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Background: In mechanically ventilated patients, diaphragm ultrasound can identify diaphragm weakness and predict weaning failure. We evaluated whether a novel operator-independent ultrasound-based medical device allowing continuous monitoring of the diaphragm (CUSdi) could reliably (1) measure diaphragm excursion (EXdi) and peak contraction velocity (PCVdi), (2) predict weaning outcome, and (3) approximate transdiaphragmatic pressure (Pdi)., Methods: In 49 mechanically ventilated patients, CUSdi was recorded during a 30-min spontaneous breathing trial (SBT), and EXdi and PCVdi were measured. In subgroups of patients, standard ultrasound measurement of EXdi and PCVdi was performed (n = 36), and Pdi derived parameters (peak and pressure time product, n = 30) were measured simultaneously., Results: The agreement bias between standard ultrasound and CUSdi for EXdi was 0.1 cm (95% confidence interval -0.7-0.9 cm). The regression of Passing-Bablok indicated a lack of systematic difference between EXdi measured with standard ultrasound and CUSdi, which were positively correlated (Rho = 0.84, p < 0.001). Weaning failure was observed in 54% of patients. One, two and three minutes after the onset of the SBT, EXdi was higher in the weaning success group than in the failure group. Two minutes after the onset of the SBT, an EXdi < 1.1 cm predicted weaning failure with a sensitivity of 0.83, a specificity of 0.68, a positive predictive value of 0.76, and a negative predictive value of 0.24. There was a weak correlation between EXdi and both peak Pdi (r = 0.22, 95% confidence interval 0.15 - 0.28) and pressure time product (r = 0.13, 95% confidence interval 0.06 - 0.20). Similar results were observed with PCVdi., Conclusions: Operator-independent continuous diaphragm monitoring quantifies EXdi reliably and can predict weaning failure with an identified cut-off value of 1.1 cm. Trial registration clinicaltrial.gov, NCT04008875 (submitted 12 April 2019, posted 5 July 2019) and NCT03896048 (submitted 27 March 2019, posted 29 March 2019)., (© 2024. The Author(s).)

Diaphragm neurostimulation consists of placing electrodes directly on or in proximity to the phrenic nerve(s) to elicit diaphragmatic contractions. Since its initial description in the 18th century, indications have shifted from cardiopulmonary resuscitation to long-term ventilatory support. Recently, the technical development of devices for temporary diaphragm neurostimulation has opened up the possibility of a new era for the management of mechanically ventilated patients. Combining positive pressure ventilation with diaphragm neurostimulation offers a potentially promising new approach to the delivery of mechanical ventilation which may benefit multiple organ systems. Maintaining diaphragm contractions during ventilation may attenuate diaphragm atrophy and accelerate weaning from mechanical ventilation. Preventing atelectasis and preserving lung volume can reduce lung stress and strain and improve homogeneity of ventilation, potentially mitigating ventilator-induced lung injury. Furthermore, restoring the thoracoabdominal pressure gradient generated by diaphragm contractions may attenuate the drop in cardiac output induced by positive pressure ventilation. Experimental evidence suggests diaphragm neurostimulation may prevent neuroinflammation associated with mechanical ventilation. This review describes the historical development and evolving approaches to diaphragm neurostimulation during mechanical ventilation and surveys the potential mechanisms of benefit. The review proposes a research agenda and offers perspectives for the future of diaphragm neurostimulation assisted mechanical ventilation for critically ill patients.

Rationale: Diaphragm dysfunction is frequently observed in critically ill patients with difficult weaning from mechanical ventilation. Objectives: To evaluate the effects of temporary transvenous diaphragm neurostimulation on weaning outcome and maximal inspiratory pressure. Methods: Multicenter, open-label, randomized, controlled study. Patients aged ⩾18 years on invasive mechanical ventilation for ⩾4 days and having failed at least two weaning attempts received temporary transvenous diaphragm neurostimulation using a multielectrode stimulating central venous catheter (bilateral phrenic stimulation) and standard of care (treatment) ( n  = 57) or standard of care (control) ( n  = 55). In seven patients, the catheter could not be inserted, and in seven others, pacing therapy could not be delivered; consequently, data were available for 43 patients. The primary outcome was the proportion of patients successfully weaned. Other endpoints were mechanical ventilation duration, 30-day survival, maximal inspiratory pressure, diaphragm-thickening fraction, adverse events, and stimulation-related pain. Measurements and Main Results: The incidences of successful weaning were 82% (treatment) and 74% (control) (absolute difference [95% confidence interval (CI)], 7% [-10 to 25]), P  = 0.59. Mechanical ventilation duration (mean ± SD) was 12.7 ± 9.9 days and 14.1 ± 10.8 days, respectively, P  = 0.50; maximal inspiratory pressure increased by 16.6 cm H 2 O and 4.8 cm H 2 O, respectively (difference [95% CI], 11.8 [5 to 19]), P  = 0.001; and right hemidiaphragm thickening fraction during unassisted spontaneous breathing was +17% and -14%, respectively, P  = 0.006, without correlation with changes in maximal inspiratory pressure. Serious adverse event frequency was similar in both groups. Median stimulation-related pain in the treatment group was 0 (no pain). Conclusions: Temporary transvenous diaphragm neurostimulation did not increase the proportion of successful weaning from mechanical ventilation. It was associated with a significant increase in maximal inspiratory pressure, suggesting reversal of the course of diaphragm dysfunction. Clinical trial registered with www.clinicaltrials.gov (NCT03096639) and the European Database on Medical Devices (CIV-17-06-020004).

Background: Diaphragm pacing allows certain ventilator-dependent patients to achieve weaning from mechanical ventilation. The reference method consists in implanting intrathoracic contact electrodes around the phrenic nerve during video-assisted thoracic surgery, which involves time-consuming phrenic nerve dissection with a risk of nerve damage. Identifying a phrenic segment suitable for dissection-free implantation of electrodes would constitute progress., Study Design: This study characterizes a free terminal phrenic segment never fully described before. We conducted a cadaver study (n = 14) and a clinical observational study during thoracic procedures (n = 54)., Results: A free terminal phrenic segment was observed on both sides in 100% of cases, "jumping" from the pericardium to the diaphragm and measuring 60 mm [95% confidence interval; 48-63] and 72.5 mm [65-82] (right left, respectively; p = 0.0038; cadaver study). This segment rolled up on itself at end-expiration and became unravelled and elongated with diaphragm descent (clinical study). Three categories of fat pads were defined (type 1: pericardiophrenic bundle free of surrounding fat; type 2: single fatty fringe leaving the phrenic nerve visible until diaphragmatic entry; type 3: multiple fatty fringes masking the site of penetration of the phrenic nerve) that depended on body mass index (p = 0.001, clinical study). Hematoxylin-eosin and toluidine blue staining (cadaver study) showed that all of the phrenic fibers in the distal, pre-branching part of the terminal segment were contained within a single epineurium containing a variable number of fascicles (right: 1 [95%CI 0.65-4.01]; left 5 [3.37-7.63]; p = 0.03)., Conclusion: Diaphragm pacing through periphrenic electrodes positioned on the terminal phrenic segment should be tested., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Key Points: 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., Abstract: Measuring twitch transdiaphragmatic pressure (P di,tw ) elicited by cervical magnetic stimulation (CMS) is considered as a reference method for the standardized evaluation of diaphragm function. Yet, the measurement of P di 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 P di,tw , and how these indices might be used to estimate P di,tw . CMS was performed in 13 healthy volunteers from 30% to 100% of maximal stimulator intensity in units of 10% in a randomized order. P di,tw was measured and the right hemidiaphragm was imaged using a custom ultrafast ultrasound sequence with 1 kHz framerate. Maximal diaphragm axial velocity (V di , max ) and diaphragm thickening fraction (TF di,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 P di,tw and V di,max and moderate for TF di,tw . V di,max correlated with P di,tw in all subjects (0.64 < ρ < 1.00, R = 0.75; all P < 0.05). TF di,tw correlated with P di,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., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Background: Diaphragm dysfunction is highly prevalent in mechanically ventilated patients. Recent work showed that changes in diaphragm shear modulus (ΔSMdi) assessed using ultrasound shear wave elastography (SWE) are strongly related to changes in Pdi (ΔPdi) in healthy subjects. The aims of this study were to investigate the relationship between ΔSMdi and ΔPdi in mechanically ventilated patients, and whether ΔSMdi is responsive to change in respiratory load when varying the ventilator settings., Methods: A prospective, monocentric study was conducted in a 15-bed ICU. Patients were included if they met the readiness-to-wean criteria. Pdi was continuously monitored using a double-balloon feeding catheter orally introduced. The zone of apposition of the right hemidiaphragm was imaged using a linear transducer (SL10-2, Aixplorer, Supersonic Imagine, France). Ultrasound recordings were performed under various pressure support settings and during a spontaneous breathing trial (SBT). A breath-by-breath analysis was performed, allowing the direct comparison between ΔPdi and ΔSMdi. Pearson's correlation coefficients (r) were used to investigate within-individual relationships between variables, and repeated measure correlations (R) were used for determining overall relationships between variables. Linear mixed models were used to compare breathing indices across the conditions of ventilation., Results: Thirty patients were included and 930 respiratory cycles were analyzed. Twenty-five were considered for the analysis. A significant correlation was found between ΔPdi and ΔSMdi (R = 0.45, 95% CIs [0.35 0.54], p < 0.001). Individual correlation displays a significant correlation in 8 patients out of 25 (r = 0.55-0.86, all p < 0.05, versus r = - 0.43-0.52, all p > 0.06). Changing the condition of ventilation similarly affected ΔPdi and ΔSMdi. Patients in which ΔPdi-ΔSMdi correlation was non-significant had a faster respiratory rate as compared to that of patient with a significant ΔPdi-ΔSMdi relationship (median (Q1-Q3), 25 (18-33) vs. 21 (15-26) breaths.min -1 , respectively)., Conclusions: We demonstrate that ultrasound SWE may be a promising surrogate to Pdi in mechanically ventilated patients. Respiratory rate appears to negatively impact SMdi measurement. Technological developments are needed to generalize this method in tachypneic patients., Trial Registration: NCT03832231 .

