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More than 50 years have passed since the first descriptionof successful transthoracic defibrillation for the treat-ment of ventricular fibrillation (VF), and it has been >40 years

since defibrillators were first introduced into the prehospital

setting in the United States and United Kingdom.14However,

despite decades of experience and >500 000 cardiac arrests

annually in the United States and Europe, the optimal strategy

for the initial management of VF has yet to be defined.5,6

Clinical Perspective on p 1002

Immediate defibrillation had long been considered the

standard treatment for VF.7 In 2002, Weisfeldt and Becker8

suggested a 3-phase model for VF that included an electrical,

a circulatory, and a metabolic phase, with immediate defibril-

lation being the optimal treatment for only the first phase in

which the interval from the onset of VF to the time of defi-

brillation is of short duration. At about the same time, initial

studies were published that described the use of delayed defi-

brillation or a period of cardiopulmonary resuscitation (CPR)

before the initial defibrillatory shock as a means to improvesurvival for VF of longer duration.9,10

This concept of delayed defibrillation was included in

the 2005 resuscitation guidelines as a treatment option to

be considered in adults with out-of hospital ventricular

BackgroundVentricular fibrillation (VF) waveform properties have been shown to predict defibrillation success and

outcomes among patients treated with immediate defibrillation. We postulated that a waveform analysis algorithm

could be used to identify VF unlikely to respond to immediate defibrillation, allowing selective initial treatment with

cardiopulmonary resuscitation in an effort to improve overall survival.

Methods and ResultsIn a multicenter, double-blind, randomized study, out-of-hospital cardiac arrest patients in 2 urban

emergency medical services systems were treated with automated external defibrillators using either a VF waveformanalysis algorithm or the standard shock-first protocol. The VF waveform analysis used a predefined threshold value

below which return of spontaneous circulation (ROSC) was unlikely with immediate defibrillation, allowing selective

treatment with a 2-minute interval of cardiopulmonary resuscitation before initial defibrillation. The primary end point

was survival to hospital discharge. Secondary end points included ROSC, sustained ROSC, and survival to hospital

admission. Of 6738 patients enrolled, 987 patients with VF of primary cardiac origin were included in the primary

analysis. No immediate or long-term survival benefit was noted for either treatment algorithm (ROSC, 42.5% versus

41.2%, P=0.70; sustained ROSC, 32.4% versus 33.4%, P=0.79; survival to admission, 34.1% versus 36.4%, P=0.46;

survival to hospital discharge, 15.6% versus 17.2%, P=0.55, respectively).

ConclusionsUse of a waveform analysis algorithm to guide the initial treatment of out-of-hospital cardiac arrest patients

presenting in VF did not improve overall survival compared with a standard shock-first protocol. Further study is

recommended to examine the role of waveform analysis for the guided management of VF.

Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00535106.(Circulation. 2013;128:995-1002.)

Key Words: atrial fibrillation cardiopulmonary resuscitation defibrillation, electric resuscitation

2013 American Heart Association, Inc.Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.113.003273

Received March 22, 2012; accepted May 7, 2013.

From the Office of Medical Affairs, Fire Department of New York, Brooklyn, NY (J.P.F., L.M., D.J.P.); Philips Healthcare, Seattle, WA (D.B.J., K.N.);Fred Hutchinson Cancer Research Center, Seattle, WA (P.-Y.L.); London Ambulance Service, London, UK (J.I., R.T.D., M.W.); Department of Emergency

Medicine, Long Island Jewish Medical Center, New Hyde Park, NY (R.A.S.); and Pulmonary Medicine Division, Department of Medicine, MontefioreMedical Center and Albert Einstein College of Medicine, Bronx, NY (D.J.P.).

Correspondence to John P. Freese, MD, Chief Medical Director, Fire Department of New York, 9 MetroTech Center, 4W-1 Brooklyn, NY 11201. E-mail

[email protected]@hotmail.com

Waveform AnalysisGuided Treatment Versus a StandardShock-First Protocol for the Treatment of Out-of-Hospital

Cardiac Arrest Presenting in Ventricular FibrillationResults of an International Randomized, Controlled Trial

John P. Freese, MD; Dawn B. Jorgenson, PhD; Ping-Yu Liu, PhD; Jennifer Innes;Luis Matallana, EMT-P; Krishnakant Nammi, MS; Rachael T. Donohoe, PhD; Mark Whitbread;

Robert A. Silverman, MD, MS; David J. Prezant, MD

Resuscitation Science
http://www.clinicaltrials.gov/mailto:[email protected]:[email protected]:[email protected]:[email protected]://www.clinicaltrials.gov/

