Alistair Lee

Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure

Background. During orthotopic liver transplantation (OLT) for acute liver failure (ALF), some patients develop acute increases in intracranial pressure (ICP). The authors tested the hypothesis that increases in ICP during OLT for ALF can be prevented by moderate hypothermia. Methods. Sixteen patients with ALF undergoing OLT were studied. Depending on the measured ICP before OLT, the patients were divided into three groups as follows: group I (n=6), did not require treatment for increased ICP (ICP <15 mm Hg); group II (n=5), had episodes of increased ICP that were controlled by conventional treatment (group I and group II patients were maintained normothermic during OLT); and group III (n=5), had uncontrolled increased ICP before OLT for which they had been cooled and underwent OLT with the median core temperature of 33.4°C (92.1°F) (range, 31.9°–33.8°C [89.4°–92.8°F]) Results. There was a significant increase in ICP during the dissection and reperfusion phases in the patients in groups I and II (P =0.004 and P =0.006, respectively). Patients in group III had no significant increase in ICP during the OLT. The increase in ICP in groups I and II was associated with an increase in cerebral blood flow, which was not observed in group III. The increase in ICP was corrected during the anhepatic phase of the operation. There was no difference in the requirement of transfusions or incidence of postoperative infection between the groups. Conclusions. Moderate hypothermia is safe and successfully prevents increases in ICP during OLT for ALF.

The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure

Background: Although renal dysfunction is a common complication of acute liver failure (ALF) with significant prognostic implications, the pathophysiological mechanisms remain unclear. The current hypothesis suggests that the renal dysfunction may mirror the hepatorenal syndrome of cirrhosis. However, ALF has distinct clinical characteristics and the circulatory derangement may be more comparable with sepsis. Objectives: To examine the relationship between the systemic inflammatory response syndrome (SIRS) and renal dysfunction in ALF, and to identify additional risk factors for renal dysfunction. Methods: A single-centre retrospective study of 308 patients with ALF was carried out. Renal dysfunction was defined according to the RIFLE criteria for acute kidney injury. Results: 67% of patients developed renal dysfunction. On univariate analysis, renal dysfunction patients were more likely to be hypothermic (p = 0.010), had a faster heart rate (p<0.001), a higher white cell count (p = 0.001) and a lower PaCO2 (p = 0.033). 78% of renal dysfunction patients and 53% of non-renal dysfunction patients had SIRS (p<0.001). On multivariate analysis, the risk factors for renal dysfunction were age (p = 0.024), fulfilled Kings College Hospital prognostic criteria (p<0.001), hypotension (p<0.001), paracetamol-induced ALF (p<0.001), infection (p = 0.077) and SIRS (p = 0.017). SIRS remained an independent predictor of renal dysfunction in the subgroup of patients with non-paracetamol-induced ALF (n = 91, p = 0.001). In contrast, in patients with paracetamol-induced ALF (n = 217), no relationship between SIRS and renal dysfunction was demonstrated (p = 0.373). Conclusion: SIRS is strongly associated with the development of renal dysfunction in patients with non-paracetamol-induced ALF. It is proposed that the systemic inflammatory cascade plays a key role in its pathogenesis.

Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy

There is increasing evidence that terlipressin is useful in patients with cirrhosis and hepatorenal syndrome, but there are no data of its use in patients with acute liver failure (ALF) in whom hepatorenal syndrome is common. Although terlipressin produces systemic vasoconstriction, it produces cerebral vasodilatation and may increase cerebral blood flow (CBF). Increased CBF contributes to intracranial hypertension in patients with ALF. The aim of this study was to evaluate the safety of terlipressin in patients with ALF with respect to cerebral hemodynamics. Six successive patients with ALF were ventilated electively for grade IV hepatic encephalopathy. Patients were monitored invasively and CBF was measured (Kety‐Schmidt technique). Measurements were made before and at 1, 3, and 5 hours after intravenous (single bolus) administration of terlipressin (0.005 mg/kg), median, 0.25 mg (range, 0.2–0.3 mg). There was no significant change in heart rate, mean arterial pressure, or cardiac output. CBF and jugular venous oxygen saturation both increased significantly at 1 hour (P = 0.016). Intracranial pressure increased significantly at 1 hour (P = 0.031), returning back to baseline values at 2 hours. In conclusion, administration of terlipressin, at a dose that did not alter systemic hemodynamics, resulted in worsening of cerebral hyperemia and intracranial hypertension in patients with ALF and severe hepatic encephalopathy. These data suggest the need to exercise extreme caution in the use of terlipressin in these patients in view of its potentially deleterious consequences on cerebral hemodynamics. (HEPATOLOGY 2004;39:471–475.)

The utilization of liver transplantation in the management of acute liver failure: Comparison between acetaminophen and non-acetaminophen etiologies†

Liver transplantation (LT) may be life‐saving in severe acute liver failure (ALF). The aim of this study was to compare the utilization of LT in acetaminophen and non‐acetaminophen ALF. Between 1992 and 2006, 469 patients with ALF were admitted, and 104 underwent LT. Acetaminophen was the most common etiology, but LT proceeded more frequently in the non‐acetaminophen cohort (acetaminophen: 45/326 patients received LT, 13.8%; non‐acetaminophen: 59/143 patients received LT, 41.3%; P < 0.01). A retrospective analysis of the individual steps in the management of patients revealed more ALF patients in the non‐acetaminophen cohort fulfilled the Kings College Hospital poor prognostic criteria (non‐acetaminophen: 91/143, 63.6%; acetaminophen: 165/326, 50.6%; P < 0.01), more patients had contraindications to LT in the acetaminophen cohort (acetaminophen: 99/165, 60%; non‐acetaminophen: 21/91, 23.1%; P < 0.01), and survival on the LT waiting list was reduced in the acetaminophen cohort (acetaminophen: 45/66, 68.2%; non‐acetaminophen: 59/70, 84.3%; P < 0.05). Post‐LT survival was similar in the 2 groups. An analysis of cohorts admitted in 1993‐1996 and 2002‐2005 revealed that LT proceeded less commonly in acetaminophen ALF in the later cohort (1993‐1996: 16/99 LT, 16.2%; 2002‐2005: 4/81 LT, 5%; P < 0.01) in comparison with the non‐acetaminophen cohort, in which transplantation proceeded more commonly in the later cohort (1993‐1996: 11/34 LT, 32.4%; 2002‐2005: 24/49 patients, 49.0%; P < 0.01). This was due to an increase in the number of patients with psychiatric contraindications to transplantation (predominantly resistant and severe alcohol dependence). In conclusion, at all decision steps between admission and emergency LT, LT is favored in non‐acetaminophen patients, and nonoperative management is favored in acetaminophen ALF patients. Liver Transpl 15:600–609, 2009.

Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage

Increased intracranial pressure and cerebral oedema in patients with chronic liver disease is rare and is more typical of acute liver failure. Transjugular intrahepatic portosystemic stent-shunt is being increasingly used in the management of uncontrolled variceal haemorrhage in patients with cirrhosis. In our institution, a total of 160 patients has undergone transjugular intrahepatic porto-systemic stent-shunt for variceal haemorrhage; 56 of these procedures were emergencies for uncontrolled variceal haemorrhage. Four of these 56 patients developed features of acute liver failure, with marked deterioration in liver function tests and elevated intracranial pressure. This unusual but important complication of transjugular intrahepatic portosystemic stent-shunt has not been reported in the literature previously, and may have important consequences both for clinical practice and in the provision of further clues to understanding the pathogenesis of increased intracranial pressure in patients with liver diseases.

