Donald W. Marion

Lack of effect of induction of hypothermia after acute brain injury

BACKGROUND Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. METHODS The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. RESULTS The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. CONCLUSIONS 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.

Treatment of Traumatic Brain Injury with Moderate Hypothermia

Background Traumatic brain injury initiates several metabolic processes that can exacerbate the injury. There is evidence that hypothermia may limit some of these deleterious metabolic responses. Methods In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in 82 patients with severe closed head injuries (a score of 3 to 7 on the Glasgow Coma Scale). The patients assigned to hypothermia were cooled to 33°C a mean of 10 hours after injury, kept at 32 to 33°C for 24 hours, and then rewarmed. A specialist in physical medicine and rehabilitation who was unaware of the treatment assignments evaluated the patients 3, 6, and 12 months later with the use of the Glasgow Outcome Scale. Results The demographic characteristics and causes and severity of injury were similar in the hypothermia and normothermia groups. At 12 months, 62 percent of the patients in the hypothermia group and 38 percent of those in the normothermia group had good outcomes (moderate, mild, or no d...

Traumatic Brain Injury-Induced Excitotoxicity Assessed in a Controlled Cortical Impact Model

Using a controlled cortical impact model of traumatic brain injury (TBI) coupled with tissue microdialysis, interstitial concentrations of aspartate and glutamate (together with serine and glutamine) were assessed in rat frontal cortex. Histological analysis indicated that the severity of injury following severe TBI (depth of deformation = 3.5 mm) was approximately twice that occurring following moderate TBI (depth of deformation = 1.5 mm). Both groups demonstrated significant postinjury maximal increases in excitatory amino acid (EAA) concentration, which were proportional to the severity of injury. The mean ± SEM fold increase in dialysate concentrations of aspartate was 38 ± 13 (n = 5) for moderate TBI and 74 ± 12 (n = 5) for severe TBI. Fold increases in glutamate concentrations were 81 ± 26 and 144 ± 23 for moderate and severe TBI, respectively. Although these increases normalized within 20–30 min following moderate TBI, concentrations of aspartate and glutamate took >60 min to normalize after severe TBI. Changes in levels of nontransmitter amino acids were much smaller. Fold increases for serine concentrations were 4.6 ± 0.6 and 7.6 ± 1.7 in moderate and severe TBI, respectively; glutamine concentrations had similar small fold increases (2.6 ± 0.2 and 4.1 ± 0.6, respectively). Calculation of interstitial concentrations following severe TBI indicated that aspartate and glutamate maximally increased to 123 ± 20 and 414 ± 66 μM, respectively. To determine the extent to which such tissue concentrations of EAAs could contribute to the injury seen in TBI, the EAA receptor agonists N‐methyl‐d‐ aspartate and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid were slowly injected into rat cortex. Remarkably similar histological injuries were produced by this procedure, supporting the notion that TBI is an excitotoxic injury.

Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury

The bcl‐2 and caspase families are important regulators of programmed cell death in experimental models of ischemic, excitotoxic, and traumatic brain injury. The Bcl‐2 family members Bcl‐2 and Bcl‐xL suppress programmed cell death, whereas Bax promotes programmed cell death. Activated caspase‐1 (interleukin‐1β converting enzyme) and caspase‐3 (Yama/Apopain/Cpp32) cleave proteins that are important in maintaining cytoskeletal integrity and DNA repair, and activate deoxyribonucleases, producing cell death with morphological features of apoptosis. To address the question of whether these Bcl‐2 and caspase family members participate in the process of delayed neuronal death in humans, we examined brain tissue samples removed from adult patients during surgical decompression for intracranial hypertension in the acute phase after traumatic brain injury (n=8) and compared these samples to brain tissue obtained at autopsy from non‐trauma patients (n=6). An increase in Bcl‐2 but not Bcl‐xL or Bax, cleavage of caspase‐1, up‐regulation and cleavage of caspase‐3, and evidence for DNA fragmentation with both apoptotic and necrotic morphologies were found in tissue from traumatic brain injury patients compared with controls. These findings are the first to demonstrate that programmed cell death occurs in human brain after acute injury, and identify potential pharmacological and molecular targets for the treatment of human head injury.—Clark, R. S. B., Kochanek, P. M., Chen, M., Watkins, S. C., Marion, D. W., Chen, J., Hamilton, R. L., Loeffert, J. E., Graham, S. H. Increases in Bcl‐2 and cleavage of caspase‐1 and caspase‐3 in human brain after head injury. FASEB J. 13, 813–821 (1999)

