Impact of Very Early Physical Therapy During Septic Shock on Skeletal Muscle: A Randomized Controlled Trial

Abstract

Objectives: As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function, the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass.

Design: Randomized controlled trial.

Setting: Tertiary mixed ICU.

Patients: Adult patients admitted for septic shock within the first 72 hours.

Interventions: Patients were assigned randomly into two groups. The control group benefited from manual mobilization once a day. The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy.

Measurements and main results: Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7. Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers. Hemodynamic values and patient perception were collected during each session. Twenty-one patients were included. Three died before the second muscle biopsy. Ten patients in the control and eight in the intervention group were analyzed. Markers of the catabolic ubiquitin-proteasome pathway, muscle atrophy F-box and muscle ring finger-1 messenger RNA, were reduced at day 7 only in the intervention group, but without difference between groups (muscle atrophy F-box: -7.3% ± 138.4% in control vs -56.4% ± 37.4% in intervention group; p = 0.23 and muscle ring finger-1: -30.8% ± 66.9% in control vs -62.7% ± 45.5% in intervention group; p = 0.15). Muscle fiber cross-sectional area (µm) was preserved by exercise (-25.8% ± 21.6% in control vs 12.4% ± 22.5% in intervention group; p = 0.005). Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group, without being suppressed. Markers of anabolism and inflammation were not modified by the intervention, which was well tolerated by the patients.

Conclusions: Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area.

Trial registration: ClinicalTrials.gov NCT01787045.

Figure 1.

Amount of mobility activities performed per patient during the first week.

Figure 2.

A, Quantitative analysis of double immunologic stain LAMP2-p62 by groups. B, Quantitative analysis of double immunologic stain LC3b-p62 by groups. Double immunologic stain. p* represents p values from difference between day 1 and day 7 for each group; p** represents p values from difference between changes of control and intervention groups. C, Representative images of double immunological stain. Pompe disease sample was used as positive control of elevated autophagy. LAMP2 = lysosomal-associated membrane protein 2, LC3b = microtubule-associated protein 1 light chain 3 beta, p62 = sequestosome 1. LAMP2 or LC3b positive areas are brown and p62 positive areas are red.

Figure 3.

Muscle fiber cross-sectional area changes by group. Skeletal muscle sections stained with adenosine triphosphatase pH 4.50; black fibers correspond to type-I fibers; gray fibers are type-IIb fibers and; pink fibers correspond to type-IIa.