Submissiveness and protection from coronary heart disease in the general population : Edinburgh Artery Study

BACKGROUND Type A behaviour and, more specifically, hostility and anger have been associated with increased risk of coronary heart disease (CHD). But less attention has been paid to other features of personality. Our aim was to assess whether a submissiveness trait, which is independent of hostility, was related to future risk of CHD in the general population. METHODS The Edinburgh Artery Study is a cohort study of a random sample of 809 men and 783 women aged 55 to 74 years. At the baseline examination in 1988, we administered the Bedford-Foulds Personality Deviance Scales. The participants were followed up for 5 years for cardiovascular events. Criteria to define events were adapted from the American Heart Association. Events were ascertained from the information and Statistics Division of the Scottish Office Home and Health Department, general practitioners, the UK National Health Service Central Register, annual questionnaires to the participants, and the second examination at the end of follow-up. FINDINGS During follow-up, 57 (7.0%) men and 28 (3.6%) women had non-fatal myocardial infarctions; 25 (3.1%) men and 8 (1.0%) women had fatal myocardial infarctions; and 48 (5.9%) men and 41 (5.2%) women developed angina pectoris. We found that mean submissiveness scores were significantly higher in men and women who did not have a non-fatal myocardial infarction than in those who did (18.88 [SE 0.15] vs 17.70 [0.40], p = 0.023 in men; 20.76 [0.17] vs 18.18 [0.86], p = 0.002 in women). In multiple logistic-regression models, submissiveness remained independently associated with risk of myocardial infarction in women only; a decreased risk of both non-fatal myocardial infarction (relative risk 0.59 [95% CI 0.40-0.85]) and, to a lesser extent, total myocardial infarction (0.69 [0.27-0.96]), was associated with an increase of 1 SD in submissiveness. INTERPRETATION The personality trait of submissiveness may be protective against non-fatal myocardial infarction, particularly in women. A better understanding is required of the complicated effects of personality on CHD development.

Energy expenditure in acetaminophen-induced fulminant hepatic failure.

Objective: To determine energy expenditure in critically ill patients suffering from acetaminophen‐induced fulminant hepatic failure and compare it with values obtained in matched, healthy control subjects and in patients studied during the anhepatic period of elective liver transplantation. Design: Prospective, controlled, observational study. Setting: A ten‐bed intensive therapy unit and a liver transplant unit at a University teaching hospital. Patients and Subjects: Sixteen patients suffering from acetaminophen‐induced fulminant hepatic failure who were sedated, paralyzed, and mechanically ventilated; 16 age‐, gender‐, and weight‐matched, awake, healthy control subjects; and 16 patients with chronic liver disease, undergoing elective liver transplantation, who were studied during the anhepatic period of surgery. Interventions: None. Measurements and Main Results: The mean energy expenditure was calculated in each case for a 30‐min period, using indirect calorimetry. In the patients undergoing liver transplantation, measurements were performed after clamping the hepatic veins and recipient hepatectomy. Energy expenditure was markedly increased in the fulminant hepatic failure group (mean energy expenditure, 4.05 [SD 0.52] kJ·kg−1·hr−1), in comparison with healthy control subjects (mean, 3.44 [0.27] kJ·kg−1·hr−1; mean difference, 18%; p < .001) and in comparison with patients during the anhepatic period of liver transplantation (mean, 3.15 [0.61] kJ·kg−1·hr−1; mean difference, 29%; p < .001). These differences were even more pronounced when a correction factor for differences in core temperature was included in the calculation. Harris‐Benedict predictions of energy expenditure were unreliable in the patients with acute liver failure. No correlations were found among energy expenditure and hemodynamic variables, the requirement for vasoconstrictors, or the presence of renal failure. Conclusions: Despite the loss of functioning liver cell mass, the metabolic rate is substantially increased in patients with acetaminophen‐induced fulminant hepatic failure. This finding is consistent with the marked systemic inflammatory response, which accompanies acute hepatic failure. The Harris‐Benedict equation is unreliable when an estimation of energy expenditure is required in patients with this condition.

