Acute Coronary Syndrome

Introduction
Background

The initial diagnosis of acute coronary syndrome (ACS) is based on history, risk factors, and, to a lesser extent, ECG findings. The symptoms are due to myocardial ischemia, the underlying cause of which is an imbalance between supply and demand of myocardial oxygen. Patients with ACS include those whose clinical presentations cover the following range of diagnoses: unstable angina, nonST-elevation myocardial infarction (NSTEMI), and STelevation myocardial infarction (STEMI). This ACS spectrum concept is a useful framework for developing therapeutic strategies.
A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a large meal. Pain is now present but is minimal. Aspirin is the single drug that will have the greatest potential impact on subsequent morbidity. In the setting of ongoing symptoms and ECG changes, nitrates titrated to 10% reduction in blood pressure and symptoms, beta-blockers, and heparin are all indicated. If the patient continues to have persistent signs and/or symptoms of ischemia, addition of a glycoprotein IIb/IIIa inhibitor should be considered.

A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complaining of shortness of breath and precordial chest tightness. Her initial vital signs are blood pressure 140/90 mm Hg and heart rate is 98. Her ECG is as shown. She is given nitroglycerin sublingually, and her pressure decreases to 80/palpation. Right ventricular ischemia should be considered in this patient.

Pathophysiology

Myocardial ischemia is most often due to atherosclerotic plaques, which reduce the blood supply to a portion of myocardium. Initially, the plaques allow sufficient blood flow to match myocardial demand. When myocardial demand increases, the areas of narrowing may become clinically significant and precipitate angina. Angina that is reproduced by exercise, eating, and/or stress and is subsequently relieved with rest, and without recent change in frequency or severity of activity that produce symptoms, is called chronic stable angina. Over time, the plaques may thicken and rupture, exposing a thrombogenic surface upon which platelets aggregate and thrombus forms. The patient may note a change in symptoms of cardiac ischemia with a change in severity or of duration of symptoms. This condition is referred to as unstable angina. Patients with STEMI have a high likelihood of a coronary thrombus occluding the infarct artery. Angiographic evidence of coronary thrombus formation may be seen in more than 90% of patients with STEMI but in only 1% of patients with stable angina and about 35-75% of patients with unstable angina or NSTEMI. However, not every STEMI evolves into a Q-wave MI; likewise, a patient with NSTEMI may develop Q waves. The excessive mortality rate of coronary heart disease is primarily due to rupture and thrombosis of the atherosclerotic plaque. Inflammation plays a critical role in plaque

destabilization and is widespread in the coronary and remote vascular beds. Systemic inflammatory, thrombotic, and hemodynamic factors are relevant to the outcome. Evidence indicates that platelets contribute to promoting plaque inflammation as well as thrombosis. A new theory of unbalanced cytokine-mediated inflammation is emerging, providing an opportunity for intervention. A less common cause of angina is dynamic obstruction, which may be caused by intense focal spasm of a segment of an epicardial artery (Prinzmetal angina). Coronary vasospasm is a frequent complication in patients with connective tissue disease. Other causes include arterial inflammation and secondary unstable angina. Arterial inflammation may be caused by or related to infection. Secondary unstable angina occurs when the precipitating cause is extrinsic to the coronary arterial bed, such as fever, tachycardia, thyrotoxicosis, hypotension, anemia, or hypoxemia. Most patients who experience secondary unstable angina have chronic stable angina as a baseline medical condition. Spontaneous and cocaine-related coronary artery dissection remains an unusual cause of ACS and should be included in the differential diagnosis, especially when a younger female or cocaine user is being evaluated. An early clinical suspicion of this disease is necessary for a good outcome. Cardiology consultation should be obtained for consideration for urgent percutaneous coronary intervention. Although rare, pediatric and adult ACS may result from the following (see Myocardial Infarction in Childhood):

ACS may occur with Marfan syndrome; Kawasaki disease; Takayasu arteritis; or cystic medial necrosis with aortic root dilatation, aneurysm formation, and dissection into the coronary artery. Anomalous origin of the left coronary artery from the pulmonary artery may occur as unexplained sudden death in a neonate. Coronary artery ostial stenosis may occur after repair of a transposition of the great arteries in the neonatal period. An aberrant left main coronary artery with its origin at the right sinus of Valsalva may cause ACS, especially with exertion. Traumatic myocardial infarction can occur in patients at any age. Accelerated atherosclerosis is known to occur in cardiac transplant recipients on immunosuppressive therapy. ACS may occur with progeria.

Irrespective of the cause of unstable angina, the result of persistent ischemia is myocardial infarction (MI).
Frequency United States

Although the exact incidence of ACS is difficult to ascertain, hospital discharge data indicate that 1,680,000 unique discharges for ACS occurred in 2001.

International

In Britain, annual incidence rate of angina is estimated at 1.1 cases per 1000 males and 0.5 cases per 1000 females aged 31-70 years. In Sweden, chest pain of ischemic origin is thought to affect 5% of all males aged 50-57 years. In industrialized countries, annual incidence rate of unstable angina is approximately 6 cases per 10,000 people.
Mortality/Morbidity

When the only therapy for angina was nitroglycerin and limitation of activity, patients with newly diagnosed angina had a 40% incidence of MI and a 17% mortality rate within 3 months. A recent study shows that the 30-day mortality rate from ACS has decreased as treatment has improved, a statistically significant 47% relative decrease in 30-day mortality rate among newly diagnosed ACS from 1987-2000. This decrease in mortality rate is attributed to aspirin, glycoprotein (GP) IIb/IIIa blockers, and coronary revascularization via medical intervention or procedures. Clinical characteristics associated with a poor prognosis include advanced age, male sex, prior MI, diabetes, hypertension, and multiple-vessel or left-mainstem disease.
Sex

Incidence is higher in males among all patients younger than 70 years. This is due to the cardioprotective effect of estrogen in females. At 15 years postmenopause, the incidence of angina occurs with equal frequency in both sexes. Evidence exists that women more often have coronary events without typical symptoms, which might explain the frequent failure to initially diagnose ACS in women.
Age

ACS becomes progressively more common with increasing age. In persons aged 40-70 years, ACS is diagnosed more often in men than in women. In persons older than 70 years, men and women are affected about equally.

Clinical
History

Typically, angina is a symptom of myocardial ischemia that appears in circumstances of increased oxygen demand. It is usually described as a sensation of chest pressure or heaviness, which is reproduced by activities or conditions that increase myocardial oxygen demand. Not all patients experience chest pain. Some present with only neck, jaw, ear, arm, or epigastric discomfort. Other symptoms, such as shortness of breath or severe weakness, may represent anginal equivalents. A patient may present to the ED because of a change in pattern or severity of symptoms. A new case of angina is more difficult to diagnose because symptoms are often vague and similar to those caused by other conditions (eg, indigestion, anxiety).

Patients may have no pain and may only complain of episodic shortness of breath, weakness, lightheadedness, diaphoresis, or nausea and vomiting. Patients may complain of the following: o Palpitations o Pain, which is usually described as pressure, squeezing, or a burning sensation across the precordium and may radiate to the neck, shoulder, jaw, back, upper abdomen, or either arm o Exertional dyspnea that resolves with pain or rest o Diaphoresis from sympathetic discharge o Nausea from vagal stimulation o Decreased exercise tolerance o Patients with diabetes and elderly patients are more likely to have atypical presentations and offer only vague complaints, such as weakness, dyspnea, lightheadedness, and nausea. Stable angina o Involves episodic pain lasting 5-15 minutes o Provoked by exertion o Relieved by rest or nitroglycerin Unstable angina: Patients have increased risk for adverse cardiac events, such as MI or death. Three clinically distinct forms exist, as follows: o New-onset exertional angina o Angina of increasing frequency or duration or refractory to nitroglycerin o Angina at rest Variant angina (Prinzmetal angina) o Occurs primarily at rest o Triggered by smoking o Thought to be due to coronary vasospasm Elderly persons and those with diabetes may have particularly subtle presentations and may complain of fatigue, syncope, or weakness. Elderly persons may also present with only altered mental status. Those with preexisting altered mental status or dementia may have no recollection of recent symptoms and may have no complaints whatsoever. As many as half of cases of ACS are clinically silent in that they do not cause the classic symptoms described above and consequently go unrecognized by the patient. Maintain a high index of suspicion for ACS especially when evaluating women, patients with diabetes, older patients, patients with dementia, and those with a history of heart failure.

Physical

Physical examination results are frequently normal. If chest pain is ongoing, the patient will usually lie quietly in bed and may appear anxious, diaphoretic, and pale. Hypertension may precipitate angina or reflect elevated catecholamine levels due to either anxiety or exogenous sympathomimetic stimulation. Hypotension indicates ventricular dysfunction due to myocardial ischemia, infarction, or acute valvular dysfunction. Jugular venous distention Third heart sound (S3) may be present. A new murmur may reflect papillary muscle dysfunction. Rales on pulmonary examination may suggest left ventricular (LV) dysfunction or mitral regurgitation.

Presence of a fourth heart sound (S4) is a common finding in patients with poor ventricular compliance due to preexisting ischemic heart disease or hypertension.

Causes

Atherosclerotic plaque is the predominant cause. Coronary artery vasospasm is less common. Alternative causes of angina include the following: o Ventricular hypertrophy due to hypertension, valvular disease, or cardiomyopathy o Embolic occlusion of the coronary arteries o Hypoxia, as in carbon monoxide poisoning or acute pulmonary disorders o Cocaine and amphetamines, which increase myocardial oxygen demand and may cause coronary vasospasm o Underlying coronary artery disease, which may be unmasked by severe anemia o Inflammation of epicardial arteries o Coronary artery dissection Risk factors for ACS should be documented and include the following: o Male gender o Diabetes mellitus (DM) o Smoking history o Hypertension o Increased age o Hypercholesterolemia o Hyperlipidemia o Prior cerebrovascular accident (CVA) - These patients constitute 7.5% of patients with ACS and have high-risk features. o Inherited metabolic disorders o Methamphetamine use o Occupational stress o Connective tissue disease

Workup
Laboratory Studies

Troponin I is considered the preferred biomarker for diagnosing myocardial necrosis. Troponins have the greatest sensitivity and specificity in detecting MI, and elevated serum levels are considered diagnostic of MI. They also have prognostic value. o For early detection of myocardial necrosis, sensitivity of troponin is superior to that of the creatine kinaseMB (CK-MB). Troponin I is detectable in serum 3-6 hours after an MI, and its level remains elevated for 14 days. o Troponin is a contractile protein that normally is not found in serum. It is released only when myocardial necrosis occurs. o Troponin should be used as the optimum biomarkers for the evaluation of patients with ACS who have coexistent skeletal muscle injury.

Troponin T has similar release kinetics to troponin I, and levels remains elevated for 14 days. False-positive results may occur in patients with renal failure. Minor elevations in troponin T level also identify patients at risk for subsequent cardiac events. Elevated troponin levels may also point to minor myocardial injury due to other causes. Zellweger et al described 4 patients with elevated troponin levels after supraventricular tachycardia without evidence of coronary artery disease and very low risk scores for ACS.1 Similarly, Koller found that endurance athletes may show elevated serum troponin levels in the absence of ACS.2 CK-MB levels begin to rise within 4 hours after MI, peak at 18-24 hours, and subside over 3-4 days. A level within the reference range does not exclude myocardial necrosis. o The upper limit of normal for CK-MB is 3-6% of total CK. A normal level in the ED does not exclude the possibility of MI. A single assay in the ED has a 34% sensitivity for MI. Serial sampling over periods of 6-9 hours increases sensitivity to approximately 90%. Serial CK-MB over 24 hours detects myocardial necrosis with a sensitivity near 100% and a specificity of 98%. o Occasionally, a very small infarct is missed by CK-MB; therefore, troponin levels should be measured for patients suspected to have MI who have negative results from serial CK-MB tests. o One study looked at using the 2-hour delta (increase or decrease) of cardiac markers as 1 of 6 criteria in making the diagnosis of ACS and MI. According to one of the Erlanger criteria, an increase in the CK-MB level of 1.5 ng/mL or greater or an increase of the cardiac troponin I level of 0.2 ng/mL or greater over 2 hours in itself would allow one to make the provisional diagnosis of ACS with a high degree of sensitivity and specificity, even if the total levels were within the normal range. Patients with recent MI were also identified by a decreasing curve of CK-MB. Using this 2-hour delta of cardiac markers greatly reduces the number of cases of MI and ACS that are overlooked in patients who are then inappropriately discharged home. Myoglobin, a low-molecular-weight heme protein found in cardiac and skeletal muscle, is released more rapidly from infarcted myocardium than troponin and CK-MB and may be detected as early as 2 hours after MI. Myoglobin levels, although highly sensitive, are not cardiac specific. They may be useful for early detection of MI when performed with other studies. Cardiac markers should be used liberally to evaluate patients with prolonged episodes of ischemic pain, with new changes on ECG, or with nondiagnostic or normal ECGs in whom the diagnosis of ACS or MI is being considered. Complete blood count is indicated to determine if anemia is a precipitant. Transfusion with packed red blood cells may be indicated. A chemistry profile is indicated. Obtain a basic metabolic profile, including a check of blood glucose level, renal function, and electrolytes levels, for patients with new-onset angina. Potassium and magnesium levels should be monitored and corrected. Creatinine levels must be considered before using an angiotensin-converting enzyme (ACE) inhibitor. Other biochemical markers o C-reactive protein (CRP) is a marker of acute inflammation. Patients without biochemical evidence of myocardial necrosis but elevated CRP level are at increased risk of an adverse event.

Interleukin 6 is the major determinant of acute-phase reactant proteins in the liver, and serum amyloid A is another acute-phase reactant. Elevations of either of these can be predictive in determining increased risk of adverse outcomes in patients with unstable angina. o Several other biomarkers have been investigated with variable sensitivity and specificity that include sCD40 ligand, myeloperoxidase, pregnancy-associated plasma protein-A, choline, placental growth factor, cystatin C, fatty acid binding protein, ischemia modified albumin, chemokines ligand-5 and -18 (mediators of monocyte recruitment induced by ischemia), angiogenin, SCUBE1 (a novel platelet protein), and others.3,4 In a study that included 107 patients presenting to an emergency department with chest pain, ischemia modified albumin was not found to have superior sensitivity and specificity over traditional biomarkers with a sensitivity of 0.86 and specificity of 0.49.5 In one study, patients presenting to the ED with suspected myocardial ischemia showing higher levels of inflammatory cytokines were associated with an increased risk of a serious cardiac event during the subsequent 3 months. However, the cytokines have limited ability to predict a serious adverse cardiac event. Erythrocyte sedimentation rate rises above reference range values within 3 days and may remain elevated for weeks. Serum lactase dehydrogenase level rises above the reference range within 24 hours of MI, reaches a peak within 3-6 days, and returns to the baseline within 8-12 days.
o

Imaging Studies

Chest radiograph may demonstrate complications of ischemia, such as pulmonary edema, or it may provide clues to alternative causes of symptoms, such as thoracic aneurysm or pneumonia. Echocardiogram often demonstrates wall motion abnormalities due to ischemia. It is of limited value in patients whose symptoms have resolved or in those with preexisting wall motion abnormalities. However, echocardiogram may be useful in identifying precipitants for ischemia, such as ventricular hypertrophy and valvular disease. Radionuclide myocardial perfusion imaging has been shown to have favorable diagnostic and prognostic value in this setting, with an excellent early sensitivity to detect acute myocardial infarction (MI) not achieved by other testing modalities. o A normal resting perfusion imaging study has been shown to have a negative predictive value of more than 99% in excluding MI. Observational and randomized trials of both rest and stress imaging in the ED evaluation of patients with chest pain have demonstrated reductions in unnecessary hospitalizations and cost savings compared with routine care. o Perfusion imaging has also been used in risk stratification after MI and for measurement of infarct size to evaluate reperfusion therapies. Novel "hot spot" imaging radiopharmaceuticals that visualize infarction or ischemia are currently undergoing evaluation and hold promise for future imaging of ACS. (See Myocardial Ischemia - Nuclear Medicine and Risk Stratification.)

Recent advances include CT coronary angiography and CT coronary artery calcium scoring. o The dual-source 64-slice CT scanners can do a full scan in 10 seconds and produce high-resolution images that allow fine details of the patient's coronary arteries to be seen. This technology allows for noninvasive and early diagnosis of coronary artery disease and thus earlier treatment before the coronary arteries become more or completely occluded. It allows direct visualization of not only the lumen of the coronary arteries but also plaque within the artery. Dual-source 64-slice CT scanning is being used with intravenous contrast to determine if a stent or graft is open or closed. o CT coronary artery scoring is emerging as an attractive risk stratification tool in patients who are low risk for acute coronary syndrome. This imaging modality exposes the patient to very little radiation (1-2 msV). No contrast is needed, and the study does not have a requirement for heart rate.6 Technetium-99m (99mTc) tetrofosmin single-photon emission computed tomography (SPECT) is a useful method to exclude high-risk patients among patients with chest pain in the emergency department. Resting cardiac magnetic resonance imaging (MRI) has exhibited diagnostic operating characteristics suitable for triage of patients with chest pain in the ED. Performed urgently to evaluate chest pain, MRI accurately detected a high fraction of patients with ACS, including patients with enzyme-negative unstable angina. MRI can identify wall thinning, scar, delayed enhancement (infarction), and wall motion abnormalities (ischemia). Coronary artery assessment may be coupled with magnetic resonance (MR) angiography in the future.

Other Tests

ECG is the most important ED diagnostic test for angina. It may show changes during symptoms and in response to treatment, which would confirm a cardiac basis for symptoms. It also may demonstrate preexisting structural or ischemic heart disease (left ventricular hypertrophy, Q waves). A normal ECG or one that remains unchanged from the baseline does not exclude the possibility that chest pain is ischemic in origin. Changes that may be seen during anginal episodes include the following: o Transient ST-segment elevations (fixed changes suggest acute MI) may be observed. In patients with elevated ST segments, consider LV aneurysm, pericarditis, Prinzmetal angina, early repolarization, and Wolff-Parkinson-White syndrome as possible diagnoses. o Dynamic T-wave changes (inversions, normalizations, or hyperacute changes) may be observed. In patients with deep T-wave inversions, consider CNS events or drug therapy with tricyclic antidepressants or phenothiazines. o ST depressions may be junctional, downsloping, or horizontal. o Diagnostic sensitivity may be increased by performing right-sided leads (V4 R), posterior leads (V8, V9), and serial recordings. ECGs from 2 patients are shown below.

A 50-year-old man with type 1 diabetes mellitus and hypertension presents after experiencing 1 hour of midsternal chest pain that began after eating a large meal. Pain is now present but is minimal. Aspirin is the single drug that will have the greatest potential impact on subsequent morbidity. In the setting of ongoing symptoms and ECG changes, nitrates titrated to 10% reduction in blood pressure and symptoms, beta-blockers, and heparin are all indicated. If the patient continues to have persistent signs and/or symptoms of ischemia, addition of a glycoprotein IIb/IIIa inhibitor should be considered.

A 62-year-old woman with a history of chronic stable angina and a "valve problem" presents with new chest pain. She is symptomatic on arrival, complaining of shortness of breath and precordial chest tightness. Her initial vital signs are blood pressure 140/90 mm Hg and heart rate is 98. Her ECG is as shown. She is given nitroglycerin sublingually, and her pressure decreases to 80/palpation. Right ventricular ischemia should be considered in this patient.

Treatment
Prehospital Care

Generally, patients transported with chest pain should initially be managed under the assumption that the pain is ischemic in origin. Prehospital interventions should be guided by the nature of the presenting complaint, individual risk factors, and associated symptoms (eg, breathing difficulty, hemodynamic instability, appearance of ectopy). Airway, breathing, and circulation should be rapidly assessed with institution of CPR, ACLS-guided interventions, or other measures as indicated for the unstable patient.

Obtain intravenous access. Administer supplemental oxygen. Aspirin (162-325 mg) should be given in the field, chewed and swallowed. Administer sublingual or aerosolized nitroglycerin if chest pain is ongoing and is believed to be cardiac in origin. Additionally, recently, the AHA has published a statement on integrating prehospital ECGs into care for ACS patients (see AHA Publishes Statement on Integrating Prehospital ECGs Into Care for ACS Patients). Prehospital integration of ECG interpretation, when AMI is present, has been shown to decrease "door to balloon time," to allow paramedics to bypass non-PCI hospitals in favor of better equipped facilities, and to expedite care by allowing an emergency physician to activate the catheterization laboratory before patient arrival. Prehospital thrombolysis allows eligible patients to receive thrombolysis 3060 minutes sooner than if treatment were given in the ED; however, prehospital thrombolysis is still under investigation and has not become a trend due to unproven benefit and due to the increase in availability of percutaneous coronary intervention (PCI) in many medical centers as an alternative to thrombolysis for STEMI.

Emergency Department Care

The ACS spectrum concept is a useful framework for developing therapeutic strategies. Antithrombin therapy and antiplatelet therapy should be administered to all patients with an ACS regardless of the presence or the absence of ST-segment elevation. Patients presenting with persistent ST-segment elevation are candidates for reperfusion therapy (either pharmacological or catheter based) to restore flow promptly in the occluded epicardial infarctrelated artery. Patients presenting without ST-segment elevation are not candidates for immediate pharmacological reperfusion but should receive anti-ischemic therapy and PCI when appropriate. "Time is myocardium" is a dictum to be remembered as survival has been shown

to correlate with time to reperfusion in patients with acute MI. Many centers set goals for, and routinely record, door-to-ECG, door-to-needle (thrombolytic therapy), or door-to-vascular access (for patients receiving PCI) times as measures of quality of care provided. Rathore et al found that any delay in primary percutaneous coronary intervention after a patient with ST-elevation myocardial infarction (STEMI) arrives at hospital is associated with higher mortality.7 In a prospective cohort study of 43,801 patients enrolled in the American College of Cardiology National Cardiovascular Data Registry, 2005-2006, longer door-to-balloon times were associated with a higher adjusted risk of in-hospital mortality, in a continuous nonlinear fashion (30 min = 3%, 60 min = 3.5%, 90 min = 4.3%, 120 min = 5.6%, 150 min = 7%, 180 min = 8.4%, P<0.001). A reduction in door-to-balloon time from 90 minutes to 60 minutes was associated with 0.8% lower mortality, and a reduction from 60 minutes to 30 minutes was associated with a 0.5% lower mortality. A recent study by Ryan et al sought to determine if point-of-care cardiac marker testing decreased length of stay in patients being evaluated for acute coronary syndrome in the ED.8 Patients were randomized to 2 groups, with 1000 patients in each group: one having point-ofcare markers and central laboratory markers and one having central laboratory markers only. Median time to discharge home was 4.6 hours (3.5-6.1 h) in central laboratory only patients and 4.5 hours (3.5-6.1 h) in the point-of-care patients. Median time to transfer to an inpatient setting for admitted patients was 5.5 hours (4.2-7.5 h) in the central laboratory patients, and 5.4 hours (4.1-7.3 h) in point-of-care group patients. Time to transfer to the floor was reduced in the point-of-care group at one site, compared with the laboratory group (difference in medians 0.45 h; 95% confidence interval [CI] -0.14 to 1.04 h). Time to ED departure for discharged patients was higher in the point-of-care group than in the laboratory group (difference in medians 1.25 h; 95% CI 0.13 to 2.36 h) at one site.8 Results between the EDs varied, with one showing that point-of-care testing decreased time to admission, and another showing that point-of-care testing increased time to discharge. Ryan et al concluded that the potential effects of point-of-care testing in the ED for patient throughput should be considered in the full context of ED operations.

