Orientador: José Roberto Fioretto / Resumo: A Síndrome do Desconforto Respiratório Agudo (SDRA) é a forma clínica mais grave da lesão pulmonar aguda e, apesar do melhor entendimento de sua fisiopatologia, a taxa de mortalidade permanece elevada. O óxido nítrico inalatório (NOi) é um vasodilatador seletivo de áreas pulmonares ventiladas, promovendo a otimização da relação ventilação/perfusão nestas áreas, com melhora da oxigenação e facilitação do esvaziamento do ventrículo direito. Tais efeitos permitiriam a redução de parâmetros ventilatórios, habitualmente elevados na SDRA, diminuindo o risco de lesão pulmonar induzida pela ventilação mecânica e a morbi/mortalidade. O estudo teve como objetivos avaliar o efeito imediato e prolongado da administração precoce de NOi associada à terapia convencional sobre a oxigenação e parâmetros ventilatórios, mortalidade, tempo de internação na UTI Pediátrica e duração da ventilação mecânica em crianças portadoras de SDRA. Dois grupos de pacientes pediátricos com SDRA foram comparados: grupo NOi (GNO; n=18), seguido prospectivamente, composto de pacientes que receberam NOi associado à terapia convencional e grupo terapia convencional (GTC; n=21), avaliado retrospectivamente, formado de pacientes que utilizaram apenas terapia convencional. Os critérios para iniciar a administração do NOi foram: saturação arterial de oxigênio < 90% a despeito de uma fração inspirada de oxigênio (FiO2) 0,6 e de uma pressão expiratória final positiva (Peep) 10 cmH2O. A resposta imediata ao NOi foi avaliada em um teste de resposta de quatro horas, considerando resposta positiva um aumento na relação PaO2/FiO2 de 10 mmHg acima dos valores basais. A terapia convencional não foi modificada durante o teste. Nos dias subseqüentes os pacientes que exibiram resposta positiva continuaram recebendo a menor dose de NOi... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Acute respiratory distress syndrome (ARDS) is the most severe manifestation and the end spectrum of acute lung injury. It has been associated with high mortality rate, despite better understanding of its pathophysiology and recent therapeutic advances. Inhalde nitric oxide (iNO)-induced vasodilation of pulmonary vasculature adjacent to well-ventilated alveoli increases blood flow to these lung areas and preferentially shunt blood away from poorly ventilated regions, matching V/Q and reducing intrapulmonary shunt. This results in improved oxygenation and reduction of both pulmonary vascular resistence and right ventricle afterload. By improving V/Q matching, iNO may allow less aggressive mechanical ventilation (MV), which minimizes the risk of ventilator-induced lung injury and mortality. The aims of this study were: 1) to determine the acute and sustained effects of iNO on some oxygenation indexes and ventilator settings, to analyze the weaning process, and to assess the safety of NO inhalation; 2) to test the hypothesis that early administration of iNO would reduce mortality rate, intensive care length of stay, and the duration of MV comparing a group of pediatric ARDS patients treated with iNO plus conventional therapy with another treated only with conventional therapy. Children with ARDS, aged between one month and 12 years were studied. There were two groups: iNO group (iNOG; n=18) composed of patients prospectively enrolled from November 1998 to 2002, and conventional therapy group (CTG; n=21) consisting of historical control patients admitted from August 1996 to August 1998. Study groups were of similar ages, gender, primary diagnoses, pediatric risk of mortality score, and mean airway pressure. PaO2/FiO2 ratio was lower (CTG: 116.9l34.5; iNOG: 71.3l24.1 - p < 0.001) and oxygenation index higher (CTG: 15.2 (7.2-32.2); iNOG: 24.3 (16.3-70.4) - p < 0.001) in the iNOG. Therapy with iNO was introduced as early as 1.5 hours after ARDS. / Doutor

O avanço da terapia intensiva na medicina veterinária vem permitindo a realização de um melhor suporte e monitorização dos animais com sepse grave. Esta é uma síndrome clínica caracterizada por alterações inflamatórias sistêmicas (SIRS) associadas a disfunções orgânicas, como, por exemplo, lesão pulmonar aguda (LPA) e síndrome do desconforto respiratório agudo (SARA). No homem, esta síndrome resulta em uma significante taxa de mortalidade, porém, na medicina veterinária ainda faltam estudos sobre este assunto. Assim, o objetivo deste estudo foi avaliar a ocorrência de complicações respiratórias em animais com sepse grave submetidos à terapia intensiva. Neste estudo foram incluídos 14 animais com sepse grave secundária à piometra. Durante