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fibrillationand EMS [emergency medical services] response

(call to arrival) intervals >4 to 5 minutes.11 Most recently,

however, randomized, controlled trials and meta-analy-

ses designed to assess the impact of delayed defibrilla-

tion found no benefit and led to recent consensus was that

there is inconsistent evidence to support or refute a delay

in defibrillation.1217

Various properties of the VF waveform have been shown

to be strongly predictive of response to defibrillation.1821

Correlations between VF waveform properties and survival

have also been shown.22,23For this reason, the utility of wave-

form analysis for the guided management of VF has been sug-

gested.2426Conceptually, using waveform analysis to identify

those patients in the electrical phase would allow them to

receive immediate defibrillation, whereas those patients in the

circulatory phase could selectively receive delayed defibril-

lation. Thus, the known benefit of early defibrillation would

be retained for those patients most likely to benefit, and an

alternative treatment (CPR) could be provided to the remain-

ing patients in an attempt to improve outcomes in this groupwith traditionally poor survival.

This prospective, international study was designed to assess

the efficacy of guided initial resuscitative management using

a waveform analysis algorithm compared with a standard

shock-first protocol for the management of out-of-hospital

cardiac arrest presenting in VF.

Methods

Study Setting and DesignThis multicenter, double-blind, randomized study was conducted bythe primary EMS systems in New York, NY, and London, UK. Theparallel-group trial was intended to demonstrate the superiority of awaveform analysis algorithm compared with a standard shock-firstprotocol for the initial treatment of out-of-hospital cardiac arrestspresenting in VF.

Study inclusion required that the patients arrest was of cardiacorigin as described by the rescuers in accordance with the Utsteinstyle,13that the initial defibrillator used during the resuscitation was

a study device, and that the subject presented in VF as determined bythe initial rhythm assessment of the automated external defibrillator(AED). Pediatric patients (age 80% and

a specificity >60% with respect to the probability of achiev-

ing return of spontaneous circulation (ROSC) after immediate

defibrillation.24Patients whose waveform analysis score met or

exceeded that threshold value were recommended for immedi-

ate defibrillation. Those whose VF waveform analysis score

was below the threshold value were recommended for a 2-min-

ute CPR interval before reanalysis. This waveform analysis was

incorporated into the rhythm assessment of the AED and did

not result in any delay in treatment recommendation. All subse-

quent rhythm analyses in the VF waveform analysis group and

all rhythm analyses in the shock-first protocol used an identical

VF identification and treatment algorithm. Prehospital providers

were blinded to device randomization, which was reversed at

specified intervals.

Because treatment differed only for those patients whose VF scores

were below the predefined threshold, the primary comparison group

was made up of those patients in the 2 arms whose initial VF scores

were below that threshold.

Data CollectionPatient data were collected according to the updated Utstein tem-

plate.13 Computerized dispatch records, prehospital care forms

completed by EMS personnel, and phone interviews with the

EMS providers were used to collect prehospital and demographic

data. Hospital data were collected by each agency directly from

the receiving hospitals. Validation of outcomes using available

national registries was also performed. Individuals responsible

for clinical data acquisition were blinded to all ECG data until the

study was complete.

AED data were transmitted from the study device to a removabledata card, which was retrieved after each use. ECG data were then

transferred to the study sponsor for analysis. VF scores generated by

the AED were validated for all patients in the waveform analysis arm,

and initial VF scores were calculated for all patients in the shock-first

arm post hoc. For those patients in the waveform analysis arm who

were recommended to a 2-minute CPR interval before reanalysis,

VF scores were also calculated after the CPR interval. Individuals

responsible for ECG data analysis were blinded to all clinical data

until the study was complete.

OutcomesThe primary outcome for this study was survival to hospital discharge.

Secondary outcomes included ROSC, sustained ROSC defined as

ROSC maintained until hospital arrival, and survival to hospitaladmission, each defined in accordance with the Utstein template.13

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Freese et al SmartCPR Trial: VF Waveform Analysis for OOHCA 997

Sample Size and Statistical AnalysisThe primary end point analysis of the study was designed to assess

survival to hospital discharge for patients whose VF presented belowthe predefined threshold. Comparison was made between thosepatients recommended to CPR before defibrillation as a result of the

waveform analysis algorithm and those treated with immediate defi-brillation. Predefined additional analyses included a primary outcomeanalysis for all VF patients and an analysis of both the overall study

population and the primary comparison group for all secondary out-comes. As described below, an a priori decision was made to performa subgroup analysis of patients in the waveform analysis arm whose

VF scores improved after the 2-minute CPR interval.Before the study, we postulated that the waveform analysis algo-

rithm would result in improved survival to hospital discharge. On thebasis of the known VF survival rates in both study sites and the rec-

ognition that patients with lower waveform analysis scores are lesslikely to survive than the population of VF arrests as a whole, we esti-mated a baseline 5% survival rate for the primary comparison group

and hypothesized an absolute improvement in survival to hospitaldischarge of 10%.

