Archives of Academic Emergency Medicine. 2020; 8(1): e15 REV I EW ART I C L E The Evolving Role of Esmolol in Management of Pre- Hospital Refractory Ventricular Fibrillation; a Scoping Re- view Dennis Miraglia1∗, Lourdes A. Miguel1, Wilfredo Alonso1 1. Department of Internal Medicine, Good Samaritan Hospital, Aguadilla, PR, United States Received: January 2020; Accepted: January 2020; Published online: 25 February 2020 Abstract: Introduction: Few studies have described their experience using esmolol, an ultra-short acting Κ-adrenergic antagonist, in the emergency department (ED) as a feasible adjuvant therapy for the treatment of refractory ven- tricular fibrillation/pulseless ventricular tachycardia (VF/pVT) out-of-hospital cardiac arrest. However, there is currently insufficient evidence to support the widespread implementation of this therapy. The aim of this scop- ing review was to summarize the current available evidence on the use of esmolol as an adjuvant therapy for refractory VF/pVT out-of-hospital cardiac arrest, as well as to identify gaps within the literature that may re- quire further research. Methods: We conducted a comprehensive literature search of MEDLINE via PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) on July 5, 2019. The search was restricted to articles that were published from January 2000 to July 2019. Google Scholar was searched and reference lists of relevant papers were examined to identify additional studies. We included any controlled clini- cal study design (randomized controlled trials and non-randomized controlled trials) and observational studies (cohort studies and case-control studies) in adults providing information on the use of esmolol as an adjuvant therapy for refractory VF/pVT out-of-hospital cardiac arrest. Results: The search yielded 2817 unique records, out of which 2 peer-reviewed articles were found relating to the research purpose totaling 66 patients 33.3% (n = 22) of which received esmolol. These studies found that sustained return of spontaneous circulation (ROSC) was significantly more common in the patients that received esmolol compared to the control group. How- ever, no statistically significant outcomes were found regarding survival to discharge and favorable neurological outcome. No randomized controlled trials were identified. Conclusion: To date, it is difficult to conclude the real benefit of esmolol as an adjuvant therapy for refractory VF/pVT out-of-hospital cardiac arrest based on the available evidence. The findings of this scoping review suggest that there is a paucity of research and limited evidence to support this therapy. Keywords: Cardiopulmonary resuscitation; esmolol; out-of-hospital cardiac arrest; ventricular fibrillation Cite this article as: Miraglia D, A. Miguel L, Alonso W. The Evolving Role of Esmolol in Management of Pre-Hospital Refractory Ventricular Fibrillation; a Scoping Review. Arch Acad Emerg Mede. 2020; 8(1): e15. 1. Introduction In 2016, the annual estimated incidence of emergency med- ical services (EMS)-assessed out-of-hospital cardiac arrest reported by the Resuscitation Outcomes Consortium (ROC) Epistry for cardiac arrest was about 356,500 people of all ages in the United States (US). Among EMS-treated out- of-hospital cardiac arrest patients, about 21% had shock- ∗Corresponding Author: Dennis Miraglia, Department of Internal Medicine, Good Samaritan Hospital, P.O. BOX: 4055, Aguadilla, PR, United States; E-mail: dennismiraglia@hotmail.com able rhythms of ventricular fibrillation/pulseless ventricu- lar tachycardia (VF/pVT). Survival to hospital discharge after EMS-treated cardiac arrest was about 11.4%, while this rate was 37.4% for bystander-witnessed VF cardiac arrest in pa- tients of all ages (1, 2). VF is a life-threatening arrhythmia that could lead to sudden cardiac death if not treated emer- gently. Currently, the American Heart Association (AHA) rec- ommends immediate electrical defibrillation as the most ef- fective treatment for VF/pVT (3, 4). However, there is a sub- group of patients in which VF remains refractory to stan- dard electrical defibrillation (5, 6). Refractory VF is defined as VF unresponsive to at least three standard defibrillation attempts and Advanced Cardiovascular Life Support (ACLS); This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem D. Miraglia et al. 2 however, currently, neither a clear consensus to the defini- tion of refractory VF nor best-established practices for the management of refractory VF exist (7). Since there is no con- sistent definition for refractory VF in the clinical literature, we used the one cited above throughout this review. Few observational studies have described their experience with pre-hospital double defibrillation to treat refractory VF/pVT. These studies have been unable to reach a conventional threshold for statistical or clinical significance, although this does not mean that it is safe to conclude that there is no dif- ference (8-11). There may be better strategies for treating pre-hospital refractory VF/pVT than the use of double defib- rillation. Incorporation of mechanical chest compressions devices (LUCAS) and earlier deployment of extracorporeal membrane oxygenation (ECMO) assisted revascularization have shown promising results. Therefore, ECMO has been in- creasingly used as a bridge to definitive treatment including revascularization (CAG and PCI) in patients with refractory cardiac arrest (12-20). The beta-blocker, esmolol has been re- cently studied as a feasible adjuvant therapy for