Anaphylaxis

1
Anaphylaxis

• Peter Mack
• October 31, 2007

2
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

3
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

4
Type I

• Cross-linkage of two IgE induce degranulation
• Complement independent

5
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)

6
Type II

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

7
Type II

• Complement
• activation
• Targeted cell
• destruction

8
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

9
Type III
Basement membrane
Endothelium
Antigen
Vasculitis, Increased capillary permeability
Complement
IgG
PMN
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Type IV

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

11
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

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Type IV
Eg. Graft-versus-host, contact dermatitis
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Intraoperative Allergic Reactions

• 15,000 - 125,000 anesthetics
• 3.4 mortality
• gt90 evoked by IV drugs occurs within 5 minutes
• Anaphylaxis is the most feared, with circulatory
  collapse, reflecting vasodilation decreased
  venous return

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Definitions

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

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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

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Recognition of Anaphylaxis During
Regional and General Anesthesia
17
Anaphylactic ReactionsIgE-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

18
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

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Anaphylactic ReactionsIgE-mediated
pathophysiology

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

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Anaphylactic ReactionsIgE-mediated
pathophysiology

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

21
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

22
Histamine

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

23
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

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Arachadonic Acid Metabolites

• Leukotrienes prostaglandins are both
  synthesized after activation of mast cells
• Metabolism of phospholipid membranes via
  lipoxygenase or cyclo-oxygenase

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Leukotrienes

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

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Prostaglandins

• PG D2
• Vasodilation
• Bronchospasm
• Pulmonary hypertension
• Increased capillary permeability

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Kinins

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

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Platelet-Activating Factor

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

29
Non-IgE-Mediated Reactions

• Other immunologic non-immunologic mechanisms
  liberate many of the same mediators producing
  clinically identical syndromes

30
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

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Complement

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

32
Complement

• C5a interacts with specific high-affinity
  receptors on PMNs platelets initiating
  leukocyte chemotaxis, aggregation activation

33
Complement

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

34
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

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Drugs Capable of Nonimmunologic Histamine Relsease

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

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Treatment Plan
Hypoxia Hypotension 2 to
Vasodilation Increased capillary permeability
Bronchospasm
Airway Maintenance 100 O2
Intravascular volume expansion Epinephrine
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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

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Watch for

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

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Managment of Anaphylaxis During General
Anesthesia
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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

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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

42
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

43
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

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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

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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

46
Catecholamines

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

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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

48
Corticosteroids

• Anti-inflammatory
• 12-24h for effect
• 0.25-1g IV hydrocortisone in IgE-mediated
  reactions
• 1-2g IV methylprednisolone in complement-mediated
• Eg. Pulmonary vasocontriction after protamine
• May attenuate late-phase reactions

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Bicarbonate

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

50
Airway Evaluation

• Laryngeal edema may occur
• Suggested by facial edema
• Leave intubated until edema subsides
• Air leak useful for patency
• Consider direct laryngoscopy

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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

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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)

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Adverse Drug Reactions

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

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Unpredictable ADRs

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

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Unpredictable ADRs

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

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Unpredictable ADRs

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

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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

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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

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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

61
Evaluation

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

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Testing

• No testing avoidance
• One drug clear temporal correlation
• Necessary
• Many drugs are given
• Preservatives

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Leukocyte Histamine Release

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

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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)

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RAST

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

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Enzyme-linked Immunosorbent Assay (ELISA)

• Similar to RAST
• Useful for protamine

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Intradermal Testing

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

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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

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Latex - Risk Factors

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

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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

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Summary

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

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Summary

• Anaphylaxis
• Bronchospasm
• Vasodilation, increased capillary permeability
• Urticaria
• Associated with profound CV collapse

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Summary

• Chemical mediators
• Histamine
• Leukotrienes Prostaglandins
• Kinins
• Platelet-activating Factor
• Complement

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Summary

• Management
• ABCs
• Volume expansion
• Epinephrine
• Antihistamines, steroids, infusions

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Summary

• Muscle relaxants
• Antibiotics
• Blood products
• Latex
• Colloids

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Summary

• Testing
• Leukocyte Histamine Release
• RAST
• ELISA
• Skin testing

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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.