Photo: ALEX HOGAN/STAT
It was late April, near the height of the Covid-19 pandemic in the big cities in the northeastern U.S., and anesthesiologist Joseph Savino was puzzled. In two months, an unexpectedly high number of coronavirus patients had died in his intensive care unit at the Hospital of the University of Pennsylvania after a stroke caused by bleeding in the brain.
All were among 15 Covid-19 patients at the Philadelphia hospital who had been on a life-support technology called ECMO that is a last resort for patients when mechanical ventilators fail to help their virus-ravaged lungs.
ECMO, for extracorporeal membrane oxygenation — essentially an artificial lung — is high-risk, but still, the number of fatal brain bleeds seemed unusual, said Savino, a critical-care specialist. It was too low, however, “to draw any substantive conclusions” about cutting back the blood-thinning drugs they were giving other Covid-19 patients on ECMO, because blood clots, not bleeds, were seen as the major risk to survival.
So Savino described the dilemma on a virtual forum on Zoom, where dozens of critical-care experts from around the world meet each week to share their experiences with Covid-19 patients. A participant from Massachusetts General Hospital in Boston said two Covid-19 ECMO patients there had also died after suffering bleeding in the brain.
“We thought that couldn’t be a coincidence,” Savino recalled in an interview. He and his team immediately reduced the doses of blood thinners for their ECMO patients. Since then, the fatal bleeding strokes have stopped.
“If our Zoom conference was yesterday, change in practice is occurring today,” Savino said. He believes the forum is improving care for Covid-19 patients.
Swamped by overflowing ICUs and the myriad not-seen-before ways the novel coronavirus attacks the body, doctors caring for the pandemic’s sickest patients are scrambling to share their experiences with each other in real time, hoping to find ways to stanch Covid-19’s devastating toll. Some 200 physicians from several countries and dozens of states have participated in the Friday Zoom sessions. As cases have surged in new hot spots in the U.S., the calls are providing doctors from Florida to Texas to Arizona fresh from-the-trenches advice on how to use ECMO, a technology that can be lifesaving for some of the most severely ill Covid-19 patients but that has worrisome drawbacks.
The sessions have featured a range of issues, from technical matters such as the size of tubing used to connect patients to the ECMO machine, to what to do about patients whose lungs haven’t improved after weeks. Doctors have presented case studies highlighting the treatment and course of individual patients and discussed the ethical challenges of determining which patients should be offered the technology.
The Zoom forum has also provided a window on the pandemic’s spread. The initial sessions in March and early April featured talks by European experts, including the head of the ICU at Paris’s huge La Pitié Salpêtrière Hospital, which treated some 80 patients with ECMO amid the pandemic’s surge in Europe. In April and May, as the epicenter shifted to the U.S., the 60- to 90-minute sessions often began with doctors from cities such as Boston, Seattle, and Philadelphia reporting on the number of patients on ventilators or ECMO in their ICUs.
This past Friday, a Houston doctor presented summaries of 11 patients on ECMO, many of them Hispanic. He mentioned a community hospital in Corpus Christi, near the hard-hit Rio Grande Valley, where about 150 patients were currently on ventilators, nearly as many as were on the devices at Mass. General at its peak. Scott Silvestry, a thoracic surgeon at AdventHealth Orlando, told the forum, “We are completely full with regards to our capacity to take Covid patients.”
At the invitation of Savino and Eduardo Rame, a cardiologist at Thomas Jefferson University Hospitals in Philadelphia and the chief organizer and moderator for the sessions, a reporter for STAT has been allowed to sit in on the virtual sessions since early May.
Rame initiated the forum in mid-March after learning from European specialists how the influx of Covid-19 patients was overwhelming ICUs in Paris and Italy.
“They were all scared,” he recalled. “They said, ‘It’s coming to you.’” He had recently left Penn to become enterprise chief of advanced cardiac and pulmonary vascular disease at Jefferson and knew from his Parisian conversations that preparing his team for the anticipated onslaught required making connections with other centers and knowing the capacity of ICUs and ECMO machines in his city and state.
He reached out to Savino and other former colleagues at Penn, and as the surge of patients began filling the ICUs in the Northeast corridor and other U.S. locations, the resulting collaboration quickly morphed into the weekly Zoom sessions. “By week four, we had 100 participants,” Rame said.
Sharing reports on individual cases doesn’t meet the rigor of clinical trials doctors typically rely on to order treatment for patients. “It isn’t science — yet,” Savino acknowledged.
But with patients showing up in the emergency room with a modest cough one day and crashing so fast they need to be put on a ventilator the next, the conventional methods of validating and disseminating clinical information through scientific journals and medical meetings weren’t sufficient. Even medical journal efforts to accelerate online publication of Covid-19 research as well as the rush by researchers to post results on so-called preprint servers before they are peer-reviewed have failed to satisfy critical-care doctors’ urgent need for help in the fast-moving pandemic.
“Science will ultimately have more answers,” Savino said. “But there are a lot of people in hospital beds that need answers now. The best we can offer is experiential learning, or learning from each other.”
