This study aimed to evaluate whether the electrical stimulation of the inspiratory plus expiratory muscle has an advantage over the electrical stimulation of the diaphragm alone. Our study showed that after four weeks of treatment, compared with control intervention, inspiratory plus expiratory neuromuscular electrical stimulation significantly improved the functional exercise capacity of patients with severe COPD; this was primarily observed in the GOLD3 subgroup.
This study was designed to be a multicenter, randomized, and controlled trial, which was not blind, as there were significant differences in function and appearance between the study and control intervention.
At present, respiratory muscle electrical stimulation To some extent replace muscle training pulmonary rehabilitation for some particular COPD patients, which can improve the patient's respiratory muscle endurance and strength [9]. A systematic retrospective study on respiratory muscle training recommends that each training time lasts 20–30 minutes [17]. The frequency of these two instruments used in this clinical trial were set to 40 Hz in beginning, and treatment time of this clinical trial was also set at 30 minutes per day, which not only increased respiratory muscle strength but also avoided respiratory muscle fatigue. Previous clinical trials have shown that neuromuscular electrical stimulation can improve respiratory muscle strength after four weeks of intervention [18]. Therefore, the outcome of effect sobservation was set to four weeks following intervention.
The 6-minute walk distance developed by the American Thoracic Society is a functional exercise test that is easy to operate, and reflects the patients’ daily exercise status with better accuracy [12]. In this study, 6MWD after four weeks of treatment was used as primary observational variable to evaluate the therapeutic effects of electrical stimulation on patients with severe COPD.
In this trial, the improvement in 6MWD in the study intervention (65.53 ± 39.45 m) was more significant than that in the control intervention (26.66 ± 32.65 m). It has been reported by previous researchers that the increase of 6MWD in the ranged between 25 m and 33 m in inspiratory neuromuscular elctrostimulation treatment [19, 20]. The reason why there was a better 6MWD improvement in our study in the study intervention may be because it combines the electrical stimulation of both diaphragm and abdominal muscles. These findings are consistent with the results of previous studies [21]. A meta-analysis showed that in subjects, the combination of inspiratory muscle training combined with expiratory muscle training is more effective in increasing exercise performance compared with inspiratory muscle training alone [22].
It is known that expiratory muscles are activated during expiration in subjects with COPD, mostly at the end of expiration [23]. Inspiratory plus expiratory neuromuscular electrical stimulation should be more helpful than inspiratory neuromuscular electrical stimulation alone in reducing the symptoms of dyspnea. Our study showed that the mMRC score of the study intervention had more improvement than that of the control intervention. Although there was no statistical difference between the two groups. The lack of statistical differences may be related to the short trial period and the small number of patients. Elctrostimulation might prevent muscle function deterioration [24], improve muscle strength and dyspnea in individuals with a low body mass index [25].
Although the therapeutic effects of COPD are often judged by the changes in FEV1, there were no significant improvements in pulmonary functions after four-week intervention in our study. Weiner et al. demonstrated that when inspiratory muscle training is used alone, there were no improvements in maximum expiratory pressure [26]. But authors observed that inspiratory muscle training combined with expiratory muscle training provided higher gains in the maximum expiratory pressure and maximum inspiratory pressure compared to the control groups [27]. These studies demonstrated the importance of improving both inspiratory and expiratory muscles in subjects with COPD. Meanwhile, according to the results of previous studies, short-term pulmonary rehabilitation may not have a significant impact on FEV1 [28]. Longer-term clinical trials may be performed in the future to validate this hypothesis.
The main expected benefit of intervention in patients with severe COPD is likely to be related to muscle activity and reinforcement. In our study, although the increase of diaphragm motion did not amount to a statistically significant difference, we observed more increase in diaphragm motion in the quiet breathing and deep breathing after four weeks of study intervention. Some reasons may explain this. First, Prieur et al. evaluated the effects of electrical stimulation on skeletal muscle oxygenation in patients with COPD [29]. They determined that deoxygenations and increase in oxygen uptake of muscle and tissue occurred during electrical stimulation. These deoxygenations might reflect a lower level of voluntary muscle activity during the electrical stimulation. This suggests that the metabolic load of the muscle was increased by electrical stimulation. Besides, electrical stimulation can improve muscle strength in peripheral muscles [25].
Although our trial was not extensive enough to detect small changes in secondary outcomes, by subgrouping the participants into GOLD 3 vs. GOLD 4, we could explore whether the effects differed between participants with different severities, and the results showed a trend of favorable outcomes in GOLD 4 patients. It suggested that individuals with lower pulmonary function may achieve significant gains in pulmonary function compared study intervention with control intervention. This may indicate that patients with a high level of impairment might respond favorably, while the trend of increase in diaphragm motion range might explain this response. The small number of participants included and the short duration of intervention might explan other unfavorable results.
There were no severe adverse events related to the intervention in the both group. There might be one adverse event related to the intervention in control group. It can be seen that the risk of electrical stimulation is minimal, and adverse events related to electrical stimulation are few and can be accepted by most subjects. These results reveal that this technique was well tolerated by the patients regardless of their disease severity.
The improvement in respiratory muscle strength is important for patients with COPD. Pulmonary rehabilitation has been demonstrated to reduce dyspnea, increase exercise capacity, and improve the quality of life in individuals with COPD [11, 6]. Respiratory muscle training is an effective way for COPD patients to recover. However, many training exercises require patients to do active work, resulting in poor patient compliance and limited treatment effects. Furthermore, many patients could not participate in these training sessions due to personal reason. Neuromuscular electrical stimulation is a passive training method that allows selected muscles to contract without the need for active work. It has been found that electrical stimulation could partly mimic the muscle training procedure and had a similar partial effect on muscle function [21].
Based on this clinical trial, inspiratory plus expiratory neuromuscular electrical stimulation represents a noval form of neuromuscular electrical stimulation, which is a promising pulmonary rehabilitation mode. Electrical stimulation of respiratory muscles has been applied in the treatment of other diseases, and a study found that functional electrical stimulation of abdominal muscles can shorten ventilation duration and ICU length of staying in mechanically ventilated patients [30]. Further study can be applied to evaluate effect of electrical stimulation in critically ill patients.
Research limitations
There are some limitations in the present study. First, the 6MWD of the participants in our trial seemed to be higher when compared to those of European patients. One reason for this discrepancy might be because all participants were recruited from stable outpatient groups. In the multicenter study reported by Waschki et al., participants achieved a mean 6MWD of 364 m with a similar FEV1 level, which may be biased to relatively severe patients [31]. Future study needs to recruit subjects with lowered functional exercise capacity. Second, our study took only four weeks and did not include a longer observation and follow-up period. Based on this research, future work should consider longer programs of intervention. Third, we did not take into account improvement conditions of muscles, functional performance, symptoms rather than dyspnea, and other health-related changes in quality of life. Future studies should preferably be designed to permit more effects to be perceived.