic vascular disease involving cardiac, cerebrovascular, or peripheral circulations. For patients who are treated in the emergency department or clinic for migraine headache with one of the standard abortive therapies discussed above, we suggest adjunctive treatment with IV or intramuscular dexamethasone (10 to 25 mg) to reduce the risk of early headache recurrence. Sublingual, oral, or rectal ergotamine is the drug of choice in relatively few patients with migraine because of issues of efficacy and side effects. Suitable candidates may be those with prolonged duration of attacks (eg, greater than 48 hours) and possibly frequent headache recurrence. Abortive treatments are usually more effective if they are given early in the course of the headache; a large single dose tends to work better than repetitive small doses. Triptan treatment, in particular, should be given at the first sign of pain in patients susceptible to cutaneous allodynia. Many oral agents are ineffective in migraine because of poor absorption secondary to migraine-induced gastric stasis. In particular, a non-oral route of administration should be selected for patients whose migraines present early with significant nausea or vomiting. Acetaminophen and many other analgesics are not advisable in the patient who requires frequent medication since they have been associated with rebound headaches.

Abortive treatment of migraine: Oral and inhalational medications Drug Oral medications NSAIDs Initial dose Maximal dose Special precaution

All NSAIDs should be avoided in patients with active gastritis, peptic ulcer disease, renal insufficiency and bleeding disorders; NSAIDs are not recommended for chronic daily use for prolonged periods of time. 50-75 mg

Indomethacin (also 25-75 mg available as 50 mg suppository) Ibuprofen 400-1200 mg Naproxen 500-1000 mg Piroxicam 20 mg Flurbiprofen 100-200 mg Sulindac 150-300 mg Aspirin 650-975 mg Trilisate 10001500 mg

Acetaminophen

650-1500 mg Ergot alkaloids (sublingual) Ergotamine (Ergomar) 2 mg/tablet Triptans Sumatriptan (Imitrex) 50 mg Marketed in the US as 25 and 50 mg tablets Zolmitriptan (Zomig) 2.5 mg Marketed in the US as 2.5 and 5 mg tablets Naratriptan (Amerge) 1-2.5 mg Rizatriptan (Maxalt) 5-10 mg Almotriptan (Axert) 6.25 or 12.5 mg Frovatriptan (Frova) 2.5 mg Inhalation medications Nasal sprays DHE 45 (Migrainol) 2 mg/puff Butorphanol (Stadol) 1 mg/puff

400-800 mg TID/QID 500 mg BID or TID 20 mg/d 100-200 mg BID 150-300 mg BID 325-650 mg every 4-6 hours 500-1500 mg Trilisate along with Disalcid, Relafen, and Daypro BID/TID represents a group of NSAIDs that may be especially helpful in elderly patients 650-1500 mg >4 g/day is associated with risk or liver toxicity every 4-6 hrs 6 mg/24 hrs Same as with other Ergotamine preparations 10 mg/week 200 mg/day Maximum recommended monthly dose for migraine is 18 tablets (50 mg) or an equal amount Maximum monthly dose is 18 tablets (5 mg) each or equal amount

10 mg/day

5 mg/day Only triptan not contraindicated with MAO inhibitors 30 mg/day Propranolol increases serum concentration of rizatriptan Two doses in 24 h 7.5 mg in 24 h

Sumatriptan (Imitrex)

20 mg/spray

1 puff; can Opioid-like side effects repeat in 6090 min. Faster onset than the tablet form; fewer side effects than injectable

Abortive treatment of migraine: combination analgesics and parenteral medications Drug Initial dose Combination analgesics* 2 capsules at onset; may Midrin Acetaminophen 325 use 1 every hour afterwards until mg Isometheptene 65 improvement or max of 5/attack mg Dichloralphenzone 100 mg 1 tablet BID Bellergal-S Ergotamine 0.6 mg Balladona 0.2 mg Phenobarbitol 40 mg Cafergot and 2 tablets at onset; may repeat if no wigraine improvement or side (oral) effects Ergotamine 1 mg Caffeine 100 mg Cafergot and 1 suppository at onset; may repeat as needed wigraine (suppository) Ergotamine 2 mg Caffeine 100 mg 2 tablets at onset may Fiorinal repeat as needed Aspirin 324 mg Caffeine 40 mg Butalbital 50 mg Same as for Fiorinal Fioricet Acetaminophen 325 mg Caffeine 40 mg Butalbital 50 mg Parenteral medications 1 mg IV/SC/IM Dihydrogotamine (DHE-45) Maximal dose Special precaution

Maximum/attack 5 Maximum 5 capsules/attack capsules, 10 per week, and 40 per month

3-4 tablets/day, 8 per Not for daily use week and 24 per month

Up to 6 tablets per Ergotamine-containing attack, up to 12 per preparations should be avoided in week and up to 24 per patients with peripheral vascular month disease, uncontrolled hypertension, and renal and liver disease 2 suppositories per Faster onset than oral; particularly headache and up to 6 useful in the presence of nausea per week

Not to exceed 6 tablets Use daily during vulnerability for per day and 24 tablets menstrual migraine; otherwise not per month for daily use. Same as for Fiorinal Same as for Fiorinal

Sumatriptan

6 mg SC injection

0.5-1.0 mg TID/BID Need pretreatment with sedating (total dose <3 mg/day) antiemetics; similar precaution for both DHE-45 and Sumatriptan as for other ergotamine preparations Max dose/attack is two 6 mg injections at least 1 hr apart

Preventive treatment of migraine in adults

Prophylactic migraine treatment may be indicated : 1. if patients are having more than four headaches per month 2. the headaches last longer than 12 hours 3. they account for a significant amount of total disability. 4. the patient's own opinion of disability, contraindication to or failure of acute therapies, cost of both acute and preventive therapies, and patient preference. Prophylactic therapy should also be considered to prevent neurologic damage in the presence of uncommon migraine conditions including hemiplegic migraine, basilar migraine, migraine with prolonged aura, and migrainous infarction. The choice of prophylactic agent depends upon the individual situation, associated medical problems, and presence of conditions that are comorbid with migraine such as depression, mania, anxiety, panic, Raynaud's syndrome, epilepsy, and stroke. As an example: o tricyclics or other antidepressants may be considered in patients who are depressed or prone to depression. o beta blockers and calcium channel blockers may be preferable in patients with hypertension, o those with disorders of the cervical spine or other musculoskeletal problems that contribute to their headaches may benefit from NSAIDs. Prophylactic migraine medications that have proven high efficacy in clinical trials include propranolol, metoprolol, timolol, amitriptyline, topiramate, and valproate. About 50 to 75 percent of patients given any of these drugs will have a 50 percent reduction in the frequency of headaches, but the doses required may lead to intolerable side effects As a result, we often begin with verapamil (a safe, tolerable, and easy to use drug), particularly in young patients with new onset episodic migraine, recognizing that the efficacy data for this approach are relatively weak. NSAIDs are first line therapy for mini-prophylaxis of menstrual migraine. Frovatriptan is an alternative. Prophylactic principles Start the drug at a low dose. Increase the dose gradually until therapeutic benefit develops, the maximum dose of the drug is reached, or side effects become intolerable. Give the chosen medication an adequate trial in terms of duration and dosage. efficacy is often first noted at four weeks and can continue to increase for three months. Avoid overuse of analgesics, opioids, triptans, and ergots. In addition, patients who use ergotamine-type medications such as methysergide should NOT use serotonin agonists (eg, triptans) within 24 hours due to the potential risk of myocardial infarction Women of childbearing potential must Avoid valproate for this group if possible, and choose the medication that will have the least adverse effect on the fetus. Migraine headaches may improve independent of treatment. If the headaches are well controlled, slowly taper the drug if possible. Many patients experience continued relief with either a lower dose or cessation of the medication.

1. 2. 3.

4. 5.

Prophylactic treatment of migraine and tension type headache Drug Starting dose Calcium channel blockers Verapamil 120 mg/day Nifedipine 30 mg/day Diltiazem 60 mg/day Nimodipine 20 mg/day Flunarazine Tricyclic antidepressants Nortriptyline 10 mg/day Amitriptyline 10 mg/day Clomipramine 10 mg/day Desipramine 10 mg/day Doxepin 10 mg/day New antidepressants SSRIs Fluoxetine 10 mg/day Paroxetine 10 mg/day Sertraline 25 mg/day Other Bupropion 75 mg/day Monoamine oxidase inhibitors Phenelzine 15 mg/day Beta blockers Propranolol 60 mg/day Nadolol 40 mg/day Timolol 10 mg/day Atenolol 50 mg/day Metoprolol 50 mg/day Serotonin antagonists Methysergide 2 mg BID Cyproheptadine Anticonvulsants Phenytoin Carbamazepine Valproate Gabapentin 4 mg QHS 300 mg/day 100 mg/day Maximum dose 720 mg/day 180 mg/day 360 mg/day 60 mg/day Special precautions

Benefit may be noted after 3 to 4 weeks on therapeutic dose; contraindicated in patients with heart block, hypotension, congestive heart failure, atrial flutter and fibrillation

125 mg/day 250 mg/day 250 mg/day 200 mg/day 250 mg/day

Established role in headache prophylaxis; contraindicated in patients with urinary retention, glaucoma and bundle branch block; severe anticholinergic effects and weight gain can be limiting

80 mg/day 40 mg/day 200 mg/day 300 mg/day 90 mg/day

Role in headache prophylaxis not established; less anticholinergic side effects; generally better tolerated

Save as a last resort; need strict dietary and medical screening; tyramine-free diet Benefit may lag 3 to 4 weeks; contraindicated in patients with asthma, diabetes mellitus, congestive heart failure, heart block; depression, impotence, or hypotension may limit use

320 mg/day 240 mg/day 40 mg/day 150 mg/day 300 mg/day

8-14 mg/day in Drug holiday is a must to prevent retroperitoneal fibrosis; divided doses sedation and weight gain limit usefulness 4-8 mg TID Cosmetic side effects mg Needs to monitor CBC, LFTs

Topiramate

200-600 TID 250 mg BID 500 mg High teratogenicity incidence TID/QID 100 mg TID 300-800 mg No blood monitoring required or 300 mg TID QHS 25 mg/day 100 mg BID Slow titration minimizes adverse events Weight loss and metabolic acidosis common

Ergot derivatives Methylergonovine 0.2 mg/day 0.2 mg/day Typical ergotamine precautions BID: twice daily; TID: three times daily; QID: four times daily; QHS: once before bedtime.

Cluster headache: Acute treatment

For patients with acute cluster headache, we recommend initial treatment with either triptans or oxygen (Grade 1A). Oxygen should be tried first if available since it is without side effects. Otherwise, subcutaneous sumatriptan 6 mg can be used as initial therapy for patients with no contraindications. For patients who have a suboptimal response to inhaled oxygen and are unable to administer or tolerate subcutaneous injections, alternatives include intranasal sumatriptan or intranasal zolmitriptan. For patients with acute cluster headache who do not respond to or tolerate oxygen and triptans, alternatives include octreotide, intranasal lidocaine and oral ergotamine.

Cluster headache: Preventive therapy

should be started as soon as possible at the onset of a cluster episode, with the goal of suppressing attacks over the expected duration of the cluster period. For patients with chronic cluster headache and those with relatively long-lasting (ie, two months or longer) active periods of episodic cluster headache, we recommend initial preventive therapy with verapamil (Grade 1B). The onset of benefit is dose dependent. The starting dose is usually 240 mg daily in three divided doses. Most patients respond to a total dose of 240 to 320 mg daily. Titration to a total dose of up to 960 mg daily may be necessary for some patients to obtain full prophylactic benefit. For patients with episodic cluster headache who have active cluster periods that last less than two months, we suggest initial preventive therapy with glucocorticoids alone (Grade 2C). We prefer prednisone 60 to 100 mg once a day for at least five days, followed by a taper with a dose reduction of 10 mg daily. Destructive surgical procedures aimed at the sensory trigeminal nerve or autonomic pathways are unproven for cluster headache prophylaxis and should be viewed with great caution. Occipital nerve stimulation and hypothalamic deep brain stimulation appear promising but remain investigational.

Tension-type headache in adults: Acute treatment

For patients with pure episodic TTH of mild to moderate severity, we recommend treatment with simple analgesics such as acetaminophen and NSAIDs (Grade 1A). We suggest initial therapy with NSAIDs rather than acetaminophen (Grade 2B). Reasonable choices include a single dose of ibuprofen 200 or 400 mg, or naproxen 375 or 550 mg. For patients with definite or probable TTH of moderate to severe intensity who are evaluated in a medical facility, we suggest treatment with intramuscular ketorolac 60 mg (Grade 2B). For patients with TTH that is unresponsive or poorly responsive to monotherapy with simple analgesics, we suggest the use of caffeine combined with simple analgesics ( acetaminophen, aspirin, or ibuprofen) (Grade 2A). We recommend NOT using combination therapies containing either butalbital or opioids for initial treatment of TTH (Grade 1C). These medications are associated with multiple risks, including tolerance, dependency, toxicity, and the development of medication overuse headache. Avoiding medication overuse headache is a major goal of therapy for TTH. This ideally requires limitation of acute therapy to nine days per month on average, and typically a maximum of two doses per treatment day. We suggest a "preemptive" prophylaxis approach to avoid the development of medication overuse

headache in patients who exhibit an increase in headache frequency or disability, and for those who have long-duration headaches.

Tension-type headache in adults: Preventive treatment

Prophylactic treatment of headaches is indicated if the headaches are frequent, long lasting, or associated with a significant amount of disability. Preventive treatment is appropriate for most patients with chronic tension-type headache (TTH), and for many patients with frequent episodic TTH. Tricyclic antidepressants, particularly amitriptyline, are the mainstay of preventive pharmacologic treatment for TTH. Other agents have been studied for TTH prophylaxis, including serotonin-norepinephrine reuptake inhibitors and anticonvulsants However, the benefit of these drugs for TTH prevention is not established, and more clinical trial data are required. Behavioral treatments for headache : cognitive-behavioral therapy, relaxation, and biofeedback. For patients with frequent episodic TTH or chronic TTH we suggest treatment with combined tricyclic antidepressant therapy plus stress management therapy rather than treatment with tricyclics alone or behavioral therapy alone (Grade 2B). For patients with frequent episodic TTH or chronic TTH who have a preference for pharmacologic treatment rather than behavioral, we suggest tricyclic therapy with amitriptyline (Grade 2B). For patients with frequent episodic TTH or chronic TTH who wish to avoid pharmacologic therapy, we suggest behavioral therapy (Grade 2B). For patients with frequent episodic TTH and chronic TTH who do not tolerate or desire more effective treatments such as amitriptyline and behavioral therapy, we suggest treatment with physical therapy that includes craniocervical exercises (Grade 2C).

Bacterial Meningitis
Epidemiology : The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitides in patients over age 50 to 60 years or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes. The major causes of healthcare-associated bacterial meningitis are staphylococci and aerobic gram-negative bacilli.

Clinical manifestations : Patients with bacterial meningitis are usually quite ill and often present soon after symptom onset. The classic triad of acute bacterial meningitis consists of fever, nuchal rigidity, and a change in mental status, although an appreciable number of patients do not have all three features. Signs of meningeal irritation Positive test The test is positive when there is resistance to extension at the knee to >135 degrees or pain in the lower back or posterior thigh. The test is positive when there is flexion of the knees and hips of the patient. The test is positive if the patient reports exacerbation of his/her headache with this maneuver.

Signs Kernig's sign

Maneuver Place patient supine with hip flexed at 90 degrees. Attempt to extend the leg at the knee. Brudzinski's sign Place patient in the supine position and passively flex the head towards the chest. Jolt accentuation Patient rotates his/her head of headache horizontally two to three times per second. Laboratory findings :

Blood cultures are often positive and can be useful in the event that cerebrospinal fluid (CSF) cannot be obtained before the administration of antimicrobials. Approximately 50 to 90 % of patients with bacterial meningitis have positive blood cultures. Two sets of blood cultures should be obtained from all patients prior to the initiation of antibiotics.

Lumbar puncture : Every patient with suspected meningitis should have CSF obtained unless a lumbar puncture (LP) is contraindicated. It is not uncommon for LP to be delayed while a computed tomographic (CT) scan is performed to exclude a mass lesion or increased intracranial pressure, which rarely leads to cerebral herniation during subsequent CSF removal. However, a screening CT scan is not necessary in the majority of patients. A CT scan of the head before LP should be performed in adult patients with suspected bacterial meningitis who have one or more of the following risk factors: 1. Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation) 2. History of central nervous system disease (mass lesion, stroke, or focal infection) 3. New onset seizure (within one week of presentation) 4. Papilledema 5. Abnormal level of consciousness

6. Focal neurologic deficit If LP is delayed or deferred, blood cultures should be obtained and antibiotics should be administered empirically before the imaging study, followed as soon as possible by the LP. o LP should be obtained in less than 4 hour of administration of antibiotic o In addition, dexamethasone (0.15 mg/kg IV every six hours) should be given shortly before or at the same time as the antibiotics if the preponderance of clinical and laboratory evidence suggests bacterial meningitis with a plan to stop therapy, if indicated, when the evaluation is complete. o Adjunctive dexamethasone should not be given to patients who have already received antimicrobial therapy because it is unlikely to improve patient outcome. The usual CSF findings in patients with bacterial meningitis are: o WBC of 1000 to 5000/microL (range of <100 to >10,000) with a percentage of neutrophils usually greater than 80 % o protein of 100 to 500 mg/dL o glucose <40 mg/dL (with a CSF:serum glucose ratio of <0.4). Despite these typical CSF findings, the spectrum of CSF values in bacterial meningitis is so wide that the absence of one of more of the typical findings is of little value A Gram stain should be obtained whenever there is suspicion of bacterial meningitis. It has the advantage of suggesting the bacterial etiology one day or more before culture results are available. It is important to note that a false-positive elevation of the CSF white blood cell count can be found after traumatic lumbar puncture, or in patients with intracerebral or subarachnoid hemorrhage in which both red blood cells and white blood cells are introduced into the subarachnoid space. WBC in blood x RBC in CSF

True WBC in CSF = Actual WBC in CSF - ------------------------------------RBC in blood Pretreatment Evaluation : If possible, crucial historical information (eg, serious drug allergies, recent exposure to an individual with meningitis), should be obtained before antibiotic treatment of presumed bacterial meningitis is instituted. Diagnostic tests : Initial blood tests should include a complete blood count with differential, and two sets of blood cultures. The initial approach to management in a patient with suspected bacterial meningitis includes performance of a lumbar puncture (LP) to determine whether the cerebrospinal fluid (CSF) findings are consistent with the diagnosis.

General Principles Of Therapy : Avoidance of delay : We recommend that antibiotic therapy be initiated immediately after the performance of the lumbar puncture (LP) or, if a computed tomography scan is to be performed before LP, immediately after blood cultures are obtained (Grade 1B). Antibiotic regimen : There are three general requirements of antibiotic therapy for bacterial meningitis: use of bactericidal drugs effective against the infecting organism, use of drugs that enter the CSF, and use of drugs with optimal pharmacodynamics. Adjunctive dexamethasone : o early intravenous administration of dexamethasone has been evaluated as adjuvant therapy in an attempt to diminish the rate of hearing loss and other neurologic complications as well as mortality in selected patients with bacterial meningitis.

o o o

When indicated, dexamethasone is given 15 to 20 minutes before or at the time of antibiotic administration. Dose : 0.15 mg/kg every 6 hours for 4 days The indications for dexamethasone in patients in the developing world with suspected or confirmed bacterial meningitis depends upon the prevalence of HIV in the population. For adults in the developed world with known or suspected pneumococcal meningitis, we recommend administration of dexamethasone (Grade 1B). For all other adults in the developed world with confirmed or suspected bacterial meningitis, we suggest NOT administering dexamethasone (Grade 2B). For adults from areas of the developing world with high HIV prevalence and known or suspected bacterial meningitis, we recommend NOT administering dexamethasone (Grade 1B). In regions of the developing world with low HIV prevalence, we suggest administering dexamethasone in patients who have bacterial meningitis confirmed by gram stain or a rapid diagnostic test (Grade 2B). In patients with known or suspected pneumococcal meningitis who are treated with dexamethasone, we suggest adding rifampin to the standard antibiotic regimen (vancomycin plus either ceftriaxone or cefotaxime) only if susceptibility studies show intermediate susceptibility (MIC 2 mcg/mL) to ceftriaxone and cefotaxime (Grade 2C). A reasonable alternative is to initiate rifampin and then discontinue it if the isolate is susceptible to the cephalosporin. Dexamethasone should be continued if the CSF Gram stain and/or the CSF or blood cultures reveal S. pneumoniae.

