The influence of esmolol on septic shock and sepsis: A meta-analysis of randomized controlled studies
a b s t r a c t
Background: Esmolol may have some potential in treating septic shock and sepsis. However, the results remain controversial. We conduct a systematic review and meta-analysis to explore the efficacy of esmolol in patients with septic shock and sepsis.
Methods: PubMed, EMbase, Web of science, EBSCO, and Cochrane Library databases are systematically searched. Randomized controlled trials assessing the efficacy of esmolol for septic shock and sepsis are included. Two investigators independently search articles, extract data, and assess the quality of included studies. Meta- analysis is performed using the random-effect model.
Results: Five RCTs are included in the meta-analysis. Overall, compared with control intervention in septic pa- tients, esmolol intervention is found to significantly increase survival rate (risk ratio (RR) = 2.06; 95% confidence interval (CI) = 1.52 to 2.79; P = 0.006), decrease heart rate (Standard Mean difference (Std. MD) = -2.43; 95% CI = -4.13 to -0.72; P = 0.005) and TnI (Std. MD = -1.91; 95% CI = -2.39 to -1.43; P b 0.00001), but has no
significant impact on mean arterial pressure (MAP) (Std. MD = 0.11; 95% CI = -0.21 to 0.44; P = 0.49), central venous pressure (Std. MD = -0.11; 95% CI = -0.50 to 0.28; P = 0.58) and central venous oxygen satu- ration (ScvO2) (Std. MD = 1.87; 95% CI = -1.53 to 5.26; P = 0.28).
Conclusions: Esmolol treatment may be able to improve survival rate, and reduce heart rate and TnI, but has no influence on MAP, CVP and ScvO2 in patients with septic shock and sepsis.
(C) 2017
Introduction
Severe sepsis, septic shock, and their complications have become the major healthcare problem that affects millions of people each year, resulting in high mortality rates [1-5]. Septic responses have an ex- tremely complex chain of events including inflammatory and anti- Inflammatory processes, humoral and cellular reactions, and cardio- circulatory abnormalities (e.g. sympathetic overactivity) [6-8]. Severe sepsis is known as a complex syndrome with the features of dysfunction of one or more organs (e.g. particularly heart dysfunction) and hemody- namic disorder [9,10]. Septic shock can negatively affect intrinsic left ventricular contractility, and severe sepsis results in persistent vasoplegia, and high mortality rate [11-13].
Beta-blockers are able to modulate cardiovascular alterations in sep- sis, and may produce important changes at metabolic, immunologic and coagulation levels [14-16]. Esmolol is reported to reduce cardiac output in proportion to the percentage decrease in heart rate, without
* Corresponding author at: No. 36 Gongyuan Road, Daqiao District, Fenghua, Ningbo, Zhejiang 315000, China.
E-mail address: [email protected] (M. Feng).
adversely affecting oxygenation [17]. esmolol administration may have the ability to increase the rate of sustained return of spontaneous circulation and intensive care unit (ICU) survival among patients with refractory ventricular fibrillation in out-of-hospital cardiac arrest [18]. Some RCTs have reported that esmolol infusion in septic patients can re- sult in the improvement of tissue metabolism and ScvO2, the reduction in ICU stay and 28-day mortality [19-21].
However, two relevant RCTs conclude that esmolol treatment has no remarkable influence on ScvO2 and hemodynamics in septic patients [20,22]. Considering these inconsistent effects, we therefore conduct a systematic review and meta-analysis of RCTs to evaluate the effective- ness of esmolol treatment in patients with septic shock and sepsis.
Materials and methods
This systematic review and meta-analysis were conducted according to the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement [23] and the Cochrane Handbook for Sys- tematic Reviews of Interventions [24]. No ethical approval and patient consent were required, because all analyses were based on previously published studies.
https://doi.org/10.1016/j.ajem.2017.11.013 0735-6757/(C) 2017
Literature search and selection criteria
Jada scores
4
4
3
3
5
PubMed, EMbase, Web of science, EBSCO, and the Cochrane library were systematically searched from inception to July 2017, with the fol- lowing keywords: esmolol, and septic shock or sepsis. To include addi- tional eligible studies, the reference lists of retrieved studies and relevant reviews were also hand-searched and the process above was performed repeatedly until no further article was identified.
Continuous intravenous infusion of milrinone that commenced with a loading dosage of 30 ug/kg and was
maintained at 0.375-0.5 ug/kg/min
Basic treatment
The inclusion criteria were as follows: (1) study population were pa-
Basic treatment
Basic treatment
Basic treatment
tients with septic shock or sepsis; (2) intervention treatments were esmolol versus usual care; (3) study design was RCT.
