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.

Citation

Thomas, M., Hayes, K., White, P., Baumer, T., Beattie, C., Ramesh, A., …Pickering, A. E. (2024). Early intravenous Beta-Blockade with esmolol in adults with severe Traumatic Brain Injury (EBB-TBI): A phase 2a intervention design study. Neurocritical Care, 40, 795–806. https://doi.org/10.1007/s12028-023-01755-9

• 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