Das akute Lungenversagen (Adult Respiratory Distress Syndrome: ARDS) stellt ein in der Intensivmedizin häufig auftretendes Krankheitsbild dar und weist trotz intensiver Bemühungen nach wie vor eine hohe Letalität auf. Ein wichtiger pathophysiologischer Faktor bei der mit dem ARDS verbundenen schweren Gasaustauschstörung ist der intrapulmonale Rechts-links-Shunt mit daraus resultierender Abnahme des Oxygenierungsindex. Um therapeutisch eine Verbesserung der Oxygenierung zu erreichen, wurde unter anderem von Gallart et al. ein Konzept entwickelt, bei dem durch den kombinierten Einsatz eines intravenös gegebenen pulmonalen Vasokonstriktors (Almitrine) und eines inhalativ gegebenen pulmonalen Vasodilatators (inhalatives Stickstoffmonoxid: iNO) die Shuntfraktion verkleinert wird (Gallart et al. 1998). Im Rahmen dieser Arbeit wurde die Kombination von iNO mit der intravenösen Gabe von zellfreiem Hämoglobin (Hemoglobin Based Oxygen Carrier, HBOC) als Vasokonstriktor am Tiermodell des akuten Lungenversagens hinsichtlich hämodynamischer Parameter und der arteriellen Oxygenierung untersucht. Die Ergebnisse wurden verglichen mit einer zweiten Versuchsgruppe, in der die Tiere lediglich iNO und Hydroxyethylstärke als Kontrollsubstanz erhielten. In Pilotversuchen wurden dafür ein Tiermodell des akuten Lungenversagens etabliert und die Auswirkungen der Gabe von HBOC bei vorbestehendem Lungenschaden untersucht. Anhand der durchgeführten Versuche konnte gezeigt werden, dass sich durch die HBOC-Gabe sowohl der systemische als auch der pulmonalarterielle Blutdruck signifikant erhöhte. Durch die zusätzliche Gabe von iNO ließ sich dieser Effekt antagonisieren. Ein additiver Effekt auf die arterielle Oxygenierung durch den kombinierten Einsatz von HBOC und iNO -im Vergleich zur alleinigen Gabe von iNO- war nachweisbar, die Unterschiede waren jedoch nicht signifikant. Weitere Untersuchungen werden zeigen müssen, ob sich dieser Effekt bei größerer Fallzahl als signifikant erweist, oder ob dieser tatsächlich nicht vorhanden sein sollte.

Made available in DSpace on 2014-06-11T19:30:29Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-02Bitstream added on 2014-06-13T19:40:09Z : No. of bitstreams: 1 gusman_pb_dr_botfm.pdf: 625469 bytes, checksum: 27745b379b0a215dafab05d5182357ac (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Desde sua primeira descrição, muito se investiu no melhor conhecimento da SARA, na identificação de sua etiologia, seus fatores de risco, seus mecanismos e mediadores, escolhendo-se métodos críticos de avaliação clínica que também pudessem definir o prognóstico. Com o objetivo de verificar se os efeitos da PEEP dependem da morfologia pulmonar, comparando sua resposta em três grupos de pacientes, descritos de acordo com os aspectos de hiperdensidades observadas nos cortes tomográficos, foram estudados 71 pacientes portadores de SARA, comparando-os a 11 voluntários sadios. Cada paciente foi submetido a exame tomográfico helicoidal de tórax em ZEEP e após implemento de PEEP de 10 cmH2O. Parâmetros hemodinâmicos e respiratórios foram mensurados nas mesmas condições. Hiperdistensão induzida pela PEEP e recrutamento alveolar foram quantificados por um software específico, Lungview®. Hiperdistensão ocorreu somente nos lobos superiores e se correlacionou significativamente com volume pulmonar caracterizado por uma densidade tomográfica de parênquima pulmonar variando entre -900 UH e -800 UH em ZEEP. Efeitos cárdio-respiratórios em PEEP foram semelhantes nos pacientes com SARA primária e secundária. O recrutamento alveolar induzido pela PEEP nos lobos inferiores se correlacionou de forma significativa com seu volume pulmonar residual. Recrutamento alveolar induzido pela PEEP foi maior nos lobos inferiores com atelectasias inflamatórias do que nos lobos inferiores com atelectasias mecânicas. A morfologia pulmonar acessada pelo exame tomográfico