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Traumatic brain injury (TBI) remains a leading cause of death and disability worldwide. Beyond the primary insult, excessive sympathetic activation contributes to secondary brain injury and poor outcomes. Beta-blockers may attenuate this hyperadrenergic surge and provide neuroprotective benefits, but their efficacy in improving long-term functional recovery remains uncertain.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating beta-blockers in adults with acute TBI. We searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov for RCTs comparing beta-blockers with placebo, usual care, or non-adrenergic comparators. Our primary outcome was long-term functional outcome, assessed with the Glasgow Outcome Scale (GOS) or its Extended version (GOS-E). Secondary outcomes included mortality, intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, and adverse events.
Results
Seven RCTs (n = 559) met inclusion; six (n = 445) contributed data to meta-analyses. Only two trials (n = 259) reported functional outcomes. Beta-blockers did not significantly reduce the risk of unfavorable neurological outcome (RR 0.81; 95% CI 0.57–1.15; very low certainty). In contrast, beta-blocker therapy was associated with a reduction in mortality (RR 0.57; 95% CI 0.39–0.82; 6 trials, n = 440; low certainty) and a shorter duration of mechanical ventilation (–1.58 days; 95% CI –2.91 to –0.26; 2 trials, n = 85; low certainty). No effect was observed on ICU or hospital stay. Adverse event reporting was sparse, but no consistent safety concerns were identified.
Conclusions
In adults with acute TBI, beta-blockers did not decrease unfavorable long-term neurological outcomes but were associated with lower mortality and shorter duration of mechanical ventilation. Given the small number of trials and very low certainty of evidence, definitive conclusions cannot be drawn, and routine use cannot be recommended. A large, well-designed RCT is needed to establish the efficacy and safety of beta-blockers in this population.
Traumatic brain injury (TBI) is a major cause of mortality and long-term disability globally [1]. Beyond the initial insult, secondary brain injury plays a critical role in patients’ outcomes. Despite advances in acute care, effective interventions to mitigate secondary damage remain limited. In moderate-to-severe TBI, excessive sympathetic activation represents a potential mechanism contributing to secondary brain injury [2]. This phenomenon appears to result from a disconnection syndrome, in which the loss of inhibitory control over excitatory autonomic centers leads to sympathetic overactivity [3]. Clinically, this excessive activation can manifest as episodes of tachycardia, arterial hypertension, tachypnea and hyperthermia, which are associated with unfavorable outcomes in acute brain injury [4, 5]. Prolonged hypersympathetic tone may also suppress the immune system [6] and is closely related to intracranial pressure [7].
The management of sympathetic hyperactivity has gained increasing attention in recent years, but considerable heterogeneity in current treatment protocols exists which reflect a lack of high-quality data to guide evidence informed decision-making [8, 9]. One potential strategy to reduce the frequency and severity of sympathetic hyperactivity are beta-blockers. By attenuating the adrenergic response and lowering the resting metabolic rate, beta-blockers may provide both neuroprotective and cardioprotective benefits, explaining their potential effects in patients with TBI [10, 11]. Lipophilic non-selective beta-blockers are theoretically more appealing due to their ability to cross the blood–brain barrier and exert central effects [12]. Their use has been associated with improved paroxysm control and decreased mortality compared to hydrophilic agents [13]. Despite these promising findings, there is insufficient evidence to recommend the routine use of beta-blockers in acute TBI. Recent systematic reviews primarily included observational studies and did not evaluate long-term functional outcomes as a primary outcome [14‐16]. To clarify this setting, we conducted a systematic review and meta-analysis of randomized controlled trials to evaluate whether the use of beta-blockers improves long-term neurological outcomes in hospitalized adult patients with acute TBI.
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Methods
Study design
Our study was conducted following the recommendations of the Cochrane Handbook for Systematic Reviews and Meta Analyses [17]. The protocol is registered in PROSPERO (CRD42024565361). We reported our findings in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) recommendations [18].
