The Frost Series #351

Case Presentation

A 34-year-old man without significant past medical history presented for shoulder arthroscopy. He reported an allergy to sulfa-containing drugs. The patient received midazolam en route to the OR. In the OR, cefazolin 2 g was administered. General anesthesia was induced with fentanyl, lidocaine, propofol, and succinylcholine.

After an uneventful endotracheal intubation, the patient developed severe bronchospasm. Sevoflurane was administered for maintenan ce of anesthesia and bronchodilatory effects. Benadryl 50 mg, ranitidine 50 mg, and dexamethasone 12 mg were administered intravenously. Albuterol 2.5 mg followed by racemic epinephrine were administered via the endotracheal tube, resulting in improved oxygenation and ventilation. The patient developed hives on his abdomen and chest. A tentative diagnosis of anaphylaxis to cefazolin was made. The surgery was cancelled and the patient was admitted to the ICU. He was successfully extubated 6 hours later and observed for 24 hours. Unfortunately, the patient declined consultation with an allergist for further workup.

Anaphylactic Reactions During Anesthesia

Anaphylactic reactions during anesthesia are very rare, with a reported incidence of 1 in 4,000 to 1 in 25,000 population and a mortality rate of 3% to 10%. They are typically difficult to diagnose because symptoms can be masked by the anesthetic and the patient is concomitantly receiving multiple medications over a short period of time.1,2 In addition, skin reactions may be missed in a patient covered with surgical drapes.

According to the 6th National Audit Project (NAP6) from the United Kingdom, the most frequent presenting clinical sign of anaphylaxis during anesthesia was hypotension, in 46% of cases. Bronchospasm was the presenting symptom in only 18% of cases, mainly in morbidly obese and asthmatic patients. Other presenting symptoms were tachycardia (9.8%), oxygen desaturation (4.7%), bradycardia (3%), reduced capnography trace (2.3%), and cardiac arrest (1.2%). The onset of presenting symptoms occurred less than 5 minutes after injection of the triggering agent in 66% of patients. Rash developed in 56% of cases, but rarely was a presenting symptom.2

Anaphylactic reactions are caused by the sudden release of mediators (such as histamine, tryptase, chymase, and cathepsin) from basophils and mast cells after exposure to a triggering agent. The World Allergy Organization defines anaphylaxis as “a severe, life-threatening generalized or systemic hypersensitivity reaction.”3 Anaphylactic reactions can be allergic (immune-mediated) and nonallergic. Allergic anaphylaxis refers to immunoglobulin E (IgE), IgG, or immune complex/complement–mediated reactions. Nonallergic anaphylaxis reactions (previously called anaphylactoid reactions) are nonimmunologically mediated.3

According to World Allergy Organization guidelines, anaphylaxis is diagnosed based on 1 of the following 3 criteria:

  • acute skin or mucosa reactions and at least respiratory compromise, hypotension, or end-organ dysfunction;
  • at least 2 of the following after exposure to a likely allergen: skin/mucosa involvement, respiratory compromise, hypotension (or end-organ failure), or persistent gastrointestinal symptoms; and
  • hypotension after exposure to a known allergen.4

Etiology of Anaphylaxis During Anesthesia

It is important to note that almost all agents used in the OR have been implicated as causes of allergic reactions, except inhalational agents.

The agents reported as causing anaphylaxis during anesthesia include antibiotics, neuromuscular blocking agents (NMBAs), sugammadex (Bridion, Merck), latex, chlorhexidine, and less frequently, patent blue dye, gelatin-based IV fluids, opioids, local anesthetics, hypnotic agents, and iodinated contrast media, etc.2,5,6


The most commonly involved antibiotics (70%) causing perioperative anaphylaxis (IgE-mediated) are beta-lactam ring antibiotics (penicillins and cephalosporins). The incidence of cross-reactivity between penicillin and cephalosporins is 10% and is attributed to the beta-lactam ring.7Vancomycin rarely triggers IgE-mediated anaphylaxis; however, rapid IV administration can cause “red man syndrome” (flushing, and erythema spreading on the face, neck, and upper body) due to massive histamine release from basophil degranulation.7


All NMBAs, both depolarizing and nondepolarizing, can cause anaphylaxis, mainly by an IgE-mediated mechanism.

The most common NMBAs reported to induce anaphylaxis are succinylcholine and rocuronium.2,7,8 Previous exposure to nonanesthetic drugs, food, household items, or cosmetics containing quaternary ammonium may potentially trigger anaphylaxis from NMBAs. Approximately 80% of anaphylaxis events caused by NMBAs occur in women, which might be explained by the use of cosmetic products containing ammonium compounds.8

There is significant geographic variation in the most frequent NMBA causing anaphylaxis. A recently published 12-year pharmacovigilance survey from France identified 680 cases of confirmed anaphylaxis by increased tryptase levels and positive skin test. Succinylcholine was the most frequent triggering agent in 64% of cases.9

An Australian study tested patients after they developed life-threatening intraoperative anaphylaxis, over a 10-year period. Eighty patients were diagnosed with NMBA-related anaphylaxis. Rocuronium was the most frequent triggering agent (56%), followed by succinylcholine (21%), vecuronium (11%), atracurium (9%), and mivacurium (3%).10


A recent retrospective study from Japan that included 15,479 patients reported sugammadex-associated anaphylaxis in 6 patients (0.039%).11


Anaphylaxis typically develops within minutes after exposure to the triggering agent. Harboe et al reported that 90% of cases occurred within 5 minutes after induction of general anesthesia.12The diagnosis is based mainly on clinical signs and supported by increased levels of plasma tryptase. However, a finding of normal tryptase levels does not rule out anaphylaxis.4 An elevation in tryptase levels, from degranulation of mast cells, occurs minutes after the exposure and has a half-life of approximately 2 hours.

