Nick Murphy

Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation

Objective To determine the relative contribution of the gastrointestinal tract and the liver in lactate metabolism in patients with acute liver failure (ALF) and the effect of liver transplantation on this. We hypothesized that the liver and gut are net producers of lactate in ALF and that this is reversed after liver transplantation. Setting A university-affiliated specialist liver transplant operating theater. Subjects Eleven patients with ALF undergoing liver transplantation. Measurements and Interventions After ethical approval, 11 patients with ALF listed for orthotopic hepatic transplantation were studied. Whole blood was analyzed for lactate concentration from radial artery (RA) catheter, portal vein (PV), and hepatic vein (HV) during the dissection phase and was repeated postreperfusion of the liver graft. Gradients across the gut and the liver were calculated to see if there was net production or consumption. Results HV lactate was significantly higher than arterial (p = .028) in patients with ALF before liver transplantation, suggesting splanchnic production of lactate. Total splanchnic lactate gradient (HV-RA) is positive in ALF. Both the gut (PV-RA) and the liver (HV-PV) were net producers of lactate. After liver transplantation, hepatic venous lactate falls below arterial levels but not significantly. The gradient across the gut (PV-RA) remained positive, but the transhepatic gradient (HV-PV) became significantly negative, showing consumption by the graft (p = .021). The magnitude of lactate consumption after transplantation correlated positively with portal venous lactate concentration (p = .029) and inversely with graft cold ischemic time (p = .007). Conclusion The liver is a net producer of lactate in patients with ALF and an elevated whole blood lactate. After liver transplantation, the graft becomes a consumer of lactate as shown by the negative lactate gradient. The degree of consumption is dependent on portal venous lactate concentration and cold ischemic time.

A multicentre randomized controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure

BACKGROUND & AIMS Animal models and human case series of acute liver failure (ALF) suggest moderate hypothermia (MH) to have protective effects against cerebral oedema (CO) development and intracranial hypertension (ICH). However, the optimum temperature for patient management is unknown. In a prospective randomized controlled trial we investigated if maintenance of MH prevented development of ICH in ALF patients at high risk of the complication. METHODS Patients with ALF, high-grade encephalopathy and intracranial pressure (ICP) monitoring in specialist intensive care units were randomized by sealed envelope to targeted temperature management (TTM) groups of 34°C (MH) or 36°C (control) for a period of 72h. Investigators were not blinded to group assignment. The primary outcome was a sustained elevation in ICP >25mmHg, with secondary outcomes the occurrence of predefined serious adverse effects, magnitude of ICP elevations and cerebral and all-cause hospital mortality (with or without transplantation). RESULTS Forty-six patients were randomized, of whom forty-three were studied. There was no significant difference between the TTM groups in the primary outcome during the study period (35% vs. 27%, p=0.56), for the MH (n=17) or control (n=26) groups respectively, relative risk 1.31 (95% CI 0.53-3.2). Groups had similar incidence of adverse events and overall mortality (41% vs. 46%, p=0.75). CONCLUSIONS In patients with ALF at high risk of ICH, MH at 33-34°C did not confer a benefit above management at 36°C in prevention of ICH or in overall survival. This study did not confirm advantage of its prophylactic use. (ISRCTN registration number 74268282; no funding.) LAY SUMMARY Studies in animals with acute liver failure (ALF) have suggested that cooling (hypothermia) could prevent or limit the development of brain swelling, a dangerous complication of the condition. There is limited data on its effects in humans. In a randomized controlled trial in severely ill patients with ALF we compared the effects of different temperatures and found no benefit on improving survival or preventing brain swelling by controlling temperature at 33-34°C against 36°C.

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER RANDOMIZED, CONTROLLED TRIAL

56 THE PROPHYLACTIVE EFFECT OF MILD HYPOTHERMIA TO PREVENT BRAIN EDEMA IN PATIENTS WITH ACUTE LIVER FAILURE: RESULTS OF A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL F.S. Larsen, N. Murphy, W. Bernal, P.N. Bjerring, J. Hauerberg, J. Wendon, EUROALF Group. Hepatology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Intensive Care, Queen Elizabeth Hospital, Birmingham, Institute of Liver Studies, London, UK; Neurosurgy, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark; Institute of Liver Studies, Kings College Hospital, London, UK E-mail: stolze@post3.tele.dk

The regulation of T-cell recruitment to the human liver during acute liver failure.