Eligibility criteria
We included randomized controlled trials comparing the effect of beta-blockers in patients with acute TBI to placebo, any control groups (without alpha- or beta-adrenergic action), or standard of care. Our study population included hospitalized adult patients (defined as individuals aged 18 years or older for at least 80% of participants) with acute TBI of any severity. To be eligible, trials must have evaluated the administration of beta-blockers initiated within two weeks post-TBI and assessed at least one of our outcomes of interest. All types and routes of administration were included. We applied no date or language restrictions.
Outcomes
Our primary outcome was long term neurological function assessed using the Glasgow Outcome Scale (GOS) or its extended version (GOS-E) [19, 20]. The GOS-E scale is an 8-point ordinal scale ranging from 1 (death) to 8 (upper good recovery) with intermediate levels including neurovegetative state, lower and upper severe disability, lower and upper moderate disability, and lower good recovery. We dichotomized the outcome into "unfavorable" (GOS 1–3; GOS-E 1–4) and “favorable” (GOS 4–5; GOS-E 5–8) neurological outcomes [21, 22]. Secondary outcomes included mortality, intensive care unit (ICU) and hospital length of stay, and duration of mechanical ventilation. Incidence of adverse events (bradycardia, hypotension, heart failure, bronchospasm, kidney injury) were also assessed.
Search strategy
We searched MEDLINE (Ovid), EMBASE (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Clinical Trials.gov database from their inception to June 27th, 2024. The search strategy was developed with an information specialist and validated according to the Peer Review of Electronic Search Strategies (PRESS) 2015 guidelines [23]. The search strategy is presented in Appendix 1.
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Trial selection and data extraction
Two reviewers (NB, THT) independently screened titles, abstracts, and full publications for eligibility. Three reviewers (MB, NB, THT) extracted data, with disagreements resolved by another reviewer (AFT). Authors were contacted for missing information. Extracted trial characteristics included author, year, duration, country, sample size. Participant data included demographics, TBI severity, clinical data (e.g., admission GCS), type of injury, ICU and hospital length of stay, and adverse events. Intervention details included drug name, dosing, timing, comparator and duration. Outcome data (GOS/GOS-E, mortality, follow-up duration) and trial methodology were recorded. Data from diagrams or graphs were extracted using WebPlotDigitizer v4.1 [24].
Risk of bias assessment
Three reviewers (MB, NB, THT) independently assessed the risk of bias of the included trials using the Cochrane RoB 2 tool [25]. This tool consists of five domains representing potential sources of bias, which reviewers categorized as “high”, “low” or “some concerns”. For each trial, we assessed the overall risk of bias based on the worst category obtained across all domains. Another reviewer was consulted in case of disagreement (AFT).
Statistical analysis plan
For continuous data, we extracted means and standard deviations, while for dichotomous data, we recorded event counts and total participants per group. We converted medians and ranges to means and standard deviations using standardized equations [26]. We conducted our analyses using Review Manager, version 8.11.0 (RevMan web, The Cochrane Collaboration, Oxford, United Kingdom) with the Der Simonian & Laird random effects models and the inverse variance method. Pooled continuous data were expressed as mean differences (MD), and dichotomous data as risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed with the I2 statistic; we considered values > 50% as representing substantial [27]. We performed prespecified subgroup analyses to test the robustness of our findings and explore potential sources of heterogeneity, including the lipophilicity of beta-blockers (high vs moderate/low), TBI severity (GCS < 13 vs. ≤ 8 vs ≥ 9), risk of bias (low vs. high/some concerns), duration of intervention (≤ 48 h vs > 48 h), or cointervention vs no cointervention. To assess whether the accumulated evidence was sufficient to support firm conclusions, we performed a trial sequential analysis (TSA) for the primary outcome using TSA software version 0.9.5.10 Beta (Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen, Denmark, 2011) [28]. The required information size was determined based on the event rates, anticipated effect size, and heterogeneity observed in the meta-analysis. Cumulative Z-scores were calculated according to the O’Brien–Fleming alpha-spending function. All analyses were two-sided, with a 5% significance level and 80% statistical power.
