Allergy and Drug Reactions

1. Allergy and Drug Reactions Michelle Gros, MD FRCPC December 2, 2009

2. Patients with Allergies Risk of allergic drug reaction: 1-3% for most drugs ~5% of adults in U.S. may be allergic to 1 or more drugs Pts often refer to adverse drug effects as allergy ~15% of adults in U.S. believe they are allergic to specific medication

3. Adverse Drug Reactions - Predictable Account for ~80% of ADRs Often dose-dependent (overdosage) Related to known pharmacologic actions of drug Inadvertent route (eg. lidocaine induced seizures or cardiovascular collapse) Side effects Most common ADRs Undesirable pharmacologic actions of drugs Occurs at usual prescribed dosages

4. Drug Interactions Represent predictable ADRs Dose-dependent Independent of allergy IV fentanyl after IV benzos in unstable patient � may cause hypotension

5. Unpredictable ADRs Usually dose-independent Usually not related to drug�s pharmacologic actions Related to immunologic response

6. Criteria to help distinguish allergic reaction from other ADRs Allergic reactions occur only in a small percentage of patients receiving the drug Clinical manifestations DO NOT resemble known pharmacologic actions Drugs administered for several weeks without complications - rarely responsible for drug allergy Time between exposure and manifestations

7. Hypersensitivity Responses (Allergy) Gell and Coombs first described classification Immune pathway functions as a protective mechanism Can react inappropriately to produce hypersensitivity or allergic response 4 basic types

8. Type 1 Reactions Anaphylactic or immediate-type hypersensitivity reactions Ag binding to IgE Abs on mast cells and basophils Physiologically active mediators released Eg. Anaphylaxis, allergic rhinitis

9. Type 1 Reactions

10. Type 2 Reactions Antibody-dependent cell-mediated cytotoxic hypersensitivity Mediated by IgG or IgM Abs directed against Ags on surface of foreign cells Ags may be either: 1) integral cell membrane components eg. A or B blood group Ags in ABO incompatibility 2) Haptens that absorb to cell surface � stimulating production of antihapten Abs eg. Autoimmune hemolytic anemia

11. Type 2 Reactions Cell damage produced by: Direct cell lysis after complete complement cascade activation Increased phagocytosis by macrophages Killer T-cell lymphocytes producing Ab-dependent cell-mediated cytotoxic effects Eg. ABO-incompatible transfusion reactions drug-induced immune hemolytic anemia heparin-induced thrombocytopenia

12. Type 2 Reactions

13. Type 3 Reactions Immune complex reactions Circulating soluble Ags and Abs bind to form insoluble complexes � deposit in microvasculature Complement is activated Neutrophils are localized to site of complement deposition to produce tissue damage Eg. serum sickness after snake bite immune complex vascular injury protamine-mediated pulmonary vasoconstriction

14. Type 3 Reactions

15. Type 4 Reactions Delayed hypersensitivity reactions Result from sensitized lymphocytes interacting with specific antigens Produces lymphokine synthesis, lymphocyte proliferation, generation of cytotoxic T cells, attracts macrophages and other inflammatory cells Cytotoxic T cells kill target cells that bear Ags identical with those that triggered the reaction

16. Type 4 Reactions Manifest in 18-24 hours Peak at 40-80 hours Disappear in 72-96 hours Examples: Tissue rejection Graft-vs-host reactions Contact dermatitis (eg. poison ivy) Tuberculin immunity

17. Type 4 Reactions

18. Immunologic Mechanisms of Drug Allergy Different immunologic responses to an antigen can occur Eg. Penicillin Anaphylaxis (Type 1) Hemolytic anemia (Type 2) Serum sickness (Type 3) Contact dermatitis (Type 4)

19. Intraoperative Allergic Reactions 1 in 5000 � 25,000 anesthetics 3.4% mortality rate >90% of allergic reactions evoked by anesthetic drugs occur within 5 mins of administration Anaphylaxis is most feared, with circulatory collapse, reflecting vasodilation and decreased venous return

20. Anaphylaxis 1st used by Portier and Richet �ana� � against �prophylaxis� � protection To describe profound shock and resulting death in dogs immediately after a 2nd challenge with a foreign antigen Mediated by antibodies

21. Anaphylactoid Non-immunologic reactions Term rarely used now Cannot be distinguished from immune-mediated reactions clinically

22. Anaphylactic Reactions Ag binding to IgE Abs � initiates anaphylaxis Prior exposure needed to produce sensitization (or substance of similar structure) Allergic history often unknown to patient Re-exposure � Ag bridges IgE Abs on surfaces of mast cells and basophils Causes release of stored mediators � histamine, tryptase, chemotactic factors