Background: The assessment of diaphragm function with diaphragm ultrasound seems to bring important clinical information to describe diaphragm work and weakness. When the diaphragm is weak, extradiaphragmatic muscles may play an important role, but whether ultrasound can also assess their activity and function is unknown. This study aimed to (1) evaluate the feasibility of measuring the thickening of the parasternal intercostal and investigate the responsiveness of this muscle to assisted ventilation; and (2) evaluate whether a combined evaluation of the parasternal and the diaphragm could predict failure of a spontaneous breathing trial., Methods: First, an exploratory evaluation of the parasternal in 23 healthy subjects. Second, the responsiveness of parasternal to several pressure support levels were studied in 16 patients. Last, parasternal activity was compared in presence or absence of diaphragm dysfunction (assessed by magnetic stimulation of the phrenic nerves and ultrasound) and in case of success/failure of a spontaneous breathing trial in 54 patients., Results: The parasternal was easily accessible in all patients. The interobserver reproducibility was good (intraclass correlation coefficient, 0.77 (95% CI, 0.53 to 0.89). There was a progressive decrease in parasternal muscle thickening fraction with increasing levels of pressure support (Spearman ρ = -0.61 [95% CI, -0.74 to -0.44]; P < 0.0001) and an inverse correlation between parasternal muscle thickening fraction and the pressure generating capacity of the diaphragm (Spearman ρ = -0.79 [95% CI, -0.87 to -0.66]; P < 0.0001). The parasternal muscle thickening fraction was higher in patients with diaphragm dysfunction: 17% (10 to 25) versus 5% (3 to 8), P < 0.0001. The pressure generating capacity of the diaphragm, the diaphragm thickening fraction and the parasternal thickening fraction similarly predicted failure or the spontaneous breathing trial., Conclusions: Ultrasound assessment of the parasternal intercostal muscle is feasible in the intensive care unit and provides novel information regarding the respiratory capacity load balance.

Rationale: Sleep deprivation can alter endurance of skeletal muscles, but its impact on respiratory command is unknown. Objectives: We aimed to assess the effect of sleep deprivation on respiratory motor output and inspiratory endurance. Methods: Inspiratory endurance was investigated twice in random order, following a normal sleep night and a sleepless night. Healthy participants were asked to breathe as long as possible until task failure against a moderate inspiratory threshold constraint. Transdiaphragmatic pressure and diaphragm electrical activity were measured throughout the trial to assess pressure output of the diaphragm and overall respiratory motor output. Cortical contribution to respiratory motor output was assessed by measurement of preinspiratory motor potential amplitude and by cervical magnetic simulation. Measurements and Main Results: Twenty healthy male participants were studied. Time to task failure was significantly shorter after sleep deprivation than after normal sleep: (30 min [interquartile range [IQR], 17-41] vs. 60 min [IQR, 45-60], P  = 0.002). At the beginning of the trial, preinspiratory motor potential amplitude was significantly lower in the sleep-deprivation condition (4.5 μV [IQR, 2.5-6.4] vs. 7.3 μV [IQR, 4.3-10.4], P  = 0.02) and correlated significantly with the duration of the endurance trial. In the sleep-deprivation condition, preinspiratory motor potential amplitude, electrical activity of the diaphragm, pressure output of the diaphragm, and Vt decreased and the respiratory rate increased significantly from the beginning to the end of the trial. Such decreases did not occur in the normal-sleep condition. Conclusions: One night of sleep deprivation reduces respiratory motor output by altering its cortical component with subsequent reduction of inspiratory endurance by half. These results suggest that altered sleep triggers severe brain dysfunctions that could precipitate respiratory failure.

Background: Intensive care unit (ICU)-acquired weakness (ICU-AW) and ICU-acquired diaphragm dysfunction (ICU-DD) occur frequently in mechanically ventilated (MV) patients. It is unknown whether they have different risk factors and different impacts on outcome. This study was designed to (1) describe the respective risk factors associated with ICU-AW and severe ICU-DD and (2) evaluate the respective impact of ICU-AW and severe ICU-DD on outcome., Methods: Post hoc analysis of two prospective cohort studies conducted in two ICUs. In patients mechanically ventilated for at least 24 h undergoing a first spontaneous breathing trial, severe ICU-DD was defined as diaphragm twitch pressure < 7 cmH 2 O and ICU-AW was defined as Medical Research Council Score < 48., Results: One hundred sixteen patients were assessed. Factors independently associated with severe ICU-DD were age, longer duration of MV, and exposure to sufentanil, and those factors associated with ICU-AW were longer duration of MV and exposure to norepinephrine. Severe ICU-DD (OR 3.56, p = 0.008), but not ICU-AW, was independently associated with weaning failure (59%). ICU-AW (OR 4.30, p = 0.033), but not severe ICU-DD, was associated with ICU mortality. Weaning failure and mortality rate were higher in patients with both severe ICU-DD and ICU-AW (86% and 39%, respectively) than in patients with either severe ICU-DD (64% and 0%) or ICU-AW (63% and 13%)., Conclusion: Severe ICU-DD and ICU-AW have different risk factors and different impacts on weaning failure and mortality. The impact of the combination of ICU-DD and ICU-AW is more pronounced than their individual impact.

The reference method for the assessment of diaphragm function relies on the measurement of transdiaphragmatic pressure (Pdi). Local muscle stiffness measured using ultrafast shear wave elastography (SWE) provides reliable estimates of muscle force in locomotor muscles. This study aimed at investigating whether SWE could be used as a surrogate of Pdi to evaluate diaphragm function. Fifteen healthy volunteers underwent a randomized stepwise inspiratory loading protocol of 0-60% of maximal isovolumetric inspiratory pressure during closed-airways maneuvers and 0-50% during ventilation against an external inspiratory threshold load. During all tasks, Pdi was measured and SWE was used to assess shear modulus of the right hemidiaphragm (SMdi) at the zone of apposition. Pearson correlation coefficients ( r) and repeated-measures correlation coefficients ( R) were computed to determine within-individual and overall relationships between Pdi and SMdi, respectively. During closed-airways maneuvers, mean Pdi correlated to mean SMdi in all participants [ r ranged from 0.77 to 0.96, all P < 0.01; R = 0.82, 95% confidence intervals (0.76, 0.86), P < 0.01]. During ventilation against inspiratory threshold loading, Pdi swing correlated to maximal SMdi in all participants [ r ranged from 0.40 to 0.90, all P < 0.01; R = 0.70, 95% confidence intervals (0.66, 0.73), P < 0.001]. Changes in diaphragm stiffness as assessed by SWE reflect changes in transdiaphragmatic pressure. SWE provides a new opportunity for direct and noninvasive assessment of diaphragm function. NEW & NOTEWORTHY Accurate and specific estimation of diaphragm effort is critical for evaluating and monitoring diaphragm dysfunction. The measurement of transdiaphragmatic pressure requires the use of invasive gastric and esophageal probes. In the present work, we demonstrate that changes in diaphragm stiffness assessed with ultrasound shear wave elastography reflect changes in transdiaphragmatic pressure, therefore offering a new noninvasive method for gauging diaphragm effort.

