Prospective Evaluation of Risk of Protamine Reactions in Patients with NPH Insulin-Dependent Diabetes

Levy, Jerrold H.; Zaidan, James R.; Faraj, Bahjat A.

doi:10.1213/00000539-198607000-00006

Cited by 94 publications

(35 citation statements)

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“…Other suggested mechanisms for hypotension following protamine administration include splanchnic pooling of blood (decreased preload), negative inotropy, and calcium chelation. ~2 Patients with a history of either 9 diabetes mellitus receiving protamine containing insulin 13 or prior exposure to protamine or allergy to fish 14 are particularly prone to these adverse reactions. Other adverse haemodynamic effects associated with protamine include a rare syndrome of pulmonary vasoconstriction,'5 hypoxemia, 16 pulmonary oedema 17 and platelet dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Prophylactic administration of histamine1 and histamine2 receptor blockers in the prevention of protamine-related haemodynamic effects

et al. 1990

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Avec le concours de candidats g~ une revascularisation coronarienne, nous avons mesurg l'effet de l'utilisation de bloqueurs des r~cepteurs histaminiques H t et 1-12 avant l' injection de protamine, sur la r~ponse hdmodynamique d cette derni&e. Les patients du Groupe 1 ne recevaient aucun pr~-traitement rnais nous injections prophylactiquement de la dyphenhydramine (anti-Hi) et de la cim~tidine (anti-H2) d ceux du Groupe H. Les moyennes des pressions art~rielles systoliques, diastoliques, des tensions veineuses centrales et du pouls avant (et aprds) r injection de protamine ~taient respectivement dans le 64 • 11 (51 • 8), 81 • 11 (65 • 10), 10 • 3 (11 + 7) mmHg et de 92 ++-10 (87 +-13) battements. min -t .Dans le Groupe 11, ces m~mes moyennes ~taient de: 113 +_ 19(113 + -17), 61 • 12(61 • 11), 79• 15(80• 13),9• 3 (9 + 2) mmHg et de 88 +-6 (86 +--4) Protamine, a highly alkaline compound, is used routinely to reverse the anticoagulation effect induced by heparin. Protamine administration is associated with adverse haemodynamic responses including acute anaphylaxis. I-3 Prophylactic treatment with histamine1 (H1) and hista-

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Section: Discussionmentioning

confidence: 99%

Prophylactic administration of histamine1 and histamine2 receptor blockers in the prevention of protamine-related haemodynamic effects

et al. 1990

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“…[3], a prospective evaluation of protamine sulfate reaction risk was made for patients taking NPH insulin. Fifty patients were randomized to a prophylactic dose of corticosteroid and/or antihistamine prior to protamine sulfate administration.…”

Section: Prospective Studiesmentioning

confidence: 99%

“…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 case reports, review articles, or of a retrospective, epidemiologic kind.…”

mentioning

confidence: 99%

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

Nybo

Madsen

2008

Basic Clin Pharma Tox

136

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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...

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“…Available data indicate that severe adverse reactions could be mediated by the immune response because protamine is a nonhuman protein. Thus, a large population of diabetic patients who previously received protamine-containing insulins, and who developed antiprotamine antibodies, were at high risk for this immunoglobin-mediated protamine response (5). On the other hand, protamine reactions could also be triggered by a nonimmunological mechanism.…”

Section: Introductionmentioning

confidence: 99%

Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): In vitro evaluation of efficacy and toxicity

et al. 2001

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Patients undergoing anticoagulation with heparin or low molecular weight heparin (LMWH) require a superior antidote that possesses more selective biological actions and a better safety profile than protamine. We had previously developed 2 low molecular weight protamine (LMWP) fractions (TDSP4 and TDSP5) from thermolysin-digested protamine as potential nontoxic, heparin-neutralizing agents. In this, the second article in this series, studies focused on in vitro evaluation of heparin/LMWHneutralizing efficacy and putative toxicity. These LMWP fractions, particularly TDSP5, were effective and fully capable of neutralizing a broad spectrum of heparin-induced anticoagulant activities (ie, aPTT, anti-Xa, and anti-IIa activities). Additionally, these LMWP fractions could neutralize the activities of commercial LMWH. As assessed by the anti-Xa assay, TDSP5 was as effective as, although less potent than, protamine in reversing the activity of MonoEmbolex (molecular weight 5000-7000) and 2 other different sizes (molecular weight of 3000 and 5000 d) of LMWH preparations. Furthermore, compared with protamine, TDSP5 exhibited a much-reduced toxicity and thus an improved safety profile, as reflected by its reduced ability to activate the complement system and cross-react with the antiprotamine antibodies, which are 2 primary indices of protamine toxicity.

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Prospective Evaluation of Risk of Protamine Reactions in Patients with NPH Insulin-Dependent Diabetes

Cited by 94 publications

References 0 publications

Prophylactic administration of histamine1 and histamine2 receptor blockers in the prevention of protamine-related haemodynamic effects

Prophylactic administration of histamine1 and histamine2 receptor blockers in the prevention of protamine-related haemodynamic effects

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

Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (II): In vitro evaluation of efficacy and toxicity

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