Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain 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.

There is still controversy over whether or not patients should be hyperventilated after traumatic brain injury, and a randomized trial has never been conducted. The theoretical advantages of hyperventilation are cerebral vasoconstriction for intracranial pressure (ICP) control and reversal of brain and cerebrospinal fluid (CSF) acidosis. Possible disadvantages include cerebral vasoconstriction to such an extent that cerebral ischemia ensues, and only a short-lived effect on CSF pH with a loss of HCO3-buffer from CSF. The latter disadvantage might be overcome by the addition of the buffer tromethamine (THAM), which has shown some promise in experimental and clinical use. Accordingly, a trial was performed with patients randomly assigned to receive normal ventilation (PaCO2 35 +/- 2 mm Hg (mean +/- standard deviation): control group), hyperventilation (PaCO2 25 +/- 2 mm Hg: HV group), or hyperventilation plus THAM (PaCO2 25 +/- 2 mm Hg: HV + THAM group). Stratification into subgroups of patients with motor scores of 1-3 and 4-5 took place. Outcome was assessed according to the Glasgow Outcome Scale at 3, 6, and 12 months. There were 41 patients in the control group, 36 in the HV group, and 36 in the HV + THAM group. The mean Glasgow Coma Scale score for each group was 5.7 +/- 1.7, 5.6 +/- 1.7, and 5.9 +/- 1.7, respectively; this score and other indicators of severity of injury were not significantly different. A 100% follow-up review was obtained. At 3 and 6 months after injury the number of patients with a favorable outcome (good or moderately disabled) was significantly (p less than 0.05) lower in the hyperventilated patients than in the control and HV + THAM groups. This occurred only in patients with a motor score of 4-5. At 12 months posttrauma this difference was not significant (p = 0.13). Biochemical data indicated that hyperventilation could not sustain alkalinization in the CSF, although THAM could. Accordingly, cerebral blood flow (CBF) was lower in the HV + THAM group than in the control and HV groups, but neither CBF nor arteriovenous difference of oxygen data indicated the occurrence of cerebral ischemia in any of the three groups. Although mean ICP could be kept well below 25 mm Hg in all three groups, the course of ICP was most stable in the HV + THAM group. It is concluded that prophylactic hyperventilation is deleterious in head-injured patients with motor scores of 4-5.(ABSTRACT TRUNCATED AT 400 WORDS)

Although experimental and pathological studies suggest an important role for ischemia in the majority of fatal cases of traumatic brain injury, ischemia has been a rare finding in most clinical studies of cerebral blood flow (CBF) in head-injured patients. The hypothesis of the present study was that cerebral ischemia occurs in the first few hours after injury, but that CBF measurements have not been performed early enough. Early measurements of CBF (by the 133Xe intravenous method) and arteriovenous oxygen difference (AVDO2) were obtained in 186 adult head-injured patients with a Glasgow Coma Scale score of 8 or less, and were correlated with neurological status and outcome. During the first 6 hours after injury, CBF was low (22.5 +/- 5.2 ml/100 gm/min) but increased significantly during the first 24 hours. The AVDO2 followed the opposite course; the decline of AVDO2 was most profound in patients with low motor scores, suggesting relative hyperemia after 24 hours. A significant correlation between motor score and CBF was found in the first 8 hours after injury (Spearman coefficient = 0.69, p less than 0.001), but as early as 12 hours postinjury this correlation was lost. A similar pattern was found for the relationship between CBF and outcome. Cerebral blood flow below the threshold for infarction (CBF less than or equal to 18 ml/100 gm/min) was found in one-third of the studies obtained within 6 hours, the incidence rapidly decreasing thereafter. A low CBF after 24 hours was not generally associated with a high AVDO2, and was probably a reflection of low oxidative metabolism rather than frank ischemia. In 24 patients, a CBF of 18 ml/100 gm/min or less was found at some point after injury; the mortality rate was significantly higher in this subgroup, and survivors did worse. In some cases, ischemia was successfully treated by reducing hyperventilation or inducing arterial hypertension. These results support the above hypothesis, and suggest that early ischemia after traumatic brain injury may be an important factor determining neurological outcome. Moreover, these data indicate that early hyperventilation or lowering of blood pressure to prevent brain edema may be harmful.

