Article

Esmolol in the management of pre-hospital refractory ventricular fibrillation: A systematic review and meta-analysis

Journal logoUnlabelled imageEsmolol in the management of pre-hospital refractory ventricular

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American Journal of Emergency Medicine

journal homepage:

fibrillation: A systematic review and meta-analysis

Dennis Miraglia, MD ?, Lourdes A. Miguel, MD, MPH, Wilfredo Alonso, MD

Department of Internal Medicine, Good Samaritan Hospital, Aguadilla, PR, United States

a r t i c l e i n f o

Article history:

Received 14 March 2020

Received in revised form 17 May 2020

Accepted 24 May 2020

Keywords:

Cardiopulmonary resuscitation Esmolol

Out-of-hospital cardiac arrest Pre-hospital cardiac arrest refractory ventricular fibrillation

a b s t r a c t

Background: Esmolol has been proposed as a viable adjunctive therapy for pre-hospital refractory ventricular fi- brillation/pulseless ventricular tachycardia (VF/pVT).

Objectives: We performed a systematic review and meta-analysis to assess the effectiveness of esmolol on pre- hospital refractory VF/pVT, compared with standard of care.

Methods: MEDLINE, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for eligible studies. Two investigators independently extracted relevant data and assessed the method- ological quality of each included study using the ROBINS-I tool. The quality of evidence for summary estimates was assessed according to GRADE guidelines. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome of interest were calculated.

Results: The search yielded 3253 unique records, of which two studies were found to be in accordance with the research purpose, totaling 66 patients, of whom 33.3% (n = 22) received esmolol. Additional evidence was pro- vided in the paper but was not relevant to the analysis and was therefore not included. Esmolol was likely asso- ciated with an increased rate of survival to discharge (RR 2.82, 95% CI 1.01-7.93, p = 0.05) (GRADE: Very low) and survival with favorable neurological outcome (RR 3.44, 95% CI 1.11-10.67, p = 0.03) (GRADE: Very low). Similar results were found for return of spontaneous circulation (ROSC) (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low) and survival to intensive care unit (ICU)/hospital admission (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low).

Conclusion: The effectiveness of esmolol for refractory VF/pVT remains unclear. Trial sequential analysis (TSA) in- dicates that the evidence is inconclusive and that further trials are required in order to reach a conclusion. There- fore, it is imperative to continue to accumulate evidence in order to obtain a higher level of scientific evidence.

(C) 2020

Introduction

Pre-hospital cardiac arrest is associated with high mortality rates [1,2]. Despite major progress in Resuscitative medicine and the develop- ment of new therapies, survival rates for patients suffering from pre- hospital refractory ventricular fibrillation/pulseless ventricular tachy- cardia (VF/pVT) remain poor [1]. Effective chest compressions are essential for providing blood flow during cardiopulmonary resuscita- tion (CPR). Early defibrillation remains the best current standard of care for patients in refractory VF/pVT cardiac arrest, as no pharmaco- logic agents have been shown to increase long-term survival [3-5]. De- fibrillation is highly effective in stopping Shockable rhythms of VF/pVT in patients experiencing cardiac arrest. However, there is a subgroup of patients in which VF/pVT remains refractory to the current standard of care [6,7]. Unfortunately, along the time continuum of resuscitation

* Corresponding author at: Department of Internal Medicine, Good Samaritan Hospital,

P.O. BOX: 4055, Aguadilla, PR, United States.

E-mail address: [email protected] (D. Miraglia).

efforts, the chances of survival decrease rapidly when CPR lasts over 30 min [8].

Efforts to treat patients with refractory cardiac arrest have led to the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as extracorporeal cardiopulmonary resuscitation to facilitate re- turn of normal perfusion and to support further resuscitation efforts [9,10]. Some studies have suggested that the beta-adrenoceptor antag- onist (?-blocker) esmolol may abort VF/pVT and increase return of spontaneous circulation (ROSC) and survival to discharge [11-19]. How- ever, the current scientific evidence we have on esmolol for refractory cardiac arrest rests principally on case reports and observational case- series, with their potentially confounding selection bias [17,18]. The limited evidence about the use of esmolol as an adjuvant therapy for the management of pre-hospital refractory VF/pVT makes this practice an off-label use of the drug and an unproven therapy.

Given the recent increase in the usage of esmolol for pre-hospital re- fractory cardiac arrest at emergency departments [13,17,18], there is a need for a review of the evidence to provide a clearer understanding of the role of esmolol in treating refractory VF/pVT. We performed a

https://doi.org/10.1016/j.ajem.2020.05.083

0735-6757/(C) 2020

systematic review and meta-analysis addressing whether esmolol can improve survival outcomes and lead to good neurological outcomes in adults suffering pre-hospital refractory VF/pVT. This paper summarizes the state of the current literature on esmolol for refractory VF/pVT and provides an up-to-date review of this area, with the aim of supporting the development of strategies for a clinical protocol that will offer a po- tential lifesaving treatment option for this specific patient population, which is in accordance with the recommendations in the current clinical guidelines.

Materials and methods

This systematic review and meta-analysis were prospectively pre- registered in PROSPERO, the International Register of Systematic Re- views on November 4, 2019 (registration number CRD42020144631). Data reporting in this review is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [20]. The review questions were formulated following the PICO scheme (P-Populations/People/Patient/Problem, I-Intervention(s), C- Comparison, O-Outcome). Question 1: Among adults resuscitated from pre-hospital cardiac arrest (P) and treated with esmolol

(I) compared with no esmolol (C), what are the rates of survival to dis- charge and survival with a favorable neurological outcome (O)? Ques- tion 2: Among adults resuscitated from pre-hospital cardiac arrest

(P) and treated with esmolol (I) compared with no esmolol (C), what are the rates of sustained ROSC and Survival to hospital admission (O)?

Inclusion and exclusion criteria

We considered for inclusion any controlled clinical study design (randomized controlled trials [RCTs] and controlled non-randomized trials [CnRTs]), and observational studies (cohort studies and case- control studies) with a control group (i.e. patients not receiving esmolol) published in English as full-text articles in indexed journals be- tween January 2000 and December 2019 that reported survival rates and neurological outcome in adults (>=18 years) resuscitated from pre-

hospital cardiac arrest on-scene or in the emergency department (ED).

Studies that did not report survival rates and neurological outcomes were excluded. In addition, studies that did not evaluate the use of esmolol in the acute management of cardiac arrest due to VF were ex- cluded. Comments, editorials, reviews and studies published in abstract form were also excluded. Studies including esmolol and other types of beta-blockade for cardiac arrest were considered for inclusion if data from a subpopulation of interest could be extracted and computed sep- arately, or if the subpopulation was N50.0% of the total. After eliminating the excluded titles and abstracts, we acquired the full texts of the chosen articles, which were then rescreened and reevaluated for eligibility using the same exclusion criteria. Any disagreement regarding inclusion or exclusion criteria was resolved via discussion.

Search strategy and study selection

We used the PRESS (Peer Review of Electronic Search Strategies) checklist to develop the research strategy [21]. A literature search was conducted on October 6, 2019. The search terms included both stan- dardized medical subject headings (MeSH) and text words. We searched MEDLINE via PubMed, Embase, Scopus, and the Cochrane Cen- tral Register of Controlled Trials (CENTRAL) using the search strings: (((“cardiopulmonary resuscitation” or “CPR” or “management” or “treatment” or “pre-hospital cardiac arrest” or “treatment” or “tech- nique” or “pre-hospital cardiac arrest” or “out-of-hospital cardiac ar- rest” or “OHCA” or “emergency department” or “ED” and ((“sudden” and “death”) or “Refractory ventricular tachycardia” or “refractory ven- tricular fibrillation” or “RVT” or “RVF” or “pulseless ventricular tachycar- dia” or “pVT” or “ventricular fibrillation” or “ventricular tachycardia” or “ventricular arrhythmia” or “heart arrest” or “cardiac arrest”)) and

“esmolol” or “beta-blockade”. The search terms were iterated until De- cember 22, 2019. The reference lists of relevant studies were screened in order to identify other studies of interest. To identify ongoing trials, we searched the WHO International Clinical Trials Registry (WHO ICTRP), and the ClinicalTrials.gov registry on December 22, 2019. The search was repeated one month prior to submission for publication to ascertain that no new literature had been published in the interim.

Data extraction and management

Data extraction was performed by the two authors using a standard- ized Microsoft Excel form. Study selection was a two-stage process. The two investigators independently screened titles and abstracts (stage 1), and the full texts of potentially eligible studies were retrieved and inde- pendently assessed for eligibility by the two review team members (stage 2). We collected descriptive characteristics such as authors, year of publication, study period, the country where the study was held, study design, research setting, study population, sample size, mea- sures, interventions, and key findings. Descriptive statistics were sum- marized by presenting the mean (standard deviation [SD]) and median (interquartile range [IQR]) for continuous variables, and num- ber and percentage for categorical variables. Disagreements were re- solved via discussion and with the involvement of a third investigator.