Hyperthermia in the Neurosurgical Intensive Care Unit

OBJECTIVEIn patients with traumatic or ischemic brain injury, hyperthermia is thought to worsen the neurological injury. We studied fever in the neurosurgical intensive care unit (ICU) population using a definition common to surgical practice (rectal temperature >38.5°C). We sought to determine fever incidence, fever duration, and peak temperature and to quantify the use of antipyretic therapy. We also attempted to determine the patient subgroups that are at highest risk for development of fever. METHODSIn a retrospective chart review of a 6-month period, all febrile episodes that occurred in a consecutive series of neurosurgical ICU patients in a university hospital setting were studied. A febrile episode was defined as a rectal temperature of at least 38.5°C; an episode lasted until the temperature fell below this threshold. RESULTSThe 428 patients studied had 946 febrile episodes. Fever occurred in 47% of patients, with a mean of 4.7 febrile episodes in each febrile patient. Fevers occurred in more than 50% of patients who were admitted to the ICU for subarachnoid hemorrhage, a central nervous system infection, seizure control, or hemorrhagic stroke, but they occurred in only 27% of patients admitted for spinal disorders. Fevers occurred in 15% of the patients who stayed in the ICU less than 24 hours, but in 93% of those who remained longer than 14 days. Despite the use of antipyretic therapy for 86% of the febrile episodes, 57% lasted longer than 4 hours and 5% lasted longer than 12 hours. CONCLUSIONFever is common in critically ill neurosurgical patients, especially those with a prolonged length of stay in the ICU or a cranial disease. If hyperthermia worsens the functional outcome after a primary ischemic or traumatic injury, as has been suggested by several studies of stroke patients, treatment of fever is a clinical issue that requires better management.

Inducible nitric oxide synthase is an endogenous neuroprotectant after traumatic brain injury in rats and mice

Nitric oxide (NO) derived from the inducible isoform of NO synthase (iNOS) is an inflammatory product implicated both in secondary damage and in recovery from brain injury. To address the role of iNOS in experimental traumatic brain injury (TBI), we used 2 paradigms in 2 species. In a model of controlled cortical impact (CCI) with secondary hypoxemia, rats were treated with vehicle or with 1 of 2 iNOS inhibitors (aminoguanidine and L-N-iminoethyl-lysine), administered by Alzet pump for 5 days and 1.5 days after injury, respectively. In a model of CCI, knockout mice lacking the iNOS gene (iNOS–/–) were compared with wild-type (iNOS+/+) mice. Functional outcome (motor and cognitive) during the first 20 days after injury, and histopathology at 21 days, were assessed in both studies. Treatment of rats with either of the iNOS inhibitors after TBI significantly exacerbated deficits in cognitive performance, as assessed by Morris water maze (MWM) and increased neuron loss in vulnerable regions (CA3 and CA1) of hippocampus. Uninjured iNOS+/+ and iNOS–/– mice performed equally well in both motor and cognitive tasks. However, after TBI, iNOS–/– mice showed markedly worse performance in the MWM task than iNOS+/+ mice. A beneficial role for iNOS in TBI is supported.

Problems with initial Glasgow Coma Scale assessment caused by prehospital treatment of patients with head injuries: results of a national survey

The rapid treatment of patients with a severe head injury often includes prehospital intubation and sedation, but such measures compromise the ability to obtain an accurate Glasgow Coma Scale (GCS) score in the emergency department (ED). Major head injury centers in the United States were surveyed to determine how they currently obtain initial GCS scores when these or other complicating circumstances exist. A two-page questionnaire was distributed to seven members of the trauma team at 17 major neurotrauma centers in which they were asked who usually determines the initial GCS score, where they are assessed, and when. Respondents were also asked how they assign scores for patients who received medications or were intubated before arrival at their hospital and how they score patients who are hypotensive, hypoxic, or have severe periorbital swelling. Most centers assess the initial GCS scores in their ED within 1 hour after the discovery of the patient by prehospital personnel. Most neurosurgeons said that hypotension and hypoxia are stabilized before the initial GCS scores are assessed and that intubated patients receive a non-numerical designation. But the majority of non-neurosurgical ED personnel said that they determine the initial GCS scores immediately after arrival of the patients in their department, regardless of hypoxia or hypotension. There also were significant discrepancies between attending neurosurgeons and their residents with regard to who actually assesses the GCS scores and how the scores are determined for patients who have received neuromuscular paralysis or sedation or who have severe periorbital swelling.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrovascular response in infants and young children following severe traumatic brain injury: a preliminary report.

