Discussion
This systematic review and meta-analysis analyzed current available evidence for the utility of beta blockers in TBI to reduce mortality and improve functional outcome. Our meta-analyses showed that patients who received beta blockers during their hospital admission exhibited lower mortality rates and better functional outcome, though at the cost of an increased risk of cardiopulmonary and infectious complications. Nevertheless, our study demonstrates the need for a larger scale, RCT to further clarify the benefit and safety of in-hospital initiation of beta blockers in TBI.
The proposed explanation for the benefit of beta blockers in TBI is based on the assumed reduction in secondary injury by limiting the catecholamine surge. The catecholamine surge is well documented to occur up to 10 days after the injury and increases cerebral edema, hypoxia, and neural apoptosis. Preventing the resultant secondary injury leads to decreased mortality and improved functional outcome, which are the main goals of TBI management. Propranolol administration in rodent TBI models increases cerebral perfusion, decreases hypoxia, and improves cerebral glucose metabolism in a dose-dependent manner.31 32 Additionally, knockout mice lacking beta-adrenergic receptors demonstrate less motor deficiency after head trauma.31 32 Although not officially included in the Brain Trauma Foundation guidelines, and despite the lack of high-quality data, several societies conditionally recommend beta blocker use in patients with severe TBI with no existing contraindications, provided that beta-blocker-related complications (eg, hypotension or bradycardia) do not occur.16 33 According to our summation of the current human data, use of beta blocker in hospitals is associated with decreased all-cause in-hospital mortality in patients with TBI. This was a pooled analysis of anyone who received a beta blocker at all during their hospital stay. However, when we separated the available data for patients who had started a beta blocker for the first time post injury and those who had been maintained on a beta blocker before their injury, the mortality benefit was no longer seen in either group. Although it is an interesting question whether the total length of beta-blocker therapy has an impact on mortality and what effect preinjury beta blocker has on outcomes, our findings do not suggest any definitive conclusion regarding this. It is possible that the proposed blunting of the catecholamine surge occurs more effectively with longer-term beta-blocker therapy prior to the injury and that acute initiation has less of an impact. However, our data presented here are not without significant bias. Relative to the total amount of patients in the overall analysis, very few data points were available for the subgroups. Few studies included analysis specifically on beta blockers initiated post injury. Instead, the majority of studies broadly included any and all patients who received one or more doses of beta blocker at any point during their admission, which leads to considerable variability and limits what effect we can reasonably attribute to the beta blockers themselves, no matter when they were started. Additionally, all of the studies in this subgroup analysis had a high risk of bias and were overall low quality as per the GRADE assessment.
Although most studies give prominence to mortality outcomes, it is certainly not the only focus in the management and rehabilitation after TBI. Despite the primary clinical goal in TBI management being full recovery and return to baseline level of function, there is limited evidence available for the effect of beta blockers on this. In fact, only three studies were identified in our review that included functional outcome in their analysis. Pooled analysis was undertaken for functional outcome at hospital discharge and at long-term follow-up despite the small number of studies, and though there was no difference in outcomes at acute care discharge, pooled long-term follow-up showed a functional benefit of using beta blockers. Functional recovery is often slow after brain injury; therefore, GOS-E as measured at discharge from acute care may not be the most appropriate time to compare this outcome. Longer-term measurements at 6 or 12 months are likely more realistic to true functional outcome. However, there are several issues to be addressed with these results. First, each study had a different definition of the GOS-E score, which showed a ‘good’ functional outcome. Each reported the number of patients above this predetermined level and not average scores for each group. The measurements ranged from including any patient with a score above 3, to those only including a score above or equal to 5. A score of 3 or 4 still signifies a severe upper or lower limb deficit and dependency on others for major daily tasks of living. This is vast difference from a score of 5, which is only a moderate disability. This inconsistency in measurements limits practical conclusions that can be made from our analysis, as these represent vast discrepancies in true function. In addition, the data on long-term follow-up is based on two smaller studies,22 26 each of which had a different time point for follow-up. Six months compared with 12 months is relatively significant in the rehabilitation from a brain injury; therefore, this inconsistency lends to the uncertainty of these results. This lack of consistent and comprehensive data regarding functional outcome outlines the need for rigorous controlled trials addressing this gap in the literature.