influenciou de forma significativa os efeitos da PEEP. Em pacientes com hiperdensidades difusas, a PEEP induziu recrutamento alveolar importante sem hiperdistensão, enquanto que nos pacientes com hiperdensidades localizadas, a PEEP induziu... / There has been some decades, a lot has been invested in the attempt of better knowledge of ARDS, characterizing in a more trustworthy way your aetiology, risk factors, its mechanisms and mediators, choosing critical methods of clinical evaluation that could also foresee the prognostic. To determine whether differences in lung morphology assessed on the CT scan influence the response to PEEP we study by a prospective study during a 53-month period in a fourteenbed surgical Intensive Care Unit of a university hospital, seventy-one consecutive patients with early ARDS. In each patient, a fast spiral thoracic CT scan was performed in ZEEP and after implementation of PEEP 10 cmH2O. Hemodynamic and respiratory parameters were also measured in the same conditions. PEEPinduced overdistension and alveolar recruitment were quantified by a specifically designed software, Lungview®. Overdistension occurred only in the upper lobes and was significantly correlated with the volume of lung characterized by a scanographic density ranging between -900 HU and -800 HU parenchyma in ZEEP conditions. Cardiorespiratory effects of PEEP were similar in patients with primary and secondary ARDS. PEEP-induced alveolar recruitment of lower lobes was significantly correlated with their resting lung volume. PEEP-induced alveolar recruitment was greater in the lower lobes with inflammatory atelectasis than in the lower lobes with mechanical atelectasis. Lung morphology assessed on the CT scan markedly influenced the effects of PEEP: in patients with diffuse hyperdensities, PEEP induced a marked alveolar recruitment without overdistension whereas, in patients with lobar hyperdensities, PEEP induced a mild alveolar recruitment associated with overdistension of previously aerated lung areas. These results... (Complete abstract click eletronic address below)

Orientador: José Roberto Fioretto / Banca: Ana Lúcia dos Anjos Ferreira / Banca: Regina Grigolli Cesar / Resumo: Fundamentação/Objetivos: Síndrome do desconforto respiratório agudo (SDRA) cursa com elevada taxa de mortalidade a despeito do melhor entendimento de sua fisiopatologia e recentes avanços no tratamento. Ventilação mecânica (VM), uma das mais importantes formas de tratamento, é baseada na utilização de estratégias protetoras com baixo volume corrente (VC) e elevada pressão expiratória final positiva (PEEP). Existem várias terapias adjuvantes, entre as quais o óxido nítrico inalatório (NOi) é conhecido por suas propriedades antiinflamatórias e efeitos benéficos sobre a oxigenação. Quando o NOi é associado à VM protetora, o gás poderia não apenas melhorar a oxigenação mas também reduzir a lesão pulmonar. Objetivo: comparar a VM protetora, com e sem NOi, quanto a oxigenação, estresse oxidativo do tecido pulmonar e lesão histológica e inflamatória dos pulmões. Métodos: Trinta coelhos foram instrumentados com traqueotomia e acessos vasculares e ventilados com FiO2 de 1,0. Lesão pulmonar aguda (LPA) foi induzida por infusão traqueal de salina aquecida (30mL/Kg, 38°C) e o estresse oxidativo do tecido pulmonar foi medido pelo método da capacidade antioxidante total (TAP). A inflamação pulmonar foi avaliada pelo contagem do número de células polimorfonucleares (PMN) recuperadas do fluido de lavagem broncoalveolar (BAL). Também foi analisado um escore de lesão pulmonar histopatológica. Os animais foram distribuídos nos seguintes grupos, cada um dos quais com 10 coelhos: a) Controle (GC): baixo VC (6mL/Kg) e PEEP de 5cmH2O; b) ventilação mecânica protetora + LPA (GVM): baixo VC (6mL/Kg) e PEEP de 10cmH2O; e c) ventilação mecânica protetora + LPA + NOi (GVM-NO): baixo VC (6mL/Kg), PEEP de 10cmH2O, e NOi de 5ppm.; d) Dez animais não instrumentados e não ventilados mecanicamente, grupo sadio (GSadio), foram estudados para o TAP. Pressão... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Background/Objectives: Acute respiratory distress syndrome (ARDS) has been associated with high mortality rate despite better understanding of its pathophysiology and recent advances in treatment. Mechanical ventilation (MV), one of the most important treatments, is based on using protective strategies with low tidal volume (VT) and high positive end expiratory pressure (PEEP). There are also many adjunctive therapies, of which inhaled nitric oxide (iNO) is known for its antiinflammatory properties and positive effects on oxygenation. When iNO is associated with protective MV, it could not only improve oxygenation but may also reduce lung injury. Objective: to compare protective MV with and without iNO for oxygenation, lung oxidative stress, inflammatory and histopathological injury. Methods: Thirty rabbits were instrumented with a tracheotomy and vascular catheters and ventilated at FiO2 1.0. Acute lung injury (ALI) was induced by tracheal infusion of warm saline (30mL/Kg, 38°C), lung oxidative stress was assessed by total antioxidant performance (TAP) assay, and pulmonary inflammation was assessed by counting of the number of polymorphonuclear leukocyte (PMN) in bronchoalveolar lavage fluid (BAL). Histopathological lung injury was assessed by a lung injury score. Animals were assigned to groups: a) Control (CG): low tidal volume (6mL/Kg) and PEEP 5cmH2O; b) ALI without iNO (LIG): low tidal volume (6mL/Kg) and PEEP 10cmH2O; and c) ALI with iNO (LINOG): low tidal volume (6mL/Kg), PEEP 10cmH2O, and iNO 5ppm; d) Ten rabbits were studied for oxidative stress analysis without ALI and MV, healthy group (HG). Ventilatory and hemodynamic parameters were recorded every 30 minutes for 4 hours. Statistical significance was set at p<0.05. Results: After induction, ALI groups were similar but worse than CG for PaO2/FiO2 (CG:438±87>LIG:80±13=LINOG:81±24;p<0.05) and pulmonary compliance... (Complete abstract click electronic access below) / Mestre

Made available in DSpace on 2014-06-11T19:25:36Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-02-09Bitstream added on 2014-06-13T20:53:44Z : No. of bitstreams: 1 campos_fj_me_botfm.pdf: 1625208 bytes, checksum: b0c89648b6d10484c83049fbb2b2478e (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Fundamentação/Objetivos: Síndrome do desconforto respiratório agudo (SDRA) cursa com elevada taxa de mortalidade a despeito do melhor entendimento de sua fisiopatologia e recentes avanços no tratamento. Ventilação mecânica (VM), uma das mais importantes formas de tratamento, é baseada na utilização de estratégias protetoras com baixo volume corrente (VC) e elevada pressão expiratória final positiva (PEEP). Existem várias terapias adjuvantes, entre as quais o óxido nítrico inalatório (NOi) é conhecido por suas propriedades antiinflamatórias e efeitos benéficos sobre a oxigenação. Quando o NOi é associado à VM protetora, o gás poderia não apenas melhorar a oxigenação mas também reduzir a lesão pulmonar. Objetivo: comparar a VM protetora, com e sem NOi, quanto a oxigenação, estresse oxidativo do tecido pulmonar e lesão histológica e inflamatória dos pulmões. Métodos: Trinta coelhos foram instrumentados com traqueotomia e acessos vasculares e ventilados com FiO2 de 1,0. Lesão pulmonar aguda (LPA) foi induzida por infusão traqueal de salina aquecida (30mL/Kg, 38°C) e o estresse oxidativo do tecido pulmonar foi medido pelo método da capacidade antioxidante total (TAP). A inflamação pulmonar foi avaliada pelo contagem do número de células polimorfonucleares (PMN) recuperadas do fluido de lavagem broncoalveolar (BAL). Também foi analisado um escore de lesão pulmonar histopatológica. Os animais foram distribuídos nos