Association of beta blockers and mortality in adults with septic shock: systematic review and meta-analysis of randomized clinical trial

Introduction: Septic shock still entails significant morbidity and mortality, with the heart being affected due to catecholamine overexpression and direct injury from sepsis. Therefore, the effect of β-blocking the receptors to improve performance is promising when attempting to reverse tachycardia and reduce mortality.

Methods: We conducted a comprehensive search across five databases for studies published up to 28 January 2024, using a PICO strategy. Ten studies were identified for quantitative analysis and included in our meta-analysis.

Results: Our meta-analysis evaluated 28-day in-hospital mortality risk across nine randomized controlled trials (RCTs) involving a total of 1,121 adults with septic shock. We found an association between β-blocker use and reduced overall mortality (OR 0.57; 95% CI 0.34–0.98; I²: 56%). This effect was significant in the esmolol subgroup (OR 0.47; 95% CI 0.26–0.82; I²: 32%), but not in the landiolol subgroup (OR 0.98; 95% CI 0.0–1,284.5; I²: 72%). Additionally, the intervention group shows a significant reduction in HR and lactate levels, as well as an increase in stroke volume index (SVI).

Conclusion: In adults with septic shock, β-blockers are associated with a reduction in 28-day in-hospital mortality, a benefit primarily observed with esmolol rather than landiolol. Furthermore, improvements in heart rate (HR) control, lactate levels, and SVI were noted. However, these findings should be interpreted with caution, and further high-quality RCTs comparing different β-blockers are necessary to better elucidate these effects.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024513610.

1 Introduction

Septic shock (SSh) remains a major condition associated with severe morbidity and mortality. The first-line treatment for SSh includes fluid resuscitation and the administration of vasopressors, alongside infection source control through eradication or antibiotic therapy (1, 2). The physiological response to SSh can lead to deleterious cardiac effects, with the heart being affected in approximately 50% of cases, either due to sepsis itself or excessive catecholamines exposure, such as from sympathetic stimulation. Tachycardia is a poor prognostic indicator in SSh patients (3–5).

It has been postulated that tachycardia, in the context of SSh, further impairs ventricular filling and, thereby reducing the stroke volume index (SVI) and subsequently cardiac output (CO). This is where the role of β-blockers (βb) comes into play; they have been proposed to mitigate these effects, with reports indicating reductions in mortality, lower inflammatory and infectious parameters, and improvements of cardiac, hemodynamic and perfusion markers (5–8).

While others systematic reviews and meta-analyses (SR-Ms) have evaluated the effect of βb on mortality, existing studies have methodological and reporting deficiencies (9–13). These include the incorporation of duplicate studies or those with incorrect intervention groups, failure to use the RoB2 for risk of bias assessment, and the omission of recent RCTs involving landiolol, which have reported no association between βb use and mortality.

Therefore, our SR-Ms aims to evaluate RCTs that incorporate both esmolol and landiolol to assess their association with mortality in patients with SSh. This focus is particularly relevant given that recent high-quality RCTs have independently demonstrated that landiolol use does not reduce mortality.

2 Materials and methods

2.1 Search strategy

Our systematic review adheres to the methodological standards outlined in the Cochrane Handbook for Systematic Reviews (14), PRISMA guidelines (15), and AMSTAR 2 criteria (16). The study protocol was registered in PROSPERO (CRD42024513610). We conducted a comprehensive search of major databases, including MEDLINE (PubMed), Scopus, EMBASE, Web of Science, Science Direct, and the Cochrane Library. Our search strategy incorporated both controlled vocabulary (e.g., MeSH, Emtree) and free terms, combined with Boolean operators, to implement our PICOS strategy (Population: adult patients with septic shock; Intervention: use of beta-blockers; Comparator: standard treatment; Outcome: 28-day in-hospital mortality; Study design: Randomized clinical trials). Keywords were carefully selected to encompass relevant exposures (“beta blockers” OR “landiolol” OR “esmolol”) and the principal outcome (“In-hospital mortality”). Secondary outcomes were “heart rate,” “stroke volume index,” “lactate,” “norepinephrine doses,” and “length of hospital stay.” A detailed outline of the search strategy is provided in the Supplementary Table 1A).

