Breath-synchronized electrical stimulation of the expiratory muscles in mechanically ventilated patients: a randomized controlled feasibility study and pooled analysis

Data are presented as medians with interquartile range [q₁–q₃], mean ± standard deviation, or percentages. Statistical analyses were performed using two-sided hypothesis tests at the 5% significance level.

See Table 1 for characteristics of the pooled study population (N = active/sham: 20/20).

Recent studies suggest that maintaining diaphragm activity during mechanical ventilation minimizes diaphragm disuse atrophy and may improve clinical outcome [4, 20]. The current study was designed to investigate the feasibility and efficacy of eliciting expiratory muscle activity in the early stages of mechanical ventilation, based on the assumption that mechanical ventilation is associated with expiratory muscle disuse atrophy. While this assumption has not been extensively studied, it is known that controlled mechanical ventilation may (partly) silence respiratory centers in the brainstem, resulting in disuse of the inspiratory and expiratory muscles [21]. In addition, data on rectus abdominis biopsies show that critically ill patients exhibit smaller myofiber cross-sectional area compared with controls [22]. The effects of critical illness and mechanical ventilation on the change in expiratory muscle thickness, however, are yet unknown but may be of clinical relevance as increasing evidence demonstrates expiratory muscle weakness at the time of ventilator weaning [1, 9, 10, 13, 23], likely as a consequence of muscle disuse. Potential explanations for how expiratory muscle weakness affect weaning or extubation outcome include inadequate secretion clearance and insufficient cough capacity, resulting in respiratory complications such as pneumonia and atelectasis. Also, the expiratory muscles support inspiration in the presence of diaphragm dysfunction [1]; weakness may thus result in reduced ventilatory capacity. In line with our earlier results [17], we report more successful extubations for the pooled active group; however, this needs confirmation in an appropriately powered study.

We demonstrate that expiratory muscle FES as applied twice daily in the Holland study with a maximum intensity of 100 mA is feasible and safe in selected critically ill patients and allows high therapy compliance after an adequate contractile response to FES was verified. No FES-related serious harm or complications were reported, and only few sessions were stopped early after meeting safety criteria.

Over the last decade, inconclusive evidence for the clinical benefits of FES in ICU patients was published [15, 24], mainly targeting limb muscles. One reason for these inconsistent results may be the lack of reporting of treatment compliance and contractile response to stimulation [25]. The effectiveness of FES in activating muscles at an adequate level depends on patient characteristics; factors such as sepsis, edema and vasopressor may play a role [26, 27]. No potential explanatory factors hampering contractile response were found in our patients that did not pass the expiratory muscle FES eligibility test (N = 2 for maximum intensity of 60 mA (no data available on whether these patients would respond at higher intensities), N = 3 for maximum intensity of 100 mA). Besides changes in Richmond Agitation-Sedation Scale, no clinical or ventilator parameters were associated with changes in applied stimulation intensity for the active group. The latter could be explained by the fact that stimulation intensity remained relatively stable, while ICU patients show more day-to-day variation in clinical signs.

Interestingly, our high success rate of contractile activation is not in line with Grunow et al. [25], studying contractile response to FES (verified visually or on palpation) in eight limb muscle groups and reporting that only 64.4% of applied stimulations led to an adequate response on the day of ICU admission; this number declined to 25% after one week. Although the expiratory muscles were not targeted in their study, their maximum stimulation intensity was 70 mA, i.e., our median threshold intensity. While a strong muscle contraction depends on many factors (e.g., pulse duration, skin/electrode interface, electrode size and location to motor point), it is plausible that increasing intensity would provide higher contractile response rates in their study. In addition, we used ultrasound to verify the initial response, which we consider a more objective measure compared to palpation, especially in patients with high body mass index or edema. Lastly, we did not experience decreases in contractile response throughout the study, likely due to the higher intensities used and pre-randomization stimulation titration.

Plasma cytokine levels were measured to evaluate whether early application of FES was associated with enhanced systemic inflammatory response. Starting expiratory muscle FES as early as possible is important, as respiratory muscle atrophy largely develops within the first 4 days of mechanical ventilation [20, 29]. However, it is important to assess whether patients tolerate the increased physical demands and whether early FES causes an inflammatory state. We did not find associations with systemic inflammatory response, but with the large variability in pro-inflammatory state of ICU patients, no clear implications can be generated about potential protective effects. This is in line with recent work [30] on limb muscle FES in ICU patients and with data in healthy subjects demonstrating that the effects of FES are similar to those of mild exercise [31], i.e., inhibiting pro-inflammatory cytokines [32]. Furthermore, Hickmann et al. [33] showed that early exercise during the onset of septic shock did not enhance inflammation and preserved muscle mass. Similar mechanisms may explain potential protective effects of FES on muscle loss, but this requires repeated measurements of cytokines during the full period of a FES protocol, which was not the focus of our study and would be of interest to address in future research.

