D-galactosamine based canine acute liver failure model

• Published in: Hepatobiliary & pancreatic diseases international 2002-08, Vol.1 (3), p.354-367
• Main Authors: Patzer, 2nd, John F, Block, Geoffrey D, Khanna, Ajai, Yin, Wen-Yao, Molmenti, Ernesto, Gerber, David, Kramer, David J, Scott, Victor L, Aggarwal, Shushma, Wagner, Robert A, Fulmer, Melissa L, Amiot, Bruce P, Mazariegos, George V
• Format: Article
• Language: English
• Subjects: acute; Animals; bioartificial; canine; Disease Models, Animal; Dogs; failure; Galactosamine; liver; Liver - enzymology; Liver - metabolism; Liver - pathology; Liver Failure, Acute - chemically induced; Liver Failure, Acute - pathology; Liver Failure, Acute - physiopathology; Male; Survival Analysis
• ISSN: 1499-3872

<正> Background: Appropriate preclinical evaluation of abioartificial liver assist device （BAL） demands alarge animal model, as presented here, that demon-strates many of the clinical features of acute liverfailure and that is suitable for clinical qualitative andquantitative evaluation of the BAL. A lethal canineliver failure model of acute hepatic failure that re-moves many of the artifacts evidenced in prior caninemodels is presented.Methods: Six male hounds, 24-30 kg, under isoflu-rane anesthesia, were administered 1.5 g/kg D-galactosamine intravenously. Canine supportive carefollowed a well-defined management protocol thatwas guided by electrolyte and invasive monitoringconsisting of arterial pressure, central venous pres-sure, extradural intracranial pressure （ICP）, pul-monary artery pressure, and end-tidal CO2. Theanimals were treated until death-equivalent, definedas inability to sustain systolic blood pressure>80mmHg for 20 minutes despite maximal fluids and 20μg·kg-1·min-1 dopamine infusion.Results: The mean survival time was 43.7±4.6hours （mean±SE）. All animals showed evidence ofprogressive liver failure characterized by increasingliver enzymes （aspartate transaminase from 26 to5977 IU/L; alanine transaminase from 32 to 9740IU/L）, bilirubin （0.25 to 1.30 mg/dl）, ammonia（19. 8 to 85. 3 μmol/L）, and coagulopathy （pro-thrombin time from 8.7 to 46 s）. Increased labilityand elevations in intracranial pressures were ob-served. All animals were refractory to maintenanceof cerebral perfusion pressure even with only mode-rately elevated intracranial pressure. Severe neuro-logic obtundation, seen in 2 of 6 animals, was associ-ated with elevations of ICP above 50 mmHg. Post-mortem liver histology showed evidence of massivehepatic necrosis. Postmortem blood and ascites mi-crobial growth was consistent with possible transloca-tion of intestinal microbes.Conclusions: The improved lethal canine liver failuremodel presented here reproduces many of the clinicalfeatures of acute liver failure. The model may proveuseful for qualitative and quantitative evaluation ofBALs.