Specialists in critical care, ECMO, and advanced lung and heart disease comprise a small community in medicine. Many of the Zoom participants have logged at least a decade or two in critical-care medicine and had either trained or were trained by others on the sessions.
“In a trusted circle, where people have known each other for years, it carries a lot of weight,” said Silvestry, a regular on the forum.
An early question for the U.S. doctors was whether to offer ECMO at all. Some early reports raised doubts it would help Covid-19 patients.
One from Wuhan, China, where the pandemic originated, and published online in The Lancet Respiratory Medicine in late February, reported that five of six patients put on ECMO died. Small numbers, but a mortality rate over 80% was way too high for a high-cost technology that requires intensive nurse staffing to manage. Another study linked ECMO with poor results among patients with multiorgan failure — a problem in part because most of the pandemic’s sickest patients had other serious medical conditions.
Using ECMO to assist the lungs in patients with respiratory failure typically involves inserting a cannula or tube in a femoral vein in the groin from which blood flows through an oxygenator to add oxygen and remove carbon dioxide. The freshened blood returns to the body via a tube inserted into the right jugular vein for travel to the heart.
The blood’s almost continuous contact with the parts of the ECMO circuit promotes blood clots, while the skin punctures needed to insert the tubes raise the chance of bleeding. Emerging evidence that the virus attacks the blood vessels and other organs compounds some risks associated with the technology.
“This disease is challenging the very technical foundation of ECMO,” Rame said.
But all was not lost for ECMO. In April, the ASAIO Journal (for American Society for Artificial Internal Organs) published a case report of a 44-year-old emergency room doctor believed to be the first successful Covid-19 ECMO patient in the U.S. Rame invited Matthew Hartman, a cardiologist at Swedish Medical Center in Seattle and lead author of the report, to present the case on the forum.
The patient likely was infected while treating other Covid-19 patients in Seattle, where the first outbreak in the U.S. occurred. But he tested negative for the virus when he first arrived at an ER with shortness of breath and a fever. He was diagnosed with pneumonia and sent home. He returned the following day with worsening symptoms, tested positive for the virus and quickly went downhill.
“He went from a guy who was talking and needed some oxygen to being on a ventilator within like 24 hours,” Hartman recalled in an interview. His condition continued to deteriorate as levels of an inflammatory cytokine called IL-6 soared, indicating his immune system’s hyper response to the virus, and he developed an acute kidney injury. Laboratory markers indicated his risk of death was 80%.
“It was sort of ECMO or nothing,” Hartman said. “The consensus was while we don’t know if we can get him through it, he’s getting sick so quickly we should at least try.”
By the third day on ECMO, his inflammatory markers began to decline and his lung function improved. On the seventh day, he was “weaned” from the technology. Four days later, he was taken off the ventilator. He was discharged on his 24th day in the hospital and has recovered.
Hartman told the Zoom forum he and his colleagues don’t know what worked — whether it was ECMO or the various drugs the patient received. His treatment while on ECMO included the antiviral hydroxychloroquine (the drug later touted by President Trump but shown in studies to be ineffective against the virus); tocilizumab, a rheumatoid arthritis drug that blocks IL-6 (but that drugmaker Roche recently reported failed to benefit Covid-19 patients in a randomized clinical trial); and high-dose vitamin C, a possible anti-inflammatory.
In the pandemic, as “people are getting sick and dying, a lot of therapies are being tried and not in a controlled fashion,” Hartman pointed out.
“It’s hard to say for the first case you did well, was it anything we did or did the stars line up,” Hartman said. And it was just one case. But it did suggest that ECMO, which itself isn’t a therapy, did its job by providing time for the patient to heal or benefit from his care. Given the patient’s kidney injury, the case also indicated people with multiorgan failure could be helped by the technology.
The Seattle case as well as other success stories from Paris and Japan offered encouragement to the Zoom sessions that ECMO was a viable option in the toolbox for desperately ill Covid-19 patients, though it is still being used sparingly.
A Covid-19 registry being compiled by Mayo Clinic and the Society of Critical Care Medicine from 235 centers in 18 countries (including 202 centers from 38 states in the U.S.) indicates that about 30% of Covid-19 patients who are hospitalized end up being treated on mechanical ventilators and that just 2% are put on ECMO.
One value of the discussions, said AdventHealth’s Silverstry, is “knowing what we’re doing in Florida is the same as what they’re doing at Mass. General and Penn. We’re doing it the same way because of connections like this.”
Participants in the Zoom sessions have shared their experiences with a range of treatment strategies: Using wider diameter tubes to move blood from the body to the oxygenator and back to the body allows for increased flow, potentially improving oxygen levels and reducing risk of clots. Aggressive use of bronchoscopy to remove thick, sticky mucous may improve function of Covid-19-ravaged lungs. Pronating patients on ventilators and ECMO — flipping them regularly to lie on their stomachs and reduce pressure on the lungs — appeared to improve breathing function and oxygen levels, though it takes at least six people to flip a patient on ECMO and some doctors on the sessions said they believe pronating is more helpful before ECMO.
