Twitch Transdiaphragmatic Pressure Research Articles

Voluntary activation of the diaphragm after inspiratory pressure threshold loading.

After a bout of isolated inspiratory work, such as inspiratory pressure threshold loading (IPTL), the human diaphragm can exhibit a reversible loss in contractile function, as evidenced by a decrease in transdiaphragmatic twitch pressure (PDI,TW ). Whether or not diaphragm fatigability after IPTL is affected by neural mechanisms, measured through voluntary activation of the diaphragm (D-VA) in addition to contractile mechanisms, is unknown. It is also unknown if changes in D-VA are similar between sexes given observed differences in diaphragm fatigability between males and females. We sought to determine whether D-VA decreases after IPTL and whether this was different between sexes. Healthy females (n=11) and males (n=10) completed an IPTL task with an inspired duty cycle of 0.7 and targeting an intensity of 60% maximal transdiaphragmatic pressure until task failure. PDI,TW and D-VA were measured using cervical magnetic stimulation of the phrenic nerves in combination with maximal inspiratory pressure maneuvers. At task failure, PDI,TW decreased to a lesser degree in females vs. males (87 ± 15 vs. 73 ± 12% baseline, respectively, p=0.016). D-VA decreased after IPTL but was not different between females and males (91 ± 8 vs. 88 ± 10% baseline, respectively, p=0.432). When all participants were pooled together, the decrease in PDI,TW correlated with both the total cumulative diaphragm pressure generation (R2 =0.43; p=0.021) and the time to task failure (TTF, R2 = 0.40; p = 0.30) whereas the decrease in D-VA correlated only with TTF (R2 =0.24; p=0.041). Our results suggest that neural mechanisms can contribute to diaphragm fatigability, and this contribution is similar between females and males following IPTL.

Effects of hypoxia on exercise-induced diaphragm fatigue in healthy males and females.

Following high-intensity, normoxic exercise there is evidence to show that healthy females, on average, exhibit less fatigue of the diaphragm relative to males. In the present study, we combined hypoxia with exercise to test the hypothesis that males and females would develop a similar degree of diaphragm fatigue following cycle exercise at the same relative exercise intensity. Healthy young participants (n=10 male; n=10 female) with a high aerobic capacity (120% predicted) performed two time-to-exhaustion (TTE; ~85% maximum) cycle tests on separate days breathing either a normoxic or hypoxic (FiO2 =0.15) gas mixture. Fatigue of the diaphragm was assessed in response to cervical magnetic stimulation prior to, immediately post-exercise, 10-, 30-, and 60-min post-exercise. Males and females had similar TTE durations in normoxia (males: 690 ± 181 s; females: 852 ± 401 s) and hypoxia (males: 381 ± 160 s; females: 400 ± 176 s) (p > 0.05). Cycling time was significantly shorter in hypoxia versus normoxia in both males and females (p < 0.05) and did not differ on the basis of sex (p > 0.05). Following the hypoxic TTE tests, males and females experienced a similar degree of diaphragm fatigue compared to normoxia as shown by 20%-25% reductions in transdiaphragmatic twitch pressure. This occurred despite the fact that exercise time in hypoxia was substantially shorter relative to normoxia and the cumulative diaphragm work was lower. We also observed that females did not fully recover from diaphragm fatigue in hypoxia, whereas males did (p < 0.05). Sex differences in the rate of diaphragm contractility recovery following exercise in hypoxia might relate to sex-based differences in substrate utilization or diaphragm blood flow.

Diaphragm Voluntary Activation After Inspiratory Pressure Threshold Loading In Healthy Humans