To further describe the pathophysiologic processes that occur in infants and young children after severe traumatic brain injury (TBI), we retrospectively reviewed the cerebral blood flow (CBF) values and 6-month Glasgow Outcome Scores (GOS) in 30 children < or = 8 years old (25 were < or = 4 years old) with a Glasgow Coma Score (GCS) on admission of < or = 8. Twelve females and 18 males (mean age 2.1 years, range 1 month to 8 years) underwent 61 CBF studies using stable xenon computed tomography at variable times from admission to 9 days after TBI. In 12 patients, PaCO2 was manipulated an average of 8.4 torr (range 5-11 torr) and a second CBF study performed to determine CO2 vasoreactivity (CO2VR), defined as the percent change in CBF per torr change in PaCO2. CBF on admission (n = 13)was 25.1+/-7.7 ml/100 g/min (mean +/- SEM) and was < or = 20 ml/100 g/min in 10 of 13 patients (77%). By 24 h and for up to 6 days after TBI, the mean CBF increased to 55.3+/-3.4 ml/100 g/min (range 2-95) which differed significantly from the admission CBF value (p < 0.05); a CBF of >70 ml/100 g/min tended to be associated with a good outcome. Poor outcome (GOS < or = 3) was seen uniformly in children under the age of 1 year and in patients with a CBF of < or = 20 ml/100 g/min any time after TBI. Poor outcome was seen in 85% of children under the age of 24 months, but in only 41% of children > or = 24 months old. Mean CO2VR was 2.1+/-0.6%/torr PaCO2 and ranged from 0.02 to 5.98%. Mean CO2VR tended to differ between good and poor outcome children (3.2+/-0.9 and 1.17+/-0.2%, respectively) and a CO2VR of < or = 2% was significantly associated with a poor outcome. Younger age, low CBF in the early period after TBI, and a CO2VR of <2% was associated with a poor outcome in this subgroup of children. Young children (<24 months) may represent a particular high-risk group with early hypoperfusion after severe TBI. This finding may be a key factor in the pathophysiology and outcome in this age group, and may need to be addressed in our future therapeutic protocols.

Biochemical, cellular, and molecular mechanisms in the evolution of secondary damage after severe traumatic brain injury in infants and children: Lessons learned from the bedside.

Objective To present a state-of-the-art review of mechanisms of secondary injury in the evolution of damage after severe traumatic brain injury in infants and children. Data Sources We reviewed 152 peer-reviewed publications, 15 abstracts and proceedings, and other material relevant to the study of biochemical, cellular, and molecular mechanisms of damage in traumatic brain injury. Clinical studies of severe traumatic brain injury in infants and children were the focus, but reports in experimental models in immature animals were also considered. Results from both clinical studies in adults and models of traumatic brain injury in adult animals were presented for comparison. Data Synthesis Categories of mechanisms defined were those associated with ischemia, excitotoxicity, energy failure, and resultant cell death cascades; secondary cerebral swelling; axonal injury; and inflammation and regeneration. Conclusions A constellation of mediators of secondary damage, endogenous neuroprotection, repair, and regeneration are set into motion in the brain after severe traumatic injury. The quantitative contribution of each mediator to outcome, the interplay between these mediators, and the integration of these mechanistic findings with novel imaging methods, bedside physiology, outcome assessment, and therapeutic intervention remain an important target for future research.

Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients.

Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F(2)-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F(2)-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score </= 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33 degrees C (within approximately 6 h) for either 24 or 48 h and then re-warmed. F(2)-isoprostane levels were assessed by ELISA in ventricular CSF samples (n = 199) on day 1, 2, and 3. The association between age, GCS score, time, gender, treatment, duration of treatment, core temperature at the time of CSF sampling, secondary hypoxemia, and CSF F(2)-isoprostane level was assessed by multivariate and dichotomous analyses. F(2)-isoprostane was approximately 2-fold higher in males than females (145.8 +/- 39.6 versus 75.4 +/- 16.6 pg/mL, day 1 p = 0.018). An effect of time after injury (p = 0.007) was reflected by a marked early peak in F(2)-isoprostane (day 1). CSF F(2)-isoprostane was also associated with hypoxemia (p = 0.04). Hypothermia tended to decrease F(2)-isoprostane levels only in males on d1 after TBI. To our knowledge, this is the first study showing gender differences in lipid peroxidation after clinical TBI. Lipid peroxidation occurs early after severe TBI in adults and is more prominent in males vs females. These results established that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.