Introdução: A obesidade é um problema de saúde pública em crescimento, sendo o principal fator de risco para os transtornos respiratórios durante o sono (TRS), como a apneia obstrutiva do sono (AOS) e a hipoventilação noturna. A cirurgia bariátrica se consolidou como possibilidade terapêutica para a obesidade significativa. A identificação precoce dos TRS na fase pré-operatória é essencial, pois acarretam um risco aumentado de complicações perioperatórias. Diversas propostas de triagem dos TRS com abordagens mais simplificadas em relação à polissonografia (PSG) têm surgido na literatura nos últimos anos, nem todas avaliadas em uma população de pacientes obesos. Objetivo: Determinar os padrões ventilatórios em obesos candidatos à cirurgia bariátrica e avaliar três estratégias de rastreamento de TRS nessa população. Métodos: Os critérios de inclusão foram pacientes com idade ≥18 anos com obesidade graus III [índice de massa corporal (IMC) ≥40 kg/m2] ou II (IMC ≥35 kg/m2) com comorbidades relacionadas à obesidade encaminhados para avaliação para cirurgia bariátrica. Foram excluídos pacientes com cardiopatia e/ou pneumopatia graves ou descompensadas. Foram avaliados 91 pacientes através de três estratégias: (1) Clínica [Escala de Sonolência de Epworth e questionários STOP-Bang, Berlim e Sleep Apnea Clinical Score (SACS), acrescidos de gasometria arterial (GA)]; (2) Oximetria (holter de oximetria durante o sono e GA) e (3) Portátil [monitorização portátil (MP) durante o sono e capnografia)]. Todos os testes realizados foram comparados com o teste padrão, a PSG, para o diagnóstico de AOS. Resultados: A amostra estudada foi composta por 77 mulheres (84,6%) com média de idade de 44,7 ± 11,5 anos e de IMC de 50,1 ± 8,2 kg/m2. Os padrões ventilatórios identificados foram ronco, hipoxemia isolada durante o sono, AOS e hipoventilação noturna em associação com AOS. Os dados polissonográficos evidenciaram AOS em 67 de 87 pacientes (77%), sendo 26 com transtorno leve, 19 moderado e 22 grave. Vinte pacientes (23%) tiveram diagnóstico de ronco e dois deles também apresentaram hipoxemia isolada durante o sono sem AOS ou hipoventilação concomitantes. Hipoventilação noturna associada com AOS foi identificada por capnografia em um paciente. Na Estratégia Clínica, o melhor resultado alcançado foi com o escore STOP-Bang ≥6 em pacientes com índice de apneia hipopneia (IAH) ≥30 (acurácia total de 82,8%). Na Estratégia Oximetria, os pontos de corte com maior sensibilidade e especificidade para IAH ≥5, ≥10, ≥15 e ≥30 foram tempo total de registro com saturação periférica de oxigênio (SpO2) <90% por, pelo menos, 5 minutos; índice de dessaturação (ID)3% ≥22 dessaturações/hora de registro e ID4% ≥10 e ≥15 dessaturações/hora de registro. Todas as áreas sobre a curva (ASC) situaram-se acima de 0,850. Para um IAH ≥5, o ID4% ≥10 apresentou sensibilidade de 97%, especificidade de 73,7%, valor preditivo positivo de 92,8% e negativo de 87,5% e acurácia total de 91,8%. Na Estratégia Portátil, o índice de distúrbios respiratórios (IDR) foi um bom preditor de AOS nos variados pontos de corte de IAH (ASC de 0,952 a 0,995). As melhores sensibilidades e especificidades foram alcançadas em pontos de corte semelhantes de IDR e IAH, especialmente nos extratos de IAH ≥10 e ≥30. A acurácia total máxima foi de 93,9% para IDR ≥5, ≥10 e ≥30 nos seus correspondentes IAH. Baseados nesses resultados, foram testadas estratégias combinadas compostas pelo questionário STOP-Bang ≥6 com ID4% ≥10 ou ≥15. O melhor equilíbrio entre sensibilidade e especificidade e a maior acurácia foram obtidos com a estratégia STOP-Bang ≥6 com ID4% ≥15 em AOS grave. Conclusões: A frequência de ocorrência de TRS nos obesos em avaliação para cirurgia bariátrica foi alta, sendo a AOS o transtorno mais encontrado. Os questionários disponíveis até o momento, isoladamente, parecem ser insuficientes para o rastreamento de AOS nessa população, à exceção do STOP-Bang ≥6 em pacientes com AOS grave. O uso de uma medida fisiológica objetiva expressa pelo holter de oximetria foi útil para rastrear AOS em pacientes obesos. A MP apresentou acurácia aumentada, especialmente nos extremos de valores de IAH, com resultados comparáveis aos da PSG. A PSG poderia ser reservada apenas para confirmação