Protein Supplementation vs Standard Feeds in Underweight Critically Ill Children: A Dual-Centre Pilot RCT

Study Overview
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Brief Summary
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This pilot trial is part of a long-term research program leading to a large trial to determine if a strategy of supplementing protein in a subset of critically ill children is superior to standard enteral nutrition care. The investigators hypothesize that protein supplementation to critically ill children with body mass index (BMI) z-score <0 reduces the length of stay in the paediatric intensive care unit (PICU) and hospital, as well as the duration of mechanical ventilation (MV).

Detailed Description
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Protein malnutrition is prevalent among critically ill children and associated with poor clinical outcomes. Current guidelines for provision of protein in daily management of critically ill children in pediatric intensive care units (PICUs) are based on limited and not high-quality evidence. The current protein supplementation approach, one-size-fits-all nutrition prescription, may not be appropriate for every critically ill child. Given the heterogeneity of the patients admitted to the PICU, a targeted approach based on individuals' needs represents a potential advancement in PICU care. The central hypothesis is that protein supplementation in PICU care leads to improved clinical outcomes in subgroups of patients only. The investigators propose a dual-centre pilot randomized controlled trial in Singapore with two major aims: To obtain key information for planning and conducting a large-scale multicentre study in Asia; and to evaluate the benefit of protein supplementation to critically ill children with body mass index (BMI) z-scores on PICU <0 The main clinical outcome of interest is total number of days of hospital stay (from PICU admission to hospital discharge). Two protein supplementation regimes (≥ 1.5g/kg/day vs. standard care) will be randomly allocated to PICU patients with body mass index (BMI) z-scores <0. The investigators will determine the effect of protein supplementation on total length of hospital stay and other clinical outcomes, and assess the impact of protein supplementation on acquired functional impairment of PICU survivors 6 months after hospital discharge. In addition, the investigators will explore whether muscle ultrasound is a biomarker for protein balance in pediatric critical illness. Upon completion of this study, the investigators will have strong preliminary data to plan, refine their study approach, and execute a future large multi-centre study across Asia. These data will ultimately guide protein provision and nutritional management of patients in PICU setting.

Official Title
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Protein Supplementation Versus Standard Feeds in Underweight Critically Ill Children: A Dual-Centre Randomized Controlled Pilot Trial

Conditions
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Critically Ill

Intervention / Treatment
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* Dietary Supplement: Enteral protein supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 28 days and 18 years of age Have a BMI z-score < 0 on PICU admission Requires respiratory support in the form of invasive or non-invasive mechanical ventilation (CPAP or BiPAP) within 24-48 hours of PICU admission, and the attending physician expects the child to require any respiratory support for at least 48 hours of PICU admission Requires enteral nutrition support for feeding (e.g., oro-gastric, nasogastric, gastrostomy, naso-jejunal, oro-jejunal) Have an expected PICU stay of > 48 hours Exclusion Criteria: Are not expected to survive this PICU admission because of palliative care (e.g., do-not-resuscitate status) or limited life support Progressive neuromuscular disease (e.g., spinal muscular atrophy, Duchenne or other muscular dystrophy, multiple sclerosis, amyotrophic lateral sclerosis) Medical conditions where increased or decreased protein intake is required, including acute kidney injury (stage 3 KDIGO criteria), chronic kidney disease (stage 4 and 5), inborn errors of metabolism, fulminant liver failure, severe burn injury Contraindications to enteral nutrition (e.g., gut hemorrhage, post-gastrointestinal surgery etc.) Diagnosed cow's milk protein allergy Parenteral nutrition Premature infants who are less than corrected gestational age of 44 weeks (gestational age + weeks after birth) Were previously enrolled in this trial Are currently enrolled in a potentially confounding trial Diagnosis of anorexia nervosa and other eating disorders On extra-corporeal membrane oxygenation (ECMO) support Conditions that required significant fluid restriction (≤75% of maintenance fluid) (e.g., post cardiac surgery etc.)

Ages Eligible for Study
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Minimum Age: 28 Days
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to enteral protein supplementation or standard care (no enteral protein supplementation) in a 1:1 ratio.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard care group<br>The participants will receive feeding as per standard of care (without protein or any other supplementations). | |
| Experimental: Study interventional group<br>The participants will receive protein supplementation to reach a final goal of 1.5 g/kg/day of protein on full feeds. | Dietary Supplement: Enteral protein supplementation<br>* The participants in the study interventional group will receive protein supplementation to reach a final goal of 1.5 g/kg/day of protein on full feeds. This will be via 100% whey protein isolate (Nestle Beneprotein). Doses will be calculated on the patient's admission weight and rounded up to the nearest 1g. Doses will not be adjusted to account for weight changes in the PICU. Protein supplementation will continue for a total of 7 days from the start of enrolment into the study or until PICU discharge, whichever is earlier. If the patient is able to take solid feeds during the study intervention period, the intervention will be stopped. However, if the device required for feeding is removed but the patient takes milk/liquid feeds fully, protein supplementation will continue.<br>* Other names: Protein isolate (Nestle Beneprotein);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of eligible patients approached for consent | Number of eligible patients who are approached for consent | Throughout study period, over 36 months | 
| Proportion of participants receiving their first protein supplementation within 72 hours of enrolment | Number of patients who received protein supplementation within 72 hours of enrolment | Throughout the study, over 24 months | 
| Participant accrual rate | Average monthly enrolment at each centre | Throughout the study, over 24 months | 
| Protocol adherence | >80% of protein target administered according to the protocol in the intervention arm | Throughout study period, over 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PICU mortality | Death in PICU | Throughout study period, over 36 months | 
| PICU length of stay | Duration of stay in the PICU | Throughout study period, over 36 months | 
| Hospital length of stay | Duration of stay in the hospital | Throughout the study period, over 36 months | 
| Adverse events | Development of adverse events such as feeding intolerance, diarrhoea, gastrointestinal bleeding | Throughout study period, over 36 months | 
| Change in muscle size | Longitudinal change in muscle size as assessed by ultrasound. Muscles for assessment include rectus femoris and diaphragm | During PICU stay, PICU discharge, hospital discharge and 6 months follow-up | 
| Anthropometry | Change in anthropometric measurements | During PICU stay, PICU discharge, hospital discharge and 6 months follow-up | 
| Functional status | Assessment of functional status via functional status scale (FSS). FSS scores ranged from 6 to 30. A higher score denotes worse outcome | PICU admission, hospital discharge and 6 months follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Critically ill, Protein supplementation, Nutrition