Nouvelles méthodes d'exploration de la fonction respiratoire des patients neuromusculaires

Neuromuscular disorders are liable to induce a restrictive syndrome. The weakness of respiratory muscles andthe associated spinal deformities lead the patients into a vicious circle, which progressively worsens the restrictivesyndrome and evolves into respiratory failure. This respiratory failure may be associated to additional factors such aschronic reduction of thoracic cage motion, sleep disordered breathing, bulbar dysfunction and ineffective cough. Therefore,dysfunction of respiratory system may have multiples origins and requires precise evaluations targeted on thecomprehension of the physiopathologic mechanisms for each disease, as they may not only allow to adapt specificallytreatment, but also to assess the new therapeutics targeted for muscle restoration that are emerging for some neuromusculardiseases. Accordingly, it is essential to acquire knowledge about the specific evolution of the different disorder, with andwithout classic treatments, and also to improve the understanding of the physiopathologic mechanisms of respiratoryfailure, combining the classic evaluation tools of respiratory function with new evaluation techniques which could provideadditional information.This thesis aims to increase the knowledge of respiratory dysfunction of some neuromuscular disorders using classicevaluation tools and also to propose new exploration methods of respiratory function for neuromuscular patients.Thus, we explored data of two specific neuromuscular disorders patients, regularly followed: FacioscapulohumeralMuscular Dystrophy (FSHD) and Duchenne Muscular Dystrophy (DMD). The analysis of FSHD seemed important asrespiratory failure is not well known and described for this disease. On the other hand, while the evolution of DMD is wellknown, the impact of noninvasive ventilation (NIV) on the evolution of respiratory function has been poorly described,whereas new therapeutic trials will be soon proposed to these patients, some of which are already under NIV.Next, to better predict the improvement of the restrictive syndrome that could be potentially obtained with muscle repairtherapies, we developed a measure of pulmonary volumes, using assistance for inspiratory and/or expiratory muscles.We also developed and validated a painless, noninvasive, non-volitional and indirect method of measurement of thediaphragmatic force, in order to obtain results independent of patients’ motivation.Hence, this thesis was able to advance knowledge of the evolution of respiratory function of some neuromuscular diseases,using traditional evaluation tools of respiratory function. Moreover, it validated new pulmonary function measuresindependent of patient’s voluntary efforts.Les maladies neuromusculaires, sont susceptibles d’évoluer vers un syndrome restrictif. La faiblesse des muscles respiratoires ainsi que les déformations rachidiennes et thoraciques associées font entrer les patients dans un cercle vicieux qui aggrave progressivement le syndrome restrictif et mène les patients vers l’insuffisance respiratoire. À cette insuffisance respiratoire peuvent se rajouter d’autres facteurs comme la réduction chronique des mouvements de la cage thoracique, les perturbations du sommeil, le dysfonctionnement bulbaire et l’inefficacité de la toux. En conséquence, la dysfonction du système respiratoire peut être d’origine multiple et impose une évaluation précise et ciblée sur la compréhension des mécanismes physiopathologiques pour chaque maladie non seulement pour proposer pour chacune un traitement adapté mais également pour apprécier les nouvelles thérapeutiques ciblées sur la réparation musculaire en émergence pour certaines pathologies neuromusculaires. Il parait donc nécessaire de mieux connaitre l’évolution de certaines pathologies, avec et sans les traitements classiques, et d’améliorer la compréhension des mécanismes physiopathologiques de l’insuffisance respiratoire en combinant les outils classiques d’évaluation de la fonction respiratoire avec des nouvelles techniques d’évaluation qui pourraient être complémentaires.Cette thèse a, par conséquent, pour objectif de renforcer les connaissances sur les dysfonctions respiratoires de certaines pathologies neuromusculaires en utilisant des outils classiques d’évaluation et de proposer nouvelles méthodes d’exploration de la fonction respiratoire des patients neuromusculaires. Ainsi, nous avons exploité les données de deux filières de patients neuromusculaires suivies régulièrement : la Dystrophie Facioscapulohumérale (DFSH) et la Dystrophie Musculaire de Duchenne de Boulogne (DDB). L’analyse de la DFSH nous paraissait importante car l’insuffisance respiratoire est très peu connue et décrite dans cette pathologie. Si, au contraire, l’évolution de la DDB est bien connue, l’effet de la ventilation noninvasive (VNI) sur l’évolution de la fonction respiratoire a été, en revanche, très peu décrit alors que de nouveaux essais thérapeutiques vont bientôt être proposés à ces patients, dont certains sont déjà sous VNI. Ensuite, pour mieux prédire le degré d’amélioration du syndrome restrictif qu’une thérapeutique de réparation musculaire pourrait potentiellement apporter, nous avons développé une mesure des volumes pulmonaires à l’aide d’une assistance des muscles inspiratoire et/ou expiratoire. Nous avons aussi développé et validé une méthode non-invasive et non-volitionnelle de mesure indirecte de la force du diaphragme, de manière à obtenir des résultats indépendants de la motivation du patient, à partir d’un examen indolore pour le patient.De ce fait, cette thèse a pu faire progresser les connaissances sur l’évolution de la fonction respiratoire de certaines pathologies neuromusculaires grâce à l’analyse des mesures classiques de la fonction respiratoire. Elle a aussi validé des nouvelles mesures d’explorations fonctionnelles indépendantes de la force volontaire du patient

