Diagnostic Evaluation of Perioperative Anaphylaxis

1. Diagnostic Evaluation of Perioperative Anaphylaxis David A. Khan, MD Professor of Medicine and Pediatrics Southwestern Medical Center Allergy & Immunology Program Director Division of Allergy & Immunology 1

2. Outline 2 Epidemiology Anesthetic Drugs Clinical Features Causal Agents Diagnostic Testing

3. Epidemiology Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429-51. 3

4. Epidemiology 4 • Incidence remains poorly defined • Few prospective studies • Uncertainty in accuracy and completeness of reports • Immune-mediated reactions account for> 60% reactions • Mortality • ~3-9%

5. Anesthetic Drugs 5 Thong BYH et al. Ann Allergy Asthma Immunol 2004;92:619–28.

6. 6

7. Causal Agents of Perioperative Reactions in France Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 7

8. Perioperative Anaphylaxis:Mayo Clinic Experience Gurrieri C et al. Anesth Analg 2011;113:1202–12. 8 • From 1992 to 2010, identified 38 patients with perioperative anaphylaxis • 18 patients had likely IgE-mediated reactions • Antibiotics most common identified agent (50%) • 7/9 cases due to cefazolin • Induction agents (16.7%) • Latex (16.7%) • NMBA (11%) • Others • Chlorhexidine, isosulfan blue, protamine, flumazenil

9. Clinical Features 9 • Clinical presentation of anaphylaxis differs somewhat in anesthetized patients vs. conscious patients • Perioperative anaphylaxis • No early warning subjective symptoms • Pruritus, dizziness, dyspnea, and malaise absent • Cutaneous findings not easily recognized • No pruritus • Patient is draped

10. Clinical Features of Perioperative Anaphylaxis 10 Changes in vitals signs or airway resistance may be attributed to affects from anesthesia medications Due to all of these features, anaphylaxis may not be recognized early in the anesthetized patient

11. Clinical Features of Perioperative Anaphylaxis 11 • Cannot differentiate IgE vs. Non-IgE mediated reactions on clinical features alone • Timing of anaphylaxis may suggest etiology • 90% reactions within minutes of induction • NMBA, antibiotic, induction agent • Maintenance of anesthesia • Latex, volume expanders, dyes, contrast

12. Perioperative Anaphylaxis: IgE vs. non-IgE Mertes PM et al. Immunol Allergy Clin N Am 2009;29:429–51. 12

13. Differential Diagnosis of Perioperative Anaphylaxis 13 • Cardiovascular • Arrhythmia, myocardial infarction, pericardial tamponade • Pulmonary edema, pulmonary embolism • Overdose of vasoreactive drug • Pulmonary • Asthma, tension pneumothorax • Sepsis • Allergy and immunology • HAE, mastocytosis, cold urticaria

14. High Risk Patients Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 14 • History of perioperative drug allergy • Patients allergic to drugs or agents likely to be used during anesthesia • Patients with prior allergic reactions during anesthesia

15. High Risk Patients Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 15 • Latex allergy • Patients with clinical signs of latex allergy • Children who have undergone several surgical interventions (e.g., spina bifida, myelomeningocoele) • Patients with food allergy to avocado, kiwi, banana, chestnut, and buckwheat

16. Severity Grading of PerioperativeAllergic Reactions Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53. 16

17. Causal Agentsof Perioperative Anaphylaxis 17

18. Neuromuscular Blocking Agents (NMBA) 18 • Most common causal agent worldwide • May not be as common in US • Most reactions are IgE-mediated • Quaternary and tertiary ammonium ions main component of allergic epitopes • Cross-sensitization is frequent amongst NMBAs ~60-70% • Higher with amino-steroid NMBAs • Sensitization to all NMBAs rare • Monosensitization frequent with succinylcholine

19. Divalency and Flexibilityof NMBAs 19 Didier A et al. J Allergy Clin Immunol 1987;79:578-84. • NMBAs have 2 substituted ammonium ions per molecule (divalent) • Divalency allows bridging of IgE molecules by a single NMBA molecule • Suxamethonium (succinylcholine) is the NMBA associated wit highest frequency of anaphylaxis when adjusted for use • Longer molecules and more flexible backbones enhance mediator release • characteristic of suxamethonium

20. Neuromuscular BlockingAgents (NMBA) 20 • 15-50% cases NMBA anaphylaxis occurs with first contact with an NMBA • Theories on cross-reactive antibodies • Exposure to substituted ammonium groups in foods, cosmetics, disinfectants, industrial material • Pholcodine hypothesis

21. Pholcodine Hypothesis Johansson SGO et al. Allergy 2010;65:498–502. 21 Pholcodine is a cough suppressant containing quaternary ammonium ion epitopes and is available in certain countries International study compared pholcodine consumption and IgE to suxamethonium

22. Pholcodine Consumption Correlated with Sensitization to Suxamethonium Regression Coefficient R 2 PHO MOR SUX PAPPC 0.037 0.035 0.015 –0.001 0.767 0.843 0.633 0.004 Johansson SGO et al. Allergy 2010;65:498–502. 22

23. IgE Sensitization to Suxamethonium Highin US Despite Lack of Pholcodine 23 Johansson SGO et al. Allergy 2010;65:498–502.

