Double sequential external defibrillation for refractory ventricular fibrillation: The DOSE VF pilot randomized controlled trial

Journal Pre-proof DOuble Sequential External Defibrillation for Refractory Ventricular Fibrillation: The DOSE VF Pilot Randomized Controlled Trial Sheldon Cheskes, Paul Dorian, Michael Feldman, Shelley McLeod, Damon C. Scales, Ruxandra Pinto, Linda Turner, Laurie J. Morrison, Ian R. Drennan, P. Richard Verbeek

PII:

S0300-9572(20)30074-5

DOI:

https://doi.org/10.1016/j.resuscitation.2020.02.010

Reference:

RESUS 8414

To appear in:

Resuscitation

Received Date:

9 December 2019

Revised Date:

26 January 2020

Accepted Date:

12 February 2020

Please cite this article as: Cheskes S, Dorian P, Feldman M, McLeod S, Scales DC, Pinto R, Turner L, Morrison LJ, Drennan IR, Verbeek PR, DOuble Sequential External Defibrillation for Refractory Ventricular Fibrillation: The DOSE VF Pilot Randomized Controlled Trial, Resuscitation (2020), doi: https://doi.org/10.1016/j.resuscitation.2020.02.010

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

CHESKES, SHELDON

DOSE VF pilot RCT

DOuble Sequential External Defibrillation for Refractory Ventricular Fibrillation: The DOSE VF Pilot Randomized Controlled Trial Sheldon Cheskes MD1,2,3, Paul Dorian4, MD, MSc, Michael Feldman MD, PhD1,5, Shelley McLeod PhD(c), MSc2,6, Damon C. Scales MD, PhD3,5,7, Ruxandra Pinto PhD7, Linda Turner PhD1 , Laurie J. Morrison MD, MSc3,5 Ian R. Drennan PhD(c)8,9, P. Richard Verbeek MD1,5 1

Sunnybrook Centre for Prehospital Medicine, Toronto, Ontario, Canada. Department of Family and Community Medicine, Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada. 3 Li Ka Shing Knowledge Institute, St. Michaels Hospital, Toronto, Ontario, Canada. 4 St. Michaels Hospital, Toronto, Ontario, Canada. 5 Department of Medicine, Division of Emergency Medicine, University of Toronto, Toronto, Ontario, Canada. 6 Schwartz/Reisman Emergency Medicine Institute, Sinai Health System, Toronto, Ontario, Canada. 7 Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 8 Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. 9 Sunnybrook Research Institute, Toronto, Ontario, Canada.

Word Count: 3338

lP

Running Title: DOSE VF pilot RCT

re

-p

ro

of

2

Jo

ur na

Corresponding Author: Dr. Sheldon Cheskes Sunnybrook Centre for Prehospital Medicine 77 Brown’s Line, Suite 100 Toronto, ON, Canada M8W 3S2 E-mail: [email protected] Telephone: (416) 667-2200 Fax: (416) 667-9776

1

CHESKES, SHELDON

DOSE VF pilot RCT

ABSTRACT Objectives: The primary objective was to determine the feasibility and safety of a cluster randomized controlled trial (RCT) with crossover comparing vector change defibrillation (VC) or double sequential external defibrillation (DSED) to standard defibrillation for patients experiencing refractory ventricular fibrillation (VF). Secondary objectives were to assess the rates of VF termination (VFT) and return of spontaneous circulation (ROSC).

of

Methods: We conducted a pilot cluster RCT with crossover in four Canadian paramedic services

ro

including all treated adult OHCA patients who presented in VF and received a minimum of three successive defibrillation attempts. Each EMS service was randomly assigned to provide standard

-p

defibrillation, VC or DSED. Agencies crossed over to an alternate defibrillation strategy after six

re

months.

Results: 152 patients were enrolled. With respect to feasibility, 89.5% of cases received the

lP

defibrillation strategy they were randomly allocated to, and 93.1% of cases received a VC or DSED shock prior to the sixth defibrillation attempt. There were no safety concerns reported. In

ur na

the standard group, 66.6% of cases resulted in VFT, compared to 82.0% in VC and 76.3% in the DSED group. ROSC was achieved in 25.0%, 39.3% and 40.0% of standard, VC and DSED groups, respectively.