Methods
Data extraction and outcome measures
The following information was extracted for the included RCTs: first author, Publication year, sample size, baseline characteristics of pa- tients, esmolol treatment, control. The author would be contacted to ac- quire the data when necessary. The primary outcome was survival rate. Secondary outcomes included MAP, CVP, heart rate, ScvO2, and TnI.
Male (n)
13
SAPS II score
21.21 +- 2.67
19
20.8 +- 5.6
21.3 +- 8.3
25
-
53
57 (49-62),
median (IQR)
Quality assessment in individual studies
38 (20-57),
median (range)
-
The Jadad Scale was used to evaluate the methodological quality of each included RCT [25]. This scale consisted of three evaluation ele- ments: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points). One point would be allocated to each el- ement if they had been mentioned in the article, and another one point would be given if the methods of randomization and/or blinding had been appropriately described. If the methods of randomization and/or blinding were inappropriate, or dropouts and withdrawals had not been recorded, then one point was deducted. The score of Jadad Scale varied from 0 to 5 points. An article with Jadad score <= 2 was considered to be of low quality. If the Jadad score >= 3, the study was thought to be of high quality [26].
Control group
Number
Age (years)
Micro pump with dosage of esmolol 0.05 mg.kg-1.min-1 Continuous intravenous infusion of
esmolol, milrinone that commenced with a loading dosage of 30 ug/kg and was maintained at 0.375-0.5 ug/kg/min
24
61.2 +- 6.4
30
Micro pump with dosage of esmolol 0.05 mg.kg-1.min-1
Esmolol infusion commenced at 25 mg x h-1
and progressively increased the rate at 20-minute intervals in increments of 50 mg x h-1
Esmolol infusion commenced at 25 mg x h-1
and progressively increased the rate at 20-minute intervals in increments of 50 mg x h-1
20
55.0 +- 25.4
77
76.6 +- 10.2
77
69 (58-78),
median (IQR)
Statistical analysis
Std. MD with 95% CI for continuous outcomes (MAP, CVP, heart rate, ScvO2, TnI), and RR with 95% CIs for dichotomous outcomes (survival rate) were used to estimate the pooled effects. All meta-analyses were performed using the random-effect model with DerSimonian and Laird weights. Heterogeneity was tested using the Cochran Q statistic (P b 0.1) and quantified with the I2 statistic, which described the varia- tion of effect size that was attributable to heterogeneity across the
Methods
Fig. 1. Flow diagram of study searching and Selection process.
Characteristics of included studies.
Fig. 2. Forest plot for the meta-analysis of survival rate.
Fig. 3. Forest plot for the meta-analysis of mean arterial pressure (MAP) mm Hg.
studies. An I2 value N 50% indicated significant heterogeneity. Sensitivity analysis was performed to detect the influence of a single study on the overall estimate via omitting one study in turn when necessary. Owing to the limited number (b 10) of included studies, publication bias was not assessed. P b 0.05 in two-tailed tests was considered statis- tically significant. All statistical analyses were performed with Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).
Results
Literature search, study characteristics and quality assessment
The flow chart for the selection process and detailed identification is presented in Fig. 1. 505 publications are identified through the initial search of databases. Ultimately, five RCTs are included in the meta- analysis [19-22,27].
The baseline characteristics of five eligible RCTs in the meta-analysis are summarized in Table 1. The five studies are published between 2013 and 2015, and sample sizes range from 41 to 154. Two RCTs are reported to be the same clinical trial, but with different follow-up times [21,27].
Four included RCTs involve septic shock [19,21,22,27], and one included RCT involves sepsis [20].
Among the five RCTs, three studies report the survival rate [19-21], three studies report the MAP, CVP and heart rate [19,20,22], two studies report the ScvO2 [19,22], and two studies report the TnI [20,22]. Jadad scores of the five included studies vary from 3 to 5, and all five studies are considered to be high-quality ones according to quality assessment.
Primary outcome: survival rate
This outcome data is analyzed with the random-effect model, and the pooled estimate of three included RCTs suggests that compared to control group for septic shock and sepsis, esmolol intervention is associ- ated with a significantly increased survival rate (RR = 2.06; 95% CI = 1.52 to 2.79; P = 0.006), with no heterogeneity among the studies (I2
= 0%, heterogeneity P = 0.46, Fig. 2).
Sensitivity analysis
No heterogeneity is observed among the included studies for the survival rate. Thus, we do not perform sensitivity analysis by omitting
Fig. 4. Forest plot for the meta-analysis of central venous pressure (CVP) mm Hg.
Fig. 5. Forest plot for the meta-analysis of heart rate (beats/min).
Fig. 6. Forest plot for the meta-analysis of Central venous oxygen saturation (ScvO2).
Fig. 7. Forest plot for the meta-analysis of TnI (ng/mL).
one study in each turn or perform subgroup analysis to detect the source of heterogeneity.
Secondary outcomes
Compared with control intervention in patients with septic shock and sepsis, esmolol intervention shows no remarkable influence on MAP (Std. MD = 0.11; 95% CI = -0.21 to 0.44; P = 0.49; Fig. 3) and
CVP (Std. MD = - 0.11; 95% CI = - 0.50 to 0.28; P = 0.58; Fig. 4),
but can significantly reduce heart rate (Std. MD = - 2.43; 95% CI =
-4.13 to -0.72; P = 0.005; Fig. 5). There is no significant difference of ScvO2 between esmolol intervention and control intervention (Std. MD = 1.87; 95% CI = - 1.53 to 5.26; P = 0.28; Fig. 6). In addition,
esmolol intervention results in lower TnI than control group in septic shock and sepsis (Std. MD = -1.91; 95% CI = - 2.39 to -1.43; P b 0.00001; Fig. 7).
Discussion
Beta-blockers have been reported to have the ability to reduce the mortality rates of patients with severe septic cardiomyopathy, and esmolol infusion can improve oxygen utilization of myocardium and help preserve myocardial function [28,29]. Our meta-analysis suggests that compared to control intervention in patients with septic shock and sepsis, esmolol treatment substantially improves survival rate, and reduces heart rate, but has no significant influence on the hemody- namics (as evidenced by the meta-analysis of MAP and CVP) and ScvO2. Septic cardiomyopathy is caused by bacterial toxins, inflammatory factors, nitric oxide and oxidative stress, and results in myocardial de- pression, decreased ejection fraction, increased end-diastolic volume index and high mortality rate [30-32]. However, the detail mechanisms for septic cardiomyopathy are still unclear. The exaggerated sympathet- ic activation in septic patients can increase the concentration of cardiac catecholamines and improve Myocardial stunning [33,34]. Tachycardia is ubiquitous in severe septic cardiomyopathy in order to compensate for the low cardiac output. Patients with tachycardia suffer from in- creased myocardial oxygen demand and cardiac load, reduced ventricu- lar diastolic time and subsequently insufficient coronary perfusion [35,
36].
TnI, Brain natriuretic peptide , and creatine kinase-MB (CK- MB) are reliable markers for identifying the risk of patients to develop sepsis-induced myocardial depression, adverse events and even mortal- ity rate [37,38]. Fast BNP decline has been reported to be associated with favorable outcomes in critical sepsis [39]. In one included RCT, esmolol treatment results in substantially decreased TnI, BNP level and CK-MB, as well as reduced 28-day mortality and improved cardiac function in
septic patients. Significantly reduced TnI levels and increased survival rate are revealed in critical sepsis after esmolol treatment in our meta- analysis.
Several limitations should be taken into account. Firstly, our analysis is based on five RCTs, but three of them have a relatively small sample size (n b 100). Overestimation of the treatment effect is more likely in smaller trials compared with larger samples. The methods of esmolol treatment for septic patients in the included RCTs are different, and it probably affects the pooling results. Next, the optimal dose and method of esmolol treatment remains elusive. Finally, some unpublished and missing data may lead bias to the pooled effect.
Conclusion
Esmolol treatment may have the ability to improve survival rate, re- duce heart rate and prevent myocardial depression in septic patients. Esmolol treatment was recommended to be administrated for septic pa- tients with caution, and more studies are needed to confirm this issue.
Acknowledgements
None.
Disclosure of potential conflicts of interest
The authors declare no conflict of interest.
Research involving human participants and/or animals
Not applicable.
References
- Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care 2004;8:222-6.
- Guillamet MC, Rhee C, Patterson AJ. Cardiovascular management of septic shock in 2012. Curr Infect Dis Rep 2012;14:493-502.
- Pravinkumar E. Cardiovascular management of septic shock. Crit Care Med 2004; 32(315) (author reply).
- Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10.
- Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (Sep- sis-3). JAMA 2016;315:775-87.
- Sanfilippo F, Santonocito C, Morelli A, Foex P. Beta-blocker use in severe sepsis and septic shock: a systematic review. Curr Med Res Opin 2015;31:1817-25.
- Dellinger RP. Cardiovascular management of septic shock. Crit Care Med 2003;31: 946-55.
- Worthley LI. What cardiovascular parameters should we aim for in the management of septic shock? (or are catecholamines being used to excess?). Crit Care Resusc 2002;4:161-3 journal of the Australasian Academy of Critical Care Medicine.
- Pulido JN, Afessa B, Masaki M, Yuasa T, Gillespie S, Herasevich V, et al. Clinical spec- trum, frequency, and significance of myocardial dysfunction in severe sepsis and septic shock. Mayo Clin Proc 2012;87:620-8.
- Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assess- ment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:762-74.
- Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care 2011;1:6.
- Werdan K, Oelke A, Hettwer S, Nuding S, Bubel S, Hoke R, et al. Septic cardiomyop- athy: hemodynamic quantification, occurrence, and prognostic implications. Clin Res Cardiol 2011;100:661-8 official journal of the German Cardiac Society.
- Baumbach P, Gotz T, Gunther A, Weiss T, Meissner W. Prevalence and characteristics of chronic intensive care-related pain: the role of severe sepsis and septic shock. Crit Care Med 2016;44:1129-37.
- Singer KE, Collins CE, Flahive JM, Wyman AS, Ayturk MD, Santry HP. Outpatient beta- blockers and survival from sepsis: results from a national cohort of Medicare bene- ficiaries. Am J Surg 2017;214(4):577-82.
- McLean AS, Taccone FS, Vieillard-Baron A. Beta-blockers in septic shock to optimize hemodynamics? No. Intensive Care Med 2016;42:1610-2.
- De Backer D, Annane D. Beta-blockers in septic shock to optimize hemodynamics? We are not sure. Intensive Care Med 2016;42:1613-4.
- Gore DC, Wolfe RR. Hemodynamic and Metabolic effects of selective beta1 adrener- gic blockade during sepsis. Surgery 2006;139:686-94.
- Lee YH, Lee KJ, Min YH, Ahn HC, Sohn YD, Lee WW, et al. Refractory ventricular fibril- lation treated with esmolol. Resuscitation 2016;107:150-5.
- Xinqiang L, Weiping H, Miaoyun W, Wenxin Z, Wenqiang J, Shenglong C, et al. Esmolol improves clinical outcome and tissue Oxygen metabolism in patients with septic shock through controlling heart rate. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2015;27:759-63.
- Wang Z, Wu Q, Nie X, Guo J, Yang C. Combination therapy with milrinone and esmolol for Heart protection in patients with severe sepsis: a prospective, random- ized trial. Clin Drug Investig 2015;35:707-16.
- Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, et al. Effect of heart Rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 2013;310:1683-91.
- Yang S, Liu Z, Yang W, Zhang G, Hou B, Liu J, et al. Effects of the ?-blockers on cardiac protection and hemodynamics in patients with septic shock: a prospective study. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 2014;26(10):714-7.
- Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for sys- tematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.
- Higgins JPTGS. Cochrane handbook for systematic reviews of interventions version
5.1.0 [updated March 2011]. The Cochrane collaboration. Available from www. cochrane-handbook.org; 2011.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.
- Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001; 135:982-9.
- Orbegozo Cortes D, Njimi H, Dell’Anna AM, Taccone FS. Esmolol for septic shock: more than just Heart rate control? Minerva Anestesiol 2014;80:254-8.
- Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, et al. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med 2005;33:2294-301.
- Fenton KE, Parker MM. Cardiac function and dysfunction in sepsis. Clin Chest Med 2016;37:289-98.
- Jozwiak M, Persichini R, Monnet X, Teboul JL. Management of myocardial dysfunc- tion in severe sepsis. Semin Respir Crit Care Med 2011;32:206-14.
- Sweeney TE, Khatri P. Septic cardiomyopathy: getting to the heart of the matter. Crit
Makara MA, Hoang KV, Ganesan LP, Crouser ED, Gunn JS, Turner J, et al. Cardiac elec- trical and structural changes during bacterial infection: an instructive model to study cardiac dysfunction in sepsis. J Am Heart Assoc 2016;5.
- Kume T, Kawamoto T, Okura H, Toyota E, Neishi Y, Watanabe N, et al. Local release of catecholamines from the hearts of patients with tako-tsubo-like left ventricular dys- function. Circ J 2008;72:106-8.
- Zaky A, Gill EA, Lin CP, Paul CP, Bendjelid K, Treggiari MM. Characteristics of sepsis- induced cardiac dysfunction using speckle-tracking echocardiography: a feasibility study. Anaesth Intensive Care 2016;44:65-76.
- Magder SA. The ups and downs of heart rate. Crit Care Med 2012;40:239-45.
- Aneman A, Vieillard-Baron A. Cardiac dysfunction in sepsis. Intensive Care Med 2016;42:2073-6.
- Klouche K, Pommet S, Amigues L, Bargnoux AS, Dupuy AM, Machado S, et al. Plasma brain natriuretic peptide and troponin levels in severe sepsis and septic shock: rela- tionships with systolic myocardial dysfunction and intensive care unit mortality. J Intensive Care Med 2014;29:229-37.
- Latini R, Caironi P, Masson S. Cardiac dysfunction and circulating cardiac markers during sepsis. Minerva Anestesiol 2016;82:697-710.
- Papanikolaou J, Makris D, Mpaka M, Palli E, Zygoulis P, Zakynthinos E. New insights into the mechanisms involved in B-type natriuretic peptide elevation and its prog- nostic value in septic patients. Crit Care 2014;18:R94.