23. Anaphylactic Reactions Arachidonic acid metabolites (leukotrienes and prostaglandins), kinins and cytokines � synthesized and released Released mediators produce a symptom complex of: Bronchospasm and upper airway edema (resp system) Vasodilation and increased capillary permeability (CVS) Urticaria (cutaneous)

24. Chemical Mediators of Anaphylaxis - Histamine Stimulates H1, H2, H3 receptors H1 activation: Releases NO from vascular endothelium Increases capillary permeability Controls airway and vascular smooth muscle H2 activation: Gastric secretion Inhibits mast cell activation Contributes to vasodilation

25. Peptide Mediators of Anaphylaxis � Arachidonic Acid Metabolites Leukotrienes and prostaglandins Leukotrienes Slow-reacting Bronchospasm Increased capillary permeability Vasodilation Coronary vasoconstriction Myocardial depression

26. Peptide Mediators of Anaphylaxis � Arachidonic Acid Metabolites Leukotrienes and prostaglandins Prostaglandins Vasodilation Bronchospasm Pulmonary hypertension Increased capillary permeability

27. Peptide Mediators of Anaphylaxis � Kinins Synthesized in mast cells and basophils Produce vasodilation, increased capillary permeability, and bronchospasm Stimulate endothelium to release prostacyclin and nitric oxide

28. Peptide Mediators of Anaphylaxis � Platelet-Activating Factor Unstored lipid Synthesized in activated human mast cells Extremely potent Aggregates and activates human platelets to release inflammatory products Causes intense wheal and flare, smooth muscle contraction and increased capillary permeability

29. Mediators of Anaphylaxis

30. Anaphylaxis - Epidemiology 1 in 10-20,000 anesthetics Exact incidence underestimated 2� under-reporting Morbidity remains unknown France � 3% of anesthesia-related deaths involve anaphylaxis 10% anaphylactic rxns in UK are fatal

31. Anaphylaxis - Epidemiology France NMBA�s most common agent Followed by latex and antibiotics Norway NMBA�s most common Latex in very few cases No causal agent in ? of cases Spain Antibiotics, then NMBA�s

32. Anaphylaxis - Epidemiology Patient characteristics: NMBA�s and latex � female patients Antibiotics � smoking (increased Abx use for URTI�s?) Hx of atopy, asthma, certain food allergies � latex Pts with asthma or on �-blockers � more severe reactions, may be refractory to treatment

33. Which drugs or agents? NMBA�s Latex Antibiotics Usually shortly after induction May occur anytime Dyes, hypnotics, local anesthetics, opioids, colloids, aprotinin, protamine, chlorhexidine, contrast agents

35. NMBA�s Frequently involved 50-70% of periop anaphylaxis According to different reports in Europe Limited data available in US and Canada NO epidemiologic study of causative agents in US or Canada

36. NMBA�s ALL NMBA�s may elicit anaphylaxis Not uncommon in pts w/o any known previous exposure to any NMBA Source of sensitizing agent unknown Quaternary ammonium ions are suggested to be allergenic determinants Commonly used chemicals (toothpastes, detergents, shampoos, cough medicines) share these determinants Also � can have uneventful previous exposure � does not preclude risk of anaphylaxis with subsequent drug exposure

37. NMBA�s Sensitivity of skin tests 95% Reproducibility excellent Cross-reactivity between NMBA�s common (~60-70%) � must investigate all NMBA�s to identify safe alternatives Cross-reactivity also shown between succinylcholine and NMBA�s Arbitrary contraindication to ALL NMBA�s cannot be accepted

38. NMBA�s Increased incidence of anaphylaxis with rocuronium in France and Norway Norwegian Medicine Agency � published alert reserving its use for urgent intubations only

39. NMBA�s Apparent increased incidence of anaphylaxis to rocuronium might be due to: Reflection of usage and market share Biased reporting of adverse effects of new drugs Statistical issues Genotypic difference This issue requires further study

40. Latex 1st case reported in 1979 � contact urticaria 1989 � 1st reports of intra-op anaphylaxis Increased risk: Health care workers Many urologic procedures Allergy to bananas, avocados, kiwis (latex-fruit syndrome)

41. Latex Brown et al reported in anesthesiologists: 24% incidence of contact dermatitis 12.5% incidence of latex-specific IgE positivity Of this group � 10% clinically asymptomatic, although IgE positive ? Early stages of sensitization ? Avoidance of latex may prevent progression to symptomatic disease Anesthesiology 89:292, 1998.

