Defective exercise-related expiratory muscle recruitment in patients with PHOX2B mutations: A clue to neural determinants of the congenital central hypoventilation syndrome.

INTRODUCTION AND OBJECTIVES: The human congenital central hypoventilation syndrome (CCHS) is caused by mutations in the PHOX2B (paired-like homeobox 2B) gene. Genetically engineered PHOX2B rodents exhibit defective development of the brainstem retrotrapezoid nucleus (RTN), a carbon dioxide sensitive structure that critically controls expiratory muscle recruitment. This has been linked to a blunted exercise ventilatory response. Whether this can be extrapolated to human CCHS is unknown and represents the objective of this study. MATERIALS AND METHODS: Thirteen adult CCHS patients and 13 healthy participants performed an incremental symptom-limited cycle cardiopulmonary exercise test. Responses were analyzed using guideline approaches (ventilation V'E, tidal volume VT, breathing frequency, oxygen consumption, carbon dioxide production) complemented by a breathing pattern analysis (i.e. expiratory and inspiratory reserve volume, ERV and IRV). RESULTS: A ventilatory response occurred in both study groups, as follows: V'E and VT increased in CCHS patients until 40 W and then decreased, which was not observed in the healthy participants (p<0.001). In the latter, exercise-related ERV and IRV decreases attested to concomitant expiratory and inspiratory recruitment. In the CCHS patients, inspiratory recruitment occurred but there was no evidence of expiratory recruitment (absence of any ERV decrease, p<0.001). CONCLUSIONS: Assuming a similar organization of respiratory rhythmogenesis in humans and rodents, the lack of exercise-related expiratory recruitment observed in our CCHS patients is compatible with a PHOX2B-related defect of a neural structure that would be analogous to the rodents' RTN. Provided corroboration, ERV recruitment could serve as a physiological outcome in studies aiming at correcting breathing control in CCHS.

Contribution of endobronchial ultrasound elastography to the characterization of mediastinal lymphadenopathy: A single-center, prospective, observational study.

BACKGROUND: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a reliable technique providing high diagnostic yield in mediastinal lymphadenopathy. However, mediastinoscopy is sometimes necessary to eliminate false-negative results. Elastography is a recent technique that can be combined with EBUS to evaluate the elasticity and consequently the nature of a tissue. The primary objective was to evaluate the diagnostic performance of EBUS-TBNA combined with elastography for the assessment of mediastinal lymph nodes. METHODS: Single-center, prospective study in patients with mediastinal lymphadenopathy. EBUS-TBNA combined with elastography was performed in each patient. Several elastographic parameters were studied: colorimetric score, average elasticity, elasticity ratio, percentage of hard areas. The final diagnosis was that obtained by TBNA cytology, histology of a surgical biopsy, when performed, or follow-up CT and PET-CT at 6 months. RESULTS: Overall, 110 lymph nodes were examined in 87 patients: 44 were malignant according to TBNA. These nodes had significantly higher elasticity ratio, percentage of hard areas and colorimetric score and significantly lower average elasticity compared to benign nodes (P<0.001). With a negative predictive value of 100%, the cut-offs defined by receiver operating characteristic curves were 1.4 for elasticity ratio, 84.8 for average elasticity, 32.6 for percentage of hard areas and 3 for colorimetric score. No adverse events were observed. CONCLUSION: Endobronchial ultrasound elastography is a non-invasive technique that can contribute to prediction of the nature of lymph nodes by distinguishing malignant from benign nodes. Although EBUS cannot replace histological examination, elastography can provide reliable complementary information when combined with EBUS.

Neuroergonomic and psychometric evaluation of full-face crew oxygen masks respiratory tolerance: a proof-of-concept study.

