Approaches and Decisions for Acute Pediatric TBI Trial

Study Overview
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Brief Summary
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Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) is an international research study designed to evaluate the impact of interventions on the outcomes of children with severe traumatic brain injury. Pediatric traumatic brain injury (TBI) is the leading killer of children, resulting in more than 7000 deaths and $2 billion in acute care costs each year. Despite this large burden of disease, advances in the field have been limited due to weak evidenced-based guidelines and the limitations of randomized, controlled trials (RCTs) to demonstrate efficacy of single treatment strategies due to wide treatment variability. ADAPT is a practical study design in a novel approach - an observational cohort study designed to evaluate the association of 6 aspects of pediatric TBI care with outcomes using statistical modeling to correct for confounding variables. Completion of this study will provide compelling evidence to change clinical practices, provide evidence for new Level II recommendations for future guidelines and lead to improved research protocols that would limit variability in TBI treatments - helping children immediately through better clinical practices and ultimately through more effective investigation.

Detailed Description
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Traumatic brain injury (TBI) is the leading cause of death in children in the US. According to the CDC, 7440 children died of TBI in 2005, but this likely underestimates the full burden of the disease. Based on the current best estimates for severe pediatric TBI (20% mortality, 50.6% unfavorable 6 mo outcome, mean age 9 y), each year 37,200 children suffer a severe TBI with up to 1.3 million life-years potentially adversely affected. Incremental improvement in outcomes could make enormous differences for the health of children, but such advances have remained elusive. Dozens of injury mechanisms have been identified after experimental TBI, yet no mitigating treatments have been translated into clinical practice. Randomized controlled trials (RCTs) of therapies, from steroids to novel pharmaceutical agents to hypothermia, have failed for adult and pediatric TBI victims. Single-center experiences have contributed to understanding, yet these largely remain insufficiently powerful to change practice. Recently, evidenced-based guidelines for 15 aspects of pediatric TBI were published that provide no level I and only 4 Level II recommendations - with such recommendations indicating therapies that must be done or should be considered based on the literature, respectively. Disappointingly, 3 of these recommendations advised against specific interventions (hypothermia, steroids and immune-enhanced diets) - emphasizing the uncertainty of the effectiveness of many commonly used therapies that leads to wide variations in clinical practice. Unsurprisingly, significant variations of clinical outcomes and basic treatment strategies for TBI have been observed. The IMPACT study merged data from over 9000 adults with TBI from 11 trials and demonstrated significant variations in outcomes from clinical sites. Similar variations in outcomes in children with TBI can be found using various administrative databases, with mortality rates varying between 12.2% - 34.4% in 11 US states. There are also variations in strategies within an international consortium and a recently completed RCT - with marked variations in strategies for first-line intracranial hypertension treatments, prevention of common secondary insults and metabolic support after pediatric TBI. The paucity of data to create robust guidelines, the failure of RCTs that tested a wide-variety of putative mechanisms and variations in outcomes and in clinical practices argues that the current understanding of contemporary therapies is inadequate. Because neither retrospective analyses from available databases nor self-reported variations in practices can determine optimal therapeutic strategies for these contemporaneous strategies, a new approach is urgently needed. ADAPT is a large, prospective, observational cohort study using an international consortium including sites from the US, EU and UK. Children with severe TBI [Glasgow coma scale (GCS) score ≤ 8 with intracranial pressure (ICP) monitoring, n = 1000, >32 sites] will be studied. The local standard of care at each site will be used and extensive data collection over the first 7 days after TBI will be performed to interrogate the effectiveness of strategies for intracranial hypertension, mitigation of specific secondary insults and metabolism. Several statistical approaches, often used in comparative effectiveness research (CER) to control for measured confounding effects, will test the following aims: Specific Aim 1: Compare the effectiveness of first-line intracranial hypertension strategies on outcome. Intracranial hypertension management is a mainstay of TBI care yet evidence for utilization the first-line therapies of cerebrospinal fluid (CSF) diversion and use of hyperosmolar solutions, is incomplete. Aim 1a: Determine the effect of CSF diversion strategies (continuous drainage, intermittent drainage and none) on outcome. Aim 1b: Determine the effect of hyperosmolar therapies (hypertonic saline, mannitol) on outcome. Specific Aim 2: Compare the effectiveness of strategies that mitigate specific secondary insults on outcome. Prophylactic hyperventilation (HV) and hypoxia may worsen outcome after TBI but have been inadequately studied. Aim 2a: Determine the effect of prophylactic HV (CO2 < 30 mm Hg) on outcome. Aim 2b: Determine the effect of hypoxia detection with brain tissue oxygen monitoring (PbO2) on outcome.

Official Title
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Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial

Conditions
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Severe Traumatic Brain Injury

Intervention / Treatment
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* Other: Observational


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admission to a study site for treatment of severe traumatic brain injury ICP monitor placed as part of the child's standard care Glasgow Coma Scale (GCS) ≤ 8 after resuscitation Age 0 - 18 y Exclusion Criteria: 1. ICP Monitor placed at another hospital 2. Diagnosis of pregnancy in clinical subject

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Children with severe TBI<br>Children with severe Traumatic Brain Injury | Other: Observational<br>* This is an observational study with no interventions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glasgow Outcome Score - Extended Pediatrics | Physician-rated assessment of functional outcome. Problems in functioning should have deteriorated from premorbid level. The categories are: 8 - Death 7 - Vegetative State (VS) 6 - Lower Severe Disability (Lower SD) 5 - Upper Severe Disability (Upper SD) 4 - Lower Moderate Disability (Lower MD) 3 - Upper Moderate Disability (Upper MD) 2 - Lower Good Recovery (Lower GR) 1 - Upper Good Recovery (Upper GR) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBI, Severe Traumatic Brain Injury, Intracranial hypertension, Cerebrospinal fluid, Hypersmolar therapies, Prophylactic hyperventilation, Metabolism, Neuropsychology