Diagnosis and treatment of intracardiac thrombosis during orthotopic liver transplantation

Intracardiac thrombus formation during orthotopic liver transplantation can be a catastrophic event leading to death. Most often this devastating complication occurs after reperfusion and may be related to massive blood transfusion, marginal liver grafts, tendencies towards hypercoagulability, or the potential role of antifibrinolytics. We report a case of an intracardiac thrombus occurring during the hepatectomy stage (stage I) of orthotopic liver transplantation. Transesophageal echocardiography was used to quickly diagnose the thrombus, allowing rapid pharmacological intervention and later guide surgical evacuation of the intracardiac thrombus via the inferior vena cava.     

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.     

Does perioperative use of aprotinin reduce the rejection rate in heart transplant recipients?

Objective: Allograft rejection continues to be one of the most common causes of mortality after heart transplantation. We investigated if perioperative use of antifibrinolytics such as aprotinin and tranexamic acid can decrease the rate of rejection after heart transplant and their effect on transfusion. Methods: A retrospective analysis was conducted on the data from patients who received a first heart transplant at Papworth Hospital between 2000 and 2005. Transplant registry and audit data were used for the study. Rejection biopsy results and treatment were used to designate rejection episodes as mild (grades 1A, 1B or 2 untreated) or severe (grades 2 treated, grades 3 and 4). The relationship between antifibrinolytics and rejection episodes was assessed using univariate and multiple Poisson regression. Kaplan–Meier methods and Kruskal–Wallis tests, respectively, were used to analyse survival/time to first rejection and transfusion. Results: There were 225 patients who underwent a first heart transplant between January 2000 and December 2005. Of these, 101 patients (44.9%) had received aprotinin, 63 (28.0%) tranexamic acid, 2 (0.9%) both (aprotinin and tranexamic acid) and 59 (26.2%) no antifibrinolytics. There was no difference in time to first rejection by antifibrinolytic treatment (p = 0.20). There was no difference in the rate of treated rejection per 100 patient-days between aprotinin and tranexamic acid groups between 0 and 3 months post-transplant, (0.6 in both), but aprotinin had a small clinical effect when compared to no treatment (0.6 vs 0.8, p = 0.54). Between 4 and 6 months, the treated and severe rejection rates were lower in the patients receiving aprotinin as compared to those receiving tranexamic acid, but these differences again did not reach statistical significance (0.1 vs 0.3, p = 0.14, 0.2 vs 0.4, p = 0.18). Aprotinin was associated with higher postoperative blood loss and transfusion requirements in the subgroup of patients that had a ventricular assist device, prior sternotomy or anticoagulant therapy. Conclusions: The use of aprotinin in heart transplant surgery may be associated with a small decrease in the incidence of treated/severe rejection within 6 months of transplantation. The perioperative use of antifibrinolytics did not influence time to first rejection or reduce blood transfusion.     

Natural and synthetic antifibrinolytics in cardiac surgery

In an effort to reduce morbidity associated with transfusion of blood products, the use of antifibrinolytics to decrease bleeding and transfusions after cardiopulmonary bypass (CPB) is receiving widespread attention. The predominant haemostatic defect induced by CPB and, therefore, the mechanisms by which natural (aprotinin) or synthetic antifibrinolytics (sigma-amino-caproic acid, tranexamic acid) exert their effects have been difficult to define. Nonetheless, all three substances appear to be effective in the treatment or in the prevention of excessive bleeding associated with cardiac surgery. However, the administration of these drugs should not attempt to replace meticulous surgical and anaesthetic care. In particular, the importance of an appropriate transfusion practice cannot be overemphasized. The efficient use of these, sometimes expensive, drugs must take into account not only the initial cost, but also the short- and long-term economic consequences for the health care provider of using, or not using, a given medication. Unfortunately, the comprehensive data on which authoritative conclusions may be reached are not yet available. Pending availability of these data, the present use of antifibrinolytics at the Montreal Heart Institute is the following: (1) patients undergoing elective primary myocardial revascularization or valve surgery do not receive prophylactic antifibrinolytics; (2) patients undergoing repeat myocardial revascularization, repeat valve surgery, or primary or repeat combined procedures, receive prophylactic sigma-aminocaproic acid; (3) sigma-aminocaproic acid may be used to treat excessive chest drainage in the postoperative period; (4) the prophylactic and the therapeutic uses of low doses of aprotinin are currently under investigation.     

