Marieke T. de Boer

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.

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.

Impact of blood loss on outcome after liver resection

Partial liver resections are the treatment of choice for patients with a malignant liver or bile duct tumor. The most frequent indications for partial liver resections are colorectal metastasis, hepatocellular carcinoma (HCC) and cholangiocarcinoma. Liver resection is the only therapy with a chance for cure in these patients. Refinements in surgical technique and increasing experience have contributed to a reduction in perioperative morbidity and mortality in recent years. Despite these improvements, partial liver resections remain a major surgical procedure and carry the risk for excessive blood loss and a subsequent need for blood transfusion. Blood transfusions have been associated with systemic side effects, such as depression of the immune system. Several studies have suggested that perioperative blood loss or transfusions have a negative impact on postoperative outcome. However, it has been debated whether this is due to a real cause-effect relationship or merely the result of more complicated surgery. We have reviewed the literature concerning studies focusing on the relationship between blood loss and blood transfusion during liver surgery for malignant tumors and postoperative outcome. Most studies were based on a retrospective analysis of single center experiences, using uni- and multivariate statistical methods. Most studies have demonstrated a significant and clinically relevant association between blood transfusion and postoperative mortality and morbidity, especially postoperative infectious complications. The effect of blood transfusions on tumor recurrence and more long-term mortality is much less clear and evidence varies depending on the type of malignancy. The strongest indication that blood transfusion may have an impact on tumor recurrence has been found for patients with early stages of HCC. However, overall, no such effect could be demonstrated for patients undergoing partial liver resection for late stages of HCC, colorectal liver metastasis or cholangiocarcinoma.

Criteria for Viability Assessment of Discarded Human Donor Livers during Ex Vivo Normothermic Machine Perfusion

Although normothermic machine perfusion of donor livers may allow assessment of graft viability prior to transplantation, there are currently no data on what would be a good parameter of graft viability. To determine whether bile production is a suitable biomarker that can be used to discriminate viable from non-viable livers we have studied functional performance as well as biochemical and histological evidence of hepatobiliary injury during ex vivo normothermic machine perfusion of human donor livers. After a median duration of cold storage of 6.5 h, twelve extended criteria human donor livers that were declined for transplantation were ex vivo perfused for 6 h at 37°C with an oxygenated solution based on red blood cells and plasma, using pressure controlled pulsatile perfusion of the hepatic artery and continuous portal perfusion. During perfusion, two patterns of bile flow were identified: (1) steadily increasing bile production, resulting in a cumulative output of ≥30 g after 6 h (high bile output group), and (2) a cumulative bile production <20 g in 6 h (low bile output group). Concentrations of transaminases and potassium in the perfusion fluid were significantly higher in the low bile output group, compared to the high bile output group. Biliary concentrations of bilirubin and bicarbonate were respectively 4 times and 2 times higher in the high bile output group. Livers in the low bile output group displayed more signs of hepatic necrosis and venous congestion, compared to the high bile output group. In conclusion, bile production could be an easily assessable biomarker of hepatic viability during ex vivo machine perfusion of human donor livers. It could potentially be used to identify extended criteria livers that are suitable for transplantation. These ex vivo findings need to be confirmed in a transplant experiment or a clinical trial.

Immediate Postoperative Low Platelet Count is Associated With Delayed Liver Function Recovery After Partial Liver Resection

Objective:To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection. Background:Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans. Methods:In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases, we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin >50 &mgr;mol/L or prothrombin time >20 seconds at any time point between postoperative day 1 and 5. Results:Patients with a low (<100 ×109/L) immediate postoperative platelet count had worse postoperative liver function, higher serum markers of liver injury, and increased mortality compared with patients with normal platelet counts (>1009/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CI, 1.1–122.4; P = 0.04 in multivariate analysis). Conclusion:After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration.

Hypothermic oxygenated machine perfusion prevents arteriolonecrosis of the peribiliary plexus in pig livers donated after circulatory death.

