Clinical Features

  • Difficult to diagnose anesthesia-related anaphylaxis because it differs from non-anesthesia related anaphylaxis in several ways
    • Early signs of anaphylaxis (e.g. pruritus, dyspnea) will not be noticed by patient
    • Cutaneous signs are hidden by surgical draping
    • Remaining signs may be non-specific (tachycardia, hypotension, increased airway resistance requiring higher ventilator pressure)
      • Most common initial features are oxygen desaturation, difficulty to ventilate, pulselessness
      • Absence of cutaneous symptoms does not exclude the diagnosis of anaphylaxis
      • Symptoms can occur in isolation (e.g. cardiac arrest)
      • 90% occur during induction of anesthesia when muscle relaxants (the most commonly implicated drugs) are infused, but reactions may occur at any time during the anesthesia
      • Clinical symptoms and severity will not allow distinction between IgE-mediated reactions and direct mast cell degranulation
  • Tryptase levels should be investigated whenever possible during the immediate hypersensitivity reaction in order to document mast cell activation
  • TIming
    • In 90% of cases, symptoms usually start within 5-10 minutes after IV administration
    • Anaphylaxis from latex and antiseptics (chlorhexidine) is usually 20-40 mins later due to slower absorption through skin or other mucosal surfaces
  • First dose reactions are not usually IgE mediated unless prior sensitization occurred, possibly with a different cross-reacting allergen


Differential DiagnosisCauses_of_severe_events_during_anesthesia.png

  • Drug overdose and interactions
  • Cardiac/vascular drug effects
  • Asthma
  • Arrhythmia
  • Pericardial tamponade
  • Pulmonary edema
  • Pulmonary embolus
  • Tension pneumothorax
  • Hemorrhagic shock
  • Venous embolism
  • Sepsis
  • C1-INH deficiency
  • Mastocytosis
  • Succinylcholine-related
    • Malignant hyperthermia
    • Myotonias and masster spasm
    • Hyperkalemia

Risk Factors

  • The main risk factor for perioperative anaphylaxis to anesthetic drugs is a previous uninvestigated severe immediate hypersensitivity during the perioperative period
At-risk group
Drug or drug class
Definite Risk
Existing drug allergy
Another drug
Multiple Surgeries, spina bifida, neural tube defects, bladder catheterization,-----
health care workers
Avocado, banana, chestnut, kiwi, papaya allergy
Gelatin plasma expanders
Effect insufficient for intervention
Egg, soy, or peanut allergy
Fish allergy
Female sex
Neuromuscular blocking drugs-----
Allergy to neuromuscular blocking drugs
No or insignificant risk
Previous exposure to neuromuscular blocking drugs
Neuromuscular blocking drugs
Family history of anesthetic anaphylaxis
All drugs
Previous minor reaction
All drugs

Common Causes




Diagnostic Approaches

General Algorithm


Neuromuscular Blocking Agents (NMBAs, Muscle Relaxants)

  • Most common cause of perioperative anaphylaxis
  • Mechanisms - most reactions occur because of direct mast cell activation, but life‐threatening reactions are usually caused by specific IgE
    • IgE-mediated
      • Most common with succinylcholine (aka suxamethonium) 23%, rocuronium 29%, vecuronium 18%, mivacurium 18%, least common with pancuronium 7%, cisatracurium 4%, atracurium 1%
      • Cross-reactivity common but allergy to all muscle relaxants is unusual
      • 15-50% of reactions occur with first exposure (suggesting direct mast cell activation and/or cross-reactivity with other drugs that the patient may be allergic to).
        • Many OTC drugs, cosmetics, and food products contain quaternary or tertiary ammonium ions similar to NMBAs which can lead to sensitization
        • "Pholcodine hypothesis" originated in Europe and suggested that exposure to pholcodine cough syrup resulted in IgE antibodies that are cross-reactive with neuromuscular blocking agents, which in turn led to a higher rate of perioperative anaphylaxis
    • Anaphylactoid direct mast cell activation
      • Most common with D-tubocurarine, atracurium, mivacurium

  • Diagnosisanesthetic_skin_testing_conc.png
    • Testing is not standardized
    • Despite a previous documented muscle relaxant-induced anaphylaxis, muscle relaxants with negative skin tests in a patient may be safely used (and is supported by various guidelines on perioperative anaphylaxis)
    • Skin testing has a high PPV if there is history of anaphylaxis to a muscle relaxant (routine screening has a low PPV)
    • SPT
      • Succinylcholine, atracurium, mivacurium - start with 10 and 5-fold dilutions (in order to avoid nonspecific histamine release)
      • All others - start with undiluted drug
    • Intradermal
      • 0.03-0.05 mL of 1000- and 100-fold dilutions, read after 20–30 min by measuring the increase of diameters of wheals and flares; ID is considered positive if the diameter of the obtained wheal is >8 mm and doubles with respect to the injection bleb (see table below)
      • Alternatively, consider using ID concentrations in table at right (from 2010 practice parameter)

Maximal concentrations for SPT and IDT (Allergy 2007)

Maximal concentrations for SPT and IDT (Allergy 2013)
Perioperative skin testing.png





  • IV barbiturates are most commonly responsible (e.g. thiopental, thioamyl, methohexital)
    • Skin testing has been reported with thioamyl at 0.01 mg/mL and thiopental at 0.2 mg/mL
    • Also, see tables above for skin testing concentrations
  • Nonbarbituates (e.g. propofol, midazolam, etomidate, ketamine)
    • Propofol (Diprivan) is a nonbarbiturate induction agent and can be used if sensitivity to barbiturates is suspected
      • Specific IgE to propofol occurs, but most propofol reactions are due to direct mast cell activation
      • See table above for skin testing
      • Propofol contains egg lecithin and soybean oil and may present a theoretical risk to egg or soy allergic patients, however, current evidence suggests that egg-allergic, soy-allergic (or peanut-allergic, as peanuts and soy are both legumes) patients are not more likely to develop anaphylaxis when exposed to propofol.


  • Phenanthrene family includes morphine, codeine; phenylpiperedine family includes alfentanyl, fentanyl, remifentanyl, sufentanyl and meperidine
    • Reaction usually anaphylactoid (due to direct mast cell activation), IgE-mediated reactions are rare
    • Fentanyl belongs to the phenylpiperidine group and does not cause anaphylactoid histamine release, but there are a few reported cases of IgE-mediated anaphylaxis to fentanyl
      • There is cross-reactivity between different opioids of the same family, but not between phenylpiperidine derivatives
    • See tables above for skin testing concentrations
    • Reducing the rate of opioid administration usually limits the severity of anaphylactoid reactions


  • Protamine (used to reverse heparin anti‐coagulation) may cause IgE-mediated or anaphylactoid reactions
  • Manufactured from fish sperm, and it is also a component of human sperm
    • Up to 70% of patients who have undergone vasectomies develop antibodies to sperm antigens and a third develops auto-antibodies to protamine
  • Independent risk factors for reaction to protamine include prior neutral protamine Hagedorn insulin use, fish allergy, and other medication allergy (?history of vasectomy), however, IgE-mediated reactions to protamine are rare, and there is no reason to contraindicate the use of protamine in patients allergic to fish or with a prior vasectomy.
  • See tables above for skin testing concentrations

Local Anesthetics

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