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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 , 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% 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%, and a recent study has confirmed the relation between protamine sulfate reactions and mortality risk . 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. To disclose the evidence-based knowledge concerning the anaphylactic reactions caused by this drug, a systematic literature review was therefore conducted.
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This systematic review shows that of 487 articles retrieved (+19 extra provided from the articles themselves), 9 retrospective and 16 prospective articles were found relevant. For retrospective studies, the incidence of an anaphylactic reaction was 0.19% consistent with the incidence reported elsewhere . However, due to their nature, those retrospective studies do not contribute to a physiological disclosure of the problem. Only 3 of the 16 prospective studies had an optimal design as far as inclusion criteria, randomization, blinding and description of symptoms were concerned. However, as prospective investigations are difficult to conduct on low-incidence phenomena, the general insistence on prospective randomized studies could perhaps be a reflex response, as this technique can only be used if there is an alternative approach: as one would need an efficacious alternative to protamine to conduct such a trial, the low number of prospective comparison trials is not necessarily surprising. The only credible alternative to protamine reversal of heparin today is heparinase I as described by Stafford-Smith et al. : this was, however, found inferior to protamine sulfate and could not be recommended as an alternative drug in general. Of note, alternatives do exist that can replace the use of heparin and protamine sulfate (e.g. the thrombin inhibitor bivalirudin) . It seems to have several advantages, for example, safe to use in patients with heparin-induced thrombocytopenia , and evidence gathered so far seems very promising.
Another well-known reason for a low number of evidence-based studies is if the subject investigated is potentially mortal, as it would be highly unethical to conduct a prospective randomized study with increased mortality as outcome. A good example on this is appendicitis: the benefit of postoperative antibiotics to prevent infection has been elicited in a Cochrane review , but a blinded, randomized outcome study of antibiotic treatment instead of appendectomy has to the knowledge of these authors not been conducted although evidence-based knowledge within this area has been requested from time to time . This empiric way of acting could in the long run leave us with unsubstantiated routines that in the worst case could be harmful. However, the role of randomized controlled trials can certainly be discussed when exploring adverse reactions, and, for example, the use of database analyses could prove helpful as well. This approach has always been a source of important information when investigating outcome of certain procedures and was also used in some of the articles found in this study (e.g. Laxenaire et al. in table 2). In addition, to reach a sufficient level of evidence, the knowledge gained through these studies will often need confirmation through, for example, a randomized trial, why these studies generally are given higher weight.
The most common factor predisposing to an anaphylactic reaction to protamine sulfate is prior treatment with NPH insulin. Thus, consideration of such a reaction perhaps should be limited to those individuals as in most studies from the mid-80s. However, many of the later studies have been conducted on diabetes patients disregarding their treatment or in a general population which contributes to the common idea of protamine sulfate causing adverse reactions in a general population without substantial evidence. In this context, a systematic literature review is a powerful tool that provides a well-structured insight into the evidence lying behind different ‘manners’, and in order to gain insight into a certain area, the literature must be profoundly scrutinized. To our knowledge, this is the first systematic literature review of studies addressing adverse reactions to protamine sulfate. Earlier studies have mainly been of a reviewing kind or have been case reports supported by a literature summary. Therefore, there is no conflict with earlier reports, but our findings does question the profoundness of reviews and literature summaries in general: often, these are performed by a specialist in the field, why the literature will be viewed in a subjective way. In order to assure that the ‘common knowledge’ is evidence-based, a thorough, systematic literature review of the matter in question should be performed. Of note, this should be considered even for illustrious routines that go a long way back: certainly, many traditions has an empiric sound nature and should be preserved, but evidence-based knowledge could from time to time add new, important aspects.
Our study has some limitations concerning the retrieval of literature and evaluation of symptoms described: composition of the literature search is critical, why a broad search strategy was applied to assure high sensitivity in the search to retrieve all relevant studies. Furthermore, the literature retrieved was thoroughly read by both authors to assure a valid evaluation, and reviews and case report literature was evaluated to extract ‘spin-off’ articles not found in the primary search. As 19 articles emerged from this, it indicates that even the most vivid literature search does not guarantee extraction of all existing literature on a certain topic. As far as evaluation of symptoms is concerned, we have relied solely on statements in the articles to distinguish between anaphylactic/anaphylactoid reactions and other types of haemodynamic instability, as no crude data were available for interpretation.
In conclusion, the retrospective studies support the general opinion concerning adverse reactions due to protamine sulfate, but evidence for the magnitude and physiological background for an actual anaphylactic reaction caused by protamine sulfate is very limited. Our findings support the low incidence of anaphylactic reactions reported in other studies (<1%), but caution should be taken due to a pronounced heterogeneity of the studies. Furthermore, a straightforward clinical implication of this work is the recommendation of a more critical appraisal of many daily routine procedures: a systematic literature review of such issues should be performed in a well-structured, repeated manner in order to accumulate new-gained insight in the task at quest. This approach should be given higher priority in all aspects of medical care, and could beneficially be included in the medical education programme and used as a tool in this context.