Nutrition and Exercise in Critical Illness

Study Overview
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Brief Summary
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This study proposes a novel early intervention combining Intravenous (IV) amino acids plus in-bed cycle ergometry exercise to improve physical outcomes in critically ill patients. The investigators hypothesize that this innovative approach will improve short-term physical functioning outcomes (primary outcome), as well as amino acid metabolism, body composition, and patient-reported outcomes at 6-month follow-up.

Detailed Description
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The evaluation of a combination of exercise and protein supplementation in intensive care unit (ICU) patients is novel and potentially very important. For instance, outside of the ICU, in other clinical conditions, the combination of protein supplementation and exercise improves protein synthesis, muscle mass, and muscle strength compared to protein or exercise alone.[63-70] Hence, an opportunity exists to improve ICU patients' physical outcomes via evaluating the combination of optimized protein intake and early exercise in the ICU setting. The proposed intervention and hypothesis: The investigators propose a multi-centered Phase II RCT, with blinded outcomes assessment, of a combination of intravenous (IV) amino acid supplementation and early in-bed cycle ergometry exercise versus usual care in ICU patients requiring mechanical ventilation. The investigators hypothesize that this novel combined intervention will: (1) improve physical functioning at hospital discharge; (2) reduce muscle wasting with improved amino acid metabolism and protein synthesis in-hospital; and (3) improve health-related quality of life, physical functioning, and healthcare resource utilization at 6 months after enrollment. Preliminary data show feasibility and safety of IV amino acids and the proposed exercise intervention. The investigators have chosen a primary outcome that correlates well with long-term outcomes including mortality, hospitalization, and quality of life. [54] If this Phase II trial is positive, investigators will seek funding for a Phase III RCT to demonstrate sustained improvements with a longer-term patient-centered primary outcome and to examine the feasibility, and facilitators/barriers of delivery of this intervention by ICU nurses, physical therapists, and others. If proven effective, this combined intervention has potential to revolutionize care of ICU patients and have a major public health impact on the growing number of ICU survivors. Objectives: To demonstrate that the innovative combination of amino acid supplementation plus early in-bed cycle ergometry exercise improves physical outcomes of ICU patients. Specific Aims of Full Phase II RCT: Short-term performance-based physical function outcomes. To determine if a combined IV amino acid supplementation and in-bed cycle ergometry exercise intervention, compared to usual care, improves in hospital muscle strength and performance-based physical functioning outcomes in critically ill patients, using a primary endpoint of six-minute walk distance (6MWD) at hospital discharge. Body composition. To determine if the combined intervention, compared to usual care, improves amino acid utilization and decreases muscle wasting in ICU patients (secondary endpoints). Patient-reported outcomes and health care utilization at 6 months. To determine if the combined intervention, compared to usual care, improves physical functioning, health-related quality of life, and healthcare utilization at 6 months after study enrollment (secondary endpoints). NEXIS Flame mechanisitic Ancillary sub study: In the proposed sub-study, the addition of bronchoaveloar lavages, blood sampling and muscle sampling measures during the participant's ICU stay will provide the ability to examine the effects of the NEXIS intervention on inflammation as a possible mechanism for improved muscle weakness. Specific Aims of the NEXIS FLAME mechanistic ancillary study: To determine if the NEXIS intervention attenuates the release of IL-17 and related cytokines to reduce systemic inflammation in humans. To determine if the NEXIS intervention reduces lung injury and neutrophilic lung inflammation in humans. To determine if the NEXIS intervention attenuates skeletal muscle fiber atrophy via down regulation of muscle proteolytic pathways. To determine if the NEXIS intervention, and exercise specifically, reduces the content of inflammatory cells in skeletal muscle.