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., Competing Interests: Conflict of interest: R. Guimarães-Costa has nothing to disclose. Conflict of interest: T. Similowski reports personal fees from AstraZeneca, Boerhinger Ingelheim France, GSK Lungpacer Inc., TEVA, Chiesi, Pierre Fabre and Invacare, and personal fees and non-financial support from Novartis, outside the submitted work. In addition, he received honoraria from Synapse Biomedical to translate the DPS/NeurRx4 user manual from English into French in 2007 and, from 2012 to 2016, Synapse Biomedical contributed to a fundraiser organised by T. Similowski to promote respiratory research. T. Similowski is also engaged in scientific collaborations with two other companies manufacturing phrenic stimulation devices. With Lungpacer Inc (Canada) he acts as a paid consultant and investigator in clinical trials, while with Atrotech-Neuroresp (France) he acts as a probono consultant (no fees or other support). Conflict of interest: I. Rivals has nothing to disclose. Conflict of interest: C. Morélot-Panzini has nothing to disclose. Conflict of interest: M-C. Nierat has nothing to disclose Conflict of interest: M.T. Bui has nothing to disclose. Conflict of interest: D. Akbar has nothing to disclose. Conflict of interest: C. Straus has nothing to disclose. Conflict of interest: N.B. Romero has nothing to disclose. Conflict of interest: P.P. Michel has nothing to disclose. Conflict of interest: F. Menegaux has nothing to disclose. Conflict of interest: F. Salachas has nothing to disclose. Conflict of interest: J. Gonzalez-Bermejo has nothing to disclose. Conflict of interest: G. Bruneteau has nothing to disclose., (Copyright ©ERS 2019.)

Background: Mechanical ventilation (MV) is a life-saving technology that restores or assists breathing. Like any treatment, MV has side effects. In some patients it can cause diaphragmatic atrophy, injury, and dysfunction (ventilator-induced diaphragmatic dysfunction, VIDD). Accumulating evidence suggests that VIDD makes weaning from MV difficult, which involves increased morbidity and mortality., Methods and Analysis: This paper describes the protocol of a randomized, controlled, open-label, multicenter trial that is designed to investigate the safety and effectiveness of a novel therapy, temporary transvenous diaphragm pacing (TTVDP), to improve weaning from MV in up to 88 mechanically ventilated adult patients who have failed at least two spontaneous breathing trials over at least 7 days. Patients will be randomized (1:1) to TTVDP (treatment) or standard of care (control) groups. The primary efficacy endpoint is time to successful extubation with no reintubation within 48 h. Secondary endpoints include maximal inspiratory pressure and ultrasound-measured changes in diaphragm thickness and diaphragm thickening fraction over time. In addition, observational data will be collected and analyzed, including 30-day mortality and time to discharge from the intensive care unit and from the hospital. The hypothesis to be tested postulates that more TTVDP patients than control patients will be successfully weaned from MV within the 30 days following randomization., Discussion: This study is the first large-scale clinical trial of a novel technology (TTVDP) aimed at accelerating difficult weaning from MV. The technology tested provides the first therapy directed specifically at VIDD, an important cause of delayed weaning from MV. Its results will help delineate the place of this therapeutic approach in clinical practice and help design future studies aimed at defining the indications and benefits of TTVDP., Trial Registration: ClinicalTrials.gov, NCT03096639 . Registered on 30 March 2017.

Background: Short-term mechanical ventilation (MV) protects against sepsis-induced diaphragmatic dysfunction. Prolonged MV induces diaphragmatic dysfunction in non-septic animals, but few reports describe the effects of prolonged MV in sepsis. We hypothesized that prolonged MV is not protective but worsens the diaphragmatic dysfunction induced by a mild sepsis, because MV and sepsis share key signaling mechanisms, such as cytokine upregulation., Method: We studied the impact of prolonged MV (12 h) in four groups (n = 8) of male Wistar rats: 1) endotoxemia induced by intraperitoneal injection of Escherichia coli lipopolysaccharide, 2) MV without endotoxemia, 3) combination of endotoxemia and MV and 4) sham control. Diaphragm mechanical performance, pro-inflammatory cytokine concentrations (Tumor Necrosis Factor-α, Interleukin-1β, Interleukin-6) in plasma were measured., Results: Prolonged MV and sepsis independtly reduced maximum diaphragm force (-27%, P = 0.003; -37%, P<0.001; respectively). MV and sepsis acted additively to further decrease diaphragm force (-62%, P<0.001). Similar results were observed for diaphragm kinetics (maximum lengthening velocity -47%, P<0.001). Sepsis and MV reduced diaphragm cross sectional area of type I and IIx fibers, which was further increased by the combination of sepsis and MV (all P<0.05). Sepsis and MV were individually associated with the presence of a robust perimysial inflammatory infiltrate, which was more marked when sepsis and MV were both present (all P<0.05). Sepsis and, to a lesser extent, MV increased proinflammatory cytokine production in plasma and diaphragm (all P<0.05); proinflammatory cytokine expression in plasma was increased further by the combination of sepsis and MV (all P<0.05). Maximum diaphragm force correlated negatively with plasma and diaphragmatic cytokine production (all p<0.05)., Conclusions: Prolonged (12 h) MV exacerbated sepsis-induced decrease in diaphragm performance. Systemic and diaphragmatic overproduction of pro-inflammatory cytokines may contribute to diaphragm weakness., Competing Interests: Alexandre Demoule reports personal fees from Maquet, grants, personal fees and non-financial support from Covidien, personal fees from MSD, grants and non-financial support from Philips, non-financial support from Drager, grants and personal fees from Resmed, personal fees from fisher & Paykel, all outside the submitted work. This does not alter his adherence to PLOS ONE policies on sharing data and materials. The other authors declare no competing interest.

