Dmitri Bezinover

Liver Transplantation for Hepatitis C From Donation After Cardiac Death Donors: An Analysis of OPTN/UNOS Data

Donation after cardiac death (DCD) liver transplantation is increasing largely because of a shortage of organs. However, there are almost no data that have specifically assessed the impact of using DCD livers for HCV patients. We retrospectively studied adult primary DCD liver transplantation (630 HCV, 1164 non‐HCV) and 54 129 donation after brain death (DBD) liver transplantation between 2002 and 2009 using the UNOS/OPTN database. With donation after brain death (DBD) livers, HCV recipients had significantly inferior graft survival compared to non‐HCV recipients (p < 0.0001). Contrary to DBD donors, DCD livers used in HCV patients showed no difference in graft survival compared to non‐HCV patients (p = 0.5170). Cox models showed DCD livers and HCV disease had poorer graft survival (HR = 1.80 and 1.28, p < 0.0001, respectively). However, the hazard ratio of DCD and HCV interaction was 0.80 (p = 0.02) and these results suggest that DCD livers on HCV disease do not fare worse than DCD livers on non‐HCV disease. The graft survival of recent years (2006–2009) was significantly better than that in former years (2002–2005) (p = 0.0482). In conclusion, DCD liver transplantation for HCV disease showed satisfactory outcomes. DCD liver transplantation can be valuable option for HCV related end‐stage liver disease.

Release of cytokines and hemodynamic instability during the reperfusion of a liver graft

The objectives of this prospective, observational study were (1) to determine whether a transplanted liver graft releases proinflammatory cytokines into the systemic circulation upon reperfusion and (2) to determine whether they contribute to any subsequent hemodynamic instability observed after graft reperfusion (if this release occurs). Blood samples from 17 consecutive patients undergoing liver transplantation were analyzed for cytokines, including tumor necrosis factor α (TNF‐α), interleukin‐1β (IL‐1β), IL‐2, IL‐6, and IL‐8. Blood samples were obtained from the radial artery, portal vein, and flush blood (a sample taken from a catheter placed above the infrahepatic inferior vena cava clamp). The amount of catecholamines necessary to maintain a mean arterial pressure between 65 and 75 mm Hg during graft reperfusion was compared with the level of cytokines. A statistical analysis was performed with the least squares method, Kendalls tau‐b test, and regression analysis. We demonstrated that flush blood from the liver grafts contained a significant amount and variety of cytokines. Most of these were removed by graft irrigation. The concentration of TNF‐α in samples obtained from flush blood at the end of liver irrigation was significantly higher than the concentration in samples obtained from the radial artery (P = 0.0067) or portal vein (P = 0.0003) before reperfusion. This correlated directly with the amount of catecholamines used to treat hemodynamic instability. Although there were increased levels of IL‐1β, IL‐2, and IL‐8 in the flush blood, there was no statistically significant correlation between the levels of these cytokines and the amount of catecholamines used. Liver Transpl, 2011.

Perioperative Use of Continuous Renal Replacement Therapy for Orthotopic Liver Transplantation

PURPOSE We present a retrospective study describing the perioperative use of continuous renal replacement therapy (CRRT) for orthotopic liver transplantation (OLT). MATERIALS AND METHODS We retrospectively reviewed the clinical course of patients who underwent OLT with the perioperative use of CRRT. The following variables were recorded: Gender, age, indication for transplantation, time when CRRT was initiated, postoperative need for CRRT, and the patient and organ (liver, kidneys) outcome up to 1 year after transplantation. RESULTS Among 105 patients who underwent OLT from 2006 to 2010; we used CRRT in 12 cases (11.4%) perioperatively, including 9 (8.3%) patients intraoperatively. Perioperative CRRT was employed for volume, electrolyte, and/or pH management. All patients who underwent CRRT perioperatively were alive at 1 month, 10 (83.3%), at 3 and 6 months and 9 (75%) at 1 year after OLT. Only 1 surviving patient (8.3%) required renal replacement therapy at 1 month after surgery. Renal replacement therapy was not required in any surviving patient up to 12 months posttransplantation. CONCLUSION Perioperative and especially intraoperative use of CRRT therapy can potentially improve the outcomes of patients undergoing OLT.

Fatal hyperammonemia after renal transplant due to late-onset urea cycle deficiency: a case report.