New Exploration Methods of Respiratory Function in Neuromuscular Diseases Patients

Les maladies neuromusculaires, sont susceptibles d’évoluer vers un syndrome restrictif. La faiblesse des muscles respiratoires ainsi que les déformations rachidiennes et thoraciques associées font entrer les patients dans un cercle vicieux qui aggrave progressivement le syndrome restrictif et mène les patients vers l’insuffisance respiratoire. À cette insuffisance respiratoire peuvent se rajouter d’autres facteurs comme la réduction chronique des mouvements de la cage thoracique, les perturbations du sommeil, le dysfonctionnement bulbaire et l’inefficacité de la toux. En conséquence, la dysfonction du système respiratoire peut être d’origine multiple et impose une évaluation précise et ciblée sur la compréhension des mécanismes physiopathologiques pour chaque maladie non seulement pour proposer pour chacune un traitement adapté mais également pour apprécier les nouvelles thérapeutiques ciblées sur la réparation musculaire en émergence pour certaines pathologies neuromusculaires. Il parait donc nécessaire de mieux connaitre l’évolution de certaines pathologies, avec et sans les traitements classiques, et d’améliorer la compréhension des mécanismes physiopathologiques de l’insuffisance respiratoire en combinant les outils classiques d’évaluation de la fonction respiratoire avec des nouvelles techniques d’évaluation qui pourraient être complémentaires.Cette thèse a, par conséquent, pour objectif de renforcer les connaissances sur les dysfonctions respiratoires de certaines pathologies neuromusculaires en utilisant des outils classiques d’évaluation et de proposer nouvelles méthodes d’exploration de la fonction respiratoire des patients neuromusculaires. Ainsi, nous avons exploité les données de deux filières de patients neuromusculaires suivies régulièrement : la Dystrophie Facioscapulohumérale (DFSH) et la Dystrophie Musculaire de Duchenne de Boulogne (DDB). L’analyse de la DFSH nous paraissait importante car l’insuffisance respiratoire est très peu connue et décrite dans cette pathologie. Si, au contraire, l’évolution de la DDB est bien connue, l’effet de la ventilation noninvasive (VNI) sur l’évolution de la fonction respiratoire a été, en revanche, très peu décrit alors que de nouveaux essais thérapeutiques vont bientôt être proposés à ces patients, dont certains sont déjà sous VNI. Ensuite, pour mieux prédire le degré d’amélioration du syndrome restrictif qu’une thérapeutique de réparation musculaire pourrait potentiellement apporter, nous avons développé une mesure des volumes pulmonaires à l’aide d’une assistance des muscles inspiratoire et/ou expiratoire. Nous avons aussi développé et validé une méthode non-invasive et non-volitionnelle de mesure indirecte de la force du diaphragme, de manière à obtenir des résultats indépendants de la motivation du patient, à partir d’un examen indolore pour le patient.De ce fait, cette thèse a pu faire progresser les connaissances sur l’évolution de la fonction respiratoire de certaines pathologies neuromusculaires grâce à l’analyse des mesures classiques de la fonction respiratoire. Elle a aussi validé des nouvelles mesures d’explorations fonctionnelles indépendantes de la force volontaire du patient.Neuromuscular disorders are liable to induce a restrictive syndrome. The weakness of respiratory muscles andthe associated spinal deformities lead the patients into a vicious circle, which progressively worsens the restrictivesyndrome and evolves into respiratory failure. This respiratory failure may be associated to additional factors such aschronic reduction of thoracic cage motion, sleep disordered breathing, bulbar dysfunction and ineffective cough. Therefore,dysfunction of respiratory system may have multiples origins and requires precise evaluations targeted on thecomprehension of the physiopathologic mechanisms for each disease, as they may not only allow to adapt specificallytreatment, but also to assess the new therapeutics targeted for muscle restoration that are emerging for some neuromusculardiseases. Accordingly, it is essential to acquire knowledge about the specific evolution of the different disorder, with andwithout classic treatments, and also to improve the understanding of the physiopathologic mechanisms of respiratoryfailure, combining the classic evaluation tools of respiratory function with new evaluation techniques which could provideadditional information.This thesis aims to increase the knowledge of respiratory dysfunction of some neuromuscular disorders using classicevaluation tools and also to propose new exploration methods of respiratory function for neuromuscular patients.Thus, we explored data of two specific neuromuscular disorders patients, regularly followed: FacioscapulohumeralMuscular Dystrophy (FSHD) and Duchenne Muscular Dystrophy (DMD). The analysis of FSHD seemed important asrespiratory failure is not well known and described for this disease. On the other hand, while the evolution of DMD is wellknown, the impact of noninvasive ventilation (NIV) on the evolution of respiratory function has been poorly described,whereas new therapeutic trials will be soon proposed to these patients, some of which are already under NIV.Next, to better predict the improvement of the restrictive syndrome that could be potentially obtained with muscle repairtherapies, we developed a measure of pulmonary volumes, using assistance for inspiratory and/or expiratory muscles.We also developed and validated a painless, noninvasive, non-volitional and indirect method of measurement of thediaphragmatic force, in order to obtain results independent of patients’ motivation.Hence, this thesis was able to advance knowledge of the evolution of respiratory function of some neuromuscular diseases,using traditional evaluation tools of respiratory function. Moreover, it validated new pulmonary function measuresindependent of patient’s voluntary efforts

