Anaphylaxis

Peter Mack October 31, 2007

Hypersensitivity Responses
1975 - Gell & Coombs described a scheme for classifying immune responses which function as protective mechanisms However, these immune pathways can react inappropriately to produce a hypersensitivity or allergic response Hypersensitivity reaction I - IV

Type I
Anaphylactic (immediate - type) Physiologically active mediators are released from mast cells & basophils Triggered by antigen binding to IgE antibodies on the membranes of these cells Eg. Anaphylaxis, allergic rhinitis

Type I
Cross-linkage of two IgE induce degranulation Complement independent

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Type II (Cytotoxic Reactions)

Antibody-dependent cell-mediated cytotoxic hypersensitivity IgG & IgM directed against antigens on foreign cells Antigens can be integral membrane components (ABO) or haptens that absorb to cell surfaces (AIHA)

Type II
Cell damage produced by:
Direct cell lysis after complete compliment cascade activation Increased phagocytosis by macrophages Killer T-cell lymphocyte producing Abdependent cell-mediated cytotoxic effects Eg. ABO incompatibility, HIT

Type II
Complement activation
Targeted cell destruction
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Type III
Circulation, soluble antigens & antibodies that bind to form insoluble complexes that deposit in the microvasculature Complement is activated & neutrophils localize to the site & produce tissue damage Eg. Serum sickness after snake antisera

Type III
Basement membrane Endothelium Antigen

Complement

Vasculitis, Increased capillary permeability

IgG

PMN

Type IV
Delayed hypersensitivity reactions Interaction of sensitized lymphocytes with specific antigens (antibody independent) Manifests 18-24h, peak 40-80h, disappears 72-96h

Type IV
Antigen-lymphocyte binding produces
Lymphokine synthesis Lymphocyte proliferation Generation of cytotoxic T-cells Attraction of macrophages

Cytotoxic T-cells specifically kill target cells that bear antigens identical to those that triggered the reaction

Type IV

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Eg. Graft-versus-host, contact dermatitis

Intraoperative Allergic Reactions

1:5,000 - 1:25,000 anesthetics 3.4% mortality >90% evoked by IV drugs occurs within 5 minutes Anaphylaxis is the most feared, with circulatory collapse, reflecting vasodilation & decreased venous return

Definitions
Anaphylaxis (Portier & Richet) ana - against prophylaxis - protection Profound shock & subsequent death in dogs after 2nd challenge with a foreign antigen Mediated by antibodies

Definitions
Anaphylactoid
When antibodies are not responsible for the reaction, or their involement cannot be proven Cannot be distinguished from one another on the basis of clinical observation

Recognition of Anaphylaxis During Regional and General Anesthesia

Systems Respiratory Symptoms Dyspnea Chest discomfort Signs Coughing Wheezing Sneezing Laryngeal edema Decreased pu lmonary compliance Fulminant pulmonary edema Acute respiratory failure Disorientation Diaphoresis Loss of consciousness Hypotension Tachycardia Dysrhythmias Decreased s ystemic vascular resistance Cardiac arrest Pulmonary hypertension Urticaria Flushing Periorbital edema Perioral edema

Cardiovascular

Dizziness Malaise Retrosternal oppression

Cutaneous

Itching Burning Tingling

Anaphylactic Reactions IgE-mediated pathophysiology

Antigen binding to IgE initiates the reaction Prior exposure to the antigen (or substance of similar structure) is required for sensitization Allergic history may be unknown

Anaphylactic Reactions IgE-mediated pathophysiology

On re-exposure, antigen binds to & bridges two immunospecific IgE Abs located on the surface of mast cells of basophils Liberates stored mediators
Histamine, tryptase, chemotactic factors

Anaphylactic Reactions IgE-mediated pathophysiology

Arachadonic acid metabolites (leukotrienes, prostaglandins) Kinins & cytokines
Synthesized & released in response to cellular activation

