Resuscitation Science

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1 Resuscitation Science Waveform Analysis Guided Treatment Versus a Standard Shock-First Protocol for the Treatment of Out-of-Hospital Cardiac Arrest Presenting in Ventricular Fibrillation Results 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 Background Ventricular 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 Results In 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 waveform analysis 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). Conclusions Use 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 Registration URL: Unique identifier: NCT (Circulation. 2013;128: ) Key Words: atrial fibrillation cardiopulmonary resuscitation defibrillation, electric resuscitation More than 50 years have passed since the first description of successful transthoracic defibrillation for the treatment 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. 1 4 However, despite decades of experience and > 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 Becker 8 suggested a 3-phase model for VF that included an electrical, a circulatory, and a metabolic phase, with immediate defibrillation being the optimal treatment for only the first phase in which the interval from the onset of VF to the time of defibrillation is of short duration. At about the same time, initial studies were published that described the use of delayed defibrillation or a period of cardiopulmonary resuscitation (CPR) before the initial defibrillatory shock as a means to improve survival 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 Received March 22, 2012; accepted May 7, 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, Montefiore Medical 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 freesej@fdny.nyc.gov or jfreesemd@hotmail.com 2013 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 996 Circulation August 27, 2013 fibrillation and EMS [emergency medical services] response (call to arrival) intervals >4 to 5 minutes. 11 Most recently, however, randomized, controlled trials and meta-analyses designed to assess the impact of delayed defibrillation found no benefit and led to recent consensus was that there is inconsistent evidence to support or refute a delay in defibrillation Various properties of the VF waveform have been shown to be strongly predictive of response to defibrillation Correlations between VF waveform properties and survival have also been shown. 22,23 For this reason, the utility of waveform analysis for the guided management of VF has been suggested Conceptually, 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 defibrillation. 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 remaining patients in an attempt to improve outcomes in this group with 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 Design This multicenter, double-blind, randomized study was conducted by the primary EMS systems in New York, NY, and London, UK. The parallel-group trial was intended to demonstrate the superiority of a waveform analysis algorithm compared with a standard shock-first protocol for the initial treatment of out-of-hospital cardiac arrests presenting in VF. Study inclusion required that the patient s arrest was of cardiac origin as described by the rescuers in accordance with the Utstein style, 13 that the initial defibrillator used during the resuscitation was a study device, and that the subject presented in VF as determined by the initial rhythm assessment of the automated external defibrillator (AED). Pediatric patients (age <18 years) and those for whom resuscitative care was terminated as a result of a do not resuscitate order were excluded, as were patients for whom data from the study device were not able to be obtained or for whom the initial AED analysis was incomplete. The waveform analysis algorithm used in this study was a Food and Drug Administration cleared product and did not require an investigational device exemption. In New York, the study was approved by the Institutional Review Board of the New York City Department of Health and Mental Hygiene and included a waiver of informed consent process consistent with existing requirements. In London, the study was approved by the Lewisham Local Research Ethics Committee. The study was overseen by an independent data safety monitoring board comprising experienced resuscitation scientists chosen for their extensive work in the field of out-of-hospital resuscitation and without financial conflict of interest pertaining to defibrillator manufacturers. This board undertook a planned interim efficacy analysis when primary outcomes were known for 75% of the anticipated sample size, also allowing an adaptive sample size adjustment. Following the predefined interim analysis plan, this board did not recommend sample size adjustment and instead recommended study termination for futility. At the time of that recommendation, the originally planned sample size requirements had been met. Treatment Protocol Patient care was provided by certified first responders/firefighters in New York and by emergency medical technicians or paramedics in both cities. All patient care was provided according to standardized prehospital protocols. These did not vary between the sites with respect to initial resuscitation management and were consistent with 2005 international resuscitation guidelines. After the arrival of certified first responders or emergency medical technicians/paramedics, CPR was initiated only until an AED was applied. All AED CPR intervals were set to 2 minutes. The study device (FR2+, Philips Healthcare, Seattle, WA) used an impedancecompensating biphasic truncated exponential waveform and fixed 150-J energies. No other interventions (advanced airway management, vascular access, pharmaceutical administration) were performed during this initial treatment phase. AEDs were randomized to either a standard shock-first protocol or VF waveform analysis algorithm. The AED recommended an immediate defibrillatory shock for all VF in the standard shock-first arm. In the waveform analysis arm, the initial rhythm analysis used a proprietary algorithm (Philips Healthcare) to analyze the VF waveform and to assign a resulting numeric VF score. 