Current Pharmaceutical Design - Volume 7, Issue 15, 2001

Traumatic brain injury is a major health problem in all developed countries. The main aim of this review is to provide a short update on the most recent advances in our knowledge of the brain's response to mechanical injuries, focusing on metabolic, cellular, subcellular, and molecular events that take place in severe head injuries. Knowledge of these events is essential for a better understanding of new pharmacological avenues and non-pharmacological strategies, such as moderate hypothermia, which are being developed to improve the outcome of this silent epidemic. We will focus on several topics that we consider to be the most significant: diffuse axonal injury, ischemia and the cascades it generates, metabolic derangements, excitotoxicity, oxidative stress, and other phenomena that have been included in the term tertiary injuries. Recent evidence has clearly demonstrated that traumatic brain lesions are highly dynamic and that the different lesions observed after closed head injury are not single events but processes set in motion by the mechanical impact. These processes are not finished until an unpredictable time after injury. We will discuss recent evidence showing that in diffuse axonal injury, primary immediate damage can coexist with axons that, although initially intact, may be evolving towards secondary disconnection. The concept of ischemic penumbra and the more recent concept of traumatic penumbra are discussed, together with recent experimental and clinical data that shed light on the non-ischemic forms of brain hypoxia. The role of excitotoxicity in mechanically-induced cell death and the molecular events that excessive release of glutamate induce, including apoptosis and delayed inflammatory processes, are reviewed. Finally, new knowledge on how central nervous system cells regulate their volume, the new family of channel water molecules known as aquaporins and their possible role in the physiopathology of the swollen brain are discussed. Basic and clinical investigations are still needed to translate the huge amount of pathophysiological knowledge acquired in the last decade into effective treatments for these patients.

Considerable effort has led to an increased interest in emerging preclinical and clinical data regarding the pathophysiological changes in the posttraumatic brain. It is widely believed that delayed cell damage and death contributes to behavioral impairment following traumatic brain injury. However, no drug therapy to attenuate this process is available at present, and the development of new therapeutic regimen is urgently warranted. This manuscript represents a compendium of recent preclinical work undertaken to evaluate new pharmacologic strategies in the experimental setting as a first step towards the development of a therapeutic armamentarium directed to improve functional recovery in head-injured patients.

The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection.Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition.New insight into the pathophysiology of severe traumatic brain injury, especially the realization that brain damage develops sequentially, initiated several new treatment approaches aiming at the interruption of pathophysiological mechanisms leading to secondary brain injury. A high number of pharmacological substances have been tested for their ability to ameliorate secondary damage after TBI, or are currently under clinical trial. Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review.Although a magical bullet for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, tailored according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.

Fever above 38C that occurs in patients with acute neurosurgical diseases appears to worsen secondary brain injury and ultimate neurologic outcomes. Laboratory investigations are quite clear regarding the adverse effects of fever in terms not only of functional outcomes, but also histologic and neurochemical injury. Several preliminary clinical studies also suggest worsened neurologic outcomes in patients who are febrile compared to those who are not. Unfortunately, however, a large prospective study of 428 patients with acute neurosurgical diseases has shown that fever is extraordinarily common during the first seven days after subarachnoid hemorrhage, stroke, and TBI. The ability to eliminate fever in most of these patients during the first five to seven days after their injury would seem desirable. Based on a phase-I trial, it appears that intravascular cooling is a promising new method for avoiding fever in the neurosurgical ICU.

It is often suggested that one reason that neuroprotection trials in head injury have not shown benefit is the insensitivity of the outcome measures employed. The review considers strengths and weaknesses of the main approaches to assessing outcome in head injury trials. Determination of a response to neuroprotection requires a measure that is both sensitive to differences in outcome and is also influenced by brain injury. Sets of tests have been proposed for use in clinical trials that include scales of disability and handicap and measures of neuropsychological impairment. The Glasgow Outcome Scale (GOS) covers the whole spectrum of outcome after head injury and is the most popular primary endpoint for head injury trials. Although the GOS is a simple scale, small changes in the distribution of outcome can be detected with appropriate sample sizes. Late outcome in survivors can be influenced by various personal and environmental factors in addition to initial brain pathology. Other rating scales and questionnaires do not appear to offer significant advantages over the GOS, but can be used to supplement the information collected. Neuropsychological tests have properties that make them attractive as outcome measures, although there are practical difficulties with using tests. Neuropsychological assessment is potentially a powerful way of testing specific hypotheses concerning the effects of treatment. All current outcome measures have limitations choice of the most appropriate endpoint will depend both on the properties of the measures available, and on the anticipated effects of treatment.