EMPIRIC THERAPY : The empiric approach to antibiotic selection in patients with suspected bacterial meningitis is directed at the most likely bacteria based on the patient's age and underlying disease status . Recommendations for empiric antimicrobial therapy for purulent meningitis based on patient age and specific predisposing condition
Predisposing factor Age <1 month 1-23 months 2-50 years >50 years Head trauma Basilar skull fracture Penetrating trauma Common bacterial pathogens Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella species Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli N. meningitidis, S. pneumoniae Antimicrobial therapy

Ampicillin plus cefotaxime; OR ampicillin plus an aminoglycoside Vancomycin plus a third-generation cephalosporin Vancomycin plus a third-generation cephalosporin S. pneumoniae, N. meningitidis, L. monocytogenes, Vancomycin plus ampicillin plus a aerobic gram-negative bacilli third-generation cephalosporin S. pneumoniae, H. influenzae, group A beta-hemolytic streptococci Staphylococcus aureus, coagulase-negative staphylococci (especially Staphylococcus epidermidis), aerobic gram-negative bacilli (including Pseudomonas aeruginosa) Aerobic gram-negative bacilli (including P. aeruginosa), S. aureus, coagulase-negative staphylococci (especially S. epidermidis) S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli (including P. aeruginosa) Vancomycin plus a third-generation cephalosporin Vancomycin plus cefepime; OR vancomycin plus ceftazidime; OR vancomycin plus meropenem Vancomycin plus cefepime; vancomycin plus ceftazidime; vancomycin plus meropenem Vancomycin plus ampicillin cefepime; OR vancomycin ampicillin plus meropenem OR OR plus plus

Postneurosurgery

Immunocompromised state

Ceftriaxone or cefotaxime. Add ampicillin if meningitis caused by Listeria monocytogenes is suspected.

1. No known immunodeficiency : o Streptococcus pneumoniae, Neisseria meningitidis, and, less often, Haemophilus influenzae and group B streptococcus are the most likely causes of community-acquired bacterial meningitis in otherwise healthy adults up to the age of 60. o Individuals aged 50 years and older are also at risk of Listeria monocytogenes meningitis. o Patients without known immune deficiency and with normal renal function should be treated empirically with the following regimen until culture and susceptibility data are available : Ceftriaxone : 2 g IV every 12 hours OR Cefotaxime : 2 g IV every 4 - 6 hours PLUS Vancomycin : 30 - 60 mg/kg IV per day in two or three divided doses PLUS Ampicillin In adults 50 years of age: 2 g IV every 4 hours

Ross 1gr 22 or 3cif 1gr 24 or6 + Vanco 1gr 12 or 3 Ampicillin 1gr 26 2. Impaired cell-mediated immunity: o Among patients with impaired cell-mediated immunity (due, for example, to lymphoma, cytotoxic chemotherapy, or high-dose glucocorticoids), coverage must be directed against Listeria monocytogenes and gram-negative bacilli (including Pseudomonas aeruginosa) as well as Streptococcus pneumoniae. o An appropriate regimen in patients with normal renal function is : Vancomycin : 30 to 60 mg/kg IV per day in two or three divided doses PLUS Ampicillin : 2 g IV every 4 hours

PLUS EITHER Cefepime:2 g IV every 8 hours OR Meropenem : 2 g IV every 8 hours

Vanco 1gr 12 or 3 + Ampicillin 1gr 26 + Cefepime 1gr 23 or Ronem 1gr 23 3. Nosocomial meningitis: o Empiric therapy for nosocomial meningitis must cover both gram-positive and gram-negative (such as Klebsiella pneumoniae and Pseudomonas aeruginosa) nosocomial pathogens. o An appropriate regimen in patients with normal renal function is: Vancomycin : 30 to 60 mg/kg IV per day in two or three divided doses PLUS EITHER Ceftazidime:2 g IV every 8 hours OR Cefepime : 2 g IV every 8 hours OR Meropenem : 2 g IV every 8 hours

Vanco 1gr 12 or 3 + Cefepime 1gr 23 or Ronem 1gr 23 or Ceftadim 1gr 23 4. Allergy to beta-lactams, we suggest (Grade 2C): Vancomycin : 30 to 60 mg/kg IV per day in two or three divided doses PLUS Moxifloxacin : 400 mg IV once daily

PLUS if Listeria coverage is required (in patients 50 and/or in those with defects in cell-mediated immunity), trimethoprim-sulfamethoxazole 10 to 20 mg/kg (of the trimethoprim component) IV per day divided every 6 to 12 hours

Regimens Based Upon Gram Stain : o Once the CSF Gram stain results are available, the antibiotic regimen should be tailored to cover the most likely pathogen. If the CSF findings are consistent with the diagnosis of acute bacterial meningitis, but the Gram stain is negative, empiric antibiotic therapy should be continued : Recommendations for antimicrobial therapy in adult with pathogen identification by positive Gram stain Microorganism Streptococcus pneumoniae Neisseria meningitidis Listeria monocytogenes Haemophilus influenzae Recommended therapy Alternative therapies Vancomycin plus a third-generation Fluoroquinolone cephalosporin Third-generation cephalosporin Penicillin G, ampicillin, chloramphenicol, fluoroquinolone, aztreonam Ampicillin or penicillin G Trimethoprim-sulfamethoxazole, meropenem Third-generation cephalosporin

Chloramphenicol, cefepime, meropenem, fluoroquinolone Ceftriaxone or cefotaxime. Some experts would add rifampin if dexamethasone is also given. Moxifloxacin is recommended given its excellent CSF penetration and in vitro activity against Streptococcus pneumoniae, although there are no clinical data available. If used, many authorities would combine moxifloxacin with vancomycin or a third-generation cephalosporin (cefotaxime or ceftriaxone). Addition of an aminoglycoside should be considered. Therapy For Specific Pathogens : Recommendations for specific antimicrobial therapy in bacterial meningitis based on isolated pathogen Microorganism, susceptibility Streptococcus pneumoniae Penicillin MIC <0.1 mcg/mL 0.1-1.0 mcg/mL Standard therapy Alternative therapies

Penicillin G or ampicillin

Third-generation cephalosporin 2.0 mcg/mL Vancomycin plus a third- Fluoroquinolone generation cephalosporin Cefotaxime or ceftriaxone Vancomycin plus a third- Fluoroquinolone MIC 1.0 mcg/mL generation cephalosporin Neisseria meningitidis Penicillin MIC <0.1 mcg/mL Penicillin G or ampicillin Third-generation cephalosporin , chloramphenicol 0.1-1.0 mcg/mL Third-generation Chloramphenicol, fluoroquinolone, meropenem cephalosporin Listeria monocytogenes Ampicillin or penicillin G Trimethoprim-sulfamethoxazole, meropenem Streptococcus agalactiae Ampicillin or penicillin G Third-generation cephalosporin Escherichia coli and other Third-generation Aztreonam, fluoroquinolone, meropenem, Enterobacteriaceae cephalosporin trimethoprim-sulfamethoxazole, ampicillin

Third-generation cephalosporin chloramphenicol Cefepime, meropenem

Pseudomonas aeruginosa Haemophilus influenzae Beta-lactamase negative Beta-lactamase positive Staphylococcus aureus Methicillin susceptible Methicillin resistant

Cefepime or ceftazidime Ampicillin Third-generation cephalosporin Nafcillin or oxacillin Vancomycin**

Aztreonam , ciprofloxacin , meropenem Third-generation cephalosporin , cefepime, chloramphenicol, fluoroquinolone, aztreonam Cefepime, chloramphenicol, fluoroquinolone, aztreonam Vancomycin, meropenem, linezolid, daptomycin Trimethoprim-sulfamethoxazole, linezolid, daptomycin Linezolid

Staphylococcus epidermidis Vancomycin** Enterococcus species Ampicillin susceptible Ampicillin plus gentamicin ... Ampicillin resistant Vancomycin plus gentamicin ... Ampicillin and vancomycin Linezolid ... resistant There may not be clinical data to support all recommendations for alternative antibiotics in patients with bacterial meningitis, Consider addition of rifampin if the MIC of ceftriaxone is >2 mcg/mL. Addition of an aminoglycoside should be considered. Choice of a specific antimicrobial regimen must be guided by in vitro susceptibility test results. ** Consider addition of rifampin. SUPPORTIVE CARE

Fluid management Careful management of fluid and electrolyte balance is important, since both over- and under-hydration are associated with adverse outcomes. Reduction of intracranial pressure Patients with bacterial meningitis who have elevations of intracranial pressure, and who are stuporous or comatose, may benefit from insertion of an intracranial pressure monitoring device. Pressures exceeding 20 mm Hg are abnormal and should be treated; there is also rationale for treating smaller pressure elevations (ie, above 15 mm Hg) to avoid larger elevations that can lead to cerebral herniation and irreversible brain stem injury. Methods to reduce intracranial pressure include elevating the head of the bed to 30, hyperventilation to maintain PaCO2 between 27 and 30 mm Hg, and use of hyperosmolar agents. Repeat CSF Analysis o Although not routinely recommended, there are settings in which repeat LP should be performed in patients with bacterial meningitis : 1. When there is no evidence of improvement by 48 hours after the initiation of appropriate therapy. 2. 2-3 days after the initiation of therapy of meningitis due to microorganisms resistant to standard antimicrobial agents (eg, penicillin-resistant pneumococcal infection), especially for those who have also received adjunctive dexamethasone therapy and are not responding as expected, or for infection caused by a Gram negative bacillus, which is much more common with nosocomial infection . 3. Persistent fever for more than eight days without another explanation. o Repeat CSF cultures should be sterile. For patients in whom repeat cultures are positive despite appropriate therapy with parenteral antibiotic therapy, administration of intrathecal (or intraventricular) antibiotics may be considered PREVENTION : Some forms of bacterial meningitis can be prevented by successful vaccination and temporary protection can be provided in certain cases with chemoprophylaxis.

Vaccines : o Among the major causes of bacterial meningitis in adults, vaccines are available for S. pneumoniae, N. meningitidis, and H. influenzae. o Polysaccharide vaccines against S. pneumoniae and N. meningitidis are recommended for adults with a variety of risk factors for infection. o Routine immunization of adults against H. influenzae type b is not recommended, except for those with prior splenectomy. Chemoprophylaxis : There is a role for post-exposure chemoprophylaxis to prevent spread of meningococcal and Haemophilus meningitis under certain circumstances, but not for pneumococcal disease. prevention of meningococcal infection : o Chemoprophylaxis should be administered to close contacts as early as possible after the primary case has been identified (ideally within 24 hours of identification of the index patient), but is of little value if administered more than two weeks after the index case. o Regimens for antimicrobial prophylaxis include : Rifampin (PO): 600 mg every 12 hours for Two days Ciprofloxacin (PO) : 500 mg Single oral dose Ceftriaxone (IM) : 250 mg Single IM dose Azithromycin : 500 mg Single oral dose (Not routinely recommended, but may be used in regions with ciprofloxacin-resistant isolates ) Prevention of Haemophilus influenza :We recommend rifampin for Hib chemoprophylaxis (Grade 1A). The dose is 20 mg/kg (maximum dose 600 mg) once per day for four days.

Management algorithm for adults with suspected bacterial meningitis

STAT" indicates that the intervention should be done emergently.

Treatment of multiple sclerosis in adults

Relapsing-remitting For disease modifying therapy of relapsing-remitting multiple sclerosis (RRMS), there are six available medications approved by the US FDA. These include three interferon beta (IFNB) drugs (Avonex, Rebif, Betaseron), as well as glatiramer acetate and mitoxantrone. Natalizumab is FDA approved as monotherapy only. It is reasonable to start newly diagnosed patients with RRMS on any one of four approved agents. These are: Interferon beta-1a (Avonex) 30 mcg intramuscular (IM) injection weekly Glatiramer acetate 20 mg subcutaneous (SC) injection daily Interferon beta-1b (Betaseron) 0.25 mg (1 mL) SC every other day Interferon beta-1a (Rebif) 22 or 44 mcg SC three times a week

Based upon clinical experience, the available clinical data, neutralizing antibody formation, side effect profile, route of administration, and MRI data, we suggest Avonex or glatiramer acetate as agents of first choice for patients with RRMS, depending upon the patient's lifestyle and laboratory data. These drugs are typically continued indefinitely unless side effects are intolerable or the patient begins to fail in terms of response, after which use of another agent can be considered. For patients with highly active RRMS who have a poor response to both beta interferons and glatiramer acetate, or intolerance of these immunomodulators, we suggest treatment with natalizumab. However, natalizumab therapy is associated with a risk of progressive multifocal leukoencephalopathy.

Secondary progressive Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone) The AAN guidelines conclude that glucocorticoid treatment has a short-term benefit on the speed of functional recovery in patients with acute attacks of MS . However, there does not appear to be any long-term improvement in the degree of functional recovery from an attack following the use of glucocorticoids. It is possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS. In my view, the same may be true for patients with SPMS who experience acute attacks. Intravenous cyclophosphamide and glucocorticoid monthly pulses According to the AAN guidelines, it is possible that younger patients with progressive MS may derive some benefit from pulse plus booster cyclophosphamide treatment. However, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (PPMS and SPMS). Methotrexate oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses The AAN guidelines conclude that, based on limited and somewhat ambiguous evidence from a single trial , it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS Consider addition of an interferon, if not currently prescribed The AAN guidelines state that it is appropriate to consider IFNB treatment for patients with SPMS who are still experiencing relapses . The effectiveness of IFNB in patients with SPMS but without relapses is uncertain. As noted above, pronounced disease progression may be another clinical feature that identifies patients with SPMS who are likely to be IFNB responders.

Primary progressive Intravenous glucocorticoid monthly pulses (typically 1000 mg of methylprednisolone). Methotrexate, oral or subcutaneous, 7.5 to 20 mg per week, with or without monthly glucocorticoid pulses The AAN guidelines conclude that, based on limited and somewhat ambiguous evidence from a single trial , it is possible that methotrexate favorably alters the disease course in patients with SPMS and PPMS. Cladribine intravenous or subcutaneous The AAN guidelines conclude that cladribine reduces gadolinium enhancement on brain MRI scans in patients with both relapsing and progressive forms of MS . Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack-rate or disease progression. Consider mitoxantrone According to the AAN guidelines, it is possible that mitoxantrone has a beneficial effect on disease progression in MS.

Treatment of acute exacerbations of multiple sclerosis For patients with an acute multiple sclerosis exacerbation that results in neurologic symptoms and increased disability or impairments in vision, strength, or cerebellar function, we recommend treatment with glucocorticoids (Grade 1B). Our preferred regimen is intravenous methylprednisolone 1000 mg daily for five days without an oral taper. Infection must first be ruled out. For patients with acute, severe neurologic deficits caused by multiple sclerosis who have a poor response to treatment with high-dose glucocorticoids, we suggest treatment with plasma exchange (Grade 2B).

PULMONOLOGY

Management of acute exacerbations of of COPD

DEFINITIONS: acute increase in symptoms beyond normal day-to-day variation , This generally includes one or more of the following cardinal symptoms: 1. Cough increases in frequency and severity 2. Sputum production increases in volume and/or changes character 3. Dyspnea increases Constitutional symptoms, an unchanged chest radiograph, a variable decrease in pulmonary function, and tachypnea are typical in acute exacerbations . However, severe cases can lead to respiratory failure and death . PRECIPITANTS : 50 - 60 % of exacerbations are due to respiratory infections (mostly bacterial and viral) o Bacterial : Haemophilus influenzae(the most common), Moraxella catarrhalis, and Streptococcus pneumonia . Pseudomonas aeruginosa and Enterobacteriaceae are also isolated, particularly from patients with severe COPD. o Viral : rhinoviruses (the most common) , Influenza, parainfluenza, coronavirus, and adenovirus , Respiratory syncytial virus and human metapneumovirus 10 % are due to environmental pollution 30 % are of unknown etiology

INITIAL EVALUATION : medical history, physical examination, CXR , and routine laboratory studies. ABG should be performed in most patients to assess the severity of the exacerbation and to establish a baseline from which improvement or deterioration can be measured. Criteria for hospitalization from the American Thoracic Society/European Respiratory Society (ATS/ERS) 2004 : 1. Inadequate response of symptoms to outpatient management 2. Marked increase in dyspnea 3. Inability to eat or sleep due to symptoms 4. Worsening hypoxemia 5. Worsening hypercapnia 6. Changes in mental status 7. Inability to care for oneself (ie, lack of home support) 8. Uncertain diagnosis 9. High risk comorbidities including pneumonia, cardiac arrhythmia, congestive heart failure, diabetes mellitus, renal failure, or liver failure.

TREATMENT GOALS : 1. 2. 3. 4. 5. 6. Identifying and ameliorating the cause of the acute exacerbation, if possible Optimizing lung function by administering bronchodilators and other pharmacologic agents Assuring adequate oxygenation and secretion clearance Averting the need for intubation, if possible Preventing complications of immobility, such as thromboemboli and deconditioning Addressing nutritional needs

OXYGEN THERAPY We suggest that all patients who are hypoxemic be given supplemental oxygen targeting a PaO2 of 60 to 70 mmHg, with an oxyhemoglobin saturation of 90 to 94 % (Grade 2C).

Venturi masks are the preferred means of oxygen delivery because they permit a precise delivered fraction of inspired oxygen (FiO2). Venturi masks can deliver an FiO2 of 24, 28, 31, 35, 40, or 60 percent. Nasal cannulae can provide flow rates up to 6 L per minute with an associated FiO2 of approximately 40 percent When higher inspired concentrations of oxygen are needed, simple facemasks can provide an FiO2 up to 55 percent using flow rates of 6 to 10 L per minute. A high FiO2 is not required to correct the hypoxemia associated with most acute exacerbations of COPD. Inability to correct hypoxemia with a relatively low FiO2 should prompt consideration of pulmonary emboli, acute respiratory distress syndrome, pulmonary edema, or severe pneumonia as the cause of respiratory failure. Adequate oxygenation must be assured, even if it leads to acute hypercapnia. Hypercapnia is generally well tolerated in patients whose arterial carbon dioxide tension (PaCO2) is chronically elevated. However, mechanical ventilation may be required if hypercapnia is associated with depressed mental status, profound acidemia, or cardiac dysrhythmias.

PHARMACOLOGIC TREATMENT We recommend that all patients having a COPD exacerbation receive both an inhaled short-acting beta adrenergic agonist and an inhaled short-acting anticholinergic agent, rather than either medication alone (Grade 1B). Beta adrenergic agonists : Typical doses of albuterol : 2.5 mg (diluted to a total of 3 mL) by nebulizer every 1-4 hours as needed Alternatively, 4 to 8 puffs (90 mcg per puff) by MDI with a spacer every 1-4 hours as needed. Increasing the dose of nebulized albuterol to 5 mg does Not have a significant impact on spirometry or clinical outcomes Anticholinergic agents Typical doses of ipratropium : 500 mcg by nebulizer every 4 hours as needed. Alternatively, 2 puffs (18 mcg per puff) by MDI with a spacer every 4 hours as needed. Glucocorticoids : We recommend that all patients having a COPD exacerbation receive systemic glucocorticoids (Grade 1A). Intravenous glucocorticoids should be given to patients who present with a severe exacerbation, who respond poorly to oral glucocorticoids, who are vomiting, or who may have impaired absorption due to decreased splanchnic perfusion (eg, patients in shock). Oral administration is used in most other patients. optimal dose of systemic glucocorticoids : IV Methylprednisolone (Solumedrol) (60 to 125 mg, 2-4 times daily) PO Prednisone (Predlone) (40 to 60 mg orally, once daily) The duration of systemic glucocorticoid therapy: varies from patient to patient and exacerbation to exacerbation, most exacerbations should be treated with full dose therapy for 7 - 10 days . taper over about 7 days . Tapering solely is not necessary if the duration of therapy is less than 3 weeks (a duration too brief to cause adrenal atrophy) inhaled glucocorticoids should Not be used as a substitute for systemic glucocorticoid.

Antibiotics: Sputum cultures should not be performed during most exacerbations of COPD. Antibiotics are indicated for many patients having a COPD exacerbation. For patients whose exacerbation of COPD is mild (defined as not requiring mechanical ventilation and having only one of the three cardinal symptoms of increased dyspnea, sputum purulence, or sputum production), we suggest that antibiotics NOT be prescribed (Grade 2B).

For patients whose exacerbation of COPD is moderate to severe (defined as requiring mechanical ventilation or having at least two of the three cardinal symptoms), we recommend antibiotic therapy (Grade 1B). The optimal antibiotic regimen for the treatment of exacerbations of COPD has not been determined. We use a "risk stratification" approach when selecting initial antibiotic therapy. The initial antibiotic regimen should target likely bacterial pathogens and take into account local patterns of antibiotic resistance. The usual duration of antibiotic therapy is 3-7 days, depending upon the response to therapy. For most patients with COPD, we suggest that antibiotics NOT be administered for the purpose of preventing exacerbations (Grade 2C).