Conclusions: Our findings suggest the DOSE-VF protocol is feasible and safe. Rates of VFT and

Jo

ROSC were higher in the VC and DSED than standard defibrillation. The results of this pilot trial will allow us to inform a multicenter cluster RCT with crossover to determine if alternate defibrillation strategies for refractory VF may impact clinical outcomes. Key Words: cardiopulmonary resuscitation, heart arrest, resuscitation, defibrillation, double sequential external defibrillation, prehospital care

2

CHESKES, SHELDON

DOSE VF pilot RCT

INTRODUCTION Out-of-hospital cardiac arrest (OHCA) accounts for over 350,000 unexpected deaths each year in North America; and nearly 100,000 of these are attributed to ventricular fibrillation or pulseless ventricular tachycardia (VF/VT).1 Patients presenting in VF/VT continue to represent the subgroup of patients for whom survival remains the greatest. However, despite significant advances in resuscitation care, some patients remain in VF/VT after multiple standard

of

defibrillation attempts, termed “refractory VF/VT”.2,3 Survival to hospital discharge for patients

ro

who remain in refractory VF/VT is reported between 4.9% to 12.7%, much lower compared to survival in recurrent VF/VT which range from 21.4% to 29.3%.4-7

-p

Double sequential external defibrillation (DSED), the technique of providing rapid

re

sequential defibrillatory shocks via two defibrillators with defibrillation pads placed in two different planes (usually anterior-lateral and anterior-posterior) has been studied for decades in

lP

the electrophysiology lab for patients in both refractory atrial fibrillation and refractory VF.8-15 From an electrophysiology perspective, Ideker et al. have demonstrated that when defibrillation

ur na

fails to terminate VF, fibrillation resumes in the region of lowest voltage and current gradient in the myocardium.16 Considering the anatomical location of the left ventricle, a posterior structure, this region is furthest from the direct line between the standard anterolateral electrode pads. Vector change defibrillation (VC) (the technique of switching defibrillation pads from anterior-

Jo

lateral to anterior-posterior after failed defibrillation attempts) may result in a higher voltage gradient in the posterior part of the ventricle, where fibrillation is most likely to restart or fail to terminate after standard pad positions. With DSED, there is the additional influence of increased voltage and energy delivered by the second shock. Immediately after initial unsuccessful defibrillation, the instantaneous wave fronts are not the same as they were during VF and may be

3

CHESKES, SHELDON

DOSE VF pilot RCT

more vulnerable to successful defibrillation than if the first “conditioning shock” had not occurred. Therefore, it is important to evaluate both VC defibrillation and DSED strategies separately to determine if either, or both, are superior to standard care. In the prehospital setting, VC and DSED, have been described in case reports, case series, and observational studies. These reports have generally employed DSED as a “last-resort” therapeutic option for patients who remain in refractory VF.17-28 As such, the results of these

of

studies may have been confounded by the late application of a defibrillation strategy in a subset

ro

of patients for whom a positive outcome is unlikely. A recently published study suggested that early application of DSED (shocks 4-8 of the resuscitation) may be associated with improved VF

-p

termination and return of spontaneous circulation (ROSC) when compared to standard

re

defibrillation.29 To date, no high quality evidence in the form of a randomized controlled trial (RCT) exists to dispute or support the efficacy of VC or DSED compared to standard

lP

defibrillation for refractory VF.

The goal of this pilot study was to examine trial logistics such as recruitment, intervention

ur na

delivery and adherence, with the aim of enhancing the efficiency and internal validity of the main trial.30,31 The primary objective of the DOSE VF internal pilot RCT was to determine the feasibility and safety for a full-scale RCT of alternative defibrillation strategies in refractory VF. Secondary objectives were to evaluate the effect of the interventions on the outcomes of VF

Jo

termination and ROSC.

4

CHESKES, SHELDON

DOSE VF pilot RCT

METHODS Setting and Design This three-arm, pilot cluster RCT with crossover was conducted in four paramedic services located in Ontario, Canada from March 8, 2018 to September 9, 2019. The services (Peel Regional Paramedic Service, Halton Region Paramedic Service, Simcoe Paramedic Service and Toronto Paramedic Service) provide emergency care and transport to a population of 4.8 million

of

people in both urban and rural settings within a geographic area of 7,680 km2. Paramedics in

ro

these regions treat over 4,000 OHCA per year. Prehospital medical care is provided by advanced care paramedics (full advanced life support skills) and primary care paramedics (basic life

-p

support skills with the addition of a small number of medications and manual defibrillation). As

re

part of the cluster randomization strategy, each of two treatment strategies (VC and DSED) were compared against a common control group (standard defibrillation). This approach was chosen to

lP

maximize efficiency, allowing comparison of two new treatments to standard care in a single three-armed randomized trial.32, 33 The clusters were defined by the paramedic service in each of

ur na

the four regions with each cluster crossing over at least once during the pilot study to receive one of three treatment approaches (standard care, VC or DSED) for six months followed by a different treatment approach. Depending on the start of enrollment in each service, crossover could occur more than once in a particular service, but a minimum of one crossover for each

Jo

service had to occur during the pilot study. Computer-generated random assignment of treatment sequence was performed by the coordinating center prior to the start of the study. Agencies were informed of their randomization assignment one month prior to trial launch or crossover, to allow time for appropriate preparations to start the trial or crossover to another defibrillation strategy. The DOSE VF pilot RCT protocol was approved by the Sunnybrook Health Sciences Centre

