Sinusoidal endothelial cells as a target for acetaminophen toxicity. Direct action versus requirement for hepatocyte activation in different mouse strains.

Hepatic congestion occurs early in acetaminophen poisoning. This study examines whether acetaminophen is toxic to sinusoidal endothelial cells (SEC), which might lead to microcirculatory disruption. Acetaminophen toxicity was examined in vivo and in vitro in SEC and hepatocytes from C3H-HEN and Swiss Webster mice. In both strains, there was significantly more toxicity to SEC than to hepatocytes; in SEC from C3H-HEN mice, acetaminophen was directly toxic, but the presence of hepatocytes was required for toxicity to Swiss SEC. Acetaminophen, 750 mg/kg, by gavage caused toxicity with variability within and between strains, but all animals died between 3.5 and 6 hr with zone 3 hemorrhagic necrosis. Pretreatment of C3H-HEN SEC with aminobenzotriazole, a suicide inhibitor of P450, abolished toxicity. Baseline glutathione (GSH) levels were comparable, but a 12-hr incubation with acetaminophen decreased GSH by 60 and 8%, respectively, in C3H-HEN and Swiss SEC in single cell type culture. In co-culture, under conditions where Swiss SEC viability declined by 73%, hepatocyte viability and GSH only decreased by 21 and 20%, respectively. In conclusion, acetaminophen was toxic to SEC. It was directly toxic to SEC in one mouse strain and required hepatocyte activation in another strain. The lack of direct toxicity to Swiss SEC may be due to the lack of an activating P450 isozyme. Zone 3 hemorrhagic necrosis in vivo was comparable in both strains, despite differences in the pathways leading to SEC toxicity in vitro. We propose that toxicity to SEC may contribute to hepatic congestion in acetaminophen intoxication.

The prognosis of oncologic patients in the pediatric intensive care unit.

OBJECTIVE: To evaluate the predicted mortality rate of oncologic patients in the PICU using the PRISM score and factors that might influence short-term outcomes. DESIGN: Retrospective study. SETTING: Pediatric ICU in a university hospital. PATIENTS AND METHODS: The medical charts of all oncologic patients admitted to the PICU during the period from January 1983 to December 1992 were reviewed. MAIN RESULTS: Over a period of 10 years, 51 oncologic patients were admitted on 57 occasions to the PICU. The mortality was 32%. This is significantly higher than the overall mortality in the PICU (8%). Comparison of observed and predicted mortality, derived from the PRISM score, using chi square goodness-of-fit tests showed a significantly higher observed mortality (x2(5) = 20.1, P < 0.01). Patients admitted for circulatory failure had the highest mortality (47%), followed by those with respiratory failure due to tachypnea/cyanosis (36%), central nervous system deterioration (27%), respiratory failure due to airway obstruction (25%), and metabolic disorders (20%). Of the 31 patients who needed mechanical ventilation, 17 died (55%), and when they needed inotropic support as well, the mortality increased to 69%. The mortality rose to 100% when the patient was admitted with a septic shock, necessitating mechanical ventilation and inotropic support. The median PRISM score was 5 in the survivor group and 18.5 in the non-survivor group; this difference was found to be significant using the Wilcoxon test (P = 0.01). However, some patients with high scores were found in the survivor group, as well as some with low scores in the non-survivor group. CONCLUSION: The decision to treat oncologic patients in a PICU remains difficult and has to be considered on an individual basis. However, oncologic patients do benefit from admission to the PICU. The PRISM score is not suitable for oncologic patients in the PICU, because it underestimates the observed mortality. Other factors like neutropenia, septic shock, the need for mechanical ventilation, and inotropic support should be taken into consideration.