This first systematic study on citrate pharmacokinetics and metabolism in critically ill patients confirms a major role of hepatic citrate metabolism by demonstrating reduced citrate clearance in cirrhotic patients. Pharmacokinetic data could provide a basis for the clinical use of citrate anticoagulation in critically ill patients. Provided dose adaptation and monitoring of ionized calcium, citrate anticoagulation seems feasible even in patients with decompensated cirrhosis. Metabolic consequences of citrate infusion were not different between groups in this study but may be more pronounced in prolonged infusion.

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Ammonia is considered the major pathogenetic factor of cerebral dysfunction in hepatic failure. The correlation between total plasma ammonia and the severity of hepatic encephalopathy (HE), however, is variable. Because ammonia that is present in gaseous form readily enters the brain, the correlation with the grade of HE of the pH-dependent partial pressure of gaseous ammonia (pNH 3 ) could be better than that of total arterial ammonia levels. To test this hypothesis, 56 cirrhotic patients with acute episodes of clinical HE (median age, 54 years; range, 21-75) were studied by clinical examination and by long-latency mediannerve sensory-evoked potentials (SEPs) N70 peak, an objective and sensitive electrophysiological measure of HE. pNH 3 was calculated from arterial blood according to published methods. The clinical grade of HE correlated (P F .001) with both pNH 3 and total ammonia, but correlation was stronger with pNH 3 (r ‫؍‬ .79 vs. .69, P ‫؍‬ .01). A similar correlation was found for N70 peak latency (r ‫؍‬ .71 with pNH 3 vs. .64 with total ammonia, respectively, P ‫؍‬ .08). In summary, arterial pNH 3 correlates more closely than total ammonia with the degree of clinical and electrophysiological abnormalities in HE. These findings support the ammonia hypothesis of HE and suggest that pNH 3 might be superior to total ammonia in the pathophysiological evaluation of HE. (HEPATOLOGY 2000;31:30-34.)Although there is little doubt that ammonia plays a major role in the pathogenesis of hepatic encephalopathy (HE), 1-3 the relation between plasma ammonia and the severity of cerebral dysfunction is variable. 4 Many investigators have described a close correlation between ammonia levels and cerebral function (for review, see Butterworth et al. 3 ), whereas others have questioned either the strength of such a correlation or even any causal relationship between ammonia and HE. 5-7 Some of this discrepancy can be resolved by accounting for the frequent use of venous ammonia levels, which are appreciably lower than arterial ammonia, to which the brain is exposed. 4 A further important reason may be related to ammonia kinetics. In biological fluids, ammonia exists in 2 forms: as ammonium ion and as gaseous, unionized ammonia (NH 3 ). 8 At a physiological pH of 7.4, 98% of total plasma ammonia is ionized and 2% is present as gaseous NH 3 . 8 In intracellular fluid where the pH is about 7.0, an even smaller fraction exists as unionized NH 3 . Because biological membranes are much more permeable to nonionized than to ionized molecules, 8 only the nonionized NH 3 freely diffuses through the blood-brain barrier. 9 Partial pressure of NH 3 (pNH 3 ) can be calculated from total ammonia and pH 10 and increases with pH. Despite an almost universal validity across species, 8 the phenomenon of pH-dependent ammonia toxicity has been largely ignored in the clinical setting. In this study, arterial pNH 3 was compared with total arterial ammonia levels regarding their correlation with the severity of HE. Cerebral dysfunction was assesse...

Septic encephalopathy occurs more frequently than generally assumed, and its severity is associated with the severity of illness. The impairment of subcortical and cortical SEP pathways was not different between patients with severe sepsis and those with septic shock.