Strength of evidence
We evaluated the strength of evidence for each outcome according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) working group statement [29]. The GRADE approach involved grading the quality of the evidence on a continuum from high, moderate, low, or very low for each outcome based on a structured approach. This grading was performed in duplicate independently by two reviewers (NB and THT).
Results
Literature research
Our initial search identified 3,567 citations, of which 477 were duplicates and removed prior to title and abstract screening. After excluding 3,090 records that did not meet the eligibility criteria and screening 35 full-text article, seven randomized controlled trials [30‐36] (n = 559) were included. Of the seven randomized controlled trials included in the systematic review, data from six trials [31‐36] (n= 445) could be pooled in the meta-analysis; quantitative data from one trial were not reported [30]. All trials except for one [31] were published in peer-reviewed journals. The characteristics of included trials are detailed in Table 1.
Propranolol 20 mg PO q 12 h and 200 mg PO/12 h to target HR between 60–100 for 14 days
13
No placebo
13
None
Surgical evacuation of hemorrhage in 44% of patients; craniectomy in 32% (most common procedure)
Urinary catecholamines
Mortality
ICU and
Hospital lengths of stay
Mechanical ventilation duration
Duration of hospitalization
ICU intensive care unit, GOS-E Glasgow outcome scale extended, IV intravenous, PO Per Os, GCS Glasgow Coma Scale
Characteristics of trials
All trials were single-center trials except one [30]. Three trials were conducted in Egypt [31, 35, 36], two in North America [33, 34], one in Europe [30] and one in Iran [32]. Patient follow-up varied across trials: Four trials [30, 34‐36] assessed outcomes only during hospitalization, while others [31‐33] included long-term follow-ups ranging from 6 to 12 months. The trials also differed in TBI severity: three [31, 33, 36] focused on severe TBI (GCS ≤ 8), two [32, 34] on moderate to severe TBI (GCS ≤ 12), one [35]on mild to moderate TBI (GCS > 10) and one [30] included all severities. Propranolol, a highly lipophilic beta-blocker, was evaluated in five trials [32‐36], whereas metoprolol, a moderately lipophilic beta-blocker, was assessed in one trial [31], and atenolol in another [30]. Four trials [31, 32, 34, 35] used the enteral route and two trials [33, 35] administered treatment intravenously and one intravenously followed by the enteral route [30]. Treatment durations ranged from 1 to 14 days, with each trial using a distinct duration. Additionally, two trials [33, 36] used clonidine as a co-intervention [33, 36]. In all trials, the treatment was initiated within 24 to 72 h after the injury. Details of beta-blocker interventions, including type, dose, route, timing of initiation and duration, are provided in Supplemental Table S1.
Risk of bias
The risk of bias assessment of trials is provided in Table 2. Most trials presented at least some concerns in one or more domains, primarily due to unclear randomization processes and potential deviations from the intended interventions [30‐32, 35, 36]. Three studies [30, 32, 36] were judged to have a high overall risk of bias, mainly related to missing outcome data and measurement of the outcome. Two trials [33, 34] were considered at low risk of bias across all domains. Details on the risk of bias for secondary outcomes are provided in Supplemental Fig. S1, Fig. 1.
Table 2
Risk of bias for the main outcome reported by trials
Two RCTs [32, 33] (n = 259) contributed to the primary outcome analysis. One was a single-center trial evaluating propranolol in combination with clonidine, was terminated early for futility, and assessed the GOS-E at three months [33]. The other trial evaluated the use of propranolol alone and assessed the GOS-E at six months [32]. Using random-effects models, an unfavorable neurological outcome occurred in 24.3% of patients (28/115) in the beta-blockers group compared to 33.3% (48/144) in the control group (RR, 0.81; 95% CI [0.57 to 1.15], I2 = 30%) (very low certainty) (Fig. 2, Table 3). No subgroups analyses could be performed due to the small number of trials. With an estimated relative risk reduction of 20% of unfavorable neurological outcome, the TSA showed that the required information size to draw definitive conclusions would be 1,355 patients, suggesting that the pooled analysis of available trials is likely prone to a type II error (Fig. S2).
