Intensive care units have been grappling with acute respiratory distress syndrome (ARDS) for over half a century, posing an ongoing formidable challenge (Pham and Rubenfeld, 2017). Globally, approximately three million patients are affected by ARDS annually, accounting for approximately 10% of ICU admissions (Rubenfeld et al., 2005; Bellani et al., 2016; Fan et al., 2018). Despite various therapeutic attempts, mortality rates related to ARDS have not decreased since the late nineties (Phua et al., 2009; Herridge et al., 2011). ARDS differs from simple pulmonary diseases as it is a clinical syndrome with diverse potential etiologies and pathophysiological characteristics. Its development and occurrence are not necessarily linked to primary lung injury but may result from an unregulated host/organ response (HOUR), commonly referred to as the “second hit” (Pan et al., 2021; Huang et al., 2023). Effective management of acute respiratory distress syndrome entails evaluating the efficacy of therapeutic interventions and preventing secondary lung injury caused by this “second hit.”

The unregulated host/organ response in critical illness is characterized by increased sympathetic drive resulting from adrenergic stimulation of catecholamines, which is a fundamental pathological feature (Dünser and Hasibeder, 2009). The lung is particularly susceptible to sympathetic overstimulation, often accompanied by hyperdynamic circulation. In lung injury cases, it is hypothesized that enhanced blood flow through the pulmonary vasculature may contribute to or exacerbate acute lung injury or even ARDS (van der Jagt and Miranda, 2012). The potential role of beta-blockers in antagonizing the adrenergic stimulation of catecholamines has been investigated in various critical conditions, such as sepsis, trauma, cardiac arrest, and burns. Growing evidence suggests that beta-blockers improve hemodynamic and metabolic factors, resulting in reduced burn healing durations (Mohammadi et al., 2009; Ali et al., 2015; Cheema et al., 2020), decreased mortality following traumatic brain injury (Mohseni et al., 2015; Ley et al., 2018), and improved neurological outcomes after cardiac arrest (Driver et al., 2014; Lee et al., 2016). In sepsis, beta-blockers may have a beneficial effect on hemodynamics and cardiac function (Morelli et al., 2016), while potentially reducing mortality (Morelli et al., 2013). Some studies have indicated that beta-blockers could reduce lung endothelial damage in ARDS by regulating pulmonary vascular flow without affecting systemic hemodynamics, suggesting their potential as therapeutic agents for ARDS treatment (Piacentini et al., 2008; Hagiwara et al., 2009). However, there is currently insufficient evidence to support the theory that beta-blocker usage reduces mortality in critically ill patients with ARDS. Therefore, a retrospective cohort analysis was conducted to validate the association between beta-blocker usage and mortality among individuals diagnosed with ARDS.

This study established a correlation between the use of beta-blockers and a reduction in the mortality rate at both 30 and 60 days for critically ill patients with ARDS. Furthermore, the relationship between beta-blocker utilization and mortality was found to vary significantly based on the severity of ARDS. These findings have the potential to significantly impact the management of ARDS.

Critical illness is characterized by an exaggerated and dysregulated host/organ response to disease, which plays a crucial and central role in its development. Despite the distinct pathophysiological mechanisms observed in ARDS and other severe diseases, various host responses can act as a “bridge,” leading to severe manifestations with differing contents and convergences of contents. Upregulation of adrenergic stimulation is a prominent pathophysiological feature of critical diseases. An increasing number of studies are investigating the use of beta-blockers to attenuate this adrenergic response (Ackland et al., 2010). Numerous studies have demonstrated the effectiveness of beta-blockers in the treatment of various critically ill patients with conditions such as sepsis, prior to major surgical procedures, burns, cardiac arrest, and traumatic brain injury. These studies have significantly contributed to enhancing our understanding of the benefits provided by beta-blockers in these specific clinical scenarios (Herndon et al., 2001; van der Jagt and Miranda, 2012; Morelli et al., 2013; Chacko and Gopal, 2015; Lee et al., 2016). The BASEL II ICU study conducted by Noveanu et al. demonstrated a potential reduction in mortality among individuals with acute respiratory failure admitted to the ICU who had been taking oral beta-1 blockers prior to admission (Noveanu et al., 2010). However, this study solely focuses on beta-blocker utilization before hospital admission and upon discharge. Due to the absence of previous studies focusing specifically on the ARDS population, limited sample size, and varied baseline characteristics, potential bias may have arisen, and the impact of beta-blocker use during ICU stay on survival outcomes among ARDS patients remains unclear. To address this, our study employed PSM to mitigate selection bias and ensure baseline variable equilibrium across different groups. We found that the use of beta-blockers was associated with reduced mortality, providing evidence supporting the potential benefits of beta-blockers in improving prognosis for patients with ARDS. Furthermore, these findings highlight the pleiotropic effects of beta-blockers in critically ill patients.

Experimental studies have demonstrated the protective effects of beta-blockers on lung function. In a rat model of lipopolysaccharide-induced sepsis, Hagiwara et al. discovered that landiolol decreased the wet-to-dry lung ratio, indicating a reduction in lung edema (Hagiwara et al., 2009). Similarly, Piacentini et al. (2008) found that Esmolol improved pulmonary flow and significantly reduced lung congestion, edema, areas of inflammation, bleeding, and overall lung injury in septic animals that were spontaneously ventilating (Piacentini et al., 2008). Moreover, in pigs with endotoxic shock, the administration of beta-blockers did not significantly affect cardiac output, but led to an increase in the PaO₂/FiO₂ ratio after 3 h, indicating improved oxygenation (Aboab et al., 2011). Based on these findings, it is plausible to hypothesize that reducing pulmonary vascular flow through beta-blockers may mitigate lung damage.

