Elevated ammonium levels during treatment with valproic acid

INTRODUCTION. Elevated ammonium levels (EAL) are one of the side effects of valproic acid (VPA) treatment. This complication has been described during long-term VPA treatment, but less in critically ill patients.OBJECTIVES. The aim of this study was to evaluate the incidence and the factors associated with EAL in those patients.METHODS. A retrospective study in a mixed 35-bed ICU care of a tertiary university hospital was conducted over a 4-year period (2007-2010). Inclusion criteria were; a) VPA therapy for more than 72 hours; b) age > 18 years; c) at least one measurement of ammonium levels during the ICU stay; d) Child C liver cirrhosis. EAL was defined as ammonium levels above 50 mcg/dL. Demographic data, comorbidities, reason for VPA treatment, biological data, concomitant therapies, presence of infection and ICU mortality were collected.RESULTS. A total of 168 patients met the inclusion criteria (median age 64 years, 95 male gender). Most of them (137/168) were admitted for neurological reasons. Overall ICU mortality was 23%. Median ammonium levels were 88 [55-121] mcg/dL. EAL was found in 121 (72%) patients; of those, 38 (31%) had ammonium levels between 100-150 mcg/dL, 11 (9%) between 150-200 mcg/dL and 13 (11%) above 250 mcg/dL. Median time from start of VPA therapy to EAL was 4 [3-5] days. Median maximum VPA level during therapy was 72 [51-88] and was significantly higher in EAL patients than in the others (76 [58-92] mcg/mL vs. 56 [39-81] mcg/mL, p< 0.01). EAL were more frequently observed in patients with sepsis (p< 0.01) and in those treated with mechanical ventilation (p< 0.01), vasopressors (p=0.05) and at least one other antiepileptic drug (p=0.02); these patients tended to have a higher ICU mortality (28% vs. 13%, p = 0.06).CONCLUSIONS. Ammonium levels are often elevated during treatment with valproic acid in ICU patients, especially in those with the greatest severity. This alteration may contribute to their alteration in brain function.