✓ This study describes the relationship between raised intracranial pressure (ICP), hypotension, and outcome from severe head injury. The study is based on information derived from the Traumatic Coma Data Bank where ICP records from a relatively large number of patients were available to help delineate the major factors influencing outcome. From the total data base of 1030 patients, 428 met minimum monitoring duration criteria for inclusion in the present analysis. Outcome was classified according to the Glasgow Outcome Scale score determined at 6 months postinjury. Arrays of comparably defined summary measures describing the patient's course were considered for ICP, blood pressure (BP), central perfusion pressure, and therapy intensity level. For instance, the array of ICP summary descriptors included the proportion of ICP readings greater than x, for x = 0 to 80 mm Hg by increments of 5 mm Hg. A total of 187 candidate summary descriptors were considered. A stepwise ordinal logistic regression was used to select the subset of candidate summary descriptors that best explained the 6-month outcome. As established previously, age, admission motor score, and abnormal pupils were each highly significant in explaining outcome. Beyond these factors, the proportion of hourly ICP readings greater than 20 mm Hg was next selected and was also highly significant in explaining outcome (p < 0.0001). In addition to the ICP factor, the cutoff point of 20 mm Hg was selected by the procedure as most indicative of outcome. With these four factors modeled, the next selected factor was the proportion of hourly BP readings less than 80 mm Hg. Again, the BP factor was highly significant in explaining outcome (p < 0.0001). As with the ICP factor, the BP cutoff point of 80 mm Hg was objectively selected as most indicative of outcome. In summary, the incidence of mortality and morbidity resulting from severe head trauma is strongly related to raised ICP and hypotension measured during the course of ICP management. Moreover, these ICP and BP factors provide a better indication of outcome than the similarly defined factors of central perfusion pressure or therapy intensity level.

Forty-six patients with severe nonpenetrating brain injury [Glasgow Coma Scale (GCS) 4-7] were randomized to standard management at 37 degrees C (n = 22) and to standard management with systemic hypothermia to 32 to 33 degrees C (n = 24). The two groups were balanced in terms of age (Wilcoxon's rank sum test, p > 0.95), randomizing GCS (chi-square test, p = 0.54), and primary diagnosis. Cooling was begun within 6 h of injury by use of cooling blankets. Metocurine and morphine were given hourly during induction and maintenance of hypothermia. Rewarming was at a rate of 1 degree C per 4 h beginning 48 h after intravascular temperature had reached 33 degrees C. Muscle relaxants and sedation were continued until core temperature reached 35 degrees C. There were no cardiac or coagulopathy-related complications. Seizure incidence was lower in the hypothermia group (Fisher's exact text, p = 0.019). Sepsis was seen more commonly in the hypothermia group, but difference was not statistically significant (chi-square test). Mean Glasgow Outcome Scale (GOS) score at 3 months after injury showed an absolute increase of 16% (i.e., 36.4-52.2%) in the number of patients in the Good Recovery/Moderate Disability (GR/MD) category as compared with Severe Disability/Vegetative/Dead (SD/V/D) (chi-square test, p > 0.287). Based on evidence of improved neurologic outcome with minimal toxicity, we believe that phase III testing of moderate systemic hypothermia in patients with severe head injury is warranted.

The release of EAAs is closely linked to the release of structural amino acids and may thus reflect nonspecific development of membrane micropores, rather than presynaptic neuronal vesicular exocytosis. The magnitude of EAA release in patients with focal contusions and ischemic events may be sufficient to exacerbate neuronal damage, and these patients may be the best candidates for treatment with glutamate antagonists in the future.

We studied the prognostic strength of the individual components of the Glasgow Coma Scale (GCS) and pupil reactivity to Glasgow Outcome Score (GOS) at 6 months post-injury. A total of 8721 moderate or severe traumatic brain injury (TBI) patient data from the IMPACT database on traumatic brain injury comprised the study cohort. The associations between motor score and pupil reactivity and 6-month GOS were analyzed by binary logistic regression and proportional odds methodology. The strength of prognostic effects were expressed as the unadjusted odds ratios presented for all individual studies as well as in meta-analysis. We found a consistent strong association between motor score and 6-month GOS across all studies (OR 1.74-7.48). The Eye and Verbal components were also strongly associated with GOS. In the pooled population, one or both un-reactive pupils and lower motor scores were significantly associated with unfavorable outcome (range 2.71-7.31). We also found a significant change in motor score from pre-hospital direct to study hospital enrollment ( p < 0.0001) and from the first in-hospital to study enrollment scores (p < 0.0001). Pupil reactivity was more robust between these time points. It is recommended that the study hospital enrollment GCS and pupil reactivity be used for prognostic analysis.