Efficacy and Safety of Antifibrinolytic Drugs in Liver Transplantation: A Systematic Review and Meta-Analysis

Although several randomized controlled trials (RCTs) have shown the efficacy of antifibrinolytic drugs in liver transplantation, their use remains debated due to concern for thromboembolic complications. None of the reported RCTs has shown a higher incidence of these complications in treated patients; however, none of the individual studies has been large enough to elucidate this issue completely. We therefore performed a systematic review and meta-analysis of efficacy and safety endpoints in all published controlled clinical trials on the use of antifibrinolytic drugs in liver transplantation. Studies were included if antifibrinolytic drugs (epsilon-aminocaproic acid, tranexamic acid (TA) or aprotinin) were compared with each other or with controls/placebo. Intraoperative red blood cell and fresh frozen plasma requirements, the perioperative incidence of hepatic artery thrombosis, venous thromboembolic events and mortality were analyzed. We identified 23 studies with a total of 1407 patients which met the inclusion criteria. Aprotinin and TA both reduced transfusion requirements compared with controls. No increased risk for hepatic artery thrombosis, venous thromboembolic events or perioperative mortality was observed for any of the investigated drugs. This systematic review and meta-analysis does not provide evidence for an increased risk of thromboembolic events associated with antifibrinolytic drugs in liver transplantation.     

Effects of nafamostat mesilate and minimal-dose aprotinin on blood-foreign surface interactions in cardiopulmonary bypass

BACKGROUND: The pharmacological inhibition of blood-foreign surface interactions is an attractive strategy for reducing the morbidity associated with cardiopulmonary bypass. We compared the inhibitory effects of nafamostat mesilate (a broad-spectrum synthetic protease inhibitor) and minimal-dose aprotinin on blood-surface interactions in clinical cardiopulmonary bypass. METHODS: Eighteen patients undergoing coronary surgery were divided into three groups: (1) the control group (heparin, 4 mg/kg; n = 6), (2) the nafamostat mesilate group (heparin plus nafamostat, 0.2 mg/kg bolus followed by 2.0 mg/kg/h during cardiopulmonary bypass; n = 6), and (3) the aprotinin group (heparin plus aprotinin, 2.0 x 10(4) KIU/kg; n = 6). Platelet count, platelet aggregation, beta-thromboglobulin, prothrombin fragment F1.2, thrombin-antithrombin complex, plasminogen activator inhibitor-1, alpha2-plasmin inhibitor-plasmin complex, D-dimer, neutrophil elastase, and interleukin-6 were measured before, during, and after bypass. Bleeding times and blood loss were recorded. RESULTS: There were no significant differences between groups in platelet count, beta-thromboglobulin, plasminogen activator inhibitor-1, interleukin-6, bleeding times, or blood loss. Platelet aggregation was better preserved at 12 hours after surgery in the nafamostat and aprotinin groups than in the control group. Prothrombin fragment F1.2, thrombin-antithrombin complex and neutrophil elastase levels were significantly reduced by aprotinin, but not by nafamostat as compared with the control group. The alpha2-plasmin inhibitor-plasmin complex and D-dimer were significantly lower with either of the drugs. Aprotinin showed better control of D-dimer than did nafamostat. CONCLUSIONS: Nafamostat mesilate fails to reduce thrombin formation and neutrophil elastase release, whereas minimal-dose aprotinin inhibits both. Neither nafamostat nor aprotinin inhibits platelet activation. Nafamostat reduces fibrinolysis during cardiopulmonary bypass, although its effect is not as potent as aprotinin.     

