Clinical Controversy

Nutrition in Clinical Practice

Volume 33 Number 3
Full Nutrition or Not? June 2018 333–338

C 2018 American Society for

Parenteral and Enteral Nutrition

DOI: 10.1002/ncp.10101
wileyonlinelibrary.com
Mary F. Stuever, DO; Ryan F. Kidner, DO, FACOS; Floria E. Chae, MD;
and David C. Evans, MD, FACS, PNS

Abstract
Enteral nutrition (EN) is widely used in intensive care units around the world, but the optimal dosing strategy during the first week
of critical illness is still controversial. Numerous studies in the past decade have provided conflicting recommendations regarding
the roles of trophic and permissive/intentional underfeeding strategies. Further complicating effective medical decision making
is the widespread, yet unintentional and persistent underdelivery of prescribed energy and protein, in addition to the trend for
recommending ever-higher amounts of protein delivery. We postulate that the key to appropriate enteral strategy lies within an
accurate and patient-specific assessment. Patients with a baseline high nutrition risk and those with increased nutrition demands,
such as those with wounds, surgery, or burns, likely require full nutrition support, in contrast with medical patients, such as those
with acute respiratory distress syndrome, who may selectively be appropriate for trophic strategies. In this analysis, we review
several key trials for and against full EN in the first week of critical illness, as well as key issues such as the role of autophagy and
immunonutrition in enteral dose selection. (Nutr Clin Pract. 2018;33:333–338)

Keywords
autophagy; critical illness; enteral nutrition; immune system; immunonutrition; nutrition support; systemic inflammatory response
syndrome

Introduction SCCM) guidelines accept that EN delivers benefits to the

patient beyond macronutrient delivery.1 These benefits in-
Clinicians have long struggled with recommendations for clude, but are not limited to, maintenance of gut integrity,
the appropriate dose of enteral nutrition (EN) in the first reduction of the gut-lung axis of inflammation, reduction
week of critical illness. Going back to the early days of of bacterial virulence, and modulation of immunity.
modern intensive care units (ICUs) and the availability of Recent randomized control trials (RCTs) have examined
commercial enteral formulas, there has been a struggle to the question whether trophic or “permissive underfeed-
balance nutrition needs with the perceived risks of feeding. ing” strategies lead to equivalent or better outcomes than
Probably the greatest barrier to early enteral feeding has
always been the low priority historically placed on nutrition
in the plan of care. Past paradigms focused on other aspects From the Department of Surgery, Division of Trauma, Critical Care
of care while permitting patients to remain NPO for long and Burn, The Ohio State University Wexner Medical Center,
Columbus, Ohio, USA.
periods. Two unrelated modern trends converge to bring
the timing of ICU nutrition support to the forefront now. Financial disclosure: None declared.
The first is an overarching trend toward improved survival Conflicts of interest: D. C. Evans discloses the following conflicts:
after critical illness that has resulted in an epidemic of Coram/CVS Caremark Advisory Board; Lyric Consulting and
Research Grant; and Abbott Speaking, Consulting, Research Grant.
nutritionally depleted patients with astounding rates of
debility and muscle mass loss. The second trend is that This article originally appeared online on May 17, 2018.
nutrition is more widely accepted as having a place in acute Podcast available: Listen to a discussion of this manuscript with NCP
care hospitalization. Nutrition risk screening is more widely Editor-in-Chief Jeanette M. Hasse, PhD, RD, LD, FADA, CNSC,
and author David C. Evans, MD. This podcast is available at:
practiced, and early oral feeding is now accepted in many https://players.brightcove.net/656326989001/default default/index.
scenarios where it was once not practiced. An example html?videoId=5775826272001
of this is that we now have protocols that support early
feeding, such as the enhanced recovery pathways follow- Corresponding Author:
David C. Evans, MD, FACS, PNS, Division of Trauma, Critical Care
ing gastrointestinal surgery. Most ICU practitioners and and Burn, OSU Wexner Medical Center, 395 W. 12th Ave., North
the national American Society for Parenteral and Enteral Doan Hall Room 634, Columbus, OH 43210-1267, USA.
Nutrition/Society of Critical Care Medicine (ASPEN/ Email: david.evans@osumc.edu
334 Nutrition in Clinical Practice 33(3)

