There is universal consensus that EN is the preferred route for nutrition therapy due to the superior physiological response and both nutritional and non-nutritional benefits [24]. Changes in gut permeability tend to occur as illness progresses and consequences include increased bacterial challenge, risk for multiple organ dysfunction syndrome, and systemic infection. It is best to intervene with nutrition early, defined as within the first 48 hours of ICU admission, while the likelihood of success and opportunity to impact the disease process is greater [12]. Early initiation of feeding provides the necessary nutrients to support gut-associated lymphoid tissue (GALT), mucosal-associated lymphoid tissue (MALT), and preserve gut integrity and microbial diversity [27]. The intestine is an effective barrier against bacteria and intraluminal toxins due to the high rate of enterocyte turnover, the mucus secreted by the goblet cells, and the large amount of protective immunological tissue; 80% of the immunoglobulins are synthesized in the GI tract [28]. Fasting states for procedures or delays in feeding longer than 3 days for any reason may contribute to disruption of intestinal integrity through atrophy and derangements in the physical structure and function of the microvilli and crypts [29]. Intestinal dysfunction leads to increased intestinal permeability and the possibility of bacterial translocation. Intestinal ischemia resulting from shock and sepsis may produce hypoxia and reperfusion injuries further affecting intestinal wall permeability [29]. In surgical patients, early enteral feeding has been found to reduce inflammation, oxidative stress, and the catabolic response to anesthesia and surgical-induced stress, help restore intestinal motility, reverse enteric mucosal atrophy, and improve wound healing [26].
We did not have sufficient data to refute the benefits of EN over PN until the paper by Harvey et al (2014), which reported no difference in mortality or infectious complications in ICU patients receiving EN or PN within 36 hours of admission and for up to 5 days [30]. This was the largest published pragmatic RCT, referred to as the CALORIES trial, which analyzed 2388 patients from 33 ICUs and resulted in controversy over what was an unchallenged approach up until this time. It was only a matter of time before other investigators would set out to confirm or negate this finding, which is what Elke and coworkers (2016) did a few years later [31]. They performed an updated systematic review and meta-analysis to evaluate the overall effect of the route of nutrition (EN versus PN) on clinical outcomes in adult critically ill patients. Similar to the Harvey et al report, they found no difference in mortality between the two routes of nutrition. However, unlike the earlier report, patients receiving EN compared to PN had a significant reduction in the number of infectious complications and ICU length of stay. No significant effect was found for hospital length of stay or days requiring mechanical ventilation. The authors suggest that EN delivery of macronutrients below predefined targets may be responsible as PN is more likely to meet or exceed these targets and overwhelm metabolic capacity in the early days of critical illness [31].
The most recent trial prompting even more discussion about early PN versus early EN in mechanically ventilated ICU patients in shock is the Reignier et al (2018) NUTRIREA-2 trial involving 2410 patients from 44 ICUs in France [32]. The investigators hypothesized that outcomes would be better with early exclusive EN compared to early exclusive PN; their hypothesis was not supported by the results, which found no difference in 28-day mortality or ICU-acquired infections. Also unexpected was the higher cumulative incidence of gastrointestinal complications including vomiting, diarrhea, bowel ischemia, and acute colonic obstruction in the EN group. The trial was stopped early after an interim analysis determined that additional enrollment was not likely to significantly change the results of the trial. Given the similarities between the CALORIES trial and this NUTRIREA-2 trial, clinicians now have mounting evidence that equivalent options for nutrition therapy exist and an appropriate selection should be made based on patient-specific indications and treatment goals. In summary, EN remains preferable to PN for the majority of adult critically ill patients due to crucial support of gut integrity, but the optimal dose or rate of delivery to favorably influence clinical outcomes in the first few days following admission remains unknown.
Use of Supplemental Parenteral Nutrition
Both the nutrition support and bench science communities have learned a great deal about PN over the 4 decades it has been in existence, with the most compelling data coming from more recent trials [31–38]. This is because it has taken many years to recover from the days of hyperalimentation or overfeeding ICU patients by providing excessive calories to meet the elevated energy demands and to reverse the hypercatabolism of critical illness. This approach contributed to the complications of hyperglycemia, hyperlipidemia, increased infectious complications, and liver steatosis, all of which gave PN a negative reputation [37]. We now have adjusted the caloric distribution and the actual formulation of PN using the recent FDA-approved lipid emulsion (Soy, Medium-chain triglycerides, Olive oil, and Fish oil; SMOF) and created protocols for administering it based on specific indications, such as loss of GI integrity or demonstrated intolerance. In general, the advances in PN have led to a safer more therapeutic formulation that has its place in critical illness. Manzanares et al [40] reported a trend toward a decrease in ventilation requirement and mortality when a fish oil–containing lipid emulsion was administered to patients who were receiving nutrition support either enterally or parenterally. The meta-analysis combined all soybean oil–sparing lipid emulsions for comparison with soybean oil and was able to show the trend for improved clinical outcomes with soybean oil–sparing lipid emulsions. The main findings of this meta-analysis were that fish oil–containing lipid emulsions may reduce infections and may be associated with a tendency toward fewer mechanical ventilation days, although not mortality, when compared with soybean oil-based strategies or administration of other alternative lipid emulsions in ICU patients [40]. Recent trial results do not change the recommendation for selecting EN first but do suggest lowering the threshold for using PN when EN alone is insufficient to meet nutrition goals. A systematic review reported no benefit of early supplemental PN over late supplemental PN and cautioned that our continued inability to explain greater infectious morbidity and unresolved organ failure limits any justification for early PN [35].
