INTRODUÇÃO: A pneumonectomia está associada à alta mortalidade e alto índice de complicações. Entre estas, o edema pulmonar pós-pneumonectomia é uma das mais graves, podendo chegar a 100% de mortalidade. Pouco se sabe acerca dos fatores etiológicos desta doença, bem como sua associação a um processo inflamatório ou estresse oxidativo. O objetivo deste estudo foi analisar os efeitos agudos da pneumonectomia esquerda sobre o pulmão remanescente de ratos quanto à avaliação funcional por gasometria e avaliação histológica por formação de edema, infiltrado inflamatório, estresse oxidativo e reatividade vascular. MÉTODOS: Trinta e um ratos Wistar foram submetidos ao estudo. Vinte e um foram submetidos à pneumonectomia esquerda, sendo sacrificados em 48 horas (11 animais) e 72 horas (10 animais). Como controle do tratamento, 10 ratos foram submetidos à operação sham, sendo 5 sacrificados em 48 horas e 5 em 72 horas. A avaliação funcional foi realizada por meio de coleta de sangue arterial, gasometria e análise da relação pO2/FiO2. A análise histológica consistiu da avaliação dos seguintes parâmetros: (1) grau de edema perivascular; (2) presença de infiltrado inflamatório obtido por meio da densidade de neutrófilos; (3) expressão tecidual imunoistoquímica da Óxido Nítrico Sintase (NOS) para a avaliação do estresse oxidativo e (4) do grau de reatividade vascular, medido por meio da relação luz parede (lumen/wall ratio). Na avaliação do estresse oxidativo, foram analisadas a isoformas induzida e endotelial da NOS (iNOS e eNOS). Além destes parâmetros, o edema pulmonar foi avaliado por meio do ganho de massa pulmonar proporcional, denominado de Índice Pulmonar (IP) e da relação do peso úmido e do peso seco (Razão U/S). A análise estatística foi realizada por meio do teste ANOVA. RESULTADOS: Não houve diferença entre os grupos quanto à relação pO2/FiO2. Quanto à análise histológica, houve diferença quanto ao edema perivascular, infiltrado inflamatório, imunoexpressão de iNOS e eNOS e reatividade vascular. Houve interação entre a pneumonectomia e o sacrifício mais tardio, com maior índice de edema perivascular neste grupo (p=0,0274). Houve menor densidade de neutrófilos nos animais submetidos à pneumonectomia tanto em 48 como 72 horas (p=0,0168). Não houve diferença na imunoexpressão tecidual de iNOS entre os animais submetidos à pneumonectomia e seus respectivos grupos controle, mas houve diminuição no grupos de 72 horas (p=0,0212). A análise imunoistoquímica da eNOS evidenciou maior expressão nos animais submetidos à pneumonectomia (p=0,0208). Quanto ao grau de reatividade vascular, houve menor razão L/P nos grupos sacrificados após 72 horas (p=0,0107), sugerindo maior vasoconstrição nestes grupos. Embora tenha havido maior ganho de massa pulmonar nos dois grupos de animais submetidos à pneumonectomia (p=0,0033), a Razão U/S não mostrou diferença entre os grupos. CONCLUSÕES: A pneumonectomia esquerda em ratos não causou alterações funcionais, mas causou alterações histológicas. Quanto a estas alterações, não foram de natureza inflamatória e nem relacionadas ao estresse oxidativo. Foram caracterizadas por edema perivascular e vasoconstrição, observados após 72 horas da operação. / INTRODUCTION: Pneumonectomy is associated with high mortality and complication rates. Of these complications, post-pneumonectomy pulmonary edema is one of the most severe with a mortality rate that can reach 100%. Little is known about the etiological factors involved in this process and its association with inflammatory process or oxidative stress. The objective of this study was to analyze the acute effects of left pneumonectomy on the remaining lung of rats based on functional assessment by blood gas analysis and on histological assessment by edema formation, inflammatory infiltrate, oxidative stress and vascular reactivity. METHODS: Thirty one Wistar rats were included in the study. Twenty one underwent left pneumonectomy and were sacrificed in 48 hours (11 animals) and 72 hours (10 animals). Ten rats underwent sham procedure for control and five were sacrificed in 48 hours and five in 72 hours. Functional assessment was conducted by arterial blood gas and pO2/FiO2 ratio analyses. Histological analysis consisted of the assessment of the following parameters: (1) degree of perivascular edema; (2) presence of inflammatory infiltrate suggested by neutrophil density; (3) immunohistochemical expression of Nitric Oxide Synthase (NOS) in tissues to assess oxidative stress and (4) the degree of vascular reactivity measured by lumen/wall ratio (L/W ratio). For the assessment of oxidative stress, induced and endothelial isoforms of NOS (iNOS and eNOS) were analyzed. In addition to these parameters, pulmonary edema was assessed by means of proportional pulmonary mass gain, called Pulmonary Ratio (PR) and of the wet/dry weight ratio (W/D Ratio). The statistical analysis was conducted using the ANOVA test. RESULTS: The histological analysis showed difference regarding perivascular edema, inflammatory infiltrate, immunoexpression of iNOS and eNOS and vascular reactivity. The rate of perivascular edema was higher in animals submitted to pneumonectomy and sacrificed after 72 hours (p=0.0274). Neutrophil density was lower in animals submitted to pneumonectomy for those sacrificed after 48 and 72 hours alike (p=0.0168). There was no difference in the immunoexpression of iNOS in tissues between animals submitted to pneumonectomy and control groups, but such immunoexpression was reduced in both 72-hour groups (p=0.0212). The immunohistochemical analysis of eNOS evidenced a higher expression in animals submitted to pneumonectomy (p=0.0208). As concerns the degree of vascular reactivity, there was a lower W/D ratio in the groups sacrificed after 72 hours (p=0.0107), suggesting greater vasoconstriction in these groups. There was no difference between the groups as to the pO2/FiO2 ratio. Although the two groups submitted to pneumonectomy had greater gain of mass (p=0.0033), there was no difference in the W/D ratio between the groups. CONCLUSIONS: Left pneumonectomy in rats did not cause functional alterations but caused histological alterations that were neither of inflammatory nature nor related to oxidative stress. The alterations included perivascular edema and vasoconstriction observed after 72 hours of the procedure.