“full-feeding” strategies. Further complicating the land- feeding (defined as 20 mL/h) for 6 days before advancement
scape is the recognition that many U.S. ICUs only suc- to full feeds vs full EN from initiation of feeding. With
ceed in delivering 60%–70% of prescribed energy when 1000 patients entered, this study is 1 of the largest trials
targeting “full” nutrition.2 Even with the most aggressive in the ICU nutrition literature. At the end of the trial,
of intentions, underfeeding may result when full feeding there was no difference in outcome with regard to mortality,
is prescribed but not closely monitored. Whether “more ventilator-free days, multiorgan failure, or infection between
is better” or trophic feeding/underfeeding strategies are the 2 feeding strategies.
enough is a study of great interest. In examining the study population, patients were young
Opponents of full feeding note that tolerance of any (mean age, 52 years), had a typical American body mass
nutrition therapy is likely to be the worst in the first week index (BMI; mean, 30), and experienced a short stay
because it represents the height of the disease process, in the ICU (close to 5 days). The major conclusion—
inflammation, and insulin resistance. More recently, au- but also major limitation of the EDEN trial—is that the
tophagy has emerged as an additional and fundamental trophic delivery of 25% of calculated goals was sufficient
mechanistic explanation of why withholding (or minimiz- in a moderately ill and generally adequately nourished
ing) early nutrition may benefit some patients. population with primary respiratory disease process. It is
very possible that these patients did not require significant
Considerations Regarding the Critical macronutrient delivery, and that trophic feeding provided
sufficient nutrition including immunological benefit, as well
Inflammatory State as other nonmeasured benefits.
In describing the persistent inflammation catabolism syn- In a large multicenter RCT, Arabi et al6 evaluated per-
drome, Moore et al3 identified 3 potential pathways for missive underfeeding, providing 40%–60% of goal energy,
patient outcome after admission to the ICU. The first vs full feeding of an intended range from 70%–100% of goal
pathway is rapid recovery, where the acute insult causes energy. Similar to those patients in the ARDSNet/EDEN
a systemic inflammatory response syndrome (SIRS) re- population, these patients had a mean age of 50 years
sponse, which is immediately opposed by the generation and a mean BMI of 29.0. ICU length of stay was slightly
of a compensatory anti-inflammatory response syndrome. longer (mean, 13 days). Both groups were intended to
In this patient population, early EN may lead to a rapid receive full protein provision, with the underfeeding study
recovery with return to homeostasis and discharge from group receiving powdered protein supplements to match the
the ICU. The second pathway and the worst scenario protein delivered to the full feeding controls. At the end of
is that an excess SIRS response to injury leads to early the trial, there were no differences in infection, ICU length
multiorgan failure syndrome and fulminant death. In this of stay, ICU mortality, or 90-day mortality. Although it was
subgroup of patients, nutrition likely would not play a role a well-designed study, the caloric composition between the
in reversing the outcome. The third pathway is that of persis- control and study groups were different, and it cannot be
tent inflammation catabolism syndrome, whereby nutrition overlooked that the protein supplementation was equivalent
therapy and other critical care management strategies fail between the 2 groups. It should also be noted that in both
to attenuate the SIRS and compensatory anti-inflammatory Arabi et al6 and EDEN, patients never achieved much >80%
response syndrome responses, and both processes continue of goal intake. Although this does not meet recommended
in an indolent, chronic manner. This patient population targets, this shortfall mirrors real-world nutrition delivery
likely stands to benefit the most from additional nutrition practices.
studies. When examining each patient, we need to keep A recent single-institution study also in patients with
these pathways in mind as we attempt to discern which ARDS actually suggested harm from a full-feeding
patient populations or disease processes would benefit strategy.7 A post hoc analysis indicated that mortality was
from trophic feeding vs full feeding for optimal patient greatest in those patients who received more feeding in the
outcomes.4 first week (hazard ratio [HR], 1.17; 95% CI. 1.07–1.28),
whereas higher energy intake later in the hospitalization
Studies Suggesting Equivalency of Feeding was protective (HR, 0.91; 95% CI, 0.83–1.0).8 Even when
they examined those patients who were screened for their
Strategies study but not enrolled, they found similar results within
The EDEN randomized trial published by the ARDSNet their instution.9 Although these data were representative
Clinical Trials Network evaluated initial trophic feeding of a single-center experience, these data further suggest
vs full enteral feeding in patients with acute lung injury.5 that patients with ARDS may not benefit from early
Patients with acute lung injury or acute respiratory distress aggressive ICU feeding. How we reconcile this data set
syndrome (ARDS) who were expected to be on mechanical with more widespread concerns in regard to the potential
ventilation for >72 hours were randomized to trophic deleterious effects of increasing caloric deficit is unclear. If
Stuever et al 335

