Clinical and Nutrition Interventions to Manage Disease-related Loss of Lean Body Mass

Journal Articles

Introduction

Butterworth CE. The skeleton in the hospital closet. Nutrition. 1974. 9:4-8.

Jensen GL, Mirtallo J, Compher C, et al. Adult starvation and disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the International Consensus Guideline Committee. JPEN J Parenter Enteral Nutr. 2010;34:156-9.

Somanchi M, Tao X, Mullin GE. The facilitated early enteral and dietary management effectiveness trial in hospitalized patients with malnutrition. JPEN J Parenter Enteral Nutr. 2011;35:209-16.

Vandewoude MF, Alish CJ, Sauer AC, Hegazi RA. Malnutrition-sarcopenia syndrome: is this the future of nutrition screening and assessment for older adults? J Aging Res. 2012;2012:651570.

White JV, Guenter P, Jensen G, et al. Consensus statement of the Academy of Nutrition and Dietetics/American Society for Parenteral and Enteral Nutrition: characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). J Acad Nutr Diet. 2012;112:730-8.

Disease-related inflammation, malnutrition, and lean body mass loss

Beyer I, Mets T, Bautmans I. Chronic low-grade inflammation and age-related sarcopenia. Curr Opin Clin Nutr Metab Care. 2012;15:12-22.

Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for malnutrition — An ESPEN Consensus Statement. Clin Nutr. 2015;34:335-40.

Corkins MR, Guenter P, DiMaria-Ghalili RA, et al. Malnutrition diagnoses in hospitalized patients: United States, 2010. JPEN J Parenter Enteral Nutr. 2014;38:186-95.

Jensen GL, Bistrian B, Roubenoff R, Heimburger DC. Malnutrition syndromes: a conundrum vs continuum. JPEN J Parenter Enteral Nutr. 2009;33:710-6.

Jensen GL, Mirtallo J, Compher C, et al. Adult starvation and disease-related malnutrition: a proposal for etiology-based diagnosis in the clinical practice setting from the International Consensus Guideline Committee. JPEN J Parenter Enteral Nutr. 2010;34:156-9.

Puthucheary ZA, Rawal J, McPhail M, et al. Acute skeletal muscle wasting in critical illness. JAMA. 2013;310(15):1591-600. Erratum in: JAMA. 2014;311(6):625. Padhke, Rahul [corrected to Phadke, Rahul]

Roberts SB, Fuss P, Heyman MB, et al. Control of food intake in older men. JAMA. 1994;272(20):1601-6. Erratum in: JAMA. 1995;273(9):702.

Roubenoff R, Heymsfield SB, Kehayias JJ, et al. Standardization of nomenclature of body composition in weight loss. Am J Clin Nutr. 1997;66:192-6.

Lean body mass in geriatric patients

Donohoe CL, Ryan AM, Reynolds JV. Cancer cachexia: mechanisms and clinical implications. Gastroenterol Res Pract. 2011;2011:601434.

Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 2012;16(2):153-66.

Kortebein P, Ferrando A, Lombeida J, et al. Effect of 10 days of bed rest on skeletal muscle in healthy older adults. JAMA. 2007;297(16):1772-4.

Schnohr P, O'Keefe JH, Marott JL, et al. Dose of jogging and long-term mortality: the Copenhagen City Heart Study. J Am Coll Cardiol. 2015;65(5):411-9.

Sullivan DH, Sun S, Walls RC. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. JAMA. 1999;281(21):2013-9.

Sullivan DH, Walls RC, Lipschitz DA. Protein-energy undernutrition and the risk of mortality within 1 y of hospital discharge in a select population of geriatric rehabilitation patients. Am J Clin Nutr.. 1991;53(3):599-605.

Maintaining lean body mass in the ICU

Allingstrup MJ, Esmailzadeh N, Wilkens Knudsen A, et al. Provision of protein and energy in relation to measured requirements in intensive care patients. Clin Nutr. 2012;31(4):462-8.

Herridge MS, Tansey CM, Matté A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-304.

Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373(9678):1874-82.

Weijs PJ, Wischmeyer PE. Optimizing energy and protein balance in the ICU. Curr Opin Clin Nutr Metab Care. 2013;16(2):194-201.

Lean body mass in surgical patients

Ali NA, O’Brien JM Jr, Hoffman SP, et al. Acquired weakness, handgrip strength, and mortality in critically ill patients. Am J Respir Crit Care Med. 2008;178(3):261-8.

