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

Study Overview
=================
Brief 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. 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.

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)

Conditions
-----------------
Critical Illness, Shock, Mechanical Ventilation, Critical Illness Myopathy, Nosocomial Infection

Intervention / Treatment
-----------------
* Procedure: low-calorie low-protein
* Procedure: standard-calorie/standard-protein


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low group<br>Patients randomized in the low group will receive a low-calorie low-protein nutrition regimen during the acute phase. | Procedure: low-calorie low-protein<br>* 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.<br>|
| Active Comparator: Standard group<br>Patients randomized in the standard group will receive a standard-calorie/standard-protein nutrition regimen during the acute phase. | Procedure: standard-calorie/standard-protein<br>* 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.<br>|

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 |