Introdução: O Edema Agudo dos Pulmões Cardiogênico (EAP) é uma condição clínica caracterizada por alta morbidade e mortalidade apesar dos avanços na terapia médica. Relatos de casos sugerem que a Apneia Obstrutiva do Sono (AOS) pode contribuir para desencadear episódios de EAP. No entanto, não existem estudos que avaliaram o impacto da AOS em pacientes com EAP. O objetivo desse estudo foi o de avaliar o impacto da AOS em eventos cardiovasculares após a recuperação de um evento confirmado de EAP. Métodos: No período de Janeiro de 2013 a Janeiro de 2015, recrutamos casos consecutivos de EAP nas Unidades de Emergências de três centros terciários de Cardiologia. Foram excluídos pacientes que não atenderam os critérios clínicos para EAP, pacientes que morreram antes de estudo do sono ou se recusaram a participar do protocolo. Após o tratamento de rotina para EAP e estabilização clínica (~30 dias), todos os pacientes com EAP confirmado foram convidados a realizar a monitorização portátil do sono. A AOS foi definida por um índice de apneia e hipopneia (IAH) >= 15 eventos/hora, excluindo-se casos com apneia predominantemente do tipo central. Realizamos o seguimento dos pacientes em busca de eventos cardiovasculares adotando critérios padronizados. O objetivo primário foi identificar a recorrência do EAP em pacientes com e sem AOS. Objetivos secundários incluíram incidência do infarto agudo do miocárdio (IAM), o óbito total e cardiovascular bem como identificar o período de ocorrência do EAP em pacientes com e sem AOS. Análise de regressão de Cox foi obtida para identificar preditores independentes de eventos. Um valor de p < 0,05 foi considerado estatisticamente significante. Resultados: Avaliamos inicialmente 255 pacientes adultos com suspeita clínica de EAP. Após as exclusões, foram estudados 104 pacientes com diagnóstico confirmado de EAP. A monitorização do sono ocorreu 31±7 dias após o episódio de EAP. A frequência da AOS nestes pacientes foi de 61% (64 pacientes). Destes, apenas 3 pacientes (3%) tinham conhecimento prévio da AOS e nenhum estava sobre tratamento específico para a AOS. Pacientes com e sem AOS não apresentaram diferenças de idade, sexo, índice de massa corpórea e fração de ejeção do ventrículo esquerdo. O seguimento médio foi de 12 ± 7meses. Trinta e um pacientes (30%) tiveram recorrência do EAP no seguimento. Em comparação com indivíduos sem AOS, os pacientes com AOS apresentaram maior recorrência do EAP (6 vs. 25 episódios, p=0,01) e maior incidência de IAM (0 vs. 15 episódios, p=0,0004). Todos os óbitos ocorreram no grupo com AOS (p=0,0001), sendo 17 óbitos totais, dos quais 13 por causas cardiovasculares. A AOS foi independentemente associada com maior recorrência de EAP (HR 3,3; IC 95% 1,2-8,8; p=0,01); incidência de IAM: (HR 2,3; IC 95% 1,1-9,5; p=0,002), óbito total (HR 6,5; 95% CI% 1,2-64,0; p=0,005) e óbito cardiovascular (HR 5,4; IC 95% 1,4-48,4; p=0,004). Entre os pacientes com AOS, aqueles que tiveram recorrência de EAP ou foram à óbito tiveram maior IAH e mais episódios de EAP cujo início dos sintomas ocorreram durante o sono. A análise de sobrevida livre de eventos após o estudo do sono mostrou que o grupo com AOS teve pior prognóstico para recorrência de EAP, incidência de IAM e óbitos totais e por causas cardiovasculares do que pacientes sem AOS. Conclusões: A AOS é muito comum, subdiagnosticada e independentemente associada com maior recorrência do EAP e morbimortalidades em pacientes que sobreviveram a um episódio prévio de EAP / Introduction: Acute cardiogenic pulmonary edema (ACPE) is a clinical condition characterized by high morbidity and mortality despite advancements in medical therapy. Case reports suggest that obstructive sleep apnea (OSA) may contribute to trigger ACPE episodes. However, no previous systematic study evaluated the impact of OSA on patients with ACPE. The aim of this study was to evaluate the impact of OSA on cardiovascular events after ACPE recovery. Methods: From January 2013 to January 2015, we recruited consecutive cases of ACPE from three Emergency Units Cardiology tertiary hospitals. We excluded patients who did not meet criteria for ACPE, died before sleep study or refused to participate in the protocol. After routine treatment for ACPE and clinical stabilization (~ 30 days), all patients with confirmed ACPE were invited to perform a portable sleep monitoring. OSA was defined by an apnea-hypopnea index (AHI) >= 15 events/hour. We excluded patients with predominantly central apnea. We carried out the follow-up searching for cardiovascular events by adopting standardized criteria. The main aim was ACPE recurrence. Secondary aims included incidence of acute myocardial infarction (AMI), total and cardiovascular deaths as well as differences in the period of occurrence of the ACPE in