Background and Aims: Severe intoxication following acetaminophen overdose is the most common cause of acute liver failure (ALF) in many Western European and North American countries. A reproducible large animal model of acetaminophen intoxication has not been successfully evaluated previously. Methods: Eight male pigs underwent acetaminophen intoxication receiving an initial enteric bolus of 250 mg/kg body weight acetaminophen followed by an acetaminophen plasma level (300–450 mg/l) adapted enteric maintenance dose of 1,000–3,000 mg/h to the onset of ALF (prothrombin time value <30%). Vital and ventilation parameters were continuously recorded until death. Saline, hydroxyethyl starch, fresh frozen plasma and erythrocyte units were used for volume substitution, and norepinephrine to prevent severe hypotension. Results: All animals developed ALF after 25 ± 3 h, which was confirmed by laboratory values, the clinical course and histological examinations. All animals died due to ALF after a further 21 ± 5 h, precipitated by cerebral edema. Conclusions: Using an initial enteric acetaminophen bolus, followed by body weight-adapted acetaminophen plasma level intoxication, it was possible to establish a reproducible, clinically relevant porcine model which may be used for the investigation of novel therapeutic approaches in this life-threatening condition.

IntroductionSeveral anhepatic pig models were developed in the past. Most models suffer from short anhepatic survival times due to insufficient postoperative intensive care unit (ICU) management. The aim of this study was to analyze anhepatic survival time under standardized intensive care therapy in a pig model.MethodsEight pigs underwent total hepatectomy after Y-graft interposition between the infrahepatic vena cava and the portal vein to the suprahepatic vena cava. An intracranial probe was inserted for intracranial pressure (ICP) monitoring. Animals received pressure-controlled ventilation under deep narcosis. Vital parameters were continuously recorded. Urinary output, blood gas analysis, haemoglobin, hematocrit, serum electrolytes, lactate, and glucose were monitored hourly, and creatinine, prothrombin time, international normalised ratio, and serum albumin were monitored every 8 hours. Sodium chloride solution 0.9%, hydroxyethyl starch 6%, fresh frozen plasma, and erythrocyte units were used for volume substitution, and norepinephrine was used to prevent severe hypotension. Serum electrolytes and acid-base balance were corrected as required. Antibiotic prophylaxis with ceftriaxon was given daily, as well as furosemide, to maintain diuresis.ResultsPostoperative survival was 100% after 24 hours, with a maximum survival of 73 (mean, 58 ± 4) hours. Haemodynamic parameters such as heart rate, mean arterial pressure, and pulse oximetry remained stable during surgical procedures and following anhepatic status due to ICU therapy until escalating at time of death. Deteriorating pulmonary function could be stabilized by increasing oxygen concentration, positive end-expiratory pressure, and maximal airway pressure. Furosemide was used to maintain diuresis until renal failure occurred. ICP started at 15-17 mmHg and increased continuously up to levels of 41-43 mmHg at time of death. All animals died as a result of multiple-organ failure.ConclusionsUsing standardized intensive care management after total hepatectomy, we were able to prolong anhepatic survival over 58 hours without the use of liver support systems. The survival benefit of liver support systems in previous animal studies should be reevaluated against our model.

In the NM+PG group all of those values are slightly lower than those in the NHB group, but there are no signifi cant differences between those groups. On the histological exam, in the NM+PG group the sinusoidal endothelial cells were well preserved. Conclusion: The strong serine protease inhibitor, NM, and PG supported sinusoidal endothelial cells. This method is promising strategy on liver transplantation from marginal donors.