High circulating ammonia concentrations are common in patients with acute liver failure (ALF) and are associated with hepatic encephalopathy (HE) and intracranial hypertension (ICH). Other risk factors are poorly characterized. We evaluated the relation of the admission arterial ammonia concentration and other clinical variables with the development of HE and ICH. Arterial ammonia was measured on admission to the intensive care unit in 257 patients; 165 had ALF and severe HE, and there were 3 control groups: acute hepatic dysfunction without severe HE (n ‫؍‬ 50), chronic liver disease (n ‫؍‬ 33), and elective surgery (n ‫؍‬ 9). Variables associated with ICH and HE were investigated with regression analysis. Ammonia was higher in ALF patients than controls. An independent risk factor for the development of severe HE and ICH, a level greater than 100 mol/L predicted the onset of severe HE with 70% accuracy. The model for end-stage liver disease (MELD) score was also independently predictive of HE, and its combination with ammonia increased specificity and accuracy. ICH developed in 55% of ALF patients with a level greater than 200 mol/L, although this threshold failed to identify most cases. After admission, ammonia levels remained high in those developing ICH and fell in those who did not. Youth, a requirement for vasopressors, and renal replacement therapy were additional independent risk factors. Conclusion: Ammonia is an independent risk factor for the development of both HE and ICH. Additional MELD scoring improved the prediction of HE. T here is now strong evidence of a central role for ammonia in the pathogenesis of hepatic encephalopathy (HE) that defines acute liver failure (ALF) and the cerebral edema (CE) and intracranial hypertension (ICH) that contribute to the high mortality seen in this condition. Elevations in the circulating ammonia concentration are a frequent finding in experimental and human ALF and appear to be closely related to these complications. 1-3 Experimental studies have demonstrated ammonia-induced changes in neurotransmitter synthesis and release, neuronal oxidative stress, impaired mitochondrial function, and osmotic disturbances resulting from astrocytic metabolism of ammonia to glutamine. [4][5][6] The net result of these changes is a marked alteration in cerebral function and astrocytic swelling. [5][6][7] Recent studies reporting circulating ammonia concentrations in patients with ALF have found levels higher than those seen in patients with HE accompanying chronic liver disease (CLD). 2,3,8,9 The magnitude of the elevation of ammonia, particularly if it is above 150 mol/L, has been reported to be related to an increased risk of major cerebral complications, including reduced consciousness level, seizures, cerebral herniation (CH), and death. 2,3,8,10,11 If confirmed, these findings have the potential to alter clinical practice; patients identified as being at high risk for HE and ICH in this way could be targeted with specific therapies to reduce the circulating ammonia concen-

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Chronic liver disease (CLD) is associated with muscle wasting, reduced exercise tolerance and aerobic capacity (AC). Measures of AC determined with cardiopulmonary exercise testing (CPET) may predict survival after liver transplantation (LT), but the relationship with nontransplant outcomes is uncertain. In patients assessed for LT, we examined the relationship of CPET AC parameters with the severity of liver disease, nutritional state, and survival with and without LT. Patients assessed for elective first LT who underwent CPET and an anthropometric assessment at a single center were studied. CPET-derived measures of AC that were evaluated included the peak oxygen consumption (VO 2 peak) and the anaerobic threshold (AT). Three hundred ninety-nine patients underwent CPET, and 223 underwent LT; 45% of the patients had a VO 2 peak < 50% of the predicted value, and 31% had an AT < 9 mL/kg/minute. The VO 2 peak and AT values correlated with the Model for End-Stage Liver Disease score, but they more closely correlated with serum sodium and albumin levels. The handgrip strength correlated strongly with the VO 2 peak. Patients with impaired AC had prolonged hospitalization after LT, and nonsurvivors had lower AT values than survivors 1 year after transplantation (P < 0.05); this was significant in a multivariate analysis. One hundred seventy-six patients did not undergo LT; the 1-year mortality rate was 34.6%. The AT (P < 0.05) and VO 2 peak values (P < 0.001) were lower for nonsurvivors. In a multivariate analysis, AT was independently associated with nonsurvival. In conclusion, AC was markedly impaired in many patients with CLD. In patients who did not undergo transplantation, impaired AT was predictive of mortality, and in patients undergoing LT, it was related to postoperative hospitalization and survival. AC should be evaluated as a modifiable factor for improving patient survival whether or not LT is anticipated. Liver Transpl 20:54-62, 2014. V C 2013 AASLD.Received June 4, 2013; accepted September 30, 2013.Many patients with chronic liver disease (CLD) develop progressive impairment of their fitness and exercise capacity.1 The clinical significance of these changes is reflected by the close association of altered musculature and exercise capacity with the risk for major disease-related complications and mortality.2-8