Trial Design

A randomized trial of continuous versus interrupted chest compressions in out-of-hospital cardiac arrest: Rationale for and design of the Resuscitation Outcomes Consortium Continuous Chest Compressions Trial Siobhan P. Brown, PhD, a Henry Wang, MD, b Tom P. Aufderheide, MD, MSc, c Christian Vaillancourt, MD, MSc, FRCP (C), d Robert H. Schmicker, MSc, a Sheldon Cheskes, MD, CCFP (EM), FCFP, e Ron Straight, BGS, MEd, f Peter Kudenchuk, MD, a Laurie Morrison, MD, MSc, FRCP (C), e M. Riccardo Colella, DO, MPH, c Joseph Condle, MSc, g George Gamez, EMT-P, h David Hostler, PhD, g Tami Kayea, EMT-P, h Sally Ragsdale, ARNP, a Shannon Stephens, EMT-P, b and Graham Nichol, MD, MPH, FRCP (C) a, The ROC Investigators Seattle, WA; Birmingham, AL; Milwaukee, WI; Ottawa, ON, Toronto, ON, Vancouver, BC; Pittsburgh, PA; Dallas, TX

The Resuscitation Outcomes Consortium is conducting a randomized trial comparing survival with hospital discharge after continuous chest compressions without interruption for ventilation versus currently recommended American Heart Association cardiopulmonary resuscitation with interrupted chest compressions in adult patients with out-of-hospital cardiac arrest without obvious trauma or respiratory cause. Emergency medical services perform study cardiopulmonary resuscitation for 3 intervals of manual chest compressions (each ~2 minutes) or until restoration of spontaneous circulation. Patients randomized to the continuous chest compression intervention receive 200 chest compressions with positive pressure ventilations at a rate of 10/ min without interruption in compressions. Those randomized to the interrupted chest compression study arm receive chest compressions interrupted for positive pressure ventilations at a compression:ventilation ratio of 30:2. In either group, each interval of compressions is followed by rhythm analysis and defibrillation as required. Insertion of an advanced airway is deferred for the first ≥6 minutes to reduce interruptions in either study arm. The study uses a cluster randomized design with every-6-month crossovers. The primary outcome is survival to hospital discharge. Secondary outcomes are neurologically intact survival and adverse events. A maximum of 23,600 patients (11,800 per group) enrolled during the post-run-in phase of the study will provide ≥90% power to detect a relative change of 16% in the rate of survival to discharge, 8.1% to 9.4% with overall significance level of 0.05. If this trial demonstrates improved survival with either strategy, N3,000 premature deaths from cardiac arrest would be averted annually. (Am Heart J 2015;169:334-341.e5.)

Approximately 10% of patients treated for out-ofhospital cardiac arrest (OHCA) survive to hospital discharge. 1 Interruption of chest compressions is associ-

From the aUniversity of Washington, Seattle, WA, bUniversity of Alabama at Birmingham, Birmingham, AL, cMedical College of Wisconsin, Milwaukee, WI, dUniversity of Ottawa, Ottawa, Ontario, Canada, eRescu, Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Sunnybrook Osler Centre for Prehospital Care, University of Toronto, Toronto, Ontario, Canada, fBritish Columbia Emergency Health Services, Vancouver, British Columbia, Canada, gUniversity of Pittsburgh, Pittsburgh, PA, and h Dallas Fire–Rescue, Dallas, TX. ClinicalTrials.gov identifier NCT01372748. Submitted June 10, 2014; accepted November 3, 2014. Reprint requests: Siobhan P. Brown, PhD, ROC, 1107 NE 45th St, Suite 505, Seattle, WA 98105-4680. E-mail: [email protected] 0002-8703 © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2014.11.011

ated with decreased survival in animal models of cardiac arrest. 2 In a swine model of nonasphyxial cardiac arrest, continuous chest compressions (CCC) are as effective as chest compressions with rescue breathing, when ventilations only interrupt compressions for 4 seconds (ie, compression:ventilation ratio 15:2). 3 In a similar swine model, CCC compared with compressions interrupted for ventilations had significantly better neurologic survival. 2 Conversely, ventilation improves outcomes in animal models of asphyxial cardiac arrest. 4 Importantly, it is difficult to distinguish the etiology of arrest in the field. The net impact of interrupting compressions to ventilate those with nonasphyxial arrest versus not interrupting compressions in those with asphyxia arrest is unclear. Observational studies suggest that CCC is associated with better survival than interrupted compressions. 5,6 Thus, the Resuscitation Outcomes Consortium (ROC) investigators designed a randomized trial to test whether

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interruption of manual compressions to provide ventilations is effective. The purpose of this manuscript is to describe the rationale and methodology for this randomized trial.

Conceptual framework Achieving adequate coronary perfusion pressure (CPP) is a marker for the successful return of spontaneous circulation (ROSC). 7,8 Once chest compressions are initiated, it takes time to develop an adequate CPP, and in the absence of effective and continuous external chest compressions, CPP decreases rapidly. 3 Interruptions in chest compressions decrease CPP with a consequent reduced chance for a successful outcome. 2 The CPP achieved during resuscitation is correlated with the quality of external compressions. 9 Current cardiopulmonary resuscitation (CPR) guidelines recommend 100 compressions per minute with complete recoil after each compression. 10 The optimal compression rate may actually be higher. 9 Some observational studies suggest that CPR quality is poor and that improved quality may be associated with improved outcomes. 11,12 The ability to maintain chest compressions during resuscitation is affected by the need to provide ventilations, defibrillator considerations (time for analysis and time required to charge), and human factors (rhythm assessment, pulse checks, advanced airway placement, and rescuer fatigue). Recognition that previous recommendations of a compression:ventilation ratio of 15:2 with stacked shocks was associated with a low CPP and fewer compressions per minute led experts to recommend a ratio of 30:2 combined with single shocks in nonintubated patients in cardiac arrest. 13 Blood in the heart and large arteries remains well saturated with O2 for several minutes after the onset of arrest. 14 Compression-induced ventilation is common with passive inhalation of gas, after elastic recoil of the chest wall during the relaxation phase. 15-19 This ventilation may be substantial 16,18-21 but can decrease after 4 to 10 minutes of CPR due to progressive atelectasis and chest wall deformity. 16,22 Spontaneous gasping (ie, agonal breathing) also contributes to total ventilation. 18,19,22,23 Supplemental oxygenation can be given during chest compression ventilation or spontaneous gasping without mechanical ventilation. 22,23 Clinical studies The use of CCC has been studied in observational studies of OHCA. Emergency medical services (EMS) providers were taught and expected to perform 200 uninterrupted compressions before rhythm analysis, in 2 rural Wisconsin communities. 24 They also were instructed to use single rather than stacked shocks and to eliminate postshock rhythm and pulse checks. Initial airway management used an oral airway with passive