27 This VF score was then compared with a predefined threshold value with a sensitivity >80% and a specificity >60% with respect to the probability of achieving return of spontaneous circulation (ROSC) after immediate defibrillation. 24 Patients whose waveform analysis score met or exceeded that threshold value were recommended for immediate defibrillation. Those whose VF waveform analysis score was below the threshold value were recommended for a 2-minute 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 subsequent 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 Collection Patient data were collected according to the updated Utstein template. 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 removable data 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. Outcomes The 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 hospital admission, each defined in accordance with the Utstein template. 13

3 Freese et al SmartCPR Trial: VF Waveform Analysis for OOHCA 997 Sample Size and Statistical Analysis The primary end point analysis of the study was designed to assess survival to hospital discharge for patients whose VF presented below the predefined threshold. Comparison was made between those patients recommended to CPR before defibrillation as a result of the waveform analysis algorithm and those treated with immediate defibrillation. Predefined additional analyses included a primary outcome analysis for all VF patients and an analysis of both the overall study population and the primary comparison group for all secondary outcomes. As described below, an a priori decision was made to perform a 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 algorithm would result in improved survival to hospital discharge. On the basis of the known VF survival rates in both study sites and the recognition that patients with lower waveform analysis scores are less likely to survive than the population of VF arrests as a whole, we estimated a baseline 5% survival rate for the primary comparison group and hypothesized an absolute improvement in survival to hospital discharge of 10%. With the use of a 2-sided α value of 0.05 and a power of 90%, the sample size requirement for primary comparison group in this study was calculated to be 400 patients. After adjustment for anticipated exclusion criteria, a 10% exclusion rate was projected, and the sample size for the primary comparison group was adjusted to 450. With an estimated 50% of waveform analysis scores presenting below the predefined threshold, this yielded a total study population of 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 ratios and 95% confidence intervals were calculated with SAS statistical software (SAS Institute Inc, Cary, NC). A value P<0.05 was considered significant. Results Study Population Enrollment began in London on May 5, 2006, and in New York City on May 13, Both sites concluded enrollment on June 30, A total of 6738 patients were enrolled during the study (Figure 1). Of these, 5614 were excluded on the basis of initial rhythm assessment: 4966 had an initial rhythm that was not VF and 648 were missing AED ECG data. Of the 1124 patients presenting in VF, 137 additional patients were excluded from the study as a result of meeting 1 predefined exclusion criteria: 79 patients with arrests of noncardiac origin, 56 patients for whom the initial AED analysis was interrupted or aborted, 8 pediatric patients, 8 patients for whom a nonstudy AED was initially used, and 5 patients for whom a do not resuscitate order was presented on scene. The characteristics and incident details for the 987 patients comprising the overall study population are shown in Table 1. There were no significant differences between the 2 arms with respect to age, sex, or ethnicity. Neither arm varied significantly with respect to incident characteristics such as location, bystander witnessed status, bystander CPR before EMS arrival, EMS response time, number of defibrillatory shocks, use of endotracheal intubation, or administration of either epinephrine or antidysrhythmics. There were significant differences between the 2 sites with respect to ethnic diversity, frequency of bystander CPR, and EMS response interval. Bystander CPR occurred more often in London (49.94% versus 24.43%; P<0.0001), and EMS response times were Figure 1. Study overview. The primary comparison group comprised patients with ventricular fibrillation (VF) below a predefined threshold who were treated with either immediate defibrillation or 2 minutes of cardiopulmonary resuscitation (CPR) before defibrillation as determined by the automated external defibrillator (AED) randomization. DNR indicates do not resuscitate; and Rx, initial treatment.

