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.

Quantitative brainstem and spinal MRI in amyotrophic lateral sclerosis: implications for predicting noninvasive ventilation needs.

BACKGROUND: Respiratory complications resulting from motor neurons degeneration are the primary cause of death in amyotrophic lateral sclerosis (ALS). Predicting the need for non-invasive ventilation (NIV) in ALS is important for advance care planning and clinical trial design. The aim of this study was to assess the potential of quantitative MRI at the brainstem and spinal cord levels to predict the need for NIV during the first six months after diagnosis. METHODS: Forty-one ALS patients underwent MRI and spirometry shortly after diagnosis. The need for NIV was monitored according to French health guidelines for 6 months. The performance of four regression models based on: clinical variables, brainstem structures volumes, cervical spinal measurements, and combined variables were compared to predict the need for NIV within this period. RESULTS: Both the clinical model (R2 = 0.28, AUC = 0.85, AICc = 42.67, BIC = 49.8) and the brainstem structures' volumes model (R2 = 0.30, AUC = 0.85, AICc = 40.13, BIC = 46.99) demonstrated good predictive performance. In addition, cervical spinal cord measurements model similar performance (R2 = 0.338, AUC = 0.87, AICc = 37.99, BIC = 44.49). Notably, the combined model incorporating predictors from all three models yielded the best performance (R2 = 0.60, AUC = 0.959, AICc = 36.38, BIC = 44.8). These findings are supported by observed positive correlations between brainstem volumes, cervical (C4/C7) cross-sectional area, and spirometry-measured lung volumes. CONCLUSIONS: Our study shows that brainstem volumes and spinal cord area are promising measures to predict respiratory intervention needs in ALS.

Proposals from a French expert panel for respiratory care in ALS patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive diaphragm weakness and deteriorating lung function. Bulbar involvement and cough weakness contribute to respiratory morbidity and mortality. ALS-related respiratory failure significantly affects quality of life and is the leading cause of death. Non-invasive ventilation (NIV), which is the main recognized treatment for alleviating the symptoms of respiratory failure, prolongs survival and improves quality of life. However, the optimal timing for the initiation of NIV is still a matter of debate. NIV is a complex intervention. Multiple factors influence the efficacy of NIV and patient adherence. The aim of this work was to develop practical evidence-based advices to standardize the respiratory care of ALS patients in French tertiary care centres. METHODS: For each proposal, a French expert panel systematically searched an indexed bibliography and prepared a written literature review that was then shared and discussed. A combined draft was prepared by the chairman for further discussion. All of the proposals were unanimously approved by the expert panel. RESULTS: The French expert panel updated the criteria for initiating NIV in ALS patients. The most recent criteria were established in 2005. Practical advice for NIV initiation were included and the value of each tool available for NIV monitoring was reviewed. A strategy to optimize NIV parameters was suggested. Revisions were also suggested for the use of mechanically assisted cough devices in ALS patients. CONCLUSION: Our French expert panel proposes an evidence-based review to update the respiratory care recommendations for ALS patients in daily practice.