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delivery of oxygen through a nonrebreather mask. During the historical control period, EMS providers were expected to use a compression:ventilation ratio of 15:2. Among patients with bystander-witnessed arrest with an initial shockable rhythm, neurologically intact survival rate was 48% during the intervention period versus 15% during the control period (P value =.001). Continuous chest compression in combination with early administration of epinephrine and delayed endotracheal intubation was assessed in 2 metropolitan cities in Arizona. 6 Among those with bystander-witnessed arrest with an initial shockable rhythm, survival was 4.7% during the control period versus 17.6% during the intervention period (odds ratio [OR] 3.0; 95% CI 1.1-8.9). Among all cardiac arrests, survival was 1.8% during the control period versus 5.4% during the intervention period (OR 8.6; 95% CI 1.8-42.0). The effect of passive versus positive pressure ventilation in combination with CCC in patients with OHCA was assessed in an observational study in regions served by 60 fire departments in Arizona. 25 Emergency medical services providers were instructed to give 200 preshock chest compressions, 200 postshock compressions before rhythm or pulse check, delayed intubation for 3 cycles of compression and rhythm analysis, and attempted intravenous or intraosseous epinephrine before or during the second cycle of chest compressions. Among patients with witnessed arrest with an initial shockable rhythm, survival was 38% with passive oxygen insufflation versus 26% with bag-mask–assisted ventilation (adjusted OR 2.5; 95% CI 1.3-4.6). Among patients with an initial nonshockable rhythm, survival did not differ. An observational study of a similar modified CPR strategy including passive oxygenation in Kansas City, MO, also showed improved survival. 26

Summary of rationale Each of these studies used observational designs with historical controls that may overestimate the benefit of treatment. 27 None used contemporary methods of CPR process monitoring to assess protocol compliance during either study period. These studies implemented multiple changes simultaneously including CPR before analysis, CCCs, reduced ventilations for ≥3 compression cycles, single rather than stacked shocks, early administration of vasopressor therapy, and elimination of postshock pulse and rhythm checks. The oxygen flow rates associated with use of a nonrebreather mask were not measured. This lack of measurement is important because low or high oxygen flow rates are achievable with nonrebreather masks. 28,29 High-dose oxygen is associated with adverse outcomes in animal models of cardiac arrest. 30 and in observational studies of cardiac arrest. 31 Therefore, it is difficult to assess the relative contribution of CCC versus other changes intended to improved survival in these observational studies. Therefore, we designed a large trial to test CCC versus ICC in patients with OHCA.

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Materials and methods

Figure 1

Design This trial is an unblinded randomized cluster design with crossover, comparing survival with hospital discharge between subjects who receive CCC or ICC in patients with nontraumatic OHCA (Figure 1). Setting Resuscitation Outcomes Consortium is a network of clinical sites and a central data coordinating center (DCC) with experience conducting large randomized trials in patients with OHCA in North America. 32-34 Eight sites are participating in this study: Birmingham, Alabama; British Columbia; Dallas-Fort Worth, TX; King County, WA; Milwaukee, WI; Ottawa, Ontario; Toronto, Ontario; and Pittsburgh, PA. Contributors and investigators are available at http://dx.doi.org/10.1016/j.ahj.2014.11.011. This study is being conducted under exception from consent for emergency research, including community consultation and public notification before enrollment, notification of patients or their legally authorized representative as soon as feasible after enrollment, and providing an opportunity to withdraw from ongoing participation. The study was approved by all applicable institutional review and research ethics boards. Its ClinicalTrials.gov registration number is NCT01372748. Population Included are adults with nontraumatic OHCA who receive chest compressions provided by ROC EMS providers dispatched to the scene. Excluded are patients with an EMS-witnessed arrest; a written advance directive to not resuscitate; blunt, penetrating, or burn-related injury; obvious cause of arrest is asphyxia, respiratory (asthma), drowning, strangulation, hanging, foreign body obstruction, or mechanical suffocation; uncontrolled bleeding or exsanguinations; known prisoners; known pregnancy; non-ROC EMS agency/provider first to initiate chest compressions or place pads; mechanical compression device used before any manual CPR by ROC personnel; advanced airway before ROC agency arrival; preexisting tracheostomy; or a priori opted out from resuscitation research. Study interventions Continuous chest compressions. Emergency medical services providers are instructed to initiate chest compressions as soon as cardiac arrest is identified. This is intended to occur as soon as feasible, that is, before electrocardiographic (ECG) leads are attached to the patient's chest. Note that it is difficult for a single provider to simultaneously initiate compressions and ventilations. We previously showed no significant difference in outcome between early rhythm analysis (~30 seconds of compressions) versus later rhythm analysis (~3 minutes

Design.

of compressions). 34 Based on these results, medical directors instructed their providers to give either 30 seconds of compressions or 2 minutes of compressions while attaching defibrillator electrodes to the chest. Providers using the latter approach may have time to apply a bag-valve mask and initiate the study intervention, before the first rhythm analysis is performed. Patients allocated to the CCC (intervention) group shall receive CCCs without pauses for ventilations (Figure 2). The airway will be opened and maintained with an oral airway and positive pressure ventilation given before insertion of an advanced airway (eg, endotracheal tube or supraglottic airway). Because insertion of an advanced airway may be associated with interruption of CPR, participating EMS agencies will defer insertion of an advanced airway until after ROSC or 3 intervals of compressions followed by rhythm analysis (ie, ~6 minutes). Positive pressure ventilation will consist of insertion of an oral airway followed by ventilations interposed at a rate of 10/min using a volume approximately 400 to 500 mL over 1 to 1.5 seconds, as compressions continue. Note that the number and skill level of EMS provider on scene may vary from case to case. 35 Note also that because early administration of epinephrine may be associated with better outcomes as compared with late (or non) administration of epinephrine, 36,37 EMS providers capable of giving advanced life support will be encouraged to obtain intravenous or intraosseous access and give epinephrine 1 mg or vasopressin 40 IU within 5 minutes of arrival. The duration of CPR before the first rhythm analysis will be 30 or 120 seconds based on local medical directive. This will be followed by 2 intervals of compressions (each of ~2 minutes duration) then rhythm analysis, which will be performed as quickly as possible after cessation of compressions (ie, goal b10 seconds). Patients in Ventricular fibrillation (VF) will be defibrillated once, followed by immediate restart of chest compressions. After 3 intervals of compressions and rhythm analysis, an advanced airway will be inserted as soon as feasible, while the study intervention continues. Then CPR will continue with compressions 100/min and ventilations

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Figure 2

Treatment in intervention group.

10/min without pause, until ROSC is achieved, resuscitation efforts are terminated, or care is transferred to emergency department staff. This approach to compression and ventilations in a patient with an advanced airway is consistent with what is recommended by current American Heart Association (AHA) guidelines for emergency cardiovascular care. 38 All other resuscitation and postresuscitation care will be per local practice. Intravenous or intraosseous access along with delivery of a vasopressor (epinephrine 1 mg or vasopressin 40 IU) is expected to occur within 5 minutes of arrival of an EMS provider capable of providing advanced life support if vasopressor therapy is required.