patients dur- ing both electrical storm (ES) and refractory VF/pVT; offering a potential lifesaving treatment option for these patients (21- 26). However, the limited evidence about the rationale be- hind the use of intravenous esmolol for the treatment of re- fractory cardiac arrest makes it a unique and unproven ther- apy still to be proven. Consequently, there seems to be a need to review the literature regarding the use of esmolol for re- fractory VF/pVT out-of-hospital cardiac arrest in more detail to: identify areas for future research, and to develop strate- gies for a clinical protocol that will offer a potential lifesaving treatment option for this specific patient population, which is in accordance with the recommendations in the current clinical guidelines. A scoping review was deemed most ap- propriate because it is exploratory in nature. All methodolo- gies will be considered in the process of this review, as there are few studies evaluating esmolol for refractory VF/pVT out- of-hospital cardiac arrest. Therefore, the scoping review will identify the feasibility of future work in this area from a vari- ety of methodological perspectives. This paper will summa- rize the state of the current literature on the use of esmolol in the emergency department (ED) as a feasible adjuvant ther- apy for refractory VF/pVT out-of-hospital cardiac arrest and identify gaps that will provide direction for future research in the area. 2. Methods We followed the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scop- ing Reviews) guidelines developed following published guid- ance from the EQUATOR Network (Enhancing the QUAlity and Transparency Of health Research) (27) and the method- ological framework for conducting a scoping review devel- oped by Arksey and O’Malley (28). A scoping review proto- col was not drafted. A scoping review is the process of map- ping the main concepts of a research area to its source and evidence available in the literature. The five stages the au- thors developed were followed in order to maintain a trans- parent method for data collection, analysis, and interpreta- tion: 1) identifying the research question; 2) identifying rele- vant studies; 3) selecting studies; 4) charting the data; and 5) collating, summarizing, and reporting the results (28). 2.1. Stage 1: Identifying the Research Question The aim of this scoping review was to gain a clear under- standing of the current available literature on the use of es- molol in the ED as an adjuvant therapy for patients with re- fractory VF/pVT out-of-hospital cardiac arrest. A scoping re- view should be undertaken to determine the value of under- taking a full systematic review and forms part of the com- plex intervention framework (29, 30). The research objec- tives of this review were to: 1) summarize the current base of evidence on this intervention for refractory VF/pVT out- of-hospital cardiac arrest; 2) identify gaps in the literature that may require further research. The review questions for this scoping review were formulated following the PICOT method. P (Population) - people (≥18 years old) who suf- fer from refractory VF/pVT out-of-hospital cardiac arrest, I (Intervention) - a pharmacology intervention (esmolol), C (Comparator) - no esmolol (control), O (Outcomes) - survival to discharge and favorable neurological outcome and long- term survival and favorable neurological outcome, T (Time) - all studies from January 2000 to July 2019 were considered. Studies were not limited according to the time of follow-up. 2.2. Stage 2: Identifying Relevant Studies Databases We searched the following databases for eligible articles on July 5, 2019: MEDLINE via PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as the reference lists of all selected articles. Addi- tionally, Google Scholar was searched for any additional cita- tions. Finally, we searched for unpublished or ongoing clin- ical trials using the WHO International Clinical Trials Reg- istry (WHO ICTRP), and the ClinicalTrials.gov registry on July 12, 2019. The search was repeated one month prior to sub- mission for publication to ascertain that no new literature was published in the interim. We believed these four search databases would reach all the relevant journals within the area of interest. Overall, 2817 articles were found using the search terms and databases. Search Terms The search strategy was developed by two investigators (DM and LM), with the help of healthcare librarians. We This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2020; 8(1): e15 used the PRESS (Peer Review of Electronic Search Strate- gies) checklist to develop the research strategy (31). The search strategy was developed according to keywords re- lated to esmolol in combination with "out-of-hospital car- diac arrest" and "refractory ventricular fibrillation". Key- words used in the search were based on the imple- mented PICO model, which was first defined for use in MEDLINE via PubMed and subsequently adapted for the other databases. The example of PubMed research query was: ((("cardiopulmonary resuscitation" [Title/Abstract] OR "CPR" [Title/Abstract] OR "management" [Title/Abstract] OR "treatment" [Title/Abstract] OR "pre-hospital cardiac ar- rest"[Title/Abstract] OR "out-of-hospital cardiac arrest" [Ti- tle/Abstract] OR "emergency department" [Title/Abstract] OR "ED" [Title/Abstract])) AND (("sudden" [Title/Abstract] AND "death") [Title/Abstract] OR "refractory ventricular tachycardia" [Title/Abstract] OR "Refractory ventricular fib- rillation"[Title/Abstract] OR "RVT" [Title/Abstract] OR "RVF" [Title/Abstract] OR "pulseless ventricular tachycardia" [Ti- tle/Abstract] OR "pVT" [Title/Abstract] OR "ventricular fib- rillation" [Title/Abstract] OR "ventricular arrhythmia" [Ti- tle/Abstract] OR "heart arrest" [Title/Abstract] OR "cardiac arrest" [Title/Abstract])) AND "esmolol" [Title/Abstract] OR "beta-blockade"[Title/Abstract]. 