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Impact of early low- calorie low- protein BMJ Open: first published as 10.1136/bmjopen-2020-045041 on 11 May 2021. Downloaded from
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)
1 2 3
Jean Reignier , Amélie Le Gouge, Jean- Baptiste Lascarrou,
4 5 6 7
Djillali Annane , Laurent Argaud, Yannick Hourmant, Pierre Asfar,
8 9 10 11
Julio Badie, Mai- Anh Nay , Nicolae- Vlad Botoc, Laurent Brisard,
12 13 14 15
Hoang- Nam Bui, Delphine Chatellier, Louis Chauvelot, Alain Combes,
16 17 18 19
Christophe Cracco, Michael Darmon, Vincent Das, Matthieu Debarre,
20 21 22
Agathe Delbove, Jérôme Devaquet, Sebastian Voicu,
23 24 25
Nadia Aissaoui- Balanant, Louis- Marie Dumont, Johanna Oziel,
26 27 28 29
Olivier Gontier, Samuel Groyer, Bertrand Guidet, Samir Jaber ,
30 31 32 33
To cite: Reignier J, Le Gouge A, Fabien Lambiotte, Christophe Leroy, Philippe Letocart, Benjamin Madeux,
Lascarrou J- B, et al. Impact of 34 35 36 37
Julien Maizel, Olivier Martinet, Frédéric Martino, Emmanuelle Mercier,
early low- calorie low- protein 38 39 40 41 42
versus standard- calorie Jean- Paul Mira, Saad Nseir, Walter Picard, Gael Piton, Gaetan Plantefeve,
43 44 45 46
standard- protein feeding Jean- Pierre Quenot, Anne Renault, Laurent Guérin, Jack Richecoeur,
47 48 49 50
on outcomes of ventilated Jean Philippe Rigaud, Francis Schneider, Daniel Silva, Michel Sirodot,
adults with shock: design 51 52 53 54
Bertrand Souweine, Florian Reizine, Fabienne Tamion, Nicolas Terzi,
and conduct of a randomised, 55 56 57 http://bmjopen.bmj.com/
controlled, multicentre, open- Didier Thévenin, Guillaume Thiéry, Nathalie Thieulot- Rolin,
58 59 60 61
label, parallel- group trial Jean- François Timsit, François Tinturier, Patrice Tirot, Thierry Vanderlinden,
(NUTRIREA-3). BMJ Open 62 63 3 2
Isabelle Vinatier, Christophe Vinsonneau, Diane Maugars, Bruno Giraudeau
2021;11:e045041. doi:10.1136/
bmjopen-2020-045041
► Prepublication history for
this paper is available online. ABSTRACT Methods and analysis NUTRIREA-3 is a randomised,
To view these files, please visit Introduction International guidelines include early controlled, multicentre, open- label trial comparing two parallel
the journal online (http:// dx. doi. nutritional support (≤48 hour after admission), 20–25 kcal/ groups of patients receiving invasive mechanical ventilation on January 12, 2023 by guest. Protected by copyright.
org/ 10. 1136/ bmjopen- 2020- kg/day, and 1.2–2 g/kg/day protein at the acute phase of and vasoactive amine therapy for shock and given early
045041). critical illness. Recent data challenge the appropriateness nutritional support according to one of two strategies: early
Received 20 September 2020 of providing standard amounts of calories and protein calorie- protein restriction (6 kcal/kg/day-0.2–0.4 g/kg/day) or
Revised 16 March 2021 during acute critical illness. Restricting calorie and protein standard calorie- protein targets (25 kcal/kg/day, 1.0–1.3 g/kg/
Accepted 20 April 2021 intakes seemed beneficial, suggesting a role for metabolic day) at the acute phase defined as the first 7 days in the ICU.
pathways such as autophagy, a potential key mechanism We will include 3044 patients in 61 French ICUs. Two primary
in safeguarding cellular integrity, notably in the muscle, end- points will be evaluated: day 90 mortality and time to
© Author(s) (or their during critical illness. However, the optimal calorie and ICU discharge readiness. The trial will be considered positive
employer(s)) 2021. Re- use protein supply at the acute phase of severe critical illness if significant between- group differences are found for one
permitted under CC BY- NC. No remains unknown. NUTRIREA-3 will be the first trial to or both alternative primary endpoints. Secondary outcomes
commercial re- use. See rights compare standard calorie and protein feeding complying include hospital-acquired infections and nutritional, clinical and
and permissions. Published by with guidelines to low- calorie low- protein feeding. We functional outcomes.
