In this retrospective study of data from 1262 septic patients, ICU mortality was lower among patients with premorbid cardioselective β-blocker exposure. Compared with non-use, premorbid cardioselective and non-selective β-blocker use was associated with lower lactate concentrations. Only cardioselective β-blocker use was associated with an improvement in 28-day ICU mortality. This study is the first to illustrate the effects of premorbid exposure to different types of β blocker on short-term mortality among septic patients. The findings encourage long-term cardioselective β-blocker use, but prospective studies are needed to confirm the protective effect of such use in septic patients.
Tachycardia increases the cardiac workload and myocardial oxygen consumption. The shortening of the diastolic filling time during tachycardia decreases the stroke volume and coronary perfusion, contributing to the reduction of the ischemic threshold. Elevated HRs are associated with increased mortality in critically ill patients [16, 17], as shown in this study, and a survival benefit of β1-adrenergic selective blockade has been found in animal models [9]. By decreasing the HR, β-blockers decrease myocardial oxygen consumption and prolong the diastolic time and coronary perfusion, reducing the risk of myocardial ischemia. Several studies have shown that diastolic dysfunction is present in about half of septic patients and is a significant predictor of mortality [18]. Β-blockers have been shown to improve the diastolic function of patients with heart failure [19].
Nevertheless, the treatment of tachycardia during septic shock remains controversial. In the early phase of septic shock, tachycardia compensates for any reduction in cardiac output; HR reduction may interfere with this physiological response, reducing cardiac output and improving oxygen delivery [20]. However, tachycardia that persists after adequate resuscitation may represent sympathetic overstimulation. In patients with tachycardia (HR > 95 bpm) who received a titrated esmolol infusion with the goal of reducing the HR to 80–94 bpm, decreased HRs were offset by increased ventricular filling time and volume, ultimately resulting in increased stroke volume, which compensated for the HR decrease [10]. Similar hemodynamic effects of β1-adrenergic selective blockade by esmolol administration have been reported [21, 22]. With adequate preloading, HR reduction improves cardiac performance and efficiency [23], with the maintenance or even increase of the stroke volume. In our study, long-term cardioselective β-blocker users had significantly lower baseline HRs on ICU admission than did non-selective β-blocker users; this difference may translate into better outcomes.
Mechanisms other than HR reduction may explain the better sepsis outcomes associated with β-blocker use. The physiological response to stress includes the increased release of catecholamines. The early phase of sepsis is typically characterized by high cardiac output with decreased vascular tone, tachycardia, and impaired myocardial function. All of these factors can be associated with the elevation of the adrenergic drive to increase global and microvascular blood flow and oxygen delivery to vital organs. The direct cardiotoxic effects of catecholamines, especially norepinephrine, had been recognized for decades. A sustained increase in cardiac adrenergic drive adversely affected myocardial biology and structure phenotype in a heart failure model. The treatment of cardiac myocytes with norepinephrine caused a 60% loss of these cells [24], and the exposure of cardiac myocytes to isoproterenol had similar effects [25]. Several animal studies have demonstrated the occurrence of β1-adrenergic receptor signaling, which is considered to be more harmful to cardiac myocytes than is β2-adrenergic receptor signaling [25, 26]; these findings suggest that β1-adrenergic receptor signaling is the key mechanism for adrenergic-driven cardiotoxicity. In a clinical trial, differences in β1-adrenergic and β2-adrenergic receptor blocking doses indicated that β1-adrenergic selective blockade had a better treatment effect for heart failure [27]. Hence, chronic β-blocker (especially cardioselective β1-blocker) use may protect the heart from the catecholamine surge that occurs during sepsis.
Esmolol also improves microvascular circulation, as determined by assessment of the sublingual microcirculatory blood flow [21]. During sepsis, physiological anticoagulation and fibrinolytic mechanisms are impaired, and the coagulation pathway shifts toward a pro-coagulant state [5]. Coagulation system dysregulation causes the dissemination of intravascular coagulation, leading to microcirculatory dysfunction and tissue production at the cellular level [17]. β1- and β2-adrenergic receptors act differently on coagulation functions. β2-adrenergic stimulation suppresses platelet aggregation [28]. β1-adrenergic stimulation inhibits fibrinolysis by reducing prostacyclin synthesis [29], whereas β2-adrenergic stimulation promotes tissue plasminogen activator release, leading to enhanced fibrinolytic activity. Thus, selective β1 blockers may reduce platelet activation via relative β2-adrenergic activation, and enhance fibrinolysis through increased plasminogen activation and prostacyclin synthesis [30]. In the present study, premorbid β-blocker users had lower baseline lactate levels than did non-users. After initial resuscitation, more premorbid selective than non-selective β-blocker users achieved > 10% lactate clearance, suggesting that selective β-blockers improve the pro-coagulation state during sepsis, which plays a role in enhancing microcirculation function.
β1- and β2-adrenergic receptors also seem to have different actions on the immune system. Th1 cells stimulate macrophages and natural killer T cells and the production of pro-inflammatory cytokines, whereas Th2 cells have the opposite actions, inhibiting macrophage activation and T-cell proliferation. Th1, but not Th2, cells have β2-adrenergic receptors. Hence, β2-receptor stimulation suppresses Th1 cell activation with a relative increase in the Th2 cell response [2]. Thus, selective β1-blockade could promote β2-adrenergic pathway activation and contribute to the suppression of the pro-inflammatory status. In septic animal models, esmolol reduced the levels of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α in blood [6] and peritoneal fluid [31]. Metoprolol reduced the hepatic expression of proinflammatory cytokines and the plasma interleukin (IL)-6 level [9]. In contrast, the non-selective β-blocker propranolol enhanced inflammation and increased the TNF-α and IL-6 levels [32, 33]. The serum levels of anti-inflammatory cytokines, such as IL-10, are increased with stimulation by the selective β1-blocker atenolol [8] and by β2-blockers [34]. Hence, the benefits of β-blockers may also be immune mediated. Selective β-blockers have anti-inflammatory effects, which could explain the lower baseline pro-inflammatory cytokine levels and better sepsis outcomes in chronic cardioselective β-blocker users in this study.
Our findings are in line with previous findings that premorbid β-blocker exposure is associated with the improvement of outcomes in patients with sepsis [11–13]. Contrary to our findings, Singer et al. [12] reported that the mortality rate was lower among patients with premorbid exposure to non-selective β blockers than among those with premorbid cardioselective β-blocker exposure. However, their study was based on Medicare administrative data, with patient inclusion in 2009–2011 according to ICD-9 diagnostic codes for sepsis, septic shock, and systemic inflammatory response syndrome, without consideration of clinical markers such as laboratory values and vital signs. In the present study, we used the Sepsis-3 criteria for patient inclusion, and considered a broad range of clinical information and data dating to 2015–2017, when sepsis management was more in line with treatment guidelines.
This study has several limitations. First, as it was retrospective, we could not determine the causal relationship between premorbid cardioselective β-blocker exposure and mortality. Second, it was based on the review of medical records from a single center. Disease severity was greater in our sample than in previous samples; thus, the observed benefits of cardioselective β-blockers in terms of sepsis outcomes may not extend to all septic patients. Third, the types of β-blocker prescribed were distributed unevenly; cardioselective β-blockers are preferred in our region when β-blocker use is indicated, and non-selective β-blocker use is predominant for certain diseases, such as liver cirrhosis, which may have caused bias. We attempted to correct for such bias by adjusting the multivariate regression and subgroup analyses for comorbidities. Finally, we only collected the data from the point of ICU admission, which may had been treated partially in the emergency department or ordinary ward.