A brief history of liver transplantation and transplant anesthesia.

In this review, we describe the major milestones in the development of organ transplantation with a specific focus on hepatic transplantation. For many years, the barriers preventing successful organ transplantation in humans seemed insurmountable. Although advances in surgical technique provided the technical ability to perform organ transplantation, limited understanding of immunology prevented successful organ transplantation. The breakthrough to success was the result of several significant discoveries between 1950 and 1980 involving improved surgical techniques, the development of effective preservative solutions, and the suppression of cellular immunity to prevent graft rejection. After that, technical innovations and laboratory and clinical research developed rapidly. However, these advances alone could not have led to improved transplant outcomes without parallel advances in anesthesia and critical care. With increasing organ demand, it proved necessary to expand the donor pool, which has been achieved with the use of living donors, split grafts, extended criteria organs, and organs obtained through donation after cardiac death. Given this increased access to organs and organ resources, the number of transplantations performed every year has increased dramatically. New regulatory organizations and transplant societies provide critical oversight to ensure equitable organ distribution and a high standard of care and also perform outcome analyses. Establishing dedicated transplant anesthesia teams results in improved organ transplantation outcomes and provides a foundation for developing new standards for other subspecialties in anesthesiology, critical care, and medicine overall. Through a century of discovery, the success we enjoy at the present time is the result of the work of well-organized multidisciplinary teams following standardized protocols and thereby saving thousands of lives worldwide each year. With continuing innovation, the future is bright.

Hyponatremia and Liver Transplantation: A Narrative Review.

Hyponatremia is a common electrolyte disorder in patients with end-stage liver disease (ESLD) and is associated with increased mortality on the liver transplantation (LT) waiting list. The impact of hyponatremia on outcomes after LT is unclear. Ninety-day and one-year mortality may be increased, but the data are conflicting. Hyponatremic patients have an increased rate of complications and longer hospital stays after transplant. Although rare, osmotic demyelination syndrome (ODS) is a feared complication after LT in the hyponatremic patient. The condition may occur when the serum sodium (sNa) concentration increases excessively during or after LT. This increase in sNa concentration correlates with the degree of preoperative hyponatremia, the amount of intraoperative blood loss, and the volume of intravenous fluid administration. The risk of developing ODS after LT can be mitigated by avoiding large perioperative increases in sNa concentration . This can be achieved through measures such as carefully increasing the sNa pretransplant, and by limiting the intravenous intra- and postoperative amounts of sodium infused. SNa concentrations should be monitored regularly throughout the entire perioperative period.

Intensive care management of acute-on-chronic liver failure.

The syndrome of acute-on-chronic liver failure combines deterioration of liver function in a patient with chronic liver disease, with the development of extrahepatic organ failure and high short-term mortality. Its successful management demands a rapid and coherent response to the development of dysfunction and failure of multiple organ systems in an intensive care unit setting. This response recognises the features that distinguish it from other critical illness and addresses the complex interplay between the precipitating insult, the many organ systems involved and the disordered physiology of underlying chronic liver disease. An evidence base is building to support the approaches currently adopted and outcomes for patients with this condition are improving, but mortality remains unacceptably high. Herein, we review practical considerations in critical care management, as well as discussing key knowledge gaps and areas of controversy that require further focussed research.

Assessment and management of coagulopathy in critically-ill patients with liver failure.

PURPOSE OF REVIEW: This review provides insight into our current understanding of the pathophysiology and treatment of coagulopathy associated with liver failure, and bleeding risk assessment. RECENT FINDINGS: Patients with end-stage liver disease (ESLD) have a rebalanced coagulation profile and are at risk for both excessive clotting and bleeding. Hypercoagulability is associated with profound endothelial dysfunction and an increased concentration of liver-independent coagulation factors. Because of this rebalanced coagulation profile, standard laboratory tests have been demonstrated to be ineffective in either predicting and/or guiding the management of coagulopathy. Viscoelastic testing, however, is able to provide a dynamic assessment of clot formation in whole blood and has been demonstrated to be invaluable in both monitoring and management of coagulation problems associated with liver failure. More recently, there is increasing interest in thrombin generation tests to monitor coagulation in patients with ESLD.Multiple institutional protocols for prophylaxis and treatment of ESLD-related thromboses have been developed. High-quality studies evaluating these approaches are lacking. SUMMARY: Patients with ESLD are at risk for excessive bleeding and clotting. Treatment of any significant coagulopathy should not be based solely on standard laboratory tests. Thrombosis prophylaxis has to be considered in susceptible populations.