All articles identified during the primary and secondary screenings were cataloged using Zotero^® 6.0.15. After removing duplicates, the documents were transferred to the Rayyan^® tool. Here, two authors (GAVT and CVQC) independently screened titles and abstracts in a blinded manner. Studies were selected by mutual agreement, with a third researcher (EDMR) resolving any disagreements. The selected papers underwent a thorough full-text review to determine their eligibility. Furthermore, reference lists and citations of the included publications were manually examined to further enhance the identification of relevant studies. For clarity, the selection process is illustrated in Figure 1. Excluded studies are shown in Supplementary Table 1B.

FIGURE 1

Figure 1. PRISMA 2020 flow diagram of the selection process of the primary studies included.

2.2 Selection criteria

We included only RCTs that assessed the use of βb in patients with SSh and their association with mortality as the primary outcome. The studies enrolled adult patients (≥ 18 years old), regardless of the infectious focus. We considered articles published up to 28 January 2024, without restrictions on language or publication date. We excluded case reports, case series, cross-sectional studies, cohort studies, case-control studies and duplicates.

2.3 Outcomes

The primary outcome was 28-day in-hospital mortality. Secondary outcomes included heart rate (HR), SVI, lactate, norepinephrine (NE) doses, and length of hospital stay (LoS).

2.4 Data extraction

Two independent researchers collected and extracted relevant information from each included study using a standardized, blinded spreadsheet. This information included authors’ names, country and year of publication, clinical and epidemiological characteristics of the population, number of participants and cases, measures of association, confounding factors, and outcomes. For dichotomous variables, we calculated odds ratios (OR) with 95% confidence intervals (CI 95%) based on the events in exposed and non-exposed groups. Missing data were reported when appropriate. For continuous variables, we gathered the mean and standard deviation (SD) for both exposed and non-exposed groups. When studies presented these variables as medians and interquartile ranges (IQR), we converted them to means and SDs using appropriate methods (17, 18).

2.5 Statistical analysis

We employed the Inverse Variance (IV) method (19) in the meta-analysis to combine adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). This analysis was performed using R^® 4.2.226 software. Forest plots were used to summarize the quantitative synthesis, utilizing the meta library, and the metabin (20) (for dichotomous variables) and metacont (20) (for continuous variables) functions. The IV method with Restricted Maximum Likelihood (REML) for tau (2) was applied. Heterogeneity among studies was assessed using Cochran’s Q test and Higgins I² statistic. In cases of statistically significant heterogeneity (I² statistics > 40%), a random effects model with Hartung-Knapp (HK) adjustment was employed. Sensitivity analysis was conducted using Influence Analysis with the InfluenceAnalysis function, and Graphic Display of Heterogeneity (GOSH) with the gosh.diagnostics function (21). Additionally, due to the variability in the measures of association for continuous variables across studies, their inclusion in the meta-analysis was deemed inappropriate.

2.6 Quality assessment

We assessed the potential risk of bias using the Risk of Bias tool version 2 (RoB2) (22). Additionally, we employed a funnel plot and conducted Egger’s test to investigate publication bias (23). If publication bias was detected, we would determine its impact on the meta-analyzed outcome and consider addressing it using the Trim and Fill function (24). Two researchers (GAVT and CVQC) independently evaluated the certainty of the evidence (CoE) for each outcome based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria (25, 26). Any discrepancies between reviewers were resolved through discussion with the lead researcher (EDMR).

