Brain Trauma Trials May Finally Be Paying Off

HONOLULU – Disappointing clinical trial results should not suggest that outcomes cannot be improved in traumatic brain injury, only that methodologies may need to be refined and study populations equalized as promising approaches come to the fore, Dr. D. James Cooper said during a plenary address at the annual congress of the Society of Critical Care Medicine.

To be sure, meaningful advances have been elusive, with various interventions producing hopeful improvements in animal models, then fizzling in human trials.

But the heterogeneity of the traumatic brain injury (TBI) population and “huge differences” in the specific trauma suffered may make study results look unfairly pessimistic, said Dr. Cooper, deputy director of the intensive care unit at Alfred Hospital, Melbourne.

Experimental treatments may be initiated too late, often because of logistical and informed-consent dilemmas, and older patients may be so unlikely to benefit that they negatively skew results.

Follow-up assessment periods may be too brief, because it increasingly appears that Glasgow Outcome Scale scores improve greatly over time, but at a very slow pace, he said.

A number of lessons have indeed been learned, even from negative clinical trials, and several promising approaches are currently under review.

Serious doubt has been cast on the efficacy of early high-dose steroids, for example, following the curtailment of the 10,000-patient randomized controlled MRC-CRASH (Corticosteroid Randomisation After Significant Head Injury) trial in the United Kingdom after excess deaths were reported in the steroid arm.

“It seems clear from the study that the use of an agent that has been very widely used, particularly in the developing world, clearly and unambiguously increases mortality, accounting for an absolute number of 3% excess deaths. I think it's abundantly clear … [that the] use of high-dose steroids should cease,” said Dr. Cooper, who also serves as associate director for Australia's National Trauma Research Institute.

Because they lower vasopressor requirements in TBI patients, lower-dose steroids are used quite commonly in the intensive care environment, he noted.

“There are no randomized controlled trials at all in this area, and it's clear to me, [based on the unequivocal MRC-CRASH results, that] there needs to be … a reevaluation” of this practice, said Dr. Cooper.

Another unexpected finding stemmed from the Australian SAFE-TBI (Saline Versus Albumin Fluid Evaluation-Traumatic Brain Injury) study, in which Dr. Cooper participated. That study of nearly 500 patients confirmed that albumin is independently associated with mortality in TBI patients when it is used for intravascular fluid resuscitation in the first 28 days. In contrast, saline was associated with lower mortality and better neurologic outcomes in patients with moderate to severe TBI.

The reasons remain unclear, although Dr. Cooper hypothesized that albumin may increase brain edema, prompting the use of other agents that could contribute to mortality; that it may increase bleeding or cause more coagulopathy; or that it may be the result of hemodilution.

A recent analysis of data from both the SAFE-TBI study and the earlier ATBIS (Australasian Traumatic Brain Injury Study) “[adds] to our strong feeling that saline alone might be worthwhile,” he said.

As a final note, Dr. Cooper outlined two ongoing international clinical trials of early decompressive craniectomy to reduce intracranial pressure, an approach he said may offer “considerable promise.”

The notion of temporarily removing the anterior portion of the skull is not a new idea, he stressed. But it has been controversial and not well studied, despite striking findings of benefit among young patients in small trials.

For example, the absolute risk of mortality was halved with early decompressive craniectomy versus medical therapy alone in a recent, 38-patient French study; but the trial was concluded early because of slow recruitment.

Dr. Cooper's government-sponsored DECRA (Early Decompression Craniectomy in Patients With Severe Traumatic Brain Injury) trial at 21 international sites (including 2 in the United States) is enrolling only patients younger than 60 years old with blunt diffuse brain injuries–strict criteria that may be more conducive to interpreting results, he said.

Thus far, 112 patients have been enrolled of 165 anticipated, which is “already many, many times higher than the largest study ever conducted of early decompressive craniectomy,” Dr. Cooper noted.

Among the first 42 patients randomized to receive surgery, the complication rate has been less than 10%, he said.