we underfeed in the first week, do we need to overcome the In an observational study, Heyland et al14 showed, in a
caloric debt? Will there be deleterious effects to patients?10 large group of ICU patients, that low-risk patients with a
There is clinical evidence to suggest targeting caloric NUTRIC score of 0–5 had no difference in mortality over
debt as an endpoint for nutrition delivery as an effective a range of caloric delivery from 0%–100% of goal energy.
strategy.11 However, in those patients determined to be at high risk
The recent NUTRIREA-2 study points to a potential by the NUTRIC score, there was a statistically significant
signal of harm from full feeding, in particular because reduction in mortality, as nutrition therapy was increased
of gastrointestinal complications, particularly ischemia. Al- from 0%–100% of goal energy (P < .0001).
though EN and parenteral nutrition were generally found In a second RCT by Johansen et al,15 a subset of patients
to be equivalent in this study of mortality, there were with complications was randomized again to an aggressive
significantly higher rates of gastrointestinal tract ischemia, interventional nutrition therapy group vs controls receiving
vomiting, and diarrhea with the use of tube feeding. No- standard therapy, all with an NRS- 2002 score >3. As a
tably, >80% of the patients were on vasopressors and result of the more aggressive nutrition therapy, the inter-
represented a severe population presumably with Nutrition vention group had a shorter hospital length of stay (14.07 vs
Risk Score 2002 (NRS-2002) scores of at least 3. This study 19.67 days; P < .05) than that of controls receiving standard
used a much broader definition of ischemia than prior therapy.
studies. For example, mucosal changes on endoscopy were Most recently, a prospective multicenter observational
noted as ischemic changes. Despite the generous definition, study again confirmed that high-risk patients appeared to
ischemia is an important finding and should prompt careful derive more benefit from additional protein and energy
consideration of full EN with pressor use.12 than low-risk patients.16 Known high-risk patients (eg,
high NUTRIC, burn patients) may benefit from aggressive
Nutrition Risk as a Key Concept in Selection of volume-based feeding strategies that can be used to further
increase nutrient delivery, but it is unclear that they result in
Feeding Strategy additional outcome benefit.17
In light of these large RCTs in the last decade suggesting
equal outcomes between underfeeding and full feeding,
what about the nutritionally high-risk patient? For nutri- Is Autophagy an Argument Against Early
tionally at-risk patient populations, we believe underfeeding
likely harms these patients. Kondrup et al13 refined modern
Enteral Nutrition?
concepts of nutrition risk with the development of the Historically, arguments against early full nutrition have fo-
NRS-2002 (Figure 1). Kondrup et al13 recognized that cused on concerns about inducing nonocclusive mesenteric
deterioration of nutrition status and disease severity both ischemia or aspiration in the early stages of critical illness.
contribute to a patient’s nutrition risk. Others argued that critically ill patients were not “ready”
NRS-2002 is 1 of 2 scoring systems that have great for nutrition or could not reach an anabolic state. Those
applicability in assigning nutrition risk and guiding con- issues have generally been resolved, and the ASPEN/SCCM
sideration of feeding strategy in the ICU. The NRS-2002 guidelines present a widely accepted approach to feeding.
involves a grid where 1–3 points are assigned for impaired A relatively new concept has entered the nutrition field,
nutrition status based on weight loss, reduced food intake, that of the concept of autophagy. It has emerged as a
and reductions in BMI. On the other side of the same grid, possible important role in nutrition; however, its clinical
the patient is assigned 1–3 points for disease severity, with role has yet to be fully discerned. Autophagy is an essential
examples given for each gradation of severity. An additional cellular process that serves as a survival mechanism and
point is assigned for age >70 years. If a patient is NPO and a source of quality control in maintaining homeostasis.
has a score ࣙ3, he or she should be considered for nutrition Specific roles include maintaining a balance between in-
support. A score ࣙ5 identifies high risk. The Nutrition Risk tracellular recycling and metabolic regulation by removing
in Critically Ill (NUTRIC) score, developed and validated aggregated and misfolded proteins, damaged organelles,
in the ICU, is used to calculate similar nutrition risk. The and excessive fat or carbohydrate stores. Autophagy also
NUTRIC score uses 5 factors to determine disease severity performs a role in immune functions such as eliminating
(age, Acute Physiology and Chronic Health Evaluation II invading pathogens, being required for antigen presentation
score, sequential organ failure assessment score, interleukin- by major histocompatibility complex class II (MHC II),
6 level [considered optional], and number of comorbidities) and development of T cells and invariant natural T killer
and 1 factor for nutrition status (hospital length of stay cells. Increasing evidence implicates mutations in the genes
before admission to the ICU). A score of 0–5 identifies involving autophagy as it relates to the various disease pro-
low risk, whereas a score of 6–10 identifies patients at high cesses including neurodegenerative, cancer, and infectious
nutrition risk.13 diseases.
336 Nutrition in Clinical Practice 33(3)