Testing the efficacy and safety of BIO101, for the prevention of respiratory deterioration, in patients with COVID-19 pneumonia (COVA study): a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: As of December, 1st, 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, resulted in more than 1 472 917 deaths worldwide and death toll is still increasing exponentially. Many COVID-19 infected people are asymptomatic or experience moderate symptoms and recover without medical intervention. However, older people and those with comorbid hypertension, diabetes, obesity, or heart disease are at higher risk of mortality. Because current therapeutic options for COVID-19 patients are limited specifically for this elderly population at risk, Biophytis is developing BIO101 (20-hydroxyecdysone, a Mas receptor activator) as a new treatment option for managing patients with SARS-CoV-2 infection at the severe stage. The angiotensin converting enzyme 2 (ACE2) serves as a receptor for SARS-CoV-2. Interaction between ACE2 and SARS-CoV2 spike protein seems to alter the function of ACE2, a key player in the renin-angiotensin system (RAS). The clinical picture of COVID-19 includes acute respiratory distress syndrome (ARDS), cardiomyopathy, multiorgan dysfunction and shock, all of which might result from an imbalance of the RAS. We propose that RAS balance could be restored in COVID-19 patients through MasR activation downstream of ACE2 activity, with 20-hydroxyecdysone (BIO101) a non-peptidic Mas receptor (MasR) activator. Indeed, MasR activation by 20-hydroxyecdysone harbours anti-inflammatory, anti-thrombotic, and anti-fibrotic properties. BIO101, a 97% pharmaceutical grade 20-hydroxyecdysone could then offer a new therapeutic option by improving the respiratory function and ultimately promoting survival in COVID-19 patients that develop severe forms of this devastating disease. Therefore, the objective of this COVA study is to evaluate the safety and efficacy of BIO101, whose active principle is 20-hydroxyecdysone, in COVID-19 patients with severe pneumonia. TRIAL DESIGN: Randomized, double-blind, placebo-controlled, multi-centre, group sequential and adaptive which will be conducted in 2 parts. Part 1: Ascertain the safety and tolerability of BIO101 and obtain preliminary indication of the activity of BIO101, in preventing respiratory deterioration in the target population Part 2: Re-assessment of the sample size needed for the confirmatory part 2 and confirmation of the effect of BIO101 observed in part 1 in the target population. The study is designed as group sequential to allow an efficient run-through, from obtaining an early indication of activity to a final confirmation. And adaptive - to allow accumulation of early data and adapt sample size in part 2 in order to inform the final design of the confirmatory part of the trial. PARTICIPANTS: Inclusion criteria 1. Age: 45 and above 2. A confirmed diagnosis of COVID-19 infection, within the last 14 days, prior to randomization, as determined by PCR or other approved commercial or public health assay, in a specimen as specified by the test used. 3. Hospitalized, in observation or planned to be hospitalized due to COVID-19 infection symptoms with anticipated hospitalization duration ≥3 days 4. With evidence of pneumonia based on all of the following: a. Clinical findings on a physical examination b. Respiratory symptoms developed within the past 7 days 5. With evidence of respiratory decompensation that started not more than 4 days before start of study medication and present at screening, meeting one of the following criteria, as assessed by healthcare staff: a. Tachypnea: ≥25 breaths per minute b. Arterial oxygen saturation ≤92% c. A special note should be made if there is suspicion of COVID-19-related myocarditis or pericarditis, as the presence of these is a stratification criterion 6. Without a significant deterioration in liver function tests: a. ALT and AST ≤ 5x upper limit of normal (ULN) b. Gamma-glutamyl transferase (GGT) ≤ 5x ULN c. Total bilirubin ≤ 5×ULN 7. Willing to participate and able to sign an informed consent form (ICF). Or, when relevant, a legally authorized representative (LAR) might sign the ICF on behalf of the study participant 8. Female participants should be: at least 5 years post-menopausal (i.e., persistent amenorrhea 5 years in the absence of an alternative medical cause) or surgically sterile; OR a. Have a negative urine pregnancy test at screening b. Be willing to use a contraceptive method as outlined in inclusion criterion 9 from screening to 30 days after last dose. 9. Male participants who are sexually active with a female partner must agree to the use of an effective method of birth control throughout the study and until 3 months after the last administration of the investigational product. (Note: medically acceptable methods of contraception that may be used by the participant and/or partner include combined oral contraceptive, contraceptive vaginal ring, contraceptive injection, intrauterine device, etonogestrel implant, each supplemented with a condom, as well as sterilization and vasectomy). 10. Female participants who are lactating must agree not to breastfeed during the study and up to 14 days after the intervention. 11. Male participants must agree not to donate sperm for the purpose of reproduction throughout the study and until 3 months after the last administration of the investigational product. 