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Anesthesiology:
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Anaphylactoid Reactions to Protamine

Kindler, Christoph H. MD; Bircher, Andreas J. MD

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To the Editor:-Some aspects of the interesting case report by Takenoshita et al. [1] merit, in our opinion, further discussion.
Acute reactions to protamine vary from mild reactions, such as erythema, urticaria, and transient mild elevations in pulmonary artery pressure to more severe reactions, which include bronchospasm, hypotension, and, although rare, cardiovascular collapse and death. [2] Protamine is also hypothesized to be a potential cause of fulminating noncardiogenic pulmonary edema after cardiopulmonary bypass. [3] The exact mechanisms by which protamine produces these adverse reactions are not completely understood and include direct, nonimmunologic release of histamine, immunoglobulin E (IgE)-mediated release, complement-fixing antiprotamine immunoglobulin G (IgG) antibodies, and protamine-heparin complexes that activate complement. [2]
The case report, as presented, contributes only partially to the understanding of adverse reactions to protamine. The acute facial edema and marked increase of tryptase in the described patient indicate a significant skin mast cell degranulation. However, an antibody-mediated mechanism is the likely cause for the increased risk of life-threatening reactions to protamine in patients with diabetes who receive neutral protamine Hagedorn insulin. [4] Binding of protamine to specific IgE or possibly to subclass 4 of IgG on mast cells or basophils may result in a release of histamine and tryptase. Unfortunately, neither IgE nor IgG antibodies to protamine were determined in this case. The positive skin tests to protamine after the incident do not necessarily confirm the hypersensitivity to protamine and may only indicate previous exposure to protamine. In addition, a recent study has established a poor specificity of protamine skin tests. [5] Intradermal injections of protamine with concentrations between 100 and 1,000 micro gram/ml induce irritative skin responses in healthy subjects [6]; 10 micro gram/ml might have been a nonirritative concentration, although Takenoshita et al. [1] did not have control subjects to test. However, the recommended protamine test dose concentration is 1 micro gram/ml. [5] In addition, out of the 11 patients taking neutral protamine Hagedorn insulin who had severe anaphylactoid reactions to protamine, only one of four patients studied by cutaneous testing had clearly positive results. [2]
In summary, the case report identifies a patient with neutral protamine Hagedorn insulin-dependent diabetes mellitus who suffered a severe anaphylactoid reaction during open heart surgery probably caused by protamine. The findings of an elevated tryptase and positive protamine skin tests remain inadequate to answer questions concerning the mechanism of this severe reaction.
Christoph H. Kindler, M.D., Staff Anesthesiologist, Department of Anaesthesia; Andreas J. Bircher, M.D., Staff Allergist and Dermatologist, Department of Dermatology, University of Basel, Kantonsspital, CH-4031 Basel, Switzerland.
(Accepted for publication August 6, 1996.)
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REFERENCES

1. Takenoshita M, Sugiyama M, Okuno Y, Inagaki Y, Yoshiya I, Shimazaki Y: Anaphylactoid reaction to protamine confirmed by plasma tryptase in a diabetic patient during open heart surgery. Anesthesiology 1996; 84:233-5.

2. Horrow JC: Protamine: A review of its toxicity. Anesth Analg 1985; 64:348-61.

3. Kindler C, Bircher A, Stulz P: Protamine-induced fulminating noncardiogenic pulmonary edema following cardiopulmonary bypass. Eur J Cardiothorac Surg 1996; 10:463-6.

4. Weiss ME, Nyhan D, Peng Z, Horrow JC, Lowenstein E, Hirshman C, Adkinson NF Jr: Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med 1989; 320:886-92.

5. Horrow JC, Pharo GH, Levit LS, Freeland C: Neither skin tests nor serum enzyme-linked immunosorbent assay tests provide specificity for protamine allergy. Anesth Analg 1996; 82:386-9.

6. Weiss ME, Adkinson NF Jr: Allergy to protamine. Clin Rev Allergy Immunol 1991; 9:339-55.

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