Englesbe MJ, Lee JS, He K, et al. Analytic morphomics, core muscle size, and surgical outcomes. Ann Surg. 2012;256(2):255-61.

Kreymann G, DeLegge MH, Luft G, et al. The ratio of energy expenditure to nitrogen loss in diverse patient groups—a systematic review. Clin Nutr. 2012;31(2):168-75.

Li C, Carli F, Lee L, et al. Impact of a trimodal prehabilitation program on functional recovery after colorectal cancer surgery: a pilot study. Surg Endosc. 2013;27(4):1072-82.

Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210(6):901-8.

Snowden CP, Prentis J, Jacques B, et al. Cardiorespiratory fitness predicts mortality and hospital length of stay after major elective surgery in older people. Ann Surg. 2013;257(6):999-1004.

Cardiac cachexia

Aquilani R, Opasich C, Verri M, et al. Is nutritional intake adequate in chronic heart failure patients? J Am Coll Cardiol. 2003;42(7):1218-23.

Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014;64(13):1388-400.

Marinescu V, McCullough PA. Nutritional and micronutrient determinants of diopathic dilated cardiomyopathy: diagnostic and therapeutic implications. Expert Rev Cardiovasc Ther. 2011;9(9):1161-70.

Prado CM, Gonzalez MC, Heymsfield SB. Body composition phenotypes and obesity paradox. Curr Opin Clin Nutr Metab Care. 2015;18(6):535-51.

Witte KK, Clark AL, Cleland JG. Chronic heart failure and micronutrients. J Am Coll Cardiol. 2001;37(7):1765-74.

Cachexia in COPD

Dingemans AM, de Vos-Geelen J, Langen R, Schols AM. Phase II drugs that are currently in development for the treatment of cachexia. Expert Opin Investig Drugs. 2014;23(12):1655-69.

Emtner M, Hallin R, Arnardottir RH, Janson C. Effect of physical training on fat-free mass in patients with chronic obstructive pulmonary disease (COPD). Ups J Med Sci. 2015;120(1):52-8.

Haehling S von, Anker SD. Treatment of cachexia: an overview of recent developments. J Am Med Dir Assoc. 2014;15(12):866-72.

Panton LB, Golden J, Broeder CE, et al. The effects of resistance training on functional outcomes in patients with chronic obstructive pulmonary disease. Eur J Appl Physiol. 2004;91(4):443-9.

Schols AM, Broekhuizen R, Weling-Scheepers CA, Wouters EF. Body composition and mortality in chronic obstructive pulmonary disease. Am J Clin Nutr. 2005;82(1):53-9.

Vogiatzis I, Simoes DC, Stratakos G, et al. Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD. Eur Respir J. 2010;36(2):301-10.

Interventions for acute illnesses

Burd NA, Andrews RJ, West DW, et al. Muscle time under tension during resistance exercise stimulates differential muscle protein sub-fractional synthetic responses in men. J Physiol. 2012;590(Pt 2):351-62.

Luiking YC, Poeze M, Deutz NE. Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability. Clin Sci (Lond). 2015;128(1):57-67.

Martindale RG, Warren M. Should enteral nutrition be started in the first week of critical illness? Curr Opin Clin Nutr Metab Care. 2015;18(2):202-6.

Monk DN, Plank LD, Franch-Arcas G, et al. Sequential changes in the metabolic response in critically injured patients during the first 25 days after blunt trauma. Ann Surg. 1996;223(4):395-405.

Okumura S, Kaido T, Hamaguchi Y, et al. Impact of preoperative quality as well as quantity of skeletal muscle on survival after resection of pancreatic cancer. Surgery. 2015;157(6):1088-98.

Interventions for chronic diseases

Devkota S, Wang Y, Musch MW, et al. Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice. Nature. 2012;487(7405):104-8.

Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am J Gastroenterol. 2011;106(4):563-73.

Wiese DM, Lashner BA, Lerner E, et al. The effects of an oral supplement enriched with fish oil, prebiotics, and antioxidants on nutrition status in Crohn's disease patients. Nutr Clin Pract. 2011;26(4):463-73.

Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases: overcoming impediments to prevention and control. JAMA. 2004;291(21):2616-22.

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Highlights

Inflammation is a key component of malnutrition in the context of disease and injury.

Better indicators of both inflammation and nutritional status are needed in the clinic.

Physical activity is crucial for maintaining muscle mass in aging adults.

Simple interventions and lifestyle changes can help older patients maintain activity and food intake.

