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

Abstract

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 Fischer's 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.

Artificial liver support in pigs with acetaminophen-induced acute liver failure

“…Previous attempts to establish a standardized APAP intoxication model[13-15,20] were unsuccessful. Thiel et al[20] administered APAP directly into the upper jejunum via an implanted catheter, and this route of administration was affected by anesthesia, laparotomy and jejunotomy.…”

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

“…The recently published acetaminophen intoxication model of Newsome et al [15] does not produce defined survival times. In addition to this, intravenous application of acetaminophen seems to produce more toxic side effects and does not reflect the clinical situation.…”

“…There is an unmet clinical need to provide a relevant, reproducible large animal model of acetaminophen-induced ALF in which to test putative therapies such as novel hepatic support systems or new pharmacological agents designed to address these issues. Numerous studies with pig models using acetaminophen to induce ALF have produced heterogeneous results [13,14,15] due to the existence of significant variations in the hepatic detoxifying metabolism of the drug related to species and age [16]. But reproducibility in the development of ALF within a reasonable time range and survival time in ALF remained unpredictable [17] and death of many pigs occurred due to toxic side effects.…”

Standardized intensive care unit management in an anhepatic pig model: new standards for analyzing liver support systems

“…In these models, hepatic failure was achieved by intoxication with galactosamine or acetaminophen [8-10], hepatic ischemia by portocaval shunting following transient clamping of the hepatic artery [11,12], and extended resection or even total hepatectomy [13-21]. Unfortunately, all aforementioned models involve various limitations, thus affecting morbidity in the assessment of a given intervention.…”