Search

Objectives: An increased risk of mortality and postoperative side effects led to aprotinin (Trasylol®) withdrawal from the market in 2008, but since 2018 aprotinin has again been used in France. The French retrospective multicentre APACHE study (AProtinin versus tranexamic Acid in Cardiac surgery patients with High-risk for Excessive bleeding) compared the efficacy of tranexamic acid versus half-dose aprotinin. The aim of this study, ancillary to the APACHE study, is to carry out a medico-economic analysis of the use of these two antifibrinolytics on an APACHE subpopulation., Methods: Economic data on reimbursement by the French health insurance system were extracted from the program for the data processing of medical information, and quantitative data on the cost of healthcare products were obtained from the hospital pharmacy software., Results: The main analysis of costs for the population shows that the global valuation was not significantly different between the two treatment groups (P=0.60), but the costs of blood products included in the related hospital stay group (Groupe Homogène de séjour [GHS]) (whole blood, platelets and plasma) were higher for the tranexamic acid group (P=0.007). In a sub-analysis of patients alive at discharge, the costs of blood products in addition to GHS (blood-derived medicines) and the costs of blood products in the GHS were higher for the tranexamic acid group (P=0.04 and 0.001, respectively)., Conclusions: The additional cost of aprotinin at the time of purchase is offset by the additional costs of blood products in the tranexamic acid group., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Background: Aprotinin, a serine protease inhibitor, has been used variably in cardiac surgery amidst ongoing debates about its safety following several previous studies. This study assesses the outcomes of aprotinin in high-risk isolated Coronary Artery Bypass Graft (iCABG) patients., Methods: The study retrospectively analysed a cohort of 1026 iCABG patients, including 51 patients who underwent aprotinin treatment. Logistic regression powered score matching was employed to compare aprotinin patients with a control group, in a propensity-matched cohort of 96 patients. The primary outcome measured was in-hospital death, with secondary outcomes including renal dysfunction, stroke, myocardial infarction, re-exploration for bleeding or tamponade, and postoperative stay durations., Results: The aprotinin cohort had high-risk preoperative patients with significantly higher EUROSCORE II values, 7.5 (± 4.2), compared to 3.9 (± 2.5) in control group. However, aprotinin group showed no statistically significant increase (p-value: 0.44) in hospital mortality with OR 2.5 [95% CI 0.51, 12.3]. Major secondary outcome rates of renal replacement therapy and postoperative stroke compared to the control group were also statistically insignificant between the two groups., Conclusion: This study suggests that aprotinin may be safely used in a select group of high-risk iCABG patients. The reintroduction of aprotinin under specific conditions reflects its potential benefits in managing bleeding in high-risk surgeries, but also underscores the complexity of its risk-benefit profile in such critical care settings. Nonetheless, it highlights the importance of carefully selecting patients and conducting additional research, including larger and more controlled studies to fully comprehend the potential risks and benefits of aprotinin., (© 2024. Crown.)

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin-kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin-angiotensin-aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled "Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions", we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.

Background: The role of aprotinin in modern cardiac surgery is not well defined. While licensed for use in isolated coronary artery bypass grafting it is more commonly used for cases deemed to be at an increased risk of bleeding. The relative efficacy, and safety profile, of aprotinin as compared to other antifibrinolytics in these high-risk cases is uncertain., Study Design and Methods: A retrospective observational study with propensity matching to determine whether aprotinin versus tranexamic acid reduced bleeding or transfusion requirements in patients presenting for surgical repair of type A aortic dissection (TAD)., Results: Between 2016 and 2022, 250 patients presented for repair of TAD. A total of 231 patients were included in the final analysis. Bleeding and transfusion were similar between both groups in both propensity matched and unmatched cohorts. Compared to tranexamic acid, aprotinin use did not reduce transfusion requirements for any product. Rates of bleeding in the first 12 h, return to theater and return to intensive care unit with an open packed chest were similar between groups. There was no difference in rates of renal failure, stroke, or death., Conclusion: Aprotinin did not reduce the risk of bleeding or transfusion requirements in patients undergoing repair of type A aortic dissections. Efficacy of aprotinin may vary depending on the type of surgery performed and the underlying pathology., (© 2024 AABB.)

Background: Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care., Objectives: To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology., Search Methods: We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP)., Selection Criteria: We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants., Data Collection and Analysis: We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received., Main Results: We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials)., Authors' Conclusions: We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical "magic shotgun". Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015-2020, after re-analysis of these clinical trials' data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.

Introduction: The European Medicines Agency restored aprotinin (APR) use for preventing blood loss in patients undergoing isolated coronary artery bypass graft (iCABG) in 2016 but requested the collection of patient and surgery data in a registry (NAPaR). The aim of this analysis was to evaluate the impact of APR reintroduction in France on the main hospital costs (operating room, transfusion and intensive unit stay) compared to the current use of tranexamic acid (TXA), which was the only antifibrinolytic available before APR reinstatement., Methods: A multicenter before-after post-hoc analysis to compare APR and TXA was carried out in four French university hospitals. APR use followed the ARCOTHOVA (French Association of Cardiothoracic and Vascular Anesthetists) protocol, which had framed three main indications in 2018. Data from 236 APR patients were retrieved from the NAPaR (N = 874); 223 TXA patients were retrospectively retrieved from each center database and matched to APR patients upon indication classes. Budget impact was evaluated using both direct costs associated with antifibrinolytics and transfusion products (within the first 48 h) and other costs such as surgery duration and ICU stay., Results: The 459 collected patients were distributed as: 17% on-label; 83% off-label. Mean cost per patient until ICU discharge tended to be lower in the APR group versus the TXA group, which resulted in an estimated gross saving of €3136 per patient. These savings concerned operating room and transfusion costs but were mainly driven by reduced ICU stays. When extrapolated to the whole French NAPaR population, the total savings of the therapeutic switch was estimated at around €3 million., Conclusion: The budget impact projected that using APR according to ARCOTHOVA protocol resulted in decreased requirement for transfusion and complications related to surgery. Both were associated with substantial cost savings from the hospital's perspective compared with exclusive use of TXA., (© 2023. The Author(s).)