Introduction

Some 3 billion people worldwide suffer from malnutrition—undernutrition or overnutrition. Over the past several decades researchers have also been increasingly aware of malnutrition in the context of disease.

Perhaps the first serious discussion of the problem appeared in a 1974 article by nutritionist Charles E. Butterworth, who referred to it as "the skeleton in the hospital closet." Today, malnutrition affects 30%–50% of hospitalized patients and is associated with poor outcomes, increased morbidity and mortality, and a heavy economic burden for health care.

There is a long-standing lack of consensus on the definition of malnutrition in the context of disease. The associated muscle wasting conditions, cachexia and sarcopenia, also lack clear definitions. Diagnosis is not simply a matter of body mass or body mass index, nor of biomarkers such as reduced albumin levels. Refining the measures of these conditions remains a challenge for researchers.

Treatment of starvation-induced malnutrition is relatively straightforward: it can generally be accomplished through a careful and gradual increase of caloric intake. But the invariable presence of inflammation in disease-associated malnutrition makes effective intervention much more complicated. The first talk of the conference introduced how inflammation is being integrated into an understanding of disease-associated malnutrition. Subsequent talks explored muscle mass loss in critical, surgical, acute, and chronic illnesses and addressed the state of the science on epidemiology, interventions, and clinical management of malnutrition in different disease contexts.

The role of inflammation and malnutrition in muscle mass loss

Malnutrition is intimately linked with inflammation, but researchers have only begun to appreciate the connection over the last decade. Historically, malnutrition was primarily caused by famine and starvation, but its prevalence in the context of disease or injury is growing and today includes both undernutrition and overnutrition. Gordon Jensen explained that researchers now realize its pathophysiology in this context invariably involves inflammation. "This insight has driven an entirely new paradigm in thinking about malnutrition," he said.

In response to illness, injury, or inflammatory disease, inflammatory cytokines are upregulated, and these in turn modulate hormone regulation and organ function and promote a catabolic state in which muscle protein is broken down. In the short term, this response is adaptive; it redirects the body's resources toward immediate needs such as healing wounds and fighting infection. However, long-term inflammation worsens patient outcomes substantially by adversely affecting recovery processes and by blunting patient responses to nutritional therapies. "This means we need to think more holistically about these interventions," he said.

Scientists are uncovering an inflammatory component in a growing number of diseases and finding new and surprising connections between inflammation and illness. Measures of malnutrition may be insufficient: clinicians often use low albumin levels to indicate malnutrition, but albumin is often a poor indicator of nutritional status because its level in the body in the setting of disease depends on inflammation, not nutrition level. Nutritional deficits may also be difficult to remedy: a controversial 2013 study published in the Journal of the American Medical Association reported that patients in the intensive care unit (ICU) experienced acute and rapid muscle loss despite nutritional support, reflecting the difficulty of meeting nutritional needs in severe inflammatory illness.

Studying malnutrition is difficult because of the lack of consensus on definitions and diagnostic measures and the absence of valid biomarkers for the condition, Jensen explained. A recent study of the 2010 Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample showed that 3.2% were diagnosed with malnutrition at discharge. The true incidence is known to be much higher. Conversely, because the clinical criteria, such as albumin levels, are not well defined, patients diagnosed with malnutrition may not in fact be malnourished. It is also difficult to measure the effects of malnutrition; the subgroup diagnosed with it had longer hospital stays, more comorbidities, and greater short-term mortality, but these adverse outcomes could have had other causes.

The field is beginning to define more concretely the muscle-wasting conditions cachexia and sarcopenia. But the prevalence of sarcopenic obesity in adults over age 60 ranges from 4.4%–84% in men and 3.6%–94% in women, depending on which of eight definitions present in the literature are applied. Jensen and his colleagues have proposed an etiology-based construct for diagnosing malnutrition in adults. This structure differentiates between pure starvation and malnutrition related to acute or chronic illness, where inflammation is present. It defines disease-related malnutrition as the point at which the severity or persistence of inflammation results in a decrease in lean body mass that is associated with functional impairment.

A framework for identifying nutritional risk. (Image courtesy of Gordon Jensen)

Inflammation can interfere with nutritional and other medical therapies, but in its absence even severe, advanced malnutrition can be easily treated. Thus, identifying the presence of inflammation, and its severity and duration, is crucial. The Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition have both adopted the proposed diagnostic framework. A working group from the two organizations developed a set of criteria—including energy intake, weight loss, and physical measures such as muscle mass and grip strength—to identify people who are moderately to severely malnourished, but Jensen noted that these measures are a work in progress. "We really need much better validated indicators of both inflammation and nutritional status than are available to us today," he said.