24. NMBAs and Non-IgE Mediated Reactions 24 • Non-IgE mediated reactions to NMBA occur with similar frequency as IgE mediated • Presumed to be due to direct nonspecific mast cell/basophil activation • Generally less severe • NMBAs associated with greatest histamine release • D-tubocurarine, atracurium, mivacurium • Rapacuronium (withdrawn from US)

25. Latex Harboe T et al. Anesthesiology 2005;102:897-903. 25 • Often cited as the second most common cause in large surveys but less common in U.S. and other countries • Study from Norway of anesthetic anaphylaxis from 1996-2001 found only 3% cases due to latex • Noted systematic reduction of latex use in Norway • Latex is the primary cause of anaphylaxis in children with spina bifida who have frequent surgeries

26. Antibiotics 26 May be highest causative agent in the U.S. with cefazolin being most common Beta-lactams most common overall Vancomycin a frequent cause of non-IgE-mediated reactions which may manifest with urticaria and even hypotension

27. Bacitracin Sharif S et al. Ann Allergy Asthma Immunol 2007;98:563–6. 27 Bacitracin anaphylaxis has been reported with topical antibiotics Most reports of intraoperative anaphylaxis from bacitracin are with irrigation during surgery Skin testing may be positive with local application only (without puncture) Bacitracin specific IgE has been detected in some cases

28. Hypnotics 28 • Commonly used hypnotics include: • Propofol, midazolam, thiopental, etomidate, ketamine, and inhalational agents • Allergic reactions to hypnotics are relatively rare • No immune-mediated reactions to inhalational agents has been reported

29. Thiopental 29 Most common barbiturate implicated in perioperative anaphylaxis Women more likely than men to react Reactions thought to be IgE-mediated Skin testing has been shown to be helpful in diagnosis

30. Propofol and Egg Allergy 30 • Propofol preparations are lipid suspensions containing egg lecithin/phosphatide and soy oil • Egg lecithin contains residual egg yolk but no egg white proteins • Estimated to be 5 mg • Few case reports of suspected allergic reactions to propofol in egg-allergic patients • Warning labels for propofol vary by country despite same manufacturer

31. Propofol and Egg Allergy Murphy A et al. Anesth Analg 2011;113:140-4. 31 • Retrospective study of 32 egg-allergic patients who received propofol at a Children’s Hospital in Sydney • IgE egg sensitization determined by • Egg SPT ≥ 7 mm or egg spIgE > 7kUA/L without a clinical history of egg allergy • Egg SPT ≥ 3 mm or egg spIgE > 0.35kUA/L with a clinical history of egg allergy • N=19, 2 with anaphylaxis

32. Propofol and Egg Allergy Murphy A et al. Anesth Analg 2011;113:140-4. 32 • Only 1 child had a reaction to propofol (erythema and urticaria 15 minutes after 2nd dose) • History of egg anaphylaxis after sucking on candy with egg albumin • Propofol likely to be safe in majority of egg-allergic children without egg anaphylaxis • Authors recommend avoidance of propofol in those with histories of egg anaphylaxis

33. Opioids 33 • Allergic reactions to opiates uncommon with anesthesia • Morphine, fentanyl, sufentanil most commonly used • Morphine more likely to cause non-IgE mediated (pseudoallergic) reactions • Rare reports of IgE-mediated reactions to opiates

34. Local Anesthetics 34 • Extremely rare cause of perioperative anaphylaxis • Most adverse reactions related to inadvertent intravascular injection with resultant systemic effects from • Local anesthetic (e.g. arrhythmias) • epinephrine

35. Colloids Laxenaire MC et al. Ann Fr Anesth Reanim 1994;13:301-10. 35 All synthetic colloids used for volume replacement have been reported to cause anaphylaxis Dextrans and gelatins more common causes than albumin or hetastarch

36. Dextran 36 Gedin H et al. Int Arch Allergy Appl Immunol 1976;52(1-4):145-59. • Most common hypothesis for severe anaphylactoid reactions to dextran is related to dextran reactive antibodies • High titer dextran reactive antibodies have been correlated with severe reactions • Immune complexes generate anaphylatoxins stimulating mast cell/basophil activation

