A dog model for acetaminophen-induced fulminant hepatic failure

Abstract

The development of a large animal model of fulminant hepatic failure produced with acetaminophen that should be useful in the development and evaluation of potential medical therapies for the important clinical problem of fulminant hepatic failure is described. Acetaminophen in dimethyl sulfoxide (600 mg/ml) given as three subcutaneous injections, with the first dose (750 mg/kg body wt) being given at noon, the second dose (200 mg/kg body wt) being given 9 h later, and the third dose (200 mg/kg body wt) being given 24 h after the initial dose consistently produces fulminant hepatic failure in dogs. The dimethyl sulfoxide vehicle, injected intramuscularly, does not influence either animal survival or hepatic function in control-treated dogs. No deaths occur within the first 36 h. By 72 h after initial drug administration, the mortality is 90%. Histopathological and biochemical investigations demonstrate a high degree of hepatocellular necrosis in nonsurviving animals without appreciable damage to the kidneys, lungs, or heart. The drug schedule and preparation outlined avoids the administration of large volumes of vehicle and results in prolonged high levels of acetaminophen in the blood sufficient to induce severe hepatic injury. Ranitidine (120 mg/kg body wt i.m.) given 30 min before each acetaminophen dose significantly reduces the mortality and hepatic necrosis produced using this model. This model satisfies all criteria established by Miller et al. for the production of a suitable large animal model of fulminant acute hepatic failure.

Figure 1

Survival rate and serum glutamic-pyruvic transaminase levels plotted across time in groups 1–4. Each panel shows the survival rate in groups 1b, 2–4 (solid line) and in group 1a (long dash line) expressed as a percentage, and the serum glutamic-pyruvic transaminase (alanine aminotransaminase) levels (short dash line) expressed as units per liter.

Figure 2

Survival rate in group 4 dogs with and without ranitidine treatment. The treated animals received a dose of 120 mg/kg body wt i.m. 30–60 min before each acetaminophen injection.

Figure 3

A. Histopathological appearance of the liver of group 4 animals. Note severe centrilobular necrosis and hemorrhage (CV = central vein) with preservation of some of the periportal hepatocytes (portal tract at bottom center) (H&E, × 200). B. The damage has resulted in central-central bridging necrosis (top center to bottom center) with preservation of periportal areas (left center and bottom right) (H&E, × 200).

Figure 4

Blood acetaminophen levels in the animals in groups 1–4. Each panel shows the acetaminophen blood level expressed as micrograms per milliliter.