Distribution of ammonia across the blood-cerebrospinal fluid barrier in patients with hepatic failure

Abstract

The distribution of ammonia between blood and cerebrospinal fluid and its relation to the theory of nonionic diffusion, has been investigated in thirty-one patients with advanced cirrhosis and in twelve patients without liver disease. Marked variability in values obtained simultaneously by the Nathan-Rodkey and Conway methods and a significant increase in measured “ammonia” occurring with an increase in diffusion time emphasize the nonspecificity of available methods. A significant increase in the mean pH of arterial blood was noted among patients with hepatic encephalopathy. Concomitant increase in mean cerebrospinal fluid pH suggested that this alkalosis was respiratory in nature. Mean pH gradients between blood and cerebrospinal fluid were similar in control subjects and patients with cirrhosis. Mean arterial and cerebrospinal fluid ammonia levels were significantly elevated in patients with cirrhosis, with or without encephalopathy. The cerebrospinal fluid ammonia concentration was linearly related to the arterial ammonia level in both control subjects and patients with cirrhosis, irrespective of pH gradients between blood and cerebrospinal fluid. Since this linear function did not intercept zero, the C CSF C BI ammonia ratio increased with increasing arterial ammonia concentration. This ratio was significantly higher in patients with cirrhosis than in control subjects and was a function of arterial ammonia concentration rather than cirrhosis per se. When expected C CSF C BI ratios, calculated from existing pH gradients, were compared with observed ratios, the discrepancy between the two was found to decrease with increasing arterial ammonia concentration. Although there was no correlation between pH gradients and observed C CSF C BI ammonia ratios at “steady state,” alteration of gradients by drug infusion resulted in qualitative changes in these ratios in the direction predicted by the pH gradient drug-distribution hypothesis. It is concluded that the distribution of ammonia in man probably follows the nonionic diffusion theory. The clouding of such relationships appears most likely to be due to artefact in the methods for measuring ammonia. Further elucidation of ammonia transport mechanisms in man must await advances in methods which will make it possible to measure true ammonia in both fluids.