12. For France only: Being affiliated with a European Social Security. Exclusion criteria 1. Not needing or not willing to remain in a healthcare facility during the study 2. Moribund condition (death likely in days) or not expected to survive for >7 days - due to other and non-COVID-19 related conditions 3. Participant on invasive mechanical ventilation via an endotracheal tube, or extracorporeal membrane oxygenation (ECMO), or high-flow Oxygen (delivery of oxygen at a flow of ≥16 L/min.). 4. Participant is not able to take medications by mouth (as capsules or as a powder, mixed in water). 5. Disallowed concomitant medication: Consumption of any herbal products containing 20-hydroxyecdysone and derived from Leuzea carthamoides; Cyanotis vaga or Cyanotis arachnoidea is not allowed (e.g. performance enhancing agents). 6. Any known hypersensitivity to any of the ingredients, or excipients of the study medication, BIO101. 7. Renal disease requiring dialysis, or known renal insufficiency (eGFR≤30 mL/min/1.73 m2, based on Cockcroft & Gault formula). 8. In France only: a. Non-affiliation to compulsory French social security scheme (beneficiary or right-holder). b. Being under tutelage or legal guardianship. Participants will be recruited from approximately 30 clinical centres in Belgium, France, the UK, USA and Brazil. Maximum patients' participation in the study will last 28 days. Follow-up of participants discharged from hospital will be performed through post-intervention phone calls at 14 (± 2) and 60 (± 4) days. INTERVENTION AND COMPARATOR: Two treatment arms will be tested in this study: interventional arm 350 mg b.i.d. of BIO101 (AP 20-hydroxyecdysone) and placebo comparator arm 350 mg b.i.d of placebo. Administration of daily dose is the same throughout the whole treatment period. Participants will receive the study medication while hospitalized for up to 28 days or until a clinical endpoint is reached (i.e., 'negative' or 'positive' event). Participants who are officially discharged from hospital care will no longer receive study medication. MAIN OUTCOMES: Primary study endpoint: The proportion of participants with 'negative' events up to 28 days. 'Negative' events are defined as respiratory deterioration and all-cause mortality. For the purpose of this study, respiratory deterioration will be defined as any of the following: Requiring mechanical ventilation (including cases that will not be intubated due to resource restrictions and triage). Requiring extracorporeal membrane oxygenation (ECMO). Requiring high-flow oxygen defined as delivery of oxygen at a flow of ≥16 L/min. Only if the primary endpoint is significant at the primary final analysis the following Key secondary endpoints will be tested in that order: Proportion of participants with events of respiratory failure at Day 28 Proportion of participants with 'positive' events at Day 28. Proportion of participants with events of all-cause mortality at Day 28 A 'positive' event is defined as the official discharge from hospital care by the department due to improvement in participant condition. Secondary and exploratory endpoints: In addition, a variety of functional measures and biomarkers (including the SpO2 / FiO2 ratio, viral load and markers related to inflammation, muscles, tissue and the RAS / MAS pathways) will also be collected. RANDOMIZATION: Randomization is performed using an IBM clinical development IWRS system during the baseline visit. Block-permuted randomization will be used to assign eligible participants in a 1:1 ratio. In part 1, randomization will be stratified by RAS pathway modulator use (yes/no) and co-morbidities (none vs. 1 and above). In Part 2, randomization will be stratified by centre, gender, RAS pathway modulator use (yes/no), co-morbidities (none vs. 1 and above), receiving Continuous Positive Airway Pressure/Bi-level Positive Airway Pressure (CPAP/BiPAP) at study entry (Yes/No) and suspicion of COVID-19 related myocarditis or pericarditis (present or not). BLINDING (MASKING): Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. All therapeutic units (TU), BIO101 b.i.d. or placebo b.i.d., cannot be distinguished in compliance with the double-blind process. An independent data-monitoring committee (DMC) will conduct 2 interim analyses. A first one based on the data from part 1 and a second from the data from parts 1 and 2. The first will inform about BIO101 safety, to allow the start of recruitment into part 2 followed by an analysis of the efficacydata, to obtain an indication of activity. The second interim analysis will inform about the sample size that will be required for part 2, in order to achieve adequate statistical power. Numbers to be randomised (sample size) Number of participants randomized: up to 465, in total Part 1: 50 (to obtain the proof of concept in COVID-19 patients). Part 2: 310, potentially increased by 50% (up to 465, based on interim analysis 2) (to confirm the effects of BIO101 observed in part 1). TRIAL STATUS: The current protocol Version is V 10.0, dated on 24.09.2020. The recruitment that started on September 1st 2020 is ongoing and is anticipated to finish for the whole study by March2021. TRIAL REGISTRATION: The trial was registered before trial start in trial registries: EudraCT , No. 2020-001498-63, registered May 18, 2020; and Clinicaltrials.gov, identifier NCT04472728 , registered July 15, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