diagnóstica em casos selecionados. / Introduction: Obesity is a growing public health problem and the main risk factor for sleep-disordered breathing (SDB), including obstructive sleep apnea (OSA) and nocturnal hypoventilation. Bariatric surgery has become an option for the treatment of significant obesity. Early detection of SDB preoperatively is essential, since these disorders are associated with an increased risk of perioperative complications. Several screening tools for SDB, with a more simplified approach than polysomnography (PSG), have been proposed in recent years, but not all of them have been evaluated in a population of obese patients. Objective: To determine ventilatory patterns in obese candidates for bariatric surgery and evaluate three SDB screening strategies in this population. Methods: Eligible participants were all patients aged ≥18 years with grade III (body mass index [BMI] ≥ 40kg/m2) or grade II (BMI ≥35 kg/m2) obesity and obesity-related comorbidities who were referred for evaluation for bariatric surgery. Exclusion criteria were heart disease and/or severe or decompensated pulmonary disease. Ninety-one patients were evaluated by three strategies: (1) Clinical (Epworth Sleepiness Scale and STOP-Bang questionnaire, Berlin questionnaire and Sleep Apnea Clinical Score [SACS] plus blood gas analysis [BGA]); (2) Oximetry (overnight Holter-oximeter monitoring and BGA); and (3) Portable (overnight portable monitoring and capnography). All tests were compared with the gold standard, PSG, for the diagnosis of OSA. Results: The sample consisted of 77 women (84.6%) with a mean (SD) age of 44.7 (11.5) years and BMI of 50.1 (8.2) kg/m2. The ventilatory patterns identified were snoring, isolated nocturnal hypoxemia, OSA, and nocturnal hypoventilation associated with OSA. Polysomnographic data showed OSA in 67 of 87 patients (77%), 26 with mild, 19 with moderate and 22 with severe disorder. Twenty patients (23%) had a diagnosis of snoring, and two of them also had isolated nocturnal hypoxemia without concomitant OSA or hypoventilation. Nocturnal hypoventilation associated with OSA was detected by capnography in one patient. In the Clinical Strategy, the best result was obtained with the STOP-Bang score ≥6 in patients with an apnea-hypopnea index (AHI) ≥30 (overall accuracy of 82.8%). In the Oximetry Strategy, the cutoff values with the highest sensitivity and specificity for AHI ≥5, ≥10, ≥15, and ≥30 were total recording time with peripheral oxygen saturation (SpO2)< 90% for at least 5 minutes, 3% oxygen desaturation index (ODI) ≥22 desaturations/hour of recording, and 4%ODI ≥10 and ≥15 desaturations/hour of recording. All areas under the curve (AUC) were above 0.850. For AHI ≥5, 4%ODI ≥10 had a sensitivity of 97%, specificity of 73.7%, positive predictive value of 92.8%, negative predictive value of 87.5%, and overall accuracy of 91.8%. In the Portable Strategy, the respiratory disturbance index (RDI) was a good predictor of OSA in various cutoff values of AHI (AUC of 0.952 to 0.995). The highest sensitivity and specificity were obtained at similar cutoff values for RDI and AHI, especially for AHI ≥10 and ≥30. The maximum overall accuracy was 93.9% for RDI ≥5, ≥10, and ≥30 in their corresponding AHI. Based on these results, combined strategies were tested consisting of the STOP-Bang score ≥6 combined with 4%ODI ≥10 or ≥15. The best balance between sensibility and specificity and the maximum accuracy were achieved with the strategy composed by STOP-Bang ≥6 and 4%ODI ≥15 in patients with severe OSA. Conclusions: The frequency of occurrence of SDB in obese individuals undergoing evaluation for bariatric surgery was high, and OSA was the most frequent occurrence. Currently available questionnaires were insufficient to screen for OSA in this population, with the exception for the STOP-Bang score ≥6 in patients with severe OSA. The use of an objective physiological measure, such as Holter-oximetry monitoring, was useful as a screening tool for OSA in obese patients. Portable monitoring showed increased accuracy, especially in extreme AHI values, with results comparable to those obtained with PSG. The PSG could be reserved only for certain cases where diagnostic confirmation is necessary.