INTRODUCTION: Preventing in-flight hypoxia in pilots is typically achieved by wearing oxygen masks. These masks must be as comfortable as possible to allow prolonged and repeated use. The consequences of mask-induced facial contact pressure have been extensively studied, but little is known about mask-induced breathing discomfort. Because breathlessness is a strong distractor and engages cerebral resources, it could negatively impact flying performances. METHODS: Seventeen volunteers (age 20-32) rated respiratory discomfort while breathing with no mask and with two models of quick-donning full-face crew oxygen masks with regulators (mask A, mask B). Electroencephalographic recordings were performed to detect a putative respiratory-related cortical activation in response to inspiratory constraint (experiment 1, n=10). Oxygen consumption was measured using indirect calorimetry (experiment 2, n=10). RESULTS: With mask B, mild respiratory discomfort was reported significantly more frequently than with no mask or mask A (experiment 1: median respiratory discomfort on visual analogue scale 0.9 cm (0.5-1.4), experiment 1; experiment 2: 2 cm (1.7-2.9)). Respiratory-related cortical activation was present in 1/10 subjects with no mask, 1/10 with mask A and 6/10 with mask B (significantly more frequently with mask B). Breathing pattern, sigh frequency and oxygen consumption were not different. CONCLUSIONS: In a laboratory setting, breathing through high-end aeronautical full-face crew oxygen masks can induce mild breathing discomfort and activate respiratory-related cortical networks. Whether or not this can occur in real-life conditions and have operational consequences remains to be investigated. Meanwhile, respiratory psychometric and neuroergonomic approaches could be worth integrating to masks development and evaluation processes.

CARE-rCortex: A Matlab toolbox for the analysis of CArdio-REspiratory-related activity in the Cortex.

BACKGROUND: Although cardio-respiratory (CR) system is generally controlled by the autonomic nervous system, interactions between the cortex and these primary functions are receiving an increasing interest in neurosciences. NEW METHOD: In general, the timing of such internally paced events (e.g. heartbeats or respiratory cycles) may display a large variability. For the analysis of such CR event-related EEG potentials, a baseline must be correctly associated to each cycle of detected events. The open-source toolbox CARE-rCortex provides an easy-to-use interface to detect CR events, define baselines, and analyse in time-frequency (TF) domain the CR-based EEG potentials. RESULTS: CARE-rCortex provides some practical tools to detect and validate these CR events. Users can define baselines time-locked to a phase of respiratory or heart cycle. A statistical test has also been integrated to highlight significant points of the TF maps with respect to the baseline. We illustrate the use of CARE-rCortex with the analysis of two real cardio-respiratory datasets. COMPARISON WITH EXISTING METHODS: Compared to other open-source toolboxes, CARE-rCortex allows users to automatically detect CR events, to define and check baselines for each detected event. Different baseline normalizations can be used in the TF analysis of EEG epochs. CONCLUSIONS: The analysis of CR-related EEG activities could provide valuable information about cognitive or pathological brain states. CARE-rCortex runs in Matlab as a plug-in of the EEGLAB software, and it is publicly available at https://github.com/FannyGrosselin/CARE-rCortex.

Riemannian Geometry Applied to Detection of Respiratory States From EEG Signals: The Basis for a Brain-Ventilator Interface.

GOAL: During mechanical ventilation, patient-ventilator disharmony is frequently observed and may result in increased breathing effort, compromising the patient's comfort and recovery. This circumstance requires clinical intervention and becomes challenging when verbal communication is difficult. In this study, we propose a brain-computer interface (BCI) to automatically and noninvasively detect patient-ventilator disharmony from electroencephalographic (EEG) signals: a brain-ventilator interface (BVI). METHODS: Our framework exploits the cortical activation provoked by the inspiratory compensation when the subject and the ventilator are desynchronized. Use of a one-class approach and Riemannian geometry of EEG covariance matrices allows effective classification of respiratory states. The BVI is validated on nine healthy subjects that performed different respiratory tasks that mimic a patient-ventilator disharmony. RESULTS: Classification performances, in terms of areas under receiver operating characteristic curves, are significantly improved using EEG signals compared to detection based on air flow. Reduction in the number of electrodes that can achieve discrimination can be often desirable (e.g., for portable BCI systems). By using an iterative channel selection technique, the common highest order ranking, we find that a reduced set of electrodes (n = 6) can slightly improve for an intrasubject configuration, and it still provides fairly good performances for a general intersubject setting. CONCLUSION: Results support the discriminant capacity of our approach to identify anomalous respiratory states, by learning from a training set containing only normal respiratory epochs. SIGNIFICANCE: The proposed framework opens the door to BVIs for monitoring patient's breathing comfort and adapting ventilator parameters to patient respiratory needs.

