Treatment of COVID-19-associated ARDS with umbilical cord-derived mesenchymal stromal cells in the STROMA-CoV-2 multicenter randomized double-blind trial: long-term safety, respiratory function, and quality of life.

BACKGROUND: The STROMA-CoV-2 study was a French phase 2b, multicenter, double-blind, randomized, placebo-controlled clinical trial that did not identify a significant efficacy of umbilical cord-derived mesenchymal stromal cells in patients with SARS-CoV-2-induced acute respiratory distress syndrome. Safety on day 28 was found to be good. The aim of our extended study was to assess the 6- and 12-month safety of UC-MSCs administration in the STROMA-CoV-2 cohort. METHODS: A detailed multi-domain assessment was conducted at 6 and 12 months following hospital discharge focusing on adverse events, lung computed tomography-scan, pulmonary and muscular functional status, and quality of life in the STROMA-CoV-2 cohort including SARS-CoV-2-related early (< 96 h) mild-to-severe acute respiratory distress syndrome. RESULTS: Between April 2020 and October 2020, 47 patients were enrolled, of whom 19 completed a 1-year follow-up. There were no significant differences in any endpoints or adverse effects between the UC-MSCs and placebo groups at the 6- and 12-month assessments. Ground-glass opacities persisted at 1 year in 5 patients (26.3%). Furthermore, diffusing capacity for carbon monoxide remained altered over 1 year, although no patient required oxygen or non-invasive ventilatory support. Quality of life revealed declines in mental, emotional and physical health throughout the follow-up period, and the six-minute walking distance remained slightly impaired at the 1-year patient assessment. CONCLUSIONS: This study suggests a favorable safety profile for the use of intravenous UC-MSCs in the context of the first French wave of SARS-CoV-2-related moderate-to-severe acute respiratory distress syndrome, with no adverse effects observed at 1 year.

Higher baseline heart rate variability in CCHS patients with progestin-associated recovery of hypercapnic ventilatory response.

After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment.Clinical Trials Identifier NCT01243697.

Serotonin and the ventilatory effects of etonogestrel, a gonane progestin, in a murine model of congenital central hypoventilation syndrome.

Introduction: Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Methods: Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The influence of etonogestrel on respiratory variables under hypercapnia was investigated using whole-body plethysmographic recording. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized in the medulla oblongata by ultra-high-performance liquid chromatography. Results: We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and Phox2b mutant without restored chemosensitivity indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Finally, the increase in serotonergic signaling by the fluoxetine application modulated the respiratory effect of etonogestrel differently between Phox2b mutant mice and their WT littermates or WT OF1 mice, a result which parallels with differences in the functional state of serotonergic metabolic pathways between these different mice. Discussion: Our work thus highlights that serotonin systems were critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.

Short-term cognitive loading deteriorates breathing pattern and gas exchange in adult patients with congenital central hypoventilation syndrome.

Question: Human PHOX2B mutations result in life-threatening sleep-related hypoventilation (congenital central hypoventilation syndrome, CCHS). Most patients retain ventilatory activity when awake through a respiratory-related cortical network. We hypothesised that this need to mobilise cortical resources to breathe would lead to breathing-cognition interferences during cognitive loading. Patients and methods: Seven adult CCHS patients (five women; median age 21) performed standard neuropsychological tests (paced auditory serial addition test - calculation capacity, working memory, sustained and divided attention; trail making test - visuospatial exploration capacity, cognitive processing speed, attentional flexibility; Corsi block-tapping test - visuospatial memory, short-term memory, working memory) during unassisted breathing and under ventilatory support. Ventilatory variables and transcutaneous haemoglobin oxygen saturation were recorded. Cortical connectivity changes between unassisted breathing and ventilatory support were assessed using electroencephalographic recordings (EEG). Results: Baseline performances were lower than expected in individuals of this age. During unassisted breathing, cognitive loading coincided with increased breathing variability, and decreases in oxygen saturation inversely correlated with an increasing number of apnoeic cycles per minute (rho -0.46, 95% CI -0.76 to -0.06, p=0.01). During ventilatory support, cognitive tasks did not disrupt breathing pattern and were not associated with decreased oxygen saturation. Ventilatory support was associated with changes in EEG cortical connectivity but not with improved test performances. Conclusions: Acute cognitive loads induce oxygen desaturation in adult CCHS patients during unassisted breathing, but not under ventilatory support. This justifies considering the use of ventilatory support during mental tasks in CCHS patients to avoid repeated episodes of hypoxia.

Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis.

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and are highly fatal. We report the results of a strategy that included identification of individuals with severe ICI myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with the CTLA4 fusion protein abatacept and the JAK inhibitor ruxolitinib. Forty cases with definite ICI myocarditis were included with pathologic confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. The abatacept dose was adjusted using CD86 receptor occupancy on circulating monocytes. The myotoxicity-related fatality rate was 3.4% (1/30) in these 30 patients versus 60% in the first quartile (P < 0.0001). These clinical results are hypothesis-generating and need further evaluation. SIGNIFICANCE: Early management of respiratory muscle failure using mechanical ventilation and high-dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis. See related commentary by Dougan, p. 1040. This article is highlighted in the In This Issue feature, p. 1027.

Impact of inspiratory threshold loading on brain activity and cognitive performances in healthy humans.

In healthy humans, inspiratory threshold loading deteriorates cognitive performances. This can result from motor-cognitive interference (activation of motor respiratory-related cortical networks vs. executive resources allocation), sensory-cognitive interference (dyspnea vs. shift in attentional focus), or both. We hypothesized that inspiratory loading would concomitantly induce dyspnea, activate motor respiratory-related cortical networks, and deteriorate cognitive performance. We reasoned that a concomitant activation of cortical networks and cognitive deterioration would be compatible with motor-cognitive interference, particularly in case of a predominant alteration of executive cognitive performances. Symmetrically, we reasoned that a predominant alteration of attention-depending performances would suggest sensory-cognitive interference. Twenty-five volunteers (12 men; 19.5-51.5 yr) performed the Paced Auditory Serial Addition Test (PASAT-A and B; calculation capacity, working memory, attention), the Trail Making Test (TMT-A, visuospatial exploration capacity; TMT-B, visuospatial exploration capacity, and attention), and the Corsi block-tapping test (visuospatial memory, short-term, and working memory) during unloaded breathing and inspiratory threshold loading in random order. Loading consistently induced dyspnea and respiratory-related brain activation. It was associated with deteriorations in PASAT-A [52 [45.5;55.5]; (median [interquartile range]) to 48 [41;54.5], P = 0.01], PASAT-B (55 [47.5;58] to 51 [44.5;57.5], P = 0.01), and TMT-B (44 s [36;54.5] to 53 s [42;64], P = 0.01), but did not affect TMT-A and Corsi. The concomitance of cortical activation and cognitive performance deterioration is compatible with competition for cortical resources (motor-cognitive interference), whereas the profile of cognitive impairment (PASAT and TMT-B but not TMT-A and Corsi) is compatible with a contribution of attentional distraction (sensory-cognitive interference). Both mechanisms are therefore likely at play.NEW & NOTEWORTHY To our knowledge, this is the first study exploring the interferences between inspiratory loading and cognition in healthy subjects with the concomitant use of neuropsychological tests and electroencephalographic recordings. Inspiratory loading was associated with dyspnea, respiratory-related changes in brain activation, and a pattern of deterioration of neuropsychological tests suggestive of attentional disruption. Inspiratory loading is therefore likely to impact cognitive performances through both motor-cognitive interference (engagement of cortical networks) and sensory-cognitive interference (dyspnea-related shift in attentional focus).

How and to What Extent Immunological Responses to SARS-CoV-2 Shape Pulmonary Function in COVID-19 Patients.

COVID-19 is a disease caused by a new coronavirus SARS-CoV-2, primarily impacting the respiratory system. COVID-19 can result in mild illness or serious disease leading to critical illness and requires admission to ICU due to respiratory failure. There is intense discussion around potential factors predisposing to and protecting from COVID-19. The immune response and the abnormal respiratory function with a focus on respiratory function testing in COVID-19 patients will be at the center of this Perspective article of the Frontiers in Physiology Series on "The Tribute of Physiology for the Understanding of COVID-19 Disease." We will discuss current advances and provide future directions and present also our perspective in this field.

