Optimal Protein Supplementation and Early Exercise In Mechanically Ventilated Patients

Study Overview
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Brief Summary
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A Pilot Randomized Controlled Trial (RCT) will be conducted where where mechanically ventilated patients will be randomized to optimal protein (Achieve 80% protein supplementation adequacy with daily titration) versus standard protein feeding. Both groups will receive standard usual early exercise therapy. Specific aim 1: To determine if optimal protein supplementation improves functional outcome of patients as measured by Functional Status Score (FSS) on Day 7. Specific aim 2: To determine if optimal protein supplementation reduces muscle loss of patients at Day 7 as measured by the Rectus Femoris thickness and cross-sectional area (RFCSA) using skeletal muscle ultrasound. Specific aim 3: To determine difference in functional recovery between groups using quality of life (QOL) scores and 6-minute walk distance at 3 months after hospital discharge. The hypothesis is protein inadequacy can be overcome with optimized protein supplementation to reduce muscle loss/sarcopenia and functional impairment in ICU survivors.

Detailed Description
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This study will be a prospective pilot randomized controlled trial. Collaboration will be between the National University Hospital (Medical, Surgical and Cardiothoracic ICUs), Centre for Healthy Aging, National University Health System (NUHS) and Physical Education & Sports Science, National Institute of Education (NIE). Patients admitted into these ICUs will be screened and those meeting the inclusion criteria will be approached for consent. If the patient is unable to consent, his/her legally acceptable representatives will be approached. This approach is routinely done in ICU studies. As with other ICU studies, potential difficulties in consenting and recruiting patients will be expected. To overcome this, all adult ICU patients at NUH will be included in the current study.

Official Title
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Attenuation of Sarcopenia Using Optimal Protein Supplementation and Early Exercise In Mechanically Ventilated Patients: A Pilot Randomized Controlled Trial (PIVOT)

Conditions
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Nutritional Deficiency, Cachexia

Intervention / Treatment
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* Dietary Supplement: Optimal protein supplementation to achieve 80% protein adequacy.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 21 years and above. Expected mechanical ventilation duration ≥ 48 hours. Expected to stay in hospital for ≥ 4 days. Exclusion Criteria: Pregnant woman. Amputation of either lower limbs. Surgery of lower limb during the current admission. 4. Any neurological/rheumatologic/orthopaedic/burn/trauma/physiological problem with feeding difficulties during 48h of intubation Wheelchair-bound, walking aids and ADL-dependent. Patient not able to feed by 48 hours AND not given parenteral feeding. Patients on Continuous Renal Replacement Therapy. Sepsis with poor prognosis. Competing trial Moribund within 48hours. COVID-19 patients. Declined to participate the study

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be randomly assigned to receive either standard feeding or optimised protein feeding based on random permuted blocks with age (≥65 years or < 65 years) and ICU site of recruitment as the stratification factors. The primary endpoint is difference in FSS between the two groups at Day 7.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Control Group<br>Standard care as per current ICU feeding regime. | |
| Experimental: Interventional Group<br>Optimal protein supplementation to achieve 80% protein adequacy through optimised protein supplementation. The protein supplementation will be increased/decreased based on the previous day's intake to achieve 80% adequacy each day by the dietician. | Dietary Supplement: Optimal protein supplementation to achieve 80% protein adequacy.<br>* Additional protein required and delivered by adding protein powder and given in bolus feeds<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional Status Score for ICU (FSS-ICU) | It is an ordinal score consisting of 5 activities (namely, Rolling in bed, Supine to Sit Transfer, Sit to Stand Transfer, Sitting Edge of Bed, Walking); each activity is scored from 0 to 7 to a total of 35. A higher score indicates a better functioning. It closely resembles Activities of Daily Living (ADL) and it is possible to even measure the pre-admission score. The FSS-ICU is measured at day 1 upon recruitment and compared to a one week period and to the time of discharge in intensive care to determine functional improvements at these time points. | Day 1 of Randomisation; Day 7 of Randomisation; Day of ICU Discharge , approximately 14 days after ICU admission | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rectus Femoris Cross-Sectional Area (RFCSA) and anterior thigh and rectus femoris thickness | RFCSA correlates well with quadriceps strength, measured by B-mode ultrasonography using linear transducer array. Pennation angle will also be calculated. The rectus femoris RFCSA and thigh thickness and pennation angle is measured at day 1 upon recruitment and compared to day 4 and then day 7 of study recruitment to determine changes in muscle loss. | Day 1 of Randomisation; Day 4 of Randomisation; Day 7 of Randomisation; Day of ICU Discharge , approximately 14 days after ICU admission | 
| Six-Minute Walk Test (6MWT) | Feasible standard measure of exercise capacity | 3 months post hospital discharge | 
| Clinical Frailty Index (CFI) | The CFI scoring is a scale from 1 to 9, 1 being very fit (best outcome) while 9 being terminally ill (worst outcome). The CFI is measured at day 1 upon recruitment and compared to point of ICU discharge to determine changes in frailty. | Day 1 of Randomisation; Day of ICU Discharge , approximately 14 days after ICU admission | 
| Blood Biomarkers | The following cytokines; IL-6, IL-10, IL-12 and TNF-1α and MCP1, HMGB1 will be analysed via blood test to monitor inflammatory reactions | Day 1 of Randomisation; Day 4 of Randomisation | 
| Indirect calorimetry (IC) | Gold standard for measurement of energy expenditure (EE) | Day 1 to Day 7 of Randomisation (daily or till extubation) |