Neurally adjusted ventilatory assist as an alternative to pressure support ventilation in adults: a French multicentre randomized trial.

PURPOSE: Neurally adjusted ventilatory assist (NAVA) is a ventilatory mode that tailors the level of assistance delivered by the ventilator to the electromyographic activity of the diaphragm. The objective of this study was to compare NAVA and pressure support ventilation (PSV) in the early phase of weaning from mechanical ventilation. METHODS: A multicentre randomized controlled trial of 128 intubated adults recovering from acute respiratory failure was conducted in 11 intensive care units. Patients were randomly assigned to NAVA or PSV. The primary outcome was the probability of remaining in a partial ventilatory mode (either NAVA or PSV) throughout the first 48 h without any return to assist-control ventilation. Secondary outcomes included asynchrony index, ventilator-free days and mortality. RESULTS: In the NAVA and PSV groups respectively, the proportion of patients remaining in partial ventilatory mode throughout the first 48 h was 67.2 vs. 63.3 % (P = 0.66), the asynchrony index was 14.7 vs. 26.7 % (P < 0.001), the ventilator-free days at day 7 were 1.0 day [1.0-4.0] vs. 0.0 days [0.0-1.0] (P < 0.01), the ventilator-free days at day 28 were 21 days [4-25] vs. 17 days [0-23] (P = 0.12), the day-28 mortality rate was 15.0 vs. 22.7 % (P = 0.21) and the rate of use of post-extubation noninvasive mechanical ventilation was 43.5 vs. 66.6 % (P < 0.01). CONCLUSIONS: NAVA is safe and feasible over a prolonged period of time but does not increase the probability of remaining in a partial ventilatory mode. However, NAVA decreases patient-ventilator asynchrony and is associated with less frequent application of post-extubation noninvasive mechanical ventilation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02018666.

[Pleural procedures in patients treated by platelet aggregation inhibitors: An opinion survey]. / Gestes pleuraux sous antiagrégants plaquettaires : une enquête d'opinion.

BACKGROUND: When pleural procedures (thoracocentesis, blind pleural biopsies and chest tube insertion) are required in patients taking long-term platelet aggregation inhibitors, the risk of bleeding must be balanced against the risk of arterial thrombosis. Currently, the bleeding risk of pleural procedures is poorly understood. OBJECTIVE: The objective of the survey was to gather the opinion of respiratory physicians regarding the bleeding risk of pleural procedures in patients taking platelet aggregation inhibitors. METHODS: We emailed a standardized questionnaire designed by the French National Authority for Health to 2697 French respiratory physicians. RESULTS: One hundred and eighty-eight of the 2697 questionnaires were returned (response rate: 7 %). The respiratory physicians declared that they performed an average of 8 pleural procedures per month. One hundred and seventy-five responders (95 %) practised pleural procedures in patients receiving platelet aggregation inhibitors; 68 of them (39 %) reported experiencing haemorrhagic complications. The bleeding risk associated with thoracentesis and chest tube insertion was considered minor by 97.8 and 65 % of responders respectively, whereas it was considered major for blind pleural biopsies by 73.4 %. Respiratory physicians were more reticent about performing pleural procedures in patients treated with clopidogrel than in those taking aspirin. CONCLUSION: This study provides an overview of how respiratory physicians perceive the bleeding risk associated with pleural procedures in patients taking platelet aggregation inhibitors.

Respiratory neuromodulation in patients with neurological pathologies: for whom and how?