Rationale: In intensive care unit (ICU) patients, diaphragm dysfunction is associated with adverse clinical outcomes. Ultrasound measurements of diaphragm thickness, excursion (EXdi) and thickening fraction (TFdi) are putative estimators of diaphragm function, but have never been compared with phrenic nerve stimulation. Our aim was to describe the relationship between these variables and diaphragm function evaluated using the change in endotracheal pressure after phrenic nerve stimulation (Ptr,stim), and to compare their prognostic value., Methods: Between November 2014 and June 2015, Ptr,stim and ultrasound variables were measured in mechanically ventilated patients <24 hours after intubation ('initiation of mechanical ventilation (MV)', under assist-control ventilation, ACV) and at the time of switch to pressure support ventilation ('switch to PSV'), and compared using Spearman's correlation and receiver operating characteristic curve analysis. Diaphragm dysfunction was defined as Ptr,stim <11 cm H 2 O., Results: 112 patients were included. At initiation of MV, Ptr,stim was not correlated to diaphragm thickness (p=0.28), EXdi (p=0.66) or TFdi (p=0.80). At switch to PSV, TFdi and EXdi were respectively very strongly and moderately correlated to Ptr,stim, (r=0.87, p<0.001 and 0.45, p=0.001), but diaphragm thickness was not (p=0.45). A TFdi <29% could reliably identify diaphragm dysfunction (sensitivity and specificity of 85% and 88%), but diaphragm thickness and EXdi could not. This value was associated with increased duration of ICU stay and MV, and mortality., Conclusions: Under ACV, diaphragm thickness, EXdi and TFdi were uncorrelated to Ptr,stim. Under PSV, TFdi was strongly correlated to diaphragm strength and both were predictors of remaining length of MV and ICU and hospital death., Competing Interests: Competing interests: B-PD has received honoraria from GlaxoSmithKline, Boehringer Ingelheim, Astra Zeneca and Roche. AD has signed research contracts with Covidien, Maquet and Philips; he has also received personal fees from Covidien and MSD. MD received personal fees from Pulsion Medical System and Astra Zeneca. Relevant to the present study, TS has received personal fees from Lungpacer and is a member of the board of a research association that has received, over the past 10 years, unrestricted research grants from Maquet, Hamilton, Covidien and Philips; he is the head of a research unit (UMRS 1158) that has signed research contracts with Air Liquide Medical Systems, France; he is listed as inventor or co-inventor on several patents, granted or pending, describing a brain-ventilator interface., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Positive pressure ventilation (PPV) is a fundamental life support measure, but it decreases cardiac output (CO). Diaphragmatic contractions produce negative intrathoracic and positive abdominal pressures, promoting splanchnic venous return. We hypothesized that: 1) diaphragm pacing alone could produce adequate ventilation without decreasing CO; 2) diaphragm pacing on top of PPV could improve CO. Of 11 anesthetized and mechanically ventilated ewes (39.6±5.9kg), 3 were discarded from analysis because of hemodynamic instability during the experiment, and 8 retained for analysis. Phrenic stimulation electrodes were inserted in the diaphragm (implanted phrenic nerve stimulation, iPS). CO was measured by the thermodilution technique (pulmonary artery catheter). CO during end-expiratory apnea served as reference. Median CO was 9.77 [6.25-11.25] lmin -1 during end-expiratory apnea, 8.25 [5.06-9.25] lmin -1 during "PPV" (-15%) (p<0.05), 9.19 [5.60-10.19] lmin -1 during "PPV-iPS" (NS vs apnea) and 9.37 [6.12-10.48] lmin -1 during "iPS" (NS vs. apnea). iPS-driven ventilation was comparable to its PPV counterpart (median 92% [74-97], NS). Diaphragm pacing alone can produce adequate ventilation without reducing CO. Superimposed onto PPV, diaphragm pacing can reduce the PPV-induced decrease in CO., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Rationale: Intensive care unit (ICU)- and mechanical ventilation (MV)-acquired limb muscle and diaphragm dysfunction may both be associated with longer length of stay and worse outcome. Whether they are two aspects of the same entity or have a different prevalence and prognostic impact remains unclear., Objectives: To quantify the prevalence and coexistence of these two forms of ICU-acquired weakness and their impact on outcome., Methods: In patients undergoing a first spontaneous breathing trial after at least 24 hours of MV, diaphragm dysfunction was evaluated using twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (a pressure <11 cm H 2 O defined dysfunction) and ultrasonography (thickening fraction [TFdi] and excursion). Limb muscle weakness was defined as a Medical Research Council (MRC) score less than 48., Measurements and Main Results: Seventy-six patients were assessed at their first spontaneous breathing trial: 63% had diaphragm dysfunction, 34% had limb muscle weakness, and 21% had both. There was a significant but weak correlation between MRC score and twitch pressure (ρ = 0.26; P = 0.03) and TFdi (ρ = 0.28; P = 0.01), respectively. Low twitch pressure (odds ratio, 0.60; 95% confidence interval, 0.45-0.79; P < 0.001) and TFdi (odds ratio, 0.84; 95% confidence interval, 0.76-0.92; P < 0.001) were independently associated with weaning failure, but the MRC score was not. Diaphragm dysfunction was associated with higher ICU and hospital mortality, and limb muscle weakness was associated with longer duration of MV and hospital stay., Conclusions: Diaphragm dysfunction is twice as frequent as limb muscle weakness and has a direct negative impact on weaning outcome. The two types of muscle weakness have only limited overlap.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder associated with respiratory muscle weakness and respiratory failure. Non-invasive ventilation alleviates respiratory symptoms and prolongs life, but is a palliative intervention. Slowing the deterioration of diaphragm function before respiratory failure would be desirable. We aimed to assess whether early diaphragm pacing could slow down diaphragm deterioration and would therefore delay the need for non-invasive ventilation., Methods: We did a multicentre, randomised, controlled, triple-blind trial in patients with probable or definite ALS in 12 ALS centres in France. The main inclusion criterion was moderate respiratory involvement (forced vital capacity 60-80% predicted). Other key eligibility criteria were age older than 18 years and bilateral responses of the diaphragm to diagnostic phrenic stimulation. All patients were operated laparoscopically and received phrenic stimulators. Clinicians randomly assigned patients (1:1) to receive either active or sham stimulation with a central web-based randomisation system (computer-generated list). Investigators, patients, and an external outcome allocation committee were masked to treatment. The primary outcome was non-invasive ventilation-free survival, analysed in the intention-to-treat population. Safety outcomes were also assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01583088., Findings: Between Sept 27, 2012, and July 8, 2015, 74 participants were randomly assigned to receive either active (n=37) or sham (n=37) stimulation. On July 16, 2015, an unplanned masked analysis was done after another trial showed excess mortality with diaphragm pacing in patients with hypoventilation (DiPALS, ISRCTN 53817913). In view of this finding, we analysed mortality in our study and found excess mortality (death from any cause) in our active stimulation group. We therefore terminated the study on July, 16, 2015. Median non-invasive ventilation-free survival was 6·0 months (95% CI 3·6-8·7) in the active stimulation group versus 8·8 months (4·2-not reached) in the control (sham stimulation) group (hazard ratio 1·96 [95% CI 1·08-3·56], p=0·02). Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure, venous thromboembolism, and gastrostomy) were frequent (24 [65%] patients in the active stimulation group vs 22 [59%] patients in the control group). No treatment-related death was reported., Interpretation: Early diaphragm pacing in patients with ALS and incipient respiratory involvement did not delay non-invasive ventilation and was associated with decreased survival. Diaphragm pacing is not indicated at the early stage of the ALS-related respiratory involvement., Funding: Hospital Program for Clinical Research, French Ministry of Health; French Patients' Association for ALS Research (Association pour la Recherche sur la Sclérose Latérale Amyotrophique); and Thierry de Latran Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The diaphragm is difficult to biopsy because of its anatomic location. We describe a new laparoscopic diaphragm biopsy technique., Material and Methods: Fifty one patients with amyotrophic lateral sclerosis gave their consent to diaphragm biopsy in the context of an implanted phrenic nerve stimulation protocol (NCT01583088). The biopsy was taken from the costal diaphragm, after opening the parietal peritoneum with scissors, and by grasping the diaphragmatic muscle over the rib with toothed laparoscopy forceps., Results: The first four electrocoagulation biopsies were unsuitable for morphologic examination. The following 47 biopsies were therefore performed without electrocoagulation. The mean size of the biopsy fragments obtained after preparation was 3 ± 1 × 2 ± 1 × 1 ± 1 mm (maximum: 4 × 3 × 2 mm). A diaphragmatic injury occurred during the section in three cases requiring immediate suture without causing pneumothorax. A small pleural effusion was observed on the postoperative chest x-ray in one patient with a spontaneously favorable outcome. Numerous stains were able to be performed on the fragments obtained., Conclusions: Diaphragm biopsy can be safely performed by laparoscopy and yields tissue suitable for our future histologic evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: The objective was to compare the impact of three assistance levels of different modes of mechanical ventilation; neurally adjusted ventilatory assist (NAVA), proportional assist ventilation (PAV), and pressure support ventilation (PSV) on major features of patient-ventilator interaction., Methods: PSV, NAVA, and PAV were set to obtain a tidal volume (VT) of 6 to 8 ml/kg (PSV₁₀₀, NAVA₁₀₀, and PAV₁₀₀) in 16 intubated patients. Assistance was further decreased by 50% (PSV₅₀, NAVA₅₀, and PAV₅₀) and then increased by 50% (PSV₁₅₀, NAVA₁₅₀, and PAV₁₅₀) with all modes. The three modes were randomly applied. Airway flow and pressure, electrical activity of the diaphragm (EAdi), and blood gases were measured. VT, peak EAdi, coefficient of variation of VT and EAdi, and the prevalence of the main patient-ventilator asynchronies were calculated., Results: PAV and NAVA prevented the increase of VT with high levels of assistance (median 7.4 (interquartile range (IQR) 5.7 to 10.1) ml/kg and 7.4 (IQR, 5.9 to 10.5) ml/kg with PAV₁₅₀ and NAVA₁₅₀ versus 10.9 (IQR, 8.9 to 12.0) ml/kg with PSV₁₅₀, P <0.05). EAdi was higher with PAV than with PSV at level₁₀₀ and level₁₅₀. The coefficient of variation of VT was higher with NAVA and PAV (19 (IQR, 14 to 31)% and 21 (IQR 16 to 29)% with NAVA₁₀₀ and PAV₁₀₀ versus 13 (IQR 11 to 18)% with PSV₁₀₀, P <0.05). The prevalence of ineffective triggering was lower with PAV and NAVA than with PSV (P <0.05), but the prevalence of double triggering was higher with NAVA than with PAV and PSV (P <0.05)., Conclusions: PAV and NAVA both prevent overdistention, improve neuromechanical coupling, restore the variability of the breathing pattern, and decrease patient-ventilator asynchrony in fairly similar ways compared with PSV. Further studies are needed to evaluate the possible clinical benefits of NAVA and PAV on clinical outcomes., Trial Registration: Clinicaltrials.gov NCT02056093 . Registered 18 December 2013.