No description available.

Le syndrome d'Ondine est une pathologie caractérisée par une abolition de la chémosensibilité au CO2/H+. Des données cliniques suggèrent que le désogestrel, un progestatif de la famille des gonanes, induit une récupération de la chémosensibilité (Straus et al., 2010). Ce travail avait pour objectif de mieux comprendre les mécanismes centraux par lesquels l'étonogestrel (ETO, le métabolite du désogestrel) permettrait d'induire une récupération de la chémosensibilité. Pour cela des approches pharmacologiques ont été couplées à de l'histologie fonctionnelle sur des préparations ex vivo de système nerveux central de rat nouveau-né. Les résultats obtenus ont mis en évidence qu’une exposition à l’ETO, dans une gamme de concentration proche de l’exposition clinique, renforce la réponse respiratoire au CO2/H+ et ce uniquement en présence du diencéphale. Plus précisément ce mécanisme aurait pour origine l’activation des neurones orexinergiques. L’analyse du profil d’expression de c-fos a montré que des structures du tronc cérébral, impliquées dans l’adaptation de la commande centrale respiratoire, étaient activées ou suractivées en présence d’ETO. Pour la majorité leur activation ou suractivation semblent dépendre de la signalisation orexinergique puisque l’effet de l’ETO est absent lors de l’antagonisation des récepteurs à l’orexine. Nous émettons alors l’hypothèse que la récupération de la chémosensibilité au CO2/H+ sous désogestrel implique, au moins en partie, les voies neuronales révélées dans notre étude. / Ondine’s curse is a disease characterized by a dysfunction of the CO2/H+ chemosensitivity. Clinical observation suggest that desogestrel, a progestin of the gonane family, have induced a recovery of CO2/H+ chemosensitivity (Straus et al., 2010).This work aimed to have a better understanding of the central mechanisms by which etonogestrel (ETO, the metabolite of desogestrel) may have induced a recovery of CO2/H+ chemosensitivity. Pharmacological exposures and c-fos expression analysis were performed in parallel on ex vivo preparations of central nervous system from newborn rats.Our results indicated that ETO strengthens the respiratory response to metabolic acidosis in a range of concentration close to the clinical exposure, by a diencephalic-dependent mechanism. More precisely our results suggested that this effect relied on the activation of diencephalic orexinergic neurons. Besides, the analysis of the c-fos expression revealed that ETO over-activated and activated several respiratory-related brainstem structures. For most of them their activation or overactivation seems to depend on the orexinergic signalisation since the increase in c-fos expression observed in response to ETO is no longer present when orexinergic receptors are antagonized. We assume that our results highlighted, at least in part, the neuronal pathway used by ETO to induce a recovery of the CO2/H+ chemosensitivity in Ondine patients.Our data open up pieces of reflexion about conditions about the mechanisms, underlined the recovery of CO2/H+ chemosensitivity in Ondine patients.