patients with and without OSA. Cox regression analysis was performed to identify independent predictors of events. A p value < 0.05 was considered statistically significant. Results: We initially evaluated 255 adult patients with clinical suspicion of ACPE. After exclusions, 104 patients were studied with a confirmed diagnosis of ACPE. The potable sleep monitoring occurred 31 ± 7 days following the ACPE episode. The frequency of OSA in these patients was 61% (64 patients). Of these, only 3 patients (3%) had prior knowledge of OSA diagnosis. None of them was on specific treatment. Patients with and without OSA showed no differences in age, sex, body mass index and left ventricular ejection fraction. The mean follow-up was 12 ± 7 months. Thirty one patients (30%) presented ACPE recurrence during the follow-up. Compared to individuals without OSA, patients with OSA had higher ACPE recurrence (6 vs. 25 episodes, p = 0.01), higher incidence of AMI (0 vs. 15 episodes, p=0.0004). All 17 deaths (13 from cardiovascular causes) occurred in the OSA group (p=0.0001). OSA was independently associated with higher ACPE recurrence (HR 3.3, 95% CI 1.2 to 8.8; p = 0.01); incidence of AMI (HR 2.3, 95% CI 1.1 to 9.5; p=0.02); total mortality (HR 6.5; 95% CI 1.2 to 164; p=0.005) and cardiovascular death (HR 5.4, 95% CI 1.4 to 48.4; p=0.004). Limiting our analysis to OSA patients, those who had ACPE recurrence or death had higher AHI and more ACPE episodes whose onset of symptoms occurred during sleep. Event-free survival analysis after the sleep study showed that OSA patients had a worse prognosis for ACPE recurrence, AMI incidence, total and cardiovascular mortality than patients without OSA. Conclusions: OSA is very common, underdiagnosed and independently associated with ACPE recurrence and morbimortality in patients with a previous ACPE episode

Multiple modulating genes and environmental factors have been implicated in the pathogenesis of high-altitude pulmonary edema (HAPE). However, at the present time, there exists an incomplete understanding of the molecular mechanisms and pathways which underlie constitutional susceptibility. Genome-wide measurements of gene expression in peripheral blood mononuclear cells (PBMCs) were performed using microarray technology. Comparison of gene expression profiles of HAPE-susceptible and resistant individuals resulted in the identification of several previously undescribed candidate genes. RhoA and Rho-kinase (ROCK), regulators of vascular smooth muscle contraction, were differentially regulated in the HAPE-susceptible cohort, as compared to both HAPE-resistant patients with acute mountain sickness (AMS+) and healthy controls (p=0.0014; p=0.0020). Furthermore, biological pathways involving RhoA and Rho-kinase were strongly upregulated in subjects with HAPE. These findings represent the first description of the RhoA/Rho-kinase signaling pathway in HAPE. Currently, few pharmacologic therapies have been demonstrated to be effective in the prevention and treatment of HAPE. The results of this study provide early evidence that Fasudil, a selective Rho-kinase inhibitor, may represent a novel therapeutic intervention effective in the prevention and/or treatment of high-altitude pulmonary edema.

INTRODUÇÃO: A pneumonectomia está associada à alta mortalidade e alto índice de complicações. Entre estas, o edema pulmonar pós-pneumonectomia é uma das mais graves, podendo chegar a 100% de mortalidade. Pouco se sabe acerca dos fatores etiológicos desta doença, bem como sua associação a um processo inflamatório ou estresse oxidativo. O objetivo deste estudo foi analisar os efeitos agudos da pneumonectomia esquerda sobre o pulmão remanescente de ratos quanto à avaliação funcional por gasometria e avaliação histológica por formação de edema, infiltrado inflamatório, estresse oxidativo e reatividade vascular. MÉTODOS: Trinta e um ratos Wistar foram submetidos ao estudo. Vinte e um foram submetidos à pneumonectomia esquerda, sendo sacrificados em 48 horas (11 animais) e 72 horas (10 animais). Como controle do tratamento, 10 ratos foram submetidos à operação sham, sendo 5 sacrificados em 48 horas e 5 em 72 horas. A avaliação funcional foi realizada por meio de coleta de sangue arterial, gasometria e análise da relação pO2/FiO2. A análise histológica consistiu da avaliação dos seguintes parâmetros: (1) grau de edema perivascular; (2) presença de infiltrado inflamatório obtido por meio da densidade de neutrófilos; (3) expressão tecidual imunoistoquímica da Óxido Nítrico Sintase (NOS) para a avaliação do estresse oxidativo e (4) do grau de reatividade vascular, medido por meio da relação luz parede (lumen/wall ratio). Na avaliação do estresse oxidativo, foram analisadas a isoformas induzida e endotelial da NOS (iNOS e eNOS). Além destes