Cardiac, respiratory, and infectious complications are common after TBI, and in many cases are directly related to the catecholamine surge and resultant autonomic imbalances.8 The use of beta blockers in hyperadrenergic states has previously been shown to be beneficial in decreasing adverse cardiopulmonary and infectious events.34–36 Contrary to this evidence, the use of beta blockers was associated with higher risk of these complications in our analyses. For pooled cardiopulmonary complications, two studies showed no difference between groups in the rates of these complications; however, they only measured bradycardia and cardiac uncoupling, respectively.9 26 The third study included had much more thorough criteria for assessing cardiopulmonary complications and was weighed heavily in our analysis.8 However, many of their complications were diagnosed prior to beta-blocker initiation; the beta-blocker group had a higher burden of chest injury, and a broad definition of respiratory failure was used. Despite these confounding factors, it is still essential to avoid bradycardia and hypotension after initiation of beta blockers in TBI. For infectious complications, the same study that diagnosed many cardiac complications prior to beta-blocker initiation also stated that many infections were diagnosed prior to beta-blocker initiation. There are growing data emerging regarding the use of beta blockers in sepsis, which, to date, suggests that use of beta blockers is associated with not only a decrease in mortality but also improved management of cardiorespiratory abnormalities.37–39 In our case, only two observational studies included data on infectious outcomes with use of beta blockers in TBI and brought with them substantial bias. Thus, this finding may not be a true phenomenon and requires further investigation.
Our study resembles a recent meta-analysis completed in 2020,40 with some key differences. We obtained similar results for the analysis of in-hospital mortality, functional outcome, and cardiopulmonary complications. In addition to updating this literature review, we built on these findings by including subgroup analyses for patients who had not been on beta blockers prior to the injury, for propranolol use specifically, for blunt injury only, and for infectious complications. Finally, our study used the more rigorous GRADE approach to systematically assess the quality of the evidence, developing a more comprehensive understanding of the quality of the available evidence and thus the reliability of recommendations based on this.
Limitations
Limitations of this study are largely due to the number of available studies on this topic, as well as the quality of the literature. Limited number of studies were available for high-yield analysis of functional outcome, further complicated by the variability in reporting of good functional outcome. Studies were predominantly retrospective cohort analyses, limiting our ability to make definitive conclusions due to inherent lack of prospective data collection and blinding. Observational studies are by definition low quality, and in our case, this was further lowered by the serious risk of bias, inconsistency, an imprecision of the included studies. There were only two RCTs available, of which neither were blinded and both had small sample sizes, and therefore were weighted very low in our analysis. Additionally, most studies did not include subset analyses for suspected confounding factors such as premorbid patient conditions, time of beta-blocker initiation within hospital, beta-blocker therapy prior to their injury, or the need for surgical intervention. A small proportion of studies did identify an inherent difference between patients who received beta blockers compared with those who did not. For example, patients receiving beta blockers tended to be older and have more severe injuries.11 17 28 However, subgroup outcomes stratified by these confounders were not provided to allow for an adjusted analysis in our case; therefore, our analysis is based on unadjusted mortality. Some studies did not assess isolated TBI but rather included all multisystem trauma patients. Although beta blockers could be beneficial for all general trauma patients, this is a significant confounder when trying to assess the effect on TBI alone. For example, Khalili et al26 did not find a benefit of beta blockers in all multisystem trauma patients, but their subgroup analysis did reveal a survival benefit of propranolol in patients with isolated severe TBI. Few studies included specific information about the dosing, time of initiation, duration, and type of beta blocker used. For those that did, there was substantial variability between studies in all of these factors. For example, some studies included patients in their beta-blocker cohort who received only one dose of beta blocker during their entire hospital stay, and timing of initiation varied from 24 hours post injury to up to 30 days after admission. Overall, there was wide variability in the methods of patient selection and beta-blocker administration, resulting in significant heterogeneity between studies. Additionally, although we attempt here to consider complications and assess long-term outcomes between groups, this is challenging to accomplish. If beta blockers do in fact decrease mortality, then patients who survive most likely will require a longer hospital stay and thus are at increased risk of inherent complications of hospital admission. Therefore, the benefit of beta blockers may lead to additional complications due to patients surviving who would have otherwise died.
