Impact of Early Low-Calorie Low-Protein Versus Standard Feeding on Outcomes of Ventilated Adults With Shock (NUTRIREA3)

Impact of Early Low-Calorie Low-Protein Versus Standard-Calorie Standard-Protein Feeding on Outcomes of Ventilated Adults With Shock: a Randomised, Controlled, Multicentre, Open-label, Parallel-group Study (NUTRIREA-3)

Among critically ill patients requiring mechanical ventilation and catecholamines for shock, nearly 40% to 50% die, and functional recovery is often delayed in survivors. International guidelines include early nutritional support (≤48 h after admission), 20-25 kcal/kg/d at the acute phase, and 1.2-2 g/kg/d protein. These targets are rarely achieved in patients with severe critically illnesses. Recent data challenge the wisdom of providing standard amounts of calories and protein during the acute phase of critical illness. Studies designed to improve enteral nutrition delivery showed no outcome benefits with higher intakes. Instead, adding parenteral nutrition to increase intakes was associated with longer ICU stays and more infectious complications. Studies suggest that higher protein intakes during the acute phase may be associated with greater muscle wasting and ICU-acquired weakness. The optimal calorie and protein supply at the acute phase of severe critical illness remains unknown. NUTRIREA-3 will be the first trial to compare standard calorie and protein feeding complying with guidelines to low-calorie low-protein feeding potentially associated with improved muscle preservation, translating into shorter mechanical ventilation and ICU-stay durations, lower ICU-acquired infection rates, lower mortality, and better long-term clinical outcomes. This multicentre, randomized, controlled, open trial will compare, in patients receiving mechanical ventilation and treated with vasoactive agent for shock two strategies for initiating nutritional support at the acute phase of ICU management (D0-D7): early calorie/protein restriction (6 kcal/kg/d/0.2-0.4 g/kg/d, Low group) or standard calorie/protein targets (25 kcal/kg/d/1.0-1.3 g/kg/d, Standard group). Patients in both groups will receive enteral or parenteral nutrition appropriate for their critical illness. Two alternative primary end-points will be evaluated: all-cause mortality by day 90 and time to discharge alive from the ICU. Second end-points will be calories and proteins delivered, nosocomial infections, gastro-intestinal complications, glucose control, liver dysfunctions, muscle function at the time of readiness for ICU discharge and quality of life at 3 months and 1 year after study inclusion.

Study Overview

• Status: Completed
• Conditions: Shock; Critical Illness; Critical Illness Myopathy; Mechanical Ventilation; Nosocomial Infection
• Intervention / Treatment: Procedure: low-calorie low-protein; Procedure: standard-calorie/standard-protein