Assessment of risk of bias in included studies

The two investigators independently assessed the risk of bias for the included studies. The Risk of Bias assessment Tool for Non-randomized Studies of Interventions (ROBINS-I) was used to assess the risk of bias [22]. Risk of bias was assessed within specified domains, including bias due to confounding, bias in selection of participants, bias in classifi- cation of interventions, bias due to deviations from intended interven- tions, bias due to missing data, bias in measurement of outcomes, bias in blinding of outcome assessment and selective reporting, and overall bias [22]. Because the risk of bias assessments are inherently subjective and there are no strict and objective criteria by which to judge bias within the ROBINS-I tool, disagreements were resolved via discussion between the two investigators.

Assessment of reporting biases

We planned to use a funnel plot to evaluate for publication bias if N10 studies were included in the review. We sought to perform tests of asymmetry to evaluate for publication bias, but this was not appropri- ate due to the small number of included studies [23,24].

Summary of findings

The quality of evidence for summary estimates was assessed by two investigators independently according to the Grading of Recommenda- tions Assessment, Development, and Evaluation (GRADE) rating system based on study design, limitations, indirectness of evidence, inconsis- tency in results across studies, imprecision in summary estimates, and the likelihood of publication bias [25-27]. Inconsistency across studies was graded as serious when heterogeneity was significant (p b 0.10 or I2 N 50%). Imprecision was graded as serious when either the lower or the upper bound of the confidence intervals (CIs) was less or N20.0% of the point estimate. Disagreements were resolved via discussion.

Strategy for data synthesis

The primary outcomes of the study were survival to discharge and survival with favorable neurological outcome. Secondary outcomes in- cluded sustained ROSC, survival to intensive care unit (ICU)/hospital ad- mission, survival at 30 days and one year, and survival with favorable neurological outcome at 30 days and one year. We used risk ratios

(RRs) with 95% CIs to measure dichotomous outcomes. All statistical tests used a two-sided p-value b0.05. We planned to use the random- effects model when the I2 value was N50% or in the presence of substan- tial variability in primary trial populations or interventions; otherwise we planned to use the fixed-effect model [28,29]. Heterogeneity was identified by visual inspection of the forest plots and by using a standard Chi2 test with a significance level of p = 0.10 The heterogeneity of the pooled data was estimated by calculating the I2 statistics, where I2 >= 50% indicates a substantial level of heterogeneity and diversity

(D2) [30,31]. Review Manager version 5.3 (Nordic Cochrane Centre,

The Cochrane Collaboration, Copenhagen 2014) was used to perform the analyses [32].

Subgroup analysis and investigation of heterogeneity

We planned to perform the following subgroup analyses if sufficient data were available: (1) risk factors (age, gender), (2) causes of cardiac arrest (cardiac or non-cardiac aetiology), and (3) follow-up (<=1 year or N1 year). We did not perform subgroup analysis to examine the rela- tionship between treatment effects and one or more study-level charac-

teristics because too few studies were identified.

Sensitivity analysis

We did not perform sensitivity analyses because the data were lim- ited due to the small number of included studies.

Trial sequential analysis

Trial sequential analysis (TSA) combines a priori information on size calculation (cumulated sample sizes of all included trials) for a meta- analysis in order to control the risks for spuriously type-I and type II er- rors than the traditional meta-analysis using unadjusted 95% CI and 5% (p = 0.05 [Z = 1.96]) thresholds for statistical significance, and pro- vides important information regarding the required sample size for such trials in statistically significant meta-analyses with too few partic- ipants [33,34]. The idea in TSA is that if the Z-curve does not cross the trial sequential monitoring boundary and the required sample size has not been reached, there is insufficient evidence to reach a conclusion. Conversely, if the cumulative Z-curve crosses the trial sequential moni- toring boundary, a sufficient Level of evidence has been reached and no further trials are needed [33]. To assess the risk of type-I errors, we used TSA. We planned to calculate the required information size to detect or reject a 30% relative risk reduction (RRR). Information size was calcu- lated as diversity-adjusted information size (DIS) [31] using a random-effect model, with a double-sided ? of 0.05 and a ? of 0.20 (power of 80.0%). The control event rates were calculated from the con- trol group. The TSA was conducted using TSA software version 0.9.5.10 Beta [35,36].

Levels of evidence

Animal models

Several animal studies have evaluated the effects of the ?-blocker esmolol administration immediately before or during resuscitation of VF arrest [37-45]. Some have examined the use of epinephrine com- bined with esmolol after the induction of myocardial infarction (MI) during resuscitation from VF arrest using cardiac and hemodynamic pa- rameters as primary endpoints [39,45], while others have examined ROSC and/or survival [37,38,40,42-44], and cerebral performance cate- gory (CPC) evaluated at 24 h after ROSC [41]. Two studies showed that administration of esmolol shortly after induction of VF resulted in signif- icantly improved resuscitation and survival [37,40]; esmolol reduced the number of Electrical shocks required for successful defibrillation and ROSC in the intervention group compared to a placebo. However,

no significant difference in coronary perfusion pressure was ob- served between the groups [37,40]. In one of these two studies, left ven- tricle function tests demonstrated better post-resuscitation contractile and relaxation in the esmolol group [37]; in the other, there were no dif- ferences in systolic or Diastolic function between pre-arrest and four- hour post-resuscitation in the esmolol group, but this group had better four-hour post-ROSC survival, along with a lower maximum systolic ar- terial pressure [40].

Better resuscitation was demonstrated when animals were treated with epinephrine plus esmolol [43] or esmolol [44] compared to a pla- cebo or epinephrine alone. Similarly, these two studies were associated with shorter resuscitation and decreased energy requirements for defi- brillation [43,44], further indicating that esmolol administration during CPR might facilitate defibrillation [30,37,38,43,44]. Another study re- ported that animals with the combined treatment of esmolol plus epi- nephrine during cardiac arrest had lesser post-cardiac arrest nerve injuries and a more favorable nerve function assessment ratio (CPC of 1 or 2) than the control groups [41]. Two studies found no differences in ROSC when compared to the control groups [38,42], and one of them found no differences in CPR time between the esmolol group and the placebo group, although the esmolol group needed fewer shocks for successful termination of VF [38], while in the other esmolol was associated with worse myocardial performance in most of the pa- rameters studied when compared to both control groups, although the number of shocks and organ perfusion did not differ between groups. Two studies have examined the use of epinephrine combined with esmolol after the induction of MI during resuscitation from VF [39,45]; one demonstrated significant effects on attenuating post-resuscitation myocardial dysfunction [45], while the other was unable to demon- strate that esmolol protects against post-arrest cardiac dysfunction de- fined as post-arrest cardiac output [39]. Although 70.0% of the animals were successfully resuscitated in the esmolol group compared to 50.0% in the control group, the study aimed to evaluate post-arrest car- diac output, not Survival outcomes, and therefore was unable to demon- strate a statistical difference in survival outcomes [39].

During resuscitation from cardiac arrest, concerns remain regarding potential adverse effects associated with the negative inotropic proper- ties of esmolol, since myocardial dysfunction often occurs after prolonged resuscitation from cardiac arrest. However, esmolol has been associated with significantly greater post-resuscitation myocardial function, compared to animals treated with epinephrine alone or with a placebo [37,43,45]. In two other studies [39,40], esmolol failed to show a significant post-resuscitation myocardial function effect. Overall, no sig- nificant harmful effects of esmolol have been identified during ongoing resuscitation from VF or survival in Animal experiments [20,37,42,43]. To date, there is no evidence for a benefit from any ultra-short-acting se- lective ?1 antagonist, such as esmolol, or any other ?-blocker in pre- hospital cardiac arrest, despite animal evidence to the contrary. One possible explanation may be that the time to first drug delivery in ani- mal resuscitation studies occurs much earlier than in pre-hospital car- diac arrest patients, which does not reflect human clinical experience. An overview of animal experiments treated with esmolol are summa- rized in Table 1.

Results

Study selection

Fig. 1 shows the study selection procedure. The initial search of MEDLINE via PubMed, Embase, Scopus, and the Cochrane Central Regis- ter of Controlled Trials (CENTRAL) yielded 3253 records, while four ad- ditional records were identified through forward search. After duplicate removal and abstract screening, 18 articles were considered for full-text analysis. Among these, 16 were excluded because they did not fulfill the inclusion criteria. Some of these studies were excluded at this level be- cause they were not relevant or because different types of beta-

Table 1

Animal experiments examining the effects of esmolol administration immediately before or during ventricular fibrillation.

Author, year, country

No. Population Start of CPR/ (Admin. of drugs)a

Initiation of defibrillationa

Treatment groups, mg/kg

No. of shocks ROSC Mean

survival (Hours)

Post-resuscitation cardiac function

Cammarata et al.

18 Sprague-Dawley ratsb

Placebo:

6 min/(8 min)

Placebo: 12 min

Placebo 14 +- 6 5/9 20 +- 11 Better post resuscitation contractile and myocardial

2004

USA [37]

Jingjun et al. 2009

China [38]

40 Yorkshire-cross domestic pigsc

Esmolol:

6 min/(8 min) Placebo:

4 min/(8 min)

Esmolol:

4 min/(8 min)

Esmolol: 12 min Placebo: 6 min

Esmolol: 6 min

Esmolol: 0.3 mg/kg 7 +- 4 9/9 50 +- 25

Placebo 3.5 +- 2.5 18/20 4-hour survival: 12/20

Esmolol: 0.5 mg/kg 1.5 +- 0.5 17/20 4-hour

survival: 16/20

relaxation in the esmolol group.