42. Latex Usually 30-60 minutes after start of surgery IV and mucous membrane exposure � associated with faster onset and more severe symptoms

43. Latex Pediatric hospital in France including OR and periop care areas Latex-free policy has been adopted No allergic reaction to latex has been reported in 25,000 anesthetized children or in healthcare workers

44. Antibiotics Primarily penicillins and cephalosporins � 70% Share a �-lactam ring May occur at 1st exposure

45. Antibiotics Specificity with skin testing 97-99%, sensitivity 50% Cross-reactivity low � 10% (attributed to common �-lactam ring) Recent meta-analysis: Pts allergic to penicillin or amoxicillin Higher incidence of rxn to 1st generation cephalosporins, but not to later generations

46. Hypnotics Thiopental or propofol � rarely reported Etomidate or ketamine � extremely rare

47. Opioids Very rare Morphine induces histamine release Cross-reactivity uncommon between fentanyl, remifentanil, sufentanil

48. Local Anesthetics Very uncommon Most due to metabolic product of esters � PABA Therefore, cross-reactivity among all LA agents in ester group Allergic rxns to amide LA agents remain anecdotal Preservatives (metabisulfite, parabens) may elicit rxn Cross-reactivity rarely seen in amide group ABSENT between esters and amides

49. Colloids Rare Gelatins (0.35%) vs. hydroxyethyl-starch (0.06%)

50. Aprotinin Risk ~ 2.8% in re-exposed pts Some fibrin glue products still contain aprotinin

51. NSAIDS Inhibition of PGE2 pathway � excessive leukotriene synthesis and subsequent mediator release � urticaria or bronchospasm IgE-mediated reactions also Fatal anaphylaxis described after oral NSAIDS

52. Antiseptics Increased reactions to chlorhexidine recently Contact dermatitis to life-threatening anaphylaxis Occurred when used for urological and gyne procedures Also insertion of central lines and epidurals Allow to dry completely before beginning invasive procedure

54. How To Diagnose Periop Anaphylaxis? Clinical History: Initial diagnosis is presumptive, yet essential Usually occurs within minutes, even 1 minute after induction May progress within minutes to become life-threatening Primarily linked to IV agents Most common initial clinical features � pulselessness, desaturation, severe bronchospasm Resp signs enhanced in pts with underlying resp disease

55. Anaphylaxis Enigma of anaphylaxis lies in: Unpredictability of happening Severity of attack Lack of prior allergic history

57. How To Diagnose Periop Anaphylaxis? Clinical History: 4-step grading scale by Ring and Messmer Grades 1 and 2 � usually NOT life-threatening Grades 3 and 4 � emergency situations Grading scale used to guide treatment with epi

59. Predictive Criteria of Anaphylaxis Severity The more rapidly anaphylaxis occurs after allergen exposure � more likely to be severe Cutaneous signs may be absent in rapidly progressive anaphylaxis (may only appear after normalization of BP) Bradycardia � as a result of Bezold-Jarisch reflex

60. Bezold-Jarisch Reflex Cardioinhibitory reflex Origin in sensory receptors of left ventricle Transmitted by unmyelinated vagal C fibres Paradoxical bradycardia occurring during extreme hypovolemia Occurs in up to 10% of pts with anaphylaxis

61. Bezold-Jarisch Reflex Bradycardia may be life-protecting adaptive mechanism Allows ventricles to fill before contracting again, despite massive hypovolemia Atropine to tx bradycardia � potential for circulatory arrest Treat with large volume expansion and epi

62. What biochemical tests? Histamine: Preformed inflammatory mediator Contained in granules of mast cells and basophils Early increase in allergic or nonallergic rxns Absence of increased histamine � does not preclude allergic rxn

63. What biochemical tests? Histamine: Plasma �-life very short (15-20 mins) Blood samples should be drawn within 30 minutes after grade 1 or 2 reaction May be increased to 2 hours after grade 3 or 4 reactions

64. What biochemical tests? Tryptase: Mast cell neutral serine protease Preformed enzyme Peaks 15-60 minutes after rxn �-life ~ 2 hours Blood samples should be drawn 15-60 minutes after grade 1 or 2 rxn, 30-120 minutes after grade 3 or 4 rxn Absence of increase does not preclude diagnosis

65. What biochemical tests? Tryptase: Nonallergic rxn (eg. histamine release) � histamine may be increased and tryptase normal Some recommend histamine and tryptase, others only tryptase