[Guide for management of patients with possible respiratory sequelae after a SARS-CoV-2 pneumonia. Support proposals developed by the French-speaking Respiratory Medicine Society. Version of 10 November 2020]. / Guide de prise en charge des séquelles respiratoires post infection à SARS-CoV-2. Propositions de prise en charge élaborées par la Société de Pneumologie de Langue Française. Version du 10 novembre 2020.

The French-speaking Respiratory Medicine Society (SPLF) proposes a guide for the management of possible respiratory sequelae in patients who have presented with SARS-CoV-2 pneumonia (COVID-19). The proposals are based on known data from previous epidemics, preliminary published data on post COVID-19 follow-up and on expert opinion. The proposals were developed by a group of experts and then submitted, using the Delphi method, to a panel of 22 pulmonologists. Seventeen proposals were validated ranging from additional examinations after the minimum assessment proposed in the SPLF monitoring guide, to inhaled or systemic corticosteroid therapy and antifibrotic agents. These proposals may evolve over time as knowledge accumulates. This guide emphasizes the importance of multidisciplinary discussion.

Prevalence and management of chronic breathlessness in COPD in a tertiary care center.

BACKGROUND: Breathlessness is the prominent symptom of chronic obstructive pulmonary disease (COPD). Despite optimal therapeutic management including pharmacological and non-pharmacological interventions, many COPD patients exhibit significant breathlessness. Chronic breathlessness is defined as breathlessness that persists despite optimal treatment of the underlying disease. Because of the major disability related to chronic breathlessness, symptomatic treatments including opioids have been recommended by several authors. The prevalence of chronic breathlessness in COPD and its management in routine clinical practice have been poorly investigated. Our aim was to examine prevalence, associated characteristics and management of chronic breathlessness in patients with COPD recruited in a real-life tertiary hospital-based cohort. METHODS: A prospective study was conducted among 120 consecutive COPD patients recruited, in stable condition, at Nancy University Hospital, France. In parallel, 88 pulmonologists of the same geographical region were asked to respond to an on-line questionnaire on breathlessness management. RESULTS: Sixty four (53%) patients had severe breathlessness (modified Medical Research Council scale≥3), despite optimal inhaled medications for 94% of them; 40% had undergone pulmonary rehabilitation within the past 2 years. The severity of breathlessness increased with increasing airflow limitation. Breathlessness was associated with increased symptoms of anxiety, depression and with osteoporosis. No relation was found with other symptoms, exacerbation rate, or cardiovascular comorbidities. Among the patients with chronic breathlessness and Hospitalized Anxiety and/or Depression score > 10, only 25% were treated with antidepressant or anxiolytic. Among the pulmonologists 46 (52%) answered to the questionnaire and expressed a high willingness to prescribe opioids forchronic breathlessness, which contrasted with the finding that none of these patients received such treatments against breathlessness. CONCLUSION: Treatment approaches to breathlessness and associated psychological distress are insufficient in COPD. This study highlights underuse of pulmonary rehabilitation and symptomatic treatment for breathlessness.

[Pulmonary function testing of dyspnea complaint by the pulmonologist]. / Investigation fonctionnelle respiratoire de la dyspnée chronique par le pneumologue.

Dyspnea results from an imbalance between ventilatory demand (linked to CO2 production, PaCO2 set-point and wasted ventilation-physiological dead space) and ventilatory capacity (linked to passive-compliance, resistance-and active-respiratory muscles-components of the respiratory system). Spirometry and static lung volumes investigate ventilatory capacity only. Ventilatory demand (increased for instance in all pulmonary vascular diseases due to increased physiological dead space) is not evaluated by these routine measurements. DLCO measurement, which evaluates both demand and capacity, depicts the best statistical correlation to dyspnea, for instance in obstructive and interstitial pulmonary diseases. Dyspnea has multiple domains and is inherently complex and weakly explained by resting investigations: explained variance is below 50%. The diagnostic strategy investigating dyspnea has to distinguish complaints related or not to exercise because dyspnea can occur independently from any effort. Cardiopulmonary exercise testing (V'O2, V'CO2, V'E and operating lung volumes measurements) allows the assessment of underlying pathophysiological mechanisms leading to functional impairment and can contribute to unmask potential underlying mechanisms of unexplained dyspnea although its "etiological diagnostic value" for dyspnea remains a challenging issue.

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.

Pharmacological treatment optimization for stable chronic obstructive pulmonary disease. Proposals from the Société de Pneumologie de Langue Française.