Lower HR, BP, and CPP were seen within 30 min post resuscitation in the esmolol group.

Karlsen et al. 2019

China [39]

20 Pigs Placebo:

10 mind/(placebo:

11 min

+ epinephrine: 13 min) Esmolol:

10 mind/(esmolol:

11 min

+ epinephrine: 13 min)

Epinephrine

+ placebo: 15 min

Epinephrine

+ esmolol: 15 min

Placebo + epinephrine: 1 mg

Esmolol 1 mg/kg + epinephrine: 1 mg

3 (1, 7) 5/10i … This study was unable to

demonstrate that esmolol protects against post-arrest cardiac dysfunction.

4 (1, 9) 7/10i

Killingsworth et al.

2004

USA [40]

16 Mixed-breed pigsb

Placebo:

8 min/(7 min)

Esmolol:

8 min/(7 min)

Placebo: 8 mine

Esmolol: 8 mine

Placebo 10 +- 8 3/8 4-hour survival: 3/8c

Esmolol: 0.1 mg/kg 5 +- 4 7/8 4-hour

survival: 7/8c

No significant difference.

Li et al. 2018

China [41]

24 Pigs Placebo:

8 min/(10 min)

Placebo: 12 min

Placebo 4.5 +- 2.3 … 24-hour survival: 5/8

This study did not really measure any post-resuscitation cardiac function. It focused in the effects

Epinephrine:

8 min/(10 min)

Epinephrine + esmolol:

8 min/(10 min)

Epinephrine: 12 min

Epinephrine

+ esmolol: 12 min

Epinephrine:

0.02 mg/kg

Epinephrine

0.02 mg/kg + esmolol

0.5 mg/kg

2.1 +- 2.0 … 24-hour survival: 7/8

2.0 +- 2.1 … 24-hour survival: 7/8

of esmolol on post-resuscitation induced impairment of nerve function.

Strohmenger et al.

1999

Austria [42]

21 Domestic pigsf Placebo:

4 min/(7 min)

Esmolol:

4 min/(7 min)

Zatebradine:

4 min/(7 min)

Placebo:

4 min

Esmolol:

4 min

Zatebradine: 4 min

Placebo 2.1 +- 1.5 7/7 3-hour survival: 7/7

Esmolol: 1 mg/kg 2.4 +- 1.6 7/7 3-hour

survival: 7/7

Zatebradine: 0.5 mg/kg 2.7 +- 1.8 7/7 3-hour

survival: 7/7

Impairment greater in the esmolol group at 5 min post-ROSC.

Tang et al. 1991

USA [43]

40 Sprague-Dawley ratsg

Grp 1:

4 min/(8 min)

Grp 1: 8 min Placebo Grp 1: 12 +- 9

Grp 2: 16 +- 10

Grp 1: 4/5

Grp 2: 3/5

Grp 1:

12 +- 11

Grp 2:

2.5 +- 1

Significantly improved in epinephrine + esmolol and phenylephrine groups.

Grp 1:

4 min/(8 min)

Grp 2:

12 min

Epinephrine:

0.03 mg/kg

Phenylephrine:

0.3 mg/kg

Epinephrine:

0.03 mg/kg + esmolol:

0.3 mg/kg

Grp 1: 20 +- 8

Grp 2: 26 +- 9

Grp 1: 3 +- 1

Grp 2: 5 +- 3

Grp 1: 6 +- 2

Grp 2: 9 +- 5

Grp 1: 5/5

Grp 2: 5/5

Grp 1: 5/5

Grp 2: 5/5

Grp 1: 5/5

Grp 2: 5/5

Grp 1:

8.2 +- 4

Grp 2:

6.6 +- 9

Grp 1:

41 +- 10

Grp 2:

38 +- 14

Grp 1:

31 +- 11

Grp 2:

30 +- 10

Theochari et al.

14 Pigsh Placebo:

5 min/(9 min)

Placebo: 10 min

Epinephrine + placebo 5.9 +- 2.8 2/6 16 +- 3.2 Esmolol increased CPP from the

sixth minutes on during CPR.

2008

Greece [44]

Esmolol:

5 min/(9 min)

Esmolol: 10 min

Epinephrine + esmolol:

0.4 mg/kg

1.4 +- 0.8 7/8 12.8

+- 1.4

Zhang et al. 2013

China [45]

24 Pigs Placebo:

8 min/(10 min)

Placebo: 12 min

Placebo 6.5 +- 1.9 6/8 24-hour survival: 5/8

The epinephrine plus esmolol group had a better hemodynamic function, (improved dP/dt

Epinephrine:

8 min/(10 min)

Epinephrine + esmolol:

8 min/(10 min)

Epinephrine: 12 min

Epinephrine

+ esmolol: 12 min

Epinephrine:

0.02 mg/kg

Epinephrine:

0.02 mg/kg + esmolol:

0.3 mg/kg

2.7 +- 1.6 7/8 24-hour

survival: 6/8

2.6 +- 1.3 8/8 24-hour

survival: 7/8

maxima and minima and cardiac output), and improved oxygen delivery and oxygen consumption.

Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. Notes: Adapted from Moher et al. [20].

Notes to Table 1

(…) = data not available; BP = blood pressure; CPP = coronary perfusion pressure; CPR = cardiopulmonary resuscitation; ESV = end-systolic volume; EDV = end-diastolic volume; Grp = group; HR = heart rate; LV = left ventricle; LVEDP = Left ventricular diastolic end pressure; RV = right ventricle; ROSC = return of spontaneous circulation; SvO2 = mixed venous oxygen saturation; VF = ventricular fibrillation.

Parameters used to evaluate myocardial function:

Cammarata et al. [37]. cardiac index, dP/dt, -dP/dt, LVEDP.

Jingjun et al. [38]. LVEDP, LV+ dp/dmax (max rate of pressure rise) and LV -dp/dtmax (max rate of pressure decay).

Karlsen et al. [39]. LV pressure (LVPmax and LVPmin) and LVP (LV dP/dtmax and dP/dtmin). LV function were assessed by MRI. Killingsworth et al. [40]. dP/dt, -dP/dt.

Li et al. [41]. Cardiac output.

Strohmenger et al. [42]. Cardiac output, dP/dt, -dP/dt, LVEDP, RV stroke volume, RV ejection fraction. Tang et al. [43]. Rate of LV pressure development (dP/dt), -dP/dt, LVEDP.

Theochari et al. [44]. Pressures of the right atrium, aortic systolic, and diastolic pressures.

Zhang et al. [45]. LV dP/dtmax (represents isovolemic contractility). LV -2dp/dtmax (estimate of myocardial relaxation).

a Refer to time in minutes after induction of VF, which was done at time zero.

b No exogenous epinephrine was administered during CPR.

c Epinephrine was administered at four and 5 min after induction of VF. At the 2-hour post-resuscitation, six pigs were randomly select from each group and applied to another SSP (VF induced by dynamic steady state pacing stimulation) protocol. The study was ended after the second VF induction was maintained for 4 min.

d Resuscitation with low-flow (2.5 l/min) venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated and mechanical ventilation restarted after myocardial infarc- tion was induced and VF was left untreated for 10 min. Identical volumes of study drug, (either esmolol 1 mg/kg or NaCl 9 mg/ml–control) were administered 1 min after the initiation of VA-ECMO, 2 min prior to 1 mg epinephrine administration and 4 min prior to the first defibrillation attempt.

e CPR was started after the first defibrillation attempt.

f Epinephrine 0.045 mg/kg was administered during CPR.

g After 2 min of compression (i.e. 6 min of VF), 0.2 ml of epinephrine (0.03 mg/kg) were administered.

h Epinephrine was administered to all animals after the first unsuccessful defibrillation.

i Although 70.0% of the animals were successfully resuscitated in the esmolol group compared to 50.0% in the control group, the study was aimed and powered to evaluate post-arrest cardiac output, not survival outcomes.

Table 2

Studies/cases describing the use of esmolol for recurrent/refractory ventricular fibrillation.

Author, year, country

No. Participants Intervention Key results

Boehm et al. 2016

USA [11]

Dantzig et al.

1991

Netherlands [12]

Hwang et al. 2019

USA [13]

Karaaslan et al.

2016

Turkey [14]

Nademanee et al.

2000

USA [15]

Srivatsa

et al. 2003

USA [16]

A 67-year-old man with a prior history of left anterior descending artery stent placement was brought by EMS to the ED because of numbness in his left arm that radiated into his chest. The ECG performed by EMS showed normal sinus rhythm. At the ED he became unresponsive and developed refractory VF. He received ACLS. In addition, he received a total of 450 mg of amiodarone. The patient received a total of five defibrillation shocks, the first four at 200 joules (J) and the fifth at 300 J.
  • A 23-year-old man who received an aortic homograft with reimplantation of the coronary arteries for aortic stenosis and insufficiency with an intractable chronic staphylococcal mediastinal infection. After the patient was transfer to the intensive care unit, multiple episodes of VF then ensued. Over 1.5 h of electrical defibrillation for eight episodes of VF was necessary despite ACLS and administration of lidocaine (4 mg/min) supplanted by procainamide (two 500 mg loading doses followed by a maintenance infusion of
  • 1.4 mg/min) before esmolol was considered.

