ARTICLE IN BRIEF
In a new study, investigators in London showed how quickly muscle loss occurs in the intensive care unit and the severity of the damage. They also showed that high protein nutrition appeared to be associated with more muscle loss.
Patients in the intensive care unit (ICU) grow considerably weaker over the course of their illness and, if they survive, it may take years to regain their muscle strength and move normally again. Doctors have been searching for explanations for skeletal muscle wasting and trying to develop ways to prevent or fix it. But no one is really sure what is going on in the muscle itself.
Now, a team of British scientists have studied muscle wasting in a large sample of patients in an ICU and identified some surprising findings that provide new insight into this common and debilitating problem. Ultimately, it could lead to treatments to slow or stop muscle wasting.
“This is the first time that anyone has used three independent measures to assess skeletal muscle wasting longitudinally in ICU patients,” said Hugh Montgomery, MD, the senior author of the study that appears in the Oct. 16 Journal of the American Medical Association (JAMA).
Dr. Montgomery and his colleagues at University College London showed how quickly muscle loss occurs and the severity of the damage. They also showed that high protein nutrition appeared to be associated with more muscle loss.
The goal was to characterize the time course and pathophysiology of acute muscle loss in these critically ill patients, and figure out how changes in muscle protein synthesis, breakdown, and other factors led to the muscle atrophy. “Understanding these biological changes that lead to muscle damage will help us design treatments for these critically ill patients,” said Dr. Montgomery.
The study took place at two hospitals in the United Kingdom. The research team recruited 63 patients within a day of admission to the ICU whom they believed would remain intubated for longer than 48 hours, would spend at least a week on the unit, and survive their illness. The average age of the patients was 55.
Family members were approached about the study and consented on behalf of their loved ones. Once the patient was alert and exhibited full mental capacity, he or she retrospectively provided consent.
The markers of muscle mass were assessed histologically, biochemically, and with ultrasound (rectus femoris cross-sectional area, or RF-CSA). Biopsy samples were taken from the quadriceps muscle. They assessed the rates of muscle protein synthesis at multiple time points throughout the first 10 days in the ICU. They looked at leg protein breakdown and balance, and serum creatine and myoglobin, which can be markers of muscle breakdown. They also looked at myostatin, which regulates muscle mass. And they measured protein concentrations in the synthesis and breakdown pathways of muscle, including in the ubiquitin proteasome signaling pathway.
At the same time they were sampling muscle, they were assessing the degree of organ failure and the severity of the patient's illness. They measured serum C-reactive protein concentrations and nutritional intake. They correlated the findings at the muscle to a number of clinical correlates.
During the study, 42 of the 63 patients had at least one muscle biopsy and 35 had two biopsies on days one and seven. On average, the cross-sectional sample of the rectus femoris decreased significantly from day one to day seven, and continued to decrease through day 10. Muscle from 28 of the patients was assessed using all three measures and they found the rectus femoris cross-sectional area decreased by 10.3 percent, the fiber cross-sectional area by 17.5 percent, and the ratio of protein to DNA by 29.5 percent.
Dr. Montgomery, Zudin Puthucheary, MRCP, and their colleagues reported that the pathways that build up muscle get shut off very early and this process leads to muscle breakdown, at the same time as pathways that switch on breakdown are activated. Thus, muscle protein fractional synthesis was depressed on day one (similar to a healthy person on a fast), and leg protein breakdown (compared to leg protein synthesis) elevated.
“It's a programmed response,” said Dr. Montgomery. By one week, synthesis was switched back on, while breakdown also remained activated: fractional synthesis rates were increased to rates similar to that of a healthy fed person, while breakdown remained high. The net balance remained catabolic. “It's as if, at this point, the engine is revving and ready to start build-up again.” An analysis of signaling molecules told a similar story.
The speed and severity of muscle wasting (assessed using ultrasound and histological muscle fibre cross-sectional area) was greater the more organs had ‘failed’: those with one organ failing had limited muscle wasting at one week, compared with around a 15 percent decrease in muscle mass in those with four organs failing. Wasting was also correlated with markers of inflammation (such as C-reactive protein), the degree of lung injury, and low hemoglobin.
The muscle biopsies also revealed a surprisingly high rate of necrosis — 40 percent — in the study patients. “This is much higher than other reports,” Dr. Montgomery said. Macrophage infiltrates littered the dead muscle cells. The “clinical variables did not correlate with the development of necrosis,” the study authors wrote. “We see that inflammatory cells come in very early and quickly,” Dr. Montgomery added.