Muscle mass loss in geriatric patients

People generally lose lean body mass as they age. The process begins in the third decade of life and accelerates after age 65. Muscle consistency in older adults becomes more fatty and loses oxidative capacity and contractile protein concentration. Inadequate physical activity is a major contributing factor to muscle degradation; others are unbalanced diet, nervous system degeneration, neuroendocrine changes, and acute and chronic illnesses—particularly ones that involve inflammation. Dennis H. Sullivan of the University of Arkansas for the Medical Sciences described simple steps that can be taken to help patients maintain physical activity levels and increase nutrient intake.

Nutrition is just one of several factors involved in determining body composition and physiologic function. (Image courtesy of Dennis H. Sullivan)

An active lifestyle slows the rate of muscle-mass and function decline. In contrast, bed rest—even in otherwise healthy people with good diets—leads to reduced muscle mass and a dramatic loss of strength and functional capacity. Sedentary people experience significant benefits from increasing their activity levels. Simply sitting up in a chair reduces mortality risk compared to total bed rest; walking just 3 miles per week, a little each day, improves long-term outcomes.

Adequate nutrient intake is crucial for maintaining health in old age. Healthy older men who lost weight for one study conducted more than two decades ago found it more difficult to regain the weight than did younger men. Intentional weight loss must be controlled in older adults, who should avoid both gradual and sudden involuntary weight loss. Yet maintaining an optimal diet gets more difficult with advancing age, as a result of acute or chronic illness, physical disability, social isolation, and the metabolic and anorexic effects of medications.

Weight loss is prevalent in hospitals and nursing homes. Sullivan and colleagues found that 21% of older hospitalized patients in a cancer-free cohort had daily nutrient intakes lower than their basal metabolic rates—meaning that "they were literally starving," he said. In another study of adults in a recuperative care and rehabilitation unit, mortality risk increased sharply with muscle mass loss, approaching 100% in patients who lost 20%–30% of their body mass. That raises a question: "Is there a threshold beyond which there is so much damage to muscle that it cannot recover?"

A checklist for potential barriers to eating in the elderly. (Image courtesy of Dennis H. Sullivan)

Cachexia is progressive weight loss and due to disease. It is often overlooked because it can be masked by edema that adds 7 kg (15 pounds) or more in fluid retention weight. Cachexia is driven by multiple mechanisms, including inflammation, and cannot be successfully treated with nutrition alone. Inflammation can be slow to resolve in older adults; in one study, Sullivan found that patients with elevated levels of IL-6 had a 5-fold greater 1-year mortality compared to patients with normal levels of the cytokine. Researchers need a better understanding of the metabolic mediators of cachexia to improve its treatment.

Numerous studies have found that essential amino acid or protein supplementation can improve muscle protein synthesis, but it is not clear whether such interventions improve long-term outcomes such as mortality, quality of life, or functional status. It is most important to remove barriers to eating, and doing so should be prioritized over any specific interventions. "Do the simple things first," Sullivan advised.

Highlights

Although mortality in the ICU has fallen by half, most people experience dramatic long-term functional loss after ICU discharge.

With adequate protein intake and exercise, as well as interventions to modulate metabolism, ICU-acquired weakness can be reversed.

Optimal recovery from surgery and critical illness requires preventing loss of muscle mass.

Supplements such as HMB and propranolol, used by athletes and in burn units, respectively, are being tested to help patients recover from hospitalization.

Maintaining muscle mass in the ICU

Mortality in the intensive care unit (ICU) has dropped by half over the past decade. Paul Wischmeyer of the University of Colorado School of Medicine posited, however, that this life-saving care is creating victims rather than survivors. Many patients never regain their quality of life after ICU discharge—not because of their illness or injury, but because of the devastating effects of immobilization and undernutrition in the ICU.

The goal of treating critically ill patients should be a return to pre-illness quality of life, but 60%–80% of patients experience profound long-term functional impairments after just 5 days in the ICU. In a 2011 study in Canada, 40–50 year old ICU survivors with a median length of ICU stay of 25 days reported zero functional capacity to accomplish everyday tasks 6 months after ICU discharge, and just 25% capacity after a year.

