INTRODUÇÃO: Recentes estudos avaliam o uso da solução salina hipertônica na concentração de 3% no tratamento de pacientes com traumatismos cranioencefálicos, entretanto, poucos trabalhos têm analisado a sua eficácia no tratamento do choque hemorrágico. O objetivo deste trabalho é avaliar os efeitos do tratamento do choque hemorrágico com a solução salina hipertônica a 3%, analisando principalmente seus possíveis efeitos benéficos na atenuação da resposta inflamatória decorrrente do choque. Para tal, esta solução será comparada a outras duas, amplamente estudadas: a solução salina hipertônica a 7,5% e a solução de Ringer lactato. MÉTODOS: Foram utilizados, neste estudo, 26 ratos Wistar. Os animais foram anestesiados com pentobarbital sódico por via intraperitoneal (50 mg/Kg) e, então, submetidos a um protocolo de choque hemorrágico controlado. Neste protocolo, os animais foram sangrados até que fosse atingida uma pressão arterial média (PAM) de 35 mmHg, em um período de 10 minutos, sendo este nível de PAM mantido por 50 minutos. Ao término deste período de choque, os animais foram randomizados em três grupos para reposição volêmica: reposição com solução de Ringer lactato (grupo RL, n=7), na dose de 33 mL/Kg; reposição com solução salina hipertônica a 3% (grupo SH3%, n=7), na dose de 10 mL/Kg; reposição com solução salina hipertônica a 7,5% (grupo SH7,5%, n=7), na dose de 4 mL/Kg. Após a infusão das soluções, metade do volume de sangue retirado foi reinfundido em todos os animais. Sangue arterial foi coletado para análise de gasometria, lactato, concentração plasmática de sódio e osmolaridade plasmática. Para avaliação da resposta inflamatória, os animais foram sacrificados quatro horas após o início do experimento, sendo obtidas amostras de sangue para determinação das concentrações plasmáticas de interleucina (IL) -6 e fator de necrose tumoral (TNF) -alfa. Amostras de tecido pulmonar e intestinal foram obtidas para avaliação histopatológica de lesão orgânica, sendo as lâminas analisadas por dois patologistas sem conhecimento prévio dos grupos, determinando-se, assim, um escore de lesão baseado em um sistema de pontuação. RESULTADOS: Todos os animais submetidos à reposição volêmica apresentaram valores adequados de PAM ao término do tratamento. Nos animais tratados com as duas concentrações de solução salina hipertônica, a concentração plasmática de sódio e o valor da osmolaridade plasmática foram significativamente maiores, quando comparados aos grupos CT e RL. A concentração plasmática de TNF-alfa foi significativamente maior nos animais tratados com a solução de Ringer lactato, não havendo, para tanto, diferenças estatísticas entre os grupos CT, SH3% e SH7,5%. Em relação a IL-6, não se observou diferenças estatisticamente significantes entre os grupos CT, SH3% e SH7,5%, sendo a concentração plasmática deste mediador inflamatório significativamente elevada no grupo RL, quando comparado ao grupo CT. O escore de lesão pulmonar foi significativamente maior no grupo RL, em comparação aos grupos SH3% e SH7,5% (5,7 ± 0,7, 2,7 ± 0,5, 2,1 ± 0,4, respectivamente). Os animais dos grupos SH3% e SH7,5% apresentaram atenuação da lesão intestinal pós-choque em comparação aos animais do grupo RL (2,3 ± 0,4, 2,0 ± 0,6, 5,9 ± 0,6, respectivamente). CONCLUSÕES: O tratamento do choque hemorrágico com as duas concentrações de solução salina hipertônica resultou em atenuação da resposta inflamatória pós-choque. A solução salina hipertônica a 3% apresentou efeitos metabólicos e imunológicos semelhantes à solução salina hipertônica a 7,5%, sendo ambas superiores em relação aos parâmetros estudados à solução de Ringer lactato. / BACKGROUND: Recent studies have been conducted examining the efficacy of 3% hypertonic saline solution (HSS) in traumatic brain injury; however, few studies have analyzed the effects of 3%HSS during hemorrhagic shock. The aim of this study was to test the potential immunomodulatory benefits of 3%HSS resuscitation over standard fluid resuscitation. METHODS: Wistar rats were bled to a mean arterial pressure (MAP) of 35 mmHg and then randomized in 3 groups: LR (lactated Ringer, 33mL/Kg, n=7), 3%HSS (10mL/Kg, n=7) and 7.5%HSS (4mL/Kg, n=7). Half of the shed blood was infused after fluid resuscitation. Animals who did not undergo shock served as controls (CT,n=5). Four hours after HS, blood was collected for evaluation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 by enzyme immunoassay. Lung and intestinal samples were obtained for histopathological analysis. RESULTS: Animals in HSS groups had significantly higher MAP than LR one hour after treatment. Osmolarity and sodium levels were markedly elevated in HSS groups. TNF-alpha and IL-6 levels were similar between CT and HSS groups, but significantly higher in LR (p<0.05). Lung injury score was significantly higher in LR when compared to 7.5%HSS and 3%HSS (5.7 ± 0.7, 2.1 ± 0.4 and 2.7 ± 0.5, respectively). Intestinal injury was attenuated in the 7.5%HSS and 3%HSS groups when compared to LR (2.0 ± 0.6, 2.3 ± 0.4 and 5.9 ± 0.6, respectively). CONCLUSIONS: Small volume resuscitation strategy modulates the inflammatory response and decrease the end-organ damage after HS. 3%HSS provides immunomodulatory and metabolic effects similar to those observed with conventional concentration of HSS.

