Enhanced Protein Intake to Support Muscle Protein Synthesis in ICU (IPA-IC)

Increased Protein Amount as a Nutritional Strategy to Enhance Muscle Protein Synthesis in ICU Patients

Rationale - Critically ill patients often experience severe skeletal muscle wasting due to an imbalance between muscle protein synthesis (MPS) and degradation, contributing to long-term impairments such as ICU-acquired weakness (ICU-AW) and post-intensive care syndrome (PICS). Effective interventions to mitigate muscle wasting remain a critical unmet need. Protein intake has been identified as a potential modulator of MPS, but anabolic resistance and conflicting evidence regarding optimal protein intake necessitate further investigation.

Objective/Hypothesis - This study aims to evaluate the effect of a normal (target: 0.8 g protein/kg/day) versus elevated (target: 1.3 g protein/kg/day) protein intake on MPS rates over four days in critically ill patients.

Population - 26 critically ill patients who are suitable for enteral nutrition, mechanically ventilated (min 3 days), and stay at the ICU for at least 7 days will be included.

Method: Patients are randomly assigned to two groups (normal or higher protein intake). Muscle biopsies and blood samples will be collected to assess muscle protein synthesis rates.

Study Overview

• Status: Recruiting
• Conditions: Critical Illness; Muscle Protein Synthetic Response to Protein
• Intervention / Treatment: Dietary supplement: Nutritionally complete Tube Feed with standard protein levels; Dietary supplement: Nutritionally complete Tube Feed with higher protein levels

Detailed Description

Complexities of Critical Illness - Critical illness encompasses the progression of severe medical conditions like major trauma or sepsis, which disrupt the body's homeostasis. This imbalance increases susceptibility to vital organ dysfunction, thereby posing imminent life-threatening consequences without prompt intensive medical support in hospitals. A key concern in critically ill patients is the rapid onset of skeletal muscle wasting, resulting in a condition known as intensive care unit-acquired weakness (ICU-AW). This muscle weakness is closely associated with extended mechanical ventilation and higher morbidity and mortality rates. Even after recovery, patients often suffer from long-term physical impairments and disabilities, resulting in post-intensive care syndrome (PICS), a condition characterized by persistent and debilitating consequences of ICU admission. Muscle weakness can last several years after ICU discharge, contributing to increased healthcare costs and a reduced quality of life. Considering the profound impact on both short- and long-term outcomes, coupled with the absence of effective strategies to prevent muscle wasting and weakness, remain major challenges in modern intensive care medicine.

Skeletal Muscle Protein Imbalance - Skeletal muscle mass is regulated by the balance between muscle protein synthesis, degradation, and folding. Under stable conditions, proteins serve structural and functional purposes crucial for growth, recovery, and adaptation. However, critical illness alters protein dynamics. Disturbance in protein folding can result in the accumulation of damaged proteins, causing a decline in protein quality, while imbalances between protein synthesis and degradation can lead to a decrease in quantity. Critically ill patients often experience a metabolic shift towards a catabolic state, wherein skeletal muscles are broken down to fulfill energy demands. Notably, during this catabolic phase, muscle proteins become a primary fuel source, with rates of muscle protein breakdown surpassing those of synthesis. This rapid muscle protein loss can result in up to 18% reduction in muscle mass within the first 10 days of ICU stay, ultimately leading to muscle atrophy.

Previous research has utilized nitrogen balance assessments and stable isotope techniques to evaluate whole-body protein turnover. However, only a few studies have specifically measured muscle protein synthesis (MPS) rates in critically ill patients using intravenous stable isotope infusions. These measurements typically cover short durations (less than 9 hours), making it challenging to extrapolate the findings to long-term outcomes due to the inherent limitations of amino acid tracer techniques. Adaptions to muscle disuse, inflammation, and catabolic stress likely occur over several days or weeks rather than hours. A promising alternative is oral deuterated water (D2O), which enables the assessment of MPS over longer periods (days or weeks). Current research by our group used D2O to provide insights into muscle synthesis rates over multiple ICU days. This pioneering study will establish critical baseline data for future research.

Protein Ingestion as a Key Modulator - To improve patient recovery, interventions targeting muscle loss are recommended. The 2019 guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN) emphasize the importance of nutritional support for mechanically ventilated ICU patients. Specifically, dietary proteins and their amino acid composition are key in mitigating skeletal muscle wasting and improving long-term clinical outcomes. However, the efficacy of dietary protein to stimulate MPS is regulated by various physiological factors such as dietary protein digestion and amino acid absorption, splanchnic amino acid retention, postprandial insulin release, skeletal muscle tissue perfusion, amino acid uptake by muscle, and intramyocellular signaling. Current international guidelines recommend elevated protein intake for critically ill patients, ranging from 1.2 to 2.0 g protein/kg body weight/day, exceeding recommendations for healthy individuals. However, while higher protein intake has been shown to enhance MPS, recent research suggests that the upper threshold of 2.0 g/kg/day may negatively impact health-related quality of life without improving functional outcomes up to 180 days post-ICU admission. Given these conflicting findings, the precise impact of elevated protein intake on MPS in critically ill patients remains unclear, warranting further investigation to determine the optimal protein requirements during critical illness. Furthermore, despite these widely accepted guidelines and intake recommendations, observational studies have reported that actual protein intake in ICU patients often falls below these targets, ranging from 0.7 to 1.2 g/kg/day. Recent research demonstrated efficient digestion and absorption of enterally administered protein. Nevertheless, post-prandial muscle protein synthesis rates were much lower in critically ill patients than in healthy volunteers. This indicates that critical illness does not impair dietary protein digestion and amino acid absorption. However, incorporating dietary protein-derived amino acids into skeletal muscle protein is blunted, representing anabolic resistance to dietary protein. This anabolic resistance underscores the complexity of muscle protein metabolism in critically ill patients and highlights the need for effective strategies to attenuate skeletal muscle wasting.