Prise en charge anesthésique des transplantations hépatiques : évolution des pratiques périopératoires en France entre 2004 et 2008

Objectives

To determine the evolution of French perioperative anaesthetic practices in liver transplantation between 2004 and 2008.

Study design

Phone survey.

Methods

In 2004 and 2008, a similar questionnaire has been administered by phone to a senior anaesthesiologist from each French centre performing adult liver transplantation (n = 21). Results were compared using Fisher test and p < 0.05 was considered significant.

Results

Between 2004 and 2008, there was a trend towards an increase of centres performing transplantation for more than 40% of Child C patients (p = 0.1). Simultaneously, work force dedicated to liver transplantation cases has been reduced since in 2008, one anaesthesiologist was in charge in 90% of the centres (p = 0.06 vs 2004). Perioperative practices remained largely heterogeneous between centres with regard to hemodynamic monitoring, fluid and blood products management, antifibrinolytics use or postoperative analgesia.

Conclusions

This French survey has shown a reduction of work force dedicated to a liver transplantation from 2004 to 2008 simultaneously with a trend towards a greater severity of liver recipients. Practices heterogeneity reflect at least in part, unresolved questions about the best perioperative management for liver transplantation and the need for guidelines. Working for standardization of our practices and multicentric trials could allow gaining a better understanding of what should be the good practices in perioperative management of liver transplantation.     

Haemostatic disorders during liver transplantation

Profound and complex coagulation disorders are encountered during liver transplantation. They include preoperative coagulation disorders related to the liver disease and haemostatic changes related to the procedure itself. They commonly lead to increased intraoperative bleeding, especially due to increased fibrinolysis, the contribution of which can be demonstrated by the relative efficacy of antifibrinolytics. Given the multifactorial nature of bleeding in liver transplantation, preoperative coagulation tests cannot predict blood loss even if some statistical relationship is occasionally found. Preoperative correction of coagulation defects has not been shown to be effective in reducing intraoperative bleeding. Throughout the procedure, a rapid and sensitive method for monitoring coagulation is necessary in order to guide the rational use of blood components and pharmacological agents. The usefulness of such a method to assist management of blood loss or blood component requirements is poorly documented and controversial.     

Transplantation of isolated hepatocytes, is it an alternative for total liver transplantation? On the treatment of hereditary hepatic metabolic diseases

Since 1976, it has been demonstrated in the small animal that isolated hepatocytes transferred into the liver can integrate into the recipient organ, survive and perform differentiated functions. This cell therapy technique can be used to partially correct for hereditary metabolic disorders in animal models of human hereditary metabolic diseases. The first methods used for hepatocytes transplantation involved a mass of hepatocytes that was clearly to limited (about 0.5% and never more than 2%). Integration fo the hepathocytes was limited by poorly understood factors. The vary variable clinicial results in the eight trials performed in the 90s is a clear demonstration. Recent work has helped understand the mechanisms limiting the integration of transplanted hepatocytes in the recipient liver. This led to the concept of repopulation, increasing the percentage of the hepatocyte mass reconstituted during the transplantation. The goal is to give the transplanted hepatocytes a proliferation advantage over he native hepatocytes. Several models have been designed and are currently being evaluated for application in humans. We are not far from new clinical trials with hepatocyte transplantation in humans for the treatment hereditary metabolic diseases. For certain disease, 3 to 5% normally functioning hepatocytes in the recipient liver would be sufficient to achieve a clinically significant effect for the patient.     

