Caroline Cassels

October 30, 2008 — In the most comprehensive meta-analysis to date, researchers have shown fever is strongly associated with worse outcomes in stroke and other types of neurological injury across multiple outcome measures.

Investigators at Massachusetts General Hospital, in Boston, analyzed data from 39 studies that included 14,431 patients with stroke and other brain injuries and found fever/elevated body temperature was consistently linked to poor outcomes regardless of the type of neurological injury or the outcome measured.

“Whether a neurological injury is ischemic, hemorrhagic, or traumatic, or the outcome measured is clinical, functional, or economic, this study provides conclusive evidence that fever is consistently associated with poor outcomes,” principal investigator David M. Greer, MD, told Medscape Neurology & Neurosurgery.

The study was recently presented at the Neurocritical Care Society annual meeting and is published in the November issue of Stroke.

Disparate Findings

Fever is a common condition in stroke and other types of brain injury, and previous research has shown a strong link to increased length of intensive care unit (ICU) and hospital stay, higher mortality, and worse overall outcomes.

However, said Dr. Greer, a direct causative link been difficult to establish.

“Historically, there has been a lot of research that has correlated fever in brain-injured patients — whether from stroke, traumatic brain injury, cardiac arrest, or subarachnoid hemorrhage — to poor outcomes. However, the wide variation in study populations and outcome measures in these studies have made it challenging to determine the true impact of high body temperatures in brain-injured patients,” he said.

To level the playing field, investigators incorporated all recent studies that addressed fever in brain-injured patients into a comprehensive meta-analysis to evaluate these disparate clinical findings.

Researchers conducted a Medline search for articles published since January 1, 1995 and identified 1139 citations. Of these, they retained 39 studies with 67 tested hypotheses contrasting outcomes of fever/higher body temperature and normothermia/lower body temperature in patients with neurological injury.

Patients in the selected studies included individuals who had ischemic and hemorrhagic stroke and neurological ICU populations including traumatic brain injury (TBI) patients.

Outcome measures included clinical, functional, and economic outcomes as assessed by mortality, the Glasgow Outcome Scale (GOS), Barthel Index, modified Rankin Scale (mRS), Canadian Stroke Scale (CSS), ICU length of stay (LOS), and hospital LOS.

Consistent Result

“Collectively, the meta-analyses presented a consistent result. In each of the 7 outcome measures evaluated, the meta-analysis indicated that fever/higher body temperature was significantly associated with worse outcome as indicated by higher mortality rate, greater disability, more dependence, worse functional outcome, greater severity, and longer stays in the hospitals and the ICU,” the authors write.

The investigators report the effect size of fever/higher body temperatures ranged from moderately small for the GOS to large for mRS, ICU LOS, and hospital LOS. In addition, in comparison with individuals with stroke or TBI who did not have fever/higher body temperatures, their counterparts with fever had a 1.3 to 3.2 times odds of a longer hospital LOS.

The results also suggest fever is associated with greater mortality and greater neurological dysfunction in patients with neurological injury.

“It didn’t matter what measure we looked at, the outcomes were all significantly and consistently worse across the board in patients who were febrile,” said Dr. Greer.

Whether fever actually causes worse outcomes or whether it is largely an effect of other causative factors is beyond the scope of this study. However, the investigators point out it is noteworthy that no other covariate examined “comes close to reaching the consistency of significance found with fever/higher body temperature.”

Hypothermia Not Ready for Prime Time

Although induced hypothermia is not standard medical practice in the management of all brain-injured patients, it is recommended by the American Heart Association in the treatment of resuscitated cardiac-arrest patients.

However, said Dr. Greer, although many in the neurocritical care community use hypothermia to treat neurologically injured patients, it remains an unproven therapy in this patient population.

“At this point, induced hypothermia is not ready for prime time. We still can’t say conclusively that it improves outcomes for brain-injured patients. We suspect that it does, we see at the bedside that when we cool brain-injured patients their intracranial pressure comes down, but we still need hard scientific evidence,” he said.

According to Dr. Greer, the current findings point to a need for a major prospective, randomized study to confirm whether aggressive efforts to prevent and control fever in neurologically injured patients improves outcomes. Studies are currently ongoing for using induced hypothermia for such conditions as ischemic stroke and traumatic brain injury.

Dr. Greer has no relevant disclosures. Study investigators Susan E. Funk, Nancy L Reaven, Myrsini Ouzounelli, MD, all from Strategic Health Resources, in La Canada, California, and Gwen C. Uman, PhD, from Vital Research, in Los Angeles, California, report receiving financial support from Medivance, under an agreement that the study be conducted independently to reduce funding bias. Accordingly, the study was designed conducted, analyzed, interpreted and written by investigators independent of Medivance and was not sent to agents of Medivance for prepublication review or approval.

Stroke. 2008; 39: 3029-3035. Collegamento all’Abstract.


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