Goals of ED care are rapid identification of patients with STEMI, exclusion of alternative causes of nonischemic chest pain, and stratification of patients with acute coronary ischemia into low- and high-risk groups. Obtain intravenous access, administer supplemental oxygen, and provide telemetry monitoring if these procedures have not already been accomplished in the prehospital phase. In addition, obtain a 12-lead ECG as soon as possible after arrival. Complete a history and physical examination, with focus on risk factors for coronary ischemia; onset, duration, and pattern of symptoms; and early identification of complications of myocardial ischemia (eg, new murmurs, CHF). Perform frequent reassessment of vital signs and symptoms in response to administered therapies. Serial ECGs and continuous ST-segment monitoring may be useful. Many EDs have an observation unit that may be an appropriate disposition for patients who meet admission criteria. Medical therapy, as discussed in Medication, is indicated.

Treatment and evaluation guidelines are available from various sources including the American College of Emergency Physicians, American College of Chest Physicians, and National Academy of Clinical Biochemistry.9,10,11
Consultations

Cardiology or interventional cardiology consultation may be indicated for patients with any of the following:

STEMI - Depending on the center, the patient may be a candidate for PCI, and immediate interventional cardiology consultation is indicated. o Ongoing symptoms highly suggestive of acute coronary ischemia and nondiagnostic ECG (eg, left bundle-branch block [LBBB]) o Ongoing symptoms refractory to aggressive medical therapy o Hemodynamic instability o Evidence of acute valvular dysfunction o Shock o Known severe aortic stenosis and ongoing symptoms o Uncertainty of the diagnosis

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial studied the impact of age on outcomes in moderate- and high-risk non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Outcomes were analyzed at 30 days and 1 year in 4 age groups, overall and among those undergoing percutaneous coronary intervention (PCI). Of 13,819 patients in the ACUITY trial, 3,655 (26.4%) were younger than 55 years of age, 3,940 (28.5%) were aged 55-64 years, 3,783 (27.4%) were aged 65-74 years, and 2,441 (17.7%) were 75 years or older. Older patients had more cardiovascular risk factors and had a higher acuity at presentation. Patients aged 75 years or older treated with bivalirudin alone had similar ischemic outcomes but significantly lower rates of bleeding compared with those treated with heparin and glycoprotein IIb/IIIa inhibitors overall and in the PCI subset.12

Medication
The goals of treatment are to preserve patency of the coronary artery, augment blood flow through stenotic lesions, and reduce myocardial oxygen demand. All patients should receive antiplatelet agents, and patients with evidence of ongoing ischemia should receive aggressive medical intervention until signs of ischemia, as determined by symptoms and ECG, resolve. The value of aspirin in primary prophylaxis for cardiovascular diseases was challenged in the Aspirin for Asymptomatic Atherosclerosis trial. In this double-blind randomized controlled trial, 28,980 men and women aged 50-75 years living in central Scotland, and recruited from a community health registry, who were free of clinical cardiovascular disease, but at higher risk of atherosclerosis and an increased risk of cardiovascular and cerebrovascular events based on low ankle brachial index (ABI), were given 100 mg aspirin (enteric coated) or placebo. The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization. Secondary end points included angina, intermittent claudication, or transient ischemic attack; as well as all-cause mortality. After a mean (SD) follow-up of 8.2 (1.6) years, none of the study end points showed statistically significant difference between groups. The rate of an initial event of major hemorrhage requiring admission to hospital was not also

statistically different between the groups. Note though that this study was powered to detect a 25% proportional risk reduction in events, which may not have been achieved.13,14
Antiplatelet agents

These agents inhibit the cyclooxygenase system, decreasing the level of thromboxane A2, which is a potent platelet activator. Antiplatelet therapy has been shown to reduce mortality rates by reducing the risk of fatal strokes and fatal myocardial infarctions.
Aspirin (Anacin, Ascriptin, Bayer Aspirin)

Early administration of aspirin in patients with AMI may reduce cardiac mortality in first month.
Dosing Adult

160-324 mg PO or chewed; suppository if patient is unable to take PO medications

Pediatric

Not established
Nitrates

These agents oppose coronary artery spasm and reduce myocardial oxygen demand by reducing both preload and afterload.

Nitroglycerin (Nitro-Bid)

Causes relaxation of the vascular smooth muscle via stimulation of intracellular cyclic guanosine monophosphate production, causing a decrease in blood pressure.
Dosing Adult

400 mcg SL or spray q5min, repeated up to 3 times If symptoms persist, administer 5-10 mcg/min IV infusion Dose should be titrated to reduce MAP by 10%, relieve symptoms, limit adverse effects of hypotension (>30% reduction in MAP or <90 mm Hg systolic), or relieve intolerable headache
Pediatric

Not established

Analgesics

These agents reduce pain, which decreases sympathetic stress, in addition to providing some preload reduction.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

DOC for narcotic analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in a number of ways and commonly titrated until desired effect obtained.
Dosing Adult

2-4 mg IV q5-15min; titrate to symptomatic relief or adverse effects (eg, lethargy, hypotension, respiratory depression)
Pediatric

Not established
Anticoagulants

These agents are used to prevent recurrence of clot after a spontaneous fibrinolysis.

Heparin

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents recurrence of a clot after spontaneous fibrinolysis.
Dosing Adult

80 U/kg IV bolus, followed by an infusion of 18 U/kg/h

Pediatric

Not established

Beta-adrenergic blockers

These agents have antiarrhythmic and antihypertensive properties as well as ability to reduce ischemia. They minimize the imbalance between myocardial supply and demand by reducing afterload and wall stress. In patients with acute MI, they have been shown to decrease infarct size as well as short- and long-term mortality, which is a function of their anti-ischemic and antiarrhythmic properties.
Metoprolol (Lopressor)

Selective beta1-adrenergic receptor blocker that decreases the automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG. Goal of treatment is to reduce heart rate to 60-90 beats/min.
Adult

5 mg slow IV infusion q5min; to a maximum dose of 15 mg or desired heart rate

Pediatric

Not established
Glycoprotein IIB/IIA inhibitors

Glycoprotein (GP) IIb/IIIa antagonists prevent the binding of fibrinogen, thereby blocking platelet aggregation. Studies to date suggest that as a class, the addition of intravenous GP IIb/IIIa inhibitors to aspirin and heparin improves both early and late outcomes, including mortality, Q-wave MI, need for revascularization procedures, and length of hospital stay. Currently, IIb/IIIb antagonists in combination with aspirin are considered standard antiplatelet therapy for patients at high risk for unstable angina. Adenosine diphosphate (ADP) antagonists are not considered standard therapy but may be used in patients unable to tolerate aspirin.
Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody. Binds to receptor with high affinity and reduces platelet aggregation by 80%. Inhibition of platelet aggregation persists for up to 48 h after end of infusion. Abciximab has been approved for use in elective/urgent/emergent percutaneous coronary intervention.
Adult

0.25 mg/kg bolus IV followed by an infusion of 0.125 mcg/kg/min; maximum 10 mcg/min for 12 h
Pediatric

Not established

Adenosine diphosphate receptor antagonists

Two thienopyridines, clopidogrel and ticlopidine, are ADP antagonists that are approved for antiplatelet activity. Both have irreversible antiplatelet activity but take several days to manifest. A potential additive benefit exists when ADP antagonists are used in conjunction with aspirin. These drugs may be considered alternatives to aspirin in patients intolerant or allergic to aspirin.

Clopidogrel (Plavix)

Generally preferred over ticlopidine because it more rapidly inhibits platelets and appears to have a more favorable safety profile.
Adult

300 mg PO loading dose, followed by 75 mg PO qd

Pediatric

Not established

Congestive Heart Failure and Pulmonary Edema

Introduction
Background

Congestive heart failure (CHF) is an imbalance in pump function in which the heart fails to adequately maintain the circulation of blood. The most severe manifestation of CHF, pulmonary edema, develops when this imbalance causes an increase in lung fluid secondary to leakage from pulmonary capillaries into the interstitium and alveoli of the lung. CHF can be categorized as forward or backward ventricular failure. Backward failure is secondary to elevated systemic venous pressure, whereas left ventricular failure is secondary to reduced forward flow into the aorta and systemic circulation. Furthermore, heart failure can be subdivided into systolic and diastolic dysfunction. Systolic dysfunction is characterized by a dilated left ventricle with impaired contractility, whereas diastolic dysfunction occurs in a normal or intact left ventricle with impaired ability to relax and receive as well as eject blood.

Chest radiograph shows signs of congestive heart failure (CHF). The New York Heart Association's functional classification of CHF is one of the most useful. Class I describes a patient who is not limited with normal physical activity by symptoms. Class II occurs when ordinary physical activity results in fatigue, dyspnea, or other symptoms. Class III is characterized by a marked limitation in normal physical activity. Class IV is defined by symptoms at rest or with any physical activity. Pathophysiology

Congestive heart failure (CHF) is summarized best as an imbalance in Starling forces or an imbalance in the degree of end-diastolic fiber stretch proportional to the systolic mechanical work expended in an ensuing contraction. This imbalance may be characterized as a malfunction between the mechanisms that keep the interstitium and alveoli dry and the opposing forces that are responsible for fluid transfer to the interstitium.

Maintenance of plasma oncotic pressure (generally about 25 mm Hg) higher than pulmonary capillary pressure (about 7-12 mm Hg), maintenance of connective tissue and cellular barriers relatively impermeable to plasma proteins, and maintenance of an extensive lymphatic system are the mechanisms that keep the interstitium and alveoli dry. Opposing forces responsible for fluid transfer to the interstitium include pulmonary capillary pressure and plasma oncotic pressure. Under normal circumstances, when fluid is transferred into the lung interstitium with increased lymphatic flow, no increase in interstitial volume occurs. However, when the capacity of lymphatic drainage is exceeded, liquid accumulates in the interstitial spaces surrounding the bronchioles and lung vasculature, thus creating CHF. When increased fluid and pressure cause tracking into the interstitial space around the alveoli and disruption of alveolar membrane junctions, fluid floods the alveoli and leads to pulmonary edema. Etiologies of pulmonary edema may be placed in the following 6 categories:
1. Pulmonary edema secondary to altered capillary permeability: Acute respiratory distress syndrome (ARDS), infectious causes, inhaled toxins, circulating exogenous toxins, vasoactive substances, disseminated intravascular coagulopathy (DIC), immunologic processes reactions, uremia, near drowning, and other aspirations 2. Pulmonary edema secondary to increased pulmonary capillary pressure: Cardiac causes and noncardiac causes, including pulmonary venous thrombosis, stenosis or veno-occlusive disease, and volume overload 3. Pulmonary edema secondary to decreased oncotic pressure found with hypoalbuminemia 4. Pulmonary edema secondary to lymphatic insufficiency 5. Pulmonary edema secondary to large negative pleural pressure with increased end expiratory volume 6. Pulmonary edema secondary to mixed or unknown mechanisms including high altitude pulmonary edema (HAPE), neurogenic pulmonary edema, heroin or other overdoses, pulmonary embolism, eclampsia, postcardioversion, postanesthetic, postextubation, and post cardiopulmonary bypass

This article is limited to cardiac causes of pulmonary edema and congestive heart failure (CHF) and its relevant emergency care.
Frequency United States

More than 3 million people have congestive heart failure (CHF), and more than 400,000 new patients present yearly. The prevalence rate of CHF is 1-2%.
Mortality/Morbidity

Approximately 30-40% of patients with congestive heart failure (CHF) are hospitalized every year. CHF is the leading diagnosis-related group (DRG) among hospitalized patients older than 65 years. The 5-year mortality rate after diagnosis was reported in 1971 as 60% in men and 45% in women. In

1991, data from the Framingham heart study showed the 5-year mortality rate for CHF essentially remaining unchanged, with a median survival of 3.2 years for males and 5.4 years for females. This may be secondary to an aging US population with declining mortality due to other diseases. The most common cause of death is progressive heart failure, but sudden death may account for up to 45% of all deaths. After auditing data on 4606 patients hospitalized with CHF between 1992-1993, the total in-hospital mortality rate was 19%, with 30% of deaths occurring from noncardiac causes. Patients with coexisting insulin-dependent diabetes mellitus have a significantly increased mortality rate.

Race

Blacks are 1.5 times more likely to die of CHF than whites are. Nevertheless, black patients appear to have similar or lower in-hospital mortality rates than white patients.

Sex

Prevalence is greater in males than in females in patients aged 40-75 years. No sex predilection is noted among patients older than 75 years.

Age

Prevalence of CHF increases with increasing age and affects about 10% of the population older than 75 years.

Clinical
History

Anxiety Dyspnea at rest Dyspnea upon exertion: This has been found to be the most sensitive symptom reported, yet the specificity for dyspnea is less than 60%. Orthopnea and paroxysmal nocturnal dyspnea (PND): These symptoms are observed; however, the sensitivity for orthopnea and PND is only 20-30%. Cough: Cough that produces pink, frothy sputum is highly suggestive of congestive heart failure (CHF). Edema Nonspecific symptoms o Weakness o Lightheadedness o Abdominal pain o Malaise o Wheezing o Nausea Past medical history o Cardiomyopathy o Valvular heart disease o Alcohol use

o o o o

Hypertension Angina Prior myocardial infarction Familial heart disease

Physical

Findings such as peripheral edema, jugular venous distention, and tachycardia are highly predictive of congestive heart failure (CHF). Overall specificity of physical examination has been reported at 90%; however, this same study reported a sensitivity of only 10-30%. Tachypnea, using accessory muscles of respiration, has been observed. Hypertension may be present. Pulsus alternans (alternating weak and strong pulse indicative of depressed left ventricle [LV] function) may be observed. The skin may be diaphoretic or cold, gray, and cyanotic. Jugular venous distention (JVD) is frequently present. Wheezing or rales may be heard on lung auscultation. Apical impulse is frequently laterally displaced. Cardiac auscultation may reveal aortic or mitral valvular abnormalities (S3 or S4). Lower extremity edema may also be noted, especially in the subacute process.

Causes

Various cardiac diseases cause congestive heart failure (CHF) and pulmonary edema. The most common cause of heart failure is coronary artery disease, which is secondary to loss of left ventricular muscle, ongoing ischemia, or decreased diastolic ventricular compliance. Other disease processes include hypertension, valvular heart disease, congenital heart disease, other cardiomyopathies, myocarditis, and infectious endocarditis. CHF is often precipitated by cardiac ischemia or dysrhythmias, cardiac or extracardiac infection, pulmonary embolus, physical or environmental stresses, changes or noncompliance with medical therapy, dietary indiscretion, or iatrogenic volume overload. One also must consider systemic processes such as pregnancy and hyperthyroidism as precipitants of CHF.

Workup
Laboratory Studies

Until recently, differentiating asthma and other pulmonary disease has been difficult in the acute setting, particularly because of the poor sensitivities and specificities of most elements of history and physical examination. The standard of care has been shotgun therapy, namely treating patients for both congestive heart failure (CHF) and an acute pulmonary process such as asthma, with both diuretics and beta-agonists. o The Breathing Not Properly Study has suggested that serum levels of beta-natriuretic peptide (BNP) and the BNP precursor, Pro-BNP, can

help identify CHF as the origin of acute dyspnea.1 This study found sensitivities of 90% with specificities of 76%. Positive predictive value was 79%, with a negative predictive value of 89%. Mueller et al found a reduction in hospital length of stay of 3 days when BNP levels were used.2 This study assumed an average length of stay of 11 days; however, the average length of stay in the United States for CHF exacerbations is approximately 4 days. Also, although the time to initiation of therapy was reduced in this study from 90 to 60 minutes, the general practice in the United States is immediate initiation of shotgun therapy. o In the primary care setting, Wright et al identified 305 patients with heart failure and then reevaluated them with or without the Pro-BNP result.3 Diagnostic accuracy improved from 52% to 60% without ProBNP and from 49% to 70% with Pro-BNP. o Maisel et al identified in the Breathing Not Properly Study a 20% increase in patients with CHF who presented with dyspnea and a history of asthma or COPD but no prior history of CHF.4 o Mueller et al found that BNP reduced time to discharge from 12 to 3 days and reduced costs of hospitalization by 15%.2 o BNP is available as a point-of-care test, with results available within 15 minutes; however, only Pro-BNP can be concomitantly used with nesiritide. o Serum levels of BNP lower than 100 pg/mL are unlikely to be from CHF. In the Breathing Not Properly Study, a BNP level of 50 pg/mL increased sensitivity from 90% to 97%, although specificity was reduced.1 levels of 100-500 pg/mL may be CHF. However, other conditions that also elevate right filling pressures (eg, pulmonary embolus, primary pulmonary hypertension, end-stage renal failure, cirrhosis, hormone replacement therapy) may also cause elevated BNP levels in this range. BNP levels more than 500 pg/mL are most consistent with CHF. o Steinhart et al derived and validated a diagnostic prediction model for acute heart failure that incorporates both clinical assessment and N-terminal pro-B-type natriuretic peptide (NT-proBNP).5 Variables used to predict acute heart failure were age, pretest probability, and log NT-proBNP. Validation of the model in 1073 patients showed that likelihood ratios for acute heart failure with NT-proBNP were 0.11 (95% confidence interval [CI], 0.06-0.19) for cut-point values less than 300 pg/mL, increasing to 3.43 (95% CI, 2.34-5.03) for values 2700-8099 pg/mL, and 12.80 (95% CI, 5.21-31.45) for values 8100 pg/mL or higher. When the model was applied to external data, 44% of patients who had been clinically classified as having intermediate probability of acute heart failure were appropriately reclassified to either low or high probability categories, with negligible (<2%) inappropriate redirection. Serum laboratory values may reveal prerenal azotemia or elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin levels, which is suggestive of a congestive hepatopathy. Cardiac enzymes and other serum markers for ischemia or infarction may also be useful. ABG levels may be of benefit in evaluation of hypoxemia, ventilation/perfusion (V/Q) mismatch, hypercapnia, and acidosis. Mild azotemia, decreased erythrocyte sedimentation rate (ESR), and proteinuria are observed in early and mild-to-moderate disease.

Increased creatinine levels, hyperbilirubinemia, and dilutional hyponatremia are observed in severe cases.

Imaging Studies

Chest radiography o Although diagnostic tests are of limited benefit in acute congestive heart failure (CHF), chest radiography is the most useful tool. A recent study showed that 1 out 5 patients admitted to the hospital with CHF lacked signs of congestion on chest radiograph.6 o Cardiomegaly may be observed with a cardiothoracic ratio greater than 50%. Pleural effusions may be present bilaterally or if they are unilateral more commonly observed on the right. o Early CHF may manifest as cephalization of pulmonary vessels, generally reflecting a pulmonary capillary wedge pressure (PCWP) of 12-18 mm Hg. As the interstitial fluid accumulates, more advanced CHF may be demonstrated by Kerley B lines (PCWP is 18-25 mm Hg). o Pulmonary edema is observed as perihilar infiltrates often in the classic butterfly pattern, reflecting a PCWP of more than 25 mm Hg. o Several limitations to chest radiography are observed when attempting to diagnose CHF. Classic radiographic progression is often not found, and as much as a 12-hour radiographic lag from onset of symptoms may occur. In addition, radiographic findings frequently persist for several days despite clinical recovery. Emergency transthoracic echocardiography o Emergency transthoracic echocardiography (ECHO) may help identify regional wall motion abnormalities as well as globally depressed or myopathic left ventricular function. o ECHO may help reveal cardiac tamponade, pericardial constriction, and pulmonary embolus. o ECHO is also useful in revealing valvular heart disease, such as mitral or aortic stenosis or regurgitation.

Other Tests

ECG is a nonspecific tool but may be useful in diagnosing concomitant cardiac ischemia, prior myocardial infarction (MI), cardiac dysrhythmias, chronic hypertension, and other causes of left ventricular hypertrophy.

Procedures

No defined role is recognized for invasive monitoring devices such as central venous placement (CVP) lines. Time-consuming placement of pulmonary artery catheters has not been shown to prolong survival, even in the coronary care unit and, thus far, has not been well studied in the emergency department (ED) setting. Cardiac catheterization may be necessary for a complete evaluation and assessment of prognosis.

Treatment
Prehospital Care

Prehospital notification by emergency medical services (EMS) personnel should alert ED staff of a patient presenting with signs and symptoms of congestive heart failure (CHF) and pulmonary edema. They should receive online medical advice for patients with high-risk presentations. Begin treatment with the ABCs. Administer supplemental oxygen, initially 100% nonrebreather facemask. Use cardiac monitoring and continuous pulse oximetry. Obtain intravenous access, as well as a prehospital ECG, if available. Provide nitroglycerin sublingual or spray for active chest pain in the patient without severe hypotension and intravenous furosemide.