parâmetros, o edema pulmonar foi avaliado por meio do ganho de massa pulmonar proporcional, denominado de Índice Pulmonar (IP) e da relação do peso úmido e do peso seco (Razão U/S). A análise estatística foi realizada por meio do teste ANOVA. RESULTADOS: Não houve diferença entre os grupos quanto à relação pO2/FiO2. Quanto à análise histológica, houve diferença quanto ao edema perivascular, infiltrado inflamatório, imunoexpressão de iNOS e eNOS e reatividade vascular. Houve interação entre a pneumonectomia e o sacrifício mais tardio, com maior índice de edema perivascular neste grupo (p=0,0274). Houve menor densidade de neutrófilos nos animais submetidos à pneumonectomia tanto em 48 como 72 horas (p=0,0168). Não houve diferença na imunoexpressão tecidual de iNOS entre os animais submetidos à pneumonectomia e seus respectivos grupos controle, mas houve diminuição no grupos de 72 horas (p=0,0212). A análise imunoistoquímica da eNOS evidenciou maior expressão nos animais submetidos à pneumonectomia (p=0,0208). Quanto ao grau de reatividade vascular, houve menor razão L/P nos grupos sacrificados após 72 horas (p=0,0107), sugerindo maior vasoconstrição nestes grupos. Embora tenha havido maior ganho de massa pulmonar nos dois grupos de animais submetidos à pneumonectomia (p=0,0033), a Razão U/S não mostrou diferença entre os grupos. CONCLUSÕES: A pneumonectomia esquerda em ratos não causou alterações funcionais, mas causou alterações histológicas. Quanto a estas alterações, não foram de natureza inflamatória e nem relacionadas ao estresse oxidativo. Foram caracterizadas por edema perivascular e vasoconstrição, observados após 72 horas da operação. / INTRODUCTION: Pneumonectomy is associated with high mortality and complication rates. Of these complications, post-pneumonectomy pulmonary edema is one of the most severe with a mortality rate that can reach 100%. Little is known about the etiological factors involved in this process and its association with inflammatory process or oxidative stress. The objective of this study was to analyze the acute effects of left pneumonectomy on the remaining lung of rats based on functional assessment by blood gas analysis and on histological assessment by edema formation, inflammatory infiltrate, oxidative stress and vascular reactivity. METHODS: Thirty one Wistar rats were included in the study. Twenty one underwent left pneumonectomy and were sacrificed in 48 hours (11 animals) and 72 hours (10 animals). Ten rats underwent sham procedure for control and five were sacrificed in 48 hours and five in 72 hours. Functional assessment was conducted by arterial blood gas and pO2/FiO2 ratio analyses. Histological analysis consisted of the assessment of the following parameters: (1) degree of perivascular edema; (2) presence of inflammatory infiltrate suggested by neutrophil density; (3) immunohistochemical expression of Nitric Oxide Synthase (NOS) in tissues to assess oxidative stress and (4) the degree of vascular reactivity measured by lumen/wall ratio (L/W ratio). For the assessment of oxidative stress, induced and endothelial isoforms of NOS (iNOS and eNOS) were analyzed. In addition to these parameters, pulmonary edema was assessed by means of proportional pulmonary mass gain, called Pulmonary Ratio (PR) and of the wet/dry weight ratio (W/D Ratio). The statistical analysis was conducted using the ANOVA test. RESULTS: The histological analysis showed difference regarding perivascular edema, inflammatory infiltrate, immunoexpression of iNOS and eNOS and vascular reactivity. The rate of perivascular edema was higher in animals submitted to pneumonectomy and sacrificed after 72 hours (p=0.0274). Neutrophil density was lower in animals submitted to pneumonectomy for those sacrificed after 48 and 72 hours alike (p=0.0168). There was no difference in the immunoexpression of iNOS in tissues between animals submitted to pneumonectomy and control groups, but such immunoexpression was reduced in both 72-hour groups (p=0.0212). The immunohistochemical analysis of eNOS evidenced a higher expression in animals submitted to pneumonectomy (p=0.0208). As concerns the degree of vascular reactivity, there was a lower W/D ratio in the groups sacrificed after 72 hours (p=0.0107), suggesting greater vasoconstriction in these groups. There was no difference between the groups as to the pO2/FiO2 ratio. Although the two groups submitted to pneumonectomy had greater gain of mass (p=0.0033), there was no difference in the W/D ratio between the groups. CONCLUSIONS: Left pneumonectomy in rats did not cause functional alterations but caused histological alterations that were neither of inflammatory nature nor related to oxidative stress. The alterations included perivascular edema and vasoconstriction observed after 72 hours of the procedure.

