NUTRIREA-2 (Holden Young - Roseman University College of Pharmacy) Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 2018;391:133–43

1. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised,
controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).
Lancet. 2018;391:133–43
Holden Young, PharmD Candidate 2021
Background
• An acute critical illness which requires mechanical ventilation can carry risk of severe malnutrition and adverse
effects such as infections, muscle wasting, delayed recovery, and increased mortality.2
• Current guidelines recommend early enteral nutrition of 20–25 kcal/kg per day during the acute phase of critical
illness but rely on a limited amount of evidence.1, 3, 4
• There is currently only one other previous trial, CALORIES, that specifically assesses the feeding route in
critically ill patients.6
NUTRIREA-2 is the first trial focused on severely ill patients treated with mechanical
ventilation and vasopressor support for shock.1
• Factors such as route, timing, and nutrition doses have not been shown to significantly affect outcomes in
critically ill patients.5
Objective
• This trial was designed to determine whether early first-line enteral nutrition had beneficial clinical effects when
compared to early first-line parenteral nutrition.
Study Design
• Randomized, open-label, controlled, multi-centered, parallel-group clinical trial.
• Patients from 44 Intensive Care Units (ICUs) all located in France were stratified by center using permutation
blocks of variable sizes, then randomized into:
1. Early enteral group received first-line enteral nutrition
2. Parenteral group received only parenteral nutrition for at least 72 hours after randomization, and was
switched to enteral nutrition one of two ways:
a. As soon as patient meets predefined criteria for hemodynamic stability (no vasopressor support for
24 consecutive hours and arterial blood lactate concentration <2 mmol/L)
b. Parenteral nutrition provided for 7 days, on day 8 patient is switched to enteral nutrition regardless
of hemodynamic stability if no contraindications are present
Inclusion Criteria Exclusion Criteria
- Adults (18 years and older)
- Expected to require > 48 hours of invasive
mechanical ventilation along with vasoactive therapy
(adrenaline, dobutamine, or noradrenaline) via a central
venous catheter for shock
- Started on nutritional support within 24 h after
endotracheal intubation
- Invasive mechanical ventilation started > 24 hours
earlier
- Surgery on the gastrointestinal (GI) tract within the
past month
- History of gastrectomy, oesophagectomy, duodeno-
pancreatectomy, bypass surgery, gastric banding, or
short bowel syndrome; gastrostomy or jejunostomy
- Specific nutritional needs, such as pre-existing long-
term home enteral or parenteral nutrition
- Active gastrointestinal bleeding
- Treatment-limitation decisions
- Adult under legal guardianship
- Pregnancy
- Breastfeeding
- Current inclusion in a randomized trial designed to
compare enteral nutrition to parenteral nutrition
- Contraindication to parenteral nutrition
Outcomes
• Primary: Day 28 all-cause mortality after randomization in the intention-to-treat population
• Secondary: Day 90 mortality; hospital mortality; ICU mortality; ICU length of stay; acute care length of stay;
days without vasopressor support, dialysis, and mechanical ventilation; ICU-acquired infection; ventilator
associated pneumonia; bacteremia; CVC-related infection; urinary tract infection; soft-tissue infection;
vomiting; diarrhea; bowel ischemia; acute colonic pseudo-obstruction
Statistics
• Investigators of the trial stated 2854 patients were required to see a 5% decrease in day 28 mortality in the
enteral group after assuming a 37% mortality rate in the parenteral group, a p-value of 0.049, and 80% power
• No statistical test was done to compare baseline characteristics between groups
• Primary outcome: Absolute difference estimate (95% CI), groups compared using Chi-square test
• Secondary outcome: Groups compared using Chi-square test

2. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised,
controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).
Lancet. 2018;391:133–43
Holden Young, PharmD Candidate 2021
• Analyses were based on an intent-to-treat basis
Results
• Trial was ended after second interim analysis because completing patient enrollment was deemed not likely to
produce a significant change in the trial’s results
• Baseline characteristics were similar between groups
o Mean age: 66 years, 67% male, Vasopressor support: 81% Norepinephrine alone
Enteral
group
(n=1202)
Parenteral
group
(n=1208)
Absolute
difference
estimate (95%
CI)
Hazard Ratio
(95% CI)
p-value
Primary outcome
Day 28 mortality 443 (37%) 422 (35%) 2.0 (-1.9-5.8) - 0.33
Secondary outcomes
Vomiting 406 (34%) 246 (24%) - 1.89 (1.62-2.20) <0.0001
Diarrhea 432 (36%) 393 (33%) - 1.20 (1.05-1.37) 0.009
Bowel ischemia 19 (2%) 5 (<1%) - 3.84 (1.43-10.3) 0.007
Acute colonic pseudo-obstruction 11 (1%) 3 (<1%) - 3.7 (1.03-13.2) 0.04
Discussion/Conclusion
• Day 28 mortality (primary outcome) is not significantly different between groups
• Enteral route is not clinically superior when compared to parenteral route for early nutritional support in
critically ill patients treated with mechanical ventilation and vasopressor support for shock
• An increased risk of gastrointestinal (GI) complications is seen with early isocaloric enteral nutrition when
compared to parenteral nutrition
Strengths
• High external validity due to the number of centers utilized in France and practical nature of the study design
• Randomization of trial and use of an objective primary outcome (all-cause mortality) provide internal validity
• First multicenter trial to adapt patient nutrition protocol (parenteral to enteral) to acute phase of critical illness
Weaknesses
• Inability to blind treatment that was provided individually from both patients and the ICU staff providing care
• Difficult to remove bias in reporting of GI complications, as GI function can be assessed with more rigor than in
patients receiving parenteral nutrition
Clinical Implications
• According to these results, early isocaloric enteral nutrition did not significantly reduce mortality in comparison
to parenteral nutrition in critically ill patients with shock but does show an increased risk of GI complications.
Further large randomized trials that compare nutrition doses (hypocaloric, normocaloric) should be conducted to
determine if hypocaloric nutrition is associated with a lower risk of GI complications and if it can be beneficial
during the acute phase of critical illness.
References
1. Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults
with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2).
Lancet. 2018;391:133–43.
2. Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical illness. N Engl J Med.
2014;370:2450–51.
3. Kreymann KG, Berger MM, Deutz NE, et al. ESPEN Guidelines on Enteral Nutrition: Intensive care. Clin
Nutr. 2006;25:210–23
4. Taylor BE, McClave SA, Martindale RG, et al. Guidelines for the Provision and Assessment of Nutrition
Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). Crit Care Med. 2016;44:390–438.
5. Preiser JC, van Zanten AR, Berger MM, et al. Metabolic and nutritional support of critically ill patients:
consensus and controversies. Crit Care. 2015;19:35.
6. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill
adults. N Engl J Med. 2014;371:1673–84.