Feasibility of a Hypoxic Challenge Test Under Noninvasive Ventilation Versus Oxygen in Neuromuscular Patients with Chronic Respiratory Insufficiency.

Ribeiro Baptista, Bruno, Morgane Faure, Gimbada Benny Mwenge, Capucine Morelot-Panzini, Christian Straus, Thomas Similowski, and Jésus Gonzalez-Bermejo. Feasibility of a hypoxic challenge test under noninvasive ventilation versus oxygen in neuromuscular patients with chronic respiratory insufficiency. High Alt Med Biol. 22:346-350, 2021. Background: The British Thoracic Society recommendations suggest that all patients with an oxygen saturation (SpO2) <85% during a hypoxic challenge test (HCT) should receive supplemental oxygen during air travel. However, neuromuscular patients already using ventilatory support are a specific population and noninvasive ventilation (NIV) during a flight could be an alternative to oxygen for hypoxemia correction, through the augmentation of ventilation. Methods: We conducted a comparative, observational study of neuromuscular patients with chronic respiratory failure, requiring nocturnal mechanical ventilation, who were planning to take a flight. HCT was performed with a ventilated canopy placed over the patient's head or the patient's home ventilator. The positive threshold value chosen for the HCT was <90% SpO2. Results: HCTs were performed on 13 adults with neuromuscular diseases using their home ventilator. Among them, 11 had a positive HCT. For all patients with a positive test, hypoxemia was corrected (SpO2 to >90%) by oxygen therapy (+9 [6-12]%, p = 0.0029). Patient's home ventilator also significantly increased the SpO2 by 8 [7-12]% (p = 0.016). Correction of SpO2 during the HCT was not different between oxygen and NIV. NIV was associated with a significant decrease in pressure, end tidal, carbon dioxide (PetCO2) (-10 [-16 to -7.5] mmHg, p = 0.04). Conclusions: The performance of an adapted HCT in home-ventilated patients with a neuromuscular pathology may be useful in a personalized treatment plan for air travel. NIV can be a new alternative to oxygen therapy for neuromuscular patients planning to take a flight.

Residual ground glass opacities three months after Covid-19 pneumonia correlate to alteration of respiratory function: The post Covid M3 study.

INTRODUCTION: Lung function in survivors of SARS-Co-V2 pneumonia is poorly known, but concern over the possibility of sequelae exists. METHODS: Retrospective study on survivors with confirmed infection and pneumonia on chest-CT. Correlations between PFT and residual radiologic anomalies at three months taking into account initial clinical and radiological severity and steroid use during acute phase. RESULTS: 137 patients (69 men, median age 59 (Q1 50; Q3 68), BMI 27.5 kg/m2 (25.1; 31.7)) were assessed. Only 32.9% had normal PFT, 75 had altered DLCO. Median (Q1; Q3) values were: VC 79 (66; 92) % pred, FEV1 81 (68; 89), TLC 78 (67; 85), DLCO 60 (44; 72), and KCO 89 (77; 105). Ground glass opacities (GGO) were present in 103 patients (75%), reticulations in 42 (30%), and fibrosis in 18 (13%). There were significantly lower FEV1 (p = 0.0089), FVC (p = 0.0010), TLC (p < 0.0001) and DLCO (p < 0.0001) for patients with GGO, lower TLC (p = 0.0913) and DLCO (p = 0.0181) between patients with reticulations and lower FVC (p = 0.0618), TLC (p = 0.0742) DLCO (p = 0.002) and KCO (p = 0.0114) between patients with fibrosis. Patients with initial ≥50% lung involvement had significantly lower FEV1 (p = 0.0019), FVC (p = 0.0033), TLC (p = 0.0028) and DLCO (p = 0.0003) compared to patients with ≤10%. There was no difference in PFT and residual CT lesions between patients who received steroids and those who did not. CONCLUSION: The majority of patients have altered PFT at three months, even in patients with mild initial disease, with significantly lower function in patients with residual CT lesions. Steroids do not seem to modify functional and radiological recovery. Long-term follow-up is needed.

