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Evaluation of Perioperative Anaphylaxis

Evaluation of Perioperative Anaphylaxis. David A. Khan, MD Professor of Medicine and Pediatrics Allergy & Immunology Program Director Division of Allergy & Immunology. 1. Outline. Epidemiology Anesthetic Drugs Clinical Features Causal Agents Diagnostic Testing. Epidemiology.

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Evaluation of Perioperative Anaphylaxis

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

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

  3. Epidemiology Mertes PM et al. Immunol Allergy Clin N Am 29 (2009) 429–451.

  4. Epidemiology • 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. Case Perioperative Anaphylaxis

  6. Perioperative Anaphylaxis Case • 35 yo presents for perioperative anaphylaxis • 6 months prior, within 10-15 minutes of induction for planned kidney transplant, developed hypotension and became pulseless, no skin findings documented and he was not hypoxic • Resuscitation for 18 minutes • Cardiac workup negative for cardiac etiology

  7. Perioperative Anaphylaxis Case • Other Drug Allergies • RCM • Itching, throat tightness • Tolerated RCM with premedication since • Heparin • Dyspnea, hypotension • Optiflux (hemodialysis membrane) • ? reaction • PMH • HTN, ESRD

  8. Perioperative Anaphylaxis Case

  9. Question • What is the most likely cause of his reaction? • Ceftriaxone • Cisatracurium • Lidocaine • Propofol

  10. Anesthetic Drugs Thong BYH et al. Ann Allergy Asthma Immunol. 2004;92:619– 628.

  11. Causal Agents of Perioperative Reactions in France Mertes PM et al. Immunol Allergy Clin N Am 29 (2009) 429–451.

  12. Perioperative Anaphylaxis:Mayo Clinic Experience • 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 Gurrieri C et al. Anesth Analg 2011;113:1202–12.

  13. Clinical Features • 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

  14. Clinical Features of Perioperative Anaphylaxis 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

  15. Clinical Features of Perioperative Anaphylaxis • 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

  16. Perioperative Anaphylaxis:IgE vs. non-IgE Mertes PM et al. Immunol Allergy Clin N Am 29 (2009) 429–451.

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

  18. High Risk Patients Mertes PM et al. J Investig Allergol Clin Immunol 2011; Vol. 21(6): 442-453 • History of Perioperative Drug Allergy • Patients allergic to drugs or agents likely to be used during anesthesia • Patients with prior allergic reactions during anesthesia

  19. High Risk Patients Mertes PM et al. J Investig Allergol Clin Immunol 2011; Vol. 21(6): 442-453 • 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

  20. Severity Grading of Perioperative Allergic Reactions Mertes PM et al. J Investig Allergol Clin Immunol 2011; Vol. 21(6): 442-453

  21. Causal Agents of Perioperative Anaphylaxis

  22. Neuromuscular Blocking Agents (NMBA) • 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

  23. Divalency and Flexibility of NMBAs • 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 Didier A et al. J Allergy Clin Immunol 1987;79:578-84.

  24. Neuromuscular Blocking Agents (NMBA) • 15-50% cases NMBA anaphylaxis occurs with 1st contact with an NMBA • Theories on cross-reactive antibodies • Exposure to substituted ammonium groups in foods, cosmetics, disinfectants, industrial material • Pholcodine hypothesis

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

  26. Phlocodine consumption correlated with Sensitization to Suxamethonium Johansson SGO et al. Allergy 2010; 65: 498–502.

  27. IgE Sensitization to Suxamethonium High in US Despite Lack of Phlocodine Johansson SGO et al. Allergy 2010; 65: 498–502.

  28. Quinolone Sensitivity and NMBA Sensitization Specific IgE to quaternary ammonium found in 53% patients with immediate reactions to quinolones vs. 3% controls J Allergy ClinImmunol: In Practice 2013;1:273-9

  29. NMBAs and non-IgE mediated Reactions • 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-turbocurarine, atracurium, mivacurium • rapacuronium (withdrawn from US)

  30. Latex • Often cited as 2nd 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 Harboe T et al. Anesthesiology 2005;102:897-903.

  31. Antibiotics 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

  32. Bacitracin Sharif S et al. Ann Allergy Asthma Immunol. 2007;98:563–566. 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

  33. Hypnotics • 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

  34. Thiopental Most common barbituate 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

  35. Propofol and Egg Allergy • 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

  36. Propofol and Egg Allergy Murphy A et al. Anesth Analg 2011;113:140-4. • 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

  37. Propofol and Egg Allergy • 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 Murphy A et al. Anesth Analg 2011;113:140-4.

  38. Opioids • 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

  39. Local Anesthetics • 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

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

  41. Dextran • 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 Gedin H et al. Int Arch Allergy Appl Immunol. 1976;52(1-4):145-59.

  42. Hapten inhibition Reduces Dextran Anaphylaxis • 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 Ljungstrom KG et al. Anaesthesia 1988;43:729-32.

  43. Vital Blue Dyes • 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.

  44. Vital Blue Dyes • Most anaphylactic reactions occur with 1st 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 Scherer K et al. Ann Allergy Asthma Immunol 2006;96:497-500.

  45. Clinical Features of Dye Anaphylaxis • 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 requiring continuous epinephrine infusion • Skin tests were positive in all cases • 8 on prick testing alone Mertes PM et al. J Allergy Clin Immunol. 2008 Aug;122(2):348-52.

  46. Blue Urticaria Parvaiz MA et al. Anaesthesia 2012, 67, 1275–1289.

  47. Vital Blue Dyes 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 Keller B et al. Am J Surgery 2007;193:122-4.

  48. Protamine Park KW. Int Anesth Clin 2004;42:135-45. Koster A et al. Ann Thorac Surg 2010;90:276-7. • 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

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