Background Intensive care unit acquired weakness is a serious problem, contributing to respiratory failure and reductions in ambulation. Currently, there is no pharmacological therapy for this condition. Studies indicate, however, that both beta-hydroxy-beta-methylbutyrate (HMB) and eicosapentaenoic acid (EPA) increase muscle function in patients with cancer and in older adults. The purpose of this study was to determine whether HMB and/or EPA administration would increase diaphragm and quadriceps strength in mechanically ventilated patients. Methods Studies were performed on 83 mechanically ventilated patients who were recruited from the Medical Intensive Care Units at the University of Kentucky. Diaphragm strength was assessed as the trans-diaphragmatic pressure generated by supramaximal magnetic phrenic nerve stimulation (PdiTw). Quadriceps strength was assessed as leg force generated by supramaximal magnetic femoral nerve stimulation (QuadTw). Diaphragm and quadriceps thickness were assessed by ultrasound. Baseline measurements of muscle strength and size were performed, and patients were then randomized to one of four treatment groups (placebo, HMB 3 gm/day, EPA 2 gm/day and HMB plus EPA). Strength and size measurements were repeated 11 days after study entry. ANCOVA statistical testing was used to compare variables across the four experimental groups. Results Treatments failed to increase the strength and thickness of either the diaphragm or quadriceps when compared to placebo. In addition, treatments also failed to decrease the duration of mechanical ventilation after study entry. Conclusions These results indicate that a 10-day course of HMB and/or EPA does not improve skeletal muscle strength in critically ill mechanically ventilated patients. These findings also confirm previous reports that diaphragm and leg strength in these patients are profoundly low. Additional studies will be needed to examine the effects of other anabolic agents and innovative forms of physical therapy. Trial registration: ClinicalTrials.gov, NCT01270516. Registered 5 January 2011, https://clinicaltrials.gov/ct2/show/NCT01270516?term=Supinski&draw=2&rank=4.

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Physical therapy (PT) is a standard component of care for mechanically ventilated (MV) patients. Recent studies have raised concerns, however, that this treatment may be relatively ineffective. The purpose of the present study was to objectively analyze the effect of PT on leg strength in MV patients. Studies were performed on 22 MV patients receiving PT for 2 weeks. To assess PT intensity, we measured: (a) exercise duration, (b) PT types (range of motion, transfers, exercise machine usage, walking, resistance training), and (c) the intensity of muscle activation using wireless electromyogram (EMG) recordings of four leg muscles. To assess the response to PT, we measured quadriceps force generation evoked by magnetic femoral nerve stimulation. We found that response to PT was poor, and leg strength before and following PT (8.6 ± 3.4 and 7.6 ± 2.8 N) was not significantly different. EMG recordings indicated that patient effort during exercises was also poor. In particular, integrated normalized EMG activity fell substantially over time during training sessions in the majority of patients (the EMG index had a median of 30.3 (25–75% CI of 16.7–46.1) for the initial exercise and decreased to 18.1 (25–75% CI of 2.6–24.4) for the final exercise, p=0.039). There was dramatic patient‐to‐patient variation in the effort made during specific types of PT, resulting in substantial time spent performing ineffective exercises. We also found that, in many cases, the weakest patients received far less PT than patients with normal strength. These data provide a potential explanation why PT in MV patients is largely ineffective. We speculate that use of novel techniques to direct exercises (EMG targeting) and to accurately measure the response to PT (magnetic twitch assessment of strength) may dramatically improve responses of MV patients to PT.Support or Funding InformationR01HL113494, 5I01BX002132, R01HL112085

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