Wischmeyer is working with a Tour de France coach to identify what ICU clinicians can learn from elite athletes about building muscle mass and strength. They are developing a post-ICU protocol called RISEN (Recovery from ICU via Surveillance, Exercise, and Nutrition) that uses body composition and muscle function assessments combined with early nutrition and exercise intervention to improve outcomes.

An ICU or surgical patient can lose a kilogram of lean body mass per day; much of this mass will be gained back as fat. Average protein delivery in the ICU is 0.6 grams per kilogram of body mass per day (g/kg/day), a third of the amount guidelines recommend. Clinical trials have shown that protein delivery in the ICU is beneficial at quantities above, but not below, 1 g/kg/day. "An additional 30 grams per day of protein—something you can do tomorrow—will change mortality in your patients," Wischmeyer said.

He noted that he had experienced ICU-acquired weakness, first as a 15-year-old who underwent 20 surgeries for inflammatory bowel disease, and again in summer 2015, when he was hospitalized for 23 days for a small-bowel obstruction. Humans are not evolved to survive such extreme trauma, Wischmeyer said. Nutrition interventions are necessary but insufficient for recovery.

Beta blockers, specifically propranolol, are routinely used to bring burn patients out of a catabolic state and may be useful in the ICU. A supplement used widely by athletes, β-hydroxy-β-methylbutyrate (HMB), is also being explored. Steroids like testosterone, also routinely used on the burn unit, may work in the ICU but can be given only after the acute phase of critical care. Muscle glycogen testing can help determine the transition from the acute to the chronic phase.

Exercise is key to recovery. A 2009 study published in The Lancet found that patients on a ventilator who began physical therapy at the earliest time possible had marked improvement in quality of life 2 weeks later. None of these patients had subsequent ICU-acquired weakness. "Nothing has ever shown that before—except exercise," Wischmeyer said. The experience of elite athletes can also point to more efficient exercise methods. The RISEN protocol involves in-depth metabolic evaluation that guides both feeding and exercise intensity. Wischmeyer reported that it is possible to promote complete recovery after an ICU stay. "We know what to do, and we have the data to do it," he said.

Muscle mass loss after surgery

Surgical stress, cancer cachexia, and critical illness have many mechanistic commonalities, explained David Evans of Ohio State University. All carry serious metabolic risks, driving up caloric and protein requirements and promoting muscle breakdown. The interplay between all three, moreover, is "synergistic in a bad way," he said.

Esophageal, gastric, pancreatic, and some colorectal surgeries in cancer patients carry the highest metabolic risks. Sarcopenia after colorectal surgery is associated with postoperative infection and longer hospital stays. Malnutrition in general raises the risk of both postoperative complications, such as infections, and lengthy hospital stays. Without adequate nutrition, patients tend to remain in a catabolic state, which interferes with wound healing. Geriatric specialists often connect these poor outcomes to frailty rather than to nutrition, but sarcopenia is the key feature of frailty.

Evans and others are working on finding ways to assess sarcopenia by quantifying muscle mass loss. Computed tomography (CT) scanning is one widely used measure that predicts outcomes and complications, especially when combined with a frailty score. CT scans work well in both healthy and ill people, while ultrasound scans are less readable in the critically ill. Surgical patients at the University of Michigan who had the lowest muscle mass (measured via CT scan) had higher mortality in the year after surgery and cost the hospital more money compared to those with higher muscle mass. Other measures of sarcopenia assess muscle fatigue and grip strength (a test of muscle function). The "get up and go" test measures how long it takes a patient to stand up and walk a designated distance. According to one study conducted at Evans's institution, the quartile of ICU patients with the lowest grip strength had over 30% mortality.

CT scans from three patients that Evans operated on in a single week. (Image courtesy of David Evans)

Building and maintaining muscle mass in patients after surgery is challenging. Most hospitalized patients need 0.8–1.2 g/kg/day of protein to compensate for muscle loss, but critical and trauma patients need much more. At least 1.8 g/kg/day of protein is needed for wound healing. It is unclear how effectively critically ill patients can utilize protein, but preoperative protein intake has been shown to improve surgical outcomes. Data from Evans and others show that a preoperative exercise regimen also helps prevent postoperative muscle loss; combining nutrition intervention and exercise preoperatively may be more effective still.

Interventions may also help patients better utilize preoperative protein. Anabolic steroids have been shown to improve lean body mass and bone mineral content in burn patients, who remain at metabolic risk for months after discharge. HMB has been shown to increase muscle mass in sports nutrition studies and in geriatric cancer and AIDS patients. It works by reducing protein degradation and by preventing the downregulation of protein synthesis. Evans's institute will soon test an oral nutritional supplementation protocol that includes HMB in pancreatic surgery patients.