    1 A 51-year-old obese Caucasian man was brought to the emergency department by emergency medical services with chest pain and shortness of breath. While in the ED he developed refractory VF. The standard ACLS algorithm was followed. He was also given ACLS-directed amiodarone intravenously at the appropriate doses and intervals (300 mg Intravenous push followed by 150 mg intravenous push) and started on amiodarone intravenous infusion. Despite several defibrillations at escalating doses of energy, his rhythm remained in VF

    1 A 61-year-old male patient with Mitral regurgitation underwent mitral valve repair surgery. During the weaning from cardiopulmonary bypass, ventricular fibrillation occurred. Internal defibrillation was performed with a charge of 10 J. After every unsuccessful defibrillation attempt, the charge was increased up to 30 J. After three attempts, amiodarone was intravenously administered in a 300-mg bolus.

    49 A prospective, observational single-center study

    that included 49 post-myocardial infarction (MI) patients with Electrical storm (>=20 episodes of VF/VT per day or >=4 VF/VT per hour) with a mean age of 57 +- 10 years, that were separated into

    two groups. Group one received ACLS-guided therapy (n = 22) and group two received adrenergic blockade (n = 27). The efficacy of sympathetic blockade was evaluated in treating electrical storm patients and compared their outcome with that of patients treated according to the ACLS guidelines. Mostly the study looked at survival. All patients were followed at the Arrhythmia Clinic (follow-up 17 +- 8 months; range six to 34 months).

    1 A 20-year-old Hispanic woman, without any significant past medical history, was brought to the emergency department due to seizures. Initial ECG revealed SVT with a heart rate ranging from 160 to 180/min. The patient then developed multiple episodes of polymorphic VT that degenerated to intractable VF following an overdose of a weight-reduction pill (episodes were precipitated by synephrine).

    After failing to successfully terminate the VF, double defibrillation and esmolol administration were attempted. The first attempt at double defibrillation was unsuccessful. While CPR was being performed, the patient received a bolus of 80 mg of esmolol IV push and an infusion of

    0.1 mg/kg/h was initiated. After the second attempt at double defibrillation there was sustained ROSC.

    Esmolol was then given at 500 ug/kg loading dose over 1 min followed by a 60 ug/kg/min maintenance infusion. Because of insufficient

    b-blockade as judged by the heart rate response, the loading dose was repeated after 10 min and the maintenance infusion was increased to 100 ug/kg/min. The recurrent VF activity was completely suppressed.

    After four standard defibrillation attempts with no subsequent ROSC, the patient was defibrillated an additional five times using Double sequential defibrillation for refractory VF. Despite the above measures, including standard and double sequential defibrillation for a total of nine times, epinephrine boluses, antiarrhythmic boluses and infusions, his rhythm remained in VF. A dose of 500 ug of esmolol Intravenous bolus was administered which resulted in sustained ROSC after approximately 20 min of cardiopulmonary resuscitation.

    Following nearly 30 unsuccessful defibrillation attempts, 1 mg/kg esmolol was intravenously administered. Three minutes after esmolol administration, the patient was successfully defibrillated with a charge of 30 J. Sustained ROSC occurred and cardiopulmonary bypass was terminated successfully after the cessation of refractory VF.

    Patients were excluded if the onset of MI was

    b72 h and if they presented with acute pulmonary edema, previous treatment with intravenous amiodarone, acute respiratory failure, acquired or congenital long QT syndrome, or recent coronary revascularization (b1 week before the onset of electrical storm). The beta-blockade strategy consisted of LSGB (n = 6), esmolol (n = 7), and propranolol (n = 14). Patients were assigned to each treatment arm according to physician preference, rather than randomly assigned.

    Defibrillation was required due to VF. Due to the recurrence of arrhythmia, intravenous magnesium was followed by lidocaine and procainamide. With this history and considering the possibility of catecholamine overdose, intravenous esmolol was started and immediately the episodes of VF ceased. This paper has three cases, two of which did not receive esmolol during resuscitation.

    Following resuscitation, the ECG demonstrated atrial fibrillation with 2-5 mm ST elevations in leads I, aVL, and V2-V6 consistent with an

    ST-segment elevation myocardial infarction . Cardiac catheterization showed mid-left anterior descending lesion. The patient was discharged home on day four with neurological intact survival.

    The ECG showed acute transmural anteroseptal ischemia between the episodes of VF. After approximately 1 h of esmolol therapy, procainamide was discontinued without recurrence of the ventricular ectopic activity. Esmolol was continued for 7 h without reappearance of the dysrhythmia. The authors did not report survival and neurological

    status at discharge. Although, the authors mentioned that the further course of the patient was uneventful.

    After the ROSC, an ECG demonstrated ST-segment elevation in leads aVR and V1 with reciprocal changes in limb and precordial leads. Cardiac catheterization showed a totally occluded proximal RCA and severe 80.0% diffuse left PDA lesion. A drug-eluting stent was successfully deployed in the proximal RCA and left PDA with resulting Thrombolysis in Myocardial Infarction flow 3. The patient was discharged home on day six with neurological intact survival.

    Following resuscitation, the patient was sent to a post-operative intensive care unit. The patient was extubated 24-hour after the surgery and discharged to the surgical ward after 48-hour. The authors did not report survival and neurological status at discharge.

    Patients in group one (n = 27) received sympathetic blockade treatment. Six LSGB, seven esmolol, and 14 propranolol. Patients in group two (n = 22) received antiarrhythmic medication as recommended by the ACLS guidelines. The one-week mortality rate was higher in group two: 18 of the 22 patients died (82.0%), all of refractory VF; six of the 27 patients in group one died (22.0%), three of refractory VF (p b 0.0001). Patients who survived the initial electrical storm event did well over the one-year follow-up period. Overall, survival in group one was 67.0%, compared with 5.0% in group two

    (p b 0.0001).

    The VF episodes ceased immediately after esmolol administration. The patient was discharged home with neurological intact survival. She remained in good condition at the one year of follow-up.

    ACLS = advanced cardiovascular life support; aVR = augmented vector right; aVR = augmented vector left; CA = cardiac arrest; CPR = cardiopulmonary resuscitation; ED = emergency department; ECG = electrocardiogram; EMS = emergency medical services; LSGB = left stellate ganglion blockade; PDA = posterior descending artery; RCA = right coronary artery; SVT = supraventricular tachycardia; ROSC = return of spontaneous circulation; VF = ventricular fibrillation; VT = ventricular tachycardia.

    Notes: The studies mentioned above are not included in the systematic review or meta-analysis.

    Notes: These patients received multiple interventions during resuscitation. This limits our understanding of whether the effect of esmolol is a true intervention effect or the effect of other concurrent treatment had anything to do with the termination of refractory VF.

    Table 3

    Characteristics and individual outcomes of the studies included in the systematic review and meta-analysis.

    Author, year, country

    No.

    Participants

    Inclusion/exclusion criteria

    Intervention/primary and secondary outcomes

    Key results

    Driver

    25

    A retrospective, single-center, study

    Patients were included if (1) their

    The patients in the intervention group

    Sustained ROSC was significantly

    et al.

    that evaluated records from January

    initial rhythm was VF or VT, and (2)

    received an esmolol loading dose of

    more common in the esmolol group,

    2014

    2011 to January 2014 in an urban

    they had CA in the ED or had

    500 ug/kg followed by a continous

    compared to the control group (66.7%

    USA [17]

    academic EDa. This study included 25 patients (>=18 years) with OHCA or ED

    pre-hospital CA and remained in arrest upon ED arrival, and (3)

    infucion of 0-100 ug/kg/minc. The objective of this study was to

    vs. 31.6%). The esmolol group also exhibited better rates of temporary

    cardiac arrest with Refractory VF/VT.

    received at least three defibrillation

    compare the outcomes of patients

    ROSC and survival to ICU admission.

    Six patients received esmolol

    attempts, 300 mg of amiodarone, and

    who received esmolol to those who

    When comparing survival rates and

    (intervention) during CA and were

    3 mg of epinephrine. Patients were

    did not receive esmolol during

    survival with good neurological

    compared to 19 patients who only

    received ACLSb. This ED received

    excluded if (1) they received esmolol

    before CA were excluded; those that

    refractory VF in the ED. They

    evaluated ROSC, survival to ICU

    outcomes, the patients that received

    esmolol demonstrated better

    pre-hospital minute-by-minute data

    received esmolol after sustained ROSC

    admission, survival to hospital

    outcomes to those that did not: 50.0%

    which was available for all patients as

    were included in the group that did

    discharge, and survival to hospital

    vs. 16.0% survived to hospital

    a scanned document generated by

    paramedics.

    not receive esmolol.

    discharge with favorable neurological

    outcomes (CPC score of 1-2d).

    discharge, and 50.0% vs. 11.0%

    survived to discharge with a CPC <= 2,

    respectively. However, there were no

    significant differences in the rates of

    survival to discharge and survival

    with good neurological outcome.