Interrupted chest compressions Emergency medical services providers are instructed to initiate chest compressions as in the intervention group. Medical directors have instructed their providers to give either 30 seconds or 2 minutes of compressions while attaching defibrillator electrodes to the chest. Patients allocated to the ICC (control)

group shall receive compressions using a compression:ventilation ratio of 30:2 (Figure 3). Ventilations will be given using positive pressure during a pause in compressions of b5-second duration. Tidal volume will be approximately 400 to 500 mL per breath. The EMS providers will be taught not to pause for any reason other than for ventilation during the first 3 CPR intervals and to perform CPR up to the moment of rhythm analysis and immediately after the shock is delivered. EMS providers will be encouraged to minimize CPR interruptions during all advanced airway placement. Defibrillations, other resuscitation, and postresuscitation care will be per local practice. After 3 intervals of compressions and rhythm analysis, an advanced airway will be inserted as soon as feasible, while the study intervention continues. Then CPR will continue without pause as in the intervention group.

Cardiopulmonary resuscitation process monitoring The ability to monitor CPR process is essential to interpretation of cardiac arrest trials, as the quality of CPR

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Figure 3

Treatment in control group.

performance is associated with improved outcomes after resuscitation. 39 Sites were required to demonstrate an ability to adequately acquire and analyze these CPR process data, including compression fraction, rate, and depth; identify and attempt to correct any observed deficiencies; and meet minimum performance standards before beginning enrollment in this trial (http://dx.doi.org/10.1016/j.ahj. 2014.11.011). In the ROC PRIMED Trial, CPR process data were available on 65% of eligible, enrolled patients. 34 Cardiopulmonary resuscitation process data will be used to assess compliance/adherence to study intervention during the trial.

Internal study monitoring As with previous studies by our collaborative group, a multidisciplinary study monitoring committee (SMC) will periodically review data masked to treatment outcome. 40 This committee assesses whether prespecified targets for performance are met for measures such as enrollment and eligibility rates, event rate, adherence/compliance

rate, retention rate, and data quality (http://dx.doi.org/ 10.1016/j.ahj.2014.11.011).

Postresuscitation care Postresuscitation care, including hospital procedures such as hypothermia and cardiac catheterization, will be monitored but not standardized in this trial. (online Appendix available at http://dx.doi.org/10.1016/j.ahj.2014.11.011). Random allocation The intervention (ie, ICC or CCC) was randomly allocated using a cluster-crossover design. Each site was subdivided into multiple clusters by EMS agency, station, or other unit as appropriate to the site's EMS structure. Randomization of clusters was stratified by site and by blocks of concealed size within sites. After 6 months on the original randomized arm, clusters crossed over to the other arm of the study. For the duration of the study, clusters are rerandomized to the same study arm or cross over every 6 months. This approach is intended to lead to balance of the study arms both within clusters and overall.

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Comparison populations The effectiveness population will consist of all randomized subjects from the post-run-in phase of the study. Safety summaries will be based on all randomized subjects from both the run-in and postrun-in phases. Outcomes The primary outcome is survival to hospital discharge. Secondary outcomes are neurologic status at discharge, measured with the modified Rankin score based on review of the clinical record, 26,27 and adverse events. Other surrogate outcomes will be collected for descriptive purposes and include the total number of defibrillatory shocks, sustained ROSC, survival to 24 hours from time of arrest, survival to awakening, survival to withdrawal of care, and inhospital morbidity. Sample size and study duration Enrollment began in June 2011. We plan to enroll a maximum of 23,600 patients (11,800 per group) during the post-run-in phase of the study. This will provide 90% power in the primary analysis to detect a change in survival to discharge from 8.1% to 9.4% with overall 2-sided α (adjusted for interim analyses) equal to .05. The baseline survival rate was based on the ROC PRIMED Trial, 33,34 and the power calculations account for a 5% loss of precision due to randomizing by cluster (with crossover). Based on historic enrollment rates in the consortium as well as initial enrolment into the trial, we estimate that the maximum enrollment will require a study duration of 4 years. Data collection and data entry Data are abstracted from source material, such as ECG files, patient care reports, and hospital records, at the clinical sites and entered into a central Web database maintained by the DCC. Data quality control measures include internal checks for consistency of the data, comparisons with reference ranges, data audits, and site visits to verify the accuracy of the data. Safety monitoring Many adverse events are commonly observed in patients who experience cardiac arrest and resuscitative efforts and may or may not be attributable to specific resuscitation therapies. These include pulmonary edema, hemodynamic instability, airway bleeding, complications of endotracheal intubation, pneumonia, sepsis, cerebral bleeding, stroke, seizures, bleeding requiring transfusion or surgical intervention, rearrest, rib fractures, sternal fractures, internal thoracic or abdominal injuries, neurologic impairment, and death. 41 An independent data safety board will monitor the rates of these prespecified events as well as any unexpected or spontaneously reported adverse events.

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Funding acknowledgement The ROC is supported by the National Heart, Lung, and Blood Institute in partnership with the US Army Medical Research & Material Command, The Canadian Institutes of Health Research–Institute of Circulatory and Respiratory Health, Defence Research and Development Canada, the Heart and Stroke Foundation of Canada, and the AHA (http://dx.doi.org/10.1016/j.ahj.2014.11.011). Resuscitation Outcomes Consortium investigators contributed to the design and conduct of the study. The authors are solely responsible for the writing and editing of the paper and its final contents.

Results Primary analyses The primary test of the null hypothesis will be performed using a test statistic calculated as difference in event rates divided by the estimated “robust” SE based on the Huber-White sandwich estimator 42,43 to account for within-cluster correlation and variability, which might depart from the classic assumptions. A 95% CI for the difference in event rates will be calculated with an adjustment for the interim analysis plan to provide a clinically meaningful quantification of the treatment effect. Interim analyses. The formal stopping boundaries are symmetric, 2-sided designs, 44 which are included in the unified family of group sequential stopping rules. 45 The tests for superiority of either intervention will be based on boundaries intermediate to the well-known designs of O'Brien and Fleming 46 and Pocock. 47 Formal interim analyses are to be performed at semiannual intervals throughout the duration of the trial. Secondary analyses Analyses of secondary outcome measures will use the Mann-Whitney test and proportional odds regression for ordinal outcomes and the χ 2 test and logistic regression for binary outcomes. Other outcomes Other outcomes will be assessed to give insight into possible mechanisms underlying any observed treatment effect. These will be summarized descriptively: results will be reported using point estimates and 95% CIs rather than P values. These analyses will be considered exploratory and will not be used as a basis for treatment recommendations. Prespecified subgroups The effect of treatment upon primary and secondary outcomes by the presence or absence of prognostic factors will be examined separately in the subgroups defined below. Tests for key interactions will also be

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performed. Subgroup analyses will be considered exploratory and will not be used as a basis for treatment recommendations. We will examine the treatment effect on survival to discharge for subgroups defined by first recorded rhythm: (a) pulseless ventricular tachycardia or VF or shockable by AED/VF or shockable, (b) pulseless electrical activity, (c) asystole, and (d) other or unknown rhythm. Tests for interaction in the listed subgroups will be done in those patients with an initial rhythm of VF/ tidal volume, unless an overall treatment effect is found in nonshockable initial rhythms. The key subgroups of interest are response time interval from call to arrival at scene b10 minutes versus ≥10 minutes, arrests witnessed by bystanders versus unwitnessed arrests, arrests in a public place versus a private location, advanced airway placement within 5 minutes of arrival of EMS provider capable of advanced life support versus N5 minutes, field cooling versus hospital cooling versus both versus neither, percutaneous coronary intervention within 4 hours after hospital arrival versus N4 hours after hospital arrival versus not performed during index hospital admission, incidence rate of neurologic status at discharge in control group by study site, bystander CPR administered versus not administered, and cardiac etiology of arrest versus noncardiac etiology.

