Ambulance and emergency sirens in New York City are wailing ceaselessly this month, as the number of reported deaths from Covid-19, the disease caused by the novel coronavirus, in the state surpassed 4,100 as of April 6. (Public health experts say that these tallies are severely undercounting the total.)
As one of the hardest-hit locations in the US so far, the city is scrambling to find enough ventilators — equipment that gets oxygen into the lungs of severe Covid-19 patients having trouble breathing on their own — for the expected surge in patients. Gov. Andrew Cuomo said at a press conference April 4 that the state had ordered 17,000 ventilators from the federal government, but “that order never came through.”
Although New York City may be the first city in the country to run out of ventilators, other cities are expected to follow. New Jersey Governor Phil Murphy recently tweeted, “Ventilators are our #1 need right now. I won’t stop fighting to get us the equipment we need to save every life we can.” Louisiana Governor John Bel Edwards predicted that his state would run out of ventilators by April 6.
But to save a Covid-19 patient’s life with a ventilator, you also need an ample supply of medications, both to be able to use the machine and to prevent agonizing pain. Experts say there’s a worrisome shortage of those, too — one that’s only expected to grow worse.
“The minute you talk about ventilators you need to talk about medications,” says Esther Choo, an associate professor of emergency medicine at Oregon Health & Science University. Choo says hospitals are already running out of medications like fentanyl, versed, propofol, and even neuromuscular blockades, what she calls “everyday bread and butter medications,” the drugs needed to induce and maintain sedation while on a ventilator. “Ventilators can’t really be used without these medications.”
Why you need medications to use ventilators
In severe cases of Covid-19, the patient's’ own immune system can cause their lungs to fill with fluid. At this point, ventilators are a critical tool for keeping people alive. Medical staff insert a tube deep into the lungs in a process called intubation, in order to deliver more oxygen from a ventilator than the patient can inhale on their own.
“You can imagine if I tried to shove a plastic tube down your throat, it’s a very human reflex not to let someone do that,” Choo says. “So we place people in deep sedation.” After the tube is placed in the trachea, patients have to stay sedated — in the case of some Covid-19 patients, that can last for several weeks. Without the right medications, “that experience can be agonizing,” Choo says.
It’s alarming that hospitals are already experiencing shortages of these drugs, knowing what’s coming. Although President Trump has invoked the wartime Defense Production Act to start producing the additional 40,000 ventilators New York alone has requested, these won’t help stem the crisis for long without the drugs needed to use them — to say nothing of the freewheeling chaos of inter-state bidding wars for scarce supplies.
The American Hospital Association estimates close to a million Americans will need ventilators during the pandemic. So far, between roughly five and 11 percent of Covid-19 patients in the US have required intensive care. Although how many Americans have needed ventilators isn’t publicly tracked, in one study in China, 17 percent of intensive care patients required ventilators.
Already, “our health systems and hospitals are seeing demand across the country on pharmaceuticals that’s unprecedented,” says Dan Kistner, a group senior vice president at Vizient, an organization that negotiates contracts for medicines on behalf of over half of hospitals and health care facilities in the US. “We have never had the amount of demand for some of these life-saving drugs as we do now.”
“If you say we need ventilators and not, and the drugs to make them go, we’re going to have a ton of ventilators sitting around not being used,” he says. “It’s like having a car without gas.”
Drug shortages were already common before the pandemic
While the Food and Drug Administration (FDA) is ostensibly in charge of ensuring the US has an adequate supply of drugs, in practice this has been difficult, even before the pandemic hit.
“Unfortunately, hospitals and health systems are way too familiar with drug shortages,” Kistner says, explaining that for at least the last decade, hospital drug shortages have been commonplace and dangerous. “The number one problem is that no one knows exactly where a drug — and at what volume — is being made today.” Because this information is regarded as a trade secret, “not even the FDA has insight into how much volume of a particular product, or the raw materials of that product, are being made.”
That said, it’s clear many active pharmaceutical ingredients (API) come from abroad: According to the Council on Foreign Relations, about 80 percent of these are thought to come from China and India, “though the exact dependence remains unknown, since no reliable API registry exists.”
This lack of transparency, coupled with quality control problems and supply chain bottlenecks, have led to frequent shortages of even “workhorse products,” such as fentanyl and hydromorphone, says Erin Fox, who manages drug information and monitors supplies at University of Utah Health Care’s four hospitals. Many of these crucial generic drugs are made by just a few companies, so “when one has a problem or needs to fix something at a factory, there’s not enough capacity at the others to pick up the slack.”