3 Results

3.1 Search results and study characteristics

Ten studies were included for qualitative synthesis and meta-analysis (27–36). All studies were RCTs conducted across various countries and continents, including Turkey, Italy, USA, UK, Japan, China, and Egypt, involving a total of 1,121 patients. Among these, 142 out of 394 patients (36%) in the βb group and 189 out of 396 patients (47%) in the control group died. The follow-up period for mortality extended up to 28 days of hospitalization, as not all studies provided follow-up data beyond this period.

Of the included studies, eight used esmolol, and two used landiolol as the βb (30, 31). Both esmolol and landiolol are cardioselective ultra-short-acting β-blockets.

All studies enrolled adult patients with SSh, primarily focusing on pneumonia, followed by abdominal infections. The βb infusion protocol in the intervention group was administered after a stabilization period in both the intervention and control groups, guided by a 24-h intravenous injection protocol. During this period, variables such as HR, SVI, and vasoactive drugs doses were measured, among others.

Additional demographic characteristics of the study population are detailed in Table 1.

TABLE 1

Table 1. General characteristics of included studies.

3.2 Risk of bias in studies

Of the nine studies included, five had a low risk of bias (29, 30, 32, 33, 36), two had a some concerns of risk of bias (28, 35) and two studies had a high risk of bias (27, 31). For further details, see Table 2.

TABLE 2

Table 2. Risk of bias of the included studies using Risk of bias tool version 2 (RoB2) of Cochrane.

3.3 Beta-blockers and mortality in septic shock

Among the ten studies included in the meta-analysis, all except Yang et al. (35) had mortality data for both the intervention (βb) and control groups. The initial meta-analysis revealed a 43% reduction in mortality risk in the intervention group (OR 0.57; 95% CI 0.34–0.98; p < 0.05). However, this analysis revealed unacceptably high heterogeneity (I²: 56%) and a prediction interval (PI) that did not demonstrate a consistent decrease in the risk of mortality in future studies (95% PI 0.14–2.29) (Figure 2A). In accordance with the Cochrane Systematic Review and Meta-analysis (SR-Ms) manual, given the significant heterogeneity, a detailed evaluation into potential sources of heterogeneity was performed. Subsequent sensitivity analysis employing Influence Analysis and GOSH, identified the study conducted by Morelli et al. (28) as an outlier. Upon its exclusion, the sensitivity analysis demonstrated minimal heterogeneity (I²: 35%). However, no significant association between βb use and reduced mortality risk was observed (OR 0.68; 95% CI 0.40–1.15; p > 0.05) (Figure 2B).

FIGURE 2

Figure 2. (A) Forest plot of beta-blocker use and mortality in adults with SSh. All studies were included in the initial meta-analysis, showing high heterogeneity, which after the detection of outliers through GOSH, Morelli et al. (28) was eliminated. (B) Forest plot after exclusion of outliers showing the effect of beta-blocker use and mortality in adults with SSh with acceptable heterogeneity.

Furthermore, subgroup analysis based on the type of βb revealed notable distinctions. Studies employing esmolol exhibited a 53% reduction in mortality risk (OR 0.47; 95% CI 0.26–0.82; p < 0.05) with low heterogeneity (I²: 32%). In contrast, studies using landiolol did not demonstrate a significant decrease in mortality risk (OR 0.98; 95% CI 0.0–1,284.5; p > 0.05), showcasing substantial heterogeneity (I²: 72%) (Figure 3).

FIGURE 3

Figure 3. Forest plot by subgroups of beta-blockers (esmolol and landiolol) and mortality in SSh, showing a reduction in risk only in the esmolol subgroup with acceptable heterogeneity, losing significant association in the landiolol subgroup.

Finally, it is important to note that when heterogeneity was analyzed by subgroups based on the risk of bias, considering the groups with “some concerns” as high risk, the meta-analysis showed an association in the high-risk (OR 0.35; 95% CI 0.14–0.90; I²: 29%) group but lost the association in the low-risk group (OR 0.85; 95% CI 0.42–1.70; I²: 27%).