Saifi et al. (2021) conducted an analysis of older patients with Coronavirus disease 2019 (COVID-19), with the majority (97.1%) experiencing respiratory failure. Their findings revealed a statistically significant association between beta-blocker therapy and a higher survival rate compared to the non-treated group (Saifi et al., 2021). In a case-control study of 20 COVID-19 patients with ARDS, Clemente-Moragón et al. (2021) demonstrated that metoprolol administration improved oxygenation and reduced lung inflammation. The researchers proposed that this beneficial effect of beta-blockers was achieved by modulating neutrophil function and preventing excessive inflammation. Additionally, the infusion of metoprolol in critically ill COVID-19 patients could positively impact oxygenation through hemodynamic changes (Clemente-Moragón et al., 2021). This effect may be attributed to a reduction in intrapulmonary shunting by lowering cardiac output and consequently improving ventilation-perfusion ratios (de Roquetaillade et al., 2022). A similar mechanism may explain why beta-blocker usage improves oxygenation in patients receiving veno-venous extracorporeal membrane oxygenation (V-V ECMO) (Bunge et al., 2019). Among patients with hyperdynamic circulation, beta-blockers have been shown to potentially decrease the amount of unoxygenated blood passing through the extracorporeal membrane and decrease intrapulmonary shunts. This may also provide some cardioprotective effects (Lynch et al., 1979). The research discussed in this paper focused specifically on COVID-19 patients with ARDS. It should be noted that critically ill patients can develop ARDS due to various factors, leading to diverse symptoms and comorbidities. In the MIMIC-IV database, all patients with ARDS were included regardless of the underlying cause, symptomatology, other medical conditions, or severity. The results of this study suggested that beta-blockers may have favorable outcomes in the overall ARDS population rather than a specific subgroup. However, it is important to mention that we did not examine changes in cardiac output and oxygenation, making it difficult to confirm whether the observed association is attributed to improved oxygenation through the reduction of intrapulmonary shunting with beta-blockers.

The precise mechanism by which beta-blockers exert their effects in patients with ARDS is not fully understood. However, several preclinical studies have provided valuable insights into the pleiotropic effects of beta-blockers. For example, a study in rats with lipopolysaccharide sepsis demonstrated that landiolol can inhibit lung injury and reduce the expression of high mobility group protein b1 (HMGB-1), a protein associated with lung injury (Hagiwara et al., 2009). Similarly, carvedilol has been found to suppress the activation of the nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome, leading to a reduction in pyroptosis and inflammatory cytokine levels in alveolar macrophages (AMs), ultimately resulting in decreased lung injury (Wong et al., 2018). Furthermore, certain beta-blockers, such as nebivolol, have been shown to enhance the bioavailability of nitric oxide and improve endothelial function in ARDS (Vassiliou et al., 2020; Kumar et al., 2021). These studies illustrate distinct mechanisms of action for beta-blockers in ARDS and emphasize the need for further investigation in this area.

Our study revealed an intriguing finding regarding beta-blockers, which displayed an extended duration of hospitalization and stay in the ICU, despite lower mortality rates. This observation aligns with previous research conducted on patients with traumatic brain injury or sepsis (Ley et al., 2018; Ge et al., 2023). However, we cannot definitively conclude whether this disparity is due to a trade-off between mortality and length of stay in the ICU/hospital. It is plausible that early mortality might have reduced the average duration of stay in the beta-blocker non-user group, necessitating further investigation. Importantly, sub-analyses examining different ARDS severities revealed a significant interaction. Specifically, the beneficial effects of beta-blockers on 30-day survival were only evident in patients with moderate or severe ARDS. In contrast, patients with mild ARDS might not exhibit the same magnitude of dysregulated host/organ response as those with moderate or severe ARDS, thereby potentially limiting the benefits of beta-blocker therapy at this level of disease severity.

This study has multiple noteworthy limitations. Firstly, like all retrospective analyses, there is a possibility of residual confounding factors. Nonetheless, we diligently endeavored to control for confounders and successfully achieved optimal balance among the PSM, IPTW, SMRW, PA, and OW groups. Secondly, it is important to consider that different treatment strategies, such as prone position ventilation and extracorporeal membrane oxygenation (ECMO) utilization, may influence patient outcomes. Thirdly, although a range was provided in the descriptive statistics, we did not specify the exact dosage and timing of beta-blocker administration in this study. Additionally, the impact of different types of beta-blockers (long-acting vs. short-acting) on prognosis was not deeply explored. Fourthly, due to the limited availability of hemodynamic measures (e.g., cardiac output) for ARDS patients in the database, we could not accurately assess the precise hemodynamic status associated with beta-blocker usage. Fifthly, the heterogeneity of ARDS may impact the treatment effect in distinct phenotypes (Beitler et al., 2022). Thus, our findings cannot be universally applied to outcomes across all phenotypes, necessitating future studies to address specific phenotypes. Finally, given that the data analyzed was derived from an observational database, further randomized trials are warranted to validate our findings.

Based on findings from this cohort study, the administration of beta-blockers demonstrated an association with reduced mortality in patients with ARDS. These results suggest that beta-blockers hold promise as a potential adjunctive treatment approach for ARDS patients in the ICU. However, it is important to acknowledge the retrospective nature of this study and the need for further investigation to validate these findings.