Acute liver failure (ALF) is a rare clinical syndrome with high mortality resulting from hepatocellular necrosis and loss of function. In seronegative hepatitis (SNH), a T‐cell‐rich infiltrate leads to immune‐mediated hepatocyte destruction, whereas in paracetamol poisoning, toxic metabolites induce hepatocyte necrosis, followed by a macrophage‐rich, lymphocytic infiltrate that is an important factor in driving repair and regeneration. The nature of the hepatic inflammatory infiltrate, key to ALF pathogenesis and outcome, is determined by the recruitment of effector cells from blood, but the molecular basis of recruitment is poorly understood. To determine the phenotype of circulating and hepatic lymphocytes in patients with ALF secondary to paracetamol overdose (POD) or SNH and investigate the molecular basis of lymphocyte recruitment.

Comparison of energy metabolism in liver grafts from donors after circulatory death and donors after brain death during cold storage and reperfusion

Donation after circulatory death (DCD) liver grafts have supplemented the donor organ pool, but certain adverse outcomes have prevented exploration of the full potential of such organs. The aim of this study was to determine key differences in basic energy metabolism between DCD and donation after brainstem death (DBD) grafts.

Use of bioelectrical impedance analysis to assess liver steatosis

BACKGROUND The shortage of donor livers has led to increased utilization of steatotic marginal livers. Bioelectrical impedance analysis (BIA) uses the principles of electric current flows through tissue, with less resistance offered if the water content is high and the opposite in the presence of fat. Our hypothesis was that liver steatosis would result in an increased resistance to current flow, and correlate with the degree of liver steatosis. METHODS Before studying cadaveric donor livers for transplantation, this study was performed in patients undergoing liver resection. A total of 37 patients undergoing liver resection for cancer were analysed with BIA, using a handheld, specially calibrated Maltron BIA analyser (BioScan 915) with modified tertrapolar electrodes. These electrodes were applied to the liver surface and resistance was recorded. To validate the results of BIA, a liver biopsy was performed. Histopathology was graded quantitatively as no steatosis, mild, moderate, or severe steatosis according the percentage of fat as well as qualitatively by type of fat (micro and macrovesicular). RESULTS Bioelectric resistance showed a correlation with macroveiscular steatosis (P = .03). CONCLUSION BIA is a simple, noninvasive technique and its use should be explored in donor livers to assess steatosis.

Multiorgan failure is the commonest cause of death in fulminant hepatic failure: a single centre experience

To the editor: The incidence of cerebral oedema as a complication of fulminant liver failure (FHF) has been reported to be as high as 80% (1). Recently, there has been a significant improvement in the supportive treatment of FHF and an observed fall in the incidence of cerebral oedema (61% in 1987 to 45% in 1993) (2). In this retrospective analysis of trends in mortality from FHF, we aimed to determine the extent of cerebral oedema as the primary cause of death in FHF during 6 years of follow-up in a single centre. The Queen Elizabeth Hospital Birmingham serves a large area of England and Wales. Transfer of FHF patients to the Liver Unit is based on local guidelines. Between 1/1/1996 and 31/12/ 2001, 503 FHF patients were admitted, 118 died (62 males; median age: 44 years, range: 19–73; liver transplant recipients: 24) and were included in this study. All 118 had grade III/IV hepatic encephalopathy, were electively ventilated and admitted to ITU. Treatment for prevention of raised intracranial pressure (ICP) included the routine insertion of ICP bolts in all patients at risk of cerebral oedema (29 patients (25%)). Data were collected from medical notes, the Liver Unit database and autopsy reports (33 patients). A broad definition of death associated with cerebral oedema was used, this included patients who had: (i) subdural bolts recording intracranial hypertension (ICH), (ii) subdural bolts and intermittent ICH without another cause of death, (iii) autopsy evidence of cerebral oedema/ICH, (iv) clinical signs of ICH, (v) a hyperacute presentation without sepsis, pneumonia, adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC) or gastrointestinal haemorrhage. Multiorgan failure (MOF) was considered the cause of death if three of the following were present: (i) renal failure requiring continuous veno-venous haemofiltration (CVVH), (ii) sepsis with positive blood culture(s), (iii) respiratory failure secondary to pneumonia/ARDS, (iv) persistent DIC despite treatment in the context of systemic sepsis. The most common cause of FHF was paracetomol overdose (POD) (n5 57; 48.3%) followed by non-A–non-B hepatitis (n5 37; 31.3%). MOF was the cause of death in 80 (67.7%) and cerebral oedema in 29 (24.5%). Of these, 14 had an ICP bolt showing ICH, and 13 had autopsy findings consistent with ICH. Figure 1 shows the causes of death for each aetiology of FHF. POD patients were significantly more likely to die of MOF (n5 33; 57.9%) than cerebral oedema (n5 20; 35.1%; Po0.05) as were nonA–non-B hepatitis patients (n5 28; 75.6% vs. n5 4; 10.8%). This study demonstrates that MOF is the most common cause of death in FHF and that this is independent of the aetiology of FHF. The overall incidence of cerebral oedema continues to fall and there are several possible explanations. Firstly, a change in guidelines has led to earlier referral and earlier treatment with N-acetyl-cysteine (NAC). Indeed, even late administration of NAC in paracetomol-induced FHF, improves outcome (3–5) and decreases the incidence of cerebral oedema (4). Secondly, the supportive medical management of FHF has also improved, guided by local protocols. Finally, current transplant criteria encourage early listing of patients with FHF, before they are at risk of developing cerebral oedema. In conclusion, this study both reiterates the prominence of MOF as a cause of death in FHF and the falling incidence of death from cerebral oedema. Our findings emphasise the importance Liver International 2004: 24: 702–703 Printed in Denmark. All rights reserved Copyright r Blackwell Munksgaard 2004

Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure: a cohort study

BACKGROUND Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death. METHODS Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK (London, Birmingham, and Edinburgh) and Denmark (Copenhagen) were studied. We developed prognostic models, excluding patients who underwent transplantation, using Cox proportional hazards in a derivation dataset, and tested in initial and recent external validation datasets. Mortality was estimated in patients who had emergency liver transplantation. Model discrimination was assessed using area under receiver operating characteristic curve (AUROC) and calibration by root mean square error (RMSE). Admission (day 1) variables of age, Glasgow coma scale, arterial pH and lactate, creatinine, international normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate. FINDINGS We developed and validated new high-performance statistical models to support decision making in patients with paracetamol-induced acute liver failure. Applied to the derivation dataset (n=350), the AUROC for 30-day survival was 0·92 (95% CI 0·88-0·96) using the day 1 model and 0·93 (0·88-0·97) using the day 2 model. In the initial validation dataset (n=150), the AUROC for 30-day survival was 0·89 (0·84-0·95) using the day 1 model and 0·90 (0·85-0·95) using the day 2 model. Assessment of calibration using RMSE in prediction of 30-day survival gave values of 0·1642 for the day 1 model and 0·0626 for the day 2 model. In the external validation dataset (n=412), the AUROC for 30-day survival was 0·91 (0·87-0·94) using the day 1 model and 0·91 (0·88-0·95) using the day 2 model, and assessment of calibration using RMSE gave values of 0·079 for the day 1 model and 0·107 for the day 2 model. Applied to patients who underwent emergency liver transplantation (n=116), median predicted 30-day survival was 51% (95% CI 33-85). INTERPRETATION The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation in paracetamol-induced acute liver failure require re-evaluation. FUNDING Foundation for Liver Research.

Biomarker differences between cadaveric grafts used in human orthotopic liver transplantation as identified by coulometric electrochemical array detection (CEAD) metabolomics.

Metabolomics in systems biology research unravels intracellular metabolic changes by high throughput methods, but such studies focusing on liver transplantation (LT) are limited. Microdialysate samples of liver grafts from donors after circulatory death (DCD; n=13) and brain death (DBD; n=27) during cold storage and post-reperfusion phase were analyzed through coulometric electrochemical array detection (CEAD) for identification of key metabolomics changes. Metabolite peak differences between the graft types at cold phase, post-reperfusion trends, and in failed allografts, were identified against reference chromatograms. In the cold phase, xanthine, uric acid, and kynurenine were overexpressed in DCD by 3-fold, and 3-nitrotyrosine (3-NT) and 4-hydroxy-3-methoxymandelic acid (HMMA) in DBD by 2-fold (p<0.05). In both grafts, homovanillic acid and methionine increased by 20%-30% with each 100 min increase in cold ischemia time (p<0.05). Uric acid expression was significantly different in DCD post-reperfusion. Failed allografts had overexpression of reduced glutathione and kynurenine (cold phase) and xanthine (post-reperfusion) (p<0.05). This differential expression of metabolites between graft types is a novel finding, meanwhile identification of overexpression of kynurenine in DCD grafts and in failed allografts is unique. Further studies should examine kynurenine as a potential biomarker predicting graft function, its causation, and actions on subsequent clinical outcomes.