Fig. 2
Meta-analysis of unfavorable neurological outcome. Legend: Glasgow Outcome Scale–Extended (GOS-E) at 6 months for Khalili et al., and at 3 months for Nordness et al.
Unfavorable neurological outcome assessed with GOS-E
333 per 1000
270 per 1000 (190 to 383)
RR 0.81 (0.57 to 1.15)
259 (2 RCTs)
⨁◯◯◯ Very lowa,b,c
The evidence is very uncertain about the effect of beta-blockers on unfavorable neurological outcome
In-Hospital Mortality
270 per 1000
154 per 1000 (105 to 222)
RR 0.57 (0.39 to 0.82)
440 (6 RCTs)
⨁⨁◯◯ Lowb,d
Beta-blockers may result in a reduction in mortality
ICU length of stay (days)
The mean ICU length of stay (All studies) was 12.5 days
MD 0.81 days higher (1.74 lower to 3.35 higher)
-
401 (5 RCTs)
⨁⨁◯◯ Lowb,c
Hospital length of stay (days)
The mean hospital length of stay was 15.7 days
MD 1.4 days higher
(5.93 lower to 8.74 higher)
-
351 (4 RCTs)
⨁⨁◯◯ Lowb,c
Duration of mechanical ventilation (days)
The mean duration of mechanical ventilation was 8.1 days
MD 1.58 days lower
(2.91 lower to 0.26 lower)
-
85 (2 RCTs)
⨁◯◯◯ Very lowb,c,d
Beta-blockers may reduce/have little to no effect on duration of mechanical ventilation, but the evidence is very uncertain
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI confidence interval, MD mean difference, RR risk ratio
GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
Explanations
a The certainty of evidence was downgraded due to concerns regarding risk of bias. Specifically, approximately 50% of the included studies did not blind outcome assessors, which increases the risk of detection bias in the measurement of the primary outcome
b The certainty of evidence was downgraded due to indirectness. There was substantial variability in the timing of outcome assessment (GOS or GOS-E) and administration of betablockers across studies, which limits the comparability of the results and may affect their applicability to clinical decision-making
c The certainty of evidence was downgraded due to imprecision. The estimated effect was associated with a wide 95% confidence interval, indicating uncertainty about the magnitude and direction of the effect
d The certainty of evidence was downgraded due to risk of bias related to the randomization process. Several included trials had inadequate or unclear methods of random sequence generation and/or allocation concealment, raising concerns about selection bias
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Secondary outcomes
Mortality
Mortality data were available for six trials (n = 440) [31‐36]. The use of beta-blockers was associated with a decreased mortality (RR 0.57; 95% CI [0.39 to 0.82], I2 = 0%) (Fig. 3, Fig. S3) and results were consistent across all subgroups (Fig. S4). One trial [30] reported mortality only qualitatively, stating that “there was no significant drug effect on in-hospital mortality, which was directly related to the severity of the head injury”. The evidence was graded as low due to indirectness and the risk of bias (Table 3).
Fig. 3
Secondary outcomes. Legend: ICU = intensive care unit; IV = inverse variance
There was no significant difference observed in lengths of stay between the beta-blocker and control groups. For ICU length of stay, the mean difference (MD) was 0.81 days longer in the beta-blocker group (95% CI −1.74 to 3.35; five trials [30‐33, 35] n = 401, I2 = 45%). For hospital length of stay, the MD was 1.4 days longer in the beta-blocker group (95% CI −5.98 to 8.74; four trials [31‐34], n = 351, I2 = 48%) (Fig. 3, Figs. S5 and S6). The results were consistent across all subgroups (Figs. S7 and S8). The certainty of evidence was graded as low due to inconsistencies between trials and imprecision (Table 3).
Duration of mechanical ventilation
The duration of mechanical ventilation was available from two trials [31, 34] (n = 85). Beta-blockers were associated with a reduced duration of mechanical ventilation, with patients requiring ventilation for 1.58 days less than those in the control group (95% CI [−2.91 to −0.26], 2 trials, n = 85, I2 = 0%) (Fig. 3, Fig. S9). We did not perform subgroup analyses due to the number of trials. The evidence was graded as low because of imprecision related to small sample sizes and a risk of bias in trial randomization (Table 3).
