L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships.

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 [[Formula: see text]; with baseline E0 = 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.

Plasma procalcitonin may be an early predictor of liver injury in acetaminophen poisoning: A prospective cohort study.

BACKGROUND AND AIMS: Acetaminophen is a common cause of poisoning and liver injury worldwide; however, patient stratification is suboptimal. We aimed to assess the contribution of admission plasma procalcitonin concentration (PCT) to better identify acetaminophen-poisoned patients likely to develop liver injury. METHODS: We conducted a prospective observational cohort study including all acetaminophen-poisoned patients requiring N-acetylcysteine admitted in a toxicological intensive care unit between 2012 and 2017. Multivariate analysis was performed using a Cox regression model to investigate factors associated with liver injury, defined as an increase in alanine aminotransferase (ALT) >100 IU/L. RESULTS: One hundred seventeen patients (age, 32 years (21-53), median [25th-75th percentiles]) were included after self-ingesting 16 g (9-30) acetaminophen and received N-acetylcysteine infusion administered within a median 6 h-delay (4-12) from exposure. Co-ingestions were reported in 77% of patients. Rumack-Matthew nomogram was non-interpretable in 47% cases. Liver injury occurred in 38 patients (32%) with a median peak ALT of 2020 IU/L (577-4248). In liver injury patients, admission PCT was significantly increased in comparison to patients without liver injury (21.5 ng/ml (3.2-44.9) versus 0.1 ng/ml (0-0.4), respectively, p < 0.01). The increase in PCT preceded the increase in ALT by 33 h (10-74). In a multivariate analysis, PCT > 1 ng/ml was significantly associated with liver injury (hazard ratio, 7.2 [95% confidence interval, 2.3-22.6; p < 0.001]). PCT (area under the receiver-operating characteristics curve, 0.91 [95%CI: 0.84-0.97]) predicted liver injury with sensitivity, specificity, negative, and positive predictive values of 0.92, 0.84, 0.96, and 0.73, respectively. CONCLUSION: PCT on admission is associated with liver injury in acetaminophen poisoning. PCT might be used as a predictive tool of liver injury to improve clinical decision-making.

False positive amphetamines and 3,4-methylenedioxymethamphetamine immunoassays in the presence of metoprolol-two cases reported in clinical toxicology.

Amphetamines, frequently used recreational drugs with high risk of toxicity, are commonly included in urine drug screens. This screening is based on enzyme immunoassay, which is a quick and easy-to-perform technique, but may lack specificity resulting from cross-reactivity with other compounds, causing false positive results. We present two cases of presumed false positive MULTIGENT® amphetamine/methamphetamine and MULTIGENT® ecstasy (Abbott®) immunoassays with the beta-blocker metoprolol. Both metoprolol-poisoned patients presented positive urine screening despite no history of drug abuse. No confirmation for amphetamine molecular structures was found with gas chromatography-mass spectrometry. The cross-reactivity was further investigated by doping urine samples with metoprolol and its two major phase-I metabolites. Metoprolol showed positive results for both amphetamine and MDMA tests at low concentrations (200 and 150 µg/mL, respectively). Metoprolol metabolites cross-reacted with the amphetamines immunoassay only, but at higher concentrations (i.e., 2000 µg/mL for α-hydroxymetoprolol and 750 µg/mL for O-demethylmetoprolol). In conclusion, false positive results in amphetamines and MDMA immunoassays are possible in the presence of metoprolol. Toxicologists should be aware of frequent analytical interferences with immunoassays and a detailed medication history should be taken into consideration for interpretation. In vitro investigation of suspected cross-reactivity should include not only the parent drug but also its related metabolites.