Inspiratory pressure threshold loading (IPTL) elicits a reduction in diaphragm contractile function (transdiaphragmatic twitch pressure; PDI,TW). It is unknown if diaphragm fatigability after IPTL is also mediated by neural mechanisms (diaphragm voluntary activation; D-VA) or if it differs on the basis of sex. PURPOSE: We sought to determine if D-VA decreases after IPTL and whether this was different between sexes. METHODS: Healthy participants (11F; 10 M) performed IPTL to task failure with an inspired duty cycle of 0.7 at 60% PDI,MAX. Cervical magnetic stimulation of the phrenic nerves was used to assess PDI,TW and D-VA. The relationship between fatigability outcomes (PDI,TW and D-VA), time to task failure, and cumulative diaphragm work were tested to explore how each factor contributes to diaphragm fatigability. RESULTS: Main effects of time (p < 0.001) and sex (p = 0.030), along with an interaction effect (p = 0.007) were observed when examining the changes in PDI,TW after IPTL. Specifically, immediately following IPTL, the decrease in PDI,TW was greater in males compared to females (24 ± 17 vs. 13 ± 15%points; p = 0.016). D-VA was 91 ± 8%baseline in males and 88 ± 11%baseline in females immediately following IPTL. We observed main effects of time, (p < 0.001) but neither the effect of sex (p = 0.177) nor the interaction between sex and time (p = 0.304) were significant, suggesting that D-VA decreases after IPTL similarly in males and females. The decrease in PDI,TW correlated with both the total cumulative diaphragm work (R2 = 0.43; p = 0.021) and time to task failure (R2 = 0.40; p = 0.030), whereas the decrease in D-VA was significantly correlated with time to task failure (R2 = 0.24; p = 0.041) and not cumulative diaphragm work (R2 = 0.19; p = 0.079). CONCLUSION: Our results indicate that neural mechanisms contribute to diaphragm fatigability and this contribution is similar between females and males after IPTL. A decrease in contractile function can be partially explained by both the amount of work performed and the total time of the IPTL task. Decreases in D-VA appear to be influenced primarily by the total time spent performing the IPTL task rather than the amount of work performed. Moreover, these contributing factors appear to be independent of sex. Supported by the Natural Sciences and Engineering Research Council of Canada.

Occurrence and Effects on Weaning From Mechanical Ventilation of Intensive Care Unit Acquired and Diaphragm Weakness: A Pilot Study.

PurposeLimb intensive care unit (ICU)-acquired weakness (ICUAW) and ICU acquired diaphragm weakness (DW) occur frequently in mechanically ventilated (MV) patients; their coexistence in cooperative and uncooperative patients is unknown. This study was designed to (1) describe the co-occurrence of the two conditions (2) evaluate the impact of ICUAW and DW on the ventilator-free days (VFDs) at 28 days and weaning success, and (3) assess the correlation between maximal inspiratory pressure (MIP) and thickening fraction (TFdi) in patients with DW.MethodsThis prospective pilot study was conducted in a single-center on 73 critically ill MV patients. Muscle weakness was defined as a Medical Research Council score < 48 in cooperative patients or a bilateral mean simplified peroneal nerve test < 5.26 mV in uncooperative patients. Diaphragm dysfunction was defined as MIP < 30 cm H2O or as a TFdi < 29%. Weaning success was defined according to weaning according to a new definition (WIND).ResultsFifty-seven patients (78%) had ICUAW and 59 (81%) had DW. The coexistence of the two conditions occurred in 48 patients (65%), without association (χ2 = 1.06, p = 0.304). In the adjusted analysis, ICUAW was independently related to VFDs at 28-days (estimate difference 6 days, p = 0.016), and WIND (OR of 3.62 for having WIND different than short weaning), whereas DW was not. The linear mixed model showed a significant but weak correlation between MIP and TFdi (p < 0.001).ConclusionThis pilot study is the first to explore the coexistence of ICUAW and DW in both cooperative and uncooperative patients; a lack of association was found between DW and ICUAW when considering both cooperative and uncooperative patients. We found a strong correlation between ICUAW but not DW with the VFDs at 28 days and weaning success. A future larger study is warranted in order to confirm our results, and should also investigate the use of transdiaphragmatic twitch pressure measurement during bilateral anterior magnetic phrenic nerve stimulation for the diagnosis of DW.

Sex Differences in Diaphragm Voluntary Activation after Exercise.

The female diaphragm develops less fatigue after high-intensity exercise compared with males. Diaphragm fatigability is typically defined as a decrease in transdiaphragmatic twitch pressure (Pdi,TW) and represents the contractile function of the muscle. However, it is unclear whether this sex difference persists when examining changes in voluntary activation, which represents a neural mechanism contributing to fatigability. This study aimed to determine if high-intensity cycling results in a decrease in diaphragm voluntary activation (D-VA) and to explore if the decrease in D-VA is different between sexes. Twenty-five participants (15 females) completed a single bout of high-intensity constant load cycling. D-VA and Pdi,TW were measured before and after exercise using cervical magnetic stimulation of the phrenic nerves to assess diaphragm fatigability. Participants were of similar aerobic fitness when expressed relative to predicted values (females: 114% ± 25% predicted, males: 111% ± 11% predicted; P = 0.769). Pdi,TW decreased relative to baseline to 85.2% ± 16.7% and 70.3% ± 12.4% baseline (P = 0.012) in females and males, respectively, immediately after exercise. D-VA also decreased in both females and males immediately after exercise. The decrease in D-VA was less in females compared with males (95.4% ± 4.9% baseline vs 87.4% ± 10.8% baseline, respectively; P = 0.018). D-VA decreases after whole-body exercise in both females and males, although the magnitude of the decrease is not as large in females compared with males. The findings of this study suggest that the female diaphragm is more resistant to both contractile and neural mechanisms of fatigability after whole-body exercise.

