Update on Cardiopulmonary Resuscitation Randall Brockman M.D. Cardiologist/Electrophysiologist Medical Officer for FDA Circ System Devices Advisory Panel Sept 2004

Several Goals To address important issues in clinical trial design for new CPR devices To provide a clinical summary of the history of CPR and devices to assist with #1 There will be a session on post-arrest hypothermia this afternoon.

Chain of Survival Rapid Access Cardiopulmonary resuscitation Early Defibrillation Advanced cardiopulmonary life support There is ample evidence of the important impact of chain of survival function on survival of out-of-hospital cardiac arrest. Early defibrillation has emerged especially as the single most important intervention. We have seen numerous interventions at various points along this chain, and while some have resulted in improvements in short term success rates (return of spontaneous circulation and short term survival), few interventions have resulted in improvement to hospital discharge and improvement in neurologic outcome. It will be important for future trials to evaluate appropriate success endpoints. How should we define those endpoints? Should a study of a new investigational device have to demonstrate improvement in hospital discharge rates and neurologic outcome when this encompasses the entire chain of survival? Alternatively, could such a trial be designed to evaluate a surrogate endpoint, with additional trials adding to the database? Following is a brief history of some of the published treatment interventions in cardiac arrest. The goal is to highlight the results of these reports, and to use these results as a framework to decide on appropriate endpoints for future CPR trials.

The Beginnings of CPR Resuscitation of arrest patients has been attempted for over a century In the 1950’s, Safar et al and Elam et al “rediscovered” mouth to mouth In 1960, Kouwenhoven described chest compression These two techniques form the critical steps of modern CPR Resuscitation of patients who have experienced a cardiopulmonary arrest has been attempted for over a century. In the 1950’s, Safar et al6 and Elam et al7 “rediscovered” mouth to mouth ventilation by reading how midwives used the technique to revive newborns. Until 1960, however, successful resuscitation was limited to victims of respiratory arrest. In 1960, Kouwenhoven8 observed that forceful chest compressions (closed-chest cardiac massage) produced respectable arterial pulses. Combined, these two techniques form the critical steps of modern cardiopulmonary resuscitation (CPR), and they have been practiced for more than 40 years.

In-hospital Cardiac Arrest Essentially unchanged over the last three to four decades Return of spontaneous circulation (ROSC) in about 30% of patients Approximately 15% of patients are discharged neurologically intact The success rate following in-hospital cardiac arrest has remained essentially unchanged over the last three to four decades, with the return of spontaneous circulation (ROSC) in about 30% of patients, and approximately 15% of patients being discharged neurologically intact

Interposed Abdominal Counterpulsation14 % occurrence P=0.02 P=NS In a randomized controlled trial of in-hospital cardiac arrest, interposed abdominal counterpulsation demonstrated improvement in the rate of return of spontaneous circulation [IAC during CPR vs. standard CPR (51% vs 27%, P = .007)]. At hospital discharge, a significantly greater proportion of patients was alive in the IAC group than in the control group (25% vs 7%, P = .02). However, only 17% of patients who received IAC during CPR survived to hospital discharge neurologically intact.14 The rate of patients being discharged neurologically intact was not statistically significantly different in the IAC-CPR group compared to the S-CPR group (17% vs 6%) and was similar to the previously reported rate. This RCT used informed consent since eligible patients were hospitalized (they were consented when they were admitted).

Out-of-hospital Arrest Hospital admission rates of 8-22% Survival to discharge with intact neurologic function 1-8% Largely unchanged despite multiple additions to the basic components of CPR Patients who suffer an out-of-hospital cardiac arrest have worse outcomes than those patients who are resuscitated in-hospital, with a hospital admission rate of between 8 and 22%, and between 1 and 8% being discharged neurologically intact.15,16 This has been largely unchanged despite additions to the basic components of CPR such as high dose epinephrine, transcutaneous pacing, and Vest CPR. However, techniques such as active compression-decompression CPR and inspiratory impedance threshold devices have demonstrated mixed findings, and AEDs have demonstrated improved survival. I will briefly go through this data.

No Long Term Benefit High dose epinephrine Vest CPR20 Short term improvement (ROSC, hospital admission) 17 No long term improvement (hospital discharge and neurologic function) 17,18,19 Vest CPR20 Trend towards increased rate of ROSC and 24 hour survival but no difference in rate of hospital discharge Transcutaneous pacing21 No improvement in rates of hospital admission or discharge In one study (unblinded RCT of over 3300 patients with OOH CA), high dose epinephrine compared to standard dose epinephrine resulted in a higher rate of ROSC (40.4% vs 36.4%) and survival to hospital admission (26.5% vs 23.6%), but there was no difference in the rate of survival to hospital discharge or neurologic status.17 In two other studies (double-blinded, RCTs totaling 1930 patients with CA), high dose epinephrine failed to demonstrate any substantial improvement in neurologic outcome or survival.18,19 Vest CPR is a pneumatically cycled circumferential thoracic vest system used to augment intrathoracic pressure during CPR. In a small unblinded RCT (34 patients with in-hospital CA), there was a trend toward an increase in ROSC and 24 hour survival but no difference in survival to hospital discharge.20 An unblinded concurrent control trial evaluated the effect of transcutaneous pacing in out-of-hospital asystolic cardiac arrest; it found no improvement in the rate of survival to hospital admission or the rate of survival to hospital discharge.21

