The New England Journal of Medicine OCTOBER 22, 2018

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill (TARGET Trial)

The TARGET Investigators (Chapman MJ, Peake SL, et al.)

Bottom Line

The TARGET trial demonstrated that in mechanically ventilated critically ill patients, the delivery of energy-dense enteral nutrition (1.5 kcal/ml) compared to routine enteral nutrition (1.0 kcal/ml) did not result in a significant difference in 90-day all-cause mortality.

Key Findings

1. The primary outcome of 90-day all-cause mortality showed no significant difference between the energy-dense group and the routine group (523 of 1,948 patients [26.8%] vs. 505 of 1,966 patients [25.7%]; relative risk, 1.05; 95% confidence interval, 0.94 to 1.16; P=0.41).

2. Secondary clinical outcomes, including mortality at ICU and hospital discharge, duration of mechanical ventilation, and length of stay, were similar between the two groups.

3. Patients in the energy-dense group experienced higher rates of gastrointestinal intolerance, specifically higher gastric residual volumes (median 250 ml vs 180 ml) and more frequent regurgitation and vomiting (19% vs 16%).

4. Increased metabolic demand was suggested by a higher prevalence of insulin use in the energy-dense group (56% vs 49%).

Study Design

Design

RCT

Double-Blind

Sample

3,957

Patients

Duration

90 days

Median

Setting

Multicenter, Australia/New Zealand

Population Mechanically ventilated, critically ill adults expected to require enteral nutrition until at least the day after randomization

Intervention Energy-dense enteral nutrition formula providing 1.5 kcal/ml

Comparator Routine enteral nutrition formula providing 1.0 kcal/ml

Outcome All-cause mortality at 90 days

Study Limitations

• The trial was conducted in established ICU settings where nutritional management is already optimized, which may limit generalizability to settings with lower baseline nutritional standards.

• The study was specifically powered to detect a mortality difference of 3.8% to 4.3%; it cannot exclude smaller, potentially clinically relevant differences.

• While blinding was robust, the pragmatic nature of the trial allowed for variability in non-nutritional clinical care that could influence outcomes.

• The trial focused on caloric density and did not specifically isolate the effects of protein or other micronutrient variables independently.

Clinical Significance

The study suggests that there is no survival benefit to prescribing energy-dense enteral nutrition in an effort to reach full caloric targets in mechanically ventilated ICU patients, and it highlights a potential cost in terms of increased gastrointestinal intolerance and metabolic burden.

Historical Context

The optimal caloric target for critically ill patients has long been a subject of controversy. Previous studies, such as EDEN (early trophic feeding) and PermiT (permissive underfeeding), have historically failed to demonstrate a clear survival benefit for aggressive caloric replacement over more conservative approaches, leading to an ongoing clinical debate regarding whether guideline recommendations for high caloric targets are necessary or beneficial.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

In the TARGET trial, why might increasing caloric density from 1.0 kcal/ml to 1.5 kcal/ml fail to improve outcomes, and how does this relate to the metabolic stages of critical illness (ebb and flow phases)?

Key Response

During the initial 'ebb' or acute phase of critical illness, the body is in a catabolic state with high endogenous glucose production. Providing excess exogenous calories (hyperalimentation) during this phase may not suppress muscle breakdown but can lead to metabolic complications like hyperglycemia and liver dysfunction, as the body is not yet in a state to utilize those calories for recovery (anabolic phase).

Resident

The TARGET trial maintained similar volumes of enteral nutrition between groups while varying caloric density. How does this study's design help clinicians differentiate between 'volume-related' and 'calorie-related' feeding intolerance in the ICU?

Key Response

By keeping the volume constant and only changing the density, the trial showed that 1.5 kcal/ml formulas were generally well-tolerated without significant increases in gastric residual volumes or vomiting compared to 1.0 kcal/ml. This suggests that 'intolerance' is often a response to the volume or the patient's underlying illness rather than the caloric concentration itself, though increased calories did not ultimately improve survival.

Fellow

Integrating the TARGET trial results with findings from the EDEN and PERMIT trials, what is the emerging consensus on the 'optimal' caloric dose in the first week of mechanical ventilation, and what role does protein delivery play in this context?

