Resistance Training and β-Hydroxy-β-Methylbutyrate for Functional Recovery in Critical Illness: A Multicenter 2×2 Factorial Randomized Trial

Purpose Combined nutrition and rehabilitation is a top research priority for ICU-acquired weakness, yet the optimal strategy and clinical benefits remain unclear. This study aimed to evaluate the independent and combined effects of resistance training (RT) and β-hydroxy-β-methylbutyrate (HMB) in critically ill adults. Methods We conducted a multicenter, single-blind, 2×2 factorial randomized controlled trial involving 266 adult ICU patients. Participants were randomized to receive RT, HMB supplementation, both interventions, or standard care. Treatments began in the ICU and continued until discharge. Primary outcomes at discharge included six-minute walk distance (6MWD) and the Short Physical Performance Battery (SPPB). Secondary outcomes included muscle strength and mass, cognitive and psychological function, and health-related quality of life at multiple time points. All-cause mortality was recorded at 1, 6, and 12 months post-discharge. Results RT significantly improved physical function at discharge, with higher SPPB scores (mean difference:1.32; P = 0.003) and longer 6MWD (56.20 m; P < 0.001), compared with patients who did not receive RT. It also increased grip strength (3.19 kg; P = 0.008), appendicular skeletal muscle mass (0.997 kg; P = 0.005), and skeletal muscle index (0.428 kg/m²; P = 0.025), and reduced anxiety and depression scores. It was associated with lower all-cause mortality at 6 months (OR, 0.51; P = 0.011) and 12 months (OR, 0.55; P = 0.014), but had no significant effect on cognitive function or health-related quality of life. HMB modestly increased phase angle (0.367; P = 0.020) without other benefits. No interaction between RT and HMB was observed across outcomes. Conclusions Tiered elastic-band RT throughout hospitalization significantly improved physical function, muscle strength and mass, and psychological outcomes, and reduced 6- and 12-month mortality in critically ill patients. HMB provided limited benefit, with modest effects on phase angle. No additive effect was observed with combined therapy. Trial registration: ChiCTR2200057685(https://www.chictr.org.cn/) was registered on March 15th, 2022.