Herman G. D. Hendriks

The Impact of Intraoperative Transfusion of Platelets and Red Blood Cells on Survival After Liver Transplantation

BACKGROUND:Intraoperative transfusion of red blood cells (RBC) is associated with adverse outcome after orthotopic liver transplantation (OLT). Although experimental studies have shown that platelets contribute to reperfusion injury of the liver, the influence of allogeneic platelet transfusion on outcome has not been studied in detail. In this study, we evaluate the impact of various blood products on outcome after OLT. METHODS:Twenty-nine variables, including blood product transfusions, were studied in relation to outcome in 433 adult patients undergoing a first OLT between 1989 and 2004. Data were analyzed using uni- and multivariate stepwise Cox’s proportional hazards analyses, as well as propensity score-adjusted analyses for platelet transfusion to control for selection bias in the use of blood products. RESULTS:The proportion of patients receiving transfusion of any blood component decreased from 100% in the period 1989–1996 to 74% in the period 1997–2004. In uni- and multivariate analyses, the indication for transplantation, transfusion of platelets and RBC were highly dominant in predicting 1-yr patient survival. These risk factors were independent from well-accepted indices of disease, such as the Model for End-Stage Liver Disease score and Karnofsky score. The effect on 1-yr survival was dose-related with a hazard ratio of 1.377 per unit of platelets (P = 0.01) and 1.057 per unit of RBC (P = 0.001). The negative impact of platelet transfusion on survival was confirmed by propensity-adjusted analysis. CONCLUSION:This retrospective study indicates that, in addition to RBC, platelet transfusions are an independent risk factor for survival after OLT. These findings have important implications for transfusion practice in liver transplant recipients.

An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII.

IMPLICATIONS The successful treatment with recombinant factor VIIa of a patient experiencing intractable bleeding after cardiac surgery is described.

Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests

BACKGROUND & AIMS Patients with liver disease often show substantial changes in their hemostatic system, which may aggravate further during liver transplantation. Recently, thrombin generation in patients with stable disease was shown to be indistinguishable from controls provided thrombomodulin, the natural activator of the anticoagulant protein C system, was added to the plasma. These results indicated that the hemostatic balance is preserved in patients with liver disease, despite conventional coagulation tests suggest otherwise. METHODS Here we examined thrombin generation profiles in serial plasma samples taken from ten consecutive patients undergoing liver transplantation. RESULTS At all time points, the endogenous thrombin potential (ETP) was slightly lower compared to healthy volunteers, despite substantially prolonged PT and APTT values. However, when thrombin generation was tested in the presence of thrombomodulin, the ETP was equal to or even higher than that in healthy subjects. In fact, thrombin generation was hardly affected by thrombomodulin, while thrombin generation in healthy subjects decreased profoundly upon the addition of thrombomodulin. In patients undergoing liver transplantation, efficient thrombin generation in the presence of thrombomodulin may be explained by decreased levels of protein C, S, and antithrombin, and by elevated levels of FVIII. CONCLUSIONS Thrombin generation in patients undergoing liver transplantation is equal or even superior to thrombin generation in healthy volunteers when tested in the presence of exogenous thrombomodulin. These results support the recently advocated restrictive use of plasma during liver transplantation and warrants further study of the prophylactic use of anticoagulants to reduce thromboembolic complications after transplantation.

Platelet Transfusion During Liver Transplantation Is Associated with Increased Postoperative Mortality Due to Acute Lung Injury

BACKGROUND: Platelet transfusions have been identified as an independent risk factor for survival after orthotopic liver transplantation (OLT). In this study, we analyzed the specific causes of mortality and graft loss in relation to platelet transfusions during OLT. METHODS: In a series of 449 consecutive adult patients undergoing a first OLT, the causes of patient death and graft failure were studied in patients who did or did not receive perioperative platelet transfusions. RESULTS: Patient and graft survival were significantly reduced in patients who received platelet transfusions, compared with those who did not (74% vs 92%, and 69% vs 85%, respectively at 1 yr; P < 0.001). Lower survival rates in patients who received platelets were attributed to a significantly higher rate of early mortality because of acute lung injury (4.4% vs 0.4%; P = 0.004). There were no significant differences in other causes of mortality between the two groups. The main cause of graft loss in patients receiving platelets was patient death with a functioning graft. CONCLUSIONS: These findings suggest that platelet transfusions are an important risk factor for mortality after OLT. The current study extends previous observations by identifying acute lung injury as the main determinant of increased mortality. The higher rate of graft loss in patients receiving platelets is related to the higher overall mortality rate and does not result from specific adverse effects of transfused platelets on the grafted liver.

