Levosimendan Does Not Reduce the Mortality of Critically Ill Adult Patients with Sepsis and Septic Shock: A Meta-Analysis

Levosimendan Does Not Reduce the Mortality of Critically Ill Adult Patients with Sepsis and Septic Shock: A Meta-Analysis

Sepsis and septic shock are among the leading causes of death worldwide, surpassing even acute myocardial infarction in mortality rates. These conditions are characterized by severe infection that triggers systemic inflammatory response syndrome (SIRS), which can progress to septic shock. According to the Sepsis 3.0 definition, septic shock is identified by persistent hypotension requiring vasopressors to maintain a mean arterial pressure above 65 mmHg and serum lactate levels greater than 2 mmol/L despite adequate volume resuscitation. A significant proportion of sepsis patients, nearly one-third, experience left ventricular systolic dysfunction, which is a key factor in the development of heart failure. The incidence of septic cardiomyopathy is reported to be as high as 40% to 60%.

The 2012 Surviving Sepsis Campaign guidelines recommended the use of dobutamine for patients with sepsis and left ventricular systolic dysfunction. However, the efficacy of dobutamine in reducing mortality remains unclear, and it is associated with increased myocardial oxygen consumption and a higher risk of arrhythmias. In contrast, levosimendan, a calcium sensitizer, has been proposed as a complementary treatment for systolic and diastolic heart dysfunction. Levosimendan increases myocardial contractility without increasing myocardial oxygen consumption, making it a potentially safer alternative. Some studies have shown that levosimendan reduces mortality in patients with perioperative and progressive heart failure. However, the results of randomized controlled trials (RCTs) and meta-analyses on the use of levosimendan in sepsis and septic shock have been inconsistent.

This meta-analysis aimed to provide an updated and comprehensive evaluation of the therapeutic value of levosimendan in adult patients with sepsis and septic shock. The primary outcome was mortality, while secondary outcomes included cardiac index and serum lactate levels. The study included 20 RCTs, encompassing 1467 patients, with 738 patients in the levosimendan group and 729 patients in the control group, which received either other inotropic drugs or placebo.

The search strategy involved querying PubMed, Embase, Cochrane Library, Wanfang Data, and CNKI up to August 2018, without language restrictions. The inclusion criteria were age over 18 years, diagnosis of sepsis or septic shock, and the use of levosimendan compared to other inotropic drugs or placebo. Studies were excluded if they were duplicate publications, animal research, or non-RCTs. The Cochrane risk bias assessment tool was used to evaluate the quality of the included studies, and data were extracted using a standardized form.

The primary outcome of this meta-analysis was mortality, which was reported in various forms across the included studies, including 28-day mortality, 30-day mortality, and intensive care unit (ICU) mortality. The analysis revealed no significant difference in mortality between the levosimendan and control groups, with a fixed-effect relative risk (RR) of 0.90 and a 95% confidence interval (CI) of 0.79 to 1.03 (P = 0.13). This suggests that levosimendan does not confer a survival benefit over other inotropic drugs or placebo in critically ill patients with sepsis and septic shock.

In terms of secondary outcomes, the cardiac index was reported in ten of the included studies. The meta-analysis showed that levosimendan improved the cardiac index, with a weighted mean difference (VMD) of 0.51 and a 95% CI of 0.06 to 0.95 (P = 0.02). This indicates that levosimendan may enhance cardiac performance in patients with sepsis and septic shock. Additionally, serum lactate levels were reported in 13 studies, and the analysis demonstrated that levosimendan significantly reduced serum lactate levels, with a VMD of -1.04 and a 95% CI of -1.47 to -0.60 (P < 0.00001). Lower serum lactate levels are associated with improved tissue perfusion and reduced risk of organ failure.

Despite these positive effects on cardiac index and serum lactate levels, the meta-analysis concluded that levosimendan does not reduce mortality in critically ill adult patients with sepsis and septic shock. This finding is consistent with the results of a large RCT by Gordon et al., which enrolled 516 patients and found no significant difference in mortality between the levosimendan and control groups. The authors of the meta-analysis suggested that the lack of a mortality benefit may be due to the inclusion of heterogeneous patient populations, as not all patients with sepsis and septic shock have impaired cardiac function. In patients with preserved cardiac function, the use of inotropic drugs may not provide additional benefits.

The pharmacological properties of levosimendan differ from those of traditional inotropic drugs like dobutamine. Levosimendan increases cardiac systolic function without affecting diastolic function by enhancing the sensitivity of cardiac myocytes to calcium ions. Importantly, it does not increase myocardial oxygen consumption, which is a significant advantage over other inotropic agents. The half-life of levosimendan is up to 80 hours, meaning that a 24-hour infusion can provide therapeutic effects for approximately one week. This prolonged action allows patients with sepsis and septic shock to achieve hemodynamic stability more effectively.

However, the meta-analysis has several limitations. First, the sample sizes of the included studies were generally small, and one study contributed 50% of the total patient population, potentially skewing the results. Second, the definitions of mortality varied across studies, with some reporting 28-day mortality, others 30-day mortality, and still others ICU or hospital mortality. This variability may have introduced bias into the analysis. Third, the methods used to measure the cardiac index differed among studies, with some using Swan-Ganz catheterization, others ultrasound measurements, and others PiCCO. These differences in measurement techniques could also affect the results. Finally, the control groups received various inotropic drugs, including dobutamine, milrinone, or standard therapy, which may have different mechanisms of action and outcomes.

In conclusion, this meta-analysis found that levosimendan does not reduce mortality in critically ill adult patients with sepsis and septic shock, despite its positive effects on cardiac index and serum lactate levels. Physicians should exercise caution when considering the use of levosimendan in this patient population. Further large-scale, homogeneous, and multi-center RCTs are needed to clarify the role of levosimendan in the treatment of sepsis and septic shock.

doi.org/10.1097/CM9.0000000000000197

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