Critical IllnessNUTRIREA3NCT03573739
Impact of Early Low-Calorie Low-Protein Versus Standard Feeding on Outcomes of Ventilated Adults With Shock
A study testing low-calorie low-protein and standard-calorie/standard-protein in people with Critical Illness and Shock, run by Nantes University Hospital at 59 sites in 2 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Critical Illness, Shock, Mechanical Ventilation
- What is being tested?
- low-calorie low-protein and standard-calorie/standard-protein
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3,044 participants
- Where
- 59 sitesin 2 countries
- Study dates
- 5 Jul 2018to 24 Dec 2021
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
59 sites in 2 countries.
59 sites in 2 countries
France58 sites
Chu Amiens Picardie
Amiens, 80054
CHU Angers
Angers, 49100
Centre Hospitalier D'Angouleme
Angoulême, 16959
Ch Annecy-Genevois
Annecy, 74374
Centre Hospitalier D'Argenteuil
Argenteuil, 95100
Hôpital du bois brulé
Beauvais, 60000
Hôpital Nord Franche Comté
Belfort, 90015
Chu Jean Minjoz
Besançon, 25030
Hôpital de Béthune
Béthune, 62408
Hôpital Avicenne AP-HP
Bobigny, 93000
Hopital Pellegrin Chu
Bordeaux, 33000
CHU Cavale Blanche
Brest, 29609
Ch Chartres Louis Pasteur
Chartres, 28630
Chu Gabriel Montpied
Clermont-Ferrand, 63003
Hopital Louis Mourier (Ap-Hp)
Colombes, 92701
Ch Dieppe
Dieppe, 76202
Chu Bocage
Dijon, 21079
Hôpital Raymond-Poincaré
Garches, 92380
Hôpital Michalon
Grenoble, 38043
Chd Les Oudairies
La Roche-sur-Yon, 85025
Chu Bicetre
Le Kremlin-Bicêtre, 94270
Centre Hospitalier Du Mans
Le Mans, 72037
CH Emile Roux
Le Puy-en-Velay, 43000
Centre Hospitalier de Lens
Lens, 62300
Chr - Hopital Roger Salengro
Lille, 59037
CH Saint-Philibert
Lomme, 59462
Hopital de La Croix-Rousse
Lyon, 69317
Hopital Edouard Herriot
Lyon, 69437
Centre Hospitalier Marc Jacquet
Melun, 77011
Centre Hospitalier de Montauban
Montauban, 82013
Hopital Saint Eloi
Montpellier, 34295
Ctre Hosp Intercomm Andre Gregoire
Montreuil, 93100
Chu de Nantes
Nantes, 44000
CHU Nantes
Nantes, 44093
Chr D'Orleans
Orléans, 86709
Hopital Lariboisiere
Paris, 75010
Hôpital Saint Louis (AP-HP)
Paris, 75010
Hopital Saint Antoine
Paris, 75012
Hopital Pitie Salpetriere
Paris, 75013
CHU Paris Cochin
Paris, 75014
G.I.H. Bichat / Claude Bernard (Ap-Hp)
Paris, 75877
Hopital Europeen Georges Pompidou
Paris, 75908
CH Pau
Pau, 64000
Chu La Miletrie
Poitiers, 86021
C.H.R. Pontchaillou
Rennes, 35033
C.H. de Rodez Hopital Jacques Puel
Rodez, 12027
Hopital Charles Nicolle Chu Rouen
Rouen, 76038
CH Saint Brieuc
Saint-Brieuc, 22000
Chu de La Reunion Site Nord
Saint-Denis, La Réunion, 97405
Ch General Delafontaine
Saint-Denis, 93205
CHU de Saint Etienne
Saint-Priest-en-Jarez, 42270
Hopital Broussais
St-Malo, 35403
Hôpital de Hautepierre CHU de Strasbourg
Strasbourg, 67098
Hopital Foch
Suresnes, 92150
CH de Bigorre
Tarbes, 65013
CHU DE TOURS Bretonneau
Tours, 37044
CH Valenciennes
Valenciennes, 59300
Centre Hospitalier Bretagne Atlantique - Vannes Auray
Vannes, 56017
About this study
Official title: 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.
