Clinical Trials in Head Injury

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63185/1/089771502753754037.pd

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces

Evaluation of Homeostatic Changes in CSF Circulation: In vivo Analysis of the Effect of Neurotransmitter Accumulation in the Extracellular Space Following Transient Global Ischemia

Accumulation of potassium and excitatory amino acids (EAA) in the extracellular space (ECS) following ischemia has been well documented. Careful monitoring of these transients is crucial to gain a better understanding of CNS pathophysiology. This study was initiated to determine if CSF concentrations of EAAs reflect those measured in the ECS. Transient global ischemia, 20 minutes in duration, was produced by clamping the left subclavian and innominate arteries combined with hemorrhagic hypotension. The accumulation of glutamate and electrolytes were measured in CSF and the extracellular fluid (ECF) of cerebral cortex. Microdialysis (MD) was utilized to measure the extracellular concentrations while direct sampling of CSF was provided via cannulation of the cisterna magna. Hydrogen clearance and laser doppler methods were used to monitor regional cortical CBF. Our results show that extracellular concentrations of potassium ([K+]ECF) and glutamate significantly increased following the initiation of ischemia (p < 0.05). The extracellular concentration of these substances decreased with the restoration of CBF. In CSF, a similar trend was observed following re-circulation (p < 0.05). However, CSF glutamate levels did not return to pre-ischemic values

A Method for Reducing Misclassification in the Extended Glasgow Outcome Score

The eight-point extended Glasgow Outcome Scale (GOSE) is commonly used as the primary outcome measure in traumatic brain injury (TBI) clinical trials. The outcome is conventionally collected through a structured interview with the patient alone or together with a caretaker. Despite the fact that using the structured interview questionnaires helps reach agreement in GOSE assessment between raters, significant variation remains among different raters. We introduce an alternate GOSE rating system as an aid in determining GOSE scores, with the objective of reducing inter-rater variation in the primary outcome assessment in TBI trials. Forty-five trauma centers were randomly assigned to three groups to assess GOSE scores on sample cases, using the alternative GOSE rating system coupled with central quality control (Group 1), the alternative system alone (Group 2), or conventional structured interviews (Group 3). The inter-rater variation between an expert and untrained raters was assessed for each group and reported through raw agreement and with weighted kappa (κ) statistics. Groups 2 and 3 without central review yielded inter-rater agreements of 83% (weighted κ = 0.81; 95% CI 0.69, 0.92) and 83% (weighted κ = 0.76, 95% CI 0.63, 0.89), respectively, in GOS scores. In GOSE, the groups had an agreement of 76% (weighted κ = 0.79; 95% CI 0.69, 0.89), and 63% (weighted κ = 0.70; 95% CI 0.60, 0.81), respectively. The group using the alternative rating system coupled with central monitoring yielded the highest inter-rater agreement among the three groups in rating GOS (97%; weighted κ = 0.95; 95% CI 0.89, 1.00), and GOSE (97%; weighted κ = 0.97; 95% CI 0.91, 1.00). The alternate system is an improved GOSE rating method that reduces inter-rater variations and provides for the first time, source documentation and structured narratives that allow a thorough central review of information. The data suggest that a collective effort can be made to minimize inter-rater variation

A Method for Reducing Misclassification in the Extended Glasgow Outcome Score

The eight-point extended Glasgow Outcome Scale (GOSE) is commonly used as the primary outcome measure in traumatic brain injury (TBI) clinical trials. The outcome is conventionally collected through a structured interview with the patient alone or together with a caretaker. Despite the fact that using the structured interview questionnaires helps reach agreement in GOSE assessment between raters, significant variation remains among different raters. We introduce an alternate GOSE rating system as an aid in determining GOSE scores, with the objective of reducing inter-rater variation in the primary outcome assessment in TBI trials. Forty-five trauma centers were randomly assigned to three groups to assess GOSE scores on sample cases, using the alternative GOSE rating system coupled with central quality control (Group 1), the alternative system alone (Group 2), or conventional structured interviews (Group 3). The inter-rater variation between an expert and untrained raters was assessed for each group and reported through raw agreement and with weighted kappa (κ) statistics. Groups 2 and 3 without central review yielded inter-rater agreements of 83% (weighted κ = 0.81; 95% CI 0.69, 0.92) and 83% (weighted κ = 0.76, 95% CI 0.63, 0.89), respectively, in GOS scores. In GOSE, the groups had an agreement of 76% (weighted κ = 0.79; 95% CI 0.69, 0.89), and 63% (weighted κ = 0.70; 95% CI 0.60, 0.81), respectively. The group using the alternative rating system coupled with central monitoring yielded the highest inter-rater agreement among the three groups in rating GOS (97%; weighted κ = 0.95; 95% CI 0.89, 1.00), and GOSE (97%; weighted κ = 0.97; 95% CI 0.91, 1.00). The alternate system is an improved GOSE rating method that reduces inter-rater variations and provides for the first time, source documentation and structured narratives that allow a thorough central review of information. The data suggest that a collective effort can be made to minimize inter-rater variation

Traumatic Brain Swelling in Head Injured Patients: Brain Edema or Vascular Engorgement?

Brain edema and vascular engorgement have been used interchangeably to describe brain swelling associated with severe brain trauma and their relative contribution of these compartments to the swelling process remains controversial. In this report, imaging techniques for measurement of brain water and blood volume have been used to study the relative contribution of blood volume and tissue water to the swelling process in severely brain injured patients. More specifically, magnetic resonance techniques for non-invasive tissue water measures founded on mathematical models and later substantiated in laboratory and clinical studies were used for measure of brain tissue water. These studies were combined with measures of cerebral blood volume utilizing indicator dilution methods. Studies indicated that brain water was increased while blood volume decreased. These studies provide compelling evidence that the major contributor to brain swelling is brain edema and not blood volume. Therapies should now be targeted toward preventing edema development and enhancing edema resolution

Effect of Secondary Insults upon Aquaporin-4 Water Channels following Experimental Cortical Contusion in Rats

Although secondary insults of hypoxia and hypotension (HH) are generally considered to cause fulminant brain edema in traumatic brain injury (TBI), the combined effect of TBI with HH on brain edema and specifically the expression of aquaporin-4 (AQP4) have not been fully elucidated. The goal of this study was to document the effect of secondary insults on brain water, AQP4 expression, electrolytes, and blood–brain barrier (BBB) permeability during the acute stage of edema development. We measured brain water content and electrolytes (series 1); BBB permeability based on Evans blue (EB) dye extravasation (series 2); and AQP4 expression using immunoblotting (series 3) at 1 h and 5 h following cortical contusion injury (CCI). Secondary insults significantly worsened BBB function at 5 h post injury. Moreover, a significant reduction of upregulation on AQP4 expression was observed in trauma, coupled with a mild secondary insult of hypoxia hypotension. These findings indicate that a secondary insult following CCI at 5 h post injury worsens brain edema, disrupts ionic homeostasis, and blunts the normal upregulation of AQP4 that occurs after trauma, suggesting that the blunting of AQP4 may contribute to the detrimental effects of secondary insults