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."
Dr. Patrick Kochanek
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.
"The take-home message is that if you are targeting neuroprotection in TBI, you better get the therapy on board fast," he added.
Better monitoring and management of fever after brain injury also is needed. Notably, the odds of death or disability increased 3.6- to fourfold for every single degree Celsius increase in a study involving 99 infants with HIE (Pediatrics 2008;122:491-9).
"We do a poor job of dealing with this issue," Dr. Kochanek said. "Just go through the ICU, particularly a pediatric ICU, and take a look at the temperature recordings of patients with head injury or cardiac arrest, and you’ll be pretty much disappointed."
The lack of surface cooling devices specifically designed for children or endovascular cooling catheters for pediatric patients prompted colleagues, led by Dr. Ericka Fink, to use iced intravenous saline 20 mL/kg infused over 15 minutes to treat fever among 18 children, aged 1 week to 17 years, with TBI, intracranial hemorrhage, or cardiac arrest. The treatment resulted in a significant reduction in core temperature after infusion for fever and a trend toward lower temperatures for induction of hypothermia (Pediatr. Crit. Care Med. 2010 [doi: 10.1097/PCC.0b013e3181fe27c7]).
"People have argued that we are treating traumatic brain injury as if we were treating cancer as a single disease."
What is uncertain is how long the brain remains vulnerable to fever after an injury, Dr. Kochanek said. "It’s one thing to be comatose and aggressively cool to control fever, and it’s quite another to do this 5 days out when you’re awake and your stress response to cooling and need for sedation become a real problem," he observed.