HONOLULU – Disappointing clinical trial results should not suggest that outcomes cannot be improved in traumatic brain injury, only that methodologies may need to be refined and study populations equalized as promising approaches come to the fore, Dr. D. James Cooper said during a plenary address at the annual congress of the Society of Critical Care Medicine.

To be sure, meaningful advances have been elusive, with various interventions producing hopeful improvements in animal models, then fizzling in human trials.

But the heterogeneity of the traumatic brain injury (TBI) population and “huge differences” in the specific trauma suffered may make study results look unfairly pessimistic, said Dr. Cooper, deputy director of the intensive care unit at Alfred Hospital, Melbourne.

Experimental treatments may be initiated too late, often because of logistical and informed-consent dilemmas, and older patients may be so unlikely to benefit that they negatively skew results.

Follow-up assessment periods may be too brief, because it increasingly appears that Glasgow Outcome Scale scores improve greatly over time, but at a very slow pace, he said.

A number of lessons have indeed been learned, even from negative clinical trials, and several promising approaches are currently under review.

Serious doubt has been cast on the efficacy of early high-dose steroids, for example, following the curtailment of the 10,000-patient randomized controlled MRC-CRASH (Corticosteroid Randomisation After Significant Head Injury) trial in the United Kingdom after excess deaths were reported in the steroid arm.

“It seems clear from the study that the use of an agent that has been very widely used, particularly in the developing world, clearly and unambiguously increases mortality, accounting for an absolute number of 3% excess deaths. I think it's abundantly clear … [that the] use of high-dose steroids should cease,” said Dr. Cooper, who also serves as associate director for Australia's National Trauma Research Institute.

Because they lower vasopressor requirements in TBI patients, lower-dose steroids are used quite commonly in the intensive care environment, he noted.

“There are no randomized controlled trials at all in this area, and it's clear to me, [based on the unequivocal MRC-CRASH results, that] there needs to be … a reevaluation” of this practice, said Dr. Cooper.

Another unexpected finding stemmed from the Australian SAFE-TBI (Saline Versus Albumin Fluid Evaluation-Traumatic Brain Injury) study, in which Dr. Cooper participated. That study of nearly 500 patients confirmed that albumin is independently associated with mortality in TBI patients when it is used for intravascular fluid resuscitation in the first 28 days. In contrast, saline was associated with lower mortality and better neurologic outcomes in patients with moderate to severe TBI.

The reasons remain unclear, although Dr. Cooper hypothesized that albumin may increase brain edema, prompting the use of other agents that could contribute to mortality; that it may increase bleeding or cause more coagulopathy; or that it may be the result of hemodilution.

A recent analysis of data from both the SAFE-TBI study and the earlier ATBIS (Australasian Traumatic Brain Injury Study) “[adds] to our strong feeling that saline alone might be worthwhile,” he said.

As a final note, Dr. Cooper outlined two ongoing international clinical trials of early decompressive craniectomy to reduce intracranial pressure, an approach he said may offer “considerable promise.”

The notion of temporarily removing the anterior portion of the skull is not a new idea, he stressed. But it has been controversial and not well studied, despite striking findings of benefit among young patients in small trials.

For example, the absolute risk of mortality was halved with early decompressive craniectomy versus medical therapy alone in a recent, 38-patient French study; but the trial was concluded early because of slow recruitment.

Dr. Cooper's government-sponsored DECRA (Early Decompression Craniectomy in Patients With Severe Traumatic Brain Injury) trial at 21 international sites (including 2 in the United States) is enrolling only patients younger than 60 years old with blunt diffuse brain injuries–strict criteria that may be more conducive to interpreting results, he said.

Thus far, 112 patients have been enrolled of 165 anticipated, which is “already many, many times higher than the largest study ever conducted of early decompressive craniectomy,” Dr. Cooper noted.

Among the first 42 patients randomized to receive surgery, the complication rate has been less than 10%, he said.

