A Reproducible Porcine Model of Acute Liver Failure Induced by Intrajejunal Acetaminophen Administration

Abstract

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.

Porcine model characterizing various parameters assessing the outcome after acetaminophen intoxication induced acute liver failure

“…The high reproducibility of ALF resulting in 100% mortality due to multiple-organ failure confirmed the results of the our previously published porcine model of acetaminophen intoxication[17]. Within the current experimental setting, continuous venovenous hemofiltration was administrated in addition to standardized intensive care therapy in order to maximally prolong survival in ALF for patients after massive acetaminophen overdose[19].…”

“…Dosage, administration and acetaminophen plasma level monitoring for a reproducible onset of acute liver failure after intrajejunal acetaminophen intoxication has been previously described in detail[17]. In brief, six pigs (6/8) received an initial enteric acetaminophen bolus of 250 mg/kg body weight via the implanted jejunal catheter.…”

“…Intensive care medication and algorithms for standardized fluid management which were used to ensure hemodynamic stability have been previously reported in detail[17,18]. Relevant vital parameters as electrocardiogram, heart rate, MAP, CVP, intracranial pressure and body temperature were recorded electronically throughout the experiment (IntelliVue MP50, Philips Medical Systems, Andover MA, United States).…”

“…Although acetaminophen toxicity has been extensively studied in rat[12,13] and mouse models[14,15], the precise pathogenic mechanisms of hepatocyte damage which are potentially reversible are still poorly understood. Recently, large models of acetaminophen intoxication have been established in porcine models[16,17] which are more appropriate to represent the human liver physiology and the clinical course of acetaminophen poisoning. These models are also of sufficient size to allow use of a representative human intensive care setting, which permits testing of novel therapeutic interventions.…”

“…Based on observations of a preliminary animal study of acetaminophen intoxication in which a distinctive pattern of portal blood flow (PBF) and alterations in thrombocyte count were measured[17], the following animal study was aimed to characterize the clinical course of PBF and changes in thrombocyte count during the development, onset and further course of acetaminophen induced ALF.…”