The insight Savino gained from his concern about fatal bleeding in the brain was part of a broader discussion that revealed wide variation in anti-coagulation regimens among centers offering ECMO.
Whether his team’s decision to reduce the dose of blood thinners prevented further brain bleeds is hard to know, he said. His ICU has had only a few new ECMO patients since then — too few to reach any conclusions. But he believes the discussions will lead to more rigorous research to identify the optimal strategy, thus advancing the science of ECMO.
The forum has also addressed another vexing problem: what to do about patients who stay alive for weeks on ECMO even though their lungs don’t seem to get better. In June, Rame invited doctors representing teams from Vienna and Chicago who had each performed an apparently successful lung transplant on a young woman whose lungs appeared beyond recovery.
Participants in the Zoom sessions congratulated the doctors on their accomplishments. Then they asked tough questions. A big worry, said Emily Blumberg, director of transplant infectious diseases at Penn, is that some patients continue to test positive for the coronavirus for weeks after the initial infection. Though doctors suspect the virus is inactive in such cases, “you would like the infection to be clinically or virologically resolved,” Blumberg said. “How you define resolution is very complicated.”
Other doctors noted that ECMO patients are often put in a drug-induced coma and paralysis to enable smooth operation of the technology. That can lead to weeks in an ICU bed that leaves them too deconditioned to be transplant candidates and makes it difficult to assess their neurological status and ability to give informed consent.
Moreover, “some patients just have long recovery phases,” Blumberg told the forum. “It’s important not to confuse a long recovery from ongoing pathogenesis that had led to irreversible destruction of the lungs.”
Indeed some doctors said they’ve seen patients with heavily damaged lungs recover after spending two months or longer on ECMO and it would be a waste of a scarce resource — donated lungs — and possibly shorten a patient’s life span to perform a transplant if the lungs could recover.
The discussions generally put cold water on the that transplants would be a viable remedy for acutely ill Covid-19 patients. But doctors wondered whether ECMO might create a cohort of patients with compromised lungs who will need a transplant a year or two down the line, putting a run on a scare resource.
ECMO itself is a scarce resource, and during a Zoom session last month, doctors debated the ethics of deciding which patients should be offered it, and how long they should be allowed to stay on the machine before someone waiting in line should get a chance. Older age and certain serious medical conditions were two considerations that pushed patients down the priority list for starting on ECMO, participants said.
Mass. General, for example, initially determined that patients with renal failure should be ruled out for ECMO, but when it turned out that a lot of very sick Covid-19 patients had renal failure, the hospital loosened that restriction, Yuval Raz, the hospital’s medical director for respiratory ECMO, told the group. At one point, the hospital set a record for the number of patients on ECMO at one time and had to suspend use of the technology for 24 hours, he said.
“Obviously, it can be hard to stop ECMO once started,” added Emily Rubin, a pulmonologist and critical care specialist at the hospital. “But it can also be hard in a very emergent situation to sort things out in enough detail to deny access to begin with.”
Other doctors noted that the drain on staffing is a major concern with ECMO. In an interview, Advent Health’s Silvestry said if he has four Covid-19 patients on ECMO, he needs eight nurses to care for them. But it requires just two or three nurses to care for eight Covid-19 patients who don’t need the technology to survive.
One of his own recent cases underscores some of the ethical challenges. He got a call from a doctor in South Florida on a night in early July who had a 28-year-old Covid-19 patient who had just given birth via C-section, who had other children, and who desperately needed ECMO. He had called five other hospitals in South Florida; all were full.
“There was fear in his voice that he could do nothing else for this patient,” Silverstry said. His hospital had one bed left, but what was the hospital’s obligation if a patient from the Orlando area needed it? He called around to colleagues in Tampa and other hospitals in the state.
None was able to take the patient. So Silvestry sent a team to transport the patient to Orlando. She was hooked up to ECMO and quickly improved. Six days later, she was sent back where she could be with her baby, Silvestry said.
“Everybody was happy,” he added, but “there was no place for people who really needed extraordinary care.”
Future topics for the sessions are likely to include managing pregnant or immediately postpartum Covid-19 patients who may need ECMO like Silvestry’s, and whether earlier or less-invasive ECMO-style interventions might improve outcomes for patients.
Based on published reports and data presented during the sessions, Rame estimates the survival rate for Covid-19 patients put on ECMO is 55% to 60%. This is in line with a 55% survival estimate for Covid-19 patients on ECMO from a registry compiled by the Extracorporeal Life Support Organization, an Ann Arbor, Mich., group that has tracked ECMO outcomes for 30 years. Rame hopes that with more data published in journals and the help of the weekly Zooms, survival for Covid-19 patients will reach 60% to 70%. “Not bad,” he said, “given survival would have been zero.”
Mass. General’s Raz said what he learned from the French in the sessions helped his patients, while Raz’s experience in turn aided doctors at Penn and other centers. “Now places in Texas, Florida, and Arizona are able to gain information from what the hospitals in the Northeast went through,” he said.
All of which reflects a level of “collaboration between centers that did not exist before,” he added. “That’s the best thing coming out of these meetings and a silver lining for the Covid era.”