Pseudomonas risk factors: 1. 2. 3. 4. Frequent administration of antibiotics (4 or more courses over the past year) Recent hospitalization (2 or more days' duration in the past 90 days) Isolation of Pseudomonas during a previous hospitalization Severe underlying COPD (FEV1 <50 % predicted)

Antiviral therapy Patients whose COPD exacerbation was triggered by influenza virus and who are diagnosed within 48 hours of the onset of influenza symptoms should be treated with oseltamivir (75 mg orally twice daily). Zanamivir is also effective in the treatment of influenza but is contraindicated in this patient population due to the risk of airway reactivity. Mucoactive agents (eg, N-acetylcysteine) Not shown to confer benefit for patients with a COPD exacerbation.

Methylxanthines ( Aminophylline and theophylline) NOT recommended for the treatment of acute exacerbations of COPD

CHEST PHYSIOTHERAPY : Mechanical techniques to augment sputum clearance, such as directed coughing, chest physiotherapy with percussion and vibration, intermittent positive pressure breathing, and postural drainage, have Not been shown to be beneficial in COPD and may provoke bronchoconstriction.

Outpatient Antibiotic treatment of acute exacerbations of COPD

Antibiotic treatment of acute exacerbations of COPD in hospitalized patients

MECHANICAL VENTILATION Noninvasive positive pressure ventilation (NPPV) mechanical ventilation delivered through a noninvasive interface, such as a face mask, nasal mask, or nasal prongs. NPPV improves numerous clinical outcomes and is the preferred method of ventilatory support in many patients with an acute exacerbation of COPD. Indications to NPPV: 1. COPD exacerbation : hypercapnic acidosis (PaCO2 >45 or pH <7.30) (Grade 1A). 2. cardiogenic pulmonary edema, (Grade 1A). 3. patients with hypoxemic respiratory failure due to causes other than cardiogenic pulmonary edema, (Grade 2B). 4. preventing recurrent respiratory failure following extubation if employed early. Potential indicators of success in NPPV use : 1. Younger age 2. Lower acuity of illness (APACHE score) 3. Able to cooperate, better neurologic score 4. Less air leaking, intact definition 5. Moderate hypercarbia (PaCO2 >45 mmHG, <92 mmHG) 6. Moderate acidemia (pH <7.35, >7.10) 7. Improvements in gas exchange and heart respiratory rates within first 2 hours Contraindications to NPPV: 1. Cardiac or respiratory arrest 2. Nonrespiratory organ failure (Severe encephalopathy (eg, GCS <10) ,Severe UGIB ,Hemodynamic instability or cardiac arrhythmia ) 3. Facial or neurological surgery, trauma, or deformity 4. Upper airway obstruction 5. Inability to cooperate/protect airway 6. Inability to clear secretions 7. High risk for aspiration Patients who fail to improve or stabilize within - 2 hours should be promptly intubated. Settings : Start with low pressure in spontaneously triggered mode with backup rate; pressure limited: 8 to 12 cm H2O inspiratory pressure; 3 to 5 cm H2O expiratory pressure ,then Gradually increase inspiratory pressure (10 to 20 cm H2O) as tolerated to achieve alleviation of dyspnea, decreased respiratory rate, increased tidal volume (if being monitored), and good patient-ventilator synchrony

Invasive mechanical ventilation: required in patients with respiratory failure who fail NPPV, do not tolerate NPPV, or have contraindications to NPPV. Indications: 1. Hypoxemia that has not corrected with supplemental oxygen delivered by either a nasal cannula or a face mask. 2. Severe respiratory acidosis, usually due to the precipitating illness or the injudicious administration of oxygen. . 3. Clinical manifestations of distress including severe dyspnea, tachypnea, nasal flaring, accessory muscle recruitment, tracheal tugging, recession of the suprasternal and intercostal spaces, pulsus paradoxus, diaphoresis, and paradoxic motion of the rib cage and abdomen . Modes :We suggest that patients with acute respiratory failure due to COPD exacerbation be ventilated with ACV or IMV/PSV, rather than IMV or PSV. Settings : o We titrate the fraction of inspired oxygen (FiO2) to achieve an arterial oxygen tension (PaO2) 60 mmHg. The arterial oxyhemoglobin saturation (SaO2) should be correlated with the PaO2 in order to determine the appropriate target SaO2 if pulse oximetry is used in lieu of arterial blood gases.

o In patients receiving intermittent mandatory ventilation (IMV) and patients who have increased inspiratory effort while triggering pressure support ventilation (PSV), we suggest flow triggering, rather than pressure triggering. In all other patients, we do not have a preference for pressure or flow triggering. o Reasonable initial settings include a trigger sensitivity of -2 cm H2O when using pressure triggering or 2 L/min when using flow triggering. Regardless of the trigger method chosen, we use an initial flow rate of 1 L/second (ie, 60 L/min) in most patients. o In patients who have intrinsic positive end-expiratory pressure (ie, intrinsic PEEP or auto-PEEP), we suggest adding applied PEEP (ie, extrinsic PEEP). An appropriate amount of applied PEEP is 80 percent of the measured auto-PEEP . o In patients receiving volume-targeted modes of mechanical ventilation (eg, ACV, IMV, IMV/PSV), tidal volumes of 5 to 7 mL/kg may decrease the risk of ventilator-induced lung injury, hyperinflation, and barotrauma. o In patients receiving ACV, we use an initial ventilator rate that is approximately four breaths per minute less than the respiratory rate. In patients receiving IMV or IMV/PSV, we base the initial ventilator rate upon our estimate of the required minute ventilation. o In patients receiving PSV, the pressure support level should be increased until the patient's respiratory rate is below 30 breaths per min because this respiratory rate suggests that the inspiratory effort has been reduced to a reasonable level. o Inhaled medications The administration of inhaled medications to mechanically ventilated patients is problematic because the medications accumulate in the ventilator tubing and the endotracheal tube. This can be overcome by delivering large amounts of bronchodilators via an in-line nebulizer. (MDI) can also be used. he following has been proposed for using MDIs in mechanically ventilated patients: Ensure that the tidal volume is greater than 500 mL during assisted ventilation, the inspiratory time (excluding the inspiratory pause) is greater than 30 percent of total breath duration, and the ventilator breaths are synchronized with the patient's inspiration. Shake the MDI vigorously. Place the canister in the actuator of a cylindrical spacer, which should be situated in the inspiratory limb of the ventilator circuit. Activate the MDI at the onset of inspiration. Institute a breath hold at end-inspiration, lasting three to five seconds. Allow passive exhalation. Repeat every 20 to 30 seconds until the total dose is delivered.

Treatment of acute exacerbations of asthma in adults

The basic principles of care are the following: Early recognition and intervention are critical for successful management of asthma exacerbations. The basic principles of care are assessment of attack severity, repeated use of inhaled beta-agonists, early administration of oral or intravenous glucocorticoids, and frequent reassessment.

INITIAL RESPONSE

Patients should be taught to monitor peak flow values and take appropriate steps upon recognition of an asthma exacerbation. These include immediate treatment with short-acting inhaled beta agonists, monitoring of medication response, and early self-administration of oral glucocorticoids, when needed

Management of asthma exacerbations: home treatment

Severity assessment:

the severity of an asthma exacerbation is assessed based upon symptoms, physical findings, peak expiratory flow measurements, transcutaneous oximetry, and, in certain circumstances, arterial blood gas measurement. Clinical danger signs : o Use of accessory muscles of respiration; brief, fragmented speech; inability to lie supine; profound diaphoresis; agitation; severe symptoms that fail to improve with initial emergency department treatment o Life-threatening airway obstruction can still occur when these signs are NOT present o Inability to maintain respiratory effort, cyanosis, and depressed mental status portend imminent respiratory arrest Measurement of expiratory airflow (peak expiratory flow rate or PEFR) is the best measure of severity; PEFR <40 percent predicted (or <200 L/minute in most adults) indicates severe obstruction; patients in severe distress are often unable to perform peak flow tests Gas exchange Severe hypoxemia (eg, SpO2 95 % despite high flow O2 treatment by nonrebreather mask) portends imminent respiratory arrest; continuous pulse oximetry monitoring should be performed Assessing hypercapnia by Arterial blood gas (ABG) evaluation : does not assist management (unless reliable SaO2 cannot be obtained) during the first few minutes if the patient is in extremis; ABG results can aid assessment if intubation is not an immediate concern; Hypercapnia (a sign of impending respiratory failure) usually does not occur unless a PEFR <25 percent of normal (generally <100 to 150 L/min) is present CXR : is generally unhelpful; obtain if complications suspected suspected complications (eg, temperature >38.3C, unexplained chest pain, leukocytosis, or hypoxemia) to roll out pneumonia, pneumothorax , diagnosis is in doubt, or patient is high-risk (eg, IV drug abuser, immunosuppressed, chronic pulmonary disease, CHF)

Standard treatments

Oxygen: give sufficient oxygen to maintain SaO2 92 % (>95 % in pregnancy) IV: establish intravenous access; may give bolus of normal saline for prolonged episode to replace insensible losses Inhaled beta agonist: The standard regimen for initial care in the emergency department is albuterol (or an equivalent) 2.5 to 5 mg by continuous flow nebulization every 20 minutes for 3 doses, then 2.5 to 10 mg every one to four hours as needed. Alternatively, albuterol can be given by MDI with a spacer, 4 to 8 puffs every 20 minutes for up to 4 hours, then every 1 to 4 hours as needed. For critically ill patients, some clinicians prefer continuous nebulization, administering 10 to 15 mg over one hour. Ipratropium bromide: may be helpful to patients with severe exacerbation who are in the emergency department, but not during hospitalization. Adult dosing of ipratropium for nebulization is 500 mcg every 20 minutes for three doses, then as needed. Alternatively, ipratropium can be administered by MDI at a dose of eight inhalations every 20 minutes, then as needed for up to three hours. Corticosteroids: Early systemic glucocorticoids should be given to all patients who have a moderate or severe exacerbation, or in whom inhaled short-acting beta agonists do not fully correct the decrement in peak flow. The optimal dose give methylprednisolone 60-125 mg IV or prednisone 40-60 mg po; alternatives include: dexamethasone 6-10 mg IV or hydrocortisone 150-200 mg IV; steroids may be given IM or orally if IV access is unavailable Magnesium sulfate: give 2 g infused intravenously over 20 minutes, is suggested for patients who have life-threatening exacerbations (ie, impending intubation for respiratory failure) or those whose exacerbation remains severe after one hour of intensive conventional therapy.

Additional treatments :

Terbutaline: may give 0.25 mg by SC injection every 20 minutes times 3 doses for severe asthma unresponsive to standard therapies; give terbutaline OR epinephrine but not both

Epinephrine: may give 0.2 to 0.5 mL of 1:1000 solution by SC injection for severe asthma unresponsive to standard therapies; give terbutaline OR epinephrine Heliox (helium and oxygen): may improve ventilation and decrease work of breathing with acute, severe airflow obstruction; be careful not to lower patient's oxygen saturation; controversial treatment. Heliox may be given alone or can be used to nebulize albuterol. may be helpful but is not standard therapy. Intravenous administration of leukotriene receptor antagonists may also be beneficial, although these preparations are not available in the United States. .

Ineffective therapies The use of intravenous methylxanthines in addition to beta-agonists, and the use of inhaled glucocorticoids instead of oral or intravenous preparations ineffective approaches that cannot be recommended . Empiric antibiotics Clinical practice guidelines recommend against empiric antibiotic therapy for the treatment of an asthma exacerbation because most respiratory infections that trigger an exacerbation of asthma are viral rather than bacterial. Indication of Endotracheal intubation and ventilation 1. 2. 3. 4. Slowing of the respiratory rate depressed mental status inability to maintain respiratory effort hypoxemia during a severe asthma exacerbation In the absence of anticipated intubation difficulty, rapid sequence intubation is preferred. Nasal intubation is not recommended. The goal of mechanical ventilation accomplished by using : o high inspiratory flow rates (80-100 L/min) o low tidal volumes (6-8 mL/kg o low respiratory rates (10-14/minute). elevations in PaCO2 must be tolerated to avoid barotrauma (ie, permissive hypercapnia).

Indications for hospitalization

patients who do not respond well after 4 to 6 hours to a setting of high surveillance and care. Severe symptoms of coughing, wheezing, and shortness of breath that preclude self-care are obvious indications for continued in-hospital care. Peak flow measurements : o A peak expiratory flow less than 40 % of predicted or of the patient's personal best value at the time of disposition is a reason for continued supervised medical care . o Some patients with a peak expiratory flow 40 to 70 % of predicted, who also demonstrate improving lung function, good asthma self-care skills, and a supportive home environment, can be discharged home . Other patients with lung function in the same range may be considered unsafe for discharge. Among the factors favoring continued observation in this group are: new onset asthma, multiple prior hospitalizations or emergency department visits for asthma, use of oral glucocorticoids at the time of presentation with the acute deterioration, and complicating psychosocial difficulties. o Most patients with a peak expiratory flow above 70 % of normal or their personal best can safely continue their care at home . Medications upon discharge : a brief course 3-10 days of oral glucocorticoids (or an injection of intramuscular glucocorticoids), a prescription for inhaled glucocorticoids, a personalized asthma action plan, and instructions to seek follow up care.

Management of asthma exacerbations: emergency department and hospital

TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS IPF

Indications For Therapy we suggest a trial of therapy in patients with the following characteristics: (Grade 2B). 1. younger age (age 50 years) 2. shorter symptomatic period ( 1 year) before initiation of therapy . 3. an earlier stage of disease, suggested by less dyspnea, mild loss of lung function, absence of oxygen desaturation (defined as <88 percent) on a 6-minute walk test. 4. increased ground glass opacity and little fibrosis on high-resolution chest ct 5. no contraindications to therapy we suggest that therapy not be offered to elderly patients with severe loss of lung function, little ground glass opacity and extensive fibrosis on high-resolution chest ct, and significant contraindications to therapy (Grade 2B). in all other patients, therapy should be considered on a case-by-case basis after carefully weighing the benefits versus the risks.

Timing of therapy: we suggest that therapy be initiated as soon as clinical or physiological evidence of impaired lung function is detected rather than waiting for evidence of progression Treatment : we suggest that glucocorticoid monotherapy not be administered as initial therapy for ipf(grade 2b). we suggest that combination therapy be used(Grade 2B). we typically use azathioprine (imuran)(2 to 3 mg/kg per day), low-dose glucocorticoids (0.25 mg/kg per day, usually less than 20 mg per day), and high-dose acetylcysteine (mucolyz)(600 mg administered as effervescent tablets orally three times per day). we recommend not using interferon gamma-1b, etanercept, colchicine, or cyclosporine as treatment for patients with ipf (Grade 1B). the role of novel agents, such as pirfenidone and bosentan, remains to be defined.

Assessing the response to therapy : a discernible response to treatment may not be evident until the patient has received 3 - 6 months of treatment. we reassess the patient's response to therapy every three months. we monitor symptoms, high resolution chest ct (HRCT), forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity (DLCO), and also resting and exercise gas exchange

Duration Of Therapy the optimal duration of therapy is unknown. we usually continue treatment for at least one year, although some clinicians suggest that two years of treatment might be more effective. Transplantation guidelines for transplantation include histologic or radiographic evidence of usual interstitial pneumonia (uip) and any of the following : 1. a diffusing capacity (dlco) < 39 % of predicted 2. a decrement in forced vital capacity (fvc) > 10 % during 6 months of follow up 3. a decrease in pulse oximetry below 88 % saturation during a 6 minute walk test

4. honeycombing on high resolution chest tomography (hrct) (fibrosis score >2 ) we suggest early referral for lung transplantation evaluation, even before the outcome of medical therapy has been determined (grade 2c).

Acute Exacerbation Of IPF definition a consensus group has proposed the following criteria for an acute exacerbation of IPF : 1. previous or concurrent diagnosis of idiopathic pulmonary fibrosis 2. unexplained development or worsening of dyspnea within 30 days 3. high-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia 4. no evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage 5. exclusion of alternative causes, including left heart failure, pulmonary embolism, and other identifiable causes of acute lung injury o patients who do not meet all five criteria should be termed "suspected acute exacerbation". we typically treat patients with broad-spectrum antibiotics and high dose glucocorticoids (eg, prednisone 1 mg per kg or solumedrol 1 to 2 gm per day intravenously), although scientific evidence for this is lacking . mechanical ventilation is often required, but is not usually successful

Diagnosis and Treatment of Bronchiectasis

Epidemiology : An estimated 110,000 people have in the United States. The prevalence increases with age and it is more common among women. Clinical findings : The classic clinical manifestations of bronchiectasis are cough and the daily production of mucopurulent and tenacious sputum lasting months to years. Less specific complaints include dyspnea, hemoptysis, wheezing, and pleuritic chest pain . Etiology : They include airway obstruction (eg, foreign body aspiration), defective host defenses, cystic fibrosis, Young's syndrome, rheumatic and systemic diseases, dyskinetic cilia, pulmonary infections, allergic bronchopulmonary aspergillosis (ABPA), and cigarette smoking. Diagnosis: The purpose of the diagnostic evaluation is radiographic confirmation of the diagnosis, identification of potentially treatable causes, and functional assessment. The evaluation consists of laboratory testing, radiographic imaging, and pulmonary function testing. Evaluation of bronchiectasis : Category Specific examples/features Acquired bronchial obstruction Foreign-body aspiration Peanut; chicken bone; tooth; grass inflorescence, etc Tumors Laryngeal papillomatosis; airway adenoma; endobronchial teratoma Hilar adenopathy Tuberculosis; histoplasmosis; sarcoidosis Diagnostic tests

Chest imaging; fiberoptic bronchoscopy Chest imaging; fiberoptic bronchoscopy PPD; chest imaging; fiberoptic bronchoscopy COPD Chronic bronchitis Pulmonary function tests Connective tissue disease Relapsing polychondritis (RP); Clinical syndrome of tracheobronchial amyloidosis RP/cartilage biopsy; biopsy for amyloid Mucoid impaction Allergic bronchopulmonary aspergillosis; Total and aspergillus specific bronchocentric granulomatosis (BG); IgE; specific aspergillus IgG; postoperative mucoid impaction Aspergillus skin test; Chest imaging; biopsy for BG Congenital anatomic defects that may cause bronchial obstruction Tracheobronchial Bronchomalacia; bronchial cyst; cartilage Chest CT imaging deficiency (Williams-Campbell syndrome); tracheobronchomegaly (Mounier-Kuhn syndrome); ectopic bronchus; tracheoesophageal fistula Vascular Pulmonary (intralobar) sequestration; Chest CT imaging pulmonary artery aneurysm Lymphatic Yellow-nail syndrome History of dystrophic, slow growing nails Immunodeficiency states IgG deficiency Congenital (Bruton's type) Quantitative immunoglobulin agammaglobulinemia; selective deficiency of levels; immunoglobulin subclasses (IgG2, IgG4); acquired immune subclass levels; impaired globulin deficiency; common variable response to immunization hypogammaglobulinemia; Nezelof's syndrome; with pneumococcal vaccine "bare lymphocyte" syndrome IgA deficiency Selective IgA deficiency ataxia-telegiectasia Quantitative immunoglobulin

levels Leukocyte dysfunction disease (NADPH Dihydrorhodamine 123 (DHR) oxidation test; nitroblue tetrazolium test; genetic testing Other rare humoral WHIM; Hypergammaglobulinemia M Neutrophil count; quantitative immunodeficiencies immunoglobulin levels (CXCR4 mutation, CD40 deficiency, CD40 ligand deficiency, and others) Abnormal secretion clearance Ciliary defects of airway Kartagener's syndrome; ciliary dyskinesis mucosa

syndrome Chronic granulomatous oxidase dysfunction)

Chest image showing situs inversus; bronchial biopsy; ciliary motility studies; electron microscopy of sperm or respiratory mucosa Cystic fibrosis Typical early childhood syndrome; later Sweat chloride; genetic (mucoviscidosis) presentation with predominantly testing sinopulmonary symptoms Young's syndrome Obstructive azoospermia with sinopulmonary Sperm count infections Miscellaneous disorders Alpha-1 antitrypsin Absent or abnormal antitrypsin synthesis and Alpha-1 antitrypsin level deficiency function Recurrent aspiration Alcoholism; neurologic disorders; lipoid History; chest imaging pneumonia pneumonia Connective tissue disease Associated with rheumatoid arthritis and Rheumatoid factor; Sjogren's syndrome antiSSA/antiSSB; salivary gland MRI or biopsy Inhalation of toxic fumes and Ammonia; nitrogen dioxide, or other irritant Exposure history; chest dusts gases; smoke; talc; silicates imaging Chronic rejection following Bone marrow, lung and heart lung History; PFT; chest CT organ transplantation transplantation; associated with obliterative imaging with inspiratory and bronchiolitis expiratory views Infections Childhood infections Pertussis; measles History of infection Bacterial infections Infections due to Staphylococcus aureus, History of infection; sputum Klebsiella, Pseudomonas aeruginosa culture Viral infections Infections due to adenovirus (particularly types History/serologic evidence of 7 and 21), influenza, herpes simplex infection Other infections Fungal (histoplasmosis); Mycobacterium Fungal culture; AFB smear tuberculosis, nontuberculous mycobacteria; and mycobacterial culture possibly mycoplasma Laboratory tests : The initial evaluation of a patient with bronchiectasis should include: 1. complete blood count with differential 2. immunoglobulin quantitation (IgG, IgM, and IgA) 3. sputum culture and smear for bacteria, mycobacteria, and fungi. Chest radiograph: The chest radiograph is abnormal in most patients with bronchiectasis.

nondiagnostic radiographic findings of bronchiectasis include linear atelectasis, dilated and thickened airways (ie, tram or parallel lines, ring shadows on cross section), and irregular peripheral opacities that may represent mucopurulent plugs.

high resolution computed tomography HRCT scan of the chest: HRCT has become the defining test of bronchiectasis. HRCT is indicated in the following settings: There are suspicious clinical findings but a relatively normal chest radiograph. The chest radiograph has abnormal findings (eg, a pneumonic infiltrate) and bronchiectasis is strongly suspected. Management decisions must be made that depend upon the extent of bronchiectasis. As an example, mapping of the chest is needed to define suspected abnormal areas and to demonstrate absent or minimal involvement in the rest of the lung if surgical resection is being contemplated. The presence (or absence) of confounding diseases needs to be defined, such as chronic obstructive lung disease, interstitial lung disease, or malignancy. Characteristic features of bronchiectasis on HRCT include airway dilatation, lack of airway tapering, bronchial thickening, and cysts. In addition, mucopurulent plugs or debris accompanied by post-obstructive air trapping may exist; when the small airways are affected, the term "tree-in-bud pattern" is applicable.