Diaphragm Dysfunction as a Determinant of Persisting Dyspnoea in Patients One Year after Invasive Mechanical Ventilation Due to COVID-19 Related ARDS

Background: Some patients with coronavirus disease 2019 (COVID-19) experience prolonged fatigue and dyspnoea without objective impairment of pulmonary or cardiac function. This study determined diaphragm function and its central voluntary activation as a possible pathophysiological correlate after severe COVID-19 acute respiratory distress syndrome (ARDS).Methods:Ten patients with severe COVID-19 ARDS treated with invasive mechanical ventilation (IMV) (6 female, age 56±14 years, 63±45 days of IMV) and ten matched healthy controls underwent pulmonary function tests (PFTs), 6-minute walk test, echocardiography, diaphragm ultrasound, and invasive recording of twitch transdiaphragmatic pressure (twPdi) following magnetic diaphragm stimulation. Twitch interpolation was used to determine the diaphragm voluntary activation index (DVAI); reflecting central diaphragm activation.Findings: One year post discharge, neither PFTs nor echocardiography were indicative of significant abnormalities in severe COVID-19 survivors. However, six patients reported persisting dyspnoea on exertion (severe in two, moderate in four). On ultrasound, the diaphragm thickening ratio was lower in patients versus controls (1.87±0.37 vs. 2.76±0.72; pInterpretation: Inspiratory muscle dysfunction with impaired central voluntary activation of the diaphragm is present one year after severe COVID-19 ARDS treated with IMV, and relates to dyspnoea.Trial Registration: This prospective case-control study was registered with number, (NCT04854863)Funding: None to declare. Declaration of Interest: The authors have no conflicts of interest to disclose.Ethical Approval: This study was approved by the local ethics committee (Ethikkommission an der Medizinischen Fakultät der Rheinisch-Westfälischen Technischen Hochschule Aachen, CTCA-A-Nr. 20-515, AZ EK 443/20).

Heart Failure Results in Inspiratory Muscle Dysfunction Irrespective of Left Ventricular Ejection Fraction

Background: Exercise intolerance in heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) results from both cardiac dysfunction and skeletal muscle weakness. Respiratory muscle dysfunction with restrictive ventilation disorder may be present irrespective of left ventricular ejection fraction and might be mediated by circulating pro-inflammatory cytokines. Objective: To determine lung and respiratory muscle function in patients with HFrEF/HFpEF and to determine its associations with exercise intolerance and markers of systemic inflammation. Methods: Adult patients with HFrEF (n = 22, 19 male, 61 ± 14 years) and HFpEF (n = 8, 7 male, 68 ± 8 years) and 19 matched healthy control subjects underwent spirometry, measurement of maximum mouth occlusion pressures, diaphragm ultrasound, and recording of transdiaphragmatic and gastric pressures following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. New York Heart Association (NYHA) class and 6-min walking distance (6MWD) were used to quantify exercise intolerance. Levels of circulating interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured using ELISAs. Results: Compared with controls, both patient groups showed lower forced vital capacity (FVC) (p < 0.05), maximum inspiratory pressure (PI_max), maximum expiratory pressure (PE_max) (p < 0.05), diaphragm thickening ratio (p = 0.01), and diaphragm strength (twitch transdiaphragmatic pressure in response to supramaximal cervical magnetic phrenic nerve stimulation) (p = 0.01). In patients with HFrEF, NYHA class and 6MWD were both inversely correlated with FVC, PI_max, and PE_max. In those with HFpEF, there was an inverse correlation between amino terminal pro B-type natriuretic peptide levels and FVC (r = −0.77, p = 0.04). In all HF patients, IL-6 and TNF-α were statistically related to FVC. Conclusions: Irrespective of left ventricular ejection fraction, HF is associated with respiratory muscle dysfunction, which is associated with increased levels of circulating IL-6 and TNF-α.

Ultrafast ultrasound coupled with cervical magnetic stimulation for non-invasive and non-volitional assessment of diaphragm contractility.