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.

Liver transplantation with preservation of the inferior vena cava. A comparison of conventional and piggyback techniques in adults

Abstract:  The aim of this study is to analyse a single centres experience with two techniques of liver transplantation (OLT), conventional (CON‐OLT) and piggyback (PB‐ES), and to compare outcome in terms of survival, morbidity, mortality and post‐operative liver function as well as operative characteristics. A consecutive series (1994–2000) of 167 adult primary OLT were analysed. Ninety‐six patients had CON‐OLT and 71 patients had PB‐ES. In PB‐ES group two revascularization protocols were used. In the first protocol reperfusion of the graft was performed first via the portal vein followed by the arterial anastomosis (PB‐seq). In the second protocol the graft was reperfused simultaneously via portal vein and hepatic artery (PB‐sim). One‐, 3‐ and 5‐yr patient survival in the CON‐OLT and PB‐ES groups were 90, 83 and 80%, and 83, 78 and 78%, respectively (p = ns). Graft survival at the same time points was 81, 73 and 69%, and 78, 69 and 65%, respectively (p = ns). Apart from the higher number of patients with cholangitis and sepsis in CON‐OLT group, morbidity, retransplantation rate and post‐operative liver and kidney function were not different between the two groups. The total operation time was not different between both groups (9.4 h in PB‐ES vs. 10.0 h in CON‐OLT), but in PB‐ES group cold and warm ischaemia time (CIT and WIT), revascularization time (REVT), functional and anatomic anhepatic phases (FAHP and AAHP) were significantly shorter (8.9 h vs. 10.7 h, 54 min vs. 63 min, 82 min vs. 114 min, 118 min vs. 160 min and 87 min vs. 114 min, respectively, p < 0.05). RBC use in the PB‐ES group was lower compared to the CON‐OLT group (4.0 min vs. 10.0 units, p < 0.05). Except for WIT and REVT there were no differences in operative characteristics between PB‐Sim and PB‐Seq groups. The WIT was significantly longer in PB‐Sim group compared with PB‐Seq group (64 min vs. 50 min, p < 0.05); however REVT was significantly shorter in PB‐Sim group (64 min vs. 97 min, p < 0.05). Results of this study show that both techniques are comparable in survival and morbidity; however PB‐ES results in shorter AAHP, FAHP, REVT and WIT as well as less RBC use. In the PB‐ES group there seems to be no adavantage for any of the revascularization protocols.

Prothrombin complex concentrate in the reduction of blood loss during orthotopic liver transplantation: PROTON-trial

BackgroundIn patients with cirrhosis, the synthesis of coagulation factors can fall short, reflected by a prolonged prothrombin time. Although anticoagulants factors are decreased as well, blood loss during orthotopic liver transplantation can still be excessive. Blood loss during orthotopic liver transplantation is currently managed by transfusion of red blood cell concentrates, platelet concentrates, fresh frozen plasma, and fibrinogen concentrate. Transfusion of these products may paradoxically result in an increased bleeding tendency due to aggravated portal hypertension. The hemostatic effect of these products may therefore be overshadowed by bleeding complications due to volume overload.In contrast to these transfusion products, prothrombin complex concentrate is a low-volume highly purified concentrate, containing the four vitamin K dependent coagulation factors. Previous studies have suggested that administration of prothrombin complex concentrate is an effective method to normalize a prolonged prothrombin time in patients with liver cirrhosis. We aim to investigate whether the pre-operative administration of prothrombin complex concentrate in patients undergoing liver transplantation for end-stage liver cirrhosis, is a safe and effective method to reduce perioperative blood loss and transfusion requirements.Methods/DesignThis is a double blind, multicenter, placebo-controlled randomized trial.Cirrhotic patients with a prolonged INR (≥1.5) undergoing liver transplantation will be randomized between placebo or prothrombin complex concentrate administration prior to surgery. Demographic, surgical and transfusion data will be recorded. The primary outcome of this study is RBC transfusion requirements.DiscussionPatients with advanced cirrhosis have reduced plasma levels of both pro- and anticoagulant coagulation proteins. Prothrombin complex concentrate is a low-volume plasma product that contains both procoagulant and anticoagulant proteins and transfusion will not affect the volume status prior to the surgical procedure. We hypothesize that administration of prothrombin complex concentrate will result in a reduction of perioperative blood loss and transfusion requirements. Theoretically, the administration of prothrombin complex concentrate may be associated with a higher risk of thromboembolic complications. Therefore, thromboembolic complications are an important secondary endpoint and the occurrence of this type of complication will be closely monitored during the study.Trial registrationThe trial is registered at http://www.trialregister.nl with number NTR3174. This registry is accepted by the ICMJE.