Conclusions A large randomized trial is underway to compare survival with hospital discharge after CCCs versus currently recommended CPR with ICCs at a rate of 30 compressions to 2 ventilations in patients with OHCA. If this trial demonstrates a significant improvement in survival with either strategy, it is estimated that N3,000 premature deaths from cardiac arrest would be averted in the United States alone.

References 1. Go AS, Mozaffarian D, Roger VL, et al. Heart Disease and Stroke Statistics—2013 update: a report from the American Heart Association. Circulation 2013;127(1):e6-245. 2. Kern KB, Hilwig RW, Berg RA, et al. Importance of continuous chest compressions during cardiopulmonary resuscitation: improved outcome during a simulated single lay-rescuer scenario. Circulation 2002;105(5):645-9. 3. Berg RA, Sanders AB, Kern KB, et al. Adverse hemodynamic effects of interrupting chest compressions for rescue breathing during cardiopulmonary resuscitation for ventricular fibrillation cardiac arrest. Circulation 2001;104(20):2465-70. 4. Berg RA, Hilwig RW, Kern KB, et al. Bystander “chest compressions and assisted ventilation independently improve outcome from piglet asphyxial pulseless” cardiac arrest. Circulation 2000;101(14): 1743-8. 5. Bobrow BJ, Spaite DW, Berg RA, et al. Chest compression-only CPR by lay rescuers and survival from out-of-hospital cardiac arrest. JAMA 2010;304(13):1447-54.

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6. Bobrow BJ, Clark LL, Ewy GA, et al. Minimally interrupted cardiac resuscitation by emergency medical services for out-of-hospital cardiac arrest. JAMA 2008;299(10):1158-65. 7. Kern K, Ewy GA, Voorhees WD, et al. Myocardial perfusion pressure: a predictor of 24-hour survival during prolonged cardiac arrest in dogs. Resuscitation 1988;16(4):241-50. 8. Paradis NA, Martin GB, Rivers EP, et al. Coronary perfusion pressure and the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263(8):1106-13. 9. Ewy GA. Cardiocerebral resuscitation: the new cardiopulmonary resuscitation. Circulation 2005;111(16):2134-42. 10. Berg RA, Hemphill R, Abella BS, et al. Part 5: adult basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S685-705. 11. Abella BS, Alvarado JP, Myklebust H, et al. Quality of cardiopulmonary resuscitation during in-hospital cardiac arrest. JAMA 2005;293(3):305-10. 12. Wik L, Kramer-Johansen J, Myklebust H, et al. Quality of cardiopulmonary resuscitation during out-of-hospital cardiac arrest. JAMA 2005;293(3):299-304. 13. Travers AH, Rea TD, Bobrow BJ, et al. Part 4: CPR overview: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S676-84. 14. Cobb LA, Eliastam M, Kerber RE, et al. Report of the American Heart Association Task Force on the future of cardiopulmonary resuscitation. Circulation 1992;85(6):2346-55. 15. Chandra NC, Gruben KG, Tsitlik JE, et al. Observations of ventilation during resuscitation in a canine model. Circulation 1994;90(6): 3070-5. 16. Idris AH, Banner MJ, Wenzel V, et al. Ventilation caused by external chest compression is unable to sustain effective gas exchange during CPR: a comparison with mechanical ventilation. Resuscitation 1994;28(2):143-50. 17. Idris AH. Reassessing the need for ventilation during CPR. Ann Emerg Med 1996;27(5):569-75. 18. Noc M, Weil MH, Tang W, et al. Mechanical ventilation may not be essential for initial cardiopulmonary resuscitation. Chest 1995;108(3):821-7. 19. Berg RA, Wilcoxson D, Hilwig RW, et al. The need for ventilatory support during bystander CPR. Ann Emerg Med 1995;26(3): 342-50. 20. Berg RA, Kern KB, Hilwig RW, et al. Assisted ventilation does not improve outcome in a porcine model of single-rescuer bystander cardiopulmonary resuscitation. Circulation 1997;95(6):1635-41. 21. Tang W, Weil MH, Sun S, et al. Cardiopulmonary resuscitation by precordial compression but without mechanical ventilation. Am J Respir Crit Care Med 1994;150(6 Pt 1):1709-13. 22. Noc M, Weil MH, Sun S, et al. Spontaneous gasping during cardiopulmonary resuscitation without mechanical ventilation. Am J Respir Crit Care Med 1994;150(3):861-4. 23. Yang L, Weil MH, Noc M, et al. Spontaneous gasping increases the ability to resuscitate during experimental cardiopulmonary resuscitation. Crit Care Med 1994;22(5):879-83. 24. Kellum MJ, Kennedy KW, Ewy GA. Cardiocerebral resuscitation improves survival of patients with out-of-hospital cardiac arrest. Am J Med 2006;119(4):335-40. 25. Bobrow BJ, Ewy GA, Clark L, et al. Passive oxygen insufflation is superior to bag-valve-mask ventilation for witnessed ventricular fibrillation out-of-hospital cardiac arrest. Ann Emerg Med 2009;54(5):656-62. [e1].

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26. Garza AG, Gratton MC, Salomone JA, et al. Improved patient survival using a modified resuscitation protocol for out-of-hospital cardiac arrest. Circulation 2009;119(19):2597-605. 27. Campbell JP, Maxey VA, Watson WA. Hawthorne effect: implications for prehospital research. Ann Emerg Med 1995;26(5):590-4. 28. Agarwal R. The low-flow or high-flow oxygen delivery system and a low-flow or high-flow nonrebreather mask. 2006;174(9):1055. author reply. 29. Vereczki V, Martin E, Rosenthal RE, et al. Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab 2006;26(6):821-35. 30. Richards EM, Fiskum G, Rosenthal RE, et al. Hyperoxic reperfusion after global ischemia decreases hippocampal energy metabolism. Stroke 2007;38(5):1578-84. 31. Kilgannon JH, Jones AE, Shapiro NI, et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303(21):2165-71. 32. Hostler D, Everson-Stewart S, Rea TD, et al. Effect of real-time feedback during cardiopulmonary resuscitation outside hospital: prospective, cluster-randomised trial. BMJ 2011;342:d512. 33. Aufderheide TP, Nichol G, Rea TD, et al. A trial of an impedance threshold device in out-of-hospital cardiac arrest. N Engl J Med 2011;365(9):798-806. 34. Stiell IG, Nichol G, Leroux BG, et al. Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest. N Engl J Med 2011;365(9):787-97. 35. Davis DP, Garberson LA, Andrusiek DL, et al. A descriptive analysis of emergency medical service systems participating in the Resuscitation Outcomes Consortium (ROC) network. Prehosp Emerg Care 2007;11(4):369-82.