seguintes grupos, cada um dos quais com 10 coelhos: a) Controle (GC): baixo VC (6mL/Kg) e PEEP de 5cmH2O; b) ventilação mecânica protetora + LPA (GVM): baixo VC (6mL/Kg) e PEEP de 10cmH2O; e c) ventilação mecânica protetora + LPA + NOi (GVM-NO): baixo VC (6mL/Kg), PEEP de 10cmH2O, e NOi de 5ppm.; d) Dez animais não instrumentados e não ventilados mecanicamente, grupo sadio (GSadio), foram estudados para o TAP. Pressão... / Background/Objectives: Acute respiratory distress syndrome (ARDS) has been associated with high mortality rate despite better understanding of its pathophysiology and recent advances in treatment. Mechanical ventilation (MV), one of the most important treatments, is based on using protective strategies with low tidal volume (VT) and high positive end expiratory pressure (PEEP). There are also many adjunctive therapies, of which inhaled nitric oxide (iNO) is known for its antiinflammatory properties and positive effects on oxygenation. When iNO is associated with protective MV, it could not only improve oxygenation but may also reduce lung injury. Objective: to compare protective MV with and without iNO for oxygenation, lung oxidative stress, inflammatory and histopathological injury. Methods: Thirty rabbits were instrumented with a tracheotomy and vascular catheters and ventilated at FiO2 1.0. Acute lung injury (ALI) was induced by tracheal infusion of warm saline (30mL/Kg, 38°C), lung oxidative stress was assessed by total antioxidant performance (TAP) assay, and pulmonary inflammation was assessed by counting of the number of polymorphonuclear leukocyte (PMN) in bronchoalveolar lavage fluid (BAL). Histopathological lung injury was assessed by a lung injury score. Animals were assigned to groups: a) Control (CG): low tidal volume (6mL/Kg) and PEEP 5cmH2O; b) ALI without iNO (LIG): low tidal volume (6mL/Kg) and PEEP 10cmH2O; and c) ALI with iNO (LINOG): low tidal volume (6mL/Kg), PEEP 10cmH2O, and iNO 5ppm; d) Ten rabbits were studied for oxidative stress analysis without ALI and MV, healthy group (HG). Ventilatory and hemodynamic parameters were recorded every 30 minutes for 4 hours. Statistical significance was set at p<0.05. Results: After induction, ALI groups were similar but worse than CG for PaO2/FiO2 (CG:438±87>LIG:80±13=LINOG:81±24;p<0.05) and pulmonary compliance... (Complete abstract click electronic access below)

Made available in DSpace on 2014-06-11T19:33:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2003Bitstream added on 2014-06-13T19:44:14Z : No. of bitstreams: 1 carpi_mf_dr_botfm.pdf: 214359 bytes, checksum: 0134d7f3e72fe3bbaff53ae651e657bf (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / 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... / 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. / FAPESP: 01/04971-3

Orientador: Luiz Antonio Vane / Banca: Yara Marcondes Machado Castiglia / Banca: José Reinaldo Cerqueira Braz / Banca: José Luiz Gomes do Amaral / Banca: Sílvia Regina Rios Vieira / Resumo: Desde sua primeira descrição, muito se investiu no melhor conhecimento da SARA, na identificação de sua etiologia, seus fatores de risco, seus mecanismos e mediadores, escolhendo-se métodos críticos de avaliação clínica que também pudessem definir o prognóstico. Com o objetivo de verificar se os efeitos da PEEP dependem da morfologia pulmonar, comparando sua resposta em três grupos de pacientes, descritos de acordo com os aspectos de hiperdensidades observadas nos cortes tomográficos, foram estudados 71 pacientes portadores de SARA, comparando-os a 11 voluntários sadios. Cada paciente foi submetido a exame tomográfico helicoidal de tórax em ZEEP e após implemento de PEEP de 10 cmH2O. Parâmetros hemodinâmicos e respiratórios foram mensurados nas mesmas condições. Hiperdistensão induzida pela PEEP e recrutamento alveolar foram quantificados por um software específico, Lungview®. Hiperdistensão