Hospira, which before its 2015 acquisition by Pfizer was the world’s largest producer of generic injectable pharmaceutical drugs, made many of these generic medications. As a result of the merger, Pfizer inherited Hospira’s quality and control problems, and even pre-Covid-19, was having trouble producing sufficient quantities.
In January, before the coronavirus was spreading widely in the US, many hospitals had a 95 percent fill rate of some common sedatives — if they ordered 100 vials, they only got 95.
Even when factory lines are running properly, these companies forecast their manufacturing out years ahead of time based on how much has sold in the past, says Fox. “With this situation, where all of a sudden we need 10 times the usual amount of sedative drugs — no manufacturer has that sitting in their warehouse.”
“The drugs that go short, always and unfortunately, are generic drugs,” says Kistner. These are the drugs that have competition in the market, while branded drugs are patent-protected and companies invest in their supply chains because the profit margins are often higher.
The pandemic has triggered an extreme spike in demand
Just how many additional patients will need ventilation and the essential accompanying medicines depends on how well social distancing measures succeed at flattening transmission rates. But according to Vizient’s data, which approximates real-time orders from over 3,000 hospitals, between January and March there was a 51 percent increase in demand for a group of sedatives and anesthetics. “This is all happening when everyone is canceling elective surgeries,” for which sedative drugs are also required, Kistner says. “So it’s really more than a 50 percent increase.”
Fox says that her hospital system in Utah normally has 80 patients a day, and is ramping up to take care of more than 200 critically ill people a day. “It’s more than double,” she says. But most of the drug wholesalers are trying to limit hoarding, and many of these medications are controlled substances, meaning “the Drug Enforcement Administration has rules about how much a hospital is allowed to buy,” she says. “You can’t just order double.”
Jennifer Davis, the system director of pharmacy services for SCL Health Medical Group in Colorado, says she is expecting a five-fold increase in patients needing these medications. “For these drugs in particular, I would say we get less than half of what we order.”
How to fix the shortage
The limited supply of these essential drugs is not an easy problem to solve. Most of the drugs needed for patients on ventilators are administered through an IV or injections, and making them is harder than making tablets that can be taken orally. They also have a built-in 21-day sterility period, where they need to be quarantined to make sure nothing is contaminated.
Kistner says that if you started making more of these drugs today, it would take a minimum of five weeks to get it into the hands of an ER doctor beside a ventilator.
“We can’t say tomorrow we’re going to make this drug and have it by the end of week,” he says.
That’s why although there are uncertainties in all of the models, “you don’t need a model to say if the country would usually use 6 million vials of sedatives a month, and now you need 10 or 12, and you can’t make these drugs overnight — you have to act now,” Kistner says.
Manufacturers of these critical medications have to do what they can now to start increasing production, but at the same time, medical staff also have to start planning for how to handle shortages. So far, we have been behind the curve in preparing for Covid-19 every step of the way.
“Hospitals will need to be flexible, and think about not just Plan A and B, but Plan C, D, E, F, and G,” Fox says. “That may mean patients get different therapies depending on what is in stock,” Davis agrees. Pharmacists and doctors can substitute second and third-line medications, or try different combinations, or even try using a feeding tube to give drugs orally (instead of by injection).
But Fox says, “We do worry about medical errors when people have to use medications they’re not as familiar with dosing, especially if you think about having to take care of so many sick patients all at once.”
Choo is advocating for the federal government to establish centralized systems that could track patients, move supplies to where they are most needed, and inform manufacturers of demand. “We need to use something like Defense Production Act to mobilize industry and create public-private partnerships and stimulate mass production of these medications,” she says. Widespread Covid-19 testing is part of this strategy — by knowing who is sick, vital medicines can be shifted to the right states at the right time.
But Fox is more cautious. “We need to think through ways to conserve products,” she says. “I don’t know if Donald Trump can make drug companies churn out more drugs when some aren’t even American drug companies.”
She also notes that although the FDA has asked companies to ramp up supply, they may not have the capacity to do so. “They may literally be limited by the total amount the factory can make in a certain amount of time.” In normal times, a solution could have been importing critical medications from other countries, but in a global pandemic, we don’t have that luxury. “Europe is having their own shortages of the same medications,” Fox says. “It’s not like there’s empty factories we can just turn on and start cranking out drugs.”
Choo adds that simply reinforcing stay-at-home measures to slow the number of critically ill patients coming into the hospital will also help. That helps spread out the demand for these medications over time, giving manufacturers a chance to keep up.
But so far, this is a looming and unsolved problem. “The thing that keeps me up at night,” says Fox, “is that there will be physicians and nurses and ventilators for patients — and not enough medication.”