Figure 1. Nutrition Risk Score-2002 Tool. APACHE, Acute Physiology and Chronic Health Evaluation; BMI, body mass index;
COPD, chronic obstructive pulmonary disease; ESPEN, European Society for Clinical Nutrition and Metabolism; mths, months;
Wt, weight.

Autophagy is stimulated by various factors, such as ing, and whole-body protein synthesis is reduced during
starvation, whereby cells adapt to these conditions by con- starvation.
verting these signals into anabolic and catabolic responses. Stimulations factors for autophagy include starvation,
Damaged cellular parts are catabolized into substrates to glucagon, oxidative stress, and glutamine. Autophagy is
generate ATP during times of starvation.18 The cell se- inhibited by the following factors: feeding, secretion of in-
questers target proteins, engulfs, and delivers them into sulin, hyperglycemia, and excess nutrients. In critical illness,
a lysosome for degradation.19,20 There are 3 methods of the interplay between autophagy and immune responses
delivery of the targeted proteins into the lysosome: microau- and inflammation is complex and has yet to be fully
tophagy, chaperone-mediated autophagy, and macroau- illustrated.21
tophagy. In microautophagy, the lysosomal membrane
extends and invaginates the cellular contents. Chaperone- Immunonutrition Strategies and Their
mediated autophagy requires a specific sequence in pro-
teins for degradation. The specific sequence is recognized
Implications for Nutrient Dosing
by HSC70, a chaperone protein, that brings them to With an ever-increasing understanding of the immune sys-
the lysosomal membranes, and LAMP-2A, a membrane tem, clinicians have sought to modulate host responses to
receptor, brings it into the lysosome. This is a highly insult/injury using a variety of pharmaconutrients. Prin-
specific and precise process because only those with the cipally these are arginine, n-3 polyunsaturated fatty acids,
specific gene sequence are degraded. Macroautophagy in- and antioxidants. The application and validation of the
volves the formation of autophagosome to trap cellular effects of these various pharmaconutrients have been prob-
contents and proteins. The autophagosome then fuses lematic to translate into the clinical setting.22 Multiple
with the lysosome and delivers its contents for degra- clinical trials have demonstrated varying outcomes, and
dation. Macroautophagy is the major method used by meta-analyses of multiple clinical trials have represented the
cells to remove damaged organelles and other debris, and strongest evidentiary foundation for these practices. An ad-
thus the term “autophagy” refers to macroautophagy; ditional challenge is there is no standard immunonutrition
it is not significantly influenced by starvation or feed- product.23 A majority of the studies have been performed
Stuever et al 337