Objectives: To determine the effect of intraoperative antifibrinolytics, including tranexamic acid (TXA), aminocaproic acid (EACA), or aprotinin, on bleeding in children undergoing cardiac surgery with cardiopulmonary bypass (CPB)., Data Sources: Relevant articles were systematically searched from Ovid MEDLINE, Ovid EMBASE, CINAHL, Cochrane Library, and Web of Science to November 15, 2021., Study Selection: Abstracts were screened, and full texts were reviewed using predetermined inclusion and exclusion criteria using the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline., Data Extraction: A standardized data extraction tool was used., Data Synthesis: Sixty-eight studies including 28,735 patients were analyzed. TXA compared with placebo resulted in a mean decrease in chest tube output of 9.1 mL/kg (95% CI, 6.0-12.3 mL/kg), I2 equals to 65.2%, p value of less than 0.001, platelet requirement of 2.9 mL/kg (95% CI, 0.1-5.8 mL/kg), I2 =72.5%, p value less than 0.001 and plasma requirement of 4.0 mL/kg (95% CI, 0.6-7.2 mL/kg), I2 equals to 94.5%, p value less than0.001. Aprotinin compared with placebo resulted in a mean decrease in chest tube output of 4.3 mL/kg (2.4-6.2 mL/kg), I2 equals to 66.3%, p value of less than 0.001, platelet transfusion of 4.6 mL/kg (95% CI, 0.6-8.6 mL/kg), I2 equals to 93.6%, p value of less than 0.001, and plasma transfusion of 7.7 mL/kg (95% CI, 2.1-13.2 mL/kg), I2 equals to 95.3%, p value of less than 0.001. EACA compared with placebo resulted in a mean decrease in chest tube output of 9.2 mL/kg (2.3-21.0 mL/kg), I2 equals to 96.4%, p value of less than 0.001, RBC transfusion of 7.2 mL/kg (95% CI, 2.4-12.1 mL/kg), I2 equals to 94.5%, p value equals to 0.002, and platelet transfusion of 10.7 mL/kg (95% CI, 2.9-18.5 mL/kg), I2 equals to 0%, p value of less than 0.001. No statistical difference was observed in chest tube output when TXA was compared with aprotinin. Subgroup analysis of cyanotic patients showed a significant decrease in chest tube output, platelet requirement, and plasma requirement for patients receiving aprotinin. Overall, the quality of evidence was moderate., Conclusions: Antifibrinolytics are effective at decreasing blood loss and blood product requirement in children undergoing cardiac surgery with CPB although the quality of evidence is only moderate., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

The efficacy of aprotinin combinations with selected antiviral-drugs treatment of influenza virus and coronavirus (SARS-CoV-2) infection was studied in mice models of influenza pneumonia and COVID-19. The high efficacy of the combinations in reducing virus titer in lungs and body weight loss and in increasing the survival rate were demonstrated. This preclinical study can be considered a confirmatory step before introducing the combinations into clinical assessment.

Background: SARS-CoV-2 virus requires host proteases to cleave its spike protein to bind to its ACE2 target through a two-step furin-mediated entry mechanism. Aprotinin is a broad-spectrum protease inhibitor that has been employed as antiviral drug for other human respiratory viruses. Also, it has important anti-inflammatory properties for inhibiting the innate immunity contact system., Methods: This was a multicentre, double-blind, randomized trial performed in four Spanish hospitals comparing standard treatment versus standard treatment + aprotinin for patients with COVID-19 between 20 May 2020 and 20 October 2021. The primary efficacy outcomes were length of hospital stay and ICU admission. The secondary endpoints were each of the primary efficacy outcomes and a composite of oxygen therapy, analytical parameters and death. Safety outcomes included adverse reactions to treatment during a 30-day follow-up period. Treatment was given for 11 days or till discharge., Results: With almost identical analytical profiles, significant differences were observed in treatment time, which was 2 days lower in the aprotinin group (p = .002), and length of hospital admission, which was 5 days shorter in the aprotinin group (p = .003). The incidence of discharge was 2.19 times higher (HR: 2.188 [1.182-4.047]) in the aprotinin group than in the placebo group (p = .013). In addition, the aprotinin-treated group required less oxygen therapy and had no adverse reactions or side effects., Conclusion: Inhaled aprotinin may improve standard treatment and clinical outcomes in hospitalized patients with COVID-19, resulting in a shorter treatment time and hospitalization compared with the placebo group. The administration of aprotinin was safe., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: Craniosynostosis surgery is associated with considerable blood loss and need for transfusion. Considering the lower estimated blood volume (EBV) of children compared to adults, excessive blood loss may quickly lead to hypovolemic shock. Therefore, reducing blood loss is important in craniosynostosis surgery. This study was conducted to evaluate the efficacy of aprotinin or tranexamic acid (TXA) in blood loss reduction in these patients., Methods: In the current randomized controlled trial, 90 eligible pediatric patients with craniosynostosis were randomly divided into three groups to receive either aprotinin, TXA, or no intervention. The absolute blood loss and transfusion amount were assessed for all patients both intraoperatively and 2 and 8 hours postoperatively., Results: Although crude values of estimated blood loss were not significantly different between groups (p = 0.162), when adjusted to the patient's weight or EBV, the values reached the significance level (p = 0.018), particularly when the aprotinin group was compared to the control group (p = 0.0154). The EBV losses 2 hours and 8 hours postoperatively significantly dropped in the TXA and aprotinin groups compared to the control group (p = 0.001 and p < 0.001, respectively). Rates of postoperative blood transfusion were significantly higher in the control group (p = 0.024). Hemoglobin and hematocrit 8 hours postoperatively were lower in the control group than in the TXA or aprotinin treatment groups (p < 0.002 and p < 0.001, respectively). There were no serious adverse events associated with the interventions in this study., Conclusions: Aprotinin and TXA can reduce blood loss and blood transfusion without serious complications and adverse events in pediatric patients undergoing craniosynostosis surgery.

Background: Acute mesenteric ischemia arises through sudden interruption of mesenteric blood flow, mostly due to an occlusion of the superior mesenteric artery and is associated with a high mortality of approximately 50% to 90%. In previous studies, the single application of β-alanine or aprotinin caused an ameliorated intestinal damage but without any systemic effects., Methods: To analyze the combined effect of β-alanine and aprotinin on acute ischemia and reperfusion of the small intestine, a model with anesthetized rats was used. Ischemia and reperfusion were initiated by occluding and reopening the superior mesenteric artery. After 120 min of ischemia and 180 min of reperfusion, the intestine was analyzed for tissue damage, the activity of the saccharase, and accumulation of granulocytes. In addition, systemic and metabolic as well as inflammatory parameters were measured in blood at certain points in time., Results: The combination of β-alanine and aprotinin resulted in a clearly stabilized mean arterial blood pressure and blood glucose level during the reperfusion period. Furthermore, the combined administration resulted in significantly reduced tissue damage parameters, cytokine and cell-free hemoglobin concentrations in blood plasma. In addition, the damage to the small intestine was significantly attenuated, so that the animals ultimately survived the entire test period because of the administration of both substances., Conclusions: Overall, the simultaneous application of both substances leads to a synergistic protection without the occurrence of undesirable side effects. The combined usage of β-alanine and aprotinin can be seen as a promising approach to inhibit the onset of acute mesenteric ischemia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

