In 2010 Myron Weisfeldt, M.D., and Joseph Ornato, M.D., published a commentary in the journal “Circulation” revealing how little attention researchers pay to sudden cardiac arrest compared to other cardiac and vascular emergencies. A review of the medical literature found nearly 7,700 randomized controlled trials on myocardial infarction, 3,600 on stroke, 4,100 on heart failure and a mere 177 on resuscitation of sudden cardiac arrest. And many of the SCA trials that had been done weren’t even conducted on people, but on animals or mannequins.
“It was staggering to us that there was so little out there,” says Ornato, professor and chairman of the department of emergency medicine at Virginia Commonwealth University in Richmond.
The surprising lack of research on resuscitation underscores the importance of Ornato and Weisfeldt’s work with the Resuscitation Outcomes Consortium (ROC), a network of 10 regional hospital and EMS systems in the United States and Canada that are conducting multi-center, randomized clinical trials for both prehospital cardiac arrest and major trauma treatments, devices and strategies. Launched in 2004, ROC is sponsored by the National Heart, Lung and Blood Institute (NHLBI), the U.S. Department of Defense, the American Heart Association and their Canadian counterparts, including the Canadian Institutes of Health Research and the Heart & Stroke Foundation of Canada.
“ROC is the first major, government-sponsored network for exploring new treatments for cardiac arrest and major trauma,” Ornato says. “We’ve never had a real serious source of funding before, at least not at the level that ROC is trying to achieve.”
Never has there been a more opportune time to conduct such studies, Ornato adds, claiming that as a profession and an industry, EMS has matured to the point where many organizations are ready to take on the complex task of conducting clinical trial research. “We are seeing dedication at a level we’ve never seen before in EMS,” he says. “We are seeing a level of professionalism, whether field providers are paid or volunteer. We are seeing our EMS crews really committed and stepping up to the plate at our ROC sites to perform high-quality research and find better treatments for our patients.”
The importance of AEDs
ROC grew out of The Pulse Workshop, held in Washington, D.C., in 2000, which brought together researchers, physicians and biomedical engineers who offered up recommendations about the type of research that was needed in CPR and major trauma, says Weisfeldt, who co-chaired the event and is director of the department of medicine at Johns Hopkins University School of Medicine in Baltimore. The recommendations included increasing funding for both basic science and clinical resuscitation research and creating a clinical trials network to study prehospital interventions that could improve outcomes.
When it comes to heart attack and stroke, one of the reasons there have been so many clinical trials is that pharmaceutical companies and biotech firms have funded them. Many of the interventions used by EMS, epinephrine, for example, are generic drugs that have been around for years, not potentially money-making brand-name drugs or devices. Though some device manufacturers funded small trials, they’re no Pfizer.
In addition to funding issues, another factor that held back resuscitation research was that it was impossible to get informed consent from unconscious patients, Weisfeldt says. Nor is there time to get consent from family members, which in any case could raise ethical issues because the family member is likely distraught.
The situation improved in 1996, when the U.S. Food and Drug Administration issued rules that allow researchers to apply to their institutional review boards for informed-consent exemptions for emergency research. Still, getting those approvals remains a lengthy process, taking from six months to a year for each research group on each project, Ornato says.
A turning point for the funding issue came a few years later, when Ornato and colleagues published the PAD trial, “Public-Access Defibrillation and Survival after Out-of-Hospital Cardiac Arrest,” in the New England Journal of Medicine. With funding from NHLBI, the team placed nearly 1,000 public access defibrillators in large office buildings, athletic facilities and malls, and trained 19,000 people how to use them.
The main finding: People who experienced a witnessed cardiac arrest in a location with a defibrillator available had double the chance of surviving. “What that study did was it got National Institutes of Health (NIH) and NHLBI interested in the idea that this area of out-of-hospital cardiac arrest was an underappreciated area for research,” Weisfeldt says.
In 2004, EMS systems and hospitals in 10 regions came together to form the Resuscitation Outcomes Consortium:
- Dallas/Forth Worth;
- Milwaukee;
- Ottawa, Ontario;
- British Columbia;
- Pittsburgh;
- Portland;
- Seattle-King County;
- Alabama;
- Toronto; and
- UCSD/San Diego
These sites received funding from the federal governments of the United States and Canada for six years. Later on, ROC added satellite centers in Memphis and Houston.
No breakthroughs, but plenty of promise
To date, ROC has published four clinical trials and more than 2 dozen observational studies. The first batch of trials hasn’t yielded any major breakthroughs.