Adverse events
We predefined adverse events of interest as cardiovascular (bradycardia, hypotension, heart failure) bronchospasm, and acute kidney injury, based on the known safety profile of beta-blockers. Three trials reported adverse events [32‐34]. One trial reported no cardiac complications or other serious adverse events [33] Another found no renal, cardiac, or hypotensive events attributed to the study drug [34]. One trial reported three cases of persistent bradycardia that led to discontinuation of the intervention [32]. These patients were enrolled in the study but discontinued beta-blocker therapy due to bradycardia. None of them experienced clinically significant complications, and all were reported to achieve a good functional recovery at discharge. No trial reported bronchospasm. Other trials did not report any adverse events.
Discussion
In our systematic review and meta-analysis, we found no significant effect of beta-blockers on long-term neurological function. Nevertheless, beta-blockers were associated with a significant reduction in mortality and duration of mechanical ventilation. No difference was observed in ICU or hospital length of stay. The incidence of reported adverse events was low. The certainty of evidence was very low for neurologic functional outcomes and the duration of mechanical ventilation, and low for other outcomes. These findings highlight the absence of high-quality trials assessing the impact of beta-blocker therapy on long-term neurological outcomes following acute TBI.
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Our findings differ from those of two recent systematic reviews and meta-analyses, suggesting that beta-blockers were associated with improved neurologic functional outcomes [15, 37]. A large propensity-matched cohort study also reported a significant association between beta-blockers and improved long-term functional outcomes in patients with severe TBI [38]. This discrepancy is likely multifactorial. First, prior reviews included observational studies, which are inherently subject to confounding, even when using propensity-score matching, which cannot fully account for unmeasured variables. Second, these reviews were conducted prior to the publication of a recent randomized controlled trial [33].
In our study, we observed a reduction in hospital mortality consistent with findings from previous reviews [14, 15, 37, 39]. This finding is also consistent with evidence from other acute neurological conditions, such as subarachnoid haemorrhage (SAH), where beta-blocker therapy has been associated with improved survival [40]. Nevertheless, the mechanisms underlying this potential mortality benefit remain unclear. In the context of TBI, a neuroprotective effect is often hypothesised, whereas in SAH, the benefit might be partly explained by the mitigation of cardiac complications frequently observed in this population. Similarly, in broader critically ill populations [41], and in patients with sepsis [42, 43] beta-blockers have also been associated with reduced mortality, although conflicting results have been reported, with some suggesting an increased risk of complications [44, 45]. These data collectively underscore the need for caution, as the effect may be context-dependent and mediated through distinct mechanisms, particularly in patients with TBI.
One of the main barriers of using beta-blockers in the acute phase TBI is safety concerns. The primary potential adverse effects include hypotension and bradycardia, with hypotension being particularly concerning due to its association with increased morbidity and mortality in TBI patients [46]. A prospective study reported that early administration of low-dose propranolol after TBI did not increase hypotensive events, although bradycardia was more frequent in the control group [47]. Among the randomized controlled trials included in our systematic review, only one reported discontinuation of beta-blocker therapy in three patients due to persistent bradycardia, without severe clinical consequences [32]. Furthermore, a recent systematic review and meta-analysis found no increased risk of cardiopulmonary adverse effects associated with the use of beta-blocker following TBI [15].
