Inspiratory response and side-effects to rapid bilateral magnetic phrenic nerve stimulation using differently shaped coils: implications for stimulation-assisted mechanical ventilation.

BACKGROUND: Rapid magnetic stimulation (RMS) of the phrenic nerves may serve to attenuate diaphragm atrophy during mechanical ventilation. With different coil shapes and stimulation location, inspiratory responses and side-effects may differ. This study aimed to compare the inspiratory and sensory responses of three different RMS-coils either used bilaterally on the neck or on the chest, and to determine if ventilation over 10 min can be achieved without muscle fatigue and coils overheating. METHODS: Healthy participants underwent bilateral anterior 1-s RMS on the neck (RMSBAMPS) (N = 14) with three different pairs of magnetic coils (parabolic, D-shape, butterfly) at 15, 20, 25 and 30 Hz stimulator-frequency and 20% stimulator-output with + 10% increments. The D-shape coil with individual optimal stimulation settings was then used to ventilate participants (N = 11) for up to 10 min. Anterior RMS on the chest (RMSaMS) (N = 8) was conducted on an optional visit. Airflow was assessed via pneumotach and transdiaphragmatic pressure via oesophageal and gastric balloon catheters. Perception of air hunger, pain, discomfort and paresthesia were measured with a numerical scale. RESULTS: Inspiration was induced via RMSBAMPS in 86% of participants with all coils and via RMSaMS in only one participant with the parabolic coil. All coils produced similar inspiratory and sensory responses during RMSBAMPS with the butterfly coil needing higher stimulator-output, which resulted in significantly larger discomfort ratings at maximal inspiratory responses. Ten of 11 participants achieved 10 min of ventilation without decreases in minute ventilation (15.7 ± 4.6 L/min). CONCLUSIONS: RMSBAMPS was more effective than RMSaMS, and could temporarily ventilate humans seemingly without development of muscular fatigue. Trial registration This study was registered on clinicaltrials.gov (NCT04176744).

The effect of diaphragm fatigue on the multidimensional components of dyspnoea and diaphragm electromyography during exercise in healthy males.

KEY POINTS: Diaphragm fatigue may increase the intensity (sensory dimension) and unpleasantness (affective dimension) of dyspnoea, which may partially explain why diaphragm fatigue negatively affects exercise performance. We hypothesized that diaphragm fatigue would negatively affect exercise performance via increases in both the intensity and unpleasantness of dyspnoea, and that the increase in dyspnoea would be mechanistically linked to an increase in diaphragmatic EMG (EMGdi ), a surrogate measure of neural respiratory drive. Fatiguing the diaphragm prior to exercise reduced cycling performance and increased both the intensity and unpleasantness of dyspnoea. The change in submaximal dyspnoea unpleasantness was significantly correlated with the change in cycling performance. Pre-fatigue of the diaphragm did not increase EMGdi during exercise and is therefore unrelated to the increase in either the sensory or affective dimension of exertional dyspnoea. ABSTRACT: The purpose of this study was to examine the effect of diaphragm fatigue on the multidimensional components of dyspnoea and diaphragm electromyography (EMGdi ) during cycling. Sixteen healthy males (age = 27 ± 5 yr, V̇O2max  = 45.8 ± 9.8 ml kg-1  min-1 ) completed two high-intensity, time-to-exhaustion cycling tests in randomized order: (i) inspiratory pressure threshold loading (PTL) prior to exercise to induce diaphragm fatigue (pre-DF) and (ii) no PTL (control). Diaphragm fatigue after PTL was confirmed via cervical magnetic stimulation of the phrenic nerves. Dyspnoea intensity and unpleasantness were measured throughout exercise with the 0-10 category-ratio Borg scale and following exercise using the Multidimensional Dyspnoea Profile (MDP). EMGdi was continuously recorded via a multipair oesophageal electrode catheter. Time-to-exhaustion decreased with pre-DF vs. control (9.0 ± 5.5 vs. 10.7 ± 7.5 min, P = 0.023). Pre-DF increased dyspnoea intensity ratings by 0.6 ± 1.0 Borg 0-10 units at the highest equivalent submaximal exercise time (HESET) a participant could achieve in both conditions (P = 0.020). Dyspnoea unpleasantness ratings increased with pre-DF by 0.5 ± 1.0, 0.7 ± 1.2 and 0.9 ± 1.4 (all P < 0.05) Borg 0-10 units during the 2nd, 3rd and 4th minutes of exercise, respectively. There was a significant correlation between the change in breathing unpleasantness ratings at HESET and the change in time-to-exhaustion (r = 0.66, P = 0.006). The immediate perception domain, a combination of peak unpleasantness and specific dyspnoea descriptor intensity ratings, was the only component of the MDP that was significantly increased with pre-DF (4.3 ± 1.9 vs. 3.6 ± 1.8, P = 0.04). There were no significant differences in EMGdi . In conclusion, diaphragm fatigue has negative effects on multiple domains of dyspnoea, which may partially explain why exercise performance decreases with it.