Emergency Department Care

Begin ED treatment of a patient presenting with signs and symptoms of congestive heart failure (CHF) and pulmonary edema with the ABCs. Administer supplemental oxygen, initially 100% nonrebreather facemask. Use cardiac monitoring and continuous pulse oximetry. Obtain intravenous access. To reduce venous return, elevate the head of the bed. Patients may be most comfortable in a sitting position with their legs dangling over the side of the bed, which allows for reduced venous return and decreased preload. Therapy generally starts with nitrates and diuretics if patients are hemodynamically stable. Many other treatment modalities may play some role in acute management. If possible, treat the underlying cause as well, if identified. This is particularly necessary for patients with known diastolic dysfunction who respond best to reductions in blood pressure, rather than to diuretics, nitrates, and inotropic agents. Serum BNP levels may be very useful in the setting of undifferentiated dyspnea, or in the future may be useful to gauge therapeutic success. Eliminate contributing factors when possible. Restrict fluid and sodium. Consider other treatment modalities, including nesiritide. Nesiritide may be useful in lieu of nitroglycerin in patients with moderate respiratory distress, particularly if the patient will not tolerate noninvasive ventilation or in the patient who cannot have nitroglycerin by protocol (ie, in an observation unit). o Data comparing nasal CPAP therapy and facemask ventilation therapy have demonstrated decreased need for intubation rates when these modalities are used.7 However, in patients with severe CHF treated with CPAP, no significant difference was found in shortterm mortality rates and length of hospital stay. Although BiPAP therapy may improve ventilation and vital signs more rapidly than CPAP, a higher incidence of MI associated with BiPAP has been reported. BiPAP and CPAP are contraindicated in the presence of acute facial trauma, the absence of an intact airway, and in patients with an altered mental status or who are uncooperative.

Alternating tourniquets, formerly a mainstay of therapy, have been used to decrease preload. Their use has been supplanted by newer therapies such as intravenous nitroglycerin and nitroprusside. Phlebotomy with removal of 500 mL of blood or via plasmapheresis is another former mainstay of therapy used to decrease preload. Its use has been supplanted by newer therapies such as intravenous nitroglycerin and nitroprusside.

Consultations

Cardiologist Critical care specialist Cardiothoracic surgeon, for possible heart valve surgery or transplantation

Medication
The goal of pharmacotherapy is to achieve a PCWP of 15-18 mm Hg and a cardiac index of more than 2.2 L/min/m2 while maintaining adequate blood pressure and perfusion to essential organs. These goals may need to be modified for some patients. Use of diuretics, nitrates, analgesics, and inotropic agents are indicated for the treatment of congestive heart failure (CHF) and pulmonary edema. Calcium channel blockers, such as nifedipine and nondihydropyridines, increase mortality and increase prevalence of recurrent CHF with chronic use. Conflicting evidence currently argues both in favor of and against the use of calcium channel blockers in the acute setting; at this time, limit their acute use to patients with diastolic dysfunction and heart failure, a condition not easily determined in the emergency department. ACE inhibitors, such as sublingual (SL) captopril or intravenous enalapril, may rapidly reverse hemodynamic instability and symptoms, possibly avoiding an otherwise imminent intubation. Haude et al compared 25 mg of SL captopril with 0.8 mg of sublingual nitroglycerin in 24 patients with class III and class IV CHF and found that captopril induces a more sustained and more pronounced improvement in hemodynamics.8 Annane et al gave 1 mg of intravenous enalapril to 20 patients presenting with acute class III and class IV CHF over 2 hours and reported rapid hemodynamic improvement with no significant adverse effects on cardiac output or hepatosplanchnic measurements.9 Captopril may play a unique role in sustaining patients with renal failure and concomitant acute CHF while awaiting definitive therapy with dialysis. Because the information on this subject is still controversial and is limited to small studies, the routine use of ACE inhibitors cannot be recommended at this time. ACE inhibitors remain a promising area in need of further study. Beta-blockers, possibly by restoring beta-1 receptor activity or via prevention of catecholamine activity, appear to be cardioprotective in patients with depressed left ventricular function. The US Carvedilol Heart Failure study group demonstrated a two-thirds decrease in mortality in patients taking carvedilol with left ventricular ejection fractions of 35% or less. Beta-blockers, particularly carvedilol, have been shown to improve symptoms in patients with moderate-tosevere heart failure. However, the role of beta-blockers in the acute setting is currently unclear; limit use until hemodynamic studies indicate that further deterioration is not possible.

Because differentiating CHF and asthma exacerbations is often difficult, treating both with the shotgun approach is often used, particularly as both may cause bronchospasm. Aerosolized beta-2 agonists, which are the more selective of beta-agonists, decrease tachycardia, dysrhythmias, and cardiac work while transiently enhancing cardiac function. Terbutaline has been shown to be successful in this setting, as well as albuterol, isoetharine, and bitolterol. Limit roles of theophylline and aminophylline in the acute setting. They are positive inotropic agents mediated by an increase in catecholamines, and they dilate coronaries and exert mild diuretic effects. Nevertheless, they can exacerbate dysrhythmias (eg, multifocal atrial tachycardia [MAT], ischemia) by increasing cardiac work. Steroids, intravenous or orally administered, have been shown to worsen preexisting heart failure due to systemic sodium retention and volume expansion, hypokalemia, and occasional hypertension. Inhaled steroids, because of their lack of systemic side effects, may be a reasonable option in this confusing patient presentation; however, given their delayed onset of action, they remain an area in need of further study. Please see the article on Asthma for dosing schedules.
Diuretics

First-line therapy generally includes a loop diuretic such as furosemide, which inhibits sodium chloride reabsorption in the ascending loop of Henle.

Furosemide (Lasix)

Administer loop diuretics IV because this allows for both superior potency and higher peak concentration despite increased incidence of side effects, particularly ototoxicity.
Adult

A reasonable approach for furosemide might be as follows: 10-20 mg IV for patients symptomatic with CHF not already using diuretics 40-80 mg IV for patients already using diuretics 80-120 mg IV for patients whose symptoms are refractory to the initial dose after 1 h of its administration Higher doses and more rapid redosing may be appropriate for the patient in severe distress
Pediatric

Not established
Nitrates

These agents reduce myocardial oxygen demand by lowering preload and afterload. In patients with severe hypertension, nitroprusside causes more arterial dilatation than nitroglycerin. Nevertheless, due to thiocyanate toxicity and the coronary steal phenomenon

associated with nitroprusside, intravenous nitroglycerin is still the therapy of choice for afterload reduction.

Nitroglycerin (Nitro-Bid, Nitrol, Nitrostat)

SL nitroglycerin and nitrospray are particularly useful in patients who present with acute pulmonary edema with a systolic blood pressure of at least 100 mm Hg. Similar to SL, nitrospray's onset is 1-3 min with a half-life of 5 min. Applicability of nitrospray may be easier, and storage is up to 4 y. One study reported significant and rapid hemodynamic improvement in 20 patients given nitrospray with pulmonary edema in an ICU setting. Topical nitrate therapy is reasonable in a patient presenting with class I to II CHF. However, in patients with more severe signs of heart failure or pulmonary edema, IV nitroglycerin is preferred because it is easier to monitor hemodynamics and absorption, particularly in the patients with diaphoresis. Because of delayed absorption, PO nitrates have little role in the acute presentations of CHF.
Adult

Nitrospray: Single spray (0.4 mg) equivalent to a single 1/150 SL; may repeat q3-5min as hemodynamics permit, up to a maximum of 1.2 mg Ointment: Apply 1-2 inches of nitropaste to chest wall Injection: Start at 20 mcg/min IV and rate to effect in 5-10 mcg increments q3-5min
Pediatric

Not established
Analgesics

Intravenous morphine is an excellent adjunct in acute therapy. In addition to being both an anxiolytic and an analgesic, its most important effect is venodilation, which reduces preload. This agent also causes arterial dilatation, which reduces systemic vascular resistance (SVR) and increases cardiac output. Narcan can also reverse the effects of morphine. However, some evidence indicates that morphine use in acute pulmonary edema may increase the intubation rate.

Morphine sulfate (Duramorph, Astramorph, MS Contin)

DOC for narcotic analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in numerous ways and is commonly titrated until desired effect is obtained.

Adult

2-5 mg IV and repeated q10-15min unless respiratory rate is <20 breaths/min or systolic blood pressure is <100 mm Hg
Pediatric

Not established
Inotropic agents

Principal inotropic agents include dopamine, dobutamine, inamrinone (formerly amrinone), milrinone, dopexamine, and digoxin. In patients with hypotension presenting with CHF, dopamine and dobutamine are usually used. Inamrinone or milrinone inhibits phosphodiesterase, resulting in an increase of intracellular cyclic adenosine monophosphate (AMP) and alteration in calcium transport. As a result, they increase cardiac contractility and reduce vascular tone by vasodilatation. Dopexamine is a new synthetic catecholamine with beta-2 and dopaminergic properties that cause vasodilation and increased inotropism but with tachycardia as well. Dopexamine may ultimately have a role as an emergent inotropic agent; however, dobutamine is probably the current agent of choice. Digoxin has no role in the emergency management of CHF due to delayed absorption and diminished efficacy at times of increased sympathetic tone. Thus, digoxin has little, if any, benefit in patients who present with atrial fibrillation and rapid ventricular response. Limit use of digoxin to chronic CHF, in which its role has been well established. These agents augment both coronary and renal blood flow.

Dopamine (Intropin)

Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effects depend on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation is produced by higher doses. Positive inotropic agent at 2-10 mcg that can lead to tachycardia, ischemia, and dysrhythmias. Doses >10 mcg cause vasoconstriction, which increases afterload.
Adult

5 mcg/kg/min IV and increase at 5 mcg/kg/min increments to a 20 mcg/kg/min dose

Pediatric

Not established

Angina Pectoris
Introduction
Background

Angina pectoris (AP) represents the clinical syndrome occurring when myocardial oxygen demand exceeds supply. The term is derived from Latin; the literal meaning is "the choking of the chest;" angere, meaning "to choke" and pectus, meaning "chest." The first English-written account of recurrent angina pectoris was by English nobleman Edward Hyde, Earl of Clarendon. He described his father as having, with exertion, "a pain in the left armso much that the torment made him pale".1 The first description of angina as a medical disorder came from William Heberden. Heberden, a prodigious physician, made many noteworthy contributions to medicine during his career. He presented his observations on "dolor pectoris" to the Royal College of Physicians in 1768. Much of his classic description retains its validity today.2 Angina pectoris has a wide range of clinical expressions. The symptoms most often associated to angina pectoris are substernal chest pressure or tightening, frequently with radiating pain to the arms, shoulders, or jaw. The symptoms may also be associated with shortness of breath, nausea, or diaphoresis. Symptoms stem from inadequate oxygen delivery to myocardial tissue. No definitive diagnostic tools that capture all patients with angina pectoris exist. This, combined with its varied clinical expression, makes angina pectoris a distinct clinical challenge to the emergency physician. The disease state can manifest itself in a variety of forms:

Stable angina pectoris is classified as a reproducible pattern of anginal symptoms that occur during states of increased exertion. Unstable angina pectoris (UA) manifests either as an increasing frequency of symptoms or as symptoms occurring at rest. Prinzmetal angina or variant angina occurs as a result of transient coronary artery spasms. These spasms can occur either at rest or with exertion. Unlike stable or unstable angina, no pathological plaque or deposition is present within the coronary arteries that elicits the presentation. On angiography, the coronary arteries are normal in appearance with spasm on angiography. Cardiac syndrome X occurs when a patient has all of the symptoms of angina pectoris without coronary artery disease or spasm.

Pathophysiology The past 2 decades has greatly expanded our overall understanding of the pathophysiology of myocardial ischemic syndromes. The primary dysfunction in angina pectoris is decreased oxygen delivery to myocardial muscle cells. The 2 predominant mechanisms by which delivery is impaired appear to be coronary artery narrowing and endothelial dysfunction. Any other mechanism that affects oxygen delivery can also precipitate symptoms.

Extracardiac causes of angina include, but are by no means limited to, anemia, hypoxia, hypotension, bradycardia, carbon monoxide exposure, and inflammatory disorders.3 The end result is a shift to anaerobic metabolism in the myocardial cells. This is followed by a stimulation of pain receptors that innervate the heart. These pain receptors ultimately are referred to afferent pathways, which are carried in multiple nerve roots from C7 through T4. The referred/radiating pain of angina pectoris is believed to occur because these afferent pathways also carry pain fibers from other regions (eg, the arm, neck, and shoulders). Coronary artery narrowing Coronary artery narrowing appears to be the etiology of cardiac ischemia in the preponderance of cases. This has clinical significance when atherosclerotic disease diminishes or halts blood flow through the coronary arterial circulation, interfering with normal laminar blood flow. The significance of even a small change in the diameter of a blood vessel can be profound. The Poiseuille law predicts this outcomethe rate of flow is decreased exponentially by any change in the radius of the lumen. As with a smaller pediatric airway, even relatively minute changes in diameter have dramatic consequences in flow rates. Thus, when a lumen is narrowed by one fifth, the flow rate is decreased by about one half. This predicts that even a small change in a coronary artery plaque size can affect the oxygenation through that vessel's territory. The epicardial vessel, where atherosclerosis often takes place, has the capacity to dilate via autoregulatory mechanisms to respond to increased demand. Angina occurs as this compensatory mechanism is overwhelmed either by large plaques (typically considered 70% or greater obstruction) or by significantly increased myocardial demand.4 Endothelial factors Endothelial factors also play an important role in angina pectoris. During sympathetic stimulation, the endothelium is subjected to mediators of both vasoconstriction and vasodilatation. Alpha-agonists (catecholamines) directly cause vasoconstriction, while endothelial nitrous oxide synthase creates nitrous oxide (NO), which counteracts this constricting force via vasodilatation. In the diseased coronary artery, NO production is reduced or absent. In this setting, the catecholamine drive can overwhelm the autoregulatory mechanisms. In addition, the endothelium of the plaque-laden artery may, in itself, be dysfunctional. This limits the ability of the intra-arterial endothelium to produce mediators, which, in a healthy artery, would protect against further vasoconstriction, assist dilatation, and provide protection from platelet aggregation. Small lesions in these vessels may produce incompletely obstructing aggregates of platelets. This would further impede flow through the affected vessel.4 In the diseased heart, these 2 factors, coronary artery narrowing and endothelial dysfunction, synergistically result in reduced oxygen delivery to the myocardium. The net result is angina pectoris. Extrinsic factors Extrinsic factors can also play a role in specific circumstances. The oxygen-carrying capacity of blood is based on a number of factors. The most important of which is the amount of

hemoglobin. Any alteration in the ability of blood to carry oxygen can precipitate angina. Anemia of any degree can result in anginal symptoms. Given a scenario where demand is increased, such as climbing a flight of stairs, increased stress, or even sexual intercourse, the anginal symptoms may appear.5 Abnormal hemoglobin, such as methemoglobin, carboxyhemoglobin, or any of a number of hemoglobinopathies, creates an environment at greater risk for precipitating angina. Other extrinsic factors that affect hemoglobin formation, such as lead poisoning or irondeficiency states, also lead to a similar decrease in oxygen-carrying capacity. Any mechanism that impedes oxygen delivery to the red blood cells has a similar effect. Therefore, any number of pulmonary causes, such as pulmonary embolism, pulmonary fibrosis or scarring, pneumonia, or congestive heart failure, can exacerbate angina. A decreased oxygen environment, such as travel to a higher elevation, has similar consequences due to the decrease in concentration of atmospheric oxygen. Variant angina The etiology of variant angina is currently not well understood. Research suggests that inflammatory mediators may result in focal coronary artery vasospasm. Another possibility is that perfusion is decreased through microvascular circulation. Spasm or intermittent narrowing of this microscopic lumen may result in transient areas of hypoperfusion and oxygen deprivation.6 Syndrome X Syndrome X is the triad of angina pectoris, a positive ECG stress test result, and a normal coronary angiogram. The pathophysiology of this disease is not well understood. Many theories exist as to the underlying pathology. Decreased oxygenation of the underlying myocardium may be the result of impaired vasodilatation, dysfunctional smooth muscle cells, poor or deficient microvascular circulation, or even structural problems on a cellular level (eg, an inappropriately functioning sodium ion channel).6
Frequency United States

An estimated 6,500,000 people in the United States experience angina pectoris. Each year, 400,000 new cases of angina pectoris develop. Conservative 2006 data show 733,000 acute coronary syndrome (ACS) discharges from hospitals.7
Mortality/Morbidity

In 2005, 1 in 5 deaths is from coronary heart disease (both angina and myocardial infarction). Coronary heart disease is the single greatest killer of American men and women.7

The estimated direct and indirect cost for Americans with coronary heart disease in 2006 was $142.5 billion.
Race

The Centers for Disease Control and Prevention (CDC) note that the prevalence of angina and/or coronary heart disease is highest and increasing in Hispanics followed by whites and black non-Hispanics (5%, 4.2%, 3.7%, respectively). This information includes the 50 US states, the District of Columbia, Puerto Rico, and the US Virgin Islands.8 7
Sex

Among Americans aged 40-74 years, the age-adjusted prevalence of angina pectoris (AP) was higher among women than men.7 Although 2005 CDC data suggest that men (5.5%) have a higher prevalence of angina and/or coronary heart disease than women (3.4%).8
Age

The incidence of new and recurrent angina increases with age but then declines at around 85 years. Statistics from American Heart Association (2008 Data) and Centers for Disease Control and Prevention.

Clinical
History

Classically, angina presents as substernal chest discomfort that occurs with exertion, but it also may occur at rest. The discomfort is frequently described as a pressure or heaviness. Other commonly used adjectives for anginal pain include dull, aching, or squeezing. Pain may radiate to one or both arms, to one or both shoulders, or to the neck or jaw. Symptoms are highly variable. The entity cannot be expected to present with the classic triad of chest pressure with exertion radiating to the left arm. The diversity of disease expression is likely related to a patient's age, sex, race, and culture. The caveat is to have a high index of suspicion for the disease. Many factors influence the expression of anginal symptoms. Familiar terms such as anginal equivalent and atypical chest pain are frequently used in these cases. In addition, systemic diseases, such as diabetes mellitus or chronic pain syndromes, may alter presenting anginal symptoms; while other diseases, such as prior cerebral vascular accident or dementia, may limit the patient's reporting of symptoms. A pain-free variant of anginasometimes referred to as silent chest painalso exists. These patients can present with complaints of shortness of breath, nausea, altered mentation, or abdominal pain.9

Chest discomfort quality o Pain o Pressure o Squeezing o Dullness

Burning Heaviness Absent chest discomfort (eg, dyspnea, vomiting, altered sensorium) Location (often diffuse to any location of C7-T4 dermatomes) o Retrosternal or substernal o Inframammary o Left sided o Right sided o Upper abdominal o Shoulder, neck, arm o Teeth, jaw, lower face (above C7 unclear etiology) o Back, scapular region Radiation o Unilateral or bilateral arms o Unilateral or bilateral shoulders o Back o Neck o Jaw, ear, or lower face Temporal o Onset to maximum discomfort is progressive. With exertion (with or without increasing frequency) At rest o Alleviation to relief is progressive. o Alleviation mediators Oxygen Nitroglycerin Reduction of stressful activity Pain medication Placebo effect (eg, "GI cocktail") Severity o Mild to severe (1/10 to >10/10) o "Like my heart pain" - Patients in the emergency department (ED) may refer to the pain as being consistent with prior heart pains.
o o o

Physical

The physical examination may reveal signs of a hyperadrenergic state. One might observe tachycardia, tachypnea, hypertension, and/or diaphoresis. In addition, ischemia may lead to the presence of crackles due to the loss in contractility with subsequent pulmonary edema or a reduction in the S1 intensity.10 That said, no definitive examination findings suggest angina. Much of the information obtained from the physical examination may suggest other comorbidities that place the patient at higher risk for anginal symptoms (eg, chronic obstructive pulmonary disease [COPD], tachycardia, pale conjunctiva). Therefore, the physical examination is necessary to qualify the patient's current physical state and comorbidities. In this manner, the emergency physician obtains a baseline physical examination. Also, as mentioned, comorbid illnesses that affect the patient's level of cardiac, pulmonary, and circulatory function can be assessed. As with many presentations to the emergency department, the physical examination in angina pectoris also serves as a marker for response to therapy. Important comorbidities that can be identified on physical examination include aortic stenosis, gastrointestinal bleeding, and airway

obstruction. Unfortunately, no examination findings are pathognomonic for angina pectoris. In addition, no physical examination findings rule out the disease state. Of note, while the reproducibility of chest wall pain with palpation may lower the likelihood of angina, this alone cannot rule out angina or myocardial infarction.11,12

Workup
Laboratory Studies

CBC (anemia, leukocytosis may suggest an alternative diagnosis) BUN and creatinine level, if intravenous contrast is anticipated Electrolyte levels are of virtually no value unless the patient is on a diuretic and concern for an abnormality exists. Cardiac enzyme levels, if positive may suggest nonST-segment elevation myocardial infarction (NSTEMI); negative results do not rule out ischemia Coagulation studies, if anticoagulation or antiplatelets are anticipated Type and screen, if surgery or transfusions are considered

Imaging Studies

Chest radiography is used to rule out an alternative diagnosis or contributing factors (eg, pneumothorax [PTX], pneumonia [PNA], congestive heart failure); it is also used to evaluate the aorta prior to anticoagulant administration. CT of the chest may be considered for evaluation of aortic or pulmonary disease; if evaluating the aorta, include the abdominal aorta. Of note, the forthcoming "triple rule out CT scan" exposes the patient to an exorbitantly high dose of radiation and should only be used in certain circumstances. Limited CT coronary scans may help to reduce the posttest probability of coronary artery disease while utilizing potentially less radiation exposure than the "triple rule out scan." Coronary artery calcification suggests the presence of an atherosclerotic plaque. Calcium scores are determined by the density of calcium and the total area. Higher calcium scores may suggest a higher risk of current or future adverse cardiac events. Multiple sites are currently conducting trials to see if this modality will benefit patients in the emergency department. Bamberg et al found that, in patients with acute chest pain and an inconclusive initial evaluation (nondiagnostic electrocardiographic findings, negative cardiac biomarkers), age and gender can serve as simple criteria to select patients who would derive the greatest diagnostic benefit from coronary computed tomographic angiography (CTA).13 In an observational cohort study in 368 low-risk patients, positive findings on 64-slice coronary CTA led to restratification to high risk, and negative findings led to restratification to very low risk, in men younger than 55 years and women younger than 65 years. In contrast, in women older than 65 years and men older than 55 years, a negative result on CTA did not result in restratification to a low-risk category. Nuclear imaging o V/Q (PE evaluation) o Resting Sestamibi (In the appropriate clinical setting, a normal study in a patient with ongoing chest pain may rule out myocardial ischemia.14 )

