Acute Valproic acid (VPA) toxicity is an emergency condition which may commonly present with
      central nervous system (CNS) depression(5). In mild poisoning, associated with VPA ingestions
      of 200 mg/kg, sedation and lethargy commonly occur(6); while in severe VPA poisoning
      associated with ingestions of 400 mg/kg or more, life threatening events are likely to occur
      as respiratory depression, metabolic acidosis, encephalopathy, hemodynamic instability, and
      cerebral edema which may progress to coma and even death -if not treated promptly. Supportive
      care along with early gastric decontamination using activated charcoal (AC) (which may only
      be given if patient presented early after ingestion), in addition to intravenous (IV)
      administration of Levocarnitine (L-Carnitine) and ensuring adequate airway protection are the
      cornerstone of treatment, but there remains no drug listed as a specific antidote for acute
      VPA intoxication. Carbapenem antibiotics augment the clearance of VPA through suppressing its
      enterohepatic recirculation, as they inhibit the acylpeptide hydrolase enzyme responsible for
      the reabsorption of the hydrolyzed valproate back to VPA active molecule. Taking advantage of
      this well-established drug-drug interaction between VPA and carbapenems resulting in
      significant drop of VPA serum concentration during concomitant use, we propose that
      administration of meropenem (member of carbapenems group) will prove effectiveness in
      managing VPA toxicity by achieving lower plasma levels of VPA and/or enhanced alertness;
      compared with standard care.

Antidote for Valproic Acid Toxicity: a New Indication for Meropenem Antibiotic.

Drug Toxicity

JUSTIFICATION AND SIGNIFICANCE:

      Valproic acid (VPA) -a branched chain carboxylic acid- introduced by the Food and Drug
      Administration in 1978 for the treatment of seizure disorders(1). In the following years, VPA
      gained further approved indications to treat bipolar and behavioral disorders(2), migraine
      prophylaxis(3) as well as other psychiatric indications(4).The growing use of VPA and its
      availability resulted in increased prevalence of VPA overdoses(5,6). The rising incidence of
      acute VPA toxicity is either resulting from suicidal attempts, accidental ingestions, or
      following VPA dose increments to achieve the desired therapeutic effect(7). Acute VPA
      toxicity is an emergency condition which may commonly present with central nervous system
      (CNS) depression(5). In mild poisoning, associated with VPA ingestions of 200 mg/kg, sedation
      and lethargy commonly occur(6); while in severe VPA poisoning associated with ingestions of
      400 mg/kg or more, life threatening events are likely to occur as respiratory depression,
      metabolic acidosis, encephalopathy, hemodynamic instability, and cerebral edema which may
      progress to coma and even death -if not treated promptly(5,8). Serum VPA concentration is the
      most functional tool in diagnosing and determining the severity of toxicity. Supportive care
      along with early gastric decontamination using activated charcoal (AC) (which may only be
      given if patient presented early after ingestion), in addition to intravenous (IV)
      administration of Levocarnitine (L-Carnitine) and ensuring adequate airway protection are the
      cornerstone of treatment, but there remains no drug listed as a specific antidote for acute
      VPA intoxication(5,9).

      Carbapenems are a group of β-lactam antibiotics with a growing need to use in the empiric and
      definitive treatment, due to the emerging resistance to antibiotics(10). A multitude of case
      reports(11-13), retrospective observational studies(14-19) and reviews(20-22) demonstrated
      that combined use of VPA and carbapenem antibiotics -mainly meropenem (16)(23)- is associated
      with a potential drug interaction that can significantly decrease VPA serum
      concentration(24). One retrospective trial included 36 patients concluded that VPA mean ± SEM
      serum concentration dropped from 50.8 ± 4.5 µg/mL to 9.9 ± 2.1 µg/mL(P < .001) following
      meropenem administration with a mean decrease of 82.1% ± 2.7%(18), while a recent prospective
      observational trial determined that the mean drop in serum VPA level was 80% ranging
      from(49%-99%)(23). However, despite VPA toxicity with fatal events being reported for over 20
      years, only a few case reports documented successful intentional use of meropenem as an
      antidote for VPA poisoning(25-27). To date, no randomized-controlled trials were conducted.

      Specific aims: Determine if meropenem is effective in treating acute VPA toxicity, manifested
      by achieving reduced VPA plasma levels and/or enhanced mentation.

      Hypothesis: Administration of meropenem combined with standard care is effective in managing
      VPA intoxication, affirmed by providing lower serum VPA concentrations and/or better level of
      consciousness; in contrast to standard care alone.

      Background: VPA is an antiepileptic drug that has psychiatric indications as well(28). VPA
      acute intoxication is a critical condition listed among fatal pharmaceutical exposures, with
      CNS toxicity being the most common manifestation and may progress to respiratory depression
      and/or coma(5). In 2018, the American Association of Poison Control Centers (AAPCC) Toxic
      Exposure Surveillance System (TESS) database reported 7699 VPA exposures, of which: 2079 were
      treated in health care facilities, 87 resulted in major toxicity, and 19 resulted in
      deaths(29). These data denote that VPA poisoning is becoming an area of growing concern among
      toxicologists.