o período de tratamento intensivo os pacientes foram monitorados por meio de: freqüências cardíaca e respiratória, pressão arterial sistólica, débito urinário, pressão venosa central, lactato, saturação venosa central de oxigênio, hemogasometria arterial e radiografias torácicas. Todos os animias (100%) apresentaram alterações respiratórias, destes três cadelas vieram a óbito (21,42%) e 11 (78,57%) receberam alta do tratamento intensivo.Os animais submetidos à terapia intensiva devido ao desenvolvimento de sepse grave secundária à piometra, necessitam de um acompanhamento radiográfico torácico diário, a fim de se estabelecer medidas de suporte respiratório adequadas e, consequentemente, obter menores taxas de mortalidade. / The advances in intensive care has allowed to offer better support to animals with severe sepsis. This is a clinical syndrome characterized by systemic inflammatory response associated with organic dysfunction, such as acute pulmonary injury (ALI) and acute respiratory distress syndrome (ARDS). In humans, this syndrome results in significant mortality, but, in veterinary medicine there are not many studies about this. The aim of this study was to evaluate the development the pulmonary complications in animals submitted to intensive care. In this study were included 14 animals with severe sepsis secondary to pyometra. During the period of intensive care the animals were evaluated: heart and respiratory rates, systolic blood pression, urine output, central venous pression lactate, lactate, central venous saturation, arterial hemogasometric and thoracic x-ray. All animals (100%) had abnormal breathing, three of these dogs eventually died (21.42%) and 11 (78.57%) out of intensive care. Animals with severe sepse secondary to pyometra underwent intensive therapy, requiring a chest radiographic daily in order to establish adequate respiratory support, and thus achieve lower mortality rates.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2015-07-21T14:58:44Z No. of bitstreams: 1 Manoel Carneiro de Oliveira Junior.pdf: 4260915 bytes, checksum: ba3950686530a475258ace49a0675cdd (MD5) / Made available in DSpace on 2015-07-21T14:58:45Z (GMT). No. of bitstreams: 1 Manoel Carneiro de Oliveira Junior.pdf: 4260915 bytes, checksum: ba3950686530a475258ace49a0675cdd (MD5) Previous issue date: 2013-09-30 / Acute respiratory distress syndrome (ARDS) is a syndrome that presents high mortality rates, and the results of both insults pulmonary or extra-pulmonary (pneumonia or septic shock) are high, and is a disease characterized by respiratory insufficiency from the inflammatory response that leads to alteration of alveolar-capillary permeability, pulmonary edema and hypoxemia refractory to high flow oxygen. One of the most important mechanisms that determined the severity of this injury is the magnitude of the injury of alveolar epithelial barrier. The possibility of repairing epithelial at an early stage is the major determinant of recovery. Many of therapeutic modalities based on the attempt to decrease lung inflammation to minimize the initial injury and much of the inflammatory process occurs through activation of local and systemic cytokines such as TNF-α and IL-1β. A growing number of studies report that Low Level Laser Therapy (LLLT) have anti-inflammatory effects in models of LPS-induced pulmonary ARDS, however, so far, only the red spectrum lasers were studied. Therefore, this study aimed to investigate the role of infra red laser (830nm), 3J/cm2, 35mw, 80 seconds per point (03 points per application), in pulmonary inflammation, lung using LPS model (intratracheal) and also extrapulmonary (intraperitoneal) inducing ARDS. The laser application was performed directly in contact with the skin in the chest three points (corresponding to the end of the trachea - Section 01 right lung - point 02 and left lung - point 03), three times, beginning 01 hour after LPS administration. BALB / c mice (n = 40) were divided into control (n = 08; not administered LPS), IT (n = 07; intratracheal administered LPS (10 µg / mouse), IT + LLLT (n = 09; intratracheal LPS administered (10 µg / mouse) + LLLT), IP (n = 07; LPS administered intraperitoneal (100 µg / mouse), IP + LLLT (n = 09; administered intraperitoneal LPS (100 µg / mouse) + LLLT). Twenty-four hours after administration of LPS and Laser, animals were euthanized and the lungs removed for studies of pulmonary inflammation: Total cell count and differential, bronchoalveolar lavage (BAL), cytokines (IL-1beta, IL-6, IL-10, KC and TNF-α), BAL levels were also analyzed quantitatively the number of