Joseph P. Ornato, MD, FACP, FACC, FACEP, FAHA Professor & Chairman, Emergency Medicine

1. Joseph P. Ornato, MD, FACP, FACC, FACEP, FAHA Professor & Chairman, Emergency Medicine Professor, Internal Medicine (Cardiology) Virginia Commonwealth University Richmond, VA Training Networks to Develop the Next Olympic Interventions:What Can We Learn from the ROC Consortium?

2. Presenter disclosure informationTraining Networks to Develop the Next Olympic Interventions:What Can We Learn from the ROC Consortium? • Joseph P. Ornato, MD, FACP, FACC, FACEP • FINANCIAL DISCLOSURE: • Cardiac Co-Chair, NIH Resuscitation Outcomes Consortium • American Editor, Resuscitation • Science Advisory Board, ZOLL Circulation • Clinical Working Group, AHA Get With The Guidelines-Resuscitation • UNLABELED/UNAPPROVED USES DISCLOSURE: • None

3. Objective • Summarize the findings, power, and pitfalls of the most recent ROC studies of out-of-hospital cardiac arrest, and the relevance of these studies to diverse EMS systems and communities.  • Highlight “hot topics” that are on the near horizon for current and upcoming ROC clinical trials.  • Illustrate the extensive measures that ROC investigators employ to ensure consistent training and protocol adherence to ensure that the network's clinical trials get correct, definitive answers to important questions relating to resuscitation in the real world.

4. Cardiac Arrest and Resuscitation An Opportunity to Align Research Prioritization and Public Health Need Ornato JP, Becker LB, Weisfeldt ML, Wright BA. Circulation 2010; 122:1876-9 43x 82x

5. Cardiac Arrest and Resuscitation An Opportunity to Align Research Prioritization and Public Health Need Ornato JP, Becker LB, Weisfeldt ML, Wright BA. Circulation 2010; 122:1876-9 27x 55x

6. Reasons for the paucity of SCD funding and researchOrnato JP, Becker LB, Weisfeldt ML, Wright BA. Circulation 2010; 122:1876-9 Investigator perception of little NIH interest in topic NIH perception of little investigator interest in topic Few grant applications Misperception that SCD is largely an untreatable problem Most of the existing therapies are generic, patent unprotected drugs or devices Few novel, patented-protected pharmaceuticals are in the pipeline Funding circle paradox Exception from informed consent challenges

7. Resuscitation Outcomes Consortium (ROC) First large-scale, governmentally-sponsored, North American effort to conduct definitive pre-hospital, randomized clinical trials in out-of-hospital cardiac arrest and severe traumatic injury Focus is on very early delivery of interventions by EMS providers, when there is optimal potential for benefit

8. Funding Partners National Heart, Lung & Blood Institute National Institute of Neurological Disorders & Stroke American Heart Association Institute of Circulatory and Respiratory Health of the Canadian Institutes of Health Research Defense Research and Development Canada Heart and Stroke Foundation of Canada U.S. Army Medical Research & Materiel Command

9. Primary ROC sites • 264+ EMS and fire agencies • 35,000+ square miles • 24 million people • 3,600+ EMS vehicles • 36,000+ EMS personnel • 100+ IRB’s • 287+ hospitals

10. ROC structure Protocol Development Subcommittee Creation and refinement (ROC Investigators) ROC Steering Committee Review and acceptance (All ROC PIs) Protocol Review Committee Peer review (NHLBI-appointed) FDA Data Safety & Monitoring Board Data quality & patient safety (NHLBI-appointed) Local Investigators Public Disclosure & Community Input Local IRBs

11. Primary research areas of interest Optimum CPR methods including alternative CPR devices Pharmacologic interventions to address the three-phase (electrical, circulatory, and metabolic) resuscitation model Optimal ventilation and oxygen delivery systems Cerebral protection and neurological preservation Optimal strategies of fluid resuscitation including permissive hypotension, timing of initiation of infusion, alternative fluids Immune modulators to alter systemic and/or regional inflammatory responses accompanying shock or shock-like states Novel hemorrhage control strategies Metabolically directed therapies (e.g., hypothermia)

