Traumatic Brain Injury

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

Stenting Procedures Equivalent in Safety and Efficacy in High-Risk Patients
Carotid artery stenting via an emboli-protection device or carotid endarterectomy provides comparable long-term efficacy and safety in high-risk patients, according to the three-year results of the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. Hitinder S. Gurm, MD, and colleagues reported in the April 10 New England Journal of Medicine on the occurrence of the prespecified major secondary end point of the study—a composite of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and three years.

A total of 334 patients with either a symptomatic carotid artery stenosis of at least 50% of the luminal diameter or an asymptomatic stenosis of at least 80%, plus one or more criteria for high surgical risk, were randomly assigned to a study group. “The criteria for high surgical risk were clinically significant cardiac disease …, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal-nerve palsy, recurrent stenosis after carotid endarterectomy, previous radical neck surgery or radiation therapy to the neck, and an age of more than 80 years,” said Dr. Gurm, Director of Carotid Interventions in Cardiovascular Medicine at the University of Michigan Health System in Ann Arbor, and coauthors.

Three-year clinical follow-up data were available for 85.6% and 70.1% of the patients in the stenting and endarterectomy groups, respectively. The major secondary end point had occurred in 41 patients in the stenting group (24.6%) and in 45 patients (26.9%) who underwent endarterectomy. Between years 1 and 3, an additional 21 patients in the stenting group and 13 patients in the endarterectomy group had an event. In that time, there were 19 additional deaths in the stenting group and 14 additional deaths in the endarterectomy group. Fifteen strokes occurred in each of the two groups at three years, including 11 ipsilateral strokes in the stenting group and nine in the endarterectomy group, of which four and one, respectively, occurred between one and three years.

The authors noted that the cumulative incidence of death was substantial, as the patients were elderly and often had coexisting conditions that increased risk of death. “In our opinion, an invasive treatment for prevention of stroke is reasonable, even in a high-risk population, if the projected five-year mortality is less than 50% and the intervention is not itself associated with an increased risk of death or other major adverse effects related to safety,” they asserted. However, because a medical-therapy group was not included in the study, Dr. Gurm and colleagues said that a comparison of safety and efficacy with antithrombotic or lipid-lowering therapies could not be completed, and they added that some practitioners may choose to treat this high-risk group in that way.
Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572-1579.

Predicting Unfavorable Outcome in Head Trauma Patients
A combination of six variables can predict unfavorable outcomes in patients with moderate head injury, reported researchers in the May Journal of Neurology, Neurosurgery, and Psychiatry. Andrea Fabbri, MD, of the Emergency Department at Azienda Unità Sanitaria Locale di Forlì in Italy, and colleagues said that these predictors can be assessed early and may be important for rapid sequence decisions made in the emergency department.

The investigative team prospectively reviewed 12,675 subjects attending the emergency department of a single general hospital between 1999 and 2005; 309 (2.4%) were identified as having moderate head injury (Glasgow Coma Scale [GCS] score, 9 to 13). The median patient age was 50, and the most common comorbidities were coronary artery disease (35.3%) and neurologic diseases (22.7%). Two hundred patients had intracranial lesions detected on CT scans (nine cases required a second scan for diagnosis). Eighty-one cases had a single lesion, and 64 had more than one lesion; the authors noted that the prevalence of intracranial lesions increased with decreasing GCS scores, from 44.2% in patients with a GCS score of 13 to 80% and 90% in those with scores of 9 and 10, respectively. Linear skull fracture was also diagnosed in 82 cases and basal skull fracture in 48.

At six-month follow-up, 45 cases had an unfavorable outcome, as determined by a Glasgow outcome scale score; 12 patients died, two were left in a permanent vegetative state, and the remaining 31 patients were severely disabled. Of the 264 cases with favorable outcome, 31 had moderate disability. Unfavorable outcomes were more common in patients classified in the Marshall categories IV, V, and VI (90%, 21.5%, and 93.7%, respectively) compared with those in categories I and II (0.9% and 5.2%, respectively), reported the researchers.