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36. Hayashi Y, Iwami T, Kitamura T, et al. Impact of early intravenous epinephrine administration on outcomes following out-of-hospital cardiac arrest. Circ J 2012;76(7):1639-45. 37. Nakahara S, Tomio J, Nishida M, et al. Association between timing of epinephrine administration and intact neurologic survival following out-of-hospital cardiac arrest in Japan: a population-based prospective observational study. Acad Emerg Med 2012;19(7):782-92. 38. Anonymous. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005;112(Suppl IV):1-243. 39. van der Hoeven J, de Koning J, can der Weyden P, et al. Improved outcome for patients with a cardiac arrest by supervision of the emergency medical services system. Neth J Med 1995;46:123-30. 40. Fleming TR. Addressing missing data in clinical trials. Ann Intern Med 2011;154(2):113-7. 41. Krischer JP, Fine EG, Davis JH, et al. Complications of cardiac resuscitation. Chest 1987;92(2):287-91. 42. Huber PJ. The behaviour of maximum likelihood estimates under non-standard conditions. Fifth Berkeley symposium on mathematical statistics and probability. Berkeley, CA: University of California Press; 1967. 43. White HD. Maximum likelihood estimation of misspecified models. Econometrica 1982;50:1-25. 44. Pampallona S, Tsiatis AA. Group sequential designs for one-sided and two-sided hypothesis testing with provision for early stopping in favor of the null hypothesis. J Stat Plann Infer 1994;42:19-35. 45. Kittelson JM, Emerson SS. A unifying family of group sequential test designs. Biometrics 1999;55(3):874-82. 46. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35(3):549-56. 47. Pocock SJ. Group sequential methods in the design and analysis of clinical trials. Biometrika 1977;64:191-9.

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Appendix Part I: contributors and investigators Alabama Resuscitation Center, University of Alabama at Birmingham, Birmingham, AL: Jeffrey D Kerby, MD, PhD, principal investigator; and Henry E Wang, MD, MS, principal investigator. Core investigators: Patrick L Bosarge, Jr, MD; and JeanFrancois Pittet, MD. Coordinators: Shannon W Stephens, EMT-P; Carolyn R Williams, BSN, BSME; Randal Gray, NREMT-P, MA Ed; Pamela Gray, EMT-P; and Grant Cobb, BS. Emergency medical services investigators/collaborators: Rusty Lowe, Donald Richardson, Shane Boyd, Robby Hallmark, David Wade, Dusty Underwood, Brian Cleveland, and David Hambright. Hospital investigators/collaborators: Willie Gilford, MD. Participating EMS Agencies: Bessemer Fire Department, Birmingham Fire and Rescue, Center Point Fire District, Hoover Fire Department, and Pelham Fire Department. University of British Columbia, Vancouver, British Columbia: James Christenson, MD, principal investigator. Coordinators: Helen Connolly and Sarah Pennington. Research assistants: Carole Hall, Daniela Todorova, and Cristina Aguirre. Emergency medical services investigators/collaborators: Rob Schlamp, Robert Wand, and Ron Straight. Hospital investigators/collaborators: Jim Goulding and Nick Balfour. Participating EMS agencies: Abbotsford Fire Department, Aggassiz Valley Fire Department, Burnaby Fire Department, City of North Vancouver Fire Department, British Columbia Ambulance, Coquitlam Fire Department, Delta Fire Department, Maple Ridge Fire Department, Mission Fire Department, New Westminster Fire Department, North Vancouver District Fire Department, Pitt Meadows Fire Department, Port Coquitlam Fire Rescue, Port Moody Fire Department, Richmond Fire Department, Surrey Fire Department, Vancouver Fire Department, West Vancouver Fire Department, White Rock Fire Department, Central Saanich Fire Department, Esquimalt Fire Department, Langford Fire Department, Oak Bay Fire Department, Sooke V Fire Department, Victoria Fire Department, Kelowna Fire, and West Kelowna. Dallas Center for Resuscitation Research, University of Texas Southwestern Medical Center, Dallas, TX: Ahamed H Idris, MD, principal investigator. Core investigators: Raymond Fowler, MD; Ronna Miller, MD; and Paul Pepe, MD. Coordinators: Paula Arellano-Cruz; Bobby Bryant, EMT-P; Max Castillo; Dixie Climer, RN; Thomas Cooper, EMT-P; Ashley Dickens; Scott Dudek; David Gallegos; Melinda Moffat, RN; Pamela Owens; Christina Podias;