Lung function tests: Pulmonary function testing is used for functional assessment of impairment due to bronchiectasis. Obstructive impairment (ie, reduced or normal FVC, low FEV1, and low FEV1/FVC) is the most frequent finding. Treatment Of Bronchiectasis TREATMENT OF INFECTION Acute exacerbation : o Exacerbations are usually caused by acute bacterial infections. o Frequently isolated pathogens include Hemophilus influenzae, Pseudomonas aeruginosa (especially mucoid types), and, less frequently, Streptococcus pneumoniae . o Symptoms of acute exacerbation of bronchiectasis o Change in sputum production o Increased dyspnea o Increased cough o Fever (temperature, >38 C) o Increased wheezing o Malaise, fatigue, lethargy, or decreased exercise tolerance o Reduced pulmonary function o Radiographic changes consistent with a new pulmonary process o Changes in chest sounds Treatment : o For outpatients with an acute exacerbation and no history of recurrent exacerbations, we suggest initiation of a fluoroquinolone antibiotic (ciprofloxacin Ceproz ) , rather than an alternative oral antibiotic (Grade 2B). o For hospitalized patients with an acute exacerbation, we suggest initiation of two intravenous antibiotics with efficacy for Pseudomonas (Grade 2B). The antibiotics should have different mechanisms of killing.

For all patients (outpatients and inpatients) with an acute exacerbation and a history of recurrent exacerbations, we suggest the initial antibiotic choice be tailored to prior sputum cultures and sensitivities, rather than chosen empirically (Grade 2C). o we suggest at least 7-10 days of antibiotic therapy (Grade 2C). Prevention : o For patients who have recurrent exacerbations, we suggest preventive antibiotics, rather than waiting until an exacerbation occurs to initiate antibiotic therapy (Grade 2B). o Our threshold for the initiation of preventive antibiotics is 3 exacerbations within year. o Strategy 1 : Daily oral ciprofloxacin (500 to 1500 mg/day in two to three divided doses) OR ciprofloxacin given for 7 to 14 days of each month. o Strategy 2 : Daily or three times weekly use of a macrolide antibiotic like azithromycin 250 mg three times weekly PROBLEMATIC PATHOGENS Pseudomonas : o Patients colonized with Pseudomonas aeruginosa have reduced quality of life indices, more extensive bronchiectasis on CT, accelerated decline in pulmonary function, and increased number of hospitalizations. o Ciprofloxacin and other quinolones currently are the only oral agents effective against Pseudomonas aeruginosa. However, resistance often develops after 1-2 treatment cycles. o IV antibiotics are needed when Pseudomonas causes repeated symptomatic episodes Mycobacterium avium complex MAC: o refers to infections caused by one of two nontuberculous mycobacterial species, either M. avium or M. intracellulare. MAC and other nontuberculous mycobacteria are often harbored in damaged lung tissue and bronchiectatic airways. o Treatment : Clarithromycin (1000 mg three times/week) or azithromycin (500 mg three times/week) PLUS Rifampin (600 mg three times/week) or rifabutin (300 mg three times/week) PLUS Ethambutol (25 mg/kg three times per week) Aspergillus species : Oral prednisone (0.5-1.0 mg/kg/day) is the cornerstone of therapy for patients with allergic bronchopulmonary aspergillosis; they may also benefit from additional therapy with a prolonged course of itraconazole (400 mg/day). Therapy initiated prior to the development of bronchiectasis may prevent or delay permanent airway destruction BRONCHIAL HYGIENE Hydration and mucus clearance : o Patients should maintain general hydration with adequate oral fluid intake. o We recommend NOT using mucolytic Dornase (DNAse) Chest physiotherapy : We suggest that all patients with bronchiectasis receive chest physiotherapy (Grade 2B).Secretion clearance/bronchial hygiene Technique Directed cough Autogenic breathing Forced expiration Chest physical therapy (CPT) (postural drainage, hand, or Advantages Inexpensive, simple Controls breathing Helps control breathing Most tested in cystic fibrosis Comment/disadvantage Chest pain may limit Requires patient cooperation Requires patient learning Needs assistant, hard to position, hypoxemia, sometimes worsens

mechanical chest clapping) Positive expiratory pressure (PEP) Oscillatory PEP

High frequency chest compression Bronchodilators There are insufficient data to routine use of bronchodilators . Antiinflammatory medications : o We suggest that patients with bronchiectasis receive inhaled glucocorticoids, rather than no antiinflammatory therapy (Grade 2B). o Systemic glucocorticoids should be reserved for acute exacerbations and should accompany antibacterial therapy. EX : fluticasone 250 mcg twice daily GASTROESOPHAGEAL REFLUX PULMONARY : There is emerging concern that GERD and bronchiectasis are associated. As a result, gastric acid suppression should be considered in most patients. Either an H2 blocker or a proton pump inhibitor can be used. REHABILITATION :There are insufficient data to routine use of pulmonary rehabilitation SURGERY and lung transplantation should be considered on a case-by-case basis Major indications : 1. Removal of destroyed lung partially obstructed by a tumor or residue of a foreign body 2. Reduction in acute infective episodes 3. Reduction in overwhelming purulent and viscid sputum production 4. Elimination of bronchiectatic airways subject to uncontrolled hemorrhage 5. Removal of an area suspected of harboring resistant organisms such as MAC or multidrug resistant tuberculosis Hemoptysis : o For patients with life-threatening hemoptysis (>600 mL/day)due to bronchiectasis, we suggest bronchial artery embolization rather than surgery, if an interventional radiology service is available (Grade 2C). o Surgical therapy is appropriate if bronchial artery embolization fails or cannot be attempted in a timely fashion.

gastroesophageal reflux Easy, inexpensive Device needs cleaning Easy, inexpensive, adds Device needs cleaning vibration to airways wall Better tolerated than CPT Very expensive, pain may limit

Clinical manifestations and diagnosis of sarcoidosis

INTRODUCTION Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that affects individuals worldwide and is characterized pathologically by the presence of noncaseating granulomas in involved organs. EPIDEMIOLOGY : The estimated prevalence of sarcoidosis is 10 to 20 per 100,000 population. Sarcoidosis is more common among blacks than whites. Blacks more commonly present with acute, severe disease, while whites more commonly present with mild, chronic disease. ETIOLOGY : The cause of sarcoidosis is unknown. CLINICAL MANIFESTATIONS Sarcoidosis typically affects young adults. In approximately one-half of cases, it is detected in asymptomatic individuals due to incidental radiographic abnormalities (eg, bilateral hilar adenopathy, reticular opacities). Common presenting symptoms include cough, dyspnea, chest pain, eye lesions, and/or skin lesions. PULMONARY IMAGING Chest radiograph : o Stage I : is defined by the presence of bilateral hilar adenopathy. o Stage II : consists of bilateral hilar adenopathy and reticular opacities. o stage III : consists of reticular opacities with shrinking hilar nodes. o Stage IV: is characterized by extensive parenchymal damage including reticular opacities, volume loss, conglomerated masses, traction bronchiectasis, calcification, cavitation, and/or cyst formation. o Nodular sarcoid Chest computed tomography : can demonstrate a variety of abnormalities in patients with sarcoidosis: o Hilar and mediastinal lymphadenopathy o Beaded or irregular thickening of the bronchovascular bundles o Nodules along bronchi, vessels, and subpleural regions o Bronchial wall thickening o Ground glass opacification o Parenchymal masses or consolidation o Parenchymal bands Cysts o Traction bronchiectasis Fibrosis with distortion of the lung architecture PET Scan : A fluorine-18-fluorodeoxyglucose (18F-FDG) PET scan may be helpful to identify occult lesions and possibly reversible granulomatous disease Radiotracer scanning : Gallium-67 lung scanning is a noninvasive test for staging the "alveolitis" found in interstitial lung diseases. It is not recommended in the routine evaluation of patients because it is difficult to interpret, it is not specific, and a negative scan does not exclude disease.

AIRWAY ABNORMALITIES : Patients with pulmonary sarcoidosis may have abnormalities of the upper and/or lower airways that are difficult or impossible to detect with routine imaging, but recognizable with alternative diagnostic modalities (eg, bronchoscopy): Endobronchial disease exists in approximately 40 percent of patients with stage I disease and approximately 70 percent of patients with stages II or III disease.

Clinically significant airway stenosis is uncommon, but may be difficult to manage when severe Upper respiratory tract disease, including submucosal noncaseating granulomas, may involve the larynx, pharynx, and/or sinuses; it should be suspected in all patients with systemic sarcoidosis

EXTRAPULMONARY SARCOIDOSIS : Sarcoidosis can involve all organ systems. The most prominent sites of extrapulmonary disease include the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system. Dermatologic : Cutaneous involvement is seen in up to 20 % of patients with sarcoidosis, and is often an early finding. Several skin lesions can occur o A maculopapular eruption is the most common subacute lesion. It usually involves the alae nares, lips, eyelids, forehead, rear of neck at the hairline, and/or previous trauma sites (eg, scars and tattoos) . o Waxy, pink nodular lesions are frequently distributed on the face, trunk, and extensor surface of the arms and legs. o Plaque-like lesions can occur in chronic sarcoidosis including lupus pernio, a violaceous discoloration of the nose, cheeks, chin, and ears. o Erythema nodosum (EN) is a panniculitis. It is a component of Lofgren's syndrome and associated with a good prognosis and spontaneous remission. o Atypical lesions may be ulcerative, psoriasiform, hypopigmented, follicular, angiolupoid, rosaeca-like, or morpheaform Ophthalmologic : Ocular involvement occurs in up to 20 % of patients with sarcoidosis and is the presenting symptom in 5 %. Lesions include: Anterior uveitis (iridocyclitis or iritis), Posterior uveitis (chorioretinitis), Retinal vasculitis, Keratoconjunctivitis, Conjunctival follicles .In addition, secondary glaucoma, cataract formation, and blindness are late complications in untreated patients. The combination of anterior uveitis, parotid gland enlargement, facial palsy, and fever (uveoparotid fever) is referred to as Heerfordt's syndrome. Sarcoidosis also affects extraocular orbital tissues, including the lacrimal glands, extraocular muscles, and optic sheath, and may present as a soft tissue orbital mass. Of these, the most common manifestation is lacrimal gland involvement. The most common symptoms in this series were a palpable mass and orbital swelling. Reticuloendothelial : It can manifest as: o Peripheral lymphadenopathy up to 40 % of patients o Hepatomegaly 20 % , Noncaseating granulomas on liver biopsy with or without hepatomegaly 75 % o Splenic enlargement 25 percent, 80 % of whom have granulomas.. Musculoskeletal : Musculoskeletal system involvement may occur in up to 10 % of patients with sarcoidosis. Manifestations include: o Acute polyarthritis (especially the ankle joints), usually in association with erythema nodosum and occasionally with acute uveitis. o Chronic arthritis with periosteal bone resorption. Radiographically, this may appear as cysts, which can mimic rheumatoid disease (show radiograph 8). This form of arthritis is usually associated with a chronic protracted course. No correlation exists between the osseous lesions and the plasma calcium concentration. o Diffuse granulomatous myositis. An uncommon complication of sarcoidosis, it indicates progressive disease and is associated with a poor prognosis. Lofgren's syndrome: Lofgren's syndrome is the combination of erythema nodosum (EN), hilar adenopathy, migratory polyarthralgias, and fever seen primarily in women. Men with acute sarcoidosis

generally present with signs of bilateral ankle arthritis, but without EN . In general, Lofgren's syndrome is associated with a good prognosis and spontaneous remission Exocrine glands : Painless swelling of the salivary glands occurs in approximately 4 percent of patients with sarcoidosis. Xerostomia and keratoconjunctivitis sicca also may be seen, producing manifestations similar to those seen in Sjgren's syndrome. Pancreatitis also occurs in some cases Renal and electrolyte : Abnormalities related to calcium metabolism are the most common renal and electrolyte abnormalities observed among patients with sarcoidosis. The defect in calcium metabolism is due to extrarenal production of calcitriol by activated macrophages. Manifestations include increased intestinal calcium absorption, hypercalciuria (which occurs in up to 50 % of cases), hypercalcemia (which occurs in 10 to 20 %), and nephrocalcinosis. If untreated, renal calcium deposition can lead to chronic renal failure and end-stage renal disease. Although granulomatous infiltration of the kidney is not uncommon, it is rarely the sole cause of renal dysfunction. Other renal complications of sarcoidosis include membranous nephropathy, a proliferative or crescentic glomerulonephritis, focal glomerulosclerosis, polyuria (due to nephrogenic and/or central diabetes insipidus), hypertension, and a variety of tubular defects. Cardiovascular : Granulomatous involvement of the ventricular septum and conduction system can lead to a variety of arrhythmias, including complete heart block and sudden death. Such involvement may be heralded by palpitations, syncope, dizziness, or chest pain.In addition, chronic pulmonary hypertension and cor pulmonale can result from severe scarring of the pulmonary parenchyma and vascular obliteration. In this setting, death from sarcoidosis usually results from right ventricular failure. Neurologic : Approximately 5 % of patients with sarcoidosis have neurologic involvement, which can occasionally be the presenting symptom . Manifestations of central nervous system (CNS) disease usually occur early, while peripheral nerve and skeletal muscle involvement is characteristically seen in the later stages. Granulomatous basal meningitis with infiltration or compression of adjacent structures is responsible for most of the CNS manifestations, including: o Hypothalamic hypopituitarism o Central diabetes insipidus o Hydrocephalus o Lymphocytic meningitis o Cranial nerve palsies, particularly facial palsy Gastrointestinal : The stomach is the most commonly involved portion of the GI tract, but sarcoidosis of the esophagus, appendix, colon, and rectum has also been described. Sarcoidosis can also involve the liver and pancreas. Small bowel sarcoidosis has been reported, but is very rare Reproductive : Sarcoidosis rarely involves the female genital tract. Systemic sarcoidosis, in the absence of significant cardiopulmonary compromise, does not affect fertility and does not increase the incidence of fetal or obstetrical complications. It will often improve during pregnancy, possibly due to increases of maternal free cortisol. Sarcoidosis can involve the testes, and must be differentiated from testicular cancer and tuberculosis. Recurrent epididymitis due to sarcoidosis rarely can occur. Thyroid : Sarcoidosis can cause diffuse goiter or, rarely, a solitary thyroid nodule. Almost all patients are euthyroid, although cases of clinical hypothyroidism caused by diffuse replacement of thyroid tissue have been reported Fatigue : Fatigue is a common symptom in patients with sarcoidosis.

LABORATORY ABNORMALITIES Anemia is uncommon. When present, it usually results from the anemia of chronic disease, although hypersplenism or autoimmune hemolytic anemia can occur in some patients.

Leukopenia (5 to 10 percent), eosinophilia (approximately 25 percent), and thrombocytopenia (rare) can be seen. The erythrocyte sedimentation rate is frequently elevated, but is not useful in assessing disease activity. Hypercalciuria is more commonly observed than hypercalcemia. Hypergammaglobulinemia (30 to 80 percent), diminished skin test reactivity, and a positive rheumatoid factor can exist. A moderate elevation in the serum alkaline phosphatase concentration implies diffuse granulomatous hepatic involvement. Arterial blood gases may be normal, or may reveal hypoxemia and hypocapnia (hyperventilation). Exercise may accentuate these abnormalities elevated Serum ACE : elevated in 75 percent of untreated patients with sarcoidosis Pulmonary function : characteristically demonstrate a restrictive defect with impaired gas exchange Bronchoalveolar lavage : elevated CD4 to CD8 ratio may be detected by bronchoalveolar lavage.

HISTOPATHOLOGY : Noncaseating granulomas are the characteristic histopathologic abnormality. DIAGNOSIS A definitive diagnostic test for sarcoidosis does not exist. Instead, the diagnosis of sarcoidosis requires three elements: 1. compatible clinical and radiographic manifestations 2. exclusion of other diseases that may present similarly 3. histopathologic detection of noncaseating granulomas. Initial evaluation : The purpose of this evaluation is to obtain additional data supporting the diagnosis of sarcoidosis, while eliminating alternative diagnoses. A comprehensive evaluation should be performed in all patients with suspected sarcoidosis, which consists of : o history, physical examination o chest radiograph o pulmonary function tests including spirometry and DLCO o peripheral blood counts o serum chemistries including creatinine, calcium, and liver enzymes o Urinalysis o Electrocardiogram o ophthalmologic examination o tuberculin skin test. o Additional studies that may be considered include a serum angiotensin converting enzyme (ACE) level, serum immunoglobulin levels, bronchoalveolar lavage . Diagnostic procedures : o Patients who present with a classical Lofgren's syndrome of fever, erythema nodosum, arthralgias, and bilateral hilar lymphadenopathy do not require biopsy if the abnormalities resolve quickly and spontaneously, and no alternative explanation for the constellation of findings exists. o Biopsy should be performed in most other cases of suspected sarcoidosis. Biopsy of accessible peripheral lesions is preferred. Fiberoptic bronchoscopy with transbronchial biopsy should be performed if an accessible peripheral lesion can not be identified. Open lung biopsy, thoracoscopic lung biopsy, or surgical mediastinal lymph node biopsy are options if bronchoscopy can not be performed or is nondiagnostic. Assess disease extent

MONITORING DISEASE ACTIVITY IN SARCOIDOSIS: Patients with active disease Every 3-4 months ROS including fever, fatigue, weight loss, visual disturbance, dyspnea, cough, palpitations, abdominal pain, numbness, tingling, lightheadedness, syncope PE including skin exam, palpation of lymph nodes, lung exam Lab tests based on sites of disease activity and medications Spirometry, diffusing capacity, ambulatory oximetry (or 6 minute walk) Every 6 months Ophthalmologic exam, if on hydroxychloroquine Every 12 months CBC and differential Creatinine Calcium AST, ALT, Alkaline phosphatase 25 hydroxy vitamin D 1,25 dihydroxy vitamin D ACE EKG, sooner if palpitations, lightheadedness, syncope Ophthalmologic exam (slit lamp, fundoscopic, tonometric), sooner if visual disturbance Chest x-ray As indicated by symptoms or other tests HRCT Echocardiogram Holter monitoring Urinalysis ACE TSH ( association of thyroid autoimmunity and sarcoidosis) Bone density when glucocorticoid therapy initiated and then every 3 years MRI with gadolinium if neurologic symptoms (unless diabetic) Patients with inactive disease for 2 or more (?) years Every 12-18 months ROS including fever, fatigue, weight loss, visual disturbance, dyspnea, cough, palpitations, abdominal pain, numbness, tingling, lightheadedness, syncope PE including skin exam, palpation of lymph nodes, lung exam Spirometry, diffusing capacity, ambulatory oximetry (or 6 minute walk) CBC and differential Creatinine Calcium Liver enzymes 1,25 dihydroxy vitamin D EKG, sooner if palpitations, lightheadedness, syncope Ophthalmologic exam, sooner if visual disturbance Treatment of pulmonary sarcoidosis with glucocorticoids Treatment of sarcoidosis should be based on clinical or laboratory evidence of dysfunction, which can be related either to pulmonary or to extrapulmonary manifestations of sarcoidosis.

