Hyperammonemia during treatment with valproate in critically ill patients

Hyperammonemia (HA) is a potential side-effect of valproate (VPA) treatment, which has been described during long-term administration. The aim of this study was to evaluate the incidence, the impact and the risk factors of HA in critically ill patients.

We reviewed the data of all adult patients treated in our mixed 35-bed Department of Intensive Care over a 12-year period (2004-2015) who: a) were treated with VPA for more than 72 h and b) had at least one measurement of ammonium and VPA levels during the ICU stay; patients with Child-Pugh C liver cirrhosis were excluded. HA was defined as ammonium levels above 60 μg/dl.

Of a total of 2640 patients treated with VPA, 319 patients met the inclusion criteria (median age 64 years; male gender 55%); 78% of them were admitted for neurological reasons and ICU mortality was 30%. Median ammonium levels were 88 [63-118] µg/dl. HA was found in 245 (77%) patients. For those patients with HA, median time from start of VPA therapy to HA was 3 [2-5] days. In a multivariable analysis, high VPA serum levels, mechanical ventilation and sepsis were independently associated with HA during VPA therapy. In 98/243 (40%) of HA patients, VPA was interrupted; VPA interruption was more frequent in patients with ammonium levels > 100 μg/dl than others (p = 0.001). HA was not an independent predictor of ICU mortality or poor neurological outcome.

In this study, HA was a common finding during treatment with VPA in acutely ill patients. VPA levels, sepsis and mechanical ventilation were risk factors for HA. Hyperammonemia did not influence patients' outcome.