Baclofen destabilises breathing during sleep in healthy humans: A randomised, controlled, double-blind crossover trial.

AIMS: Periodic breathing is frequent in patients with severe heart failure. Apart from being an indicator of severity, periodic breathing has its own deleterious consequences (sleep-related oxygen desaturations, sleep fragmentation), which justifies attempts to correct it irrespective of the underlying disease. Animal models and human data suggest that baclofen can reconfigure respiratory central pattern generators. We hypothesised that baclofen, a GABAB agonist, may thus be able to correct periodic breathing in humans. METHODS: Healthy volunteers were exposed to hypoxia during sleep. Participants who developed periodic breathing (n = 14 [53 screened]) were randomly assigned to double-blind oral baclofen (progressively increased to 60 mg/d) or placebo. The primary outcome was the coefficient of variation (CoVar) of respiratory cycle total time considered as an indicator of breathing irregularity. Secondary outcomes included the CoVar of tidal volume, apnoea-hypopnoea index, sleep fragmentation index and ventilatory complexity (noise limit). RESULTS: The analysis was conducted in 9 subjects after exclusion of incomplete datasets. CoVar of respiratory cycle total time significantly increased with baclofen during non-rapid eye movement sleep (median with placebo 56.00% [37.63-78.95]; baclofen 85.42% [68.37-86.40], P = .020; significant difference during the N1-N2 phases of sleep but not during the N3 phase). CoVar of tidal volume significantly increased during N1-N2 sleep. The apnoea-hypopnoea index, sleep fragmentation index and ventilatory complexity were not significantly different between placebo and baclofen. CONCLUSION: Baclofen did not stabilise breathing in our model. On the contrary, it increased respiratory variability. Baclofen should probably not be used in patients with or at risk of periodic breathing.

Awakening efficacy of a vibrotactile device in patients on home nocturnal ventilatory assistance and healthy subjects as family caregiver proxies.

The objective of this study was to test the capacity of vibrotactile stimulation transmitted to the wrist bones by a vibrating wristband to awaken healthy individuals and patients requiring home mechanical ventilation during sleep. Healthy subjects (n = 20) and patients with central hypoventilation (CH) (Congenital Central Hypoventilation syndrome n = 7; non-genetic form of CH n = 1) or chronic obstructive pulmonary disease (COPD) (n = 9), underwent a full-night polysomnography while wearing the wristband. Vibrotactile alarms were triggered five times during the night at random intervals. Electroencephalographic (EEG), clinical (trunk lift) and cognitive (record the time on a sheet of paper) arousals were recorded. Cognitive arousals were observed for 94% of the alarms in the healthy group and for 66% and 63% of subjects in the CH and COPD groups, respectively (p < 0.01). The percentage of participants experiencing cognitive arousals for all alarms, was 72% for healthy subjects, 37.5% for CH patients and 33% for COPD patients (ns) (94%, 50% and 44% for clinical arousals (p < 0.01) and 100%, 63% and 44% for EEG arousals (p < 0.01)). Device acceptance was good in the majority of cases, with the exception of one CH patient and eight healthy participants. In summary this study shows that a vibrotactile stimulus is effective to induce awakenings in healthy subjects, but is less effective in patients, supporting the notion that a vibrotactile stimulus could be an effective backup to a home mechanical ventilator audio alarm for healthy family caregivers.

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

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

Current Perspectives for the use of Gonane Progesteronergic Drugs in the Treatment of Central Hypoventilation Syndromes.

BACKGROUND: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be lifethreatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives. OBJECTIVE: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of potential clinical interest for the treatment of CHS. METHODS: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins. RESULTS: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA signaling in the respiratory network, medullary serotoninergic systems, and supramedullary areas. CONCLUSION: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood.

Measuring Ventilatory Activity with Structured Light Plethysmography (SLP) Reduces Instrumental Observer Effect and Preserves Tidal Breathing Variability in Healthy and COPD.