      Supportive care and ensuring adequate airway protection are the cornerstone of treatment;
      yet, no drug specified as an antidote for managing VPA intoxication(5). Carbapenem
      antibiotics augment the clearance of VPA through suppressing its enterohepatic recirculation,
      as they inhibit the acylpeptide hydrolase enzyme responsible for the reabsorption of the
      hydrolyzed valproate back to VPA active molecule(21). Taking advantage of this
      well-established drug-drug interaction between VPA and carbapenems resulting in significant
      drop of VPA serum concentration during concomitant use(15,17,23), we propose that
      administration of meropenem (member of carbapenems group) will prove effectiveness in
      managing VPA toxicity by achieving lower plasma levels of VPA and/or enhanced alertness;
      compared with standard care.

      Research design and methodology:

      Operational definitions of research variables:

      VPA toxicity: Ingestion of VPA, at doses higher than 60 mg/kg/day, with a serum VPA
      concentration above the therapeutic threshold of 100 µg/mL and/or altered sensorium.

      Standard care: Encompasses supportive care: administration of IV fluids, endotracheal
      intubation for securing airway in patients with altered sensorium, benzodiazepines should be
      administered only if seizures occur and L-carnitine 100 mg/kg IV in cases of hyperammonemia.

      Primary outcome: Evaluate serum VPA concentrations among the two study groups. Secondary
      outcome: Assess patients level of consciousness according to the Glasgow Coma Scale (GCS)
      among the placebo and treatment groups.

      Study Design and Location: This is a multicentered, randomized (1:1), double blinded, placebo
      controlled study where eligible patients will be randomly assigned into two groups using
      simple random sample technique, each patient will either receive: IV meropenem 1gram every 8
      hours together with standard care; or placebo along with standard care. Computer generated
      random number tables, will be used to allocate patients to either treatment or placebo
      groups. We will make the participant and the assessing physician unaware of the treatment.
      The study will be conducted in three poison control centers (PCC) in Egypt: (1) poison
      control center of Ain Shams university hospitals; (2) poison control center of Alexandria
      university hospitals; (3) poison control center of Tanta university hospitals. We will obtain
      their institutional review board and/or ethics committee approval to conduct the study
      protocol prior to study initiation.

      Interventions and Monitoring: Serial VPA serum concentrations to be assessed every two to
      four hours until a steady significant declined level is noted, while neurological status
      assessment of patients will be performed according to the GCS three times daily.

      Sample Size & Power: Based on VPA toxicity levels, mean VPA serum level of 378.3 mg/mL ±
      310.2 mg/mL were reported(7), following meropenem administration, the mean drop in serum VPA
      level was 80%(18,23). Owing to this data, we estimated that a minimum of 48 patients will be
      needed to confirm this effect (α= 5% and power of 90 %).

      Study duration: Reviewing annual reports of PCCs in Egypt, a single PCC received 44 cases of
      VPA toxicity throughout the year 2011(30). Hence, an estimated one-year duration will be
      sufficient to conduct our study over three PCCs in Egypt.

      Proposed statistical analysis: Data will be presented as mean ± standard deviation or median
      with interquartile range. Differences between the two groups will be tested using independent
      sample t-test or Mann-Whitney U-test. Univariate analysis for comparing different demographic
      data between meropenem group and placebo group using Chi square test and t-test as
      applicable, Linear regression will be used to adjust for confounders. The analysis will be
      carried out according to the intention to treat principle.

      Differences will only be considered significant at P <0.05 and statistical analysis will be
      performed using the Stata statistical software, version 16.0.

      Study Limitations: 1) VPA overdoses may occur among patients with history of epilepsy.
      Meropenem is a drug that possess seizure potential, but mainly seizures were reported in
      patients with history of epilepsy and patients with declined renal function. Meanwhile,
      overall seizure rate being 0.7% among immunocompetent patients (24). Meropenem dosage
      reduction is recommended in patients with advanced age and/or patients with renal impairment.

      Compliance to the recommended dosage regimens in addition to bedside digital
      electroencephalogram (EEG) tracings will be urged in epileptic patients.

      2) The results of this study would only apply to patients with the study inclusion criteria,
      further studies should be conducted to cover the excluded criteria population.

      Anticipated results: Meropenem with standard care will exhibit effectiveness in VPA toxicity
      treatment, by achieving lower mean serum concentrations of VPA and/or higher median GCS
      denoting improved sensorium; when compared with standard care alone.

Meropenem Injection

Antidote for Valproic Acid Toxicity: a New Indication for Meropenem Antibiotic. A Randomized Placebo-controlled Trial

Clinical pharmacist

Glasgow coma scale ranging from 3 (not responsive) to 15 (responsive)

Meropenem 1 gram intravenous every 8 hours

Antidote for Valproic Acid Toxicity: a New Indication for Meropenem Antibiotic.

About this trial

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