Safety of coagulation factor concentrates guided by ROTEM™-analyses in liver transplantation: results from 372 procedures.

BACKGROUND: Most centres use fresh frozen plasma (FFP) based protocols to prevent or treat haemostatic disturbances during liver transplantation. In the present study, we used a rotational thrombelastometry (ROTEM™, TEM, Munich, Germany) guided haemostasis management with fibrinogen concentrates, prothrombin complex concentrates (PCC), platelet concentrates and tranexamic acid without FFP usage and determined the effect on 30 day mortality. METHODS: Retrospective data analysis with 372 consecutive adult liver transplant patients performed between 2007 and 2011. RESULTS: Thrombelastometry guided coagulation management resulted in a transfusion rate for fibrinogen concentrates in 50.2%, PCC in 18.8%, platelet concentrates in 21.2%, tranexamic acid in 4.5%, and red blood cell concentrates in 59.4%. 30 day mortality for the whole cohort was 14.2%. The univariate analyses indicated that nonsurvivors received significantly more fibrinogen concentrates, PCC, red blood cell concentrates, platelet concentrates, and infusion volume, and had a higher MELD score. However, association with mortality was weak as evidenced by receiver operating characteristic curve analyses. Further univariate analyses demonstrated, that up to 8 g of fibrinogen did not increase mortality compared to patients not receiving the coagulation factor. Multivariate analysis demonstrated that platelet concentrates (p = 0.0002, OR 1.87 per unit), infused volume (p = 0.0004, OR = 1.13 per litre), and MELD score (p = 0.024; OR 1.039) are independent predictors for mortality. Fibrinogen concentrates, PCC, and red blood cell concentrates were ruled out as independent risk factors. CONCLUSIONS: ROTEM™ guided substitution with fibrinogen concentrates and PCC does not negatively affect mortality after liver transplantation, while the well-known deleterious effect associated with platelet concentrates was confirmed.

Perioperative thrombotic complications associated with pediatric liver transplantation: a UNOS database evaluation.

BACKGROUND: This retrospective UNOS database evaluation analyzes the prevalence of preoperative portal vein thromboses (PVT), and postoperative thromboses leading to graft failure in pediatric patients undergoing liver transplantation (LT). METHODS: The evaluation was performed in three age groups: I (0-5), II (6-11), III (12-18) years old. Factors predictive of pre- and postoperative thromboses were analyzed. RESULTS: Between 2000 and 2015, 8982 pediatric LT were performed in the US. Of those, 390 patients had preoperative PVT (4.3%), and 396 (4.4%) had postoperative thromboses. The prevalence of both types of thromboses was less in Group III than in the other two groups (3.20% vs 4.65%, p = 0.007 and 1.73% vs. 5.13%, p < 0.001, respectively). The prevalence of postoperative thromboses was significantly higher in Group I than in the other two groups (5.49% vs. 2.51%, p < 0.001). Preoperative PVT was independently associated with postoperative thromboses (OR = 1.7, p = 0.02). Children less than 5 years of age were more likely to develop postoperative thromboses leading to graft failure (OR = 2.9, p < 0.001). CONCLUSION: Younger children undergoing LT are prone to pre-and postoperative thrombotic complications. Preoperative PVT at the time of transplantation was independently associated with postoperative thromboses. Perioperative antithrombotic therapy should be considered in pediatric patients undergoing LT.

Donor Leucocytosis Predicts Bacterial and Fungal Contamination of the Preservation Solution in Visceral Organ Transplantation.

