(991) Comparison of Treatment Options for Valproate-Associated Hyperammonemia in Critically Ill Patients

Introduction: Valproic acid (VPA)-associated hyperammonemia can lead to devastating consequences, including cerebral herniation and death. The most effective treatment option remains unknown. This study compared the safety and efficacy of lactulose monotherapy, levocarnitine monotherapy, lactulose in combination with levocarnitine, and no ammonia-lowering therapy in the management of VPA-associated hyperammonemia in critically ill patients.

Methods: This retrospective, multi-center study evaluated adult patients admitted to an intensive care unit (ICU) for ≥24 hours between January 1, 2014 and September 1, 2022. Eligible patients received ≥1 dose of VPA or divalproex, had ≥1 serum ammonia level ≥50 µmol/L, and had ≥2 serum ammonia levels drawn. Patients with cirrhosis, hepatotoxicity, or lactulose use prior to admission were excluded. The primary endpoint was the proportion of patients with ≥20% reduction in serum ammonia levels at 48 hours following initiation of ammonia-lowering therapy. Secondary endpoints included ICU and hospital length of stay (LOS), in-hospital mortality, and the incidence of lactulose-associated hypokalemia and diarrhea.

Results: A total of 43 patients met criteria for inclusion (lactulose n=15, levocarnitine n=6, combination therapy n=7, no ammonia-lowering therapy n=15). VPA was dose reduced or discontinued in 20 (46.5%) and 11 (25.6%) of the total population, respectively. The proportion of patients who achieved ≥20% reduction in serum ammonia levels at 48 hours was not statistically different between groups (lactulose [35.7%], levocarnitine [20%], combination therapy [57.1%], no ammonia-lowering therapy [60%], p=0.347). Patients in the combination therapy group experienced numerically higher ICU and hospital LOS and in-hospital mortality. Among patients who received lactulose, 4.5% experienced severe hypokalemia and 27.3% experienced severe diarrhea.

Conclusions: Hyperammonemia is a potentially devastating consequence of VPA therapy. This study found no difference in efficacy between various treatment modalities. However, results suggest combination therapy with lactulose and levocarnitine is safe and may enhance ammonia excretion compared to monotherapy.