2.3. Stage 3: Study Selection Inclusion and Exclusion Criteria We used the PCC (Population, Concept, and Context) frame- work to delineate eligibility criteria (32). Studies were eligible for inclusion if they reported on the use of esmolol as an ad- juvant therapy for patients (≥18 years old) undergoing resus- citation for refractory VF/pVT out-of-hospital cardiac arrest and included any controlled clinical study design (random- ized controlled trials and non-randomized controlled trials) and observational studies (cohort studies and case-control studies) with a control group (i.e. patients not receiving es- molol) and were published between January 2000 and July 2019. This time period was selected because a preliminary review suggested there would not be any relevant articles prior to the year 2000. Studies were excluded if they were not written in English, included in-hospital cardiac arrest, re- ported on animal studies, reported on traumatic cardiac ar- rest, reported on pediatric cardiac arrest, reported cardiac ar- rests in pregnancy, and patients had received esmolol for ar- rhythmias other than VF/pVT. The databases were searched by one author (DM). Following the search and the automatic removal of duplicates, the titles and abstracts were subse- quently appraised for eligibility by two independent authors (DM and LM). The full texts of titles and abstracts were re- viewed for studies that were considered potentially relevant. Any discrepancies regarding the selection of articles retained for full-text review were resolved by discussion with a third Figure 1: Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart. reviewer (WA). The selection process is described in Figure 1. 2.4. Stage 4: Charting the Data The charting of data is a descriptive-analytical method that is used to extract the information from individual articles (28). Excel 2019 (Microsoft, Redmond, WA) was utilized for this stage. We collected descriptive characteristics such as first author, year of publication, study period, the country where the study was held, study design, research setting, study pop- ulation, sample size, measures, interventions, key findings, and limitations. Data for all reported outcomes were ex- tracted from every study included in the review by two in- dependent reviewers (DM and LM). Discrepancies regarding the extracted data were resolved by discussion with a third re- viewer (WA). Descriptive statistics were summarized by pre- senting the median (IQR) for continuous variables and num- ber and percentage for categorical variables. Table 1 provides an overview of the articles selected for inclusion. 2.5. Stage 5: Collating, Summarizing, and Re- porting the Results A total of 7 studies were identified as relevant to the review. Two studies were noted to be directly related to the use of esmolol as an adjuvant therapy for refractory VF/pVT out- of-hospital cardiac arrest. The remaining 5 studies were ap- plicable to in-hospital cardiac arrest. These studies were ex- cluded at this level because different types of beta-blockers other than esmolol were used as adjuvant therapy. The dis- carded articles were approved by the authors before the qual- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem D. Miraglia et al. 4 Table 1: Details of characteristics and outcomes of studies included in the scoping review Author, year, country Design, setting, and participants Intervention Key results Driver et al. 2014 United States of America (24) A retrospective investigation from January 2011 to January 2014 in an urban academic ED. This study included 25 patients (≥18 years old) with out-of- hospital or ED cardiac arrest with refractory VF/pVT who were resistant to at least ≥3 defibril- lations, 3 mg of epinephrine, and 300 mg of amiodarone. Six patients received esmolol (inter- vention) in the ED during CA and were compared to those who did not (control). Patients received esmolol 500 mcg/kg bolus followed by a 0–100 mcg/kg/min maintenance infu- sion. Key outcomes of patients who re- ceived esmolol (n = 6) compared with those who did not (n = 19). The esmolol group exhibited bet- ter rates of temporary ROSC and survival to ICU admission. When comparing survival rates and sur- vival with favorable neurological outcome, the patients that re- ceived esmolol had better out- comes than those who did not. However, no statistically signifi- cant outcomes were found in sur- vival to discharge and favorable neurological outcome. Overall, 4 (66.7%) in the esmolol group vs. 6 (31.6%) in the control group had sustained ROSC and survived to ICU admission, respectively. Three (50%) vs. 3 (15.8%) sur- vived to hospital discharge and 3 (50%) vs. 2 (10.5%) survived to discharge with a CPC ≤ 2. Lee et al. 2016 South Korea (25) A retrospective single-center pre- post study that evaluated records from January 2012 to December 2015. This study included 41 pa- tients (≥18 years old) with refrac- tory VF out-of-hospital cardia ar- rest who were resistant to ≥3 de- fibrillations, 3 mg of epinephrine, 300 mg of amiodarone, and had no ROSC after >10 min of CPR). Sixteen patients received esmolol (intervention) at the ED during CA and were