Abstract Cardiovascular abnormalities are frequent after non-traumatic intracranial hemorrhage (NT-IH). They have mainly been studied in patients with subarachnoid hemorrhage (SAH), in which they have been reported to be associated with a poorer outcome. The aim of this observational clinical study was to evaluate cardiovascular abnormalities in patients with NT-IH requiring intensive care: clinical picture, predisposing factors and impact on outcome were examined. Additionally, the validity of cardiac output (CO) monitoring via uncalibrated arterial pressure waveform analysis (APCO, FloTrac/Vigileo™) was evaluated. The thesis was comprised of retrospective (n=229) and prospective (n=108) studies. The cardiovascular abnormalities evaluated were repolarization abnormalities (RAs) in electrocardiography (ECG), myocardial injury and dysfunction, and neurogenic pulmonary edema (NPE). Cardiovascular dysfunction severity was assessed using the Sequential Organ Failure Assessment cardiovascular (SOFAcv) score. Predisposing factors for RAs and NPE were examined. The one-year mortality and functional outcome were assessed. APCO was compared with the intermittent bolus thermodilution technique (TDCO). Cardiovascular abnormalities were almost universal after NT-IH and comparable after intracerebral hemorrhage (ICH) and SAH. Each RAs (QT interval prolongation, ischemic-like ECG changes and morphological end-repolarization abnormalities) had characteristic predisposing factors. The Acute Physiology And Chronic Health Evaluation (APACHE) II score &#8805;20 and systemic interleukin 6 concentration &#62;40 pg/mL were independent predictors for NPE. In the retrospective study the mortality rate was 32% after SAH and 44% after ICH. In the prospective study the rates for mortality were 18% vs. 29% and for a poor functional outcome 41% vs. 69%, respectively. Ischemic-like ECG changes were associated with a poorer functional outcome. APCO underestimated CO compared to TDCO and was biased by low systemic vascular resistance (SVR). In conclusion, cardiovascular abnormalities after NT-IH are comparable after SAH and ICH. Predisposing factors for each RAs vary. Inflammatory mechanisms play an important role in NPE development. Ischemic-like ECG changes are associated with a poorer one-year functional outcome. The validity of APCO is insufficient and biased by low SVR in patients with NT-IH. / Tiivistelmä Sydämen ja verenkierron toimintahäiriöt ovat yleisiä ei-traumaattisen aivoverenvuodon (NT-IH) jälkeen. Niitä on tutkittu lähinnä lukinkalvonalaisvuotopotilailla (SAV), joilla niiden on todettu olevan yhteydessä huonompaan ennusteeseen. Tässä havainnoivassa kliinisessä tutkimuksessa selvitettiin tehohoidettujen NT-IH -potilaiden sydämen ja verenkierron toimintahäiriöiden kliinistä oirekuvaa, altistavia tekijöitä ja vaikutusta ennusteeseen. Tutkimuksessa arvioitiin myös valtimopainekäyräanalyysiin perustuvan monitorointimenetelmän (APCO, FloTrac/Vigileo™) luotettavuutta mitattaessa sydämen minuuttitilavuutta. Väitöskirjatyö koostui retrospektiivisesta (n=229) ja prospektiivisesta (n=108) tutkimuksesta. Tutkittavia toimintahäiriöitä olivat elektrokardiografiassa (EKG) nähtävät repolarisaatiohäiriöt (RAs), sydänlihaksen vaurio ja supistumishäiriö sekä keuhkopöhö. Sydämen ja verenkierron toimintahäiriön yleistä vaikeusastetta arvioitiin SOFAcv -pisteytyksellä. RAs:lle ja keuhkopöhölle altistavia tekijöitä määritettiin. Potilaiden kuolleisuus ja toiminnallinen ennuste selvitettiin vuoden seuranta-aikana. APCO:a verrattiin lämpölaimennusmenetelmään (TDCO). Sydämen ja verenkierron toimintahäiriöitä esiintyi lähes kaikilla, eivätkä ne oirekuvaltaan eronneet aivokudoksen sisäistä vuotoa (ICH) ja SAV:a sairastavilla potilailla. Eri RAs:llä (QT-ajan pidentyminen, iskeemistyyppiset EKG-muutokset ja loppurepolarisaation morfologiset poikkeavuudet) oli kullekin ominaiset altistavat tekijät. APACHE II –pisteet &#8805;20 ja veren interleukiini 6 –pitoisuus &#62;40 pg/ml ennustivat keuhkopöhön kehittymistä. Retrospektiivisessä aineistossa kuolleisuus oli 32&#160;% SAV-potilailla ja 44&#160;% ICH-potilailla. Prospektiivisessa aineistossa kuolleisuus ja huono toiminnallinen ennuste olivat vastaavasti 18&#160;% vs. 29&#160;% ja 41&#160;% vs. 69&#160;%. Iskeemistyypiset EKG-muutokset olivat yhteydessä huonompaan toiminnalliseen ennusteeseen. APCO aliarvioi TDCO:a matalan systeemiverenkierron vastuksen (SVR) kasvattaessa harhaa. Yhteenvetona todettakoon, että sydämen ja verenkierron toimintahäiriöt eivät eroa SAV- ja ICH-potilailla. Eri RAs:lle altistavat kullekin ominaiset tekijät. Tulehdukselliset mekanismit ovat keskeisiä keuhkopöhön kehittymisessä. Iskeemistyyppiset EKG-muutokset ovat yhteydessä huonompaan toiminnalliseen ennusteeseen. APCO:n luotettavuus NT-IH -potilailla on riittämätön, ja harhaa lisää matala SVR.