Twitch transdiaphragmatic pressure elicited by cervical magnetic stimulation of the phrenic nerves is a fully non-volitional method for assessing diaphragm contractility in humans, yet it requires invasive procedures such as oesophageal and gastric catheter balloons. Ultrafast ultrasound enables a very high frame rate allowing the capture of transient events, such as muscle contraction elicited by nerve stimulation (twitch). Whether indices derived from ultrafast ultrasound can be used as an alternative to the invasive measurement of twitch transdiaphragmatic pressure is unknown. Our findings demonstrate that maximal diaphragm tissue velocity assessed using ultrafast ultrasound following cervical magnetic stimulation is reliable, sensitive to change in cervical magnetic stimulation intensity, and correlates to twitch transdiaphragmatic pressure. This approach provides a novel fully non-invasive and non-volitional tool for the assessment of diaphragm contractility in humans. Measuring twitch transdiaphragmatic pressure (Pdi,tw ) elicited by cervical magnetic stimulation (CMS) is considered as a reference method for the standardized evaluation of diaphragm function. Yet, the measurement of Pdi requires invasive oesophageal and gastric catheter-balloons. Ultrafast ultrasound is a non-invasive imaging technique enabling frame rates high enough to capture transient events such as evoked muscle contractions. This study investigated relationships between indices derived from ultrafast ultrasound and Pdi,tw , and how these indices might be used to estimate Pdi,tw . CMS was performed in 13healthy volunteers from 30% to 100% of maximal stimulator intensity in units of 10% in a randomized order. Pdi,tw was measured and the right hemidiaphragm was imaged using a custom ultrafast ultrasound sequence with 1kHz framerate. Maximal diaphragm axial velocity (Vdi ,max ) and diaphragm thickening fraction (TFdi,tw ) were computed. Intra-session reliability was assessed. Repeated-measures correlation (R) and Spearman correlation coefficients (ρ) were used to assess relationships between variables. Intra-session reliability was strong for Pdi,tw and Vdi,max and moderate for TFdi,tw . Vdi,max correlated with Pdi,tw in all subjects (0.64<ρ<1.00, R=0.75; all P < 0.05). TFdi,tw correlated with Pdi,tw in eight subjects only (0.85<ρ<0.93, R=0.69; all P<0.05). Coupling ultrafast ultrasound and CMS shows promise for the non-invasive and fully non-volitional assessment of diaphragm contractility. This approach opens up the prospect of both diagnosis and follow-up of diaphragm contractility in clinical populations.

Inspiratory Muscle Fatigue Is Not Different In Response To Long Vs. Short-duration High-intensity Exercise

Maximal isokinetic power (PISO) at the limit of short duration (<6 min) high-intensity constant-power exercise (TlimSHORT) is not different from task power. Conversely, PISO at the limit of long duration (>7 min) high-intensity constant-power exercise (TlimLONG) exceeds task power. This suggests that while TlimSHORT is predominantly limited by locomotor neuromuscular fatigue, other physiological mechanisms contribute to exercise limitation in TlimLONG. One possibility for this difference in the mechanism of exercise intolerance is that the severity of exercise-induced inspiratory muscle fatigue is greater in TlimLONG vs. TlimSHORT due to a larger cumulative work of breathing in the longer-duration task. PURPOSE: To determine whether the magnitude of exercise-induced inspiratory muscle fatigue is greater in TlimLONG vs. TlimSHORT. METHODS: Ten healthy adults (3 females; 25 ± 3 yr) completed a maximal ramp-sprint test (RIT) to determine critical power (CP), V̇O2peak and peak ramp power (RITpeak). Maximal constant-power exercise was then performed at 1) 50% (TlimSHORT), and 2) 25 % (TlimLONG) of the difference between CP and RITpeak. PISO (6 s effort at 80 r/min) was measured at intolerance. Inspiratory muscle fatigue was assessed as the pre- to post-test reduction in magnetically evoked transdiaphragmatic (Pditw) twitch pressure. RESULTS: TlimLONG was longer than TlimSHORT (10.3 ± 2.6 vs. 5.2 ± 1.1 min; P < 0.001), but V̇O2peak was not different between tests (3.7 ± 0.8 vs. 3.7 ± 0.8 L/min; P > 0.05). PISO at intolerance was not different from task power in TlimSHORT (294 ± 101 vs. 241 ± 58 W; P = 0.11). Conversely, PISO at intolerance was greater than task power in TlimLONG (341 ± 106 vs. 215 ± 53 W; P = 0.008). Cumulative diaphragm pressure-time product was higher in TlimLONG vs. TlimSHORT (5945 ± 1956 vs. 2729 ± 1004 cmH2O/s; P < 0.001). Both TlimLONG and TlimSHORT induced a reduction in Pditw (-15 ± 13% vs. -19 ± 13%, respectively; P < 0.05). However, the magnitude of exercise-induced inspiratory muscle fatigue was not different between tests (P > 0.05). CONCLUSIONS: Despite PISO at intolerance being greater than task power in TlimLONG but not TlimSHORT, inspiratory muscle fatigue was not different between tests and therefore may not contribute to differences in exercise limitation in TlimLONG vs. TlimSHORT.