Introdução: Este estudo foi desenhado para avaliar o impacto da reposição de fluidos na aeração pulmonar, oxigenação e hemodinâmica pacientes com diagnóstico de choque séptico e síndrome do desconforto respiratório agudo (SDRA). Métodos: Durante o período de 1 ano, um estudo prospectivo observacional foi realizado com 32 pacientes com diagnóstico de choque séptico e SDRA. Os parâmetros cardiorrespiratórios foram mensurados utilizando um cateter de Swan-Ganz (n = 29) ou um cateter de PICCO (n = 3). A aeração pulmonar e o fluxo sanguíneo regional pulmonar foram avaliados pelo exame de ultrassom pulmonar à beira-leito. As medidas foram realizadas antes (T0), ao final (T1) e 40 minutos após (T2) a infusão de fluidos, consistindo em um litro de solução salina administrado em 30 minutos nas primeiras 48 horas do início do choque séptico e SDRA. Resultados: O escore de ultrassom pulmonar aumentou em 23% em T2, de 13 no tempo basal a 16 (p < 0,001). O índice cardíaco e as pressões de enchimento cardíaco aumentaram significativamente em T1 (p < 0,001) e retornaram aos valores de base em T2. O aumento no escore de ultrassom pulmonar secundário à infusão de fluidos foi estatisticamente correlacionado com o aumento do índice cardíaco e não foi associado ao aumento do \"shunt\" pulmonar ou ao aumento do fluxo sanguíneo regional pulmonar. Em T1, PaO2/FiO2 aumentou significativamente (p < 0,005) de 144 (123 - 198) a 165 (128 - 226) e retornou aos valores de base em T2, e o escore de ultrassom pulmonar continuou a aumentar. Conclusão: A reposição de fluidos precoce melhora transitoriamente a hemodinâmica e deteriora a aeração pulmonar. As mudanças na aeração podem ser observadas à beiraleito com o auxílio do ultrassom pulmonar e podem ser úteis como medida protetora contra a reposição excessiva de fluidos / Introduction: The study was designed to assess the impact of fluid loading on lung aeration, oxygenation and hemodynamics in patients with septic shock and acute respiratory distress syndrome (ARDS). Methods: During a 1-year period, a prospective observational study was performed in 32 patients with septic shock and ARDS. Cardiorespiratory parameters were measured using Swan Ganz (n=29) or PiCCO catheters (n=3). Lung aeration and regional pulmonary blood flows were measured using bedside transthoracic ultrasound. Measurements were performed before (T0), at the end of volume expansion (T1) and 40 minutes later (T2), consisting of 1-L of saline over 30 minutes during the first 48h following onset of septic shock and ARDS. Results: Lung ultrasound score increased by 23 % at T2, from 13 at baseline to 16 (p < 0.001). Cardiac index and cardiac filling pressures increased significantly at T1 (p < 0.001) and returned to control values at T2. The increase in lung ultrasound score was statistically correlated with fluid loading-induced increase in cardiac index and was not associated with increase in pulmonary shunt or regional pulmonary blood flow. At T1, PaO2/FiO2 significantly increased (p < 0.005) from 144 (123 to 198) to 165 (128 to 226) and returned to control values at T2 whereas lung ultrasound score continued to increase. Conclusions: Early fluid loading transitorily improves hemodynamics and oxygenation and worsens lung aeration. Aeration changes can be detected at the bedside by transthoracic lung ultrasound which may serve as a safeguard against excessive fluid loading

INTRODUÇÃO: A insuficiência respiratória acomete grande parte dos pacientes oncológicos levando a altos índices de mortalidade. A ventilação não invasiva (VNI) pode auxiliar seu manejo, mas seus efeitos ainda são pouco conhecidos sobre os mecanismos de defesa pulmonar. OBJETIVOS: Observar o efeito da VNI com máscara facial usando-se geradores de fluxo com pressão positiva contínua (CPAP) e ventilador microprocessado no modo pressão de suporte + pressão positiva ao final da expiração (PSV + PEEP), a fim de verificar impacto nas propriedades viscoelásticas do muco respiratório e o conforto proporcionado ao paciente. MÉTODOS: A VNI foi instalada após diagnóstico de insuficiência respiratória em dezenove pacientes, admitidos nas unidades de tratamento intensivo do Hospital A. C. Camargo, sendo nove submetidos ao CPAP e dez com PSV + PEEP. Foram colhidos antes e após uma hora de VNI: os dados clínicos, secreção nasal, gasometria, e o grau de conforto através de uma escala visual. As propriedades físicas do muco (transportabilidade in vitro, adesividade e wettabilidade ou hidrofobicidade) foram avaliadas respectivamente no palato de rã, máquina da tosse e ângulo de contato. RESULTADOS: Os grupos eram homogêneos entre si em relação à idade, sexo, tipo e estadiamento do tumor e SAPS II. Em relação às propriedades físicas do muco, houve um aumento da transportabilidade in vitro do muco nasal com o sistema PSV + PEEP (p = 0,04) e um aumento na wettabilidade no grupo CPAP (p = 0,06). Os dois sistemas foram eficazes em melhorar significativamente os sinais vitais, a PaO2/FiO2, o padrão e o conforto respiratório e em evitar a intubação traqueal nas primeiras 24 horas (p < 0,05). Entretanto, independentemente do tipo de sistema de VNI usado, foram encontrados altos índices de intubação endotraqueal