The Société de Pneumologie de Langue Française proposes a decision algorithm on long-term pharmacological COPD treatment. A working group reviewed the literature published between January 2009 and May 2016. This document lays out proposals and not guidelines. It only focuses on pharmacological treatments except vaccinations, smoking cessation treatments and oxygen therapy. Any COPD diagnosis, based on pulmonary function tests, should lead to recommend smoking cessation, vaccinations, physical activity, pulmonary rehabilitation in case of activity limitation, and short-acting bronchodilators. Symptoms like dyspnea and exacerbations determine the therapeutic choices. In case of daily dyspnea and/or exacerbations, a long-acting bronchodilator should be suggested (beta-2 agonist, LABA or anticholinergics, LAMA). A clinical and lung function reevaluation is suggested 1 to 3 months after any treatment modification and every 3-12 months according to the severity of the disease. In case of persisting dyspnea, a fixed dose LABA+LAMA combination improves pulmonary function (FEV1), quality of life, dyspnea and decreases exacerbations without increasing side effects. In case of frequent exacerbations and a FEV1≤70%, a fixed dose long-acting bronchodilator combination or a LABA+ inhaled corticosteroids (ICS) combination can be proposed. A triple combination (LABA+LAMA+ICS) is indicated when exacerbations persist despite one of these combinations. Dyspnea in spite of a bronchodilator combination or exacerbations in spite of a triple combination should lead to consider other pharmacological treatments (theophylline if dyspnea, macrolides if exacerbations, low-dose opioids if refractory dyspnea).

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.

Inspiratory muscle training during pulmonary rehabilitation in chronic obstructive pulmonary disease: A randomized trial.

Although recommended by international guidelines, the benefit of inspiratory muscle training (IMT) in addition to rehabilitation remains uncertain. The objective was to demonstrate the effectiveness of IMT on dyspnea using Borg scale and multidimensional dyspnea profile questionnaire at the end of a 6-minute walk test (6MWT) in patients with chronic obstructive pulmonary disease (COPD) with preserved average maximum inspiratory pressure (PImax) of 85 cm H2O (95% of predicted (pred.) value) and admitted for a rehabilitation program in a dedicated center. In a randomized trial, comparing IMT versus no IMT in 32 COPD patients without inspiratory muscle weakness (PImax >60 cm H2O) who were admitted for pulmonary rehabilitation (PR) for 3 weeks, we evaluated the effect of IMT on dyspnea, using both Borg scale and multidimensional dyspnea profile (MDP) at the end of the 6MWT, and on functional parameters included inspiratory muscle function (PImax) and 6MWT. All testings were performed at the start and the end of PR. In unadjusted analysis, IMT was not found to be associated with an improvement of either dyspnea or PImax. After adjustment on confounders (initial Borg score) and variables of interaction (forced expiratory volume in 1 second (FEV1)), we found a trend toward an improvement of "dyspnea sensory intensity", items from MDP and a significant improvement on the variation in the 2 items of MDP ("tight or constricted" and "breathing a lot"). In the subgroup of patients with FEV1 < 50% pred., 5 items of MDP were significantly improved, whereas no benefit was observed in patients with FEV1 > 50% pred. IMT did not significantly improve dyspnea or functional parameter in COPD patients with PImax > 60 cm H2O. However, in the subgroup of patients with FEV1 < 50% pred., MDP was significantly improved.

Diaphragm pacing restores olfaction in tetraplegia.

High cervical spinal cord injuries induce extreme handicap and tactile isolation. Tracheotomised tetraplegic patients are also bound to be olfaction deprived. By restoring negative pressure inspiration, diaphragm pacing (DP) should improve olfaction. We tested olfaction in 10 consecutive tetraplegics during positive pressure mechanical ventilation and DP, using the University of Pennsylvania Smell Identification Test (UPSIT). Quality of life was assessed using the Satisfaction with Life Scale (SWLS). Self-perceived benefits of DP were studied using an in-house questionnaire. Olfaction was very poor during positive pressure mechanical ventilation (UPSIT, mean+/-SD 17.1+/-6.4, anosmia or severe microsmia). It improved during DP (35.2+/-1.9, normosmia or mild microsmia; p<0.0001) and SWLS was 18.5+/-4.2. Nine patients stated that DP had improved their quality of life. This was driven by better mobility (ranked first), improved self-image and relationships with others (ranked second), improved olfaction and better feeling of security (both ranked third). Improved olfaction is among the benefits of DP and should be mentioned to patients considered for this therapy. Furthermore, attention to olfaction is warranted in tracheotomised ventilator-dependent patients, as a putative path towards improvement of quality of life.

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.

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.