• Study Type: Interventional
• Enrollment (Actual): 3044
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens Picardie
  • Angers, France, 49100
    • CHU Angers
  • Angoulême, France, 16959
    • Centre Hospitalier d'Angoulème
  • Annecy, France, 74374
    • CH Annecy-Genevois
  • Argenteuil, France, 95100
    • Centre Hospitalier D'Argenteuil
  • Beauvais, France, 60000
    • Hôpital du bois brulé
  • Belfort, France, 90015
    • Hôpital Nord Franche Comté
  • Besançon, France, 25030
    • CHU Jean Minjoz
  • Bobigny, France, 93000
    • Hopital Avicenne AP-HP
  • Bordeaux, France, 33000
    • Hopital Pellegrin Chu
  • Brest, France, 29609
    • CHU Cavale Blanche
  • Béthune, France, 62408
    • Hôpital de Béthune
  • Chartres, France, 28630
    • Ch Chartres Louis Pasteur
  • Clermont-Ferrand, France, 63003
    • Chu Gabriel Montpied
  • Colombes, France, 92701
    • Hôpital Louis Mourier (AP-HP)
  • Dieppe, France, 76202
    • Ch Dieppe
  • Dijon, France, 21079
    • CHU Bocage
  • Garches, France, 92380
    • Hôpital Raymond-Poincaré
  • Grenoble, France, 38043
    • Hôpital Michalon
  • Le Puy en Velay, France, 43000
    • CH Emile Roux
  • Lens, France, 62300
    • Centre Hospitalier de Lens
  • Lille, France, 59037
    • Chr - Hopital Roger Salengro
  • Lomme, France, 59462
    • CH Saint-Philibert
  • Lyon, France, 69437
    • Hôpital Edouard Herriot
  • Lyon, France, 69317
    • Hopital de la Croix-Rousse
  • Melun, France, 77011
    • Centre Hospitalier Marc Jacquet
  • Montauban, France, 82013
    • Centre Hospitalier de Montauban
  • Montpellier, France, 34295
    • Hopital Saint Eloi
  • Montreuil, France, 93100
    • Ctre Hosp Intercomm Andre Gregoire
  • Nantes, France, 44093
    • Chu Nantes
  • Nantes, France, 44000
    • CHU de Nantes
  • Orléans, France, 86709
    • CHR d'Orléans
  • Paris, France, 75010
    • Hopital Lariboisiere
  • Paris, France, 75012
    • Hôpital Saint Antoine
  • Paris, France, 75010
    • Hôpital Saint Louis (AP-HP)
  • Paris, France, 75013
    • Hopital Pitie Salpetriere
  • Paris, France, 75014
    • CHU Paris Cochin
  • Paris, France, 75877
    • G.I.H. Bichat / Claude Bernard (Ap-Hp)
  • Paris, France, 75908
    • Hôpital Européen Georges Pompidou
  • Pau, France, 64000
    • CH Pau
  • Poitiers, France, 86021
    • CHU La Miletrie
  • Rennes, France, 35033
    • C.H.R. Pontchaillou
  • Rodez, France, 12027
    • C.H. de Rodez Hopital Jacques Puel
  • Rouen, France, 76038
    • Hopital Charles Nicolle Chu Rouen
  • Saint Brieuc, France, 22000
    • CH Saint Brieuc
  • Saint Priest en Jarez, France, 42270
    • Chu de Saint Etienne
  • Saint-Denis, France, 93205
    • CH General Delafontaine
  • Saint-Malo, France, 35403
    • Hôpital Broussais
  • Strasbourg, France, 67098
    • Hôpital de Hautepierre CHU de Strasbourg
  • Suresnes, France, 92150
    • Hôpital Foch
  • Tarbes, France, 65013
    • CH de Bigorre
  • Tours, France, 37044
    • CHU DE TOURS Bretonneau
  • Valenciennes, France, 59300
    • Ch Valenciennes
  • Vannes, France, 56017
    • Centre Hospitalier Bretagne Atlantique - Vannes Auray
  • la Roche sur Yon, France, 85025
    • CHD les Oudairies
  • le Mans, France, 72037
    • Centre Hospitalier du Mans
  • le kremlin Bicêtre, France, 94270
    • CHU Bicêtre
  • La Réunion
    • St Denis, La Réunion, France, 97405
      • CHU de La Réunion site nord
• Guadeloupe
  • Pointe-à-pitre, Guadeloupe, 97159
    • CHU Pointe à Pitre - Abymes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Invasive mechanical ventilation started in the ICU within the past 24 h, or started before ICU admission with ICU admission within the past 24 h, for an expected duration of at least 48 hours after inclusion
• Treatment with a vasoactive agent for shock (adrenaline, dobutamine, or noradrenaline)
• Nutritional support expected to be started within 24 h after intubation or within 24 h after ICU admission when mechanical ventilation was started before ICU admission
• Age older than 18 years
• Patient and/or next-of-kin informed about the study and having consented to participation in the study. If the patient is unable to receive information and no next-of-kin can be contacted during screening for the study, trial inclusion will be completed as an emergency procedure by the ICU physician, in compliance with the French law.