with different concentrations of nutrients, because there is tiple observational studies, most notably that of Weijs et
no standard dose or concentration of formula feeds. One al,28 noted the important contribution of protein intake
factor that seems to be consistent is that those receiving rather than overall energy intake in improving outcomes
immunonutrition received higher levels of nitrogen, which in nonseptic patients. How to respond in these situations
thus becomes a confounding factor or a possible treatment remains unclear. When intentionally underfeeding a select
bias not directly related to the immunomodulation, but population, it may be critical to ensure a normal level of
rather increased nutrient delivery.24 specific nutrients, whether it is protein in these nonseptic pa-
When taking these factors into consideration, the ques- tients or specific immunonutrients in postoperative patients.
tion of trophic feeds vs full feeding is difficult to answer. Unfortunately, the evidence base today does not adequately
There is obvious concern of not providing the correct address the role of specialized nutrition when otherwise
“doses” of immunonutrition in the setting of trophic underfeeding.
feeding.25 Therefore, more studies comparing the thera- Decisions made in the first week of hospitalization in
peutic thresholds of pharmaconutrients are required. If regard to a patient’s nutrition must be taken in the con-
the clinical situation calls for an immunonutrition strategy, text of determining a patient’s nutrition risk. To optimize
then we must tread lightly because there is little to no patient outcome, we need to identify those patients who
support for a “trophic immunonutrition.” Postoperative are high risk and who may need to get to goal sooner
SICU, wound care, and burns stand out as clear areas (full feeds) to achieve the full benefits of the intended
where immunonutrition is widely used.26 How the role of therapy.
underfeeding should be addressed in ARDS in regards to
specific lung anti-inflammatory formulae is perhaps more Statement of Authorship
perplexing.27 M. F. Stuever, R. F. Kidner, F. E. Chae, and D. C. Evans
contributed to conception/design of the manuscript; M. F.
Stuever, R. F. Kidner, F. E. Chae, and D. C. Evans con-
Conclusions tributed to acquisition, analysis, or interpretation of the data;
International consensus guidelines state that any patient M. F. Stuever, R. F. Kidner, F. E. Chae, and D. C. Evans
drafted the manuscript; M. F. Stuever, R. F. Kidner, F. E.
without a contraindication to EN should have at least
Chae, and D. C. Evans critically revised the manuscript; and
trophic EN started as soon as possible. Determination of
M. F. Stuever, R. F. Kidner, F. E. Chae, and D. C. Evans
nutrition risk and early evaluation of tolerance to EN will agree to be fully accountable for ensuring the integrity and
be paramount to optimizing patient outcomes. If the patient accuracy of the work. All authors read and approved the final
is determined to be at low nutrition risk based on normal manuscript.
nutrition status and low disease severity (as confirmed
by an NRS-2002 score <3 or a NUTRIC score ࣘ5), it References
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