Neurosurgical intervention was required in 16.5% of the patients, which the investigators indicated was associated with favorable outcome. “In particular, in Marshall category V, the prevalence of unfavorable outcome dropped to nearly 20% following neurosurgical intervention, confirming the importance of mass lesion evacuation in these cases,” they stated.

Of the 18 variables considered, six were independently associated with unfavorable outcome at six months: basal skull fracture, subarachnoid hemorrhage, coagulopathy, subdural hematoma, modified Marshall category, and GCS. “This ­combination of variables predicts the six-month outcome with high sensitivity (95.6%) and specificity (86%),” said the authors. They noted that although coagulopathy was the third strongest predictor of unfavorable outcome in the model, after GCS and Marshall category, the exclusion of coagulopathy did not significantly impair the sensitivity for outcome prediction.
Fabbri A, Servadei F, Marchesini G, et al. Early predictors of unfavourable outcome in subjects with moderate head injury in the emergency department. J Neurol Neurosurg Psychiatry. 2008;79(5):567-573.

Coffee and Tea Drinkers May Have Increased Protection From Cerebral Infarction
Men who drink eight or more cups of coffee or two or more cups of tea per day may have a significantly decreased stroke risk than men whose daily consumption is less than that, according to a study published in the March 27 online Stroke. The effect was independent of known cardiovascular risk factors, added Susanna C. Larsson, PhD, from the Division of Nutritional Epidemiology at the Karolinska Institute in Stockholm, and colleagues.

Data on the participants—26,556 Finnish men ages 50 to 69—were collected prospectively as part of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. All were smokers (five or more cigarettes per day) with no history of stroke at baseline. About 2.5% of the cohort reported that they never drank coffee, and 64% said that they never drank tea.

During the mean 13.6 years of follow-up, there were 2,702 cerebral infarctions, 383 intracerebral hemorrhages, 196 subarachnoid hemorrhages, and 84 unspecified strokes. “After adjustment for age, supplementation group, and cardiovascular risk factors, both coffee consumption and tea consumption were statistically significantly ­inversely associated with risk of cerebral infarction but not of intracerebral or subarachnoid hemorrhage,” the authors said. The relative risk (RR) of cerebral infarction for the men who drank the most coffee (eight or more cups per day) compared with those who drank the least (less than two cups per day) was 0.77, and the relationship was mediated in a dose-response fashion. High consumption of tea (two or more cups per day) also protected against cerebral infarction (RR compared with nondrinkers, 0.79).

“Caffeine intake also showed an inverse association with cerebral infarction,” stated Dr. Larsson and colleagues (RR for median of 880 vs 189 mg/day, 0.76). However, because a previous study had found that supplementation of the dietary antioxidant α-tocopherol had also decreased a patient’s risk of cerebral infarction, the researchers added that “this association may reflect the correlation between caffeine intake and other potentially protective factors in coffee and tea rather than a direct association between caffeine and cerebral infarction.”
Larsson SC, Männistö S, Virtanen MJ, et al. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008 Mar 27; [Epub ahead of print].

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

HONOLULU—New approaches to improving outcomes of traumatic brain injury (TBI) have not shown much benefit when tested during randomized clinical trials—but at least intensivists have learned not to use magnesium sulfate or high-dose steroids for neuroprotection, or albumin for fluid resuscitation, said Jamie Cooper, MD, at the Society of Critical Care Medicine's 37th Critical Care Congress.

Dr. Cooper, who is Deputy Director of the Intensive Care Unit at Alfred Hospital in Melbourne, said that major, well-designed trials of neuroprotective agents that previously had performed well in preclinical studies have shown no benefits. He attributed the negative results in human trials of TBI in part to the difficulty of balancing the many variables that may affect study results, such as heterogeneity of patients and the different types and causes of head injuries (eg, penetrating vs blunt injuries).

Timing is also a factor, and many of the interventions tested may have been started too late, suggested Dr. Cooper. “The future must lie in starting neuroprotective or prophylactic treatments prior to reaching the hospital. However, performing such a trial would be quite difficult.”

One of the difficulties for researchers would be obtaining informed consent in the prehospital setting, particularly in the ambulance, where patients might be unable to give consent themselves and where the next of kin may not be available. “We have to start looking at settings where waived consent can be assumed,” Dr. Cooper projected.