37. Hapten inhibition Reduces Dextran Anaphylaxis 37 Ljungstrom KG et al. Anaesthesia 1988;43:729-32. • Very low molecular weight dextran (dextran 1) has been infused prior to clinical dextran injections to prevent anaphylactoid reactions • Study from Sweden compared dextran use between 1975-1979 and dextran use with dextran 1 between 1983-1985 • Reduced severe reactions from 22/100,000 to 1.2/100,000 units • Reduced fatal reactions from 23 to 1

38. Vital Blue Dyes 38 • Vital dyes have been used for many years in a variety of settings • Use for lymphatic mapping in the context of sentinel lymph node biopsy in cancer surgery has increased along with increasing reports of anaphylactic reactions • Montgomery et al (2002) performed a meta-analysis of 2,392 patients, and calculated the incidence of allergic reactions to vital blue dyes: • Patent blue: 1.8% • Isosulfan blue (lymphazurin): 1.4% • Most reactions were mild Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500.

39. Vital Blue Dyes Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500. 39 • Most anaphylactic reactions occur with first exposure to the dye • An unproven hypothesis states sensitization against vital dyes is facilitated by the common use of patent blue and other structurally closely related triarylmethane dyes in everyday life • color textiles, cosmetics, detergents, paints, inks, antifreeze, cold remedies, laxatives, and suppositories

40. Clinical Features of Dye Anaphylaxis 40 Mertes PM et al. J Allergy Clin Immunol 2008;122(2):348-52. • Review of 14 cases of perioperative anaphylaxis to patent blue V dye use in lymphatic mapping • Reactions characteristics • Relatively severe 6/14 grade 3 reactions • Average of 30 minutes to onset of symptoms • 65% cases reactions prolonged requiringcontinuous epinephrine infusion • Skin tests were positive in all cases • 8 on prick testing alone

41. Blue Urticaria 41 Parvaiz MA et al. Anaesthesia 2012;67:1275–89.

42. Vital Blue Dyes Keller B et al. Am J Surgery 2007;193:122-4. 42 Isosulfan blue and patent blue V are structurally similar and have highest rates of reaction Methylene blue rare cause of anaphylaxis Some patients exhibit positive skin tests to patent blue and methylene blue suggesting potential for cross-reactivity

43. Protamine Park KW. Int Anesth Clin 2004;42:135-45. Koster A et al. Ann Thorac Surg 2010;90:276-7. 43 • Agent used to reverse heparin anticoagulation • Rare cause of anaphylaxis • Incidence 0.19-0.69% • Mechanisms unclear • IgE, IgG, complement • Multiple proposed risk factors • Diabetics on NPH insulin • Fish allergy, vasectomized men, other drug allergy • Bivalirudin is an alternative for protamine allergic patients

44. Protamine and Fish Allergy Greenberger PA et al. Am J Med Sci 1989;298(2):104-8. Levy JH et al. J Thorac Cardiovasc Surg 1989;98(2):200-4. 44 • Protamine prepared from sperm of salmon or related species • Case reports of fish allergic patients and protamine anaphylaxis • In vitro studies by Greenberger found no evidence for cross-reactivity between IgE to salmon and protamine • Prospective evaluation of 6 fish allergic patients found none had adverse reaction to protamine

45. Antiseptics Garvey LH et al. J Allergy Clin Immunol 2007;120:409-15. 45 • Chlorhexidine digluconate is a common disinfectant • Home uses: mouthwash toothpaste, ointments, suppositories • Medical uses: swabs for disinfection prior to epidural/spinal anesthesia, surgical incisions, urinary catheterization • Chlorhexidine is becoming more recognized as a cause of perioperative anaphylaxis

46. Chlorhexidine Garvey LH et al. J Allergy Clin Immunol 2007;120:409-15. 46 • Retrospective study of 22 Danish patients with history of chlorhexidine allergy • 12/22 positive skin tests • 11/22 positive chlorhexidine sp IgE • Clinical characteristics • Most patients males • Most had previous mild reactions on prior exposure • Hypotension common • Urologic procedures common precipitant

47. Povidone- Iodine Chong YY et al. Singapore Med J 2008;49(6):483-7. 47 Multiple case reports of anaphylaxis to topical povidone-iodine including during surgery Positive skin tests have been reported

48. Miscellaneous Causes of Perioperative Anaphylaxis • Hydroxyzine • Oxytocin • Aprotinin • Pantoprazole • Hydrocortisone • NSAIDs • Neostigmine • Radiocontrast media • Blood products • Hydatid cyst rupture 48 Numerous other agents have been reported to cause perioperative anaphylaxis

49. Diagnostic Approach to Perioperative Anaphylaxis 49

50. Decisional Algorithm for a Patient Reporting a Hypersensitivity Reaction During Previous Anesthesia and Who Has Not Undergone an Allergy Workup 50 Mertes PM et al. J Investig Allergol Clin Immunol 2011;21(6):442-53.