Topical application of antifibrinolytic drugs for on-pump cardiac surgery: a systematic review and meta-analysis

Amir Abrishami 0 Frances Chung 0 Jean Wong 0 0 A. Abrishami , MD F. Chung, MD J. Wong, MD ( &) Department of Anesthesia, Toronto Western Hospital, University Health Network , 2-434 McLaughlin Wing, 399 Bathurst Street, Toronto, ON , Canada M5T 2S8 Purpose This systematic review aimed to evaluate the efficacy and safety of topical application of antifibrinolytic drugs to reduce postoperative bleeding and transfusion requirements in patients undergoing on-pump cardiac surgery. Methods We searched The Cochrane Library, MEDLINE, EMBASE and SCI-EXPANDED for all randomized controlled trials on the topic. Trial inclusion, quality assessment, and data extraction were performed independently by two authors. Standard meta-analytic techniques were applied. Results Eight trials (n = 622 patients) met our inclusion criteria. The medication/placebo was applied into the pericardial cavity and/or mediastinum at the end of cardiac surgery. Seven trials compared antifibrinolytic agents (aprotinin or tranexamic acid) versus placebo. They showed that, on average, topical use of antifibrinolytic agents reduced the amount of 24-h postoperative chest tube (blood) loss by 220 ml (95% confidence interval: -318 to -126, P \ 0.00001, I2 = 93%) and resulted in a saving of 1 unit of allogeneic red blood cells per patient (95% confidence interval: -1.54 to -0.53, P 0.0001, I2 = 55%). The incidence of blood transfusion was not significantly changed following topical application of the medications. One study comparing topical versus intravenous administration of aprotinin found comparable results - between the two methods of administration for the abovementioned outcomes. No adverse effects were reported following topical use of the medications. Conclusion This review suggests that topical application of antifibrinolytics can reduce postoperative bleeding and transfusion requirements in patients undergoing on-pump cardiac surgery. These promising findings need to be confirmed by more trials with large sample size using patient-related outcomes and more assessments regarding the systemic absorption of the medications. Resume Objectif Le but de cette etude methodique etait devaluer lefficacite et linnocuite de lapplication topique dagents anti-fibrinolytiques afin de reduire les saignements et les besoins transfusionnels postoperatoires chez les patients subissant une chirurgie cardiaque avec circulation extracorporelle. Methode Nous avons fouille les bases de donnees suivantes afin dextraire toutes les etudes randomisees controlees traitant de cette question : The Cochrane Library, MEDLINE, EMBASE et SCI-EXPANDED. Linclusion des etudes, levaluation de la qualite et lextraction des donnees ont ete realisees de facon independante par deux auteurs. Des techniques de metaanalyse standard ont ete utilisees. Resultats Huit etudes (n = 622 patients) ont satisfait a` nos crite`res dinclusion. Le medicament/placebo a ete applique dans la cavite pericardique et/ou dans le mediastin a` la fin de la chirurgie cardiaque. Sept etudes ont compare des agents anti-fibrinolytiques (aprotinine ou acide tranexamique) a` un placebo. Ces etudes ont montre que, en moyenne, lapplication topique dagents anti-fibrinolytiques a reduit les pertes sanguines des drains thoraciques durant les premie`res 24 h postoperatoires de 220 ml (intervalle de confiance 95% : 318 a` 126, P \ 0,00001, I2 = 93 %) et a permis de sauver un culot globulaire allogenique par patient (intervalle de confiance 95% : 1,54 a` 0,53, P \ 0,0001, I2 = 55 %). Lincidence de transfusion na pas subi de modification significative a` la suite de lapplication topique des medicaments. Une etude comparant lapplication topique a` ladministration intraveineuse daprotinine a donne des resultats comparables entre les deux methodes dadministration pour les devenirs mentionnes ci-dessus. Aucun effet secondaire na ete rapporte en relation avec lapplication topique des medicaments. Conclusion Notre etude sugge`re que lapplication topique dagents anti-fibrinolytiques peut reduire les saignements et les besoins transfusionnels postoperatoires chez les patients subissant une chirurgie cardiaque avec circulation extra-corporelle. Ces resultats prometteurs devraient cependant etre confirmes par dautres etudes presentant une taille dechantillon plus importante examinant les devenirs associes aux patients et comprenant dautres evaluations concernant labsorption systemique des medicaments. On-pump cardiac surgery can be associated with excessive bleeding due to several factors such as increased fibrinolysis induced by extracorporeal circulation and surgical trauma.1 As a result, 23.851.9% of patients require blood transfusion, and re-exploration is performed in 26% of the cases to control bleeding.2 In spite of the recent advances in surgical techniques and the perioperative care, the amount of bleeding remains as high as 6001200 ml. Hence, in most centres, a median of 2 to 3 units of red blood cells (RBCs) per patient is required.3 Patients undergoing cardiac surgery are vulnerable to the consequences of blood loss which can lead to increased mortality, morbidity, and poor quality of life.4 Issues such as the cost of blood, limited availability, and the potentially harmful effects of transfusion necessitate developing more effective methods to minimize surgical blood loss. Antifibrinolytic agents (aprotinin, tranexamic acid, and e-aminocaproic acid) have been shown to inhibit fibrinolysis and, thus, reduce bleeding in cardiac surgery.5 However, recent studies on large numbers of patients have raised growing concerns about the serious adverse effects observed following systemic administration of antifibrinolytic agents. These complications include increased mortality,6 renal toxicity,5,7,8 anaphylactic reactions,9 graft vessel occlusion,10 the risk of myocardial infarction (in high-risk cardiac surgery) following aprotinin use,11 and, because of its mechanism of action, the potential risk of thromboembolic events after tranexamic acid administration.12 Due to the natural barrier properties of the pericardium, which prevents free diffusion of substances, recent experimental studies have shown that local application of different medications into the pericardial cavity can lead to desirable therapeutic efficacy without significant systemic absorption.1315 In light of these findings, topical application of antifibrinolytics may be an effective and safe pharmacological strategy to minimize blood loss in cardiac surgery.1621 This systematic review aims to evaluate the best available evidence about the safety and efficacy of the topical use of antifibrinolytic drugs to reduce postoperative blood loss and transfusion requirements in adult patients having on-pump cardiac surgery. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 2, 2008), MEDLINE from January 1966 to July 2008, EMBASE from January 1980 to July 2008, and Scienc (...truncated)