e mortalidade no seguimento destes pacientes. CONCLUSÃO: As propriedades físicas do muco (transportabilidade in vitro e wettabilidade) se alteraram após uma hora de uso da VNI e parecem ser dependentes da temperatura e umidificação dentro da máscara. A VNI mostrou-se útil em reverter a insuficiência respiratória em pacientes selecionados, ou pelo menos em trazer conforto para pacientes hipoxêmicos que a princípio recusam a intubação endotraqueal / INTRODUCTION: Respiratory failure is a common situation among cancer patients leading to high rates of mortality. Noninvasive ventilation (NIV) can help its management, but its effects are still unknown regarding the pulmonary defense mechanisms. OBJECTIVES: Observe the effect of NIV with facial mask using a flow generator with continuous positive pressure (CPAP) and standard intensive care unit ventilator using pressure support ventilation + positive end expiratory pressure (PSV + PEEP), to verify impact on the physical properties of respiratory mucus and the comfort provided to the patient. METHODS: NIV was started after diagnosis of respiratory failure in nineteen patients, admitted in the intensive care unit of the A. C. Camargo Hospital. Nine patients were submitted to CPAP and ten to PSV + PEEP. Nasal mucus, blood gases, and the degree of comfort through a visual scale were accessed before and after one hour. The physical properties of nasal mucus (transportabilility in vitro, adhesivity and wettability or hydrofobicity) were evaluated respectively by frog palate, cough machine and contact angle. RESULTS: Groups had similar characteristics about age, sex, tumor and SAPS II score. Regarding the physical properties of the mucus, there was an increase in mucus transportability (by the frog palate model) with the system PSV + PEEP (p = 0.04) and an increase in the contact angle in the CPAP groupo (p = 0.06). The two systems were effective in improving the vital signs, the PaO2/FiO2, the respiratory pattern and comfort and avoiding endotracheal intubation in the first 24 hours (p < 0.05). However, regardless of the type of NIV system used, high rates of endotracheal intubation and mortality were found. CONCLUSION: The physical properties of the mucus (transportability in vitro and wettability) changed after an hour of use of the NIV as a result of temperature and humidification into the mask. NIV was useful in reversing the respiratory failure in selected patients, or at least in bringing comfort for those who refuse endotracheal intubation

Introdução: As estratégias ventilatórias protetoras têm contribuído para a redução da letalidade da Síndrome do Desconforto Respiratório Agudo (SDRA), mas ainda está em debate qual, entre as diversas existentes, é a mais eficaz. A estratégia ARDSNet, muito utilizada na prática clínica, prioriza a redução do volume corrente para minimizar a hiperdistensão. As estratégias Open Lung Approach (OLA), além de procurarem reduzir a hiperdistensão, buscam minimizar o colapso pulmonar para evitar a atelectasia cíclica. Os métodos para ajuste da PEEP ideal nas estratégias OLA apresentam imperfeições: difícil implementação, não permitem avaliação regional do pulmão ou não podem ser realizados a beira leito. Uma estratégia OLA guiada por Tomografia de Impedância Elétrica (TIE) que permite a avaliação regional pulmonar de modo contínuo e a beira leito pode trazer benefícios. Objetivo: Comparar os efeitos fisiológicos (imagem, mecânica e trocas gasosas) ao longo de 42 h entre duas estratégias ventilatórias protetoras em um modelo suíno de SDRA (estratégia ARDSNET X estratégia guiada por TIE: (PEEPTIE). Comparar a mecânica pulmonar e troca gasosa nas duas estratégias ao final das 42 h de ventilação, em uma mesma condição de ventilação, para avaliar efeitos duradouros das estratégias sobre o parênquima pulmonar. Métodos: Sete porcos foram submetidos a ventilação mecânica por 42 horas em cada uma das duas estratégias. A lesão pulmonary foi induzida com lavagem de solução fisiológica associada a ventilação lesiva. No grupo PEEPTIE, a PEEP foi ajustada pela TIE após manobra de recrutamento, mantendo o pulmão com o mínimo de colapso menor que 5%), enquanto que na estratégia ARDSNet era ajustada através da tabela PEEPxFiO2. O volume corrente foi mantido entre 4-6ml/Kg em ambas estratégias, com a pressão de platô menor que 30 cmH2O. Resultados: Oxigenação e mecânica pulmonary eram semelhantes em ambos os grupos após a lesão pulmonar. Durante as 42h de protocolo, a troca gasosa foi significativamente maior no grupo PEEPTIE quando comparado ao grupo ARDSNet tanto no início (p< 0.01) quanto ao final do protocolo(p< 0.01). A PEEP inicial não foi diferente nas duas estratégias (p= 0.14), mas foi significantemente maior no grupo PEEPTIE (p< 0.01) em grande parte do período de 42 h e também ao final. Não houve diferença na pressão de platô entre os grupos (p=0.05). O delta de pressão foi significativamente maior no grupo ARDSNet no começo (p= 0.03) e ao final do protocolo (p= 0.00). Atelectasia cíclica (p < 0.01) e a porcentagem de tecido não-aerado (p= 0.029) foram significativamente maiores no grupo ARDSNet. Ao final do protocolo, nos mesmos ajuste de ventilação, a complacência pulmonar