Clinical application of bioartificial liver support systems

OBJECTIVE: To review the present status of bioartificial liver (BAL) devices and their obtained clinical results. BACKGROUND: Acute liver failure (ALF) is a disease with a high mortality. Standard therapy at present is liver transplantation. Liver transplantation is hampered by the increasing shortage of organ donors, resulting in high incidence of patients with ALF dying on the transplantation waiting list. Among a variety of liver assist therapies, BAL therapy is marked as the most promising solution to bridge ALF patients to liver transplantation or to liver regeneration, because several BAL systems showed significant survival improvement in animal ALF studies. Until today, clinical application of 11 different BAL systems has been reported. METHODS: A literature review was performed using MEDLINE and additional library searches. Only BAL systems that have been used in a clinical trial were included in this review. RESULTS: Eleven BAL systems found clinical application. Three systems were studied in a controlled trial, showing no significant survival benefits, in part due to the insufficient number of patients included. The other systems were studied in a phase I trial or during treatment of a single patient and all showed to be safe. Most BAL therapies resulted in improvement of clinical and biochemical parameters. CONCLUSIONS: Bioartificial liver therapy for bridging patients with ALF to liver transplantation or liver regeneration is promising. Its clinical value awaits further improvement of BAL devices, replacement of hepatocytes of animal origin by human hepatocytes, and assessment in controlled clinical trials.     

Review of the clinical experience with a modified release form of tacrolimus [FK506E (MR4)] in transplantation

Abstract:  Non-compliance in solid transplantation recipients is a major factor in acute graft rejection, which influences patient survival. Nowadays, tacrolimus is one of the most widely used immunosuppressant agents together with cyclosporine following kidney and liver transplantation with a standardized twice-daily dosing regimen. To improve the patients' compliance to the prescribed immunosuppressive therapy, FK506E (MR4), a modified release (MR) oral dosage form of tacrolimus has been developed for a once-daily dosing regimen. This report reviews the most recent results of clinical trials with MR tacrolimus after kidney and liver transplantation.     

Therapeutic drug monitoring of mycophenolic acid in solid organ transplant patients treated with mycophenolate mofetil: review of the literature

Mycophenolate mofetil (MMF) has conventionally been administered at a fixed dose without routinely monitoring blood levels of mycophenolic acid (MPA), the active metabolite. The contribution of therapeutic drug monitoring (TDM) during MMF therapy remains controversial. A literature review was performed to explore the usefulness of TDM for MPA in solid organ transplantation. In addition, emphasis was placed on the potential clinical benefits and limitations of TDM for MPA. Available studies have limitations and report conflicting results. Although early after transplantation MPA area under the curve might have predictive value for the risk of acute rejection, predose levels appear less reliable. With regard to MPA toxicity, most studies showed no correlation between MPA pharmacokinetics and adverse effects. TDM is hampered by several factors such as the considerable intra-subject variability of MPA pharmacokinetics and the increasing number of different drug combinations. Proposed target ranges are restricted to the early posttransplant period when MMF is used in combination with cyclosporine. The current review of the literature indicates no clear support for a substantial clinical benefit of TDM and more data from prospective randomized trials are needed.     

Renal transplantation with early steroid withdrawal

Steroids are effective immunosuppressants in renal transplantation but are associated with significant adverse effects. As a result, there has been increased interest in protocols utilizing steroid minimization. Initial trials stopped steroids at approximately 3 months, when the highest risk phase for acute rejection was over. As two randomized trials using cyclosporine and mycophenolate mofetil without induction therapy showed an unacceptably high acute rejection rate, more recent interest has focused on the cessation of steroids very early, usually within the first week after transplantation. Most protocols have used antibody induction combined with calcineurin inhibitors and mycophenolic acid derivatives. Uncontrolled studies have shown a low rate of acute rejection, but the most recent randomized controlled trials have demonstrated an increased risk of acute rejection. These trials have not shown any consistent difference in short-term patient or graft survival. Cardiovascular risk factors do not appear to be consistently improved by early steroid withdrawal. Most trials lack sufficient follow-up (5 years or more) to assess the impact of the increased acute rejection rate seen with early steroid withdrawal on long-term outcomes. Thus, the use of such protocols remains investigational.     