Trial designers also are trying to determine whether to include older patients in trials, which outcome measurement to use, and when to measure outcomes since TBI improves slowly over time.

Dr. Cooper described three landmark randomized controlled trials that provide important guidance on what not to do for head injury patients. These were the SAFE (Saline vs Albumin Fluid Evaluation) study, which showed that albumin fluid resuscitation produced worse outcomes than saline resuscitation; the CRASH (Corticosteroid Randomization After Significant Head Injury) study, which concluded that corticosteroids should not be used routinely in the treatment of head injury; and a randomized controlled trial of magnesium sulfate conducted by Temkin et al, which showed that patients who received magnesium infusions had worse outcomes than did controls.

In the original SAFE study, published in 2004, 6,997 ICU patients were randomized to fluid resuscitation with albumin or saline. The researchers found that there were no significant differences between the groups in new single- or multiple-organ failure, or in mean days spent in the ICU, days spent in the hospital, days of mechanical ventilation, or days on renal-replacement therapy. These findings led the FDA in 2005 to call for more evaluation of albumin in patients with TBI.

In the post hoc evaluation, the SAFE investigators reevaluated data for 231 TBI patients from the original study randomized to fluid resuscitation with albumin and 229 TBI patients randomized to fluid resuscitation with saline. At 24 months, 33.2% of patients in the albumin group versus 20.4% in the saline group had died (relative risk [RR], 1.63). Albumin resuscitation nearly doubled mortality in the subgroup of patients with severe brain injury (mortality rate, 41.8% with albumin vs 22.2% with saline; RR, 1.88). There was no demonstrable benefit from albumin in any subgroup.

“The outcome curves move apart quickly. All the action seems to have happened in those early days, perhaps in the first two weeks after injury,” Dr. Cooper said. “Most of the deaths occurred early, within 28 days. Differences in outcomes were maintained up to 24 months.”

Dr. Cooper noted that the biological mechanism behind this “rather striking finding” is unknown. He speculated that in the injured brain, albumin might cross the blood-brain barrier and not exit, thus increasing brain edema.

“This also adds to the strength of our feeling that saline resuscitation alone might be worthwhile. These results are likely to change practice in many parts of the world,” Dr. Cooper remarked.

The CRASH trial examined the effect of IV corticosteroids in 10,000 adults with clinically significant head injuries. The trial had been designed to accrue 20,000 patients but was stopped early by the data-monitoring committee after interim analysis showed significantly worse outcomes in the patients randomized to a 48-hour infusion of methylprednisolone compared with those who received placebo.

Specifically, the CRASH investigators found that at six months after injury, mortality in placebo-treated patients was 22.3%, versus 25.7% in steroid-treated patients (RR, 1.15). “This was a highly significant difference in this very large trial,” Dr. Cooper said.

“It seems clear from the CRASH trial that an agent that has been very widely used internationally clearly increased mortality after TBI—by about 3%. We can therefore improve survival of TBI simply by avoiding use of this agent,” he maintained.

“We know that there is pituitary insufficiency, both in ICU patients in general and in TBI patients specifically. Low-dose replacement therapy with low-dose corticosteroids decreases vasopressor requirements in patients with head injury. Some clinicians use low-dose steroids quite commonly in the ICU environment. However, there are no randomized trials at all addressing this area. There needs to be a real practice reevaluation, after the findings of the CRASH study,” Dr. Cooper said.

Finally, Dr. Cooper discussed the 2007 study by Temkin et al of magnesium sulfate as a neuroprotectant. In this double-blind trial, 499 patients with moderate or severe TBI were randomized to one of two doses of magnesium or to placebo and treated for five days, beginning within eight hours of injury. The primary outcome variable was a composite measure of mortality, seizures, functional measures, and neuropsychological tests at six months after injury.

The investigators found no benefit from the higher dose of magnesium versus the lower dose on the composite primary outcome, significantly worse outcomes in patients treated with the lower dose of magnesium than in those treated with placebo, and higher mortality among patients taking the higher dose of magnesium than among those taking placebo.

