Traumatic Brain Injury Research: State of Play and Unmet Needs

The failure of clinical neuroprotection in traumatic brain injury (TBI) is well documented. Experimental medicine strategies may allow better optimization of candidate therapies, but a more fundamental re-engineering of translation may be warranted.  There is cause for optimism: the success of protocol driven management suggests that t clinical neuroprotection does not represent an insurmountable problem. However, the complexity of clinical TBI is an important confounder: the variability of TBI, the impact brief periods of prehospital hypoxia or hypotension, or the profound effect of variations in the quality of clinical management may simply dilute treatment effects beyond detectability.  The development of robust risk adjustment schemes may provide an important tool to deal with these issues.  We also need to recognise the changing epidemiology of TBI, which now involves older patients, and more commonly affects developing economies.  Not accounting for these changing trends in clinical trials runs the risk of reducing their generalisability.  We also need to tailor individual TBI therapies more carefully, based on genotype, stage of disease evolution, and particular risk factors for the side effects of therapy – thus moving increasingly into an era of stratified or personalized medicine. The increasing use of bedside physiological and metabolic monitoring raises the hope that this may be an increasingly achievable aspiration.  Perhaps one of the first advantages of such rationally targeted therapy may be to avoid therapies that cause harm, or limit their use to patients and situations where their benefit (and hence their risk-benefit ratio) is maximal.    It is worth noting that the increasing effectiveness of modern neurocritical care in controlling ICP has substantially blunted our ability to use intracranial hypertension as a useful surrogate outcome.  While clinical remains the ultimate test of efficacy, we need to find new biomarkers that can provide robust interim evidence of probable efficacy in preliminary studies. Modern imaging techniques may provide important tools in this context.  It is also important to ensure that healthcare delivery systems are optimally organised to maximise outcome.  However, questions such as the optimal location of care, and the implementation of complex physiologically targeted critical care may not be easily studied using conventional clinical trials.  There is therefore a strong argument to adopt comparative effectiveness research as an additional tool study new and existing therapies in TBI.