neutrophils in the lung parenchyma in lung tissue using histomorphometry techniques. Results showed that LLLT significantly reduced pulmonary and extra-pulmonary LPS induced in both configurations Experimental of ARDS, as evidenced by a reduction in the number of total cells and neutrophils in BAL, reduced levels of IL-1β, IL-6, KC, and TNF-α in BAL fluid as well as the number of neutrophils in the lung parenchyma. Therefore, we conclude that the 830nm infrared laser is effective in reducing pulmonary inflammation in both models pulmonary or extrapulmonary LPS-induced experimental ARDS. / A síndrome do desconforto respiratório agudo (SDRA) é uma síndrome que apresenta altas taxas de mortalidade, que pode ser resultante tanto de insultos pulmonares como extrapulmonares. A síndrome é caracterizada pela insuficiência respiratória proveniente da resposta inflamatória que cursa com alteração de permeabilidade alvéolo-capilar, edema e hipoxemia refratária aos altos fluxos de oxigênio. Um dos mais importantes mecanismos que determinam a severidade desta injúria é a magnitude da lesão da barreira epitélio alveolar. A possibilidade de reparação do epitélio em um estágio precoce é o maior determinante da recuperação. Muitas das modalidades terapêuticas baseiam-se na tentativa de diminuição da inflamação pulmonar para minimizar a lesão inicial, a qual se deve em grande parte ao processo inflamatório mediado pela ativação local e sistêmica por citocinas como TNF-α e IL-1β. Um número crescente de estudos relata que o laser de baixa intensidade apresenta efeitos antiinflamatórios em modelos de SDRA induzida por LPS e isquemia e reperfusão da artéria pulmonar. No entanto, até o momento, apenas lasers no espectro vermelho (650 – 655 nm) foram estudados. Portanto, o presente estudo tem como objetivo investigar o papel do laser de baixa intensidade (LBI), na faixa do infravermelho (830nm), 3J/cm2, 35mw, 80 segundos por ponto (03 pontos por aplicação), na inflamação pulmonar, usando um modelo de SDRA de origem pulmonar (LPS intratraqueal) e também extrapulmonar (LPS intraperitoneal). A aplicação do laser foi realizada diretamente em contato com a pele, em três pontos do tórax (correspondente ao final da traquéia - ponto 01, pulmão direito - ponto 02 e do pulmão esquerdo ponto 03), por três vezes, 01 hora após a administração de LPS. Camundongos BALB/c (n = 40) machos foram distribuídos em Controle (n = 08; não administrado com LPS), IT 10 (n = 07; LPS intratraqueal; 10 µg/camundongo), IT + Laser (n = 09; LPS intratraqueal; 10µg/camundongo + Laser), IP (n= 07; LPS intraperitoneal; 100µg/ camundongo), IP + Laser (n = 09; LPS intraperitoneal; 100 µg/camundongo + Laser). Os animais foram eutanaziados vinte e quatro horas após a administração de LPS. Foi avaliada a contagem de células totais e diferenciais no lavado bronco alveolar (LBA), os níveis de citocinas (IL-1β, IL-6, IL 10, KC e TNF-α), a densidade de neutrófilos no parênquima pulmonar. Os resultados demonstraram que o LBI significativamente reduziu o número de células totais e de neutrófilos no Lavado Bronco Alveolar (LBA), o número de neutrófilos no parênquima pulmonar, e os níveis de citocinas pró-inflamatórias no LBA tanto no modelo de SDRA pulmonar quanto extrapulmonar. Portanto, concluímos que o laser infravermelho 830nm é eficaz para reduzir a inflamação pulmonar, em ambos os modelos de SDRA intrapulmonar e extrapulmonar induzida por LPS.

Die Analyse komplexer Zusammenhänge durch Modellierung und Simulation hat in der Medizin stark zugenommen. Bei der funktionellen Analyse des respiratorischen Systems bilden Ventilationsmechanik und Gasaustausch zwei wesentliche Schwerpunkte, die sich in komplexen Modellen vereinigen lassen. Die Identifikation der Parameter eines vereinigten Modells anhand von Messungen bei Patienten liefert differenzierte Informationen über deren Zustand. Die allgemeinen Rahmenbedingungen bei dieser wie bei jeder anderen Identifikation sind philosophischer Natur und werden in einem erkenntnistheoretischen Kapitel behandelt. Schwerpunkte der Identifikation des vereinigen Modells sind: Ventilationsmechanik, anatomischer Totraum und Perfusionsverteilung.:Verzeichnis der Abkürzungen IX 1 Einleitung 1 2 Modellierung und Modelle – die Widerspiegelung der Realität 3 3 Modelle des respiratorischen Systems 11 3.1 Atmung und maschinelle Beatmung 11 3.2 Anatomie 12 3.3 Physiologie 14 3.4 Modelle der Ventilationsmechanik 18 3.5 Modelle für Gasaustausch, -mischung und -transport 21 3.6 Vereinigtes Modell der Ventilationsmechanik und des Gasaustauschs 22 3.7 Modelle und Entscheidungsunterstützungssysteme 23 3.8 