Indications for treatment of pulmonary sarcoidosis : Worsening pulmonary symptoms, including: cough, shortness of breath, chest pain or discomfort, and hemoptysis. Deteriorating lung function, as assessed by serial testing at three to six month intervals that demonstrates one or more of the following: a fall in total lung capacity of 10 % or more; a fall in forced vital capacity of 15 % or more; a decrease in diffusing capacity of 20 percent or more; or worsened gas exchange at rest or with exercise. Progressive radiographic changes, including: worsening of interstitial opacities, development of cavities, progression of fibrosis with honeycombing, or development of signs of pulmonary hypertension.

Therapy is NOT indicated in the following groups of patients: o Asymptomatic patients with stage I disease (bilateral hilar lymphadenopathy, with or without erythema nodosum). Such patients have a high rate of spontaneous remission. o Asymptomatic patients with Stage II radiographic changes and normal or mildly abnormal lung function (mild restrictive or obstructive findings with normal gas exchange). These patients can be followed for three to six months to demonstrate any progression of disease before instituting therapy. It is important to document impairment of lung function or gas exchange in this setting before starting therapy, because approximately 50 percent of patients with stage II radiographic changes will have radiographic resolution by 36 months. o Asymptomatic patients with Stage III disease and normal or mildly abnormal lung function. These patients can also be closely followed for three to six months. However, because only approximately 33 percent of patients with stage III radiographic changes show disease resolution after five years, the majority of these patients will require therapy. Indications for treatment of extrapulmonary sarcoidosis Other indications for therapy include severe discomfort or inability to work as a result of fever, weakness, fatigue, arthralgia, neuropathy, disfiguring skin disease, upper airway disease, or hepatic insufficiency. Treatment of ocular, neurologic, myocardial, or renal sarcoidosis or hypercalcemia is indicated even when symptoms are slight, because severe loss of vision, fatal arrhythmias, or insidious renal damage may ensue . PROTOCOL FOR USE OF GLUCOCORTICOIDS The optimal dose of glucocorticoids is not known, so that choosing a dose requires balancing the risk of adverse effects with the likelihood of response. Theoretically, one wishes to choose the lowest dose necessary to obtain optimal benefit in those patients who have the potential for glucocorticoid responsiveness. Daily oral glucocorticoids Therapy is initiated with relatively high doses of oral prednisone. This is followed by a slow taper to the lowest effective dose for a total duration of therapy between six and 12 months. There are three phases in the treatment protocol:

For the first four to six weeks, we recommend treating with a daily dose of 0.5 to 1 mg/kg ideal body weight (usually 30 to 60 mg/day). After four to six weeks, the patient should be reevaluated. If the patient's condition is felt to be stable or improved, the dose is tapered (by 5- to 10-mg decrements every four to eight weeks) down to 0.25 to 0.5 mg/kg (usually 15 to 30 mg/day). If the patient continues to be stable or improved, the dose continues to be tapered until a maintenance dose is reached (approximately 0.25 mg/kg of ideal body weight or less per day, usually 10 to 15 mg daily). Since relapses in symptoms, such as cough, dyspnea and chest pain, are common (occurring in about 60 percent of patients), we recommend that the maintenance dose be continued for at least six to eight months, giving a total treatment period of about one year. Frequently, a brief course of higher doses (increases of 10 to 20 mg above the maintenance dose given for two to four weeks) is required to relieve the recurrent symptoms.

Alternate day therapy with oral glucocorticoids Alternate day therapy with oral prednisone has also been recommended, but there are few data available to suggest that it is effective. A starting dose of 40 mg of prednisone every other day for three months can be used . If the patient improves, the dose is lowered by 10 mg at three-month intervals. Treatment is continued for one year to achieve an inactive status and is then discontinued if the patient is stable. Alternate day therapy has also been used after initial daily therapy with prednisone. If there is reactivation of the disease after tapering of the prednisone, the dose is increased to the last effective dose and continued for a subsequent three to six months. Some patients may require maintenance of therapy to control their symptoms. If there is no improvement after three months, the dose is continued at 40 mg on alternate days or is increased to 60 mg until there is improvement (usually six to 12 months). High-dose oral glucocorticoids therapy High-dose oral glucocorticoid therapy (80 to 100 mg/day) may be warranted in patients with cardiac, neurologic, ocular, or upper airway disease. This level is continued until the disease is under control (usually four to 12 weeks). Once improvement is achieved, the dose is tapered as described for the maintenance phase above. Inhaled glucocorticoids Inhaled glucocorticoids have been recommended for the treatment of pulmonary sarcoidosis, but adequate data supporting their efficacy is lacking . Inhaled glucocorticoids appear to modulate the alveolitis of sarcoidosis and provide clinical benefit in some subjects, despite the lack of significant changes in lung function. As an example, one double-blind placebo-controlled trial of 2000 mcg/day of fluticasone in 44 patients found no significant differences in lung function, although nonstatistical improvements in cough, breathlessness, wheeze, and general health perception were noted . Budesonide (800 to 1600 mcg twice daily) has been the most frequently studied inhaled glucocorticoid. Triamcinolone acetonide, flunisolide, or fluticasone can be used as alternative therapy. Many clinicians recommend a trial of inhaled glucocorticoids for: Cough with or without airway hyperreactivity. Early stage disease with mild pulmonary symptoms or lung function abnormalities. Use as an alternative to oral prednisone for patients who require long-term low dose prednisone (5 to 10 mg daily) for control of their pulmonary disease.

Treatment Of Community-Acquired Pneumonia In The Outpatient

We support the IDSA/ATS guideline recommendations for empiric treatment of CAP in non-hospitalized patients: For uncomplicated pneumonia in patients who have no significant comorbidities and/or use of antibiotics within the last three months. o we suggest treatment with an advanced macrolide (Grade 2A): Azithromycin (500 mg on day one followed by four days of 250 mg a day, or 500 mg for three days, or 2 g as single dose microsphere regimen) OR Clarithromycin XL (two 500 mg tablets once daily). o We suggest NOT using fluoroquinolones for uncomplicated ambulatory patients with CAP (Grade 2B). For non-hospitalized patients with comorbidities (ie, COPD, liver or renal disease, cancer, diabetes, chronic heart disease, alcoholism, asplenia, or immunosuppression), or recent antibiotic use: We recommend one of the following oral regimens (Grade 2A): o A respiratory fluoroquinolone (gemifloxacin 320 mg daily, levofloxacin 750 mg daily, or moxifloxacin 400 mg daily) o Combination therapy with a beta-lactam plus a macrolide Amoxicillin 1 g three times daily OR Amoxicillin-Clavulanate (Clavoxil) 2 g twice daily OR Cefpodoxime (Oraceg)200 mg twice daily OR Cefuroxime (Cefurox) 500 mg twice daily PLUS o Azithromycin 500 mg on day one followed by 4 days of 250 mg a day OR o Clarithromycin 250 mg twice daily or XL 1000 mg once daily. Treatment duration and response : We recommend antibiotic treatment for a minimum of five days, although a shorter duration may be indicated with azithromycin because of its prolonged half-life. Therapy should not be stopped until the patient is afebrile for 48 to 72 hours and is clinically stable. When this is achieved, the persistence of other symptoms (eg, dyspnea, cough) is not an indication to extend the course of antibiotic therapy.

INDICATIONS FOR HOSPITALIZATION CURB-65 : Confusion (based upon a specific mental test or disorientation to person, place, or time) Urea >40 mg/dL Respiratory rate >30 breaths/minute Blood pressure [BP] (systolic <90 mmHg or diastolic <60 mmHg) Age >65 years score of 2 : should be admitted to the hospital score of 3 or more : should be assessed for ICU care, particularly if the score was 4 or 5.

Treatment Of Community-Acquired Pneumonia In The Hospital TREATMENT REGIMENS Not Requiring ICU Admission: we suggest one of the following regimens (Grade 1B): o Combination therapy with ceftriaxone (1 to 2 g IV daily) or cefotaxime (1 to 2 g IV every 8 hours) PLUS azithromycin (500 mg IV or orally daily). o Monotherapy with a respiratory fluoroquinolone given either IV or orally except as noted (levofloxacin 750 mg daily or moxifloxacin 400 mg daily or gemifloxacin 320 mg daily [only available in oral formulation]). o Coverage for drug-resistant pathogens, such as Pseudomonas or methicillin-resistant Staphylococcus aureus, should be included in patients with risk factors. Admitted to an ICU :For hospitalized patients requiring ICU care, We recommend o intravenous combination therapy with a potent anti-pneumococcal beta-lactam (ceftriaxone 2 g daily or cefotaxime 2 g every eight hours) PLUS either : advanced macrolide (azithromycin 500 mg daily) fluoroquinolone (levofloxacin 750mg daily or moxifloxacin 400mg daily). o Coverage for drug-resistant pathogens, such as Pseudomonas or methicillin-resistant Staphylococcus aureus, should be included in patients with risk factors. in patients (particularly those with bronchiectasis or COPD and frequent antimicrobial or glucocorticoid use) who may be infected with Pseudomonas aeruginosa or other resistant pathogens, therapy should include agents effective against the pneumococcus, P. aeruginosa, and Legionella spp. Combination therapy with a beta-lactam antibiotic and fluoroquinolone: o Piperacillin-tazobactam (4.5 g every six hours) OR o Imipenem (500 mg IV every six hours) OR o Meropenem (1 g every eight hours) OR o Cefepime (2 g every eight hours) OR o Ceftazidime (2 g every 8 hours) PLUS o Ciprofloxacin (400 mg every 8 hours) OR o Levofloxacin (750 mg daily) For beta-lactam allergic patients, options include: o aztreonam (2 g every 6 hours) plus levofloxacin (750 mg daily); OR o aztreonam plus moxifloxacin plus an aminoglycoside. The fluoroquinolones may be administered orally when the patient is able to take oral medications. The dose of levofloxacin is the same when given intravenously and orally, while the dose of ciprofloxacin is 750 mg orally twice daily. If the Gram stain suggests S. aureus, we recommend treatment for MRSA with the addition of vancomycin (15 mg/kg every 12 hours, adjusted for renal function) OR linezolid (600 mg intravenously twice daily) until the results of culture and susceptibility testing are known. Linezolid may be given orally when the patient is able to receive oral medications. We suggest empiric therapy of MRSA in patients : o when pneumonia develops in a person known to be colonized with CA-MRSA o in those with risk factors for (eg, contact sport participants, injection drug users, living in crowded conditions, men who have sex with men, prisoners). o in young, previously healthy adults with a recent influenza-like illness. If MRSA is not isolated, coverage for this organism should be discontinued.

Timing of antimicrobial initiation : within 6 hours of arrival at hospital . Clinical response to therapy: o Patients should demonstrate some improvement in clinical parameters by 72 hours, although fever may persist with lobar pneumonia. o Cough from pneumococcal pneumonia may not clear for a week o abnormal chest x-ray findings usually clear within four weeks but may persist for 12 weeks in older individuals, and those with underlying pulmonary disease. Switch to oral therapy o We suggest switching from intravenous to oral therapy when patients are hemodynamically stable, demonstrate some clinical improvement (in fever, respiratory status, white blood count) and are able to take oral medications (Grade 2A). Duration of hospitalization o We suggest hospital discharge when the patient can take oral medication; we suggest not keeping the patient overnight for observation following the switch (Grade 2B). Duration of therapy o patients with CAP should be treated for a minimum of 5 days o Before stopping therapy, the patient should be : 1. afebrile for 48 to 72 hours 2. breathing without supplemental oxygen (unless required for preexisting disease) 3. have no more than one clinical instability factor (HR >100, RR >24, , SBP 90) o Longer durations of therapy are needed in the following settings: 1. If the initial therapy was not active against the subsequently identified pathogen 2. If extrapulmonary infection is identified (eg, meningitis or endocarditis) 3. If the patient has documented P. aeruginosa or S. aureus pneumonia, or pneumonia caused by some unusual and less common pathogens (eg, Burkholderia pseudomallei, fungus) o The duration of therapy in these patients should be individualized based upon the clinical response to treatment and patient comorbidities. Follow-up chest radiograph o Routine follow-up chest x-rays for patients who are responding clinically within the first week are unnecessary. We suggest a follow-up chest x-ray at 7 to 12 weeks after treatment for patients who are over age 40 years or are smokers, to document resolution of the pneumonia and exclude underlying diseases, such as malignancy (Grade 2C). We suggest that empiric treatment regimens be modified when results of diagnostic studies indicate a specific pathogen, and coinfection is unlikely based upon clinical or epidemiological data (Grade 2B).

Organism Streptococcus pneumoniae Penicillin nonresistant; MIC <2 microgram/mL

Preferred antimicrobial(s) Penicillin G, amoxicillin

Alternative antimicrobial(s) Macrolide, cephalosporins (oral [cefpodoxime, cefprozil, cefuroxime, cefdinir, cefditoren] or parenteral [cefuroxime, ceftriaxone, cefotaxime]), clindamycin, doxycyline, respiratory fluoroquinolone* Vancomycin, linezolid, high-dose amoxicillin (3 g/day with penicillin MIC 4 microgram/mL)

Penicillin resistant; MIC microgram/mL Haemophilus influenzae Non-beta-lactamase producing Beta-lactamase producing Mycoplasma pneumoniae/Chlamydophila pneumoniae Legionella species Chlamydophila psittaci Coxiella burnetii Francisella tularensis Yersinia pestis Bacillus anthracis (inhalation)

Agents chosen on the basis of susceptibility, including cefotaxime, ceftriaxone, fluoroquinolone Amoxicillin Secondor third-generation cephalosporin, Ogmentinin Macrolide, a tetracycline

Fluoroquinolone, clarithromycin Fluoroquinolone, clarithromycin Fluoroquinolone

doxycycline, doxycycline,

azithromycin, azithromycin,

Enterobacteriaceae

Pseudomonas aeruginosa

Burkholderia pseudomallei Acinetobacter species Staphylococcus aureus Methicillin susceptible Methicillin resistant Bordetella pertussis Anaerobe (aspiration)

Fluoroquinolone, azithromycin A tetracycline A tetracycline Doxycycline Streptomycin, gentamicin Ciprofloxacin, levofloxacin, doxycycline (usually with second agent) Third-generation cephalosporin, carbapenem (drug of choice if extended-spectrum beta-lactamase producer) Antipseudomonal beta-lactam plus (ciprofloxacin or levofloxacin or aminoglycoside) Carbapenem, ceftazadime Carbapenem

Doxycyline Macrolide Macrolide Gentamicin, streptomycin Doxycyline, fluoroquinolone Other fluoroquinolones; beta-lactam, if susceptible; rifampin; clindamycin; chloramphenicol Beta-lactam/beta-lactamase fluoroquinolone inhibitor ,

Aminoglycoside plus (ciprofloxacin or levofloxacin)

Fluoroquinolone, TMP-SMX Cephalosporin-aminoglycoside, ampicillin-sulbactam, colistin

Antistaphylococcal penicillin Cefazolin, clindamycin Vancomycin or linezolid TMP-SMX Macrolide TMP-SMX Beta-lactam/beta-lactamase inhibitor , Carbapenem clindamycin Influenza virus See associated topic reviews Mycobacterium tuberculosis Isoniazid plus rifampin plus ethambutol Depends on susceptibility pattern. plus pyrazinamide Coccidioides species For uncomplicated infection in a Amphotericin B normal host, no therapy generally recommended; for therapy, itraconazole, fluconazole Histoplasmosis Itraconazole** Amphotericin B** Blastomycosis Itraconazole** Amphotericin B** ciprofloxacin is appropriate for Legionella and most gram-negative bacilli (including H. influenzae). Azithromycin is more active in vitro than clarithromycin for H. influenzae. Imipenem-cilastatin, meropenem, ertapenem. Piperacillin-tazobactam for gram-negative bacilli, ticarcillin-clavulanate, ampicillin-sulbactam or amoxicillin-clavulanate. Ticarcillin, piperacillin, ceftazidime, cefepime, aztreonam, imipenem, meropenem. Nafcillin, oxacillin flucloxacillin.

The Nonresponding Pneumonia: The most common cause of treatment failure is the lack of response by the host despite appropriate antibiotics. Risk factors for treatment failure include : o Neoplasia o aspiration pneumonia o neurologic disease o multilobar pneumonia o Legionella or gram-negative infection o high pneumonia severity index (>90) o antibiotic-resistant pathogen o cavitation o pleural effusion o liver disease o leukopenia.

NORMAL VERSUS DELAYED RESOLUTION OF PNEUMONIA : Determining whether a patient has nonresolving or progressive pneumonia must also take into account several factors that affect the expected rate of resolution. These include: Comorbidities Comorbid conditions often slow the resolution of pneumonia : o COPD : Impaired cough and mucociliary clearance o Alcoholism : Aspiration, malnutrition, impaired neutrophil function o Neurologic disease : Aspiration, impaired clearance of secretions and cough o Heart failure : Edema fluid, impaired lymphatic drainage o Chronic kidney disease : Hypocomplementemia, impaired macrophage and neutrophil function, reduced humoral immunity o Malignancy : Impaired immune function, altered colonization, effects of chemotherapy o Human immunodeficiency virus : Impaired cell-mediated and humoral immunity o Diabetes mellitus : Impaired neutrophil function and cell-mediated immunity Age Approximately 90 % of patients younger than 50 years of age show radiographic resolution by 4 weeks, compared with only 30 % of patients older than 50, even in the absence of concurrent disease . Severity Radiographic resolution of severe pneumonia is estimated at 10 weeks, compared with 3 to 4 weeks for mild to moderate pneumonia. Infectious agent The rate of radiographic and clinical improvement varies with the particular infectious agent causing the pneumonia. In general, resolution is more rapid with Mycoplasma pneumoniae, nonbacteremic Streptococcus pneumoniae, Chlamydophila (formerly Chlamydia) species, and Moraxella catarrhalis than with other organisms

MISDIAGNOSIS OF NONBACTERIAL PATHOGENS Pathogen Mycobacterium tuberculosis (tuberculosis) Atypical mycobacteria (bronchiectasis) Nocardia (nocardiosis) Actinomyces israelii (actinomycosis) Aspergillus (aspergillosis) Endemic fungi: Histoplasma capsulatum (histoplasmosis) Coccidioides immitis Populations at risk Elderly, immigrants, HIV-positive COPD, HIV-positive Immunocompromised host Aspiration risk, chest wall involvement Immunocompromised host, Evidence of vascular invasion Mississippi River Valley Southwestern United States

(coccidioidomycosis) Blastomyces dermatitidis (blastomycosis) Coxiella burnetii (Q fever) Francisella tularensis (tularemia) Chlamydia psittaci (psittacosis) Yersinia pestis (plague) Leptospira interrogans (leptospirosis) Pseudomonas pseudomallei (melioidosis) Paragonimus westermani (paragonimiasis) Hantavirus Anthrax

Southeast and midwest United States Exposure to cats, cattle, or sheep Exposure to rabbits or ticks Avian sources Exposure to rats Exposure to rats Southeast Asia (rodent exposure), mimics tuberculosis Asia/Africa/Central and South America Southwestern United States with exposure to mice More common in Asia Minor, Iran, Turkey, Greece, South Africa; contact with infected animal carcasses or hides

RESISTANT BACTERIAL PATHOGENS : The presence of a resistant pathogen is an important consideration for any pneumonia that is not responding appropriately to antibiotic therapy. Although penicillin-resistant Streptococcus pneumoniae (pneumococcus) is the organism of most concern, multi-drug-resistant Haemophilus influenzae and Pseudomonas aeruginosa as well as methicillin-resistant Staphylococcus aureus are possible causes of a nonresolving pneumonia. The suspicion of penicillin-resistant S. pneumoniae should be especially high in the following situations : 1. Close exposure to young children; the rates of carriage and infection due to penicillin-resistant pneumococci are highest in children under the age of 5 years 2. Prior treatment with a beta-lactam antibiotic (within the past 6 months) 3. Previous pneumonia within the past year 4. Hospitalization within the past 3 months 5. Hospital-acquired (nosocomial) infection

Development Of Complications From The Initial Pneumonia : Empyema : The patients with empyema were more likely to be younger and to be illicit drug users. The most common cultured pathogen was Streptococcus milleri, suggesting a role for aspiration. , Evaluation of a possible empyema is initially facilitated by imaging techniques such as CT and ultrasound. In a patient with nonresolving pneumonia, demonstration of any significant amount of pleural fluid should prompt consideration of a diagnostic thoracentesis to rule out empyema. Lung abscess : Predisposing factors that should raise the suspicion of abscess formation include alcoholism, seizures, poor oral hygiene, and previous aspiration. Chest radiography typically demonstrates an air-liquid level, but chest CT is more sensitive and can confirm the diagnosis in difficult cases. Most patients with lung abscess do well with conservative management and a prolonged course of antibiotics. However, several factors are associated with increased abscess-related mortality and may warrant a more aggressive approach. These include age-related factors (pediatric or elderly populations), large cavity size, longer duration of symptoms prior to therapy, lower lobe location, association with malignant disease, and the presence of multiple abscesses.