ocorreu somente nos lobos superiores e se correlacionou significativamente com volume pulmonar caracterizado por uma densidade tomográfica de parênquima pulmonar variando entre -900 UH e -800 UH em ZEEP. Efeitos cárdio-respiratórios em PEEP foram semelhantes nos pacientes com SARA primária e secundária. O recrutamento alveolar induzido pela PEEP nos lobos inferiores se correlacionou de forma significativa com seu volume pulmonar residual. Recrutamento alveolar induzido pela PEEP foi maior nos lobos inferiores com atelectasias inflamatórias do que nos lobos inferiores com atelectasias mecânicas. A morfologia pulmonar acessada pelo exame tomográfico influenciou de forma significativa os efeitos da PEEP. Em pacientes com hiperdensidades difusas, a PEEP induziu recrutamento alveolar importante sem hiperdistensão, enquanto que nos pacientes com hiperdensidades localizadas, a PEEP induziu... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: There has been some decades, a lot has been invested in the attempt of better knowledge of ARDS, characterizing in a more trustworthy way your aetiology, risk factors, its mechanisms and mediators, choosing critical methods of clinical evaluation that could also foresee the prognostic. To determine whether differences in lung morphology assessed on the CT scan influence the response to PEEP we study by a prospective study during a 53-month period in a fourteenbed surgical Intensive Care Unit of a university hospital, seventy-one consecutive patients with early ARDS. In each patient, a fast spiral thoracic CT scan was performed in ZEEP and after implementation of PEEP 10 cmH2O. Hemodynamic and respiratory parameters were also measured in the same conditions. PEEPinduced overdistension and alveolar recruitment were quantified by a specifically designed software, Lungview®. Overdistension occurred only in the upper lobes and was significantly correlated with the volume of lung characterized by a scanographic density ranging between -900 HU and -800 HU parenchyma in ZEEP conditions. Cardiorespiratory effects of PEEP were similar in patients with primary and secondary ARDS. PEEP-induced alveolar recruitment of lower lobes was significantly correlated with their resting lung volume. PEEP-induced alveolar recruitment was greater in the lower lobes with inflammatory atelectasis than in the lower lobes with mechanical atelectasis. Lung morphology assessed on the CT scan markedly influenced the effects of PEEP: in patients with diffuse hyperdensities, PEEP induced a marked alveolar recruitment without overdistension whereas, in patients with lobar hyperdensities, PEEP induced a mild alveolar recruitment associated with overdistension of previously aerated lung areas. These results... (Complete abstract click eletronic address below) / Doutor

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

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / O metapneumovÃrus humano (MPVh) à um vÃrus que tem se destacado como um dos agentes mais freqÃentes de infecÃÃes respiratÃrias agudas (IRA) virais na infÃncia. Este estudo teve como objetivos: observar a freqÃÃncia das infecÃÃes causadas pelo MPVh em crianÃas atendidas por IRA no Hospital Infantil Albert Sabin, hospital pediÃtrico de referÃncia do estado do CearÃ, no perÃodo de janeiro de 2006 a dezembro de 2007; descrever aspectos de sazonalidade dessas infecÃÃes relacionando-as com a ocorrÃncia de chuvas e a circulaÃÃo de outros vÃrus respiratÃrios; descrever as caracterÃsticas clÃnico-epidemiolÃgicas dos pacientes infectados pelo MPVh, comparando com os pacientes negativos e com os positivos para outros vÃrus e avaliar a tÃcnica de IFI como mÃtodo de diagnÃstico para a detecÃÃo do MPVh. Amostras de secreÃÃo de nasofaringe foram coletadas de crianÃas com sintomas de IRA e submetidas à tÃcnica de imunofluorescÃncia indireta para detecÃÃo dos seguintes vÃrus