Mechanical ventilation (MV) is the primary form of therapeutic support for patients with acute respiratory failure (ARF) or acute respiratory distress syndrome (ARDS) until the underlying disease is resolved. However, as patient disease state and response to MV are highly variable, clinicians often rely on experience to set MV. The result is more variable care, as there are currently no standard approaches to MV settings. As a result of the common occurrence of MV and variability in care, MV is one of the most expensive treatments in critical care. Thus, an approach capable of guiding patient-specific MV is required and this approach could potentially save significant cost. This research focuses on developing models and model-based approaches to analyse and guide patient-specific MV care. Four models and metrics are developed, and each model is tested in experimental or clinical trials developed for the purpose. Each builds the understanding and methods necessary for an overall approach to guide MV in a wide range of patients. The first model, a minimal recruitment model, captures the recruitment of an injured lung and its response to positive end expiratory pressure (PEEP). However, the model was only previously validated in diagnosed ARDS patients, and was not proven to capture behaviours seen in healthy patients. This deficiency could potentially negate its ability to track disease state, which is crucial in providing rapid diagnosis and patient-specific MV in response to changes in patient condition. Hence, the lack of validation in disease state progression monitoring from ARDS to healthy, or vice-versa, severely limits its application in real-time monitoring and decision support. To address this issue, an experimental ARDS animal model is developed to validate the model across the transition between healthy and diseased states. The second model, a single compartment linear lung model, models the lung as a conducting airway connected to an elastic compartment. This model is used to estimate the respiratory mechanics (Elastance and Resistance) of an ARDS animal model during disease progression and recruitment manoeuvres. This model is later extended to capture high resolution, patient-specific time-varying respiratory mechanics during each breathing cycle. This extended model is tested in ARDS patients, and was used to titrate patient-specific PEEP using a minimum elastance metric that balances recruitment and the risk of lung overdistension and ventilation-induced injury. Studies have revealed that promoting patients to breathe spontaneously during MV can improve patient outcomes. Thus, there is significant clinical trend towards using partially assisted ventilation modes, rather than fully supported ventilation modes. In this study, the patient-ventilator interaction of a state of the art partially assisted ventilation mode, known as neurally adjusted ventilatory assist (NAVA), is investigated and compared with pressure support ventilation (PS). The matching of patient-specific inspiratory demand and ventilator supplied tidal volume for these two ventilation modes is assessed using a novel Range90 metric. NAVA consistently showed better matching than PS, indicating that NAVA has better ability to provide patient-specific ventilator tidal volume to match variable patient-specific demand. Hence, this new analysis highlights a critical benefit of partially assisted ventilation and thus the need to extend model-based methods to this patient group. NAVA ventilation has been shown to improve patient-ventilator interaction compared to conventional PS. However, the patient-specific, optimal NAVA level remains unknown, and the best described method to set NAVA is complicated and clinically impractical. The Range90 metric is thus extended to analyse the matching ability of different NAVA levels, where it is found that response to different NAVA levels is highly patient-specific. Similar to the fully sedated MV case, and thus requiring models and metrics to help titrate care. More importantly, Range90 is shown to provide an alternative metric to help titrate patient-specific optimal NAVA level and this analysis further highlights the need for extended model-based methods to better guide these emerging partially assisted MV modes. Traditionally, the respiratory mechanics of the spontaneously breathing (SB) patient cannot be estimated without significant additional invasive equipment and tests that interrupt normal care and are clinically intensive to carry out. Thus, respiratory mechanics and model-based methods are rarely used to guide partially assisted MV. Thus, there is significant clinical interest to use respiratory mechanics to guide MV in SB patients. The single compartment model is extended to effectively capture the trajectory of time-varying elastance for SB patients. Results show that without additional invasive equipment, the model was able estimate unique and clinically useful respiratory mechanics in SB patients. Hence, the extended single compartment model can be used as ‘a one model fits all’ means to guide patient-specific MV continuously and consistently, for all types of patient and ventilation modes, without interrupting care. Overall, the model-based approaches presented in this thesis are capable of capturing physiologically relevant patient-specific parameters, and thus, characterise patient disease state and response to MV. With additional, larger scale clinical trials to test the performance and the impact of model-based methods on clinical outcome, the models can aid clinicians to guide MV decision making in the heterogeneous ICU population. Hence, this thesis develops, extends and validates several fundamental model-based metrics, models and methods to enable standardized patient-specific MV to improve outcome and reduce the variability and cost of care.

