PROJECT SUMMARY More than 750,000 Americans require mechanical ventilation annually, and intensive care unit (ICU) survivors experience substantial impairments after hospital discharge, including persistent muscle weakness, impaired physical functioning, reduced quality of life, and decreased long-term survival. There is an urgent need for new strategies to improve the physical recovery of ICU patients. Across North America, studies repeatedly demonstrate that ICU patients are undernourished and immobilized via prolonged bed rest throughout their critical illness. However, available evidence suggests that both amino acid supplementation and exercise, implemented early during patients' ICU stay, may improve outcomes. Additional data demonstrate that, when combined, these two interventions may behave synergistically to improve muscle mass and physical functioning. A combined amino acid supplementation and exercise intervention has not been investigated in critically ill patients. Thus, we propose a Phase II randomized controlled trial of an innovative combination of intravenous amino acid supplementation and early in-bed cycle ergometry exercise versus usual care in critically ill patients. We hypothesize that this novel combined intervention will increase physical functioning at the time of hospital discharge; reduce muscle wasting; improve amino acid metabolism and protein synthesis; with improved health-related quality of life, physical functioning, and healthcare resource utilization. Our preliminary data show feasibility and safety of both the amino acid and exercise intervention. The combined intervention can be delivered to ICU patients, even if sedated or comatose, since the in-bed cycle ergometry exercise device (already commercially available and FDA-approved for this purpose) automatically adjusts between passive or active mode depending on patient status. Moreover, this exercise intervention does not pose cardiopulmonary risk when delivered during critical illness. Our research team reflects the interdisciplinary nature of ICU care, with world-class expertise in all areas of this grant, including critical care nutrition; exercise/rehabilitation; ICU nursing, clinical care, and coordination; amino acid metabolism measurement; and body composition analysis. Our team has unparalleled experience with coordinating multi-site ICU-based RCTs, and has successful prior collaborations. Hence, the team is well positioned to conduct this novel RCT that aims to change the paradigm for nutrition and exercise in the ICU and improve physical outcomes for the growing number of ICU survivors.