1. The Devil is in the Details R. J. Frascone, MD, FACEP R. J. Frascone, MD, FACEP Medical Director EMS Medical Director EMS Regions Hospital EMS, St. Paul, MN Regions Hospital EMS, St. Paul, MN Professor of Emergency Med Professor of Emergency Med University of Minnesota University of Minnesota 1

2. These trials were studying two different things, in two very different ways  The RESQ Trial studied the combination of ACD/ITD CPR vs S-CPR  ROC PRIMED studied ITD CPR vs S-CPR

3. But,  The RESQ Trial looked at only ACD/ITD vs S-CPR  ROC PRIMED looked at two different things: Early vs late defibrillation and ITD CPR vs S-CPR and they did it with a multifactoral approach  Both trials were complex, but PRIMED was extraordinarily complex

4. First A Review (sorry)

5. The Physio lo gy of CPR

6. Standard CPR

7. Cardiac Pump Theory: Heart squeezed between sternum and spine. Thoracic Pump Theory: Chest acts as bellows. Compression causes positive intrathoracic pressure:  Blood leaves the heart from higher pressure state (inside the heart) to the lower pressure state (systemic circulation) 7 Compression Phase

8. Vacuum develops in the chest, drawing air back into the lungs and blood back into the heart (preload). Vacuum develops in the chest, drawing air back into the lungs and blood back into the heart (preload). ↑ PRELOAD leads to ↑ CARDIAC OUTPUT 8 Chest Wall Recoil Phase

9. The Inefficiency of Standard CPR The decompression phase is totally dependent on the normal elastic recoil of the chest. What’s the problem with that??

10. 10

11. Inefficiency #1 Filling of the heart (preload) is dependent upon the chest wall’s ability to recoil during decompression phase. Filling of the heart (preload) is dependent upon the chest wall’s ability to recoil during decompression phase. Chest wall recoil may be compromised by: Chest wall recoil may be compromised by: A stiff chest A stiff chest Broken ribs Broken ribs Just doing it wrong Just doing it wrong 11

12. Complete Chest Wall Recoil Incomplete Chest Wall Recoil Results in reduced preload Results in reduced preload 12

13. Inefficiency #2 Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Heart stops filling as soon as vacuum is equalized. Heart stops filling as soon as vacuum is equalized. 13

14. ACD CPR

15. 15 Metronome Force Gauge Handle Suction Cup

16. 16 Actively compressing the chest, increasing IP pressure and thereby forcing blood out of chest, j ust like s-CPR. Actively compressing the chest, increasing IP pressure and thereby forcing blood out of chest, j ust like s-CPR. Same position as standard CPR Same position as standard CPR 40 – 50 cm (1 ½ - 2”) 40 – 50 cm (1 ½ - 2”) Soft chest: 65 lbs Soft chest: 65 lbs Average chest: 90 lbs Average chest: 90 lbs Stiff chest: 110 lbs Stiff chest: 110 lbs

17. 17 But, unlike S-CPR it actively decompresses the chest, decreasing IP pressure, thereby drawing blood into the chest. But, unlike S-CPR it actively decompresses the chest, decreasing IP pressure, thereby drawing blood into the chest. Typically 15-20 lbs Typically 15-20 lbs

18. ACD-CPR Optimizes Chest Wall Recoil 18 S-CPRACD-CPR

19. Does it Work?

22. ACD CPR The Problem is: Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Heart stops filling as soon as vacuum is equalized. Heart stops filling as soon as vacuum is equalized.

23. Inefficiency #2 Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Air rushes in through an open airway and wipes out the vacuum we’re relying on to fill the heart. Heart stops filling as soon as vacuum is equalized. Heart stops filling as soon as vacuum is equalized. 23

24. The Solution Enter the Impedence Threshold Device Enter the Impedence Threshold Device(ITD)

25. 25 Patient can be freely ventilated. Patient Ventilation Patient can freely exhale. Chest Compression

26. 26 Air will enter if patient creates at least -10 cmH 2 O pressure with respiratory effort. Spontaneous Breathing Influx of air is prevented, enhancing the vacuum in the chest. Chest Decompression

27. Greater vacuum (negative pressure) in the chest during chest wall recoil phase 27

28. ACD CPR w/ Sham ITD ACD CPR w/ Facemask + ITD 28 Plaisance et al. Crit Care Med 2005;33(5):990-994 ACD CPR w/ ET + ITD Ventilation

29. Improved Blood Pressure 29 mmHg Pirrallo et al. Resuscitation 2005;(66):13-20 and Plaisance et al. Circulation 2000;(101):989-994. P<0.05 for differences between S-CPR & S-CPR + ITD, and ACD-CPR & ACD-CPR + ITD