compared to those who did not (control). Patients received esmolol 500 mcg/kg bolus followed by a 0–100 mcg/kg/min maintenance infu- sion. Key outcomes of patients who received esmolol (n = 16) com- pared with those who did not (n = 25). Sustained ROSC was sig- nificantly more common in the esmolol group, compared to the control group (p = 0.007). The es- molol group also exhibited better rates of temporary ROSC and sur- vival to ICU admission. However, there were no significant differ- ences in the rates of survival to discharge and favorable neuro- logical outcome (p = 0.36). Over- all, 9 (56.3%) in the esmolol group vs. 4 (16%) in the control group had sustained ROSC and survived to ICU admission, respectively. Three (18.8%) vs. 2 (8%) survived to discharge and had a CPC ≤ 2 at 30, 90, and 180 days. CA = cardiac arrest; CPC = cerebral performance category; ED = emergency department; ICU = intensive care unit; pVT = pulseless ventric- ular tachycardia; ROSC = return of spontaneous circulation; VF = ventricular fibrillation; CPR = cardiopulmonary resuscitation. Notes: Neurological outcomes were evaluated using the Glasgow-Pittsburgh cerebral performance category (CPC) scale. Favorable neuro- logical outcomes were defined as a CPC score of 1–2. itative analysis was completed. Finally, a total of 2 observa- tional studies were included. Tables 2–4 summarize details of the studies according to demographics, presentation, resus- citative parameters, and outcomes. 2.6. Ongoing Consultation It is suggested that a scoping review should include the con- sultation of experts in the area of research (28). Consultation was not included in this study due to this approach being rel- atively new and esmolol being used off-label with no infor- mation available from randomized controlled trials. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2020; 8(1): e15 Table 2: Esmolol in out-of-hospital cardiac arrest patients with refractory VF/pVT Author, year, country Study design Patients, n Received es- molol, n Age,median (IQR), yr Male, n(%) Witnessed arrest n (%) Bystander CPR, n (%) Initial rhythm VF, n (%) Defibrillat- ion attempts, median (IQR) Driver et al. RO 25 6 54.5 (47–59) 6 (100) 5 (83.3) 3/4a b 5 (83.3 ) 6.5c (5–9.5) 2014 USA(24) Lee et al. RO 41 16 58 (45.8–72) 14 (87.5) 14 (87.5) 11(68.8) 14 (87.5) 6 (6–8.75) 2016 SK(25) CPR = cardiopulmonary resuscitation; RO = retrospective observational; VF = ventricular fibrillation; VT = ventricular tachycardia; USA = United States of America; SK = South Korea. Notes: Total percentages refer to studies with available data. All continuous variables are reported as median interquartile range (IQR) unless specified otherwise a Refers to the patient who arrested in the ED; one patient was awake on EMS arrival, then arrested. b Refers to mechanical CPR with LUCAS device. c Refers to implantable cardioverter-defibrillator (ICD) firings (approximately every 2-3 min) until it failed 30 min after ED arrival; does not include ICD firings for one patient. 3. Results 3.1. Study Populations and Settings The initial electronic database search yielded 2817 records. We first removed 1274 duplicates and then eliminated 1536 papers following inspection of the titles and abstracts. We read the full text of each of the 7 remaining articles. Following the inclusion criteria outlined above, 2 retrospective obser- vational studies were found relating to the research purpose totaling 66 patients, 33.3% (n = 22) of which received esmolol (24, 25). No randomized or non-randomized controlled tri- als on esmolol for refractory VF/pVT out-of-hospital cardiac arrest were identified or ongoing at the time of the search. All studies were published between 2014 and 2016, while pa- tient enrollment periods extended to as early as 2011. Both studies were conducted in a single center with percutaneous coronary intervention capability, but at different institutions. One study was performed in the US (24) and 1 in South Korea (25). Regarding demographics, all articles identified patients as having pre-hospital or ED refractory VF/pVT at some point during the cardiac arrest. The sample sizes of the patients that received esmolol ranged from 6 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 cardiopulmonary re- suscitation (CPR) and were attended by EMS providers. 3.2. Focus and Outcomes There was no substantial heterogeneity of outcome mea- surement across studies. The definition of refractory VF and a clear protocol was uniform across studies. All stud- ies compared the use of esmolol (intervention) with no es- molol (control) in adult patients with refractory VF/pVT out- of-hospital cardiac arrest. Both studies enrolled patients with pre-hospital cardiac arrest and diagnosis of VF/pVT who did not respond to at least 3 deïňĄbrillation attempts, 3 mg of epinephrine, 300 mg of amiodarone and remained in arrest upon ED arrival. All patients in the esmolol group received a loading dose of 500 mcg/kg esmolol, followed by a con- tinuous infusion of 0–100 mcg/kg/min (24, 25). All stud- ies reported on sustained return of spontaneous circulation (ROSC >20 min of spontaneous circulation without recur- rence of cardiac arrest) (33), total ED CPR time, total CPR time, survival to intensive care unit (ICU) admission, sur- vival to discharge and favorable neurological outcome. One study reported data about the predominance of acute coro- nary syndrome and emergency coronary revascularization (24). One study reported on survival and favorable neuro- logical outcomes 30 days, 3 