CPR is “cardiopulmonary resuscitation.” ECPR is “extracorporeal CPR.” The ATTEST randomized double-blind clinical trial (RCT) provided dramatic evidence of the efficacy of ECPR. But the INCEPTION RCT seemed to provide equally strong evidence of a lack of efficacy. The key difference is the high level of experience and dedication of those implementing the ATTEST RCT, and the lack of experience, and likely lower dedication of those in the INCEPTION RCT. Dr. Demetris Yannopoulos has improved his techniques through trial and error, probably in some ways that he can articulate and in other ways that are harder to articulate. Gary Klein with his naturalistic decision-making research, writes that experience gives emergency workers a quick “recognition” of what needs to be done in different situations.
At what point in the development of a therapy do you perform the canonical RCT? In the case of Emil Freireich’s four drug chemo-cocktail for curing childhood leukemia, he continually improved the ingredients and doses of the cocktail. If an RCT had been performed too early in that process, the result would have been a lack of efficacy, and a therapy would have been abandoned that had the potential to be developed into a useful efficacious therapy. Ditto for Vince DeVita’s development of his chemo-cocktail for curing Hodgkin’s Lymphoma. Ditto also for the development of the drug that eventually proved efficacious in the For Blood and Money book, where Stanford cancer doctor and Pharmacyclics co-founder acquired and developed cancer therapy Imbruvica, but abandoned it after an RCT of it failed. But Miller was ousted by major Pharmacyclics stock-holder, and entrepreneurial non-scientist, Bob Duggan, who did not want to give up on Imbruvica. Duggan persevered, overseeing its further development, until a later RCT was performed that proved efficacy.
In an earlier entry, I documented a much simpler and cheaper CPR innovation that also promises to improve heart failure therapy, called “neuroprotective CPR” (NCPR). Which one, if either, of ECPR or NCPR should we endorse? Ideally, in a fully function medical marketplace, we could comfortably say: “let the market decide.” Entrepreneurial scientists and physicians could develop the therapies and see how many willing patients would be willing to pay for each. Maybe the more expensive ECPR therapy would initially only be bought by the better-off. But as Yannopoulos improves it, as he is already working to do, making it simpler and cheaper, it would eventually be appealing to a broader customers. In Openness, I claim that this is the common path of a great many breakthrough innovations in areas outside of medicine.
Notice that the ECPR was heavily funded by the Helmsley Trust, a private foundation. This is consistent with my claim that medical innovation benefits from a diversity of funding sources, especially of private funding sources that are more likely to fund a diversity of methods and to take chances with heterodox ideas, partly motivated by private funders’ greater mission-orientation due to having more ‘skin-in-the-game.’
Notice also that Yannopoulos’s implementation of ECPR was constrained by a scarcity of trained personnel. Yannopoulos could not act as a nimble entrepreneur because massive regulations limit nimble entrepreneurship in healthcare. This is especially try on labor market issues where massive labor market regulations pile on top of massive healthcare regulations. Breakthrough innovations are usually implemented by small nimble start-ups. To create Disneyland, Walt Disney created WED Enterprises, instead of try to created it with the large incumbent The Walt Disney Company. Jonathan Bush tried nimble labor market innovation in healthcare, but was stymied by regulations. So in the ECPR case, Yannopoulos had the beds to care for more cardiac arrest patients, but could not fill those rooms because of a lack of trained healthcare workers. He could not simply offer higher pay. He was part of a larger organization where he had limited decision-rights that reduced his nimble control. (On the importance of decision-rights, see Koch 2007.)
(p. 27) In reality, by the time a patient without a pulse arrives in the E.R., we know what the outcome is going to be. We continue CPR and shock the patient if we can. We insert a breathing tube and connect it to a ventilator. We inject medications: adrenaline, heart-rhythm drugs. But these treatments almost always fail.
. . .
Demetris Yannopoulos, an interventional cardiologist and professor at the University of Minnesota Medical School who created its Center for Resuscitation Medicine, refused to accept that this was the best doctors could do. In 2014, he began performing ECPR, a treatment that was starting to catch on in a few places, mostly in Asia and Europe. To his surprise, patients he didn’t expect to survive ended up doing well. . . .
When a patient in cardiac arrest is placed on an extracorporeal membrane oxygenation (ECMO) machine, as Sauer was, the treatment is called ECPR. The type of ECMO intervention used in ECPR provides full life support, which means it does the work of both lungs and heart. (Another type of ECMO, used on Covid-19 patients, helps just with breathing.) ECMO evolved from the heart-lung machines that started being used during heart surgery in the 1950s.
. . .