Problemstellung und Motivation 25 4 Modellstruktur – Verteilungsmuster lungenphysiologischer Parameter 27 4.1 Grundlagen 27 4.2 Verteilungen lungenphysiologischer Parameter 28 4.3 Approximation – Struktur des vereinigten Modells 30 5 Messungen am Patienten 32 5.1 Vorbereitung 32 5.2 Protokoll 34 6 Ventilationsmechanik 36 6.1 Systemtheoretische Grundlagen der Identifikation 36 6.1.1 Systemtheoretische Ein-/Ausgangsbeschreibung 37 6.1.2 Selektion der Methoden zur Identifikation 38 6.2 Übertragungsfunktionen der Modelle 46 6.2.1 Zeitkontinuierliche Modelle 46 6.2.2 Zeitdiskrete Modelle 48 6.3 Rückrechnung der identifizierten Parameter in physikalische 50 6.4 Gütekriterium, Restriktion und Vergleichsmethode 51 6.5 Ergebnisse der Identifikation 53 6.5.1 Thoraxmechanik 53 6.5.2 Mechanik des respiratorischen Systems 57 6.6 Diskussion 68 7 Anatomischer Totraum 74 7.1 Grundlagen 74 7.2 Identifikation des Anstiegs der Phase III des Exspirogramms 75 7.3 Identifikation des seriellen Totraums 77 7.4 Diskussion 81 8 Perfusionsverteilung und Gasaustausch 84 8.1 Grundlagen 84 8.2 Blutgasmodelle 85 8.3 Modelle des stationären Gasaustauschs 87 8.4 Modell des an die Ventilationsmechanik gekoppelten Gasaustauschs 92 8.5 Diskussion 96 9 Zusammenfassung 99 A Anhang 102 A-1 Fachglossar 102 A-2 Indirekte Messung der Pleuradruckänderung mit ösophagealem Ballon 105 A-3 Grundlagen der multiplen Inertgaseliminationstechnik (MIGET) 106 A-4 Anmerkungen zum Abtasttheorem 108 A-5 Bestimmung der Flow-Sensor-Kennlinie mit einer Kalibrierspritze 109 A-6 Rückrechnung der identifizierten in physikalische Parameter 110 A-7 Dokumentation zum Einfluß der Filterperiodendauer TF auf die Standardabweichung des Identifikationsfehlers 113 Literaturverzeichnis 115 / The analysis for complex relationships using modeling and simulation in medicine has substantially increased. Ventilation mechanics and gas exchange are the key elements of the functional analysis of the respiratory system and can be united in a complex model. The parameter identification of the unified model based on patient measurements provides detailed information about the patient's status. The general framework of this and other identifications is philosophical and discussed in an epistemological chapter. The key topics of the identification of the unified model are ventilation mechanics, anatomical dead space, and perfusion distribution.:Verzeichnis der Abkürzungen IX 1 Einleitung 1 2 Modellierung und Modelle – die Widerspiegelung der Realität 3 3 Modelle des respiratorischen Systems 11 3.1 Atmung und maschinelle Beatmung 11 3.2 Anatomie 12 3.3 Physiologie 14 3.4 Modelle der Ventilationsmechanik 18 3.5 Modelle für Gasaustausch, -mischung und -transport 21 3.6 Vereinigtes Modell der Ventilationsmechanik und des Gasaustauschs 22 3.7 Modelle und Entscheidungsunterstützungssysteme 23 3.8 Problemstellung und Motivation 25 4 Modellstruktur – Verteilungsmuster lungenphysiologischer Parameter 27 4.1 Grundlagen 27 4.2 Verteilungen lungenphysiologischer Parameter 28 4.3 Approximation – Struktur des vereinigten Modells 30 5 Messungen am Patienten 32 5.1 Vorbereitung 32 5.2 Protokoll 34 6 Ventilationsmechanik 36 6.1 Systemtheoretische Grundlagen der Identifikation 36 6.1.1 Systemtheoretische Ein-/Ausgangsbeschreibung 37 6.1.2 Selektion der Methoden zur Identifikation 38 6.2 Übertragungsfunktionen der Modelle 46 6.2.1 Zeitkontinuierliche Modelle 46 6.2.2 Zeitdiskrete Modelle 48 6.3 Rückrechnung der identifizierten Parameter in physikalische 50 6.4 Gütekriterium, Restriktion und Vergleichsmethode 51 6.5 Ergebnisse der Identifikation 53 6.5.1 Thoraxmechanik 53 6.5.2 Mechanik des respiratorischen Systems 57 6.6 Diskussion 68 7 Anatomischer Totraum 74 7.1 Grundlagen 74 7.2 Identifikation des Anstiegs der Phase III des Exspirogramms 75 7.3 Identifikation des seriellen Totraums 77 7.4 Diskussion 81 8 Perfusionsverteilung und Gasaustausch 84 8.1 Grundlagen 84 8.2 Blutgasmodelle 85 8.3 Modelle des stationären Gasaustauschs 87 8.4 Modell des an die Ventilationsmechanik gekoppelten Gasaustauschs 92 8.5 Diskussion 96 9 Zusammenfassung 99 A Anhang 102 A-1 Fachglossar 102 A-2 Indirekte Messung der Pleuradruckänderung mit ösophagealem Ballon 105 A-3 Grundlagen der multiplen Inertgaseliminationstechnik (MIGET) 106 A-4 Anmerkungen zum Abtasttheorem 108 A-5 Bestimmung der Flow-Sensor-Kennlinie mit einer Kalibrierspritze 109 A-6 Rückrechnung der identifizierten in physikalische Parameter 110 A-7 Dokumentation zum Einfluß der Filterperiodendauer TF auf die Standardabweichung des Identifikationsfehlers 113 Literaturverzeichnis 115

No description available.

