Value of Adrenergic Blockade in Acute Severe TBI Questioned

Megan Brooks

April 28, 2016

VANCOUVER — Adrenergic blockade with the β-blocker propranolol and α2-agonist clonidine did not increase ventilator-free days after severe traumatic brain injury (TBI) in a randomized controlled trial.

These two agents are "commonly used" in the intensive care unit for severe TBI "but did not result in any change in ventilator-free days after severe TBI" in this study, noted lead investigator Mayur Patel, MD, MPH, trauma surgeon and assistant professor of surgery at Vanderbilt University School of Medicine, Nashville, Tennessee.

"We need larger studies to inform why neurointensivists, ICU [intensive care unit] physicians, and traumatologists continue to employ this strategy," Dr Patel concluded.

He reported results from the Decreasing Adrenergic or Sympathetic Hyperactivity after Severe Traumatic Brain Injury (DASH After TBI) study here at the American Academy of Neurology (AAN) 2016 Annual Meeting.

Trial Halted for Futility

In an interview with Medscape Medical News following his "data blitz" presentation, Dr Patel said there are a variety of reasons that these two agents might be used in severe TBI patients. Severe TBI is associated with sympathetic hyperactivity and more days of mechanical ventilation. "The belief is that adrenergic blockade might help with sympathetic storming, and in retrospective reviews it's been shown to help with mortality, or capillary leak."

The DASH After TBI study tested the "primary hypothesis" that adrenergic blockade after TBI with centrally acting sympatholytic agents (propranolol and clonidine) would decrease sympathetic outflow and ultimately increase time off the ventilator, he explained.

The phase 2 double-blind, placebo-controlled, single-center pilot study enrolled patients with severe TBI aged 16 to 64 years with intracranial hemorrhage on head computed tomography and Glasgow Coma Scale (GCS) score of 8 or less within 24 hours of admission.

The interventional group received propranolol and clonidine for 7 days. Propranolol was dosed a 1 mg intravenously every 6 hours and clonidine was dosed at 0.1 mg by mouth (enterally) every 12 hours. The placebo group received paired intravenous and enteral placebos.

For power to detect a difference of 2 ventilator-free days, the investigators planned to enroll 100 patients; however, the study was halted at 50% accrual for futility at the interim analysis after 47 patients were enrolled.

With 21 patients in the interventional group and 26 in the placebo group, "there was no difference in the primary endpoint of ventilator-free days, which is a composite outcome of time on the ventilator and mortality," Dr Patel reported.

Table. DASH After TBI: Outcomes

Outcome Adrenergic Blockade (95% CI) Placebo (95% CI)
Median ventilator-free days 17.2 (0 - 19.8) 15.7 (0 - 19.3)
Mortality (%) 24 (OR, 0.71; 0.15 - 3.07) 31

CI, confidence interval; OR, odds ratio.


Dr Patel said his group will likely "embark with the NIH [National Institutes of Health] to build a larger trial to try to confirm these findings and look at other relevant endpoints to see if there is a benefit outside of ventilator-free days."

A Multifactorial "Dirty" Disease

Ross D. Zafonte, DO, Harvard Medical School, Spaulding Rehabilitation and Massachusetts General Hospital, Boston, who wasn't involved in the study, told Medscape Medical News that he's not all that surprised by the findings.

"This was mostly an acute study looking for signal to noise with adrenergic blockade with clonidine and propranolol and their metric was total ICU ventilator days," he said.

"The idea is the adrenergic surge that occurs after brain injury causes a lot of comorbidities, but so many of those are multifactorial that they may not have been able to get around that cleanly with just the simple blockade," he explained.

"Many of the acute neuroprotection studies have not been positive, through no one's fault. It happens because this is a really complex disease that interacts at multiple different sites," he added. "There is not a clean mechanism in that you block 'A' and you're done."

"What we can say," continued Dr Zafonte, "is that in this preliminary study adrenergic blockade did not diminish the number of ICU ventilator days associated with overall sympathetic tone, which is a problem for many of these patients, either hyperadrenergic state acutely related to the injury or a secondary effect that occurs with dysautonomia where the autonomic system is thrown off. It doesn't mean, however, that [the intervention] didn't in some way positively influence long-term outcome, but we don't have that data."

"The other issue may have been timing," he said. "Just because something doesn't work at one point doesn't mean it doesn't work at another, and that's the dirty story with this disease. Dosing, timing and other things, and linking it to a biomarker" would be worth studying further, Dr Zafonte concluded.

The study had no commercial funding. Dr Patel has received research support for activities with KCRN Research as an advisory board member. Dr Zafonte has disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 2016 Annual Meeting. Emerging Science Platform Session. Abstract 007. Presented April 19, 2016.


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