30. Many other trials both in animals and human that prove the effectiveness of the ITD alone or in combination with ACD

31. Putting it all together ACD/ITD CPR in humans

35. Paris Survival Study: ACD CPR  ITD Prehospital study Prehospital study 200 patients/arm (ACD vs. ACD/ITV) 200 patients/arm (ACD vs. ACD/ITV) ROSC: ROSC: 38.5% - ACD 38.5% - ACD 48% - ACD/ITV 48% - ACD/ITV ICU admission ICU admission 28.5% - ACD 28.5% - ACD 39.5 – ACD/ITV 39.5 – ACD/ITV 24 Hour Survival 24 Hour Survival 22% - ACD 22% - ACD 32% - ACD/ITV 32% - ACD/ITV

36. The ResQ Trial

37. 37 Tom P. Aufderheide, MD; Ralph J. Frascone, MD; Marvin A. Wayne, MD; Brian D. Mahoney, MD; Robert A. Swor, DO; Robert M. Domeier, MD; Michael L. Olinger, MD; Richard G. Holcomb, PhD; David E. Tupper, PhD; Demetris Yannopoulos, MD; Keith G. Lurie, MD

39. S-CPR (Control) S-CPR (Control) ITD + ACD-CPR (Intervention) ITD + ACD-CPR (Intervention) 39

40. Survival to hospital discharge with favorable neurologic function (measured with a modified Rankin Scale [mRS] ≤ 3), is higher in patients receiving an ITD + ACD-CPR compared to patients receiving Standard CPR (S-CPR). 40

41.  Prospective, randomized, controlled clinical trial with data analyzed on intent to treat basis  Seven US sites (population base: 2.3 million):  46 EMS agencies  4950 EMS providers  25 IRBs  Patients assigned, based upon weekly block randomization, to control or intervention group  Study period: February 2005 – July 2010  All study personnel blinded to aggregate data 41

42. Results

43. Survival to Hospital Discharge with Favorable Neurologic Outcome *53% improvement P = 0.019 OR 1.58 CI (1.07, 2.36) * 43

44. 44 Age at Time of Arrest (years) Survival to Hospital Discharge with Favorable Neurologic Outcome

45. 45 P=1.00 for differences based on gender Odds ratio for effect of intervention based on gender: 1.60 95% CI (1.10, 2.33) Survival to Hospital Discharge with Favorable Neurologic Outcome

46. Cumulative Enrollment 2006200720082009Control5172387713 Intervention6168395703 Total113407821416

47. Control (N = 813) Intervention (N = 840) P-value One-Year Survival 48 (5.9%) 74 (8.8%) 0.030 Emotional: Beck Depression Inventory (BDI) (Score range: 0 – 63) 5.2 ± 6.3 5.5 ± 5.9 0.862 Functional: Disability Rating Score (DRS) (Score range: 0 – 29) 1.4 ± 3.1 2.2 ± 5.7 0.358 Cognitive: Cognitive Abilities Screening Instrument (CASI) Score range: (0 – 100) 92.9 ± 12.0 94.5 ± 4.5 0.473 47

48. Compared to standard CPR, ITD + ACD-CPR resulted in significantly increased survival to hospital discharge with favorable neurological function (53%). Compared to standard CPR, ITD + ACD-CPR resulted in significantly increased survival to hospital discharge with favorable neurological function (53%). One year after OOHCA, survival rates with similar neurologic function were also significantly higher in the intervention group (49%). One year after OOHCA, survival rates with similar neurologic function were also significantly higher in the intervention group (49%). 48

49. Aufderheide et al. A trial of an impedance threshold device in out-of-hospital cardiac arrest. NEJM 2011365;798-806. 49

50. Purpose To determine if use of an active (versus sham) ITD during standard CPR (no ACD used) would improve rates of hospital discharge with functional neurological survival in adult (modified Rankin Scale [mRS] score ≤3 ), non-traumatic, out of hospital cardiac arrests To determine if use of an active (versus sham) ITD during standard CPR (no ACD used) would improve rates of hospital discharge with functional neurological survival in adult (modified Rankin Scale [mRS] score ≤3 ), non-traumatic, out of hospital cardiac arrests

51. Description/Methods 10 sites in US and Canada Prospective, randomized, blinded Subjects: adults with arrest from presumed cardiac etiology 2 x 2 multivariate study design Analyze Early (30 secs CPR) vs Analyze Later (3 min CPR) Stiell et al. NEJM 2011 Sham vs Active ITD Aufderheide et al. NEJM 2011 Impact of immediate CPR feedback utilizing QCPR device @ three sites Hostler et al. BJM 2011