COVID-19 is a contagious multisystem inflammatory disease caused by a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We studied the efficacy of Aprotinin (nonspecific serine proteases inhibitor) in combination with Avifavir ® or Hydroxychloroquine (HCQ) drugs, which are recommended by the Russian Ministry of Health for the treatment therapy of moderate COVID-19 patients. This prospective single-center study included participants with moderate COVID-19-related pneumonia, laboratory-confirmed SARS-CoV-2, and admitted to the hospitals. Patients received combinations of intravenous (IV) Aprotinin (1,000,000 KIU daily, 3 days) and HCQ (cohort 1), inhalation (inh) treatment with Aprotinin (625 KIU four times per day, 5 days) and HCQ (cohort 2) or IV Aprotinin (1,000,000 KIU daily for 5 days) and Avifavir (cohort 3). In cohorts 1-3, the combination therapy showed 100% efficacy in preventing the transfer of patients ( n = 30) to the intensive care unit (ICU). The effect of the combination therapy in cohort 3 was the most prominent, and the median time to SARS-CoV-2 elimination was 3.5 days (IQR 3.0-4.0), normalization of the CRP concentration was 3.5 days (IQR 3-5), of the D-dimer concentration was 5 days (IQR 4 to 5); body temperature was 1 day (IQR 1-3), improvement in clinical status or discharge from the hospital was 5 days (IQR 5-5), and improvement in lung lesions of patients on 14 day was 100%.

Background: The purpose of this systematic review is to evaluate the efficacy of antifibrinolytics in non-cardiac thoracic surgery., Methods: We searched for all randomized controlled trials on this topic. A set of strict inclusion and exclusion criteria was developed. Six studies were meta-analysed together then in subgroups of topical tranexamic acid and intravenous aprotinin. We compared postoperative chest drain output, transfusions requirements and duration of hospital stay where available to determine the efficacy of topical tranexamic acid or intravenous aprotinin in reducing blood loss., Results: The use of antifibrinolytics reduces 24-h chest drain output (-290.21 mL [-524.75, -55.66], P = 0.02, I 2  = 98%), red blood cell transfusion requirements (-1.27 units [-2.24, -0.30], P = 0.01, I 2  = 100%) and shortened duration of hospital stay (-1.81 days [-3.25, -0.36], P = 0.01, I 2  = 96%). The subgroup analysis also supported this trend., Conclusion: We conclude that the use of antifibrinolytics appears to reduce postoperative blood loss by reducing chest drain output, transfusion requirements and length of stay after thoracic surgery., (© 2021 Royal Australasian College of Surgeons.)

Background: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19., Methods: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement., Discussion: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome., Trial Registration: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Patellar tendinopathy, or jumper's knee is a common musculoskeletal condition characterized by progressive activity-related pain on the anterior aspect of the knee and tenderness on the patellar tendon. A conservative method is often the first choice of treatment, which can include anti-inflammatory medication, injection therapies, physiotherapy, eccentric exercises, extra corporeal shock wave therapy, orthosis, etc. Although there are several treatment options available, the management of patellar tendinopathy is still controversial. The literature reveals many different injection methods are being used by clinicians for the treatment of patellar tendinopathy. Platelet rich plasma, corticosteroids, autologous blood, and aprotinin are the most commonly used injection treatments. Injection therapies give promising results in the management of Patellar tendinopathy. However, due to low quality research and variation in the protocol and population it is difficult to provide a firm conclusion on its effectiveness. More high-quality clinical studies are recommended to determine the effectiveness of injections and at which stage of Patellar tendinopathy they are the most effective. This review can provide insight to clinicians involved in the management of this condition.

Cardiac surgery is usually associated with significant blood loss, which often necessitates blood transfusion. In order to decrease the risks associated with the latter, pharmacological as well as nonpharmacological strategies have been used to reduce blood loss. Among the pharmacological approaches, antifibrinolytic drugs are the mainstay. Aprotinin, which was the first ubiquitously used drug, fell into disrepute only to re-emerge after much debate. The decline of aprotinin paved the way for the lysine analogs. However, we must be aware with the side effects of these drugs as well as the dose modification required in special situations. Nonsaccharide glycosaminoglycans have been under investigation to overcome the drawbacks of the lysine analogs. It remains to be seen whether these drugs can replace the traditional antifibrinolytics., Competing Interests: None

Burns are one of the most common injuries that are complicated by many challenges including infection, severe inflammatory response, excessive expression of proteases, and scar formation. The aim of this study was to investigate the effect of botulinum toxin type A (BO) and aprotinin (AP) separately or in combination (BO-AP) in healing process. Four burn wounds were created in each rat and randomly filled with silver sulfadiazine (SSD), BO, AP and BO-AP. The rats were euthanized after 7, 14, and 28 days, and their harvested wound samples were evaluated by gross pathology, histopathology, gene expression, biochemical testing, and scanning electron microscopy. Both BO and AP significantly reduced expression of interleukin-1β (IL-1β) and transforming growth factor-β1 (TGF-β1) at the 7th post wounding day. Moreover, they inhibited scar formation by reducing the TGF-β1 level and increasing basic fibroblast growth factor (bFGF) at the 28th day. AP by decreasing protease production showed more effective role than BO in wound regeneration. AP increased tissue organization and maturation and improved cosmetic appearance of wounds, at 28 days. The best results gained when combination of BO and AP were used in healing of burn wounds. Treatment by BO-AP significantly subsided inflammation compared to the BO, AP, and SSD treated wounds. Treatment with BO-AP also reduced collagen density and led to minimal scar formation. Combination of botulinum toxin type A and aprotinin considerably increased structural and functional properties of the healing wounds by reducing scar formation and decreasing production of proteases.

