Comparison of exercise intensity during four early rehabilitation techniques in sedated and ventilated patients in ICU: a randomised cross-over trial

This was a randomised, controlled cross-over study carried out in an 18-bed ICU between November 2016 and July 2017. The study was approved by our institutional review board (Comité de Protection des Personnes Nord-Ouest 3). In conformity with the Declaration of Helsinki, written, informed consent to participate in the study was required from all patients. When consent was given by a proxy, the patient was informed as soon as possible and written consent was obtained. The published study protocol [20] (trial registration NCT02920684) complied with the Consolidated Standards of Reporting Trials (CONSORT) guidelines for clinical trials.

Inclusion criteria were that patients must be over 18 years of age, intubated for at least 24 h and ventilated with “pressure support”. To avoid changes in cardiac output related to other factors such as pain, stress etc., only sedated patients with a Ramsay score greater than 4 were included. Patients were excluded if they had a pacemaker or other contraindications to electrical stimulation, if they were ventilated under “assist control ventilation”, or were conscious. Other criteria are listed in the study protocol [20].

All patients participated in four consecutive 10-min sessions of bed exercise: 10 min of PROM, 10 min of quadriceps electrical stimulation, 10 min of passive cycle-ergometery (MotoMed Letto II®) and 10 min of FES cycling (RehaMove®, Hasomed, Germany). The order of the interventions was randomised using a Latin square design [20]. For the in-bed cycle-ergometry (passive peddling and FES cycling), the peddling frequency was set to 20 rev/min [2]. For the exercises involving quadriceps electrical stimulation (quadriceps electrical stimulation alone and FES-cycling), a rectangular, intermittent, bidirectional current with no ramp was used, and the intensity was modulated to obtain a palpable muscle contraction. The other electrical stimulation parameters were identical for all patients (length 300 μs, frequency 35 Hz) [20]. During FES cycling, electrical stimulation was synchronised with knee extension. A 30-min rest period was allowed between each intervention in order for the cardiorespiratory system to return to its baseline state.

A power calculation showed that 19 subjects should be included to detect a difference between groups in mean CO of 1.1 L, and to reject the null hypothesis with power of 90% and associated type I probability error of 0.05. It was thus planned to include 20 patients in total [20]. Descriptive statistics are reported as counts and percentages for categorical data and means and standard deviations or medians and interquartile ranges for continuous variables. To compare the effect of the different exercises on the primary endpoint across the different measurement times (baseline, 3 min, 6 min and 9 min), a linear mixed effects model with a random intercept was used for each participant, and interactions between exercise type and measurement time were analysed. The same model was used to compare the effect of the interventions on THb, HbO₂ and HHb; however, baseline measures were not included since they were zero in all patients. For the other secondary endpoints, the effect of the interventions on the difference between baseline measurements and mean values during the exercises was also assessed using a linear mixed model with a random intercept for each participant and analysis of interactions between exercise type and measurement time. All models were adjusted for the intervention sequence. The statistical significance of the interactions was assessed using the likelihood ratio test. All analyses were performed using R version 3.4.2 and lme4 and lsmeans software. A two-tailed p value of 0.05 was considered significant.

There were no differences in cardiac output at rest before each exercise (see Table 2). Figure 2 shows cardiac output over time. Cardiac output increased significantly (+ 1 L/min) after 9 min of FES cycling. There was no change in cardiac output over time during PROM, passive cycle ergometry or quadriceps electrical stimulation. There were no differences between the increase in cardiac output during FES cycling in patients with or without cardiorespiratory comorbidities (chronic obstructive pulmonary disease (COPD) or chronic heart failure).

There were no differences between the secondary outcomes at rest before each exercise. There was a significant increase in heart rate, TAPSE and MAP during FES cycling (see Table 3). MAP also increased during passive cycle ergometry. Cardiorespiratory parameters did not change during the other exercises.

PASP was significantly higher during FES cycling than PROM and quadriceps electrical stimulation (respectively, 51 (95% CI 36–67) mmHg vs. 45 (95% CI 32–59) mmHg (p = 0.007) vs. 46 (95% CI 35–57) mmHg (p < 0.001)).

Respiratory rate was significantly higher during FES cycling than during PROM and quadriceps electrical stimulation (respectively, 24 (95% CI 19–30) c/min vs. 20 (95% CI 16–24) c/min (p < 0.001) vs. 21 (95% CI 16–26) c/min (p = 0.005)).

At the end of the PROM, the level of THb had decreased significantly by 23% (95% CI − 41.5 to − 4.9) (p = 0.046). This led to a significant reduction in HHb level (− 27% (95% CI − 50 to − 4) (See Fig. 3). HbO₂ did not change.

At the end of the passive cycle-ergometry, there was a non-significant increase in THb (+ 12.7% (95% CI − 5.6 to 31) (p = 0.3) compared with rest, with an associated non-significant increase in HbO₂ (+ 11% (95% CI − 7 to 30).

There was a non-significant increase in THb (+ 19.5% (95% CI − 1.1 to 37.8) (p = 0.08) at the end of the quadriceps electrical stimulation. This produced a non-significant increase in HHb (+ 15.5% (95% CI − 7.2 to 38.2). There was no change in HbO₂. The non-significant increase in THb (+ 10.3% (95% CI − 8 to 28.6) (p = 0.3) during FES cycling was induced by a significant increase in HHb of 24% (95% CI 1.1–46.7). HbO₂ decreased significantly by 13% (95% CI − 31.8 to − 4.7). No adverse events occurred during the exercises.