With the use of a 2-sided value of 0.05 and a power of 90%,

the sample size requirement for primary comparison group in thisstudy was calculated to be 400 patients. After adjustment for antici-

pated exclusion criteria, a 10% exclusion rate was projected, andthe sample size for the primary comparison group was adjusted to450. With an estimated 50% of waveform analysis scores presentingbelow the predefined threshold, this yielded a total study populationof 900 patients that would be required from the combination of the

2 study sites.The primary end point analysis was conducted with a Fisher exact

test, and other differences within the primary comparison group were

assessed with multivariate logistic regression analyses. Odds ratiosand 95% confidence intervals were calculated with SAS statisticalsoftware (SAS Institute Inc, Cary, NC). A value P

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significantly shorter in New York (4 minutes 3 seconds versus

5 minutes 41 seconds; P

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initial waveform score and, among those in the waveform

analysis arm, an increase in VF score after the 2-minute CPR

interval.

Further subgroup analyses were performed for the wave-

form analysis arm, comparing those patients for whom the VF

score increased after the CPR interval with those for whom

the score declined. ECG data were available for 204 of 262

patients, and a total of 105 of these patients (51.5%) experi-

enced an increase in VF score before the first defibrillatory

shock (Table 4). Those whose VF scores had increased after

the CPR interval had higher survival rates for all secondary

survival end points (ROSC, 41.90% versus 19.19%, P

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was no difference in survival to hospital discharge (11.65%

versus 5.05%; P=0.13). In patients in whom the increase in

VF score exceeded the predefined threshold value, compared

with those whose score did not achieve the threshold, there

was a significant increase in all survival end points (ROSC,

61.29% versus 25.43%, P

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demonstrated the prognostic value of waveform analysis

scores as a determinant of resuscitation outcomes, and we

further identified a subgroup of patients for whom guided

management via waveform analysis was associated with

improved waveform characteristics and for whom additional

study appears warranted to understand the factors associated

with this finding. Further studies are needed to objectively

measure the CPR being performed, to assess its relation to

changes in the VF characteristics, and to examine the use of

other strategies to optimize the initial resuscitation strategies

for patients with low-quality VF.

AcknowledgmentsWe thank the following individuals for their time, effort, and assis-tance in completing this study: Emily Mydynski, Meera Shenoy,Chris Choe, Stacy Gehman, James Russell, Bradley Kaufman, DougIsaacs, Andrew Werner, Gilbert Caicedo, Dulce McCorvey, FredaScott, James Braun, Savahanna Lien, Paul Barbara, Kevin Munjal,Fionna Moore, and, most important, the men and women of the FireDepartment of New York and the London Ambulance Service.

Sources of FundingThe Fire Department of New York and London Ambulance Servicereceived grant support for the study from Philips Healthcare.

DisclosuresNone.

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CLINICAL PERSPECTIVEIn the 3 most recent iterations of resuscitation guidelines, recommendations for ventricular fibrillation (VF) have varied,

including immediate shock, delayed defibrillation, and most recently the recognition of inconsistent evidence for the most

appropriate initial resuscitation strategy for VF. In this study, we sought to implement an automatic external defibrillator

based VF waveform algorithm for the initial treatment of VF among out-of-hospital cardiac arrest patients compared witha standard shock-first protocol. Overall survival between the 2 study arms was equivalent; thus, this study does not provide

definitive evidence to clarify the inconsistency concerning the initial treatment of VF. Among patients with low-quality VF

who were given 2 minutes of cardiopulmonary resuscitation before initial defibrillation, despite published data suggesting

that an improvement in VF score is to be expected, there was wide variation among those patients with regard to the result-

ing VF score, ranging from significant improvement to marked decline. Although these changes in VF score positively cor-

related to outcome, the study design did not allow the identification of causative factors or comparison with the shock-first

arm. These results suggest a potential for the future use of such technologies to guide prognostic or treatment decisions,

emphasize the need to address the quality of CPR during any resuscitation, and yield a number of additional questions for

future research.

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