Despite preventative measures, traumatic brain injury (TBI) remains the leading cause of death and disability in children – affecting thousands of children each year in the US and abroad. According to the CDC, traumatic brain injury (TBI) results in 1.4 million emergency visits, 275,000 hospital visits, 52,000 deaths and more than $56 billion in acute care costs each year. Costs for long-term care and lost productivity are much greater – with estimates of over $99 billion per year for motor vehicle injuries alone in 2005. For the past several decades, TBI has been the leading killer of US children with 7000 deaths of children < 19 y in 2005. Moreover, children < 4 y have the highest incidence of any group (http://www.cdc.gov/traumaticbraininjury/pdf/blue_book.pdf). Non-governmental sources confirm this burden of disease. One study estimates that at least 145,000 children were living with a TBI-related disability in 2005 and the overall total life costs (medical costs and productivity losses) of injuries for children < 14 y of age was $60.4 billion. Using estimates of mortality and unfavorable outcome from the most recent trial [20% mortality, 50.6% unfavorable outcomes at 6 m [measured by dichotomous Glasgow Outcome Scale – Extended Pediatric Revision (GOS-E Peds)], mean age = 9 y, normal life-expectancy = 77.9 y], approximately 1.3 million life-years are potentially adversely affected by TBI every year. Overall, pediatric TBI is a leading public health problem in the US and worldwide with substantial costs to its victims and society. Any incremental improvements in outcome could impact thousands of lives.
Extensive efforts have been made to determine the optimal approaches to TBI care and to develop novel neuroprotective therapies for adult and pediatric TBI victims. Observational studies, such as those utilizing the Traumatic Coma Databank, provided insight on the natural history of TBI. These studies also provided a platform to understand basic aspects of TBI care, including appropriate clinical outcomes to be tested. These preclinical hypotheses were translated into clinical trials over the past decades, with multi-centered RCTs considered the “gold-standard” for advancing clinical practice.
Unfortunately, these efforts have not led to the anticipated breakthroughs. In a recent review of the 33 randomized controlled trials (RCTs) of various therapies for adult TBI victims completed within the last several decades, none of the multi-centered RCTs proved their hypotheses by demonstrating improved patient outcomes. A wide variety of therapeutic mechanisms were targeted including steroids, cannabinoids, calcium-channel antagonists, glutamate antagonists, magnesium, decompressive surgery, hypothermia and others, with all demonstrating efficacy in preclinical models and/or small clinical trials. While the particular cause of each failure remains uncertain, many have argued that variations in clinical practices at the sites overwhelmed any potential experimental signal from the therapy being tested. Specifically, Lingsma and colleagues demonstrated that inter-center differences were the most important determinant of patient outcomes in the International Mission on Prognosis and Clinical Trial in Traumatic Brain Injury (IMPACT) study – which combined data from 10 RCTs and 3 observational trials in adults with severe TBI. These authors argue convincingly that these differences in outcomes across sites diminish the ability of RCTs to detect differences between experimental and control groups – theoretically hindering all PIs from proving their hypotheses of novel therapies.
For pediatric TBI, the therapies evaluated in RCTs were different, yet the results were quite similar. We identified a total of 9 RCTs that tested a TBI-related therapies that were (i) published in English, (ii) included only children with severe TBI and (iii) had identifiable, clinically-relevant outcomes). Of these, only the 3 hypothermia studies were multi-centered. One RCT demonstrated the effectiveness of hypertonic saline (HTS) at lowering intracranial pressure, but none demonstrated efficacy of the therapy to improve overall outcome. Hutchison and colleagues published the only multi-centered phase III RCT – testing the efficacy of early hypothermia. In this trial of 225 children, early hypothermia failed to improve 6 m outcomes or mortality. Similar to the NABIS:H trial, these authors noted substantial variation in several aspects of TBI care, including hypotension/ inadequate cerebral perfusion pressure (CPP) in the hypothermia group and increased HTS administration in the normothermia group. Recently, another multi-centered, phase III RCT for hypothermia (Pediatric Traumatic Brain Injury Consortium: Hypothermia, the “Cool Kids Trial”) was stopped for futility and a detailed analysis of the variability observed within this trial is presented below. It is clear that multi-centered RCTs for TBI have failed to demonstrate effectiveness of a wide-number of therapies – undoubtedly from a host of reasons – arguing that other approaches may advance the field.