5

CHESKES, SHELDON

DOSE VF pilot RCT

Research Ethics Board and registered with clinicaltrials.gov (NCT03249948). The study was conducted under waiver of informed consent. All adult (≥ 18 years) patients remaining in refractory VF during non-traumatic OHCA of presumed cardiac etiology were eligible for study inclusion. Patients suffering a traumatic cardiac arrest, patients with pre-existing do not resuscitate medical directives, and those suffering cardiac arrest secondary to drowning, hypothermia, hanging or suspected drug overdose were excluded.

of

Patients presenting in pulseless VT were also excluded.

ro

Study Protocol

All paramedics followed a provincial protocol (consistent with American Heart

-p

Association guidelines) for treatment of patients in VF.34 Cardiopulmonary resuscitation (CPR)

re

was performed prior to defibrillator pad application. Each rhythm analysis occurred at standard two-minute intervals. VF was determined by paramedic manual defibrillator rhythm analysis,

lP

after which defibrillation was provided. For all patients, the first three defibrillation attempts occurred with defibrillation pads placed in the anterior-lateral position (standard defibrillation).

ur na

Eligible patients remaining in VF after three consecutive shocks (following two minute CPR intervals) delivered by paramedics (defibrillation shocks provided by bystander and/or fire services prior to paramedic arrival were not counted), received one of three defibrillation strategies:

Jo

Strategy 1 (Standard Defibrillation): All subsequent defibrillation attempts occurred with the defibrillation pads placed in an anterior-lateral configuration. Strategy 2 (VC Defibrillation): All subsequent shocks were delivered using anterior-posterior pad placement. Transfer of pads to the anterior-posterior position from the initial standard

6

CHESKES, SHELDON

DOSE VF pilot RCT

anterior-lateral configuration occurred as soon as possible during the two-minute cycle of CPR following the third defibrillation attempt with minimal interruptions in CPR. Strategy 3 (DSED): Paramedics applied a second set of defibrillation pads after the first three shocks (via a second EMS or fire defibrillator) in the anterior-posterior position. Application of defibrillation pads for the second defibrillator occurred as soon as possible during the two-minute cycle of CPR following the third shock with minimal interruptions in CPR. All subsequent

of

defibrillation attempts were carried out using sequential defibrillation shocks provided by two

ro

defibrillators. To ensure shocks were not applied at the exact same moment, we employed a short delay to provision of the second defibrillator shock through a single paramedic pressing the

-p

“shock button” on each defibrillator in rapid sequence as opposed to simultaneously to avoid

re

possible defibrillator damage previously reported with simultaneous DSED.35 Dispatch deployment strategies ensured two defibrillators were available as frequently as possible for all

lP

cardiac arrests when paramedic services were randomized to the DSED arm of the study. The paramedic services of the City of Toronto, Regions of Peel and Halton employed Zoll X

ur na

series defibrillators (Zoll Medical Chelmsford, Massachusetts) during the study. County of Simcoe paramedic services employed Lifepak15 defibrillators (Stryker Corporation, Seattle, Washington) during the study. Energy provided by Zoll defibrillators was 120J, 150 and 200 J for shocks 1-3 respectively. Energy provided by Lifepack 15 defibrillators was 200, 300, 360 joules

Jo

for shocks 1-3 respectively. All vector change shocks or DSED shocks were provided at 200 joules for Zoll defibrillators and 360 joules for Lifepack defibrillators. All anterior-lateral and anterior-posterior pad positions were as per manufacturer specifications.

7

CHESKES, SHELDON

DOSE VF pilot RCT

Paramedic Training and Oversight In conjunction with the paramedic services, Sunnybrook Centre for Prehospital Medicine provided training to over 2,500 paramedics in the four participating services. Prior to the launch of the trial, paramedics received standardized in-person training in the techniques of VC and DSED defibrillation using a combination of didactic (one hour), video and simulated scenarios (two hours). During the trial, each medical director provided continuous feedback regarding

of

study protocol performance and compliance. Monthly study updates were provided by the

ro

investigators to all participating services on paramedic study performance. Measurement and Study Definitions

-p

For the purpose of our study, refractory VF was defined as patients who presented in VF,

re

had three successive standard defibrillation attempts and remained in VF at the time of the fourth rhythm analysis. VF termination was defined as the absence of VF at the subsequent rhythm

lP

check following defibrillation and two minutes of CPR.

Using a computerized structured data abstraction form, trained research personnel

ur na

reviewed the ambulance call reports (ACR) and extracted patient data. ACRs were reviewed to collect data on Utstein variables, event characteristics and treatment received. CPR quality and defibrillation data were abstracted from the compression acceleration signal and impedance channel measurements recorded by the defibrillator. Data for all defibrillations during each

Jo

resuscitation were abstracted up to the point of first ROSC or transfer of care at the receiving emergency department. ROSC was defined as the restoration of an organized rhythm noted on the defibrillator files with a corresponding documentation of ROSC or a blood pressure noted on the paramedic ambulance call report.