Short-term effects of Lumacaftor/Ivacaftor (Orkambi™) on exertional symptoms, exercise performance, and ventilatory responses in adults with cystic fibrosis.

RATIONALE: Lumacaftor/ivacaftor (LUM/IVA) modestly improves lung function following 1 month of treatment but it is unknown if this translates into improvements in exercise endurance and exertional symptoms. METHODS: Adult CF participants completed a symptom-limited constant load cycling test with simultaneous assessments of dyspnea and leg discomfort ratings pre- and 1 month post-initiation of LUM/IVA. RESULTS: Endurance time, exertional dyspnea and leg discomfort ratings at submaximal exercise did not change significantly. There was a significant inverse correlation between changes in leg discomfort and endurance time (r = - 0.88; p = 0.009) following 1-month of LUM/IVA. CONCLUSIONS: Overall, 1-month of LUM/IVA did not increase endurance time or modify exertional dyspnea or leg discomfort ratings. However, individuals who experienced a reduction in leg discomfort following LUM/IVA had an improvement in endurance time. Future studies with a larger sample size are needed to verify these findings and to assess the long-term effects of LUM/IVA on exercise outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02821130. Registered July 1, 2016.

A multidimensional assessment of dyspnoea in healthy adults during exercise.

PURPOSE: (1) To determine whether healthy humans can distinguish between the intensity and unpleasantness of exertional dyspnoea; (2) to evaluate the reliability of qualitative dyspnoea descriptors during exercise; and (3) to assess the reliability of the Multidimensional Dyspnoea Profile (MDP) METHODS: Forty-four healthy participants (24M:20F, 25 ± 5 years) completed maximal incremental cycling tests on three visits. During visit 1, participants rated the intensity and unpleasantness of dyspnoea simultaneously throughout exercise using the modified 0-10 category-ratio Borg scale. On visits 2 and 3, participants rated either the intensity or unpleasantness of dyspnoea alone at the same measurement times as visit 1. On all visits, participants selected qualitative descriptors throughout all exercise intensities from a list of 4, selected relevant qualitative descriptors from a list of 15 at peak exercise, and completed the MDP. RESULTS: Participants rated their dyspnoea intensity significantly higher for a given minute ventilation ([Formula: see text]) compared to dyspnoea unpleasantness (dyspnoea-[Formula: see text] slope: 0.08 ± 0.02 vs. 0.07 ± 0.03 Borg 0-10/L min-1, p < 0.001) during visit 1. The onset of intensity ratings occurred at a significantly lower work rate compared to unpleasantness ratings measured on the same exercise test (52 ± 41 vs. 91 ± 53 watts, p < 0.001). Dyspnoea intensity and unpleasantness remained significantly different for a given ventilation even when measured independently on separate exercise tests (p < 0.05). There was good-to-excellent reliability (ICC > 0.60) for the use of qualitative dyspnoea descriptors and the MDP to measure dyspnoea at peak exercise. CONCLUSION: Exercise-induced dyspnoea in healthy adults can differ in the sensory and affective dimensions, and can be measured reliably using qualitative descriptors and the MDP.