Key Response

Large-scale trials (EDEN, PERMIT, TARGET) consistently show that reaching full caloric targets early (via either high-density formulas or early trophic feeding) does not improve mortality compared to moderate or 'permissive' underfeeding. Fellows should note that TARGET focused on total calories; however, current interest is shifting toward whether high protein delivery—independent of non-protein calories—might be the more critical variable for preserving lean body mass.

Attending

Given that the TARGET trial showed no mortality benefit for 1.5 kcal/ml EN and a higher incidence of insulin requirements, how should this evidence influence the cost-benefit analysis of using specialized high-density formulas in your unit's standard feeding protocol?

Key Response

The study suggests that routine use of energy-dense formulas (1.5 kcal/ml) increases the risk of hyperglycemia and the need for insulin therapy without providing a survival advantage. From a stewardship perspective, standard 1.0 kcal/ml formulas are likely more cost-effective and safer for the 'average' ICU patient, reserving 1.5 kcal/ml formulas for specific populations like those requiring strict fluid restriction.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The TARGET trial used 90-day mortality as its primary endpoint. Discuss the potential for a 'type II error' regarding functional outcomes; specifically, could the study have missed a significant benefit in physical recovery or muscle mass preservation by not using a more sensitive physiological or mechanistic primary endpoint?

Key Response

Nutrition is a supportive intervention rather than a primary 'cure.' While 90-day mortality is the gold standard for ICU trials, it is influenced by many factors outside of nutrition. A PhD researcher would argue that 'patient-centered' outcomes like the Short Physical Performance Battery or ultrasound-measured muscle thickness might have revealed benefits of higher caloric intake that mortality data obscures.

Journal Editor

As a reviewer, how would you evaluate the 'pragmatic' nature of the TARGET trial, specifically regarding the observed 400 kcal/day separation between groups and the potential for unblinding due to the physical properties of 1.5 kcal/ml versus 1.0 kcal/ml formulas?

Key Response

A tough reviewer would flag that while the study intended to deliver 'full energy,' the actual difference delivered was roughly 400 kcal/day, which might be too small a delta to see a mortality difference. Furthermore, 1.5 kcal/ml formulas are visibly more viscous; if clinicians noticed this, it could introduce subtle bias in the administration of prokinetics or sedation, although the large sample size and blinded formula containers mitigated this risk.

Guideline Committee

The 2016 ASPEN/SCCM guidelines and recent ESPEN updates suggest moving toward 25-30 kcal/kg/day in the post-acute phase. Based on TARGET, should these guidelines be revised to de-emphasize the 'caloric target' in the first 7 days of mechanical ventilation?

Key Response

The TARGET trial provides high-level evidence (Level 1) that reaching ~1800 kcal/day (1.5 kcal/ml group) versus ~1300 kcal/day (1.0 kcal/ml group) early in the ICU stay does not improve 90-day mortality. Guideline committees may use this to suggest that 'routine' energy-dense feeding is not superior to standard feeding, aligning with a shift toward 'hypocaloric' or 'permissive underfeeding' strategies in the early acute phase of critical illness.

Clinical Landscape

Noteworthy Related Trials

2012

EDEN Trial

n = 1,000 · NEJM

Tested

Trophic enteral nutrition (approx 400 kcal/day)

Population

Patients with acute lung injury

Comparator

Full enteral nutrition (approx 1,300 kcal/day)

Endpoint

60-day mortality

Key result: There were no significant differences in mortality, ventilator-free days, or infection rates between the two groups.

2015

PermiT Trial

n = 894 · JAMA

Tested

Permissive underfeeding (40-60% of calculated requirements)

Population

Critically ill adults expected to require mechanical ventilation for more than 48 hours

Comparator

Standard enteral feeding (70-100% of requirements)

Endpoint

90-day mortality

Key result: Permissive underfeeding resulted in similar 90-day mortality compared to standard enteral feeding.

2018

NutriREA-2 Trial

n = 2,400 · Lancet

Tested

Early enteral nutrition

Population

Critically ill patients receiving invasive mechanical ventilation and vasopressors

Comparator

Early parenteral nutrition

Endpoint

Day 28 mortality

Key result: Early enteral nutrition did not result in lower mortality compared with early parenteral nutrition and was associated with more gastrointestinal complications.

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