Resistance training and β-hydroxy-β-methylbutyrate for functional recovery in critical illness: a multicenter 2 × 2 factorial randomized trial

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. We conducted a multicenter, open-label, 2 × 2 factorial randomized controlled trial with blinded outcome assessment in 266 adult ICU patients. Participants were randomized to receive RT, HMB supplementation, combined 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, patient-reported outcomes, and mortality at 1, 6, and 12 months. Analyses followed the intention-to-treat principle, using linear mixed-effects models to estimate the independent and interactive effects of RT and HMB. RT significantly improved physical function at discharge, with higher SPPB scores (mean difference:1.32 points; P = 0.003) and longer 6MWD (56.20 m; P < 0.001), compared with patients who did not receive RT. It was associated with lower 6-month (OR, 0.51; P = 0.011) and 12-month mortality (OR, 0.55; P = 0.014), and 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). RT reduced fatigue and improved sleep quality and psychological symptoms (P < 0.05), but had no effect on cognition or overall quality of life. HMB modestly increased phase angle (0.367; P = 0.020) and reduced fatigue (–1.069 points, P = 0.005), but had no effect on other outcomes; hyperglycemia occurred in 3 of 134 patients receiving HMB. No interaction between RT and HMB was detected. This expanded trial provides novel evidence that RT not only improves physical function but also increases muscle mass, enhances patient-reported outcomes, and lowers 6- and 12-month mortality in critically ill patients. HMB supplementation offered only modest effects on phase angle and fatigue, with no synergistic benefit when combined with RT. ChiCTR2200057685 ( https://www.chictr.org.cn/ ) was registered on March 15th, 2022.