There are yet no clinical applications of FES targeting the respiratory muscles of ICU patients under mechanical ventilation. Transvenous phrenic nerve pacing is currently being studied as potential intervention for improving diaphragm strength in difficult-to-wean patients (NCT03096639). However, this technique is invasive, increasing risks associated with subclavian vein cannulation and blood stream infections. In contrast, we focused on employing breath-synchronized expiratory muscle FES in the early phase of critical illness, aiming to prevent (or attenuate) the development of muscle disuse in selected patients with an anticipated expected prolonged duration of mechanical ventilation. We reason that this could be a novel noninvasive application within a respiratory muscle-protective ventilation strategy.

For the pooled data, we observed a between-group difference in total abdominal expiratory muscle thickness changes on day 3, favoring the active group. Although effects were small, our observations are in line with Dall’Acqua et al. [28], showing that FES of the rectus abdominis muscle (note that this muscle is to a limited extent involved in expiration [1], therefore not specifically targeted in our study) of ICU patients resulted in muscle mass preservation in the active group, while thickness decreased in the sham group. However, we found no between-group differences on day 5, likely resulting from insufficient sample size and observer variability (see ‘Strengths and limitations’ section).

In the pooled analysis of clinical outcomes using the cumulative incidence competing risks method, we report between-group differences in median ventilation duration and ICU length of stay. As the incidence rate of the event of interest was influenced by competing events (particularly death in the sham group) and the estimates might not be stable given the small sample size, we also calculated the median ventilation duration and ICU length of stay for those patients that experienced the event of interest. No between-group differences were found for these subgroups. A next step would be to test the treatment effect of expiratory muscle FES in a study powered on clinical endpoints. Assuming a median effect size with 60% of patients successfully extubated on day 9 for the intervention group versus 45% of patients in the sham group, a next study would require 254 participants (hazard approach; two-sided log-rank test with two-sided alpha of 0.05, beta of 0.1, mortality on day 9 of 20%, and 10% of patients lost to follow-up).

This study has some limitations. First, it was designed with the assumption that ultrasound could provide sufficient insights into the effects of expiratory muscle FES on muscle mass preservation. Despite using a standardized protocol [19], obtaining reliable ultrasound measurements in ICU patients can be challenging. Changes in expiratory muscle thickness can reflect actual changes in muscle thickness (i.e., atrophy or hypertrophy), but could also be affected by observer variability and patient characteristics. For example, motion of abdominal contents with respiration could passively stretch the abdominal expiratory muscles. Also, abdominal expiratory muscles have more degrees of freedom to move compared to the diaphragm; active contraction of one muscle layer could directly influence the position of the adjacent layer. For this reason, we evaluated changes in total abdominal expiratory muscle thickness and used a linear mixed model to account for individual changes, but the study was not powered sufficiently to draw any conclusions on these results. In contrast, ultrasound is valuable for verifying contractile response to stimulation (Additional file 1: Figure 4). Second, sample size was small and patients were enrolled relatively late after intubation. This resulted in a highly selected study population prone to prolonged mechanical ventilation. Because of this reason, the absence of protocolized ventilator and weaning strategies, and post-randomization events (particularly death in the sham group), results on clinical outcomes should be interpreted with caution and generalizability of the findings is limited. Third, this study lacks a robust outcome parameter to assess physiological effects of expiratory muscle FES, including dose–response relationships. The dosage of 30-min stimulation sessions twice daily was chosen based on a few practical and physiological considerations. First, while the rate of expiratory muscle atrophy is yet unknown, diaphragm atrophy rapidly occurs after the start of mechanical ventilation [20, 29]. Hence, we wanted to limit the delay between stimulation sessions to a maximum duration of 24 h, which is only possible to guarantee by including more than one stimulation session per day. Second, it is known that the force evoked from a muscle by electrical stimulation could decline rapidly over time because of repetitive activation of the same motor units. We therefore reasoned that limiting the stimulation session duration to 30 min would help to ensure a strong muscle contraction throughout the session. Other considerations included availability of study personnel and possible interference with clinical protocols/activities. Nevertheless, a next study should consider different FES protocols in order to find the optimal session frequency and duration for improving clinical outcomes. Moreover, although it would be interesting to assess muscle changes on a cellular or functional level and in response to different expiratory muscle FES protocols, such measurements would require repeated muscle biopsies or assessment of gastric twitch pressures in response to stimulation of the expiratory muscle nerve roots, respectively. We did not perform these invasive and technically challenging techniques in our study, but focused on the feasibility and efficacy of employing expiratory muscle FES in the early phase of ICU stay. Addressing such physiological endpoints would be of interest in order to better understand the potential effects of expiratory muscle FES on maintaining muscle function.