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:

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.

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

20. Patients with acute kidney injury (AKI) as defined by meeting any of the KDIGO criteria (below) and not receiving renal replacement therapy:

    1. Increase in serum creatinine by ≥ 0.3 mg/dl within 48 hours or
    2. Increase in serum creatinine to ≥ 1.5 times baseline** or
    3. Urine volume <0.5 ml/kg/h for 6 hoursⴕ

There is no plan to share IPD.