ECG Results may be normal or show signs of ischemia. Main use is to establish a baseline and R/O acute ST-segment elevation myocardial infarction (STEMI). Intraluminal coronary artery sonography (ICAS) is a highly invasive modality that may provide additional information to a patient's coronary artery anatomy and disease. Coronary atherosclerosis, which does not result in coronary artery narrowing, may be missed by conventional forms of coronary angiography. If clincially suspected, ICAS may be utilized to detect the presence or absence of such lesions. ICAS is not readily available; as such, it is highly unlikely that ICAS will be utilized from the emergency department in the foreseeable future.
o o

Treatment
Prehospital Care

Often, patients with angina pectoris rest or lie down to alleviate the pain. If the patient is not naive to cardiac disease, he or she may have access to nitroglycerin. Often, the patient uses nitroglycerin at home to palliate his or her symptoms. A patient who has known stable angina often is able to report what exacerbates the condition and what (as well as how often) is a "normal" number of tablets for him or her to use prior to alleviation of anginal symptoms. Patients are often instructed by their physicians that the use of more than 3 tablets of nitroglycerin necessitates a higher level of care (eg, calling for an ambulance). Some patients are instructed to take aspirin as well. A knowledgeable patient who reports a change in the pattern or presentation of his or her symptoms should be suspected as having worsening or unstable angina. However, any patient who presents to the ED with symptoms of angina should be assessed promptly for signs of acute myocardial infarction (AMI). Most prehospital care for angina pectoris consists of administering nitroglycerin, oxygen, and aspirin. The ability to obtain a prehospital ECG is becoming more prevalent.
Emergency Department Care

In the ED, the patient who complains of chest discomfort needs to be immediately assessed for AMI as well as other high-risk diagnoses (eg, aortic dissection, pulmonary embolism). Vital in this assessment is an early ECG and a rapid history and physical examination. Should this initial encounter not reveal a definitive diagnosis, then a more focused history and physical examination needs to be performed. Serial ECGs, especially in the setting of changing symptoms, is imperative. Labeling the ECGs with the patient's level of pain is often useful. A consecutive series of ECGs taken when a patient is having "10/10" pain, "3/10" pain, and "0/10" pain may yield valuable information that would not be readily apparent with an isolated cardiogram. Continuous telemetry monitoring is recommended for higher-risk patients.15

The patient who presents with chest pain is presumed to have underlying clinically significant cardiac pathology (ie, unstable angina or NSTEMI). The initial treatment consists of administration of oxygen, aspirin, nitroglycerin, morphine, and a beta-blocker. Given an altered, yet nondiagnostic ECG and no contraindications, further treatment with heparin (low-molecular weight or unfractionated), clopidogrel, or other antiplatelet agents may be initiated. Most often, an additional

abnormal marker (eg, an elevated serum troponin, myoglobin, or CPK level) will be verified prior to antiplatelet therapy. For persistent symptoms unresponsive to initial therapy, glycoprotein inhibitors can be considered. These appear to demonstrate an additional benefit in the patient population who will be undergoing cardiac catheterization (PCI).16 Persistent pain, in spite of this treatment, suggests either AMI or an alternative diagnosis. In the case of AMI, angioplasty or thrombolytics should be administered if available and not contraindicated. The American College of Cardiology offers an excellent evidenced-based online treatment resource (see American College of Cardiology Clinical Statements/Guidelines). Atypical presentations of angina, unfortunately, are often diagnosed retrospectively. This subset of patients is identified either when their condition progresses to STEMI or through elevated serum marker levels or cardiac dysrhythmia (often ventricular tachycardia or fibrillation). It cannot be understated that the variance of expression of angina pectoris makes it imperative that the clinician have a high level of suspicion for the disease. Little value exists in relying on a constancy of expression or on ECG, history, or physical examination alone for making the diagnosis. Angina pectoris should be considered as well as an extensive differential diagnosis, in just about any patient who presents to the ED with chest pain with or without other nonspecific complaints. Syndrome X and Prinzmetal angina are not diagnosed in the ED, but the patient's medical records or primary care physician may be helpful in recognizing these disorders. Admission is indicated for patients with unstable angina.

Consultations

In the setting of unstable angina or AMI, consultation with a cardiologist is warranted.

Medication
The goal of all of the following medications is either to improve myocardial oxygen and glucose supply or to reduce myocardial oxygen and glucose demand. The use of thrombolytics in unstable angina and NSTEMI are not useful and potentially harmful. They should be reserved for use in STEMI when indicated.17 (For more information, see American College of Cardiology Clinical Statements/Guidelines.)
Anti-platelet agents

These agents inhibit platelet aggregation.

Aspirin (Anacin, Bayer Aspirin, Ascriptin)

Aspirin inhibits platelet cyclooxygenase-1, which blocks the formation of thromboxane A2, thus inhibiting platelet aggregation. Aspirin is arguably the most cost-effective medication in medicine.

Adult

81-325 mg PO qd
Pediatric

Not established
Clopidogrel (Plavix)

Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. May have a positive influence on several hemorrhagic parameters and may exert protection against atherosclerosis not only through inhibition of platelet function but also through changes in the hemorrhagic profile. May have additive effect when used in combination with aspirin. Useful alternative therapy in patients with a salicylate allergy.
Adult

75 mg PO qd
Pediatric

Not established
Vasodilators

These agents relieve chest discomfort by improving myocardial oxygen supply, which, in turn, dilate epicardial and collateral vessels, improving blood supply to the ischemic myocardium.

Nitroglycerin (Nitro-Bid, Deponit)

Reduces preload and ventricular pressures, thus reducing myocardial oxygen demand. NTG also promotes coronary vasodilatation, which promotes improved myocardial blood flow. Reflex tachycardia may be harmful, concomitant beta-blocker usage may offset this reaction.
Adult

400 mcg SL or spray q5min, repeated up to 3 times If symptoms persist, administer 5-10 mcg/min IV infusion Titrate dose to reduce MAP by 10%, relieve symptoms, limit adverse effects of hypotension (>30% reduction in MAP or <90 mm Hg systolic), or relieve intolerable headache

Pediatric

Not established
Analgesics

These agents reduce pain, which decreases sympathetic stress, in addition to providing some preload reduction.

Morphine sulfate (Astramorph, MS Contin, MSIR)

Reduces pain and possibly anxiety associated with angina pectoris. Use judiciously in setting of hypotension.
Adult

2-4 mg IV q5-15min; titrate to symptomatic relief or adverse effects (eg, lethargy, hypotension, respiratory depression)
Pediatric

Not established
Beta-adrenergic blockers

This category of drugs has the potential to suppress ventricular ectopy due to ischemia or excess catecholamines. In the setting of myocardial ischemia, beta-blockers have antiarrhythmic properties and reduce myocardial oxygen demand, secondary to elevations in heart rate and inotropy.

Metoprolol (Lopressor, Toprol XL)

These agents decrease myocardial oxygen demand by reducing heart rate, contractility, and arterial pressure. Shown to improve survival in patients with MI.
Adult

5 mg slow IV infusion q5min to maximum dose of 15 mg or desired heart rate

Pediatric

Not established

Calcium channel blockers

When beta-blockade is contraindicated in the setting of continuing angina, a nondihydropyridine calcium antagonist (eg, verapamil, diltiazem) may be used as initial therapy in the absence of severe LV dysfunction or other contraindications (see ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/NonST-Elevation Myocardial Infarction). Though controversial, long-acting nifedipine may have some benefit in stable angina.18

Verapamil (Calan SR, Covera-HS, Verelan)

During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
Adult

240-480 mg/d PO divided tid/qid

Pediatric

Not established
Anticoagulants

Anticoagulants interfere with platelet aggregation and clot formation thus reducing arterial clot burden and promoting continued myocardial oxygen and glucose delivery. These agents do not digest present clots, they help prevent secondary formation during and after spontaneous fibrinolysis. Often, the decision of when and which anticoagulant to use is decided jointly by the emergency physician and cardiologist.

Heparin

Unfractionated heparin potentiates the effect of antithrombin, an enzyme that inactivates factors IIa, IXa, and Xa. This leads to an anticoagulant effect. Because of a relatively narrow therapeutic window, laboratory monitoring is required.
Adult

Typically provided as initial bolus, followed by continuous drip; bolus and drip rate are both dependent on weight of patient and other factors; these rates are often protocol driven at each institution
Pediatric

Not established

Platelet aggregation inhibitors

These agents block the GP IIb/IIIa receptor on platelets. Once the platelet is activated, these receptors change configuration, facilitating fibrinogen and ligand binding. GP IIb/IIIa receptor binding of fibrinogen is the final step leading to platelet aggregation. Thus, these agents stymie platelet aggregation.

Abciximab (ReoPro)

Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent percutaneous coronary intervention. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion.
Adult

0.25 mg/kg IV bolus, followed by 0.125 mcg/kg/min infusion for 12 h; not to exceed 10 mcg/min
Pediatric

Not established
Oxygen

Promotes a higher PaO2, thus improving myocardial oxygen delivery

Adult

2-4 L/nasal cannula, increase prn

Pediatric

None

Heart Failure
Introduction
Background

Heart failure is a syndrome manifesting as the inability of the heart to fill with or eject blood due to any structural or functional cardiac conditions.1 Heart failure may be caused by myocardial failure but may also occur in the presence of nearnormal cardiac function under conditions of high demand. Heart failure always causes circulatory failure, but the converse is not necessarily the case because various noncardiac conditions (eg, hypovolemic shock, septic shock) can produce circulatory failure in the presence of normal, modestly impaired, or even supranormal cardiac function. In terms of incidence, prevalence, morbidity, and mortality, the epidemiologic magnitude of heart failure (HF) is staggering. According to the American Heart Association, heart failure is a condition that affects nearly 5.7 million Americans of all ages and is responsible for more hospitalizations than all forms of cancer combined. It is the number 1 cause for hospitalization among Medicare patients. With improvement in survival of acute myocardial infarctions and a population that continues to age, heart failure will continue to increase in prominence as a major health problem in the United States. For additional resources, please visit Medscapes Heart Failure Resource Center.
Pathophysiology Regardless of the precipitating event, the common pathophysiologic state that perpetuates the progression of heart failure is extremely complex. Compensatory mechanisms exist on every level of organization from sub-cellular all the way through organ-to-organ interactions. Only when this network of adaptations becomes overwhelmed does heart failure ensue. In this section, we focus on those adaptations that represent significant therapeutic targets in the treatment of heart failure.

Most important among these adaptations are the (1) Frank-Starling mechanism, in which an increased preload helps to sustain cardiac performance; (2) alterations in myocyte regeneration and death; (3) myocardial hypertrophy with or without cardiac chamber dilatation, in which the mass of contractile tissue is augmented; and (4) activation of neurohumoral systems, especially the release of norepinephrine by adrenergic cardiac nerves, which augments myocardial contractility and includes activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), and other neurohumoral adjustments that act to maintain arterial pressure and perfusion of vital organs. In acute heart failure, the finite adaptive mechanisms that may be adequate to maintain the overall contractile performance of the heart at relatively normal levels become maladaptive when trying to sustain adequate cardiac performance.

The primary myocardial response to chronic increased wall stress is myocyte hypertrophy, death/apoptosis, and regeneration.2 This process eventually leads to remodeling, usually the eccentric type. Eccentric remodeling further worsens the loading conditions on the remaining myocytes and perpetuates the deleterious cycle. The idea of lowering wall stress to slow the process of remodeling has long been exploited in treating heart failure patients.3 However, the concept of the heart as a self-renewing organ is a relatively recent development.4 The rate of myocyte turnover has been shown to increase during times of pathologic stress.2 In heart failure, this mechanism for replacement becomes overwhelmed by an even faster increase in the rate of myocyte loss. This imbalance of hypertrophy and death over regeneration is the final common pathway at the cellular level for the progression of remodeling and heart failure. This new paradigm for myocyte biology has created an entire field of research aimed directly at augmenting myocardial regeneration. The reduction of cardiac output following myocardial injury sets into motion a cascade of hemodynamic and neurohormonal derangements that provoke activation of neuroendocrine systems, most notably the above-mentioned adrenergic systems and RAAS. The release of epinephrine and norepinephrine, along with the vasoactive substances endothelin-1 (ET-1) and vasopressin, causes vasoconstriction, which increases afterload, and, via an increase in cyclic adenosine monophosphate (cAMP), causes an increase in cytosolic calcium entry. The increased calcium entry into the myocytes augments myocardial contractility and impairs myocardial relaxation (lusitropy). The calcium overload may also induce arrhythmias and lead to sudden death. The increase in afterload and myocardial contractility (known as inotropy) and the impairment in myocardial lusitropy lead to an increase in myocardial energy expenditure and a further decrease in cardiac output. The increase in myocardial energy expenditure leads to myocardial cell death/apoptosis, which results in heart failure and further reduction in cardiac output, perpetuating a cycle of further increased neurohumoral stimulation and further adverse hemodynamic and myocardial responses as described above. In addition, the activation of the RAAS leads to salt and water retention, resulting in increased preload and further increases in myocardial energy expenditure. Increases in renin, mediated by decreased stretch of the glomerular afferent arteriole, reduced delivery of chloride to the macula densa and increased beta1-adrenergic activity as a response to decreased cardiac output. This results in an increase in angiotensin II (Ang II) levels and, in turn, aldosterone levels. This results in stimulation of the release of aldosterone. Ang II, along with ET-1, is crucial in maintaining effective intravascular homeostasis mediated by vasoconstriction and aldosteroneinduced salt and water retention. Research indicates that local cardiac Ang II production (which decreases lusitropy, increases inotropy, and increases afterload) leads to increased myocardial energy expenditure. Ang II has also been shown both in vitro and in vivo to increase the rate of myocyte apoptosis.5 In this fashion, Ang II has similar actions to norepinephrine in heart failure. Ang II also mediates myocardial cellular hypertrophy and may promote progressive loss of myocardial function. The neurohumoral factors above lead to myocyte hypertrophy and interstitial fibrosis, resulting in increased myocardial volume and increased myocardial mass, as well as myocyte loss. As a result, the cardiac architecture changes, which in turn leads to further increase in myocardial volume and mass.

In the failing heart, increased myocardial volume is characterized by larger myocytes approaching the end of their life cycle. As more myocytes drop out, an increased load is placed on the remaining myocardium and this unfavorable environment is transmitted to the progenitor cells responsible for replacing lost myocytes. Progenitor cells become progressively less effective as the underlying pathologic process worsens and myocardial failure accelerates. These features, namely the increased myocardial volume and mass, along with a net loss of myocytes, are the hallmark of myocardial remodeling. This remodeling process leads to early adaptive mechanisms, such as augmentation of stroke volume (Starling mechanism) and decreased wall stress (Laplace mechanism), and later, maladaptive mechanisms such as increased myocardial oxygen demand, myocardial ischemia, impaired contractility, and arrhythmogenesis. As heart failure advances, there is a relative decline in the counterregulatory effects of endogenous vasodilators, including nitric oxide (NO), prostaglandins (PGs), bradykinin (BK), atrial natriuretic peptide (ANP), and B-type natriuretic peptide (BNP). This occurs simultaneously with the increase in vasoconstrictor substances from the RAAS and adrenergic systems. This fosters further increases in vasoconstriction and thus preload and afterload, leading to cellular proliferation, adverse myocardial remodeling, and antinatriuresis with total body fluid excess and worsening congestive heart failure symptoms. Both systolic and diastolic heart failure result in a decrease in stroke volume. This leads to activation of peripheral and central baroreflexes and chemoreflexes that are capable of eliciting marked increases in sympathetic nerve traffic. While there are commonalities in the neurohormonal responses to decreased stroke volume, the neurohormone-mediated events that follow have been most clearly elucidated for individuals with systolic heart failure. The ensuing elevation in plasma norepinephrine directly correlates with the degree of cardiac dysfunction and has significant prognostic implications. Norepinephrine, while directly toxic to cardiac myocytes, is also responsible for a variety of signal-transduction abnormalities, such as downregulation of beta1-adrenergic receptors, uncoupling of beta2-adrenergic receptors, and increased activity of inhibitory G-protein. Changes in beta1-adrenergic receptors result in overexpression and promote myocardial hypertrophy. ANP and BNP are endogenously generated peptides activated in response to atrial and ventricular volume/pressure expansion. ANP and BNP are released from the atria and ventricles, respectively, and both promote vasodilation and natriuresis. Their hemodynamic effects are mediated by decreases in ventricular filling pressures, owing to reductions in cardiac preload and afterload. BNP, in particular, produces selective afferent arteriolar vasodilation and inhibits sodium reabsorption in the proximal convoluted tubule. BNP inhibits renin and aldosterone release and, therefore, adrenergic activation as well. Both ANP and BNP are elevated in chronic heart failure. BNP, in particular, has potentially important diagnostic, therapeutic, and prognostic implications. Other vasoactive systems that play a role in the pathogenesis of heart failure include the endothelin (ET) receptor system, adenosine receptor system, vasopressin, and tumor necrosis factor-alpha (TNF-alpha). Endothelin, a substance produced by the vascular endothelium, may contribute to the regulation of myocardial function, vascular tone, and peripheral resistance in heart failure. Elevated levels of endothelin-1 (ET-1) closely correlate with the severity of heart failure. ET-1 is a potent vasoconstrictor and has exaggerated vasoconstrictor effects in the renal vasculature, reducing renal plasma blood flow, glomerular filtration rate (GFR), and sodium

excretion. TNF-alpha has been implicated in response to various infectious and inflammatory conditions. Elevations in TNF-alpha levels have been consistently observed in heart failure and seem to correlate with the degree of myocardial dysfunction. Experimental studies suggest that local production of TNF-alpha may have toxic effects on the myocardium, thus worsening myocardial systolic and diastolic function. Thus, in individuals with systolic dysfunction, the neurohormonal responses to decreased stroke volume result in temporary improvement in systolic blood pressure and tissue perfusion. However, in all circumstances, the existing data support the notion that these neurohormonal responses contribute to the progression of myocardial dysfunction in the long term. In diastolic heart failure (heart failure with normal ejection fraction [HFNEF]), the same pathophysiologic processes leading to decreased cardiac output that occur in systolic heart failure also occur, but they do so in response to a different set of hemodynamic and circulatory environmental factors that depress cardiac output. In HFNEF, altered relaxation and increased stiffness of the ventricle (due to delayed calcium uptake by the myocyte sarcoplasmic reticulum and delayed calcium efflux from the myocyte) occur in response to an increase in ventricular afterload (pressure overload). The impaired relaxation of the ventricle leads to impaired diastolic filling of the left ventricle (LV). An increase in LV chamber stiffness occurs secondary to any one of the following 3 mechanisms or to a combination thereof:

A rise in filling pressure (ie, movement of the ventricle up along its pressure-volume curve to a steeper portion, as may occur in conditions such as volume overload secondary to acute valvular regurgitation or acute LV failure due to myocarditis) A shift to a steeper ventricular pressure-volume curve, occurring most commonly as a result of not only increased ventricular mass and wall thickness, as observed in aortic stenosis and long-standing hypertension, but also due to infiltrative disorders (such as amyloidosis), endomyocardial fibrosis, and myocardial ischemia A parallel upward displacement of the diastolic pressure-volume curve, generally referred to as a decrease in ventricular distensibility, usually caused by extrinsic compression of the ventricles.

Whereas volume overload, as observed in chronic aortic and/or mitral valvular regurgitant disease, shifts the entire diastolic pressure-volume curve to the right, indicating increased chamber stiffness, pressure overload that leads to concentric LV hypertrophy (as occurs in aortic stenosis, hypertension, and hypertrophic cardiomyopathy) shifts the diastolic pressurevolume curve to the left along its volume axis so that at any diastolic volume ventricular diastolic pressure is abnormally elevated, although chamber stiffness may or may not be altered. Increases in diastolic pressure lead to increased myocardial energy expenditure, remodeling of the ventricle, increased myocardial oxygen demand, myocardial ischemia, and eventual progression of the maladaptive mechanisms of the heart that lead to decompensated heart failure. Another clinically important process in the development of heart failure is the generation of

arrhythmias. While life-threatening rhythms are more common in ischemic versus nonischemic cardiomyopathy, arrhythmia imparts a significant burden in all forms of heart failure. In fact, some arrhythmias even perpetuate heart failure. The most significant of all rhythms associated with heart failure are the life-threatening ventricular arrhythmias. Structural substrates for ventricular arrhythmias common in heart failure, regardless of the underlying cause include (1) ventricular dilatation, (2) myocardial hypertrophy, and (3) myocardial fibrosis. At the cellular level, myocytes may be exposed to increased stretch, wall tension, catecholamines, ischemia, and electrolyte imbalance. The combination of these factors contributes to an increased incidence of arrhythmogenic sudden cardiac death in patients with heart failure.
Frequency United States

Heart failure is the fastest-growing clinical cardiac disease entity in the United States, affecting 2% of the population. In 2006, 1.1 million patients were admitted to the hospital for acute decompensated heart failure in the United States, almost double the number seen 15 years ago. In addition, 3.4 million visits for heart failure were outpatient. 550,000 new cases of heart failure are diagnosed and 300,000 deaths are caused by heart failure each year. The rehospitalization rates6 during the 6 months following discharge are as much as 50%. Nearly 2% of all hospital admissions in the United States are for decompensated heart failure, and heart failure is the most frequent cause of hospitalization in patients older than 65 years with an annual incidence of 10 per 1,000. The average duration of hospitalization is about 6 days. In 2008, the estimated total cost of heart failure in the United States was $37.2 billion. This represents 1-2% of all healthcare expenditures. For updated statistics and epidemiology please see the American Heart Association and National Institutes of Health official Web sites or published summaries.7

International

Heart failure is a worldwide problem, but little accurate financial data are available. As discussed elsewhere, the most common cause of heart failure in industrialized countries is ischemic cardiomyopathy. Other causes, including Chagas disease and valvular cardiomyopathy, assume a more important role in underdeveloped countries than in the United States. However, as underdeveloped countries urbanize and become more affluent, the rate of heart failure increases in concordance with rates of diabetes, hypertension, a more processed diet, and a more sedentary lifestyle. This was illustrated in a population study in Soweto, South Africa. As the community transformed into a more urban and westernized city, an increase in diabetes and hypertension was met with an increased rate of heart failure.8 In terms of treatment, a 2006 study of European nations showed few important international differences in uptake of key therapies amongst European countries with widely differing cultures and economic status for patients with heart failure. In contrast, studies of sub-Saharan Africa, where health care resources are more limited, have shown poor outcomes in certain

populations.9 For instance, hypertensive heart failure carries a 25% one-year mortality in some countries and HIV-associated cardiomyopathy generally progresses to death within 100 days of diagnosis in patients who are not treated with antiretroviral drugs. While data in developing countries is not as robust as in Western society, a few clear trends are apparent: (1) Causes tend to be largely nonischemic, (2) patients tend to present at a younger age, (3) outcomes are largely worse where health care resources are limited, and (4) isolated right heart failure tends to be more prominent with a variety of postulated causes from tuberculous pericardial disease to lung disease and pollution.
Mortality/Morbidity

In unselected samples from the community, rates of improvement in mortality have been about 20% in both short- and long-term followup between 1985 and 1995.10 This translated to a 6month increase in survival. However, despite recent advances in the management of patients with heart failure, morbidity and mortality rates remain high, with an estimated 5-year mortality rate of 50%.