Physiological Factors Associated with Unsatisfied Inspiration at Peak Exercise in Healthy Adults.

INTRODUCTION: Contrary to common belief, a growing body of evidence suggests that unsatisfied inspiration (UI), an inherently uncomfortable quality of dyspnea, is experienced by ostensibly healthy adults during high-intensity exercise. Based on our understanding of the mechanisms of UI among people with chronic respiratory conditions, this analysis tested the hypothesis that the experience of UI at peak exercise in young, healthy adults reflects the combination of high ventilatory demand and critical inspiratory constraints. METHODS: In a retrospective analysis design, data included 321 healthy individuals (129 females) aged 25 ± 5 yr. Data were collected during one visit to the laboratory, which included anthropometrics, spirometry, and an incremental cardiopulmonary cycling test to exhaustion. Metabolic and cardiorespiratory variables were measured at peak exercise, and qualitative descriptors of dyspnea at peak exercise were assessed using a list of 15 descriptor phrases. RESULTS: Thirty-four percent of participants ( n = 109) reported sensations of UI at peak exercise. Compared with the non-UI group, the UI group achieved a significantly higher peak work rate (243 ± 77 vs 235 ± 69 W, P = 0.016, d = 0.10), rate of O 2 consumption (3.32 ± 1.02 vs 3.27 ± 0.96 L·min -1 , P = 0.018, d = 0.05), minute ventilation (120 ± 38 vs 116 ± 35 L·min -1 , P = 0.047, d = 0.11), and breathing frequency (50 ± 9 vs 47 ± 9 breaths per minute, P = 0.014, d = 0.33), while having a lower exercise-induced change (peak-baseline) in inspiratory capacity (0.07 ± 0.41 vs 0.20 ± 0.49 L, P = 0.023, d = 0.29). The inspiratory reserve volume to minute ventilation ratio at peak exercise was also lower in the UI versus non-UI group. Dyspnea intensity and unpleasantness ratings were significantly higher in the UI versus non-UI group at peak exercise (both P < 0.001). CONCLUSIONS: Healthy individuals reporting UI at peak exercise have relatively greater inspiratory constraints compared with those who do not select UI.

Effects of the Elevation Training Mask® 2.0 on dyspnea and respiratory muscle mechanics, electromyography, and fatigue during exhaustive cycling in healthy humans.

OBJECTIVES: Examine the effects of the Elevation Training Mask® 2.0 (ETM) on dyspnea, and respiratory muscle function and fatigue during exercise. DESIGN: Randomized crossover. METHODS: 10 healthy participants completed 2 time-to-exhaustion (TTE) cycling tests while wearing the ETM or under a sham control condition. During the sham, participants were told they were breathing air equivalent to "9000 ft" (matched to the selected resistance valves on the ETM according to the manufacturer), but they were breathing room air. Dyspnea and leg discomfort were assessed using the modified 0-10 category-ratio Borg scale. Qualitative dyspnea descriptors at peak exercise were selected from a list of 15. Crural diaphragmatic electromyography (EMGdi) and transdiaphragmatic pressure (Pdi) were measured via a multipair esophageal electrode balloon catheter. Participants performed maximal respiratory maneuvers before and after exercise to estimate the degree of respiratory muscle fatigue. RESULTS: Exercise with the ETM resulted in a significant decrease in TTE (p = 0.015), as well as increased dyspnea at baseline (p = 0.032) and during the highest equivalent submaximal exercise time (p = 0.0001). The increase in dyspnea with the ETM was significantly correlated with the decrease in exercise time (r = 0.73, p = 0.020). EMGdi and Pdi were significantly increased with the ETM at all time points (all p < 0.05). There was a significant increase in the selection frequency of "my breath does not go in all the way" at peak exercise with the ETM (p = 0.02). The ETM did not induce respiratory muscle fatigue. CONCLUSIONS: Exercising with the ETM appears to decrease exercise performance, in part, by increasing the sensation of dyspnea.