Anaphylactic Reactions IgE-mediated pathophysiology

Bronchospasm, upper airway edema Vasodilation, increased capillary permeability Urticaria
Challenge in sensitized individuals usually produces immediate clinical manifestations

Clinical Mediators
Histamine (H1, H2, H3 receptors) H1 - releases NO from vascular endothelium, increases capillary permeability, contracts airways & vascular smooth muscle H2 - gastric secretions, inhibits mast cell activation, & contributes to vasodilation

Histamine
Undergoes rapid metabolism by histamine N-methyltransferase & diamine oxidase located in endothelial cells

Peptide Mediators
Factors that cause granulocyte migration (chemotaxis) & collection at the site of inflammatory stimulus Eosinophilic chemotactic factor of anaphylaxis (ECF-A)
Draws eosinophils, but role is uncertain as eosinophils release enzymes that can inactivate histamine & leukotrienes

Arachadonic Acid Metabolites

Leukotrienes & prostaglandins are both synthesized after activation of mast cells Metabolism of phospholipid membranes via lipoxygenase or cyclooxygenase

Leukotrienes
C4, D4, E4 Slow reacting
Bronchoconstriction (> histamine) Increased capillary permeability Vasodilation Coronary vasoconstriction Myocardial depression

Prostaglandins
PG D2 Vasodilation Bronchospasm Pulmonary hypertension Increased capillary permeability

Kinins
Vasodilation Increased capillary permeability Bronchoconstriction
Stimulates vascular endothelium to release vasoactive factors
Prostacyclin, NO

Platelet-Activating Factor
Synthesized in activated mast cells Extremely potent Causes platelets to aggregate and release inflammatory products PAF causes profound wheal-andflare response, smooth muscle contraction & increase capillary permeability

Non-IgE-Mediated Reactions
Other immunologic & nonimmunologic mechanisms liberate many of the same mediators producing clinically identical syndromes

Complement
activation follows both immunologic (Ab-mediated, i.e., classic pathway) or nonimmunologic (alternative) pathways to include a series of multimolecular, self-assembling proteins that liberate biologically active complement fragments of C3 & C5

Complement
C3a & C5a anaphylatoxins Release histamine, contract smooth muscle, increase capillary permeability and stimulate interleukin synthesis

Complement
C5a interacts with specific highaffinity receptors on PMNs & platelets initiating leukocyte chemotaxis, aggregation & activation

Complement
Aggregated leukocytes embolized to various organs, producing microvascular occlusion & liberation of inflammatory mediators such as arachadonic acid metabolites, O2 free radicals & lysosomal enzymes

Nonimmunologic Release of Histamine

Many molecules administered in the perioperative period release histamine in a dose-dependent, nonimmunologic fashion Mechanism not fully understood Involves selective mast cell & basophil activation Cutaneous mast cells are the only cell population that releases histamine in response to drugs & endogenous stimuli

Drugs Capable of Nonimmunologic Histamine Relsease

Antibiotics (Vancomycin) Basic compounds Hyperosmotic agents Muscle relaxants (d-turbocurarine, atracurium, mivacurium) Opioids (morphine, meperidine, codeine) Thiobarbiturates

Treatment Plan
Hypoxia Hypotension 2 to Vasodilation Increased capillary permeability Bronchospasm

Airway Maintenance 100% O2 Intravascular volume expansion Epinephrine

Treatment Plan
Titrated to desired effect with careful monitoring Reactions can be protracted requiring aggressive therapy Manifestations may recur after successful treatment
monitor in ICU x 24h

Watch for
Persistent hypotension Pulmonary hypertension Lower respiratory obstruction Laryngeal obstruction May continue for 5-32h despite vigorous therapy

Managment of Anaphylaxis During General Anesthesia

Initial Therapy
Stop of limit further antigen administration Maintain airway & administer 100% O2
Profound V/Q mismatch can accompany anaphylaxis ABGs may be useful to follow

Initial Therapy
D/C all anesthetic drugs
Vapours are not the bronchodilator of choice after anaphylaxis Worsen hypotension Interfere with bodys compensatory response to CV collapse