4 998 Circulation August 27, 2013 Table 1. Baseline Patient and Incident Characteristics for the Overall Study Population Shock First (n=500) Waveform Analysis (n=487) Age, median (range), y 65 (18 97) 64 (18 97) Male sex, n (%) 388 (78) 352 (72) Race, n (%) Asian 22 (4) 19 (4) Black 68 (14) 76 (16) White 286 (57) 257 (53) Hispanic 38 (8) 48 (10) Mixed 0 (0) 2 (0) Other 21 (4) 17 (3) Unknown 65 (13) 68 (14) Location of arrest, n (%) Residence 276 (55) 297 (61) Business 40 (8) 37 (8) Public location 124 (25) 111 (23) Other 60 (12) 42 (9) Bystander witnessed, n (%) 395 (79) 388 (80) Bystander CPR, n (%) 183 (37) 161 (33) Response time, median (range), min 4.30 (0 27) 4.28 (0 20) Shocks, median (range), n 2 (1 16) 2 (0 18) Endotracheal intubation, n (%) 367 (73) 371 (76) Epinephrine administered, n (%) 374 (75) 366 (75) Antidysrhythmic administered, n (%) 148 (30) 127 (26) CPR indicates cardiopulmonary resuscitation. significantly shorter in New York (4 minutes 3 seconds versus 5 minutes 41 seconds; P<0.0001). Waveform Analysis Table 2 describes the normalized initial waveform analysis scores for the overall patient population and for specific subgroups characterized by patient or incident characteristics. Female patients and those whose arrests were witnessed by EMS providers were more likely to have an initial waveform analysis score above the predefined threshold, whereas those with unwitnessed arrests and patients for whom the EMS response time exceeded 5 minutes were more likely to have an initial waveform analysis score below threshold. Outcome Of the 987 patients with out-of-hospital VF cardiac arrests who made up the study population, 8 (0.8%) were lost to follow-up. No survival differences were noted between the 2 arms for the overall study population or for the primary comparison group (Table 3). For the overall study population, no differences were noted between the 2 arms for any outcome end point. ROSC (42.5% versus 41.2%; P=0.70), sustained ROSC (32.4% versus 33.4%; P=0.79), survival to hospital admission (34.1% versus 36.4%; P=0.46), and survival to hospital discharge (15.6% versus 17.2%; P=0.55) were similar between the waveform analysis algorithm and the standard shock-first protocol, respectively. Table 2. Initial VF Waveform Analysis Scores Median Score* Maximum Score* Minimum Score* Greater Than the Threshold Fraction, % All arrests (n=984) Male sex (n=739) Female sex (n=285) Age 80 y (n=822) Age <80 y (n=163) Race Asian (n=40) Black (n=143) White (n=543) Hispanic (n=86) Other (n=40) Unknown (n=132) EMS-witnessed arrests (n=52) Bystander witnessed arrests (n=780) Unwitnessed arrests (n=178) Response time 5 min (n=614) Response time >5 min (n=368) EMS indicates emergency medical services; and VF, ventricular fibrillation. *All scores were normalized. Percentage of patients presenting above the predefined threshold VF waveform analysis score. For the primary comparison group, those patients with an initial VF score below the predefined threshold, there was no difference between the shock-first arm and waveform analysis arm for the primary end point of survival to hospital discharge (7.25% versus 7.19%; P=1.00), and no difference was found for any secondary survival end point (ROSC, 29.39% versus 26.98%, P=0.57; sustained ROSC, 21.76% versus 20.14%, P=0.83; survival to admission, 21.76% versus 22.66%, P=0.84). Multivariate logistic regression analysis (Figure 2) for the primary comparison group demonstrated that only younger age, female sex, and initial waveform analysis score were positively associated with the primary end point of survival to hospital discharge. A positive correlation was also noted for all secondary survival end points for female sex and Table 3. Outcome Measures for All Study Patients and the Primary Analysis Group Shock First (n=500) All VF, n (%) Waveform Analysis (n=487) VF Less Than the Threshold, n (%) Shock First (n=278) Waveform Analysis (n=262) ROSC 206 (41) 206 (43) 75 (27) 77 (29) Sustained ROSC 167 (33) 158 (32) 56 (20) 57 (22) Survival to admission 181 (36) 166 (34) 62 (23) 58 (22) Survival to discharge 83 (17) 74 (16) 20 (7) 19 (7) ROSC indicates return of spontaneous circulation; and VF, ventricular fibrillation.

