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.

[Evaluation of permanent disability levels in occupational pulmonary diseases]. / Comment évaluer en 2019 les taux d'incapacité permanente des pathologies professionnelles pulmonaires ?

Compensation for occupational pulmonary diseases requires the establishment of guidelines based on standardized and objective criteria, in order to provide compensation that is as fair as possible to patients who suffer from them. A review of the elements necessary for the examination of an individual file was carried out by a working group. It is accepted that respiratory functional exploration is the key element in assessing the level of permanent disability in all of these conditions, with the exception of thoracic malignancies. Guiding scales have been developed for the respiratory impairment of three types of conditions: occupational asthma, thoracic malignancy, and other respiratory diseases. Additional criteria for increasing the permanent disability level are also proposed in order to take into account professional prejudice, in particular the possibility or not of continuing the occupational activity, in the same job or after changing to another. For certain respiratory diseases, a periodic reassessment of the initially attributed permanent disability level is recommended as well as the initial one at the time of definitive cessation of occupational activity.

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.

Does training respiratory physicians in clinical respiratory physiology and interpretation of pulmonary function tests improve core knowledge?

Lung function tests have a major role in respiratory medicine. Training in lung function tests is variable within the European Union. In this study, we have shown that an internship in a lung function tests laboratory significantly improved the technical and diagnostic skills of French respiratory trainees.

Disease volumes as a marker for patient response in malignant pleural mesothelioma.

BACKGROUND: The goal of this study was to create a comprehensive model for malignant pleural mesothelioma patient survival utilizing continuous, time-varying estimates of disease volume from computed tomography (CT) imaging in conjunction with clinical covariates. PATIENTS AND METHODS: Serial CT scans were obtained during the course of clinically standard chemotherapy for 81 patients. The pleural disease volume was segmented for each of the 281 CT scans, and relative changes in disease volume from the baseline scan were tracked over the course of serial follow-up imaging. A prognostic model was built using time-varying disease volume measurements in conjunction with clinical covariates. RESULTS: Over the course of treatment, disease volume decreased by an average of 19%, and median patient survival was 12.6 months from baseline. In a multivariate survival model, changes in disease volume were significantly associated with patient survival along with disease histology, Eastern Cooperative Oncology Group performance status, and presence of dyspnea. CONCLUSIONS: Analysis of the trajectories of disease volumes during chemotherapy for patients with mesothelioma indicates that increasing disease volume was significantly and independently associated with poor patient prognosis in both univariate and multivariate survival models.

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.

[Primary central nervous system lymphoma presenting with central neurogenic hyperventilation. A case report and review of the literature]. / Hyperventilation neurogène centrale révélant un lymphome cérébral primitif. Une observation et revue de la littérature.

INTRODUCTION: Central neurogenic hyperventilation (CNH) in an awake patient is a rare entity. OBSERVATION: We report here a 54-year-old patient who developed central neurogenic hyperventilation as the initial presentation of a primary central nervous system lymphoma located in the brainstem. CONCLUSION: The patient's hyperventilation resolved completely with chemotherapy for primary CNS lymphoma. Most of the cases reported in the literature are related to a diffuse tumor of the brainstem with an intriguing overrepresentation of primary CNS lymphoma. The pathogenesis of CNH is discussed.

Effects of upper airway anaesthesia on respiratory-related evoked potentials in humans.

Cortical potentials evoked by mid-inspiratory occlusion arise from numerous receptors, many of which are probably within the upper airway. Their precise nature is not known. The aim of the current study was to improve knowledge of this by studying the effects of topical upper airway anaesthesia on respiratory-related evoked potentials. Respiratory-related evoked potentials were described through the averaging of electroencephalogram (EEG) epochs following mid-inspiratory occlusions (C3-CZ; C4-CZ). A total of 21 healthy volunteers (13 male, aged 22-52 yrs) were studied during mouth breathing, before and after topical upper airway anaesthesia (lidocaine). Moreover, 15 subjects were studied during nose breathing with and without anaesthesia. Six subjects were studied whilst inhaling L-menthol. Typical potentials were present in all the subjects, their components featuring normal amplitudes and latencies. The route of breathing and upper airway anaesthesia did not modify the EEG responses to inspiratory occlusions, qualitatively or quantitatively, during mouth or nose breathing. L-menthol had no effect. Upper airway receptors sensitive to topical anaesthesia are unlikely to contribute significantly to mid-inspiratory occlusion-evoked potentials. On the contrary, deeper receptors, such as joint and muscle receptors, could contribute dominantly to these potentials.