Comparison of arterial pressure and plethysmographic waveform-based dynamic preload variables in assessing fluid responsiveness and dynamic arterial tone in patients undergoing major hepatic resection

BACKGROUND Dynamic preload variables to predict fluid responsiveness are based either on the arterial pressure waveform (APW) or on the plethysmographic waveform (PW). We compared the ability of APW-based variations in stroke volume (SVV) and pulse pressure (PPV) and of PW-based plethysmographic variability index (PVI) to predict fluid responsiveness and to track fluid changes in patients undergoing major hepatic resection. Furthermore, we assessed whether the PPV/SVV ratio, as a measure of dynamic arterial elastance (Eadyn), could predict a reduction in norepinephrine requirement after fluid administration. METHODS Thirty patients received i.v. fluid (15 ml kg(-1) in 30 min) after hepatic resection and were considered responders when stroke volume index (SVI) increased ≥20% after fluid administration. SVV and SVI were measured by the FloTrac-Vigileo(®) device, and PVI was measured by the Masimo Radical 7 pulse co-oximeter(®). RESULTS The areas under a receiver operating characteristic curve for SVV, PPV, and PVI were 0.81, 0.77, and 0.78, respectively. In responders, all dynamic variables, except PVI, decreased after fluid administration. Eadyn predicted a reduced norepinephrine requirement (AUC = 0.81). CONCLUSIONS In patients undergoing major hepatic resection, both APW- and PW-based dynamic preload variables predict fluid responsiveness (preload) to a similar extent. Most variables (except PVI) also tracked fluid changes. Eadyn, as a measure of arterial elastance (afterload), might be helpful to distinguish the origin of hypotension. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, NCT01060683.

Effects of acidosis, alkalosis, hyperthermia and hypothermia on haemostasis: results of point of care testing with the thromboelastography analyser

In this study we assessed the effects of changes in pH, temperature, and their combination in whole blood on thromboelastographic variables. Blood was collected from six healthy volunteers. Thromboelastograph (TEG series 5000; Haemoscope Corporation, Illinois, USA) channels were set at temperatures of 32, 37, and 39°C and each was filled with artificially acidified, alkalified, and neutral blood, respectively. Acidification (pH 6.95) significantly impairs thromboelastographic variables reaction time r (from 23.3 to 33.7 min; P = 0.0280), kinetic time k (from 8.7 to 16.1 min; P = 0.028), angle α (from 24.3° to 13.8°; P = 0.028), prothrombin time (from 11.4 to 12.1 s; P = 0.044), and activated partial thromboplastin time (from 29.3 to 45.0 s; P = 0.028). A temperature drop from 37 to 32°C in blood of neutral pH significantly impaired k (from 8.7 to 10.2 min; P = 0.028) and α (from 24.3° to 21.0°; P = 0.027), whereas maximum amplitude ma significantly increased (from 46.5 to 52.5 mm; P = 0.027). A temperature rise from 37 to 39°C at pH 7.37 did not affect any of the TEG variables. Artificial alkalization (pH 7.68) at a temperature of 37°C had no effect on any of the measured variables. Acidosis causes a significant impairment of clot formation and clot strength. Hypothermia had the same effects, but to a lesser extent. These findings emphasize the need for correction of acidosis and hypothermia to normalize haemostasis.

Analysis of differences in outcome of two European liver transplant centers

Authors analyzed the differences in the outcome of two European liver transplant centers differing in case volume and experience. The first was the Transplantation and Surgical Clinic, Semmelweis University, Budapest, Hungary (SEB) and the second the University Medical Center Groningen, Groningen, The Netherlands (UMCG). We investigated if such differences could be explained. The 1‐, 3‐ and 5‐year patient survival in the UMCG was 86%, 80%, and 77% compared with 65%, 56%, and 55% in SEB. Graft survival at the same time points was 79%, 71%, and 66% in the UMCG and 62%, 55%, and 53% in SEB. Significant differences were present regarding the donor and recipient age, diagnosis mix, disease severity and operation variables, per‐operative transfusion rate, vascular complications, postoperative infection rate, and need for renal replacement. To determine factors correlating with survival, a separate uni‐ and multivariate analysis was performed in each center individually, between study parameters and patient survival. In both centers, peri‐operative red blood cell (RBC) transfusion rate was a significant predictor for patient survival. The difference in blood loss can be explained by different operation techniques and shorter operation time in SEB, with consequently less time spent on hemostasis. It was jointly concluded that measures to reduce blood loss by adapting the operation technique might lead to improved survival and reduced morbidity.