BMJ. hypothesised that nutritional support with calorie and
For numbered affiliations see protein restriction during acute critical illness decreased Ethics and dissemination The NUTRIREA-3 study has
end of article. day 90 mortality and/or dependency on intensive care unit been approved by the appropriate ethics committee.
(ICU) management in mechanically ventilated patients Patients are included after informed consent. Results will
Correspondence to be submitted for publication in peer- reviewed journals.
Professor Jean Reignier; receiving vasoactive amine therapy for shock, compared Trial registration number NCT03573739.
jean. reignier@ chu- nantes. fr with standard calorie and protein targets.
Reignier J, et al. BMJ Open 2021;11:e045041. doi:10.1136/bmjopen-2020-045041 1
Open access
INTRODUCTION Strengths and limitations of this study BMJ Open: first published as 10.1136/bmjopen-2020-045041 on 11 May 2021. Downloaded from
Severe critical illness is associated during the acute phase
with anorexia, metabolic disorders, endocrine dysfunc- ► NUTRIREA-3 is a pragmatic randomised controlled trial whose large
tion and a major catabolic response responsible for severe number of patients recruited in numerous intensive care units (ICUs)
1
skeletal and diaphragmatic muscle wasting. Among crit- enhance the reliability and general applicability of the results.
ically ill patients requiring mechanical ventilation (MV) ► We included a well- defined population of very severely critically ill
and catecholamines for shock, nearly 40%–50% die, and patients requiring at least vasoactive drugs and mechanical ventila-
functional recovery is often delayed in survivors.2 Nutri- tion, at high risk for death or protracted recovery, and therefore most
tional support is crucial, as malnutrition is associated likely to benefit from improved early nutritional support.
with poor outcomes. Prescribing nutritional support in ► We used two strong patient- centred primary outcomes, that is,
the critically ill is the result of a complex decision-making 90- day mortality and ICU dependency, and we evaluated important
process designed to optimise three key parameters: the secondary outcomes, including long-term function, in keeping with
timing, the dose and the route of artificial feeding. Inter- recommendations about studies of nutritional support in critically
national guidelines encourage early nutritional support ill patients.
(≤48 hours after admission), via the enteral route if not ► NUTRIREA-3 is the first study to evaluate the potential benefits of
calorie and protein restriction versus standard calorie and protein
contraindicated, with 20–25 kcal/kg/day, and 1.2–2 g/ targets during early nutritional support, using very different amounts
3 4
kg/day protein at the acute phase. These targets are of calories and proteins.
rarely achieved in patients with severe critical illnesses, ► A limitation is that blinding of nutritional strategies is not feasible.
who frequently experience gastroparesis responsible for
5
intolerance to enteral nutrition (EN). Observational low- protein feeding at the early phase of critical illness
studies have indicated that calorie and protein deficien- improves muscle preservation, thereby improving
cies were associated with nosocomial infections, intensive outcomes, and most notably diminishing mortality and
care unit (ICU)- acquired weakness, delayed weaning off
MV, longer stays and higher mortality.6–12 dependency on ICU care.
However, recent data challenge the appropriateness of
providing standard amounts of calories and protein during METHODS AND ANALYSIS
13 14
the acute phase of critical illness. Studies showed no Trial design
15 16
outcome benefits with higher intakes. Instead, adding NUTRIREA-3 is a randomised, controlled, multicentre,
parenteral nutrition (PN) to increase intakes was associ- open- label trial comparing two parallel groups of patients.
ated with longer ICU stays and more infectious complica-
tions.17 18 Higher protein intakes during the acute phase Participants, interventions, outcomes
may be associated with greater muscle wasting and ICU- Participating units
1 19 http://bmjopen.bmj.com/
acquired weakness. Restricting calorie and protein Of the 61 French ICUs participating in the study, 34
intakes seemed beneficial, suggesting a role for metabolic are in university hospitals. All participating ICU staff
pathways such as autophagy, a potential key mechanism members have attended training in the study procedures
in safeguarding cellular integrity, notably in the muscle, and protocols for providing nutritional support.
20 21
during critical illness. The recent EDEN and PERMIT
trials showed no differences in patient outcomes between Study population and recruitment modalities
hypocaloric and standard feeding.22–24 However, in both Inclusion criteria are age older than 18 years; invasive
studies, calorie intakes were below-target in the standard MV for an expected duration of at least 48 hours after
groups. Moreover, patients in both PERMIT trial groups inclusion, started in the ICU within the past 24 hours, or on January 12, 2023 by guest. Protected by copyright.
received similar protein intakes, as protein solutions were started before ICU admission with ICU admission within
added in the hypocaloric group. Last, the TARGET trial the 24 hours after intubation; treatment with a vasoactive
demonstrated no benefit of delivering 100% vs 70% of agent for shock (epinephrine, dobutamine or norepi-
the recommended calorie intake on outcomes of criti- nephrine); nutritional support expected to be started
25 within 24 hours after intubation or within 24 hours after
cally ill patients. Thus, the optimal calorie and protein
supply at the acute phase of severe critical illness remains ICU admission when MV was started before ICU admis-
14 26–29 sion; and patient and/or next-of- kin informed about
unknown.