Background: Neurally adjusted ventilatory assist (NAVA), regulated exclusively by the electromyographic activity (EA) of the diaphragm (EAdi), could affect the distribution of neural drive to the various inspiratory muscles. The objective of this study was to compare EAdi, EA of the scalene (EAscal), and EA of the alae nasi (EAan), according to the ventilatory mode and assist level in 12 mechanically ventilated patients., Methods: Seven assist levels of pressure support ventilation (PSV) and NAVA were sequentially applied. EAdi, EAscal, and EAan were quantified and expressed as a percentage of their maximum values. The relative contributions of extradiaphragmatic muscles to inspiratory efforts were assessed by calculating EAscal/EAdi and EAan/EAdi ratios. Three assist levels for each of the two ventilatory modes that resulted in EAdi values of 80 to 100%, 60 to 80%, and 40 to 60% were assigned to three groups (N1, N2, and N3). Results are expressed as median and interquartile range., Results: EA of inspiratory muscles decreased during PSV and NAVA (P < 0.0001). Although EAdi remained constant within groups (P = 0.9), EAscal was reduced during NAVA compared with PSV in N1 and N3 (65% [62 to 64] and 27% [18 to 34] in NAVA vs. 90% [81 to 100] and 49% [40 to 55] in PSV, P = 0.007). Altogether, EAscal/EAdi and EAan/EAdi ratios were lower in NAVA than PSV (0.7 [0.6 to 0.7] and 0.7 [0.6 to 0.8] in NAVA vs. 0.9 [0.8 to 1.1] and 0.9 [0.7 to 1.1] in PSV, P < 0.05)., Conclusions: NAVA and PSV both reduced extradiaphragmatic inspiratory muscle activity, in proportion to the level of assistance. Compared with PSV, NAVA resulted in a predominant contribution of the diaphragm to inspiratory effort.

Thoracoabdominal breathing movements are a complex source of postural disturbance, but there are contradictory reports in the literature with inspiration described as having either a backward or a forward disturbing effect. To elucidate the mechanisms underlying this phenomenon, the present study studied the postural disturbance caused by isolated contractions of the diaphragm. Eight male and four female healthy subjects followed an original paradigm of phrenic nerve stimulation (bilateral and unilateral) and "diaphragmatic" voluntary sniff maneuvers in the seated and standing postures. Center of gravity (CG) acceleration was calculated from force plate recordings, and respiratory kinematics were assessed with thoracic and abdominal sensor belts. CG and respiratory signals revealed that, while seated, bilateral phrenic stimulation and sniff maneuvers consistently produced expansion of the abdomen associated with a forward peak of CG acceleration. In the standing posture, the direction of the CG peak was reversed and always directed backward. Unilateral phrenic stimulation induced an additional medial-lateral acceleration of the CG, directed toward the nonactive side while seated, but in the opposite direction while standing. These results suggest that isolated diaphragmatic contractions produce a constant disturbing pattern for a given posture, but with opposite effects between standing and seated postures. This could be related to the different biomechanical configuration of the body in each posture, corresponding to distinct kinematic patterns of the osteoarticular chain. In addition, the lateral component of the CG acceleration induced by unilateral diaphragm contractions could be clinically relevant in patients with hemidiaphragm paralysis., (Copyright © 2014 the American Physiological Society.)

Background: Acute diaphragmatic dysfunction has been reported in septic and cardiogenic shock, but few data are available concerning the effect of hemorrhagic shock on diaphragmatic function. The authors examined the impact of a hemorrhagic shock on the diaphragm., Methods: Four parallel groups of adult rats were submitted to hemorrhagic shock induced by controlled exsanguination targeting a mean arterial blood pressure of 30 mmHg for 1 h, followed by a 1-h fluid resuscitation with either saline or shed blood targeting a mean arterial blood pressure of 80 mmHg. Diaphragm and soleus strip contractility was measured in vitro. Blood flow in the muscle microcirculation was measured in vivo using a Laser Doppler technique. Muscle proinflammatory cytokine concentrations were also measured., Results: Hemorrhagic shock was characterized by a decrease in mean arterial blood pressure to 34 ± 5 mmHg (-77 ± 4%; P< 0.05) and high plasma lactate levels (7.6 ± 0.9 mM; P < 0.05). Although tetanic tension of the diaphragm was not altered, hemorrhagic shock induced dramatic impairment of tetanic tension of the soleus (-40 ± 19%; P < 0.01), whereas proinflammatory cytokine levels were low and not different between the two muscles. Resuscitation with either blood or saline did not further modify either diaphragm or soleus performance and proinflammatory cytokine levels. The shock-induced decrease in blood flow was much more pronounced in the soleus than in the diaphragm (-75 ± 13% vs. -17 ± 10%; P = 0.02), and a significant interaction was observed between shock and muscle (P < 0.001)., Conclusion: Diaphragm performance is preserved during hemorrhagic shock, whereas soleus performance is impaired, with no further impact of either blood or saline fluid resuscitation.

Rationale: Diaphragmatic insults occurring during intensive care unit (ICU) stays have become the focus of intense research. However, diaphragmatic abnormalities at the initial phase of critical illness remain poorly documented in humans., Objectives: To determine the incidence, risk factors, and prognostic impact of diaphragmatic impairment on ICU admission., Methods: Prospective, 6-month, observational cohort study in two ICUs. Mechanically ventilated patients were studied within 24 hours after intubation (Day 1) and 48 hours later (Day 3). Seventeen anesthetized intubated control anesthesia patients were also studied. The diaphragm was assessed by twitch tracheal pressure in response to bilateral anterior magnetic phrenic nerve stimulation (Ptr,stim)., Measurements and Main Results: Eighty-five consecutive patients aged 62 (54-75) (median [interquartile range]) were evaluated (medical admission, 79%; Simplified Acute Physiology Score II, 54 [44-68]). On Day 1, Ptr,stim was 8.2 (5.9-12.3) cm H2O and 64% of patients had Ptr,stim less than 11 cm H2O. Independent predictors of low Ptr,stim were sepsis (linear regression coefficient, -3.74; standard error, 1.16; P = 0.002) and Simplified Acute Physiology Score II (linear regression coefficient, -0.07; standard error, 1.69; P = 0.03). Compared with nonsurvivors, ICU survivors had higher Ptr,stim (9.7 [6.3-13.8] vs. 7.3 [5.5-9.7] cm H2O; P = 0.004). This was also true for hospital survivors versus nonsurvivors (9.7 [6.3-13.5] vs. 7.8 [5.5-10.1] cm H2O; P = 0.004). Day 1 and Day 3 Ptr,stim were similar., Conclusions: A reduced capacity of the diaphragm to produce inspiratory pressure (diaphragm dysfunction) is frequent on ICU admission. It is associated with sepsis and disease severity, suggesting that it may represent another form of organ failure. It is associated with a poor prognosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00786526).