66. Skin Tests Gold standard Exposes mast cells of skin to suspected allergen

67. Why to perform skin tests? Premedication (H1 +/- H2 receptor antagonists, steroids) has not proven to be preventative Identify culprit agent Prove pathophysiologic mechanism of rxn (allergic vs. nonallergic) Suggest safe alternative drug for future

68. When to perform skin tests? 4-6 week delay after reaction To avoid false negative test because of mast cell depletion

69. How to perform skin tests? According to clinical history All drugs injected just before reaction AND latex must be tested Read tests after 15-20 minutes Prick tests, followed by intradermal tests

70. Diagnosis Should link clinical history with biochemical tests and skin tests Severe clinical history + increased tryptase + skin test positivity to suspected agent Confirms diagnosis Agent should be avoided Not a severe clinical history +/- increased histamine + normal tryptase + neg skin test Non-allergic reaction (histamine release with drugs such as mivacurium, vancomycin) Agent used with caution

72. Treatment Titrated to desired effect with careful monitoring Severe reactions need aggressive therapy May be protracted with persistent hypotension, pulmonary HTN, lower resp obstruction, or laryngeal obstruction May persist 5-32 hours despite vigorous therapy All pts should be admitted to ICU for monitoring � manifestations may recur after successful treatment

73. Treatment � Initial Therapy Stop offending agent Maintain airway and 100% O2 Profound V/Q abnormalities can occur Follow ABG�s D/C all anesthetic drugs Inhalational agents NOT bronchodilators of choice, especially during hypotension

74. Treatment � Initial Therapy Volume Expansion Hypovolemia rapidly follows Significant changes in vascular permeability Up to 50% transfer of intravascular fluid into interstitial space within 10 minutes Fluid therapy early Start with 2-4 L of crystalloid or colloid Additional 25-50 mL/kg may be necessary

75. Treatment � Initial Therapy Volume Expansion If refractory hypotension after volume expansion and epi: Need additional hemodynamic monitoring TEE � rapid assessment of intraventricular volume and ventricular function Colloids have not proven to be more effective than crystalloids

76. Treatment � Initial Therapy Epinephrine Drug of choice a-adrenergic effects � vasoconstrict to reverse hypotension �2-receptor stimulation � bronchodilates and inhibits mediator release by increasing cAMP in mast cells and basophils Route and dose depend on patient�s condition

77. Treatment � Initial Therapy Epinephrine Poor outcomes associated with either late or absent administration of epi, or inadequate dosing Rapid intervention and careful titration Pts under GA � altered responses Pts under spinal or epidural � partially sympathectomized � may need even larger doses

78. Treatment � Initial Therapy Epinephrine Clinical severity scale by Ring and Messmer Grades 1 -4

79. Treatment � Initial Therapy Epinephrine Never injected during grade 1 reactions Titrated boluses 10-20 �g for grade 2 Titrated boluses 100-200 �g for grade 3 High dose epi for grade 4 (1-3 mg over 3 mins) Pts with laryngeal edema without hypotension � subcutaneous epi Epi should not be given IV to pts with Normal BP

80. Secondary Treatment - Antihistamines H1 receptors mediate many of adverse effects Diphenhydramine 0.5-1 mg/kg Antihistamines DO NOT inhibit anaphylactic reactions or histamine release Compete with histamine at receptor sites Indications for H2 receptor antagonists remain unclear

81. Secondary Treatment - Catecholamines Epi infusions for persistent hypotension 5-10 �g/min Norepi for refractory hypotension secondary to decreased SVR (5-10 �g/min)

82. Secondary Treatment - Aminophylline Nonspecific phosphodiesterase inhibitor Bronchodilates Decreases histamine release by increasing cAMP Increases R and L ventricular contractility Decreases PVR Loading dose of 5-6 mg/kg IV over 20 mins, followed by infusion of 0.5-0.9 mg/kg/hr

83. Secondary Treatment - Steroids Anti-inflammatory effects Require 12-24 hours to work Unproven Exact dose and preparation unclear Recommend: 0.25-1 g IV hydrocortisone � for IgE mediated rxns 1-2 g methylprednisolone � for rxns believed to be complement mediated (eg. protamine rxn) May be important for late phase reactions that occur 12-24 hours after

84. Secondary Treatment - Bicarb Acidosis develops quickly Decreases effectiveness of epi 0.5 � 1 mEq/kg and follow ABG�s

85. Alternative Therapy - Vasopressin May get desensitization of adrenergic receptors Vasopressin as alternative Vasoconstrictive effects at V1 receptors Vasopressin decreases nitric oxide 2nd messenger � cGMP