We designed the NUTRIREA-3 trial to compare stan- the study and having consented to participation in the
dard calorie and protein feeding complying with guide- study. If the patient is unable to receive information and
lines to low- calorie low- protein feeding in a well- defined no next- of- kin can be contacted during screening for the
group of severely ill ICU patients requiring at least MV study, trial inclusion will be completed as an emergency
and vasoactive drugs. These patients typically have poor procedure by the ICU physician, in compliance with
outcomes with long ICU stays, high frequencies of ICU- French law.
1 30 Exclusion criteria are specific nutritional needs, such
acquired weakness and infections, and high mortality.
Reported impacts of nutritional support were greatest in as pre- existing long- term home EN or PN, for chronic
3 4 31 32 bowel disease; dying patient, not-to- be- resuscitated order
the most severely ill ICU patients. Our hypothesis
is that, in those severe critically ill patients, low-calorie or other treatment limitation decision at ICU admission;
2 Reignier J, et al. BMJ Open 2021;11:e045041. doi:10.1136/bmjopen-2020-045041
Open access
BMJ Open: first published as 10.1136/bmjopen-2020-045041 on 11 May 2021. Downloaded from
http://bmjopen.bmj.com/
Figure 1 Study interventions. ICU, intensive care unit.
pregnancy, recent delivery or lactation; adult under from D0 to D7. On D8, the calorie target will be 30 kcal/
guardianship; and department of corrections inmate. kg/day and the protein target 1.2–2.0 g/kg/day.
Daily nutritional intakes needed to meet the allocated
Interventions calorie target will be calculated based on BW. In obese on January 12, 2023 by guest. Protected by copyright.
After study inclusion, patients will be allocated at random patients (body mass index, BMI >30 kg/m²), the BW
to one of two nutritional support strategies (figure 1). yielding a BMI of 30 kg/m2will be used. In patients with
2
The designated feeding strategy will be initiated as soon BMI <18.5 kg/m , the following corrected BW will be used:
as possible after randomisation (in all patients, within 24 (ideal BW +actual BW)/2. The calorie/protein ratios of
hours after intubation or ICU admission in patients with nutritional solutions currently available in French hospi-
MV started before admission) and continued until extu- tals will ensure that the protein intake complies with the
bation and withdrawal of vasoactive support, or death, or allocated nutritional regimen.
day 7, whichever occurs first.
In the low- calorie low- protein (low) group, the calorie Nutritional support protocol
target will be 6 kcal/kg/day and the protein target The nutritional support protocol, including measures
0.2–0.4 g/kg/day during the acute phase, that is, from D0 designed to evaluate tolerance, is standardised as indi-
to D7. On D8, the calorie target will be 30 kcal/kg/day cated below.
and the protein target 1.2–2.0 g/kg/day.
In the standard- calorie/standard- protein (Standard) General principles of nutritional support in both study arms
group, the first-line calorie target calculated based on Nutritional support is started as soon as possible after rando-
body weight (BW) is 25 kcal/kg/day and the protein misation and no later than 24 hours after intubation or
target 1.0–1.3 g/kg/day during the acute phase, that is, after ICU admission if intubation preceded ICU admission.
Reignier J, et al. BMJ Open 2021;11:e045041. doi:10.1136/bmjopen-2020-045041 3
Open access
Randomised controlled trials showed that feeding route Minimal regurgitation or vomiting triggered by tracheal BMJ Open: first published as 10.1136/bmjopen-2020-045041 on 11 May 2021. Downloaded from
during the acute phase had no impact on major clinical aspiration or oral cavity care is not taken to indicate
outcomes of critically ill patients when isocaloric nutrition intolerance. EN intolerance leads to the following two
was provided in both arms.33 34 Thus, during the acute measures. First, treatment with a prokinetic agent is
phase, bedside physicians will be free, each day, to choose initiated after confirmation that there are no contrain-
the best feeding route, according to clinical consider- dications. The study ICUs use the prokinetic agent of
ations, to ensure that the calorie target is achieved. After their choice, according to their standard practice. The
the acute phase, enteral feeding remains the preferred prokinetic agent is discontinued when EN at the highest
route in patients without contraindications.4 Thus, on day prescribed flow rate has been well tolerated for 48 hours.