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Denzil Ray, EMT-P; Brendon Sledge, EMT-P; and David Waks, EMT-P. Emergency medical services investigators/collaborators: Fernando Benitez, MD; Steve Corder, EMT-P; Lynne Dees, PhD, LP, NREMT-P; Steven Deutsch, EMT-P; George Gamez, EMT-P; Todd Hamessley, EMT-P; Steve Heath, EMT-P; Marshal Isaacs, MD; Tami Kayea, EMT-P; Richard LaChance, EMT-P; Shelley Lovato; Larry Martin, EMT-P; Lu Ann McKee, RN; Bobby Muse, EMT-P; Kenny Navarro; Shawn Price, EMT-P; Paul Rosenberger; Norman Seals; Jack Sides, EMT-P; Jason Steindorf, EMT-P; Tricia Swavey, EMT-P; George Tomasovic, EMT-P; Martin Wade, EMT-P. Hospital investigators/collaborators: Sean Black, MD; Compton Broders, MD; Matthew Bush, MD; John Garrett, MD; Lawrence Hum, MD; Michael Ramsay, MD; Robert Simonson, MD. Participating EMS agencies: Carrollton Fire Department, Dallas Fire Rescue, Irving Fire Department, and Mesquite Fire Department. Milwaukee Resuscitation Research Center, Medical College of Wisconsin, Milwaukee, WI: Tom P Aufderheide, MD, principal investigator. Core investigators: Ronald G Pirrallo, MD, MHSA; Karen J Brasel, MD, MPH; M Riccardo Colella, DO, MPH; and John P Klein, PhD. Coordinators: Joseph Brandt, BS, NREMT-P; Walter Bialkowski, MS; Melissa Boettcher, BS; Jamie Jasti, BS; Samantha Gauger, BS; Christopher Sandoval, BS, NREMT-P; Benjamin Hermanson, BS; Katherine Burpee, BA; Geri Price, BS; Amy Hessenthaler, BA; Melissa Mena, BS; Stephanie Zellner, BS; Bethany Quering, BA; Justin Jasti, BS; Megan Goldberg, BS; Caroline Herdeman, BA; Madeline Zeisse, BS; Tonia Qaisar, BA; William Von Rueden, BS; Ashley Wuerl, BA; Kelly Mccormick, BS; Pamela Walsh, AS, CCRC. Emergency medical services investigators/collaborators: Rosemarie Forster, MSOLQ, RHIA; Lauryl Pukansky, BS, RHIA; Kenneth Sternig, MS-EHS, BSN, EMT-P; Erik Viel, MPA, EMT-P; Eugene Chin, RN, EMT-P; Kim Krueger, RN, EMT-P; Del Szewczuga, RN, EMT-P; Rebecca Funk, BS, RHIA, EMT-B; Gail Jacobsen, BS; Janis Spitzer; Jon Cohn; Mike Jankowski, BA, EMT-P; Robert Whitaker; Mark Rohlfing; Tom Rosandish; Adam Remington; Joe Knitter; Robert Ugaste; and Timothy Saidler. Hospital investigators/collaborators: Thomas Reminga, MD; Dennis Shepherd, MD; Peter Holzhauer, MD; Jonathan Rubin, MD; Craig Skold, MD; Orlando Alvarez, MD; Heidi Harkins, MD; Edward Barthell, MD; William Haselow, MD; Albert Yee, MD; John Whitcomb, MD; Eduardo E Castro, MD; Steven Motarjeme, MD; Paul Coogan, MD; Keith Rader, MD; Jeff Glaspy, MD; Gary Gerschke, MD; Howie Croft, MD; Mike Brin, MD; Cory Wilson, MD; Anne Johnson, MD; William Kumprey, MD; Khalid A Ateyyah, MD; David Gourlay, MD; Olga

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Kaslow, MD. Participating EMS agencies: Cudahy Fire Department, Franklin Fire Department, Greendale Fire Department, Greenfield Fire Department, Hales Corners Fire Department, Milwaukee County Airport Fire Department, Milwaukee Fire Department, North Shore Fire Department, Oak Creek Fire Department, South Milwaukee Fire Department, Wauwatosa Fire Department, and West Allis Fire Department. Ottawa/OPALS Regional Clinical Center (RCC), Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada: Ian Stiell, MD, principal investigator. Core investigators: Christian Vaillancourt, MD; and George A Wells, PhD. Coordinators: Cathy Clement, RN; Ghislaine Lepage, CHIM; Jane Banek, CHIM; Patricia Gerrard; Veronica Whitham, BSc; Angela Marcantonio; Andrew Gleeson, ACP; Peter Perryman, ACP; Amelie Michaud, ACP; Jeff Wells, PCP. Emergency medical services investigators/collaborators: Douglas Munkley, MD; Jason Prpic, MD; Justin Maloney, MD; Andrew Affleck, MD; Paul Bradford, MD; John Trickett, BScN; Kevin Smith, ACP; Rick Ferron, ACP; Norm Gale, ACP; Wayne Gates, ACP; Tim Beadman, ACP; Cathie Hedges, ACP; Joe Pedulla, ACP; Karen Lutz-Graul, ACP; Laura McCleary, ACP; Dave Hobler, PCP; Amie Maurice, PCP; Lori Poole, PCP; Jay Loosley, ACP; Jeff Monas, ACP; Randy Mellow, ACP; Neal Roberts, ACP. Hospital investigators/collaborators: Jonathan Dreyer, MD; Nicole Sykes, BScN, RN; Elaine Graham, ACP; Renee MacPhee, PhD; Michael Austin, MD; Rob Luke, ACP; Jason Lewis (RPPEO). Participating EMS agencies: Ottawa Paramedic Service, Waterloo Region EMS, Middlesex London EMS, Niagara Region EMS, Sudbury EMS, Superior North EMS, and County of Essex-Windsor EMS. Participating fire services: London Fire Services, Niagara Falls Fire Services, St Catharine's Fire Department, Thunder Bay Fire & Rescue Services, Waterloo Fire Department, and Cambridge Fire Department. Pittsburgh Resuscitation Network, the University of Pittsburgh, Pittsburgh, PA: Clifton Callaway, MD, PhD, principal investigator. Core investigators: Ron Roth, MD; Jon Rittenberger, MD, MS; Francis Guyette, MD, MS; Samuel Tisherman, MD. Coordinators: Joseph Condle, Ashley Brienza, Danielle Gruen, Jorge Mena, Raeanne Sylvester, Melissa Repine, Timothy Markham, Alyse Rettura, and Tara Tatone. Emergency medical servicesinvestigators/collaborators: Paul Sabol; Anthony Shrader; Greg Stull; William Groft; Mark Bocian; Ronald Roth, MD; Heather Walker, MD. Hospital investigators/collaborators: Heather Walker, MD; Chadd Nesbit, MD; Kristen Seaman, MD. Participating EMS agencies: City of Pittsburgh EMS, City of Pittsburgh Fire, and Mutual Aid Ambulance Seattle-King County Center for Resuscitation Research