Objectives: The upcoming release of aprotinin in paediatric cardiac surgery prompted a re-evaluation of its use in comparison to tranexamic acid (TXA) focusing on their effect on exposure to blood transfusions as well as severe postoperative morbidity or mortality., Methods: This retrospective study was conducted in a tertiary children hospital from 2002 to 2015. Patients receiving aprotinin (Aprotinin group: 2002-2007) were compared with those receiving TXA group (2008-2015) using propensity score analysis. Primary outcome measures were 'exposure to blood products' and 'severe postoperative morbidity or mortality'. High-risk subgroups that included neonates, complex (Risk Adjusted Classification for Congenital Heart Surgery-1 ≥ 3) and redo surgery were also analysed., Results: The study included 2157 patients, 1136 in the Aprotinin group and 1021 in the TXA group. Exposure to blood products was significantly higher in the Aprotinin group (78% vs 60%; P < 0.001) as well as in the complex and redo surgery subgroups. Incidence of mortality and/or severe morbidity was higher in the Aprotinin group (33% vs 28%; P = 0.007), as well as in the neonate group. However, cardiopulmonary bypass priming volume and intraoperative fluid balance were significantly decreased, and the use of modified ultrafiltration significantly increased in the TXA group., Conclusions: In our population, children receiving aprotinin were more frequently transfused and were at a higher risk of developing severe postoperative morbidity or mortality than those receiving TXA. Subgroups at high risk of bleeding or inflammation did not seem to benefit from aprotinin. These differences might be explained by a safer profile of TXA, but also attributed to major changes in our patient blood management strategies over years., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objective: Left ventricular free wall rupture is a catastrophic complication of acute myocardial infarction. Sutureless repair has been reported to be an effective surgical procedure for left ventricular free wall rupture. However, the outcomes of sutureless repair remain unclear., Methods: Between January 2001 and December 2016, 42 patients were treated for left ventricular free wall rupture at Jichi Medical University. Of them, 35 consecutive patients undergoing sutureless repair using the TachoComb (CSL Behring, Tokyo, Japan) or TachoSil (Nycomed, Zurich, Switzerland) patches were included in this study. No patient required cardiopulmonary bypass. The oozing type of left ventricular free wall rupture was observed in 33 patients (94%), and the blow-out type was observed in 2 patients (6%). The rupture sites were the anterior wall in 16 patients (46%), the posterior-lateral wall in 11 patients (31%), and the inferior wall in 8 patients (23%)., Results: The in-hospital mortality rate was 17% (6 patients). Re-rupture after sutureless repair occurred in 17% (6 patients). Of them, 4 cases (67%) of re-rupture occurred within 24 hours after surgery. The 2 patients with blow-out type left ventricular free wall rupture experienced re-rupture. Three patients required mitral valve surgery after sutureless repair during the admission. The overall survivals at 1, 5, and 10 years were 71.4%, 68.6%, and 62.9%, respectively. Multivariable analysis revealed that re-rupture was an independent predictor for decreased survival (hazard ratio, 58.6; 95% confidence interval, 4.9-701.6; P = .001). Postoperative pseudoaneurysm formation was not detected during the follow-up., Conclusions: Sutureless repair using TachoComb/TachoSil patches can be a viable treatment option for left ventricular free wall rupture. Care should be taken when applying this technique in cases of the blow-out type left ventricular free wall rupture., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Fibrinolytic activation is a major and preventable source of bleeding in neonates and children undergoing cardiac surgery with cardiopulmonary bypass. Based on the existing literature (adult and pediatric; cardiac and noncardiac), prophylactic administration of antifibrinolytic agents can help reduce fibrinolytic activation, and consequently reduces perioperative bleeding and the requirement for blood product transfusion. Due to the increased risk of renal failure and mortality reported in adults undergoing cardiac surgery, aprotinin should not be considered as a safe option in neonates and children. Further well-designed studies would be required before the prophylactic administration of aprotinin could be considered in pediatric cardiac surgery. The lysine analogs, tranexamic acid and ϵ-aminocaproic acid,, should be considered as safe and effective antifibrinolytic agents. Although no major side effects have been reported following the administration of lysine analogs in children undergoing cardiac surgery, high-dose tranexamic acid should not be recommended in order to avoid the increased risk of clinical seizures. Despite the recent advances made in our understanding of the pharmacokinetics of tranexamic acid and ϵ-aminocaproic acid,, the optimal plasmatic concentration to be targeted remains unknown. Further studies are therefore urgently needed to better define the optimal dose regimen to be used in neonates and children. In the meantime, the dose regimen published in the most recent pharmacokinetic studies can be used. Although no studies have assessed the effect of massive bleeding and transfusion on the plasmatic concentrations of the lysine analogs, additional boluses might be considered in the presence of bleeding and/or when signs of fibrinolytic activations are observed on viscoelastic hemostatic assays., (© 2018 John Wiley & Sons Ltd.)

We perform a meta-analysis from published randomized controlled trials to assess the efficacy and safety of aprotinin in total hip arthroplasty (THA). The following electronic databases were searched: PubMed (1966 to December 2018), EMBASE (1974 to December 2018), the Cochrane Library (1974 to December 2018), and Web of Science (1990 to December 2018). We also used Google Search to search for more potentially eligible studies up to December 2018. The methodological quality of the included studies was assessed independently by the two reviewers described by the Cochrane Collaboration for Systematic Reviews. Data analysis was performed with STATA13.0. Four randomized controlled trials were included in the meta-analysis. Our study indicated that intravenous aprotinin was associated with improved outcomes in terms of total blood loss, hemoglobin decline, and transfusion rates. There was no significant difference regarding the length of stay and the risk of deep venous thrombosis and pulmonary embolism. Intravenous aprotinin was effective and safe to use in reducing total blood loss after total hip arthroplasty. Further high-quality studies are required to confirm the conclusion., (© 2019 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Background: Significant blood loss is still one of the most frequent complications in spinal surgery, which often necessitates blood transfusion. Massive perioperative blood loss and blood transfusion can create additional risks. Aprotinin, tranexamic acid (TXA), and epsilon-aminocaproic acid (EACA) are antifibrinolytics currently offered as prophylactic agents to reduce surgery-associated blood loss. The aim of this study was to evaluate the efficacy and safety of aprotinin, EACA, and low/high doses of TXA in spinal surgery, and assess the use of which agent is the most optimal intervention using the network meta-analysis (NMA) method., Methods: Five electronic databases were searched, including PubMed, Cochrane Library, ScienceDirect, Embase, and Web of Science, from the inception to March 1, 2018. Trials that were randomized and compared results between TXA, EACA, and placebo were identified. The NMA was conducted with software R 3.3.2 and STATA 14.0., Results: Thirty randomized controlled trial (RCT) studies were analyzed. Aprotinin (standardized mean difference [SMD]=-0.65, 95% credibility intervals [CrI;-1.25, -0.06]), low-dose TXA (SMD = -0.58, 95% CrI [-0.92, -0.25]), and high-dose TXA (SMD = -0.70, 95% CrI [-1.04, -0.36]) were more effective than the respective placebos in reducing intraoperative blood loss. Low-dose TXA (SMD = -1.90, 95% CrI [-3.32, -0.48]) and high-dose TXA (SMD = -2.31, 95% CrI [-3.75, -0.87]) had less postoperative blood loss. Low-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) and high-dose TXA (SMD = -1.07, 95% CrI [-1.82, -0.31]) significantly reduced total blood loss. However, only high-dose TXA (SMD = -2.07, 95% CrI [-3.26, -0.87]) was more effective in reducing the amount of transfusion, and was significantly superior to low-dose TXA in this regard (SMD = -1.67, 95% CrI [-3.20, -0.13]). Furthermore, aprotinin (odds ratio [OR] = 0.16, 95% CrI [0.05, 0.54]), EACA (OR = 0.46, 95% CrI [0.22, 0.97]) and high dose of TXA (OR = 0.34, 95% CrI [0.19, 0.58]) had a significant reduction in transfusion rates. Antifibrinolytics did not show a significantly increased risk of postoperative thrombosis. Results of ranking probabilities indicated that high-dose TXA had the greatest efficacy and a relatively high safety level., Conclusions: The antifibrinolytic agents are able to reduce perioperative blood loss and transfusion requirement during spine surgery. And the high-dose TXA administration might be used as the optimal treatment to reduce blood loss and transfusion.