5 Freese et al SmartCPR Trial: VF Waveform Analysis for OOHCA 999 Odds Ratio 95% CI p Age ROSC ( ) SROSC ( ) Admission ( ) Discharge 0.67 ( ) Gender (male) ROSC ( ) SROSC ( ) Admission ( ) Discharge ( ) Initial Waveform Analysis Score ROSC ( ) SROSC ( ) Admission ( ) < Discharge ( ) Improved Waveform Analysis Score with CPR ROSC ( ) SROSC ( ) Admission ( ) < Discharge 2.57 ( ) Note: For graphical representation, the odds ratios were truncated at Figure 2. Multivariate logistic regression analysis for survival correlation (odds ratios and 95% confidence intervals). 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 waveform 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%) experienced 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<0.001; sustained ROSC, 33.65% versus 13.13%, P<0.001; survival to admission, 36.89% versus 11.11%, P<0.001), although there Table 4. Secondary Analysis Among Patients in the Waveform Analysis Arm Whose VF Scores Decreased or Increased After the Initial CPR Interval Waveform Analysis With Decreased VF Score (n=99) Waveform Analysis With Increased VF Score (n=105) Age, median (range), y 63 (18 97) 65 (28 96) 0.20 Male sex, n (%) 77 (78) 75 (71) 0.33 White race, n (%) 52 (53) 58 (55) 0.78 EMS witnessed, n (%) 7 (8) 5 (5) 0.56 Bystander witnessed, n (%) 73 (74) 80 (76) 0.87 Bystander CPR, n (%) 23 (23) 32 (30) 0.27 Response time, median (range), min 4.4 (2 15) 4.78 (1 20) 0.30 Initial VF score (normalized) ( ) ( ) 0.41 ROSC achieved at any point, n (%) 19 (19) 44 (42) <0.001 SROSC 13 (13) 35 (33) <0.001 Hospital admission 11 (11) 38 (36) <0.001 Live discharge from hospital 5 (6) 11 (10) 0.13 CPR indicates cardiopulmonary resuscitation; EMS, emergency medical services; ROSC, return of spontaneous circulation; SROSC, sustained return of spontaneous circulation; and VF, ventricular fibrillation. Note: for graphical representation, the odds ratios were truncated at P

6 1000 Circulation August 27, 2013 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<0.001; sustained ROSC, 53.33% versus 18.50%, P<0.001; survival to admission, 68.97% versus 16.76%, P<0.001; survival to discharge, 20.69% versus 6.36%, P=0.02). Discussion In this study that used waveform analysis algorithm to guide the initial treatment of out-of-hospital cardiac arrest patients presenting in VF, there were no improvements in overall survival compared with a standard shock-first protocol. Despite decades of out-of-hospital resuscitation experience involving the use of transthoracic defibrillation, the optimal initial resuscitation strategy for VF remains undefined. Recent advances in the understanding of the pathophysiologic basis and electrophysiology of VF have led to the suggested 3-phase model for VF and testing of alternative treatment strategies such as CPR before initial defibrillation, particularly when the interval from VF onset to initial treatment is prolonged However, more recent studies designed to validate such treatment strategies have failed to replicate the results of the earlier reports that had demonstrated benefit from a CPR-first strategy In 2011, the Resuscitation Outcomes Consortium published the results of the largest study to date examining the question of whether CPR before defibrillation, applied as a standard strategy for all VF, would improve outcomes. Enrolling a total of 2432 patients with VF arrests, the study found no difference in survival between patients receiving immediate defibrillation and those receiving CPR before defibrillation. 