INTRODUCTION: Contamination of the preservation solution may contribute to septic complications that can occur after transplantation and cause higher morbidity and mortality among recipients. The aim of this study was to determine potential donor-related predictors of positive microbiological findings in the preservation solution. DESIGN: We retrospectively studied 16 donor parameters on data from our center for microbiological findings in the preservation solution used in solid-organ recovery. From January 2008 through December 2011, 976 solid organs were transplanted, and in 167, the solution was positive for contaminants. RESULTS: The most frequently detected contaminant was coagulase-negative staphylococci. Only the donor leucocyte count (cutoff at 9.1 × 109/L) predicted positive microbiological findings in the preservation solution ( P = .0024). Multivariable regression analysis found that donor age, donor sex, intensive care unit stay, total number of organs recovered, and leucocyte count differentiated various categories of potentially pathogenic bacteria. CONCLUSION: Donor leucocyte count higher than 9.1 × 109/L predicts contamination of preservation solution.

Rotational thromboelastometry can detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis.

BACKGROUND & AIMS: Patients with progressive liver disease exhibit complex coagulation disorders. Factor XIII plays a crucial role in the last steps of haemostasis, and its deficiency is associated with an increased incidence of bleeding diathesis. However, current conventional coagulation tests cannot detect factor XIII deficiency. In this study, we examined factor XIII activity and the ability of rotational thromboelastometry to detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis. METHODS: We retrospectively studied 74 patients with cirrhosis, comparing the results of conventional coagulation tests (international normalized ratio, activated partial thromboplastin time, platelet count, fibrinogen level), rotational thromboelastometry, factor XIII activity and clinical scores. RESULTS: Patients with cirrhosis exhibited reduced factor XIII activity. Factor XIII activity was positively correlated with conventional coagulation parameters and rotational thromboelastometry values, such as maximum clot formation (MCF)extem (r=.48, P<.0001) and MCFfibtem (r=.60, P<.0001). However, maximum lysis (ML)extem and MLaptem were not correlated with factor XIII activity. Three-month mortality rates (P=.0469) and bleeding complications (P<.0001) were significantly associated with lower factor XIII activity. Patients with haemorrhage exhibited significantly altered rotational thromboelastometry values. CONCLUSIONS: Reduced levels of MCFextem and MCFfibtem but not high levels of MLextem and MLaptem are associated with factor XIII deficiency in patients with liver disease. Therefore, substituting factor XIII should be considered for such patients to strengthen clot formation in patients experiencing haemorrhage or those who have undergone interventions.

Low transferrin and high ferritin concentrations are associated with worse outcome in acute liver failure.

BACKGROUND & AIMS: Serum ferritin and transferrin have been identified as prognostic markers in patients with chronic diseases. In this study, we investigated if these parameters can predict outcome in patients with acute liver failure. METHODS: A total of 102 consecutive patients with acute liver failure were retrospectively analysed. The patients were grouped by outcome: spontaneous recovery vs liver transplantation and/or death or survival vs death. Routine laboratory parameters, transferrin and ferritin concentrations in serum, and anthropomorphic data collected on admission were analysed. RESULTS: Non-spontaneously recovering patients had higher ferritin (12 252±25 791 vs 4434.4±9027.2 µg/L; P<.05) and lower transferrin levels (140.4±66.7 vs 206.9±65.8 mg/dL; P<.05) than spontaneously recovering patients. Similarly non-survivors exhibited higher serum ferritin and lower transferrin than non-transplanted survivors. Patients with severe hepatic inflammation (A3) had higher ferritin levels compared to patients with mild-moderate inflammation (A1-2) (5280±5094 vs 2361±2737 µg/L; P=.025). ROC analysis of single parameters was performed in non-transplanted patients, resulting in an area under the curve, sensitivity and specificity of 0.812%, 83.3%, and 77.1% for age, 0.871%, 84.1% and 75% for transferrin and 0.802%, 91.7% and 62.9% for ferritin. A model incorporating age, MELD and transferrin had the best predictive value with an area under the curve of 0.947, a sensitivity of 100% and corresponding specificity of 77.8%. CONCLUSIONS: High ferritin and low transferrin levels are associated with worse outcome in patients with acute liver failure. A model incorporating age, MELD score and transferrin outperformed MELD score for 90-day overall survival of non-transplanted patients.

