The Effect of High Protein and Early Resistance Exercise Versus Usual Care in Critically Ill Patients (EFFORT-X)

The Effect of High Protein and Early Resistance Exercise Versus Usual Care on Muscle Mass, Strength and Quality, Clinical Outcomes, Functional Outcomes and Quality of Life in Mechanically Ventilated Critically Ill Patients

This is a 2-arm, parallel-group, randomized controlled trial that investigates the effect of combined high protein and early resistance exercise versus usual care on muscle mass, quality and strength, clinical outcomes, functional outcomes and quality of life in mechanically ventilated critically ill patients

Study Overview

• Status: Active, not recruiting
• Conditions: Critical Illness
• Intervention / Treatment: Other: High protein and early exercise; Other: Usual Care

Detailed Description

With the advancement of critical care, about 80% of ICU patients are surviving critical illness. However, ICU survivors often experience significant post-ICU morbidities including muscle weakness and impairments in physical functioning that can persist for years. We hypothesized that early intervention with two of the most basic features of critical care: nutrition (feeding high protein) together with mobility (early resistance exercise) may help to attenuate muscle loss, thereby reducing the severity of ICU-acquired weakness and its associated physical impairments. A 2-arm, parallel-group, randomized controlled trial is proposed to investigate the effect of the combined interventions. The intervention will be conducted for up to 28 days in the ICU. Outcome measurements will be conducted by a blinded assessor at baseline (within 24 hours of randomization), Day 10 post-randomization, before hospital discharge and at 6-month post-randomization. Ultrasound and bioelectrical impedance analysis will be conducted to measure muscle mass and quality. Manual muscle testing, handgrip and knee extension strength will also be measured. Physical function will be assessed by a series of test including the six minutes walk test. Telephone interview will be conducted to administer quality of life questionnaires at 6 months. These combined simple and non-invasive interventions, if proven effective, may potentially revolutionize critical care.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Malaysia
  • Kuala Lumpur, Malaysia, 50603
    • University of Malaya

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18 years old and above
2. Mechanically ventilated and expected to remain mechanically ventilated for an additional 48 hours from screening

3. High nutritional risk (at least one of the following):

   • BMI ≤ 25 or ≥ 35
   • Moderate to severe malnutrition as defined by Subjective Global Assessment (SGA)
   • Frailty (Clinical Frailty Scale ≥ 5 from proxy)
   • SARC-F (note: 'sarc-f' is the full name, not an abbreviation) questionnaire ≥ 4
   • From point of screening, projected duration of mechanical ventilation of >4 days

Exclusion Criteria:

1. >96 continuous hours of mechanical ventilation before screening
2. Expected death or withdrawal of life-sustaining treatments within 7 days from screening
3. Pregnant (Note: post-partum and lactating patients are not excluded from the trial)
4. The responsible clinician feels that the patient either needs low or high protein
5. Patient requires parenteral nutrition only and site does not have products to reach the high protein dose group.
6. Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted)
7. Lower extremity injury or impairments that prevents them walking prior to hospital discharge (e.g. amputation, knee/hip injury)
8. Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment
9. Pre-existing primary severe systemic neuromuscular disease resulting in severe weakness pre-ICU (e.g., Guillain Barre)
10. Intracranial or spinal process affecting motor function
11. Patients in hospital >5 days prior to ICU admission
12. Not expected to stay ≥4 days after enrollment
13. Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion criteria met)
14. Lower extremity injury or impairments that prevents cycling (e.g. amputation, knee/hip injury)
15. Weight ≥150 kg
16. Physician declines enrolment for Exercise

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Protein and Early Exercise; High protein is defined as a protein prescription of ≥2.2 gram/kg body weight; Early exercise is defined as exercise by using cycle ergometry for 45 minutes per day within 24 hours of randomization	Other: High protein and early exercise; High protein is defined as protein prescription of ≥2.2 gram/kg body weight and early exercise is defined as starting cycle ergometry intervention within 24 hours of randomization
Active Comparator: Usual Care; Usual care has a protein prescription of ≤1.2 gram/kg body weight and exercise prescription as per the discretion of attending clinicians	Other: Usual Care; Usual care group has protein prescription of ≤1.2 gram/kg body weight and exercise at the discretion of attending clinicians