months, and 6 months later (25). Overall, both studies found that sustained ROSC was sig- nificantly more common in patients that received esmolol compared to the control group. However, no statistically significant outcomes were found regarding survival to dis- charge and favorable neurological outcome. Neurological outcomes were evaluated using the Glasgow-Pittsburgh cere- bral performance category (CPC) scale. Good neurological outcomes were defined as a CPC score of 1–2 (34, 35). The first study was published in 2014 by driver et al. Overall, in this study 5 (83.8%) of the patients in the esmolol group had witnessed arrest and 5 (83.8%) had VF as the first doc- umented heart rhythm before receiving esmolol. Further- more, VF was successfully terminated into sustained ROSC in 4 (66.7%) patients. In addition, 83.8% received emergent car- diac catheterization and 60% of them were diagnosed as hav- ing a ST segment elevation myocardial infarction (STEMI). Ultimately, 3 (50%) of the patients included in this study had a CPC score equal to 1 or 2 on discharge. The authors reported that sustained ROSC was significantly more com- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem D. Miraglia et al. 6 mon in the esmolol group compared to the control group (66.7% vs. 31.6%). However, there were no significant differ- ences in survival rates (50% vs. 15.8%), and good neurolog- ical outcomes between the two groups (50% vs. 10.5%). All Patients in this study received conventional CPR by first re- sponders and most had automated CPR with a LUCAS device (Physio-control) and an impedance threshold device (ITD) (ResQPODTM) when they were transported to the ED (24). The second study was published in 2016 by Lee et al. Overall, in this study 14 (87.5%) of the patients in the esmolol group had witnessed arrest and 11 (68.8%) had VF as the first doc- umented heart rhythm before receiving esmolol. Further- more, VF was successfully terminated into sustained ROSC in 9 (56.3%) patients. In addition, 93.8% of the arrests had cardiac origin, but the study did not report if any of the pa- tients suffered from acute coronary syndrome or received emergent reperfusion therapy. Ultimately, 3 (18.8%) of the patients included in this study had a CPC score equal to 1 or 2 on discharge, and 30 days, 3 months and 6 months later. This study found similar results to the study described above. The authors reported that sustained ROSC was significantly more common in the esmolol group compared to the control group (56.3% vs. 16.0%, p = 0.007). However, there were no significant differences in survival rates and good neurologi- cal outcomes 30 days, 3 months and 6 months later (18.8% vs. 8%, p = 0.36) (25). 4. Discussion This scoping review sought to describe the available evidence and identify the gaps in the literature on the use of esmolol as a feasible adjuvant therapy for the treatment of refractory VF/pVT out-of-hospital cardiac arrest. Our scoping review revealed that only 2 studies have evaluated the use of esmolol as an adjuvant treatment for adult patients with refractory VF/pVT out-of-hospital cardiac arrest. Both of these stud- ies showed that sustained ROSC was significantly more com- mon in the esmolol group, compared to the control group. Survival to discharge and favorable neurological outcome were at least 2-fold better in the esmolol group, compared to the control group, although these increases were not sta- tistically significant. One study did not report data regarding 30-day, 6-month and long-term survival and favorable neu- rological outcome (24). The findings of these studies sug- gest that esmolol may considerably improve the probability of successful ROSC, but not survival, as approximately 2/3 of the patients that had sustained ROSC did not survive to discharge. A major limitation discovered in this review is the paucity of research and lack of literature to support this ther- apy. We identified these as the main important gaps in the available literature. Furthermore, our review revealed that all studies were observational in nature and conducted on a small number of patients. In addition, we did not iden- tify any studies assessing the cost-effectiveness of esmolol for pre-hospital refractory VF. We did not identify any reg- istered or ongoing clinical trials on esmolol for refractory VF out-of-hospital cardiac arrest on the International Clin- ical Trials Registry Platform. Despite these limitations, the findings from this review highlight an area of research that may contribute to improving survival of people with refrac- tory VF/pVT out-of-hospital cardiac arrest, but would need to be investigated in a more robust manner. Epinephrine has been a longstanding treatment for cardiac arrest patients; yet, the literature has not shown an increase in survival rates when it has been used in higher doses (36). During pro- longed resuscitation from cardiac arrest there is an increase in sympathetic tone, at least partially, due to the mecha- nism of epinephrine. The activation of β-adrenoreceptors by epinephrine causes up to 4-fold increase in myocardial oxygen consumption in patients with VF/pVT via its positive chronotropic and inotropic effects (37, 38). In addition, coro- nary blood flow may be reduced to up to 40%, increasing my- ocardial ischemia (37). Esmolol has shown promising results to support the effectiveness of beta-1 selective blockade in refractory VF/pVT (21, 23-26). Esmolol as an adjuvant ther- apy may be an alternative treatment for these patients since it is an ultra-short