Evaluating the effects of Esmolol on cardiac function in patients with Septic cardiomyopathy by Speck-tracking echocardiography—a randomized controlled trial

Sepsis is considered the main cause of death in critically ill patients worldwide [1, 2]. Heart is susceptible to Sepsis and is clinically manifested as Sepsis Induced Cardiomyopathy (SIC), which has an incidence of 50% in Sepsis patients and even up to 70% in Septic Shock patients [3, 4]. SIC is also one of the causes of increased mortality in patients with Sepsis or Septic Shock [5‐7]. In the case of Sepsis, the host fights against infection by activating the hemodynamic, metabolic, and immune processes. During the progress, it will partly activate the sympathetic nervous system and promote the release of catecholamine hormones [8]. Recommended as the first-line vasoactive agent in the treatment of Sepsis by the guidelines, norepinephrine is extensively adopted in clinical practice. Excessive stress caused by the release of endogenous catecholamines and the application of exogenous catecholamines acts directly on the myocardium of patients with Sepsis, resulting in increased myocardial contractility and tachyarrhythmia [9], an independent risk factor for death in patients with severe Sepsis and Septic Shock [10, 11].

Tachyarrhythmia can impair ventricular filling and increase myocardial oxygen consumption, making the use of β -blockers for correcting tachyarrhythmia a treatment option for SIC. Currently, the use of β-blockers in the treatment of SIC patients is still controversial [7, 12]. Previous studies have shown that Esmolol can improve the 28-day mortality in patients with Sepsis, and is safe and effective in reducing heart rate, exerting no significant adverse effects on tissue perfusion [13‐17]. However, when Sepsis occurs, especially after Septic Shock, the hemodynamics are in an unstable state, while β-blockers act directly on myocardium, causing a decrease in myocardial contractility, and further aggravating hemodynamic instability [18]. To this end, it is urgent to find an effective and feasible method to evaluate the changes of myocardial contractility in the treatment of SIC with β -blockers and monitor hemodynamics closely.

The diagnosis of SIC is still limited to the left ventricular ejection fraction (LVEF) obtained by transthoracic echocardiography (TTE) [19, 20], which is affected by various factors, making its clinical application widely doubted. Speckle-tracking echocardiography (STE) is a new echocardiographic method that can better evaluate cardiac function. The global longitudinal strain (GLS) is the most commonly used strain measurement method and represents the ratio of the maximum longitudinal length change during myocardial contraction to the original length during diastole. Less affected by the pre- and post-load heart state, it can better evaluate myocardial function and is considered to improve the accuracy of SIC diagnosis [21, 22].

The hypothesis was proposed that Esmolol can effectively reduce heart rate in SIC patients without damaging myocardial contractility and worsening hemodynamics. The purpose of this study was to evaluate myocardial contractility with STE after the heart rate was reduced to the target value with the application of Esmolol, with its effect on 28-day and 90-day mortality recorded.

Patients admitted to the Intensive Care Department of Tianjin Third Central Hospital (Grade III, Class A) with 30 comprehensive ICU beds from March 1, 2020 to September 30, 2021 were selected as the study subjects, and the study was approved by the Ethics Committee of Tianjin Third Central Hospital. All subjects were followed up to 90 days after discharge, with death as an end point.

Given its negative inotropic effect, the application of Esmolol is still widely controversial as one treatment of SIC. This study showed that all SIC patients achieved the target HR after Esmolol, and there was no significant reduction in left ventricular contractility, and the indicators of GEF and dP/dtmx were increased, and the short-term mortality rate was reduced compared with those with uncontrolled HR.

Whether the use of β-blockers in the treatment of SIC worsens hemodynamics remains controversial as well. A large multi-center study showed that early application of β-blockers during acute myocardial infarction reduced the risk of reinfarction and ventricular fibrillation, but increased the incidence of cardiogenic shock, especially at the first day after admission [29]. In addition, a meta-analysis for heart failure after myocardial infarction also suggested that the use of β-blockers within 24 h after myocardial infarction would increase the mortality incidence of patients with cardiogenic shock [18], which might be attributed to the negative inotropic effect of β-blockers. Helen Paur et al. found that the application of β-blockers would aggravate the negative inotropic effect of adrenaline dependence in the case of stress cardiomyopathy [30]. Proceeding from this controversial point, further investigation was conducted on whether the myocardial contractility of SIC patients was impaired after β-blockers lowering the HR.