In short, this prospective study aims to evaluate the effect of normal vs. elevated enteral protein administration on muscle protein synthesis rates and muscle characteristics in critically ill patients. This research will provide valuable insights to develop effective nutritional interventions to address skeletal muscle wasting in critical illness.

• Study Type: Interventional
• Enrollment (Estimated): 26
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Michèlle Hendriks, MSc; Phone Number: +31 43 388 1184; Email: michelle.hendriks@maastrichtuniversity.nl

Study Locations

• Belgium
  • Limburg
    • Hasselt, Limburg, Belgium, 3500
      • Recruiting
      • Jessa Hospital Campus Virga Jesse
      • Contact: Björn Stessel, Prof. Dr.; Phone Number: +3211 33 55 77; Email: bjorn.stessel@jessazh.be
      • Contact: Michèlle Hendriks, MSc; Phone Number: +31 43 388 1184; Email: michelle.hendriks@maastrichtuniversity.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged ≥ 18 years
• Suitability for enteral nutrition (i.e., no GI failure, absence of complete intestinal obstruction, no major intra-abdominal sepsis)
• Expected mechanical ventilation of minimal three days
• Expected ICU stay of at least seven days

Exclusion Criteria:

• BMI ≥ 40 kg/m²
• Spinal cord injury
• Chronic corticosteroid use before hospital admission
• severe allergies or intolerances (e.g., to cow's milk protein, fish, soy, pea protein or galactosemia)
• Severe kidney and/or liver failure
• Requirements for dialysis
• Bleeding disorders, including anticoagulant and antiplatelet therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Normal protein amount	Dietary supplement: Nutritionally complete Tube Feed with standard protein levels; Containing standard protein levels to target normal protein amount of 0.8 g of protein/kg body weight/day
Experimental: Elevated protein amount	Dietary supplement: Nutritionally complete Tube Feed with higher protein levels; Containing higher protein levels to target elevated protein amount of 1.3 g of protein/kg body weight/day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myofibrillar protein fractional synthetic rate	The myofibrillar protein synthesis rates are calculated using D2O.	1-4 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma amino acids concentrations	Determining differences in plasma amino acids concentration between groups receiving normal versus elevated protein levels through enteral nutrition	1-4 days
Mixed muscle protein fractional synthetic rate	The mixed muscle protein synthesis rates are calculated using D2O.	1-4 days
Muscle fiber size in µm²	Muscle fiber size will be assessed using immunofluorescence staining.	Final intervention day (after 4 days of enteral feeding)
Proportion (%) of muscle fiber types (type I and type II)	Fiber proportion will be assessed using immunofluorescence staining.	Final intervention day (after 4 days of enteral feeding)
Myonuclei quantity	Myonuclei quantity will be assessed using immunofluorescence staining.	Final intervention day (after 4 days of enteral feeding)
Mitochondrial respiration	Mitochondrial respiration will be assessed using Oroboros Instruments (Oroboros O2k FluoRepirometer).	Final intervention day (after 4 days of enteral feeding)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age in years	Heteroanamnesia	Baseline
Body mass in kg	Heteroanamnesia	Baseline
Height in m	Heteroanamnesia	Baseline
BMI in kg/m²	Calculated from height and body mass	Baseline
Clinical health data	Clinical health data (Smoker status, Reason for ICU admission, Comorbidities, Highest recorded temperature, Respiratory rate, Blood pressure, Heart rate, Glasgow Coma Scale, Charlson Comorbidity Index, Rockwood Clinical Frailty Index, APACHE II score, APACHE IV score, APS score, SAPS II, Medications, Routine blood test results, Length of ICU and hospital stay, Days in study, Survival outcomes, Muscle biopsy time points, Nutritional intake, Study product compliance, Study product tolerance) will be collected by the attending physician, healthcare staff, and the laboratory technicians.	Baseline

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Danone Global Research & Innovation Center

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: November 20, 2024
• First Submitted That Met QC Criteria: November 28, 2024
• First Posted (Actual): December 3, 2024

Study Record Updates

• Last Update Posted (Actual): December 10, 2025
• Last Update Submitted That Met QC Criteria: December 3, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Critical Illness
• Other Study ID Numbers: 2024/223

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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