Abstract
BackgroundThe efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. However, published data do not provide a clear picture of the benefits and risks of this drug. We report a retrospective multicentre study on the use of i.v. sodium benzoate in patients treated for UCD between 2000 and 2010 in the 6 French reference centres for metabolic diseases.ResultsSixty-one patients with UCDs - 22 ornithine transcarbamylase (20 confirmed, 2 suspected), 18 arginino-succinate synthetase, 15 carbamoyl phosphate synthetase, 3 arginosuccinate lyase, 1 arginase deficiency, 1 N-acetylglutamate synthetase, 1 HHH syndrome - required i.v. sodium benzoate over the course of 95 acute episodes (NH3 > 100 μmol/L or high-risk situations, i.e., gastroenteritis, surgery). Forty out of 61 patients experienced only one episode of decompensation (neonatal coma, 68.6 %). The most frequent cause of late decompensation was infection (55.5 %). A loading dose of i.v. sodium benzoate (median 250 mg/kg over 2 h) was administered for 41/95 acute episodes. The median maintenance dose was 246.1 mg/kg/day, administered via peripheral venous infusion in all cases except one via a central line. The total median duration of i.v. sodium benzoate treatment per episode was 2 days (0–13 days). The median durations of hospitalization in intensive care and metabolic units were 4 days (0–17 days) and 10 days (0–70 days), respectively. Eight patients died during the neonatal coma (n = 6) or surgery (n = 2). The median plasma ammonium level before treatment was 245.5 μmol/L (20.0–2274.0 μmol/L); it decreased to 40.0 μmol/L in patients who were alive (13.0–181.0 μmol/L) at the end of treatment with i.v. sodium benzoate. A decrease in ammonium level to ≤ 100 μmol/L was obtained in 92.8 % of episodes (64/69 of the episodes recorded for the 53 surviving patients). Five patients required another treatment for hyperammonemia (sodium phenylacetate + sodium benzoate, haemofiltration). Eighteen side effects were reported related to the i.v. infusion (local diffusion, oedema).ConclusionThis 10-year retrospective study shows that i.v. sodium benzoate associated with an emergency regimen is an effective and safe treatment for acute episodes of UCD.
Highlights
The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known
Hyperammonemia is found in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome caused by a mutation in the SLC25A15 gene, which encodes the mitochondrial ornithine and citrulline transporter [4], and in lysinuric protein intolerance (LPI) caused by inherited recessive mutations in the SLC7A7 gene, which encodes for the cationic amino-acids transporter subunit y + LAT1 located on the basolateral plasma membrane of epithelial cells and macrophages
Hyperammonemia can be associated with other inherited metabolic diseases such as organic acidurias, mitochondrial fatty acid oxidation defects and Carbonic anhydrase VA (CAVA) deficiency, a new disease regulating carbamoyl phosphate synthetase 1, and with liver failure and certain cases of iatrogenic intoxication, e.g., those caused by sodium valproate [5]
Summary
The efficacy and safety of intra-venous (i.v.) sodium benzoate for treating acute episodes of hyperammonemia in urea cycle enzyme disorders (UCD) is well known. The urea cycle is the single metabolic pathway that eliminates circulating ammonia, which is the nitrogen waste product from protein catabolism and a potent neurotoxin. It involves a series of biochemical steps in which nitrogen is removed from the blood and converted to urea, which is non-toxic and excreted in the urine. Hyperammonemia can be associated with other inherited metabolic diseases such as organic acidurias, mitochondrial fatty acid oxidation defects and Carbonic anhydrase VA (CAVA) deficiency, a new disease regulating carbamoyl phosphate synthetase 1, and with liver failure and certain cases of iatrogenic intoxication, e.g., those caused by sodium valproate [5]
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