A single-centre, two-arm, parallel randomised controlled trial (RCT) to compare the combined effect of early intravenous bolus amino acid supplementation and mobilisation versus standard of care on changes in muscle mass over the first week in ICU. Half of study participants will receive the study intervention (an intravenous bolus amino acid supplement combined with in-bed cycling), while the other half will receive standard of care only.

Critical illness survivors often suffer from severe muscle mass depletion and a profound long-term functional impairment. Hence effective strategies, or a combination of strategies, are needed to reduce skeletal muscle wasting during critical illness. Although amino acids and mobilisation are both known to stimulate the mechanistic target of rapamycin pathway (MTOR) pathway for muscle protein synthesis in healthy adults, there are no trials to date investigating the combined approach of combined cycle ergometry and bolus amino acid supplementation on muscle accretion in the ICU.

Inclusion Criteria:

• Adult patient (≥18 years) admitted to medical/surgical ICU of Tygerberg Academic Hospital (TBH)
• Expected length of mechanical- or non-invasive ventilation > 48 hours
• Receiving enteral (EN) and/or parenteral nutrition (PN) as per standard care and for a minimum of 5 days
• Expected ICU length of stay of 7 days

Exclusion Criteria:

• Spinal cord lesion or intracranial process associated with muscle weakness
• Acute/chronic degenerative neuromuscular condition
• Fulminant hepatic failure/severe chronic liver disease (MELD score ≥20) or renal failure (based on KDIGO) not on Renal Replacement Therapy
• Untreated thrombosis, or thrombosis where therapeutic levels of anticoagulants have not been reached at the time of inclusion
• Any condition deemed inappropriate by the overseeing doctor- such as precautions or contraindications related to the movement as a result of trauma and/or surgery to the spine, pelvis or lower limbs, or haemodynamic instability.
• Other: imminent death or withdrawal of treatment, pregnancy, lower limb amputation/s or fractures, readmission after previous randomisation, long-term corticosteroid therapy, morbidly obese (BMI ≥ 40kg/m2)

Owing to the nature of the intervention, blinding of participants and treating clinicians was not feasible. However, blinding was maintained for primary outcome assessments, namely: (1) laboratory personnel responsible for biopsy analyses were blinded to group allocation, and (2) ultrasound image analysis was conducted by a blinded assessor. Furthermore, investigators responsible for secondary outcome measures with a subjective component, i.e., MRC sum score and 6MWT assessment, were blinded. Recognising the importance of clearly reporting blinding procedures in RCTs to enhance internal validity and adhere to CONSORT recommendations, the following measures were implemented:

• The combined study intervention was performed in the morning, and outcome assessments were blinded in the afternoon with a sufficient interval to avoid overlapping.
• The participants were prompted not to disclose their perceptions of group allocation during the outcome assessments.