Assigning figures for inpatient mortality rates is difficult because the causes and the severity of heart failure vary considerably. The most recent estimates of inpatient mortality rates indicate that death occurs in up to 520% of patients. Hypoxemia that occurs in decompensated heart failure, which may be severe, can result in diffuse end-organ damage including myocardial ischemia or myocardial infarction and hypoxic brain injury. Respiratory failure with hypercapnic respiratory acidosis may occur in severe decompensated heart failure, requiring mechanical ventilation if medical therapy is delayed or unsuccessful. Endotracheal intubation and mechanical ventilation are associated with their own risks, including aspiration (during the intubation process), mucosal trauma (more common with nasotracheal intubation than orotracheal intubation), and barotrauma. In patients with heart failure, the risk of cardiac sudden death from ventricular tachycardia (VT) or ventricular fibrillation (VF) is considerable, and the degree of risk is correlated with the degree of decompensation and the degree of LV dysfunction. Recognition of the role of ventricular arrhythmias and advances in their treatment have resulted in decreased mortality rates in individuals with heart failure. Progressive renal insufficiency is common in patients with long-standing heart failure as well as acutely decompensated heart failure. Furthermore, renal function is at least as powerful an adverse prognostic factor as most clinical variables, including ejection fraction and New York Heart Association (NYHA) function class. Although renal dysfunction predicts all-cause mortality, it is most predictive of death from progressive heart failure, which suggests that it is a manifestation of and/or exacerbating factor for left ventricular dysfunction.11 Liver dysfunction due to passive hepatic congestion is particularly common in patients with right-sided heart failure with elevated right ventricular (RV) pressure that is transmitted back into the portal vein. o Mild jaundice, mild abnormalities in coagulation, and derangements in liver metabolism of medications, some of which are used in the treatment of heart failure, may result from this liver dysfunction. o Toxic levels of medications such as warfarin, theophylline, phenytoin, and digoxin can result from delayed liver metabolic clearance of

these drugs in the presence of decompensated heart failure, thereby leading to potentially fatal bleeding, cardiac dysrhythmias, and neurologic abnormalities. Patients with heart failure have high rates of depression compared with the general population; in addition, depression may confer a negative prognostic impact when present in patients with heart failure, with an increased risk of both rehospitalization and mortality. Reported prevalence rates have ranged from 11-25% for outpatients and 35-70% for inpatients. Even more so than in the general population, depression in heart failure patients goes largely untreated with published rates of around 7% of patients with heart failure who are clinically depressed receiving antidepressant medication.12

Race

The incidence and prevalence of heart failure are higher in African Americans, Hispanics, Native Americans, and recent immigrants from nonindustrialized nations, Russia, and the former Soviet republics.

The higher prevalence of heart failure in African Americans, Hispanics, and Native Americans is directly related to the higher incidence and prevalence of hypertension and diabetes. This problem is particularly exacerbated by a lack of access to health care and to substandard preventive health care of the most indigent of these and other groups; many persons within these groups are without adequate health insurance coverage. The higher incidence and prevalence of heart failure among recent immigrants from nonindustrialized nations is largely due to a lack of prior preventive health care and to a lack of treatment or to substandard treatment for common conditions such as hypertension, diabetes, rheumatic fever, and ischemic heart disease.

Sex

Men and women have equivalent incidence and prevalence of heart failure. However, many differences between men and women are observed.

Women tend to develop heart failure later in life. Women are more likely to have preserved systolic function. Women develop depression more commonly than men. Women have similar, but more pronounced, signs and symptoms. Women survive longer with heart failure than men do.

Age

The prevalence of heart failure increases with age. The prevalence is 1-2% of the population younger than 55 years and increases dramatically to a rate of 10% of those older than 75 years. Nonetheless, heart failure can occur at any age, depending on the cause.

Clinical
History

The NYHA classification of heart failure (see Staging), which varies slightly from the above categorization of heart failure symptoms, is widely used in practice and in clinical studies to quantify clinical assessment of heart failure. Breathlessness, a cardinal symptom of LV failure, may manifest with progressively increasing severity as (1) exertional dyspnea, (2) orthopnea, (3) paroxysmal nocturnal dyspnea, (4) dyspnea at rest, and (5) acute pulmonary edema. Other cardiac symptoms of heart failure include chest pain/pressure and palpitations. Patients often manifest noncardiac symptoms of heart failure like anorexia, nausea, weight loss, bloating, fatigue, weakness, oliguria, nocturia, and cerebral symptoms of different severity ranging from anxiety to memory impairment and confusion.

Exertional dyspnea o The principal difference between exertional dyspnea in patients who are healthy and exertional dyspnea in patients with heart failure is the degree of activity necessary to induce the symptom. As heart failure first develops, exertional dyspnea may simply appear to be an aggravation of the breathlessness that occurs in healthy persons during activity. o As LV failure advances, the intensity of exercise resulting in breathlessness progressively declines; however, subjective exercise capacity and objective measures of LV performance at rest in patients with heart failure are not closely correlated. Exertional dyspnea, in fact, may be absent in sedentary patients. Orthopnea o This early symptom of heart failure may be defined as dyspnea that develops in the recumbent position and is relieved with elevation of the head with pillows. As in the case of exertional dyspnea, the change in the number of pillows required is important. o In the recumbent position, decreased pooling of blood in the lower extremities and abdomen occurs. Blood is displaced from the extrathoracic to the thoracic compartment. The failing LV, operating on the flat portion of the Frank-Starling curve, cannot accept and pump out the extra volume of blood delivered to it without dilating. As a result, pulmonary venous and capillary pressures rise further, causing interstitial pulmonary edema, reduced pulmonary compliance, increased airway resistance, and dyspnea. o Orthopnea occurs rapidly, often within a minute or two of recumbency, and develops when the patient is awake. Orthopnea may occur in any condition in which the vital capacity is low. Marked ascites, whatever its etiology, is an important cause of orthopnea. In advanced LV failure, orthopnea may be so severe that the patient cannot lie down and must sleep sitting up in a chair or slumped over a table. o Cough, particularly during recumbency, may be an "orthopnea equivalent." This nonproductive cough may be caused by pulmonary congestion and is relieved by the treatment of heart failure. Paroxysmal nocturnal dyspnea o Paroxysmal nocturnal dyspnea usually occurs at night and is defined as the sudden awakening of the patient, after a couple hours of sleep, with a feeling of severe anxiety, breathlessness, and

suffocation. The patient may bolt upright in bed and gasp for breath. Bronchospasm increases ventilatory difficulty and the work of breathing and is a common complicating factor of paroxysmal nocturnal dyspnea. On chest auscultation, the bronchospasm associated with a heart failure exacerbation can be difficult to distinguish from an acute asthma exacerbation, although other clues from the cardiovascular examination should lead the examiner to the correct diagnosis. Both types of bronchospasm can be present in the same individual. o In contrast to orthopnea, which may be relieved by immediately sitting up in bed, paroxysmal nocturnal dyspnea may require 30 minutes or longer in this position for relief. Episodes of this may be so frightening that the patient may be afraid to resume sleeping, even after the symptoms have abated. Dyspnea at rest is the result of the following mechanisms: o Decreased pulmonary function Decreased compliance Increased airway resistance o Increased ventilatory drive Hypoxemia due to increased pulmonary capillary wedge pressure (PCWP) Ventilation/perfusion (V/Q) mismatching due to increased PCWP and cardiac output Increased carbon dioxide production o Respiratory muscle dysfunction Decreased respiratory muscle strength Decreased endurance Ischemia Acute pulmonary edema is defined as the sudden increase in pulmonary capillary pressure (usually more than 25 mm Hg) as a result of acute and fulminant left ventricular failure. It is a medical emergency and has a very dramatic clinical presentation. Patient appears extremely ill, poorly perfused, restless, sweaty, with an increased work of breathing and using respiratory accessory muscles, tachypneic, tachycardic, hypoxic and coughing with frothy sputum that on occasion is blood tinged. Chest pain/pressure may occur as a result of either primary myocardial ischemia from coronary disease or secondary myocardial ischemia from increased filling pressure, poor cardiac output and therefore poor coronary diastolic filling, or hypotension and hypoxemia. Palpitations are the sensation a patient has when the heart is racing. It can be secondary to sinus tachycardia due to decompensated heart failure, or more common due to atrial or ventricular tachyarrhythmias. Fatigue and weakness o These symptoms are often accompanied by a feeling of heaviness in the limbs. o Fatigue and weakness are generally related to poor perfusion of the skeletal muscles in patients with a lowered cardiac output. Although generally a constant feature of advanced heart failure, episodic fatigue and weakness are common in earlier stages. Nocturia o Nocturia may occur relatively early in the course of heart failure. Recumbency reduces the deficit in cardiac output in relation to oxygen demand; renal vasoconstriction diminishes and urine formation increases. This may be troublesome for the patient with

heart failure because it may prevent the patient from obtaining much-needed rest. o Oliguria is a late finding in heart failure and is found in patients with markedly reduced cardiac output from severely reduced LV function. Cerebral symptoms: Confusion, memory impairment, anxiety, headaches, insomnia, bad dreams or nightmares, and, rarely, psychosis with disorientation, delirium, or hallucinations may occur in elderly patients with advanced heart failure, particularly in those with cerebrovascular atherosclerosis. Predominant right-sided heart failure o Ascites, congestive hepatomegaly, and anasarca due to elevated right-sided heart pressures transmitted backward into the portal vein circulation may result in increased abdominal girth and epigastric and right upper quadrant (RUQ) abdominal pain. Other gastrointestinal symptoms, caused by congestion of the hepatic and gastrointestinal venous circulation, include anorexia, bloating, nausea, and constipation. In preterminal heart failure, inadequate bowel perfusion can cause abdominal pain, distention, and bloody stools. Distinguishing right-sided heart failure from hepatic failure is often clinically difficult. o Dyspnea, prominent in LV failure, becomes less prominent in isolated right-sided heart failure because of the absence of pulmonary congestion. On the other hand, when cardiac output becomes markedly reduced in patients with terminal right-sided heart failure (as may occur in isolated RV infarction and in the late stages of primary pulmonary hypertension and pulmonary thromboembolic disease), severe dyspnea may occur as a consequence of the reduced cardiac output, poor perfusion of respiratory muscles, hypoxemia, and metabolic acidosis.

Physical

General appearance o Patients with mild heart failure appear to be in no distress after a few minutes of rest, but they may be obviously dyspneic during and immediately after moderate activity. Patients with LV failure may be dyspneic when lying flat without elevation of the head for more than a few minutes. Those with severe heart failure appear anxious and may exhibit signs of air hunger in this position. o Patients with recent onset of heart failure are generally well nourished, but those with chronic severe heart failure are often malnourished and sometimes even cachectic. o Chronic marked elevation of systemic venous pressure may produce exophthalmos and severe tricuspid regurgitation and may lead to visible pulsation of the eyes and of the neck veins. o Central cyanosis, icterus, and malar flush may be evident in patients with severe heart failure. o In mild or moderate heart failure, stroke volume is normal at rest; in severe heart failure, it is reduced, as reflected by a diminished pulse pressure and a dusky discoloration of the skin. o With very severe heart failure, particularly if cardiac output has declined acutely, systolic arterial pressure may be reduced. The pulse may be weak, rapid, and thready; the proportional pulse pressure

(pulse pressure/systolic pressure) may be markedly reduced. The proportional pulse pressure correlates reasonably well with cardiac output. In one study, when pulse pressure was less than 25%, it usually reflected a cardiac index of less than 2.2 L/min/m2. Evidence of increased adrenergic activity o Increased adrenergic activity is manifested by tachycardia, diaphoresis, pallor, peripheral cyanosis with pallor and coldness of the extremities, and obvious distention of the peripheral veins secondary to venoconstriction. o Diastolic arterial pressure may be slightly elevated. Pulmonary rales o Rales heard over the lung bases are characteristic of heart failure of at least moderate severity. With acute pulmonary edema, rales are frequently accompanied by wheezing and expectoration of frothy, blood-tinged sputum. o The absence of rales certainly does not exclude elevation of pulmonary capillary pressure due to LV failure. Systemic venous hypertension: This is manifested by jugular venous distention. Normally, jugular venous pressure declines with respiration; however, it increases in patients with heart failure, a finding known as the Kussmaul sign (also found in constrictive pericarditis). This reflects an increase in right atrial pressure and therefore right-sided heart failure. Hepatojugular reflux: This represents distension of the jugular vein induced by applying manual pressure over the liver. The patient's body should be positioned at a 45 angle. This is found in patients with elevated left-sided filling pressures and reflects elevated capillary wedge pressure and leftsided heart failure. Edema o Although a cardinal manifestation of heart failure, edema does not correlate well with the level of systemic venous pressure. In patients with chronic LV failure and low cardiac output, extracellular fluid volume may be sufficiently expanded to cause edema in the presence of only slight elevations in systemic venous pressure. o Usually, a substantial gain of extracellular fluid volume (ie, a minimum of 5 L in adults) must occur before peripheral edema is manifested. o Edema, in the absence of dyspnea or other signs of LV or RV failure, is not solely indicative of heart failure and can be observed in many other conditions, including chronic venous insufficiency, nephrotic syndrome, or other syndromes of hypoproteinemia or osmotic imbalance. Hepatomegaly o Hepatomegaly is prominent in patients with chronic right-sided heart failure, but it may occur rapidly in acute heart failure. o When occurring acutely, the liver is usually tender. o In patients with considerable tricuspid regurgitation, a prominent systolic pulsation of the liver, attributable to an enlarged right atrial V wave, is often noted. A presystolic pulsation of the liver, attributable to an enlarged right atrial A wave, can occur in tricuspid stenosis, constrictive pericarditis, restrictive cardiomyopathy involving the RV, and pulmonary hypertension (primary or secondary). Hydrothorax (pleural effusion) o Hydrothorax is most commonly observed in patients with hypertension involving both systemic and pulmonary systems.

Hydrothorax is usually bilateral, although when unilateral, it is usually confined to the right side of the chest. o When hydrothorax develops, dyspnea usually intensifies because of further reductions in vital capacity. Ascites o This finding occurs in patients with increased pressure in the hepatic veins and in the veins draining into the peritoneum. o Ascites usually reflects long-standing systemic venous hypertension. Protodiastolic (S3) gallop: This is the earliest cardiac physical finding in decompensated heart failure in the absence of severe mitral or tricuspid regurgitation or left-to-right shunts. Cardiomegaly o A nonspecific finding, cardiomegaly nonetheless occurs in most patients with chronic heart failure. o Notable exceptions include heart failure from acute myocardial infarction, constrictive pericarditis, restrictive cardiomyopathy, valve or chordae tendineae rupture, or heart failure due to tachyarrhythmias or bradyarrhythmias. Pulsus alternans (during pulse palpation, this is the alternation of one strong and one weak beat without a change in the cycle length) Pulsus alternans occurs most commonly in heart failure due to increased resistance to LV ejection, as occurs in hypertension, aortic stenosis, coronary atherosclerosis, and dilated cardiomyopathy. o It is usually associated with an S3 gallop, signifies advanced myocardial disease, and often disappears with treatment of heart failure. Accentuation of P2 heart sound, S3 gallop, and systolic murmurs o This accentuation is a cardinal sign of increased pulmonary artery pressure. It disappears or improves after treatment of heart failure. o Mitral and tricuspid regurgitation murmurs are often present in patients with decompensated heart failure because of ventricular dilatation. These murmurs often disappear or diminish when compensation is restored. Note that correlation between the intensity of the murmur of mitral regurgitation and its significance in patients with heart failure is poor. Severe mitral regurgitation may be accompanied by an unimpressively soft murmur. o The presence of an S3 gallop in adults is important, pathologic, and often the most apparent finding on cardiac auscultation in patients with significant heart failure. Cardiac cachexia o Cardiac cachexia is found in long-standing heart failure, particularly of the RV, because of anorexia from hepatic and intestinal congestion and sometimes because of digitalis toxicity. Occasionally, impaired intestinal absorption of fat and (rarely) protein-losing enteropathy occur. o Patients with heart failure may also exhibit increased total metabolism secondary to augmentation of myocardial oxygen consumption, excessive work of breathing, low-grade fever, and elevated levels of circulating TNF. Fever: Fever may be present in severe decompensated heart failure because of cutaneous vasoconstriction and impairment of heat loss.

Causes

From a clinical standpoint, classifying the causes of heart failure into 3 broad categories is useful: (1) underlying causes, comprising structural abnormalities (congenital or acquired) that affect the peripheral and coronary arterial circulation, pericardium, myocardium, or cardiac valves, thus leading to the increased hemodynamic burden or myocardial or coronary insufficiency responsible for heart failure; (2) fundamental causes, comprising the biochemical and physiological mechanisms, through which either an increased hemodynamic burden or a reduction in oxygen delivery to the myocardium results in impairment of myocardial contraction; and (3) precipitating causes. Note that most patients who present with significant heart failure do so because of an inability to provide adequate cardiac output in that setting. This is often a combination of the causes listed above in the setting of an abnormal myocardium. The list of causes responsible for presentation of a patient with a congestive heart failure exacerbation is very long, and searching for the proximate cause to optimize therapeutic interventions is important. Overt heart failure may be precipitated by progression of the underlying heart disease. A previously stable compensated patient may develop heart failure that is clinically apparent for the first time when the intrinsic process has advanced to a critical point, such as with further narrowing of a stenotic aortic valve or mitral valve. Alternatively, decompensation may occur as a result of failure or exhaustion of the compensatory mechanisms but without any change in the load on the heart in patients with persistent severe pressure or volume overload.

Precipitating causes of heart failure o Inappropriate reduction of therapy: The most common cause of decompensation in a previously compensated patient with heart failure is inappropriate reduction in the intensity of treatment, whether dietary sodium restriction, physical activity reduction, drug regimen reduction, or, most commonly, a combination of these measures. o Arrhythmias Tachyarrhythmias, most commonly atrial fibrillation Marked bradycardia Atrioventricular dissociation Abnormal intraventricular conduction o Systemic infection or development of unrelated illness Systemic infection precipitates heart failure by increasing total metabolism as a consequence of fever, discomfort, and cough, which increases the hemodynamic burden on the heart. Septic shock, in particular, can precipitate heart failure by the release of endotoxin-induced factors that can depress myocardial contractility. o Pulmonary embolism: Patients with heart failure, particularly when confined to bed, are at high risk of developing pulmonary emboli, which can increase the hemodynamic burden on the RV by further elevating RV systolic pressure, possibly causing fever, tachypnea, and tachycardia. o Physical, environmental, and emotional excesses: Intense, prolonged physical exertion or severe fatigue, such as may result from prolonged travel or emotional crises, or severe climate changes,

either to a hot, humid environment or to a bitterly cold environment, are relatively common precipitants of cardiac decompensation. o Cardiac infection and inflammation Myocarditis or infective endocarditis may directly impair myocardial function and exacerbate existing heart disease. The anemia, fever, and tachycardia that frequently accompany these processes are also deleterious. In the case of infective endocarditis, the additional valvular damage that ensues may precipitate cardiac decompensation. o Excessive intake of water and/or sodium o Administration of cardiac depressants or drugs that cause salt retention o High-output states: Profound anemia, thyrotoxicosis, myxedema, Paget disease of bone, Albright syndrome, multiple myeloma, glomerulonephritis, cor pulmonale, polycythemia vera, obesity, carcinoid syndrome, pregnancy, or nutritional deficiencies (eg, thiamine deficiency, beriberi) can precipitate the clinical presentation of heart failure because of increased myocardial oxygen consumption and demand beyond a critical level (ie, beyond the ability of the underlying myocardial oxygen supply to meet these demands). In particular, consider whether the patient has underlying coronary artery disease or valvular heart disease. o Development of a second form of heart disease Patients with one form of underlying heart disease that may be well compensated can develop heart failure when a second form of heart disease ensues. For example, a patient with chronic hypertension and asymptomatic LV hypertrophy may be asymptomatic until a myocardial infarction develops and precipitates heart failure. Underlying causes o Systolic heart failure Coronary artery disease Diabetes mellitus Hypertension Valvular heart disease (stenosis or regurgitant lesions) Arrhythmia (supraventricular or ventricular) Infections and inflammation (myocarditis) Peripartum cardiomyopathy Congenital heart disease Drug induced (either recreational like alcohol and cocaine, or therapeutic drugs with cardiac side effects like doxorubicin) Idiopathic cardiomyopathy Rare conditions (endocrine abnormalities, rheumatologic disease, neuromuscular conditions) o Diastolic heart failure Coronary artery disease Diabetes mellitus Hypertension Valvular disease (aortic stenosis) Hypertrophic cardiomyopathy Restrictive cardiomyopathy (amyloidosis) Constrictive pericarditis o Acute heart failure Acute valvular (mitral or aortic) regurgitation

Myocardial infarction Myocarditis Arrhythmia Drug induced (eg, cocaine, calcium channel blocker or betablocker overdose) Sepsis o High-output heart failure Anemia Systemic arteriovenous fistulas Hyperthyroidism Beriberi heart disease Paget disease of bone Albright syndrome (fibrous dysplasia) Multiple myeloma Pregnancy Glomerulonephritis Polycythemia vera Carcinoid syndrome o Right heart failure Left ventricular failure Coronary artery disease (ischemia) Pulmonary hypertension Pulmonary valve stenosis Pulmonary embolism Chronic pulmonary disease Neuromuscular disease Fundamental causes: See Pathophysiology.