8

CHESKES, SHELDON

DOSE VF pilot RCT

Feasibility Targets and Outcomes Avery et al.,31 has outlined the potential advantages of internal pilot study data, which include piloting key study logistics such as recruitment, intervention delivery and adherence. The authors suggest the pilot phase may form the first part of the main trial and the outcome data generated may contribute to the final analyses. For internal pilot studies, it is recommended that

of

prespecified ‘progression’ or ‘decision’ criteria are used to indicate whether targets have been

ro

met during the internal pilot phase and the main trial should proceed.31

We a-priori defined our first feasibility target as the successful delivery of the allocated

-p

intervention in 80% of eligible patients. We believed this would account for the pragmatic reality

re

that a second defibrillator (for DSED) would not always be guaranteed during each resuscitation. Our second feasibility target was for 80% of enrolled patients to receive an intervention shock

lP

(VC or DSED) prior to the sixth shock, consistent with our previously published work suggesting improved rates of VF termination and ROSC with earlier as opposed to later DSED.29

ur na

We did not pre-specify a patient recruitment target, but rather estimated monthly trial recruitment for each paramedic service. Based on historic rates of refractory VF seen in our previous research29 we estimated a minimum of 110 patients would be enrolled in the pilot trial. To account for differences in the start date of each service, enrollment was continued beyond our

Jo

initial calculation to ensure each service underwent a minimum of one crossover while spending a minimum of three months in a second arm of the study (minimum time of 9 months in the pilot) to maximize information related to study feasibility and enrollment rate. With respect to safety, we assessed ACR and service reports for any mention of defibrillator damage following DSED, as well as complaints of chest burns and concerns from

9

CHESKES, SHELDON

DOSE VF pilot RCT

paramedics, emergency department staff, patients or their families. Lastly, regarding obtainment of outcome data, we evaluated the effect of standard defibrillation, VC and DSED on the outcomes of VF termination and ROSC to help inform the sample size of the main RCT. The unit of analysis for the feasibility comparisons was the individual patient. All patients were analyzed according to randomized treatment assignment (intention-to-treat analysis); while analyses were also performed according to the treatment received by each patient, the treatment

of

received by all correctly randomized patients and the treatment received by all correctly

ro

randomized patients who received optimal VC or DSED shock timing (shock 4). Descriptive statistics were summarized using means and standard deviations (SD), medians with interquartile

-p

range (IQR), where appropriate.

re

RESULTS

During the study period, 152 patients were enrolled. Table 1 describes the demographic

lP

characteristics of the study population by intervention allocation. The three arms of the trial were well matched with respect to Utstein variables, with high rates of bystander witnessed and

ur na

bystander CPR. Table 2 displays the resuscitation characteristics and treatment provided by intervention allocation. The three intervention arms were similar with respect to system response times and treatment characteristics, however there was a slightly lower rate of intubation in the standard arm. CPR quality provided by paramedics during the resuscitation was compliant with

Jo

the current guidelines.36,37 The number of shocks provided was greatest in the standard arm and lowest in the DSED arm of the trial, while time to first ROSC was similar in all three arms. With regards to feasibility, 89.5% patients received the defibrillation strategy they were

randomized, demonstrating good compliance overall. Specifically, for those randomized to VC

10

CHESKES, SHELDON

DOSE VF pilot RCT

and DSED, 89.1% and 83.6% respectively received the defibrillation strategy they were allocated to. All cases randomized to standard defibrillation received there allocated therapy. In total, 93.1 % of patients received an intervention shock prior to the sixth defibrillation attempt (Figure 1). Of note, 77% of patients received an intervention shock at shock 4, which was the earliest time an intervention shock could have been provided according to the study protocol. Five patients received an intervention shock prior to defibrillation attempt 4 due to inadvertent

of

inclusion of prior shocks from a fire service. These patients remained in the primary analysis

ro

according to the intention to treat principle.

Overall, 12.6 patients were enrolled per month in the pilot study (Figure 2). With regards

-p

to safety, there were no reported cases of defibrillator malfunction, skin burns, difficulty with pad

re

placement or concerns expressed by paramedics, patients, families, or emergency department staff about the trial.

lP

In the standard defibrillation group, there was VF termination in 66.6% of cases, compared to 82.0% in the VC group and 76.3% in the DSED group (Figure 3). ROSC was

ur na

achieved in 25.0%, 39.3% and 40.0% of standard, VC and DSED groups, respectively. The rate of ROSC at ED arrival was higher in the VC (24.6%) and DSED (32.7%) groups, compared to the standard defibrillation group (19.4%). VF was terminated at the 4th standard shock or first intervention shock in 22.2% of standard cases, 37.7% of VC cases, and 34.5% of DSED cases.

Jo

Similar results were noted in the per treatment analysis, per randomization analysis and per randomization with optimal intervention shock analysis, as depicted in Supplementary Figures 13.

