Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children

PLoS One. 2017 Jul 7;12(7):e0180280. doi: 10.1371/journal.pone.0180280. eCollection 2017.


Background: There are no therapies shown to improve outcome after severe traumatic brain injury (TBI) in humans, a leading cause of morbidity and mortality. We sought to verify brain exposure of the systemically administered antioxidant N-acetylcysteine (NAC) and the synergistic adjuvant probenecid, and identify adverse effects of this drug combination after severe TBI in children.

Methods: IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 years-of-age admitted to a Pediatric Intensive Care Unit after severe TBI (Glasgow Coma Scale [GCS] score ≤8) requiring an externalized ventricular drain for measurement of intracranial pressure (ICP). Patients were recruited from November 2011-August 2013. Fourteen patients (n = 7/group) were randomly assigned after obtaining informed consent to receive probenecid (25 mg/kg load, then 10 mg/kg/dose q6h×11 doses) and NAC (140 mg/kg load, then 70 mg/kg/dose q4h×17 doses), or placebos via naso/orogastric tube. Serum and CSF samples were drawn pre-bolus and 1-96 h after randomization and drug concentrations were measured via UPLC-MS/MS. Glasgow Outcome Scale (GOS) score was assessed at 3 months.

Results: There were no adverse events attributable to drug treatment. One patient in the placebo group was withdrawn due to adverse effects. In the treatment group, NAC concentrations ranged from 16,977.3±2,212.3 to 16,786.1±3,285.3 in serum and from 269.3±113.0 to 467.9±262.7 ng/mL in CSF, at 24 to 72 h post-bolus, respectively; and probenecid concentrations ranged from 75.4.3±10.0 to 52.9±25.8 in serum and 5.4±1.0 to 4.6±2.1 μg/mL in CSF, at 24 to 72 h post-bolus, respectively (mean±SEM). Temperature, mean arterial pressure, ICP, use of ICP-directed therapies, surveillance serum brain injury biomarkers, and GOS at 3 months were not different between groups.

Conclusions: Treatment resulted in detectable concentrations of NAC and probenecid in CSF and was not associated with undesirable effects after TBI in children.

Trial registration: NCT01322009.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Acetylcysteine / blood
  • Acetylcysteine / cerebrospinal fluid
  • Acetylcysteine / pharmacokinetics*
  • Acetylcysteine / pharmacology
  • Adjuvants, Pharmaceutic / pharmacokinetics*
  • Adjuvants, Pharmaceutic / pharmacology
  • Adolescent
  • Antioxidants / pharmacokinetics*
  • Antioxidants / pharmacology
  • Biomarkers / blood
  • Body Temperature
  • Brain Injuries, Traumatic / blood
  • Brain Injuries, Traumatic / cerebrospinal fluid
  • Brain Injuries, Traumatic / drug therapy*
  • Brain Injuries, Traumatic / mortality
  • Child
  • Child, Preschool
  • Double-Blind Method
  • Drug Administration Schedule
  • Female
  • Glasgow Coma Scale
  • Glasgow Outcome Scale
  • Humans
  • Intracranial Pressure / drug effects
  • Intubation, Gastrointestinal
  • Male
  • Probenecid / blood
  • Probenecid / cerebrospinal fluid
  • Probenecid / pharmacokinetics*
  • Probenecid / pharmacology
  • Survival Analysis


  • Adjuvants, Pharmaceutic
  • Antioxidants
  • Biomarkers
  • Probenecid
  • Acetylcysteine

Associated data