global (p=0.021) e regional (p= 0.002) foram significativamente maiores no grupo PEEPTIE, bem como a troca gasosa (p= 0.048). Conclusões: a estratégia PEEPTIE, quando comparada a estratégia ARDSNet determinou melhor oxigenação, menor grau de colapso e de atelectasia cíclica, além de melhor mecânica pulmonar, tanto global, quanto regional. Esta melhora foi mantida ao final das 42 horas, quando os dois grupos eram ventilados com os mesmos ajustes, sugerindo que a estratégia PEEPTIE determinou menor dano pulmonar / Introduction: Protective ventilatory strategies have contributed for the reduction in Acute Respiratory Distress Syndrome (ARDS) mortality, but so far there is still debate which strategy is more effective. The ARDSNet strategy, used widely in the clinical practice, emphasizes in tidal volume reduction to minimize hiperdistension. The Open Lung Approach (OLA), besides the reduction of hiperdistension, emphasizes reduction of lung collapse to avoid tidal recruitment. The methods to adjust ideal PEEP in the OLA strategies have some imperfections: difficult implementation, do not allow regional lung evaluation or cant be performed at the bedside. The OLA strategy guided by Electrical Impedance Tomography (EIT) which allows a continuous and regional lung evaluation can bring benefits. Objective: Compare physiological effects (image, mechanics and gas exchange) during a period of 42 hours between two protective ventilatory strategies in an ARDS suine model (ARDSNet strategy x strategy guided by EIT PEEPTIE). Compare lung mechanics and gas exchange in both strategies at the end of 42 hours of ventilation, in the same ventilation condition, to evaluate the strategies longtime effects on lung parenchyma. Methods: Seven suines were submitted to mechanical ventilation for 42 hours in each ventilator strategy. Lung injury was induced by saline lavage associated to injurious mechanical ventilation. In the PEEPTIE arm, PEEP was selected by the electrical impedance tomography after a recruitment maneuver, trying to keep lung collapse at minimum, while the ARDSnet group followed a PEEPxFiO2 table. Tidal volume of 4-6ml/kg was maintained in both strategies, with a plateau pressure not higher than 30 cmH2O. Results: Oxygenation and lung mechanics were equally impaired in both arms after injury. During the 42 hours of protocol, gas exchange was significantly higher in the PEEPTIE arm as compared to the ARDSNet arm in the beginning (p< 0.01) and at the end of the protocol (p< 0.01). PEEP at the beginning of the protocol was similar between groups (p= 0.14), but at most part of the protocol and at the end, PEEP was significantly higher in the PEEPTIE arm (p< 0.01).There were no difference in plateau pressure (p=0.06). Driving pressure was significantly higher in the ARDSNet arm at the beginning (p= 0.03) and at the end (p= 0.00). Tidal recruitment was significantly higher in the ARDSNet arm (p < 0.01), and a higher percentage of non-aerated lung tissue (p= 0.029). At the end of the protocol, global lung compliance was significantly higher in the PEEPTIE arm (p=0.021), as for regional lung compliance (p= 0.002) and gas exchange (p= 0.048). Conclusion: The PEEPTIE strategy when compared to the ARDSNet strategy determined better gas exchange, lower percentage of collapse and tidal recruitment, besides better lung mechanics (global and regional). This improvement was maintained at the end of the 42 hours, when both groups were ventilated with the same parameters, suggesting that the PEEPTIE strategy determined less lung injury

Mechanical ventilation in itself can harm the lung and cause ventilator-induced lung injury (VILI), which can induce or aggravate acute respiratory distress syndrome (ARDS). Much debate remains over pivotal concepts regarding the pathophysiology of VILI, especially about the precise contribution, kinetics, and primary role of potential VILI mechanisms. Consequently, it remains largely unknown how best to design a well-timed and full-bodied mechanical ventilation strategy. Little is known also about small airways dysfunction in ARDS. Dynamic positron emission tomography (PET) with [18F]fluoro-2-deoxy-D-glucose (18F-FDG) can be used to image cellular metabolism, which during lung inflammation mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. We studied the regional evolution of inflammation using dynamic PET/CT imaging of 18F-FDG in VILI and during different lung-protective mechanical ventilation strategies. By dynamic CT we investigated also the location and magnitude of peripheral airway closure and alveolar collapse under high and low distending pressures and high and low inspiratory oxygen fraction. Piglets were submitted to an experimental model of early ARDS combining repeated lung lavages and injurious mechanical ventilation. The animals were subsequently studied during sustained VILI, or submitted to distinct approaches of lung-protective mechanical ventilation: the one recommended by the ARDS Network (ARDSNet), or to one defined as open lung approach (OLA). The normally and poorly aerated regions - corresponding to intermediate gravitational zones - were the primary targets of the inflammatory process accompanying