respiratÃrios: MPVh, vÃrus sincicial respiratÃrio (VSR), influenza A e B, adenovÃrus e parainfluenza 1, 2 e 3. Durante os 24 meses de estudo, foram colhidas amostras de 1276 crianÃas sendo detectado algum vÃrus respiratÃrio em 380 (29,78%) amostras. O MPVh foi o segundo vÃrus respiratÃrio mais encontrado representando um total de 8,69% de todas as amostras e de 29% dentre as amostras positivas para os vÃrus pesquisados. NÃo foi observado para o MPVh um padrÃo de sazonalidade nem correlaÃÃo com perÃodo chuvoso. A maioria dos pacientes positivos para MPVh foram atendidos na emergÃncia (89,2%). A mÃdia de idade dos pacientes positivos para o MPVh foi de 27 meses sendo significativamente superior que a das crianÃas infectadas pelo VSR (15 meses), adenovÃrus (14 meses) e vÃrus parainfluenza 3 (18 meses). Dentre os pacientes infectados pelo MPVh, 53,2% tiveram o diagnÃstico de infecÃÃes das vias aÃreas superiores e 46,7% tiveram o diagnÃstico de infecÃÃes das vias aÃreas inferiores. As infecÃÃes por MPVh apresentaram o mesmo espectro de infecÃÃes causadas pelos demais vÃrus pesquisados. O MPVh associou-se mais a casos de pneumonia que levaram à hospitalizaÃÃo das crianÃas infectadas do que outros vÃrus analisados. Mais da metade dos pacientes infectados pelo MPVh utilizaram o aerossol / salbutamol no seu tratamento (68,5%). A tÃcnica de IFI mostrou-se bastante eficaz como mÃtodo de diagnÃstico para a detecÃÃo do MPVh nesse estudo / The human metapneumovÃrus (hMPV) is a newly discovered virus that has been considered as one of the most common agents of acute respiratory infections (ARI) virus in childhood. The objectives of this study were: 1) to observe the frequency of infections caused by hMPV among children attending Hospital Infantil Albert Sabin, a major pediatric hospital in CearÃ, from January 2006 to December 2007; 2) to describe aspects of seasonality of these infections relating them to the occurrence of rain and the circulation of other respiratory viruses, 3) to describe the clinical and epidemiological characteristics of patients infected by hMPV, compared with positive and negative patients for other viruses; 4) to evaluate the IFI assay as a method of diagnosis for the detection of hMPV. Nasopharyngeal aspirates were collected from children with symptoms of ARI and submitted to indirect immunofluorescence assays for the detection of the following respiratory viruses: hMPV, respiratory syncytial virus (RSV), influenza A and B, adenovirus and parainfluenza 1, 2 and 3. During the 24 months of study, samples were collected from 1276 and respiratory viruses were demonstrated in 380 (29.78%) samples. The hMPV was the second most frequently detected respiratory viruses representing a total of 8.69% of all samples and 29% among the samples positive for the virus analyzed. It was not observed for hMPV a pattern of seasonality or correlation with the rainy season. Most patients positive for hMPV were attended in the emergence (89.2%). The mean age of patients infected by hMPV was 27 months, wich is significantly older than that for VSR (15 months), adenovirus (14 months) and parainfluenza virus 3 (18 months). Among patients infected by hMPV, 53.2% had a diagnosis of infections of the upper airways and 46.7% had a diagnosis of infections of the lower airways. The hMPV infections showed the same spectrum of infections caused by other viruses analyzed. The hMPV associated to more cases of pneumonia that led to the hospitalization of children infected than other viruses analyzed. More than half of these patients used the aerosol / salbutamol as conduct therapy (68.5%). The IFI assay proved to be quite effective as a method of diagnosis for the detection of hMPV in this study