Official Title
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Nutrition and Exercise in Critical Illness (The NEXIS Trial): A Randomized Trial of Combined Cycle Ergometry and Amino Acids in the ICU

Conditions
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Acute Respiratory Failure

Intervention / Treatment
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* Drug: IV amino acids
* Device: In-bed cycle ergometry exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years old. Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation ≥ 48 hours. Expected ICU stay ≥ 4 days after enrollment (to permit adequate exposure to the proposed intervention). Exclusion Criteria: >96 continuous hours of mechanical ventilation before enrollment. Expected death or withdrawal of life-sustaining treatments within this hospitalization. No expectation for any nutritional intake within the subsequent 72 hours. Severe chronic liver disease (MELD score ≥20) or acute fulminant hepatitis. Documented allergy to the amino acid intervention. Metabolic disorders involving impaired nitrogen utilization Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted). Pre-existing primary systemic neuromuscular disease (e.g. Guillain Barre). Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion criteria met). Intracranial or spinal process affecting motor function Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment. Patients in hospital >5 days prior to ICU admission Lower extremity impairments that prevent cycling (e.g. amputation, knee/hip injury). Remaining intubated for airway protection only Weight ≥150kg Physician declines patient enrollment Insufficient IV access Pregnant Incarcerated

Ages Eligible for Study
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Minimum 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IV amino acid + in-bed cycle ergometry<br>Beginning within 96 hours of initiation of mechanical ventilation, participants will receive the combined intervention that includes IV amino acids supplementation and in-bed cycle ergometry exercise | Drug: IV amino acids<br>* IV amino acids delivered by continuous infusion, such that the total enteral and IV protein will be between 2.0-2.5 g/kg/day as a combination of amino acid infusion plus standard feeding.<br>* Other names: Clinisol 15% (Baxter) - sulfite-free (Amino Acid) Injection;Device: In-bed cycle ergometry exercise<br>* In-bed cycle ergometry exercise delivered in 45-minute sessions once-daily 5 days per week according to a detailed specific protocol that includes a safety check in combination with vigorous verbal encouragement from trained research staff delivering the intervention to promote active cycling. Cycling is protocolized to provide graduated increases in resistance during each session and between daily sessions. Cycling will continue through ICU discharge or 21 calendar days after randomization. The intervention will specifically occur during ICU stay.<br>* Other names: MotoMed Letto II Cycle Ergometer;|
| No Intervention: Usual care<br>Participants randomized to the usual care arm will receive usual care protein and exercise. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical functioning | 6-minute walk distance | Hospital discharge (up to 26 weeks after randomization) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall strength-upper extremity | MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 upper extremity subscales. | Hospital discharge (up to 26 weeks after randomization) | 
| Overall strength-lower extremity | MRC Sum-score (Medical Research Council (MRC) Scale for Muscle Strength). Subscales scored 0-5, where 5 is normal. Total score is the sum of the 6 lower extremity subscales. | Hospital discharge (up to 26 weeks after randomization) | 
| Quadriceps force-lower extremity strength | Hand held dynamometry | Hospital discharge (up to 26 weeks after randomization) | 
| Distal strength-hand grip strength | Hand held dynamometry | ICU and hospital discharge (up to 26 weeks after randomization) | 
| Overall Physical Functional status - Short Physical Performance Battery | Short Physical Performance Battery | ICU and hospital discharge (up to 26 weeks after randomization) | 
| Overall Physical Functional status - Functional Status Score - ICU | Functional Status Score - ICU 5 items are performed: rolling, transfer from supine to sit, sitting at the edge of bed, transfer from sit to stand, and walking Each task is evaluated using an eight-point ordinal scale ranging from 0 (unable to perform) to 7 (complete independence) Item scores are summed The total score ranges from 0-35, with higher scores indicating better physical functioning. | ICU and hospital discharge (up to 26 weeks after randomization) | 
