Nutrition and Exercise in Critical Illness (NEXIS)

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

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.

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.

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

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.

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.

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.

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.

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.

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.

Katz Index of Independence in Activities of Daily Living (Katz ADL) Total score where 6 = High (patient independent) 0 = Low (patient very dependent)

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.

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.

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

Fat-free and fat mass can be measured with D2O in body fluids using gas chromatography-tandem mass spectrometry.

Blood IL-17, IL-23, IL-6, TNFα, CXCK1, CXCL5, CXCL8, CCL2, SP-D, KL-6, vWF, and leukocyte counts with differential

Single muscle fiber cross-sectional area (CSA), UPS expression, MuRF1 expression, myosin protein content (all from vastus lateralis sampling)

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

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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.