Background and Aims:: The lungs participate in the modulation of the circulating inflammatory factors induced by coronary artery bypass grafting. We investigated whether aprotinin-which has been suggested to interact with inflammation-influences lung passage of key inflammatory factors after coronary artery bypass grafting., Material and Methods:: A total of 40 patients undergoing coronary artery bypass grafting were randomized into four groups according to aprotinin dose: (1) high dose, (2) early low dose, (3) late low dose, and (4) without aprotinin. Pulmonary artery and radial artery blood samples were collected for the evaluation of calculated lung passage (pulmonary artery/radial artery) of the pro-inflammatory factors interleukin 6 and interleukin 8, 8-isoprostane, myeloperoxidase and the anti-inflammatory interleukin 10 immediately after induction of anesthesia (T1), 1 min after releasing aortic cross clamp (T2), 15 min after releasing aortic cross clamp (T3), 1 h after releasing aortic cross clamp (T4), and 20 h after releasing aortic cross clamp (T5)., Results:: Pulmonary artery/radial artery 8-isoprostane increased in patients with high aprotinin dose as compared with lower doses (1.1 range 0.97 vs 0.9 range 1.39, p = 0.001). The main effect comparing high aprotinin dose with lower doses was significant (F(1, 38) = 7.338, p = 0.01, partial eta squared = 0.16) further supporting difference in the effectiveness of high aprotinin dose for pulmonary artery/radial artery 8-isoprostane., Conclusion:: According to the pulmonary artery/radial artery equation, the impact of aprotinin on 8-isoprostane after coronary artery bypass grafting is dose dependent. Aprotinin may aid the lung passage of circulating factors toward a beneficial anti-inflammatory milieu.

Nephrotic syndrome is the most extreme manifestation of proteinuric kidney disease and characterized by heavy proteinuria, hypoalbuminemia, and edema due to sodium retention and hyperlipidemia. To study the pathophysiology of this syndrome, rodent models have been developed based on the injection of toxic substances such as doxorubicin causing podocyte damage. In mice, only few strains are susceptible to this model. In wildtype 129S1/SvImJ mice, the administration of doxorubicin by rapid intravenous injection to the retrobulbar sinus induces experimental nephrotic syndrome that features all the symptoms of human disease including sodium retention and edema. After the onset of proteinuria, mice exhibit increased urinary serine protease activity that leads to the activation of the epithelial sodium channel (ENaC) and sodium retention. Pharmacological inhibition of urinary serine proteases by the treatment with sustained release aprotinin abrogates ENaC activation and prevents sodium retention. This model is ideal to study the pathophysiology of proteasuria, i.e., the excretion of active serine proteases that cause ENaC activation by the proteolysis of its γ-subunit. This can be regarded as the primary mechanism of ENaC activation and sodium retention in proteinuric kidney disease.

Background: The role of steroids to mitigate the deleterious effects of pediatric cardiopulmonary bypass (CPB) remains a matter of debate; therefore, we aimed to assess preferences in administering corticosteroids (CSs) and the use of other anti-inflammatory strategies in pediatric cardiac surgery., Methods: A 19-question survey was distributed to consultants in pediatric cardiac anesthesia from 12 centers across the United Kingdom and Ireland., Results: Of the 37 respondents (37/60, 62%), 24 (65%) use CSs, while 13 (35%) do not use steroids at all. We found variability within 5 (41%) of the 12 centers. Seven consultants (7/24, 29%) administer CSs in every case, while 17 administer CSs in selected cases only (17/24, 71%). There was variability in the dose of steroid administration. Almost all consultants (23/24, 96%) administer a single dose at induction, and one administers a two-dose regimen (1/24, 4%). There was variability in CS indications. Most consultants (24/37, 66%) use modified ultrafiltration at the conclusion of CPB. Fifteen consultants (15/32, 47%) report the use of aprotinin, while only 3 use heparin-coated circuits (3/24, 9%)., Conclusions: We found wide variability in practice in the administration of CSs for pediatric cardiac surgery, both within and between units. While most anesthetists administer CSs in at least some cases, there is no consensus on the type of steroid, the dose, and at which patient groups this should be directed. Modified ultrafiltration is still used by most of the centers. Almost half of consultants use aprotinin, while heparin-coated circuits are infrequently used.