Correlação dos graus de obstrução na DPOC com lactato e teste de caminhada de seis minutos Correlation of levels of obstruction in COPD with lactate and six-minute walk test

Contextualização: A doença pulmonar obstrutiva crónica (DPOC), importante causa de morbimortalidade em todo mundo, leva não só ao comprometimento pulmonar, mas também a alterações sistémicas, com repercussões sobre músculos esqueléticos e a capacidade de realizar esforços, mensurável pelo teste de caminhada de seis minutos (TC6’). Objectivos: correlacionar obstrução da DPOC com lactato de repouso, frequência cardíaca de repouso, bem como com distância percorrida. Correlacionar distância percorrida com gasometria e ainda correlacionar dessaturação ao TC6’ com lactato e frequência cardíaca pós-TC6’. Método: Portadores de DPOC realizaram espirometria, gasometria e TC6’, que avaliou: distância percorrida, frequência cardíaca (FC), lactato capilar (Lct) pré e pós-TC6’, além de dessaturação ao TC6’. Resultados: Foram avaliados 91 doentes abrangendo todos os graus de obstrução. Os parâmetros pós-TC6’, como FC e Lct, aumentaram de maneira significativa com a realização do mesmo. A queda da saturação da hemoglobina ao oxigénio diante do TC6’ também foi significativa. A análise de correlação significativa mostrou-se positiva entre VEF1 e distância percorrida, negativa entre VEF1 e FC de repouso e negativa entre distância percorrida e PaCO2, sendo não significante para as demais variáveis. Conclusões: A progressão da obstrução na DPOC, bem como valores maiores de PaCO2, contribuem para a redução da distância percorrida no TC6’. O grau de obstrução na DPOC leva a alteração hemodinâmica com o aumento da frequência cardíaca de repouso destes doentes.Chronic obstructive pulmonary disease (COPD) is a leading cause of morbid-mortality world wide, leading not only to pulmonary damage but also to multisystemic impairment, with repercussions on skeletal muscles and the ability to undertake effort, as measured in the six-minute walk test (6-MWT). Aims: To correlate the level of obstruction in COPD with lactate concentration and heart rate (HR) at rest, and distance walked. To correlate distance walked with blood gas analysis and correlate desaturation in 6-MWT with post 6-MWT lactate concentration and heart rate. Methods: COPD patients underwent spirometry, blood gas analysis and 6-MWT to evaluate distance walked, heart rate, capillary lactate (CL) concentration pre- and post 6-MWT, and desaturation with 6-MWT. Results: 91 patients with all levels of obstruction were evaluated. HR and CL increased significantly post 6-MWT. The decrease in peripheral saturation of haemoglobin to oxygen observed with 6-MWT was also significant. The distance walked was shorter the greater the obstruction. The correlation analysis was significantly positive between FEV1 and distance walked, negative between FEV1 and HR at rest and negative between distance walked and PaCO2, and not significant for the other variables. Conclusions: Increased obstruction in COPD and higher PaCO2 values contribute to a reduction in distance walked in 6-MWT. The level of obstruction in COPD leads to a haemodynamic impairment with increased HR at rest of these patients

Correlação dos graus de obstrução na DPOC com lactato e teste de caminhada de seis minutos