Highlights

Heart failure patients who are obese have better survival rates than normal-weight and underweight patients, but the benefit may be attributable to higher muscle mass.

Micronutrient deficiencies, particularly of iron, may play a role in cardiac cachexia and provide a target for intervention.

Chronic obstructive pulmonary disease patients with cachexia have much worse outcomes than those without, but the condition is rarely identified, and even more rarely treated.

More research is needed on the efficacy of nutrition and other types of interventions.

Cardiac cachexia and muscle mass loss

Although heart failure, which is also called cardiac cachexia, is the most common reason for adult hospitalization in the U.S., cardiology lags behind other specialties in making muscle mass loss a focus for treatment. Peter A. McCullough of Baylor University Medical Center discussed macronutrient- and micronutrient-based interventions for cardiac patients.

Obese heart failure patients have long been reported as having better survival than normal-weight and underweight patients. But recent work on this conundrum has shown that the benefit is in fact specific to individuals who are not just obese but also have higher muscle mass. Thus, the so-called obesity paradox underscores the importance of muscle mass in disease outcomes.

Obese people with heart failure have better survival than people with the disease who are of recommended weight or underweight. This is referred to as the obesity paradox, or the reverse epidemiology of the disease. (Image courtesy of Peter A. McCullough)

Cachexia is defined as weight loss greater than 5% of body mass, or weight loss greater than 2% of body mass with either sarcopenia or a body mass index under 20. It often involves reduced food intake and measures of systemic inflammation. Most patients with refractory cachexia have less than 3 months of expected survival.

Heart failure involves a change in the metabolic function of heart muscle cells with increasing insulin resistance, but researchers have a poor understanding of the heart as a metabolic organ. In healthy hearts, free fatty acids are the major substrate of metabolism in myocardial cells, but as disease sets in, the preferred substrate becomes glucose. Visceral fat forms around the heart, but the reason for this change is unknown. There are 12 approved therapies that improve outcomes in heart failure, but none target the metabolic dimensions of the disease. Nutritional supplementation offers a promising strategy to do so.

Although heart failure patients do not have wounds of the sort ICU or surgical patients have, many patients probably have inadequate caloric and protein intake and reduced energy availability. McCullough proposed that HMB supplementation may be especially beneficial. No trials of HMB in heart failure are underway.

Several strands of evidence suggest that micronutrient deficiencies may play a role in heart failure. Beriberi, a thiamine deficiency condition, causes heart failure. Magnesium deficiency is related to arrhythmias. Diuretic drugs, a mainstay treatment to maintain fluid balance in heart failure, lead to the loss of many water soluble vitamins. ACE inhibitors create zinc deficiency, and beta blockers and statins reduce coenzyme Q10 availability. Many of these micronutrients influence calcium signaling, which directly affects cardiomyocyte function.

Micronutrient deficiencies can affect myocyte function. (Image courtesy of Peter A. McCullough)

McCullough recommended that laboratory tests should check cardiac patients' micronutrient status. Iron deficiency may be especially debilitating, leading to exercise intolerance and affecting survival rates. Several clinical trials have found that iron supplementation improves quality of life and functional measures and reduces hospitalization resulting from heart failure. Patients generally get 3 mg of iron per day from oral supplements, but that amount is not enough: dietary supplementation of 1–1.5 grams of iron over approximately 6 months is probably optimal.

Cachexia in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a lung disease in which cachexia is a common symptom, affecting 40% of patients. Melissa J. Benton of the University of Colorado at Colorado Springs reported that COPD patients with cachexia spend twice as long in the hospital as do those without it, and their hospital costs are double those of the other patients.

In COPD patients, hypoxia and the effort required to breathe increases energy dependence at rest, leading to an overall negative energy balance. Patients often become inactive, which is both "an effect of hypoxia, but also a cause of further muscle breakdown," Benton said.

The resulting cachexia is rarely identified, and even more rarely treated. Yet cachexic patients have a much higher mortality rate, so early identification and intervention should be the goal. But few biomarkers for cachexia exist. Weight loss and BMI are not reliable, because in sarcopenic obesity muscle loss is masked by weight gain.