The use of a mouthpiece to measure ventilatory flow with a pneumotachograph (PNT) introduces a major perturbation to breathing ("instrumental/observer effect") and suffices to modify the respiratory behavior. Structured light plethysmography (SLP) is a non-contact method of assessment of breathing pattern during tidal breathing. Firstly, we validated the SLP measurements by comparing timing components of the ventilatory pattern obtained by SLP vs. PNT under the same condition; secondly, we compared SLP to SLP+PNT measurements of breathing pattern to evaluate the disruption of breathing pattern and breathing variability in healthy and COPD subjects. Measurements were taken during tidal breathing with SLP alone and SLP+PNT recording in 30 COPD and healthy subjects. Measurements included: respiratory frequency (Rf), inspiratory, expiratory, and total breath time/duration (Ti, Te, and Tt). Passing-Bablok regression analysis was used to evaluate the interchangeability of timing components of the ventilatory pattern (Rf, Ti, Te, and Tt) between measurements performed under the following experimental conditions: SLP vs. PNT, SLP+PNT vs. SLP, and SLP+PNT vs. PNT. The variability of different ventilatory variables was assessed through their coefficients of variation (CVs). In healthy: according to Passing-Bablok regression, Rf, TI, TE and TT were interchangeable between measurements obtained under the three experimental conditions (SLP vs. PNT, SLP+PNT vs. SLP, and SLP+PNT vs. PNT). All the CVs describing "traditional" ventilatory variables (Rf, Ti, Te, Ti/Te, and Ti/Tt) were significantly smaller in SLP+PNT condition. This was not the case for more "specific" SLP-derived variables. In COPD: according to Passing-Bablok regression, Rf, TI, TE, and TT were interchangeable between measurements obtained under SLP vs. PNT and SLP+PNT vs. PNT, whereas only Rf, TE, and TT were interchangeable between measurements obtained under SLP+PNT vs. SLP. However, most discrete variables were significantly different between the SLP and SLP+PNT conditions and CVs were significantly lower when COPD patients were assessed in the SLP+PNT condition. Measuring ventilatory activity with SLP preserves resting tidal breathing variability, reduces instrumental observer effect and avoids any disruptions in breathing pattern induced by the use of PNT-mouthpiece-nose-clip combination.

Normal sleep on mechanical ventilation in adult patients with congenital central alveolar hypoventilation (Ondine's curse syndrome).

BACKGROUND: The purpose of this study was to describe the sleep structure (especially slow wave sleep) in adults with congenital central hypoventilation syndrome (CCHS), a rare genetic disease due to mutations in the PHOX2B gene. Fourteen patients aged 23 (19.0; 24.8) years old (median [1rst-3rd quartiles]) with CCHS underwent a sleep interview and night-time attended polysomnography with their ventilatory support. Their sleep variables were compared to those collected in 15 healthy control subjects matched for age, sex and body mass index. RESULTS: The latency to N3 sleep was shorter in patients (26.3 min [24.0; 30.1]) than in controls (49.5 min [34.3; 66.9]; P = 0.005), and sleep onset latency tended to be shorter in patients (14.0 min [7.0; 20.5]) than in controls (33.0 min [18.0; 49.0]; P = 0.052). Total sleep time, sleep stage percentages, sleep fragmentation as well as respiratory and movement index were within normal ranges and not different between groups. CONCLUSIONS: Normal sleep in adult patients with CCHS and adequate ventilator support indicates that the PHOX2 gene mutations do not affect brain sleep networks. Consequently, any complaint of disrupted sleep should prompt clinicians to look for the usual causes of sleep disorders, primarily inadequate mechanical ventilation. Shorter N3 latency may indicate a higher need for slow wave sleep, to compensate for the abnormal respiratory-related cortical activity during awake quiet breathing observed in patients with CCH.

New insights into sucking, swallowing and breathing central generators: A complexity analysis of rhythmic motor behaviors.