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rectus femoris cross-sectional area (RFCSA)	RFCSA measured by ultrasonography	Change in RFCSA between Day 1 and Day 10 of randomization
Rectus femoris cross-sectional area (RFCSA)	RFCSA measured by ultrasonography	Change in RFCSA between Day 1 of randomization and within 72 hours before discharge from the hospital
Rectus femoris linear depth (RF LD)	RF LD measured by ultrasonography	Change in RF LD between Day 1 and Day 10 of randomization
Rectus femoris linear depth (RF LD)	RF LD measured by ultrasonography	Change in RF LD between Day 1 of randomization and within 72 hours before discharge from the hospital

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quadriceps muscle echogenicity	Quadriceps muscle echogenicity measured by ultrasonography	Day 1 and Day 10 of randomization, and within 72 hours before discharge from the hospital
Quadriceps muscle pennation angle	Quadriceps muscle pennation angle measured by ultrasonography	Day 1 and Day 10 of randomization, and within 72 hours before discharge from the hospital
Quadriceps muscle fascicle length	Quadriceps muscle fascicle length measured by ultrasonography	Day 1 and Day 10 of randomization, and within 72 hours before discharge from the hospital
Functional Status Score for the Intensive Care Unit (FSS-ICU)	An assessment that consist of rolling, transfer from supine to sit, sitting at the edge of bed, transfer from sit to stand and walking	Day 1 of randomization (surrogate interview), within 72 hours before discharge from the ICU and hospital (by trained physiotherapist)
Short Physical Performance Batteries (SPPB)	An assessment that consist of balance test, gait speed test and chair stand test	Within 72 hours before discharge from the ICU and hospital
Handgrip strength	Handgrip strength of both hands by using handgrip dynamometer	Within 72 hours before discharge from the ICU and hospital
6 minutes walk test	To evaluate how far the subject can walk in 6 minutes time	Within 72 hours before discharge from the hospital
Manual muscle testing	Bilateral muscle strength for shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension and ankle dorsiflexion	Within 72 hours before discharge from the hospital
Knee extension strength	Knee extension strength measured by Handheld Dynamometer	Within 72 hours before discharge from the hospital
Mortality	Percentage of patient who died	Percentage of Patient who died within this ICU or hospital admission, at day 60 and 6 months post-randomization
Time-to-discharge alive from the hospital	Time-to-discharge alive from the hospital	Time elapsed from randomization to hospital discharge (for a maximum of 6 months from randomization)
Length of mechanical ventilation	Duration of mechanical ventilation	Total time from start to end of mechanical ventilation for a maximum of 6 months from randomization
Health-related Quality of life by 36-item short form survey (SF-36)	SF-36 is a questionnaire that will be administered by telephone interview	6 months after randomization
Health-related Quality of life by Euro Quality of Life 5 Dimension 5 level (EQ-5D-5L)	EQ-5D-5L is a questionnaire that will be administered by telephone interview	6 months after randomization
Katz Activities of Daily Living (ADL)	Katz ADL is a questionnaire that will be administered by either surrogate or telephone interview	Day 1 of randomization (surrogate interview) and 6 months after randomization (telephone interview)
Lawton Instrumental Activities of Daily Living (IADL)	Lawton IADL is a questionnaire that will be administered by either surrogate or telephone interview	Day 1 of randomization (surrogate interview) and 6 months after randomization (telephone interview)

Collaborators and Investigators

• Sponsor: University of Malaya
• Investigators: Principal Investigator: Zheng Yii Lee, University of Malaya

Publications and helpful links

General Publications

• Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011 Apr 7;364(14):1293-304. doi: 10.1056/NEJMoa1011802.
• Arabi YM, Casaer MP, Chapman M, Heyland DK, Ichai C, Marik PE, Martindale RG, McClave SA, Preiser JC, Reignier J, Rice TW, Van den Berghe G, van Zanten ARH, Weijs PJM. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017 Sep;43(9):1239-1256. doi: 10.1007/s00134-017-4711-6. Epub 2017 Apr 3.
• Heyland DK, Stapleton RD, Mourtzakis M, Hough CL, Morris P, Deutz NE, Colantuoni E, Day A, Prado CM, Needham DM. Combining nutrition and exercise to optimize survival and recovery from critical illness: Conceptual and methodological issues. Clin Nutr. 2016 Oct;35(5):1196-206. doi: 10.1016/j.clnu.2015.07.003. Epub 2015 Jul 16.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2019
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: January 31, 2020
• First Submitted That Met QC Criteria: February 6, 2020
• First Posted (Actual): February 7, 2020

Study Record Updates

• Last Update Posted (Actual): March 27, 2025
• Last Update Submitted That Met QC Criteria: March 24, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: exercise; muscle; protein
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Critical Illness
• Other Study ID Numbers: MREC ID NO: 20181115-6890

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