ECPR by itself doesn’t actually cure anything. But by providing fresh blood flow to the brain and other organs, it lets the body rest and gives doctors time to fix the underlying problem, if it’s fixable. . . . After patients are hooked up to ECMO, angiograms of their hearts are typically performed to determine whether they have clogged arteries — as about 85 percent do. In Sauer’s case, Yannopoulos found a blockage in his largest heart vessel, the left anterior descending artery, also known as “the widow maker.” He inserted a stent to open it back up.
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(p. 28) Several years after the program started, Yannopoulos, Bartos and their team conducted the first randomized, controlled trial of ECPR. The results were published in The Lancet in 2020 as the ARREST trial. . . .
After enrolling just 30 patients, the ARREST trial was stopped early by an N.I.H. board because the patients who got ECPR did so much better than the control-group subjects who received standard resuscitation, and it would have been unethical to continue the study. After six months, 43 percent of the 14 patients who got ECPR were alive with good brain function, compared with zero in the control group.
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The Helmsley Trust gave Yannopoulos grants totaling $19.4 million, which enabled him to add this “hub and spoke” mobile component to his program: The university hospital would be the hub, and a truck and some local hospitals would be the spokes. “It was a real big bet,” Panzirer told me.
To reach patients in areas that were more suburban and rural, Yannopoulos first had to team up with surrounding health systems. Competition is more often the norm among health systems, rather than collaboration, but he persuaded his chief executive, James Hereford, to gather his counterparts from other institutions. Eventually, they were willing to work together. But they had to sort out a lot more than simply agreeing to collaborate. How would insurers pay for what they were doing? Would the initial hospital get the money, or would the university hospital? Would malpractice coverage protect doctors outside their own institutions? What about transport?
Every question could be turned into a reason for hospital administrators and lawyers to say no.
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(p. 29) The economics of ECPR are in line with those of other established lifesaving interventions, like dialysis and heart transplants. And if patients don’t survive, ECPR may perfuse their bodies with enough oxygen to keep their organs eligible for donation. The program in Minnesota costs about $3.2 million a year to operate, which is covered by its revenue. This doesn’t include the start-up funding from the Helmsley Trust, however, or the significant groundwork Yannopoulos laid before that — or his personal sacrifices. “When I started, I had hair and my beard was black,” says Yannopoulos, who is mostly bald and gray. For seven years, he was not paid for his ECPR work; some years, he was on call every day. Today, he still spends about 6,500 hours on call annually. “It’s the force of his will more than anything,” Hereford says when explaining why the program has succeeded.
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Yannopoulos has invited physicians from all over to visit his program; afterward, he often hears from them that replicating his work at their home institutions — getting health and E.M.S. systems to collaborate, finding institutional support and start-up funding, coordinating 24/7 staffing — seems too daunting. For these reasons, Yannopoulos regards his ECPR program as “an administrative and political achievement, rather than a scientific or technological one.”
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(p. 30) The trial, called INCEPTION, compared ECPR with standard care across 10 medical centers in the Netherlands. It was the first randomized, controlled trial to look at ECPR across multiple facilities, and unlike the ARREST trial, it found that ECPR resulted in similar survival as standard treatments. . . .
Yet there are reasons to interpret the study as saying more about the real-world challenges of developing and implementing ECPR programs than it does about the treatment itself. In the INCEPTION trial, it took roughly a half-hour longer for patients to get on an ECMO machine once they arrived at the hospital than it did in the ARREST study. Of the patients who got ECPR, 12 percent were not successfully connected to the machines, compared with zero in ARREST. Several Dutch hospitals handled only a couple of ECPR cases a year, which means they hadn’t yet acquired the right skills. “I think they were destined for failure because of that rollout, with no experience up front,” Bartos says.
Experience matters profoundly: According to a 2022 paper based on data from the Extracorporeal Life Support Organization, an international nonprofit that Robert Bartlett founded, patients treated at centers that perform fewer than 10 ECPR procedures yearly have 64 percent lower odds of survival; for every 10-case increase, the odds go up 11 percent. (The Minnesota program treats about 150 every year.)
Not only does the procedure itself require mastery, but so, too, does the care in the I.C.U. afterward — an ineffable art as much as a precise science.
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(p. 45) . . . it’s not much of a surprise to hear Yannopoulos ask, “What does INCEPTION have to do with what we’re doing?” His program was carefully developed, with deep expertise, over years, to achieve the best outcomes; INCEPTION studied what would happen if a lot of hospitals started doing ECPR tomorrow.
Engineering the ideal ECPR program can feel like a maddening calculus involving experience, availability and distance — all to beat time. To treat patients faster, maybe doctors should go directly to the scene. For more than a decade, doctors in France have been doing just that, performing ECPR on the streets of Paris, in Métro stations, even on the oak parquet floors of the Louvre. Early on, Lionel Lamhaut, the head of Paris’s ECMO team, was told that he was “a cowboy to try to do something outside the hospital.” But as he and his colleagues persisted, they “started a new way of thinking.”