We present a case of severe hyperammonemia with subsequent brain herniation in an adult man after renal transplantation. After successful surgery and an initially uneventful postoperative course, the patient developed significant mental status changes associated with seizure activity. His condition rapidly deteriorated, requiring mechanical ventilation and cardiovascular support. Laboratory studies at that time demonstrated an increased serum ammonia level without evidence of liver or kidney dysfunction. Further investigation revealed an increased orotic acid level in the urine, suggesting a urea cycle disorder (UCD). Despite aggressive therapy, the patients condition continued to deteriorate. Magnetic resonance imaging demonstrated severe brain edema with no cerebral perfusion; after consultation with the family, care was withdrawn. The combination of hyperammonemia and elevated urine orotic acid with normal liver and kidney function suggested a UCD. It is important to note that patients with a UCD may be free of symptoms for many years. Several factors are able to trigger the disease in adulthood, leading to encephalopathy and death. In this case, the patients seizures were initially assumed to be a side effect of immunosuppressive therapy. Further diagnostic measures were only performed late in the course of the disease, which delayed the diagnosis of UCD.

Perioperative exacerbation of valproic acid-associated hyperammonemia: a clinical and genetic analysis.

We present a case of significant deterioration of chronic hyperammonemia after general anesthesia for neurosurgery despite aggressive treatment. Preoperative evaluation demonstrated that hyperammonemia was most likely related to valproic acid treatment. Genomic analysis revealed that the patient was heterozygotic for a missense polymorphism in the carbamoyl phosphate synthase 1 gene (4217C>A, rs1047891). This mutation was previously suggested to be associated with chronic hyperammonemia. Replacement of threonine with asparagine decreases the activity of carbamoyl phosphate synthase in the urea cycle. Genetic screening can potentially identify a population at risk before initiation of antiepileptic therapy.

Use of a Third-Generation Perfluorocarbon for Preservation of Rat DCD Liver Grafts

BACKGROUND Cold storage in any of the commonly used preservation solutions is not always adequate for donation after cardiac death (DCD) liver grafts due to prolonged warm ischemic time. In this study, we used a third-generation perfluorocarbon (PFC), Oxycyte, for DCD liver graft preservation in a rat model. MATERIALS AND METHODS Twenty-eight rats (14 in each group) were used. Thirty minutes after cardiopulmonary arrest, livers were harvested and flushed with a cold and pre-oxygenated solution of either University of Wisconsin (UW) or UW + 20% PFC. After 8 h of cold preservation in either of the investigated solutions, liver graft specimens were analyzed for evidence of ischemic injury. Hemotoxylin and eosin staining (H and E), as well as immunohistochemical analysis with anti-cleaved caspase 3 antibody, was performed. Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the preservation solution were analyzed at 1 and 8 h during preservation. RESULTS In the PFC group, the degree of cell congestion, vacuolization and necrosis were all significantly less than in the UW group (P = 0.002-0.004). The number of cells with a positive cleaved caspase 3 antibody reaction was reduced by about 50% in comparison with the UW group (P < 0.006). The AST level in the PFC group was significantly less than in the UW group after 8 h of preservation (P < 0.048). CONCLUSION The addition of PFC to UW solution significantly decreases the degree of histologic damage in rat DCD liver grafts. This preservation strategy can be potentially helpful for organ preservation after prolonged warm ischemia.

Assessment of standard laboratory tests and rotational thromboelastometry for the prediction of postoperative bleeding in liver transplantation.

Background Perioperative bleeding remains a major challenge in liver transplantation. We aimed to compare standard laboratory tests with thromboelastometry (ROTEM ® ) with regard to their ability to predict postoperative non-surgical bleeding. Methods Data from 243 adult liver transplant recipients from January 2012 to May 2014 were evaluated retrospectively. Upon admission to the intensive care unit, coagulation status was assessed using standard laboratory tests [prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen concentration, and platelet count] and ROTEM ® whole blood coagulation assays. Bleeding was defined as transfusion of ≥ 3 units of red blood cells or reoperation for non-surgical bleeding within 48 h after transplantation. Coagulation test results were analysed using receiver operating characteristics (ROC) in order to identify variables predictive of postoperative bleeding. Coagulation management was based on ROTEM ® -guided factor concentrate treatment. Results The overall incidence of bleeding was 12.3% ( n =30). Twenty-three (9.5%) patients underwent reoperation and seven (2.9%) received ≥3 units of red blood cells and non-operative management. Standard laboratory tests predictive of postoperative bleeding were aPTT and PT [area under the ROC curve (AUC) 0.688 and 0.623, respectively]. Tests predictive of bleeding with ROTEM ® were CT EXTEM , CFT INTEM , A10 FIBTEM , and MCF FIBTEM , with AUCs of 0.682, 0.615, 0.615, and 0.611, respectively. Fibrinogen concentration, platelet count, and other ROTEM ® variables failed to demonstrate predictive value for postoperative bleeding (AUC <0.6). Dialysis-dependent kidney failure, 30 day mortality, and median model for endstage liver disease score were all significantly higher in bleeding patients. Conclusions Although both postoperative standard laboratory tests and ROTEM ® assays could identify patients at risk for postoperative bleeding, ROTEM ® assays demonstrated a greater predictive value for impaired fibrinogen polymerization-related coagulopathy.