early VILI, which may be attributed to the small volume of the aerated lung that receives most of ventilation. The ARDSNet strategy did not attenuate global pulmonary inflammation during 27h and led to a concentration of inflammatory activity in the upper and poorly aerated lung regions. The OLA, in comparison with the ARDSNet approach, resulted in sustained and better gas exchange and lung mechanics. Moreover, the OLA strategy resulted in less global and regional inflammation. Dynamic CT data suggested that a significant amount of airway closure and related reabsorption atelectasis occurs in acute lung injury. Whether potential distal bronchioles injury (“bronchiolotrauma”) is a critical and decisive element in ventilator-associated lung injury is a matter for future studies.

Les deux formes d'inflammation pulmonaire en réanimation sont la pneumonie et le syndrome de détresse respiratoire aiguë (SDRA). Nous avons conçu un test diagnostique rapide basé sur l'autofluorescence des neutrophiles alvéolaires. S'appuyant sur une étude expérimentale, puis sur une étude clinique randomisée, nous avons montré que les sondes d'intubation avec ballonnets coniques diminuaient les micro-inhalations sans prévenir l'incidence des pneumonies post-opératoire. Une grande variabilité des pressions des ballonnets coniques pose la question de leur effet délétère. La thérapie cellulaire basée sur les cellules souches mésenchymateuses (CSM) est prometteuse. L'étude des effets thérapeutiques des vésicules extracellulaires issues de CSM (VE-CSM) constitue un nouvel axe de recherche. Dans 2 modèles murins de SDRA, puis dans un modèle de poumons humains ex vivo, nous avons démontré des effets thérapeutiques des VE-CSM. Nous avons ensuite étudié les lymphocytes T régulateurs (Treg) pulmonaires et systémiques dans le SDRA. Cette étude a montré un déficit quantitatif plutôt que fonctionnel de la population Treg pulmonaire dans le SDRA, avec une cinétique évoquant un recrutement des Treg circulants vers le compartiment pulmonaire au cours de la maladie. En conclusion, nos travaux ont développé de nouvelles stratégies diagnostiques et préventives des pneumonies de réanimation, afin de réduire leur impact en termes de morbi-mortalité. Les bénéfices thérapeutiques des CSM et des VE-CSM dans le SDRA expérimental, ainsi que l'altération du phénotype Treg observé chez nos patients, ouvrent de nouveaux champs de recherche vers le développement d'immunothérapies innovantes. / Pneumonia and acute respiratory distress syndrome (ARDS) are two facets of severe acute lunginflammation, often met in intensive care unit (ICU). Rapid diagnosis of pneumonia remains essential inorder to optimize their management. We worked on setting up a quick test diagnosis based on theintensity of alveolar neutrophils autofluorescence. The validation of this test in a multicenter cohort isunderway. Preventing microaspiration across the cuff remains a priority to prevent pneumonia inmechanically ventilated patients. Based on the results of an ex vivo study followed by a clinicalrandomized trial, we showed that tapered-cuff endotracheal tube prevented microaspiration in the exvivo model, without lowering intraoperative microaspirations and postoperative pneumonia rate aftermajor vascular surgery. Both studies yielded similar results concerning the higher variation of cuffpressureover time, which leads to the question of their safety of use in terms of potential resultingtracheal wall ischemia.Pneumonia represents 80% of the cause of ARDS, which can be viewed as lung uncontrolledinflammatory response. Cell-based therapy using mesenchymal stem cells (MSC) is a growing field ofresearch in ARDS therapy. Despite numerous beneficial effects in ARDS, their capacity of self-renewalpoints them out as a potential cancer inducer in the mid-long term. In this context, evaluating thetherapeutic effects of extracellular vesicles-released from MSC (EV-MSC) represents a novel approach.We showed therapeutic effects of EC-CSM in two murine model of ARDS induced by endotoxin or liveEscherichia coli bacteria, and in another ex vivo human lung preparation.We then focused our research on temporal and compartmental dynamics of regulatory T cells(Treg) phenotypes in ARDS patients. This prospective observational clinical study showed that Early ARDSwas characterized with an alveolar compartment fully polarized towards pro-inflammatory state andneutrophils chemotaxis. In lung compartment, and compared to control patients, ARDS patients showeda quantitative Tregs deficiency, which partially recovered over time, while activation markers wereoverexpressed in both Tregs and effectors T cells (Teff). Conversely, patients with ARDS had a higherproportion of systemic Tregs compared to controls. Significant increased proportion in circulating Th1,Th22, and ILC1 subsets, and decreased proportion in ILC3 subsets were also found in ARDS patientscompared to controls.In conclusion, we developed novel strategies to diagnose and prevent pneumonia in ICU, whichremains essential to improve patients’ outcomes. Therapeutic effects of MSC and EV-MSC, as well asTreg phenotype alterations pave the way for development of novel immunoregulatory therapies.