    Lee

    41

    A retrospective, single-center,

    Patients were included if they met the

    The patients in the intervention group

    Sustained ROSC was significantly

    et al.

    pre-post study that evaluated records

    following criteria: (1) age of

    received an esmolol loading dose of

    more common in the esmolol group,

    2016

    South Korea [18]

    from January 2012 to December 2015 in an EDe of a tertiary referral center.

    This study included 41 patients

    (>=18 years) with refractory VF OHCA.

    >=18 years, (2) OHCA with initial VF or VT, and (3) refractory VF (ventricular fibrillation that was resistant to >=3

    defibrillations, 3 mg of epinephrine,

    500 ug/kg followed by a continous infucion of 0-100 ug/kg/minc. The primary outcome was sustained ROSC

    (N20 min of spontaneous circulation

    compared to the control group (56.0% vs. 16.0%, p = 0.007). The esmolol group also exhibited better rates of

    temporary ROSC and survival to ICU

    Sixteen patients received esmolol

    300 mg of amiodarone, and no ROSC

    without recurrence of cardiac arrest).

    admission. However, there were no

    (intervention) during CA and were

    after N10 min of CPR). Patients were

    The secondary outcomes were

    significant differences in the rates of

    compared to 25 patients who only

    excluded if they had (1) severe head

    survival to ICU admission, survival to

    survival to discharge 3 (18.8%) vs. 2

    received ACLS. The pre-phase (January

    trauma or acute active bleeding, (2)

    hospital discharge, and survival with

    (8.0%) and survival with good

    2012 to December 2013) of the study

    severe sepsis, (3) VF that developed

    Favorable neurological outcomes CPC

    neurological outcomes 3 (18.8) vs. 2

    included patients with refractory VF

    during resuscitation for initial asystole

    score of 1-2 at 30 days, three

    (8.0%) (p = 0.36). Additionally, there

    from OHCA who did not receive

    or PEA, (4) terminal stage

    months, and six months.

    were no significant differences in the

    esmolol, and the post-phase (January

    malignancy, (5) a history of severe

    rates of good neurological outcomes at

    2014 to December 2015) included

    Neurological deficits, or (6) had

    30 days, three months and six months

    patients with refractory VF from

    received beta-blocker therapy before

    (p = 0.36).

    OHCA who received esmolol.

    the cardiac arrest.

    ACLS = advanced cardiovascular life support; CA = cardiac arrest; CPR = cardiopulmonary resuscitation; CPC = cerebral performance category; ED = emergency department; ICU = intensive care unit; OHCA = out-of-hospital cardiac arrest; PEA = pulseless electrical activity; ROSC = return of spontaneous circulation; VF = ventricular fibrillation; VT = ventricular tachycardia.

    Notes: Neurological outcomes were evaluated using the Glasgow-Pittsburgh CPC scale. Good neurological outcomes were defined as a CPC score of 1-2.

    a This study was conducted in an ED with an annual census of approximately 100,000 patients. This facility is a Level I trauma center and is a designated ST-elevation myocardial in- farction receiving center, with the capability for 24/7 emergency percutaneous intervention as well as therapeutic hypothermia.

    b All patients received standard Manual CPR initially by First responders and most had Automated CPR with a LUCAS device (Physio-control, Redmond, WA) and an impedance threshold device (ITD) (ResQPOD(TM); Advanced Circulatory Systems Inc., Roseville, MN).

    c Most of the patients received epinephrine, amiodarone, and sodium bicarbonate before receiving the loading dose of esmolol.

    d Cerebral performance category was estimated for all survivors using descriptions from follow-up encounters.

    e This study was conducted in an ED of a tertiary referral center with an annual census of approximately 80,000 patients.

    Table 4

    Details and baseline characteristics between the experimental group and control group of the included studies.

    Author, year, country

    Enrollment

    Patients, (n)

    Patient groups, (n)

    Age, year; Median (IQR)

    Male, n (%)

    witnessed arrest, n (%)

    Bystander CPR, n (%)

    Initial rhythm VF, n (%)

    Totals

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Driver et al.

    2011-2014

    25

    6

    19

    54.5

    54.5

    6

    18

    5

    16

    3/4

    14/18 (77.8)

    5

    18

    2014

    (47-59)

    (47-59)

    (100)

    (94.7)

    (83.3)

    (84.2)

    (75.0)a,b

    (83.3)

    (94.7)

    USA [17]

    Lee et al.

    2012-2015

    41

    16

    25

    58

    52

    14

    19

    14

    17

    11

    16

    14

    21

    2016

    (45.8-72)

    (43.5-64.5)

    (87.5)

    (76.0)

    (87.5)

    (68.0)

    (68.8)

    (64.0)c

    (87.5)

    (84.0)

    South Korea [18]

    CPR = cardiopulmonary resuscitation; EMS = emergency medical services; VF = ventricular fibrillation.

    Notes: Total percentages refer to studies with available data. All continuous variables are reported as median interquartile range (IQR) unless specified otherwise. Notes: All studies were retrospective observational single-center.

    a One patient arrested in the emergency department; one patient was awake on EMS arrival, then arrested.

    b Refers to mechanical CPR with Lund University Cardiopulmonary Assist System (LUCAS) device. All patient in the esmolol group received mechanical CPR versus 84.2% in the control group.

    c One patient arrested on arrival to the emergency department.

    Table 5

    Advanced cardiovascular life support interventions between the experimental group and control group of the included studies.

    Author, year, country

    Sigle shock, median (IQR)

    Epinephrine, (mg), median (IQR)

    Amiodaron, (mg), median (IQR)

    Sodium bicarbonate, (meq), median (IQR)

    Esmolol loading dose, ug/kg

    Esmolol drip,

    ug/kg/min

    Total CPR time (min), median (IQR)

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Driver et al. 2014

    6.5

    7

    6

    6

    375

    450

    225

    150

    500

    ..

    0-100

    ..

    63

    57

    USA [17]

    (5-9.5)a

    (5-8)

    (5-7.75)

    (5-7)

    (300-450)

    (300-450)

    (200-288)

    (100-250)

    (57-83)

    (39-66)

    Lee et al. 2016

    6

    5

    6

    6

    450

    300

    0

    0

    500

    ..

    0-100

    ..

    55

    67

    South Korea [18]

    (6-8.75)

    (5-6.5)

    (3.3-9)

    (5-8)

    (300-450)

    (300-450)

    (0-40)

    (0-160)

    (35.3-70.3)

    (45.5-64.5)

    (..) = not applicable; CPR = cardiopulmonary resuscitation; meq = milliequivalents.

    Notes: All continuous variables are reported as median interquartile range (IQR) unless specified otherwise. Notes: Collapsed-time to esmolol administration was no reported.

    a Does not include Implantable cardioverter defibrillator (ICD) firings for one patient; ICD fired approximately every 2-3 min until it failed 30 min after emergency department arrival.

    Table 6

    Post-esmolol outcomes between the experimental group and control group of the included studies.

    Author, year, country

    Temporary ROSCa, n (%)

    Sustained ROSCb, n (%)

    STEMI, n (%)

    Survival to ICU admission, n (%)

    Survival to discharge, n (%)

    CPC <= 2 at discharge, n (%)

    CPC <= 2 at 3 and 6 months, n (%)

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Esmolol

    Control

    Driver et al.

    4

    8

    4

    6

    3/5

    1/7

    4

    6

    3

    3

    3

    2

    2014

    (66.7)

    (42.1)

    (66.7)

    (31.6)

    (60.0)c

    (14.3)?

    (66.7)

    (31.6)

    (50.0)

    (15.8)

    (50.0)

    (10.5)

    USA [17]

    Lee et al.

    13

    6

    9

    4

    9

    4

    3

    2

    3

    2

    3

    2

    2016

    (81.3)

    (24.0)

    (56.3)

    (16.0)

    (56.3)

    (16.0)

    (18.8)

    (8.0)

    (18.8)

    (8.0)

    (18.8)

    (8.0)

    South Korea [18]

    (…) = data not available; CPR = cardiopulmonary resuscitation; CPC = cerebral performance category; ICU = intensive care unit; ROSC = return of spontaneous circulation; STEMI = ST- elevation myocardial infarction.

    Notes: Total percentages refer to studies with available data.

    a Refers to non-fleeting return of restored circulation lasting N30 s, but b20 min.

    b Refers to 20 min of spontaneous circulation without cardiac arrest.

    c Five (83.3%) patients in the esmolol group received emergent cardia catheterization versus 3 (15.8%) patients in the control group. It is unknown if the remainder of the patients had STEMI.

    blockade were used for cardiac arrest. The discarded articles were ap- proved by the authors before the analysis was completed. Other studies on esmolol for refractory VF were summarized in the paper but were not relevant to this analysis and were therefore not included (Table 2). Finally, the remaining studies were included in our review, comprising two observational studies directly related to the use of esmolol for pre-hospital refractory VF/pVT [17,18]. Tables 3-6 summa- rize details of the articles selected for inclusion according to demo- graphics, presentation, Resuscitative parameters, and outcomes. No randomized clinical trials were identified in the International Clinical Trials Registry Platform (http://www.who.int/ictrp/en/), which in- cludes entries in ClinicalTrials.gov (www.clinicaltrials.gov).