52. Results

53. Results Overall results in sham vs active ITD were similar (≈6%) Overall results in sham vs active ITD were similar (≈6%) November 2, 2009, NIH announced study terminated early (at the 2/3 enrollment point) as it was not going to be possible to detect any overall significant difference between either of the study groups (AnE vs AnL, or sham vs active ITD) even if study continued to 14,000 patients (stopped because of futility) November 2, 2009, NIH announced study terminated early (at the 2/3 enrollment point) as it was not going to be possible to detect any overall significant difference between either of the study groups (AnE vs AnL, or sham vs active ITD) even if study continued to 14,000 patients (stopped because of futility) No safety concerns with ITD No safety concerns with ITD

54. Conclusion Compared with standard CPR, use of the ITD did not significantly improve functional survival from out-of- hospital cardiac arrest. Compared with standard CPR, use of the ITD did not significantly improve functional survival from out-of- hospital cardiac arrest. When implemented under similar conditions, routine use of the ITD is not supported. When implemented under similar conditions, routine use of the ITD is not supported.

55. What are the Problems with ROC? The Devil is in the Details

56. Protocols Three different BLS protocols Three different BLS protocols ALS protocols per site medical director ALS protocols per site medical director

57. Various ROC Study Protocols BLS CPR Method ITD Study 1 AE vs AL Study 2 QCPR Study 3 Sites Participating 30:2 compression to ventilation ratio Sham vs Active ITD 30 secs vs 180 secs of CPR before analyze and shock Did not participate Milwaukee, WI Milwaukee, WI Dallas, TX Dallas, TX San Diego, CA San Diego, CA Portland, OR Portland, OR Birmingham, AL Birmingham, AL Ottawa, CA Ottawa, CA Toronto, CA Toronto, CA Feedback ON vs Feedback OFF Pittsburgh, PA Pittsburgh, PA Thunder Bay, ON Thunder Bay, ON Continuous chest compressions with asynchronous ventilations @ 10/min Did not participate Vancouver, CA Vancouver, CA Did not participate Feedback ON vs Feedback OFF Seattle (King County), WA Seattle (King County), WA 57 1 Aufderheide et al. NEJM 2011 2 Stiell et al. NEJM 2011 3 Hostler et al. BMJ 2011

58. Study Protocol Respond to scene and determine pulselessness. Perform 1 – 4 simultaneously: 1. 1. Review enrollment criteria for AE vs AL study a) a) If eligible and in V-Fib, perform either 30 secs or 3 min of CPR prior to analyzing and shocking if indicated. b) b) If eligible and in asystole or PEA, or not eligible, perform conventional resuscitation 2. 2. Review enrollment criteria for QCPR study a) a) If eligible, place QCPR device; then, based upon cluster randomization, audible and visual feedback either will or will not be given to rescuers. b) b) If not eligible, do not place QCPR device and perform conventional resuscitation. 3. 3. Review enrollment criteria for ITD study a) a) If eligible, select ITD in serialized order and place on patient. b) b) If not eligible, perform conventional resuscitation. 4. 4. Perform other conventional activities of resuscitation (e.g. airway management, IV/IO, administer medications, defibrillate)

59. ROC ITD Placement Intervals 59

60. Device Placement Intervals ROC PRIMED Study ResQTrial Study 60

61. Problems Complicated Analyze Early vs Analyze Later & QCPR protocols, multivariate design caused multiple problems: Complicated Analyze Early vs Analyze Later & QCPR protocols, multivariate design caused multiple problems: ITD placement was very delayed (up to 14 minutes) ITD placement was very delayed (up to 14 minutes) Almost 40% of cases did not have ITD placed within the planned time interval (under 5 minutes) Almost 40% of cases did not have ITD placed within the planned time interval (under 5 minutes) All the patients who survived in under approximately 4 minutes were not eligible for the ITD All the patients who survived in under approximately 4 minutes were not eligible for the ITD Essentially all cases of early use were on asystolic patients Essentially all cases of early use were on asystolic patients Treatment protocols were inconsistent Treatment protocols were inconsistent

62. ResQTrial: Impact of Time to Device Placement on Survival 62 Survival to Hospital Discharge with Favorable Neurological Outcome (%) Time from 911 Call to Randomized CPR Method (min) Average Time of Device Placement in ResQTrial (7.1 min) ACD-CPR + ITD Standard CPR

63. ROC PRIMED All the patients who survived in under approximately 4 minutes were not eligible for the ITD.

64. The Bottom Line Two Very Different Studies ResQ Trial studied ResQ Trial studied ACD/ITD Combination ACD/ITD Combination ROC PRIMED studied ROC PRIMED studied ITD Alone ITD Alone

65. In Addition… Early survivors were excluded from getting the ITD (under 4 minutes) Early survivors were excluded from getting the ITD (under 4 minutes) ITD was used early on probable, non-survivors (asystole) ITD was used early on probable, non-survivors (asystole) ITD way to late for the device to be successful ITD way to late for the device to be successful

66. 66