Clinical trial NCT03021902: Nutrition and Exercise in Critical Illness
Official title: Nutrition and Exercise in Critical Illness (The NEXIS Trial): A Randomized Trial of Combined Cycle Ergometry and Amino Acids in the ICU
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Acute Respiratory Failure
Lead sponsor: Clinical Evaluation Research Unit at Kingston General Hospital
Sponsor class: OTHER
Collaborators: name: University of Vermont
name: Johns Hopkins University
First posted: 2017-01-16
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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:

1. 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.
2. 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).
3. 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:

1. To determine if the NEXIS intervention attenuates the release of IL-17 and related cytokines to reduce systemic inflammation in humans.
2. To determine if the NEXIS intervention reduces lung injury and neutrophilic lung inflammation in humans.
3. To determine if the NEXIS intervention attenuates skeletal muscle fiber atrophy via down regulation of muscle proteolytic pathways.
4. To determine if the NEXIS intervention, and exercise specifically, reduces the content of inflammatory cells in skeletal muscle.

Eligibility criteria: Inclusion Criteria:

1. ≥18 years old.
2. Requiring mechanical ventilation with actual or expected total duration of mechanical ventilation ≥ 48 hours.
3. Expected ICU stay ≥ 4 days after enrollment (to permit adequate exposure to the proposed intervention).

Exclusion Criteria:

1. \>96 continuous hours of mechanical ventilation before enrollment.
2. Expected death or withdrawal of life-sustaining treatments within this hospitalization.
3. No expectation for any nutritional intake within the subsequent 72 hours.
4. Severe chronic liver disease (MELD score ≥20) or acute fulminant hepatitis.
5. Documented allergy to the amino acid intervention.
6. Metabolic disorders involving impaired nitrogen utilization
7. Not ambulating independently prior to illness that lead to ICU admission (use of gait aid permitted).
8. Pre-existing primary systemic neuromuscular disease (e.g. Guillain Barre).
9. Neuromuscular blocker infusion (eligible once infusion discontinued if other inclusion criteria met).
10. Intracranial or spinal process affecting motor function
11. Pre-existing cognitive impairment or language barrier that prohibits outcomes assessment.
12. Patients in hospital \>5 days prior to ICU admission
13. Lower extremity impairments that prevent cycling (e.g. amputation, knee/hip injury).
14. Remaining intubated for airway protection only
15. Weight ≥150kg
16. Physician declines patient enrollment
17. Insufficient IV access
18. Pregnant
19. Incarcerated

Primary outcomes:
measure: Physical functioning
timeFrame: Hospital discharge (up to 26 weeks after randomization)
Secondary outcomes:
measure: Overall strength-upper extremity
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Overall strength-lower extremity
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Quadriceps force-lower extremity strength
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Distal strength-hand grip strength
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: Overall Physical Functional status - Short Physical Performance Battery
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: Overall Physical Functional status - Functional Status Score - ICU
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: Mortality
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: Length of ventilation
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: ICU stay
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: Hospital stay
timeFrame: ICU and hospital discharge (up to 26 weeks after randomization)
measure: ICU readmission
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Re-intubation
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Hospital-acquired infections
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Discharge location (e.g. home vs. rehab)
timeFrame: Hospital discharge (up to 26 weeks after randomization)
measure: Body composition - Ultrasound
timeFrame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
measure: Body composition - CT - Chest when clinically available
timeFrame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
measure: Body composition - CT - Abdominal Scan when clinically available
timeFrame: Enrollment, hospital discharge, & ICU discharge (up to 26 weeks after randomization)
measure: Health-related quality of life - SF-36
timeFrame: Telephone survey at 6 months
measure: Health-related quality of life - EQ-5D-5L
timeFrame: Telephone survey at 6 months
measure: Physical functioning - Katz ADL
timeFrame: Hospital discharge (proxy) and telephone survey at 6 months
measure: Physical functioning - Lawton IADL
timeFrame: Telephone survey at 6 months
measure: Physical functioning/participation - return to work
timeFrame: Telephone survey at 6 months
measure: Physical functioning/participation - living location
timeFrame: Telephone survey at 6 months
measure: Mental and Cognitive Functioning - MoCA-BLIND
timeFrame: Telephone survey at 6 months
measure: Mental and Cognitive Functioning - HADS
timeFrame: Telephone survey at 6 months
measure: Mental and Cognitive Functioning - IES-R
timeFrame: Telephone survey at 6 months
measure: Health Care Resource Utilization
timeFrame: Telephone survey at 6 months
measure: Body composition - DEXA Scan
timeFrame: At Hospital Discharge
measure: Body Composition - Heavy water
timeFrame: Enrollment, Days 1-7
measure: Plasma and muscle protein synthesis - Heavy water
timeFrame: Enrollment, Days 1-7
measure: NEXIS FLAME - Circulating inflammatory mediators
timeFrame: Enrollment, Days 3, 5, and 8
measure: NEXIS FLAME - Lung Inflammation
timeFrame: Enrollment, Day 5
measure: NEXIS FLAME - Muscle area
timeFrame: Enrollment, Day 5
measure: NEXIS FLAME - Muscle inflammation
timeFrame: Enrollment, Day 5
Other outcomes:
Locations:
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Burlington
country: United States
facility: University of Vermont College of Medicine
state: Vermont
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
Study officials:
affiliation: Queen's University
name: Daren K Heyland, MD, MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Vermont
name: Renee D Stapleton, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Johns Hopkins University
name: Dale M Needham, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Parry SM, Berney S, Koopman R, Bryant A, El-Ansary D, Puthucheary Z, Hart N, Warrillow S, Denehy L. Early rehabilitation in critical care (eRiCC): functional electrical stimulation with cycling protocol for a randomised controlled trial. BMJ Open. 2012 Sep 13;2(5):e001891. doi: 10.1136/bmjopen-2012-001891. Print 2012.
citation: Fan E, Zanni JM, Dennison CR, Lepre SJ, Needham DM. Critical illness neuromyopathy and muscle weakness in patients in the intensive care unit. AACN Adv Crit Care. 2009 Jul-Sep;20(3):243-53. doi: 10.1097/NCI.0b013e3181ac2551.
citation: Dowdy DW, Dinglas V, Mendez-Tellez PA, Bienvenu OJ, Sevransky J, Dennison CR, Shanholtz C, Needham DM. Intensive care unit hypoglycemia predicts depression during early recovery from acute lung injury. Crit Care Med. 2008 Oct;36(10):2726-33. doi: 10.1097/CCM.0b013e31818781f5.
citation: Al-Dorzi HM, Stapleton RD, Arabi YM. Nutrition priorities in obese critically ill patients. Curr Opin Clin Nutr Metab Care. 2022 Mar 1;25(2):99-109. doi: 10.1097/MCO.0000000000000803.
citation: Heyland DK, Day A, Clarke GJ, Hough CT, Files DC, Mourtzakis M, Deutz N, Needham DM, Stapleton R. Nutrition and Exercise in Critical Illness Trial (NEXIS Trial): a protocol of a multicentred, randomised controlled trial of combined cycle ergometry and amino acid supplementation commenced early during critical illness. BMJ Open. 2019 Jul 31;9(7):e027893. doi: 10.1136/bmjopen-2018-027893.