Case Studies in Physiology: Cardiopulmonary exercise testing and inspiratory muscle training in a 59-year-old, 4 years after an extrapleural pneumonectomy.

This case report characterizes the physiological responses to incremental cycling and determines the effects of 12 wk of inspiratory muscle training (IMT) on respiratory muscle strength, exercise capacity, and dyspnea in a physically active 59-yr-old female, 4 years after a left-sided extrapleural pneumonectomy (EPP). On separate days, a symptom-limited incremental exercise test and a constant work rate (CWR) test at 75% of peak work rate (WR) were completed, followed by 12 wk of IMT and another CWR test. IMT consisted of two sessions of 30 repetitions twice daily for 5 days per week. Physiological and perceptual variables were measured throughout each exercise test. The participant had a total lung capacity that was 43% predicted post-EPP. A rapid and shallow breathing pattern was adopted throughout exercise, and the ratio of minute ventilation to carbon dioxide output was elevated for a given work rate. Oxygen uptake was 71% predicted and WR was 88% predicted. Following IMT, maximal inspiratory pressure improved by 36% (-27.1 cmH2O) and endurance time by 31 s, with no observable changes in any submaximal or peak cardiorespiratory variables during exercise. The intensity and unpleasantness of dyspnea increased by 2 and 3 Borg 0-10 units, respectively, at the highest equivalent submaximal exercise time achieved on both tests. Despite having undergone a significant reduction in lung volume post-EPP, the participant achieved a relatively normal peak incremental WR, which may reflect a high level of physical conditioning. This case report also demonstrates that IMT can effectively increase respiratory muscle strength several years following EPP.NEW & NOTEWORTHY Constraints on tidal volume expansion and the adoption of a rapid and shallow breathing pattern result in a ventilatory limitation and increased ventilatory inefficiency during exercise in a patient several years after extrapleural pneumonectomy (EPP). Inspiratory muscle training can effectively increase respiratory muscle strength after EPP.

Reliability of diaphragm voluntary activation measurements in healthy adults.

Voluntary activation can be used to assess central fatigue of the diaphragm after tasks such as exercise or inspiratory muscle loading. Cervical magnetic stimulation (CMS) of the phrenic nerves elicits an involuntary contraction, or twitch, of the diaphragm. This twitch is quantified based on a measure of transdiaphragmatic pressure and can be used to evaluate diaphragm contractile function and diaphragm voluntary activation (diaphragm-VA). The test-retest reliability of diaphragm-VA using CMS is currently unknown. Thirteen participants (4 male, 9 female; aged 25 ± 3 years) performed a series of interpolated twitch manoeuvres, which included a maximal inspiratory effort against a semi-occluded mouthpiece and 2 CMS-stimuli, 1 during the inspiratory manoeuvre and 1 after when the participant returned to functional residual capacity to quantify diaphragm-VA. Intraclass correlation coefficients (ICCs) and standard error of measurement (SEM) measured between-day and within-session reliability of diaphragm-VA, respectively. Maximal diaphragm-VA values were 91% (SD: 6; SEM: 3.9) and 92% (SD: 5; SEM: 2.2) during visits 1 and 2 (p = 0.68), respectively, and displayed "good" between-day reliability (ICC: 0.88; 95% confidence interval: 0.67-0.95; SEM: 2.7). Our results suggest that assessing diaphragm-VA using CMS is reliable in young healthy adults. Measuring diaphragm-VA may provide additional insight into the consequences and mechanisms of diaphragm fatigue. Novelty: Magnetic stimulation of the phrenic nerves can reliably measure voluntary activation of the diaphragm. Diaphragm voluntary activation can be used to provide additional insight into fatigability of the diaphragm.