Acute Respiratory Distress Syndrome (ARDS) following hemorrhagic shock/resuscitation (S/R) is an important contributor to late morbidity and mortality in trauma patients. S/R promotes ARDS by inducing oxidative stress that primes cells of the innate immune system for excessive responsiveness to small inflammatory stimuli, termed the “twohit” hypothesis. Activated alveolar macrophages (AM) play a central role and when recovered from S/R animals exhibit an exaggerated responsiveness to lipopolysaccharide (LPS) with increased activation of the proinflammatory transcription factor NF-κB, and augmented expression of cytokines. LPS triggers AM signalling through Toll like receptor 4 (TLR4), which resides in plasma membrane lipid rafts. The objective of this work is to define cellular mechanisms of macrophage priming by oxidative stress following shock resuscitation. The main hypothesis investigated is that altered cellular distribution of TLR4 can lead to macrophage priming and antioxidant resuscitation strategies can diminish these effects. AM of rodents, exposed in vivo to oxidant stress following S/R, increase their surface levels of TLR4, which in turn results in augmented NF-κB translocation in response to small doses of LPS. Furthermore, in vitro H2O2 treatment of RAW 264.7 macrophages results in similar TLR4 surface translocation. Depletion of intracellular calcium, disruption of the cytoskeleton or inhibition of the Src kinases prevents the H2O2-induced TLR4 translocation, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy iii transfer between TLR4 and lipid rafts as well as biochemical raft analysis demonstrated that oxidative stress redistributes TLR4 to surface lipid rafts. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-ß-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Further, AM priming by oxidative stress can be diminished by early exposure to resuscitation regimens with direct or indirect systemic antioxidant effects, such as 25% albumin, N-acetylcysteine and hypertonic saline. Hyperosmolarity was found to modulate AM TLR4 gene and protein expression. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system. Targeting the TLR4 signalling pathway early during shock resuscitation may represent an anti-inflammatory strategy able to ameliorate late morbidity and mortality following S/R.

Acute Respiratory Distress Syndrome (ARDS), an age-old clinical problem facing the Emergency Department and Intensive Care Units of all health systems, is a common debilitating lung condition consequent upon severe systemic inflammation. Although several studies have gone into understanding the epidemiology and pathogenesis of the disease thus making way for new advances in treatment strategies, there seems to be no known study tailored to its prevention. Neutrophil extravasation within the tissues during inflammation is the hallmark of this syndrome. Our study sought to block excessive neutrophil infiltration by inhibiting the biosynthesis of some essential proteins necessary for the process. In this initial study, neutrophil transmigration was successfully reduced by 66% using protein synthesis inhibitors, a combination of puromycin and anisomycin. Our strategy, if fine-tuned, could form the basis of a new clinical strategy for the prevention of ARDS.

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.