All patients with suspected or confirmed anaphylaxis should be referred for an allergy consult and skin testing to identify the allergen.


The first step in treating anaphylaxis is to discontinue the suspected offending agent and administer 100% oxygen. Epinephrine is the drug of choice for the treatment of anaphylaxis. By causing immediate vasoconstriction, epinephrine increases venous return and cardiac output. In addition, it has positive inotropic effects, causes bronchodilation, and inhibits release of mast cells and basophils. Depending on the severity of the reaction, epinephrine can be administered in IV boluses of 10 to 200 mcg, repeated and titrated based on clinical response, and this can be followed, if necessary, by a continuous infusion (1-4 mcg /min).5,7,13

Vasopressin (2-unit bolus, repeated as necessary) should be administered in cases refractory to epinephrine administration.13 Methylene blue was reported to successfully treat anaphylaxis in cases unresponsive to epinephrine administration.14 The use of corticosteroids is controversial, with no apparent benefit in the immediate treatment of anaphylaxis.

For patients treated with beta-blockers, glucagon (1-mg bolus, repeated as necessary) should be administered. Fluid replacement therapy to counteract profound anaphylaxis-induced vasodilation should be started immediately after suspecting anaphylaxis. The decision to proceed with surgery after a suspected or confirmed anaphylactic reaction should be made individually based on the severity of the reaction.15


  • NMBAs and antibiotics are the agents most frequently reported to cause perioperative anaphylaxis.
  • Anaphylaxis in the perioperative period most likely is underreported.
  • Early diagnosis of anaphylaxis is crucial.
  • Sugammadex can cause anaphylaxis.
  • Epinephrine with fluid administration is the primary treatment for anaphylaxis.


  1. Berkeley AV. Anaphylaxis in the operating room. Medscape. October 25, 2017. article/ 2500072-overview#a2. Accessed April 5, 2019.
  2. Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: epidemiology and clinical features of perioperative anaphylaxis in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121(1):159-171.
  3. Johansson SG, Bieber T, Dahl R, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004;113(5):832-836.
  4. Simons FE, Ardusso LR, BilÒ MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13-37.
  5. Dewachter P, Mouton-Faivre C, Emala CV. Anaphylaxis and anesthesia: controversies and new insight. Anesthesiology. 2009;111(5):1141-1150.
  6. Kroigaard M, Garvey LH, Gillberg L, et al. Scandinavian Clinical Practice Guidelines on the diagnosis, management and follow-up of anaphylaxis during anaesthesia. Acta Anaesthesiol Scand. 2007;51(6):655-670.
  7. Mertes PM, Tajima K, Regnier-Kimmoun MA, et al. Perioperative anaphylaxis. Med Clin North Am. 2010;94(4):761-789.
  8. Chacko T, Ledford D. Peri-anesthetic anaphylaxis. Immunol Allergy Clin North Am. 2007;27(2):213-230.
  9. Petitpain N, Argoullon L, Masmoudi K, et al. Neuromuscular blocking agents induced anaphylaxis: Results and trends of a French pharmacovigilance survey from 2000 to 2012. Allergy. 2018;73(11):2224-2233.
  10. Sadleir PH, Clarke RC, Bunning DL, et al. Anaphylaxis to neuromuscular blocking drugs: incidence and cross-reactivity in Western Australia from 2002 to 2011. Br J Anaesth. 2013;110(6):981-987.
  11. Miyazaki Y, Sunaga H, Kida K, et al. Incidence of anaphylaxis associated with sugammadex. Anesth Analg. 2018;126(5):1505-1508.
  12. Harboe T, Guttormsen AB, Irgens A, et al. Anaphylaxis during anesthesia in Norway: a 6-year single-center follow-up study. Anesthesiology. 2005;102(5):897-903.
  13. Harper NJN, Cook TM, Garcez T, et al. Anaesthesia, surgery, and life-threatening allergic reactions: management and outcomes in the 6th National Audit Project (NAP6). Br J Anaesth. 2018;121(1):172-188.
  14. Bauer CS, Vadas P, Kelly KJ. Methylene blue for the treatment of refractory anaphylaxis without hypotension. Am J Emerg Med. 2013;31(1):264.e3-264.e5.
  15. Sadleir PHM, Clarke RC, Bozic B, et al. Consequences of proceeding with surgery after resuscitation from intra-operative anaphylaxis. Anaesthesia. 2018;73(1):32-39.