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!