Implanted phrenic nerve stimulation is a technique restoring spontaneous breathing in patients with respiratory control failure, leading to being dependent on mechanical ventilation. This is the case for quadriplegic patients with a high spinal cord injury level and for patients with congenital central hypoventilation syndrome. The electrophysiological diaphragm explorations permits better patient selection, confirming on the one hand a definite issue with central respiratory command and on the other hand the integrity of diaphragmatic phrenic nerves. Today there are two different phrenic stimulation techniques: the quadripolar intrathoracic stimulation and the bipolar intradiaphragmatic stimulation. Both techniques allow patients to be weaned off their mechanical ventilator, improving dramatically their quality of life. In fact, one of the systems (phrenic intradiaphragmatic stimulation) was granted social security reimbursement in 2009, and now both are reimbursed. In the future, phrenic intradiaphragmatic stimulation may find its place in the intensive care unit, for patients needing it temporarily, for example, after certain surgeries with respiratory complications as well as diaphragmatic atrophies induced by prolonged mechanical ventilation.

Multifaceted bench comparative evaluation of latest intensive care unit ventilators.

BACKGROUND: Independent bench studies using specific ventilation scenarios allow testing of the performance of ventilators in conditions similar to clinical settings. The aims of this study were to determine the accuracy of the latest generation ventilators to deliver chosen parameters in various typical conditions and to provide clinicians with a comprehensive report on their performance. METHODS: Thirteen modern intensive care unit ventilators were evaluated on the ASL5000 test lung with and without leakage for: (i) accuracy to deliver exact tidal volume (VT) and PEEP in assist-control ventilation (ACV); (ii) performance of trigger and pressurization in pressure support ventilation (PSV); and (iii) quality of non-invasive ventilation algorithms. RESULTS: In ACV, only six ventilators delivered an accurate VT and nine an accurate PEEP. Eleven devices failed to compensate VT and four the PEEP in leakage conditions. Inspiratory delays differed significantly among ventilators in invasive PSV (range 75-149 ms, P=0.03) and non-invasive PSV (range 78-165 ms, P<0.001). The percentage of the ideal curve (concomitantly evaluating the pressurization speed and the levels of pressure reached) also differed significantly (range 57-86% for invasive PSV, P=0.04; and 60-90% for non-invasive PSV, P<0.001). Non-invasive ventilation algorithms efficiently prevented the decrease in pressurization capacities and PEEP levels induced by leaks in, respectively, 10 and 12 out of the 13 ventilators. CONCLUSIONS: We observed real heterogeneity of performance amongst the latest generation of intensive care unit ventilators. Although non-invasive ventilation algorithms appear to maintain adequate pressurization efficiently in the case of leakage, basic functions, such as delivered VT in ACV and pressurization in PSV, are often less reliable than the values displayed by the device suggest.

[Adjuvant surgical resection for multidrug-resistant tuberculosis: A review]. / Chirurgie et tuberculose multi/ultrarésistante : une revue de la littérature réhabilite une intervention adjuvante à l'antibiothérapie chez des patients sélectionnés.

INTRODUCTION: The frequency of multi and extensively drug resistant pulmonary tuberculosis (MDR/XDR-TB) is increasing worldwide, with major issues related to treatment modalities and outcome. In this setting, the exact benefits associated with surgical resection are still unknown. METHODS: We performed a literature review to determine the indications, morbidity, mortality and bacteriological success associated with the surgical management of MDR/XDR-TB patients. RESULTS: Altogether, 177 publications dealing with surgical resection and MDR/XDR-TB have been analyzed, including 35 surgical series and 24 cohort studies summarized in one meta-analysis. The surgical series reported success rates from 47% to 100%, complication rates from 0 to 29%, and mortality rates from 0 to 8%. The published meta-analysis reported a statistically significant association between surgical resection and treatment success (OR 2.24, IC95% 1.68-2.97). However, all these studies were associated with selection bias. International consensual guidelines included a multidisciplinary assessment in a reference centre, a personalized and prolonged antibiotic treatment and a medico-surgical discussion on a case-to-case basis. PERSPECTIVES: These guidelines are now applied for the management of patients with MDR/XDR-TB in our centre. Further studies are required to avoid further increase in the burden of MDR/XDR-TB and to establish the optimal timing of medical and surgical treatments.