8, in the absence of contraindications to EN, PN will be Second, if gastric intolerance persists despite prokinetic
stopped in those patients fed via the parenteral route, and therapy, the flow rate is decreased by 25 mL/hour every
EN started. From day 8 onwards, supplemental PN may 6 hours until the signs of intolerance resolve. There-
be added in the event of intolerance to EN precluding fore, EN is stopped (and the gastric tube placed under
the achievement of the predefined calorie targets. suction) only in patients with intolerance despite a flow
Nutritional support is prescribed as a flow rate (mL/ rate ≤25 mL/hour. All interruptions in EN delivery must
hour) and started at the prescribed flow rate (as opposed be reported to the physician in charge of the patient. This
to increased gradually). The feed is delivered continu- precaution is particularly important in patients receiving
ously over the 24-hour cycle, with no interruptions. Actual insulin. EN is resumed at the prescribed flow rate (appro-
feed delivery is monitored regularly based on the volumes priate to the patient’s needs) after 6 hours have elapsed
delivered relative to the predefined daily calorie targets. with no further signs of intolerance. Patients at high risk
In addition, special attention is directed to avoiding for gastric intolerance, such as those turned in the prone
delays. Any interruption in feed delivery is reported to position for acute respiratory distress syndrome, receive
the ICU physician in charge. Except in special situations, prophylactic prokinetic treatment starting at the first turn
nutritional support is not interrupted while transporting 36 37
in the prone position.
the patient. However, when EN or PN must be inter-
rupted (eg, for a specific gastrointestinal or radiological Parenteral nutrition
investigation), the flow rate is not increased to compen- Ternary admixtures packaged in bags and containing
sate for the interruption. Finally, all patients are in the the three groups of macronutrients are used according
semi- recumbent supine position (torso inclined 30°–45° to standard practice in each participating centre. Supple-
relative to the horizontal plane). mental electrolytes are supplied in a solution separate
After extubation, regardless of time since randomisa- from the parenteral feed, according to the needs of
tion, decisions about the continued need for, and optimal each patient. PN is delivered continuously via a central
route of, nutritional support are made by the physician venous catheter (CVC). Special attention is directed to http://bmjopen.bmj.com/
in charge of the patient. Patients who are reintubated preventing infections by complying with the standard
within 7 days after trial inclusion are managed until the protocols for CVC insertion and maintenance used in
end of the acute phase according to the arm they were each of the participating centres. Proper CVC position is
randomised to during the first intubation period. checked on a radiograph.
Enteral nutrition Additional intakes
Isoosmotic isocaloric normal- protein polymeric prepa- Additional water, electrolytes, vitamins and trace elements
rations are used during the first week in both groups, are given intravenously according to the needs of each on January 12, 2023 by guest. Protected by copyright.
after which the choice of feed is at the discretion of the individual patient as assessed by the physician in charge
physician. The feed is delivered via a 14-French silicone
and using the standard preparations and protocols avail-
gastric tube. Tube position in the middle of the stomach able in each study ICU.
is checked on a radiograph obtained at ICU admission
or immediately after tube placement, as well as when the Monitoring of intestinal transit
tube is changed or repositioned. The volume and appearance of the stools are monitored
A predefined protocol is used to manage upper gastro- daily. The occurrence of constipation (no stool for more
intestinal intolerance to EN. This protocol was used in than 6 days) or diarrhoea (more than 300 mL of liquid
34 stool or 4 loose stools per day) will be reported and
the NUTRIREA-2 trial. To minimise the risk of gastric
intolerance and consequently of vomiting, the volume will lead to the appropriate diagnostic and therapeutic
15 38 39
of supplemental water given enterally will be as small management. EN is not stopped for diarrhoea,
as possible during the first study week. Residual gastric which leads to the following measures. First, treatments
35 that accelerate bowel transit, including prokinetic agents,
volume is not monitored. The tolerance of EN is
defined based only on episodes of significant vomiting or are stopped. Second, a stool test for Clostridium difficile
regurgitation (passage of enteral nutrition formula into toxin is performed in patients receiving antibiotics. Third,
the mouth, outside the mouth or into the endotracheal the enteral solution is changed if the first measure is inef-
tube in the absence of care procedures or mobilisation). fective and the C. difficile toxin test is negative. Finally, if
4 Reignier J, et al. BMJ Open 2021;11:e045041. doi:10.1136/bmjopen-2020-045041
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