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.

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Preliminary evidence has shown that intracerebral hemorrhages, either spontaneous (sICH) or traumatic (tICH) often expand over time. An association between hemorrhage expansion and clinical outcomes has been described for sICH. The intent of this prospective, observational study was to characterize the temporal profile of hemorrhage progression, as measured by serial computed tomography (CT) scanning, with the aim of better understanding the natural course of hemorrhage progression in tICH. There was also a desire to document the baseline adverse event (AE) profile in this patient group. An important motive for performing this study was to set the stage for subsequent studies that will examine the role of a new systemic hemostatic agent in tICH. Subjects were enrolled if they had tICH lesions of at least 2 mL on a baseline CT scan obtained within 6 h of a head injury. CT scans were repeated at 24 and 72 h. Clinical outcomes and pre-defined AEs were documented. The data showed that 51% of the subjects demonstrated an increase in tICH volume, and that most of the increase occurred early. In addition, larger hematomas exhibited the greatest expansion. Thromboembolic complications were identified in 13% of subjects. This study demonstrates that tICH expansion between the baseline and 24-h CT scans occurred in approximately half of the subjects. The earlier after injury that the initial CT scan is obtained, the greater is the likelihood that the hematoma will expand on subsequent scans. The time frame during which hemorrhagic expansion occurs provides an opportunity for early intervention to limit a process with adverse prognostic implications.

The traditional practice of elevating the head in order to lower intracranial pressure (ICP) in head-injured patients has been challenged in recent years. Some investigators argue that patients with intracranial hypertension should be placed in a horizontal position, the rationale being that this will increase the cerebral perfusion pressure (CPP) and thereby improve cerebral blood flow (CBF). However, ICP is generally significantly higher when the patient is in the horizontal position. This study was undertaken to clarify the issue of optimal head position in the care of head-injured patients. The effect of 0 degree and 30 degrees head elevation on ICP, CPP, CBF, mean carotid pressure, and other cerebral and systemic physiological parameters was studied in 22 head-injured patients. The mean carotid pressure was significantly lower when the patient's head was elevated at 30 degrees than at 0 degrees (84.3 +/- 14.5 mm Hg vs. 89.5 +/- 14.6 mm Hg), as was the mean ICP (14.1 +/- 6.7 mm Hg vs. 19.7 +/- 8.3 mm Hg). There was no statistically significant change in CPP, CBF, cerebral metabolic rate of oxygen, arteriovenous difference of lactate, or cerebrovascular resistance associated with the change in head position. The data indicate that head elevation to 30 degrees significantly reduced ICP in the majority of the 22 patients without reducing CPP or CBF.

The hypothesis that cerebral arteriovenous difference of oxygen content (AVDO2) can be used to predict cerebral blood flow (CBF) was tested in patients who were comatose due to head injury, subarachnoid hemorrhage, or cerebrovascular disease. In 51 patients CBF was measured daily for 3 to 5 days, and in 49 patients CBF was measured every 8 hours for 5 to 10 days after injury. In the latter group of patients, when a low CBF (less than or equal to 0.2 ml/gm/min) or an increased level of cerebral lactate production (CMRL) (less than or equal to -0.06 mumol/gm/min) was encountered, therapy was instituted to increase CBF, and measurements of CBF, AVDO2, and arteriovenous difference of lactate content (AVDL) were repeated. When data from all patients were analyzed, including those with cerebral ischemia and those without, AVDO2 had only a modest correlation with CBF (r = -0.24 in 578 measurements, p less than 0.01). When patients with ischemia, indicated by an increased CMRL, were excluded from the analysis, CBF and AVDO2 had a much improved correlation (r = -0.74 in 313 measurements, p less than 0.01). Most patients with a very low CBF would have been misclassified as having a normal or increased CBF based on the AVDO2 alone. However, when measurements of AVDO2 were supplemented with AVDL, four distinct CBF patterns could be distinguished. Patients with an ischemia/infarction pattern typically had a lactate-oxygen index (LOI = -AVDL/AVDO2) of 0.08 or greater and a variable AVDO2. The three nonischemic CBF patterns had an LOI of less than 0.08, and could be classified according to the AVDO2. Patients with a normal CBF (mean 0.42 +/- 0.12 ml/gm/min) had an AVDO2 between 1.3 and 3.0 mumol/ml. A CBF pattern of hyperemia (mean 0.53 +/- 0.18 ml/gm/min) was characterized by an AVDO2 of less than 1.3 mumol/ml. A compensated hypoperfusion CBF pattern (mean 0.23 +/- 0.07 ml/gm/min) was identified by an AVDO2 of more than 3.0 mumol/min. These studies suggest that reliable estimates of CBF may be made from AVDO2 and AVDL measurements, which can be easily obtained in the intensive care unit.