3.4 SVI, HR and NE doses like hemodynamic parameters

Only four RCTs assessed SVI as a measure of hemodynamics (28, 32, 33, 35). In these studies, the use of esmolol was associated with a significant increase of SVI compared to the control group (MD 3.45; 95% CI 1.91–4.98; p < 0.05) with low heterogeneity (I²: 20%) (Figure 4A). Additionally, among seven studies (29, 30, 32–36), the intervention group exhibited a significant reduction in HR compared to the control group (MD −11.4; 95% CI −20.9 to −1.75; p < 0.05). However, this analysis showed high heterogeneity (I²: 95%). When assessing heterogeneity through Influence Analysis, Xinqiang et al. (34) behaved as an outlier; but its exclusion, did not substantially decrease heterogeneity (I²: 90%). Subgroup analysis based on the type of βb revealed that statistical significance persisted for both the esmolol and landiolol groups (MD −12.24; 95% CI −23.92 to −0.56; p < 0.05 and MD −11.37; 95% CI −20.98 to −1.75; p < 0.05, respectively), without reducing heterogeneity (I²: 95%) (Figure 4B). Finally, when evaluating five RCTs (27–30, 32), we found no association between the use of beta-blockers and NE doses (MD −0.0; 95% CI −0.09 to 0.09; I²: 0%) (Figure 4C).

FIGURE 4

Figure 4. Forest plot of the effect of beta-blocker use in SSh on (A) improvement of SVI; (B) reduction of HR. (C) No effect is evident on the dose of NE used.

3.5 Lactate as a marker of perfusion

Data on lactate values were extracted from eight studies (25–28, 30–32, 34). Lactate levels were serially measured in both intervention and control groups at baseline and every 24 h. We reported lactate values in both groups at 72 h, during which both groups had completed the initial stabilization phase and βb administration. Of the eight studies, only Whitehouse et al. (30) evaluated landiolol, while the remaining studies assessed esmolol. Although the intervention group exhibited a decrease in lactate values at 72 h, this reduction was not statistically significant compared to the control group (MD −0.39; 95% CI −0.79 to 0.02; p > 0.05) with high heterogeneity (I²: 83%) (Figure 5A). Heterogeneity assessment through Influence Analysis identified Whitehouse et al. (30) and Liu et al. (32) as outliers. Excluding these studies revealed a significant reduction in lactate levels in the intervention group (MD −0.40; 95% CI −0.58 to −0.22; p < 0.05), and a decrease in heterogeneity (I²: 33%) (Figure 5B).

FIGURE 5

Figure 5. Forest plot of the effect of beta-blocker use in SSh on serum lactate. (A) No association is shown on lactate concentration, but with very high heterogeneity. (B) Sensitivity analysis, where, through Influence Analysis, Liu et al. (32) and Whitehouse et al. (30) are excluded for being outliers.

3.6 LoS

Seven studies that evaluated the length of hospital stay (27–30, 32, 34, 36) showed a very slight reduction in duration in the intervention group, but without statistical significance compared to the control group (MD −0.83; 95% CI −4.8 to 3.14; p > 0.05), with high heterogeneity (I²: 90%) (Figure 6).

FIGURE 6

Figure 6. Forest plot of the effect of beta-blocker use in SSh on LoS, showing no association.

3.7 GRADE assessment and funnel plot

We used GRADE to assess the certainty of evidence (CoE) regarding the association between βb use and mortality in SSh. We found no publication bias [Egger’s test (23): −0.35; 95% CI −5.4 to 4.7; p > 0.1] (Figure 7). Table 3 shows a total reduction of 43% in overall mortality risk with βb use. Subgroup analysis indicates that esmolol is linked to a 53% reduction in mortality risk, with moderate certainty of evidence for this effect. Conversely, landiolol does not demonstrate a significant reduction in mortality risk in SSh, with a low certainty of evidence.