Introduction: Patients with the congenital central hypoventilation syndrome (CCHS) suffer from life-threatening hypoventilation when asleep, making them dependent on mechanical ventilation (MV) at night or during naps. State-of-art respiratory management consists of intermittent positive-pressure ventilation via a tracheotomy or mask. In some patients hypoventilation is permanent, in which case ventilatory support must be extended to the waking hours. Diaphragm pacing can prove useful in such situations. 
, Methods and Results: This report describes the case of a 26-year-old woman with CCHS in whom failure to achieve adequate MV led to life-threatening pulmonary hypertension (PH), with a systolic pulmonary artery pressure (PAP) of 80 mmHg and right ventricular hypertrophy, despite optimization of all possible measures and despite extensive therapeutic education efforts. Diaphragm pacing using laparoscopically implanted intradiaphragmatic phrenic nerve stimulation electrodes corrected alveolar hypoventilation and lastingly reversed PH (systolic PAP below 40 mmHg after 2 months, sustained after 2 years). Diaphragm pacing induced shoulder pain, however, involving the chronic use of analgesics. The pacing had to be stopped for tolerance reasons after two years, leading to PH worsening and the need for diurnal MV. 
, Conclusions: Diaphragm pacing appears likely effective to restore alveolar ventilation and reverse PH in adult CCHS patients.

Purpose: To compare breathing pattern descriptors and diaphragm electromyographic activity (EAdi)-derived indices obtained from a neurally adjusted ventilatory assist catheter during a spontaneous breathing trial (SBT) in patients successfully and unsuccessfully separated from the ventilator and to assess their performance as a potential marker to discriminate these two categories of patients., Methods: Fifty-seven ready-to-wean patients were included in a prospective observational study. During a 30-min SBT (pressure support 7 cmH(2)O, zero end expiratory pressure), tidal volume (V (T)) and respiratory rate (RR) were obtained from the flow signal at baseline and at 3, 10, 20 and 30 min during the SBT. EAdi-derived indices were simultaneously computed: maximum of the EAdi (EAdi(max)), area under the inspiratory curve of EAdi (EAdi(AUC)), the difference between EAdi(max) and EAdi(min) (∆EAdi), EAdi(max)/V (T), EAdi(AUC)/V (T) and ∆EAdi/V (T). Patients, successfully (success group; n = 35) and unsuccessfully (failure group; n = 22) separated from the ventilator were compared., Results: At baseline, the breathing pattern was similar in the two groups, whereas EAdi(max) and EAdi(AUC) were significantly lower in the success group (p < 0.05). In the failure group, RR and RR/V (T) increased significantly during the trial, V (T) decreased, whereas EAdi(max) and EAdi(AUC) did not change. At 3 min, the areas under the receiver operating characteristic-curve of RR/V (T) and the EAdi-derived indices to predict weaning outcome were 0.83 for the rapid shallow breathing index (RSBI), 0.84 for EAdi(max)/V (T) , 0.80 for EAdi(AUC)/V (T) (0.80) and 0.82 for ∆EAdi/V (T). The coefficient of variation for V (T) decreased in the failure group while that for EAdi(max) remained unchanged., Conclusions: EAdi-derived indices provide reliable and early predictors of weaning outcome. However, the performance of these indices is not better than the RR/V (T).

Objectives: Phrenic nerve stimulation for diaphragm pacing allows patients with central respiratory paralysis to be weaned from mechanical ventilation. Two procedures are available, either intrathoracic (bilateral thoracotomy) or intradiaphragmatic (four ports laparoscopy). The present experimental work assesses the feasibility, safety and efficacy of a trans-mediastinal implantation of intradiaphragmatic phenic nerve stimulation electrodes using a flexible gastroscope through a cervical incision., Methods: We operated on nine ewes. After selective bronchial intubation, we dissected the latero-tracheal space and opened both mediastinal pleura. We then introduced a flexible gastroscope into the pleural cavities, in a sequential manner. The phrenic nerves were located and followed up to the diaphragm dome. Electrodes loaded within a long, pliable needle were introduced through the adjacent intercostal space and implanted in each hemidiaphragm, at a 'tendinous' location (as close as possible to the entry of the nerve in the central tendon), and at a more lateral 'muscular' location. Postoperatively, the animals were ventilated using bilateral phrenic nerve stimulation. After euthanasia, abdominal verification of the electrodes position was performed through a laparotomy., Results: The mediastinal and pleural parts of the procedure were uneventful. The insertion of electrodes was associated with transdiaphragmatic puncture and small abdominal haematomas in the first two animals studied. After a slight modification of the insertion technique, this was not observed anymore. Phrenic nerve stimulation produced efficient ventilation, with tidal volumes significantly higher when delivered at the tendinous site than at the muscular site., Conclusions: The trans-mediastinal implantation of intradiaphragmatic phrenic nerve stimulation electrodes is feasible, appears reasonably safe, and allows efficient ventilation.

In amyotrophic lateral sclerosis (ALS) patients, respiratory insufficiency is a major burden. Diaphragm conditioning by electrical stimulation could interfere with lung function decline by promoting the development of type 1 muscle fibres. We describe an ancillary study to a prospective, non-randomized trial (NCT00420719) assessing the effects of diaphragm pacing on forced vital capacity (FVC). Sleep-related disturbances being early clues to diaphragmatic dysfunction, we postulated that they would provide a sensitive marker. Stimulators were implanted laparoscopically in the diaphragm close to the phrenic motor point in 18 ALS patients for daily conditioning. ALS functioning score (ALSFRS), FVC, sniff nasal inspiratory pressure (SNIP), and polysomnographic recordings (PSG, performed with the stimulator turned off) were assessed before implantation and after four months of conditioning (n = 14). Sleep efficiency improved (69 ± 15% to 75 ± 11%, p = 0.0394) with fewer arousals and micro-arousals. This occurred against a background of deterioration as ALSFRS-R, FVC, and SNIP declined. There was, however, no change in NIV status or the ALSFRS respiratory subscore, and the FVC decline was mostly due to impaired expiration. Supporting a better diaphragm function, apnoeas and hypopnoeas during REM sleep decreased. In conclusion, in these severe patients not expected to experience spontaneous improvements, diaphragm conditioning improved sleep and there were hints at diaphragm function changes.

Electrical stimulation can enhance muscle function. We applied repetitive cervical magnetic phrenic stimulation (rCMS) to induce diaphragm contractions in 7 healthy subjects (800 ms trains; transdiaphragmatic pressure (Pdi) measurements; tolerance ratings). Each rCMS train produced a sustained diaphragm contraction. Sixty-five percent of the maximal available output at 15 Hz proved the best compromise between Pdi and discomfort with nonfatiguing contractions. rCMS appears feasible and should be investigated for diaphragm conditioning in appropriate clinical populations.

Objective: Diaphragm pacing by phrenic nerve (PN) stimulation is currently used for patients with central respiratory paralysis to be weaned from mechanical ventilation. Electrodes are inserted either through bilateral thoracotomy or through four ports laparoscopy. The aim of this experimental work is to demonstrate the feasibility of trans-mediastinal bilateral implantation of PN electrodes using a flexible gastroscope introduced through a cervical incision in human cadavers., Methods: Ten refrigerated and non-embalmed cadavers were used. The gastroscope was introduced through a cervical incision into the latero-tracheal space and then subsequently into both pleura by opening the mediastinal pleura. After identification of the PN, electrodes were introduced through an intercostal space to the desired diaphragmatic location using a long, pliable needle with the electrode loaded in its lumen., Results: Results are described for each hemi-diaphragm not for an anatomic subject. Mediastinal exploration and introduction of the video gastroscope into the pleural cavities proved easy in all subjects. Pleural adherences were present in five hemi-diaphragms. The central tendon of both hemi-diaphragms could be identified unambiguously in all the subjects. Identification of the entry point of the phrenic nerve into the diaphragm was straightforward in 10 hemi-diaphragms. In the remaining 10, this proved more difficult because of mediastinal fat or lung parenchyma. Introduction of the electrode-holding needles through the intercostal space and their insertion close to the phrenic nerve entry point was also easy. Withdrawal of the needle from the diaphragm and 'capture' of the hook were successful on the first attempt in 14 hemi-diaphragms, but failed in six others in whom a second attempt was necessary., Conclusion: Trans-mediastinal implantation of PN stimulation electrodes is possible using a flexible endoscope. This application of endoscopic surgery could allow a minimally invasive placement of PN electrodes in patients with central respiratory paralysis, for example, at the time of tracheostomy., (Copyright © 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