11

CHESKES, SHELDON

DOSE VF pilot RCT

DISCUSSION We conducted the first pilot RCT assessing the feasibility and impact of the alternative defibrillation strategies of VC and DSED compared to standard defibrillation for the treatment of refractory VF. We have described our findings in a manner consistent with the CONSORT 2010 extension to randomised pilot and feasibility trials.38 With respect to protocol adherence, our results suggest the DOSE-VF protocol is feasible and can be appropriately applied in a “real

of

world” environment. 89.5% of patients received the allocated defibrillation strategy according to

ro

the randomization schedule. The most common cause for VC randomized patients to receive standard care was VF termination after the fourth standard shock while paramedics prepared to

-p

perform a VC defibrillation. For DSED randomized patients, an inability to have a second

re

defibrillator available was the most common cause for protocol non-compliance. Our inability to achieve perfect compliance with the protocol reflects the reality in which paramedics practice.

lP

Although there were situations when a second defibrillator was not available and times when paramedics were not able to provide an intervention defibrillation at the earliest time (shock 4), it

ur na

is remarkable that 77% of patients received an intervention shock at the fourth defibrillation attempt, with a further 12% of patients receiving an intervention defibrillation one shock later. There were no reported cases of defibrillator malfunction, skin burns, difficulty with pad placement or concerns expressed by paramedics, patients, families, or emergency department

Jo

staff about the trial. The pilot feasibility was stopped on September 9, 2019 as all feasibility objectives were met. In our intention to treat analysis, as well as three supplementary analyses, both VC

defibrillation and DSED appeared to improve VF termination and ROSC compared to standard defibrillation for refractory VF. Our findings contrast with previous observational studies18,19,25,26

12

CHESKES, SHELDON

DOSE VF pilot RCT

which suggest that DSED is inferior to standard defibrillation for refractory VF, yet they are consistent with our previously published research suggesting earlier DSED may be superior to standard defibrillation in this cohort of patients.29 It is important to note that our current pilot RCT was performed in a manner that differed from previous research in this area. We employed cluster crossover randomization in multiple paramedic services in both rural and urban communities and achieved consistent results in all analyses performed. We controlled for timing

of

of intervention shocks while maintaining high quality CPR, two metrics which are rarely

feedback ensured high compliance with the study protocol.

ro

described in previous studies. As well, our high level of medical oversight and paramedic

-p

Our three arm approach to the study of alternative strategies to defibrillation in refractory

re

VF was meant to provide insight into the still widely debated topic of whether energy or vector play a predominant role in the potential benefit of DSED.8,9,10,12,16,27 Our preliminary data

lP

suggests the vector or plane of defibrillation may have a role in terminating VF when a previous vector is unsuccessful. This finding may have significant therapeutic implications for the future

ur na

treatment of refractory VF, particularly in rural communities where the availability of two defibrillators to perform DSED may be limited. One of the benefits of our internal pilot design is the opportunity to make minor

operational modifications to the main trial based on information gleaned from the pilot work.31

Jo

During the course of the pilot study, it became apparent that minor modifications may strengthen the conduct of the main RCT. The most critical of these modifications involves the inclusion of fire department first responder shocks in cases randomized to VC defibrillation and DSED. The pilot trial protocol did not include these shocks which were provided in 28% of enrolled cases, which resulted in later “intervention shocks” delivered to the patient. The exclusion of fire shocks

13

CHESKES, SHELDON

DOSE VF pilot RCT

may have underestimated the potential benefit of VC and DSED to improve VF termination and ROSC. The main DOSE VF RCT (clinicaltrials.gov NCT04080986) was subsequently launched following minor modifications gleaned from the pilot RCT and the recommendations of the Data and Safety Monitoring Board. Our pilot study is not without limitations. Enrollment in the standard arm was lower than either intervention arm due to cluster randomization, with the largest enrolling site not being

of

randomized to standard care during the pilot study. Ideally, cluster randomization should balance

ro

all three arms as each agency spends the same amount of time in each arm of the study. However, this was an internal pilot study designed to achieve feasibility objectives, not a desired sample

-p

size with equal numbers of patients in all arms of the trial. It is worth noting the ROSC rate in the

re

standard arm of our pilot study is consistent with our historic findings in this cohort of patients.29 Although the study included both urban and rural settings, the majority of patients were enrolled

lP

in the urban setting where a second defibrillator is more often available. Finally, our study took place with a high degree of medical oversight and paramedic feedback, which may not be

ur na

possible in all EMS services. CONCLUSIONS

Findings from our pilot RCT suggest the DOSE VF protocol is feasible and safe. Rates of VFT and ROSC were higher in the VC and DSED than standard defibrillation. The results of this

Jo

pilot trial will allow us to inform a multicenter cluster RCT with crossover to determine if alternate defibrillation strategies for refractory VF may impact patient-centered, clinical outcomes.

