Presentation 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
Roseman University of Health Sciences
College of Pharmacy
September 13, 2019

2. Background
• Acute critical illness requiring mechanical ventilation may lead to risk
of severe malnutrition in patients.2
• Current ESPEN Guidelines on Enteral Nutrition
• Recommends 20-25 kcal/kg of enteral nutrition per day during acute phase of
critical illness.1, 3, 4
• Only one previous trial (CALORIES) assessed feeding routes in critically
ill patients.6

3. 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

4. Methods
• Study Design
• Randomized
• Open-label
• Controlled
• Multi-centered: 44 Intensive Care Units (ICUs) across France
• Parallel-group

5. Methods
• Patients were stratified using blocks of varying sizes, then randomized
into:
• Enteral group receiving only enteral nutrition for duration of trial
• Parenteral group received parenteral nutrition for at least 72 hours after
randomization, and was switched to enteral nutrition one of two ways:
• Patient met predefined criteria for hemodynamic stability (no vasopressor support for 24
consecutive hours and arterial blood lactate concentration <2 mmol/L)
• After 7 days of parenteral nutrition and no contraindications, patients were switched to
enteral nutrition

6. Methods – Inclusion/Exclusion Criteria
InclusionCriteria 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

7. 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

8. Statistics
• Investigators determined that 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
• Analyses were based on an intent-to-treat basis

9. Results
• Trial was ended after second interim analysis as completing patient
enrollment was deemed unlikely to produce a significant change in
the trial results
• Baseline characteristics were similar between groups
• Mean age: 66 years, 67% male, Vasopressor support: 81% Norepinephrine
alone

10. Results
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

11. Conclusion/Discussion
• Day 28 mortality (primary outcome) is not significantly different
between groups
• Enteral route is not clinically superior to parenteral route for critically
ill patients requiring mechanical ventilation and vasopressor support
for shock
• An increased risk of gastrointestinal (GI) complications is seen with
enteral nutrition when compared to parenteral nutrition

12. Strengths
• High external validity due to the amount 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 (parenteral to enteral)
to acute phase of critical illness

13. Weaknesses
• Inability to blind treatment that was provided from patients and ICU
staff
• Difficult to remove bias in reporting of GI complications
• GI function can be assessed more thoroughly in enteral fed patients than in
patients receiving parenteral nutrition

14. Clinical Implications
• Further large randomized trials comparing nutrition doses
(hypocaloric, normocaloric) should be conducted
• Determine whether hypocaloric nutrition is associated with a lower risk of GI
complications
• Possible benefits of hypocaloric nutrition during the acute phase of critical
illness.
• Find a treatment that reduces mortality in critically ill patients and minimizes
risk of GI complications

15. 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.

16. Questions?
Thank you