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Interventions that mitigate secondary brain injury have the potential to improve outcomes for patients and reduce the impact on communities and society. Increased circulating catecholamines are associated with worse outcomes and there are supportive animal data and indications in human studies of benefit from beta-blockade after severe traumatic brain injury. Here, we present the protocol for a dose-finding study using esmolol in adults commenced within 24\u00a0h of severe traumatic brain injury. Esmolol has practical advantages and theoretical benefits as a neuroprotective agent in this setting, but these must be balanced against the known risk of secondary injury from hypotension. The aim of this study is to determine a dose schedule for esmolol, using the continual reassessment method, that combines a clinically significant reduction in heart rate as a surrogate for catecholamine drive with maintenance of cerebral perfusion pressure. The maximum tolerated dosing schedule for esmolol can then be tested for patient benefit in subsequent randomized controlled trials.<\/jats:p>\n                  <jats:p>\n                    <jats:italic>Trial registration<\/jats:italic>\n                    ISRCTN, ISRCTN11038397, registered retrospectively 07\/01\/2021\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.isrctn.com\/ISRCTN11038397\">https:\/\/www.isrctn.com\/ISRCTN11038397<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1007\/s12028-023-01755-9","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T17:01:40Z","timestamp":1686589300000},"page":"795-806","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Early Intravenous Beta-Blockade with Esmolol in Adults with Severe Traumatic Brain Injury (EBB-TBI): Protocol for a Phase 2a Intervention Design Study"],"prefix":"10.1007","volume":"40","clinical-trial-number":[{"clinical-trial-number":"isrctn11038397","registry":"10.18810\/isrctn"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3407-6762","authenticated-orcid":false,"given":"Matt","family":"Thomas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kati","family":"Hayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Ramesh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Culliford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gareth","family":"Ackland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Pickering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,6,12]]},"reference":[{"key":"1755_CR1","unstructured":"Parsonage M. 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