Infecções por Plasmodium spp. podem acarretar em complicações pulmonares (1 a 40% dos casos), que podem resultar no desenvolvimento da síndrome do desconforto respiratório agudo (SDRA). Esta síndrome é caracterizada por inflamação aguda, lesão do endotélio alveolar e do parênquima pulmonar, disfunção e aumento da permeabilidade da barreira alvéolo-capilar pulmonar e, consequente, formação de efusão pleural. Neste sentido, os mecanismos de regulação da permeabilidade das células endoteliais e as junções interendoteliais têm papel crítico na manutenção do endotélio pulmonar. O objetivo do estudo foi determinar precocemente o desenvolvimento da SDRA associada à malária por tomografia computadorizada por emissão de fóton único (SPECT/CT), além de identificar alterações nas junções interendoteliais das células endoteliais pulmonares primárias de camundongos DBA/2 (CEPP-DBA/2), após contato com os eritrócitos parasitados de Plasmodium berghei ANKA (EP-PbA). Os nossos resultados demonstraram que é possível identificar alterações na aeração pulmonar no 5° e 7° dia após a infecção e, consequentemente, diferenciar os animais que desenvolveriam SDRA daqueles que evoluiriam para hiperparasitemia (HP). Além disso, observamos em CEPP-DBA/2 que o contato direto com EP-PbA aumenta da abertura das junções interendoteliais e da permeabilidade vascular. Assim, avaliamos a diminuição da expressão das proteínas das junções interendoteliais que contribuem para o aumento da permeabilidade vascular, por imunofluorescência e Western Blot. Apesar da SDRA ter sido identificada há mais de 50 anos, ainda não se conhece formas de diagnóstico precoce e os mecanimos efetivos de desenvolvimento desta enfermidade, que permitam um tratamento efetivo e que evite a morte do paciente. Portanto, sugere-se que a técnica de SPECT/CT seja uma importante ferramenta de diagnóstico para identificação precoce de SDRA associado a malária. / Infections by Plasmodium spp. can lead to pulmonary complications (1 to 40% of the cases), that can result in the development of acute respiratory distress syndrome (ARDS). This syndrome is characterized by the acute inflammation, injury of the alveolar endothelium and pulmonary parenchyma, dysfunction and increased permeability of the pulmonary alveolar-capillary barrier and, consequently, formation of pleural effusion. In this aspect, mechanisms of regulation of endothelial cell permeability and interendothelial junctions play a critical role in the maintenance of the pulmonary endothelium. The present study aimed to determine the early development of single-photon emission computed tomography (SPECT/CT) associated malaria ARDS in addition to identifying changes in the interendothelial junctions of the primary pulmonary endothelial cells of DBA/2 mice (CEPP-DBA/2) after contact with erythrocytes infected with Plasmodium berghei ANKA (EP-PbA). Our results demonstrated that is possible to identify changes in lung aeration on the 5th and 7th day after infection and, consequently, differentiate the animals that should develop ARDS from those that would evolve to hyperparasitemia (HP). In addition, we observed in CEPP-DBA/2 that direct contact with EP-PbA increases the opening of the interendothelial junctions and vascular permeability. Thus, we evaluated that decrease the expression of interendothelial junction proteins contribute to the increase of vascular permeability, by immunofluorescence and Western Blot. Although ARDS was identified more than 50 years ago, it is not yet known what forms of early diagnosis, and the effective mechanisms of development of this disease, that allow an effective treatment and that prevent the death of the patient. Therefore, it is suggested that the SPECT/CT technique is a valuable tool to promote the early identification of ARDS associated with malaria.

Acute respiratory distress syndrome (ARDS) is a pulmonary disease caused by surfactant dysfunction as a result of various types of trauma including sepsis and smoke inhalation. ARDS has a mortality rate of ~40% and affects ~150,000 people in the United States annually. Mechanical ventilation is a necessary life sustaining therapy to reopen collapsed airways. However, without a sufficient amount of active surfactant, the pressure required to reopen the airway increases significantly. Unfortunately, conventional ventilation, while necessary, can cause ventilator-induced lung injury. Atelectrauma is a type of lung injury that occurs at low volumes, and involves a repeated recruitment and de-recruitment (RecDer) of lung airways that induces mechanical stress on the epithelial lining. Our goal is to elucidate the fluid mechanics of RecDer in compliant airway models designed to mimic pulmonary airways. Here we design and build an apparatus that allows us to evaluate airway model compliance. Secondly, we characterize “tube laws” of these compliant airway models using this apparatus and identify suitable lab-manufactured airway models for experimentation. Finally, we investigate the RecDer phenomena in these models by measuring the frequency of de-recruitment as a result of the change in tube angle orientation and find a maximum frequency associated with angle orientation and reopening velocity. This research may provide a starting point for investigating further implications of RecDer, both mechanically and biologically, as well as developing novel ventilation waveforms to improve outcomes in ARDS patients. / acase@tulane.edu