“Craniectomy is a promising tactic,” suggested Dr. Cooper. “The procedure may minimize damage to the underlying brain, when conventional measures to control intracranial pressure have started to fail. It must be noted, though, that no studies have definitively shown us that decreasing intracranial pressure increases favorable outcomes.”

“These data have led clinicians, intensivists, and neurosurgeons to a somewhat pessimistic view of how we could possibly make things better in TBI,” commented Dr. Cooper.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.

SAVANNAH, GA—Psychiatric comorbidity after traumatic brain injury (TBI) is common and, even after a mild injury, can have a serious impact on a patient's life. In research presented at the 19th Annual Meeting of the American Neuropsychiatric Association, Vani Rao, MD, and colleagues reported on the prevalence and impact of post-TBI depression, aggression, and sleep disturbances.

Aggression and Depression Post-TBI
In one study reported by Dr. Rao and colleagues, 27.9% of 68 patients evaluated within three months of their TBI experienced symptoms of aggression; those patients were also significantly more likely to have new-onset major depression, poorer social functioning, and an increased dependency for activities of daily living. The likelihood of aggression was increased with each of the correlates: 62-fold with post-TBI psychosocial impairment, eightfold with new-onset major depression, and by 8% with post-TBI dependence for activities of daily living.

“Aggression—more specifically verbal agitation—is common after TBI,” said Dr. Rao in an interview with Neurology Reviews. “It should not be ruled out as rude or bad behavior. Patients presenting with anger or agitation should be evaluated for depression, as early diagnosis and treatment of these conditions can lead to more effective recovery and rehabilitation.” Dr. Rao is an Associate Professor of Psychiatry at Johns Hopkins University in Baltimore and Medical Director of the Brain Injury Clinic at Johns Hopkins Bayview Medical Center.

The research team also suggested that damage to the frontotemporal lobe and basal ganglia may increase the risk of major depression after TBI. In a pilot study that examined brain metabolic ratios of N-acetyl aspartate to creatine and regional brain volumes, those areas showed significantly reduced function in 10 case participants who developed major depression following TBI, as compared with seven controls who did not.

None of the participants had a history of major depression, and the cases presented between three months and five years after TBI. The case participants were significantly older than the control participants (mean age, 52.4 vs 27.4). About 60% of case participants had moderate to severe TBI, and all controls had injuries of that severity. Gray matter volume was significantly reduced in the right frontal lobe among cases. Neuropsychologic tests showed significantly reduced frontal functioning and a trend toward reduced temporal functioning. Metabolism was also reduced in the right basal ganglia of the group with major depression. Dr. Rao noted that some of the findings may be secondary to the older age among cases, however.

Subdural frontal lesions were also identified as a risk factor for depression after mild TBI in a third study conducted by Dr. Rao’s group. Within 12 months of the injury, about one-quarter of the 30 patients were depressed; in addition to the increased frequency of subdural frontal lesions, they also had a higher anxiety score, medical comorbidity, increased frequency of verbal aggression, postconcussive syndrome, poorer social functioning than before TBI, and increased dependency for activities of daily living.

Sleep Disturbances After TBI
Sleep disturbances are another common occurrence after TBI and, as Dr. Rao and colleagues reported in a fourth study, mood disorders such as depression and anxiety disorders may play a role in their manifestation. Fifty-four patients reported that daytime sleepiness, sleep disturbance, awakening with shortness of breath or headache, and poor sleep adequacy were greater three months after TBI than before their injury. Hamilton Depression Scale and Clinical Anxiety Scale scores significantly predicted sleep adequacy, sleep disturbance, daytime sleepiness, and total sleep scores, explained the authors. They suggested that the treatment of patients with mood disorders following TBI might reduce subsequent sleep problems.

Dr. Rao noted that although neurologists and psychiatrists are aware of many post-TBI neuropsychiatric sequelae, the interrelated nature of these comorbidities suggests that patients would be better served if the two groups of specialists worked together to provide the comprehensive care that TBI patients require. “Early diagnosis and treatment not only can help [patients] in terms of improvement and stabilization in mood and behavior but can help with rehabilitation and recovery,” she added.