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at the University of Washington, University of Washington, Seattle, WA: Peter J Kudenchuk, MD, principal investigator. Coordinators: Sally Ragsdale, RN, MN; Deborah Sampson, RN, BSN; Debi Solberg, RN, MN. Emergency medical services investigators/collaborators: Steve Perry RN, Mobile Intensive Care Paramedic (MICP); Jonathen Larsen, EMS coordinator. Participating EMS agencies: Bellevue Fire Department, Bothell Fire Department, Burien Fire King County Fire Department (KCFD) 2, Kirkland Fire KCFD 41, Renton Fire and Emergency Services, Snoqualmie Fire, Duvall Fire KCFPD 45, Eastside Fire & Rescue, Enumclaw Fire KCFPD 28, Fall City Fire KCFPD 27, Kent Fire Department, Maple Valley Fire and Life Safety KCFPD no. 43, Mercer Island Fire Department, KCFD no. 44 Mountain View, North Highline Fire KCFD 11, Northshore/Kenmore Fire KCFD 16, Port of Seattle Fire Department, KCFPD no. 47 Ravensdale/Palmer, Redmond Fire Department, SeaTac Fire Department, Seattle Fire Department, Shoreline Fire KCFD 4, Skykomish Fire KCFD 50, KCFD no. 20 Skyway, Snoqualmie Pass Fire 51, South King County Medic 1, South King Fire & Rescue, Tukwila Fire Department, Valley Regional Fire Authority, Vashon Island Fire KCFD 13, and Woodinville Fire KCFD 36. Toronto Regional Resuscitation Research Out of Hospital Network (Toronto Regional RescuNET), University of Toronto, Toronto, Ontario, Canada: Laurie J Morrison, MD, MSc, FRCPC, principal investigator. Core investigators: Michael Feldman, MD; P Richard Verbeek, MD, FRCPC; Paul Dorian, MD, MSc; Paul Hoogeveen, BSc, MD, CCFP (EM), FCFP; Phillip Moran, MD, FRCPC, FACEP; Sheldon Cheskes, MD, CCFP (EM), FCFP; Steven Brooks, MD, MHSc. Coordinators: Adam Byers, Barbara Heckaden, Brett Emerson, Carrie Harrison, Cathy Zhan, David Falconer, Dina Braga, Donna Chen, Evelina Kadic, Grace Burgess, Haewon Le-Koo, Hannelore Mueller, Jennifer Walker, Kerri Bath, Laura Wernham, Lauren Lewarne, Lily Chen, Marisa Reymen, Markus Kernen, Mathew Common, Mediha Kadic, Michelle Gaudio, Mohammad Qovaizi, Nancy Liu, Oleg Gavrylyuk, Paula Oke, Precilla D'Souza, Rishab Chadha, Roman Nowickyj, Selena Lui, Suja Mathew, Tyrone Perreira, Selamawit Tessema, Shannon Brown, and Steve Driscoll. Emergency medical services investigators/collaborators: Andy Benson, Attila Bodo, Dana Bradshaw, Dave Lang, Dave Mokedanz, Garrie Wright, Gary Mcauley, Greg Sage, and Gord Weir. Kenneth Webb, Marcy Addley, Mark Diotte, Michael Gamba, Mike Gerrard, Scott Gorsline, Scott Richardson, Steven Marcellus, Susan McConnell, Terri Burton, Tim Waite, Trevor Shea, Verena Jones, Warren Beckett, Wendy Pellet, and William Douglas. Hospital investigators: Andrew Baker, MD, FRCPC;

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Arthur Slutsky, MD, MSc, MD; Carmine Simone, MD; Damon Scales, MD; Donna McRitchie, MD; Howard Clasky, MD; Jamie Hutchinson, MD; Jim Bowen; Joanne Meyer; Joseph Chien, MD; Michael Christian, MD; Michelle Welsford, MD; Niall Ferguson, MD; and Steven Brooks, MD. Participating EMS agencies: Ajax Fire and Emergency Services, Brampton Fire and Emergency Services, Clarington Fire Services, Central East Prehospital Care Program, District of Muskoka, Durham Region EMS, Halton Region EMS, Mississauga Fire and Emergency Services, Muskoka Ambulance Communication Center, Muskoka Ambulance Service, Muskoka EMS, Peel Regional Paramedic Services, Pickering Fire Services, Sunnybrook Centre for Prehospital Medicine, Toronto EMS, Toronto Fire Services, Uxbridge Fire Services, Whitby Fire and Emergency Services, and Simcoe Regional Emergency Services. Steering committee: Chair: Myron Weisfeldt, MD, Johns Hopkins University School of Medicine, Baltimore, MD. Cochair—Cardiac: Joseph P Ornato, MD, Virginia Commonwealth University Health System, Richmond, VA. National Heart, Lung, and Blood Institute, Bethesda, MD: George Sopko, MD, MPH; Debra Egan, MPH; David Lathrop, PhD; Patrice Desvigne Nickens, MD; Colin Wu, PhD; Phyllis Mitchell, PhD; Monica Shah, MD; Ellen Rosenberg, BSN, MHA; and Gail Pearson, MD. Clinical Trial Center, University of Washington, Seattle, WA: Susanne May, PhD; Graham Nichol, MD, MPH; Eileen Bulger, MD; Gerald van Belle, PhD; Scott Emerson, MD, PhD; Judy Powell, BSN; Berit Bardarson, RN; Amy Gest, MPA; Andrea Cook, PhD; Eric Meier, BS; Luis Crouch, BS; Sean Devlin, MS; Danielle Schroeder, BS; Colleen Sitlani, MS; Kent Koprowicz, MS; Siobhan P Brown, PhD; Liz Thomas, MS; Erin Gabriel, MS; Ken Wu, MS; Rob Schmicker, MS; Robert B Ledingham, MS; Richard Moore, BS; Ben Bergsten-Buret; Chi Shen, MS; Winnie Kirdpoo, BS; Jackie Berhorst; Anna Leonen, MS; Yang Wang, PhD; and Al Hallstrom, PhD. Part II: internal study monitoring To be considered for participation in the CCC protocol, an agency must show proficiency with most of the following Epistry benchmarks as determined by the SMC. Resuscitation Outcomes Consortium agencies have 9 months from the date of the first agency entry into the run-in phase to do so. Mandatory criteria: ∙ Outcome measures: ∙ Missing vital status b1.0% of cases at the site at 90 days past episode date ∙ Cardiopulmonary resuscitation process: ∙ Electrocardiographic download and CPR process data (≥1 minute of CPR fraction, compression rate, or compression depth) available for 75% of treated cases within 60 days of episode date

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∙ Seventy-five percent of episodes with compression fraction N0.60 for 3 of first 5 minutes ∙ At least 80% of the following 12 items must be achieved for participation in the CCC trial: ∙ Less than 2% missing/unknown data for the following data points: ∙ Less than 5% missing time of epinephrine administration ∙ Bystander CPR ∙ Witnessed status ∙ First EMS cardiac arrest rhythm ∙ Location of arrest ∙ Time from call received at dispatch to first vehicle arrival ∙ Prehospital disposition including ROSC status at emergency department arrival ∙ Timeliness of data ∙ Eighty-five percent of treated episodes entered within 3 days of episode date ∙ Seventy-five percent of enrollment and prehospital forms completed within 20 days of episode date ∙ Seventy-five percent of time record and CPR process forms completed within 45 days of episode date ∙ Seventy-five percent of episodes must have a 30-day vital status within 60 days of episode date; case enrollment ∙ Treated enrollment should not be consistently below the lower bound based on the agency's estimated enrollment rate from the PRIMED trial or from prior Epistry reporting.