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Coronaviridae family is composed of a number of ribonucleic acid (RNA)-containing viruses currently classified into two genera, the coronavirus and torovirus. The family is classified together with the Arteviridae in the order Nidovirales. Coronaviruses are enveloped single stranded positive sense RNA viruses about 80-160 nm in diameter. The coronavirus is, as in the case of all positive sense RNA virus, a messenger, and the naked RNA is infectious. The 5′-two thirds of the genome encodes for a polyprotein that contains all the enzymes necessary for replication, whereas the 3′-one third encodes for all the structural proteins that mediate viral entry into the host cell. The structural proteins include spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins.Nucleocapsid protein is one of the most crucial structural components of coronaviruses;hence major attention has been focused on characterization of this protein. Some laboratories have demonstrated that this protein interferes with different cellular pathways, thus implying it to be a key regulatory component of the virus (Zakhartchouk, Viswanathan et al. 2005). Furthermore, it has been shown that severe acute respiratory syndrome (SARS)-N protein interacts with cellular proteins, including cyclophilin A (CypA), heterogenous nuclear ribonucleoprotein (hnRNP) A1, human ubiquitin-conjugating enzyme, cyclin dependent kinase (CDK)-cyclin complex protein, Ikappaßalpha (IkBα), cytochrome (Cyt) P450 etc. For the purpose of this study, the focus is based on CypA interaction with human coronavirus (HCoV) NL63-N protein. These interactions might play a role in the pathology of HCoV-NL63. Using glutathione-S-transferase (GST), the interaction of CypA with the nucleocapsid protein can be clearly demonstrated to be direct and specific. Since the N protein is involved in viral RNA packaging to form a helical core, it is suffice to say that both NL63-N and CypA are possibly within the HCoV-NL63 replication/transcription complex and NL63-N/human CypA interaction might function in the regulation of HCoV-NL63 RNA synthesis. In addition, the results will demonstrate that HCoV-NL63-N has only a specific domain for interacting with CypA.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Raymond R. Rowland / Severe acute respiratory syndrome (SARS) is caused by an enveloped, positive-stranded RNA virus, the SARS coronavirus (SARS-CoV). Coronaviruses along with the arteriviruses are placed in the order, Nidovirales. Even though nidovirus replication is restricted to the cytoplasm, the nucleocapsid protein (N) of several coronaviruses and arteriviruses, localize to the nucleolus during infection. Confocal microscopy of N protein localization in Vero cells infected with the SARS-CoV or transfected with the SARS-CoV N gene failed to show presence of N in the nucleoplasm or nucleolus. Recombinant N remained cytoplasmic after the addition of leptomycin B (LMB), a drug that inhibits nuclear export. SARS-CoV N possesses a unique lysine-rich domain, located between amino acids 369-389, which possesses several nuclear localization signal (NLS) and nucleolar localization signal (NoLS) motifs. A chimeric protein composed of the 369-389 peptide substituted for the NLS of equine infectious anemia virus (EIAV) Rev protein (ERev) showed no nuclear localization activity. Three negatively charged amino acids, located at positions 372, 377 and 379 in SARS-CoV N were hypothesized to play a role in the loss of nuclear targeting. Substitution of aspartic acid-372 with alanine restored nuclear localization to the chimeric protein. A full-length recombinant SARS-N protein with the alanine-372 substitution localized to the nucleus. Therefore, the presence of an aspartic acid at position 372 is sufficient to retain N in the cytoplasm The mechanistic basis for how aspartic acid-372 interrupts nuclear transport is unknown, but may lie in the electrostatic repulsion with negatively charged amino acids located within the NLS binding pocket of importin-alpha.