Reduction of blood transfusion need with aprotinin in orthopedic surgery. Spanish Study Group on the Use of Aprotinin in Hip Arthroplasty (GEEEAAC)

Aprotinin is a protease inhibitor of interest for its antifibrinolytic effect of reducing perioperative bleeding in certain types of surgery, with wide use in heart surgery, liver transplantation and vascular surgery. The application of aprotinin during orthopedic surgery has recently been suggested. Such use is controversial, as there is lack of consensus as to the type of patient for whom aprotinin administration would be indicated, the surgical procedure during which it would be most effective (hip or knee arthroplasty, spinal arthrodesis, major tumor or septic surgery), the doses to administer, its safety and its real efficacy for conserving homologous blood. That is to say, there is no agreement as to the cost/benefit relation of aprotinin for the various types of orthopedic surgery. This critical review of the literature leads to the conclusion that aprotinin is a promising drug for use in orthopedic surgery, given that published studies have established the benefit in blood product savings and decreased blood loss during surgery.     

A review of aprotinin in orthotopic liver transplantation: can its harmful effects offset its beneficial effects?

Blood transfusion can adversely affect patient outcome and graft survival in orthotopic liver transplantation (OLT). With this respect, prophylactic aprotinin administration decreases blood loss, transfusion requirements, and the hemodynamic changes associated with graft reperfusion in patients undergoing OLT. However, data indicate limiting the use of aprotinin in OLT: (a) clinical, biological, echocardiographic, and postmortem findings recorded in patients with chronic liver disease or undergoing OLT suggest that a continuous prothrombotic state exists in these patients. Whether the inhibition of fibrinolysis associated with aprotinin therapy will expose some patients to untoward thrombosis is questionable; (b) aprotinin does not appear to alter postoperative outcome in patients undergoing OLT; (c) aprotinin decreases blood transfusion requirements only when surgery is associated with significant blood loss. However, at the present time, median transfusion requirements of 2 to 5 red blood cell units are required in OLT.     

Minimizing blood loss in liver transplantation: progress through research and evolution of techniques

Blood loss during liver transplantation has long been recognized as an important cause of morbidity and, especially in the early days, also mortality. It is well known that blood transfusions are associated with an increased risk of postoperative complications, such as infections, pulmonary complications, protracted recovery, and a higher rate of reoperations. Many studies have been performed during the past decades to elucidate the mechanisms of increased blood loss in liver transplantation. In the late 1980s, primary hyperfibrinolysis was identified as an important mechanism of bleeding during liver transplantation. This has provided the scientific basis for the use of antifibrinolytic drugs in liver transplant recipients. Several randomized, controlled studies have shown the efficacy of these compounds in reducing blood loss and transfusion requirements during liver transplantation. In addition, increasing experience and improvements in surgical technique, anesthesiological care and better graft preservation methods have contributed to a steady decrease in blood transfusion requirements in most liver transplant programs. Several centers are now reporting liver transplantation without any need for blood transfusion in up to 30% of their patients. Despite these improvements, most patients undergoing liver transplantation still require blood transfusions that have a negative impact on outcome, emphasizing the need for further attempts to control blood loss by surgeons and anesthesiologists. This paper provides an overview of the clinical and research developments, which have contributed to a reduction in blood loss and transfusion requirements, resulting in an important reduction in morbidity and mortality after liver transplantation during the last two decades.     

Aprotinin in pediatric neuromuscular scoliosis surgery

Reduction of blood transfusions in patients with neuromuscular scoliosis can decrease potential complications such as immune suppression, infection, hemolytic reaction and viral transmission. Aprotinin (Trasylol^®, Bayer), an antifibrinolytic, has proven to be effective in reducing blood loss in cardiac and liver surgery, but little data exists in patients undergoing spinal fusion for neuromuscular scoliosis. The purpose of this study was to evaluate the safety and efficacy of aprotinin in pediatric neuromuscular scoliosis patients undergoing spinal fusion. The medical records of all patients undergoing initial spinal fusions for neuromuscular scoliosis between January 1999 and March 2003 were reviewed to determine demographic data, perioperative data, wound drainage and number of transfusion required. Cases were compared to a matched group of historical controls. We had 14 patients in the aprotinin group and 17 in the control group. Total blood loss in the aprotinin group was significantly lower compared to the control group (715 vs. 2,110 ml; P = 0.007). Significantly less blood loss occurred in the aprotinin group when blood loss per kilogram was evaluated as well (23 vs. 60 ml/kg, respectively; P = 0.002). Intra-operative packed red blood cell (PRBC) transfusions were also significantly lower in the aprotinin group (1.25 vs. 3.16 units; P = 0.001). No clinical evidence of anaphylaxis, deep vein thrombosis (DVT) or renal failure was observed in the aprotinin group. After considering the price of drug therapy, operating room time, and the cost of blood products, the use of aprotinin saved an average of $8,577 per patient. In our series, the use of aprotinin resulted in decreased blood loss and a decreased rate of transfusions in children with neuromuscular scoliosis undergoing extensive spinal fusion. At out institution, the use of aprotinin is safe and cost effective for patients with neuromuscular scoliosis.     

Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial

BACKGROUND: Coagulopathy caused by cirrhosis may contribute to excessive bleeding during hepatectomy. We evaluated the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in cirrhotic patients undergoing partial hepatectomy. METHODS: Patients were randomized to rFVIIa 50 or 100 mug/kg or placebo, administered intravenously 10 minutes before surgery and every second hour during surgery. The primary efficacy end points were the proportion of patients receiving red blood cell (RBC) transfusions and the amount of RBCs transfused. The RBC transfusion trigger was blood loss of 500 mL. Safety end points included thromboembolic and adverse events. RESULTS: No statistically significant effect of rFVIIa treatment on efficacy end points was observed. Serious and thromboembolic adverse events occurred at similar incidences in the study groups. CONCLUSIONS: Using blood loss as a transfusion trigger, the efficacy of rFVIIa in reducing the requirement for RBC transfusion was not established in this study. No safety concerns were identified.     

The Impact of Aprotinin on Renal Function After Liver Transplantation: An Analysis of 1043 Patients

Renal dysfunction is frequently seen after orthotopic liver transplantation (OLT). Aprotinin is an antifibrinolytic drug which reduces blood loss during OLT. Recent studies in cardiac surgery suggested a higher risk of postoperative renal complications when aprotinin is used. The impact of aprotinin on renal function after OLT, however, is unknown. In 1,043 adults undergoing OLT, we compared postoperative renal function in patients who received aprotinin (n = 653) or not (n = 390). Using propensity score stratification (C-index 0.82) and multivariate regression analysis, aprotinin was identified as a risk factor for severe renal dysfunction within the first week, defined as increase in serum creatinine by >or= 100% (OR = 1.97, 95% CI = 1.14-3.39; p = 0.02). No differences in renal function were noted at 30 and 365 days postoperatively. Moreover, no significant differences were found in the need for renal replacement therapy (OR = 1.52, 95% CI = 0.94-2.46; p = 0.11) or in 1-year patient survival rate (OR = 1.14, 95% CI = 0.73-1.77; p = 0.64) in patients who received aprotinin or not. In conclusion, aprotinin is associated with a higher risk of transient renal dysfunction in the first week after OLT, but not with a higher need for postoperative renal replacement therapy or an increased risk of mortality.     

Aprotinin and renal dysfunction after pediatric cardiac surgery

BACKGROUND: Aprotinin is a potent antifibrinolytic drug, which reduces postoperative bleeding and transfusion requirements. Recently, two observational studies reported increased incidence of renal dysfunction after aprotinin use in adults. Therefore, the aim of the study was to investigate the safety of aprotinin use in pediatric cardiac surgery patients. METHODS: Data were prospectively and consecutively collected from 657 pediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). The database was assessed with regard to a possible relationship between aprotinin administration and dialysis and between aprotinin and postoperative renal dysfunction [defined as 25% decrease in the creatinine clearance (Ccr) compared with the preoperative value] by propensity-score adjustment and multivariable methods. RESULTS: The incidence of dialysis (9.6% vs 4.1%; P = 0.005) and renal dysfunction (26.3% vs 16.1%; P = 0.019) was higher in patients who received aprotinin; however, propensity adjusted risk ratios were not significant [odds ratio (OR) of dialysis: 1.22; 95% confidence interval (CI) 0.46-3.22; OR of renal dysfunction 1.26; 95% CI: 0.66-1.92]. Aprotinin significantly reduced blood loss in the first postoperative 24 h. The main contributors of renal dysfunction were CPB duration, cumulative inotropic support, age, preoperative Ccr, amount of transfusion and pulmonary hypertension. CONCLUSIONS: Despite the higher incidences of renal dysfunction and failure in the aprotinin group, an independent role of the drug in the development of renal dysfunction or dialysis could not be demonstrated in pediatric cardiac patients undergoing CPB.     

Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation.

Patients undergoing orthotopic liver transplantation (OLT) have excessive blood loss during surgery that requires blood transfusions, leading to increased postoperative morbidity and mortality. We studied the efficacy and safety of activated recombinant factor VII (rFVIIa) in reducing transfusion requirements in OLT. This multicenter, randomized, double-blind, placebo-controlled trial enrolled patients undergoing OLT because of cirrhosis (Child-Turcotte-Pugh class B or C). Patients received a repeated intravenous bolus regimen of rFVIIa 60 or 120 microg/kg or placebo. The primary efficacy endpoint was the total number of red blood cell (RBC) units transfused during the perioperative period. A total of 182 patients were analyzed for efficacy and 183 for safety. No significant effect of rFVIIa was observed on the number of RBC units transfused or intraoperative blood loss compared with the placebo group. A significantly higher number of patients in the rFVIIa study groups avoided RBC transfusion. Administration of rFVIIa but not placebo restored the preoperative prolonged prothrombin time to normal value during surgery. Patients receiving rFVIIa and placebo did not experience a significant difference in rate of thromboembolic events. Additionally, there was no statistically significant effect of rFVIIa treatment on hospitalization rate, total surgery time, and the proportion of patients undergoing retransplantation. In conclusion, use of rFVIIa during OLT significantly reduced the number of patients requiring RBC transfusion. There was no increase in thromboembolic events with rFVIIa administration compared with placebo.     

Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery?

Studies have shown that antifibrinolytic (aprotinin, tranexamic acid, epsilon-aminocaproic acid) reduce blood loss in orthopedic surgery. However, most lacked sufficient power to evaluate the efficacy and safety on clinical outcomes. This meta-analysis aims to evaluate whether intravenous antifibrinolytics, when compared with placebo, reduce perioperative allogeneic erythrocyte transfusion requirement in adults undergoing orthopedic surgery and whether it might increase the risk of venous thromboembolism. From MEDLINE, EMBASE, and the Cochrane Controlled Trials Register, the authors identified 43 randomized controlled trials in total hip and knee arthroplasty, spine fusion, musculoskeletal sepsis, or tumor surgery performed to July 2005 (for aprotinin, 23 trials with 1,268 participants; tranexamic acid, 20 with 1,084; epsilon-aminocaproic acid, 4 with 171). Aprotinin and tranexamic acid reduced significantly the proportion of patients requiring allogeneic erythrocyte transfusion according to a transfusion protocol. The odds ratio was 0.43 (95% confidence interval, 0.28-0.64) for aprotinin and 0.17 (0.11-0.24) for tranexamic acid. Results suggest a dose-effect relation with tranexamic acid. Epsilon-aminocaproic acid was not efficacious. Unfortunately, data were too limited for any conclusions regarding safety. Although the results suggest that aprotinin and tranexamic acid significantly reduce allogeneic erythrocyte transfusion, further evaluation of safety is required before recommending the use of antifibrinolytics in orthopedic surgery.     