Inspiratory flow-resistive breathing, respiratory muscle-induced systemic oxidative stress, and diaphragm fatigue in healthy humans.

We questioned whether the respiratory muscles of humans contribute to systemic oxidative stress following inspiratory flow-resistive breathing, whether the amount of oxidative stress is influenced by the level of resistive load, and whether the amount of oxidative stress is related to the degree of diaphragm fatigue incurred. Eight young and healthy participants attended the laboratory for four visits on separate days. During the first visit, height, body mass, lung function, and maximal inspiratory mouth and transdiaphragmatic pressure (Pdimax) were assessed. During visits 2-4, participants undertook inspiratory flow-resistive breathing with either no resistance (control) or resistive loads equivalent to 50 and 70% of their Pdimax (Pdimax50% and Pdimax70%) for 30 min. Participants undertook one resistive load per visit, and the order in which they undertook the loads was randomized. Inspiratory muscle pressures were higher (P < 0.05) during the 5th and Final min of Pdimax50% and Pdimax70% compared with control. Plasma F2-isoprostanes increased (P < 0.05) following inspiratory flow-resistive breathing at Pdimax70%. There were no increases in plasma protein carbonyls or total antioxidant capacity. Furthermore, although we evidenced small reductions in transdiapragmaic twitch pressures (PdiTW) after inspiratory flow-resistive breathing at Pdimax50% and Pdimax70%, this was not related to the increase in plasma F2-isoprostanes. Our novel data suggest that it is only when sufficiently strenuous that inspiratory flow-resistive breathing in humans elicits systemic oxidative stress evidenced by elevated plasma F2-isoprostanes, and based on our data, this is not related to a reduction in PdiTW.NEW & NOTEWORTHY We examined whether the respiratory muscles of humans contribute to systemic oxidative stress following inspiratory flow-resistive breathing, whether the amount of oxidative stress is influenced by the level of resistive load, and whether the amount of oxidative stress is related to the degree of diaphragm fatigue incurred. It is only when sufficiently strenuous that inspiratory flow-resistive breathing elevates plasma F2-isoprostanes, and our novel data show that this is not related to a reduction in transdiaphragmatic twitch pressure.

ICU outcomes can be predicted by noninvasive muscle evaluation: a meta-analysis

The relationship between muscle function in critically ill patients assessed using bedside techniques and clinical outcomes has not been systematically described. We aimed to evaluate the association between muscle weakness assessed by bedside evaluation and mortality or weaning from mechanical ventilation, and the capacity of each evaluation tool to predict outcomes. Five databases (PubMed, Embase, CINAHL, Cochrane Library, Science Direct) were searched from January 2000 to December 2018. Data were extracted and random effects meta-analyses were performed. 60 studies were analysed, including 4382 patients. Intensive care unit (ICU)-related muscle weakness was associated with an increase in overall mortality with odds ratios ranging from 1.2 (95% CI 0.60-2.40) to 4.48 (95% CI 1.49-13.42). Transdiaphragmatic twitch pressure had the highest predictive capacity for overall mortality, with a sensitivity of 0.87 (95% CI 0.76-0.93) and a specificity of 0.36 (95% CI 0.27-0.43). The area under the curve (AUC) was 0.74 (95% CI 0.70-0.78). Muscle weakness was associated with an increase in mechanical ventilation weaning failure rate with an odds ratio ranging from 2.64 (95% CI 0.72-9.64) to 19.07 (95% CI 9.35-38.9). Diaphragm thickening fraction had the highest predictive capacity for weaning failure with a sensitivity of 0.76 (95% CI 0.67-0.83) and a specificity of 0.86 (95% CI 0.78-0.92). The AUC was 0.86 (95% CI 0.83-0.89). ICU-related muscle weakness detected by bedside techniques is a serious issue associated with a high risk of death or prolonged mechanical ventilation. Evaluating diaphragm function should be a clinical priority in the ICU.