Hepatic artery and biliary complications in liver transplant recipients with radioembolization bridging treatment for hepatocellular carcinoma.

BACKGROUND: Locoregional bridging treatments are commonly applied in patients with hepatocellular carcinoma (HCC) prior to liver transplantation to prevent tumor progression during waiting time. It remains unknown whether pre-transplant radioembolization treatment may increase the prevalence of hepatic artery and biliary complications post-transplant. METHODS: We performed a retrospective review of 173 consecutive patients with HCC who underwent liver transplantation at our transplant center between January 2007 and December 2016. RESULTS: Radioembolization bridging treatment was applied in 42 patients while 131 patients received other or no forms of bridging treatment. The overall prevalence of intra-operative and early post-operative hepatic artery complications was 9.5% in the radioembolization group and 9.2% in the control group (P = 1.000). Biliary complications were significantly less frequent in the radioembolization group (4.8% vs 17.6%, P = .0442). In multivariable analysis, radioembolization was not significantly associated with an increased risk of arterial complications. Considering biliary complications, radioembolization bridging treatment was the only factor significantly associated with decreased odds (OR 0.187 (0.039, 0.892), P = .036). CONCLUSIONS: Radioembolization is not associated with higher odds of hepatic artery complications following liver transplantation. There may even be a protective effect regarding biliary complications. Radioembolization as a bridge to transplantation may effectively be applied without compromising successful liver transplantation.

Citrate shows protective effects on cardiovascular and renal function in ischemia-induced acute kidney injury.

BACKGROUND: Ischemia and reperfusion (I/R) is one of the major causes of acute kidney injury (AKI). Citrate reduces hypoxia-induced mitochondrial energetic deficits in isolated proximal tubules. Moreover, citrate anticoagulation is now frequently used in renal replacement therapy. In the present study a rat model of I/R-induced AKI was utilized to examine renal protection by citrate in vivo. METHODS: AKI was induced by bilateral renal clamping (40 min) followed by reperfusion (3 h). Citrate was infused at three different concentrations (0.3 mmol/kg/h; 0.6 mmol/kg/h and 1.0 mmol/kg/h) continuously for 60 min before and 45 min after ischemia. Plasma calcium concentrations were kept stable by infusion of calcium gluconate. The effect of citrate was evaluated by biomonitoring, blood and plasma parameters, histopathology and tissue ATP content. RESULTS: In comparison to the normoxic control group bilateral renal ischemia led to an increase of creatinine and lactate dehydrogenase activity and a decrease in tissue ATP content and was accompanied by a drop in mean arterial blood pressure. Infusion of 1.0 mmol/kg/h citrate led to lower creatinine and reduced LDH activity compared to the I/R control group and a tendency for higher tissue ATP content. Pre-ischemic infusion of 1.0 mmol/kg/h citrate stabilized blood pressure during ischemia. CONCLUSIONS: Citrate has a protective effect during I/R-induced AKI, possibly by limiting the mitochondrial deficit as well as by beneficial cardiovascular effects. This strengthens the rationale of using citrate in continuous renal replacement therapy and encourages consideration of citrate infusion as a therapeutic treatment for AKI in humans.

Single-Center Experience on Liver Transplantation for Model for End-Stage Liver Disease Score 40 Patients.