Introdução: O Edema Agudo dos Pulmões Cardiogênico (EAP) é uma condição clínica caracterizada por alta morbidade e mortalidade apesar dos avanços na terapia médica. Relatos de casos sugerem que a Apneia Obstrutiva do Sono (AOS) pode contribuir para desencadear episódios de EAP. No entanto, não existem estudos que avaliaram o impacto da AOS em pacientes com EAP. O objetivo desse estudo foi o de avaliar o impacto da AOS em eventos cardiovasculares após a recuperação de um evento confirmado de EAP. Métodos: No período de Janeiro de 2013 a Janeiro de 2015, recrutamos casos consecutivos de EAP nas Unidades de Emergências de três centros terciários de Cardiologia. Foram excluídos pacientes que não atenderam os critérios clínicos para EAP, pacientes que morreram antes de estudo do sono ou se recusaram a participar do protocolo. Após o tratamento de rotina para EAP e estabilização clínica (~30 dias), todos os pacientes com EAP confirmado foram convidados a realizar a monitorização portátil do sono. A AOS foi definida por um índice de apneia e hipopneia (IAH) >= 15 eventos/hora, excluindo-se casos com apneia predominantemente do tipo central. Realizamos o seguimento dos pacientes em busca de eventos cardiovasculares adotando critérios padronizados. O objetivo primário foi identificar a recorrência do EAP em pacientes com e sem AOS. Objetivos secundários incluíram incidência do infarto agudo do miocárdio (IAM), o óbito total e cardiovascular bem como identificar o período de ocorrência do EAP em pacientes com e sem AOS. Análise de regressão de Cox foi obtida para identificar preditores independentes de eventos. Um valor de p < 0,05 foi considerado estatisticamente significante. Resultados: Avaliamos inicialmente 255 pacientes adultos com suspeita clínica de EAP. Após as exclusões, foram estudados 104 pacientes com diagnóstico confirmado de EAP. A monitorização do sono ocorreu 31±7 dias após o episódio de EAP. A frequência da AOS nestes pacientes foi de 61% (64 pacientes). Destes, apenas 3 pacientes (3%) tinham conhecimento prévio da AOS e nenhum estava sobre tratamento específico para a AOS. Pacientes com e sem AOS não apresentaram diferenças de idade, sexo, índice de massa corpórea e fração de ejeção do ventrículo esquerdo. O seguimento médio foi de 12 ± 7meses. Trinta e um pacientes (30%) tiveram recorrência do EAP no seguimento. Em comparação com indivíduos sem AOS, os pacientes com AOS apresentaram maior recorrência do EAP (6 vs. 25 episódios, p=0,01) e maior incidência de IAM (0 vs. 15 episódios, p=0,0004). Todos os óbitos ocorreram no grupo com AOS (p=0,0001), sendo 17 óbitos totais, dos quais 13 por causas cardiovasculares. A AOS foi independentemente associada com maior recorrência de EAP (HR 3,3; IC 95% 1,2-8,8; p=0,01); incidência de IAM: (HR 2,3; IC 95% 1,1-9,5; p=0,002), óbito total (HR 6,5; 95% CI% 1,2-64,0; p=0,005) e óbito cardiovascular (HR 5,4; IC 95% 1,4-48,4; p=0,004). Entre os pacientes com AOS, aqueles que tiveram recorrência de EAP ou foram à óbito tiveram maior IAH e mais episódios de EAP cujo início dos sintomas ocorreram durante o sono. A análise de sobrevida livre de eventos após o estudo do sono mostrou que o grupo com AOS teve pior prognóstico para recorrência de EAP, incidência de IAM e óbitos totais e por causas cardiovasculares do que pacientes sem AOS. Conclusões: A AOS é muito comum, subdiagnosticada e independentemente associada com maior recorrência do EAP e morbimortalidades em pacientes que sobreviveram a um episódio prévio de EAP / Introduction: Acute cardiogenic pulmonary edema (ACPE) is a clinical condition characterized by high morbidity and mortality despite advancements in medical therapy. Case reports suggest that obstructive sleep apnea (OSA) may contribute to trigger ACPE episodes. However, no previous systematic study evaluated the impact of OSA on patients with ACPE. The aim of this study was to evaluate the impact of OSA on cardiovascular events after ACPE recovery. Methods: From January 2013 to January 2015, we recruited consecutive cases of ACPE from three Emergency Units Cardiology tertiary hospitals. We excluded patients who did not meet criteria for ACPE, died before sleep study or refused to participate in the protocol. After routine treatment for ACPE and clinical stabilization (~ 30 days), all patients with confirmed ACPE were invited to perform a portable sleep monitoring. OSA was defined by an apnea-hypopnea index (AHI) >= 15 events/hour. We excluded patients with predominantly central apnea. We carried out the follow-up searching for cardiovascular events by adopting standardized criteria. The main aim was ACPE recurrence. Secondary aims included incidence of acute myocardial infarction (AMI), total and cardiovascular deaths as well as differences in the period of occurrence of the ACPE in patients with and without OSA. Cox regression analysis was performed to identify independent predictors of events. A p value < 0.05 was considered statistically significant. Results: We initially evaluated 255 adult patients with clinical suspicion of ACPE. After exclusions, 104 patients were studied with a confirmed diagnosis of ACPE. The potable sleep monitoring occurred 31 ± 7 days following the ACPE episode. The frequency of OSA in these patients was 61% (64 patients). Of these, only 3 patients (3%) had prior knowledge of OSA diagnosis. None of them was on specific treatment. Patients with and without OSA showed no differences in age, sex, body mass index and left ventricular ejection fraction. The mean follow-up was 12 ± 7 months. Thirty one patients (30%) presented ACPE recurrence during the follow-up. Compared to individuals without OSA, patients with OSA had higher ACPE recurrence (6 vs. 25 episodes, p = 0.01), higher incidence of AMI (0 vs. 15 episodes, p=0.0004). All 17 deaths (13 from cardiovascular causes) occurred in the OSA group (p=0.0001). OSA was independently associated with higher ACPE recurrence (HR 3.3, 95% CI 1.2 to 8.8; p = 0.01); incidence of AMI (HR 2.3, 95% CI 1.1 to 9.5; p=0.02); total mortality (HR 6.5; 95% CI 1.2 to 164; p=0.005) and cardiovascular death (HR 5.4, 95% CI 1.4 to 48.4; p=0.004). Limiting our analysis to OSA patients, those who had ACPE recurrence or death had higher AHI and more ACPE episodes whose onset of symptoms occurred during sleep. Event-free survival analysis after the sleep study showed that OSA patients had a worse prognosis for ACPE recurrence, AMI incidence, total and cardiovascular mortality than patients without OSA. Conclusions: OSA is very common, underdiagnosed and independently associated with ACPE recurrence and morbimortality in patients with a previous ACPE episode