Diffusional screening in real 3D human acini--a theoretical study.

Gas exchange at the acinar level involves several physico-chemical phenomena within a complex geometry. A gas transport model, which takes into account both the diffusion into the acinus and the diffusion across the alveolar membrane, is used to understand gas mixing in realistic systems. It is first shown that the behaviour of the system, computed on model geometries in 3D, only depends on the topological structure of the acinus. Taking advantage of this property, a new efficient method based on random walks on a lattice is used to compute gas diffusion in structures taken from real morphological data. This approach shows that, at rest, the human acinus efficiency is only 30-40%. These results provide a new evidence of the existence of diffusional screening at the acinar level. This implies permanent spatial inhomogeneity of oxygen and carbon dioxide partial pressure. The notion of an "alveolar gas" is reinterpreted as a spatial average of the gas distribution. This model casts new light on the respiratory properties of other gas mixtures, such as helium-oxygen.

Facilitation of the diaphragm response to transcranial magnetic stimulation by increases in human respiratory drive.

The human respiratory neural drive has an automatic component (bulbospinal pathway) and a volitional component (corticospinal pathway). The aim of this study was to assess the effects of a hypercapnia-induced increase in the automatic respiratory drive on the function of the diaphragmatic corticospinal pathway as independently as possible of any other influence. Thirteen healthy volunteers breathed room air and then 5 and 7% hyperoxic CO2. Cervical (cms) and transcranial (tms) magnetic stimulations were performed during early inspiration and expiration. Transdiaphragmatic pressure (Pdi) and surface electromyogram of the diaphragm (DiEMG) and of the abductor pollicis brevis (apbEMG) were recorded in response to cms and tms. During inspiration, Pdi,cms was unaffected by CO2, but Pdi,tms increased significantly with 7% CO2. During expiration, Pdi,cms was significantly reduced by CO2, whereas Pdi,tms was preserved. DiEMG,tms latencies decreased significantly during early inspiration and expiration (air vs. 5% CO2 and air vs. 7% CO2). DiEMG,tms amplitude increased significantly in response to early expiration-tms (air vs. 5% CO2 and air vs. 7% CO2) but not in response to early inspiration-tms. DiEMG,cms latencies and amplitudes were not affected by CO2 whereas 7% CO2 significantly increased the apbEMG,cms latency. The apbEMG,tms vs. apbEMG,cms latency difference was unaffected by CO2. In conclusion, increasing the automatic drive to breathe facilitates the response of the diaphragm to tms, during both inspiration and expiration. This could allow the corticospinal drive to breathe to keep the capacity to modulate respiration in conditions under which the automatic respiratory control is stimulated.

Unaltered respiratory-related evoked potentials after acute diaphragm dysfunction in humans.

Respiratory muscles play an important role in the origin of respiratory sensations. Data dissecting the role of the diaphragm and other inspiratory muscles are scarce. This study aimed to determine the impact of diaphragm dysfunction following inspiratory resistive loading on respiratory-related evoked potentials considered as a neurophysiological substrate of certain types of respiratory sensations. Altogether, nine subjects aged 25-50 yrs (six females) participated in the study. Transdiaphragmatic pressure output of cervical magnetic stimulation (with subdivision in oesophageal and gastric component), and respiratory-related evoked potentials (C3 and C4 derivations in the international 10-20 system) following mid-inspiratory occlusions were studied before and after an inspiratory-resistive loading challenge. Predominant diaphragm dysfunction was observed in seven subjects (average 28% reduction in transdiaphragmatic pressure, from 27.25-19.91 cmH2O, with increased oesophageal-to-gastric pressure ratio). The latencies and amplitudes of all the components of the respiratory-related evoked potentials were unchanged. The study concluded that predominant diaphragm fatigue does not affect respiratory-related evoked potentials.

A phylogenetic hypothesis for the origin of hiccough.