Objective: To determine the effectiveness and safety of aprotinin use in adult patients undergoing thoracic aortic surgery., Design: Single-center, retrospective study., Setting: All cases performed at a single university hospital., Participants: Between January 2004 and December 2014, 846 adult patients underwent thoracic aortic surgery. Due to missing or duplicated data on primary outcomes, 314 patients were excluded. The final sample of 532 patients underwent surgery on the thoracic aorta., Interventions: The patients were divided in the following 2 groups: 107 patients (20.1%) received aprotinin during the surgery, which represented the study group, whereas the remaining 425 patients (79.9%) underwent surgery without the use of aprotinin., Measurements and Main Results: To adjust for patient selection and preoperative characteristics, a propensity score-matched analysis was conducted. Mean total blood loss at 12 hours after surgery was similar between the 2 groups. The blood product transfusion rates did not differ in the 2 groups, except for the rate of fresh frozen plasma transfusion being significantly higher in the aprotinin group. Re-exploration for bleeding and the incidence of a major postoperative bleeding event were similar between the groups. Rates of in-hospital mortality, renal failure, and cerebrovascular accidents did not show any statistically significant difference. Aprotinin did not represent a risk factor for mortality over the long term (hazard ratio 1.14, 95% confidence interval 0.62-2.08, p = 0.66)., Conclusions: The use of aprotinin demonstrated a limited effect in reducing postoperative bleeding and prevention of major bleeding events. Aprotinin did not adversely affect early outcomes and long-term survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Acute lung injury (ALI) is one of the most common extra-pancreatic complications of acute pancreatitis. In this study, we examined the protective effect of protease inhibitor aprotinin and a matrix metalloproteinase inhibitor (MMPi) on pulmonary inflammation in rats with severe pancreatitis-associated ALI., Method: A rat model of acute pancreatitis (AP) was established by injecting sodium glycodeoxycholate (GDOC) into the pancreatic duct. Pharmacological interventions included pretreatment with a protease inhibitor aprotinin (10mg/kg) and a matrix metalloproteinase inhibitor (MMPi, 100g/kg). The extent of pancreatic and lung injury and systemic inflammation was assessed by examinations of blood, bronchoalveolar lavage (BAL), and lung tissue. Pancreatic or lung tissue edema was evaluated by tissue water content. Pulmonary arterial pressure and alveolar-capillary membrane permeability were evaluated post-injury via a catheter inserted into the pulmonary artery in an isolated, perfused lung model., Results: Pre-treatment with aprotinin or MMPi significantly decreased amylase and lactate dehydrogenase (LDH), and the wet/dry weight ratio of the lung and pancreas in AP rats. Compared to the GDOC alone group, administration of aprotinin or MMPi prevented pancreatitis-induced IL-6 increases in the lung. Similarly, treatment with aprotinin or MMPi significantly decreased the accumulation of white blood cells, oxygen radicals, nitrite/nitrates in both blood and BAL, and markedly reduced lung permeability., Conclusion: Pretreatment with either aprotinin or MMPi attenuated the systemic inflammation and reduced the severity of lung and pancreas injuries. In short, our study demonstrated that inhibition of protease may be therapeutic to pulmonary inflammation in this GDOC-induced AP model., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Background: Fibrin sealants are topical agents used to reduce perioperative blood loss; however, their efficacy in total hip arthroplasty (THA) remains uncertain. The purpose of this study was to determine if a fibrin sealant containing aprotinin as an antifibrinolytic agent, TISSEEL (Baxter, Deerfield, IL), reduces postoperative blood loss and transfusion during THA when compared with intravenous (IV) tranexamic acid (TXA) and control groups., Methods: Three retrospective uniform cohorts of primary THA procedures were identified, from a prospectively maintained database: 1 group who received TISSEEL, 1 group who received 1 g IV TXA, and 1 group who received neither (control). There were 80 patients in each group. Outcome measures included the lowest measured hemoglobin during postoperative hospitalization, greatest decrease in hemoglobin from preoperative to postoperative values, and blood transfusion rates., Results: The minimum postoperative hemoglobin level was significantly lower for TISSEEL patients compared with that of IV TXA patients (P = .021) and no different when compared with that of control patients (P = .134). Patients receiving fibrin sealant had a greater hemoglobin level decrease compared with that of IV TXA (P = .029) and control (P = .036). Postoperative transfusion rates were no different for the group receiving TISSEEL compared with those of control (P = .375) and were statistically greater when compared with those of IV TXA (P = .002)., Conclusion: TISSEEL fibrin sealant does not reduce postoperative blood loss or transfusions; however, IV TXA reduced postoperative transfusions compared with TISSEEL and control. Therefore, TXA is recommended to reduce perioperative blood loss, while, utilization of a fibrin sealant requires further refinements before being adopted for routine use in THA., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The pathophysiological role of pancreatic digestive hydrolases in intestinal ischemia-reperfusion (I/R) injury is still not clear. Here, we studied whether ischemia-induced injury to the small intestine can be explained by the autodigestion hypothesis., Materials and Methods: Mesenteric I/R was induced in rats by superior mesenteric artery occlusion (90 min) and reopening (120 min). Thirty minutes before superior mesenteric artery occlusion, aprotinin (14.7 mg/kg), orlistat (5 mg/kg), and their combination or α1-proteinase inhibitor (60 mg/kg) were injected into the lumen of the small intestine. Systemic and vital parameters, intestinal microcirculation, and mucosal barrier function were monitored during the observation phase; markers of small intestinal injury, as well as trypsin-, chymotrypsin-, elastase-, and lipase-like activities in intestinal effluates were assessed at the end., Results: The pattern of small intestinal injury correlated inversely with the local alterations in microvascular tissue perfusion and corresponded with the intestinal distribution of trypsin-like activity. Aprotinin almost completely inhibited trypsin-like activity (P < 0.05) and significantly reduced intestinal tissue injury. Combined with orlistat, it also increased the postischemic blood pressure (P < 0.05) but not the intestinal barrier function. Macroscopic as well as the histologic alterations were decreased by α1-proteinase inhibitor, which significantly improved postischemic blood pressure (P < 0.05)., Conclusions: The I/R-induced pattern of small intestinal injury is likely to result from both local differences in tissue ischemia and the digestive activity of migrated pancreatic trypsin. Therefore, administration of aprotinin and orlistat into ischemic small intestines may be a therapeutic option in patients with a poor diagnosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Low pulmonary vascular resistance index (PVRI) reflects favorable redundant pulmonary circulation following coronary artery bypass grafting with cardiopulmonary bypass surgery (CPB). This randomized study investigated whether aprotinin given in different modalities impacts PVRI after coronary artery bypass grafting. A total of 40 patients undergoing coronary artery bypass grafting were randomized to four groups according to aprotinin dose: (1) high dose, (2) early low dose, (3) late low dose, and (4) without aprotinin. Oxygenation index, pulmonary shunt, alveolar-arterial oxygen gradient and PVRI were determined. PVRI was calculated as the transpulmonary pressure gradient divided by cardiac index multiplied by 80. The results showed that PVRI remained relative low in all patients provided aprotinin regardless of treatment dosage; PVRI increased at 4 h after restarting ventilation after CPB in patients without aprotinin as compared with aprotinin (266 ± 137, 266 ± 115, 244 ± 86 vs. 386 ± 121, dynes-s-cm - 5 , respectively, p = .047). Elevated postoperative PVRI was predictive for patients without aprotinin (AUC 0.668; SE 0.40; p < .0001; CI 0.590-0.746). There were no statistical differences in oxygenation index, pulmonary shunt or alveolar-arterial oxygen gradient between the groups. In conclusion, aprotinin maintains a low PVRI in elective patients with healthy lungs during CPB. We suggest that aprotinin maintains pulmonary arterial endothelial integrity.

