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Beta-blockers and Traumatic Brain Injury: A Systematic Review, Meta-analysis, and Eastern Association for the Surgery of Trauma Guideline

Alali, Aziz S. MD, PhD*; Mukherjee, Kaushik MD, MSCI, FACS†,‡; McCredie, Victoria A. MD, PhD§,*; Golan, Eyal MD, MSc, PhD(c)*,§,¶; Shah, Prakesh S. MD, MSc, FRCPC||; Bardes, James M. MD‡,**,††; Hamblin, Susan E. PharmD‡‡; Haut, Elliott R. MD, PhD, FACS‡,§§; Jackson, James C. PsyD¶¶,||||; Khwaja, Kosar MD, MBA, MSc, FRCSC‡,***; Patel, Nimitt J. MD, FACS‡,†††; Raj, Satish R. MD, MSCI‡‡‡; Wilson, Laura D. CCC-SLP, PhD§§§,¶¶¶; Nathens, Avery B. MD, PhD, MPH, FACS||||||,****; Patel, Mayur B. MD, MPH, FACS‡,††††,‡‡‡‡

doi: 10.1097/SLA.0000000000002286

Objective: To determine if beta-(β)-blockers improve outcomes after acute traumatic brain injury (TBI).

Background: There have been no new inpatient pharmacologic therapies to improve TBI outcomes in a half-century. Treatment of TBI patients with β-blockers offers a potentially beneficial approach.

Methods: Using MEDLINE, EMBASE, and CENTRAL databases, eligible articles for our systematic review and meta-analysis (PROSPERO CRD42016048547) included adult (age ≥ 16 years) blunt trauma patients admitted with TBI. The exposure of interest was β-blocker administration initiated during the hospitalization. Outcomes were mortality, functional measures, quality of life, cardiopulmonary morbidity (e.g., hypotension, bradycardia, bronchospasm, and/or congestive heart failure). Data were analyzed using a random-effects model, and represented by pooled odds ratio (OR) with 95% confidence intervals (CI) and statistical heterogeneity (I2).

Results: Data were extracted from 9 included studies encompassing 2005 unique TBI patients with β-blocker treatment and 6240 unique controls. Exposure to β-blockers after TBI was associated with a reduction of in-hospital mortality (pooled OR 0.39, 95% CI: 0.27–0.56; I2 = 65%, P < 0.00001). None of the included studies examined functional outcome or quality of life measures, and cardiopulmonary adverse events were rarely reported. No clear evidence of reporting bias was identified.

Conclusions: In adults with acute TBI, observational studies reveal a significant mortality advantage with β-blockers; however, quality of evidence is very low. We conditionally recommend the use of in-hospital β-blockers. However, we recommend further high-quality trials to answer questions about the mechanisms of action, effectiveness on subgroups, dose-response, length of therapy, functional outcome, and quality of life after β-blocker use for TBI.

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*Interdepartmental Division of Critical Care, University of Toronto, Toronto, ON, Canada

Division of Acute Care Surgery, Department of Surgery, Loma Linda University Medical Center, Loma Linda, CA

Eastern Association for the Surgery of Trauma, Chicago, IL

§Department of Critical Care, University Health Network, Toronto, ON, Canada

Division of Critical Care and Department of Medicine, Mackenzie Health, Toronto, ON, Canada

||Department of Pediatrics, University of Toronto, Toronto, ON, Canada

**Department of Surgery, West Virginia University, Morgantown, WV

††Department of Surgery, USC+LAC, Los Angeles, CA

‡‡Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, TN

§§Departments of Surgery, Anesthesiology/Critical Care Medicine, and Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

¶¶Division of Pulmonary and Critical Care Medicine and Center for Health Services Research, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN

||||Research Service, Nashville Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, TN

***Departments of Surgery and Critical Care Medicine, McGill University Health Centre, Montreal, QC, Canada

†††Division of Trauma, Critical Care, and Burns, Department of Surgery, MetroHealth Medical Center, Cleveland, OH

‡‡‡Department of Cardiac Sciences, Libin Cardiovascular Institute, University of Calgary, AL, Canada

§§§Department of Communication Sciences and Disorders, Oxley College of Health Sciences, The University of Tulsa, Tulsa, OK

¶¶¶Department of Hearing and Speech Sciences, Vanderbilt University School of Medicine, Nashville, TN

||||||Department of Surgery, University of Toronto, Toronto, ON, Canada

****Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

††††Division of Trauma, Emergency General Surgery, and Surgical Critical Care, Departments of Surgery, Neurosurgery, and Hearing and Speech Sciences, Section of Surgical Sciences, Vanderbilt Brain Institute, Vanderbilt Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN

‡‡‡‡Surgical Service, General Surgery Section, Nashville VA Medical Center, Tennessee Valley Healthcare System, US Department of Veterans Affairs, Nashville, TN.

Reprints: Mayur B. Patel, MD, MPH, FACS, 1211 21st Avenue South, 404 Medical Arts Building, Nashville, TN 37212. E-mail:

Vanderbilt Faculty Research Scholars Program (MBP); National Institutes of Health NHLBI R01HL111111 (MBP), NIGMS R01GM120484 (MBP), and NCATS UL1TR000445 for REDCap (all authors).

Presentated at: Guidelines Plenary Session, 29th Annual Scientific Assembly of the Eastern Association for the Surgery of Trauma meeting in San Antonio, TX on January 16, 2016.

Dr MBP has been or is supported by the Vanderbilt Institute for Clinical and Translational Research awards (VR1584, VR5351, VR9276, VR12073) via CTSA grant UL1TR000011 (NCRR/NCATS/NIH), a 2013 EAST Trauma Foundation Research Scholarship, and speaker fees from Pfizer. Drs ERH and MBP have served on the EAST Guidelines Section and Board of Directors. Dr ERH is the primary investigator of a AHRQ grant (R01HS024547) of a PCORI contract (CE-12-11-4489). Dr ERH receives book royalties from Lippincott, Williams, Wilkins (“Avoiding Common ICU Errors”), consultant and speaker fees from VHA/Vizient IMPERATIV Advantage Performance Improvement Collaborative, and consultant and speaker fees for the Illinois Surgical Quality Improvement Collaborative. Dr ERH was the paid author of a paper commissioned by the National Academies of Medicine.

The authors report no conflicts of interest.

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