12. Exception from Consentin ROC Trials Community consultation and public notification Meetings, random digit dialing telephone surveys Bracelets Process used to notify patient/next of kin after enrollment and give opportunity to opt out Verbal and written consent as required by regulations Access to hospital record included in exception from consent in cardiac trial Written consent for ongoing participation in clinical trials obtained before discharge if further interventions done in hospital

13. CPR Process Monitoring Recommended by PRC, DSMB CTC obtained in kind equipment donation Variation in technical capability, timeliness of availability of equipment Sites needed to demonstrate acquisition of these data before active enrollment in trial ROC has already collated the largest # of OHCA cases with CPR process data

14. ROC publications (as of Sept 2012) • 43 scientific papers • JAMA, Circulation, Resuscitation, Prehospital Emergency Care • 32 abstracts at national meetings • AHA, ReSS, NAEMSP, SAEM

15. ROC EPISTRY 30 sec CPR Interruption ETCO2 Signal ET Tube Placement • Epidemiological Registry = Epistry • Participating ROC sites began collecting cardiac arrest data on December 1, 2005. • CPR process data • # cases per year • 17,500 cardiac arrests • 10,000 major traumas • 120,000 total cases

16. EPISTRY Studies

17. Regional variation in OOH-CA survival Resuscitation Outcomes Consortium (ROC)Nichol et al. JAMA 2008; 300:1423-31

18. Role of chest compression depth during out-of-hospital cardiac arrest Stiell IG et al. Crit Care Med. 2012 Apr;40(4):1192-8 2010 AHA BLS GLs: Compress at least 2” (50 mm) • 1,029 adult patients from 7 US/Canadian EMS systems in ROC Epistry • Quality CPR data from 2006-9 • Found inadequate compression depth in 50% of patients by 2005 GLs (1.5-2”), nearly 100% by 2010 GLs (at least 2”)

19. Chest compression fraction vs. survival in OHCA with initial VFChristenson J et al. Circulation. 2009;120:1241-1247 N= 100 74 117 143 72 • 506 OOH-CA patient with initial VF

20. Chest compression fraction vs. ROSC in non-VF patientsVaillancourt et al. Resuscitation 2011; 82:1501-7 • 2,103 adult OOH-CA patients • 10 US & Canadian centers • Median compression rate= 110/min • Median CCF= 71% • ROSC= 24.2% • Survival to hospital discharge= 2.0%

21. Initial CA rhythm vs. patient location in OOH-CA Weisfeldt ML et al. NEJM 2011; 364:313-21

22. Preshock, postshock, and perishock pauses Cheskes S et al. Circulation 2011;124:58-66 N= 815

23. Ancillary Studies

24. Real-time feedback during CPR substudyHostler D et al. BMJ 2011;342:512 • Prospective, cluster-randomized trial with crossover at 2-7 months • Phillips MRx monitor-defibrillator with/without audible/visual feedback

25. Randomized Clinical Trials

26. A Factorial Design of “An Active Impedance Threshold Valve versus Sham Valve” and “Analyze Early vs. Analyze Later” Incorporated 2 interventions to improve hemodynamics during CPR: Chest compressions before rhythm analysis Impedance threshold device (ITD) ROC PRIMED

27. Theoretical importance of myocardial ATP Myocardial Cell<10% ATP Myocardial Cell30-40% ATP Myocardial Cell100% ATP

28. AE vs. AL design Analyze Early Analyze Later

29. Analyze/shock VF early (30s CPR) vs. later (3 min CPR)Stiell et al. NEJM 2011; 365:787-97 9,933 adult OOH-CA patients Randomly assigned to 30-60s vs. 180s of EMS-administered CPR prior to analysis/shock if indicated Primary endpoint= survival to hospital discharge with MRS ≤3

30. Early versus later rhythm analysis in patients with out-of-hospital cardiac arrestStiell IG, et al. N Engl J Med. 2011;365(9):787-97

31. Enhances venous return and cardiac output by increasing negative intra-thoracic pressure during decompression phase of CPR Promising preliminary results Randomize real vs. sham valve ResQPod – Advanced Circulatory Systems Impedance Threshold Device

