A patient opens their lunch box in the Covid-19 intensive care unit on Christmas Eve at the United Memorial Medical Center in Houston, Texas.

Recovery From an ICU Stay Is Tough. Could More Protein Help?

Paul Wischmeyer was a teenage athlete when he learned firsthand just how devastating an intense illness can be. After spending the better part of a year severely sick and frequently hospitalized with undiagnosed severe inflammatory bowel disease, his colon perforated, landing him in the intensive care unit. When he finally recovered, he went from being a starter on his high school basketball team to being too weak to walk down the court — profoundly disabled from just being in the hospital.

He built back his strength over the next few years, and eventually worked his way through medical school as a personal trainer in a competitive bodybuilding gym, where he helped clients sculpt their physiques by providing them with targeted workouts and having them add protein and other nutritional supplements to their diets. But it wasn’t until his training in critical care medicine that Wischmeyer began to thread together his interest in bodybuilding with his interest in ICU recovery.

Critical care experts have long known that a stay in the ICU can lead to long-term weakness lasting months or even years after discharge, regardless of the specific illness. Wischmeyer was especially struck by his patients’ massive loss of muscle, which reminded him of his own experience. “I’d watch people lose half their body weight in a short period of time and not be able to walk,” he says.

Today, Wischmeyer, a critical care and nutrition physician at Duke University, is a leading voice among clinicians and scientists investigating whether increasing protein intake during and after hospitalization could be an important and long-overlooked component of recovery. Lean muscle melts away startlingly quickly in ICU patients, and muscle-wasting is a predictor of long-term impairment after hospitalization, studies show. Proponents of the approach say that protein, a nutritional cornerstone for body builders, may help critically ill patients retain muscle or rebuild it as well. “Protein is what everyone is interested in in right now,” says Zudin Puthucheary, a clinical senior lecturer in intensive care at Queen Mary University of London. (Wischmeyer, like many researchers in the nutrition field, has received funding from industry.)

But some question whether simply adding more protein to patients’ diets will translate into increased muscle mass and better functioning. While several studies suggest that boosting protein levels early on after critical illness or surgery may improve recovery, they have mostly been small, and other studies have not shown a benefit. “Protein provision might be important, but there aren’t large studies to understand that yet,” said Renee Stapleton, a pulmonologist and critical care physician at the University of Vermont Medical Center. A handful of such studies are currently underway, but whether they will bring clarity to the protein picture remains to be seen.

Clinicians have a name for the long-term disability some people experience after an ICU stay: ICU-acquired weakness. Critical care physician Margaret Herridge of Toronto General Hospital began quantifying the effect some two decades ago. More than half of people in their 40s and 50s who spend a week on a ventilator don’t return to work a full year after their hospital stay, she found, and a third never do. Even five years later, patients on average recover only three-quarters of the stamina and 6-minute walking distance of their age- and sex-matched peers.

The Covid-19 pandemic has highlighted this issue by bringing huge waves of patients to the ICU. People hospitalized with Covid-19 tend to stay in the ICU longer than other patients, and that, along with the drugs and sedation they receive, likely ratchets up the risk of disability afterwards. “I think Covid has highlighted for the general public a lot more about what happens in the ICU,” including the challenge of reaching a full recovery, says Lee-anne Chapple, a critical care dietician at the University of Adelaide in Australia.

Researchers think that the massive muscle wasting that occurs during a critical illness deserves much of the blame for making recovery difficult. “The first thing we do when anything bad happens is we stop making muscle,” says Puthucheary. Not only that, the body also breaks down existing muscle through a process called catabolism. During muscle catabolism, proteins stored in muscle tissue are broken down into smaller molecules called amino acids and energy is released. That breakdown happens quickly: A person who undergoes surgery or who spends time in the ICU can lose up to a kilogram, or 2.2 pounds, of muscle mass per day during the acute stages of their illness.

“I’d watch people lose half their body weight in a short period of time and not be able to walk,” Wischmeyer says.

Theoretically, adding more protein to a patient’s diet can help minimize the muscle loss. Yet nutrition has traditionally gotten short shrift in medicine, some experts say; a 2019 report from researchers at Harvard University called for better education about nutrition during medical training. This is especially relevant to critical care, a specialty in which monitoring vital statistics, stamping out infections, and generally ensuring survival has been paramount, says Daren Heyland, a critical care physician at Queen’s University in Kingston, Canada. But the mindset is shifting as physicians start considering nutrition as something that is “really modulating the underlying disease process,” rather than merely playing a supporting role, Heyland says. “It is a major paradigm shift.”