<p>The recognition that supportive mechanical ventilation can also damage the lung, the so called ventilation induced lung injury (VILI), has revived the more than 40 year long debate on the optimal level of PEEP to be used. It is established that the prevention of VILI improves patient outcome and that PEEP exerts protective effects by preventing unstable diseased alveoli from collapsing. Therefore, the term “open lung PEEP” (OL-PEEP) has been introduced as the end-expiratory pressure that keeps the lung open after its collapse has been eliminated by an active lung recruitment manoeuvre. The determination of such an optimal level of PEEP under clinical circumstances is difficult and remains to be investigated.</p><p>The aim of this study was to investigate the usefulness of breath by breath monitoring of dynamic compliance (Cdyn) as a clinical means to identify OL-PEEP at the bedside and to demonstrate the improvement in lung function resulting from its application.</p><p>In a porcine lung lavage model of acute lung injury PEEP at maximum Cdyn during a decremental PEEP trial after full lung recruitment was related to the onset of lung collapse and OL-PEEP could be found 2 cmH₂O above this level Ventilation at OL-PEEP was associated with improved gas exchange, efficiency of ventilation, lung mechanics and less than 5% collapse on CT scans. In addition, dead space, especially its portion related to alveolar gas changed characteristically during recruitment, PEEP titration and collapse thereby helping to identify OL-PEEP.</p><p>The beneficial effects of OL-PEEP on lung function and mechanics was demonstrated in a porcine model of VILI. OL-PEEP improved lung function and mechanics when compared to lower or higher levels prior to or after lung recruitment. By using electrical impedance tomography it could be shown that PEEPs within the range of 14 to 22 cmH₂O resulted in a similar redistribution of both ventilation and perfusion to the dorsal regions of the lung. OL-PEEP resulted in the best regional and global matching of ventilation and perfusion explaining the drastic improvements in gas exchange. Also regional compliance was greatly improved in the lower half of the lung as compared to all other situations.</p><p>In ARDS patients OL-PEEP could be identified applying the same protocol. The physiological changes described could now be reproduced and maintained during a four hours study ventilation period in real patients at four study centres.</p><p>In conclusion, the usefulness of dynamic compliance for identifying open lung PEEP during a decremental PEEP trial was demonstrated under experimental and clinical conditions. This PEEP should then be used as an essential part of any lung protective ventilation strategy. The impact of ventilating ARDS patients according to the principles described in these studies on outcome are currently being evaluated in an international randomized controlled trial.</p>