Contexte: Le syndrome de détresse respiratoire aigüe (SDRA) est associé à une dysfonction vasculaire pulmonaire. Objectifs: Préciser le retentissement cardiaque de cette dysfonction vasculaire pulmonaire en recherchant la fréquence et le pronostic du foramen ovale perméable, du passage transpulmonaire de bulles en échographie de contraste, du cœur pulmonaire aigu (CPA), de la dysfonction systolique ventriculaire droite ainsi que de la déformation ventriculaire gauche au cours du SDRA. Nous avons aussi évalué la tolérance hémodynamique de la ventilation en Pression Expiratoire Positive (PEP) élevée. Méthodes: Les explorations étaient menées par échographie trans-œsophagienne (ETO) traditionnelle et en signature acoustique. Résultats: La faisabilité de l'ETO en décubitus ventral est bonne. Le foramen ovale perméable, détecté chez 19% des patients, est associé à une moins bonne réponse à l'augmentation de la PEP et à un recours aux thérapeutiques de sauvetage plus fréquent. Le passage de bulles transpulmonaire ne rend pas compte du seul shunt intra-pulmonaire anatomique, et dépend plus des conditions hémodynamiques (augmentation du débit cardiaque associée au sepsis) que de la ventilation. Le CPA, retrouvé chez 22% des patients, est associé à une pression motrice plus élevée, et au sepsis ; il est fréquemment associé à une insuffisance circulatoire, avec une mortalité plus élevée à J28. La quantification de la déformation ventriculaire gauche systolique par l'index d'excentricité est un bon marqueur de CPA, mais pas la dysfonction contractile ventriculaire droite évaluée en signature acoustique. Enfin, nous n'avons pas retrouvé de lien robuste entre la tolérance hémodynamique et l'efficacité respiratoire (recrutement alvéolaire) des niveaux de PEP élevés, sous réserve d'un nombre limité de patients. Conclusion: Les conséquences cardiaques de la dysfonction vasculaire pulmonaire restent fréquentes et associées à un pronostic péjoratif, avec des implications respiratoires et circulatoires. / Context: Acute respiratory distress syndrome (ARDS) leads to pulmonary vascular dysfunction Aims: We assessed cardiac consequences of pulmonary vascular dysfunction by detecting patent foramen ovale and transpulmonary bubbles transit using contrast echocardiography, acute cor pulmonale, right ventricle systolic dysfunction and left ventricle deformation during ARDS. We also assessed hemodynamic tolerance of high positive end expiratory pressure (PEEP). Methods: Transesophageal echocardiography (TEE) was performed with standard measurements and speckle tracking. Results: TEE could be safely performed in prone position. Patent foramen ovale was detected in 19% of patients, and was associated with a poor oxygenation response to PEEP, and greater use of adjunctive interventions. Transpulmonary bubbles transit was not solely related to anatomical intrapulmonary shunt, but was merely influenced by hemodynamic status (increased cardiac output associated with sepsis). Acute cor pulmonale occurred in 22% of patients, and was associated with a higher driving pressure and with sepsis; it was often associated with circulatory failure, with higher day-28 mortality. Left ventricle systolic deformation (evaluated by eccentricity index) but not right ventricle contractile impairment (evaluated with speckle tracking) was associated with acute cor pulmonale. Finally, we did not find a robust relation between hemodynamic tolerance and alveolar recruitment with higher PEEP levels, but the limited number of patients restricted the power of the analysis. Conclusion: Cardiac consequences of pulmonary vascular dysfunction remain frequent and associated with a poorer prognosis, with respiratory and circulatory implications.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-12T10:40:54Z No. of bitstreams: 1 fernandofonsecadosreis.pdf: 924331 bytes, checksum: 98e7db5298b53ee7d673e1dcf9a8a468 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T17:13:54Z (GMT) No. of bitstreams: 1 fernandofonsecadosreis.pdf: 924331 bytes, checksum: 98e7db5298b53ee7d673e1dcf9a8a468 (MD5) / Made available in DSpace on 2016-01-25T17:13:54Z (GMT). No. of bitstreams: 1 fernandofonsecadosreis.pdf: 924331 bytes, checksum: 98e7db5298b53ee7d673e1dcf9a8a468 (MD5) Previous issue date: 2015-08-04 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introdução: A lesão pulmonar induzida pela ventilação (VILI) é caracterizada por uma resposta inflamatória secundária ao stress/strain não fisiológicos impostos aos pulmões durante a ventilação mecânica. Apesar do conhecimento de que após a retirada do estímulo lesivo, os pulmões tendem a se recuperar, os efeitos de medicações anti-inflamatórias nesta recuperação ainda são