The effect of aprotinin in a model of uncontrolled hemorrhagic shock

BACKGROUND: Aprotinin has been shown to promote clot formation through its antifibrinolytic activity, by inhibiting the plasmin-induced complement activation and by protecting the platelets adhesive surface receptors. It has been successfully used in cardiac and liver transplantation surgery. OBJECTIVE: To evaluate the effect of aprotinin in a model of uncontrolled intra-abdominal bleeding as a basis for its potential use in trauma patients. METHODS: Twenty rats were randomly divided into 2 groups. All animals were operated on and bleeding was induced by transecting 1 lobe of the liver. In the treatment group a single dose of 30,000 U/kg of aprotinin was administered 5 minutes after the injury. The animals were monitored for hemodynamic parameters, blood loss volume, and mortality rates. RESULTS: At 120 minutes from trauma induction a significant difference in mean blood pressure was observed: 67+/-22 mm Hg in the treatment group versus 53+/-28 mm Hg in the control group (P=.04). This difference remained consistent until the end of the experiment. Treatment with aprotinin also resulted in a tendency to an increased survival rate (P=.05) and increased mean survival time: 175+/-46 minutes as compared to 123+/-48 minutes in the controls (P=.027). CONCLUSIONS: Early administration of aprotinin resulted in temporary hemodynamic stabilization and prolonged survival in a model of uncontrolled bleeding. Further studies are needed to establish the possible use of aprotinin in the treatment of trauma patients.     

High‐dose aprotinin,blood product transfusions,and short‐term outcome in neonates and infants: a pediatric cardiac surgery center experience

Background: The efficacy of aprotinin, the most popular antifibrinolytic agent in congenital cardiac surgery, was still uncertain in small infants when its prophylactic use was suspended for safety reasons. The aim of this study is to describe associations between the prophylactic use of high‐dose aprotinin, the need for blood product transfusions, and short‐term outcome in neonates and infants with cardiac surgery. Methods/materials: This retrospective study included all patients younger than 1 year undergoing surgery with cardiopulmonary bypass through 42 months, before and after withdrawal of aprotinin. Each patient who received aprotinin was matched with a control with similar baseline and surgical characteristics, who have not received any antifibrinolytic agent. Associations between the use of aprotinin and the exposure to red blood cells, fresh frozen plasma, and platelet transfusions were estimated from a logistic regression model, and the exposure to additional transfusions from a polytomous regression model. Results: Matching resulted in two groups of 283 patients each, well balanced except for the priming volume and the ultrafiltration rate, larger in the aprotinin group. After adjustment for the priming volume and ultrafiltration rate, there was no significant association between the use of aprotinin, the exposure to any blood product transfusion, or the exposure to additional transfusions, the rate of re‐exploration for bleeding, and short‐term outcome. Two patients in the control group required re‐exploration for bleeding. Conclusions: No association was found between the prophylactic use of aprotinin, blood product transfusions, and short‐term outcome in this population of neonates and infants.     

Aminocaproic Acid (Amicar) as an Alternative to Aprotinin (Trasylol) in Liver Transplantation

Introduction

This study compared clinical outcomes for a large number of liver transplant patients receiving intraoperative epsilon-aminocaproic acid (EACA), aprotinin, or no antifibrinolytic agent over an 8-year period.

Patients and Methods

Records for deceased donor liver transplants were reviewed. Data included antifibrinolytic agent, blood loss, early graft function, and postoperative complications. Study groups included low-dose aprotinin, high-dose aprotinin, EACA (25 mg/kg, 1-hour infusion), or no antifibrinolytic agent.

Results

Data were included for 1170 consecutive transplants. Groups included low-dose aprotinin (n = 324 [28%]), high-dose aprotinin (n = 308 [26%]), EACA (n = 216 [18%]), or no antifibrinolytic (n = 322 [28%]). EACA had the lowest intraoperative blood loss and required the fewest transfusions of plasma. Patients receiving no agent required the most blood transfusions. Early graft loss was lowest in the EACA group, and 90-day and 1-year patient survival rates were significantly higher for the low-dose aprotinin and EACA groups according to Cox regression. Complications were similar, but there were more episodes of deep vein thrombosis in patients receiving EACA.