Sucking, swallowing and breathing are dynamic motor behaviors. Breathing displays features of chaos-like dynamics, in particular nonlinearity and complexity, which take their source in the automatic command of breathing. In contrast, buccal/gill ventilation in amphibians is one of the rare motor behaviors that do not display nonlinear complexity. This study aimed at assessing whether sucking and swallowing would also follow nonlinear complex dynamics in the newborn lamb. Breathing movements were recorded before, during and after bottle-feeding. Sucking pressure and the integrated EMG of the thyroartenoid muscle, as an index of swallowing, were recorded during bottle-feeding. Nonlinear complexity of the whole signals was assessed through the calculation of the noise limit value (NL). Breathing and swallowing always exhibited chaos-like dynamics. The NL of breathing did not change significantly before, during or after bottle-feeding. On the other hand, sucking inconsistently and significantly less frequently than breathing exhibited a chaos-like dynamics. Therefore, the central pattern generator (CPG) that drives sucking may be functionally different from the breathing CPG. Furthermore, the analogy between buccal/gill ventilation and sucking suggests that the latter may take its phylogenetic origin in the gill ventilation CPG of the common ancestor of extant amphibians and mammals.

Desogestrel enhances ventilation in ondine patients: Animal data involving serotoninergic systems.

Congenital central hypoventilation syndrome (CCHS) is a neurorespiratory disease characterized by life-threatening sleep-related hypoventilation involving an alteration of CO2/H(+) chemosensitivity. Incidental findings have suggested that desogestrel may allow recovery of the ventilatory response to CO2. The effects of desogestrel on resting ventilation have not been reported. This study was designed to test the hypothesis that desogestrel strengthens baseline ventilation by analyzing the ventilation of CCHS patients. Rodent models were used in order to determine the mechanisms involved. Ventilation in CCHS patients was measured with a pneumotachometer. In mice, ventilatory neural activity was recorded from ex vivo medullary-spinal cord preparations, ventilation was measured by plethysmography and c-fos expression was studied in medullary respiratory nuclei. Desogestrel increased baseline respiratory frequency of CCHS patients leading to a decrease in their PETCO2. In medullary spinal-cord preparations or in vivo mice, the metabolite of desogestrel, etonogestrel, induced an increase in respiratory frequency that necessitated the functioning of serotoninergic systems, and modulated GABAA and NMDA ventilatory regulations. c-FOS analysis showed the involvement of medullary respiratory groups of cell including serotoninergic neurons of the raphe pallidus and raphe obscurus nuclei that seem to play a key role. Thus, desogestrel may improve resting ventilation in CCHS patients by a stimulant effect on baseline respiratory frequency. Our data open up clinical perspectives based on the combination of this progestin with serotoninergic drugs to enhance ventilation in CCHS patients.

Increased ventilatory variability and complexity in patients with hyperventilation disorder.

It has been hypothesized that hyperventilation disorders could be characterized by an abnormal ventilatory control leading to enhanced variability of resting ventilation. The variability of tidal volume (VT) often depicts a nonnormal distribution that can be described by the negative slope characterizing augmented breaths formed by the relationship between the probability density distribution of VT and VT on a log-log scale. The objectives of this study were to describe the variability of resting ventilation [coefficient of variation (CV) of VT and slope], the stability in respiratory control (loop, controller and plant gains characterizing ventilatory-chemoresponsiveness interactions) and the chaotic-like dynamics (embedding dimension, Kappa values characterizing complexity) of resting ventilation in patients with a well-defined dysfunctional breathing pattern characterized by air hunger and constantly decreased PaCO2 during a cardiopulmonary exercise test. Compared with 14 healthy subjects with similar anthropometrics, 23 patients with hyperventilation were characterized by increased variability of resting tidal ventilation (CV of VT median [interquartile]: 26% [19-35] vs. 36% [28-48], P = 0.020; slope: -6.63 [-7.65; -5.36] vs. -3.88 [-5.91; -2.66], P = 0.004) that was not related to increased chemical drive (loop gain: 0.051 [0.039-0.221] vs. 0.044 [0.012-0.087], P = 0.149) but that was related to an increased ventilatory complexity (Kappa values, P < 0.05). Plant gain was decreased in patients and correlated with complexity (with Kappa 5 - degree 5: Rho = -0.48, P = 0.006). In conclusion, well-defined patients suffering from hyperventilation disorder are characterized by increased variability of their resting ventilation due to increased ventilatory complexity with stable ventilatory-chemoresponsiveness interactions.