Key Mechanisms of Secondary Neuronal Damage After Brain Trauma

Abstract

Progress in the successful application of novel therapies in the treatment of severe traumatic brain injury (TBI) in humans has been disappointing [1]. Currently, treatment is limited to field stabilization and supportive neurointensive care, the application of clinically accepted strategies to control intracranial hypertension, and surgical resection of mass lesions [2]. A number of novel therapies have shown promise in contemporary experimental models of severe TBI [3], but none has been successfully translated to clinical use via a randomized controlled clinical trial demonstrating a beneficial effect on outcome. Examples of important failures include the trials of two agents targeting oxidative injury, tirilazad [4] and Superoxide dismutase (SOD) [5], and one targeting excitotoxicity, Selfotel [6]. Both oxidative injury and excitotoxicity are felt to represent important mechanisms of secondary damage in laboratory models and in the clinical condition [3, 7]. Even mild hypothermia (32-34°C), the most promising therapy as applied in experimental models of TBI [8–11] and in preliminary clinical investigation [12–15], failed to demonstrate unequivocal efficacy in a recent multicenter randomized controlled clinical trial of severe TBI. Some of these failures may reflect the considerable difficulties encountered in conducting successful randomized clinical trials in the setting of acute brain injury, such as the lack of knowledge of temporal therapeutic windows of opportunity for any therapy and the inability to select appropriate patients during the acute phase [1, 4, 16]. For example, Shiozaki et al. [16] reported that therapeutic hypothermia, applied after severe TBI in adults was ineffective in the absence of intracranial hypertension. However, delaying the application of hypothermia until intracranial hypertension has developed would very likely diminish its efficacy [17, 18].KeywordsTraumatic Brain InjuryIntracranial HypertensionCerebral Blood VolumeSevere Traumatic Brain InjuryAxonal InjuryThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.