The sarcopenic obese scan (middle) shows much less muscle mass than either the frail or the obese scans, but it is very difficult for clinicians to pick up that muscle loss without the scan. (Image presented by Melissa J. Benton courtesy of Ellen Evans, University of Georgia)

Fat-free mass index (FFMI), which assesses muscle mass relative to height, provides a good measure in COPD patients because it is specific to muscle mass and the criteria and technology used for the test are well validated and simple to use. Two gold-standard measures of body composition, dual-energy X-ray absorptiometry (DEXA) and air displacement plethysmography (Bod Pod), work well but are costly and lab-based; another approach called bioelectrical impedance analysis (BIA) is cheaper and portable, so it could be used in primary care clinics.

Although tools for identifying cachexia exist, interventions are lacking. Nutrition interventions show the strongest results in COPD. A 2012 meta-analysis showed that oral nutritional supplements increase body mass, muscle mass, and strength; but not enough data exist to assess whether the intervention improves muscle function. Some work points to a ceiling effect for the amount of protein these patients can incorporate. Research on the therapeutic effects of exercise is sparse, but one promising study used resistance training to add 3 kg of muscle in COPD patients over 12 weeks. Exercise combining endurance and strength may be have better effects, and low-intensity exercise may be more therapeutic than high-intensity exercise.

A few novel therapies are also in development. A myostatin inhibitor is in a phase II clinical trial, but data are not yet available. In a pilot study, 7 COPD patients with cachexia were given the hormone ghrelin, an appetite stimulant; the patients' food intake increased and they had higher body mass, with 0.5 kg more muscle mass, after 3 weeks. A 1997 study administered growth hormone combined with pulmonary therapy to 16 patients, and their muscle mass increased by more than 2 kg.

Highlights

Early intervention with resistance exercise and protein supplementation is so far the most effective intervention for muscle loss in critical illness.

Amino acids, hormones, and microbiome-based interventions are being explored for building muscle mass in acute illness.

Microbiome dysregulation plays a role in many chronic diseases and provides a target for low-risk intervention.

Nutrition interventions are effective in inflammatory bowel disease.

Nutrition interventions in acute illness

Acutely ill patients develop systemic inflammation, as well as moderate hyperglycemia and relative resistance to insulin—all of which contribute to the loss of lean body mass. David Evans, speaking on behalf of Robert Martindale of Oregon Health & Science University, explained that the metabolic response to acute illness varies widely. Protecting muscle mass through nutritional therapy requires the right timing, formulation, delivery route, and activity level.

In a 1996 study, trauma patients were found to have a sharp increase in resting energy expenditure, losing 16% of lean body mass during the first 3 weeks in hospital. Muscle unloading and decreased protein synthesis add to the effects of acute inflammation to drive this loss. Other research has shown that a treatment regimen combining hypercaloric parenteral (e.g., intravenous) feeding and anti-inflammatory agents does not reverse this process. Successful interventions include transitioning patients to enteral feeding as soon as possible, administering protein supplementation and other metabolic modulators, maintaining glycemic control, and supporting the microbiome.

Evans noted that acute inflammation is an appropriate response to acute illness or injury; ideally, however, for best therapeutic effect inflammation must be resolved or modulated rather than simply inhibited. Omega-3 fatty acids reduce inflammation in an appropriate way in critically ill patients. They also generate specialized pro-resolving molecules (SPMs) that resolve inflammation in part by promoting the formation of M2 (immunoregulatory) macrophages versus M1 (proinflammatory) macrophages.

Omega-3 fatty acids (EPA and DHA) help modulate inflammation in critically ill patients via multiple mechanisms. (Image courtesy of Robert Martindale)

Several studies have shown beneficial effects of fish oils in surgical and intensive care populations. These benefits include attenuating hyperdynamic effects of stress and promoting early recovery after traumatic brain injury. The amino acid arginine has also consistently shown benefits in animal models. In humans, it has been found to support wound healing, to boost nitrogen retention in critical illness, and, in a small study of patients undergoing septic shock, to decrease protein breakdown. Another amino acid, glutamine, was originally thought to be promising for preventing protein breakdown in the body, but recent studies have questioned its efficacy. One area of particular interest to Martindale, Evans said, is therapeutically influencing the microbiome, perhaps through the use of probiotics. Multiple benefits of promoting healthy microbiota have been identified in recent years.

ICU-acquired weakness must be treated through physical activity as soon as possible. Even patients who cannot walk can be passively exercised on a stationary bicycle. The demonstrated benefits of activity include improved strength and mobility, a higher rate of hospital discharge, and fewer complications. Combining resistance exercise with protein supplementation is crucial for maintaining strength and muscle mass after acute illness, and early intervention is key. "Mortality has improved to the point where we can't really use it as an endpoint anymore," Evans said, "so we need to treat the patient, not the disease itself."

Several promising interventions are under investigation. Martindale and his colleagues are conducting a multicenter trial on an analogue of the appetite-stimulating hormone ghrelin in ICU patients. Testosterone analogs have been useful in non-ICU populations, but may not be appropriate for use in critically ill patients. Leucine, a precursor to β-hydroxy-β-methylbutyrate (HMB), has long been reported to build muscle mass; it probably works by stimulating the mTOR signaling pathway. It is not well studied in the ICU but deserves examination, as does HMB.

Nutrition interventions in chronic disease

Chronic diseases such as heart disease, stroke, autoimmune disorders, and cancer account for 60% of deaths worldwide and present an economic burden for health care systems. Many of these conditions are somewhat preventable and lifestyle-related. Gerard Mullin of Johns Hopkins Medicine pointed out that these diseases often share risk factors—including tobacco and alcohol use, inactivity, and poor diet—which are connected through genetic regulation and additional environmental triggers.

Inflammation is one such mechanism activated by numerous risk factors. Another common thread in chronic diseases is disruption in the gut microbiome. Mullin described how nutrition interventions that regulate the microbiome might be useful in one chronic inflammatory disease—inflammatory bowel disease (IBD). Diet, which can in some cases alter the microbiome, provides clinicians with a possible way to help patients manage their disease.

A summary of all scientific reports linking IBD to disruption of the microbiome. (Image courtesy of Gerard Mullin)

The microbiome plays a clear role in the pathogenesis of IBD. Multiple studies have shown that refined sugar, artificial sweeteners, foods high in saturated fats, and processed grains can dysregulate the microbiome and induce inflammation. One recent study showed that milk fat induces dysbiosis by spurring the growth of a specific bacterial population, stimulating cytokine production, and induces IBD in an animal model. Another recent study of IBD showed that nutrients can change the intestinal milieu in a way that alters the motility of the gastrointestinal (GI) tract and affects immune regulation, epithelial barrier function, and other factors, activating inflammation both directly and through the host microbiome.

Evidence also suggests that enteral nutrition (that is, delivered through the GI tract via oral nutritional supplements (ONS) or tube feeding (TF)) is effective in inducing remission of Crohn's disease, a type of IBD. Possible mechanisms include reduced inflammation after eliminating saturated fats in the diet; decreased antigenic load, perhaps improving barrier defense; and microbiome alteration. "Maybe this multi-pronged attack is what's leading to good outcomes," Mullin said. Clinical trials have shown that elimination diets—in which patients identify and avoid specific foods that trigger their disease—are effective for treating IBD.

In a 2011 study, an oral nutritional supplement enriched with omega 3 fatty acids, antioxidants, and prebiotics appeared to be very effective in ulcerative colitis patients who were unresponsive to corticosteroids, reducing phospholipid fatty acid levels, increasing omega 3 fatty acid levels, improving quality of life, and reducing disease activity. There is also evidence for the efficacy of other specific nutrition interventions, such as omega 3 fatty acids alone, curcumin (a component of turmeric), and probiotics. Pharmaceutical interventions are effective in IBD, but generally carry far greater risk because these drugs tend to have side effects. Studies have also pointed to the efficacy of nutritional therapies in other unrelated conditions, such as chronic kidney disease.

Researchers are just beginning to understand the role of the microbiome in chronic diseases like IBD, and recent research suggests that microbiome dysregulation is also a factor in malnutrition in children in the developing world, Mullin said. Thus it may be possible to target the microbiome in a wide range of conditions that involve malnutrition, including IBD.

How do different disease states affect body composition and inflammation?

How could measures for clinically identifying malnutrition be improved?

How should existing nutritional therapies be combined to treat malnutrition when inflammation is present?

Is there a threshold in older adults for the loss of muscle mass and function beyond which there is so much damage to muscle that it cannot recover?

Can nutrition, metabolic, and exercise interventions in the ICU prevent massive long-term functional loss after discharge?

What kinds of interventions would help surgical patients build muscle preoperatively to improve outcomes?

How does protein metabolism affect cardiomyocytes?

Can micronutrition supplementation improve outcomes in heart failure?

Can nutritional supplementation be improved, or combined with other interventions, to push patients past the so-called ceiling effect limiting the amount of nutrition their bodies can accept?

Can nutrition interventions effectively target the microbiome to treat a broader range of chronic diseases?