BACKGROUND: Organ shortage and waiting list mortality have led to changes in the allocation policy in Eurotransplant. AIM: To identify factors influencing the survival of liver transplanted patients with model for end-stage liver disease (MELD) score of 40. PATIENTS AND METHODS: Data of listed adult patients who reached a MELD score 40 in the period 12/2006-06/2010 were reviewed. Donor/graft and recipient characteristics, and operative details were analyzed. Statistical analysis encompassed Kaplan-Meier analysis/log-rank test as well as univariate and multivariable regression analyses. RESULTS: Forty-eight patients achieved a MELD score 40. Thirty patients were transplanted, whereas 18 patients were not. Three-month, 1-year, and 5-year patient and graft survival for transplanted patients was 53, 50, and 47 %, respectively. Three-month and 1-year survival after listing was 11 and 6 % for not transplanted patients, respectively (p < 0.0001). Multivariable analysis revealed pre-operative dialysis (p = 0.0246) and portal vein thrombosis (PVT) (p = 0.0231) to be independent prognostic factors for post-transplant patient survival. A point scoring system was created, which reached statistical significance (p = 0.0007). One-year and 5-year survival for scores 0, 1, and 2 were 72 and 64, 42 and 42 and 0 %, respectively. There was no statistical difference in transplantation costs between patients who survived or died (p = 0.1578). CONCLUSIONS: At our center, coexistence of pre-operative dialysis and PVT represents a clear contraindication for LT regarding MELD score 40 patients.

Donor information based prediction of early allograft dysfunction and outcome in liver transplantation.

BACKGROUND & AIMS: Poor initial graft function was recently newly defined as early allograft dysfunction (EAD) [Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943]. Aim of this analysis was to evaluate predictive donor information for development of EAD. METHODS: Six hundred and seventy-eight consecutive adult patients (mean age 51.6 years; 60.3% men) who received a primary liver transplantation (LT) (09/2003-12/2011) were included. Standard donor data were correlated with EAD and outcome by univariable/multivariable logistic regression and Cox proportional hazards to identify prognostic donor factors after adjustment for recipient confounders. Estimates of relevant factors were utilized for construction of a new continuous risk index to develop EAD. RESULTS: 38.7% patients developed EAD. 30-day survival of grafts with and without EAD was 59.8% and 89.7% (P < 0.0001). 30-day survival of patients with and without EAD was 68.5% and 93.1% (P < 0.0001) respectively. Donor body mass index (P = 0.0112), gGT (P = 0.0471), macrosteatosis (P = 0.0006) and cold ischaemia time (CIT) (P = 0.0031) were predictors of EAD. Internal cross validation showed a high predictive value (c-index = 0.622). CONCLUSIONS: Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT.

Prophylactic plasma and platelet transfusion in the critically Ill patient: just useless and expensive or even harmful?

It is still common practice to correct abnormal standard laboratory test results, such as increased INR or low platelet count, prior to invasive interventions, such as tracheostomy, central venous catheter insertion or liver biopsy, in critically ill patients. Data suggest that 30-90 % of plasma transfused for these indications is unnecessary and puts the patient at risk. Plasma transfusion is associated with a high risk of transfusion-associated adverse events such as transfusion-associated circulatory overload (TACO), transfusion-related lung injury (TRALI), transfusion-related immunomodulation (TRIM), and anaphylaxis/allergic reactions. Therefore, the avoidance of inappropriate plasma transfusion bears a high potential of improving patient outcomes. The prospective study by Durila et al., published recently in BMC Anesthesiology, provides evidence that tracheostomies can be performed without prophylactic plasma transfusion and bleeding complications in critically ill patients despite increased INR in case of normal thromboelastometry (ROTEM) results. Thromboelastometry-based restrictive transfusion management helped avoid unnecessary plasma and platelet transfusion, and should reduce the incidence of transfusion-related adverse events and transfusion-associated hospital costs. Therefore, the authors believe that thromboelastometry-based strategies should be implemented to optimize patient blood management in perioperative medicine.

Coagulation management with factor concentrates in liver transplantation: a single-center experience.

