Serious Anaphylactic Reactions due to Protamine Sulfate: A Systematic Literature Review

Abstract

Anaphylactic reactions caused by injection of protamine sulfate during cardiac surgery are a well-known complication. A systematic literature review was therefore conducted to gather evidence of the knowledge concerning these side effects, and to see if any prospective randomized studies supported this. Studies investigating the effect of protamine sulfate in human beings were extracted from MEDLINE, Embase and the Cochrane Library, retrieving 487 articles. Abstracts were evaluated by both authors, and referred articles not found in the primary search were furthermore extracted from reviews and case reports, resulting in a total of 272 relevant articles. Of these, 9 retrospective studies and 16 prospective studies were performed in an evidence-based manner. However, only 3 of the 16 prospective articles had an optimal design as far as inclusion criteria, randomization, and description of symptoms were concerned. Incidence of anaphylactic reactions in the prospective studies was 0.69% compared to 0.19% in the retrospective studies, but caution should be taken due to a pronounced heterogeneity of those studies. One study found heparinase I unsuitable as replacement for protamine sulfate. Overall, our findings support the low incidence of anaphylactic reactions reported in previous studies, but of note only few prospective investigations was conducted on the subject. Our study also emphasizes the need for critical appraisal of many routine procedures: in all aspects of medical care, systematic literature review conducted in a well-structured, repeated manner should be given high priority.Protamine sulfate is a strongly alkaline polypeptide, mainly used to reverse anticoagulant effects of heparin. When injected intravenously, the alkaline protamine combines with the acidic heparin to form a neutral salt, thereby eliminating the anticoagulating properties of heparin. Another major use of protamine sulfate occurs in neutral protamine Hagedorn (NPH ) insulin, where complexion with insulin delay absorption and prolong the duration of action. Although being a relatively safe drug, it can cause severe systemic reactions with pronounced morbidity and mortality [1], and protamine sulfate is reported as one of the most common causes of life-threatening adverse reactions during cardiac surgery when used for rapid neutralization of heparin. Anaphylactic reactions to protamine sulfate have been known for many years, but the incidence reported varies from 0.06% to 10.6% [2] and range from minor haemodynamic instability to fatal cardiovascular collapse. The incidence of catastrophic reactions to protamine sulfate during cardiovascular surgery is reported to be 0.13% [3], and a recent study has confirmed the relation between protamine sulfate reactions and mortality risk [4]. The protamine-heparin complexes are thought to be responsible for the adverse effects observed, including allergic reactions, systemic hypotension and increased pulmonary arterial pressure, but most articles gathering this knowledge have been either...

Practical Guidelines for Perioperative Hypersensitivity Reactions

“…Hypersensitivity reactions mediated by IgG, IgE, complement activation, and nonspecific histamine release have been reported [17,98]. Patients who have been previously exposed to this drug are at higher risk of developing a reaction, whether the drug was given for blocking heparin effect or combined with insulin.…”

Un temps de céphaline activée élevé n’est pas associé à un rebond d’héparine après une chirurgie cardiaque

“…However, excess protamine may be harmful to the patient as it can have its own anticoagulant and hemodynamic effects. [16][17][18][19] Thus, it is important to diagnose the presence of circulating heparin in the postoperative cardiac surgical patient. We hypothesized that persistence of residual circulating heparin may be reflected by elevation of APTT, a test that is routinely available.…”

Un petit peu de connaissances sur la coagulation peut s’avérer dangereux!

“…Il est clair pour tous que la protamine n'est pas un médicament inoffensif, et ses effets secondaires sont discutés en profondeur ailleurs. 2,3 Le fait que la protamine soit elle-même une antithrombine et un inhibiteur plaquettaire est peu reconnu. En administrant davantage de protamine en réponse à un aPTT élevé, une équipe médi-cale pourrait inconsciemment augmenter plutôt que réduire les saignements du patient.…”

“…Clearly, protamine is not an innocuous drug, as its side effects are extensively discussed elsewhere. 2,3 The fact that protamine is itself an anti-thrombin agent and a platelet inhibitor is little appreciated. By administering more protamine in response to an elevated aPTT, a physician team could unwittingly increase, rather than abate, bleeding.…”