L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships
Philippe Nguyên, L Chevillard, Ahmed S. Gouda, H. Gourlain, Laurence Labat, Isabelle Malissin, Nicolas Deye, Sébastian Voicu, Bruno Mégarbane
Abstract
Abstract Background Valproic acid (VPA) poisoning is responsible for life-threatening neurological and metabolic impairments. Despite only low-level evidence of effectiveness, L-carnitine has been used for years to prevent or reverse VPA-related toxicity. We aimed to evaluate the effects of L-carnitine used to treat acute VPA poisoning on the time-course of plasma VPA concentrations and VPA-related toxicity. We designed a single-center cohort study including all VPA-poisoned patients admitted to the intensive care unit. We studied VPA toxicokinetics using a nonlinear mixed-effects model-based population approach and modeled individual plasma VPA/blood lactate concentration relationships. Then, we evaluated L-carnitine-attributed effects by comparing VPA elimination half-lives and time-courses of blood lactate levels and organ dysfunction [assessed by the Sequential Organ Failure Assessment (SOFA) score] between matched L-carnitine-treated and non-treated patients using a multivariate analysis including a propensity score. Results Sixty-nine VPA-poisoned patients (40F/29 M; age, 41 years [32–47]) (median [25th–75th percentiles]; SOFA score, 4 [1–6]) were included. The presumed VPA ingested dose was 15 g [10–32]. Plasma VPA concentration on admission was 231 mg/L [147–415]. The most common manifestations were coma (70%), hyperlactatemia (3.9 mmol/L [2.7–4.9]) and hyperammonemia (127 mmol/L [92–159]). VPA toxicokinetics well fitted a one-compartment linear model with a mean elimination half-life of 22.9 h (coefficient of variation, 28.1%). Plasma VPA (C)/blood lactate concentration (E) relationships were well described by an exponential growth equation [ $$E={E}_{0}\times {e}^{k\cdot C}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>E</mml:mi> <mml:mo>=</mml:mo> <mml:msub> <mml:mi>E</mml:mi> <mml:mn>0</mml:mn> </mml:msub> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mi>e</mml:mi> </mml:mrow> <mml:mrow> <mml:mi>k</mml:mi> <mml:mo>·</mml:mo> <mml:mi>C</mml:mi> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> ; with baseline E 0 = 1.3 mmol/L (43.9%) and rate constant of the effect, k = 0.003 L/mg (59.5%)]. Based on a multivariate analysis, peak blood lactate concentration was the only factor independently associated with L-carnitine administration (odds ratio, 1.9, 95% confidence interval, 1.2–2.8; P = 0.004). We found no significant contribution of L-carnitine to enhancing VPA elimination, accelerating blood lactate level normalization and/or preventing organ dysfunction. Conclusions VPA poisoning results in severe toxicity. While L-carnitine does not contribute to enhancing VPA clearance, its impact on accelerating blood lactate level normalization and/or preventing organ dysfunction remains uncertain. Investigating VPA toxicokinetics and concentration/effect relationships may help understanding how to improve VPA-poisoned patient management.