- Conditions
- Critical Illness, Shock, Mechanical Ventilation, Critical Illness Myopathy, Nosocomial Infection
- Being tested
- low-calorie low-protein, standard-calorie/standard-protein
- Medical subject headings
- Critical Illness, Shock, Cross Infection
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
low-calorie low-proteinProcedure or surgery
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.
standard-calorie/standard-proteinProcedure or surgery
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.
| Study group | Role | What they receive |
|---|---|---|
| Low group | Experimental | Patients randomized in the "low group" will receive a low-calorie low-protein nutrition regimen during the acute phase. Receives: Procedure: low-calorie low-protein |
| Standard group | Active comparator | Patients randomized in the "standard group" will receive a standard-calorie/standard-protein nutrition regimen during the acute phase. Receives: Procedure: standard-calorie/standard-protein |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 90 days
Secondary outcomes (31)
Number of calories (in kcal) delivered daily enterally and/or parenterally
Measured: 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
Measured: from day 0 to day 7
Proportion of patients who achieved their calorie target
Proportion of patients who achieved their calorie target
Measured: from day 0 to day 7
Protein supply
Protein supply (g) given daily enterally and/or parenterally
Measured: from day 0 to day 7
Volume of fluids
Volume of fluids (in mL) received daily
Measured: 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).
Measured: from day 0 to day 7
Changes in daily maximum blood glucose levels
Measured: from day 0 to day 7
Proportion of patients with hypoglycaemia
Measured: from day 0 to day 7
insulin dose
Total insulin dose received daily
Measured: from day 0 to day 7
insulin treatment
Days on insulin treatment
Measured: from day 0 to readiness for ICU discharge, an average of 10 days
Proportion of patients with at least one ICU-acquired infection.
Measured: 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).
Measured: 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
Measured: from day 0 to extubation, an average of 7 days
Proportion of patients with at least one episode of liver dysfunction during follow-up
Measured: 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
Measured: 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
Measured: from day 0 to extubation, an average of 7 days
Proportion of patients with at least one documented episode of bowel ischaemia
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: from day 0 to day 7 and readiness for ICU discharge, an average of 10 days
Hospital stay
Hospital stay length (days in hospital)
Measured: from day 0 to hospital discharge, an average of 23 days
Duration of mechanical ventilation
Days on mechanical ventilation
Measured: from day 0 to extubation, an average of 7 days
ICU mortality
Proportions of patients dead during the ICU stay
Measured: from day 0 to ICU discharge, an average of 23 days
Mortality at day 28
Proportions of patients dead until day 28 after randomization
Measured: from day 0 to day 28
Hospital mortality
Proportions of patients dead during the hospital stay
Measured: 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.
Measured: from day 0 to day 7
Total number of active mobilizations
Evaluation of mobilisation during the ICU stay using predetermined criteria.
Measured: 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).
Measured: 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
Measured: 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.
Measured: 3 months and 1 year after study inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2018
- Study start5 Jul 2018
- Primary completion16 Dec 2020
- Study completion24 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Critical IllnessStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- This multicentre randomised controlled open trial compares two parallel groups of patients receiving mechanical ventilation and vasoactive amine therapy and given early nutritional support according to one of two strategies: 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/1.0-1.3g/kg/d: Standard group) at the acute phase of ICU management (D0-D7).
- Masking
- None (open label)
- Enrolment
- 3,044 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nantes University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Ministry of Health, France, University Hospital, Tours
- Responsible party
- Sponsor
- Investigators
- Jean Reignier, MD, PhD, Principal investigator, Nantes University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03573739
- Sponsor's protocol ID
- RC18_0006
- Acronym
- NUTRIREA3
- Status last verified
- Apr 2022
- First submitted
- 7 Jun 2018
- Last updated
- 14 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Reignier J, Plantefeve G, Mira JP, Argaud L, Asfar P, Aissaoui N, Badie J, Botoc NV, Brisard L, Bui HN, Chatellier D, Chauvelot L, Combes A, Cracco C, Darmon M, Das V, Debarre M, Delbove A, Devaquet J, Dumont LM, Gontier O, Groyer S, Guerin L, Guidet B, Hourmant Y, Jaber S, Lambiotte F, Leroy C, Letocart P, Madeux B, Maizel J, Martinet O, Martino F, Maxime V, Mercier E, Nay MA, Nseir S, Oziel J, Picard W, Piton G, Quenot JP, Reizine F, Renault A, Richecoeur J, Rigaud JP, Schneider F, Silva D, Sirodot M, Souweine B, Tamion F, Terzi N, Thevenin D, Thiery G, Thieulot-Rolin N, Timsit JF, Tinturier F, Tirot P, Vanderlinden T, Vinatier I, Vinsonneau C, Voicu S, Lascarrou JB, Le Gouge A; NUTRIREA-3 Trial Investigators; Clinical Research in Intensive Care; Sepsis (CRICS-TRIGGERSEP)Group. Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3). Lancet Respir Med. 2023 Jul;11(7):602-612. doi: 10.1016/S2213-2600(23)00092-9. Epub 2023 Mar 20.
PubMed 36958363Reignier 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, Guerin L, Richecoeur J, Rigaud JP, Schneider F, Silva D, Sirodot M, Souweine B, Reizine F, Tamion F, Terzi N, Thevenin D, Thiery 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.
PubMed 33980526