Resumo: Contextualização: A doença pulmonar obstrutiva crónica (DPOC), importante causa de morbimortalidade em todo mundo, leva não só ao comprometimento pulmonar, mas também a alterações sistémicas, com repercussões sobre músculos esqueléticos e a capacidade de realizar esforços, mensurável pelo teste de caminhada de seis minutos (TC6â).Objectivos: correlacionar obstrução da DPOC com lactato de repouso, frequência cardíaca de repouso, bem como com distância percorrida. Correlacionar distância percorrida com gasometria e ainda correlacionar dessaturação ao TC6â com lactato e frequência cardíaca pós-TC6â.Método: Portadores de DPOC realizaram espirometria, gasometria e TC6â, que avaliou: distância percorrida, frequência cardíaca (FC), lactato capilar (Lct) pré e pós-TC6â, além de dessaturação ao TC6â.Resultados: Foram avaliados 91 doentes abrangendo todos os graus de obstrução. Os parâmetros pós-TC6â, como FC e Lct, aumentaram de maneira significativa com a realização do mesmo. A queda da saturação da hemoglobina ao oxigénio diante do TC6â também foi significativa. A análise de correlação significativa mostrou-se positiva entre VEF1 e distância percorrida, negativa entre VEF1 e FC de repouso e negativa entre distância percorrida e PaCO2, sendo não significante para as demais variáveis.Conclusões: A progressão da obstrução na DPOC, bem como valores maiores de PaCO2, contribuem para a redução da distância percorrida no TC6â. O grau de obstrução na DPOC leva a alteração hemodinâmica com o aumento da frequência cardíaca de repouso destes doentes.Rev Port Pneumol 2009; XV (1): 11-25 Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbid-mortality world wide, leading not only to pulmonary damage but also to multi-systemic impairment, with repercussions on skeletal muscles and the ability to undertake effort, as measured in the six-minute walk test (6-MWT).Aims: To correlate the level of obstruction in COPD with lactate concentration and heart rate (HR) at rest, and distance walked. To correlate distance walked with blood gas analysis and correlate desaturation in 6-MWT with post 6-MWT lactate concentration and heart rate.Methods: COPD patients underwent spirometry, blood gas analysis and 6-MWT to evaluate distance walked, heart rate, capillary lactate (CL) concentration preâ and post 6MWT, and desaturation with 6-MWT.Results: 91 patients with all levels of obstruction were evaluated. HR and CL increased significantly post 6-MWT. The decrease in peripheral saturation of haemoglobin to oxygen observed with 6-MWT was also significant. The distance walked was shorter the greater the obstruction. The correlation analysis was significantly positive between FEV1 and distance walked, negative between FEV1 and HR at rest and negative between distance walked and PaCO2, and not significant for the other variables.Conclusions: Increased obstruction in COPD and higher PaCO2 values contribute to a reduction in distance walked in 6-MWT. The level of obstruction in COPD leads to a haemodynamic impairment with increased HR at rest of these patients.Rev Port Pneumol 2009; XV (1): 11-25 Palavras-chave: Doença pulmonar obstrutiva crónica, lactato, teste de esforço, dessaturação ao exercício, Key-words: Chronic obstructive pulmonary disease, lactate, exercise test, exercise desaturatio

Adjunctive inspiratory muscle training for patients with COVID-19 (COVIDIMT): protocol for randomised controlled double-blind trial

IntroductionA significant number of patients with COVID-19 may experience dyspnoea, anxiety, depression, pain, fatigue and physical impairment symptoms, raising the need for a multidisciplinary rehabilitation approach, especially for those with advanced age, obesity, comorbidities and organ failure. Traditional pulmonary rehabilitation (PR), including exercise training, psychosocial counselling and education, has been employed to improve pulmonary function, exercise capacity and quality of life in patients with COVID-19. However, the effects of inspiratory muscle training (IMT) in PR programmes remain unclear. This study aimed to determine whether the addition of a supervised IMT in a PR is more effective than PR itself in improving dyspnoea, health-related quality of life and exercise capacity in symptomatic patients with post-COVID-19.Methods and analysisThis parallel-group, assessor-blinded randomised controlled trial, powered for superiority, aimed to assess exercise capacity as the primary outcome. A total of 138 are being recruited at two PR centres in Brazil. Following baseline testing, participants will be randomised using concealed allocation, to receive either (1) standard PR with sham IMT or (2) standard PR added to IMT. Treatment effects or differences between the outcomes (at baseline, after 8 and 16 weeks, and after 6 months) of the study groups will be analysed using an ordinary two-way analysis of variance.Ethics and disseminationThis trial was approved by the Brazilian National Ethics Committee and obtained approval on 7 October 2020 (document number 4324069). The findings will be disseminated through publications in peer-reviewed journals and conference presentations.Trial registration numberNCT04595097

A Survey of Empirical Results on Program Slicing

International audienceBACKGROUND:Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.METHODS:This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.FINDINGS:Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).INTERPRETATION:Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding