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A reproducible rabbit model of acetaminophen induced acute hepatic failure (AHF) and multi-organ failure (MOF)

Background

Acetaminophen overdose is the commonest cause of AHF in the UK. Patients may require liver transplantation and intensive care for support for MOF. Acetaminophen (APAP) metabolism is catalysed by cytochrome P450 (CYP450). This leads to formation of the toxic metabolite N-acetyl-p-benzoquinone (NAPQI). NAPQI detoxification requires glutathione. Both prior CYP450 induction and glutathione depletion exacerbate hepatic damage.

Aim

To develop a reproducible rabbit model of AHF and MOF paralleling, clinical, biochemical and histological patterns of human disease.

Method

CYP450 was induced in New Zealand White Rabbits (n = 8) using 20-methylcholanthrene (80 mg/kg i.p.) dissolved in corn oil. The glutathione synthetase inhibitor buthionine sulphoxime (2 mmol/kg i.v.) was administered just prior to APAP administration, (500 mg/kg s.c.) 4-hourly for 24 h.

Clinical observations were recorded and arterial blood sampledover 48 h.

Results

Clinical: Grade I-III encephalopathy (modified from Zimmerman et al.) occurred at 8–12, 12–18,. 18–36 h, respectively. Mortality was 75% at 48 h, preceded by a short period of grade IV encephalopathy.

Biochemistry: Expressed as mean values ± s( n–1)

Histology: Liver: Centrilobular necrosis was prominent on the surface of the liver at 24 h, with extensive severe coagulative necrosis at 48 h. Kidney: Acute tubular necrosis at 24 h.

Conclusion

Preliminary data suggests that we have developed a reproducible rabbit model of AHF and associated MOF, however, further characterisation is required.

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Rahman, T., Selden, C. & Hodgson, H. A reproducible rabbit model of acetaminophen induced acute hepatic failure (AHF) and multi-organ failure (MOF). Crit Care 3, P184 (2000). https://doi.org/10.1186/cc557

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Keywords

  • Glutathione
  • Acetaminophen
  • APAP
  • Zealand White Rabbit
  • Acute Tubular Necrosis