| Mortality | Chart review | ICU and hospital discharge (up to 26 weeks after randomization) | 
| Length of ventilation | Chart review | ICU and hospital discharge (up to 26 weeks after randomization) | 
| ICU stay | Chart review | ICU and hospital discharge (up to 26 weeks after randomization) | 
| Hospital stay | Chart review | ICU and hospital discharge (up to 26 weeks after randomization) | 
| ICU readmission | Chart review | Hospital discharge (up to 26 weeks after randomization) | 
| Re-intubation | Chart review | Hospital discharge (up to 26 weeks after randomization) | 
| Hospital-acquired infections | Chart review | Hospital discharge (up to 26 weeks after randomization) | 
| Discharge location (e.g. home vs. rehab) | Chart review | Hospital discharge (up to 26 weeks after randomization) | 
| Body composition - Ultrasound | Ultrasound of quadriceps | Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) | 
| Body composition - CT - Chest when clinically available | Chest CT | Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) | 
| Body composition - CT - Abdominal Scan when clinically available | Abdominal CT scan at 3rd lumbar vertebra | Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization) | 
| Health-related quality of life - SF-36 | 36-Item Short Form Health Survey (SF-36) All items are scored so that a high score defines a more favorable health state. Each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100 Items in the same scale are averaged together to create the 8 scale scores. Items that are left blank (missing data) are not taken into account when calculating the scale scores. Scale scores represent the average for all items in the scale that the respondent answered. | Telephone survey at 6 months | 
| Health-related quality of life - EQ-5D-5L | EuroQol Group standardized measure of health status (EQ-5D-5L) | Telephone survey at 6 months | 
| Physical functioning - Katz ADL | Katz Index of Independence in Activities of Daily Living (Katz ADL) Total score where 6 = High (patient independent) 0 = Low (patient very dependent) | Hospital discharge (proxy) and telephone survey at 6 months | 
| Physical functioning - Lawton IADL | Lawton Instrument Activities of Daily Living Scale (Lawton IADL) A summary score ranges from 0 (low function, dependent) to 8 (high function, independent) for women and 0 through 5 for men to avoid potential gender bias. | Telephone survey at 6 months | 
| Physical functioning/participation - return to work | Return to baseline work/activity | Telephone survey at 6 months | 
| Physical functioning/participation - living location | Living location | Telephone survey at 6 months | 
| Mental and Cognitive Functioning - MoCA-BLIND | MoCA-BLIND The total possible score is 22 points; a score of 18 or above is considered normal | Telephone survey at 6 months | 
| Mental and Cognitive Functioning - HADS | Hospital Anxiety and Depression Scale The HADS questionnaire has seven items each for depression and anxiety subscales. Scoring for each item ranges from zero to three, with three denoting highest anxiety or depression level. A total subscale score of >8 points out of a possible 21 denotes considerable symptoms of anxiety or depression. | Telephone survey at 6 months | 
| Mental and Cognitive Functioning - IES-R | Impact of Events Scale Scoring for each item ranges from 0-4 Total score ranges from 0-88, where a total score of 33 or over signifies the likely presence of PTSD | Telephone survey at 6 months | 
| Health Care Resource Utilization | Admission to ICU, hospital, rehabilitation & nursing facility | Telephone survey at 6 months | 
| Body composition - DEXA Scan | Whole Body DEXA Scan | At Hospital Discharge | 
| Body Composition - Heavy water | Fat-free and fat mass can be measured with D2O in body fluids using gas chromatography-tandem mass spectrometry. | Enrollment, Days 1-7 | 
| Plasma and muscle protein synthesis - Heavy water | Muscle protein synthesis will be analyzed with chromatography and mass spectrometry techniques. | Enrollment, Days 1-7 | 
| NEXIS FLAME - Circulating inflammatory mediators | Blood IL-17, IL-23, IL-6, TNFα, CXCK1, CXCL5, CXCL8, CCL2, SP-D, KL-6, vWF, and leukocyte counts with differential | Enrollment, Days 3, 5, and 8 | 
| NEXIS FLAME - Lung Inflammation | Bronchoalveolar lavage neutrophil counts, IL-17A, CXCL5, and protein | Enrollment, Day 5 | 
| NEXIS FLAME - Muscle area | Single muscle fiber cross-sectional area (CSA), UPS expression, MuRF1 expression, myosin protein content (all from vastus lateralis sampling) | Enrollment, Day 5 | 
| NEXIS FLAME - Muscle inflammation | Muscle macrophages (CD45+, CD206+) | Enrollment, Day 5 |