17 Although our study also sought to apply CPR before initial defibrillation attempts, it differed in that the use of the VF waveform analysis algorithm allowed the selective application of this therapy only for those patients whose analysis suggested that immediate defibrillation was not likely to result in ROSC. The predefined threshold value used in this study demonstrated the ability to distinguish between patients who are likely to respond to immediate defibrillation and those who are not. This would suggest that waveform analysis would be useful for recommending alternative treatment strategies such as CPR before defibrillation for those with poorer-quality wave forms in an attempt to improve their probability of survival. However we found no difference between guided treatment for VF using a waveform analysis algorithm and a universal shock-first protocol with respect to survival to hospital discharge or any intermediate survival end point. In addition to supporting prior work in demonstrating that the initial waveform analysis score for VF is strongly correlated with all survival end points, our study found a correlation between survival and later VF waveform analysis scores, which may explain some of the disparate results in the literature on the use of delayed defibrillation. Among patients who received CPR before defibrillation, only half demonstrated an increase in VF score after the CPR interval. However, this is a potentially important finding given that CPR is expected to result in an improvement in VF waveform properties It is important to consider a number of factors that could be responsible for the varied changes in waveform analysis score after the CPR interval. One possibility is that any meaningful improvement in waveform quality is a function of the quality of CPR administered to patients with poor waveform and that, even though defibrillation was delayed for 2 minutes, better CPR in some patients led to better waveform and therefore better response to defibrillation. Because we did not determine CPR quality in this study, we cannot confirm this hypothesis. Other possibilities remain, and although we found no difference in available patient or incident characteristics between those whose scores improved with CPR and those whose scores did not improve, other factors such as the patient s cardiac history, prior myocardial infarctions, or degree of active myocardial ischemia at the onset of VF may have prevented an improvement in VF quality during the CPR interval It is also possible that the improvement in VF score was prognostic but not a direct result of the CPR interval itself, and as the main study result indicates, there is no survival benefit of administering 2 minutes of CPR before attempting defibrillation. Because our study was limited in that it was not designed to provide such comparative analyses for the subgroup with this postrandomization measure or to analyze survival differences between this population and any control group, conclusions related to improvement in VF score cannot be specifically supported, and further study is recommended to address these questions. This study has several additional limitations. Although the protocol for resuscitation and postresuscitation prehospital care was standardized at each study site, there was no standardization of postresuscitation inpatient care at either site, including the lack of routine use of therapeutic hypothermia at either site during the study period. Second, our study used only 1 waveform analysis parameter, and it is possible that other waveform characteristics may have yielded different results. Additionally, there was no ability to measure CPR performance during the study, allowing the possibility that the lack of any benefit in the waveform analysis group was the result of poor CPR performance rather than a failure of the analysis. Given the known variability in the quality of CPR that is provided in the prehospital setting, including the frequent failure to deliver effective or any compressions, high-quality CPR may not have been provided. 37,38 Without quality compressions, the likelihood of successful defibrillation declines. 39,40 Finally, the inability to evaluate CPR performance limits the ability to further interpret the subgroup analysis that demonstrated improved outcomes among those patients treated with CPR before defibrillation for whom an improvement in VF score was noted after the 2-minute CPR interval. Without such a measurement, it is impossible to discern whether this improvement was a result of and directly related to highquality CPR performance or merely a prognostic value that was unrelated to CPR delivery. Conclusions VF waveform analysis to selectively guide the initial management of out-of-hospital cardiac arrest patients presenting in VF did not result in improved overall survival. We