Other Problems to Be Considered

Heart failure should be differentiated from pulmonary edema associated with injury to the alveolar-capillary membrane caused by diverse etiologies (ie, noncardiogenic pulmonary edema, adult respiratory distress syndrome [ARDS]). Increased capillary permeability is observed in trauma, hemorrhagic shock, sepsis, respiratory infections, administration of various drugs, and ingestion of toxins such as heroin, cocaine, and toxic gases. Several features may differentiate cardiogenic from noncardiogenic pulmonary edema. In heart failure, a history of an acute cardiac event or that of progressive symptoms of heart failure is usually present. The physical examination reveals S3 gallop, elevated jugular venous distention, and crackles upon auscultation. Patients with noncardiogenic pulmonary edema have a warm periphery, a bounding pulse, and an absence of S3 gallop and jugular venous distention. Differentiation is often made based on PCWP measurements from invasive hemodynamic monitoring. PCWP is generally more than 18 mm Hg in HF and is less than 18 mm Hg in noncardiogenic pulmonary edema, but superimposition of chronic pulmonary vascular disease can make this distinction more difficult to discern. With the advent of BNP level testing, reliably differentiating cardiac from noncardiac causes of pulmonary edema is now possible.

Workup
Laboratory Studies

CBC count: This study aids in the assessment of severe anemia, which may cause or aggravate heart failure. Leukocytosis may signal underlying infection. Otherwise, CBC counts are usually of little diagnostic help. Electrolytes o Serum electrolyte values are generally within reference ranges in patients with mild-to-moderate heart failure before treatment. However, in severe heart failure, prolonged, rigid sodium restriction, coupled with intensive diuretic therapy and the inability to excrete water, may lead to dilutional hyponatremia, which occurs because of a substantial expansion of extracellular fluid volume and a normal or increased level of total body sodium. o Potassium levels are usually within reference ranges, although the prolonged administration of diuretics may result in hypokalemia. Hyperkalemia may occur in patients with severe heart failure who show marked reductions in GFR and inadequate delivery of sodium to the distal tubular sodium-potassium exchange sites of the kidney, particularly if they are receiving potassium-sparing diuretics and/or ACE inhibitors. Renal function tests o BUN and creatinine levels can be within reference ranges in patients with mild-to-moderate heart failure and normal renal function, although elevated BUN and BUN/creatinine ratios may also be present. o Patients with severe heart failure, particularly those on large doses of diuretics for long periods, may have elevated BUN and creatinine levels indicative of renal insufficiency because of chronic reductions of renal blood flow from reduced cardiac output. Diuretics may aggravate renal insufficiency when these patients are overmedicated with diuretics and become volume depleted. Liver function tests o Congestive hepatomegaly and cardiac cirrhosis are often associated with impaired hepatic function, which is characterized by abnormal values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), and other liver enzymes. o Hyperbilirubinemia, secondary to an increase in both the directly and indirectly reacting bilirubin, is common. In severe cases of acute RV or LV failure, frank jaundice may occur. o Acute hepatic venous congestion can result in severe jaundice, with a bilirubin level as high as 15-20 mg/dL, elevation of AST to more than 10 times the upper reference range limit, elevation of the serum alkaline phosphatase level, and prolongation of the prothrombin time. Both the clinical and the laboratory pictures may resemble viral hepatitis, but the impairment of hepatic function is rapidly resolved by successful treatment of heart failure. In patients with longstanding heart failure, albumin synthesis may be impaired, leading to hypoalbuminemia and intensifying the accumulation of fluid. o Fulminant hepatic failure is an uncommon, late, and sometimes terminal complication of cardiac cirrhosis.

B-type natriuretic peptide o BNP is a 32-amino acid polypeptide containing a 17-amino acid ring structure common to all natriuretic peptides. Unlike ANP, whose major storage sites are in both the atria and ventricles, the major source of plasma BNP is the cardiac ventricles, suggesting that BNP may be a more sensitive and specific indicator of ventricular disorders than other natriuretic peptides. The release of BNP appears to be in direct proportion to ventricular volume and pressure overload. BNP is an independent predictor of high LV end-diastolic pressure and is more useful than ANP or norepinephrine levels for assessing mortality risk in patients with heart failure. o BNP levels are higher in older patients, women, and patients with renal dysfunction or sepsis. o BNP levels may be disproportionately lower in patients who are obese or have hypothyroidism or advanced end-stage heart failure (the latter due to increased fibrosis). o BNP levels correlate closely with the NYHA classification of heart failure. o BNP levels of more than 100 pg/mL have better than a 95% specificity and greater than a 98% sensitivity when comparing patients without heart failure to all patients with heart failure. Even BNP levels of more than 80 pg/mL have greater than a 93% specificity and 98% sensitivity in the diagnosis of heart failure. Furthermore, BNP levels, in several pilot studies, had a strong correlation with the severity of illness and were very reliable in differentiating HF from pulmonary disease. o BNP levels are not indicated in monitoring treatment of heart failure. (Class III recommendation13 ) o Measurement of BNP and N-terminal proBNP (NT-proBNP) can be useful in the evaluation of patients presenting to urgent care setting in whom the clinical diagnosis of heart failure is uncertain (Class IIa recommendation13 ). o In a pilot study, BNP levels correlated highly with clinical outcomes. Patients with decreased BNP levels during their hospital stay, along with decreases in NYHA classification, had good outcomes, whereas patients whose hospital stay ended in death or re-admission within 30 days of discharge had only minimal decreases of BNP levels or rising levels of BNP despite improvement or no change in their NYHA classification. In addition, the last measured BNP level was the single most reliable variable in predicting short-term outcomes in patients with heart failure. o Steinhart et al derived and validated a diagnostic prediction model for acute heart failure that incorporates both clinical assessment and NT-proBNP. Variables used to predict acute heart failure were age, pretest probability, and log NT-proBNP. Validation of the model in 1073 patients showed that likelihood ratios for acute heart failure with NT-proBNP were 0.11 (95% confidence interval [CI], 0.06-0.19) for cut-point values less than 300 pg/mL, increasing to 3.43 (95% CI, 2.34-5.03) for values 2700-8099 pg/mL, and 12.80 (95% CI, 5.2131.45) for values 8100 pg/mL or higher. When the model was applied to external data, 44% of patients who had been clinically classified as having intermediate probability of acute heart failure were appropriately reclassified to either low or high probability categories with negligible (<2%) inappropriate redirection.14

Imaging Studies

Chest radiography o Chest radiographs may be helpful in distinguishing cardiogenic pulmonary edema (CPE) from other pulmonary causes of severe dyspnea. o Classic radiographic findings demonstrate cardiomegaly (in patients with underlying CHF) and alveolar edema with pleural effusions and bilateral infiltrates in a butterfly pattern. The other signs are loss of sharp definition of pulmonary vasculature, haziness of hilar shadows, and thickening of interlobular septa (Kerley B lines). o Chest radiographs in patients with abrupt onset are usually helpful but can be limited because a delay of as long as 12 hours is possible from the onset of dyspnea due to acute heart failure to the development of classic abnormal findings on radiographs. o In long standing biventricular chronic heart failure, chest radiographs may only show cardiomegaly without alveolar edema or pleural effusions due to adaptive lung mechanism with increased arterial vasoconstriction and lymphatic drainage. Echocardiography o Determines LV/RV size and function, LV wall motion abnormalities, valvular function and abnormalities, diastolic function, presence or absence of pericardial abnormalities or intracardiac masses; evaluates intracardiac filling pressures. o Transesophageal echocardiography is particularly useful in patients who are on mechanical ventilation or morbidly obese and in patients whose transthoracic echocardiogram is suboptimal in its imaging. It is an easy and safe alternative to conventional transthoracic echocardiography and provides superior imaging quality compared to conventional transthoracic echocardiography. Radionuclide multiple gated acquisition scan o Radionuclide multiple gated acquisition (MUGA) scan is a reliable imaging technique for evaluation of both LV and RV function and wall motion abnormalities. LV ejection fraction, as determined by MUGA scanning, is often used for serial assessment of LV function post chemotherapy, because of its reliability. o However, this study is limited in its assessment of valvular heart disease and pericardial disease. Cardiac magnetic resonance imaging (cMRI) o cMRI is quickly gaining popularity as an imaging modality for heart failure. o Benefits of cMRI include the ability to obtain a great deal of information with one noninvasive test. cMRI provides detailed functional and morphologic information. cMRI is able to assess ischemic versus nonischemic disease, infiltrative disease, valvular and congenital disorders, hypertrophic disease, as well as determine viability.

Other Tests

Arterial blood gas (ABG) o ABG usually reveals mild hypoxemia in patients who have mild-tomoderate heart failure. ABG is more accurate than pulse oximetry for

measuring oxygen saturation. Patients with severe heart failure may have signs and symptoms ranging from severe hypoxemia, or even hypoxia, along with hypercapnia, to decreased vital capacity and poor ventilation. o ABG helps to assess the presence of hypercapnia, a potential early marker for impending respiratory failure. Hypoxemia and hypocapnia occur in stages 1 and 2 of pulmonary edema because of V/Q mismatch. In stage 3 of pulmonary edema, right-to-left intrapulmonary shunt develops secondary to alveolar flooding and further contributes to hypoxemia. In more severe cases, hypercapnia and respiratory acidosis are usually observed. The decision regarding intubation and use of mechanical ventilation is frequently based on the presence of hypercapnic respiratory failure with acidosis discovered on ABG in patients with fulminant pulmonary edema. Venous blood gas is a good indirect marker of the blood circulation time and therefore of cardiac output and cardiac performance. Patients who have advanced heart failure have low cardiac output and slower circulation time, which translates into an increased oxygen extraction by the tissue and therefore lower saturation of oxygen (<60% saturation) Pulse oximetry o Pulse oximetry is highly accurate at assessing the presence of hypoxemia and, therefore, the severity of heart failure. o Patients with mild-to-moderate heart failure show modest reductions in oxygen saturation, whereas patients with severe heart failure may have severe oxygen desaturation, even at rest. o Patients with mild-to-moderate heart failure may have normal oxygen saturations at rest, but they may exhibit marked reductions in oxygen saturations during physical exertion or recumbency, necessitating the use of continuous oxygen until compensation either returns oxygen saturation to normal during exertion and recumbency or on a permanent basis if oxygen desaturation during exertion and/or recumbency exist during compensated severe heart failure. o Pulse oximetry is useful for monitoring the patient's response to supplemental oxygen and other therapies. Electrocardiography o The presence of left atrial enlargement and LV hypertrophy is sensitive (although nonspecific) for chronic LV dysfunction. o ECG may suggest an acute tachyarrhythmia or bradyarrhythmia as the cause of heart failure. o ECG may aid in the diagnosis of acute myocardial ischemia or infarction as the cause of heart failure or may suggest the likelihood of prior myocardial infarction or presence of coronary artery disease as the cause of heart failure. o ECG is of limited help when an acute valvular abnormality or LV systolic dysfunction is considered to be the cause of heart failure; however, the presence of left bundle branch block (LBBB) on an ECG is a strong marker for diminished LV systolic function.

Procedures

Right-sided heart catheterization o Normal right-sided hemodynamics include right atrial pressure (RAP) of less than 7 mm Hg, right ventricular pressure (RVP) of less than

30/7 mm Hg, pulmonary pressure (PAP) of less than 30/18, pulmonary capillary wedge pressure (PCWP) of less than 18 mm Hg, cardiac index (CI) more than 2.2 L/min/m2. o PCWP can be measured by using a pulmonary arterial catheter (Swan-Ganz catheter). This helps differentiate cardiogenic causes of decompensated heart failure from noncardiogenic causes such as ARDS, which occurs secondary to injury to the alveolar-capillary membrane rather than to alteration in Starling forces. A PCWP exceeding 18 mm Hg in a patient not known to have chronically elevated left atrial pressure is indicative of cardiogenic decompensated heart failure. In patients with chronic pulmonary capillary hypertension, capillary wedge pressures exceeding 25 mm Hg are generally required to overcome the pumping capacity of the lymphatics and produce pulmonary edema. o Large V waves may be observed in the PCWP tracing in patients with significant mitral regurgitation because large volumes of blood regurgitate into a poorly compliant left atrium. This raises pulmonary venous pressure and may cause pulmonary edema. o Cardiogenic shock is the result of a severe depression in myocardial function. Although many definitions for cardiogenic shock have been proposed, the following provides a useful guideline: Cardiogenic shock is present when systolic blood pressure is less than 80 mm Hg, the cardiac index is less than 2.0 L/min/m2, and the PCWP is greater than 18 mm Hg. This form of shock can occur from a direct insult to the myocardium (eg, large acute myocardial infarction, severe cardiomyopathy) or from a mechanical problem that overwhelms the functional capacity of the myocardium (eg, acute severe mitral regurgitation, acute ventricular septal defect). The prognosis of patients with cardiogenic shock is poor, with in-hospital mortality rates of 50-90%. o Invasive hemodynamic monitoring is indicated for patients who have respiratory distress, signs of impaired perfusion, and when intracardiac pressures cannot be determined based on clinical examination or if there is no improvement in clinical status despite maximal heart failure therapy (Class I recommendation13 ). Left-sided heart catheterization and coronary angiography o Left-sided heart catheterization and coronary angiography should be undertaken when the etiology of heart failure cannot be determined by clinical or noninvasive imaging methods or when the etiology is likely to be due to acute myocardial ischemia or myocardial infarction. Coronary angiography is particularly helpful in patients with LV systolic dysfunction and known or suspected coronary artery disease in whom myocardial ischemia is thought to play a dominant role in the reduction of LV systolic function and the worsening of heart failure. o Specific rationales for right- and left-sided heart catheterization include the need to determine the etiologic significance and severity of mitral and/or aortic valvular disease in patients with heart failure in whom the cause-effect relationship of valvular heart disease with regard to heart failure is unclear. Furthermore, right- and left-sided heart catheterization should be performed in patients in whom constrictive pericarditis is considered a likely cause of heart failure.

Right ventricular endomyocardial biopsy is only indicated in patients presenting with heart failure when a specific diagnosis is suspected that would influence therapy (Class IIa recommendation13 ). The six-minute walk test is a good indicator of functional status and prognosis in patients with heart failure. It evaluates distance walked, dyspnea index on a Borg scale from 0 to 10, oxygen saturation, and heart rate response to exercise. Normal values are walking more than 1500 feet. Patients who walk less than 600 feet have severe cardiac dysfunction and this translates into a worse short- and long-term prognosis. Cardiopulmonary stress test (maximal exercise stress testing with measurement of respiratory gas exchange) evaluates cardiac and pulmonary performance with exercise. Values of peak oxygen consumption of less than 50% of predicted or less than 14 cc/kg/min reflect poor cardiac performance and a survival of less than 50% within the next year, therefore facilitating referral for cardiac transplant or mechanical circulatory device placement.

Staging

A classification of patients with heart disease based on the relation between symptoms and the amount of effort required to provoke them has been developed by the NYHA. o Class I: No limitations. Ordinary physical activity does not cause undue fatigue, dyspnea, or palpitations. o Class II: Slight limitation of physical activity. Such patients are comfortable at rest. Ordinary physical activity results in fatigue, palpitations, dyspnea, or angina. o Class III: Marked limitation of physical activity. Although patients are comfortable at rest, less-than-ordinary activity leads to fatigue, dyspnea, palpitations, or angina. o Class IV: Symptomatic at rest. Symptoms of CHF are present at rest; discomfort increases with any physical activity. The 2001 ACC/AHA heart failure guidelines introduced a staging classification for heart failure complementary to NYHA classification to reflect the progression of disease. o Stage A Patients at risk of developing heart failure, without evidence of structural heart disease (diabetes mellitus, hypertension, coronary artery disease, OSA, obesity, metabolic syndrome, family history of cardiomyopathy, use of cardiotoxins) o Stage B - Patients with asymptomatic LV dysfunction (post-MI LV dysfunction, valvular cardiomyopathy, dilated cardiomyopathy); includes NYHA Class I patients o Stage C Symptomatic LV dysfunction; includes NYHA Class II and III patients o Stage D End-stage refractory heart failure; includes NYHA Class IV patients Based on cardiac output heart failure can be classified in low-output failure (most of the conditions) or high-output failure (beriberi, Paget disease, pregnancy, anemia, AV fistula, sepsis). Based on the ventricle affected, heart failure can be classified in LV failure, RV failure, or biventricular failure. Based on the LVEF, heart failure can be classified in patients with LV systolic dysfunction (LVEF <40%) and patients with preserved LVEF (LVEF >40%).

Based on the onset of symptoms, heart failure can be acute or chronic

Treatment
Medical Care

Diagnosis and Management of Acute Heart Failure (AHF) Acute heart failure is rapid or gradual onset of signs and symptoms of heart failure that result in urgent, unplanned hospitalization or office or emergency department visit. This is the result of a sudden increase in filling pressures leading to systemic and pulmonary congestion, regardless of the cardiac output. Acute heart failure accounts for more than 1 million hospitalizations per year in United States. The incidence of heart failure hospitalizations has tripled during the last 3 decades. The expenditure related to heart failure exceeds 34 billion dollars per year and it is mainly related to hospitalizations. Despite the advances in heart failure treatment, a systematic approach to acute heart failure has only recently been emphasized, as reflected in the updated ACCF/AHA heart failure guidelines from 2009.13 Most patients who present with acute heart failure have exacerbation of chronic heart failure with only 15-20% having acute de novo heart failure. More than 50% of patients with acute heart failure have preserved LVEF (>40%). Less than 10% of patients presenting with acute heart failure are hypotensive and require inotropic therapy. Pulmonary edema is a medical emergency and only one of the presentations of acute heart failure. Inhospital mortality remains as high as 20% for patients who present with creatinine more than 2.75 mg/dl, SBP <115 and BUN>43 mg/dL (ADHERE registry). Post discharge mortality and rehospitalization within 3 months can reach 10-20% and 30-50% at the end of 12 months. However, 50% of the readmissions in this population will be related to a different diagnosis than heart failure. Acute heart failure can present as fluid overload alone with or without signs of hypoperfusion, end-organ dysfunction and shock. A systematic and expeditious approach is required, starting in the emergency room, continuing during hospitalization and extending after discharge to the outpatient setting. Prior myocardial infarction, hypertension, diabetes mellitus, arrhythmias, valvular disease, cardiovascular accident, renal dysfunction, COPD, and anemia are among the most common etiologies for acute heart failure. Common factors that precipitate heart failure hospitalizations are noncompliance with medicine, sodium or fluid excess, acute ischemia, uncontrolled blood pressure, uncontrolled arrhythmias, drugs (NSAIDs, calcium channel blockers, thiazolidinediones, anti-TNF antibodies), pulmonary embolus, excessive alcohol or other substance abuse, infections, and endocrine abnormalities (hypo or hyperthyroidism). A thorough history and physical examination allow the physician to determine the volume and the perfusion status and proceed with therapy. Diagnostic laboratory work-up is the same as described above and include assessment of blood counts, liver and kidney function, myocardial

injury biomarkers (CK total, MB, troponin I), BNP or NT pro-BNP, chest radiograph, electrocardiogram, and echocardiogram. Emergency department care consists of stabilizing the patients clinical condition; establishing the diagnosis, etiology, and precipitating factors; and initiating therapies to rapidly provide symptom relief. Use of oxygen if blood oxygen saturation is less than 90% and noninvasive positive pressure ventilation (NIPPV) provides patients with respiratory support to avoid intubation. NIPPV has shown to decrease the rate of intubation and mechanical ventilation by 50% and decrease the hospital mortality by 40%. No difference has been noted between continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BIPAP). Use of analgesics as morphine sulfate and benzodiazepines helps with the anxiety, distress, and dyspnea. Morphine sulfate also decreases preload. If arrhythmia is present and uncontrolled ventricular response is thought to contribute to the clinical scenario of acute heart failure, then either pharmacologic rate control or emergent cardioversion with restoration of sinus rhythm is recommended. Relief of congestion is achieved using intravenous diuretics and vasodilators. If patient is hypotensive, use of either inotropic therapies and/or mechanical circulatory support (intraaortic balloon pump, extracorporeal membrane oxygenator, left ventricular assist device) in addition to continuous hemodynamic monitoring is indicated. Hospitalization occurs on either telemetry or in an ICU setting with a small percentage on the floor or observation unit. The goal is to continue the diagnostic and therapeutic processes started in the ED. Patients volume and hemodynamic status is optimized using careful clinical monitoring and the heart failure medical regimen is optimized. Heart failure education, behavior modification, and exercise and diet recommendation are made. The patient must be on a stable oral regimen for at least 24 hours before discharge. To ensure compliance and understanding of a complex medical regimen, a follow-up phone call is made 3 days after discharge by a nurse with training in heart failure. Ideally, the patient should be seen in clinic 7-10 days after discharge. 2006 heart failure guidelines are as follows:15 These guidelines recommend hospitalization for acute heart failure if the following are present:

Severe decompensated heart failure (low blood pressure, renal dysfunction, altered mentation) Dyspnea at rest Hemodynamically significant arrhythmia Acute coronary syndrome

Hospitalization should be considered if the follow are present:

Worsening congestion (weight gain >5 kg) Worsening signs and symptoms of systemic or pulmonary congestion, even in the absence of weight gain Major electrolyte abnormalities Associated comorbid conditions Repeat implantable cardioverter-defibrillator firings New diagnosis of heart failure with signs of active congestion

Stevenson and colleagues postulated treatment for acute heart failure based on volume and perfusion status of the patient (warm and wet, warm and dry, cold and wet, cold and dry)16 Diuretics remain the mainstay of therapy and current standard of care for acute heart failure. Intravenous administration of a loop diuretic (furosemide, bumetanide, torsemide) is preferred initially due to potential poor absorption of the oral forms in the presence of bowel edema. The dose and frequency of administration depend on the diuretic response 2-4 hours after the first dose administered. If the response is inadequate, then increasing the dose and/or increasing the frequency can help enhance diuresis. The patient is considered diuretic resistant if either (1) more than 80 mg IV bolus furosemide or more than 2 mg/kg furosemide is needed for appropriate response or (2) more than double of the diuretic dose or a second agent in the form of a thiazide diuretic is needed. Volume status, sodium, water intake and hemodynamic status for signs of poor perfusion need to be reevaluated in case of diuretic resistance. Although initially diuretic resistance was though to be a side effect of diuretics, a meta-analysis demonstrated this phenomenon is mostly a result of advanced heart failure. Eventually, alternate strategies such as hemodialysis or ultrafiltration may be used to overcome it. Other agents, such as vasopressin antagonists and adenosine receptor blockers, can be used to assist diuretics. Transition to oral diuretic therapy is made upon reaching near-euvolemic state. The dose of oral diuretic dose is usually equal to the IV dose. Usually 40 mg daily of furosemide is equivalent to 20 mg of torsemide and 1 mg of bumetanide. Weight, sign and symptoms, fluid balance, electrolyte levels, and renal function have to be monitored carefully on a daily basis.