The assessment of the lung weight in vivo is possible with the quantitative computer tomography (qCT) analysis. Especially in acute lung injury (ALI) the knowledge of the lung weight can help to identify the etiology of lung-dysfunction. The current definition of ALI is orientating on parameters such as impaired oxygenation or radiological opacifications. With this definition a heterogeneous group is captured. There might be dysfunction of the lung due to atelectasis or due to edema, both leading to impaired oxygenation. For the clinician it is important to differentiate between atelectasis and edema. For example, in patients with edematous lungs the clinician is focusing on prevention of secondary lung injury whereas in atelectasis the clinician is targeting a more aggressive treatment. The method of qCT has the potential to differentiate atelectasis from edema and could thus provide valuable information for managing trauma patients fulfilling commonly used criteria for ALI. So far a reference value for normal lung weights in ventilated patients is not available. In recent studies the lung weights of ALI-Patients where compared to healthy spontaneous breathing patients. Effects of a positive end expiratory pressure ventilation (PEEP) or possible influence of intravenous fluid substitution were ignored. The aim of this work was define a reference value of normal lung-weights in ventilated trauma patients. To reveal possible effects of PEEP or intravenous fluid substitution on the lung weight we provided a comparison group of spontaneous breathing trauma patients. In this prospective observational study CTs of trauma patients with normal lungs who underwent emergency CT were selected and two subgroups formed for spontaneous breathing (n = 31) and mechanically ventilated patients (n = 44). The decision whether a lung was normal was based on independent reviewers of the CT images. The arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) had to be greater than 400mmHg. Demographic data, ventilation and clinical parameters of each patient where obtained from the patient data management system. In demographic data mechanically ventilated patients did not differ from the spontaneous breathing patients (only significant variation in sex, with a higher male proportion in the ventilated group). Mechanically ventilated patients were ventilated with PEEP of 10 mmHg at the time of the CT acquisition. The PaO2/FiO2 ratio was 550  74 mmHg. Mechanically ventilated patients received significant more intravenous fluid substitution (p = 0.02). The lung weight in mechanically ventilated patients was 873  124 g Standard deviation (SD), in spontaneous breathing patients 866  169 g SD. The validity of our method was reviewed by placing a water filled plastic bottle next to the thorax. The mass was calculated in two ways: by quantitative computed tomography and by the volumetric mass density of water. A deviation of 2% could be shown Our results suggest that lung weights of mechanically ventilated patients with normal lungs do not differ from those of other with normal lungs (Gattinoni 2006, Puybasset 2000). In conclusion, a moderate PEEP neither a moderate intravenous fluid substitution do not affect the lung weight. The lung weights assessed in this work can be used as reference values, especially, for the group of the trauma-associated ALI. With these results it is possible to identify pathological lung weights. Furthermore it gives a tool in identifying the etiology of ALI and therefore it helps the clinician in making the right therapeutic decisions.:Bibliografische Beschreibung 3 Abkürzungsverzeichnis 4 Einleitung 6 Gewichtsbestimmungen in der Medizin 6 Quantitative Computertomographie (qCT): Volumen- und Massebestimmung 7 Klinische Anwendung von Analysen des Lungengewichtes 9 Zielsetzung 11 Patienten und Methoden 12 Maschinell beatmete Patienten (maschinell B.) 12 Spontan atmende Patienten (spontan A.) 14 CT-Untersuchung 14 Quantitative CT-Analyse: Segmentierung der CT-Bilder 15 Validierung der Methodik 18 Auswertung der ROI 18 Statistische Analyse 19 Ergebnisse 21 Demographische Daten 21 Ergebnisse der Lungengewichtsanalyse 25 Ergebnisse der Validierung 28 Diskussion 30 Ausblick 40 Zusammenfassung / Abstract 41 Literaturverzeichnis 46

