Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and...Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/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 lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of 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 massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.展开更多
基金This study was partially supported by a grant from Excorp Medical, Inc, Oakdale, MN., Steritek J7000 Intracranial Pressure Monitor provided by Ladd Research Industries, Williston, VT., and Datex Capnomac Ultima Anesthesia Monitor provided by Datex, Helsi
文摘Background: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demon- strates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that re- moves many of the artifacts evidenced in prior canine models is presented. Methods: Six male hounds, 24-30 kg, under isoflu- rane anesthesia, were administered 1.5 g/kg D- galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pres- sure, extradural intracranial pressure (ICP), pul- monary artery pressure, and end-tidal CO_2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure>80 mmHg for 20 minutes despite maximal fluids and 20 μg·kg^(-1)·min^(-1) dopamine infusion. Results: The mean survival time was 43.7±4.6 hours (mean±SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/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 lability and elevations in intracranial pressures were ob- served. All animals were refractory to maintenance of 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 massive hepatic necrosis. Postmortem blood and ascites mi- crobial growth was consistent with possible transloca- tion of intestinal microbes. Conclusions: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.