Effects of the Turbine™ on Ventilatory and Sensory Responses to Incremental Cycling.

INTRODUCTION: The Turbine™ is a nasal dilator marketed to athletes to increase airflow, which may serve to reduce dyspnea and improve exercise performance, presumably via reductions in the work of breathing (WOB). However, the unpublished data supporting these claims were collected in individuals at rest that were exclusively nasal breathing. These data are not indicative of how the device influences breathing during exercise at higher ventilations when a larger proportion of breathing is through the mouth. Accordingly, the purpose of this study was to empirically test the efficacy of the Turbine™ during exercise. We hypothesized that the Turbine™ would modestly reduce the WOB at rest and very low exercise intensities but would have no effect on the WOB at moderate to high exercise intensities. METHODS: We conducted a randomized crossover study in young, healthy individuals (7M:1F; age = 27 ± 5 yr) with normal lung function. Each participant performed two incremental cycle exercise tests to exhaustion with the Turbine™ device or under a sham control condition. For the sham control condition, participants were told they were breathing a low-density gas to reduce the WOB, but they were actually breathing room air. The WOB was determined through the integration of ensemble averaged esophageal pressure-volume loops. Standard cardiorespiratory measures were recorded using a commercially available metabolic cart. Dyspnea was assessed throughout exercise using the 0-10 Borg scale. RESULTS: Peak V˙O2 and work rate were not different between conditions (P = 0.70 and P = 0.35, respectively). In addition, there was no interaction or main effect of condition on dyspnea, ventilation, or WOB throughout the exercise (all P > 0.05). CONCLUSION: These findings suggest that the Turbine™ does not reduce the WOB and has no effect on dyspnea or exercise capacity.

The Impact of Cycling Cadence on Respiratory and Hemodynamic Responses to Exercise.

PURPOSE: The physiological consequences of freely chosen cadence during cycling remains poorly understood. We sought to determine the effect of cadence on the respiratory and hemodynamic response to cycling exercise. METHODS: Eleven cyclists (10 males, 1 female; age, 27 ± 6 yr; V˙O2max = 60.8 ± 3.7 mL·kg·min) completed four, 6-min constant-load cycling trials at 10% below their previously determined gas exchange threshold (i.e., 63% ± 5% peak power) while pedaling at 60, 90, and 120 rpm, and a freely chosen cadence (94.3 ± 6.9 rpm) in randomized order. Standard cardiorespiratory parameters were measured and an esophageal electrode balloon catheter was used to assess electromyography of the diaphragm (EMGdi) and the work of breathing (Wb). Leg blood flow index (BFI) was determined on four muscles using near-infrared spectroscopy with indocyanine green dye injections. RESULTS: Oxygen uptake (V˙O2) increased as a function of increasing cadence (all pairwise comparisons, P < 0.05). The EMGdi and Wb were significantly greater at 120 rpm compared with all other conditions (all P < 0.01). Vastus medialis and semitendinosus BFI were significantly greater at 120 rpm compared with 60 and 90 rpm (all P < 0.05). Gastrocnemius BFI was higher at 120 rpm compared with all other cadences (all P < 0.01). No difference in BFI was found in the vastus lateralis (P = 0.06). Blood flow index was significantly correlated with the increase in V˙O2 with increasing cadence in the medial gastrocnemius (P < 0.001) and approached significance in the vastus lateralis (P = 0.09), vastus medialis (P = 0.06), and semitendinosus (P = 0.09). There was no effect of cadence on Borg 0-10 breathing or leg discomfort ratings (P > 0.05). CONCLUSIONS: High cadence cycling at submaximal exercise intensities is metabolically inefficient and increases EMGdi, Wb, and leg muscle blood flow relative to slower cadences.