Pulmonary edema occurs when fluid leaks from the pulmonary capillary network into the lung interstitium and alveoli. When the heart is not able to pump blood to the body efficiently, fluid can back up into the veins that take blood through the lungs to the left atrium. This then builds up the pressure in the blood vessels and fluid is pushed into the alveoli in the lungs. The fluid reduces normal oxygen movement through the lungs and can cause impaired gas exchange and respiratory failure. There are many causes of congestive heart failure that may lead to pulmonary edema such as heart attack, any diseases of the heart that weaken or stiffen the heart muscle, a leaking or narrowed heart valve, and sudden, severe high blood pressure. Pulmonary edema is a strong indicator of congestive heart failure in patients and therefore can be used as a gauge for congestive heart failure. One way to diagnose cardiogenic pulmonary edema constantly is through the continuous monitoring of the transthoracic impedance throughout the day. One method to achieve this constant monitoring is through the use of a cardiac pacemaker or an implantable cardioverter defibrillator (ICD). Many patients who are at risk of heart failure have these medical devices implanted already. In these implantable cardiac devices, the connected cardiac leads can be utilized to continually screen several impedance vectors for decreases in impedance in the thoracic cavity. A pacemaker or ICD that implements Pulmonary Edema Monitoring is designed to continuously monitor these impedance vectors and alert the patient to seek medical attention. This thesis will discuss the implementation of Pulmonary Edema Monitoring via screening of multiple impedance vectors in a pacemaker or implantable cardioverter defibrillator and the effectiveness of this monitoring method. Furthermore, the design, implementation, and testing of this feature will be explored in greater detail.

Le syndrome de détresse respiratoire aiguë (SDRA) est caractérisé par des dommages au niveau de la barrière alvéolo-capillaire, résultant en la formation d’un œdème pulmonaire et une réponse inflammatoire exacerbée. Sans résolution rapide de ces paramètres, le syndrome progresse vers le développement de fibrose menant à l’insuffisance respiratoire. Or, il a été établi que la réparation de l’épithélium alvéolaire est une étape cruciale pour la résolution du SDRA. Une meilleure compréhension des mécanismes de réparation de l’épithélium alvéolaire est donc nécessaire afin de proposer de nouvelles thérapies pour le SDRA, pour lequel aucun traitement efficace n’existe. Il a été montré que les mécanismes de réparation sont régulés par des protéines membranaires, non seulement par les récepteurs aux facteurs de croissance et les intégrines, mais également par les canaux ioniques, en particulier les canaux potassiques. L’objectif principal de cette étude était donc de caractériser l’impact de la modulation des canaux potassiques KCa3.1 et KvLQT1 dans la résolution du SDRA. Dans un premier temps, nos résultats ont montré le rôle coopératif du canal potassique KCa3.1, de la matrice extracellulaire et de l’intégrine-β1 dans les processus de réparation de l’épithélium alvéolaire in vitro. Nous avons montré que la matrice de fibronectine et le KCa3.1 étaient impliqués dans la migration et dans la réparation de monocouches de cellules alvéolaires de cultures primaires de rat. Dans un deuxième temps, nous avons étudié l’impact de la modulation du canal potassique KvLQT1 dans certains aspects physiopathologiques du SDRA à l’aide de modèles in vivo. Nous avons montré que KvLQT1 n’était pas seulement impliqué dans les mécanismes de réparation de l’épithélium alvéolaire, mais également dans la résorption de l’œdème pulmonaire et la résolution de la réponse inflammatoire. Nos résultats démontrent que les canaux potassiques, tels que KCa3.1 et KvLQT1, pourraient être identifiés en tant que cibles thérapeutiques potentielles pour le SDRA. / Acute respiratory distress syndrome (ARDS) is characterized by alveolar-capillary barrier damage, resulting in the formation of pulmonary oedema and an exacerbated inflammatory response. Without rapid recovery of these parameters, there is a gradual development of fibrosis, leading to respiratory failure. It has been established that alveolar regeneration is a critical step for the resolution of ARDS. A better understanding of alveolar epithelial repair mechanisms is hence necessary to identify new therapies for ARDS, for which no effective treatment exist. It has been shown that repair mechanisms are regulated by membrane proteins, not only by growth factor receptors and integrins, but also by ion channels, in particular potassium channels. Therefore, the main objective of this study was to characterize the impact of KCa3.1 and KvLQT1 potassium channels modulation in the resolution of ARDS. First, our results have shown the cooperative role of the potassium channel KCa3.1, the extracellular matrix and the β1-integrin in alveolar epithelial repair processes in vitro. We have shown that the fibronectin matrix and KCa3.1 are involved in the migration and repair of primary cultures of rat alveolar cell monolayers. Our data also revealed a putative relationship between Kca3.1 and the β1-integrin. Second, we studied the impact of KvLQT1 potassium channel modulation on ARDS pathophysiological aspects with in vivo models. We showed that KvLQT1 was not only involved in alveolar epithelial repair, but also in the resolution of pulmonary oedema and inflammatory response. Taken together, our data demonstrate that potassium channels, such as KCa3.1 and KvLQT1, may be identified as potential therapeutic targets for the resolution of ARDS.