Background Livers derived from donation after circulatory death (DCD) are increasingly accepted for transplantation. However, DCD livers suffer additional donor warm ischemia, leading to biliary injury and more biliary complications after transplantation. It is unknown whether oxygenated machine perfusion results in better preservation of biliary epithelium and the peribiliary vasculature. We compared oxygenated hypothermic machine perfusion (HMP) with static cold storage (SCS) in a porcine DCD model. Methods After 30 min of cardiac arrest, livers were perfused in situ with HTK solution (4°C) and preserved for 4 h by either SCS (n = 9) or oxygenated HMP (10°C; n = 9), using pressure-controlled arterial and portal venous perfusion. To simulate transplantation, livers were reperfused ex vivo at 37°C with oxygenated autologous blood. Bile duct injury and function were determined by biochemical and molecular markers, and a systematic histological scoring system. Results After reperfusion, arterial flow was higher in the HMP group, compared to SCS (251±28 vs 166±28 mL/min, respectively, after 1 hour of reperfusion; p = 0.003). Release of hepatocellular enzymes was significantly higher in the SCS group. Markers of biliary epithelial injury (biliary LDH, gamma-GT) and function (biliary pH and bicarbonate, and biliary transporter expression) were similar in the two groups. However, histology of bile ducts revealed significantly less arteriolonecrosis of the peribiliary vascular plexus in HMP preserved livers (>50% arteriolonecrosis was observed in 7 bile ducts of the SCS preserved livers versus only 1 bile duct of the HMP preserved livers; p = 0.024). Conclusions Oxygenated HMP prevents arteriolonecrosis of the peribiliary vascular plexus of the bile ducts of DCD pig livers and results in higher arterial flow after reperfusion. Together this may contribute to better perfusion of the bile ducts, providing a potential advantage in the post-ischemic recovery of bile ducts.

The effect of a multimodal fast-track programme on outcomes in laparoscopic liver surgery: a multicentre pilot study

OBJECTIVES This study was conducted to evaluate the added value of an enhanced recovery after surgery (ERAS) programme in laparoscopic liver resections for solid tumours. METHODS Patients undergoing laparoscopic liver resection between July 2005 and July 2008 were included. Indications for resections included presumed benign and malignant liver lesions. Primary outcome was total length of hospital stay (LOS). Secondary outcomes were functional recovery, complications, conversions, blood loss and duration of operation. RESULTS Thirteen patients were treated by laparoscopic liver resections in the ERAS programme in one centre (group 1). Their outcomes were compared with outcomes of 13 laparoscopic procedures performed either before the introduction of the ERAS programme during 2003-2005 in the same centre or during the same period in other centres using traditional care (group 2). Median total LOS was 5.0 days (range 3-10 days) in group 1 and 7.0 days (3-12 days) in group 2. This difference was not statistically significant. Functional recovery occurred 2 days earlier in group 1 (median 3.0 days [range 1-7 days] vs. median 5.0 days [range 2-8 days]; P < 0.044). There were no significant differences in complications, conversions or duration of operation. Blood loss was significantly less in the ERAS group (median 50 ml [range 50-200 ml] vs. median 250 ml [range 50-800 ml]; P < 0.002). CONCLUSIONS This exploratory, multicentre, fast-track laparoscopic liver resection study is the first such study conducted. Although small, the study suggests that a multimodal enhanced recovery programme in laparoscopic liver surgery is feasible, safe and may lead to accelerated functional recovery and reductions in LOS.