Serum creatine kinase and myoglobin were slightly elevated on day one but both decreased by day seven. These levels were not correlated with the changes observed in the rectus femoris muscle.
The investigators are now trying to figure out the mechanism and identify ways to prevent muscle from breaking down. If the ‘breakdown’ is so well orchestrated, then it is likely to serve a biological purpose. Dr. Montgomery thinks that this may be to conserve energy: about 80 percent of the cell's energy is used to make protein. Perhaps in keeping with this observation, they found that the more protein that patients were fed, the more muscle was breaking down.
“This was totally unexpected,” said Dr. Montgomery. The current trend in attempting to strengthen muscle in ICU patients is to provide more nutrition, not less. But this finding suggests that this may actually make things worse. “It might be that we should intermittently feed ICU patients or not feed them at all,” said Dr. Montgomery.
The researchers are now conducting a study to see whether feeding patients three times a day rather than continuously will alter outcome. Skeletal muscle weakness can lead to long-term disability. Many people say that they want to get back to work and can't because of problems with muscle weakness and mobility, said Dr. Montgomery.
EXPERTS WEIGH IN
“This is a very elegant study and the authors should be congratulated for performing an array of assessments to assess skeletal muscle wasting in ICU patients,” said Leigh Ann Callahan, MD, a professor of medicine in the division of pulmonary, critical care and sleep medicine at the University of Kentucky. “Skeletal muscle weakness is associated with poor outcomes — short and long-term. The major problem is that, currently, there are no good treatments to prevent or reverse ICU-acquired weakness.”
“Most clinicians think that the muscle wasting is primarily due to immobility. But this study shows that it is not so simple,” she added.
In an October study in Critical Care Medicine, Gerald Supinski, MD, and Dr. Callahan measured diaphragm muscle strength in ICU patients and found that diaphragm strength was profoundly reduced in mechanically ventilated ICU patients. Infection was a major risk factor for diaphragm weakness, and outcomes were significantly worse in the weak patients.
“It is important to understand that loss of muscle mass — a measure of muscle quantity — doesn't necessarily correlate with muscle force generating capacity (force/CSA). You can have a muscle that atrophies but maintains its force generating capacity and vice versa. This study, however, did not assess the impact of muscle atrophy on muscle contractility.”
The British group found that the limb muscle wasting was linked to inflammatory markers, but not to increases in protein levels of the E3 ligases, Murf1, and atrogin, key proteins in the ubiquitin proteasomal pathway, which are thought to be important in most forms of muscle atrophy. Moreover, myostatin mRNA levels were not increased in the muscle biopsies. Dr. Callahan believes that this is an important finding, which underscores the complexity of muscle weakness acquired during critical illness.
She found it interesting that enriched feeding actually increased loss of muscle mass. “Many clinicians think that we need to provide better nutrition and get patients up and moving, but no one has clearly shown that this improves muscle function. It is just assumed that it would. But again, these findings suggest it is a complicated process.”
“These findings raise a number of questions. Clinicians have assumed that nutrition and mobility would fix this but now we need to look for other ways.”
In an accompanying editorial in JAMA, a team of clinicians from the University of Toronto — Jane Batt, MD, Claudia Dos Santos, MD, and Margaret Herridge, MD, wrote: “Given the complexity of ICU-acquired weakness, it is the rare study that concurrently assesses patients from both molecular and functional perspectives. This approach is essential to define the clinical significance of specific mechanistic processes.”
Stephan A. Mayer, MD, professor of neurology and neurosurgery and director of neurocritical care at Columbia University Medical Center, was intrigued by the study. He's been watching this problem in the ICU for decades. “When you are critically ill, your muscles just melt away,” he explained. “Even when the dust settles and the acute illness has passed, patients can remain on the ventilator for weeks because their diaphragm muscles are so weak. This puts patients at high risk for death and disability.”
He said that the trend now is early mobilization — getting people up and moving, even on a ventilator. “But it takes a tremendous amount of manpower,” he said. “And no one has done a study to see if this really works to prevent muscle atrophy.”
“The researchers have worked out the biological detail in an elegant way,” said Dr. Mayer. “They showed that the muscles are degenerating and dying so quickly that there are compensatory mechanisms to rebuild muscle that are upregulated and working on overdrive to no benefit of the muscle. If we can understand the mechanism of loss, we might be able to develop a treatment that stops this process.”
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