Le maintien de la PCO2 et du pH du sang artériel est vital. Le principal mécanisme de cette régulation, chez les mammifères, est le chémoréflexe respiratoire central au CO2, une hyperventilation en réponse à l’hypercapnie, dont les bases neurales sont l’enjeu d’un débat persistant. Notre travail s’intéresse aux rôles supposés d’un groupe d’interneurones du niveau facial du tronc cérébral, le « noyau rétrotrapézoïde », dans le chémoréflexe au CO2 et l’accélération du rythme respiratoire autour de la naissance. Notre approche est inspirée par la symptomatologie respiratoire du syndrome d’Ondine ou CCHS (apnées et abrogation du chémoréflexe) et son gène causal, codant le facteur de transcription Phox2b, exprimé par les neurones du RTN. Nous avons disséqué le rôle du RTN dans le chémoréflexe central en étudiant les propriétés anatomiques et fonctionnelles in vitro chez l’embryon, et in vivo chez l’animal postnatal, de modèles murins - perte et gain de fonction –ciblant le RTN de la manière la plus sélective possible par génétique intersectionnelle. Ces modèles sont basés (i) sur l’historique d’expression des facteurs de transcription Phox2b, Lbx1, Atoh1 spécifiant les neurones du RTN au cours du développement et (ii) sur la transposition, chez la souris, de mutations humaines, Phox2b27Ala/+ et Lbx1fs/fs affectant ces facteurs, et qui sont respectivement, diagnostique, et proposé comme telle, du CCHS. L’ensemble des mutants étudiés récapitulent chez la souris, des traits phénotypiques exclusifs chez l’embryon et à la naissance: l’abrogation anatomique du RTN, le ralentissement du rythme respiratoire et la perte complète du chémoréflexe. Nos travaux montrent donc que le RTN est un composant obligatoire du circuit chémoréflexe. Nous montrons de plus, que le chémoréflexe n’est pas requis pour la survie des souriceaux à la naissance, cette dernière pourrait être liée au déficit conjoint d’une autre structure de même identité que le RTN, son homologue segmentaire au niveau trigéminal du tronc cérébral: le groupe péri-trigéminal. / The maintenance of PCO2 and pH in arterial blood is vital. The principal mechanism through which this is achieved in mammals is the respiratory chemoreflex, a hyperventilation response to hypercapnia, whose circuitry is still elusive and the matter of a persistent debate. Our work deals with the putative roles of a group of interneurons at facial level of the brainstem, the “retrotrapezoïd nucleus”, in the CO2 chemoreflex and in the acceleration of breathing around birth. Our approach is inspired by the respiratory symptoms of Ondine’s curse or CCHS (apneas and abrogation of the chemoreflex) and its causal gene, encoding the transcription facteur Phox2b, expressed in RTN neurons. We have dissected the role of the RTN by studying the anatomical and functional properties in vitro in embryos and in vivo at birth and postnatally, of gain and loss of function mutant mouse models, as selective as possible towards the RTN through intersectional strategies. Our models are based (i) on the history of expression of the transcription factors Phox2b, Lbx1, Atoh1 that specify RTN neurons during development and (ii) on the transfer into the mouse of the human mutations Phox2b27Ala/+ and Lbx1fs/fs that target these factors and are respectively diagnostic and candidate diagnostic for CCHS. Compoundly, the mutants recapitulate exclusive phenotypic traits in the embryo and at birth: anatomical abrogation of the RTN, a slowed down respiratory rhythm and the complete loss of chemoreflex. Our work demonstrates that the RTN is an obligatory component of the chemoreflex circuit. Furthermore, we show that the chemoreflex is not required for survival at birth and that the latter may be put at risk by the joint deficiency of another structure sharing the same molecular identity with the RTN, in fact its segmental homologue at trigeminal level of the brainstem: the peri-trigeminal group.

