Acute illness results in a severe catabolic state with marked proteolysis and loss of lean body mass. Loss of lean body mass has profound consequences, resulting in marked functional disability and increasing the risk of falls, bone fractures, and generalized frailty. The consequences of acute illness on functional outcomes are best illustrated by the study of Herridge and colleagues,1 who followed 109 patients who had survived acute respiratory distress syndrome. In their study, patients had lost 18% of their baseline body weight by the time they were discharged, and all complained of weakness and fatigue; at 12 months, the distance walked in 6 minutes was 66% of that predicted. Furthermore, after 5 years of follow-up, functional ability had not improved over values at 1 year.
Early nutrition is widely believed to limit the catabolism of acute illness and improve patient outcomes, including functional status. Nutritional support is, therefore, considered an essential component of the management of all acutely ill hospital inpatients, with current practice for both patients in the intensive care unit (ICU) and those not in the ICU emphasizing early and targeted nutritional support. However, does the evidence support these practices? Recently a number of high-quality trials2,3 of critically ill patients have failed to demonstrate improved patient outcomes with early targeted nutritional support. Indeed, the study by Casaer et al4 demonstrated that early parenteral nutrition achieving high protein and caloric targets was associated with a worse outcome than delayed parenteral nutrition. Similarly, malnourished critically ill patients may be harmed by early aggressive enteral nutrition.
Can the unequivocal evidence from critically ill patients be extrapolated to noncritically ill hospital inpatients (non-ICU), particularly those of borderline baseline nutritional status? This question is addressed by the pivotal systematic review and meta-analysis by Gomes and colleagues.5 This study demonstrates that, among medical inpatients who are malnourished or at nutritional risk, targeted nutritional support provided during hospitalization is associated with significantly lower rates of mortality and nonelective hospital readmissions, as well as higher energy and protein intakes with greater weight gain.
There are a number of possible biological explanations for the contrasting benefits of nutritional support for inpatients in the ICU and those not in the ICU. Distinct metabolic pathways are involved in the synthesis and degradation of muscle. In critical illness, loss of muscle mass results from an imbalance between muscle proteolysis and protein synthesis, with proteolysis overwhelming an inadequate synthetic response. Forkhead box O is a family of transcriptional factors that plays a major role in muscle wasting, primarily by increasing expression of muscle RING-finger 1 and muscle atrophy F-box.6 Forkhead box O is activated by inflammation and sepsis. It is likely that ongoing and persistent inflammation in critically ill patients results in a catabolic process with muscle proteolysis that cannot be reversed by high-quality nutritional support. However, for inpatients without ongoing inflammation, the provision of high-quality nutritional support (especially with increased leucine) will favor protein synthesis over proteolysis. Furthermore, nutritional intake suppresses autophagy with inadequate clearance of pathogens and damaged cells, and this may theoretically be harmful in the setting of acute infections.
There is another intriguing possibility to explain the differences in outcomes between the studies of the critically ill patients in the ICU and those in the non-ICU wards. In the studies included in the meta-analysis by Gomes et al,5 the overwhelming majority of patients received oral nutritional supplements (ONS)—that is, they received supplemental nutrition by mouth intermittently during the course of the day. This is illustrated by the 2 largest studies included in the meta-analysis. In the study by Deutz et al,7 all the patients in the intervention group received a specialized ONS (high-protein, β-hydroxy-β-methylbutyrate formulation). In the study by Schuetz et al,8 91% of patients in the treatment group received ONS in combination with enriched hospital nutrition. In that study, enteral nutrition was used for 8 patients (0.8%) and parenteral nutrition was used for 12 patients (1.1%) in the intervention group. These findings contrast sharply with all the studies performed of critically ill patients, for whom nutrition was provided as either continuous enteral feeding (via a feeding tube or nasogastric tube) or a continuous intravenous infusion of parenteral nutrition. It is critically important to recognize that no species on this planet eats continuously (day and night), and such an evolutionary design would seem absurd. The alimentary tract and metabolic pathways of humans appear to have evolved for intermittent ingestion of nutrients a few times a day.6 Humans have evolved as intermittent meal eaters and are not adapted to a continuous inflow of nutrients; normal physiology appears to be altered when this approach is adopted. Continuous, as opposed to intermittent, enteral feeding likely limits protein synthesis.6 Muscle protein synthesis requires a pulsatile increase in branch-chain amino acids (particularly leucine) with or without concomitant pulses in insulin levels. Animal data demonstrate that muscle protein synthesis following a meal is rapid (within 30 minutes) and sustained for about 2 hours but then declines toward baseline in parallel with the postprandial changes in circulating insulin and amino acids.9 Bohé and colleagues10 measured the latency and duration of the stimulation of human muscle protein synthesis during a continuous infusion of amino acids in humans. The rate of muscle protein synthesis increased after 30 minutes, reached a peak at 2 hours, and rapidly returned to baseline levels by 4 hours despite continuous amino acid availability. These findings are supported by experimental studies where the continuous supply of amino acids has been demonstrated to blunt protein synthesis.6
The findings of the systematic review and meta-analysis by Gomes et al5 are important. They suggest that all hospital inpatients should undergo screening using a validated nutrition-screening tool. Those patients at nutritional risk should receive individualized nutritional support including the provision of a high-quality ONS. The optimal “whey” to feed critically ill patients in the ICU has yet to be determined; however, less may be more.6
Published: November 20, 2019. doi:10.1001/jamanetworkopen.2019.15707
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Marik PE. JAMA Network Open.
Corresponding Author: Paul E. Marik, MD, Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, 825 Fairfax Ave, Ste 410, Norfolk, VA 23507 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
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Marik PE. Nutritional Support Among Medical Inpatients—Feed the Cold (and Malnourished) and Starve the Febrile. JAMA Netw Open. 2019;2(11):e1915707. doi:10.1001/jamanetworkopen.2019.15707
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