7 Freese et al SmartCPR Trial: VF Waveform Analysis for OOHCA 1001 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. Acknowledgments We thank the following individuals for their time, effort, and assistance in completing this study: Emily Mydynski, Meera Shenoy, Chris Choe, Stacy Gehman, James Russell, Bradley Kaufman, Doug Isaacs, Andrew Werner, Gilbert Caicedo, Dulce McCorvey, Freda Scott, James Braun, Savahanna Lien, Paul Barbara, Kevin Munjal, Fionna Moore, and, most important, the men and women of the Fire Department of New York and the London Ambulance Service. Sources of Funding The Fire Department of New York and London Ambulance Service received grant support for the study from Philips Healthcare. None. Disclosures References 1. Zoll PM, Linenthal AJ, Gibson W, Paul MH, Norman LR. Termination of ventricular fibrillation in man by externally applied electric countershock. N Engl J Med. 1956;254: Nagel EL, Hirschman JC, Mayer PW, Frank D. Telemetry of physiologic data: an aid to fire rescue in a metropolitan area. South Med J. 1968;61: Grace WJ, Chadbourn JA. The mobile coronary care unit. 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8 1002 Circulation August 27, Menegazzi JJ, Wang HE, Lightfoot CB, Fertig KC, Chengelis NL, Sherman LD, Callaway CW. Immediate defibrillation versus interventions first in a swine model of prolonged ventricular fibrillation. Resuscitation. 2003;59: Eftestøl T, Wik L, Sunde K, Steen PA. Effects of cardiopulmonary resuscitation on predictors of ventricular fibrillation defibrillation success during out-of-hospital cardiac arrest. Circulation. 2004;110: Kern KB, Garewal HS, Sanders AB, Janas W, Nelson J, Sloan D, Tacker WA, Ewy GA. Depletion of myocardial adenosine triphosphate during prolonged untreated ventricular fibrillation: effect on defibrillation success. Resuscitation. 1990;20: Maldonado FA, Weil MH, Tang W, Bisera J, Gazmuri RJ, Johnson B, D Alessio A. Myocardial hypercarbic acidosis reduces cardiac resuscitability. Anesthesiology. 1993;78: Indik JH, Donnerstein RL, Berg RA, Hilwig RW, Berg MD, Kern KB. Ventricular fibrillation frequency characteristics are altered in acute myocardial infarction. Crit Care Med. 2007;35: Ristagno G, Li Y, Tang W, Sun S, Weil MH. Comparison between ischemic and electrically induced ventricular fibrillation. Crit Care Med. 2006;34:S432 S Wik L, Kramer-Johansen J, Myklebust H, Sørebø H, Svensson L, Fellows B, Steen PA. Quality of cardiopulmonary resuscitation during out-of-hospital cardiac arrest. JAMA. 2005;293: Olasveengen TM, Wik L, Kramer-Johansen J, Sunde K, Pytte M, Steen PA. Is CPR quality improving? A retrospective study of out-of-hospital cardiac arrest. Resuscitation. 2007;75: Edelson DP, Abella BS, Kramer-Johansen J, Wik L, Myklebust H, Barry AM, Merchant RM, Hoek TL, Steen PA, Becker LB. Effects of compression depth and pre-shock pauses predict defibrillation failure during cardiac arrest. Resuscitation. 2006;71: Eftestøl T, Sunde K, Steen PA. Effects of interrupting precordial compressions on the calculated probability of defibrillation success during out-ofhospital cardiac arrest. Circulation. 2002;105: Clinical Perspective In 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 with a 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 resulting VF score, ranging from significant improvement to marked decline. Although these changes in VF score positively correlated 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.