title: Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, UK. P.N.Newsome@bham.ac.uk
authors.forename: Philip N
authors.initials: PN
authors.lastname: Newsome
authors.forename: Neil C
authors.initials: NC
authors.lastname: Henderson
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Nelson
authors.forename: Costas
authors.initials: C
authors.lastname: Dabos
authors.forename: Celine
authors.initials: C
authors.lastname: Filippi
authors.forename: Chris
authors.initials: C
authors.lastname: Bellamy
authors.forename: Forbes
authors.initials: F
authors.lastname: Howie
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clutton
authors.forename: Tim
authors.initials: T
authors.lastname: King
authors.forename: Alistair
authors.initials: A
authors.lastname: Lee
authors.forename: Peter C
authors.initials: PC
authors.lastname: Hayes
authors.forename: John N
authors.initials: JN
authors.lastname: Plevris
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000097:blood; D004195:Disease Models, Animal; D018450:Disease Progression; D005165:Factor V / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism; D007427:Intracranial Pressure; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis*; D009682:Magnetic Resonance Spectroscopy; D008991:Monitoring, Physiologic / Q000379:methods*; D011379:Prognosis; D013318:Stroke Volume; D015996:Survival Rate; D013552:Swine; D014655:Vascular Resistance
chemical_list: D000082:Acetaminophen; D005165:Factor V; D005167:Factor VII; D003577:Cytochrome P-450 Enzyme System