The most salient findings of our study are that mobilization by passive cycling resulted in a faster decrease in myofibrillar protein catabolism than with standard care without a detectable change in muscle thickness or in electromyographic variables and that no significant dose-effect of passive cycling or synergism with increased calories/protein intake and passive mobilization was found.
The model used in this clinical study is unique, as only patients with minimal muscular activity for a period of at least 7 days were studied. The increased rate of myofibrillar protein catabolism was confirmed by the supra-normal values of the 3-MH-to creatinine ratio. Admittedly, pure passive stretch was not investigated when neuromuscular blockade was not used. Therefore, these results may be confounded by the reflex arc and upper neuronal influences on tone and spasticity. However, the design of this study is a reflection of the current standard of care, since muscle paralysis is rarely used in the type of patient included in this study. The effects of standard physiotherapy only (passive mobilization and turning twice a day) on protein catabolism are probably minimal, as suggested by the slight decrease in the 3-MH-to creatinine ratio observed in group A. No potentially confounding factors, such as new sepsis, surgery or hypoxemia, were noted during the study period. However, in patients with ongoing sepsis or recent surgery, acute inflammatory changes in muscle metabolism may differ from those present in long-stay neurological patients. These patients were probably representative of a typical ICU population of long-stayers, in whom acquired weakness is a major issue. Nevertheless, as most patients were admitted for a neurological diagnosis, whether the findings of this study can be applied to non-neurological patients is unclear.
The use of the 3-MH-to creatinine ratio as an index of myofibrillar protein catabolism, was described in 1978 [13
] and validated in 1981 for critically ill patients with sepsis or trauma [14
]. The 3-MH-to creatinine ratio has been shown to decrease over time after surgical injury [15
]. The faster decrease in the 3-MH-to creatinine ratio in patients treated with passive mobilization compared to standard care (sub-study 1) reflects the decreased myofibrillar protein catabolism, and is consistent with the slight decrease in nitrogen balance. Admittedly, some unrecorded changes in renal function may have influenced the 3-MH-to creatinine ratio [14
]. The influence of changes in non-muscular protein metabolism, including changes in the protein turnover of the gastrointestinal tract, can also not be assessed from the present data. Indeed, the rate of muscle loss follows a logarithmic curve, implying a decreased rate of muscle loss after the acute inflammatory phase. The differences in time interval between admission in the ICU and study inclusion may have introduced a risk of ‘lead-time bias’.
Increased protein turnover involving an increased rate of protein synthesis followed by increased breakdown cannot be excluded. To evaluate the influence of these factors, more sophisticated or more invasive techniques, such as stable isotope methods or muscle biopsy, would be needed.
The absence of any effect of passive cycling on muscle thickness could be related to changes in the water and fat content of the muscles and surrounding tissues, perhaps related to changes in the muscle glycogen content. Muscle strength cannot anyway be deduced from measurements of muscle thickness, unlike muscular cross-sectional area. Others have shown slow changes in limb perimeters in critically ill patients [17
]. Computerized tomography would probably have been ideal for accurate quantification of muscle mass [18
], although this technique has not been widely used in ICU patients. Instead, we used echography with a 10-Hz probe, a technique that has been validated to assess the magnitude of ICU-acquired muscle wasting [19
]. Variance in ultrasound measurements was minimized because the same, experienced radiologist collected these data and the technique used was standardized. The changes in muscle thicknesses seen in critically ill patients have been reported to be very heterogeneous [17
]. Of note, after spinal cord injury in children, passive cycling increased muscle bulk only when associated with electrical stimulation of the quadriceps [20
]. In the ICU, preliminary data suggest that neuromuscular electrical stimulation (NMES) provides some muscular activity even very early during critical illness, potentially helping preserve muscle mass [21
] and increase muscle strength [22
The lack of association between the interventions tested in sub-studies 2 and 3 (increased duration of cycling and increased intake of calories and proteins, respectively) and the ultrasound estimates of muscle thickness could also be related to the relatively short time interval (7 days) between the two measurements. In particular, the slope of the 3-MH-to creatinine ratio over time tended to be steeper in group C (long-duration cycling, decrease of 34 % from baseline) than in group B (27% from baseline), implying that the inclusion of a larger number of patients would allow a more accurate assessment of a dose-response effect, which was not the primary aim of the present study. The lack of a synergistic effect of increased calories and nitrogen with passive mobilization could be related to the amino-acid composition of the enriched formula, and/or to an excessive caloric load [23
Interpretation of these data is limited because of the small number of patients who could be studied until the end of the 7-day period. The comparability of the groups at baseline is not established, because the proportion of primarily neurological patients differed, as did the time from ICU admission to study inclusion. However, the aim of the study was to assess the effects of passive cycling in all types of immobile patient at any time during the ICU stay. Differences in the concentrations of 3MH-to-creatinine ratio between sub-study 1 and sub-studies 2 and 3 could reflect lower muscle protein catabolism in groups C and D. Nonetheless, the relative change over time is probably a better reflection of the effect of the intervention than absolute values. For this reason, we preferred to use paired values (day 0 and day 7) to show the relative changes in the 3MH/creatinine ratio measured in samples processed simultaneously. The delay between admission to the ICU and inclusion in the study was also variable, in relation with the course of the disease: Some patients were awake at the time of admission and en developed a complication (loss of consciousness or requirement for sedation). This could confound our assessment of the effect of passive cycling, because muscle loss/protein catabolism could have begun well before the intervention. Unfortunately the doses of sedative used in some patients, the mean blood glucose level and the organ failure score during the study period were not recorded. No neuromuscular blocking agent was given during the study. However, regardless of the effects of passive mobilization, the set-up of the present trial might be helpful to evaluate and score the severity of muscular weakness.
Despite these limitations, we believe that our observations in this pilot “proof-of-concept” study, i.e., a decrease in myofibrillar protein catabolism and tolerance to passive cycling in patients with a prolonged period of minimal muscular activity, opens the way for further investigations. Changes in muscle blood flow, water/fluid shifts, stretching of the connective tissue or muscular contractions should be recorded in future evaluations. Obviously, larger study samples, longer periods of observation and intervention, and more frequent or longer duration sessions will be needed to fully evaluate the effects of passive mobilization on muscle function and recovery.