Vasodilators are recommended as first-line therapy for patients with acute heart failure in the absence of hypotension in addition to diuretic therapy for relief of symptoms. Vasodilators will decrease preload, afterload, or both. Nitrates are potent venodilators. They decrease preload, therefore decreasing LV filling pressure and relieving shortness of breath. They also selectively produce epicardial coronary artery vasodilatation and help with myocardial ischemia. Although nitrates can be used in different forms (sublingual, oral, transdermal, intravenous) the most common route in acute heart failure is intravenous. Their use is limited by tachyphylaxis and headache. Sodium nitroprusside is a potent balanced arterial and venous vasodilator resulting in a very efficient decrease of intracardiac filling pressures. It requires not only careful hemodynamic monitoring using indwelling catheters but also monitoring for cyanide toxicity, especially in the presence of renal dysfunction. It is particularly helpful for patients who present with severe pulmonary congestion in the presence of hypertension and severe mitral regurgitation. The drug should be titrated to off rather than abruptly stopped due to the rebound potential. Nesiritide (human BNP analog) is a vasodilator that subjectively has been demonstrated to alleviate dyspnea faster when compared with diuretics alone or in combination with low-dose nitroglycerin (VMAC trial). The drug can be initiated if systolic blood pressure is greater than 100 mm Hg at a continuous drip of 0.005 mcg/kg/min with or without an IV bolus of 2 mcg/kg. Continuous infusion can be titrated to a maximum of 0.03 mcg/kg/min, although this dose has been associated with more renal dysfunction and hypotension and the additional decongestive benefit at a

higher dose is questionable. Long-term effects on mortality as well as renal function are still under investigation. Inotropes improve short-term symptoms and hemodynamics in patients with evidence of cardiogenic shock and end-organ dysfunction. Their use long term (REMATCH trial) or in patients not in cardiogenic shock (normotensive and without evidence of end organ perfusion) (OPTIME CHF) is not indicated and increases mortality. An adrenergic agonist (dopamine, dobutamine, epinephrine, norepinephrine), a phosphodiesterase inhibitor (milrinone, enoximone) or a calcium sensitizer (levosimendan) can be used.

Adrenergic agonists are used in case of significant hypotension to improve cardiac output and organ perfusion.

Dobutamine is a beta-receptor agonist, increases inotropy and chronotropy and decreases afterload therefore improving end-organ perfusion Doses of 5-10 mcg/kg/min are used although in the presence of a beta-blocker higher doses may be necessary. Careful hemodynamic and patient monitoring is required. Dopamine has beta-receptor agonist properties in doses of 3-7.5 mcg/kg/min and can be used as a positive inotrope. Initiation of it can precipitate arrhythmia due to inhibition of norepinephrine uptake. Doses of more than 7.5 mcg/kg/min will produce more peripheral vasoconstriction via alpha stimulation and can precipitate heart failure. Doses of more than 10 mcg/kg/min are used mostly for refractory hypotension in the presence of cardiogenic shock. In doses of less than 3 mcg/kg/min, it produces splanchnic vasodilation due to the stimulation of dopaminergic receptors. Milrinone is a phosphodiesterase inhibitor (PDEi) which increases inotropy, chronotropy and lusitropy acting via cGMP to increase the intramyocardial ATP. It is a potent vasodilator agent, both veno and arterial vasodilator, and it is used in patients with pulmonary hypertension. Milrinone can be used in presence of a beta-blocker. Milrinone is thought to create less tachycardia since it does not directly stimulate beta-receptors. Milrinone is usually initiated at 0.25 mcg/kg/min and can be titrated up to 0.75 mc/kg/min. The half-life is 2.4-6 hours and the drug needs to be adjusted for renal function. Milrinone is usually avoided in patients with severe hypotension. Milrinone should not be used routinely in patients with HF exacerbation in the absence of cardiogenic shock since it has been shown to increase mortality (OPTIME-CHF). Oral therapy with ACEI/ARB is usually continued. Adjustment of dose or temporary withholding may be necessary if hypotension persists and hinders diuresis or if renal function worsens. Beta-blockers are usually continued in the same dose or a slightly reduced dose with the exception of the situations requiring intravenous inotropic therapy where they are temporarily stopped. Usually, beta-blockers are resumed prior to discharge if patient condition allows. Ultrafiltration (UNLOAD trial) is now a class IIa recommendation for patients with refractory heart failure not responsive to medical therapy.

Invasive hemodynamic monitoring, although not indicated for stable patients with heart failure responding appropriately to medical therapy (ESCAPE trial showed no mortality or hospitalization benefit), is recommended in the following situations for patients with acute decompensated heart failure (Class IIa recommendation):

Patients with uncertain fluid status, perfusion, or systemic or pulmonary vascular resistance. Patients with persistent symptomatic hypotension despite initial therapy. Patients with worsening in renal function despite initial therapy. Patients who require parenteral vasoactive agents. Patients who may be considered for advanced device therapy or transplantation.

Invasive hemodynamic monitoring should be performed to guide therapy in patients with respiratory distress, impaired perfusion or where intracardiac pressures cannot be determined based on clinical examination. (Class I recommendation13 )

Patients are ready for discharge when exacerbating factors have been addressed, volume status has been optimized, diuretic therapy has been successfully transitioned to oral medication with discontinuation of intravenous vasodilator and inotropic therapy for at least 24h, and oral chronic heart failure therapy has been achieved with stable clinical status. Patient and family education should be completed and extensive postdischarge instructions and follow up in 3-7 days must be arranged. Difficult and complicated patients should be referred to a disease management program.1
A study by Anker et al examined how treatment with ferric carboxymaltose (IV iron) would decrease symptoms in patients with heart failure, reduced left ventricular ejection fraction, and iron deficiency (with or without anemia). In this study, 459 patients with NYHA functional class II or III were randomly given (in a 2:1 ratio) 200 mg IV ferric carboxymaltose or placebo (saline). At 24 weeks, 50% of subjects receiving ferric carboxymaltose reported much or moderately improved on the self-reported Patient Global Assessment compared with 28% of subjects receiving placebo (odds ratio [OR], 2.51; 95% confidence interval [CI], 1.75-3.61). Subjects with an NYHA functional class I or II at 24 weeks included 47% in the ferric carboxymaltose group compared with 30% in the placebo group (OR for oneclass improvement 2.40; 95% CI, 1.55-3.71). This study shows a significant benefit of using IV iron in patients with heart failure and iron deficiency to improve patient symptoms.17 Heart Failure with Normal Left Ventricular Systolic Function (HFNEF)

HFNEF represents 50-55% of hospitalized patients. Prevalence in the population increases dramatically with age and it is more common in women than in men. Other nomenclature includes heart failure due to diastolic dysfunction or heart failure with preserved systolic function. Inhospital mortality seems to be slightly lower when compared with patients with systolic dysfunction in the ADHERE registry, despite similar hospitalization length of stay. The same registry noted the increased in-hospital mortality when patients had a BUN greater than 37 mg/dL, creatinine greater than 2 mg/dL, and SBP <125 mm Hg. Patients with HFNEF in this registry were not as likely to receive therapy with ACEI/ARB, beta-blockers, or diuretics. More than 70% of patients at discharge had lost less than 10 lb and 50% were still symptomatic.

The most common risk factors for developing HFNEF are old age, female gender, hypertension, diabetes mellitus, coronary disease, obesity, and chronic kidney disease. Pathophysiology of HFNEF consists of LV concentric remodeling, impaired LV filling capacity, increased LV stiffness, impaired active relaxation with significant activation of RAAS and SNS. The Frank Starling curve in HFNEF is shifted left and upward. Minor changes in preload, afterload, or heart rate may lead to acute decompensation. The European Society of Cardiology proposed the following 3 conditions to establish the diagnosis of HFNEF: (1) Signs and symptoms of heart failure, (2) LVEF more than 50% (although 40-50% is still considered by most cardiologists to be HFNEF), (3) evidence of elevated LV filling pressure by either invasive hemodynamics, echo (E/E>15) or BNP/NT proBNP measurements (>200 pg/mL). Treatment is directed to alleviating symptoms and addressing the underlying condition triggering HFNEF. There is a paucity of randomized controlled studies addressing HFNEF. Control of blood pressure, volume, or other risk factors is the mainstay of the therapy. Lifestyle modification is important, including a low sodium diet, restricted fluid intake, daily weights, exercise, and weight loss. Evaluation of cardiac ischemia or sleep apnea as potential precipitating factors should also be considered.

Careful diuretic therapy is recommended to avoid hypotension. ACEI/ARBs are used as indicated for patients with evidence of atherosclerotic disease, post-myocardial infarction, diabetes melitis, and hypertension. Use of candesartan in CHARM-Preserved18 , irbesartan in IPRESERVED, or perindopril in PEP-CHF revealed no change in mortality; however, the trend was toward improved morbidity and hospitalizations. Some evidence shows LV reverse remodeling using losartan and valsartan with improvement in diastolic function and regression of LVH. Beta-blockers are indicated for patients with prior myocardial infarction, hypertension, and atrial fibrillation for control of ventricular rate. In the ADHERE registry, the subset of patients with HFNEF not treated with betablocker had a higher mortality potentially due to the higher incidence of coronary artery disease in this population. Aldosterone receptor blockers are indicated in hypertension and reduce myocardial fibrosis, although no randomized controlled studies have been performed to evaluate their role in HFNEF. Calcium channel blockers may improve exercise tolerance via the vasodilatory properties and nondihydropyridine calcium channel blockers are also used for ventricular rate control in patients with atrial fibrillation. Amlodipine has antianginal properties and is also indicated in hypertension. Restoration of sinus rhythm should be considered if the patient remains symptomatic despite above efforts. Use of digitalis or inotropes in patients with HFNEF is not indicated.

Right Ventricular Failure and Cardio-Renal Syndrome

RV failure is a clinical syndrome that impairs the ability of RV to fill with or eject blood. Clinical manifestations consist of fluid retention (peripheral edema, ascites, anasarca), low cardiac output (fatigue, exercise intolerance), and atrial or ventricular arrhythmias.

Pathophysiology of RV failure involves pressure overload (chronic LV failure, pulmonary embolism, pulmonary hypertension, congenital heart disease where RV is the systemic ventricle), volume overload (tricuspid regurgitation, pulmonary valve insufficiency, atrial septal defect, carcinoid, rheumatic valve disease), ischemia, intrinsic myocardial disease (arrhythmogenic right ventricular dysplasia, sepsis, cardiomyopathy), pericardial disease, complex congenital heart disease. RV tolerates volume better than pressure overload. Compensatory mechanisms include RAAS, SNS, natriuretic peptides, endothelin system, and cytokines. These in turn lead to RV remodeling, altered gene expression, RV dysfunction, and eventually RV failure. Management of RV failure includes treatment of the underlying cause; optimization of preload, afterload, and RV contractility; maintenance of sinus rhythm; and AV synchrony. Hypotension should be avoided since it can potentially lead to further RV ischemia. General measures should be applied such as sodium and fluid restriction, moderate physical activity avoiding isometric exercises, avoiding pregnancy, compliance with medications, avoiding or rapid treatment of precipitating factors such as sleep apnea, PE, sepsis, arrhythmia, ischemia, high altitude, anemia, and hypoxemia. In patients with severe hemodynamically compromising RV failure, inotropic therapy is used with dobutamine 2-5 mcg/kg/min, dobutamine and nitric oxide, or dopamine alone. Milrinone is preferred if the patient is tachycardic or on beta-blockers. Use of ACEI/ARB is beneficial if RV failure is secondary to LV failure; their efficacy is not known in isolated RV failure. The same recommendation applies for use of beta-blockers. The role of nesiritide in RV failure is not well defined. Use of digoxin in RV failure associated with COPD, not associated with LV dysfunction, appears not to improve exercise tolerance or RVEF. Anticoagulation indications are standard for evidence of intracardiac thrombus, thromboembolic event, pulmonary arterial hypertension, paroxysmal or persistent atrial fibrillation/flutter, and mechanical right-sided valves. Hypoxemia should be corrected and positive pressure should be avoided when mechanical ventilation is needed. Atrial septostomy can be considered as a palliative measure in very symptomatic patients who failed standard therapy. RV mechanical assist device is only indicated for RV failure secondary to LV failure or postcardiac transplantation. Prognosis of RV failure is dependent on the etiology (better for volume overload, pulmonary stenosis, and Eisenmenger syndrome). Decreased exercise tolerance predicts poor survival. Cardiorenal syndrome reflects advanced cardio-renal dysregulation manifested by acute heart failure, worsening renal function, and diuretic resistance. It is equally prevalent in patients with HFNEF as well as patients with heart failure and LV systolic dysfunction. Worsening renal function is one of the 3 predictors of increased mortality in hospitalized patients with heart failure regardless of the LVEF (ADHERE registry).

Cardiorenal syndrome can be classified into 5 types:

1. CR1 - Rapid worsening of cardiac function leading to acute kidney injury (HFNEF, acute heart failure, cardiogenic shock, and RV failure) 2. CR2 - Worsening renal function due to progression of chronic heart failure 3. CR3 - Abrupt and primary worsening of kidney function leading to acute cardiac dysfunction (heart failure, arrhythmia, ischemia) 4. CR4 - Chronic kidney disease leading to progressive cardiac dysfunction, LVH, diastolic dysfunction 5. CR5 - Combination of cardiac and renal dysfunction due to acute and chronic systemic conditions.

Pathophysiology for CR1 and CR2 is complex and multifactorial involving neurohormal activation (RAAS, SNS, AVP, natriuretic peptides, adenosine receptor activation), low arterial pressure, and high central venous pressure, leading to lower transglomerular perfusion pressure and decreased availability of diuretics to the proximal nephron. This results in an increased reabsorption of sodium and water and poor diuretic response; hence, diuretic resistance despite escalating doses of oral or intravenous diuretics and need for combination diuretic therapy or ultrafiltration. A sudden increase in creatinine can be seen after initiation of diuretic therapy and is often mistaken on clinical examination as overdiuresis or intravascular depletion even in the presence of fluid overload, prompting most physicians to decrease and/or stop ACEI/ARB and/or diuretics. When diuresis or ultrafiltration is continued, an improvement in renal function, decrease in total body fluid, and increased response to diuretics as CVP is lowered is noted. Use of low-dose dopamine to increase kidney perfusion has contradictory data with no randomized controlled studies. Use of nesiritide, a synthetic natriuretic peptide, to increase diuresis has not been studied and should not be used unless the patient is in pulmonary edema and needs heart failure symptom relief. A meta-analysis of several trials using nesiritide suggests the potential of worsening renal function, although this has not been demonstrated in prospective trials. The EVEREST trial showed that the vasopressin antagonist tolvaptan in acute heart failure in addition to diuretic therapy facilitates diuresis; however, it has no impact on mortality or hospitalizations.19 Currently, adenosine receptor antagonists are in trial to evaluate their role in acute heart failure.
Treatment of Patients at High Risk for Developing Heart Failure (Stage A)

This population includes patients who have risk factors for developing heart failure (eg, hypertension, diabetes mellitus, obesity, metabolic syndrome, sleep apnea, patients with family history of dilated cardiomyopathy or using cardiotoxins). These patients should be treated with aggressive risk factor modification, education, and ACEI/ARB if diabetes mellitus or vascular disease is present (HOPE, SOLVD-prevention). Patients who have a family history of dilated cardiomyopathy should be screened with a comprehensive history and physical examination

together with echocardiography and transthoracic echocardiography every 2-5 years. Treatment of Heart Failure With LV Systolic Dysfunction (Stages B,C,D)

Medical therapy of heart failure focuses on 3 main goals: (1) preload reduction, (2) reduction of systemic vascular resistance (afterload reduction), and (3) inhibition of both the RAAS systems and vasoconstrictor neurohumoral factors produced by the sympathetic nervous system in patients with heart failure. The first 2 goals provide symptomatic relief. While reducing symptoms, inhibition of the RAAS and neurohumoral factors also results in significant reductions in morbidity and mortality rates. Preload reduction results in decreased pulmonary capillary hydrostatic pressure and reduction of fluid transudation into the pulmonary interstitium and alveoli. Afterload reduction results in increased cardiac output and improved renal perfusion, which facilitates diuresis in the patient with fluid overload. Inhibition of the RAAS and sympathetic nervous system produces vasodilation, thereby increasing cardiac output and decreasing myocardial oxygen demand. Stage B includes asymptomatic patients with LV dysfunction from previous myocardial infarction, LV remodeling from left ventricular hypertrophy, and asymptomatic valvular dysfunction. In addition to heart failure education and aggressive risk factor modification, treatment with ACEI/ARB (SOLVD-prevention, SAVE, VALIANT) and/or beta-blockade (SOLVD prevention, SAVE, Capricorn) is indicated. Evaluation for coronary revascularization either percutaneously or surgically as well as correction of valvular abnormalities may be indicated. Implantation of an internal cardiodefibrillator (ICD) for primary prevention of sudden death in patients with LVEF less than 30% more than 40 days post-myocardial infarction, is reasonable if expected survival is more than 1 year (MADIT II). There is less evidence for implantation of an ICD in patients with nonischemic cardiomyopathy, LVEF less than 30%, and no heart failure symptoms. There is no evidence for use of digoxin in these populations (DIG trial).20 Aldosterone receptor blockade with eplerenone is indicated for postmyocardial infarction LV dysfunction (EPHESUS). Stage C includes patients with NYHA Class II and III heart failure and Stage D include patients with refractory end-stage heart failure (Class IV). Therapeutic measures that improve symptoms and mortality and morbidity include use of ACEI/ARBs, beta-blockers, aldosterone receptor blockers, hydralazine and nitrates in combination, and cardiac resynchronization with or without an implantable cardioverterdefibrillator. ACEIs are recommended for all patients with current or prior symptoms of heart failure and reduced LVEF unless contraindicated (SOLVD, SAVE, AIRE, TRACE, Consensus) (Class I ACCF/AHA recommendation, level of Evidence A). ACEIs block RAAS, decrease afterload, and prevent LV remodeling. They increase survival and decrease rate of heart failure hospitalization. Optimal dosing of ACEIs improves symptoms and decrease hospitalization, although it has no impact on mortality or LVEF (ATLAS). Side effects include, but are not limited to, worsening renal function, hyperkalemia, hypotension, cough, rash, change in taste, angioedema, and renal abnormalities in the fetus if administered during the first trimester of

pregnancy. If cough develops, the patient can be switched to an ARB. If angioedema occurs, the ACEI should be immediately discontinued. There is a 1% chance that an ARB can also cause angioedema. ARBs are recommended for patients with current or prior symptoms of heart failure and evidence of LV systolic dysfunction who are intolerant to ACEIs (Class I, level of Evidence A) (VAL-Heft, Charm-Alternative).21 ARBs block RAAS, decrease afterload, and prevent LV remodeling. Their use increases survival and decreases hospitalization rate. ARBs are not superior to ACEIs. Pregnancy still constitutes a contraindication. Blood pressure, renal function, and potassium need to be monitored carefully. ARBs are reasonable first-line therapy for patients with mild-to-moderate heart failure symptoms and LV dysfunction when patients are already taking them for other indications. (Class IIa, level of Evidence A). ARBs can also be used as add-on therapy for patients with refractory heart failure symptoms despite optimal heart failure therapy (Class IIb, level of Evidence B) (Charm-Added, Optimaal).22 Concomitant use of ACEIs, ARBs, and aldosterone receptor blockers is contraindicated due to risk of renal failure and hyperkalemia. Use of one of the 3 beta-blockers proven to reduce mortality (bisoprolol-CIBIS II23 , carvedilolCopernicus24 , US carvedilol, metoprolol succinate-MERIT HF) is recommended for all stable patients with current or prior symptoms of heart failure and reduced LVEF, unless contraindicated (Class I, level of Evidence A). Beta-blockers inhibit sympathetic nervous system and decrease mortality, hospitalizations, and risk of sudden death. They improve LV function, exercise tolerance, and heart failure functional class. Beta-blockers should not be used in patients with cardiogenic shock or requiring vasopressors. Titration should be performed carefully on an outpatient basis every 2 weeks to maximum tolerated or maximum recommended doses (bisoprolol start dose 1.25-10 mg daily, carvedilol 3.125-25 mg bid or 50 mg bid if patients weight exceeds 180 lb; metoprolol succinate 12.5200 mg daily). Aldosterone antagonists are weak diuretics that improve mortality and risk of sudden death by blocking aldosterone effects, therefore decreasing myocardial and vascular inflammation, collagen production, preventing apoptosis, decreasing RAAS and sympathetic nervous system stimulation, and acting as a membrane stabilizer preventing arrhythmia. Their use is a Class I, level of Evidence B recommendation for patients with moderately severe and severe heart failure and reduced LV systolic function (RALES) who can be carefully monitored for preserved renal function and normal potassium concentration. Spironolactone 12.5-50 mg daily is indicated for Class III-IV patients with heart failure as add on to optimal heart failure therapy. Eplerenone 25-50 mg daily is indicated for post-myocardial infarction LV dysfunction with heart failure symptoms. Side effects of spironolactone include gynecomastia and impotence in men and breast tenderness and decreased libido in women. These hormonal side effects are not present in eplerenone. Both drugs are contraindicated if creatinine is more than 2 mg/dL in women and more than 2.5 mg/dL in men, or potassium is more than 5 mEg/dL. Follow-up renal function and potassium is recommended 7-10 days after initiation. Combined use of ACEIs or ARBs with aldosterone antagonists is contraindicated due to high risk of renal failure and hyperkalemia.

