Collins, Thomas R.
ARTICLE IN BRIEF
In a prospective review of data from one of the largest registries on intracerebral hemorrhage outcomes, researchers observed that those who had received hyperosmolar therapy had worse outcomes than those who did not receive the treatment.
PHILADELPHIA—A new study calls into question the use of hyperosmolar therapy for treating intracerebral hemorrhage (ICH). In a review of outcomes from a registry of patients with ICH, investigators said those treated with hyperosmolar therapy experienced significantly worse outcomes than those who did not receive the treatment.
The study — presented here at the AAN Annual Meeting in April — reviewed data from the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) trial, a multicenter study led by the University of Cincinnati. The study focuses on finding risk factors for ICH among Caucasians, African-Americans, and Hispanics, and is thought to be the largest epidemiological, prospective, case-control ICH registry available.
Hyperosmolar therapy involves administering agents by bolus or infusion to reduce intracranial pressure (ICP), which can be life-threatening. In this study, the agents used were either mannitol or hypertonic saline or both; they act by increasing osmotic gradient across the blood-brain barrier, and thus reduce intracellular water content, especially in vasogenic edema conditions.
“However, very few studies have actually looked at the outcomes,” said Manan Shah, MD, chief resident in the department of neurology at the University of Texas Health Science Center at San Antonio, one of the centers involved in the ERICH study. “The objective of our study was to identify the effect of hyperosmolar therapy on three-month functional outcomes in the primary ICH population.”
He acknowledged that a major obstacle in evaluating the data was matching hyperosmolar patients with reasonable controls. [The trial, which was not randomized, used prospective, observational data.]
“One of the challenges in the study was to adjust multiple confounders of severity, which can affect the treatment decision,” Dr. Shah said.
To address this, researchers used a “propensity-scoring” model, a method to reduce bias by adjusting for all the background information regarding treatment selection. Patients treated with hyperosmolar therapy were matched with those who had not received this therapy but who were considered to share the same treatment probability, using several criteria, Dr. Shah said. Those criteria included age, the location of the hemorrhage, log ICH volume, craniotomy, the presence of intraventricular hemorrhage, and their grade on the Glasgow Coma Scale — factors that help determine the ICH score, which predicts 30-day mortality.
Of 790 ERICH subjects for whom sufficient data were available, 145 had been given hyperosmolar therapy as of the end of 2012. They were matched with controls, for whom there were no significant differences in all the variables considered in the propensity scoring model analysis.
Using the Modified Rankin Scale, they considered a three-month score of 3 (slight disability) or lower to be a “good” outcome, while anything over 3 was a “bad” outcome. [The scale measures the degree of disability or dependence in daily living activities from 0, for no disability, to 6 for death.]
Approximately 77 percent — 112 of the 145 patients who received hyperosmolar therapy — had a bad outcome, while 33 had a good outcome. Among those who did not receive hyperosmolar treatment, only 92 had a bad outcome, while 53 had a good outcome (p =.0055).
“In our study, the use of hyperosmolar therapy was associated with worse three-month outcomes even after matching for variables associated with worse outcomes,” Dr. Shah said. “This questions the efficacy and safety of hyperosmolar therapy in primary ICH.”
There are a few reasons why hyperosmolar therapy might yield worse outcomes, Dr. Shah said. “We believe that the problems with the use (of the therapy) in primary ICH are related to the difference in pathophysiology. There is a component of cytotoxic edema and a mass effect of the clot itself, which are refractory to hyperosmolar therapy.” He added that disruption of the blood-brain barrier might also play a role.
Dr. Shah said the study was limited in that the data are not truly randomized. Plus, the effects of mannitol compared with hypertonic saline couldn't be assessed because many patients actually received both.
“The data [were] also limited regarding the strength of the agent, the duration of the therapy, and treatment setting,” he said.
More work is needed, he said, to further understand the role of this therapy for these patients — specifically, to define the patient populations that might benefit versus those who might not, the outcomes associated with the different hyperosmolar agents used, and the outcomes related to administration by bolus or infusion.
Stephan A. Mayer, MD, a professor of neurology and neurological surgery and director of the Institute for Critical Care Medicine at the Icahn School of Medicine at Mount Sinai, said the most likely explanation for the worse results in the hyperosmolar group is that those patients are simply sicker.
“Statistical attempts to match patient groups that are fundamentally different have limitations,” said Dr. Mayer, who was not involved with the study. “You can basically match or control for certain variables related to disease severity but you really can't control for everything.”
Most likely, the difference between the groups was due to “uncontrolled confounding variables,” Dr. Mayer continued. “Nonetheless, the study has value in that it raises at least the possibility that there might be some downsides to hyperosmolar therapy that are unknown.”
One way to study the question in a better way might be to look at patients who are “borderline” on whether to receive hyperosmolar therapy or not and randomly assign them to receive it or not, he said.
“This report might encourage somebody to proceed with that kind of study,” said Dr. Mayer. “I don't think that this report's going to change clinical practice. I don't think it should.”
Natalia Rost, MD, MPH, a director of the acute stroke service at Massachusetts General Hospital, whose research focuses on damage to the brain caused by stroke, agrees that more research is needed.
“What we've thought before is that in a situation when there is increased pressure inside of the brain…we want to lower it down,” she said. “There are several ways to lower (the pressure) — there are some that are definitive, like when you drain the fluid out of it. The non-interventional way of lowering it would be to give this hyperosmolar therapy, and we use it across different diseases certainly — including ICH and traumatic brain injury.
“The novelty of this study is that they actually tried to look systematically at the patients and matched them with this propensity score analysis.”
Nonetheless, she said, there are drawbacks in the study design. The propensity analysis included many factors, but “the truth is that there are many more.” One of those, she said, is timing.
“If at one center you wait too long to give them hyperosmolar therapy, they'll die before they reap the benefits,” she said.
An audience member pointed out that only 790 of 12,000 patients from the ERICH were included in the analysis. Patients with a more severe condition would be less likely to include all the necessary data, which might have biased the results, he said.
Dr. Rost said the number of missing subjects should be cause for caution when considering the study's findings. “Those patients could be different,” she said. “They might have been the ones that could have changed the entire equation.”
“I think it will deserve a future study in a more procedural type of way, where you say, we're going to randomize it,” Dr. Rost said. “This is just something that we don't hear very often at this meeting, but it was refreshing.”
EXPERTS COMMENT ON FINDINGS ON HYPEROSMOLAR THERAPY
This study was selected by members of the Neurology Today editorial advisory board as one of the noteworthy papers from the AAN Annual Meeting.