Conclusions

These results suggest that transitioning from aprotinin to EACA did not result in worse outcomes. In addition to decreased intraoperative blood loss, a trend toward improved graft and patient survival was seen in patients receiving EACA.     

Removal of aprotinin from low-dose aprotinin/tranexamic acid antifibrinolytic therapy increases transfusion requirements in cardiothoracic surgery

This retrospective study investigated whether withdrawal of aprotinin from combined low-dose aprotinin/tranexamic acid (TXA) antifibrinolytic therapy altered postoperative blood loss and transfusion requirements in patients undergoing cardiothoracic surgery employing cardiopulmonary bypass (CPB). The study included data from patients receiving a combination of low-dose aprotinin (2×10(6)?KIU in CPB prime; n=615) and 2000?mg TXA or patients receiving TXA only (n=587). In both groups, TXA was given after protamine administration. Study endpoints were blood loss, transfusion requirements and reoperation. There were no differences in EuroSCORE, CPB time, antiangial medication and baseline coagulation parameters between groups. There were more males in the TXA group (85%) as compared to the TXA+aprotinin group (77%; P=0.02). Postoperative blood loss (0.80±0.69 vs. 0.66±0.52?l; P=0.001) and transfusion of fresh frozen plasma (0.6±0.7 vs. 0.4±0.6?U; P<0.001), packed cells (3.9±5.5 vs. 2.7±3.3?U; P<0.001) and platelets (0.7±0.6 vs. 0.5±0.6?U; P<0.001) was higher in the TXA group than in patients receiving combined therapy, respectively. There were more reoperations for bleeding in the TXA group (53 vs. 34, respectively; P=0.03) with similar mortality and deterioration in glomerular filtration rate. In conclusion, withdrawal of aprotinin from combined antifibrinolytic therapy is associated with increased blood loss, transfusion requirements and reoperations.     

The intra-operative use of trasylol (aprotinin) in liver transplantation

Abstract. Aprotinin has been reported to reduce blood loss in difficult cases requiring cardiopulmonary bypass surgery and more recently in liver transplantation. Over a 9-month period we compared the effects of an intra-operative infusion of aprotinin on transfusion requirements and coagulation profiles in 12 patients undergoing liver transplantation for end-stage cirrhosis with an equal number of consecutive transplants in patients with similar pathology who did not receive aprotinin. Transfusion of blood and blood products was reduced to one-third in the aprotinin-treated group. Operative time was also significantly reduced, as was ICU stay post-operatively. Aprotinin profoundly inhibits fibrinolysis and this is likely to be the major effect by which blood loss is reduced. Thromboelastography revealed severe fibrinolytic changes in the anhepatic stage in 4 of 6 controlled patients; this accelerated in 3 following reperfusion of the new graft. By contrast, only 1 patient of 12 in the aprotinin-treated group showed fibrinolytic activity in the anhepatic period, and none showed evidence of fibrinolysis following reperfusion of the new graft.     

Efficacy of aprotinin in reducing blood loss in spinal fusion for idiopathic scoliosis

Aprotinin is a proteinase inhibitor with antifibrinolytic properties that has found widespread application during cardiac surgical procedures due to its ability to decrease blood loss and transfusion requirements. Recently it has been used by orthopedic surgeons in hip replacement and other major surgeries except for scoliosis surgery, which is known to be associated with major blood loss. To evaluate the effect of aprotinin in reducing blood loss during spinal fusion surgery for idiopathic scoliosis, a double-blind randomized prospective clinical study was performed. Forty-three patients with idiopathic scoliosis underwent spinal fusion and instrumentation and were divided randomly into two groups. Fifteen patients received aprotinin, whereas 28 patients received placebo. The aprotinin group had less blood loss than the placebo group. The transfusion requirement was less in the aprotinin group than the placebo group. Although the difference was not significant statistically, the benefit of aprotinin in reducing blood loss in spinal surgery for idiopathic scoliosis was consistent.     