32. Impedance Threshold Device Bag Valve Mask Set-up Endotracheal Tube Set-up

33. Physiological Effects of the ITD Compression Recoil Phase No flow More negative pressure (suction) increases venous return on the recoil upstroke Recoil

34. Clinical Trial of ITD in HumansAufderheide TP, et al. Crit Care Med. 2005; 33(4):734-40 N= 230 OOH-CA pts randomized to ITD vs. sham Milwaukee EMS All patients Initial PEA PEA anytime

35. Randomize use of real vs. sham valve Devices indistinguishable BVM as well as ET use ITD Study Design

36. ITD primary outcome Aufderheide et al. N Engl J Med 2011; 365(9):798-806 * Difference, CI, and p-value for mITT population adjusted for sequential monitoring

37. MRS ≤3 in a priori subgroups Aufderheide et al. N Engl J Med 2011; 365(9):798-806

38. Current Randomized Clinical Trials

39. Minimally Interrupted Cardiopulmonary Resuscitation (MICR) by EMSBobrow et al. JAMA 2008; 299:1158-65Peberdy MA, Ornato JP: JAMA 2008; 299:1188-90 62 EMS agencies in Arizona 75% of state population 200 CCs first Rhythm check Single DF 200 CCs post-DF Early epinephrine Delayed intubation

40. ROC continuous chest compression (CCC) vs. 30:2 trial (n= 23,600) CCC ~2 mins ~2 mins CCC UNTIL INTUBATION /KING, MAX 120 SEC 30 [120] SEC CCC UNTIL MONITOR/AED 200 CONTINUOUS CHEST COMPRESSIONS 200 CONTINUOUS CHEST COMPRESSIONS IV/IO Epi/Vaso*; BVM at 10:1 STANDARD ACLS 30:2 ~2 mins ~2 mins 30:2 CPR UNTIL INTUBATION /KING, MAX 120 SEC 30 [120] SEC CPR AT 30:2 UNTIL MONITOR/AED 150 CHEST COMPRESSIONS AT 30:2 150 CHEST COMPRESSIONS AT 30:2 End of Protocol IV/IO Epi/Vaso*; BVM at 30:2 Bout #2 Bout #3 Bout #4 Bout #1

41. Amiodarone, Lidocaine, or Placebo Study (ALPS) • About 24% of cardiac arrests are due to VF/VT • 70% will re-fibrillate after the first shock • Antiarrhythmic drugs (good or bad?): • Unlikely to chemically convert patients out of VF/VT • May increase probability of shock success • May prevent VT/VF recurrence after defibrillation • May result in higher incidence of bradycardia/asystole • May improve, not change, or worsen patient outcome • Current options: • Lidocaine • Amiodarone

42. ARREST TrialKudenchuk P et al. N Engl J Med 1999; 341:871-8 Persistent or recurrent VF/VT • Continue CPR • Intubate at once • Obtain IV access • Epi 1 mg IV q 3-5 min Amio 300 mg Placebo • DF 360 J within 30-60 sec • IIb medications • Lidocaine • Bretylium • Mg sulfate • Procainamide • (Na bicarb) • DF 360 J 30-60 sec after med dose • Pattern “drug-shock”, “drug-shock”

43. ARREST TrialKudenchukP et al. N Engl J Med 1999; 341:871-8 N= 504 p= .03

44. Drug Therapy during CPROlasveengen TM et al. JAMA 2009; 302:2222-9 815 OOH-CA pts in Oslo, Norway Randomized to ACLS vs. no drugs ALS response time interval= 10 min VF= 33-34% both groups

45. ALPS study design

46. Summary • Summarized the findings, power, and pitfalls of the most recent ROC studies of out-of-hospital cardiac arrest, and the relevance of these studies to diverse EMS systems and communities.  • Highlighted “hot topics” that are on the near horizon for current and upcoming ROC clinical trials.  • Illustrated the extensive measures that ROC investigators employ to ensure consistent training and protocol adherence to ensure that the network's clinical trials get correct, definitive answers to important questions relating to resuscitation in the real world.