{'fraction_non_alphanumeric': 0.03044496487119438, 'fraction_numerical': 0.0117096018735363, 'mean_word_length': 5.612903225806452, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Should Aprotinin be reconsidered for use in pediatric surgery?

Aprotinin is a potent antifibrinolytic that inhibits several serine proteases, specifically plasmin, trypsin, chymotrypsin, kallikrein, and thrombin. Its action on plasmin independently inhibits fibrinolysis. It also has minor inhibitory effects on the contact activation phase of coagulation (FXII and thrombin) that both initiate coagulation and promote fibrinolysis. It preserves platelet function by blocking the plasmin-induced degradation of platelet glycoprotein 1b (the platelet receptor for VWF and collagen). In addition, an antiinflammatory role has been suggested based on reduced leukocyte activation and cytokine release (1,2). Animal studies suggest that this reduced inflammatory response could even improve neurological outcome during CPB; but this has not been confirmed in human studies (3). Furthermore, human studies suggest that it might even reduce the incidence of stroke (4). The broad-spectrum effects of aprotinin on multiple serine proteases in the coagulation and fibrinolytic cascades are thought to make it more potent than the lysine analogues, tranexamic acid (TXA), and epsilon-aminocaproic acid (EACA). Aprotinin was first approved in 1993 by the FDA in the USA for use to reduce blood loss during coronary artery bypass grafting (5). A 2002 report by Haas from Germany endorsed it as ‘Aprotinin A Blood-Saving Substance’ in providing a significant blood-saving effect when administered intraoperatively in cardiac and noncardiac surgery (6). Aprotinin was the most widely used and efficacious antifibrinolytic for reducing bleeding and blood transfusion associated with major surgery, such as cardiovascular surgery, until its abrupt withdrawal from the European, Canadian, and US markets in 2008 after suspension of its license. This was based on safety concerns from four observational studies (7–10) but mainly due to one randomized controlled trial (RCT) that questioned the safety of aprotinin. The RCT was the ‘Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART trial): A comparison of Aprotinin and Lysine Analogues in High Risk Cardiac Surgery’ published in NEJM 2008 (11). This multicenter blinded randomized trial involved over 2000 high-risk adult cardiac surgical patients undergoing complex cardiac surgery. The 30-day mortality, incidence of myocardial infarction, cardiogenic shock, right heart failure, renal failure, and risk of massive blood loss were higher with aprotinin than with the lysine analogues; TXA or EACA. The investigators concluded that: ‘Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with Aprotinin compared with the lysine analogues precludes its use in high-risk cardiac surgery’. Therefore, FDA recommended its withdrawal from the market, and hence, it suddenly became unavailable worldwide for both adults and children. However, as highlighted in a 2013 BJA article ‘Aprotinin and Cardiac Surgery: a Sorry Tale of Evidence Misused’ (12), there were major design flaws with BART; (i) Only high-risk adult cardiac surgical patients were included, and there was no stratification of treatment allocation by procedure, patient risk profile, or participating center; (ii) Lack of placebo control; (iii) It was not designed or powered to target mortality as a primary outcome parameter; (iv) The trial was terminated early, and therefore, it did not reach target patient enrollment per power analysis to detect difference in postoperative bleeding; (v) Confounding by indication could have biased the analysis; and (vi) Concerns regarding the possible under dosing of heparin as the celite activated clotting time test is prolonged with aprotinin. Although aprotinin remains unavailable in the USA, it has subsequently has been reintroduced into the Canadian in 2011 (13) & European markets in 2012 (14) since Howell et al.’s further analysis and criticism of the BART trial in: ‘Putting the Record Straight on Aprotinin as Safe and Effective: Results From a Mixed Treatment Meta-Analysis of Trials of Aprotinin’, which concluded that: ‘This meta-analysis including BART demonstrates no increase in the risk of in-hospital mortality for adult patients undergoing cardiac surgery treated with Aprotinin relative to either placebo or other antifibrinolytic agents’(15). Aprotinin was the most commonly used antifibrinolytic medication in children (undergoing heart surgery and other high bleeding risk surgeries) until it was taken off the market. It had been widely reported to be efficacious for use in pediatric cardiac, orthopedic, and craniofacial surgery in decreasing blood loss and transfusion compared with placebo. Eaton in a 2008 article, ‘Antifibrinolytic Therapy in Surgery for Congenital Heart Disease’, a thorough qualitative review of the literature, concluded that all three antifibrinolytics were equally efficacious in reducing bleeding and transfusion; however, Aprotinin may have unique beneficial antiinflammatory effects (16). There was not enough evidence