These criteria may be modified in the future at the discretion of the SMC. The SMC will also monitor the data of EMS agencies in the run-in phase of the CCC trial on a monthly basis. These agencies will be progressed to the evaluable phase after a period of 2 to 6 months if they meet the following benchmarks. ∙ Electrocardiographic download and CPR process data (≥1 minute of CPR fraction) available for 75% of cases within 30 days of episode date ∙ Continuous compressions arm—75% of episodes with CPR fraction N0.75 for 3 of first 5 minutes ∙ 30:2 arm—75% of episodes with available CPR process with CPR fraction N0.55 for 3 of first 5 minutes ∙ N75% of preshock pause b20 seconds for all shocks given within the first 5 minutes ∙ Adherence to medical director–authorized ventilation strategy ∙ Less than 5% of advanced airways placed b5 minutes after arrival of first EMS provider for non-EMS– witnessed episodes ∙ Less than 5% of administration of first dose epinephrine or pressor N10 minutes after arrival of first Advanced Life Support (ALS) provider

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∙ Less than 2% missing/unknown data for the following data points: ∙ First EMS cardiac arrest rhythm ∙ Time of epinephrine or pressor administration, if given ∙ Time of airway placement (other than bag/mask), if placed ∙ Eighty-five percent of episodes entered within 3 days of episode date; 95% within 7 days

These criteria may be modified in the future at the discretion of the SMC. Part III: postresuscitation care Context Initial critical care management of the postcardiac arrest patient has a large influence on neurologic recovery and survival. 48-52 Case-control studies have evaluated the effectiveness of combinations of hospital-based treatments in patients resuscitated from cardiac arrest in a variety of settings. 53-58 All have reported improved outcomes when compared with historical controls. Moreover, an analysis of observational data from the ROC cardiac arrest registry demonstrated that patients who were transported to a receiving hospital that had a coronary catheterization laboratory had better outcomes compared with those who were not. 59 Differences in initial critical care may explain some of the differences in survival rate for subjects admitted to different hospitals after resuscitation from cardiac arrest. 60 Collectively, these studies demonstrate that hospital-based care of those resuscitated from OHCA impacts patient outcomes and potentially modifies the effect of interventions for cardiac arrest. Thus, experts have recommended a standardized approach to try to achieve optimal outcomes after resuscitation from cardiac arrest. 61 Hypothermia-related care We are aware that some providers use paralytic or sedative drugs to secure and maintain advance airway devices after resuscitation from cardiac arrest. These agents may also reduce shivering and hence increase the rate of cooling during induction of hypothermia. However, some providers do not use paralytic agents. Two trials that monitored treatment adherence observed improved outcomes with hypothermia compared with no hypothermia after OHCA. 62,63 In contrast, induced hypothermia (IH) without documented achievement of a therapeutic temperature range was not associated with benefit among 8,316 patients resuscitated from inhospital cardiac arrest. 64 Therefore, use of paralytic and sedative agents will be mandated and monitored. Correct position of the temperature probe in the esophagus will be verified by chest radiograph as soon as feasible. The SMC will monitor compliance with cooling in hospital and require remediation if compliance/adherence does not need a priori performance standards. Approach to other elements of postresuscitation care The effectiveness of each component of postresuscitation care remains unclear because observational studies may

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overestimate the magnitude of the effects of treatment 65,66 But we will compared with randomized designs. disseminate guidelines on postresuscitation care to staff of the hospitals who participate in this trial. As well, we will monitor components of hospital-based postresuscitation care including timing of prognosis assessment and withdrawal of care, primary percutaneous coronary intervention (PCI); hemodynamic monitoring; hemodynamic support; seizure monitoring, prevention, and control; insulin therapy; and implantable defibrillator therapy, if any, for enrolled subjects. A summary of this information will be provided to hospitals periodically. Included in this report will be a descriptive summary of the individual hospital's processes of care in the above domains compared with an anonymized aggregate summary of processes of care among all other participating receiving hospitals. The relevant site investigator will determine the appropriate recipient of such reports at each hospital, for example, hospital intensive care committee or equivalent. Furtheremore, the SMC will monitor processes of care in these domains. If performance deviates from expectations, the site investigator will be required by SMC to work with the local hospital to address these concerns. In this manner, postresuscitation care will be monitored but will not be standardized in this trial. Part IV: funding acknowledgement The ROC is supported by a series of cooperative agreements to 7 regional clinical centers and 1 data coordinating center (5U01 HL077863—University of Washington Data Coordinating Center, HL077866—Medical College of Wisconsin, HL077867—University of Washington, HL077871—University of Pittsburgh, HL077872—St Michael's Hospital, HL077881—University of Alabama at Birmingham, HL077885—Ottawa Hospital Research Institute, and HL077887—University of Texas Southwestern Medical Center/Dallas) from the National Heart, Lung, and Blood Institute in partnership with the US Army Medical Research & Material Command, The Canadian Institutes of Health Research–Institute of Circulatory and Respiratory Health, Defence Research and Development Canada, the Heart and Stroke Foundation of Canada, and the AHA. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.

Supplementary Appendix References 1. Skrifvars MB, Hilden HM, Finne P, et al. Prevalence of “do not attempt resuscitation” orders and living wills among patients suffering cardiac arrest in four secondary hospitals. Resuscitation 2003;58(1):65-71. 2. Langhelle A, Tyvold SS, Lexow K, et al. In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A

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comparison between four regions in Norway. Resuscitation 2003;56(3):247-63. 3. Mullner M, Sterz F, Binder M, et al. Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. J Cereb Blood Flow Metab 1997;17(4):430-6. 4. Longstreth Jr WT, Diehr P, Cobb LA, et al. Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation. Neurology 1986;36(9):1186-91. 5. Calle PA, Buylaert WA, Vanhaute OA. Glycemia in the post-resuscitation period. The Cerebral Resuscitation Study Group. Resuscitation 1989;17 Suppl.:S181-8. [discussion S99-206]. 6. Oddo M, Schaller MD, Feihl F, et al. From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest. Crit Care Med 2006;34(7):1865-73. 7. Sunde K, Pytte M, Jacobsen D, et al. Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation 2007;73(1):29-39. 8. Knafelj R, Radsel P, Ploj T, et al. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation 2007;74(2):227-34. 9. Wolfrum S, Pierau C, Radke PW, et al. Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to acute ST-segment elevation myocardial infarction undergoing immediate percutaneous coronary intervention. Crit Care Med 2008;36(6):1780-6. 10. Rittenberger JC, Guyette FX, Tisherman SA, et al. Outcomes of a hospital-wide plan to improve care of comatose survivors of cardiac arrest. Resuscitation 2008;79(2):198-204.

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11. Gaieski DF, Band RA, Abella BS, et al. Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation 2009;80:418-24. 12. Wolcke BB, Mauer DK, Schoefmann MF, et al. Comparison of standard cardiopulmonary resuscitation versus the combination of active compression-decompression cardiopulmonary resuscitation and an inspiratory impedance threshold device for out-of-hospital cardiac arrest. Circulation 2003;108(18):2201-5. 13. Herlitz J, Engdahl J, Svensson L, et al. Major differences in 1-month survival between hospitals in Sweden among initial survivors of out-of-hospital cardiac arrest. Resuscitation 2006;70(3):404-9. 14. Nichol G, Aufderheide TP, Eigel B, Neumar RW, Lurie KG, Bufalino VJ, et al. Regional systems of care for out-of-hospital cardiac arrest: a policy statement from the American Heart Association. Circulation 2010;121(5):709-29. 15. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557-63. 16. Anonymous. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8). 17. Nichol G, Huszti E, Kim F, et al. Does induction of hypothermia improve outcomes after in-hospital cardiac arrest? Resuscitation 2013;84(5):620-5. 18. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000;342(25):1878-86. 19. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000;342(25):1887-92.