NONINFECTIOUS ETIOLOGIES 1. Neoplastic disorders a. Bronchogenic carcinoma b. Bronchoalveolar cell carcinoma c. Lymphoma 2. Immunologic disorders a. Vasculitis: b. Wegener's granulomatosis c. Diffuse alveolar hemorrhage d. Bronchiolitis obliterans-organizing pneumonia (BOOP) e. Eosinophilic pneumonia syndromes f. Acute eosinophilic pneumonia g. Chronic eosinophilic pneumonia h. Acute interstitial pneumonia i. Pulmonary alveolar proteinosis j. Sarcoidosis k. Systemic lupus erythematosus 3. Drug toxicity 4. Pulmonary vascular abnormalities a. Congestive heart failure b. Pulmonary embolism Evaluation Of Nonresolving Pneumonia o The diagnostic evaluation of treatment failure in pneumonia begins with a careful history, physical examination. o In stable or slowly improving pneumonia, especially in the presence of comorbidities or host factors which are known to delay the resolution of pneumonia, careful observation with or without therapy is warranted for 4 to 8 weeks. If there is no resolution or progression of disease, a more aggressive diagnostic approach is appropriate . o If further evaluation is necessary, it should include chest CT :. Chest CT can detect pleural effusion, lung abscess, or central airway obstruction. It may also detect noninfectious causes such as bronchiolitis obliterans organizing pneumonia . Since empyema and parapneumonic effusion can contribute to nonresponse, thoracentesis should be performed in all nonresponding patients with significant pleural fluid accumulation. o When pneumonia fails to resolve or when there is clinical progression, fiberoptic bronchoscopy should be considered. Patients with a negative bronchoscopic examination have a good chance of merely having a slowly resolving pneumonia, particularly if they are smokers or over age 55. Bronchoscopy can evaluate the airway for obstruction due to a foreign body or malignancy, which can cause a postobstructive pneumonia. Protected brushings and bronchoalveolar lavage (BAL) may be obtained for microbiologic and cytologic studies; in some cases, transbronchial biopsy may be helpful. The microbiologic evaluation of the nonresponding patient can be complicated by the effect of the initial antimicrobial therapy that may reduce the yield of pathogen isolation, or select for colonization with resistant organisms. In addition, BAL may reveal evidence of noninfectious disorders or, if there is a lymphocytic rather than neutrophilic alveolitis, viral or Chlamydophila infection o Diseases not readily or typically diagnosed with fiberoptic bronchoscopy include pulmonary vasculitis syndromes, bronchiolitis obliterans organizing pneumonia, and diffuse alveolar damage of various etiologies. o With a worsening chest radiograph and progressive symptoms accompanied by a negative bronchoscopy, further evaluation with thoracoscopic or open lung biopsy may be necessary

VACCINATION Patients with CAP should be appropriately vaccinated for influenza and pneumococcal. Vaccination can be performed at hospital discharge or during outpatient treatment. Screening for influenza vaccination status is warranted from October through March in patients age 50 and older or with other indications for vaccination Summary of seasonal influenza vaccination recommendations for adults, 2009 o Annual vaccination against influenza is recommended for any adult who wants to reduce the risk of becoming ill with influenza or of transmitting it to others. o Vaccination is recommended for all adults without contraindications in the following groups, because these persons either are at higher risk for influenza complications, or are close contacts of persons at higher risk: 1. persons aged 50 years 2. women who will be pregnant during the influenza season 3. persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, cognitive, neurologic/neuromuscular, hematological or metabolic disorders (including diabetes mellitus) 4. persons who have immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus) 5. residents of nursing homes and other long-term care facilities

health-care personnel household contacts and caregivers of children aged <5 years and adults aged 50 years, with particular emphasis on vaccinating contacts of children aged <6 months 8. household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza Screening for pneumococcal vaccination status is warranted in patients age 65 or older or with other indications for vaccination Recommendations for the use of pneumococcal polysaccharide vaccine (Pneumovax) Immunocompetent persons 1. Persons aged 65 years 2. Persons aged 19-64 years with chronic cardiovascular disease, chronic pulmonary disease (including asthma), or diabetes mellitus 3. Persons aged 19-64 years who smoke cigarettes, or who have alcoholism, chronic liver disease, cerebrospinal fluid leaks, or cochlear implants 4. Persons aged 19-64 years living in special environments or social settings such as chronic care facilities Immunocompromised persons aged 19 years, including those with HIV infection, malignancy, chronic renal disease, nephrotic syndrome, congenital immunodeficiency; those receiving immunosuppressive chemotherapy (including glucocorticoids); asplenia; and post organ or bone marrow transplantation. Recommendations for revaccination with Pneumovax: o Immunocompetent persons :Persons aged 65 years , Second dose of vaccine if patient received vaccine 5 years previously and was aged <65 years at the time of vaccination. o Immunocompromised persons aged 19 years, including those with HIV infection, malignancy, chronic renal disease, nephrotic syndrome, congenital immunodeficiency; those receiving immunosuppressive chemotherapy (including glucocorticoids); asplenia; and post organ or bone marrow transplantation , Single revaccination if 5 years have elapsed since receipt of first dose.

6. 7.

SMOKING CESSATION Smoking cessation should be a goal for hospitalized patients with CAP who smoke. PERFORMANCE MEASURES 1. Assessment of arterial oxygenation by arterial blood gas or pulse oximetry 2. Screening and administration of pneumococcal vaccination if indicated for patients age 65 or older 3. Blood cultures performed in the emergency department should be obtained prior to initial antibiotic received in the hospital 4. Blood cultures performed within 24 hours prior to or 24 hour after hospital arrival for patients admitted or transferred to the intensive care unit within 24 hours of hospital arrival 5. Receipt of the first dose of antibiotic within six hours of arrival at hospital 6. Antibiotic selection consistent with current guidelines during the first 24 hours of hospitalization 7. Adult smoking cessation advice/counseling, if warranted 8. Screening for influenza vaccination status, administration of influenza vaccine if indicated, for patients age 50 and older, discharged during October-March

RHEUMATOLOGY

Antiphospholipid Syndrome
CLASSIFICATION CRITERIA : 1. at least one of the following clinical criteria + 2. at least one of the following laboratory criteria.

Clinical Criteria: One or more episodes of venous, arterial, or small vessel thrombosis and/or morbidity with pregnancy.
o o o o

Thrombosis :imaging or histologic evidence of thrombosis in any tissue or organ, Pregnancy morbidity :Otherwise unexplained death at 10 weeks gestation of a morphologically normal fetus, One or more premature births before 34 weeks of gestation because of eclampsia, preeclampsia, or placental insufficiency, Three or more embryonic (<10 week gestation) pregnancy losses unexplained by maternal or paternal chromosomal abnormalities or maternal anatomic or hormonal causes.

Laboratory Criteria : The presence of antiphospholipid antibodies , on two or more occasions at least 12 weeks apart and no more than 5 years prior to clinical manifestations, as demonstrated by one or more of the following:
o

IgG and/or IgM aCL in moderate or high titer (>40 units GPL or MPL or > 99th % for the testing laboratory) o Antibodies to 2-glycoprotein-I (2-GP-I) of IgG or IgM isotype at a titer >99th % for the testing laboratory. o Lupus anticoagulant (LA) activity detected according to published guideline . DIAGNOSIS : Clinical suspicion should be raised in the following scenarios: 1. one or more otherwise unexplained thrombotic or thromboembolic events. 2. One or more specific adverse outcomes related to pregnancy 3. Otherwise unexplained thrombocytopenia or prolongation of PT or aPTT. TREATMENT

acute thrombotic events in patients with aPL: the first therapy is heparin. We recommend low molecular weight (LMW) heparin for most APS-associated thrombotic events (Grade 1B). The pregnant patient : Heparin also plays a critical role in the treatment of the pregnant patient with the APS, because warfarin is contraindicated in pregnancy. o For women with aPL and prior thrombosis, we suggest antepartum and postpartum thromboprophylaxis (Grade 2C). o For women with aPL and no prior thrombosis, we suggest either close clinical surveillance, prophylactic unfractionated heparin, or prophylactic low molecular weight heparin antepartum, and postpartum thromboprophylaxis (Grade 2C). o For women with aPL and one or more fetal loss at or after 10 weeks of gestation, we suggest combined therapy with low dose ASA and prophylactic LMWH during pregnancy (Grade 2C). o For selected women with aPL and a history of multiple embryonic losses in whom other etiologies have been excluded, we suggest low dose ASA and prophylactic LMWH therapy during pregnancy (Grade 2C). o For women with aPL and a history of early and severe preeclampsia or fetal growth restriction necessitating delivery before 34 weeks of gestation, we suggest low dose ASA therapy in the second and third trimesters (Grade 2C). We may prescribe heparin or LMWH with low dose ASA in cases of ASA failure or when placental examination shows extensive thrombosis.

Chronic management As with other thromboses, patients should be transitioned from heparin to warfarin. We recommend an INR range between 2.0 and 3.0 rather than more intensive anticoagulation (Grade 1A). Duration of chronic therapy we recommend lifelong anticoagulation for patients with the APS (Grade 1B). Prophylaxis of the asymptomatic patient o In the absence of symptoms or a history of symptoms attributable to the APS, we do not recommend the use of aspirin as prophylaxis (Grade 2B). o For patients with SLE and aPL but no APS manifestations, the combination of low-dose aspirin and hydroxychloroquine may be considered (Grade 2C) .

An ApprocheVASCULITIS
The presence of vasculitis should be considered in patients who present with systemic symptoms in combination with evidence of single and/or multiorgan dysfunction. Primary vasculitis: 1. Large artery: Takayasus Giant cell arteritis 2. Medium artery: Polyarteritis nodosa Kawasaki 3. Medium /small artery: Wegeners granulomatosis Churg-Strauss arteritis Microscopic polyangiitis Behcets disease 4. Small vessel : cryoglubenimea Henoch- Schonlein purpura Leucocytoclastic vasculitis Secondary Vasculitis Infections o Hepatitis A, B, and C o HIV o Bacterial endocarditis o Other bacterial, viral, fungal, and parasitic infections Neoplasms o Hairy cell leukemia o Multiple myeloma o Other hematologic and solid malignancies Autoimmune Diseases o SLE o Rheumatoid arthritis o Sjgren's syndrome o Inflammatory myopathies o Scleroderma o Relapsing polychondritis o IBD o Primary biliary cirrhosis Medications o Antimicrobials , Vaccines , Antithyroid agents , Anticonvulsants , Antiarrhythmics , Diuretics , Anticoagulants ,Antineoplastics , Hematopoietic growth factors, NSAIDs , Leukotriene inhibitors , Psychotropic drugs, Allopurinol , TNF modulatory agents Clinical features suggestive of vasculitis o Although neither sensitive or specific, common complaints and signs of vasculitis include fatigue, weakness, fever, arthralgias, abdominal pain, hypertension, renal insufficiency (with an active urine sediment containing red and white cell and occasionally red cell casts), and neurologic dysfunction.

o The diagnosis of vasculitis is often delayed because the clinical manifestations can be mimicked by a number of other disorders. However, the presence of certain signs is strongly suggestive. As examples: o Mononeuritis multiplex Mononeuritis multiplex (or asymmetric polyneuropathy) is highly suggestive of vasculitis (particularly polyarteritis nodosa), since diabetic neuropathy is the only other common cause of this problem in developed countries. o Palpable purpura Patients with palpable purpura alone are likely to have cutaneous leukocytoclastic vasculitis of the hypersensitivity vasculitis type; if the purpura is present with systemic organ involvement, such patients are likely to have HSP or microscopic polyarteritis. Pulmonary-renal involvement o The combination of hemoptysis and renal involvement suggestive of glomerulonephritis suggests the diagnosis of Wegener's granulomatosis or microscopic polyangiitis. However, certain other disorders, particularly anti-glomerular basement membrane (anti-GBM) antibody disease, may cause an identical combination of findings. History history of drugs (which may produce hypersensitivity vasculitis history of hepatitis (hepatitis C virus is responsible for most cases of mixed cryoglobulinemia and some cases of polyarteritis), history of any disorder known to be associated with a vasculitis (such as systemic lupus erythematosus. Physical examination : A careful physical examination helps to determine the extent of vascular lesions, the distribution of affected organs, and the presence of additional disease processes. As mentioned above, certain findings, such as mononeuritis multiplex and palpable purpura, are highly suggestive of an underlying vasculitic process. Investigations to consider in a patient with suspected vasculitis: Urinalysis Renal function : urea, creatinine, creatinine clearance , 24 hr protein excretion Other biochemistry : LFT & CRP ,CPK , PEP , HIV Haematology : CBC, eosinophils & ESR Immunology : RF , ANCA , Anti GBM , ANA , Ds-DNA ,C3 , C4 ,Cryoglobulins Microbiology : blood, sputum culture , MSU, stool culture ,virology: Hep B/C Radiology : CXR, sinus XR , CT scan, MRI, Angiography 2D Echo : (to look for SBE/myxoma) Biopsy (often needed to confirm diagnosis) skin, nose, lung, kidney, rectum, nerve, muscle, ANA suggests the presence of an underlying connective tissue disorder, particularly SLE Complement Low C4 present in mixed cryoglobulinemia and Low C3 present in SLE ANCA ANCA against proteinase 3 (weak cationic) has a cytoplasmic or cANCA pattern ANCA against myeloperoxidase (strongly cationic) has a perinuclear or pANCA pattern Other ANCA against elastase, cathepsin G, Azurocidin, lactoferrin also exist ANCA test has been found to be positive in: 1. Vasculitis 2. Inflammatory bowel disease 3. Autoimmune liver disease & SLE 4. Infections 5. Malignancies C-ANCA positive in 90% Wegeners patients , may reflect disease activity , may predict relapse P-ANCA positive in : 15% WG , 60% MPA , 50% CSS , 10% PAN Electromyography useful if a systemic vasculitis is suspected and neuromuscular symptoms are present, such as a mononeuritis multiplex.

Arteriography Arteriograms are helpful in identifying and characterizing a vasculitis of large and medium-sized arteries, such as polyarteritis nodosa, Takayasu's arteritis, and giant cell arteritis with an aortic arch syndrome. In these conditions, angiographic abnormalities may not be pathognomonic, but usually support a diagnosis when combined with other clinical data. Angiograms of mesenteric or renal arteries in polyarteritis nodosa may show aneurysms, occlusions, and vascular wall irregularities In the patient suspected of having polyarteritis nodosa in whom an obvious area for biopsy is absent, a mesenteric angiogram should be considered, particularly in the presence of abdominal pain. In contrast, angiography is unlikely to be helpful in assessing a small vessel vasculitis, such as microscopic polyangiitis. The affected vessels in this disorder are below the resolution of usual angiograms. The decision to biopsy and/or perform angiography in a patient suspected of a vasculitis is based upon an overall clinical assessment and the relative complications associated with each procedure in a particular clinical setting. As an example, arteriography alone is usually performed to confirm the diagnosis of Takayasu's arteritis. The arteriographic changes tend to be most pronounced in the region of the aortic arch and its primary branches, areas relatively inaccessible for biopsy. In contrast, involvement of the skin is characteristic of patients with a leukocytoclastic vasculitis; the skin is easily accessible for biopsy, a procedure not associated with significant morbidity. However, the observed changes are not specific unless there is IgA deposition, establishing the diagnosis of HSP.

CLASSIFICATION CRITERIA
Takayasu's arteritis : at least 3 of the 6 criteria are present 1. Age at disease onset 40 years 2. Claudication of the extremities 3. Decreased pulsation of one or both brachial arteries 4. Difference of at least 10 mmHg in systolic blood pressure between the arms 5. Bruit over one or both subclavian arteries or the abdominal aorta 6. Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or other causes Giant cell arteritis : at least 3 of the following 5 criteria : 1. Age 50 years at time of disease onset 2. Localized headache of new onset 3. Tenderness or decreased pulse of the temporal artery 4. Erythrocyte sedimentation rate (ESR) greater than 50 mm/h (Westergren) 5. Biopsy which includes an artery, and reveals a necrotizing arteritis with a predominance of mononuclear cells or a granulomatous process with multinucleated giant cells If an elevated ESR is excluded, but scalp tenderness and claudication of the jaw, tongue, or with deglutition are added as criteria Polyarteritis nodosa : at least 3 of the following 10 criteria : 1. Otherwise unexplained weight loss > 4 kg 2. Livedo reticularis 3. Testicular pain or tenderness 4. Myalgias (excluding that of the shoulder and hip girdle), weakness, or polyneuropathy 5. Mononeuropathy or polyneuropathy 6. New onset diastolic blood pressure > 90 mmHg 7. Elevated levels of serum blood urea nitrogen (>40 mg/dL) or creatinine (>1.5 mg/dL ) 8. Evidence of hepatitis B virus infection via serum antibody or antigen serology 9. Characteristic arteriographic : not resulting from noninflammatory disease processes

10. A biopsy of small- or medium-sized artery containing polymorphonuclear cells Kawasaki disease fever lasting 5 days or more without any other explanation, with at least 4 of 5 following : 1. Bilateral conjunctival injection 2. Oral mucous membrane changes, injected or fissured lips, injected pharynx, or strawberry tongue 3. Peripheral extremity changes, including erythema of palms or soles or edema of hands or feet (acute phase), and periungual desquamation (convalescent phase) 4. Polymorphous rash 5. Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter ( Churg-Strauss arteritis : at least 4 of the following 6 criteria : 1. Asthma (a history of wheezing or the finding of diffuse high pitched wheezes) 2. Eosinophilia of >10 percent on differential white blood cell count 3. Mononeuropathy (including multiplex) or polyneuropathy 4. Migratory or transient pulmonary opacities detected radiographically 5. Paranasal sinus abnormality 6. Biopsy of blood vessel showing the accumulation of eosinophils in extravascular areas Wegener's granulomatosis : at least 2 of the following 4 criteria : 1. painful or painless oral ulcers or purulent or bloody nasal discharge. 2. Abnormal chest radiograph showing nodules, fixed infiltrates, or cavities. 3. Abnormal urinary sediment (microscopic hematuria or red cell casts). 4. Granulomatous inflammation on biopsy of an artery or perivascular area . Microscopic polyangiitis Some patients have equivalent vasculitic lesions to those observed in Wegener's granulomatosis, but, at least at presentation, do not have symptomatic or histologic respiratory involvement; such individuals are considered to have microscopic polyarteritis. some patients subsequently develop classic respiratory tract lesions ; and ANCA are typically present . Hypersensitivity vasculitis : at least 3 of the following 5 criteria : 1. Age >16 2. Use of a possible offending drug in temporal relation to the symptoms 3. Palpable purpura 4. Maculopapular rash 5. Biopsy of a skin lesion showing neutrophils around an arteriole or venule Henoch-Schnlein purpura : at least 3 of the following 6 criteria : 1. Palpable purpura 2. Bowel angina 3. Gastrointestinal bleeding 4. Hematuria 5. Age at onset 20 years lesion 6. No new medications Isolated central nervous system vasculitis Specific criteria for a diagnosis of isolated central nervous system vasculitis (ICNSV) have not yet been formulated. ICNSV is a rare disorder which is most commonly diagnosed in the patient with CNS symptoms and signs in combination with evidence of a cerebral vasculitis by angiography and leptomeningeal biopsy. Essential cryoglobulinemic vasculitis Specific criteria for a diagnosis of essential cryoglobulinemic vasculitis have not yet been formulated. The diagnosis is typically made from the history, skin purpura, low complement levels, demonstration of circulating cryoglobulins, and histology showing small vessel inflammation with immune deposits found in the vascular walls.

