Effect of temperature variation on toxicity and metabolism of ammonia in mice

Hepatic coma has often been considered in relation to ammonia toxicity. In view of the frequency of fever in patients with liver disease and the use of hypothermia in the surgical management of esophageal varices, the effect of temperature variation on the toxicity and cerebral metabolism of ammonia in mice has been investigated. The toxicity of intravenously administered ammonium chloride was compared in normal mice and those during induced hyperthermia and hypothermia. Ammonia toxicity was increased at elevated body temperature, whereas hypothermia afforded marked protection against it. Observed changes in blood pH and calculated changes in the pK of ammonia in relation to body temperature variation were discussed in relation to their effect on the ionization of ammonia. The passage into the brain and detoxication of exogenously administered ammonium chloride was investigated in normothermic, hyperthermic, and hypothermic mice. There was no evidence of abnormal metabolism of ammonia by the brain during hyperthermia. The increased toxicity of ammonia at elevated body temperature is believed to be due to a direct metabolic effect of hyperthermia on the brain unrelated to dehydration or stress. There was decreased passage of ammonia into the brain during hypothermia. This is believed to be due to a fall in cerebral blood flow at a low body temperature. An apparent delay in detoxication of ammonia by the brain during hypothermia also was noted. The protective effect of hypothermia against ammonia toxicity is believed to be due both to a decreased influx of ammonia into the brain and the reduction of cerebral metabolism and oxygen demand.