Although there is no uniform definition of SIC at present, LVEF decline is often considered a diagnostic criterion [20]. Given that GLS is less affected by cardiac preload and afterload, and can detect cardiac function damage earlier than LVEF, it is frequently recommended to replace LVEF as a new method evaluating left ventricular function [31‐33]. To this end, GLS was hereby adopted as an indicator to guarantee the evaluation accuracy, and GEF and dP/dtmx were used as well. It can be found from the results of the present study that after Esmolol lowering the HR of patients in Group E, indicators of GLS, GEF and dP/dtmx were not significantly worsened, and SVRI and SV were increased. At the same time, compared with Group C, indicators of GLS, GEF, dP/dtmx, SVRI and NT-proBNP were improved in Group E, and the difference was statistically significant. The results can be explained from the following three points: First, in order to suppress the excessive inflammatory response in Sepsis, the secretion of endogenous catecholamine hormones is increased through the neuroinflammatory reflex in the body [34]. In the meanwhile, the body also mobilizes the adrenergic effect to increase heart function [35] and correct the microcirculation disorder and tissue hypoxia caused by the imbalance of oxygen supply and demand during Sepsis/Septic Shock. Over-stimulation of catecholamines may lead to the collapse of the cardiovascular system, presenting weakened myocardial contractility and tachyarrhythmia that can damage ventricular filling, cause myocardial ischemia, and further damage myocardial contractility. However, Esmolol can improve ventricular filling and myocardial perfusion after lowering HR, thereby avoiding damage to myocardial contractility. A meta-analysis of β-blockers used in patients with severe Sepsis and Septic Shock confirmed their efficacy to improve the prognosis of patients without causing hemodynamic deterioration [36]. Secondly, existing studies have summarized the pathophysiological mechanism of SIC as excessive release of inflammatory factors during Sepsis, which leads to a series of direct injuries, such as cardiovascular dysfunction, imbalance of calcium homeostasis, mitochondrial dysfunction, and down-regulation of β-adrenergic receptor expression, and causes cardiac insufficiency ultimately [19‐21]. Takeshi Suzuki et al. found that Esmolol could inhibit the release of pro-inflammatory factors in their study on the regulation of cardiac function in Sepsis mice [37]. Luyao Zhang et al. proposed in the study of Esmolol on mice with severe pancreatitis that continuous infusion of Esmolol could reduce inflammatory response, and protect lung and pancreas [38]. The above studies have confirmed that Esmolol effectively protects the myocardium by inhibiting the release of inflammatory factors. Finally, studies have shown that ventricular-arterial decoupling persists during Septic Shock. Increased static arterial elasticity caused by tachycardia will increase ventricular-arterial decoupling [39, 40]. A. Morelli et al. found in a prospective observational study on the correlation between Esmolol reducing HR and improving arterial elasticity in patients with Septic Shock that Esmolol could reduce static arterial elasticity and restore the ventricular-artery coupling, thereby improving cardiovascular efficacy [41]. Wei Du et al. also claimed that Esmolol may restore vascular waterfall after acute endotoxemia [42]. Antoine Kimmoun et al. proposed that selective β1 blockers can enhance cardiac intrinsic contractile force and vascular responsiveness to catecholamines when added to standard Septic Shock therapy [43]. All these indicate that Esmolol can improve ventricular-artery coupling and vascular tension after stabilizing HR, thereby increasing myocardial contractility.

In the present study, it was also found that the dosage of norepinephrine was very high at baseline in both groups. As is showed in baseline demographic and clinical characteristics, such as SOFA score and APACHE II score, the patients had a higher degree of critical ills, which were associated with the high dose of norepinephrine at baseline. Our hospital is a tertiary A-level hospital, and is also the location of the provincial critical care medicine quality control center where the patients admitted to are in a high degree of critical illness. The patients admitted to the ICU always suffer from various critical diseases and most of them are whose disease had progressed after treatment in other wards of the hospital. Patients were already suffering from severe sepsis or septic shock when transferred to the ICU, which may have contributed to the high dosage of norepinephrine use at baseline. The dosage of norepinephrine in group E increased after Esmolol. However, norepinephrine dose also increased in group C at 48 h, and there was no significant difference compared with group E. In addition, Fig. 2 shows that the dosage of norepinephrine decreased over time in both groups. These results suggest that an increase in norepinephrine dose after Esmolol was associated with a higher degree of critical illness and instability or progression of the disease, rather than the effect of Esmolol. Martin Balik et al. found no increase in the dose of norepinephrine after applying Esmolol in patients with Septic Shock [44]. Fuchs et al. also proposed that the use of vasoactive drugs did not increase in a study of the correlation between the use of Esmolol and 90-day mortality in patients with severe Sepsis and Septic Shock [45]. Bruno Levy et al. found in a study of the hemodynamic effects of early use of Esmolol in patients with highly dynamic Septic Shock that rapid use of Esmolol for controlling HR in the early stages of Septic Shock led to a decrease in cardiac index and an increased risk of hypotension [46]. In order to reduce the influence of Esmolol on hemodynamics, all subjects were hereby treated with standardized treatment for 24 h to ensure adequate tissue perfusion. Although there was no significant difference in norepinephrine dose between the two groups at any time, the decline trend of norepinephrine dose in group E was better. This correlates with the fact that Esmolol itself has an anti-inflammatory effect, as well as decreased myocardial oxygen consumption and improved systemic oxygen delivery after a decrease in heart rate.