Treatment of Vasculitis Treatment of Takayasu arteritis Glucocorticoids The mainstay of therapy for Takayasu arteritis is glucocorticoids. Initial glucocorticoid dose 45 to 60 mg of prednisone. gradually reduced when the symptoms and laboratory tests related to the inflammatory process have improved. We recommend a maximum reduction of 10 % of the daily amount per week. Long-term low-dose prednisone therapy may be necessary to prevent progression of arterial stenoses. Glucocorticoids can be discontinued if the disease goes into remission, while the dose should be increase if exacerbations occur. Assessing response to treatment A decrease and eventual disappearance of constitutional symptoms is expected and is typically accompanied by a decrease in acute phase reactants such as ESR and CRP levels. CT or MRI scans can also be used to follow the response to treatment. patient with disease refractory to glucocorticoids: we recommend trials of mycophenolate, methotrexate, or leflunomide and reserve cyclophosphamide . It is possible that anti-TNF agents will be useful in this setting as an alternative to cyclophosphamide. Revascularization Percutaneous transluminal angioplasty or bypass grafts may be considered in late cases when irreversible arterial stenosis has occurred and significant ischemic symptoms are present . Angioplasty is preferable when the lesions are amenable to catheter-based therapy. However, percutaneous intervention is less likely to be successful when stenosis or occlusions affect lengthy portions of an artery or the artery is heavily scarred. Continued inflammation in a treated segment may result in restenosis following angioplasty, with or without stenting; restenosis is less likely following bypass grafting than angioplasty, when performed after initiation of treatment, or if revascularization is followed by antiinflammatory therapy . Aortic valve surgery Progressive aortic regurgitation may require surgical therapy. Treatment of giant cell (temporal) arteritis Uncomplicated GCA Initial dose of glucocorticoids If GCA is not complicated by symptoms or signs of ischemic organ damage (eg, visual loss), we suggest an initial dose of glucocorticoid equivalent to 40 to 60 mg of prednisone in a single dose (Grade 2C). If potentially reversible symptoms persist or worsen, the dose may increased until symptomatic control is achieved. Dose reduction and monitoring If the initial dose of prednisone was 60 mg/day it can generally be reduced to 50 mg/day after two weeks and to 40 mg/day at the end of a month. After that, the dose can be gradually reduced by approximately 10 % of the total daily dose each one or two weeks. After achieving a daily dose of 10 mg, the prednisone taper should be slowed substantially, such that patients remain on some prednisone (in progressively lower doses) for 9 to 12 months. Tapering in 1 mg decrements once the daily dose is less than 10 mg is appropriate. Laboratory testing (hemoglobin, ESR or serum CRP) prior to each decrease in glucocorticoid dose is ideal We recommend the addition of low-dose aspirin (80 to 100 mg/day) therapy in order to reduce the risk of visual loss, transient ischemic attacks, or stroke (Grade 1B). Visual loss o we suggest use of intravenous pulse methylprednisolone 1000 mg intravenously each day for 3 days (Grade 2C), then followed by 1 mg/kg per day PO (maximum of 60 mg/day) o we recommend low-dose aspirin in GCA . o for patients without contraindications to anticoagulation, warfarin therapy in addition to low-dose aspirin may also be considered in this setting. Monitoring for development of aortic aneurysm We recommend that yearly CXR be performed for up to 10 years to identify patients with thoracic aortic aneurysms prior to rupture or dissection. If aneurysmal dilatation is detected, monitoring with CT every 6 to 12 months is recommended. Medical management is

indicated for thoracic aneurysms between 3 and 5 cm in diameter, while surgical treatment may be considered for patients with larger or rapidly enlarging aneurysms. Treatment of polyarteritis nodosa PAN : Mild PAN: (constitutional symptoms, arthritis, anemia, but normal renal function, no gastrointestinal involvement, and no neurologic deficits) ,isolated cutaneous disease . o We recommend glucocorticoid monotherapy (Grade 1B). o We suggest an initial regimen of prednisone at a dose of 1 mg/kg per day (maximum 60 to 80 mg/day) for approximately 4 weeks. o Once significant improvement occurs, prednisone is tapered slowly for an overall course of approximately 9 months. o For patients with mild disease who do not respond to glucocorticoids alone, or who relapse as the dose of prednisone is tapered, treatment is as for severe PAN. Moderate and severe PAN: For patients who initially have more serious disease (eg, renal insufficiency, or gastrointestinal, cardiac or neurologic involvement), who are able to tolerate an oral regimen, we recommend initiating treatment with a combination of glucocorticoids and cyclophosphamide (Grade 1B). o Prednisone (1 mg/kg per day, maximum of 60 to 80 mg per day) given concurrently. The initial high dose is continued for 2 to 4 weeks, until significant improvement is observed. The dose should then be tapered slowly, for an overall course of approximately six months. o Oral cyclophosphamide, 1.5 to 2 mg/kg per day For patients unable to tolerate an oral regimen (eg, due to gastrointestinal involvement) and those patients with severe, life-threatening manifestations or worsening mononeuropathy multiplex, we suggest the following regimen: o Intravenous methylprednisolone given initially for 3 days, followed by the oral prednisone regimen. o Monthly intravenous infusions of cyclophosphamide (initial dose 600 to 750 mg/m2 per month). Duration of therapy: We recommend a minimum of 6 months and a maximum of 12 months of cyclophosphamide (Grade 1B). We suggest that patients who require cyclophosphamide because of glucocorticoid-resistant disease, can discontinue cyclophosphamide after disease control for approximately 6 to 9 months (Grade 2C). o We recommend NOT using plasmapheresis for treatment of idiopathic PAN (Grade1B). o We suggest treating hypertension with ACEi or ARBs (Grade 2B). Treatment of Wegener's granulomatosis and microscopic polyangiitis : INITIAL THERAPY : We recommend combination cyclophosphamide-glucocorticoid therapy in the initial treatment of most patients with WG or MPA. This is particularly indicated in those with life-threatening disease, including patients with a serum creatinine concentration greater than 2.0 mg/dL, pulmonary involvement resulting in hypoxemia, CNS disease, and/or bowel perforation/infarction. Daily oral cyclophosphamide-glucocorticoid regimen Cyclophosphamide is given orally in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. When initiating glucocorticoid therapy, there is disagreement among experts and among the authors as to whether therapy should be begun with pulse methylprednisolone (7 to 15 mg/kg to a maximum dose of 500 to 1000 mg/day for three days) in all patients or only in those with necrotizing or crescentic glomerulonephritis or more severe respiratory disease. Oral glucocorticoid therapy, either from day 1 or day 4 if pulse methylprednisolone is given, typically consists of 1 mg/kg per day (maximum of 60 to 80 mg/day) of oral prednisone (or its equivalent). A variety of prednisone tapering schemes have been employed. In general, the initial high dose should be continued for two to four weeks. If significant improvement is observed at this time, the dose of prednisone may be

tapered slowly, with the goal of reaching 20 mg of prednisone per day by the end of two months and an overall glucocorticoid course of between six and nine months. Alternate day glucocorticoid regimens, once recommended in WG, are not generally employed now. Monthly intravenous cyclophosphamide An alternative to daily oral cyclophosphamide is intravenous monthly pulse cyclophosphamide therapy. Monthly cyclophosphamide is typically administered in doses of 0.5 to 1.0 g/m2 body surface area for three to six months, until a stable remission is induced. Prednisone is given concurrently with monthly intravenous cyclophosphamide, using similar regimens as with daily oral cyclophosphamide. Methotrexate A methotrexate-based regimen, in conjunction with glucocorticoids, is an option in patients with mild disease . This primarily includes those with pulmonary nodules or infiltrates without respiratory compromise, and/or ocular disease. Although this regimen can be used to treat patients with glomerulonephritis and normal or near-normal serum creatinine, it is not recommended given the high rate of relapse. If the regimen is used, patients require close follow-up. A methotrexate-based regimen may be particularly attractive in such patients who have limited bone marrow reserve from past cyclophosphamide use, a history of cyclophosphamide-induced bladder injury, or concerns relating to major cyclophosphamide toxicity. Methotrexate should not be administered to patients with a serum creatinine concentration above 2.0 mg/dL given the increased risk of toxicity in those with renal dysfunction, and patients should not receive concurrent trimethoprim-sulfamethoxazole. One regimen consists of oral methotrexate at an initial dose of 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose of 20 to 25 mg/week . Glucocorticoids are administered concurrently with methotrexate. The dosing regimen for prednisone is the same as that previously described for prednisone when used with daily oral cyclophosphamide therapy. Plasma exchange We suggest itin selected groups of patients with WG or MPA: 1. Patients with anti-GBM antibodies as well as ANC 2. Patients with severe pulmonary hemorrhage on presentation (as defined radiographically or by arterial oxygen saturation) or those with worsening pulmonary hemorrhage despite the combination of high-dose glucocorticoids and cyclophosphamide 3. Patients who have advanced renal dysfunction at presentation, as defined by a serum creatinine level above 5.8 mg/dL and/or dialysis dependence we suggest 7 sessions of plasma exchange over two weeks (60 mL/kg at each session) In general, albumin can be used as the replacement fluid. However, if the patient has had a recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors. If a severe infection develops in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels MAINTENANCE THERAPY : Once complete remission is achieved, which usually occurs within three to six months, cyclophosphamide is discontinued and either methotrexate (which is an option only among those with a serum creatinine concentration 2.0 mg/dL) OR azathioprine is initiated (which is preferred by most physicians for patients with glomerulonephritis) o initial dose of Azathioprine : 2 mg/kg per day in most patients. The dose can be lowered to 1.5 mg/kg per day at one year from the time of initiation of induction therapy o initial dose of methotrexate : 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose of 20 to 25 mg/week. with folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg/week, 24 hours after methotrexate) Duration of maintenance therapy 12 to 18 months after stable remission has been induced. For patients who have experienced serial disease relapses following the discontinuation of maintenance therapy,

long-term maintenance therapy should be continued, particularly for those who remain ANCA-positive during clinical remission. Slow tapering of glucocorticoids is initiated once there is a significant response, which usually occurs after one month. Some physicians, however, maintain a low-dose, possibly alternate day regimen for as long as immunosuppressive therapy is continued. In the European trial, the maintenance dose was 7.5 mg/day of prednisolone (equivalent to approximately 10 mg/day of prednisone) Treatment of Kawasaki disease: In patients with KD, we recommend a single dose of IVIG (2 gm/kg) administered over 8 to 12 hours (Grade 1A). It is preferable that IVIG be administered within the first 10 days of illness before aneurysms typically develop, but IVIG should be administered even beyond this 10-day window in patients with evidence of persistent vasculitis or systemic inflammation (eg, persistent fever). In patients with KD, we suggest that aspirin be administered in the acute phase of illness (Grade 2C). We typically use 80 to 100 mg/kg per day in four divided doses (maximum dose 4 g per day). decreased to 3 to 5 mg/kg per day 48 hours after the resolution of fever. Aspirin is continued until laboratory markers (eg, platelet count and ESR) return to normal, unless coronary artery abnormalities are detected by echocardiography. we do NOT suggest using glucocorticoids for initial therapy (Grade 2B). Complications in patients with KD primarily result from coronary artery thrombosis in inflamed vessels with aneurysms. Treatment is directed toward control of vascular inflammation (eg, IVIG and aspirin) and prevention/treatment of arterial thrombosis including antiplatelet, anticoagulant, and/or thrombolytic therapy (such as urokinase). In severe cases, percutaneous coronary intervention (PCI), coronary artery bypass graft surgery, or cardiac transplantation may be required. Treatment of Churg-Strauss syndrome : Systemic glucocorticoids Most patients with CSS respond favorably to high-dose glucocorticoid therapy. Doses of 0.5 to 1.5 mg/kg per day are most frequently administered for 6 to 12 weeks or until disease manifestations have completely resolved. The higher dose is required for patients with vasculitis, especially if cardiac or renal function is impaired, or a neuropathy is present. With acute multiorgan disease, intravenous glucocorticoid (eg, methylprednisolone 1 g daily for three days) may be needed as initial therapy, followed by oral glucocorticoid therapy as noted . A portion of patients will need long-term low dose oral glucocorticoid therapy. Monitoring is best achieved by eosinophil count and ESR. Persistence of ANCA positivity in CSS does not appear to adequately reflect disease activity and. Radiographic manifestations may remain stable or may rapidly regress with glucocorticoid treatment. Other therapies Additional treatment options include the following: o Inhaled glucocorticoids may be useful for the management of upper and lower respiratory tract disease. o Cyclophosphamide, azathioprine, and high-dose intravenous immune globulin have been used with apparent benefit in patients with severe fulminant disease (glomerulonephritis) , and in patients unresponsive to glucocorticoids o Several patients with disease unresponsive to glucocorticoids and cyclophosphamide have improved with a regimen of glucocorticoids and interferon-alpha o Plasma exchange occasionally has been used in conjunction with other therapies. Treatment of Henoch-Schnlein purpura : Hospitalization is indicated : 1. Inability to maintain adequate hydration with oral intake 2. Severe abdominal pain 3. Significant gastrointestinal bleeding 4. Changes in mental status

5. Severe joint involvement limiting ambulation and/or self-care 6. Renal insufficiency (elevated creatinine), hypertension, and/or nephrotic syndrome in patients with joint and/or abdominal pain, we suggest the use of a NSAIDs (Grade 2C). We typically use naproxen (Xinar) (10 to 20 mg/kg divided into two doses per day). A maximum dose of naproxen of 1500 mg per day may be used for a few days provided that adequate hydration is maintained. If more than a week of NSAID treatment is necessary, the dose of naproxen should not exceed 1000 mg per day. In patients with severe abdominal pain that interferes with their oral intake and who fail to respond to NSAIDs, we suggest the use of oral prednisone (1 to 2 mg/kg per day), with a maximum dose of 60 to 80 mg per day (Grade 2C). In patients who cannot tolerate oral medications, equivalent doses of parenteral methylprednisolone may be administered (0.8 to 1.6 mg/kg per day, maximum dose of 64 mg per day). Treatment of Hypersensitivity vasculitis : Discontinuation of the inciting drug or antigen Treatment should be aimed at the underlying infection, such as the administration of interferon and ribavirin to those with hepatitis C virus and cryoglobulinemia. In patients with more severe or persistent cutaneous disease not due to infection, drugs such as colchicine, antihistamines, and dapsone may be helpful. Occasionally, combinations of these drugs (eg, dapsone and pentoxifylline) are more effective than single therapy . Immunosuppressive therapy with corticosteroids or cytotoxic agents should be reserved for the infrequent patient with fulminant or progressive disease, Treatment Of Cryoglobulinemia Syndromes Mild disease Mild symptoms, such as fatigue, arthralgias and myalgias, in the absence of clear evidence for end-organ damage, warrant conservative therapy. Cold avoidance, analgesics, and NSAIDs are typically recommended at first, while low-dose steroids are used for symptoms not responsive to NSAIDs. When successful, response usually occurs within several days. Moderate to severe disease Moderate-to-severe disease, as evidenced by pathologically-proven, CGrelated, end-organ-threatening vasculitis or thrombosis, usually warrants chemotherapy or immunosuppressive therapy depending upon the type of CG present. Concomitant antiviral therapy may be employed when there is evidence of a treatable viral infection and no contraindications. Type I chemotherapy and/or radiation therapy for bone lesions is indicated for treatment of the underlying hematological malignancy or plasma cell disorder. For non-malignancy-related type I disease, oral steroids such as prednisone, 1 to 2 mg/kg/day, as well as cyclophosphamide, eg, 0.5 to 1.0 g/m2 intravenously every three to six weeks or 2 mg/kg/day orally for longer-term management Type II and III immunosuppression and may also require plasmapheresis. These treatment modalities may be combined with antiviral therapy when indicated. Severe disease Severe disease due to the hyperviscosity syndrome or vasculitis in Type I CG, or life or organ threatening vasculitis in mixed CG (Types II or III) usually warrants the addition of plasmapheresis to quickly reduce the CG burden. Other therapies may include medications directed against B cells (rituximab) or TNF (infliximab), which have been successfully used in HCV-associated cryoglobulinemia. These approaches may also be applicable to cryoglobulinemic disease that is not associated with HCV infection Plasmapheresis initiated at three or more liters, three times per week for three weeks or until the resolution of a life-threatening state. Treatment of Primary angiitis of the central nervous system PACNS We suggest treating biopsy-confirmed PACNS and disease in which the evidence for PACNS is strong even in the absence of a positive biopsy should be treated with the combination of glucocorticoids and cyclophosphamide (Grade 2C).

Treatment of acute gout

The goal of therapy in an acute gout attack is prompt and safe termination of pain and disability. NSAIDs/COX-2 inhibitors : We recommend nonsteroidal antiinflammatory drugs (NSAIDs) as first line therapy for most patients with acute gout who have no contraindications to their use (Grade 1B). In the absence of data suggesting greater efficacy of one NSAID versus another, we often administer a potent NSAID (such as naproxen 500 mg twice daily or indomethacin 50 mg three times daily) for reduction of acute gouty inflammation, especially if treatment is initiated within 24 hours of the onset of symptoms. In an attack of several days duration a longer course of treatment may be necessary and an antiinflammatory agent with fewer gastroduodenal side effects (such as nabumetone or a selective COX-2 inhibitor) may be preferred. Aspirin is usually avoided because of the paradoxical effects of salicylates on serum urate.

Colchicine: Oral colchicine is effective for acute gout but frequently causes unpleasant side effects. For patients intolerant of NSAIDs and for whom glucocorticoid therapy is not appropriate, or for those who have used colchicine with success in the past, we suggest its use (Grade 2B). colchicine dose : 0.5 mg per hour until one of the following occurs: o there is relief of the gouty inflammation o a total dose of 6 mg is reached (10 -12 tablet) o nausea, vomiting, or especially diarrhea limits further use. Once the inflammation has been controlled, the frequency of dosing can be reduced to 0.6 mg twice daily and continued, if gastrointestinal tolerance permits, until resolution of the attack is achieved. An alternative regimen, recommended by a task force of the EULAR Standing Committee for International Clinical Studies, is colchicine 0.5 mg three times daily Because the use of intravenous colchicine has been associated with serious systemic adverse effects (including death) in 2008 the US FDA stopped it .

Glucocorticoids: For patients who cannot take NSAIDs or colchicine and who are not candidates for intraarticular corticosteroid injection because of polyarticular disease, we suggest use of oral glucocorticoids (Grade 2B). We often use : o prednisone in doses of 30 - 50 mg/day for 1-2 days, then taper over 7-10 days Treatment options in patients who are unable to take oral medications include intraarticular or intravenous glucocorticoids, intramuscular or subcutaneous ACTH, and in locales where it is still available, cautious use of intravenous colchicine. For patients unable to take oral medications, with only one or two actively inflamed joints, and in whom infection has been ruled out, we suggest intraarticular glucocorticoids (Grade 2B). o Triamcinolone acetonide (Alphacort): 40 mg for a large joint (eg, knee), 30 mg for medium joints (wrist, ankle, elbow) and 10 mg for small "spaces" can be used, or an equivalent dose of depomethylprednisolone. For patients with polyarticular involvement, existing or easily established intravenous access, and no contraindications to glucocorticoids, we suggest systemic administration of a parenteral glucocorticoid (Grade 2B).

o dose : 20 mg methylprednisolone twice daily, with stepwise reduction by half of each dose when improvement begins and maintenance of at least 4 mg twice daily for 5 days For patients with no intravenous access, intramuscular or subcutaneous ACTH may be used . Interleukin-1 inhibition has been reported to be effective in some cases but randomized controlled trials are needed to better assess the usefulness and safety of this approach and it is not recommended at this time.

Patients taking antihyperuricemic therapy : In patients who have had recurrent attacks of acute gouty arthritis, antihyperuricemic therapy (eg, allopurinol, probenecid) is used for long-term prophylaxis but has no role in the treatment of active gouty inflammation. However, once treatment with an antihyperuricemic agent has been initiated, most authorities believe that it should not be interrupted during an acute attack.

SPECIAL CIRCUMSTANCES 1. Chronic tophaceous gout : are treated in the same way . 2. End-stage renal disease and gout :treated with intraarticular or oral glucocorticoids as described above. Colchicine is generally avoided and, in patients not yet on dialysis, there is concern about worsening renal function with an NSAID.

Prevention of recurrent gout

Upon resolution of an acute gouty attack, the patient is said to have entered an intercritical (between attacks) period. Intervals between attacks of acute gouty arthritis are of variable duration. Most untreated patients with gout will experience a recurrent episode within two years.