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.     

Eficácia e segurança de antifibrinolíticos em cirurgia oncológica: uma revisão sistemática e metanálise

Background and objectivesThe administration of antifibrinolytics has been shown to be effective in reducing blood loss and the need for transfusions in surgeries. However, few studies have evaluated these drugs in cancer surgery. The objective was to review the efficacy and safety of the treatment with antifibrinolytics in patients who underwent oncologic surgeries.ContentsAn electronic bibliographic research was conducted in PubMed, OVID, MEDLINE, EMBASE, EBSCO and in the Cochrane Library data basis in order to identify randomized clinical trials performed in any type of oncologic surgery. The data evaluated were blood loss, need for transfusion and incidence of arteriovenous thromboembolism. Five randomized controlled trials evaluating 838 patients met the inclusion requirements. In the analysis of the incidence of thromboembolic events in the five RCTs, there was no statistically significant difference between the administration of tranexamic acid when compared with the placebo (OR = 0.36, 95% IC: 0.11–1.19, p = 0.09, I² = 0%). However, when total estimated blood loss and need for blood transfusion are analyzed, the use of tranexamic acid was associated with a significant reduction over placebo (MD = ‐135.79, 95% CI: ‐179.50 to ‐92.08, p < 0.00001, I² = 68%) and (OR = 0.45, 95% CI: 0.32–0.65, p < 0.00001, I² = 60%), respectively.ConclusionsThis meta‐analysis found no evidence that the administration of antifibrinolytics increases the risk of thromboembolic complications in patients submitted to oncologic surgery, and has shown evidence that it is effective in reducing total perioperative blood loss and the need for blood transfusion.     

Why Did it Take so Long to Start a Non-Heart-Beating Donor Program in Belgium ?

Ischemia-reperfusion injury of the liver causes severe organ dysfunction after both extended liver resections and liver transplantation. In experimental models, ischemic preconditioning has repeatedly been shown to protect the liver from injury after warm and cold ischemia-reperfusion. Herein, we summarize the experimental and clinical evidence considering protection of tissue by ischemic preconditioning and we conclude that it is now time to initiate prospective randomized multicenter trials, in order to confirm the benefit of ischemic preconditioning for the patients undergoing major liver surgery and liver transplantation.     

Ischemic preconditioning: enough evidence to support clinical application in liver surgery and transplantation?

Ischemia-reperfusion injury of the liver causes severe organ dysfunction after both extended liver resections and liver transplantation. In experimental models, ischemic preconditioning has repeatedly been shown to protect the liver from injury after warm and cold ischemia-reperfusion. Herein, we summarize the experimental and clinical evidence considering protection of tissue by ischemic preconditioning and we conclude that it is now time to initiate prospective randomized multicenter trials, in order to confirm the benefit of ischemic preconditioning for the patients undergoing major liver surgery and liver transplantation.     

Classification of portal vein anatomy for partial liver transplantation

The anatomy of the portal vein is usually classified as 3 to 5 patterns and simple compared with the anatomy of the hepatic artery. The variety of portal vein anatomy was examined in 287 living donors for liver transplantation. More than 90% of donors showed a normal bifurcation type; 6% showed the trifurcation type. Only 3% displayed a separate origin of the right paramedian and the right lateral branches. There was no anomalous pattern that had not been reported previously. In our series, we conclude that it is rare for 2 or more stumps of portal vein to appear in partial liver transplantation. The frequency is much less if the left liver or the right lateral liver graft is used for adult-to-adult living donor liver transplantation.     