A large international randomized controlled trial study showed that the use of β-blockers in the perioperative period, especially when combined with hypotension, could significantly increase the risk of death [47]. A meta-analysis aimed at recommending optimal treatment for patients with combined sepsis and heart failure concluded that the routine use of β blockers is not recommended due to the negative inotropic effect of β-blockers and lack of high-quality RCTs[48]. The present study showed that the 28-day and 90-day mortality of patients in Group E was lower than that of those in Group C, and the difference was statistically significant. Similarly, logistic regression analysis also showed that the use of Esmolol reduced the risk of death, indicating that Esmolol was beneficial for SIC patients. The study by Andrea Morelli et al. proved that the application of β-blockers to control tachyarrhythmia in patients with Septic Shock could reduce short-term mortality without increasing adverse complications [13]. In a multi-center, prospective, and randomized controlled study, it was also found that short-acting β-blockers used in patients with Sepsis could not only quickly stabilize HR, but would also not increase the incidence of adverse events or reduce mortality [49]. By analyzing the reasons, the present study found that the oxygen delivery of patients was improved after the use of Esmolol, and there was a significant correlation between oxygen delivery and patient outcomes. The reduction of mortality of patients with Esmolol was considered related to the improvement of oxygen delivery. Emanuel P. Rivers et al. affirmed that maintenance of tissue normoxia, reversal of tissue hypoxia and avoidance of tissue dysoxia mattered considerably in preventing oxygen debt, cell injury, organ failure and death [50]. The meta-analysis also found that lactic acid production during shock was largely attributed to tissue hypoxia and anaerobic glycolysis due to inadequate oxygen delivery [51]. In addition, ScvO2 improved with Esmolol, while persistently low ScvO2 reflected underlying cardiac dysfunction and was associated with increased 90-day mortality [52]. Meanwhile, Esmolol has other various potential therapeutic effects on patients with Sepsis, including improving heart function, inhibiting the production of inflammatory factors, correcting hypermetabolism, and improving coagulation disorders [53], and may therefore reduce mortality in SIC patients through a variety of action mechanisms.

It was found in a prospective cohort study that the use of Esmolol in patients with severe Sepsis could reduce the duration of mechanical ventilation [54]. C. Fuchs et al. found while studying the correlation between continuous use of β-blockers in the acute phase of severe Sepsis and Septic Shock and the 90-day mortality rate that β-blockers could reduce the length of ICU stay in patients with Sepsis Shock [45]. Compared with Group C patients, no statistically significant differences were hereby found in Group E patients in terms of mechanical ventilation time, ICU length of stay, and total length of stay. Given that pneumonia occupied a large proportion of all the causes of Sepsis in this study, it might have caused the difference in the study results.

This study has the following strengths: First of all, STE, which is less affected by cardiac preload and afterload and can be used to assess myocardial contractility more accurately, was used to assess myocardial contractility before and after Esmolol treatment in SIC patients for the first time; Secondly, a prospective randomized study design was adopted, which can well prevent selectivity bias and more accurately evaluate the effect of Esmolol; Thirdly, hemodynamic changes during medication were monitored in real time to ensure patient safety; Finally, PICCO parameters were firstly used to evaluate the effects of Esmolol on cardiac function. However, this study is still subject to the following limitations: Firstly, there is no definite threshold of STE for the evaluation of left ventricular dysfunction. However, the threshold value of left ventricular dysfunction in this study was obtained from previous large-scale studies, which reduced the possibility of exaggerating or covering up the fact of cardiac function; Secondly, STE was only used in this study for the continuous evaluation of changes in cardiac function of the enrolled patients for 7 days, failing to evaluate the influence of Esmolol on long-term cardiac function and hemodynamics. However, based on the use of vasoactive drugs and changes in hemodynamic parameters for 7 consecutive days, it can be reasonably proposed that long-term application of Esmolol will not cause hemodynamic instability; Finally, considering the effect of Esmolol on HR, the researchers could not be blinded in this study, but the selected parameters were all objective parameters less affected by subjective factors, and could affectively prevent information bias.

In summary, the myocardial contractility did not deteriorate, and the systemic vascular tension was improved after Esmolol reducing the HR of SIC patients. The application of Esmolol in SIC patients did reduce their short-term mortality, thought it failed to reduce the mechanical ventilation time, ICU hospital stay or total hospital stay. STE does not have a threshold for SIC diagnosis, and further large-scale studies are needed for confirmation.