Exclusion Criteria:

• Specific nutritional needs, such as pre-existing long-term home enteral or parenteral nutrition, for chronic bowel disease
• Dying patient, not-to-be-resuscitated order, or other treatment limitation decision at ICU admission
• Pregnancy, recent delivery, or lactation
• Adult under guardianship
• Department of corrections inmate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low group; Patients randomized in the "low group" will receive a low-calorie low-protein nutrition regimen during the acute phase.	Procedure: low-calorie low-protein; In the low-calorie low-protein (Low) group, the calorie target will be 6 kcal/kg/day and the protein target 0.2-0.4 g/kg/d during the acute phase, i.e. from D0 to D7. On D8, the calorie target will be 30 kcal/kg/d and the protein target 1.2-2.0 g/kg/d.
Active Comparator: Standard group; Patients randomized in the "standard group" will receive a standard-calorie/standard-protein nutrition regimen during the acute phase.	Procedure: standard-calorie/standard-protein; In the standard-calorie/standard-protein (Standard) group, the first-line calorie target calculated based on body weight is 25 kcal/kg/day and the protein target 1.0-1.3 g/kg/d during the acute phase, i.e. from D0 to D7. On D8, the calorie target will be 30 kcal/kg/d and the protein target 1.2-2.0 g/kg/d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to discharge alive from the ICU.	A patient will be considered ready for ICU discharge by the bedside physicians as soon as all predefined clinical conditions for ICU discharge are fulfilled, regardless of ward-bed availability.	From date of ICU admission until the date of first documented date when predefined clinical conditions for ICU discharge are fulfilled, an average of 10 days.
D-90 mortality	All-cause mortality by day 90	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of calories (in kcal) delivered daily enterally and/or parenterally		from day 0 to day 7
Ratio of prescribed over calories delivered	Ratio (as a %) of prescribed over calories delivered daily enterally and/or parenterally	from day 0 to day 7
Proportion of patients who achieved their calorie target	Proportion of patients who achieved their calorie target	from day 0 to day 7
Protein supply	Protein supply (g) given daily enterally and/or parenterally	from day 0 to day 7
Volume of fluids	Volume of fluids (in mL) received daily	from day 0 to day 7
Changes in Sequential Organ Failure Assessment (SOFA) score	SOFA scores can range from 0 (no organ failure) to 24 (most severe level of multi-organ failure).	from day 0 to day 7
Changes in daily maximum blood glucose levels		from day 0 to day 7
Proportion of patients with hypoglycaemia		from day 0 to day 7
insulin dose	Total insulin dose received daily	from day 0 to day 7
insulin treatment	Days on insulin treatment	from day 0 to readiness for ICU discharge, an average of 10 days
Proportion of patients with at least one ICU-acquired infection.		from day 0 to readiness for ICU discharge, an average of 10 days
Proportion of patients with each type ICU-acquired infection	e.g. (Ventilator-associated pneumonia, bacteremia, Central venous catheter-related infections, Urinary tract infections, soft tissue infections).	from day 0 to readiness for ICU discharge, an average of 10 days
Proportion of patients with at least one episode of vomiting or regurgitation while on mechanical ventilation		from day 0 to extubation, an average of 7 days
Proportion of patients with at least one episode of liver dysfunction during follow-up		from day 0 to readiness for ICU discharge, an average of 10 days
Proportion of patients with at least one episode of diarrhoea	defined as liquid stools in a volume greater than 300 mL/24 hours in patients with a faecal collector or as more than four loose stools/24 hours	from day 0 to extubation, an average of 7 days
Proportion of patients with at least one episode of constipation	no stool for more than 6 days	from day 0 to extubation, an average of 7 days
Proportion of patients with at least one documented episode of bowel ischaemia		from day 0 to readiness for ICU discharge, an average of 10 days
Mean changes in serum albumin	measured at baseline, at the end of mechanical ventilation, on day 7 (in patients on mechanical ventilation for more than 7 days), and at ICU discharge	from day 0 to day 7 and readiness for ICU discharge, an average of 10 days
Mean changes in serum pre-albumin	measured at baseline, at the end of mechanical ventilation, on day 7 (in patients on mechanical ventilation for more than 7 days), and at ICU discharge	from day 0 to day 7 and readiness for ICU discharge, an average of 10 days
Changes in serum C-reactive protein (CRP)	measured at baseline, at the end of mechanical ventilation, on day 7 (in patients on mechanical ventilation for more than 7 days), and at ICU discharge	from day 0 to day 7 and readiness for ICU discharge, an average of 10 days
Changes in mean body weight	determined at baseline, on day 7, and at ICU discharge	from day 0 to day 7 and readiness for ICU discharge, an average of 10 days
Hospital stay	Hospital stay length (days in hospital)	from day 0 to hospital discharge, an average of 23 days
Duration of mechanical ventilation	Days on mechanical ventilation	from day 0 to extubation, an average of 7 days
ICU mortality	Proportions of patients dead during the ICU stay	from day 0 to ICU discharge, an average of 23 days
Mortality at day 28	Proportions of patients dead until day 28 after randomization	from day 0 to day 28
Hospital mortality	Proportions of patients dead during the hospital stay	from day 0 to hospital discharge, an average of 23 days
Proportions of patients mobilized	Evaluation of mobilisation during the ICU stay using predetermined criteria.	from day 0 to day 7
Total number of active mobilizations	Evaluation of mobilisation during the ICU stay using predetermined criteria.	from day 0 to day 7
Muscle function	Muscle function at the time of readiness for ICU discharge as assessed with the Medical Research Council (MRC) score. The MRC score ranges from 0 (no muscle activity) to 60 (normal muscle function).	On the day of readiness for ICU discharge, an average of 10 days
Proportion of patients with at least one criterion for persistent altered health status	at the time of readiness for ICU discharge	On the day of readiness for ICU discharge, an average of 10 days
SF-36 score	The Short Form (SF)-36 is a multipurpose health survey with 36 questions. Questionnaires will be completed during a phone call to the patient by an independent blinded research nurse or psychologist.	3 months and 1 year after study inclusion