Le Syndrome de Détresse Respiratoire Aiguë (SDRA) est la forme la plus sévère d’agression alvéolaire aiguë. Il estcaractérisé par un dommage alvéolaire diffus, suivi d’une phase de réparation nécessaire à la guérison. Bien queles monocytes/macrophages soient des acteurs incontournables de la pathogénie et de la résolution du SDRA, leurpolarisation et leur rôle dans la réparation alvéolaire restent mal connus chez l’Homme. L’hypothèse défendue parcette thèse est que l’environnement alvéolaire module la différenciation et la polarisation desmonocytes/macrophages au cours du SDRA, et que les macrophages alvéolaires ainsi polarisés participentactivement à la réparation et à sa régulation. Les principaux résultats de nos travaux ont permis d’établir que : 1)l’environnement alvéolaire de SDRA inhibe la différenciation des monocytes en fibrocytes (précurseursmésenchymateux associés à la fibroprolifération et à pronostic péjoratif). L’inhibition est majoritairement due à laSerum Amyloid protein P (SAP), provenant en partie du relargage de ses stocks matriciels pulmonaires à la faveurde la lésion alvéolaire ; 2) l’environnement alvéolaire de SDRA induit une polarisation anti-inflammatoire desmacrophages se rapprochant de la polarisation induite in vitro par l’IL-10 ; 3) les macrophages anti-inflammatoirespolarisés par le lavage broncho-alvéolaire (LBA) de patients SDRA favorisent la réparation alvéolaire épithéliale viala production polarisation-dépendante d’Hepatocyte Growth Factor (HGF). Cette production macrophagique d’HGFest amplifiée via une boucle autocrine PTGS2/PGE2 chez l’Homme ; 4) ces résultats semblent étayés par lesdonnées obtenues sur une cohorte clinique qui montrent que les concentrations de sCD163 (marqueur depolarisation anti-inflammatoire) et d’HGF rapportées au nombre de macrophages alvéolaires sont plus élevéeschez les patients survivants que chez les patients décédés de SDRA. L’ensemble de nos travaux démontrent pour lapremière fois chez l’Homme le rôle bénéfique de l’environnement alvéolaire sur les monocytes/macrophages,d’une part en inhibant leur différenciation en fibrocytes contribuant ainsi à limiter la fibroprolifération pulmonaire,et d’autre part en induisant un phénotype macrophagique anti-inflammatoire, contribuant à limiter l’inflammationengendrée par la lésion alvéolaire initiale et favorisant la réparation épithéliale via la production d’HGF. Lesdonnées physiopathologiques obtenues pourraient permettre d’envisager la reprogrammation anti-inflammatoiredes macrophages comme une cible thérapeutique du SDRA en cas d’excès d’inflammation ou de fibro-proliférationavec réparation aberrante. / Acute Respiratory Distress Syndrome (ARDS) is the most severe form of acute lung injury. ARDS is characterized bydiffuse alveolar damage followed by a phase of alveolar repair necessary to recovery. Althoughmonocytes/macrophages are key actors of pathogenicity and resolution of ARDS, little is known about theirpolarization and role on alveolar repair during human ARDS. The hypothesis of our studies was that ARDS alveolarenvironment modulates differentiation and polarization of monocytes and macrophages, and that polarizedmacrophages are involved in alveolar repair and its regulation. The main results of our work have shown that: 1)ARDS alveolar environment inhibited monocytes differentiation into fibrocytes (mesenchymal progenitorsassociated with fibroprolifération and a poor prognosis), mainly through its Serum Amyloid P (SAP) content,originating, at least in part, from the release of SAP associated with lung connective tissue during ARDS; 2) ARDSalveolar environment drove an anti-inflammatory macrophage polarization, close to that induced by IL-10 in vitro;3) anti-inflammatory macrophages polarized by broncho-alveolar lavage (BAL) from ARDS patients favored alveolarepithelial repair through a polarization-dependent production of Hepatocyte Growth Factor (HGF). This HGFproduction is amplified by an autocrine PTGS2/PGE2 dependent loop in human macrophages; 4) these results mayhave clinical relevance, since sCD163 (a marker of anti-inflammatory polarization) and HGF concentrations,expressed relatively to BAL macrophage count, were higher in ARDS survivors than non-survivors. Taken together,our works demonstrate for the first time the beneficial role of the ARDS alveolar environment onmonocytes/macrophages, inhibiting their differentiation into fibrocytes, thus limiting excessive lungfibroproliferation, and inducing an anti-inflammatory macrophage polarization, thus limiting the inflammationgenerated by the initial alveolar damage and favoring epithelial repair through HGF production. The datapresented in this thesis may allow considering anti-inflammatory macrophage repolarization as a potential newtherapeutic target of ARDS with excessive inflammation or fibro-proliferation with aberrant repair.