Conflict of Interest Statement

14

CHESKES, SHELDON

DOSE VF pilot RCT

Dr. Cheskes has received speaking honorarium for educational events on CPR quality from Zoll Medical and Stryker Corporation. Dr. Cheskes has received grant funding from the Laerdal Foundation for the DOSE VF pilot RCT. Dr. Cheskes has received grant funding from HSF Canada for the DOSE VF RCT. Dr. Cheskes has received grant funding from Zoll Medical for AED on the Fly, Community Responder Program for Peel Region and Monitoring Ventilation during OHCA research studies. Dr. Cheskes sits on the Advisory Board of Drone Delivery

of

Canada. Dr. Morrison is the Robert and Dorothy Pitts Chair in Acute Care and Emergency

ro

Medicine funded by St Michael’s Foundation and the University of Toronto for which she

-p

receives salary support. No other authors have any conflicts of interest to declare.

re

Acknowledgements

We would like to acknowledge the hard work and dedication of all paramedics in the Regions of

lP

Peel, Halton, Simcoe and the City of Toronto, Ontario, Canada during the DOSE VF pilot RCT.

Jo

ur na

Research in the prehospital setting would not be possible without their tireless efforts.

15

CHESKES, SHELDON

DOSE VF pilot RCT

REFERENCES

1.

Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update. Circulation. 2014;129:e28–e292.

2.

Slovis CM, Wrenn KD. The technique of reversing ventricular fibrillation: improve the odds of success with this five-phase approach. J Crit Illn. 1994 Sep;9(9):873–89. Weaver WD, Cobb LA, Copass MK, Hallstrom AP. Ventricular defibrillation: a

of

3.

comparative trial using 175-J and 320-J shocks. N Engl J Med 1982;307:1101-6.

Yannopoulos D, Bartos JA, Martin C, Raveendran G, Missov E, Conterato M, et al.

ro

4.

-p

Minnesota resuscitation consortium’s advanced perfusion and reperfusion cardiac life support strategy for out-of-hospital refractory ventricular fibrillation. J Am Heart Assoc

Holmén J, Hollenberg J, Claesson, A, et al. Survival in ventricular fibrillation with

lP

5.

re

2016;5.

emphasis on the number of defibrillations in relation to other factors at resuscitation. Resuscitation. 2017;113: 33-38.

Sakai T, Iwami T, Tasaki O, et al. Incidence and outcomes of out-of-hospital cardiac arrest

ur na

6.

with shock-resistant ventricular fibrillation: data from a large population-based cohort. Resuscitation. 2010 Aug;81(8):956–6. Van Alem AP, Post J, Koster RW, VF Recurrence: Characteristics and Patient Outcome

Jo

7.

in Out-of-Hospital Cardiac Arrest. Resuscitation 2003;59:181-188.

8.

Hoch DH, Batsford WP, Greenberg SM, et al. Double sequential external shocks for refractory ventricular fibrillation. Am Coll Cardiol 1994:23:1141-5.

16

CHESKES, SHELDON 9.

DOSE VF pilot RCT

Marrouche NF, Bardy GH, Frielitz HJ, Gunther J, Brachmann J. Quadruple pads approach for external cardioversion of atrial fibrillation. Pacing Clin Electrophysiol. 2001;24:1321–1324.

10.

Jones DL, Klein GJ, Guiraudon, Sharma AD. Sequential pulse defibrillation in humans: orthogonal sequential pulse defibrillation with epicardial electrodes. J Am Coll Cardiol 1988;11:590-596. Kerber RE, Martins B, Kienzle MG, et al. Energy, current, and success in defibrillation

of

11.

ro

and cardioversion: clinical studies using an automated impedance-based method of energy adjustment. Circulation 1988;77:1038-46.

Chang MS, Inouye H, Kallok MJ, Zipes DP. Double and Triple Sequential Shocks reduce

-p

12.

Coll Cardiol 1986;8:1393-1405.

Pagan-Carlo LA, Allan JJ, Spencer KT, Birkett CL, Myers R, Kerber RE. Encircling

lP

13.

re

ventricular fibrillation threshold in pigs with and without myocardial infarction. J Am

overlapping multipulse shock waveforms for transthoracic defibrillation. J Am Coll

14.

ur na

Cardiol 1998;32(7):2065-71.

Alaeddini J, Feng Z, Feghali G, Dufrene S, Davison NH, Abi-Samra FM. Repeated dual external direct cardioversions using two simultaneous 360-J shocks for refractory atrial fibrillation are safe and effective. Pacing Clin Electrophysiol. 2005;28:3–7. Gerstein NS, Shah MB, Jorgensen KM. Simultaneous use of two defibrillators for the

Jo

15.

conversion of refractory ventricular fibrillation. Cardiothorac Vasc Anesth 2015;29:4214.

17

CHESKES, SHELDON 16.

DOSE VF pilot RCT

Ideker RE, Wolf PD, Alferness, C, Krassowska W, Smith WM. Current Concepts for Selecting the Location, Size and Shape of Defibrillation Electrodes. PACE 1991;14:227240.