In the first two studies, researchers did multi-center trials comparing hypertonic saline vs. ordinary saline in patients with severe traumatic brain injury (TBI) or trauma patients in shock. Smaller studies had suggested the high salt content of the hypertonic saline could reduce brain swelling in TBI and compensate for blood loss in shock patients, but the studies were halted after it was determined that the hypertonic saline wasn’t superior to ordinary saline.
In a third trial, researchers looked at using an inspiratory impedance threshold device (ITD) to lower pressure in the chest between compressions during resuscitation. In theory, this would improve venous return and blood flow to the organs. The study was rigorous and double-blinded, meaning that one group of patients was resuscitated using the actual device and the other was treated using an identical looking “sham” device, and responders didn’t know which the patient had received. The soon-to-bepublished study found no significant benefit in outcome when using the ITD.
A fourth trial looked at whether automated, real-time audio feedback during CPR would help survival rates. Twenty-one EMS agencies in three ROC regions participated. Though there was “modest” improvement in CPR technique in the group that received the audio feedback, there was no difference in survival to hospital discharge.
There’s no question it would have been more thrilling to determine a treatment that worked instead of getting a “negative” finding—that is, determining that something doesn’t work. But that’s the nature of randomized clinical trials, especially those done in large groups of patients at multiple sites. In fact, time and time again, studies that look promising in observational research or in single-center trials don’t hold up to the more rigorous standards of the double-blinded, multi-center trials.
Double-blinded, placebo controlled trials are the most rigorous and are considered the gold standard of research. But they’re difficult and expensive. Researchers have to concoct elaborate schemes to make sure no one can tell who is getting the real vs. the sham treatment. Say a medication is to be delivered by syringe: The real treatment and the placebo have to look, weigh and smell identical, so that over time medics don’t begin to notice one is a bit different from the other.
The purpose of double-blinding is to eliminate subtle, often unintentional, bias, Ornato says. If medics know they’re trying out a new treatment that they believe works, they might work extra hard and offer better treatment than they would normally. Conversely, medics might avoid even attempting to treat someone who they’re pretty sure isn’t going to make it so that the treatment doesn’t appear to work less well.
“When new ideas, new drugs, new devices or new strategies are tested in a single center or in this case a single EMS agency, they are generally very focused trials on a very specific, narrow population of patients,” Ornato says. “The providers are very enthusiastic, are usually trained very, very thoroughly, and if they have a positive result we are all really excited. Yet when that same exact therapy is applied to a large population that isn’t as carefully selected, and is administered by a very large number of providers—in other words, the real world—you often find out things weren’t quite as good or generalizable for the majority of patients in the hands of the majority of providers.
“ROC’s primary mission is to perform effectiveness trials to define what is the proven effective treatment when used by typical EMS systems in the real world of clinical care.”
ROC is just getting started
Though negative studies don’t get a lot of press, they serve an important purpose: enabling researchers to answer definitively whether something works, and if it doesn’t, to move on in the search for better options.
Considering the amount of research that’s been done on other aspects of cardiovascular health, research about resuscitation and trauma is in its infancy, Ornato says. (His literature review didn’t count the number of trauma studies, but those, too, are paltry compared to heart attacks, stroke and heart failure, he says.) Recently, ROC was renewed through 2013 with $10 million a year in funding. Today, there are some 270 EMS and fire agencies and 30,000 EMS personnel participating.
“We have several trials under our belt and a number that are unfolding,” Ornato says. “Our ROC agencies, EMS providers and their receiving hospitals have been through this drill a number of times, so it’s getting a lot easier.”
ROC is also collecting reams of data, which has already yielded important insights. A study published earlier this year by Weisfeldt and his colleagues in the New England Journal of Medicine, for example, determined that cardiac arrests with a shockable rhythm occur much more often in public than at home, possibly because people who go into cardiac arrest at home tend to be older and have other chronic diseases compared to those who are active. This helps to explain why placing AEDs in public places has been beneficial, but has failed to improve survival in two randomized trials when AEDs were placed in the homes of high-risk cardiac patients, Ornato says.
Upcoming trials will investigate the use of estrogen for treating patients with traumatic brain injury, as animal studies have suggested this hormone may have anti-inflammatory protective effects on the brain. In another trial, researchers will study whether limiting fluids for trauma patients with uncontrolled bleeding may help in clotting and to stop bleeding.
They’re also preparing to launch a study in which patients would receive the standard American Heart Association guidelines of 30 compressions to two ventilations for one in which there are longer intervals of compressions between ventilations, Weisfeldt says.
Weisfeldt predicts that one day, up to half of all people nationwide with an initial shockable rhythm will survive cardiac arrest. And for those in whom an arrest is witnessed and there’s an AED nearby, he says: “You will have an 80 to 85 percent success rate of having them walk out of the hospital alive.”
