Dataset Information

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

ABSTRACT:

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 One patient in the placebo group was withdrawn due to adverse effects.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

ClinicalTrials.gov NCT01322009.

SUBMITTER: Clark RSB

PROVIDER: S-EPMC5501440 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Clark Robert S B RSB Empey Philip E PE Bayır Hülya H Rosario Bedda L BL Poloyac Samuel M SM Kochanek Patrick M PM Nolin Thomas D TD Au Alicia K AK Horvat Christopher M CM Wisniewski Stephen R SR Bell Michael J MJ

PloS one 20170707 7

<h4>Background</h4>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.<h4>Methods</h4>IRB-approved, randomized, double-blind, placebo controlled Phase I study in children 2 to 18 ...[more]

PMID: 28686657

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Project description:ImportanceIntracranial pressure (ICP) monitoring is a mainstay of therapy for children with traumatic brain injury (TBI), but its overall association with patient outcome is unclear.ObjectiveTo test the hypothesis that ICP monitoring is associated with improved functional survival of children with severe TBI.Design, setting, and participantsA propensity-weighted effectiveness analysis was conducted using 2 linked national databases with data from 30 US children's hospitals from January 1, 2007, to December 31, 2012, on 3084 children with severe TBI. Clinical events including neurosurgical procedures were identified using validated computable phenotypes. Data analysis was conducted from September 1, 2016, to March 1, 2017.ExposurePlacement of an ICP monitor.Main outcomes and measuresA composite of hospital mortality, discharge to hospice, or survival with placement of new tracheostomy and gastrostomy tubes.ResultsOf the 3084 children in the study (1128 girls and 1956 boys; mean [SD] age, 7.03 [5.44] years), 1002 (32.4%) underwent ICP monitoring, with substantial hospital variation (6% to 50% by hospital). Overall, 484 children (15.7%) experienced the primary composite outcome. A propensity approach using matching weights generated good covariate balance between those who did and those who did not undergo ICP monitoring. Using a propensity-weighted logistic regression model clustered by hospital, no statistically significant difference was found in functional survival between monitored and unmonitored patients (odds ratio of poor outcome among those who underwent ICP monitoring, 1.31; 95% CI, 0.99-1.74). In a prespecified secondary analysis, no difference in mortality was found (odds ratio, 1.16; 95% CI, 0.89-1.50). Prespecified subgroup analyses of children younger and older than 2 years of age and among those with unintentional and inflicted (intentional) injuries also showed no difference in outcome with ICP monitoring.Conclusions and relevanceWith the use of linked national data and validated computable phenotypes, no evidence was found of a benefit from ICP monitoring on functional survival of children with severe TBI. Intracranial pressure monitoring is a widely but inconsistently used technology with incompletely demonstrated effectiveness. A large prospective cohort study or randomized trial is needed.

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Dataset Information

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

Background

Methods

Results

Conclusions

Trial registration

Publications

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

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