acting beta-1 selective adrenergic recep- tor blocker and a perfect sympatholytic agent, which is ex- tremely cardioselective and has a quick onset of action. It has the fastest onset (90 seconds) and the shortest half-life ([t1/2] = 9 minutes) among beta-blockers (39). Esmolol is also able to mitigate the depression of 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 refrac- tory VF. Due to its quick onset and offset, it is ideal for these patients, without having the excessive/prolonged effects of the drug during and after resuscitation (37-40). When es- molol is administered as a bolus, it is followed by a contin- uous infusion, the onset of activity occurs within 2 minutes, with 90% of b-blockade at 5 minutes (39). Generally, for car- diac arrest patients, a loading dose of 500 mcg/kg over one minute has been administered prior to a maintenance infu- sion dose of 0–100 mg/kg/min (24, 25). Esmolol, as an ad- juvant therapy for refractory VF/pVT, could be easily used in the ED and in-patient hospital settings. However, esmolol is not readily available for pre-hospital use, and, as a result, pa- tients who experience refractory out-of-hospital cardiac ar- rest are reliant on rapid transportation to the closest hospi- tals prepared to handle these types of patients. Hence, de- spite the current advances in pre-hospital care and the feasi- bility to provide quick access to perfusion/reperfusion ther- apies, the main goal of pre-hospital care for patients with refractory cardiac arrest is rapid transport to definitive care This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2020; 8(1): e15 Table 3: Esmolol in the out-of-hospital cardiac arrest patients with refractory VF/pVT Author, year, country Adrenaline, (mg), median (IQR) Amiodaron, (mg), median (IQR) Esmolol loading dose (mcg/kg) Esmolol Drip, (mcg/kg/min) Total CPR time (min), median (IQR) Temporary ROSC a , n(%) Sustained ROSC b , n(%) Survival to ICU admis- sion, n(%) Driver et al. 2014 USA (24) 6 (5–7.75) 375 (300–450) 500 0–100 63 (57–83) 4 (66.7) 4 (66.7) 4 (66.7) Lee et al. 2016 SK (25) 6 (3.3–9) 450 (300–450) 500 0–100 55 (35.3–70.3) 13 (81.3) 9 (56.3) 9 (56.3) CPR = cardiopulmonary resuscitation; ICU = intensive care unit; ROSC = return of spontaneous circulation; VF = ventricular fibrillation; VT = ventricular tachycardia; USA = United States of America; SK = South Korea. Notes: Total percentages refer to studies with available data. All continuous variables are reported as median interquartile range (IQR) unless specified otherwise. a Refers to non-fleeting spontaneous circulation lasting >30 seconds but <20 minutes. b Refers to 20 min of spontaneous circulation without cardiac arrest. Table 4: Esmolol in the out-of-hospital cardiac arrest patients with refractory VF/pVT Author, year, country Survival to dis- charge, n(%) 30-day Survival, n(%) 3 and 6 months Survival, n(%) CPC≤2 at dis- charge , n(%) CPC≤2 at 30 days, n (%) CPC≤2 at 3 and 6 months, n (%) Driver et al. 2014 USA (24) 3 (50) . . . . . . 3 (50) . . . . . . Lee et al. 2016 SK (25) 3 (18.8) 3 (18.8) 3 (18.8) 3 (18.8) 3 (18.8) 3 (18.8) CPC = cerebral performance category; ellipses (...) = data not available; VF = ventricular fibrillation; VT = ventricular tachycardia; USA = United States of America; SK = South Korea. Notes: Total percentages refer to studies with available data. while supporting patients (18-20, 41). The results of these studies are not to be generalized as these studies were per- formed at a single medical center and had a small sample size; however, these studies showed a signal of benefit and a feasible adjuvant treatment strategy for one of the most dif- ficult challenges of resuscitative medicine. 5. Limitations This study had some limitations. First, the primary limita- tion of the scoping review methodology is the lack of qual- ity assessment of the included articles. However, the goal of a scoping review is simply to identify research that has been conducted, not necessarily to assess quality (28). While the quality assessment was not a goal of the research, qual- ity should be considered before applying these findings in clinical practice. Second, the scientific evidence we used has limitations due to small sample size and the nature of single-centered, retrospective, non-randomized, observa- tional studies with their subjective potential for selection bias. Third, the studies did not report collapse time to es- molol bolus or maintenance infusion; in addition, there was a lack of follow-up in one study and as a consequence, no long-term survival or functional outcomes were reported. Fourth, all of the studies included in this review listed at least two or three limitations in the discussion section of the arti- cle, and there is a risk of bias if the authors of the included articles did not mention all the true limitations of their stud- ies. Fifth, there might be considerable differences between EMS and variations in the transport of patients. Finally, the rationale for undertaking an early scoping review is now rec- ognized in that such review has, among other things, the po- tential to influence the design of future primary studies and systematic reviews. Furthermore, we plan to conduct a sys- tematic review, which will allow us to incorporate studies that have been published after the cut-off date of our searches and thereby, ensure an up to date review on this important topic. 