Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury: A Phase 2a Intervention Design Study

Matt Thomas*, Kati Hayes, Paul White, Thomas Baumer, Clodagh Beattie, Aravind Ramesh, Lucy Culliford, Gareth L. Ackland, Anthony E. Pickering

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Background
Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed.

Methods
We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score.

Results
Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5–7) received esmolol. The optimal starting dosage of esmolol was 10 μg/kg/min, with increments every 30 min of 5 μg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen.

Conclusions
Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low.

Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 (https://www.isrctn.com/ISRCTN11038397).
Original languageEnglish
Pages (from-to)1009-1019
Number of pages11
Journalneurocritical care
Volume41
Issue number3
Early online date28 Jun 2024
DOIs
Publication statusPublished - 1 Dec 2024

Bibliographical note

Publisher Copyright:
© 2024. The Author(s).

Keywords

  • Adaptive clinical trial
  • Traumatic brain injuries
  • Adrenergic beta-antagonists
  • Intensive Care Unit

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