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

Critical Care Wu et al. Critical Care (2025) 29:438 https://doi.org/10.1186/s13054-025-05660-9 Open Access RESEARCH Resistance training and β-hydroxy-βmethylbutyrate for functional recovery in critical illness: a multicenter 2 × 2 factorial randomized trial Tingting Wu1,2,3, Yueqing Wei4, Jing Xiong5, Jingbing Wu6, Xiuxia Lin7, Yaoning Zhuang8, Chenjuan Luo9, Meilian Xu10, Xuexian Chen11, Zhizhong Lin12* and Hong Li13* Abstract 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, 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. Results 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. Conclusions 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 *Correspondence: Zhizhong Lin Hong Li Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Wu et al. Critical Care (2025) 29:438 Page 2 of 14 patients. HMB supplementation offered only modest effects on phase angle and fatigue, with no synergistic benefit when combined with RT. Trial registration ChiCTR2200057685 (https://www.chictr.org.cn/) was registered on March 15th, 2022. Keywords Intensive care unit, Resistance training, Rehabilitation, Beta-hydroxy-beta-methylbutyrate, ICU-acquired weakness Introduction Advances in critical care have significantly improved survival among intensive care unit (ICU) patients [1, 2]. However, survival alone does not equate to recovery. Many survivors experience lasting impairments in physical, cognitive, and psychological function, collectively referred to as post–intensive care syndrome (PICS) [3]. Among these, physical dysfunction is particularly common and is strongly linked to ICU-acquired weakness (ICUAW) [4]—a neuromuscular complication affecting nearly half of ICU survivors [5]. ICUAW is independently linked to extubation failure, prolonged mechanical ventilation, extended hospitalization, long-term disability, and increased mortality [6], with its effects often persisting for five years after discharge [7]. Currently, no pharmacologic treatments are available to reverse ICUAW, highlighting the urgent need for effective strategies to restore physical function. As a result, non-drug interventions, particularly nutrition and physical rehabilitation, are increasingly being explored [8, 9]. Evidence supporting these interventions remains mixed, likely due to variations in study design, intervention methods, and outcome definitions [6, 10]. Most previous trials evaluated combined exercise and nutrition programs versus usual care, making it difficult to isolate their individual or additive effects [11, 12]. This approach also constrains our understanding of how these strategies may interact biologically. Findings from nutritionfocused research are similarly inconsistent. While some studies report that protein supplementation enhances the benefits of exercise [13], others show minimal or even harmful effects, particularly in patients with severe illness or kidney dysfunction [49]. Given these mixed results, attention has turned to specific compounds that may offer more targeted anabolic effects. One such compound is β-hydroxy-β-methylbutyrate (HMB), a metabolite of leucine that has been shown to promote muscle protein synthesis and reduce breakdown through well-established molecular pathways [14]. Recent meta-analyses suggest that HMB enhances muscle mass and strength in older adults and those with sarcopenia [15, 16], particularly when combined with resistance training (RT) [17]. Importantly, HMB supplementation has a strong safety profile, with no evidence of hepatic, renal, hematologic, or genotoxic effects (e.g., gene mutations or chromosomal damage), even with long-term use [14]. However, evidence in critically ill patients remains limited and inconclusive [18]. These discrepancies likely reflect heterogeneity in patient populations, intervention protocols, and study methodologies [18]. These limitations underscore the need for adequately powered, standardized trials with harmonized rehabilitation protocols to assess the independent and synergistic effects of HMB (...truncated)