The occurrence of hiccoughs (hiccups) is very widespread and yet their neuronal origin and physiological significance are still unresolved. Several hypotheses have been proposed. Here we consider a phylogenetic perspective, starting from the concept that the ventilatory central pattern generator of lower vertebrates provides the base upon which central pattern generators of higher vertebrates develop. Hiccoughs are characterized by glottal closure during inspiration and by early development in relation to lung ventilation. They are inhibited when the concentration of inhaled CO(2) is increased and they can be abolished by the drug baclofen (an agonist of the GABA(B) receptor). These properties are shared by ventilatory motor patterns of lower vertebrates, leading to the hypothesis that hiccough is the expression of archaic motor patterns and particularly the motor pattern of gill ventilation in bimodal breathers such as most frogs. A circuit that can generate hiccoughs may persist in mammals because it has permitted the development of pattern generators for other useful functions of the pharynx and chest wall muscles, such as suckling or eupneic breathing.

Evidence that ventilatory rhythmogenesis in the frog involves two distinct neuronal oscillators.

In Rana catesbeiana the upper airways are used for two distinct yet highly coordinated ventilatory behaviours: buccal ventilation and lung inflation cycles. How these behaviours are generated and coordinated is unknown. The purpose of this study was to identify putative rhythmogenic brainstem loci involved in these ventilatory behaviours. We surveyed the isolated postmetamorphic brainstem to determine sites where local depolarization, produced by microinjecting the non-NMDA glutamate receptor agonist, AMPA, augmented the ventilatory motor patterns. Two sites were identified: a caudal site, at the level of cranial nerve (CN) X, where AMPA injections caused increased buccal burst frequency but abolished lung bursts, and a rostral site, between the levels of CN VIII and IX, where injections increased the frequency of both types of ventilatory bursts. These two sites were further examined using GABA microinjections to locally inhibit cells. GABA injected into the caudal site suppressed the buccal rhythm but the lung rhythm continued, albeit at a different frequency. When GABA was injected into the rostral site the lung bursts were abolished but the buccal rhythm continued. When the two sites were physically separated by transection, both rostral and caudal brainstem sections were capable of rhythmogenesis. The results suggest the respiratory network within the amphibian brainstem is composed of at least two distinct but interacting oscillators, the buccal and lung oscillators. These putative oscillators may provide a promising experimental model for studying coupled oscillators in vertebrates.

Effects of muscle group recruitment on sniff transdiaphragmatic pressure and its components.

Measuring maximal sniff pressures is an easy way of assessing inspiratory muscle strength. During a static manoeuvre, the pattern of inspiratory muscle recruitment during a sniff can vary from one individual to another. We therefore assessed how voluntarily changing muscle recruitment would affect sniff oesophageal, gastric and transdiaphragmatic pressures (Pes,sn, Pga,sn and Pdi,sn, respectively). Ten normal subjects (age 27-38 years) performed natural sniff manoeuvres ("nat"), and preferentially diaphragmatic ("dia") or extradiaphragmatic ("extradia") sniff manoeuvres, after having learnt to dissociate between the inspiratory muscle groups. Abdominal displacements were monitored using a belt-mounted strain gauge. Natural patterns of muscle recruitment varied among subjects. On average, Pes,sn,nat was [median (range)] 81 (21-105) cmH2O. All of the subjects were able to modify inspiratory muscle recruitment voluntarily. Pes,sn was not significantly affected by the type of manoeuvre performed, as opposed to Pdi,sn, which, as expected, increased with both the diaphragmatic and extradiaphragmatic manoeuvres [Pdi,sn,dia 132 (99-157) cmH2O, Pdi,sn,extradia 96 (50-146) cmH2O, P<0.05]. Whatever the manoeuvre, there was no correlation between Pes and Pdi, but Pga and Pdi were correlated during both the diaphragmatic (r = 0.82, P < 0.05) and the extradiaphragmatic manoeuvre (r = 0.70, P < 0.05). Pes,sn may have limitations as an index of diaphragm function, but by showing its independence from inspiratory muscle recruitment, this study contributes to its validation as a robust index of global inspiratory muscle strength that is particularly well suited for follow-up studies. This should extend to Pes,sn substitutes measured at the airway opening.