RISK REDUCTION : Obesity :We suggest that patients with gout, particularly if they are overweight, be instructed in a diet that emphasizes caloric restriction, allowing an increased proportion of protein, replacement of refined with complex carbohydrates, and decreased saturated fat (Grade 2C). Diet : The increased dietary protein should come from low fat dairy products, not red meat or fish (Grade 2C). Alcohol We suggest that patients with gout limit intake of beer and spirits (Grade 2C). Hypertension and diuretics : Both essential hypertension and diuretic use are independently associated with hyperuricemia and gout. However, given the benefits of thiazide diuretics in patients with hypertension and low cost, we suggest switching to another antihypertensive drug only if hypertension can be easily controlled by another agent and cost is not a significant issue (Grade 2C). Losartan in particular has uricosuric effects and may be a good alternative agent although, in patients who are also taking a uric acid lowering agent, the additional benefit of stopping diuretics or adding losartan are likely to be minimal.

PHARMACOLOGIC ANTIHYPERURICEMIC THERAPY Indications :We recommend antihyperuricemic therapy in patients with a history of gout who have frequent and disabling attacks of gouty arthritis, clinical or radiographic signs of chronic gouty joint disease, tophi, otherwise unexplained renal insufficiency, recurrent nephrolithiasis, or urinary uric acid excretion >1100 mg/day (Grade 1B). Goals :We suggest that antihyperuricemic therapy be titrated to a dose that results in a serum urate range <6 mg/dL [<357 micromol/L] (Grade 2C). Lowering the serum uric acid slowly (no more than 0.6 mg/dL/month) is suggested (Grade 2C). A goal <5 mg/dL [<297 micromol/L] may speed resolution of tophi. Uricosuric drugs o Indications o Agents and dosing o Side effects and interactions o Other drugs Xanthine oxidase inhibitors o Indications :in contrast to uricosuric drugs, which are indicated only in patients who have impaired renal excretion of uric acid, xanthine oxidase inhibitors are likely to be effective in virtually all circumstances warranting urate-lowering therapy for gout. However, safety considerations limit their use in some patients. o Allopurinol : We usually initiate allopurinol treatment at 100 mg daily in patients with weight-adjusted creatinine clearances >40 ml/min and titrate the dose according to the antihyperuricemic effect achieved. The half-life of oxypurinol is prolonged in renal failure, necessitating a reduction in the starting allopurinol dose for patients with more severe renal functional impairment as discussed below (see "Prophylaxis in advanced chronic kidney disease" below).

Serum urate levels begin to fall within two days of allopurinol administration and reach stable levels in one to two weeks. Thus, when titrating allopurinol dosage, the urate-lowering effect of the current dose can be assessed after two or three weeks of treatment. Allopurinol may not induce goal serum urate levels early in the course of therapy of patients with extensive tophaceous deposits. However, true refractoriness to the drug is rare, and most often reflects a failure of patient adherence or of physician-patient communication o Febuxostat : We suggest using febuxostat as antihyperuricemic therapy for patients for whom uricosuric therapy is either contraindicated or ineffective when they are also intolerant of, or allergic to, allopurinol (Grade 2B). Febuxostat might also be appropriate initial pharmacologic uratelowering therapy for some patients with mild to moderate CKD if the cost is not prohibitive Choice of therapy o We suggest that if a uricosuric is being considered, the choice of antihyperuricemic therapy be based on results of 24 hour urine testing (Grade 2C). o Uricosuric drugs are suggested as initial therapy for patients under the age of 60 who excrete <800 mg [4.76 mmol] of uric acid per day on a standard diet, as long as they don't have renal insufficiency, a history of urolithiasis, or tophi (Grade 2C). o Patients with mild to moderate renal insufficiency may take the uricosuric drug benzbromarone, where available. o Other factors that should be considered for individual patients when deciding on antihyperuricemic therapy include difficulties with adherence associated with taking a drug multiple times daily (uricosuric drugs) compared with once daily (allopurinol or febuxostat), and the potential for adverse effects associated with long-term xanthine oxidase inhibitor therapy. Repeated active encouragement by the clinician may improve adherence to the recommended regimen. PROPHYLAXIS DURING INITIATION OF ANTIHYPERURICEMIC THERAPY Colchicine prophylaxis :We recommend low dose prophylactic colchicine (0.6 mg twice daily for patients with normal renal and hepatic function) during the initiation of antihyperuricemic therapy (Grade 1A). NSAID prophylaxis : is an alternative in patients who cannot tolerate colchicine (Grade 2C). Duration of therapy : o We suggest that colchicine be continued for 6 months after normal serum urate values have been obtained in patients without tophi (Grade 2C). o The duration of prophylactic therapy is uncertain in patients with tophi. We suggest continuing colchicine until resolution of the tophi or it is clear that tophaceous deposits will not resolve despite persistent normouricemia (Grade 2C). PROPHYLAXIS IN ADVANCED CHRONIC KIDNEY DISEASE SURGERY We suggest a reduced starting dose of allopurinol and smaller increments when titrating allopurinol doses for patients with chronic kidney disease (Grade 2C).

Estimated creatinine clearance Starting dose range Titration schedule 100 mL/min 100-300 mg/day 100 mg every 2-3 weeks 80-99 mL/min 100-200 mg/day 100 mg every 2-3 weeks 40-79 mL/min 100 mg/day 50-100 mg every 2-3 weeks 10-39 mL/min 50 mg/day 50 mg every 2-3 weeks SURGERY :Surgery for gout is appropriate for patients with complications of tophaceous disease, including infection, nerve compression, joint deformity, and intractable pain. Some patients also desire surgery for cosmetic reasons.

Screening for osteoporosis

Risk factor screening Assessment of fracture risk in all adults is important . The principal BMD-independent risk factors to consider include advanced age, previous fragility fracture, glucocorticoids, risk of falls, smoking, alcohol, and family history of fracture.

BMD screening : o We suggest BMD assessment in all women 65 years of age and older (Grade 2B). o We suggest BMD assessment in postmenopausal women less than 65 years if one of the above risk factors is present (Grade 2B). o We suggest NOT performing routine BMD measurements in premenopausal women (Grade 2C). o We suggest NOT performing routine BMD measurements in men (Grade 2C). However, BMD assessment in men who have risk factors for osteoporosis is important. For screening BMD, we suggest DXA over peripheral measurements (Grade 2B). If data demonstrating the ability of a peripheral measurement to successfully monitor response to therapy becomes available, screening with a peripheral measurement would be preferred due to cost, portability, and availability. For screening site of measurement, we suggest DXA of hip and spine (Grade 2C). However, measurement of the hip alone could be sufficient in older individuals. In women and men with normal baseline measurements who have risk factors for ongoing bone loss (eg, glucocorticoid use, hyperparathyroidism), we suggest follow-up measurements (approximately every one to two years), as long as the risk factor persists (Grade 2C). In women with normal baseline measurements and no risk factors for accelerated bone loss, we suggest a follow-up DXA in three to five years (Grade 2C). Diagnosis and evaluation of osteoporosis in postmenopausal women Clinical manifestations Osteoporosis is a silent disease until fracture occurs. Complications of fractures include pain, deformity, disability and loss of height. Definition Osteoporosis is defined as low bone mass with microarchitectural disruption, resulting in increased skeletal fragility and fracture. Although bone strength is comprised of many components, bone mineral density (BMD) is measured most frequently in clinical practice. The WHO has established diagnostic thresholds for low bone mass and osteoporosis based upon BMD measurements of the hip : Diagnostic categories for osteopenia and osteoporosis based upon bone mineral density measurement by DXA Normal : A value for bone mineral density (BMD) within one standard deviation of the young adult female reference mean (T-score greater than or equal to -1 SD). Low bone mass (osteopenia) : A value for BMD more than one but less than 2.5 standard deviations below the young adult female reference mean (T-score less than -1 and greater than -2.5 SD). Osteoporosis : A value for BMD 2.5 or more standard deviations below the young adult female reference mean (T-score less than or equal to -2.5). Severe (established) osteoporosis :A value for BMD more than 2.5 standard deviations below the young adult female reference mean in the presence of one or more fragility fractures.

Assessment o All postmenopausal women with osteoporosis should have a history, physical examination, and basic laboratory evaluation. o The need for additional laboratory evaluation depends upon initial evaluation and Z-score (show table 3). Individuals with abnormalities on basic laboratory testing and/or individuals with Z-scores -2.0 require evaluation for secondary causes of osteoporosis . o Laboratory evaluation for postmenopausal osteoporosis Initial laboratory tests o Complete chemistry profile (including ALP) o Complete blood count o Calcium, phosphorus o 25 hydroxyvitamin D o Urinary calcium excretion Additional laboratory tests if indicated o 24 hour urine for free cortisol o Ferritin and carotene levels o Estradiol , FSH, LH , Prolactin o Iron and total iron binding capacity o Magnesium o Serum tryptase and histamine levels o 1,25 dihydroxyvitamin D o Homocysteine o Intact PTH o Skin biopsy for connective tissue o TSH disorders o Celiac screen o COL1A genetic testing for o Serum protein electrophoresis/urine osteogenesis imperfecta protein electrophoresis o Serum and urine markers of bone o Erythrocyte sedimentation rate turnover o Rheumatoid factor Use of biochemical markers of bone turnover in osteoporosis While the use of BTMs in clinical trials has been helpful in understanding the mechanism of action of therapeutic agents, their role in the care of individual patients is not well established. Potential roles of BTMs in clinical practice include prediction of fracture risk, monitoring response to therapy, and improving compliance with therapy. There is no consensus on the optimal strategy for monitoring patients on antiresorptive therapy. However, we use the following approach: o For patients starting on therapy, we perform a DXA of the hip and spine after two years, and if BMD is stable or improved, less frequent monitoring thereafter. o For patients with conditions that might interfere with drug absorption or efficacy or patients who are reluctant to take anti-osteoporosis medications regularly, we typically measure fasting urinary NTX, serum CTX, or serum P1NP before and three to six months after starting bisphosphonates or other antiresorptive therapy. If the marker has not decreased by 50 (NTX) or 30 (CTX, P1NP) percent, noncompliance or poor absorption, often related to an insufficient time interval between drug intake and food ingestion, should be considered. This approach (with markers of bone resorption) is only useful with antiresorptive therapy, not with recombinant PTH (markers would increase). There is no consensus on a role for BTMs in the diagnosis of osteoporosis or the selection of candidates for therapy.

There is currently insufficient data to support the use of BTMs for deciding when to restart bisphosphonate therapy after a drug holiday or for the assessment of risk (osteonecrosis of the jaw) in bisphosphonatetreated patients undergoing invasive dental procedures.

Bone turnover markers Formation OC BALP Assay Circadian rhythm S* Y S* N Y LSC 21 percent 28 percent 21 percent percent/24 Comments Lack of standardization, rapidly degraded in serum, requires collection on ice Cross-reactivity with liver isoform (15 to 20 percent)

P1NP/P1CP S* Resorption NTX CTX

U*,S U,S*

Y Y

D-PYR U Y PYD U* Y HYP U Reflects bone resorption and dietary intake TRACP5b S Y 17 percent OC: Osteocalcin; BALP: Bone-specific alkaline phosphatase; P1NP: N-terminal propeptide of type 1 procollagen; P1CP: C-terminal propeptide of type 1 procollagen; NTX: cross-linked N-telopeptide of type 1 collagen; CTX: cross-linked C- telopeptide of type 1 collagen; D-PYR: Free deoxypyridinoline; PYD: Free pyridinoline; HYP: Hydroxyproline; TRACP5b: isoform 5b of tartrate resistant acid phosphatase. S: serum, collection of serum should be performed in the morning after an overnight fast; U: urinary excretion, collection of urine should be performed in the morning (usually second AM void, fasting); LSC: Least significant change; Circadian rhythm: higher in the early morning.

35 percent (S), 70 percent (U) 30 percent (S), 80 percent (U) 26 percent 36 percent

Management Of Osteoporosis In Postmenopausal Women Nonpharmacologic therapy : We suggest adequate calcium and vitamin D for all postmenopausal women with osteoporosis (Grade 2B). o In general, we suggest 1200 mg of elemental calcium daily, total diet plus supplement, and 800 IU of vitamin D daily. Some patients require additional vitamin D supplementation. Important additional lifestyle measures include exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use for all postmenopausal women with osteoporosis.

National Osteoporosis Foundation guidelines for pharmacologic intervention in postmenopausal women and men 50 years of age : 1. History of hip or vertebral fracture. 2. T-score -2.5 (DXA) at the femoral neck, total hip, or spine, after appropriate evaluation to exclude secondary causes. 3. Other prior fractures and T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine, as measured by DXA. 4. T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine and secondary causes associated with high risk of fracture, such as glucocorticoid use or total immobilization.

5. T-score between -1 and -2.5 at the femoral neck, total hip, or spine, and a 10-year probability of hip fracture 3 % or a 10-year probability of any major osteoporosis-related fracture 20 % based upon the US-adapted WHO algorithm. Clinical risk factors for fracture 1. 2. 3. 4. 5. 6. 7. 8. 9. Advancing age Previous fracture Glucocorticoid therapy Parental history of hip fracture Low body weight Current cigarette smoking Excessive alcohol consumption Rheumatoid arthritis Secondary osteoporosis (eg, hypogonadism or premature menopause, malabsorption, chronic liver disease, inflammatory bowel disease)

Pharmacologic therapy : In addition to nonpharmacologic therapy, we recommend that postmenopausal women with established osteoporosis (T-score -2.5) or fragility fracture (hip or vertebral) be treated with a pharmacologic agent (Grade 1A). For the treatment of high risk postmenopausal women with T-scores between -1.0 and -2.5, we also suggest pharmacologic therapy (Grade 2B). A reasonable cut point that may be cost-effective in some settings is a 10-year probability of hip fracture or combined major osteoporotic fracture of 3.0 or 20 percent, respectively For the treatment of osteoporosis in postmenopausal women, we suggest bisphosphonates as first-line therapy (Grade 2B). We favor bisphosphonates over raloxifene for osteoporosis treatment because they increase bone mineral density (BMD) more than raloxifene and randomized trials have documented hip fracture efficacy. For most postmenopausal women with osteoporosis, we suggest alendronate or risedronate, over oral ibandronate (Grade 2B).. Oral ibandronate may be more convenient for patients, but a reduction in hip fracture risk has not been established in randomized trials. We suggest an intravenous bisphosphonate formulation for patients who cannot tolerate oral bisphosphonates, or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes (Grade 2B). Zoledronic acid is the only intravenous bisphosphonate that has demonstrated efficacy for fracture prevention and is therefore our agent of choice. However, long-term safety data beyond three years in patients with osteoporosis is lacking. We suggest raloxifene for postmenopausal women with osteoporosis (low bone mineral density [T score <2.5] and no fragility fractures) who cannot tolerate or are not candidates for any bisphosphonates (Grade 2B). We suggest PTH therapy for postmenopausal women with severe osteoporosis (low bone mineral density [T score <-2.5] and at least one fragility fracture) who are unable to tolerate any of the available bisphosphonates (Grade 2B). In postmenopausal women with severe osteoporosis (low bone mineral density [T score <-2.5] and at least one fragility fracture) who continue to fracture after one year of bisphosphonate therapy, we suggest discontinuing the bisphosphonate and switching to human recombinant PTH therapy (Grade 2B).

Other candidates for parathyroid hormone are postmenopausal women with osteoporosis who are unable to tolerate bisphosphonates or who have relative contraindications to bisphosphonates (achalasia, scleroderma esophagus, esophageal strictures), in addition to relative contraindications to SERMS (thrombosis, hot flashes), or who fail other osteoporosis therapies (fracture with loss of BMD in spite of compliance with therapy).

Prevention of osteoporosis
Nonpharmacological All patients should receive nonpharmacological therapy in order to preserve BMD, bone microarchitecture, and strength. For maximizing peak bone mass during the bone-forming years, we suggest healthy lifestyle measures, including adequate calcium intake, adequate vitamin D intake, physical activity (although not excessive), and avoidance of cigarette smoking and alcohol. For prevention of subsequent bone loss in adults, we suggest similar healthy lifestyle measures that include regular, weight-bearing exercise, avoidance of cigarette smoking, and limitation of alcohol to an average of no more than two drinks daily. We suggest calcium supplements in individuals with inadequate dietary calcium intake (Grade 2B). Recommended calcium intake for postmenopausal women is at least 1200 mg daily. We suggest vitamin D supplementation if dietary intake is inadequate (Grade 2C). Recommended vitamin D intake is at least 400 int. units daily in younger individuals, and at least 800 int. units daily in older adults.

Pharmacological Patients should be selected for pharmacological intervention based upon fracture risk, as determined by a combination of BMD and clinical risk factors. The risk factors that are best validated include advanced age, prior fragility fracture, parental history of hip fracture, glucocorticoid use, excess alcohol intake, rheumatoid arthritis, and current cigarette smoking. Patients with the highest probability of fracture are most likely to benefit from drug therapy. For the majority of postmenopausal women, we suggest not using pharmacological therapy for prevention of osteoporosis (Grade 2B). For postmenopausal women who are candidates for and desire pharmacological therapy for prevention of osteoporosis, we recommend bisphosphonates or raloxifene as first-line choices (Grade 2B). There are nonskeletal considerations with raloxifene that may play an important role in the selection of patients for therapy: a reduction in breast cancer risk, but an increase in thromboembolic events and hot flashes, and no apparent effect on heart disease or the endometrium. The bisphosphonate dose for prevention is alendronate 5 mg daily or 35 mg once weekly, risedronate 5 mg daily, 35 mg once weekly, 75 mg on two consecutive days once monthly, or 150 mg once monthly, ibandronate 150 mg once monthly, and zoledronic acid 5 mg IV once every two years.

Prevention and treatment of glucocorticoid-induced osteoporosis What follows are the broad guidelines that we use to minimize glucocorticoid-induced bone loss in individuals taking 5 mg prednisone equivalent daily for 3 months However, therapy must be adjusted according to the unique circumstances of the patient in question.

We recommend calcium and vitamin D supplementation for all patients receiving regular glucocorticoid therapy ( 5 mg daily for 3 months). Most individuals require 1200 mg of elemental calcium daily, total diet plus supplement, and 800 IU of vitamin D daily. In postmenopausal women and men already at high risk for fracture (elderly, prior fragility fracture) and on chronic glucocorticoid therapy ( 5 mg daily for 3 months), we recommend oral bisphosphonate therapy. We recommend the weekly formulations for patient convenience (alendronate 35 mg/week for prevention, 70 mg/week for treatment; risedronate 35 mg/week for prevention or treatment). We recommend caution when considering bisphosphonates in premenopausal women. It is important to consider the potential for harm to the fetus in women who become pregnant who are currently receiving or were recently treated with bisphosphonates. We suggest replacement of testosterone in men receiving prolonged glucocorticoid therapy who develop hypogonadism. Although estrogen replacement therapy prevents bone loss in postmenopausal women receiving glucocorticoid therapy, estrogen-progestin therapy is no longer a first-line approach for the prevention or treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and perhaps coronary disease. In contrast, oral contraceptives or estrogen replacement therapy can be suggested to premenopausal women with menstrual irregularities while taking glucocorticoids. Because glucocorticoids cause hypercalciuria, 24-hour urinary calcium excretion should be measured whenever any of the above therapies are chosen. The addition of a thiazide diuretic plus salt restriction could be considered if substantial hypercalciuria is present (defined as calcium excretion above 400 mg/day).

Diagnosis and evaluation of osteoporosis in men

Diagnosis The WHO has established diagnostic thresholds for low bone mass and osteoporosis based upon BMD measurements of the hip . A DXA T-score -2.5 is consistent with osteoporosis, whereas a T-score between -1.0 and -2.5 is osteopenia. We suggest not performing routine bone mineral density testing in men (Grade 2C). Measurement of bone density is suggested for men with clinical manifestations of low bone mass, such as radiographic osteopenia, history of low trauma fractures, loss of more than 1.5 inches in height, as well as in those with risk factors for fracture, such as long-term glucocorticoid therapy, hypogonadism, primary hyperparathyroidism, and intestinal disorders . Evaluation The goal of the evaluation of men with low bone mass (T-score below -2.0) or fragility fracture is to rule out secondary causes. Many secondary etiologies of osteoporosis can be determined on history and physical examination. In addition, most men with low bone mass or fragility fracture should have basic laboratory testing.

Laboratory evaluation for men osteoporosis Initial laboratory tests o Complete chemistry profile (including alkaline phosphatase) o Complete blood count o Calcium, phosphorus o 25 hydroxyvitamin D o Testosterone o Urinary calcium excretion o Additional laboratory tests if indicated o 24 hour urine for free cortisol o Ferritin and carotene levels o FSH, LH o Iron and total iron binding capacity o Prolactin o Serum tryptase and histamine levels o Magnesium o Homocysteine o 1,25 dihydroxyvitamin D o Skin biopsy for connective tissue o Intact PTH disorders o TSH o COL1A genetic testing for osteogenesis o Celiac screen imperfecta o Serum protein/urine electrophoresis o Serum and urine markers of bone o Erythrocyte sedimentation rate turnove o Rheumatoid factor