17.

Cabanas JG, Myers J, Williams G, De Maio V, Bachman MW. Double sequential external defibrillation in out-of-hospital refractory ventricular fibrillation: a report of ten cases. Prehosp Emerg Care 2015;19:126-30. Ross EM, Redman TT, Harper SA, Mapp JG, Wampler DA, Miramontes DA. Dual

of

18.

ro

defibrillation in out-of-hospital cardiac arrest: A retrospective cohort analysis. Resuscitation 2016;106:14-17.

Beck LR, Ostermayer DG, Ponce JN, Srinivasan S,Wang HE. Effectiveness of

-p

19.

re

Prehospital Dual Sequential Defibrillation for Refractory Ventricular Fibrillation and Ventricular Tachycardia Cardiac Arrest. Prehospital Emergency Care. DOI:

20.

lP

10.1080/10903127.2019.1584256

Johnston M, Cheskes S, Ross G, Verbeek PR. Double sequential external defibrillation

ur na

and survival from out-of-hospital cardiac arrest: a case report. Prehosp Emerg Care 2016:1-5.

21.

Lybeck AM, Moy HP, Tan DK. Double sequential defibrillation for refractory ventricular

fibrillation: A case report. Prehosp Emerg Care 2015;19:554-7. Leacock BW. Double simultaneous defibrillators for refractory ventricular fibrillation.

Jo

22.

Emerg Med 2014;46:472-4.

23.

Cortez E, Krebs W, Davis J, Keseg DP, Panchal AR. Use of double sequential external defibrillation for refractory ventricular fibrillation during out-of-hospital cardiac arrest. Resuscitation 2016;108:82-86.

18

CHESKES, SHELDON 24.

DOSE VF pilot RCT

Emmerson AC, Whitbread M, Fothergill RT. Double sequential defibrillation therapy for out-of-hospital cardiac arrests: The London experience. Resuscitation 2017;117:97-101.

25.

Delorenzo A, Nehme Z, Yates J, Bernard S, Smith K. Double sequential external defibrillation for refractory ventricular fibrillation out-of-hospital cardiac arrest: A systematic review and meta-analysis. Resuscitation 2019;135:124-129.

26.

Mapp JG, Hans AJ, Darrington AM, Ross EM, Ho CC, Miramontes DA, Harper SA,

of

Wampler DA. Prehospital Double Sequential Defibrillation: A Matched Case–Control

27.

ro

Study. Academic Emergency Medicine. https://doi.org/10.1111/acem.13672

Pourmand A, Galvis, BS, Yamane D. The controversial role of dual sequential

-p

defibrillation in shockable cardiac arrest. Am J Emerg Med

28.

re

https://doi.org/10.1016/j.ajem.2018.05.078.

Davis M, Schappert A, Van Aarsen K, Loosley J, McLeod SL, Cheskes S. A descriptive

lP

analysis of defibrillation vector change for prehospital refractory ventricular fibrillation. CJEM. 2018;20(S1):S67.

Cheskes S, Wudwud A, Turner L, McLeod S, Summers J, Morrison LJ , Verbeek PR. The

ur na

29.

impact of double sequential external defibrillation on termination of refractory ventricular fibrillation during out-of-hospital cardiac arrest. Resuscitation 2019;139:275-271.

30.

Kistin C, Silverstein M. Pilot studies: a critical but potentially misused

Jo

component of interventional research. JAMA 2015;314:1561–2.

31.

Avery KNL, Williamson PR, Gamble C, et al. Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot

studies. BMJ Open 2017;7:e013537. doi:10.1136/bmjopen-2016-013537.

19

CHESKES, SHELDON 32.

DOSE VF pilot RCT

Parmar MK, Carpenter J, Sydes MR. More multi-arm randomised trials of superiority are needed. Lancet 2014; 384(9940):283-284.

33.

Freidlin B, Korn EL, Gray R, Martin A. Multi-arm clinical trials of new agents: some design considerations. Clin Cancer Res. 2008;14(14):4368-71.

34.

Advanced Life Support Patient Care Standards. Emergency Health Regulatory and

http://www.ontariobasehospitalgroup.ca/Educational-

35.

ro

Resources/Downloads_GetFile.aspx?id=17205.

of

Accountability Branch Ministry of Health and Long-Term Care. May 2018.

Gerstein NS, McLean R, Stecker EC, Schulman PM. External Defibrillator Damage

-p

Associated With Attempted Synchronized Dual-Dose Cardioversion. Annals of EM.

36.

re

2018;71:109-112.

Hazinski MF, Nolan JP, Aickin R, Bhanji F, Billi JE, Callaway CW, et al. Part 1: execu-

lP

tive summary: 2015 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation

37.

ur na

2015;132(Suppl. (1)):S2–39.

Nadkarni VM, Nolan JP, Billi JE, Bossaert L, Bottinger BW, Chamerlain D, et al. Part2: international collaboration in resuscitation science: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care and science with

Jo

treatment recommendations. Circulation 2010;122:S276–82.