Initial Therapy
Volume expansion
Hypovolemia (up to 40% loss of intravascular fluid into interstitial space) 2-4 L crystalloid/ colloid initially (an additional 25-50 ml/kg may be necessary) Refractory hypotension additional monitoring
TEE can assess intravascular volume, ventricular function & any other occult cause of CV dysfunction Useful to guide therapy

Fulminant noncardiogenic pulmonary edema

Require intravascular volume repletion with careful hemodynamic monitoring until capillary dysfunction improves

Initial Therapy
Epinephrine
Drug of choice
- adrenergic combats hypotension 2 causes bronchodilation & inhibits mediator release by cAMP in mast cells & basophils

Route & dose depend on patients condition Rapid & timely as pts under GA may have altered sympathoadrenergic responses, whereas pts under regional may be partially sympathectomized & require larger doses

Initial Therapy
Epinephrine
50-100 g bolus Titrated to restore BP along with additional volume Complete CV collapse (0.1-1 mg) Laryngeal edema (w/o hypotension) may give sc

Secondary Treatment
Antihistamine
0.5-1.0 mg/kg diphenhydramine (H1) Does not inhibit the reaction, or release of histamine Competes for receptor sites H2 antagonists remain unclear

Catecholamines
Epinephrine infusions for persistent hypotension or bronchospasm
0.05-0.1g/kg/min (5-10g/min) & titrate to correct BP Norepinephrine may also be useful in refractory hypotension 2 SVR
0.05-0.1g/kg/min (5-10g/min)

Aminophylline
Nonspecific phosphodiesterase inhibitor Bronchodilates & histamine release from MC & Bs by cAMP contractility & pulmonary vascular resistance Persistent bronchospasm & hemodynamic stability
IV loading dose 5-6 mg/kg over 20 min 0.5-0.9 mg/kg/hr

Corticosteroids
Anti-inflammatory 12-24h for effect 0.25-1g IV hydrocortisone in IgEmediated reactions 1-2g IV methylprednisolone in complement-mediated
Eg. Pulmonary vasocontriction after protamine

May attenuate late-phase reactions

Bicarbonate
Acidosis develops quickly Diminishes effect of epinephrine Refractory hypotension & acidosis 0.5-1 mEq/kg q5min Follow ABGs

Airway Evaluation
Laryngeal edema may occur
Suggested by facial edema

Leave intubated until edema subsides Air leak useful for patency Consider direct laryngoscopy

Perioperative Management
Allergic drug reactions account for 6-10% of all adverse reactions The risk of an allergic drug reactions ~ 1-3% for most drugs ~5% of adults (1 or more drugs) ~15% of adults believe they are allergic to specific drugs

Adverse Drug Reactions

Predictable ADR account for ~80% of all reactions Dose dependent Known pharmacologic action Most serious, predictable ADR are toxic & directly related to dose (OD)

Adverse Drug Reactions

Side effects are the most common adverse drug reaction and are undesirable pharmacologic actions of the drugs at usual prescribed dosages.

Unpredictable ADRs
Not dose dependent Not related to pharmacologic actions Immunologic response of the individual Proving the immunologic mechanism may be a challenge

Unpredictable ADRs
Occur only in a small percentage of pts receiving the drug Clinical manifestations do not resemble known pharmacologic actions

Unpredictable ADRs
In the absence of prior drug exposure, allergic symptoms rarely appear After sensitization the reaction can occur rapidly on re-exposure

Immunologic Mechanisms
All 4 mechanisms
Eg. Penicillin - different reaction in different pts or spectrum in same pt

In the same pt - anaphylaxis (I), hemolytic anemia (II), serum sickness (III), contact dermatitis (IV) Any one antigen can produce a diffuse spectrum of responses