Hydralazine and nitrate combination reduces both preload and afterload. The combination is recommended to improve outcomes for patients self-described as African Americans with moderate-to-severe symptoms of heart failure on optimal medical therapy with ACEIs/ARBs, beta-blockers, and diuretics (Class I, level of Evidence B) (A-Heft trial). The combination of hydralazine and nitrates can be added in patients with LV dysfunction who continue to have moderate-to-severe heart failure symptoms despite optimal heart failure therapy for symptom control (Class IIa, level of Evidence B). A combination of hydralazine and nitrate can be reasonable in patients with current or prior symptoms of heart failure and LV dysfunction who cannot tolerate ACEIs or ARBs due to drug intolerance, hypotension, or renal insufficiency (Class IIb, level of Evidence C) (V-Heft). Implantable cardioverter-defibrillators (ICDs) are a Class I, level of Evidence A recommendation for secondary prevention of sudden cardiac death in patients with current or prior heart failure symptoms and LV dysfunction who survived cardiac arrest, have evidence of ventricular fibrillation or hemodynamically unstable ventricular tachycardia (MADIT I). ICD therapy is a Class I, level of Evidence A recommendation for primary prevention of sudden death in patients with nonischemic dilated cardiomyopathy or ischemic heart disease at least 40 days post-myocardial infarction who have an LVEF 35% or less, have NYHA Class II or III heart failure, are on optimal heart failure therapy, and have a life expectancy of more than 1 year. (SCD-Heft, MADIT II) Patients with heart failure and low LVEF often have electrical conduction abnormalities, left bundle brunch block (LBBB) being common. Prognosis of patients with reduced LVEF and LBBB is worse than in patients without LBBB. LBBB leads to delayed activation of myocardium and therefore mechanical dyssynchrony, which clinically translates in inefficient LV contraction with increased LV end diastolic pressure, increased mitral regurgitation, and pulmonary wedge pressure, decreased cardiac output which leads to decreased exercise tolerance and progression of heart failure symptoms. Using RV and LV pacing can restore the mechanical synchrony (cardiac resynchronization) and can lead to LV reverse remodeling with decrease in cardiac pressures, mitral regurgitation and improved LVEF and exercise tolerance. Cardiac resynchronization therapy (CRT) is indicated for patients with LVEF 35% or less, sinus rhythm, and NYHA Class III and IV symptoms who are on optimal medical therapy and have evidence of cardiac desynchrony as evident by QRS duration more than 120 msec with or without an ICD (Class I, level of Evidence A) (COMPANION, CARE-HF).25 CRT with or without an ICD, maybe reasonable for patients with chronic atrial fibrillation, LVEF 35% or less, NYHA Class III and IV, QRS duration more than 120 msec on optimal medical therapy (Class IIa, level of Evidence B). CRT with or without an ICD is reasonable for patient who have frequent RV pacing, LVEF 35% or less, NYHA Class III and IV, and are on optimal heart failure therapy (Class IIa, level of Evidence C -- DAVID trial). The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) studied the potential benefit of CRT with biventricular pacing in patients with an ejection fraction of 30% or less, a QRS duration of 130 msec or more, and New York Heart Association class I or II symptoms. Over the course of 4.5 years, 1820 patients were randomly assigned to receive CRT plus an implantable cardioverter-defibrillator (ICD) or ICD alone. CRT was associated with a significant reduction in left ventricular

volumes and improvement in the ejection fraction. No significant difference occurred between the 2 groups studied in the overall risk of death.26
Levy et al found that, in moderately symptomatic heart failure patients with an ejection fraction of 35% or less, primary prevention with an ICD provides no benefit in some cases but substantial benefit in others, and that ICD benefit can be predicted. Analysis of data from the placebo arm of the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) showed that patients could be classified into 5 groups on the basis of predicted 4-year mortality. In the treatment arm, ICD implantation decreased relative risk of sudden cardiac death by 88% in patients with the lowest baseline mortality risk versus 24% in the highest-risk group (P=0.009 for interaction). ICD treatment decreased relative risk of total mortality by 54% in the lowest-risk group but provided no benefit (2%) in the highest-risk group (P=0.014 for interaction).27 Therapeutic measures assisting with symptom relief include diuretics, digoxin, inotropes, oxygen, and morphine.

Diuretic therapy improves symptoms by decreasing preload, afterload, and intracardiac filling pressures. Diuretics continue to be a Class I, level of Evidence C recommendation for heart failure. First-line diuretic therapy is a loop diuretic (furosemide, bumetanide, torsemide) in the lowest efficient dose either once or twice a day, although it can be used up to 3-4 times a day depending on the individual response and renal function. Response to diuretic therapy often depends on bioavailability of the drug (better on an empty stomach) and nutritional level (loop diuretics are bound to proteins for renal delivery). If the patient does not respond to the above strategy, a thiazide diuretic (hydrochlorothiazide or metolazone) can be added 30 minutes prior to the loop diuretic to enhance response. Potassium-sparing diuretics (spironolactone, eplerenone) are used usually in addition to the loop diuretics. Careful monitoring of renal function and potassium is necessary for all diuretics.
Digoxin has been a cornerstone for the treatment of heart failure for decades and is the only oral inotropic support agent currently used in clinical practice. Digoxin acts by inhibiting the Na+/K+ ATPase transport pump and inhibits sodium and potassium transport across cell membranes. This increases the velocity and shortening of cardiac muscle, resulting in a shift upward and to the left of the ventricular function (Frank-Starling) curve relating stroke volume to filling volume or pressure. This occurs in healthy and failing myocardium and in atrial and ventricular muscle. The positive inotropic effect is due to an increase in the availability of cytosolic calcium during systole, thus increasing the velocity and extent of myocardial sarcomere shortening. Digoxin is a Class IIa, level of Evidence B recommendation for patients with heart failure who continue to have symptoms despite optimal medical therapy as it showed in the DIG trial to decrease hospitalization rate. Digoxin does not affect heart failure mortality. Digoxin is also an effective agent against atrial tachyarrhythmias at rest in patients with LV dysfunction, but it has limited efficacy in controlling the ventricular rate of atrial arrhythmias during exertion. Daily dosage remains 0.125-0.25 mg. The dosage has to be adjusted for drug-drug

interactions as well as renal function. There are numerous drug-drug interactions such as with amiodarone, propafenone, quinidine, verapamil, nifedipine, diltiazem, levothyroxine, cyclosporine, flecainide, disopyramide, omeprazole, tetracycline, and erythromycin. Adjustment of digoxin dose is important to avoid digoxin toxicity. If renal insufficiency is present, clearance of digoxin is reduced and dose needs to be adjusted to avoid toxicity. Manifestations of digoxin toxicity include cardiac arrhythmias, including heart block, neurologic complaints such as confusion or visual disturbances, and GI symptoms with nausea and vomiting. Although therapeutic range is referenced as less than 2 ng/dL, a retrospective analysis from the DIG trial has shown levels above 1 ng/dL can be associated with increased mortality. Intravenous Digibind is used as an antidote for digoxin toxicity.

Inotropic therapy with either beta-agonists (dopamine, dobutamine) or PDEi (milrinone) is used for acute heart failure and evidence of cardiogenic shock with end-organ dysfunction (see acute heart failure for details). Long-term use of an infusion of a positive inotropic drug may be harmful and is not recommended for patients with current or prior symptoms of heart failure and reduced LVEF, except for palliation in patients with end-stage disease who cannot be stabilized with standard medical therapy (Class III, level of Evidence C). In stage C and D patients with evidence of LV dysfunction and atrial fibrillation, treating them with a strategy of rhythm or rate control is reasonable (Class IIa, level of Evidence B) (AFCHF).
Patients with heart failure and depressed LVEF are thought to have an increased risk of thrombus formation due to low cardiac output. Anticoagulation with an INR goal 2-3 is indicated in the presence of LV thrombus, thromboembolic event with or without evidence of an LV thrombus, and paroxysmal or chronic atrial arrhythmias. Routine anticoagulation with warfarin in patients with normal sinus rhythm, heart failure, and LV dysfunction has proven not to be superior to aspirin alone in decreasing death, myocardial infarction, and stroke, and can be associated with an increased risk of bleeding in the Coumadin arm (WATCH trial).28

Oxygen and morphine should be used for patients with respiratory distress due to heart failure and evidence of hypoxemia. Drugs that can exacerbate heart failure should be avoided (NSAIDs, calcium channel blockers, most of antiarrhythmic drugs except class III) (Class I, level of Evidence B). Use of nutritional supplements as well as hormonal therapies should be avoided in this population (Class III, level of Evidence C).
Exercise training is beneficial as an adjunctive approach to improve clinical status in patients with current or prior symptoms of heart failure and reduced LVEF (Class I, level of Evidence B). Maximal exercise testing with or without measurement of

gas exchange is reasonable to facilitate prescription of appropriate exercise level in patients presenting with heart failure (Class IIa, level of Evidence C). Patients should be encouraged to exercise daily for at least 20-30 minutes in a lowintensity, endurance-enhancing activity such as walking, biking, or swimming. Regular exercise improves quality of life and efficiency of oxygen use at the tissue level.

Comorbidities should be treated aggressively. Sleep apnea has an increased prevalence in heart failure and is associated with increased mortality due to further neurohormonal activation, although randomized controlled data is lacking. Anemia is also common in chronic heart failure. Whether anemia is a reflection of the severity of heart failure or contributes to worsening heart failure is not clear. Poor nutrition, ACEI, RAAS, inflammatory cytokines, hemodilution, and renal dysfunction are potential etiologies of anemia in heart failure. Anemia in heart failure is associated with increased mortality. Replacement therapy safety and efficacy is unknown, although iron supplementation seems to be beneficial and safe. Dietary sodium restriction to 2-3 g/d is recommended. Fluid restriction to 2 L/d is recommended for patients with evidence of hyponatremia (Na <130 mEg/dL) or in patients with difficult to control fluid status despite high-dose diuretics and sodium restriction. Caloric supplementation is recommended for patients with evidence of cardiac cachexia. Education and enrollment of family members in disease management programs is recommended for advanced heart failure patients. Patients with refractory end-stage heart failure (stage D, NYHA Class IV) are often difficult to manage as outpatients. Therefore referral to a heart failure program with expertise in management of refractory heart failure is useful. Options of end-of-life care should be discussed with patient and family, including the option of ICD inactivation. Eligible patients should be referred for cardiac transplantation or mechanical circulatory support implantation either as a bridge to transplant or destination therapy (see Surgical Care). Although continuous infusion of inotropes maybe considered in this population for palliation of symptoms, intermittent infusion is not recommended.13 Education of patient and family about prognosis, functional status and survival is important for end-of-life decisions and care. Referral to palliative and hospice care to help with patient comfort and care maybe appropriate.
Surgical Care

Coronary revascularization either percutaneously or surgically can improve LV function, heart failure symptoms, survival, and functional status.13 Patients with history of coronary artery disease should have comprehensive evaluation for evidence of ischemia even in the absence of symptoms to establish the amount of viable, hibernating myocardium. The increase in LVEF units can reach as much as 10% and can be achieved up to 1 year after revascularization. Surgical ventricular reconstruction in patients with heart failure with anteroapical myocardial infarction when coupled with surgical coronary revascularization has not shown to improve mortality, cardiac hospitalizations, or quality of life (STICH trial) (formerly called DOR procedure). Surgical ventricular reconstruction is not indicated for patients with nonischemic dilated cardiomyopathy and refractory end-stage heart failure (Class III, Level of Evidence C).

Valvular surgery is indicated for primary valvular abnormalities leading to development of heart failure. Surgical repair/replacement of secondary valvular abnormalities related to the enlargement of the LV is not thought to be beneficial. The effectiveness of mitral valve repair or replacement for severe mitral regurgitation in refractory end-stage heart failure is not well established (Class IIb, Level of Evidence C). Assisted circulation in the treatment of heart failure include intraaortic balloon pump (IABP) and short- or long-term ventricular assist device (VAD), either paracorporeal or fully implantable. o IABP is inserted percutaneously via the femoral artery with the distal end of the pump placed just distally to the aortic knob and the origin of left subclavian artery. Fluoroscopy may be used for correct positioning of the balloon, and a subsequent chest radiograph should be obtained to document satisfactory balloon placement. IABP inflates in diastole, providing augmentation of coronary and carotid flow and deflates in systole, assisting decrease in afterload and LV intracardiac pressures, therefore decreasing myocardial oxygen consumption and increasing cardiac output. IABP is indicated for patients with cardiogenic shock as a bridge to revascularization or VAD implantation. It can also provide stabilization of unstable angina prior to revascularization and assist with management of pulmonary edema especially in acute/severe mitral regurgitation while allowing definitive surgical correction. It also helps with preand postoperative management of patients with LV/RV dysfunction. The absolute contraindications for IABP counterpulsation are aortic dissection, severe aortic regurgitation, presence of a large arteriovenous shunt, and severe coagulopathy. The relative contraindications are severe peripheral vascular disease, recent thrombolytic therapy, and bleeding diathesis IABP complications include vascular access problems at the site of cannulation, limb ischemia, mild thrombocytopenia, infection, bleeding, thromboembolic events to other organs including kidneys or intestines o VAD can be used short term in postcardiotomy shock patients, postmyocardial infarction cardiogenic shock patients, or patients with acute myocarditis or refractory ventricular tachyarrhythmia and in patients with decompensated chronic heart failure. Long-term support can be provided by implantable VADeither pulsatile (Thoratec, Heartmate XVE) or axial flow device (Heartmate II). The long-term support can be used as a bridge to transplant or as destination therapy when patients are not transplant candidates. Data from the REMATCH trial supports better survival in patients with end-stage heart failure treated with LVAD rather than inotropes. Complications from VAD include bleeding, infections, thromboembolic events, mechanical failure, right heart failure, multisystem organ failure, and increased sensitization. Cardiac transplantation is indicated for patients with end-stage heart failure who have failed maximal medical and surgical therapy as the last option for improved survival and quality of life. Other indications for cardiac transplantation include end-stage restrictive cardiomyopathy or constrictive pericarditis, end-stage hypertrophic cardiomyopathy, refractory angina, refractory ventricular tachycardia, complex congenital heart disease, acute

myocarditis unresponsive to maximal medical therapy, and failed cardiac allograft either from rejection or coronary disease. Patients eligible for cardiac transplantation have to be younger than 70 years, have no evidence of permanent end organ dysfunction, cancer, severe pulmonary hypertension, have good social support, and be compliant. Consultations

Consultation with subspecialists depends on the underlying cause of CHF. Heart failure is now an area of subspecialization within cardiology.

If the acute episode is attributed to an acute MI, acute cardiac ischemia, or acute dysrhythmia, consultation with a cardiologist is warranted. If the episode is attributed to fluid overload in patients with renal failure, consultation with a nephrologist is indicated for emergent/urgent hemodialysis. If heart failure results from acute valvular dysfunction, consultation with a cardiothoracic surgeon and a cardiologist for urgent valve replacement may be indicated, depending on the integrity of the valve involved. In patients who develop cardiogenic shock, consultation with a cardiologist is generally indicated in order to rapidly diagnose and aggressively treat with various modalities (pharmacologic and/or mechanical), to maximize cardiac performance and improve hemodynamics, and, in some cases, to place an intraaortic balloon pump to serve as a temporizing measure prior to surgery (ie, for valve replacement or coronary revascularization).

Diet

Patients admitted with heart failure or pulmonary edema should maintain a low-salt diet in order to minimize fluid overload. Monitor fluid balance closely.
Activity

Patients with decompensated heart failure should be placed on complete bed rest until their decompensation is resolved. This is necessary to maximally reduce myocardial oxygen demand and to avoid exacerbation of the abnormal hemodynamics and symptoms of heart failure. Once the patient with heart failure has been stabilized, activity should be gradually and progressively increased. Emphasize the importance of cardiac rehabilitation to all patients with heart failure who require improved cardiac fitness. Encourage patients to exercise daily for at least 20-30 minutes in a low-intensity, endurance-enhancing activity such as walking, biking, or swimming. Regular exercise improves the quality of life for these patients and improves efficiency of oxygen utilization at the tissue level, thus reducing the workload of the heart in the role of oxygen delivery to end organs and muscles

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Human B-type natriuretic peptides (hBNPs)

Dilate veins and arteries. Used in the treatment of acute severe CHF.

Nesiritide (Natrecor)

Recombinant DNA form of hBNP, which dilates veins and arteries. hBNP binds to particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells. Binding to receptor causes increase in cGMP, which serves as second messenger to dilate veins and arteries. Reduces PCWP and improves dyspnea in patients with acutely decompensated CHF.
Adult

2 mcg/kg IV bolus over 60 sec; follow by 0.01 mcg/kg/min continuous infusion; bolus volume (mL) = 0.33 X patient weight (kg); infusion flow rate of bolus (mL/h) = 0.1 X patient weight (kg)
Pediatric

Not established
Diuretics

May improve symptoms of venous congestion through elimination of retained fluid and preload reduction. Used in CHF. Help counteract the sodium and water retention caused by activation of the RAAS.
Furosemide (Lasix)

Increase excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. Bumetanide does not appear to act in the distal renal tubule. Dose must be individualized to patient. Depending on response, administer at small dose increments until desired diuresis occurs.
Adult

20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states; depending on response, administer at increments of 20-40 mg no sooner than 6-8 h after previous dose
Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; not to administer more frequently than q6h

Spironolactone (Aldactone)

For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.
Adult

25-200 mg/d PO qd or divided bid

Pediatric

1.5-3.5 mg/kg/d PO qd or divided qid

Angiotensin receptor blockers

Interfere with the binding of formed Ang II to its endogenous receptor. Used primarily when patients are intolerant of ACE inhibitors because of adverse effects but are gaining wider use as first-line vasodilator agents. Equally effective as ACE inhibitors.
Valsartan (Diovan)

Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of reninangiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For use in patients unable to tolerate ACE inhibitors.
Adult

80 mg/d PO; may increase to 160 mg/d if needed

Pediatric

Not established
Vasodilators

The use of a vasodilators reduces SVR, thus allowing more forward flow and improving cardiac output. Indicated for CHF.

Nitroglycerin (Nitrostat, Deponit, Transderm-Nitro Patch)

Isosorbide dinitrate (Isordil), Isosorbide mononitrate (Imdur)--First-line therapy for patients who are not hypotensive. Provides excellent and reliable preload reduction. Higher doses

provide mild afterload reduction. Has rapid onset and offset (both within minutes), allowing rapid clinical effects and rapid discontinuation of effects in adverse clinical situations.
Adult

Nitroglycerin Topical: Apply topically 1/2-2" q6h Transdermal: 0.3-0.6 mg/h qd Intravenous: 0.2-10 mcg/kg/min IV infusion; titrate by 10 mcg/min increments until desired hemodynamic effect achieved or until maximally tolerated dose reached Spray: Single spray (0.4 mg), which is equivalent to single 1/150 sublingual; dose may be repeated q3-5min as hemodynamics permit, up to maximum of 1.2 mg Isosorbide dinitrate: 10-80 mg PO bid/qid Isosorbide mononitrate: 30-90 PO mg qd
Pediatric

Not established
Isosorbide dinitrate and hydralazine (BiDil)

Fixed-dose combination of isosorbide dinitrate (20 mg/tab), a vasodilator with effects on both arteries and veins, and hydralazine (37.5 mg/tab), a predominantly arterial vasodilator. Indicated for heart failure in black patients, based in part on results from the African American Heart Failure Trial. Two previous trials in the general population of patients with severe heart failure found no benefit but suggested a benefit in black patients. Compared with placebo, black patients showed a 43% reduction in mortality rate, a 39% decrease in hospitalization rate, and a decrease in symptoms from heart failure.
Adult

1 tab PO tid; may titrate upward, not to exceed 2 tab tid

Pediatric

Not established
Inotropic agents

Augment both coronary and cerebral blood flow present during the low flow states. Used in severe acute CHF with low cardiac output.

Digoxin (Lanoxin, Lanoxicaps)

Cardiac glycoside with direct inotropic effects in addition to indirect effects on cardiovascular system. Acts directly on cardiac muscle, increasing myocardial systolic contractions. Indirect actions result in increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increase in mean arterial pressure.

Adult

0.125-0.375 mg PO qd
Pediatric

Not established
Norepinephrine (Levophed)

Naturally occurring catecholamine with potent alpha-receptor and mild beta-receptor activity. Stimulates beta1- and alpha-adrenergic receptors, resulting in increased cardiac muscle contractility, heart rate, and vasoconstriction. Increases blood pressure and afterload. Increased afterload may result in decreased cardiac output, increased myocardial oxygen demand, and cardiac ischemia. Generally reserved for use in patients with severe hypotension (eg, systolic blood pressure <70 mm Hg) or hypotension unresponsive to other medication.
Adult

0.5-1 mcg/min IV infusion initially, titrated to effect; not to exceed 30 mcg/min

Pediatric

Not established
Beta-adrenergic blockers

Inhibit chronotropic, inotropic, and vasodilatory responses to beta-adrenergic stimulation. Particularly useful in the patient with elevated blood pressure and relative tachycardia. Inhibits sympathetic nervous stimulation, particularly E and norepinephrine and blocks alpha1adrenergic vasoconstrictor activity. Has moderate afterload reduction properties and results in slight preload reduction as well.
Metoprolol XL (Toprol)

Selective beta1-adrenergic blocker at lower doses; inhibits beta2-receptors at higher doses. Does not have intrinsic sympathomimetic activity. May reduce cardiac output, but does not appear to decrease peripheral vascular resistance to any significant degree.
Adult

100 mg PO qd; titrate to maximum dose of 400 mg/d PO in 1-2 divided doses.
Pediatric

Not established

Angiotensin-converting Enzyme (ACE) Inhibitors

Inhibit renal systemic and tissue generation of Ang II by ACE; decrease metabolism of bradykinin (BK). Their blockade of Ang II and the delayed clearance of BK by ACE blocks the direct vasoconstriction of Ang II, as well as the activation of the sympathetic nervous system, and promotes arterial and venous dilation. In addition, ACE inhibitors reduce intracavitary pressures and diminish Wass stress, thereby decreasing myocardial oxygen demand. They inhibit the release of aldosterone, thereby reducing intravascular volume and preload. Among vasodilators, the ACE inhibitors are the most balanced vasodilators, having an equal effect on reducing both afterload and preload.
Captopril (Capoten)

Lisinopril (Prinivil, Zestril); Ramipril (Altace); Fosinopril (Monopril)--Prevent conversion of Ang I to Ang II (a potent vasoconstrictor), resulting in increased levels of plasma renin and a reduction in aldosterone secretion.
Adult

6.25-12.5 mg PO tid; not to exceed 150 mg tid

Pediatric

Not established