38.

Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L et al. and on behalf of the PAFS consensus group. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. Pilot and Feasibility Studies (2016) 2:64 DOI 10.1186/s40814-016-0105-8

20

DOSE VF pilot RCT

Jo

ur na

lP

re

-p

ro

of

CHESKES, SHELDON

21

CHESKES, SHELDON

DOSE VF pilot RCT

-p

ro

of

Figure 1. Feasibility objective of percent of patients receiving an intervention shock prior to the sixth defibrillation attempt.

Jo

ur na

lP

re

Figure 2. Monthly enrollment per site during the study period.

22

of

CHESKES, SHELDON DOSE VF pilot RCT Figure 3. Flow chart of enrolled patients (intention to treat analysis).

ro

Assessed for eligibility n=152

-p

Excluded n=0

re

Patients enrolled n=152

Allocated to vector change n=61 (40.1%) Received vector change n=51 Received standard n=10 (VF termination prior to AP pad placement) Received DSED n=0

Allocated to DSED n=55 (36.2%) Received DSED n=49 Received standard n=6 (No second defibrillator available) Received vector change n=0

Lost to follow-up n=0 Discontinued intervention n=0

Lost to follow-up n=0 Discontinued intervention n=0

Lost to follow-up n=0 Discontinued intervention n=0

VF termination n=24 (66.6%) ROSC at any time n=9 (25.0%) ROSC at ED arrival n=7 (19.4%)

VF termination n=50 (82.0%) ROSC at any time n=24 (39.3%) ROSC at ED arrival n=15 (24.6%)

VF termination n=42 (76.3%) ROSC at any time n=22 (40.0%) ROSC at ED arrival n=18 (32.7%)

Jo

ur na

lP

Allocated to standard n=36 (23.7%) Received standard n=52 Received vector change n=0 Received DSED n=0

23

CHESKES, SHELDON

DOSE VF pilot RCT

Table 1. Demographic characteristics of included population. Standard (n=36)

Vector Change (n=61)

DSED (n=55)

Mean (SD) age

64.4 (14.9)

63.6 (13.0)

64.4 (14.4)

Male

28 (77.8%)

56 (91.8%)

49 (89.1%)

Bystander witnessed

23 (63.9%)

44 (72.1%)

38 (69.1%)

Bystander CPR

21 (58.3%)

32 (52.5%)

33 (60.0%)

Public Location

12 (33.3%)

21 (34.4%)

18 (32.7%)

Median (IQR) Response Time (minutes)⃰

7.5 (4.0)

7.2 (3.3)

7.6 (3.5)

ro

of

Variable

Jo

ur na

lP

re

-p

Where: DSED = double sequential external defibrillation, SD = standard deviation; IQR = interquartile range; CPR = cardiopulmonary resuscitation. ⃰ 911 call to arrive scene (excludes fire first response)

24

CHESKES, SHELDON

DOSE VF pilot RCT

Standard (n=36)

Vector Change (n=61)

DSED (n=55)

Median (IQR) time from initial call to first shock

11.1 (6.2)

11.0 (4.4)

10.7 (4.2)

Prehospital intubation

14 (38.9%)

35 (57.4%)

30 (54.5%)

5.2 (6.7)

4.8 (5.9)

5.8 (6.5)

4.0 (1.1)

4.4 (4.2)

111.3 (6.8)

112.6 (7.7)

112.4 (7.2)

6.1 (1.2)

5.9 (1.1)

5.7 (1.0)

83.0 (6.2)

81.5 (6.0)

ro

re

80.4 (10.4)

6.8 (2.1) NA

4.3 (2.3)

NA

NA

3.3 (2.7)

NA

lP

Median (IQR) preshock pause (seconds) Median (IQR) postshock pause (seconds) Mean (SD) compression rate Mean (SD) compression depth Mean (SD) chest compression fraction Mean (SD) number of standard shocks Mean (SD) number of vector change shocks Mean (SD) number of DSED shocks

of

Variable

-p

Table 2. Event characteristics.

NA

NA

2.8 (2.2)

29 (80.6%)

45 (73.8%)

42 (76.4%)

Mean (SD) Amiodarone dose (mg)

413.8 (65.3)

403.3 (77.2)

385.7 (75.1)

Epinephrine given

34 (94.4%)

60 (98.4%)

49 (89.1%)

ur na

Amiodarone given

Jo

Mean (SD) 4.2 (2.0) 4.4 (2.0) 4.1 (3.0) Epinephrine dose (mg) Median (IQR) time to 15.0 (11.0) 13.5 (7.0) 15.0 (11.3) first ROSC Mean (SD) number of 5.6 (1.6) 5.1 (2.1) 5.9 (2.2) shocks to first ROSC DSED = Double sequential external defibrillation; IQR = interquartile range; SD = standard deviation; ROSC = return of spontaneous circulation.

25