    Study characteristics

    The overall risk of bias within individual studies was judged as seri- ous for both studies, with confounding bias, selection of participants, and measurement of outcomes being the primary sources [17,18]. The overall risk of bias within both studies was judged as serious because they included at least one category with serious risk of bias. Both studies were at moderate risk of selection bias. Both studies were at overall low risk of bias for classification of interventions and deviations from intended interventions. One study was at moderate risk of bias for miss- ing data [17]. The other study was at low risk of bias for missing data [18]. Both studies were at moderate risk of bias for measurement of

    Table 7

    ROBINS-I assessment of risk of bias in included studies.

    Author, year, country

    Bias due to confoundinga

    Bias in selection of participants

    Bias in classification of interventions

    Bias due to deviations from intended interventions

    Bias due to missing data

    Bias in measurement of outcomes

    Bias in selection of the reported result

    Overall

    Driver et al. 2014

    S

    M

    L

    L

    M

    M

    L

    S

    USA [17]

    Lee et al.

    S

    M

    L

    L

    L

    M

    L

    S

    2016

    South Korea [18]

    Risk of bias: L = low risk; M = moderate risk; S = serious risk. Notes: The overall risk of bias within both studies was judged as serious risk of bias because they included at least one category with serious risk of bias. Both studies were at serious risk of bias for confounding, at moderate risk of selection bias, and at moderate risk in measurement of outcomes. Both studies were at low risk of bias for classification of interventions and de- viations from intended interventions. One study was at moderate risk of bias for missing data and the other was at low risk of bias for missing data. Both studies were at moderate risk of bias for measurement of outcomes and low risk of bias for selection of reported results.

    a Both studies were at serious risk of bias from confounding because of the potential for unmeasured variables. Risk of bias from confounding was considered serious when confounding was not inherently controlled (i.e. no or limited adjustment).

    Table 8

    GRADE Summary of findings.

    Certainty assessment Summary of findings

    No of patients Effects Certainty

    Number of Studies, design

    Risk of bias Inconsistency Indirectness Imprecision Othersb Esmolol Control Relative

    (95% CI)

    Absolute (95% CI)

    Survival with a favorable neurological outcome

    observational studiesa

    Serious limitations

    No serious limitations

    No serious limitations

    No serious limitations

    Strongly suspectedc

    6/22 (27.3%)

    4/44 (9.1%)

    RR 3.34

    (1.11-10.67)

    213 more per 1000 (from 10 more to 879 more)

    ????

    Very low

    Survival to hospital discharge

    2 observational studiesa

    Serious limitations

    No serious limitations

    No serious limitations

    No serious limitations

    Strongly suspectedc

    6/22 (27.3%)

    5/44 (11.4%)

    RR 2.82

    (1.01-7.93)

    207 more per 1000 (from 8 fewer to 788 more)

    ????

    Very low

    sustained return of spontaneous circulation

    2 observational studiesa

    Serious limitations

    No serious limitations

    No serious limitations

    No serious limitations

    Strongly suspectedc

    13/22 (59.1%)

    10/44 (22.7%)

    RR 2.63

    (1.37-5.07)

    370 more per 1000 (from 84 more to 925 more)

    ????

    Very low

    Survival to ICU/hospital admission

    2 observational studiesa

    Serious limitations

    No serious limitations

    No serious limitations

    No serious limitations

    Strongly suspectedc

    13/22 (59.1%)

    7/44 (15.9%)

    RR 2.63

    (1.37-5.07)

    259 more per 1000 (from 59 more to 648 more)

    ????

    Very low

    The risk in the intervention group (and its 95% confidence interval) is based on the comparison group and the relative effect of the intervention (and its 95% CI). CI = confidence interval; RR = risk ratio.

    GRADE Working Group grades of evidence

    High-certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

    Moderate-certainty: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different

    Low-certainty: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.

    Very low-certainty: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect. Notes: The overall certainty of evidence was graded as very low for each outcome based on GRADE criteria.

    Notes: Wide confidence intervals were observed in the pooled data indicating that we have little knowledge about the effect, and that further information is needed. Notes: Large magnitude of effect was present but it was not sufficient enough to increase the quality of evidence because the presence confounders (relative risk [RR] = 2-5 with no plau- sible confounders).

    a Driver et al. [17], Lee et al. [18].

    b Includes assessment of publication bias, magnitude of effect, dose-response gradient, and plausible residual confounding or biases leading to spurious effect when the results show no effect.

    c We planned to use a funnel plot to evaluate for publication bias, but this was not possible due to the limited number of studies.

    outcomes and low risk of bias for selection of reported results. Table 7 includes the risk of bias assessments using the ROBINS-I tool. Given that the body of evidence was from observational studies, it was initially classified as low quality evidence (i.e. permitting low confidence in the estimated effect). Table 8 includes the GRADE summary of findings.

    Both articles were published between 2014 and 2016, while patient enrollment periods extended to as early as 2011. Both studies were single-center hospital based, with capability for emergency percutane- ous coronary intervention. One study was performed in the United States (US) [17] and the other in South Korea [18]. Both studies enrolled patients with pre-hospital cardiac arrest and diagnosis of refractory VF/ pVT who did not respond to at least three defibrillation attempts, 3 mg of epinephrine, and 300 mg of amiodarone, and who remained in arrest upon ED arrival. One study also included patients that had ED refractory cardiac arrest [17]. All patients in the esmolol group received a loading dose of esmolol 500 ug/kg, and this dose was followed by a continuous infusion of 0-100 ug/kg/min. The sample sizes of the patients that re- ceived esmolol ranged from six to 16, the median age of the patients ranged from 54 to 58 years, and the percentage of males ranged from 87.5% to 100%. Most cardiac arrests were witnessed by a bystander, who initiated CPR in 66.7% of the patients in the esmolol group and 69.8% in the control group. The initial documented heart rhythm was VF in 86.4% of the patients in the esmolol group and 88.6% in the control group. Temporary ROSC occurred in 86.4% of the patients in the esmolol group and 31.8% in the control group. Sustained ROSC occurred in 59.1% of the patients in the esmolol group and 22.7% in the control group. Sur- vival to ICU/hospital admission occurred in 59.1% of the patients in the esmolol group and 22.7% in the control group. Survival to discharge oc- curred in 27.3% of the patients in the esmolol group and 11.4% in the control group. Survival to discharge with favorable neurological out- come occurred in 27.3% of the patients in the esmolol group and 9.1% in the control group. One study reported on survival with favorable

    neurological outcome at 30 days, three months, and six months [18]. One study reported data regarding the predominance of acute coronary syndrome and the patients that received emergency coronary revascu- larization [17]. None of the studies reported specify Major adverse events. Neurological outcomes were evaluated using the Glasgow- Pittsburgh CPC scale. Good neurological outcomes were defined as a CPC score of 1 or 2 [46].

    Primary outcomes of interest

    Fig. 2 shows forest plots depicting comparisons of esmolol with con- trol group for each outcome of interest. The pooled RR with 95% CI showed that esmolol had a likely effect on survival to discharge (RR 2.82, 95% CI 1.01-7.93, p = 0.05) (GRADE: Very low) [17,18]. We

    found no heterogeneity when pooling these studies (heterogeneity: tau2 = 0.00; Chi2 = 0.08; df = 1 (p-value = 0.79); I2 statistic = 0%). There was no statistical significance at the study level but there was modest statistical significance at the meta-analysis level. We are uncer- tain of the effects of esmolol on survival to discharge as the quality of the evidence has been assessed as very low. One of the studies that met the eligibility criteria for the quantitative data synthesis did not report sur- vival to discharge at 30 days, six months, or longer [17]. A similar result was found for survival with favorable neurological outcome (RR 3.44, 95% CI 1.11-10.67, p = 0.03) (GRADE: Very low) [17,18]. We found

    no heterogeneity when pooling these studies (heterogeneity: tau2 = 0.00; Chi2 = 0.38; df = 1 (p-value = 0.54); I2 statistic = 0%). There was no statistical significance at the study level but there was modest statistical significance at the meta-analysis level. We are uncertain of the effects of esmolol on survival with favorable neurological outcome as the quality of the evidence has been assessed as very low. One of the studies that met eligibility criteria for the quantitative data synthesis

    did not report survival with favorable neurological outcome at 30 days, six months, or longer [17].

    Secondary outcomes of interest

    Fig. 2 shows forest plots depicting comparisons of esmolol with con- trol group for each outcome of interest. The pooled RR with 95% CI showed that esmolol is likely associated with increased ROSC (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low) [17,18]. We

    found no heterogeneity when pooling these studies (heterogeneity: tau2 = 0.00; Chi2 = 0.62; df = 1 (p-value = 0.43); I2 statistic = 0%). There was no statistical significance at the study level except for one study [18]. In this study, the intervention did show to be better than the control. There was statistical significance at the meta-analysis level. We are uncertain of the effects of esmolol on ROSC as the quality of the evidence has been assessed as very low. A similar result was found for survival to ICU/hospital admission (RR 2.63, 95% CI 1.37-5.07, p = 0.004) (GRADE: Very low) [17,18]. We found no hetero- geneity when pooling these studies (heterogeneity: tau2 = 0.00; Chi2 = 0.62; df = 1 (p-value = 0.43); I2 statistic = 0%). There was no statistical significance at the study level except for one study [18]. In this study, the intervention did appear to be better than the control. There was statistical significance at the meta-analysis level. We are un- certain of the effects of esmolol on survival to ICU/hospital admission as the quality of the evidence has been assessed as very low.