The recognition that supportive mechanical ventilation can also damage the lung, the so called ventilation induced lung injury (VILI), has revived the more than 40 year long debate on the optimal level of PEEP to be used. It is established that the prevention of VILI improves patient outcome and that PEEP exerts protective effects by preventing unstable diseased alveoli from collapsing. Therefore, the term “open lung PEEP” (OL-PEEP) has been introduced as the end-expiratory pressure that keeps the lung open after its collapse has been eliminated by an active lung recruitment manoeuvre. The determination of such an optimal level of PEEP under clinical circumstances is difficult and remains to be investigated. The aim of this study was to investigate the usefulness of breath by breath monitoring of dynamic compliance (Cdyn) as a clinical means to identify OL-PEEP at the bedside and to demonstrate the improvement in lung function resulting from its application. In a porcine lung lavage model of acute lung injury PEEP at maximum Cdyn during a decremental PEEP trial after full lung recruitment was related to the onset of lung collapse and OL-PEEP could be found 2 cmH2O above this level Ventilation at OL-PEEP was associated with improved gas exchange, efficiency of ventilation, lung mechanics and less than 5% collapse on CT scans. In addition, dead space, especially its portion related to alveolar gas changed characteristically during recruitment, PEEP titration and collapse thereby helping to identify OL-PEEP. The beneficial effects of OL-PEEP on lung function and mechanics was demonstrated in a porcine model of VILI. OL-PEEP improved lung function and mechanics when compared to lower or higher levels prior to or after lung recruitment. By using electrical impedance tomography it could be shown that PEEPs within the range of 14 to 22 cmH2O resulted in a similar redistribution of both ventilation and perfusion to the dorsal regions of the lung. OL-PEEP resulted in the best regional and global matching of ventilation and perfusion explaining the drastic improvements in gas exchange. Also regional compliance was greatly improved in the lower half of the lung as compared to all other situations. In ARDS patients OL-PEEP could be identified applying the same protocol. The physiological changes described could now be reproduced and maintained during a four hours study ventilation period in real patients at four study centres. In conclusion, the usefulness of dynamic compliance for identifying open lung PEEP during a decremental PEEP trial was demonstrated under experimental and clinical conditions. This PEEP should then be used as an essential part of any lung protective ventilation strategy. The impact of ventilating ARDS patients according to the principles described in these studies on outcome are currently being evaluated in an international randomized controlled trial.

Acute Respiratory Distress Syndrome (ARDS) following hemorrhagic shock/resuscitation (S/R) is an important contributor to late morbidity and mortality in trauma patients. S/R promotes ARDS by inducing oxidative stress that primes cells of the innate immune system for excessive responsiveness to small inflammatory stimuli, termed the “twohit” hypothesis. Activated alveolar macrophages (AM) play a central role and when recovered from S/R animals exhibit an exaggerated responsiveness to lipopolysaccharide (LPS) with increased activation of the proinflammatory transcription factor NF-κB, and augmented expression of cytokines. LPS triggers AM signalling through Toll like receptor 4 (TLR4), which resides in plasma membrane lipid rafts. The objective of this work is to define cellular mechanisms of macrophage priming by oxidative stress following shock resuscitation. The main hypothesis investigated is that altered cellular distribution of TLR4 can lead to macrophage priming and antioxidant resuscitation strategies can diminish these effects. AM of rodents, exposed in vivo to oxidant stress following S/R, increase their surface levels of TLR4, which in turn results in augmented NF-κB translocation in response to small doses of LPS. Furthermore, in vitro H2O2 treatment of RAW 264.7 macrophages results in similar TLR4 surface translocation. Depletion of intracellular calcium, disruption of the cytoskeleton or inhibition of the Src kinases prevents the H2O2-induced TLR4 translocation, suggesting the involvement of receptor exocytosis. Further, fluorescent resonance energy iii transfer between TLR4 and lipid rafts as well as biochemical raft analysis demonstrated that oxidative stress redistributes TLR4 to surface lipid rafts. Preventing the oxidant-induced movement of TLR4 to lipid rafts using methyl-ß-cyclodextrin precluded the increased responsiveness of cells to LPS after H2O2 treatment. Further, AM priming by oxidative stress can be diminished by early exposure to resuscitation regimens with direct or indirect systemic antioxidant effects, such as 25% albumin, N-acetylcysteine and hypertonic saline. Hyperosmolarity was found to modulate AM TLR4 gene and protein expression. Collectively, these studies suggest a novel mechanism whereby oxidative stress might prime the responsiveness of cells of the innate immune system. Targeting the TLR4 signalling pathway early during shock resuscitation may represent an anti-inflammatory strategy able to ameliorate late morbidity and mortality following S/R.

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