The practice of providing protein in the range of 1.2–2.0 g/kg actual body weight early in critical illness is suggested by expert consensus in the 2016 SCCM/ASPEN guidelines [12]; however, the evidence for efficacy remains controversial. It is argued that the evidence for benefit comes from observational studies, not from prospective RCTs, and that the patients at high risk are often excluded from study protocols. It has also been suggested that in patients with limited vital organ function increased protein delivery may lead to organ compromise. In a recent (2017) paper, Rooyackers et al discussed the post-hoc analyses of data from the EPANIC Trial stating the statistical correlation between protein intake and outcomes indicate that protein was associated with unfavorable outcomes, possibly by inhibiting autophagy [41].
The nutrition support community may have widely varying approaches to feeding critically ill patients but most experts agree that protein may be the most important macronutrient delivered during critical illness. There is consensus that the hypercatabolism associated with stress induces proteolysis and the loss of lean muscle mass, which may affect clinical and functional outcomes beyond the ICU stay. Using multiple assessment modalities, Puthucheary et al (2013) demonstrated a reduction in the rectus femoris muscle of 12.5% over the first week of hospitalization in the ICU and up to 17.7% by day 10. These numbers imply that sufficient protein of at least 1.2 g/kg/day should be provided to minimize these losses, even if the effect on overall outcome remains unknown [42]. Evidence is lacking for whether or not we can prevent the muscle wasting that occurs in critical illness with increased protein dosing. We also need to better identify the possible risks involved with a high-protein intake at the level of the individual patient. A secondary analysis done by Heyland et al (2013) determined that no specific dose or type of macronutrient was found to be associated with improved outcome [43]. It is clear that more large-scale RCTs of protein/amino acid interventions are needed to prove that these nutrition interventions have favorable effects on clinically important outcomes, including long-term physical function.
Polymeric vs Immune-Modulating Nutrients
The Marik and Zaloga (2008) systematic review on immunonutrition in the critically ill convinced most clinicians that while fish-oil based immunonutrition improves the outcome of medical ICU patients, diets supplemented with arginine, with or without glutamine or fish oils, do not demonstrate an advantage over standard enteral products in general ICU, trauma, or burn patients[44]. What followed these trials examining early formulations of immunonutrition was decades of well-intentioned research dedicated to elucidating the mechanism of action for individual immune-modulating nutrients for various populations, including those with acute lung injury/acute respiratory distress syndrome (ARDS) [45–47], sepsis/systemic inflammatory response syndrome [48–50], head and neck cancer [51], upper and lower GI cancer [52–55], and severe acute pancreatitis [56]. Our understanding of immunonutrition and the administration of this formulation in specific disease conditions has grown considerably yet clinicians are still asking exactly what is the role of immunonutrition and who stands to benefit the most from immune-modulating nutrition therapy. The enteral formulations currently available have a proprietary composition and dosage of individual nutrients which yield unpredictable physiologic effects. In addition, the pervasive problem of underfeeding during hospitalization prevents adequate delivery of physiologic doses of nutrients thus contributing to the widely variable research results.
Prevailing expert opinion today is that the majority of critically ill patients will benefit from nutrition support initiated early and delivered consistently; the standard polymeric formula will suffice for the majority of patients with surgical ICU patients potentially deriving benefit from immunonutrition that supports a reduction in infectious complications [57]. In the recent multiple-treatment meta-analysis performed by Mazaki et al (2015) involving 74 studies and 7572 patients, immunonutrition was ranked first for reducing the incidence of 7 complications according to the surface under the cumulative ranking curve; these were as follows: any infection, 0.86; overall complication, 0.88; mortality, 0.81; wound infection, 0.79; intra-abdominal abscess, 0.98; anastomotic leak, 0.79; and sepsis, 0.92. immunonutrition was ranked second for reducing ventilator-associated pneumonia and catheter-associated urinary tract infection (CAUTI), behind immune-modulating PN. The authors stated that immunonutrition was efficacious for reducing the incidence of complications in GI surgery unrelated to the timing of administration [57]. The 2014 publication of results from the MetaPlus Trial [58]challenged the published recommendations for the use of immunonutrition in the medical critically ill population. This trial used high-protein immunonutrition or standard formula for 301 adult critically ill patients in 14 European ICUs with diagnoses such as pneumonia or infections of the urinary tract, bloodstream, central nervous system, eye, ear, nose or throat, and the skin and soft tissue. Even with higher than average target energy intakes of 70% for the high protein immunonutrition group and 80% for the high protein standard group, there were no statistically significant differences in the primary outcome of new infections, or the secondary outcomes of days on mechanical ventilation, Sequential Organ Failure Assessment scores, or ICU and hospital length of stay. However, the 6-month mortality rate of 28% was higher in the medical subgroup [58]. Using these results, as well as existing publications of negative outcomes in medical ICU patients [44,46], the SCCM/ASPEN Guidelines Committee updated its position in 2016 to suggest that immunonutrition formulations or disease-specific formulations should no longer be used routinely in medical ICU patients, including those with acute lung injury/ARDS [12]. The Committee did suggest that these formulations should be reserved for patients with traumatic brain injury and for surgical ICU patients. The benefit for ICU postoperative patients has been linked to the synergistic effect of fish oil and arginine, which must both be present to achieve outcome benefits. A meta-analysis comprised of 35 trials was conducted by Drover et al [58], who reported that administering an arginine and fish oil-containing formula postoperatively reduced infection (RR 0.78; 95% CI, 0.64 to 0.95; P = 0.01) and hospital length of stay (WMD –2.23, 95% CI, –3.80 to –0.65; P = 0.006) but not mortality, when compared to use of a standard formula. Similar results were reported in a second meta-analysis [56], thus providing supportive evidence for the current SCCM/ASPEN recommendation to use an immune-modulating formula (containing both arginine and fish oils) in the SICU for the postoperative patient who requires EN therapy [12].