Background: This study aimed to demonstrate the noninferior efficacy of TachoSil vs. TachoComb in Japanese patients undergoing liver resection and to assess the safety of TachoSil vs. TachoComb in these patients., Methods: This randomized, double-blind, noninferiority study (JapicCTI-090684) involved participants scheduled for liver resection/living donors (age ≥ 20 years). TachoSil or TachoComb (1:1 allocation ratio) was applied to control persistent exudative bleeding after primary hemostasis during liver resection/removal for donation. The primary outcome was hemostasis 5 min after study treatment application. The 95% confidence interval (CI) for the difference in the proportion of participants with hemostasis 5 min after application of TachoSil/TachoComb was determined; noninferiority of TachoSil was indicated if the lower limit of the CI was ≥-14%. Adverse events (AEs) were recorded., Results: All participants in the efficacy analysis (TachoSil: 54/54, 100%; TachoComb: 54/54, 100%) achieved hemostasis 5 min after study treatment application. Therefore, TachoSil was noninferior to TachoComb. All participants experienced ≥1 AE; however, none discontinued because of an AE. Most (≥97.8%) AEs were mild or moderate in severity., Conclusions: These findings confirm the safety profile and noninferior hemostatic efficacy of TachoSil compared with TachoComb.

Background To prevent postoperative middle lobe torsion after a right upper lobectomy, we introduced a novel technique of interlobar fixation using collagen fleece coated with fibrin. In this study, the prophylactic effects of this method on the incidence of postoperative pulmonary torsion were analyzed. Methods Between April 2001 and December 2015, 3786 pulmonary resection procedures (excluding total pneumonectomy) were performed in our institution, and prophylactic interlobar fixation was selectively applied when intraoperative examination indicated that the patient was at high risk of postoperative pulmonary lobe torsion. As a control group, 842 patients who underwent pulmonary resection procedures between January 1996 and April 2001 were reviewed. Results During the study period, 10 (0.3%) patients underwent prophylactic middle lobe fixation (to the lower lobe after a right upper lobectomy in 9, and to the upper lobe after a right lower lobectomy in one). Pulmonary lobar (middle lobe) torsion occurred in only one patient (after right upper lobectomy); thus the incidence of this complication was 0.1% among patients who underwent a right upper lobectomy and 0.03% among all pulmonary resection procedures. The rates during the study period were marginally significantly lower than those in the control period (1.3% and 0.24%, respectively; p = 0.071 and p = 0.087, respectively). Conclusion Prophylactic middle lobe fixation might be useful for preventing postoperative pulmonary middle lobe torsion.

Background: Aprotinin has been reapproved for use in Europe and in Canada. We sought to determine if its reintroduction was still pertinent given the widespread administration of tranexamic acid, another antifibrinolytic shown to reduce bleeding and transfusions., Study Design and Methods: After institutional review board approval, we examined the cardiac surgery database (2012-2015; 3322 patients). Major transfusion was defined as 4 or more red blood cell units. A stratified multivariate logistic regression analysis identified predictors of major transfusion; 1064 patients were matched by propensity score to compare outcomes of patients with or without major transfusion., Results: Cardiopulmonary bypass (CPB) was used in 2342 patients; 98.9% received tranexamic acid versus 15.2% (149/980) in off-pump coronary artery bypass graft patients. Major transfusion was required in 758 patients (23%). Age, low body mass index, low preoperative hemoglobin or platelet count, recent use of P2Y12 receptor blockers, chronic kidney disease, NYHA functional class, left ventricular ejection fraction of less than 30%, prior cardiac surgery, urgency, type of cardiac surgery, and duration of CPB were all independent predictors of major transfusions (all p < 0.05). Major transfusion was associated with a more than threefold increase in mortality (7.1% vs. 2.1%; p < 0.001) and increases in major adverse events (p < 0.001)., Conclusions: Despite the use of tranexamic acid, 23% of cardiac surgery patients require a major transfusion. We identified predictors of major transfusion and showed that major transfusion is associated with important increases in mortality and morbidity. We conclude that there is still a need for an effective and safe blood-sparing drug in cardiac surgery., (© 2016 AABB.)

Comparative results of treatment of thrombotic complications in the injured persons with combined trauma of trunk in two groups were adduced. The scheme of prophylax3 is and treatment of thrombotic complications was proposed; application of this scheme have permitted to reduce their rate in 5 times, from 54.5 to 11.2%.

In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues., (Copyright © 2015 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.)

Background/purpose: Postoperative pancreatic fistula formation remains a source of significant morbidity following distal pancreatectomy. The aim of this study was to evaluate the rate of clinically significant fistulas (International Study Group on Pancreatic Fistula grade B and grade C) after distal pancreatectomy using a fibrinogen/thrombin-based collagen fleece (TachoComb, TachoSil) with a stapled closure., Methods: Seventy-five patients underwent distal pancreatectomy at our institution between January 2005 and March 2014. A fibrinogen/thrombin-based collagen fleece was applied to the staple line of the pancreas before stapling., Results: Twenty-six patients (34.7%) developed a pancreatic fistula, 8 patients (10.7%) developed a grade B fistula, and no patients developed a grade C fistula. The duration of the drain was significantly different in patients with or without a pancreatic fistula (8.0 ± 4.5 vs. 5.4 ± 1.3 days, P = .0003). Histological analysis showed that there was a tight covering with the fibrinogen/thrombin-based collagen fleece., Conclusion: The fibrinogen/thrombin-based collagen fleece (TachoComb, TachoSil) with a stapled closure has low rates of fistula formation and provides a safe alternative to the conventional stapled technique in distal pancreatectomy., (© The Author(s) 2015.)