Although, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents one of the biggest challenges in the world today, the exact immunopathogenic mechanism that leads to severe or critical Coronavirus Disease 2019 (COVID-19) has remained incompletely understood. Several studies have indicated that high systemic plasma levels of inflammatory cytokines result in the so-called “cytokine storm”, with subsequent development of microthrombosis, disseminated intravascular coagulation, and multiorgan-failure. Therefore, we reasoned those elevated inflammatory molecules might act as prognostic factors. Here, we analyzed 245 serum samples of patients with COVID-19, collected at hospital admission. We assessed the levels of heat shock protein 27 (HSP27), soluble suppressor of tumorigenicity-2 (sST2) and 20S proteasome at hospital admission and explored their associations with overall-, 30-, 60-, 90-day- and in-hospital mortality. Moreover, we investigated their association with the risk of ventilation. We demonstrated that increased serum sST2 was uni- and multivariably associated with all endpoints. Furthermore, we also identified 20S proteasome as independent prognostic factor for in-hospital mortality (sST2, AUC = 0.73; HSP27, AUC = 0.59; 20S proteasome = 0.67). Elevated sST2, HSP27, and 20S proteasome levels at hospital admission were univariably associated with higher risk of invasive ventilation (OR = 1.8; p < 0.001; OR = 1.1; p = 0.04; OR = 1.03, p = 0.03, respectively). These findings could help to identify high-risk patients early in the course of COVID-19.

Die Durchführung einer maschinellen Beatmungstherapie im Rahmen eines akuten Lungenversagens birgt die Gefahr potenzieller Nebenwirkungen und Komplikationen. Oberste Priorität ist, die Lunge durch die maschinelle Beatmung nicht zusätzlich zu schädigen und einen beatmungs-induzierten/-assoziierten Lungenschaden (VILI/VALI) zu vermeiden. Forschungsergebnisse konnten zeigen, dass Beatmungsstrategien mit niedrigem positivem endexspiratorischem Druck (PEEP) sowie hohen Tidalvolumina (VT) zu einer vermehrten Überdehnung der Alveolen sowie vermehrtem zyklischen Öffnen und Kollabieren instabiler Alveolarregionen führt, wodurch Scherkräfte entstehen, welche die Lunge schädigen. Dies kann den Verlauf der Erkrankung maßgeblich beeinflussen und zudem zu einer erhöhten Letalität führen. Uneinigkeit besteht weiterhin bezüglich der Wahl des für den individuellen Patienten adäquaten PEEP. So ermöglicht die Verwendung der ARDSnet-Tabelle zwar eine unkomplizierte bettseitige Auswahl des PEEP anhand der erforderlichen inspiratorischen Sauerstoffkonzentration, berücksichtigt jedoch nicht die individuellen atemmechanischen Gegebenheiten. Verfahren zur bettseitigen Ermittlung individueller krankheitsspezifischer und atemmechanischer Charakteristika sind deutlich aufwendiger und bedürfen eines hohen Maßes an praktischer Erfahrung. In der hier vorliegenden Studie wurde ein tierexperimenteller Langzeitversuch (24 h) mit Auslösung eines akuten Lungenversagens (ARDS) durch ein Salzsäure-Aspirationsmodell am Schwein durchgeführt. Es erfolgte der randomisierte Vergleich dreier Beatmungsstrategien: ARDS-low-PEEP-Tabelle (ARDSnet-Gruppe), Open Lung Concept (OLC-Gruppe) sowie Elektroimpedanztomographie (EIT-Gruppe), zur Findung der optimalen Beatmungsstrategie im Rahmen eines akuten Lungenversagens. Die Versuchsreihe wurde durch die Tierschutzbehörde der Landesdirektion Leipzig nach §8 des Tierschutzgesetztes (Aktenzeichen TVV 35/11) genehmigt und in der Veterinärmedizinischen Fakultät der Universität Leipzig durchgeführt.:Inhaltsverzeichnis Abkürzungs- und Akronymverzeichnis 1 Einführung in die Thematik 1.1 Einleitung 1.2 Das akute Lungenversagen - Acute Respiratory Distress Syndrome (ARDS) - Definition und Pathophysiologie 1.3 Salzsäure-Aspiration als ARDS-Modell 1.4 Dynamische Parameter der Atemmechanik und deren Bedeutung im ARD 1.4.1 Bedeutung der Compliance und ihre Messung 1.4.2 Driving Pressure (∆p) 1.5 Maschinelle Beatmung 1.6 Verglichene Beatmungsstrategien 1.6.1 ARDSnetwork Protokoll (ARDSnet-Gruppe) 1.6.2 Open Lung Concept (OLC-Gruppe) 1.6.3 Elektroimpedanztomographie (EIT-Gruppe) 1.7 Quantitative Auswertung der Computertomographie (CT) - Tidale Rekrutierung 2 Zielstellung 3 Publikationsmanuskript 4 Zusammenfassung der Arbeit 5 Ergänzendes Material 6 Literaturverzeichnis 7 Darstellung des eigenen Beitrags 8 Selbstständigkeitserklärung 9 Teilnahmebescheinigung der Vorlesung: „Gute wissenschaftliche Praxis“ an der medizinischen Fakultät der Universität Leipzig 10 Curriculum Vitae - Lebenslauf 11 Publikationen 12 Danksagung

Das ARDS gilt, trotz verschiedenster Möglichkeiten der intensivmedizinischen Therapie, immer noch als die schwerste Form einer Lungenparenchymverletzung mit einer hohen Letalität. Zu Beginn der Erkrankung zeigt sich eine große Diskrepanz zwischen zunehmender Hypoxie und blandem Röntgen-Thorax-Befund. Die Röntgen-Thorax-Aufnahme bildet somit einen wichtigen diagnostischen Bestandteil. Die Kriterien einer einfachen Durchführung, guten Reproduzierbarkeit, hohen Aussagekraft und der Möglichkeit einer Verlaufsbeurteilung machen die Röntgen-Thorax-Liegendaufnahme zu einem wichtigen Bestandteil der intensivmedizinischen Diagnostik. Untersucht wurden retrospektiv 1575 Röntgen-Thorax-Aufnahmen von 33 Patienten mit dem Krankheitsbild des ARDS. Das Patientenkollektiv setzte sich aus 14 Frauen und 19 Männern im Alter von 12 bis 63 Jahren zusammen. Die Überlebensrate des untersuchten Patientenkollektives betrug 87,9%. Pro Patient wurden durchschnittlich 48 Röntgen-Thorax-Aufnahmen (zwischen 10 und 148 Aufnahmen) angefertigt. Die Aufnahmen wurden im Hinblick auf ihre Qualität, Strahlenexposition und ihre Übereinstimmung mit klinischen Parametern untersucht. Für die Beurteilung der Inter- und Intraobservervariabilität wurden verschiedenen Untersuchern 60 Röntgen-Thorax-Aufnahmen exemplarisch zur Bewertung vorgelegt. Aufgrund der schwierigen Aufnahmebedingungen bei Intensivpatienten sind verdrehte und verkippte Röntgen-Thorax-Aufnahmen nicht zu vermeiden. Trotz dieser Qualitätseinbußen ist ihr Informationsgehalt ein wichtiges Kriterium der intensivmedizinischen Diagnose und Therapie. Die Strahlenexposition der Röntgen-Thorax-Liegendaufnahmen und der daraus zu errechnende Lebenszeitverlust sind im Hinblick auf die Schwere und die hohe Letalität der Grunderkrankung als verschwindend gering zu betrachten. Die Röntgen-Scores nach Murray, Morel, Miniati, Rommelsheim und Ostendorf sind in der Diagnostik und Verlaufsbeurteilung des ARDS weit verbreitet. Sie sind in Handhabung und Gewichtung der Veränderungen jedoch sehr unterschiedlich. Zusammenhänge zwischen klinischen Parametern konnten für alle Scores, sowie für einen neuen Score beobachtet werden. Dabei ergaben sich für alle Scores ähnliche Beziehungen. Unter Berücksichtigung der Handhabung der einzelnen Röntgen-Scores, der Inter- und Intraobservervariabilität, sowie der Übereinstimmung mit klinischen Parametern sind der Röntgen-Score nach Rommelsheim, sowie der neue Röntgen-Score für den klinischen Alltag zu empfehlen. / Radiological Quantification of Chest X-Rays of the Lung Oedema of Patients with Adult Respiratory Distress Syndrome (ARDS) The ARDS is still regarded as the most serious form of lung parenchyma injury with a high lethality in spite of various possibilities of intensive care therapies. In the beginning of the illness a high discrepancy between an increasing hypoxia and a mostly inconspicouos chest X-ray result can be observed. Therefore, the chest X-ray forms an essential part of the diagnostic basis. It is characterized by simple implementation, a good reproducibility, a high meaningfulness and the possibility to judge the course of the illness. This makes the chest X-ray very valuable for the intensive care diagnosis. 1575 chest X-rays from 33 patients with ARDS symptoms were evaluated. The patients consisted of 14 women and 19 men between 12 and 63 years of age. The overall survival rate for all patients was 87.9%. An average of 48 (ranging from 10 to 148) chest X-rays were taken per patient. They were examined with regard to quality, radiation dose and correspondence to clinical variables. In order to judge the interobserver and intraobserver variability 60 chest X-rays were evaluated by different examiners. Due to the difficult conditions while taking the chest X-rays distorted and tilted chest X-rays cannot be avoided. Despite this loss of quality their content of information is an important criterion for the intensive care diagnosis and treatment. The loss of lifetime due to the radiation dose received can be ignored compared to the severeness and the high lethality of the basic illness. The chest X-ray scores according to Murray, Morel, Miniati, Rommelsheim and Ostendorf are commonly used for diagnostic purposes and to judge the course of the ARDS. However, their handling and their weightning of changes varies a lot. Correlations between all scores, a new score and the clinical variables were observed. All scores, including the new score, showed similar relations between the score ranking and the clinical variables. Considering the handling of the different chest X-ray scores, their interobserver and intraobserver variability and their correlation to clinical variables the chest X-ray score according to Rommelsheim and the new score can be recommended for daily use.