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Anaphylactic & Anaphylactoid Reactions During Surgery - An Outline

Below is an outline from a talk given to the Department of Anesthesia at UCSF. A case presentation was given on a patient who had two life-threatening episodes of anaphylaxis after opthalmologic surgery. The second episode might have been prevented if the proper workup had been performed.

Although specific skin testing instructions are given below, the following is not intended as a guide for diagnosing and treating surgical anaphylaxis.

Implicated Substances In Perioperative Period

  • latex - a true IgE-mediated allergy, it is becoming recognized as a major health issue. A reasonably good RAST is available for latex.
  • thiopental (up to 50% in one study), IgE-mechanism implicated, skin testing may be helpful.
  • propofol, possible IgE mechanism, possible cross-reactivity with muscle relaxants, ? whether reasonable to skin test (only reported by one group).
  • muscle relaxants (6/27 patients in one study) esp. succinylcholine. IgE-mechanism implicated, and skin testing may be helpful. There is cross-reactivity among drugs of the same class, but reactions may occur less often with certain ones - vecuronium, for example).
  • Opioids (non-immunologic release of histamine from mast cells) - difficult to interpret skin test.
  • local anesthetics - if true allergy exists at all, it is VERY rare.
  • IV contrast - unclear mechanism, although not thought to be IgE-mediated. There is a misconception: contrast allergy has no relation to seafood allergy.
  • antibiotics (esp. penicillin and other beta-lactam drugs).
  • Protamine (esp. diabetics or vasectomized males).
  • ethylene dioxide (sterilizing equipment).
  • methylmethacrylate (bone cement) ? allergic mechanism.
  • volume expanders: all can probably cause direct-histamine release.
    • dextran (even with prophylaxis with dextran-1) - no good skin test since not IgE-mediated
    • gelatins, not that uncommon
    • albumin
    • Hetastarch, reaction rate 0.0004 to 0.006 %. No standardized skin test

High Risk Groups

▪ Females in regards to muscle relaxant allergy. There may be sensitization to quaternary ammonium compounds common in cosmetics.
▪ Atopic patients (?). There is a higher (in some studies) incidence of atopics in reactors.

Skin Tests

As mentioned above, skin testing may be helpful in certain cases. Immediate-type skin tests are the most rapid and reliable method for demostrating the presense of IgE-antibody. They are best used to evaluate allergy to drugs that are high-molecular weight proteins, i.e., complete antigens (chymopapain, insulin, streptokinase, heterologous serum). Skin testing for low-molecular weight drugs, or incomplete antigens (sulfas, thiobarbiturates, muscle relaxants) are less reliable because we don't know the metabolites that end up forming the haptens. These haptens are essential in promoting the immune response.

Exception: penicillin and related drugs, since the metabolites are well characterized. So, skin testing can be very informative.


  1. Patient must be off histamine-blocking agents.
  2. Positive (Histamine) and negative (saline) controls must be used.
  3. Use standard dilutions, the highest dilutions that have been shown to not cause irritant or non-specific reactions in controls. If no standard known, you must use control volunteers to determine a proper, non-irritating dilution.
  4. Do the skin testing approximately 2-4 weeks, and less than 3 months, after the event. If too soon, there may be may have depletion of mediators or IgE.
  5. Have resusitation equipment available, as there is a theoretic risk of a severe reaction.
  6. Always do prick test first, usually at 1:10 or undiluted. Put a drop of solution on forearm (or upper back) and prick through with a sharp needle (27 gauge, e.g.). If negative at 15-20 minutes, perform intradermal test.
  7. Intradermals: inject 0.02 ml of solution, just enough to raise a small (2mm) bleb. Read results at 15-20 minutes.
  8. Positive test consists of a wheal of approximately 4mm (or at least 50% of control) with erythema. N.B. what constitutes a positive reaction is not at all standardized, it is different for different authors.
  9. Results are uninterpretable if a wheal and flare is present where the negative saline control was applied (i.e., dermatographism), or if there is no reaction to histamine (pt. on antihistamines or antidepressants).

Considerations when doing skin testing:

False positive:

  • irritant reaction
  • non-immunologic histamine release (opiates, muscle relaxants, thiobarbituates, vancomycin, gelatin).

False negative:

  • non-IgE mechanism of event
  • mediator or IgE depletion (tested too soon after event)
  • anti-histamine therapy
  • testing material is not the relevant antigen

Sensitivity and Specificity of skin testing for most drugs is not known because of lack of challenge data (mainly due to ethical considerations - near deaths have resulted from challenges). For penicillin and hymenoptera venom, rechallenge of skin test positive patients results in 50% reaction rate. Reaction rate for skin test negative patients is very low for PCN and hymenoptera - but these antigens are well characterized.

Because of the paucity of studies on this subject, there is only relatively reliable evidence of validity of testing to thiopental, succinylcholine, and latex. These three have had an IgE mechanism reasonably confirmed by RAST testing. However, it is reasonable to test to other drugs.


  • Skin test positive: A positive test is helpful, and may represent true hypersensitivity. It can give you some good information on what to avoid and on the risks to the patient. Plan:
    • avoid drug and cross-reactors
    • premedicate with Prednisone (usually 40 to 60 mg in an adult) at 13, 7, 1 hours and benadryl at one hour before the procedure.
    • all drugs thought to cause direct histamine release (opiates, for example) should be given SLOWLY, and at the lowest possible dose.
  • Skin test negative: Negative test not that helpful, may be "missing the boat"
    • premedicate regardless
    • carefully give histamine releasers


Lastly, it's important to note that you can you can confirm a anaphylactic(-oid) reaction with serum tryptase within 4 hours of the event. Tryptase is a protease contained in mast cells, and is a very good marker for mast cell activity. Histamine levels may also be helpful, but it must be drawn immediately after the event (histamine has a much shorter half-life than tryptase).

Neil Gershman, M.D.
May 13, 1994

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