In humans, anatomy indicates that the phrenic nerve mainly arises from the C4 cervical root, with variable C3 and C5 contributions. How this translates into functional innervation is unknown. The diaphragm response to electrical stimulation of C3, C4 and C5 was described in three patients undergoing surgical laryngeal reinnervation with an upper phrenic root (surface chest electrodes at anterior, lateral and posterior sites; oesophageal and gastric pressures (Pes and Pga) to derive transdiaphragmatic pressure (Pdi)). Anatomically, the phrenic nerve predominantly originated from C4. Phrenic stimulation elicited motor responses at the three sites in the three patients, as did C4 stimulation. It produced Pdi values of 9, 11, and 14cmH(2)O in the three patients, respectively, vs. 9, 9, and 7cmH(2)O for C4. C3 stimulation produced modest Pdi responses, whereas C5 stimulation could produce Pdi responses close to those observed with C4 stimulation. These singular observations confirm the dominance of C4 in diaphragm innervation but suggest than C5 can be of importance., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Rationale: Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans., Objectives: To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena., Methods: Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2-3 h; n = 10) and from brain-dead organ donors (MV for 24-249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-κB, and calpains)., Measurements and Main Results: TwPtr decreased progressively during MV, with a mean reduction of 32 ± 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 ± 4.8 vs. 4.7 ± 0.6% area), decreased cross-sectional area of muscle fibers (1,904 ± 220 vs. 3,100 ± 329 μm²), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm., Conclusions: Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.

Expulsive maneuvers (EMs) caused by simultaneous contraction of diaphragm and abdominal muscles shift substantial quantities of blood from the splanchnic circulation to the extremities. This suggests that the diaphragm assisted by abdominal muscles might accomplish ventilation and circulation simultaneously by repeated EMs. We tested this hypothesis in normal subjects by measuring changes (Δ) in body volume (Vb) by whole body plethysmography simultaneously with changes in trunk volume (Vtr) by optoelectronic plethysmography, which measures the same parameters as whole body plethysmography plus the volume of blood shifts (Vbs) between trunk and extremities: Vbs = ΔVtr-ΔVb. We also measured abdominal pressure, pleural pressure, the arterial pressure wave, and cardiac output (Qc). EMs with abdominal pressure ~100 cmH(2)O for 1 s, followed by 2-s relaxations, repeated over 90 s, produced a "stroke volume" from the splanchnic bed of 0.35 ± 0.07 (SD) liter, an output of 6.84 ± 0.75 l/min compared with a resting Qc of 5.59 ± 1.14 l/min. Refilling during relaxation was complete, and the splanchnic bed did not progressively empty. Diastolic pressure increased by 25 mmHg during each EM. Between EMs, Qc increased to 7.09 ± 1.14 l/min due to increased stroke volume and heart rate. The circulatory function of the diaphragm assisted by simultaneous contractions of abdominal muscles with appropriate pressure and duration at 20 min(-1) can produce a circulatory output as great as resting Qc, as well as ventilation. These combined functions of the diaphragm have potential for cardiopulmonary resuscitation. The abdominal circulatory pump can act as an auxiliary heart.

The comparatively low compliance of the mammalian lung results in an evolutionary dilemma: the origin and evolution of this bronchoalveolar lung into a high-performance gas-exchange organ results in a high work of breathing that cannot be achieved without the coupled evolution of a muscular diaphragm. However, despite over 400 years of research into respiratory biology, the origin of this exclusively mammalian structure remains elusive. Here we examine the basic structure of the body wall muscles in vertebrates and discuss the mechanics of costal breathing and functional significance of accessory breathing muscles in non-mammalian amniotes. We then critically examine the mammalian diaphragm and compare hypotheses on its ontogenetic and phylogenetic origin. A closer look at the structure and function across various mammalian groups reveals the evolutionary significance of collateral functions of the diaphragm as a visceral organizer and its role in producing high intra-abdominal pressure., (Copyright 2010 Elsevier B.V. All rights reserved.)

Inspiratory loading in awake humans is associated with electroencephalographic signs of supplementary motor area (SMA) activation. To provide evidence for a functional connection between SMA and the diaphragm representation in the primary motor cortex (M1(DIA)), we tested the hypothesis that modulating SMA activity using repetitive transcranial magnetic stimulation (rTMS) would alter M1(DIA) excitability. Amplitude and latency of diaphragm motor evoked potentials (MEP(DIA)), evoked through single pulse M1(DIA) stimulation, before and up to 16 min after SMA stimulation, were taken as indicators of M1(DIA) excitability. MEPs from the first dorsal interosseous muscle (FDI, MEP(FDI)) served as a control. Four SMA conditioning sessions were performed in random order at 1-wk intervals. Two aimed at increasing SMA activity (5 and 10 Hz, both at 110% of FDI active motor threshold; referred to as 5Hz and 10Hz, respectively), and two aimed at decreasing it (1 Hz either at 110% of FDI active or resting motor threshold, referred to as aMT or rMT, respectively). The 5Hz protocol increased MEP(DIA) and MEP(FDI) amplitudes with a maximum 11-16 min poststimulation (P = 0.04 and P = 0.02, respectively). The 10Hz protocol increased MEP(FDI) amplitude with a similar time course (P = 0.03) but did not increase MEP(DIA) amplitude (P = 0.32). Both aMT and rMT failed to decrease MEP(DIA) or MEP(FDI) amplitudes (P = 0.23 and P = 0.90, respectively, for diaphragm and P = 0.48 and P = 0.14 for FDI). MEP(DIA) and MEP(FDI) latencies were unaffected by rTMS. These results demonstrate that 5-Hz rTMS over the SMA can increase the excitability of M1(DIA). These observations are consistent with the hypothesis of a functional connection between SMA and M1(DIA).

Background: Upper airway collapse does not occur during wake in obstructive sleep apnea patients. This points to wake-related compensatory mechanisms, and possibly to a modified corticomotor control of upper airway dilator muscles. The objectives of the study were to characterize the responsiveness of the genioglossus to transcranial magnetic stimulation during respiratory and non-respiratory facilitatory maneuvers in obstructive sleep apnea patients, and to compare it to the responsiveness of the diaphragm, with reference to normal controls., Methods: Motor evoked potentials of the genioglossus and of the diaphragm, with the corresponding motor thresholds, were recorded in response to transcranial magnetic stimulation applied during expiration, inspiration and during maximal tongue protraction in 13 sleep apnea patients and 8 normal controls., Main Results: In the sleep apnea patients: 1) combined genioglossus and diaphragm responses occurred more frequently than in controls (P < 0.0001); 2) the amplitude of the genioglossus response increased during inspiratory maneuvers (not observed in controls); 3) the latency of the genioglossus response decreased during tongue protraction (not observed in controls). A significant negative correlation was found between the latency of the genioglossus response and the apnea-hypopnea index; 4) the difference in diaphragm and genioglossus cortico-motor responses during tongue protraction and inspiratory loading differed between sleep apnea and controls., Conclusion: Sleep apnea patients and control subjects differ in the response pattern of the genioglossus and of the diaphragm to facilitatory maneuvers, some of the differences being related to the frequency of sleep-related events.