FIGURE 7

Figure 7. Funnel plot of the included studies in the meta-analysis on the effect of beta-blocker use and mortality in SSh with Egger’s test: –0.35; 95% CI –5.4 to 4.7; p > 0.1. No publication bias is evident.

TABLE 3

Table 3. Certainty of evidence through GRADE.

4 Discussion

4.1 Beta-blockers and mortality risk

Our meta-analysis of nine randomized controlled trials (RCTs) involving a total of 1,121 patients reveals that β-blocker (βb) use in patients with SSh reduces mortality by up to 43% (OR 0.57; 95% CI 0.34–0.98; I²: 56%). This result includes both esmolol (seven studies) and landiolol (two studies). However, subgroup analysis based on the type of βb revealed that the benefit persists only in the esmolol subgroup (OR 0.47; 95% CI 0.26–0.82; I²: 32%), while no significant mortality reduction is observed in the landiolol subgroup (OR 0.98; 95% CI 0.0–1,284.5; I²: 72%).

Profound hemodynamic instability in patients with SSh ultimately leads to multiple organ dysfunction and increased mortality. The potential benefits of βb in various medical conditions suggest their potential use in critically ill patients with SSh, where reflex tachycardia leads to decreased SVI and, consequently, cardiac output (CO). β-blockers can help mitigate this response by controlling or reducing HR, thereby allowing more time for ventricular filling, improving both SVI and CO. This physiological mechanism supports that βb use can reduce inflammatory markers, improve perfusion indicators (such as lactate levels), an enhance hemodynamic variables [such as SVI, CO, and cardiac index (CI)] (6, 8, 37, 38).

In addition to the well-documented role of βb in improving hemodynamic parameters, they are proposed to have a significant function in modulating the dysregulated inflammatory response observed in sepsis. βb attenuate the deleterious cardiac effects of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which induce an up-regulation of adrenergic receptors, thereby exacerbating hemodynamic instability. The administration of beta-blockers helps to mitigate these effects. Additionally, βb are postulated to play a role in modulating lymphocyte apoptosis driven by the inflammatory processes inherent in sepsis and sepsis-induced coagulopathy (3, 11).

Some SR-Ms evaluate βb, but ours has several strengths over existing research, such as incorporating more recent, higher-quality RCTs from diverse international settings, including the latest studies evaluating landiolol; thereby advancing the current state of knowledge in this field.

Huang et al. (12) in an SR-Ms assessing the efficacy and safety of esmolol in patients with SSh, included fourteen randomized controlled trials (RCTs), the largest number of studies reviewed to date. They focused on 28-day in-hospital mortality as the primary outcome and found that esmolol use was associated with a reduced mortality risk (RR = 0.66, 95% CI = 0.56–0.77, p < 0.001; I²: 0%), based on data from nine RCTs (eight Chinese studies and one Italian). However, methodological aspects of this study need to be addressed, such as using the Jadad scale for risk of bias assessment instead of RoB2. Additionally, the study selection process was not rigorous enough, incorporating an RCT with a different intervention group (milrinone and esmolol), which distorts the average mortality data and other outcomes.

Zhang et al. (10) in an SR-Ms exploring the benefits of esmolol in patients with SSh, analyzed eight RCTs and found that βb use reduces mortality (RR 0.68; 95% CI 0.52–0.88; I²: 45%). However, the study has methodological limitations, including the inclusion of RCTs with some risk of bias, except for Liu et al. (32). Additionally, like other published SR-Ms, this analysis duplicated a study reported in another journal and included an RCT with an inadequate outcome (combining milrinone and esmolol as the intervention group) (39), potentially altering the overall RR result.