AGENTS I MPLICATED IN ALLERGIC REACTIONS DURING ANESTHE SIA Anesthetic Agents Induction agents (cremophor-solubili zed drugs, barbiturates, etomidate, propofol) Local anesthetics (para-aminobenzoic ester agents) Muscle relaxants (succinylcholine, gallamine, pancur onium, d-tubocurarine, metocurine, atracurium, vecuronium, mivacurium, doxacurium, rocuronium) Opioids (meperidine, morphine, fentanyl) Other Agents Antibiotics (cephalosporins, penicilli n, sulfonamides, vancomycin) Aprotinin Blood products (whole blood, packed cells, fresh frozen plasma, platelets, cryoprecipitate, fibrin glue, gamma globulin) Bone cement Chymopapain Corticosteroids Cyclosporin Drug additives (preservatives) Furosemide Insulin Mannitol Methylmethacrylate Nonsteroidal anti-inflammatory drugs Protamine Radiocontrast dye Latex (natural rubber) Streptokinase Vascular graft material Vitamin K Colloid volume expanders (dextrans, protein fractions, albumin, hydroxyethyl startch)

Anesthetic Drugs
Nearly all have been implicated Muscle relaxants top the list
Cross-sensitivity between succinylcholine & NDNMB Quaternary ammonium Alternates should not be chosen without testing

Anesthetic Drugs
Life threatening reactions are more likely to occur in patients with a history of allergy, atopy or asthma Does not mandate further testing, pretreatment or avoidance of specific drugs

Evaluation
Identification can be difficult Circumstantial evidence of temporal connection in vitro & in vivo methods are uncommon Direct challenge (obvious hazards) Drug-specific IgE

Testing
No testing & avoidance
One drug & clear temporal correlation

Necessary
Many drugs are given Preservatives

Leukocyte Histamine Release

Incubate pts leukocytes with offending drug & measure histamine release as a marker for basophil activation False positives Difficult to perform

Radioallergosorbant Test (RAST)

in vitro detection of specific IgE directed towards particular antigens Pt serum exposed to antigen, a complex forms if specific IgE present Concentration is calculated (more quantitative than skin testing)

RAST
Avoids re-exposure Limited by commercial availability of drug-specific antigens False positives (pts with elevated IgE levels) Meperidine, succinylcholine, thiopental

Enzyme-linked Immunosorbent Assay (ELISA)

Similar to RAST Useful for protamine

Intradermal Testing
Most common method Demonstrate wheal-and-flare Simple, safe, useful Requires re-exposure

Latex
Important cause of peri-operative anaphylaxis Sap from the tree Hevea brasiliensis (Rubber tree) 1979 - 1st case, contact dermatitis 1989 - intraoperative anaphylaxis 1991 - FDA Dear Colleague

Latex - Risk Factors

Health care workers Children with spina bifida Frequent catheterizations Foods (bananas, avocados, kiwis) Atopy

Latex
24% incidence of contact dermatitis
Early stage of sensitization avoidance

12.5% incidence of latex-specific IgE positivity in anesthesiologists If proven strict avoidance is essential Avoidance of anitgen exposure is the best preventative therapy Pretreatment is of little use

Summary
4 types of hypersensitivities
3 involve antibodies Anaphylaxis mediated by IgE Anaphylactoid is Ab independent

Summary
Anaphylaxis
Bronchospasm Vasodilation, increased capillary permeability Urticaria

Associated with profound CV collapse

Summary
Chemical mediators
Histamine Leukotrienes & Prostaglandins Kinins Platelet-activating Factor Complement

Summary
Management
ABCs Volume expansion Epinephrine Antihistamines, steroids, infusions

Summary
Muscle relaxants Antibiotics Blood products Latex Colloids

Summary
Testing
Leukocyte Histamine Release RAST ELISA Skin testing

References
Barash P. Clinical Anesthesia, 4th ed. Ch 49. Lippincott. 2001. Miller R. Millers Anesthesia, 6th ed. Ch 27. Churchill. 2005. Roizen M. Essence of Anesthesia Practice, 2nd ed. 2002 Dunn P. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 7th ed. p324. Lippincott. 2007.