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

BackgroundThe development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF.Method35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased.ResultsCytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n = 4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg), increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min) and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome.Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02) and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14) coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischers ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06.ConclusionWe have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems.

Comparison of hepatic artery and portal vein reperfusion during orthotopic liver transplantation.

BACKGROUND During orthotopic liver transplantation (OLT), it is standard procedure to reperfuse the liver via the portal vein (PV) despite having a lower oxygen content and perfusion pressure than the hepatic artery (HA). There are no published studies that describe graft function and outcome when the HA is used for reperfusion. We report a retrospective comparison of graft outcome after HA or PV reperfusion when the piggyback technique was used. METHODS We identified 26 patients who had undergone OLT with HA reperfusion and 26 patients reperfused via the PV. Demographics, primary diagnosis, surgeon, warm and cold ischemic times, and blood product use were recorded. In each patient, whole blood lactate concentration, prothrombin time (PT), and alanine aminotransferase (ALT) were measured at defined time points during and after surgery as indices of graft lactate metabolism, synthetic function, and reperfusion injury, respectively. Thirty-day and 1-year outcome data were recorded. Data were compared between the HA and PV groups. RESULTS Demographics, blood product use, primary diagnosis, cold ischemic time, and surgeon were similar between the groups. Warm ischemic time was longer in the HA group (mean [SD] HA 51.2 [14.7], PV 40 [9.1] min, P=0.002). Blood lactate concentrations were similar at all time points. There was no difference in 24-hr postoperative PT between the groups (median [InterQuartile (IQ) range] HA 17.5 [16-28.3], PV 19 [16-24] sec, P=0.85). Peak postoperative ALT values were comparable (median [IQ range] HA 1031 [668-1701], PV 1107 [754-1824] IU/ml, P=0.78). There were no statistically significant differences in 30-day or 1-year mortality, but more early deaths occurred in the HA group. Using our data, we calculated that a prospective randomized trial would need approximately 300 patients to be sure that mortality was the same with both techniques. CONCLUSION We have demonstrated no clinically or statistically significant differences in indices of graft function, reperfusion injury, or outcome between primary HA or PV reperfusion.

Influence of cyclic guanosine monophosphate changes on hemodynamics after reperfusion in liver transplantation

Orthotopic liver transplantation (OLT) is often associated with hemodynamic instability upon reperfusion, recognized as postreperfusion syndrome. Changes in vascular tone due to humoral factors released upon reperfusion of the graft have been suggested as a possible mechanism. In this study, we looked at the perioperative changes in cyclic guanosine monophosphate (cGMP), a mediator of vascular smooth muscle relaxation, and investigated its relationship with hemodynamic parameters. cGMP was measured in the plasma of 14 patients undergoing OLT by radioimmunoassay serially at the preanhepatic and anhepatic phases, and after reperfusion at 30, 60, and 120 min. Hemodynamic data recorded were systemic and pulmonary arterial pressures, cardiac output, and pulmonary and systemic vascular resistance. cGMP decreased markedly after reperfusion from a baseline level of 5.33+/-0.7 ng/ml to 1.63+/-0.5 ng/ml (P<0.01). Pulmonary arterial pressure increased from 17+/-1.21 mmHg to 23.5+/-1.9 mmHg (P<0.05), and pulmonary vascular resistance increased from 62.8 +/-12.9 dynes/sec/cm5 to 135+/-42.7 dynes/sec/cm5 (P<0.01). Changes in cardiac output and systemic vascular resistance were not significant. The changes in cGMP correlated with pulmonary arterial pressure (r=0.74, P=0.005) and pulmonary vascular resistance (r=0.7, P=0.01). These data confirm the occurrence of hemodynamic changes during OLT, and provide evidence to suggest that the reduction in cGMP after reperfusion may mediate the vascular changes.