Respiratory Muscle and Lung Function in Lung Allograft Recipients: Association with Exercise Intolerance

Background: In lung transplant recipients (LTRs), restrictive ventilation disorder may be present due to respiratory muscle dysfunction that may reduce exercise capacity. This might be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Objective: We investigated lung respiratory muscle function as well as circulating pro-inflammatory cytokines and exercise capacity in LTRs. Methods: Fifteen LTRs (6 female, age 56 ± 14 years, 63 ± 45 months post-transplantation) and 15 healthy controls matched for age, sex, and body mass index underwent spirometry, measurement of mouth occlusion pressures, diaphragm ultrasound, and recording of twitch transdiaphragmatic (twPdi) and gastric pressures (twPgas) following magnetic stimulation of the phrenic nerves and the lower thoracic nerve roots. Exercise capacity was quantified using the 6-min walking distance (6MWD). Plasma IL-6 and TNF-α were measured using enzyme-linked immunosorbent assays. Results: Compared with controls, patients had lower values for forced vital capacity (FVC; 81 ± 30 vs.109 ± 18% predicted, p = 0.01), maximum expiratory pressure (100 ± 21 vs.127 ± 17 cm H₂O, p = 0.04), diaphragm thickening ratio (2.2 ± 0.4 vs. 3.0 ± 1.1, p = 0.01), and twPdi (10.4 ± 3.5 vs. 17.6 ± 6.7 cm H₂O, p = 0.01). In LTRs, elevation of TNF-α was related to lung function (13 ± 3 vs. 11 ± 2 pg/mL in patients with FVC ≤80 vs. >80% predicted; p < 0.05), and lung function (forced expiratory volume after 1 s) was closely associated with diaphragm thickening ratio (r = 0.81; p < 0.01) and 6MWD (r = 0.63; p = 0.02). Conclusion: There is marked restrictive ventilation disorder and respiratory muscle weakness in LTRs, especially inspiratory muscle weakness with diaphragm dysfunction. Lung function impairment relates to elevated levels of circulating TNF-α and diaphragm dysfunction and is associated with exercise intolerance.

Characteristics of respiratory muscle involvement in myotonic dystrophy type 1

The pathophysiology of respiratory muscle weakness in myotonic dystrophy type 1 (DM1) remains incompletely understood. 21 adult patients with DM1 (11 men, 42 ± 13 years) and 21 healthy matched controls underwent spirometry, manometry, and diaphragm ultrasound. In addition, surface electromyography of the diaphragm and the obliquus abdominis muscle was performed following cortical and posterior cervical magnetic stimulation (CMS) of the phrenic nerves or magnetic stimulation of the lower thoracic nerve roots. Magnetic stimulation was combined with invasive recording of the twitch transdiaphragmatic and gastric pressure (twPdi and twPgas) in 10 subjects per group. The following parameters were reduced in DM1 patients compared to control subjects: maximum inspiratory pressure (MIP; 40.3 ± 19.2 vs. 95.8 ± 28.5 cmH2O, p < 0.01), diaphragm thickening ratio (DTR; 2.0 ± 0.4 vs. 2.7 ± 0.6, p < 0.01), twPdi following CMS (10.8 ± 8.3 vs. 21.4 ± 10.1 cmH2O, p = 0.03), and amplitude of diaphragm compound muscle action potentials (0.10 ± 0.25 vs. 0.46 ± 0.35 mV; p = 0.04). MIP and DTR were significantly correlated with the muscular impairment rating scale (MIRS) score. Maximum expiratory pressure (MEP) was reduced in DM1 patients compared to controls (41.3 ± 13.4 vs. 133.8 ± 28.0 cmH2O, p < 0.01) and showed negative correlation with the MIRS score. Pgas following a maximum cough was markedly lower in patients than in controls (71.9 ± 43.2 vs. 102.4 ± 35.5 cmH2O) but without statistical significance (p = 0.06). In DM1, respiratory muscle weakness relates to clinical disease severity and involves inspiratory and probably expiratory muscle strength. Axonal phrenic nerve pathology may contribute to diaphragm dysfunction.

Respiratory muscle weakness in facioscapulohumeral muscular dystrophy.

The purpose of this study was to comprehensively evaluate respiratory muscle function in adults with facioscapulohumeral muscular dystrophy (FSHD). Fourteen patients with FSHD (9 men, 53 ± 16 years of age) and 14 matched controls underwent spirometry, diaphragm ultrasound, and measurement of twitch gastric and transdiaphragmatic pressures (twPgas and twPdi; n = 10) after magnetic stimulation of the lower thoracic nerve roots and the phrenic nerves. The latter was combined with recording of diaphragm compound muscle action potentials (CMAPs; n = 14). The following parameters were significantly lower in patients vs controls: forced vital capacity (FVC); maximum inspiratory and expiratory pressure; peak cough flow; diaphragm excursion amplitude; and thickening ratio on ultrasound, twPdi (11 ± 5 vs 20 ± 6 cmH2 O) and twPgas (7 ± 3 vs 25 ± 20 cmH2 O). Diaphragm CMAP showed no group differences. FVC correlated inversely with the clinical severity scale score (r = -0.63, P = .02). In FSHD, respiratory muscle weakness involves both the diaphragm and the expiratory abdominal muscles.