The original work presented in this thesis investigates some of the mechanisms that may be responsible for the aetiology of altitude-related cough. Particular attention is paid to its relationship to the long recognised, but poorly understood, changes in lung volumes that occur on ascent to altitude. The literature relevant to this thesis is reviewed in Chapter 1.<p><p>Widespread reports have long existed of a debilitating cough affecting visitors to high altitude that can incapacitate the sufferer and, on occasions, be severe enough to cause rib fractures (22, 34, 35). The prevalence of cough at altitude has been estimated to be between 22 and 42% at between 4200 and 4900 m in the Everest region of Nepal (10, 29). Traditionally the cough was attributed to the inspiration of the cold, dry air characteristic of the high altitude environment (37) but no attempts were made to confirm this aetiology. In the first formal study of cough at high altitude, nocturnal cough frequency was found to increase with increasing altitude during a trek to Everest Base Camp (5300 m) and massively so in 3 climbers on whom recordings were made up to 7000 m on Everest (8). After 9 days at 5300 m the citric acid cough threshold, a measure of the sensitivity of the cough reflex arc, was significantly reduced compared with both sea level and arrival at 5300 m.<p><p>During Operation Everest II, a simulated climb of Mount Everest in a hypobaric chamber, the majority of the subjects were troubled above 7000 m by pain and dryness in the throat and an irritating cough despite the chamber being maintained at a relative humidity of between 72 and 82% and a temperature of 23ºC (18). This argued against the widely held view that altitude-related cough was due to the inspiration of cold, dry air. <p><p>In the next major hypobaric chamber study, Operation Everest III, nocturnal cough frequency and citric acid cough threshold were measured on the 8 subjects in the study. The chamber temperature was maintained between 18 and 24ºC and relative humidity between 30 and 60% (24). This work is presented in Chapter 2 and, demonstrated an increase in nocturnal cough frequency with increasing altitude which immediately returned to control values on descent to sea level. Citric acid cough threshold was reduced at 8000 m compared to both sea level and 5000 m values. Changes in citric acid cough threshold at lower altitudes may not have been detected because of the constraints on subject numbers in the chamber. The study still however demonstrated an increase in clinical cough and a reduction in the citric acid cough threshold at extreme altitude, despite controlled environmental conditions, and thus refuted the long held belief that altitude-related cough is solely due to the inspiration of cold, dry air. <p><p>If altitude-related cough is not simply due to the inspiration of cold, dry air, other possible aetiologies are:<p>•\ / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

L’association lésionnelle d’une contusion pulmonaire et d’un état de choc hémorragique est fréquente et constitue un réel chalenge thérapeutique. La prise en charge de ce choc va nécessiter une réanimation hémodynamique dans laquelle le remplissage vasculaire tient une place centrale. Mais dans ce contexte de poumon contus, il devra être raisonné car délétère sur le plan pulmonaire, notamment en terme d'oedème et d'altération de la compliance. Ce remplissage devra donc être titré, basé sur des objectifs tensionnels clairs et un monitorage hémodynamique fiable. L'utilisation de solutés à haut pouvoir d'expansion volémique (sérum salé hypertonique, colloïdes) présente un intérêt, de même que l'introduction précoce de vasopresseurs. Le monitorage hémodynamique permettra de conduire cette réanimation sur des objectifs de pression artérielle, sur des indices de précharge dépendance et sur la mesure de l'eau pulmonaire extravasculaire. Notre travail, basé sur des études expérimentales et cliniques, a pour objectif de caractériser les modalités actuelles de prise en charge d’une contusion pulmonaire, sur les plans hémodynamiques et respiratoires. / Pulmonary contusion is often associated with hemorrhagic shock, constituting a challenge in trauma care. For patients who have sustained lung contusions, fluid resuscitation should be carefully performed, because injured lungs are particularly vulnerable to massive fluid infusions with an increased risk of pulmonary edema and compliance impairment. Fluid administration should be included in an optimized and goal directed resuscitation, based on blood pressure objectives and hemodynamical monitoring. The use of fluids with high volume-expanding capacities (hypertonic saline, colloids) is probably interesting, as well as early introduction of vasopressors. Hemodynamic monitoring will allow to conduct resuscitation on blood pressure objectives, on preload parameters and on extravascular lung water measurement.Our work, based on experimental and clinical studies, objective to characterize the current modalities of ventilatory and hemodynamical aspect of pulmonary contusion care.