Mammalian ventilation is driven by automatic structures producing "metabolic" ventilation. Respiratory neuroplasticity can adapt this control to developmental, environmental, and disease-related changes. A corticospinal diaphragm pathway accounts for behavioural disruptions of metabolic ventilation. It should be sensitive to use-dependent short-term plasticity. However, the brainstem-generated permanent diaphragm activity could alter the learning-related corticospinal plasticity (metaplasticity). To test this hypothesis, eight healthy volunteers (six women, 21-25) were studied before and after having learnt to produce prominent diaphragm contractions during voluntary inspiratory manoeuvres. Diaphragm training resulted in (1) a decreased liminal stimulation intensities; (2) an increased number of responding sites on the diaphragm mapping with focal stimulation (5.1+/-3.3 versus 9+/-4.4, p=0.004 in relaxed conditions; 8.9+/-5 versus 15.3+/-4.5, p<0.0001, with underlying voluntary facilitation); (3) shortened motor evoked potentials latencies in response to non-focal stimulation (17.2+/-1.6 ms versus 16.2+/-1.4 ms, p=0.03 in relaxed conditions, and 16.8+/-1.1 ms versus 15.2+/-1.6 ms, p=0.003, with facilitation). These results are closely comparable with similar data in locomotor muscle. They provide a neurophysiological basis for the capacity of normal humans to rapidly acquire diaphragmatic skills.

Assessing diaphragm function is clinically and physiologically pertinent. It can rely on the measurement of pressure responses to phrenic stimulation. Combining mouth pressure (Pm) with cervical magnetic stimulation (CMS) is painless and easy to perform, but Pm-CMS poorly reflects esophageal pressure (Pes-CMS) because of poor pressure transmission across the airway. We reasoned that the mouth opening and neck flexion that are associated with the measurement of Pm-CMS would impair upper airway dynamics and further hinder pressure transmission. Therefore, we assessed the CMS-related pressure measured in a nasal mask (Pmask; mouth closed) without neck flexion as a possible surrogate of Pes-CMS, in 14 men and 3 women, age 24.5+/-2.2. Pes-CMS was 15.7+/-4.3 cmH2O, significantly higher than Pm-CMS (13.5+/-5.6 cmH2O, P<0.0001) but not different from Pmask-CMS (15.2+/-4.9 cmH2O). The concordance correlation coefficient was low (0.6808) between Pes-CMS and Pm-CMS. It was higher between Pes-CMS and Pmask-CMS (0.8730). Pm-CMS wrongly classified five subjects as abnormal (<10 cmH2O), versus 1 for Pmask and 5 for Pm (P=0.025). Passing and Bablok regressions found no difference between Pes-CMS and Pmask-CMS, but identified a systematic difference and a proportional error between Pes-CMS and Pm-CMS. We conclude that Pmask-CMS is a better surrogate of Pes-CMS than Pm-CMS.

Unlabelled: The modulation of activity of the upper airway dilator and respiratory muscles plays a key role in the regulation of ventilation, but little is known about the link between their neuromuscular activation processes in vivo. This study investigated genioglossus and diaphragm responses to transcranial magnetic stimulation applied in different facilitatory conditions. The amplitude and latency of motor-evoked potential responses and the stimulation intensity threshold leading to a motor response (motor threshold) were recorded with stimulation applied at the vertex and anterolateral area in 13 awake normal subjects. Stimuli were applied during inspiration with and without resistance, during expiration with and without maximal tongue protrusion and during deep inspiration. In each stimulation location and condition, no diaphragmatic response was obtained without previous genioglossus activity (diaphragmatic and genioglossus responses latencies during expiration: 18.1 +/- 2.9 and 6.3 +/- 2.6 ms, respectively, mean +/- s.d., P < 0.01). Genioglossus motor-evoked potential amplitude, latency and motor threshold were significantly modified with tongue protrusion with a maximal effect observed for stimulation in the anterolateral area. Deep inspiration was associated with a significant facilitatory effect on both genioglossus and diaphragm motor responses. The facilitatory effects of respiratory and non-respiratory manoeuvres were also observed during focal stimulation where isolated genioglossus responses were observed. Genioglossus and diaphragm differed in their motor threshold both at baseline and following facilitatory manoeuvres., Conclusions: (1) transcranial magnetic stimulation-induced genioglossus response systematically precedes that of diaphragm; (2) this sequence of activation is not modified by respiratory and non-respiratory manoeuvres; and (3) the genioglossus and diaphragm are differently influenced by these manoeuvres in terms of latency of the motor response and of motor threshold.

Unlabelled: The human ventilation depends on bulbospinal and corticospinal commands. This study assessed their interactions in five healthy volunteers (two men, age 25-35) through the description of diaphragm and abductor pollicis brevis (APB) motor potentials (DiMEPs, abpMEPs) evoked by transcranial magnetic stimulation (TMS) during relaxed expiration and tidal inspiration and during wake and sleep. NREM decreased corticospinal excitability and REM further did so, for both the diaphragm and the APB. During wake, inspiration shortened supine DiMEPs latencies (expiration 18.56+/-1.90ms; inspiration 17.37+/-1.48ms, P<0.001). This persisted during sleep in an augmented manner (expiration: 21.05+/-1.39ms; inspiration 18.69+/-1.17ms, P=0.002). Inspiration had no effect on apbMEPs during wake and sleep., In Conclusion: (1) the tidal bulbospinal input to phrenic motoneurones is sufficient to modulate the throughput of the corticospinal pathway to these neurones; (2) this modulation is best seen after the sleep related removal of corticospinal and/or afferent inputs.

Background: Breathing in humans is dually controlled for metabolic (brainstem commands) and behavioral purposes (suprapontine commands) with reciprocal modulation through spinal integration. Whereas the ventilatory response to chemical stimuli arises from the brainstem, the compensation of mechanical loads in awake humans is thought to involve suprapontine mechanisms. The aim of this study was to test this hypothesis by examining the effects of inspiratory resistive loading on the response of the diaphragm to transcranial magnetic stimulation., Results: Six healthy volunteers breathed room air without load (R0) and then against inspiratory resistances (5 and 20 cmH2O/L/s, R5 and R20). Ventilatory variables were recorded. Transcranial magnetic stimulation (TMS) was performed during early inspiration (I) or late expiration (E), giving rise to motor evoked potentials (MEPs) in the diaphragm (Di) and abductor pollicis brevis (APB). Breathing frequency significantly decreased during R20 without any other change. Resistive breathing had no effect on the amplitude of Di MEPs, but shortened their latency (R20: -0.903 ms, p = 0.03) when TMS was superimposed on inspiration. There was no change in APB MEPs., Conclusion: Inspiratory resistive breathing facilitates the diaphragm response to TMS while it does not increase the automatic drive to breathe. We interpret these findings as a neurophysiological substratum of the suprapontine nature of inspiratory load compensation in awake humans.

A quadriplegic patient experienced post-traumatic exteriorisation of the subcutaneous receiver of a phrenic pacemaker. In the absence of infection and stimulation dysfunction in the patient, the device was reimplanted with full success at 1 year. This strategy can, exceptionally, be considered if removal and subsequent implantation is impossible or refused.

Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.

It is unknown whether changes in corticomotor excitability follow exercise in healthy humans. We hypothesized that a fall in the diaphragm and quadriceps motor-evoked potential (MEP) amplitude elicited by transcranial magnetic stimulation of the motor cortex would occur after an incremental exercise task. In 11 healthy subjects, we measured transdiaphragmatic pressure and isometric quadriceps tension in response to supramaximal peripheral magnetic nerve stimulation. MEPs were recorded from these muscles in response to transcranial magnetic stimulation. After baseline measurements, subjects performed a period of submaximal exercise (gentle walking). Measurements were repeated 5 and 20 min after this. The subjects then exercised on a treadmill with an incremental protocol to exhaustion. Transcranial magnetic stimulation was performed at baseline and at 5, 20, 40, and 60 min after exhaustive exercise, and force measurements were obtained at baseline, 20 min, and 60 min. Mean exercise duration was 18 +/- 4 min, and mean maximum heart rate was 172 +/- 10 beats/min. Twitch transdiaphragmatic pressure and twitch isometric quadriceps tension were not different from baseline after exercise, but a significant decrease was observed in diaphragm MEP amplitude 5 and 20 min after exercise (60 +/- 38 and 45 +/- 24%, respectively, of baseline, P = 0.0001). At the same times, the mean quadriceps MEPs were 59 +/- 39 and 74 +/- 32% of baseline (P < 0.0001 and P < 0.01, respectively). Studies using paired stimuli confirmed a likely intracortical mechanism for this depression. Our data confirm significant depression of both diaphragm and quadriceps MEPs after incremental treadmill exercise.