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

BACKGROUND: The 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. METHOD: 35kg 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. RESULTS: Cytochrome 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 mumol/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 Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. CONCLUSION: We 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.

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 King's 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.

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 degrees C (92.1 degrees F) (range, 31.9 degrees -33.8 degrees C [89.4 degrees -92.8 degrees 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.

Metabolic, cardiovascular, and acid-base status after hepatic artery or portal vein reperfusion during orthotopic liver transplantation.

During liver transplantation, reperfusion traditionally is performed through the portal vein. After anecdotal observations that patients who underwent reperfusion first through the hepatic artery were more hemodynamically stable, we performed an exploratory, prospective, observational, nonrandomized study to compare cardiovascular stability, acid-base status, and metabolic gas exchange between patients who underwent reperfusion through either the portal vein or hepatic artery. We studied 20 patients undergoing liver transplantation (10 patients, reperfusion first through the portal vein; 10 patients, reperfusion first through the hepatic artery). Cardiovascular and acid-base parameters were compared at times before and after anastomosis of each vessel, and epinephrine use was recorded. Oxygen consumption (VO2) and carbon dioxide elimination (VCO2) were measured continuously by using an indirect calorimeter. Alanine aminotransferase (ALT) concentrations 24 hours after transplantation were compared as an index of reperfusion injury. Cardiovascular changes (mean arterial pressure, cardiac output) were similar for both groups, but more epinephrine was administered to the portal-vein group (P =.014). There was a greater increase in PaCO2 after portal reperfusion (median portal vein, 1.01 kPa; hepatic artery, 0.29 kPa; P =.015) and a trend toward more severe acidemia. VO2 increased more rapidly in the portal-vein group (P =.005), but overall changes in VO2 during the study period were similar. There were no differences in VCO2 between the groups or ALT concentrations 24 hours posttransplantation. These observational data suggest that hepatic arterial reperfusion may be associated with reduced epinephrine requirements and a slower rate of acid release, which could be advantageous in unstable patients. VO2 increases more slowly after hepatic artery reperfusion, which could indicate slower reoxygenation of the graft. Further studies of the relative merits of each technique are warranted.

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.

Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension.

BACKGROUND AND AIMS: About 20% of patients with acute liver failure (ALF) die from increased intracranial pressure (ICP) while awaiting transplantation. This study evaluates the clinical effects and pathophysiologic basis of hypothermia in patients with ALF and intracranial hypertension that is unresponsive to standard medical therapy. METHODS: Fourteen patients with ALF who were awaiting orthotopic liver transplantation (OLT) and had increased ICP that was unresponsive to standard medical therapy were studied. Core temperature was reduced to 32 degrees C-33 degrees C using cooling blankets. RESULTS: Thirteen patients were successfully bridged to OLT with a median of 32 hours (range, 10-118 hours) of cooling. They underwent OLT with no significant complications related to cooling either before or after OLT and had complete neurologic recovery. ICP before cooling was 36.5 +/- 2.7 mm Hg and was reduced to 16.3 +/- .7 mm Hg at 4 hours, which was sustained at 24 hours (16.8 +/- 1.5 mm Hg) ( P < .0001). Mean arterial pressure and cerebral perfusion pressure increased significantly, and the requirement for inotropes was reduced significantly. Hypothermia produced sustained and significant reduction in arterial ammonia concentration and its brain metabolism, cerebral blood flow, brain cytokine production, and markers of oxidative stress. CONCLUSIONS: Moderate hypothermia is an effective and safe bridge to OLT in patients with ALF who have increased ICP that is resistant to standard medical therapy. Hypothermia reduces ICP by impacting on multiple pathophysiologic mechanisms that are believed to be important in its pathogenesis. A large multicenter trial of hypothermia in ALF is justified.

Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow.

BACKGROUND/AIMS: The study aims were to determine the role of inflammation in the pathogenesis of increased intracranial pressure (ICP) in patients with acute liver failure (ALF) and its interplay with cerebral blood flow (CBF) and ammonia. METHODS: Twenty-one patients with ALF were studied from the time they were ventilated for grade 4 encephalopathy until receiving specific treatment for increased ICP. Depending upon the ICP, the patients were divided into two groups; those that required specific treatment (ICP>20 mmHg, group 1: n=8, ICP: 32 (28-54) mmHg); and those that did not (ICP< or =20 mmHg, group 2: n=13, ICP: 15 (10-20) mmHg). RESULTS: Inflammatory markers, arterial ammonia and CBF were significantly higher in the group 1 patients. TNFalpha levels correlated with CBF (r=0.80). Four patients from group 2 developed surges of increased ICP (32 (15-112) hours from enrolment). These were associated increases in markers of inflammation and TNFalpha, and an increase in CBF. There was no change in these inflammatory markers, CBF or ICP in the other 9 group 2 patients. CONCLUSIONS: The results of this study suggest that inflammation plays an important synergistic role in the pathogenesis of increased ICP possibly through its effects on CBF.