[Prevention of COPD exacerbation: a fundamental challenge]. / Prévention des exacerbations de BPCO : un enjeu fondamental.

INTRODUCTION: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a cause of suffering for patients and a burden for healthcare systems and society. Their prevention represents individual and collective challenge. The present article is based on the work of a group of experts who met on 5th and 6th May 2011 and seeks to highlight the importance of AECOPD. STATE OF THE ART: In the absence of easily quantifiable criteria, the definition of AECOPD varies in the literature, making identification difficult and affecting interpretation of study results. Exacerbations increase mortality and risk of cardiovascular disease. They also increase the risk of developing further exacerbations, accelerate the decline in lung function and contribute to reduction in muscle mass. By limiting physical activity and affecting mental state (anxiety, depression), AECOPD are disabling and impair quality of life. They increase work absenteeism and are responsible for about 60% of the global cost of COPD. PERSPECTIVES: Earlier identification with simple criteria, possibly associated to patient phenotyping, could be helpful in preventing hospitalization. CONCLUSIONS: Given their immediate and delayed impact, AECOPD should not be trivialized or neglected. Their prevention is a fundamental issue.

[COPD and erythropoiesis: interactions and consequences]. / BPCO et érythropoïèse : interactions et conséquences.

Erythropoiesis is modified in chronic obstructive pulmonary disease (COPD). Tobacco smoke, hypoxaemia, systemic inflammation, and infectious exacerbations are the main factors involved. Polymorphisms in genes involved in the regulation of erythropoiesis probably explain the individual susceptibility and variability in the response. The roles of comorbidities related to COPD and the impact of treatment on erythropoiesis are important confounding factors. While polycythaemia is often related to tobacco smoke and hypoxaemia, it has become less common due to the improvement of COPD follow-up and especially the initiation of long-term oxygen therapy. The control of the main causes is often sufficient, but in cases of severe polycythaemia an erythrapheresis is indicated. Anaemia has recently been reported as a more common and serious complication. It increases dyspnoea and reduces physical activity and quality of life. Its impact on survival and the requirements for healthcare has recently been confirmed. The main approach to the management of anaemia remains exclusion of any curable causes, reducing exacerbations and systemic inflammation, and controlling the comorbidities. Though erythropoietin has some benefits in the so-called "anaemia of chronic disease", this still remains to be confirmed in patients with COPD.

Ventilatory response to exercise does not evidence electroencephalographical respiratory-related activation of the cortical premotor circuitry in healthy humans.

AIM: The neural structures responsible for the coupling between ventilatory control and pulmonary gas exchange during exercise have not been fully identified. Suprapontine mechanisms have been hypothesized but not formally evidenced. Because the involvement of a premotor circuitry in the compensation of inspiratory mechanical loads has recently been described, we looked for its implication in exercise-induced hyperpnea. METHODS: Electroencephalographical recordings were performed to identify inspiratory premotor potentials (iPPM) in eight physically fit normal men during cycling at 40 and 70% of their maximal oxygen consumption ((V)·O(2max) ). Relaxed pedalling (0 W) and voluntary sniff manoeuvres were used as negative and positive controls respectively. RESULTS: Voluntary sniffs were consistently associated with iPPMs. This was also the case with voluntarily augmented breathing at rest (in three subjects tested). During the exercise protocol, no respiratory-related activity was observed whilst performing bouts of relaxed pedalling. Exercise-induced hyperpnea was also not associated with iPPMs, except in one subject. CONCLUSION: We conclude that if there are cortical mechanisms involved in the ventilatory adaptation to exercise in physically fit humans, they are distinct from the premotor mechanisms activated by inspiratory load compensation.