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. . . as much money as the Helmsley Trust has given, it is not enough to overcome some of the structural limitations in the American health care system. The organization funded a multimillion-dollar expansion of the cardiovascular I.C.U. at Yannopoulos’s hospital to add 12 more spacious rooms specifically designed to accommodate patients on ECMO. But on a weekend in January when I visited, the I.C.U. was closed to new ECPR patients: Not enough nurses were available to work, so four beds in the unit were kept empty.
Even as Yannopoulos and his team hit administrative roadblocks like these, they are still trying to redefine what is medically possible. Recently, a 74-year-old man collapsed on the streets of St. Paul and went into cardiac arrest. Forty-two minutes after the first 911 call, the man was already on ECMO and had regained his pulse. Yannopoulos was optimistic about the case, given how quickly ECMO was started, even though the patient had not been shocked with a defibrillator — which meant he technically fell outside the protocol and should not have received ECPR at all. (After a week in the I.C.U., the man died when his family decided to stop all treatment.)
The man’s heart was almost certainly in pulseless electrical activity (P.E.A.), which many experts think should not be treated with ECPR. Of the three published ECPR randomized, controlled trials, only one did not limit the intervention to people with shockable rhythms. That ambitious trial, in Prague, included patients whose hearts were in the same P.E.A. pattern as the St. Paul man’s. The study was stopped early when it appeared that ECPR wasn’t saving significantly more people than standard care was. These enigmatic cases that lack shockable rhythms are vexing: When the Prague data was reanalyzed without these patients, the findings were favorable for ECPR.
Yannopoulos is undeterred by the Prague results. “You have to decide what’s more important: your survival rate” — what is often used in studies and by institutions to justify support for a program — “or the number of patients you actually save.” Because its program is now well established, Yannopoulos’s team is starting to treat patients with less promising rhythms, even though that may drive down its overall survival rate. . . .
Yannopoulos wonders if, in a decade or perhaps less, ECPR science will still require the same specially trained teams using the same high-tech equipment — at least before patients get to the hospital. Instead, he imagines small cannulas that will be easy to place in the patient’s neck and attached to compact, simple machines that provide some blood flow to the brain. In his vision, which he is currently working to realize, medics could be trained to start people on this, and then doctors could transition them to regular ECMO once they reach the hospital. If the brain is protected, the rest of the body can eventually recover.
. . .
“There is this idea that people in cardiac arrest, you cannot harm them,” Yannopoulos says. For some doctors, that means cycling relentlessly through chest compressions and medications, so they feel as if they did everything they could. For others, it means briefly going through the motions, so they feel as if they did something. And for still others, it has always seemed kindest to do nothing at all, to let their patients die peacefully. Because almost none of them lived — no matter what the doctors did. “But now we know what is possible,” Yannopoulos says. “So if you’re not achieving that, then you are harming them in a way, right?”
For the full story see:
Helen Ouyang. “Reinventing CPR.” The New York Times Magazine (Sunday, March 31, 2024): 22-31 & 45.
(Note: ellipses added.)
(Note: the online version of the story was updated June [sic] 19, 2024, and has the title “The Race to Reinvent CPR.”)
Some references relevant to my discussion at the start of this entry are:
Bush, Jonathan, and Stephen Baker. Where Does It Hurt?: An Entrepreneur’s Guide to Fixing Health Care. New York: Portfolio, 2014.
DeVita, Vincent T., and Elizabeth DeVita-Raeburn. The Death of Cancer: After Fifty Years on the Front Lines of Medicine, a Pioneering Oncologist Reveals Why the War on Cancer Is Winnable–and How We Can Get There. New York: Sarah Crichton Books, 2015.
Diamond, Arthur M., Jr. Openness to Creative Destruction: Sustaining Innovative Dynamism. New York: Oxford University Press, 2019.
Klein, Gary A. Seeing What Others Don’t: The Remarkable Ways We Gain Insights. Philadelphia, PA: PublicAffairs, 2013.
Klein, Gary A. Sources of Power: How People Make Decisions. 20th Anniversary ed. Cambridge, MA: The MIT Press, 2017.
Klein, Gary A. Streetlights and Shadows: Searching for the Keys to Adaptive Decision Making. Cambridge, MA: The MIT Press, 2009.
Koch, Charles G. The Science of Success: How Market-Based Management Built the World’s Largest Private Company. Hoboken, NJ: Wiley & Sons, Inc., 2007.
Silberner, Joanne. “How a Plunger Improved CPR.” The New York Times (Tues., June 27, 2023): D5.
Taleb, Nassim Nicholas. Skin in the Game: Hidden Asymmetries in Daily Life. New York: Random House, 2018.
Vardi, Nathan. For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug. New York: W. W. Norton & Company, 2023.
