A randomized controlled trial to determine whether beta-hydroxy-beta-methylbutyrate and/or eicosapentaenoic acid improves diaphragm and quadriceps strength in critically Ill mechanically ventilated patients

Abstract

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://ichgcp.net/clinical-trials-registry/NCT01270516?term=Supinski&draw=2&rank=4 .

Keywords: Beta-hydroxy-beta-methylbutyrate; Diaphragm weakness; Eicosapentaenoic acid; Limb muscle weakness; Mechanical ventilation; Respiratory failure.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Consort diagram. We initially screened 345 patients and consent was obtained from 83. Of these, 10 failed to complete initial measurements of diaphragm size and strength, with the remaining 73 patients randomized to the four treatment arms. Several patients were lost or withdrew during the treatment administration phase in each study group (i.e. 3 in the control (placebo), 4 in the EPA, 5 in the HMB and 5 in the HMB + EPA arm) due to death, transfer, or request to be removed from the study. In the remaining patients, we obtained data examining changes in diaphragm strength (PdiTw), diaphragm size, quadriceps strength (QuadTw) and quadriceps size between initial, pre-treatment and final, post-treatment measurements

Fig. 2

The average duration of physical therapy per day (top panel) and the average duration of occupational therapy per day (bottom panel) is presented for the four groups of patients included in the current study, i.e. placebo treated control patients, patients treated with EPA, patients treated with HMB, and patients treated with the combination of HMB and EPA. Both figures present data for individual subjects included in the four experimental groups. Group means for the experimental groups are presented as vertical bars (top of bar) and error bars indicate the 95% CI of the mean for the experimental groups. The mean duration of physical therapy per day was 3.23 min (95% CI 1.43–5.04), 4.72 min (95% CI 2.12–7.31), 2.12 min (95% CI 0.48–3.77), and 3.27 min (95% CI 1.48–5.06), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.278). The mean duration of occupational therapy per day was 2.8 min (95% CI 1.4–4.2), 3.1 min (95% CI 1.5–4.7), 1.5 min (95% CI 0.2–2.5), and 3.2 min (95% CI 1.5–4.9), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.267)

Fig. 3

Prescribed caloric intakes, actual delivered caloric intakes, and calories/kg/day are presented for the four experimental groups. The prescribed caloric intake per day was 1526 kcal (95% CI 1325–1727), 1284 kcal (95% CI 994–1574), 1426 kcal (95% CI 1223–1629), and 1276 kcal (95% CI 1022–1530), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.337). The mean caloric intake per day was 1207 kcal (95% CI 952–1462), 1010 kcal (95% CI 742–1279), 1096 kcal (95% CI 894–1298), and 912 kcal (95% CI 663–1160), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.296). The mean caloric intake/Kg per day was 15.1 (95% CI 11.5–18.7), 12.1 (95% CI 8.9–15.3), 13.0 kcal (95% CI 10.0–16.0), and 14.5 kcal (95% CI 9.3–19.7), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.641). As a result, there were no significant differences in caloric intake (Kcal/Day) or caloric intake normalized to body weight (Kcal/Kg) between the four groups

Fig. 4

Prescribed protein intakes, actual delivered protein intakes, and protein/kg/day are presented for the four experimental groups. The prescribed protein intake in grams was 94 (95% CI 85–103), 78 (95% CI 65–91), 87 (95% CI 76–98), and 78 (95% CI 69–87), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.086). The mean protein intake in grams was 78 (95% CI 68–88), 68 (95% CI 55–81), 76 (95% CI 65–87), and 66 (95% CI 57–75), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.276). The mean protein intake in Gm/Kg was 0.96 (95% CI 0.84–1.08), 0.78 (95% CI 0.62–0.94), 0.86 (95% CI 0.69–1.03), and 0.92 (95% CI 0.75–1.09), respectively for Control, EPA, HMB, and HMB + EPA groups (p = 0.373). As a result, there were no significant differences in protein intake (Kcal/Day) or protein intake normalized to body weight (Kcal/Kg) between the four groups

Fig. 5

The change in diaphragm strength (PdiTw) between initial measurements and measurements made after drug treatment are presented for the four experimental groups in the top panel. Data is displayed as the log difference (y-axis) of pre- and post-treatment diaphragm twitch measurements for individual subjects included in the four experimental groups. The mean log difference for diaphragm twitch pressure (PdiTw) pre- and post-treatment was 0.18 (95% CI − 0.14 to 0.49), 0.09 (95% CI − 0.60 to 0.78), 0.31 (95% CI − 0.07 to 0.68), and 0.12 (95% CI − 0.27 to 0.50), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.894). As a result, there was no significant difference in change of PdiTw over time between the four experimental groups. Change in diaphragm thickness between initial and post-treatment measurements is presented for the four experimental groups in the bottom panel. The mean log difference for diaphragm thickness pre- and post-treatment was − 0.01 (95% CI − 0.10 to 0.09), 0.04 (95% CI − 0.03 to 0.10), 0.04 (95% CI − 0.04 to 0.13), and 0.01 (95% CI − 0.11 to 0.13), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.839). As a result, there was no significant difference in changes in diaphragm thickness over time between the four experimental groups

Fig. 6

Change in quadriceps strength (QuadTw) between initial and post-treatment measurements is presented for the four experimental groups in the top panel (same format as in Fig. 5). The mean difference for quadriceps twitch force pre- and post-treatment was 2.26 (95% CI − 0.51 to 5.0), 1.12 (95% CI − 0.34 to 2.59), 0.26 (95% CI − 3.01 to 3.57), and 0.18 (95% CI − 2.07 to 2.43), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.535). As a result, there was no significant difference in changes in quadriceps strength over time between the four experimental groups. Change in quadriceps thickness between initial and post-treatment measurements is presented for the four experimental groups in the bottom panel. The mean difference for quadriceps twitch thickness pre- and post-treatment was − 0.08 (95% CI − 0.39 to 0.23), − 0.33 (95% CI − 0.77 to 0.11), − 0.34 (95% CI − 0.74 to 0.06), and − 0.15 (95% CI − 0.58 to 0.27), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.647). As a result, there was no significant difference in changes in quadriceps thickness over time between the four experimental groups

Fig. 7

The duration of mechanical ventilation after randomization to treatment is presented for the four experimental groups using the format in Fig. 2. The mean log of mechanical ventilation duration was 1.63 (95% CI 1.10–2.15), 2.05 (95% CI 1.59–2.51), 2.03 (95% CI 1.57–2.49), and 1.71 (95% CI 1.38–2.05), respectively, for Control, EPA, HMB, and HMB + EPA groups (p = 0.372). There was no significant difference in the time required to wean patients from mechanical ventilation between the four experimental groups