Advances in care can come from a variety of scientific approaches, not just from RCTs. Unbiased summaries of the available literature – from prospective observational studies, retrospective analyses or other study designs as well as RCTs – may also enlighten the field to therapeutic strategies that should be offered to all children with a given disease. For pediatric TBI, evidenced-based guidelines were first published in 2003 and have recently been revised. For the new guidelines, an expert panel (15 clinicians including pediatric neurosurgeons, emergency medicine physicians, intensivists, anesthesiologists, neurologists and surgeons and 3 methodologists) were selected by the Brain Trauma Foundation based on their expertise. This panel determined topics for inclusion within the guidelines based on (i) the sufficiency of the evidence within the topic and (ii) the link between the topic and outcomes. Based on these criteria, 15 topics (see Table) were selected including 8 medical interventions (hyperosmolar therapies, temperature, CSF diversion, barbiturates, hyperventilation, corticosteroids, analgesia/sedation/neuromuscular blockade and nutrition/glucose). A doctoral-level librarian performed extensive literature searches to identify articles that met the inclusion criteria – clearly defined patient population of children with severe TBI, identifiable independent variables (treatments) and dependent variables (outcomes), adequate sample size – for each topic. Level I, II and III recommendations were made for therapies that “must be done”, “should be considered” and “may be considered”, respectively. The guidelines underwent peer-review by an additional 14 external reviewers and were reviewed and endorsed by 10 associations/societies including AAP – Section on Neurological Surgery, American Association of Neurological Surgeons, Society of Critical Care Medicine, Child Neurology Society, European Society of Pediatric and Neonatal Intensive Care and the Paediatric Intensive Care Society-UK.
The new guidelines shed light on our inadequate knowledge of treatments for pediatric TBI. Specifically, there was insufficient evidence to support a Level I recommendation for any of the topics. Moreover, there was evidence to support only 4 Level II recommendations for medical therapies ” (i), the use of corticosteroids is not recommended to improve outcome or reduce ICP, (ii) moderate hypothermia beginning early after severe TBI for only 24 h should be avoided, (iii) an immune-enhanced diet should be avoided and (iv) HTS should be considered for treatment of intracranial hypertension. In summary, the existing literature cannot recommend that a clinician “must do” any aspect of the 15 therapies or maneuvers identified by the pediatric neurotrauma community. Importantly, there is only evidence that a clinician “should consider” use of HTS during intracranial hypertension episodes with the remaining 3 level II recommendations (hypothermia, steroids, immune-enhanced diets) suggesting that therapies should be avoided. Analysis of the level III recommendations offers clinicians little guidance as well (with precise wording of all 14 recommendations outlined in the Table). As an example, the guidelines can only recommend that ICP monitoring “may be considered” and can only suggest that a threshold of 20 mm Hg “may be considered”. However, many of the other recommendations are predicated on providing therapies during intracranial hypertension ” which would not be diagnosed without the ICP monitor providing the necessary data and the clinician deciding on an appropriate threshold for ICP. Furthermore, basic questions regarding therapies that are widely believed to improve outcome and must be answered by the clinician caring for a child with severe TBI ” will CSF diversion lead to improved outcome?; are hyperosmolar therapies effective?; does prophylactic hyperventilation harm recovery?; should new methods to monitor for brain hypoxia be utilized?; how many calories are needed for optimal recovery?; when should glucose be administered? ” remain unaddressed by the guidelines. This lack of evidence frustrates evidenced-based clinical decision-making for all children with TBI and introduces uncontrollable variability into research protocols that attempt to standardize practices at multiple sites to successfully detect an experimental signal of a prospective therapy.
We are left with a conundrum: (i) high-quality, multi-centered RCTs are needed to generate guidelines compelling enough to change practice and improve outcomes; (ii) we lack sufficient understanding on fundamental aspects of TBI care that experts agree are associated with outcomes; (iii) therefore, we cannot develop clinical protocols for multi-center RCTs that limit variability of these practices; (iv) ultimately leading to failed RCTs and no advances in TBI care. For the leading killer of children, an alternate approach is essential and we have assembled an international team of investigators to pursue this alternative.
Comparative effectiveness research (CER) is defined by the Institute of Medicine (IOM) as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care as any clinical research strategy” . The choice of study designs to accomplish this broad goal can vary. For instance, if two therapies both have proven efficacy in phase III trials, then an RCT comparing the effectiveness of these two therapies is warranted and would constitute a CER approach. As outlined above, there are no proven therapies in pediatric TBI. However, observational studies using CER methodologies can determine important associations between therapies and outcomes by using statistical methods to control for confounders.
The ADAPT investigators will enroll 1,000 children with a severe traumatic brain injury who require the placement of an ICP monitor an observational cohort study to test the address the following aims:
- Specific Aim 1: Compare the effectiveness of first-line intracranial hypertension strategies.
- Specific Aim 2: Compare the effectiveness of strategies that mitigate iatrogenic ischemia and hypoxia.
- Specific Aim 3: Compare the effectiveness of strategies that provide metabolic support on outcome.