Objective: A fibrinogen/thrombin-based collagen fleece (TachoComb) is a powerful topical hemostatic agent that has been widely used in various surgical specialties with a favorable outcome. The purpose of this study was to investigate the effect of TachoComb application on postoperative complications after tonsillectomy., Materials and Methods: A total of 1633 children had undergone tonsillectomy with or without adenoidectomy were included in this study. After removal of both tonsils, 1057 patients (64.7%) were treated with TachoComb on the tonsillectomy site and 576 without TachoComb. Post-tonsillectomy pain, hemorrhage rates, re-admission rates, and emergency surgery rates for post-tonsillectomy hemorrhage were evaluated between patients who received TachoComb and those who did not., Results: TachoComb treatment significantly reduced post-tonsillectomy pain and emergency surgery rates for post-tonsillectomy hemorrhage. However, postoperative hemorrhage rate and re-admission rates for post-tonsillectomy hemorrhage were not statistically significant between TachoComb treatment group and control group. No patients had complications or adverse reactions after TachoComb treatment., Conclusions: The use of TachoComb after tonsillectomy significantly reduces pain and emergency surgery for severe post-tonsillectomy hemorrhage without an apparent adverse effect. Therefore, TachoComb may be a useful adjuvant in terms of efficacy and safety after tonsillectomy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Atrioventricular (AV) disruption is a rare but fatal complication after prosthetic mitral valve replacement. Surgical management is controversial and ranges from epicardial tissue sealing to open repair using autologous or xenogenic patch techniques to autotransplantation of the heart. We report the successful repair of an AV disruption Type I using an extracorporeal life support (ECLS) system for effective ventricular unloading followed by epicardial patch closure. The surgical management of AV disruption benefits from the use of ECLS, as it allows effective decompression of the heart without requiring full heparinization., (© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma., Objectives: To assess the effect of antifibrinolytic drugs in patients with acute traumatic injury., Search Methods: We ran the most recent search in January 2015. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), PubMed and clinical trials registries., Selection Criteria: Randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA], epsilon-aminocaproic acid and aminomethylbenzoic acid) following acute traumatic injury., Data Collection and Analysis: From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria, and extracted data. One review author assessed the risk of bias for key domains.Outcome measures included: mortality at end of follow-up (all-cause); adverse events (specifically vascular occlusive events [myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism] and renal failure); number of patients undergoing surgical intervention or receiving blood transfusion; volume of blood transfused; volume of intracranial bleeding; brain ischaemic lesions; death or disability.We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach., Main Results: Three trials met the inclusion criteria.Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only.One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock.The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high). This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data.There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain.There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population., Authors' Conclusions: TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.  TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains.Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.

The results of treatment of 92 patients, suffering an acute ileus, were analyzed. After urgent operative interventions for an acute ileus the recurrence have occurred in 19.6% patients. To reduce the operative intervention traumaticity the preference was given to local viscerolysis conduction. For the adhesions occurrence prophylaxis a barrier medicines were used, what have promoted the reduction of contents of a connective tissue metabolites, excluding oxyprolin, concentration of which have exceeded such in a control, what have guaranteed the risk lowering for postoperative adhesions occurrence.

There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

The aim of this study was to develop aprotinin-loaded microemulsion (MA) for intravenous administration and evaluate the biodistribution and therapeutic potential of developed formulation in acute pancreatitis models in rats. Phase diagrams were constructed to identify microemulsion region and the optimal microemulsion was evaluated for physicochemical properties and treatment effect in rats, and comparisons made with the solution of aprotinin (SA). To evaluate the biodistribution of the drug by gamma scintigraphy aprotinin was radiolabeled with (99m)Tc radionuclide. Mild and severe acute pancreatitis was induced in rats by subcutaneous injections of cerulein and introductal infusion of 3% sodium taurocholate into the bile-pancreatic duct, respectively. In addition, serum amylase and pancreatic tissue myeloperoxidase activities were measured to evaluate the pancreatic damage. According to gamma scintigraphy and biodistribution studies, accumulation times and distribution of (99m)Tc-MA and SA were different. While MA was highly uptake by reticuloendothelial system, SA was mostly excreted by kidneys and bladder. Compared with the mild acute pancreatitis group, treatment with MA significantly decreased the serum amylase activity and pancreas myeloperoxidase activity. Furthermore, the protease inhibitor molecule aprotinin has therapeutic potential in acute pancreatitis. Finally, MA may be suggested as a promising alternative for treatment of acute pancreatitis.

Background: Coagulopathy is a major issue in children undergoing high-risk pediatric cardiac surgery. Use of anti-fibrinolytics is well documented in adults, but recently there are questions raised about safety and effectiveness of their use on routine use. Tranexamic acid is a potent anti-fibrinolytic, but its role is not fully understood in children. This study aims to study the benefits tranexamic acid in controlling postoperative bleeding in pediatric cardiac surgical patients., Methods and Results: Fifty consecutive children who underwent cardiac surgery were randomized prospectively to receive either aprotinin (Group A; n = 24) or tranexamic acid (Group B; n = 26) from September 2009 to February 2010 were studied. Primary end points were early mortality, postoperative drainage, reoperation for bleeding and complications. Mean age and body weight was smaller in Group A (Age: 48.55 vs. 64.73 months; weight 10.75 vs. 14.80 kg) respectively. Group A had more cyanotic heart disease than Group B (87.5% vs. 76.92%). Mean cardiopulmonary bypass time (144.33 vs. 84.34 min) and aortic cross-clamp time (78.5 vs. 41.46 min) were significantly higher in group A. While the blood and products usage was significantly higher in Group A, there was no difference in indexed postoperative drainage in first 4, 8 and 12 h and postoperative coagulation parameters. Mean C-reactive protein was less in Group A than B and renal dysfunction was seen more in Group A (25% vs. 7.6%). Mortality in Group A was 16.66% and 7.6% in Group B., Conclusion: Anti-fibrinolytics have a definitive role in high-risk children who undergo open-heart surgery. Tranexamic acid is as equally effective as aprotinin with no additional increase in morbidity or mortality.

Purpose: This randomized, controlled, single-blinded multicenter study evaluated the efficacy of latest-generation fibrin sealant containing synthetic aprotinin as fibrinolysis inhibitor as supportive treatment for hemostasis after elective partial hepatectomy., Methods: Adult subjects undergoing resection of at least one liver segment were assigned to treatment with fibrin sealant or manual compression with a surgical gauze swab if persistent oozing necessitated additional hemostatic measures after primary control of arterial and venous bleeding. The primary outcome measure was the proportion of subjects with intraoperative hemostasis at 4 min after start of randomized treatment application. Secondary efficacy outcome measures included intraoperative hemostasis at 6, 8, and 10 min, intra- and postoperative rebleedings, transfusion requirements, and drainage volume., Results: Seventy subjects were randomized. Hemostasis at 4 min was achieved in 29/35 (82.9 %) fibrin sealant subjects compared with 13/35 (37.1 %) control subjects (p < 0.001). Significantly more fibrin sealant subjects achieved hemostasis at 6 (p < 0.001), 8 (p = 0.028), and 10 min (p = 0.017). The number of rebleedings was low in both study arms. Transfusion requirements and 48-h drainage volumes were similar between the study arms. No adverse events related to study treatment were reported., Conclusions: Fibrin sealant was shown to be safe and superior to manual compression in the control of parenchymal bleeding after hepatic resection. The use of synthetic aprotinin as fibrinolysis inhibitor further improves the safety margin of fibrin sealant by eliminating the risk of transmission of bovine spongiform encephalopathy and other bovine pathogens.