Myocardial perfusion imaging is an effective screening test for coronary artery disease in liver transplant candidates

A reliable screening test for coronary artery disease (CAD) in liver transplant (LT) candidates with end‐stage liver disease is essential because a high percentage of perioperative mortality and morbidity is CAD‐related. In this study, the effectiveness of myocardial perfusion imaging (MPI) for identification of significant CAD in LT candidates was evaluated. Records of 244 patients meeting criteria for MPI were evaluated: 74 met inclusion criteria; 40 had a positive MPI and cardiology follow‐up; 27 had a negative MPI and underwent LT; and seven had a negative MPI and then had coronary angiography or a significant cardiac event. A selective MPI interpretation strategy was established where MPI‐positive patients were divided into high, intermediate, and low CAD risk groups. The overall incidence of CAD in this study population was 5.1% and our strategy resulted in PPV 20%, NPV 94%, sensitivity 80%, and specificity 50% for categorizing CAD risk. When applied only to the subset of patients categorized as high CAD risk, the strategy was more effective, with PPV 67%, NPV 97%, sensitivity 80%, and specificity 94%. We determined that renal dysfunction was an independent predictive factor for CAD (p < 0.0001, odds ratio = 8.1), and grades of coronary occlusion correlated significantly with chronic renal dysfunction (p = 0.0079).

Association Between Plasma Cyclic Guanosine Monophosphate Levels and Hemodynamic Instability During Liver Transplantation

The activation of cyclic guanosine monophosphate (cGMP) production in patients with end‐stage liver disease (ESLD) has been associated with hemodynamic instability during orthotopic liver transplantation (OLT). The aim of this prospective, observational study was to investigate the involvement of cGMP in the mediation of profound hypotension during liver graft reperfusion. An additional objective was to determine whether preoperative cGMP levels are associated with intraoperative hemodynamic instability. Forty‐four consecutive patients undergoing OLT were included in the study. Blood samples for cGMP analysis were obtained from (1) the radial artery before the surgical incision; (2) the radial artery, portal vein, and flush blood during the anhepatic phase; and (3) the radial artery 20 minutes after liver graft reperfusion. On the basis of a statistical analysis, the patients were divided into 2 groups: group 1 (preoperative cGMP level ≥ 0.05 μmol/L) and group 2 (preoperative cGMP level < 0.05 μmol/L). We demonstrated a significant correlation between the preoperative levels of cGMP and the amount of catecholamine required to maintain hemodynamic stability during reperfusion (r = 0.52, P < 0.001), the length of the hospital stay (r = 0.38, P = 0.01), and the length of the intensive care unit (ICU) stay (r = 0.44, P = 0.004). We also demonstrated a significantly higher intraoperative catecholamine requirement (P < 0.001) and a prolonged postoperative ICU stay (P = 0.02) in group 1 patients versus group 2 patients. In conclusion, this study demonstrates increased baseline cGMP production in patients with ESLD, which is significantly associated with severe hypotension during OLT. We suggest that preoperative levels of cGMP correlate with hemodynamic instability during liver graft reperfusion. Liver Transpl 19:191–198, 2013.

Analysis of acute pain scores and skin conductance measurements in infants

BACKGROUND Skin conductance (SC) has been previously used to measure acute post-operative pain in adults and older children (>1year old).We have investigated the ability of SC to predict the severity of post-operative pain scores in the exclusively infant population. METHODS Infants (ages 6-12months) scheduled for elective surgery were recruited for the study. Data for behavioral pain scores and SC values - frequency of electrodermal responses per second (EDR/s), peak and basal levels, were recorded in the post-anesthesia care unit (PACU). Blood samples were collected for genomic studies, including single nucleotide polymorphisms (SNP) in morphine opioid receptor (MOR) A118G and the catechol-O-methyltransferase (COMT) G1947A genes. RESULTS 31 infants, mean age 8.9months (±1.9); mean weight 8.5kg (±1.1) were included in the final study analysis. With every 0.1 unit increase in peak values noted on SC, the odds of higher pain scores were found to be 5% greater (p=0.03). For predictability of moderate to severe pain, the area under the curve, sensitivity and specificity were 0.64, 90.9% and 51.4% respectively for peak values and 0.66, 54.5% and 79.4% respectively for EDR/s values. Genotyping performed in 16 out of 31 infants demonstrated that the carriers of MOR 118G allele had consistently higher basal SC values in the PACU. CONCLUSION Peak SC values may serve as indicators of unmitigated pain. Further studies are needed to fully investigate the effect of MOR A118G SNP on the post operative pain scores and SC values in the larger infant population in order to validate both the clinical significance of the skin conductance for routine pain assessment in infants and the observed genetic effect.