Long-Term Results of Urgent Revascularization for Hepatic Artery Thrombosis After Pediatric Liver Transplantation

Hepatic artery thrombosis (HAT) after pediatric orthotopic liver transplantation (OLT) is a serious complication resulting in bile duct necrosis and often requiring retransplantation. Immediate surgical thrombectomy/thrombolysis has been reported to be a potentially successful treatment for restoring blood flow and avoiding urgent retransplantation. The long‐term results of this strategy remain to be determined. In 232 pediatric liver transplants, we analyzed long‐term outcomes after urgent revascularization for early HAT. HAT developed in 32 patients (13.7%). In 16 children (50%), immediate surgical thrombectomy was performed in an attempt to salvage the graft. Fourteen patients (44%) underwent urgent retransplantation, and 2 (6%) died before further intervention. Immediate thrombectomy resulted in long‐term restoration of the hepatic artery flow in 6 of 16 patients (38%) and in 1‐ and 5‐year graft and patient survival rates of 83% and 67%, respectively. In 10 patients, revascularization was unsuccessful, and retransplantation was inevitable. The 1‐ and 5‐year patient survival rates in this group decreased to 50% and 40%, respectively. After immediate retransplantation, the 5‐year patient survival rate was 71%. In conclusion, immediate surgical thrombectomy for HAT after pediatric OLT results in long‐term graft salvage in about one‐third of patients. However, when thrombectomy is unsuccessful, long‐term patient survival is lower than the survival of patients who underwent immediate retransplantation. Liver Transpl 16:847–855, 2010.

The Clinical Relevance of the Anhepatic Phase During Liver Transplantation

This study assesses the relation between the anhepatic phase duration and the outcome after liver transplantation. Of 645 patients who underwent transplantation between 1994 and 2006, 194 were recipients of consecutive adult primary piggyback liver transplants using heart‐beating donors. The anhepatic phase was defined as the time from the physical removal of the liver from the recipient to recirculation of the graft. Other noted study variables were the cold and warm ischemia times, donor and recipient age, donor and recipient body mass index, perioperative red blood cell (RBC) transfusion, indication for transplantation, and Model for End‐Stage Liver Disease score. The primary outcome parameter was graft dysfunction, which was defined as either primary nonfunction or initial poor function according to the Ploeg‐Maring criteria. The median anhepatic phase was 71 minutes (37–321 minutes). Graft dysfunction occurred in 27 patients (14%). Logistic regression analysis showed an anhepatic phase over 100 minutes [odds ratio (OR), 4.28], a recipient body mass index over 25 kg/m2 (OR, 3.21), and perioperative RBC transfusion (OR, 3.04) to be independently significant predictive factors for graft dysfunction. One‐year patient survival in patients with graft dysfunction was 67% versus 92% in patients without graft dysfunction (P < 0.001). A direct relation between the anhepatic phase duration and patient survival could, however, not be established. In conclusion, this study shows that liver transplant patients with an anhepatic phase over 100 minutes have a higher incidence of graft dysfunction. Patients with graft dysfunction have significantly worse 1‐year patient survival. Liver Transpl 15:1050–1055, 2009.

Role of Fibrin Sealants in Liver Surgery

Background: Fibrin sealants are widely used in liver surgery. The aim of this article is to review the literature on evidence of hemostatic and biliostatic capacities of different fibrin sealants in liver surgery. Methods: In PubMed, a literature search was done with the search terms ‘fibrin sealant’ or ‘fibrin glue’ combined with ‘liver resection’ or ‘bile leakage’. Thirteen comparative fibrin sealant studies were selected. Results: In general, these studies have shown a reduced time to hemostasis when fibrin sealants were used. So far, only a few studies have been published that have focused on postoperative resection surface-related complications. There is no strong evidence that fibrin sealants reduce the incidence of bile leakage after liver resection. Important new evidence shows that bile contains profibrinolytic activity that causes lysis of the clot formed by the fibrin sealant at least in vitro. Conclusions: Fibrin sealants can be effective as an adjunct to achieve hemostasis during liver resections. However, considering lack of evidence on the efficacy of fibrin sealants in reducing postoperative resection surface-related complications, routine use of fibrin sealants in liver surgery cannot be recommended.