MADISON, WIS. – The one-size-fits-all approach to traumatic brain injury may be facing the same demise observed in the management and treatment of cancer and its protean forms.
"One of the arguments for why traumatic brain injury has been so difficult to get anything to work in a clinical trial is that we’ve been really naive in terms of trying to consider it one disease," said Dr. Patrick Kochanek, director of the Safar Center for Resuscitation Research at the University of Pittsburgh. "People have argued that we are treating traumatic brain injury as if we were treating cancer as a single disease. Maybe we need to do classifications."
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Dr. Patrick Kochanek
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To punctuate the point, Dr. Kochanek highlighted the now-classic computed tomography slide by the renowned neurosurgeon Dr. Geoffrey Manley, vice chair of neurological surgery at University of California, San Francisco, that illustrates six unique paths to a Glasgow Coma Scale score of four in traumatic brain injury (TBI) – epidural hematoma, contusion/hematoma, diffuse axonal injury, subdural hematoma, subarachnoid/intraventricular hemorrhages, and diffuse swelling.
The need to target distinct TBI subgroups was further illustrated by results from the recent NABISH II (National Acute Brain Injury Study: Hypothermia II), which failed to confirm the overall benefit of early hypothermia as a neuroprotectant among 232 patients with severe TBI. Subgroup analyses, however, revealed a significantly improved outcome in patients with hematomas treated with hypothermia, while those with diffuse brain injuries appeared to do worse (Lancet Neurol. 2011;10:131-9).
Pediatric considerations only further magnify the challenge of translating neuroprotective therapies for TBI to clinical practice, Dr. Kochanek said at the annual meeting of the Midwest Society for Pediatric Research. Diffuse cerebral swelling, the most common cause of brain death following severe TBI in both adults and children, is 3.5 times more common in children than in adults and typically more common in younger age groups than in older children.
Hypothermia has been shown to reduce intracranial pressure after pediatric TBI and to be beneficial in pediatric cardiac arrest and hypoxic-ischemic encephalopathy (HIE). Still, a lack of quality data demonstrating a consistent benefit has contributed to the lack of a recommendation of prophylactic hypothermia in pediatric severe head trauma management. Hopes for additional, high-quality data were dashed after the $11.5 million-dollar, multicenter Cool Kids trial evaluating 48 hours of hypothermia within 6 hours of injury recently was stopped for futility.
It’s possible that 6 hours is too late for a therapeutic window or that patients are rewarmed too early during peak edema or too fast, thereby exacerbating hypotension, or that the brain responds differently to hypothermia following TBI versus HIE or cardiac arrest, Dr. Kochanek suggested.
A biomarker trial led by colleague Dr. Rachel Berger used serial serum neuron-specific enolase measurements to demonstrate that neuronal death is frequently delayed in HIE, but predominantly acute in children with TBI (Dev. Neurosci. 2006;28:327-35). This may explain why hypothermia and other therapies have not been effective other than to reduce intracranial pressure after TBI, he said.
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