Early intravenous Beta-Blockade with esmolol in adults with severe Traumatic Brain Injury (EBB-TBI): A phase 2a intervention design study

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

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 dose 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 centre, 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 hours of injury to reduce heart rate by 15% from baseline of the preceding 4 hours while ensuring cerebral perfusion pressure (CPP) was maintained above 60mmHg. In cohorts of three the starting dose and dose increments were escalated according to pre-specified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity (DLT) was defined as failure to maintain CPP triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dose-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.

Results
Sixteen patients (6 (37.5%) female; mean age 36 years (standard deviation 13 years) with a median Glasgow Coma Scalecore of 6.5 (interquartile range 5 – 7) received esmolol. The optimal starting dose of esmolol was 10 micrograms per kilogram per minute, with increments every 30 minutes of 5 mcg.kg.min-1, as it was the highest dose with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to standardised mortality ratio of 0.63). One dose limiting toxicity event and no serious adverse haemodynamic effects were seen.

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

• Journal Article Type: Article
• Acceptance Date: May 10, 2023
• Online Publication Date: Jun 12, 2023
• Publication Date: Apr 30, 2024
• Deposit Date: Jun 4, 2024
• Publicly Available Date: Jun 5, 2024
• Journal: Neurocritical Care
• Print ISSN: 1541-6933
• Publisher: Springer (part of Springer Nature)
• Peer Reviewed: Peer Reviewed
• Volume: 40
• Pages: 795–806
• DOI: https://doi.org/10.1007/s12028-023-01755-9
• Public URL: https://uwe-repository.worktribe.com/output/12032814