Noninvasive Prediction of Twitch Transdiaphragmatic Pressure: Insights from Spirometry, Diaphragm Ultrasound, and Phrenic Nerve Stimulation Studies

Background: Twitch transdiaphragmatic pressure (twPdi) following magnetic stimulation (MS) of the phrenic nerves is the gold standard for non-volitional assessment of diaphragm strength. Expiratory muscle function can be investigated using MS of the abdominal muscles and measurement of twitch gastric pressure (twPgas). Objectives: To investigate whether twitch pressures following MS of the phrenic and lower thoracic nerve roots can be predicted noninvasively by diaphragm ultrasound parameters and volitional tests of respiratory muscle strength. Methods: Sixty-three healthy subjects underwent standard spirometry, measurement of maximum inspiratory (PI_max) and expiratory pressure (PE_max), and diaphragm ultrasound. TwPdi following cervical MS of the phrenic nerve roots and twPgas after lower thoracic MS (twPgas-Thor) were measured using esophageal and gastric balloon catheters inserted transnasally. Using surface electrodes, compound muscle action potentials (CMAP) were simultaneously recorded from the diaphragm or obliquus abdominis muscles, respectively. Results: Forced expiratory flow (FEF_25–75) was significantly correlated with twPdi (r = 0.37; p = 0.003) and its components (twPgas and twitch esophageal pressure, twPes). Diaphragm excursion velocity during tidal breathing was correlated to twPes (r = 0.44; p = 0.02). No prediction of twitch pressures was possible from CMAP amplitude, forced vital capacity (FVC), or PI_max. TwPgas-Thor was correlated with FEF_25–75 (r = 0.46; p = 0.05) and diaphragm thickness at total lung capacity (r = 0.38; p = 0.04) but could not be predicted from CMAP amplitude, FVC, or PE_max. Conclusions: TwPdi and twPgas-Thor cannot be predicted from volitional measures of respiratory muscle strength, diaphragm and abdominal CMAP, or diaphragm ultrasound. Invasive recording of esophageal and gastric pressures following MS remains indispensable for objective assessment of respiratory muscle strength.

Assessment of Central Drive to the Diaphragm by Twitch Interpolation: Normal Values, Theoretical Considerations, and Future Directions

Background: The twitch interpolation technique is a promising tool for assessing central drive to the diaphragm. It is used to quantify the degree of voluntary diaphragm activation during predefined breathing maneuvers. Objectives: This study was designed to (a) determine reference values for the level of voluntary activation of the diaphragm using the twitch occlusion technique in healthy adults and (b) explore the association between central drive to the diaphragm and volitional tests of respiratory muscle strength. Methods: Twenty-seven healthy volunteers aged 26 ± 14 years (18 male) were enrolled. Twitch transdiaphragmatic pressure (Pdi) was determined at relaxed functional residual capacity in response to cervical magnetic stimulation (CMS) of the phrenic nerves. The subjects were then instructed to gradually increase voluntary activation of the diaphragm, and the effects of superimposed magnetic stimuli on voluntary Pdi were assessed. Results: The twitch Pdi amplitude following CMS linearly decreased with increasing inspiratory effort. The resulting diaphragm voluntary activation index (DVAI) during maximal voluntary contraction was 75 ± 15% irrespective of gender or age. Twitch duration, half relaxation time, and area under the curve of superimposed Pdi deflections did not show a linear but an exponential association with increasing voluntary activation of the diaphragm. More than 2/3 of the decrease in the above values was evident after 1/3 of voluntary diaphragm contraction. Forced vital capacity (FVC) was inversely correlated with the DVAI. Conclusions: Twitch interpolation allows for assessment of central drive to the diaphragm. The maximum DVAI is independent of gender or age, and significantly related to FVC but not to maximum inspiratory pressure or Pdi as direct measures of diaphragm strength.

