PRIMED for Failure?

      Last November, enrollment in the ROC PRIMED clinical trial ended early.

   The trial had been examining a pair of cardiac arrest interventions: use of an impedance threshold device (ITD)—a fist-size plastic device attached to the face mask or breathing tube to improve circulation by enhancing changes in pressures within the chest—during CPR by EMS providers, and early vs. delayed strategies of assessing the heart's rhythm in relation to when CPR was begun.

   The PRIMED trial was part of the Resuscitation Outcomes Consortium (ROC), the largest clinical research network studying prehospital treatments for cardiac arrest in the U.S. and Canada. According to a National Institutes of Health press release, the study's independent monitoring board and the National Heart, Lung and Blood Institute (NHLBI), its lead sponsor, stopped enrollment based on preliminary data suggesting that neither strategy significantly improved survival.

   That this multisite, multifactorial, multimillion-dollar randomized clinical trial was terminated prematurely raises anew the question of what is the best way to evaluate the limited tools we have available today to restore life after out-of-hospital cardiac arrest. This clinical problem remains the leading cause of death among Americans—with a toll 100-fold higher, for example, than H1N1 in 2009. Despite a half-century of effort and excellent research, we now have yet another huge and inconclusive study that many have erroneously interpreted as confirming the futility of cardiac arrest resuscitation.

   What should we think about this scientific process of prospective, randomized clinical trials in resuscitation research? Aren't they the gold standard? How should the EMS community think about performing CPR before defibrillation, and should we use the ResQPOD ITD? ROC PRIMED revealed neither positive nor negative findings in its early-vs.-delayed study arm (early analysis entailed performing 30 seconds of CPR before analyzing and shocking; late analysis required three minutes of CPR first), and conclusions were similarly neutral related to functional vs. placebo ITDs. Perhaps it is time to ask a more fundamental question: Why do we continue to look for a single silver bullet to treat cardiac arrest when we know that every complex disease conquered by modern medicine was done so with a multipronged approach?

   HIV infection, for example, is only treatable when three or more drugs are used simultaneously and continuously to prevent the deadly virus from mutating and replicating. In lymphoma, a combination of drugs and radiation therapy is now very often curative. Isn't it time to admit that no single device, drug or intervention, used alone, will significantly improve survival from cardiac arrest, and only a combination of therapies, implemented in a systems-based approach, is the answer?

   Even the AED, now considered an essential element in the resuscitation arsenal, was found to actually increase mortality rates when deployed on all first responder vehicles in Seattle from 1975–93, until Dr. Leonard Cobb showed CPR was needed before defibrillation to prevent unintended harmful effects.

PRIMED FLAWS

   Were I to design an animal study of the ITD's efficacy, would I select an animal model with an eightfold variability in baseline response, or a more uniform population to test my hypothesis? The neurologically intact survival rates at baseline in the ROC PRIMED study groups ranged from 1.1% in Alabama to 8.1% in Seattle.¹ Why did ROC use some cities where, given the baseline survival rates (e.g., Birmingham's 1.1%), a poor outcome was nearly certain? The ITD would have to have magical powers to demonstrate a difference in that clinical site!

   Further, why were there three different basic life support CPR protocols in the ROC PRIMED study? Some sites used continuous CPR with a face mask; some used the AHA guidelines' 30:2 compression-to-ventilation ratio; and one site that tested only the ITD, with no early/late analysis arm, used uninterrupted chest compressions during CPR with a face mask. What happened to the basic scientific principle of evaluating one variable at a time to see if something new makes a difference? ROC PRIMED suffered from too many arms with uncontrolled variables; therefore, it is no surprise its results were neutral and unconvincing.

   There was another major flaw to this study as well: Is it fair to expect any technology or intervention to make a difference when the primary outcome of neurological function at hospital discharge is so impacted by the quality of postresuscitation care? The ROC PRIMED study did not track who was treated with therapeutic hypothermia and who was not!

   Frankly, I'm surprised the study was even undertaken, given how much we know about the chaotic field laboratory and the challenges of finding the truth with so many moving and uncontrolled parts.

   I've been writing about the ResQPOD since 2005, and my EMS personnel in Minnesota have used it for the past four years with good success. I have read a series of clinical studies from across the country related to how the device works and how it works best when CPR is done correctly, especially when chest compressions are started right away and the ResQPOD is added first to a face mask with a tight seal, and then to an advanced airway. The ResQPOD makes a difference when it is incorporated into systems of care, per the AHA guidelines. As EMS medical director in Minnesota, I am actively involved in a statewide effort to deploy all of the highly recommended 2005 AHA interventions (see Table 1) for patients in cardiac arrest, including the ResQPOD (which has a Class IIa recommendation to increase circulation and the chances for a return of spontaneous circulation), in a program called Take Heart America (www.takeheartamerica.org). This systems-based approach has already been shown to almost double survival rates for patients with out-of-hospital cardiac arrest, and is the most effective way I know that we will ever be able to change outcomes for these patients.^2,3 Our EMS colleagues in Wake County, NC, saw the value of a systems-based approach years ago, and their data demonstrate the effect it can have on survival. They started with a baseline survival rate well below the national average of 5% and almost quadrupled their overall survival after adopting the 2005 CPR guidelines, the ResQPOD and therapeutic hypothermia (see Figures 1, 2).

CONCLUSION

   So let's forget the quick fix, the easy way out, the search for the silver bullet, and get serious about reducing the death toll from this all-too-common tragic event. We can do this by refocusing our research efforts on building and evaluating "best practice" systems of care and stopping performing large multisite clinical trials with multiple uncontrolled variables that only add confusion, not clarity. I suspect some pearls of wisdom will come from the ROC PRIMED study, but we need to remember that no single intervention listed in the 2005 AHA CPR guidelines has ever been shown in a prospective, randomized clinical trial to improve neurologically intact survival rates. Let's not throw the baby out with the bathwater. Let's continue to teach and perform all of the interventions shown in Table 1 and concentrate on postresuscitation care like induced hypothermia and early coronary revascularization.⁴ When measures like these are used together in a systems-based approach, we can truly make progress against this deadly disease state.

   More research is needed in the field of cardiac arrest. However, the future lies not in searching for a silver bullet, but in researching what a combination of therapies in a systems-based approach can do to move the needle toward improved neurologically intact survival.

References

   1. Nichol G, Thomas E, Callaway CW, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA 300(12): 1,423–31, 2008.

   2. Lurie K, Steinkamp J, Lick C, et al. Take Heart America: A community-based sudden cardiac arrest survival initiative is saving lives by implementing the most highly recommended 2005 American Heart Association resuscitation guidelines. Circulation 118: S1464, 2008.

   3. Aufderheide TP, Alexander C, Lick C, et al. From laboratory science to six emergency medical services systems: New understanding of the physiology of cardiopulmonary resuscitation increases survival after cardiac arrest. Crit Care Med 36(11): S397-S404, 2008.

   4. Lurie K, Schnettler P, Steinkamp J, et al. Level one cardiac arrest centers are clinically and cost-effective. Circulation 118: S1485-S1486, 2008.

   Keith Wesley, MD, FACEP, is a board-certified emergency physician who has been involved in EMS since 1989. He is EMS medical director for the state of Minnesota, as well as for HealthEast Medical Transportation in St. Paul.