Active-Compression Decompression Several studies found no improvement22,23 Another study24 comparing ACD-CPR to S-CPR found improvement in several endpoints P=0.0004 P=0.002 % occurrence Active compression-decompression CPR uses a suction device applied to the sternum to allow active chest-wall decompression in order to enhance negative intrathoracic pressure during the decompression phase, with the goal of enhancing venous blood return. Active compression-decompression CPR compared to standard CPR has demonstrated mixed findings. Two studies (both unblinded group crossover control trials of OOH CA totaling 1436 patients) demonstrated no difference in survival to hospital admission, survival to hospital discharge, or neurologic outcomes.22,23 However, a different study (this was an OUS unblinded, parallel group crossover design in 750 victims of OOH CA) demonstrated an improvement in ROSC (~45% vs ~30%), 24 hour survival (26% vs 13.6%), and hospital discharge without neurologic impairment (5.5% vs 1.9% ).24 This latter study by Plaisance which demonstrated improved outcomes differed from the other two in that a physician was present on the scene of the arrest to guide ACLS. In addition, the EMS personnel involved had been using the ACD-CPR technique for several years, raising the possibility of a learning curve effect. P=0.03

Combination devices Inspiratory impedance threshold devices combined with ACD-CPR26,27 P=0.033 P=0.02 P=0.41 % occurrence Inspiratory impedance threshold devices have been combined with ACD-CPR devices. Inspiratory impedance threshold devices are designed to help maintain the increased negative intrathoracic pressure generated during active decompression in order to augment venous return. Comparing ACD-CPR + ITD to S-CPR, two studies (both RCTs involving a total of 610 OOH CA victims, one was blinded, the other did not report) demonstrated these devices to increase the 24 hour survival rates (37% vs 22% in one study, 32% vs 22% in the second study) but were not found to change the survival to hospital discharge rate (18% vs 13% and 5% vs 4%). The first trial excluded subjects for whom the known time from collapse to initiation of CPR was > 15 minutes; the second study excluded subjects for whom the known time from collapse to initiation of CPR was > 30 minutes, which likely explains the difference in survival to hospital discharge rates. 26,27 These results again highlight the notion that short-term survival does not necessarily predict long-term survival. P=0.63

Automatic External Defibrillators28,29 % occurrence On the other hand, AEDs seem to improve more than short-term survival in out-of-hospital cardiac arrest. Two single-arm, unblinded trials of out-of-hospital arrest were performed. When compared to published survival rates, patients who received early defibrillation from an AED had an improved survival to hospital discharge (in the Casino study28, 53% for VF, 38% for all cardiac arrest) and improvement in hospital discharge rate with intact neurologic function (40% in the Long-Term Outcomes of Out-of-Hospital Cardiac Arrest after Successful Early Defibrillation with AED study29 which evaluated VF arrest only). Comparison is made to the previously published rates of 1-8% survival to hospital discharge in OOH CA.

Public Access Defibrillation30 A recently published study of public-access defibrillation (The PAD trial - an unblinded RCT comparing AED + CPR to CPR only) demonstrated improvement in survival to hospital discharge (23% vs 14%) with similar functional status amongst the survivors.30

Summary Survival rates with intact neurologic function have changed little over the past 30-40 years Choosing appropriate endpoints for clinical trials will be important to determine which devices will facilitate improvement in long-term outcomes Fostering an environment to enhance clinical research in this field will be important Survival rates with intact neurologic function have changed little over the past 30-40 years Recent medical devices such as AEDs and possibly ACD-CPR ± ITD appear to be capable of having an impact Choosing appropriate endpoints for clinical trials will be important to determine which devices will facilitate improvement in long-term outcomes The question remains if improvements in the chain of survival also lead to additional quality-of-life benefit in those who survive cardiac arrest. And importantly, can we accept short-term improvement in survival as a surrogate for long-term improvement? Conversely, in light of the chain of survival concept, is it reasonable to expect an individual medical device to lead to long-term improvement, or can we accept improvements in each step along the chain, with the ultimate goal of improving long-term outcomes when each step along the chain is strengthened? And finally, fostering an environment to enhance clinical research in this field will be important. If asked about how we can foster clinical research Answer – I think accepting endpoints along the chain of survival rather than requiring long-term improvement with intact neurologic function could foster research in this area. Now I’d like to introduce Elizabeth Tritschler who will give you a Regulatory History of CPR Devices.