86. Airway Evaluation Laryngeal edema may occur Suggested by facial edema Leave intubated until edema subsides Air leak useful Consider direct laryngoscopy

87. Non-IgE mediated reactions Other immunologic and nonimmunologic mechanisms Release many of same mediators Independent of IgE Clinical syndrome identical with anaphylaxis

88. Non-IgE mediated reactions - Complement C3a and C5a � anaphylatoxins Release histamine from mast cells and basophils Contract smooth muscle Increase capillary permeability Cause interleukin synthesis

89. Non-IgE mediated reactions � Complement � C5a Causes leukocyte aggregation and activation Aggregated leukocytes embolize to organs Microvascular occlusion Liberation of inflammatory products Involved in: Transfusion reactions Protamine reactions ARDS Septic shock

90. Nonimmunologic Histamine Release Many agents involved Dose-dependent Mechanisms not well understood Selective mast cell and not basophil activation Antihistamine pretreatment Does not inhibit histamine release Competes with histamine at receptor May attenuate decrease in SVR

91. Drugs Capable of Nonimmunologic Histamine Release Antibiotics (vancomycin) Hyperosmotic agents Muscle relaxants (atracurium, mivacurium) Opioids (morphine, meperidine, codeine) thiobarbiturates

92. Should I give a test dose of IV antibiotic?

93. Should I give a test dose of IV antibiotic? No Predictive testing would require serial challenges with increasing doses Starting with a minuscule dose Allowing at least 30 minutes between each dose This approach is impossible within the constraints of an operating list

94. Should I avoid cephalosporins in a patient who gives a history suggestive of penicillin allergy?

95. Should I avoid cephalosporins in a patient who gives a history suggestive of penicillin allergy? Most patients with a history of penicillin-related rash � not allergic to cephalosporins However, many suitable alternatives to cephalosporins If convincing history of anaphylaxis � avoid 1st generation cephalosporins

96. Should I use crystalloid or colloid in the immediate management?

97. Should I use crystalloid or colloid in the immediate management? No evidence that one is better than the other If colloid given before clinical signs of anaphylaxis: Should be discontinued Replaced with crystalloid or colloid of different class

98. Should I give an H2-blocking drug as part of immediate management?

99. Should I give an H2-blocking drug as part of immediate management? No evidence to support the use of H2-blocking drugs in this situation

100. What should I say to a patient who wishes to be screened for anesthetic allergy preoperativley?

101. What should I say to a patient who wishes to be screened for anesthetic allergy preoperativley? If no history of previous anesthetic anaphylaxis � preoperative screening is of no value Sensitivity and specificity of skin tests and blood tests is relatively low If pretest probability is very low (no positive history) � neither a neg. or pos. test is likely to be predictive of outcome

102. Should I avoid propofol in patients who are allergic to eggs, soya, or nuts?

103. Should I avoid propofol in patients who are allergic to eggs, soya, or nuts? No published evidence Propofol contains purified egg phosphatide and soya-bean oil Likely that manufacturing process removes or denatures proteins responsible for egg and soya allergy

104. Patient with previous anaphylaxis during anesthetic presents for emergency surgery without being tested Latex-free environment Inhalational agents likely safe (unless MH) View previous records if possible Avoid all drugs given prior to anaphylaxis (except inhalationals) Avoid all NMBA�s if pt received NMBA (cross reactivity)

105. Patient with previous anaphylaxis during anesthetic presents for emergency surgery without being tested Previous records not available: Avoid all NMBA�s if possible (risk vs. benefit) Amide LA agents likely safe for regional or local Avoid chlorhexidine (allergy to proviodine less common) Avoid histamine-releasing drugs eg. Morphine No evidence for pretreatment with hydrocortisone or histamine-blocking drugs

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

107. Anaphylaxis Bronchospasm Vasodilation, increased capillary permeability Urticaria Profound CV collapse

108. Mediators Histamine Leukotrienes and prostaglandins Kinins Platelet-activating factor complement

109. Management ABCs Volume expansion Epinephrine Antihistamines, steroids, infusions

110. Common Drugs Involved Muscle relaxants Antibiotics Latex Blood products Colloids

111. References Barash P. Clinical Anesthesia, 5th ed. Ch 49. 200? Miller R. Miller�s Anesthesia, 6th ed. Ch 27. 2005. Dewachter, Mouton-Faivre, Emala: Anaphylaxis and Anesthesia: Controversies and New Insights. Anesthesiology 3(5): 1141-1150, 2009. Harper, Dixon, et al: Guidelines: Suspected Anaphylactic Reactions Associated with Anaesthesia. Anaesthesia 64: 199-211, 2009.