Pharmacological approaches to reducing blood loss and transfusions in the surgical patient

Purpose

To review the efficacy, effectiveness and safety of hemostatic drugs to reduce surgical blood loss.

Methods

Analysis of randomized controlled trials and metaanalyses exploring the efficacy of desmopressin, aprotinin, lysine analogues and recombinant activated factor VII (rFVIIa) on clinically important endpoints.

Main findings

Although potentially useful in surgical patients with mild hemophilia or type I von Willebranďs disease, desmopressin has no proven benefit in patients without previous hemostatic defects. Aprotinin has been studied extensively in cardiopulmonary bypass surgery, with evidence of a blood sparing effect. Additional benefits are suggested. The drug is less consistently effective in liver transplantation and major orthopedic surgery. Although rare, hypersensitivity reactions to aprotinin may occur, especially on re-exposure. Tranexamic acid can reduce blood transfusion in cardiac surgery, liver transplantation and total knee arthroplasty surgery with a satisfactory safety profile. Epsilon aminocaproic acid has not been investigated adequately, despite its widespread use. While rFVIIa may be beneficial in controlling massive coagulopathic bleeding in trauma and surgical patients, there is currently no evidence to support its prophylactic use in elective surgical patients.

Conclusion

Aprotinin and tranexamic acid are valuable pharmacologic options for reducing surgical bleeding. The expected benefit of these drugs is highly dependent on the actual blood usage for a given procedure at the institutional level. More studies using clinically significant endpoints are necessary to assess the relative efficacy and optimal dosing of these drugs.

     

The intra-operative use of trasylol (aprotinin) in liver transplantation

Aprotinin has been reported to reduce blood loss in difficult cases requiring cardiopulmonary bypass surgery and more recently in liver transplantation. Over a 9-month period were compared the effects of an intra-operative infusion of aprotinin on transfusion requirements and coagulation profiles in 12 patients undergoing liver transplantation for end-stage cirrhosis with an equal number of consecutive transplants in patients with similar pathology who did not receive aprotinin. Transfusion of blood and blood products was reduced to one-third in the aprotinin-treated group. Operative time was also significantly reduced, as was ICU stay post-operatively. Aprotinin profoundly inhibits fibrinolysis and this is likely to be the major effect by which blood loss is reduced. Thromboelastography revealed severe fibrinolytic changes in the anhepatic stage in 4 of 6 controlled patients; this accelerated in 3 following reperfusion of the new graft. By contrast, only 1 patient of 12 in the aprotinin-treated group showed fibrinolytic activity in the anhepatic period, and none showed evidence of fibrinolysis following reperfusion of the new graft.     

Effect of nafamostat mesilate on serum activities of pancreatic enzymes and plasma hormone levels

To evaluate the effect of nafamostat mesilate, a potent protease inhibitor, on the pancreatic enzymes and the endocrine system in patients undergoing open-heart surgery with extracorporeal circulation, serum activities of amylase, trypsin, alpha 1-antitrypsin (alpha 1AT) and pancreatic secretory trypsin inhibitor (PSTI), and plasma levels of cortisol and catecholamines were measured. Seven patients (nafamostat group) received intravenous nafamostat mesilate 0.5 mg.kg-1.hr-1 during cardiopulmonary bypass (CPB). The remaining seven patients (non-nafamostat group) did not receive any protease inhibitor. Both groups showed the same changes in serum activities of pancreatic enzymes during CPB. In sera, the levels of amylase, trypsin and alpha 1AT decreased during CPB. Amylase and trypsin activities returned toward the preanesthetic levels after CPB, while alpha 1AT remained at lower levels. PSTI was unchanged during CPB. Plasma cortisol levels markedly increased during and after CPB, but there was no difference between nafamostat group and non-nafamostat group. Nafamostat group showed lower plasma dopamine levels and higher epinephrine levels compared with non-nafamostat group. The result suggests that nafamostat mesilate administered during CPB could not influence the changes in the activities of pancreatic enzymes. Further studies are needed to clarify the effect of this protease inhibitor on the endocrine system.