incertos. Objetivo: Avaliar o efeito da dexametasona nas trocas gasosas, edema, inflamação e histologia pulmonar em diferentes momentos após indução da VILI, em ratos Wistar. Métodos: Os animais foram inicialmente alocados em dois grupos conforme recebessem dexametasona (grupo dexametasona – GD, n=26) ou salina (grupo controle – GC, n=31) intraperitoneal (i.p.). Após 30 minutos, os animais foram ventilados durante 1 hora, para indução da VILI, com os seguintes parâmetros: volume corrente (VT) de 35 ml/Kg, pressão positiva ao final da expiração (PEEP) de 0 cmH2O, frequência respiratória (FR) de 18 /min e fração inspirada de oxigênio (FIO2) de 100%. Em seguida os grupos GD e GC foram alocados para serem eutanasiados em diferentes momentos: 0h, 4h, 24h e 168h após a ventilação lesiva. Antes da eutanásia, eles foram anestesiados e ventilados por 10 minutos (VT de 6 ml/kg, FR de 80 /min, PEEP de 2 cmH2O, FIO2 de 100%), para estabilização e coleta da gasometria. Após a eutanásia, foram analisados o edema pulmonar, a citologia do lavado broncoalveolar (LBA) e a histologia pulmonar. Um grupo sham (GS, n=6), foi ventilado por 10 minutos com os mesmos parâmetros e analisado para comparação com os grupos GD e GC. Resultados: VILI foi observada no GC, o qual apresentou um maior escore de lesão pulmonar aguda comparada com GS em 0h, 4h e 24h (p <0,05). A dexametasona reduziu a injúria pulmonar, e o escore no GD não foi significativamente diferente do GS, e foi menor que no GC 4h e 24h (p < 0,05). A contagem de neutrófilos no LBA aumentou tanto no GC quanto no GD, atingindo pico 4h após VM (p < 0,05). No entanto, a contagem de neutrófilos atingiu menores níveis no GD comparado com GC em 4h e 24h (p < 0,05). A dexametasona também atenuou o prejuízo na oxigenação que foi observado no GC imediatamente após a VM lesiva. Conclusões: Neste modelo experimental, a dexametasona reduziu a inflamação e a lesão pulmonar induzida pela ventilação mecânica com alto VT, resultando em melhor oxigenação após a VILI. Estes resultados reforçam a importância do biotrauma na patogênese da VILI, e a necessidade do estudo de terapias anti-inflamatórias para prevenção e tratamento dessa condição. / Introduction: Ventilator induced lung injury (VILI) is characterized by inflammatory response to a non-physiological stress/strain imposed to the lungs, during mechanical ventilation (MV). Although it is known that, after the removal of the harmful stimulus, the lungs tend to recover, the effects of anti-inflammatory drugs on this recovery is still uncertain. Objectives: To evaluate the effects of dexamethasone on arterial blood gases, edema, inflammation, and lung histology at different times after VILI induction in Wistar rats. Methods: The animals were initially allocated into two groups according to the intraperitoneal administration of dexamethasone (dexamethasone group – DG, n=26), or saline (control group – CG, n=31). After 30 minutes, VILI was induced by one hour of MV with the following settings: tidal volume (VT) of 35 ml/Kg, respiratory rate (RR) of 18 /min, positive end-expiratory pressure (PEEP) of 0 cmH2O, and fraction of inspired oxygen (FIO2) of 100%. Then, the animals in the DG and the CG groups were allocated to be submitted to euthanasia at different times: 0, 4, 24 and 168 hours, after the injurious MV. Before euthanasia, they were anesthetized and ventilated for 10 minutes (VT of 6 ml/kg, RR of 80 /min, PEEP of 2 cmH2O, FIO2 of 100%) for stabilization, and arterial blood gases analysis. After euthanasia, lung edema, total and differential cell count in the bronchoalveolar lavage (BAL) fluid and lung histology were analyzed. A sham group (SG, n=6) was ventilated for 10 minutes with the same settings, and analyzed for comparisons with the CG and DG groups. Results: VILI was observed in the CG, which presented a higher acute lung injury score compared to the SG, at 0h, 4h and 24h (p <0.05). The dexamethasone decreased the lung injury, and the score in the DG was not significantly different from the SG, and was lower than the CG 4h and 24h (p <0.05). BAL neutrophil counts increased both in the CG and in the DG, peaking at 4h after MV (p < 0.05). However, the neutrophil counts reached lower levels in DG, compared to CG at 4h and 24h (p <0.05). Dexamethasone also improved the oxygenation impairment that was seen in the CG immediately after the injurious MV. Conclusions: In this experimental model, dexamethasone decreased the inflammation and the lung injury induced by mechanical ventilation with high VT. These findings highlight the importance of the biotrauma in the VILI pathogenesis, and the necessity of carrying out researches on anti-inflammatory therapies to prevent and treat this condition.