The principle of physical exercise is to increase muscle work in order to increase metabolic energy demand. The increase in muscle activity leads to an increase in metabolic consumption of O₂ and cardiac output in order to maintain muscle perfusion and sufficient levels of O₂ [16‐18]. Of the four interventions, only FES cycling increased cardiac output. The increase was considerable, around 15% (1 L/min). The slight increase in cardiac frequency suggests that stroke volume increased, thus demonstrating a global increase in cardiac activity [21]. This increase was clinically significant and showed that FES cycling produced a cardiac response to the exercise, in contrast with the other interventions that did not modify cardiac activity. Moreover, the other cardiovascular and respiratory parameters also increased with FES cycling. Although this may be difficult to interpret clinically, based on principles from applied physiology, the increase in TAPSE, MAP, PASP and respiratory rate confirms our hypothesis of an increase in cardiac activity and exercise intensity [15, 16, 22, 23].

Few physiological data are available in the literature on early rehabilitation in the ICU. The majority of studies simply report cardiac frequency or SpO₂ [24, 25]. Moreover, FES cycling is a relatively new technique and therefore few studies have evaluated its use in the ICU [26]. Muraki et al. observed an increase in cardiac output and oxygen consumption (VO₂) during FES cycling in patients with American Spinal Injury Association (ASIA) A- paraplegia, with no changes during passive leg cycling [27]. A study in critically ill patients observed a 1% increase in cardiac output with passive leg cycling in sedated patients [28]. These results are in accordance with the present study, which showed that neither of the passive techniques induced a cardiac response. Moreover, there is little rationale to support the use of passive exercises to improve muscle function [29]. However, the results of the present study also showed that quadriceps electrical stimulation did not increase cardiac output. Although several studies have reported the benefits of neuromuscular electrical stimulation in the ICU [4, 30], other studies have found no benefits and further studies are necessary to determine the true effects of this intervention [31]. It is important to note that quadriceps electrical stimulation can prevent muscle atrophy by improving glucose metabolism [30, 32, 33].

Changes in the microcirculation in the vastus lateralis muscle during the interventions were evaluated using NIRS. THb reflects the blood volume of the tissue under the probe, and it is assumed that HHb reflects muscle O₂ extraction [34, 35]. During the PROM, muscle blood volume reduced, probably as a result of the vertical position of the femur during the flexion movements, as has been described previously in passive leg raising [36]. The lack of a muscle strengthening effect was reinforced by the decrease in HHb during the intervention. Conversely, during passive leg cycling, blood volume did not decrease significantly. Although the position of the limb was similar to that during the PROM, we believe that the regular rhythm of the passive cycling (20 rotations/min) altered the circulation in the lower limb [37]. However, the lack of change in HHb demonstrates that the passive cycle-ergometery did not effectively increase muscle metabolism.

During the quadriceps electrical stimulation, HHb increased (although not significantly), suggesting an increase in muscle metabolism. This is in accordance with the literature that shows that neuromuscular stimulation has an effect on local metabolism, but not on the cardiovascular system [38, 39]. This lack of effect on cardiac output probably explains why several studies have failed to show changes in functional capacity following quadriceps electrical stimulation [31].

During the FES cycling, there was a significant reduction in HbO_2, and a significant increase in HHb, despite the increase in cardiac output. This demonstrates that this exercise induced muscle consumption of O₂ and increased muscle metabolism [40].

In our clinical practice, we try to use exercises that involve voluntary movement, in preference out of bed. However, many studies have shown that a large proportion of rehabilitation in our ICU is carried out in bed [6, 10‐12], and this is also the case in our ICU. The results of this study suggest interventions that induce muscle contractions, particularly FES cycling, should be used to provide higher-intensity early rehabilitation for sedated patients who are confined to bed. Passive interventions can be used to prevent ankylosis but studies are needed to evaluate their effectiveness.

This study has several limitations. The main limitation is that the long-term effects on muscle parameters, such as muscle fibre atrophy, and short and long-term functional capacity were not evaluated. Furthermore, it is important to bear in mind that an increase in exercise intensity may not improve the patient’s prognosis. Although our results showed differences in exercise metabolism between the four types of early rehabilitation exercises, the study was not designed to evaluate functional capacity. However, the results provide a strong physiological rationale for the use of interventions that combine muscle contractions and movement therapy. We chose to evaluate cardiac output based on the linear relationship between this parameter and exercise intensity [15‐17], however, cardiac output does not actually quantify the intensity of the exercise. The exercise response is also dependent on the oxidation of macronutrients, and a measurement of energy expenditure using calorimetry could have precisely quantified the exercise intensity. The second limitation is the fact that only sedated patients who were confined to bed were included, thus the results can only be generalised to this specific population. Nevertheless, positioning and exercising out of bed have already been shown to be effective, while there is a lack of studies of the benefits of in-bed rehabilitation. Moreover, it is these patients who are the most at risk of developing ICU-acquired weakness [41, 42]. We chose to evaluate sedated patients to avoid the effects of confounding factors, such as stress or discomfort, on cardiac output. Another limitation is the lack of statistical power for the evaluation of changes in muscle metabolism, which probably resulted in the lack of significance in the NIRS parameters. Moreover, NIRS only provides an estimation of the parameters evaluated and its application is limited to 3–4 cm below the probe [43]. However, it provided complementary information that was useful for the interpretation of the cardiovascular results.