The nature of respiratory muscle weakness in patients with late-onset Pompe disease

Late-onset Pompe disease (LOPD) causes myopathy of skeletal and respiratory muscles, and phrenic nerve pathology putatively contributes to diaphragm weakness. The aim of this study was to investigate neural contributions to diaphragm dysfunction, usefulness of diaphragm ultrasound, and involvement of expiratory abdominal muscles in LOPD. Thirteen patients with LOPD (7 male, 51±17 years) and 13 age- and gender-matched controls underwent respiratory muscle strength testing, ultrasound evaluation of diaphragm excursion and thickness, cortical and cervical magnetic stimulation (MS) of the diaphragm with simultaneous recording of surface electromyogram and twitch transdiaphragmatic pressure (twPdi; n = 6), and MS of the abdominal muscles with recording of twitch gastric pressure (twPgas; n = 6). The following parameters were significantly reduced in LOPD patients versus controls: forced vital capacity (p<0.01), maximum inspiratory and expiratory pressure (both p<0.001), diaphragm excursion velocity (p<0.05), diaphragm thickening ratio (1.8 ± 0.4 vs. 2.6 ± 0.6, p<0.01), twPdi following cervical MS (12.0 ± 6.2 vs. 19.4 ± 4.8 cmH2O, p<0.05), and twPgas following abdominal muscle stimulation (8.8 ± 8.1 vs. 34.6 ± 17.1 cmH2O, p<0.01). Diaphragm motor evoked potentials and compound muscle action potentials showed no between-group differences. In conclusion, phrenic nerve involvement in LOPD could not be electrophysiologically confirmed. Ultrasound supports assessment of diaphragm function. Abdominal expiratory muscles are functionally involved in LOPD.

Transdiapragmatic pressure and contractile properties of the diaphragm following magnetic stimulation

Insufficient normal values exist regarding twitch transdiaphragmatic pressure (twPdi) derived from standardized cervical and cortical magnetic stimulation (MS) of the diaphragm.Therefore, 63 subjects (24 men, 39 women; 34 ± 13 years) underwent transcortical and posterior cervical MS of the diaphragm with simultaneous recording of twitch oesophageal and gastric pressures (twPes, twPgas).Following cortical MS at functional residual capacity, twPdi amplitudes showed high intra-individual variability which was markedly reduced when an inspiratory pressure trigger was applied. Lower limit of the 95% confidence interval computed around the mean value (LLN) was 12 cmH2O, independent of gender or age. Following cervical MS of the phrenic nerves, twPdi amplitudes were well reproducible and unaffected by gender, but age-dependent (age 18–30: LLN 23 cmH2O; age ≥ 30: LLN 16 cmH2O; p < 0.05).The inspiratory pathway can be assessed using cervical MS of the phrenic nerves. If transcranial motor cortex stimulation of the diaphragm is also applied, a standardized inspiratory pressure trigger is recommended. Dynamics of diaphragm contraction appear to be age-dependent.

Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures.

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function.

Effect of diaphragm fatigue on subsequent exercise tolerance in healthy men and women.

Women are more resistant to diaphragmatic fatigue (DF) and experience an attenuated inspiratory muscle metaboreflex relative to men. The effects of such sex-based differences on whole body exercise tolerance are yet to be examined. It was hypothesized that DF induced prior to exercise would cause less of a reduction in subsequent exercise time in women compared to men. Healthy men ( n = 9, age = 24 ± 3 yr) and women ( n = 9, age = 24 ± 3 yr) completed a maximal incremental cycle test on day 1. On day 2, subjects performed isocapnic inspiratory pressure-threshold loading (PTL) to task failure followed by a constant load submaximal time-to-exhaustion (TTE) exercise test at 85% of the predetermined peak work rate. On day 3, subjects performed the same exercise test without prior induced DF. Days 2 and 3 were randomized and counterbalanced. Magnetic stimulation of the phrenic nerve roots was used to nonvolitionally assess DF by measurement of transdiaphragmatic twitch pressure ( Pdi,tw). A similar degree of DF was produced in both sexes following PTL [ Pdi,tw (% change from baseline): M = -24.6 ± 7.8%, W = -23.1 ± 5.4%; P = 0.54)]. There was a significant reduction in TTE with prior induced DF compared with the control condition in both men (10.9 ± 3.5 min vs. 13.0 ± 3.2 min, P = 0.05) and women (10.1 ± 2.4 min vs. 12.2 ± 3.3 min, P = 0.03) that did not differ in magnitude between the sexes (M = -15.8 ± 19.5%, W = -14.5 ± 19.2%, P = 0.89). In conclusion, DF negatively and equally impairs exercise tolerance independent of sex. NEW & NOTEWORTHY Women are more resistant to diaphragmatic fatigue (DF) relative to men. The effect of DF on exercise tolerance is currently being debated. Our findings show that DF negatively and equally affects exercise tolerance in healthy men and women. Mechanisms beyond the inspiratory muscle metaboreflex (e.g., dyspnea, central fatigue, breathing pattern) may explain the absence of a sex-based difference.