Similarly, Li et al. (9) conducted an SR-Ms analyzing six RCTs in order to assess the prognosis of βb use in patients with SSh. Their meta-analysis of four RCTs reported a mortality reduction of up to 41% in the intervention group (RR 0.59; 95% CI 0.48–0.74; I²: 0%), consistent with our data. However, the study has methodological shortcomings, as one of the six RCTs had an erroneous intervention group (combining milrinone and esmolol) (39), and another study was an analytical version of Morelli’s original work (40). Moreover, the risk of bias assessment using the Jadad scale, suggest that the quality of the studies’ is moderate to high. However, this assessment might differ if evaluated with RoB2 tool per Cochrane and PRISMA guidelines.

Interestingly, RCTs with esmolol as the intervention do not consistently exhibit high quality according to the RoB2 assessment. In contrast, RCTs evaluating landiolol, which generally demonstrate better methodological quality, fail to show a reduction in mortality. This discrepancy could be attributed to limitations in study designs or specific drug effects, despite esmolol and landiolol being ultra-short-acting βb with similar pharmacokinetic properties. However, Ikeshita et al. (41), in an experimental study in mice, showed that landiolol is more versatile due to slightly greater cardioselectivity and fewer cardiodepressant effects than esmolol, although both drugs exhibit comparable negative chronotropic effects.

Finally, Hasegawa et al. (11) conducted an SR-Ms similar to ours, evaluating the impact of ultra-short-acting βb on mortality in SSh patients. It incorporates six RCTs with esmolol and one RCT with landiolol, concluding that there is a significant reduction in mortality in the experimental group (RR 0.68; 95% CI 0.54–0.85; I²: 31%). However, like the previous SR-Ms, one study has a different experimental group (milrinone plus esmolol), and it does not evaluate subgroups for the two types of ultra-short-acting βb (esmolol vs. landiolol and mortality effect in each subgroup), which are addressed in our report.

It is important to emphasize that our research is the first to incorporate recent RCTs using landiolol as a βb. We meticulously reviewed several databases and included only those RCTs that address our PICO question. This approach contrasts with other published SR-Ms, which often include studies with duplicates or inappropriate intervention groups, such as those assessing the combination of esmolol with milrinone, which deviates significantly from our PICO question. Additionally, we adhered to Cochrane and PRISMA guidelines for risk of bias assessment using RoB2 tool, rather than relying on less suitable scales. Our analysis also involved a thorough exploration of heterogeneity using Influence Analysis and GOSH, with findings validated through the GRADE approach.

4.2 Beta-blockers and hemodynamic parameters

In our results, additionally, βb use in patients with SSh improves hemodynamic parameters, showing an increase in SVI, assessed in four studies (MD 3.45; 95% CI 1.91 to 4.98; I²: 23%). β-blockers also significantly reduce heart rate (HR) (MD −11.37; 95% CI −20.98 to −1.75; I²: 95%) and lactate levels (MD −0.30; 95% CI −0.60 to −0.01; I²: 64%). This effect is maintained only in the esmolol subgroup (MD −0.37; 95% CI −0.55 to −0.18; I²: 45%), while no significant effect is observed in the landiolol subgroup (MD 0.80; 95% CI −0.06 to 1.66). Furthermore, no association was found between β-blocker use and the dosage of vasoactive agents such as norepinephrine (NE) or LoS.

Although the RCTs used primarily evaluate mortality as their main outcome, they have also assessed hemodynamic parameters, perfusion markers such as lactate, and even inflammatory markers in patients with SSh.

Furthermore, Huang et al. (12) reported that the intervention group experienced significant reductions in HR (SMD −17; 95% CI −2.24 to −1.17; I²: 90%) and troponin I levels (SMD −1.61; 95% CI −2.06 to −1.16; I²: 69%) but found no significant differences in mean arterial pressure (MAP) (SMD 0.13; 95% CI −0.03 to 0.29; I²: 0%).