Antifibrinolytic treatment in subarachnoid haemorrhage: Present state

Summary Two randomised controlled clinical trials in patients with recently ruptured intracranial aneurysms were undertaken using tranexamic acid (AMCA) to prevent early recurrent bleeding.In our accumulated series of 105 patients 53 were given AMCA and 52 were controls. 13% of the AMCA-treated patients and 31% of the controls rebled. In patients treated with AMCA the recurrent bleedings took place later than the rebleeding in the control patients.Vasospasm and delayed cerebral ischaemic deficits were seen more frequently in patients treated with AMCA. Total mortality from rebleeding and cerebral ischaemia was 25% in AMCA-treated patients and 19% in the controls during the six weeks' observation time.Coagulation factors remained unaffected by the drug. Local fibrinolysis in the cerebrospinal fluid decreased after one week in patients treated with AMCA. After two weeks the fibrinolytic activity was similar in AMCA-treated patients and in the controls.After experimental subarachnoid haemorrhage in 90 rabbits. AMCA was found to suppress plasminogen activator activity, mainly in the leptomeninges. This occurred however only during the first few postbleeding days.Antifibrinolytic agents only appear to reduce the risk of recurrent bleeding during the first ten day period after the primary aneurysm rupture. However they also seem to produce delayed cerebral ischaemia in patients with subarachnoid haemorrhage.Synthetic antifibrinolytics evidently shift the incidence of rebleeding curve to the right but these drugs are probably of diminished value in the subsequent weeks of risk.     

An ideal liver support system and xenotransplantation

Currently, the rapid increase in the number of candidates for orthotopic liver transplantation has resulted in a shortage of donor organs and, especially for fulminant hepatic failure, an urgent need for transplantations. Thus the need for a liver support system as a "bridge" before liver transplantation is also urgent, as is the need for treatment of reversible acute liver disease. Various liver support systems have been proposed, for example, cross-circulation systems, extracorporeal liver support systems, hemodialysis, and hemadsorption, but these are not considered to function sufficiently. Demetriou's system, Sussman's system, and Gerlach's system have reached clinical trials. The ideal liver support system should have significant metabolic capacity, the ability to be used in continuous treatment, simplicity of use, biocompatibility, ready availability, consistency, economy, and safety from viral infection, but no system meets all of these criteria.     

Reperfusion of the Liver Allograft with Blue Blood: Is It Still the Royal Perfusate?

The technique of liver transplantation has become relatively standardized. Although not commonly practiced, arterial reperfusion has been shown in both animal and human trials to offer hemodynamic and functional benefits to liver allograft recipients. Whether this is the result of shortening the time to re-establishing arterial perfusion or an effect of the sequence which the liver is revascularized remains unknown. Further randomized clinical trials are needed to answer this question and support our practice of arterial reperfusion.     

Invited commentary to: ‘the artificial liver — Liver support systems’ (eur. surg. 2002;34:194–198)

Summary   Background: Attempts to replace liver function with extracorporeal procedures date back to the 1950s. The absence of evidence of effectiveness with regard to mortality and the successful introduction of liver transplantation caused these procedures to be applied very rarely. With the development of new technologies and the shortage of organs for transplantation, several groups introduced liver support systems once more into clinical practice. The idea is to inhibit further liver damage and to reduce or eliminate the negative effects of insufficient liver function on various organs and organ systems. The ultimate purpose is to improve morbidity and mortality in patients with acute and acute-on-chronic liver failure and to reduce the need for liver transplantation. Methods: We have reviewed the literature addressing different forms of extracorporeal therapies in patients with acute and acute-on-chronic liver failure. Results: In trials carried out so far, the use of extracorporeal therapy was shown to eliminate the various toxins and to improve organ function. However, there have yet been no controlled trials on mortality. While the available systems of detoxification are technically highly advanced, hybrid systems using liver cells have not yet succeeded in resolving all the problems. Conclusions: Over the past 30 years, a variety of supportive therapies for patients with acute liver failure have been proposed, including charcoal haemoperfusion, haemodialysis, plasmapheresis,ex vivo liver perfusion and cross circulation, but none have proved efficacious when studied in carefully controlled trials. In recent years the removal of albuminbound substances has gained increasing interest especially in acute-on-chronic liver failure. Preliminary results using this new detoxification system are encouraging.