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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 One patient in the placebo group was withdrawn due to adverse effects.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 ?g/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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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:OBJECTIVES:A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study. DESIGN:Randomized prospective clinical trial. SETTING:Ten ICUs in the United States. PATIENTS:One hundred nineteen severe traumatic brain injury patients. INTERVENTIONS:Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended. MEASUREMENTS AND MAIN RESULTS:A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy. CONCLUSIONS:Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.

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.

Project description:ImportanceDiversion of cerebrospinal fluid (CSF) has been used for decades as a treatment for children with severe traumatic brain injury (TBI) and is recommended by evidenced-based guidelines. However, these recommendations are based on limited studies.ObjectiveTo determine whether CSF diversion is associated with improved Glasgow Outcome Score-Extended for Pediatrics (GOS-EP) and decreased intracranial pressure (ICP) in children with severe TBI.Design, setting, and participantsThis observational comparative effectiveness study was performed at 51 clinical centers that routinely care for children with severe TBI in 8 countries (US, United Kingdom, Spain, the Netherlands, Australia, New Zealand, South Africa, and India) from February 2014 to September 2017, with follow-up at 6 months after injury (final follow-up, October 22, 2021). Children with severe TBI were included if they had Glasgow Coma Scale (GCS) scores of 8 or lower, had intracranial pressure (ICP) monitor placed on-site, and were aged younger than 18 years. Children were excluded if they were pregnant or an ICP monitor was not placed at the study site. Consecutive children were screened and enrolled, data regarding treatments were collected, and at discharge, consent was obtained for outcomes testing. Propensity matching for pretreatment characteristics was performed to develop matched pairs for primary analysis. Data analyses were completed on April 18, 2022.ExposuresClinical care followed local standards, including the use of CSF diversion (or not), with patients stratified at the time of ICP monitor placement (CSF group vs no CSF group).Main outcomes and measuresThe primary outcome was GOS-EP at 6 months, while ICP was considered as a secondary outcome. CSF vs no CSF was treated as an intention-to-treat analysis, and a sensitivity analysis was performed for children who received delayed CSF diversion.ResultsA total of 1000 children with TBI were enrolled, including 314 who received CSF diversion (mean [SD] age, 7.18 [5.45] years; 208 [66.2%] boys) and 686 who did not (mean [SD] age, 7.79 [5.33] years; 437 [63.7%] boys). The propensity-matched analysis included 98 pairs. In propensity score-matched analyses, there was no difference between groups in GOS-EP (median [IQR] difference, 0 [-3 to 1]; P = .08), but there was a decrease in overall ICP in the CSF group (mean [SD] difference, 3.97 [0.12] mm Hg; P < .001).Conclusions and relevanceIn this comparative effectiveness study, CSF diversion was not associated with improved outcome at 6 months after TBI, but a decrease in ICP was observed. Given the higher quality of evidence generated by this study, current evidence-based guidelines related to CSF diversion should be reconsidered.

Project description:BACKGROUND:Early tracheostomy has been associated with shorter hospital stay and fewer complications in adult trauma patients. Guidelines for tracheostomy have not been established for children with severe traumatic brain injury (TBI). The purpose of this study was to (1) define nationwide trends in time to extubation and time to tracheostomy and (2) determine if early tracheostomy is associated with decreased length of stay and fewer complications in children with severe TBI. METHODS:Records of children (<15 years) with severe TBI (head Abbreviated Injury Severity [AIS] score ?3) who were mechanically ventilated (>48 hours) were obtained from the National Trauma Data Bank (2007-2015). Outcomes after early (?14 days) and late (?15 days) tracheostomy placement were compared using 1:1 propensity score matching to control for potential confounding by indication. Propensity scores were calculated based on age, race, pulse, blood pressure, Glasgow Coma Scale motor score, injury mechanism, associated injury Abbreviated Injury Severity scores, TBI subtype, craniotomy, and intracranial pressure monitor placement. RESULTS:Among 6,101 children with severe TBI, 5,740 (94%) were extubated or died without tracheostomy, 95% of the time within 18 days. Tracheostomy was performed in 361 children (6%) at a median [interquartile range] of 15 [10, 22] days. Using propensity score matching, we compared 121 matched pairs with early or late tracheostomy. Early tracheostomy was associated with fewer ventilator days (14 [9, 19] vs. 25 [19, 35]), intensive care unit days (19 [14, 25] vs. 31 [24, 43]), and hospital days (26 [19, 41] vs. 39 [31, 54], all p < 0.05). Pneumonia (24% vs. 41%), venous thromboembolism (3% vs. 13%), and decubitus ulcer (4% vs. 13%) occurred less frequently with early tracheostomy (p < 0.05). CONCLUSIONS:Early tracheostomy is associated with shorter hospital stay and fewer complications among children with severe TBI. Extubation without tracheostomy is rare beyond 18 days after injury. LEVEL OF EVIDENCE:Prognostic and epidemiological, retrospective comparative study, level III.

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.

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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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