Similarly, Zhang et al. (10) also reported that in six RCTs that the intervention group achieved adequate HR control and reduction at 72 h (DM −1.91; 95% CI −3.23 to −0.60; I²: 94%). Additionally, this research showed a statistically significant HR reduction from 12 to 72 h of treatment (SMD −1.91; 95% CI −3.23 to −0.60; I²: 94%), an improvement in CI only at 72 h (SDM −0.40; 95% CI −0.73 to −0.07; I²: 0%), and reduced troponin I levels from 24 to 72 h (SMD −1.62; 95% CI −2.54 to −0.73; I²: 73%). However, no significant differences were observed in central venous pressure (CVP) (SMD 0.03; 95% CI −0.29 to 0.36; I²: 0%), SVI (SMD 0.43; 95% CI −0.54 to 1.41; I²: 88%), lactate levels (SMD −0.40; 95% CI −0.93 to 0.12; I²: 80%), and MAP (SMD 0.07; 95% CI −0.25 to 0.39; I²: 0%).

Additionally, Li et al. (9) the study also found a significant reduction in HR (SMD −2.01; 95% CI −3.03 to −0.98; I²: 93%) and troponin I levels (SMD −19.91; 95% CI −2.39 to −1.43; I²: 0%), but no improvement between esmolol use and SatVCO2 (SMD 1.87; 95% CI −1.53 to 5.36; I²: 97%), lactate levels (SMD 0.77; 95% CI −0.66 to 2.21; I²: 94%), CVP (SMD 0.18; 95% CI −0.02 to 0.39; I²: 0%), or MAP (SMD 0.18; 95% CI −0.02 to 0.39; I²: 0%).

4.3 Strengths

Our study has numerous strengths. First, we carried out a comprehensive search strategy, covering six essential databases and exclusively RCT studies, allowing a robust epidemiological evaluation of cause and effect. Second, we used a rigorous methodology to conduct our review and meta-analysis, including a thorough quality assessment of studies and a statistical analysis to address heterogeneity. Third, our results are both robust and reliable, as evidenced by our careful assessment of heterogeneity and identification of outliers, with consistent findings across individual studies. Fourth, this is the first SR-Ms of adequate quality that incorporates the most recent RCTs conducted with landiolol.

4.4 Limitations

However, it is important to acknowledge some limitations in our study. First, only a few completed studies have explicitly addressed our PICO question; most studies are in Chinese, making them difficult to access. Second, while current studies adhere to the Sepsis-3 definition of SSh, older studies still rely on the SIRS criteria, creating inconsistencies in the data. Finally, there are only two RCTs involving landiolol, and none employ a three-arm design to compare β-blockers, placebo, and both together; which limits our ability to fully elucidate the specific effects of esmolol and to definitively assess landiolol’s impact on mortality in SSh patients.

5 Conclusion

Our study suggests that using β-blockers (βb) in patients with SSh can reduce mortality; however, this effect is observed exclusively with esmolol, and there is no group effect since landiolol does not demonstrate similar effects. Consistent with these findings, better HR control is also evidenced, improving hemodynamic parameters such as SVI and enhanced perfusion (reduction in lactate) in the experimental group. However, given the current evidence, these results should be interpreted with caution. To further elucidate the effects of β-blockers, additional RCTs with robust designs are needed, particularly those that evaluate landiolol specifically or employ a three-arm study design comparing both β-blockers to placebo.

Data availability statement

The original contributions presented in this study are included in this article/Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

GV-T: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. CQ-C: Methodology, Supervision, Writing – original draft. EM-R: Conceptualization, Formal analysis, Methodology, Project administration, Writing – original draft. MC-C: Validation, Visualization, Writing – review & editing. NS-P: Data curation, Formal analysis, Writing – original draft. YA-Á: Data curation, Formal analysis, Investigation, Writing – original draft. HA-G: Funding acquisition, Project administration, Resources, Writing – review & editing. WG-A: Data curation, Methodology, Writing – original draft. PZ-A: Funding acquisition, Project administration, Writing – review & editing.

Funding

The authors declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2024.1448573/full#supplementary-material

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