BACKGROUND: Allogeneic blood products transfusion during liver transplantation (LT) can be associated with increased morbidity and mortality. Data on thromboelastometry (ROTEM)-guided coagulation management with coagulation factor concentrates (CFCs)-fibrinogen concentrate and/or prothrombin complex concentrate (PCC)-are sparse. We aimed to retrospectively evaluate the safety events observed with this approach in our clinic. STUDY DESIGN AND METHODS: LT patients from January 2009 to December 2010 (n = 266) were identified by chart review. A ROTEM-based algorithm with CFC guided the hemostatic therapy. Doppler ultrasound was used to evaluate thrombosis in the hepatic artery, portal vein, and hepatic veins. Stroke, myocardial ischemia, pulmonary embolism, and transfusion variables were recorded. Patients receiving CFC were included in the CFC group (n = 156); those not receiving CFC were included in the non-CFC group (n = 110). Safety events were compared between these two groups. RESULTS: Allogeneic transfusion(s) in the 266 patients was low, with medians of 2 (interquartile range [IQR], 0-5), 0 (IQR 0-0), and 0 (IQR 0-1) units for red blood cells (RBCs), fresh-frozen plasma (FFP), and platelets (PLTs), respectively. Ninety-seven of 266 LTs (36.5%) were performed without RBCs transfusion, 227 (85.3%) without FFP, and 190 (71.4%) without PLTs. There were no significant differences in thrombotic, thromboembolic, and ischemic adverse events occurrence between the CFC group and the non-CFC group (11/156 patients vs. 5/110; p = 0.31). CONCLUSION: In LT, ROTEM-guided treatment with fibrinogen concentrate and/or PCC did not appear to increase the occurrence of thrombosis and ischemic events compared to patients who did not receive these concentrates.

Liver transplantation for acute liver failure: are there thresholds not to be crossed?

Factors predicting survival after liver transplantation (LT) for irreversible acute liver failure (ALF) are rare. The aim of this study was to identify prognostic preoperative factors of patients with ALF that predict mortality after LT to avoid futile transplantation. From chart review, we identified 57 patients receiving transplants for ALF from 12/2000 to 09/2010. Recipient and donor data were analyzed and correlated with in-hospital mortality and patient survival by univariable/multivariable logistic regression and Cox proportional hazards. The survival rates at 30 days and 12 months were 77.2% and 64.9%, respectively. The in-hospital mortality rate was 29.8%. Follow-up of patients discharged from the hospital alive showed 30-day and 12-month survivals of 100% and 92.5%, respectively. Multivariable analysis of factors known preoperatively showed that the lowest pH of the recipient before LT (P = 0.03) was independently associated with in-hospital mortality, and the recipient's BMI (P = 0.03) and the lowest pH before LT (P = 0.03) were independently associated with patient survival. A pH of 7.26 was the calculated cutoff (ROC) for increased in-hospital mortality. Donor factors did not affect patient survival. Patients with ALF and a pH ≤ 7.26 have the worst outcome after liver transplantation. Therefore, emergency liver transplantation should be critically discussed for each individual.

MELD at POD 1 as a predictor of outcome in liver allografts with peak AST >5000 U/l.

Perioperative liver graft injury is associated with elevation of aminotransferases after orthotopic liver transplantation (OLT). Values above 5000 U/l usually are regarded as extreme liver graft injury (ELGI). Some patients and organs recover from this critical condition. The aim of the study was to evaluate factors contributing to graft and patient survival after ELGI. From chart review we identified 64 of 917 OLT adult patients (median age 54.2 years; 68.8% males) transplanted between 11/2003 and 02/2012, who presented ELGI after OLT. Donor and recipient factors were analyzed and correlated with the outcome by univariable and multivariable methods. Multivariable cox proportional hazards showed that recipient's BMI (P = 0.01), model for end stage liver disease (MELD) score before OLT (P = 0.02) and laboratory MELD score 24 h after OLT (P = 0.01) were independently associated with patient survival. 30-days and 12-months survival in patients with a postoperative laboratory MELD higher than 31 was 21.4%, while patients with a postoperative laboratory MELD lower than 31 displayed 30-days and 12-months survival rates of 80% and 71.8%, respectively (P < 0.001). Retransplantation in the setting of ELGI after OLT should be based on all available data. Utilization of the postoperative labMELD enables the transplant physician within 24 h after transplantation to identify necessity of retransplantation objectively.