6. Conclusion Current research shows promising results on the use of es- molol as feasible adjuvant therapy for refractory VF/pVT out- of-hospital cardiac arrest. However, there is a paucity of re- search and a lack of literature to support this therapy. We ur- gently need studies on esmolol, to identify differences in im- portant clinical outcomes such as survival to discharge and favorable neurological outcome. As studies become available on this topic, they will help us justify its use and application in clinical practice. It is recommended to evaluate these out- comes in randomized controlled trials in order to obtain a higher level of scientific evidence. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem D. Miraglia et al. 8 7. Appendix 7.1. Perspective As mentioned above, we plan to conduct a systematic review and meta-analysis in a second research to evaluate the ef- ficacy of esmolol in patients with refractory VF/pVT out-of- hospital cardiac arrest. 7.2. Acknowledgements The authors would like to thank the library staff from the Vet- erans Affairs Caribbean Healthcare System Library Service for assistance with producing the search strategy. 7.3. Authors Contributions DM, LM and WA were responsible for the project design. DM and LM were responsible for the initial database search, data abstraction, and drafted the original manuscript. All authors reviewed, proofread, and approved the final version of the manuscript. DM takes responsibility for the paper as a whole. Authors ORCIDs Dennis Miraglia: 0000-0002-3887-3320 7.4. Funding Support The author(s) received no financial support for the research, authorship, and/or publication of this article. 7.5. Conflict of Interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 7.6. Availability of data and materials All data generated or analyzed during this study are included in this published article. 7.7. Consent for publication Not applicable. 7.8. Ethics approval and consent to participate This study uses only data that have already been published and does not need any ethical approval. References 1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 up- date: a report from the American Heart Association. Cir- culation. 2017;135(10):e146-e603. 2. Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation. 2011;123(4):e18-e209. 3. Al-Khatib S, Stevenson W, Ackerman M, Bryant W, Callans D, Curtis A, et al. AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A report of the American College of Cardi- ology/American Heart Association Task Force on Clin- ical Practice Guidelines and the Heart Rhythm Society [published online ahead of print October 30, 2017]. Heart Rhythm https://doi org/101016/j hrthm. 2017;35. 4. Link MS, Berkow LC, Kudenchuk PJ, Halperin HR, Hess EP, Moitra VK, et al. Part 7: adult advanced cardio- vascular life support: 2015 American Heart Associa- tion guidelines update for cardiopulmonary resuscita- tion and emergency cardiovascular care. Circulation. 2015;132(18_suppl_2):S444-S64. 5. Koster RW, Walker RG, Chapman FW. Recurrent ven- tricular fibrillation during advanced life support care of patients with prehospital cardiac arrest. Resuscitation. 2008;78(3):252-7. 6. Sakai T, Iwami T, Tasaki O, Kawamura T, Hayashi Y, Rinka H, et al. Incidence and outcomes of out-of-hospital car- diac arrest with shock-resistant ventricular fibrillation: data from a large population-based cohort. Resuscita- tion. 2010;81(8):956-61. 7. Lybeck AM, Moy HP, Tan DK. Double sequential defibril- lation for refractory ventricular fibrillation: a case report. Prehospital Emergency Care. 2015;19(4):554-7. 8. Ross EM, Redman TT, Harper SA, Mapp JG, Wampler DA, Miramontes DA. Dual defibrillation in out-of-hospital cardiac arrest: a retrospective cohort analysis. Resusci- tation. 2016;106:14-7. 9. Emmerson AC, Whitbread M, Fothergill RT. Double se- quential defibrillation therapy for out-of-hospital car- diac arrests: The London experience. Resuscitation. 2017;117:97-101. 10. Cheskes S, Wudwud A, Turner L, McLeod S, Summers J, Morrison LJ, et al. The impact of double sequential exter- nal defibrillation on termination of refractory ventricular fibrillation during out-of-hospital cardiac arrest. Resus- citation. 2019;139:275-81. 11. Beck LR, Ostermayer DG, Ponce JN, Srinivasan S, Wang HE. Effectiveness of prehospital dual sequential defibril- lation for refractory ventricular fibrillation and ventric- ular tachycardia cardiac arrest. Prehospital Emergency Care. 2019;23(5):597-602. 12. Kagawa E, Dote K, Kato M, Sasaki S, Nakano Y, Ka- jikawa M, et al. Should we emergently revascular- ize occluded coronaries for cardiac arrest? Rapid- response extracorporeal membrane oxygenation and intra-arrest percutaneous coronary intervention. Circu- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 9 Archives of Academic Emergency Medicine. 2020; 8(1): e15 lation. 2012;126(13):1605-13. 13. Avalli L, Maggioni E, Formica F, Redaelli G, Migliari M, Scanziani M, et al. Favourable survival of in-hospital compared to out-of-hospital refractory cardiac arrest pa- tients treated with extracorporeal membrane oxygena- tion: an Italian tertiary care centre experience. Resusci- tation. 2012;83(5):579-83. 14. Haneya A, Philipp A, Diez C, Schopka S, Bein T, Zim- mermann M, et al. A 5-year experience with cardiopul- monary resuscitation using extracorporeal life support in non-postcardiotomy patients with cardiac arrest. Resus- citation. 2012;83(11):1331-7. 15. Johnson NJ, Acker M, Hsu CH, Desai N, Vallabhajosyula P, Lazar S, et al. Extracorporeal life support as rescue strat- egy for out-of-hospital and emergency department car- diac arrest. Resuscitation. 2014;85(11):1527-32. 