Bei einem akuten Lungenversagen senkt maschinelle Beatmung mit niedrigen Atemzugvolumina das Risiko für einen Ventilationsassoziierten Lungenschaden (VALI). Allerdings sind weitere Beatmungseinstellungen (Positive End-Exspiratory Pressure [PEEP], Recruitment Maneuver [RM]) zur Reduktion eines VALI Gegenstand aktueller klinischer und grundlagentechnischer Forschung. Studiendaten produzieren diesbezüglich ein heterogenes Meinungsbild. Ein restriktives Management von PEEP und Lungenrekrutierung (ARDSnet-PEEP-Tabelle) findet gleichermaßen Befürworter wie Studien, welche die Minimierung von tidaler Rekrutierung (TR) durch RM und/oder PEEP-Titrierung als lungenprotektives Management propagieren. In diesem experimentellen 24-Stunden-Langzeitversuch mit akutem Lungenversagen (ARDS) durch ein klinisch relevantes, experimentelles Salzsäure-Aspirationsmodell am Schwein wurden drei verschiedene, randomisierte Beatmungsstrategien durch individuelle PEEP-Einstellung anhand der ARDSnet-PEEP-Tabelle (ARDSnet-Gruppe), des Open- Lung-Concept (OLC-Gruppe) und des EIT-generierten SDRVD (EIT-Gruppe) untersucht. Hinsichtlich der Frage nach lungenprotektiver, individueller Beatmung und der Vermeidung eines VALI wurden Parameter der quantitativen Computertomographie (CT), der non-invasiven bettseitigen Elektroimpedanztomographie (EIT) und aus histologischen Untersuchungen (Diffuse Alveolar Damage [DAD] Score) herangezogen und verglichen.:I. Inhaltsverzeichnis II. Abkürzungsverzeichnis 1. Einführung in die Thematik 1.1 Akutes Lungenversagen – Acute Respiratory Distress Syndrome (ARDS) 1.1.1 Definition, Epidemiologie, Ätiologie und Pathogenese des ARDS 1.1.2 Lungenprotektive maschinelle Beatmung und Ventilationsassoziierter Lungenschaden (VALI) bei Patienten mit ARDS 1.2 In der Studie verglichene Beatmungsstrategien 1.2.1 ARDS Network Protokoll (ARDSnet-Gruppe) 1.2.2 Open Lung Concept (OLC-Gruppe) 1.2.3 Elektroimpedanztomographie (EIT-Gruppe) 1.3 ARDS – Bildmorphologie (CT und EIT) und Histologie (DAD-Score) 1.3.1 Elektroimpedanztomographie (EIT) – Standard deviation of regional ventilation delay (SDRVD) 1.3.2 Computertomographie (CT) – Lungenkollaps und Tidale Rekrutierung 1.3.3 Histologie – Diffuse Alveolar Damage Score (DAD-Score) 1.4 Statistische Methoden 1.5 Wissenschaftliche Zielsetzung 2. Publikationsmanuskript 3. Zusammenfassung 4. Literaturverzeichnis 5. Anlagen (Supplemental Material) 6. Darstellung des eigenen Beitrags 7. Selbstständigkeitserklärung 8. Teilnahmebescheinigung: Vorlesung zur „Guten wissenschaftlichen Praxis“ an der Medizinischen Fakultät der Universität Leipzig 9. Wissenschaftlicher Lebenslauf 10. Publikationen 11. Danksagung

MUDr. Michal Otáhal Biomechanický model interakce oběhu a ventilace za podmínek UPV Abstract: Conventional mechanical ventilation provides gas exchange in conditions of respiratory failure by application positive airway pressure in the respiratory system. Due to the significant change in pressure conditions inside the thorax during conventional artificial ventilation the circulation can be significantly affected. Recruitment maneuver (RM) techniques can be a part of ventilation strategy in patients with the Acute Respiratory Distress Syndrome (ARDS), that are used to re-aerate collapsed parts of the lung parenchyma. During these RMs a significantly higher airway pressure is used than in protective ventilation strategy, which can limit the flow through the lung capillary network and can significantly affect the systemic hemodynamics of the patient. The aim of this work was to develop an optimized animation model of ARDS, then to compare the influence that has the application of different types of recruitment maneuvers on hemodynamics and to create a biomechanical simulation model of interaction and blood circulation and its verification with data obtained during the implementation of different types of RM in the experimental animal ARDS model. Results from the experimental animal model and simulations...