Ironically, this shift is driven by improvements in critical care. Today, doctors can save people from trauma and illnesses that would have led to death just two decades ago. “With all this great technology, are we creating survivors — or victims?” Wischmeyer says. “There’s this epidemic of impaired quality of life that we have to address. And I think that is drawing a lot more attention to nutrition.”

Dietary guidelines recommend that a healthy adult should consume around 0.8 grams of protein per kilogram of body weight each day. Current intensive care guidelines, meanwhile, suggest that adults receive 1.2 to 2 grams of protein per kilogram per day, generally delivered through a feeding tube. Wischmeyer and other experts advocate for amounts at the high end of that range, depending on a person’s age and other factors. Yet it’s not just a question of raising protein targets; clinicians need to ensure those targets are actually being met as studies in U.S. hospitals show that patients are often getting less than half the recommended amount. “We are not getting anywhere near the lowest level” of recommended protein, says Wischmeyer.

Nutrition interventions are challenging to study — particularly in critically ill people, who are a heterogenous group. A blood pressure pill has a measurable physiological effect, and a clinician can see within hours of administering it whether it has done its job. But that’s not the case for something like protein. Not only would it take much longer to effect a change in body composition, there are no tests to track whether muscle cells are actually able to use the protein, says Chapple. Additionally, the timeframe of ICU interventions is generally limited to the week or two that a person spends there.

Most critical care studies have tested whether an intervention improves mortality in the months or year after an illness. But expecting a week of protein shakes to determine whether a person lives or dies is unrealistic, Wischmeyer says. Only recently have some studies begun using more nuanced endpoints measuring changes in a person’s quality of life, such as their ability to stand up from a seated position or walk a certain distance.

Still, the idea that patients will benefit from increased protein does align with what researchers know about building back muscle after its intense loss, which was comprehensively demonstrated in a study called the Minnesota Starvation Experiment. The study, which ran from 1944 to 1945 — and would probably not pass an ethics review today — tracked the effects on 36 men of slashing caloric intake in half for six months. The researchers found that the loss of lean muscle mass was extraordinarily hard to reverse, and doing so required sharply increasing the men’s calories and protein intake for as long as two years.

Past studies of athletes have helped researchers understand the cellular processes that occur when a person gains muscle. But it’s not clear how these processes work in critically ill people, says Arthur van Zanten, a critical care physician at Gelderse Valley Hospital and a professor at the Wageningen University and Research in the Netherlands. His work has shown that these patients usually have poorly functioning mitochondria — organelles that provide energy to cells in the form of adenosine triphosphate, or ATP. Without enough energy, the body can’t build muscle, no matter how much protein a patient consumes, van Zanten says.

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Puthucheary and his colleagues are conducting a small study to test whether ketones — an alternative fuel source derived from the body’s breakdown of fat — or an amino acid metabolite called hydroxy methylbutyrate might work better. But given the altered physiology associated with critical illness, building muscle may simply prove too difficult, he says. For this reason, Puthucheary is also focusing on trying to prevent muscle wasting, which likely involves a different set of metabolic mechanisms. “Rather than making someone who’s sick unsick, we are trying to work with the sick physiology,” he says.

As researchers continue to investigate how exactly protein and related factors can affect the physiological processes that underlie recovery, a handful of large randomized trials of between 800 to 4,000 participants are currently investigating the basic question of whether increasing protein intake in the ICU improves recovery. A smaller trial combines protein delivery with exercise. “In the next two or three years we will know exactly what is happening,” says van Zanten. “I’m personally convinced the higher protein groups will do better.”

Puthucheary is less certain — for one thing, because most of them don’t include exercise, which is also a key component of building muscle, he says — but time will tell.

Other studies are exploring interventions that begin after a patient has recovered enough to leave the ICU. Wischmeyer’s team, for example, is using principles from elite athletic training to develop a diet and training regimen that people can start in the hospital, right after they leave the ICU, and then they can continue at home. Van Zanten and his colleagues are also investigating nutritional and other strategies for promoting recovery in the months after an ICU stay.

That long-term window is virtually unexplored, yet that period may offer an untapped opportunity, van Zanten says. In the ICU, clinicians can monitor precisely what nutrients a person receives, but that’s much tougher after discharge. People’s food intake often slumps when they are sent home, but with inflammation and catabolism resolving, it’s when protein and other nutritional interventions, as well as physical activity, are likely to be especially effective. It may not always be possible to restore function fully, says van Zanten, “but I am very convinced that we can do a better job.”

Alla Katsnelson is a science journalist based in Northampton, Massachusetts. Her work has appeared in Chemical & Engineering News, Scientific American, The New York Times, and other outlets.