Le syndrome d’apnées obstructives du sommeil (SAOS) est associé à de nombreuses co-morbidités métaboliques et cardiovasculaires. L’hypoxie intermittente chronique, une des composantes du SAOS, induit des mécanismes intermédiaires délétères tels que stress oxydatif, inflammation, insulino-résistance ou encore dyslipidémie, à l’origine de ces comorbidités. Ces mécanismes intermédiaires sont également communs à d’autres pathologies respiratoires chroniques telles que la bronchopneumopathie chronique obstructive (BPCO) et le syndrome d’obésité hypoventilation (SOH).L’hypoxie intermittente et les mécanismes intermédiaires associés sont aussi à l’origine de l’existence et de la progression de la stéatopathie métabolique (« non alcoholic fatty liver disease »). Ce lien entre pathologies respiratoires chroniques et atteinte hépatique est un mécanisme essentiel mais plus récemment étudié des co-morbidités dans le SAOS et la BPCO. Différents biomarqueurs cardiométaboliques ont donc été étudiés dans ces pathologies respiratoires chroniques à la fois pour caractériser les co-morbidités et l’atteinte systémique et pour apprécier l’impact de différentes thérapeutiques. La première partie de cette thèse sera consacrée à une revue systématique des différents biomarqueurs cardio-métaboliques liés à chacune de ces 3 pathologies respiratoires chroniques : SAOS, BPCO et SOH.Le traitement du SAOS par pression positive continue (PPC) a un effet bénéfique sur les symptômes fonctionnels liés à cette pathologie. Cependant, l’impact de la PPC sur d’autres conséquences cardio-métaboliques délétères du SAOS reste encore à démontrer par des essais randomisés contrôlés, notamment sur l’atteinte hépatique.Dans la seconde partie de cette thèse, nous détaillerons l’impact de la PPC sur les différents marqueurs cardiométaboliques du SAOS à l’aide d’une revue systématique puis d’une étude randomisée contrôlée sur l’impact de la PPC sur les marqueurs d’atteinte hépatique.Par ailleurs, les patients atteints de SAOS, BPCO ou SOH reçoivent du fait de leur polypathologie (multimorbidité) des traitements médicamenteux multiples qui visent à contrôler au mieux les co-morbidités. Il est donc primordial de considérer la prise en charge globale de ces patients du point de vue de leurs traitements instrumentaux (PPC et ventilation non invasive) mais aussi en considérant l’impact des traitements médicamenteux associés. En effet, les traitements médicamenteux peuvent interférer avec la sévérité de la pathologie elle-même et impacter les biomarqueurs liés aux comorbidités associées. La troisième partie de cette thèse sera consacrée à l’étude d’un antihypertenseur chez le patient SAOS et envisagera l’influence des médicaments sur la pertinence de l’usage des bicarbonates comme marqueurs diagnostiques du SOH.En conclusion, nous insisterons sur la nécessité d’une prise en charge intégrée multi systémique et d’une prise en charge personnalisée de ces patients. / Obstructive sleep apnea (OSA) is associated with related metabolic and cardiovascular comorbidities. Chronic intermittent hypoxia the hallmark of OSA induces deleterious intermediary mechanisms such as oxidative stress, systemic inflammation, insulin resistance and dyslipidemia. Cardiovascular and metabolic comorbidities are also key features of other chronic respiratory diseases such as chronic obstructive pulmonary disease (COPD) and obesity hypoventilation syndrome (OHS). Chronic hypoxia and deleterious intermediary mechanisms also trigger occurrence and progression of non alcoholic fatty liver disease. This link between chronic respiratory diseases and liver injury is observed through modifications of specific liver biomarkers in OSA and COPD. A variety of cardiometabolic biomarkers have been studied for stratification of cardio-metabolic risk and assessing treatment impact in chronic respiratory diseases. The first part of this PhD thesis is a systematic review of cardio-metabolic biomarkers in 3 respiratory diseases: OSA, COPD and OHS.Continuous positive airway pressure (CPAP) the first line therapy for OSA improves symptoms and quality of life. However, CPAP effects on cardio-metabolic consequences remains still debated. In the second part of the PhD thesis, we will address CPAP impact on different cardiometabolic biomarkers and more specifically in markers of liver injury by reporting original results of a randomized controlled trial (RCT).Polypharmacy is usual in patients with OSA, COPD or OHS. Beyond CPAP or non invasive ventilation treatment, it is essential address the contribution of associated medications. Indeed, pharmacological treatments can interfere with the severity of the disease and control of associated comorbidities. The third part of the thesis will present a RCT evaluating Bosentan in hypertensive OSA patients and will present how medications for comorbidities decrease bicarbonate diagnosis value for OHS.We will conclude by underlining the crucial importance of personalized medicine and integrated care in chronic respiratory diseases.

No description available.