    Random errors

    The pooled RRs (95% CIs) and p-values of the primary and secondary outcomes of interest suggest that esmolol compared to control likely in- crease favorable outcomes. However, the TSA showed that the studies did not even reach half of the required information size for the primary outcome of survival to discharge and the secondary outcome of ROSC (Figs. 3-4). The cumulated Z-curve crosses the traditional boundary (p = 0.05) but not the trial sequential monitoring boundary indicating lack of firm evidence for a beneficial effect of 30% RRR of the interven- tion when the analysis is adjusted for repetitive testing on accumulating data. There is insufficient information to reject or detect an intervention effect of 30% RRR as the required information size is not yet reached. Based on the TSA, the naive 95% CI and 5% thresholds for statistical sig- nificance would not be sufficient to claim conclusive results. Therefore, the results of the TSA indicate that the evidence is inconclusive and that further trials are required. Future research is very likely to have an im- portant impact on the estimated effect of this intervention, which could be either dramatically beneficial or dramatically harmful.

    Discussion

    This review aimed to identify the literature reporting on the use of esmolol for the management of adults with pre-hospital refractory VF/ pVT and quantitatively summarize whether this intervention improves patient-centered outcomes. We identified two observational studies

    Image of Fig. 2

    Image of Fig. 3 Image of Fig. 4

    Fig. 3. Trial sequential analysis (TSA) for a relative risk reduction (RRR) of survival to discharge of 40% of esmolol during refractory cardiac arrest in two studies with 66 patients reporting survival to discharge. We planned to calculate the required information size to detect or reject a 30% RRR. However, we used a RRR of 40% instead of 30% as the program could not draw with 30% due to too little accrued information out of the required information. A required diversity-adjusted information size (DIS) of 1252 patients was calculated based on a control event proportion of 11.4%, esmolol induced RRR of survival to discharge of 40%, ? = 0.05 two-sided, ? = 0.20 (power = 80%), and diversity D2 = 0%. After 66 patients have been randomized, the TSA-adjusted CI of RR 2.82 is from 0.04 to 191.08. The cumulated Z-curve is crossing the traditional boundary (p = 0.05) but not the trial sequential monitoring boundary indicating lack of firm evidence for a beneficial effect of 40% RRR of the intervention when the analysis is adjusted for repetitive testing on accumulating data. There is insufficient information to reject or detect an intervention effect of 40% RRR of survival to discharge as the required information size is not yet reached. Future research is very likely to have an important impact on the estimated effect of this intervention, which could be either dramatically beneficial or dramatically harmful.

    involving the use of esmolol at the ED for the treatment of refractory VF/ pVT. Additionally, we summarized the levels of evidence of studies that have evaluated the effects of esmolol during resuscitation of cardiac ar- rest from VF but which were not relevant to this analysis and were therefore not included. When we compared esmolol versus no esmolol, we found that participants in the esmolol group were more likely to reach survival to discharge (RR 2.82, 95% CI 1.01-7.93, p = 0.05) and survival with favorable neurological outcome (RR 3.44, 95% CI 1.11-10.67, p = 0.03). Similar results were found for ROSC (RR 2.63, 95% CI 1.37-5.07, p = 0.004) and survival to ICU/hospital admission

    Fig. 4. Trial sequential analysis (TSA) for a relative risk reduction (RRR) of ROSC of 30% of esmolol during refractory cardiac arrest in two studies with 66 patients reporting ROSC. A required diversity-adjusted information size (DIS) of 1055 patients was calculated based on a control event proportion of 22.7%, esmolol induced RRR of ROSC of 30%, ? = 0.05 two-sided, ? = 0.20 (power = 80%), and diversity D2 = 0%. After 66 patients have been randomized, the TSA-adjusted CI of RR 2.63 is from 0.18 to 38.27. The cumulated Z- curve crosses the traditional boundary (p = 0.05) but not the trial sequential monitoring boundary indicating lack of firm evidence for a beneficial effect of 30% RRR of the intervention when the analysis is adjusted for repetitive testing on accumulating data. There is insufficient information to reject or detect an intervention effect of 30% RRR of ROSC as the required information size is not yet reached. Future research is very likely to have an important impact on the estimated effect of this intervention, which could be either dramatically beneficial or dramatically harmful.

    (RR 2.63, 95% CI 1.37-5.07, p = 0.004). The GRADE quality of evidence was graded as very low for each outcome and as having a high risk of confounding. We are uncertain of the effects of esmolol on any of the outcomes as a result of this assessment; additionally, the optimal infor- mation size was not achieved for the meta-analysis, and sequential test- ing on an accumulated number of participants did not surpass trial sequential monitoring boundaries. Therefore, the conclusion should be that the intervention might be beneficial, but larger sample sizes are needed as the estimates are still inconclusive. Cautious interpretation of overall effect estimates is therefore warranted, but to inform the cur- rent discussion, we also presented the pooled odds ratios (ORs) esti- mate for the primary and secondary outcomes, despite obvious limitations (Comparisons 1-2).

    Fig. 2. Forest plot of comparison: 1 Adults treated at the emergency department with esmolol (intervention) compared with control group (no esmolol) for refractory ventricular fibrillation out-of-hospital cardiac arrest. The result and its 95% confidence interval (CI) are presented by a diamond, with the risk ratio (95% CI) and its statistical significance given alongside. Squares or diamonds to the right of the solid vertical line favours the intervention group, but this is conventionally significant (p b 0.05) only if the horizontal line or diamond does no overlap the solid line. Squares indicate study-specific risk ratio. The size of the box is proportional to the percent weight that each study contributed in the pooled risk ratio. Horizontal lines indicate 95% CI. A diamond indicates the pooled risk ratio with 95% CI. The weigh indicates how much an individual study contributes to the pooled estimate. M-H stands for the Mantel-Haenszel method in meta-analysis.

    Comparison 1

    Pooled risk ratios with 95% confidence intervals comparing esmolol therapy versus advanced cardiovascular life support.

    Outcome or subgroup title

    No. of studies

    No. of participants

    Statistical method

    Effect size

    Survival to hospital discharge

    2

    66

    Risk Ratio (M-H, Random, 95% CI)

    2.82 [0.01-7.93]

    Survival with a favorable neurological outcome

    2

    66

    Risk Ratio (M-H, Random, 95% CI)

    3.44 [1.11-10.67]

    Sustained return of spontaneous circulation

    2

    66

    Risk Ratio (M-H, Random, 95% CI)

    2.63 [1.37-5.07]

    Survival to ICU/hospital admission

    2

    66

    Risk Ratio (M-H, Random, 95% CI)

    2.63 [1.37-5.07]

    Comparison 2

    Pooled odds ratios with 95% confidence intervals comparing esmolol therapy versus advanced cardiovascular life support.

    Outcome or subgroup title

    No. of studies

    No. of participants

    Statistical method

    Effect size

    Survival to hospital discharge

    2

    66

    Odds Ratio (M-H, Random, 95% CI)

    3.69 [0.92-14.85]

    Survival with a favorable neurological outcome

    2

    66

    Odds Ratio (M-H, Random, 95% CI)

    4.42 [1.05-18.56]

    Sustained return of spontaneous circulation

    2

    66

    Odds Ratio (M-H, Random, 95% CI)

    5.76 [1.79-18.52]

    Survival to hospital/ICU admission

    2

    66

    Odds Ratio (M-H, Random, 95% CI)

    7.83 [2.37-25.90]

    Esmolol is a relatively old ?-blocker, yet a major limitation discov- ered in this review is the paucity of research and lack of literature supporting its use as adjunctive therapy for pre-hospital refractory VF/ pVT. Research has been limited for many reasons. There is no defined protocol for the use of esmolol for cardiac arrest patients, possibly due to relatively infrequent use of the drug during resuscitation of cardiac arrest patients. Currently, there are no planned or ongoing randomized clinical trials, so the scientific evidence there is rests primarily on case reports, and likely represents no more than publication bias and obser- vational studies with their potentially confounding selection bias [11- 18]. These render its use problematic, without a strong evidence base for its clinical efficacy. The use of esmolol in cardiac arrest is sporadic and often part of aggressive resuscitation efforts to facilitate return of normal perfusion, which means that esmolol is often used as adjuvant or Salvage therapy in combination with other interventions, such as me- chanical chest compressions devices, impedance threshold devices, double/dual defibrillation, and deployment of VA-ECMO used as ECPR, which has increasingly been used in patients with refractory cardiac ar- rest as a bridge to definitive treatment, including transport to percuta- neous coronary intervention (PCI) capable centers or expedite access to cardiac catheterization laboratory for early coronary angiogra- phy (CAG) and, when necessary, coronary revascularization.

    In several studies, ?-blockers have been shown to increase ROSC, im- prove post-resuscitation myocardial function, diminish arrhythmia re- currence, and increase the chance of survival to discharge [19]. However, there has never been great evidence for the practice. There have been many studies looking at other ?-blockers over the past de- cades for cardiac arrest, but these studies were done either in animals [47-54] or were single cases published many years ago [55-62], except for one in-hospital study that evaluated the ultra-short-acting ?1– selective blocker landiolol, which shares similarities to esmolol, such as the metabolism pathway; however, landiolol presents faster pharma- cokinetics, acts with higher potency, and have higher cardioselectivity [63]. In 2000 a non-randomized in-hospital single-center study in- cluded 49 patients who had electrical storm (ES) associated with recent myocardial infarction. Patients were divided into two groups. Patients in group one (n = 27) received sympathetic blockade treatment with left stellate ganglionic blockade (SGB) 22.2%, propranolol 58.9%, and esmolol 25.9%. Patients in group two (n = 22) received antiarrhythmic medication as recommended by the Advanced cardiac life support guidelines [4]. One-week mortality was four-fold greater in the ACLS group (82.0% of the 22 patients). Patients who survived the initial ES event did well over the one-year follow-up period. Overall survival in group one was 67.0%, compared with 5.0% in group two (p b 0.0001). This study suggests that sympathetic blockade could be beneficial dur- ing the treatment of recurrent/refractory VF/VT [15].

    Refractory VF is an uncommon clinical scenario with few treatment recommendations [4,64,65]. RCTs of epinephrine in pre-hospital cardiac arrest have failed to show statistically significant improvement in sur- vival to discharge with a favorable neurological outcome, although there has been a significantly improved likelihood of achieving ROSC [66-68]. During prolonged resuscitation there is a boost in sympathetic tone due to epinephrine administration. The activation of ?-adrenergic receptors by epinephrine in cardiac arrest constricts arterioles, poten- tially increasing arterial (aortic) diastolic pressure during CPR, therefore increasing Coronary blood flow and the chance of ROSC. The activation of ?-adrenoreceptors by epinephrine may have potentially harmful ef- fects on the heart, by reducing coronary blood flow by up to 40.0% [69], increasing myocardial oxygen consumption by up to four-fold and the risk of myocardial ischemia in patients with VF arrest via its pos- itive chronotropic and inotropic effects [70-73], increasing the severity of post-resuscitation myocardial dysfunction, increasing the develop- ment of new dysrhythmias, and increasing the risk of recurrent cardiac arrest [43,73-76]. Potentially harmful effects may also occur via ?- adrenergic stimulation, which impairs microvascular blood flow due to platelet activation, which promotes thrombosis, thus increasing the

    severity of cerebral ischemia during resuscitation and after ROSC [77,78].

    Esmolol has shown promising results in supporting the effectiveness of beta-1 selective blockade in achieving ROSC [17,18], although the benefits must be weighed against the harm of increasing ROSC without improving survival and favorable neurological outcome. Esmolol is ex- tremely cardioselective and has very low lipophilicity, which is ideal for these patients due to its ultra-short acting beta-1 selective adrener- gic receptor blocker activity, as well as its quick onset of action. It has the fastest onset (90 s) and the shortest half-life ([t1/2] = 9 min) of any ?- blocker approved for human use in the US; as a result, there is less risk of excessive or prolonged effects from the drug (i.e. increase incidence of hypotension and bradycardia) during and after resuscitation, compared to other ?-blockers [79-82]. Esmolol is also able to mitigate the depres- sion of the VF threshold produced by high doses of epinephrine used during cardiac arrest due to its ability to dampen the sympathetic tone, which is one of the proposed mechanisms behind the use of esmolol for refractory VF [38,81,82]. At this time, there is inadequate ev- idence to either support the use of esmolol during refractory cardiac ar- rest or the routine use of a ?-blocker after cardiac arrest. However, the initiation of an oral or intravenous (IV) ?-blocker may be considered early after post-resuscitation from cardiac arrest due to VF/pVT (Class IIb, LOE C-LD) [4].

    Our results preclude any firm conclusion about the efficacy of

    esmolol for refractory VF/pVT, however. Future studies should address the best timing for the administration of the ?-blocker esmolol for re- fractory cardiac arrest. Generally, for adults resuscitated from pre- hospital refractory cardiac arrest, an IV loading dose of <=500 ug/kg/min over 1 min is administered followed by a continuous IV drip of 0-100

    ug/kg/min [17,18]. Nevertheless, optimal timing for the administration of esmolol for pre-hospital refractory VF/pVT remains unclear. In order to get the best results from this practice, any drug used during resusci- tation, including esmolol, should perhaps be administered following the electrical phase, in the hemodynamic phase; however, in pre- hospital cardiac arrest, epinephrine (Class IIb, LOE B-R) and antiarrhyth- mics (i.e. amiodarone) (Class IIb, LOE B-R), as well as esmolol, are typi- cally delayed beyond 10 min, and primarily administered late in the metabolic phase, which has been the case for esmolol, thus the chances of survival are reduced [83]. If esmolol results in ROSC, but subsequent outcomes result in complications, more patients with severe neurolog- ical disabilities, and death, it is not an effective intervention. This is sim- ilar to the PARAMEDIC2 (Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Car- diac Arrest) trial involving patients with pre-hospital cardiac arrest, where epinephrine increased the chances of ROSC and survival at 30 days but made no difference to survival with favorable neurological out- come compared to a placebo (Current Controlled Trials number ISRCTN73485024) [68].

    Limitations

    Our review should be interpreted in the context of certain limita- tions. First, all the included studies were non-randomized and observa- tional in nature, single-center, with small sample sizes, and had risk of bias, in particular confounding and selection bias. Second, esmolol as ad- junctive therapy for refractory VF/pVT is a nascent therapy, thus re- search involving it is limited. Third, in the two studies included in this review, both listed at least two or three limitations in their discussion section. The most common limitations were small sample size and being single-center and observational in nature, followed by unmea- sured confounders. In terms of methodology, this review was limited to four databases and articles published in English. These criteria may have biased the results and limited the evidence. The limitations listed are only the major limitations we encountered, along with those ad- dressed in each individual study, and hence there is a risk of bias if the

    authors of any of the articles included in the review did not include all the true limitations of their studies.

    Furthermore, owing to the lack of randomized clinical trials, the ef- fect estimate for our primary and secondary outcomes derived from the meta-analysis clearly cannot be interpreted as supporting the exis- tence of a true causal effect. Nor can it rule it out, as it is obviously under- powered in terms of detecting any significant effects. Additional studies may clarify the situation. It is this relatively small number of patients that resulted in each study as having even smaller numbers of patients in the intervention group. To compound this, all the data presented in this review are single-center experiences and hence cannot be easily generalized at a large scale. Therefore, our ability to draw conclusions is severely limited by the quality of the primary data, and thus it is very important for the reader to be aware of the limitations of our meta-analysis, and of the studies on which it is based. All of this pro- vides insufficient evidence to support the widespread implementation of this therapy. What is clinically important is that randomized trial of esmolol or any other ?-blocker for refractory VF/pVT has not been con- ducted. These trials will have to be powered enough to detect small-size differences, but the patient population of interest is so small and rarely encountered that a definitive trial will be very difficult. Despite these limitations, the rationale for undertaking an early scoping review [84] or systematic review [85] is now recognized, in that such reviews have, among other things, the potential to influence the design of future primary studies.

    Conclusions

    The pooled RR (95% CIs) and p-value estimates suggest that the use of esmolol in adult cardiac arrest with a refractory shockable rhythm (VF/pVT) may be associated with improved outcomes. TSA indicates that the evidence is inconclusive and that further trials are required in order to reach a conclusion. Using GRADE-methodology we conclude that the quality of the evidence is very low and is at high risk of con- founding. We further conclude that future research is very likely to have an important impact on the estimated effect of this intervention, which could be either dramatically beneficial or dramatically harmful. It is recommended that these outcomes be evaluated in RCTs in order to obtain a higher level of scientific evidence to help us justify its use and application in this specific patient population.

    Research priorities“>Research priorities
  • High-quality study examining the safety and effectiveness of esmolol compared to standard of care in the management of pre-hospital re- fractory VF/pVT in terms of survival to discharge and Neurologically intact survival.
  • What is the efficacy of bundlED treatments, such as epinephrine and esmolol, as to whether the bundle with synergistic effects or a single agent is related to any observed effect, in terms of survival to dis- charge and Neurologically intact survival?
  • What is the optimal timing for esmolol administration?
  • What are the benefits and risks of esmolol on post-resuscitation myocardial dysfunction?
  • Acknowledgments

    The authors would like to thank the library staff from the Veterans Affairs Caribbean Healthcare System Library Service for assistance with producing the search strategy.

    Author contributions

    DM, LM, and WA were responsible for the project design. DM and LA were responsible for data abstraction, statistical analysis, and interpre- tation. DM drafted the original manuscript. All authors reviewed and

    approved the final version of the manuscript. DM takes responsibility for the paper as a whole.

    Funding

    This project had no sponsors and did not receive any funding support.

    Declaration of competing interest

    None of the authors have conflicts of interest to disclose.

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