Our findings should be interpreted with caution given the incomplete and inconsistent reporting of clinically relevant safety outcomes across trials. Only a few trials systematically monitored adverse events. Although no major safety signals were identified, this lack of standardized and comprehensive safety reporting limits the ability to draw firm conclusions regarding the tolerability of beta-blockers after TBI. On the other hand, all trials in our review administered beta-blockers prophylactically, aiming to limit the early sympathetic surge following TBI. However, it remains unclear whether a prophylactic approach is optimal. A strategy focused on treating patients with clinical evidence of sympathetic hyperactivity might improve the risk–benefit balance and warrants further investigation. Similarly, although paroxysmal sympathetic hyperactivity has been proposed as one possible manifestation of sustained sympathetic overactivity following TBI [2, 48], none of the included trials were specifically designed to target it. Only one trial [33] prospectively collected Clinical Features Scale (CFS) scores [49], a component of the Paroxysmal Sympathetic Hyperactivity-Assessment Measure (PSH-AM) [49, 50]. Whether early beta-blocker therapy can reduce the risk or severity of paroxysmal sympathetic hyperactivity remains speculative and requires dedicated studies using standardized PSH definitions.
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Our systematic review has several strengths. It provides the highest level of evidence available for evaluating the effects of beta-blockers in TBI. We developed a highly sensitive search strategy across multiple databases and trial registries to ensure the identification of all trials. Additionally, we strictly adhered to standardized methodological guidelines, ensuring a rigorous systematic review and meta-analysis. All clinically relevant and safety outcomes that could influence the clinical decision to use beta-blockers were carefully considered, providing a broad and nuanced perspective on their potential benefits and risks.
Our study also has limitations. First, despite the high global burden of TBI, with millions of cases annually, the total number of patients randomized in clinical trials evaluating beta-blockers after TBI remains extremely limited. Second, our meta-analysis of the primary outcome relied on data from only two small RCTs [32, 33], which limited statistical power. These trials also differed in design: one trial evaluated propranolol in combination with an α2-agonist [33], while the other assessed propranolol monotherapy [32], with functional outcomes measured at different follow-up time points. This methodological heterogeneity, combined with the limited sample size, resulted in a very low certainty of evidence and limits the robustness of our findings, underscoring the need for a large, well-designed randomized trial to properly address this question. Consistent with this, our TSA confirmed that the current cumulative evidence remains below the required information size to draw firm conclusions. Third, key questions remain regarding the optimal type, timing, dosage, administration route, and duration of beta-blocker therapy after TBI. The trials included in our review varied widely across these parameters, with some using lipophilic agents such as propranolol or metoprolol, others using hydrophilic agents such as atenolol, and with treatment durations ranging from a few days to two weeks. Such differences in design makes it difficult to determine whether the observed signals of benefit are drug-specific, dose-dependent, or related to treatment strategy (e.g., prophylactic versus targeted to sympathetic hyperactivity). Subgroup analyses can help assess whether these differences explain the direction of effect. However, we were unable to perform all planned subgroup analyses due to limited data availability, which prevented us from adequately exploring potential variations in treatment effect. According to the GRADE framework [29], these unexplained differences contribute to the indirectness of the evidence and were considered when downgrading the certainty of the evidence.
Conclusion
In patients with TBI, we found that the use of beta-blockers was not associated with a reduced risk of unfavorable long-term neurological outcome. It was however associated with a significant reduction in in-hospital mortality and duration of mechanical ventilation. The limited power of our study and the very low certainty of evidence prevent definitive conclusions and do not support the routine clinical use of beta-blockers to improve outcomes. A well-designed and adequately powered randomized controlled trial investigating the efficacy and safety of beta-blockers in this population is needed.
Acknowledgements
MB received fellowship training grants from the Fondation des Gueules Cassées (France), the Société Française d’Anesthésie Réanimation (France), and the Canada Research Chair in Critical Care Neurology and Trauma. AFT is the chairholder of the Canada Research Chair in Critical Care Neurology and Trauma.
Declarations
Ethics approval and consent to participate
This meta-analysis involved secondary data from published studies, exempting it from Institutional Review Board approval.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
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Beta-blockers in adults with acute traumatic brain injury: a systematic review and meta-analysis of randomized controlled trials
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Marwan Bouras
Nicolas Beaulieu
Tomas Hayg Torkomyan
Sarah O’Connor
Olivier Costerousse
François Lauzier
Ryan Zarychanski
Michael Verret
Shane W. English
Bourke Tillmann
Ian Ball
Marat Slessarev
Alexis F. Turgeon
Canadian Traumatic Brain Injury Research Consortium
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