Collaborators and Investigators

• Sponsor: Nantes University Hospital
• Collaborators: Ministry of Health, France; University Hospital, Tours
• Investigators: Principal Investigator: Jean REIGNIER, MD, PhD, Nantes University Hospital

Publications and helpful links

General Publications

• Reignier J, Le Gouge A, Lascarrou JB, Annane D, Argaud L, Hourmant Y, Asfar P, Badie J, Nay MA, Botoc NV, Brisard L, Bui HN, Chatellier D, Chauvelot L, Combes A, Cracco C, Darmon M, Das V, Debarre M, Delbove A, Devaquet J, Voicu S, Aissaoui-Balanant N, Dumont LM, Oziel J, Gontier O, Groyer S, Guidet B, Jaber S, Lambiotte F, Leroy C, Letocart P, Madeux B, Maizel J, Martinet O, Martino F, Mercier E, Mira JP, Nseir S, Picard W, Piton G, Plantefeve G, Quenot JP, Renault A, Guérin L, Richecoeur J, Rigaud JP, Schneider F, Silva D, Sirodot M, Souweine B, Reizine F, Tamion F, Terzi N, Thévenin D, Thiéry G, Thieulot-Rolin N, Timsit JF, Tinturier F, Tirot P, Vanderlinden T, Vinatier I, Vinsonneau C, Maugars D, Giraudeau B. Impact of early low-calorie low-protein versus standard-calorie standard-protein feeding on outcomes of ventilated adults with shock: design and conduct of a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3). BMJ Open. 2021 May 11;11(5):e045041. doi: 10.1136/bmjopen-2020-045041.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2018
• Primary Completion (Actual): December 16, 2020
• Study Completion (Actual): December 24, 2021

Study Registration Dates

• First Submitted: June 7, 2018
• First Submitted That Met QC Criteria: June 28, 2018
• First Posted (Actual): June 29, 2018

Study Record Updates

• Last Update Posted (Actual): April 6, 2022
• Last Update Submitted That Met QC Criteria: April 5, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Disease Attributes; Iatrogenic Disease; Shock; Critical Illness; Cross Infection
• Other Study ID Numbers: RC18_0006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No