HONOLULU – Disappointing clinical trial results should not suggest that outcomes cannot be improved in traumatic brain injury, only that methodologies may need to be refined and study populations equalized as promising approaches come to the fore, Dr. D. James Cooper said during a plenary address at the annual congress of the Society of Critical Care Medicine.

To be sure, meaningful advances have been elusive, with various interventions producing hopeful improvements in animal models, then fizzling in human trials.

But the heterogeneity of the traumatic brain injury (TBI) population and “huge differences” in the specific trauma suffered may make study results look unfairly pessimistic, said Dr. Cooper, deputy director of the intensive care unit at Alfred Hospital, Melbourne.

Experimental treatments may be initiated too late, often because of logistical and informed-consent dilemmas, and older patients may be so unlikely to benefit that they negatively skew results.

Follow-up assessment periods may be too brief, because it increasingly appears that Glasgow Outcome Scale scores improve greatly over time, but at a very slow pace, he said.

A number of lessons have indeed been learned, even from negative clinical trials, and several promising approaches are currently under review.

Serious doubt has been cast on the efficacy of early high-dose steroids, for example, following the curtailment of the 10,000-patient randomized controlled MRC-CRASH (Corticosteroid Randomisation After Significant Head Injury) trial in the United Kingdom after excess deaths were reported in the steroid arm.

“It seems clear from the study that the use of an agent that has been very widely used, particularly in the developing world, clearly and unambiguously increases mortality, accounting for an absolute number of 3% excess deaths. I think it's abundantly clear … [that the] use of high-dose steroids should cease,” said Dr. Cooper, who also serves as associate director for Australia's National Trauma Research Institute.

Because they lower vasopressor requirements in TBI patients, lower-dose steroids are used quite commonly in the intensive care environment, he noted.

“There are no randomized controlled trials at all in this area, and it's clear to me, [based on the unequivocal MRC-CRASH results, that] there needs to be … a reevaluation” of this practice, said Dr. Cooper.

Another unexpected finding stemmed from the Australian SAFE-TBI (Saline Versus Albumin Fluid Evaluation-Traumatic Brain Injury) study, in which Dr. Cooper participated. That study of nearly 500 patients confirmed that albumin is independently associated with mortality in TBI patients when it is used for intravascular fluid resuscitation in the first 28 days. In contrast, saline was associated with lower mortality and better neurologic outcomes in patients with moderate to severe TBI.

The reasons remain unclear, although Dr. Cooper hypothesized that albumin may increase brain edema, prompting the use of other agents that could contribute to mortality; that it may increase bleeding or cause more coagulopathy; or that it may be the result of hemodilution.

A recent analysis of data from both the SAFE-TBI study and the earlier ATBIS (Australasian Traumatic Brain Injury Study) “[adds] to our strong feeling that saline alone might be worthwhile,” he said.

As a final note, Dr. Cooper outlined two ongoing international clinical trials of early decompressive craniectomy to reduce intracranial pressure, an approach he said may offer “considerable promise.”

The notion of temporarily removing the anterior portion of the skull is not a new idea, he stressed. But it has been controversial and not well studied, despite striking findings of benefit among young patients in small trials.

For example, the absolute risk of mortality was halved with early decompressive craniectomy versus medical therapy alone in a recent, 38-patient French study; but the trial was concluded early because of slow recruitment.

Dr. Cooper's government-sponsored DECRA (Early Decompression Craniectomy in Patients With Severe Traumatic Brain Injury) trial at 21 international sites (including 2 in the United States) is enrolling only patients younger than 60 years old with blunt diffuse brain injuries–strict criteria that may be more conducive to interpreting results, he said.

Thus far, 112 patients have been enrolled of 165 anticipated, which is “already many, many times higher than the largest study ever conducted of early decompressive craniectomy,” Dr. Cooper noted.

Among the first 42 patients randomized to receive surgery, the complication rate has been less than 10%, he said.