Pharmacological Neuroprotection in Severe Traumatic Brain Injury
The basic pathophysiology of TBI consists of an initial, primary injury including rapid deformation of brain tissue with destruction of brain parenchyma and blood vessels and acute loss of neuronal and glial cells. A key concept in the management of TBI is that not all cell death occurs at the time of primary injury; instead, a cascade of molecular and neurochemical secondary events occur during the initial hours and days with a complex temporal profile. Ultimately, this secondary injury cascade markedly exacerbates the primary injury. Pharmacological attenuation of this secondary injury cascade with the aim of neuroprotection using, e.g. reactive oxygen species scavengers, glutamate receptor modulator, endocannabinoids, hypothermia or magnesium sulphate, has received much attention over several decades in numerous preclinical publications. To date, more than 20 phase III clinical trials have been conducted, and several trials are ongoing (Maas et al. 2010, www.clinicaltrials.gov). Unfortunately, these trials all failed to demonstrate clinical efficacy, and there is no neuroprotective compound currently available for TBI patients. So is neuroprotection for TBI a dead concept not to be pursued clinically or experimentally? Arguably, no. There are likely numerous reasons for the failure of neuroprotective compounds used in clinical trials for TBI, including heterogeneous patient samples and general neurointensive care management. With few exceptions, the pharmacological and hypothermia TBI trials conducted to date have been rather small and have been frequently criticised in terms of study design, route of administration, time window and patient selection (e.g. Marklund and Hillered 2011; Maas et al. 2010). It should be emphasised that TBI is not one disease; instead, all the different subtypes of TBI may require markedly different treatments. Lack of early mechanistic or established surrogate endpoints and the insensitivity of the rather global outcome measures are specific problems in clinical TBI research. It is also obvious that numerous mistakes have been made in the past when attempting to translate preclinical information into the complex human situation. Such shortcomings of preclinical studies include the use of rodent TBI models reaching at most a moderate level of injury, and additionally, only rarely are pharmacological compounds administered beyond the first post-injury hours. Important lessons for future trials include improved patient classification, knowledge of brain penetration and action of the evaluated compound and more carefully defined and detailed outcome measures. Likely, future pharmacological management of TBI patients needs to combine neuroprotective drugs with compounds enhancing regeneration. Until such pharmacological treatment options are developed, neuroprotection for patients suffering from severe TBI is best provided by improved neurointensive care management with the avoidance, detection and treatment of avoidable factors such as seizures, fever, hypotension, hypoxemia, hyper- and hypoglycaemia, low CPP and high ICP. The present chapter reviews important aspects of pharmacological neuroprotection in severe traumatic brain injury. Hypothermia-induced neuroprotection is discussed in another chapter of this book ( Chap. 61).
KeywordsSevere Traumatic Brain Injury Magnesium Sulphate Primary Injury Traumatic Axonal Injury Pharmacological Treatment Option
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