16. Sakamoto T, Morimura N, Nagao K, Asai Y, Yokota H, Nara S, et al. Extracorporeal cardiopulmonary resuscita- tion versus conventional cardiopulmonary resuscitation in adults with out-of-hospital cardiac arrest: a prospec- tive observational study. Resuscitation. 2014;85(6):762-8. 17. Kim SJ, Jung JS, Park JH, Park JS, Hong YS, Lee SW. An optimal transition time to extracorporeal cardiopul- monary resuscitation for predicting good neurological outcome in patients with out-of-hospital cardiac arrest: a propensity-matched study. Critical Care. 2014;18(5):535. 18. Stub D, Bernard S, Pellegrino V, Smith K, Walker T, Shel- drake J, et al. Refractory cardiac arrest treated with me- chanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation. 2015;86:88-94. 19. Yannopoulos D, Bartos JA, Raveendran G, Conterato M, Frascone RJ, Trembley A, et al. Coronary artery disease in patients with out-of-hospital refractory ventricular fibril- lation cardiac arrest. Journal of the American College of Cardiology. 2017;70(9):1109-17. 20. Yannopoulos D, Bartos JA, Martin C, Raveendran G, Missov E, Conterato M, et al. Minnesota resuscitation consortium’s advanced perfusion and reperfusion car- diac life support strategy for outâĂŘofâĂŘhospital re- fractory ventricular fibrillation. Journal of the American Heart Association. 2016;5(6):e003732. 21. Nademanee K, Taylor R, Bailey WE, Rieders DE, Kosar EM. Treating electrical storm: sympathetic blockade ver- sus advanced cardiac life support–guided therapy. Circu- lation. 2000;102(7):742-7. 22. Killingsworth CR, Wei C-C, Dell’Italia LJ, Ardell JL, Kings- ley MA, Smith WM, et al. Short-acting Κ-adrenergic antagonist esmolol given at reperfusion improves sur- vival after prolonged ventricular fibrillation. Circulation. 2004;109(20):2469-74. 23. de Oliveira FC, Feitosa-Filho GS, Ritt LEF. Use of beta- blockers for the treatment of cardiac arrest due to ven- tricular fibrillation/pulseless ventricular tachycardia: a systematic review. Resuscitation. 2012;83(6):674-83. 24. Driver BE, Debaty G, Plummer DW, Smith SW. Use of es- molol after failure of standard cardiopulmonary resusci- tation to treat patients with refractory ventricular fibril- lation. Resuscitation. 2014;85(10):1337-41. 25. Lee YH, Lee KJ, Min YH, Ahn HC, Sohn YD, Lee WW, et al. Refractory ventricular fibrillation treated with esmolol. Resuscitation. 2016;107:150-5. 26. Hwang CW, Gamble G, Marchick M, Becker TK. A case of refractory ventricular fibrillation successfully treated with low-dose esmolol. BMJ Case Reports CP. 2019;12(3):e228208. 27. Moher D, Schulz KF, Simera I, Altman DG. Guidance for developers of health research reporting guidelines. PLoS medicine. 2010;7(2). 28. Arksey H, O’Malley L. Scoping studies: towards a methodological framework. International journal of so- cial research methodology. 2005;8(1):19-32. 29. Mays N, Roberts E, Popay J. Synthesising research evi- dence. Studying the organisation and delivery of health services: Research methods. 2001;220. 30. Richards DA. The complex interventions framework. Complex interventions in health: Routledge; 2015. p. 27- 41. 31. McGowan J, Sampson M, Salzwedel DM, Cogo E, Foer- ster V, Lefebvre C. PRESS peer review of electronic search strategies: 2015 guideline statement. Journal of clinical epidemiology. 2016;75:40-6. 32. Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Annals of in- ternal medicine. 2018;169(7):467-73. 33. Jacobs I, Nadkarni V, Arrest ITFoC, Outcomes CR, PAR- TICIPANTS C, Bahr J, et al. Cardiac arrest and cardiopul- monary resuscitation outcome reports: update and sim- plification of the Utstein templates for resuscitation reg- istries: a statement for healthcare professionals from a task force of the International Liaison Committee on Re- suscitation (American Heart Association, European Re- suscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Founda- tion, Resuscitation Councils of Southern Africa). Circu- lation. 2004;110(21):3385-97. 34. Raina KD, Callaway C, Rittenberger JC, Holm MB. Neu- rological and functional status following cardiac arrest: method and tool utility. Resuscitation. 2008;79(2):249-56. 35. Rittenberger JC, Raina K, Holm MB, Kim YJ, Callaway CW. Association between Cerebral Performance Cate- gory, Modified Rankin Scale, and discharge disposition after cardiac arrest. Resuscitation. 2011;82(8):1036-40. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem D. Miraglia et al. 10 36. Hilwig RW, Kern KB, Berg RA, Sanders AB, Otto CW, Ewy GA. Catecholamines in cardiac arrest: role of al- pha agonists, beta-adrenergic blockers and high-dose epinephrine. Resuscitation. 2000;47(2):203-8. 37. Gazmuri RJ, Becker J. Cardiac resuscitation: the search for hemodynamically more effective methods. Chest. 1997;111(3):712. 38. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RlJ. Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation. 1995;92(10):3089- 93. 39. Wiest DB, Haney JS. Clinical pharmacokinetics and ther- apeutic efficacy of esmolol. Clinical pharmacokinetics. 2012;51(6):347-56. 40. Bourque D, Daoust R, Huard V, Charneux M. Κ-Blockers for the treatment of cardiac arrest from ventricular fibril- lation? Resuscitation. 2007;75(3):434-44. 41. Rubertsson S, Karlsten R. Increased cortical cerebral blood flow with LUCAS; a new device for mechanical chest compressions compared to standard external com- pressions during experimental cardiopulmonary resus- citation. Resuscitation. 2005;65(3):357-63. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Limitations Conclusion Appendix References