RESUMO
BACKGROUND: Extracorporeal carbon dioxide removal (ECCO2-R) allows lung protective ventilation using lower tidal volumes (VT) in patients with acute respiratory failure. The dynamics of spontaneous ventilation under ECCO2-R has not been described previously. This retrospective multivariable analysis examines VT patterns and investigates the factors that influence VT, in particular sweep gas flow and blood flow through the artificial membrane. METHODS: We assessed VT, respiratory rate (RR), minute ventilation (MV), and levels of pressure support (0-24 cm H2O), sweep gas flow (0-14 L/min) and blood flow through the membrane (0.8-1.8 L/min) in 40 patients from the moment they were allowed to breathe spontaneously. Modest hypercapnia was accepted. RESULTS: Patients tolerated moderate hypercapnia well. In a generalized linear model the increase in sweep gas flow (P<0.001), a low PaCO2 (P=0.029), and an increased breathing frequency (P<0.001) were associated with lower VT. Neither blood flow through the membrane (P=0.351) nor the level of pressure support (P=0.595) influenced VT size. CONCLUSION: Higher sweep gas flow is associated with low VT in patients on extracorporeal lung assist and augmented spontaneous ventilation. Such a technique can be used for prolonged lung protective ventilation even in the patient's recovery period.
Assuntos
Dióxido de Carbono/isolamento & purificação , Respiração Artificial/métodos , Volume de Ventilação Pulmonar , Adulto , Feminino , Humanos , Hipercapnia/terapia , Masculino , Pessoa de Meia-Idade , Troca Gasosa Pulmonar , Taxa Respiratória , Estudos RetrospectivosRESUMO
Currently, many centers use venovenous extracorporeal membrane oxygenation (VV-ECMO) as an adjunctive means of gas exchange to mechanical ventilation (MV) in patients with severe ARDS and refractory hypoxemia. One of the most interesting and controversial issues in the management of these patients is how to set the ventilatory strategy. The support provided by VV-ECMO makes the balance between risks and benefits of MV remarkably different from the conventional setting, since the need for MV to facilitate oxygenation and carbon dioxide clearance is greatly reduced or abolished during VV-ECMO. Therefore, the risks of causing ventilator-induced lung injury are of foremost importance; however, the issue of the optimum ventilatory strategy during VV-ECMO has not received sufficient consideration. This paper will describe the diverse MV strategies applied during VV-ECMO in clinical practice and will highlight specific pathophysiological considerations that are crucial in the process of defining optimal ventilation settings in patients with ARDS supported with VV-ECMO.
Assuntos
Oxigenação por Membrana Extracorpórea/métodos , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Adulto , Humanos , Lesão Pulmonar Induzida por Ventilação Mecânica/epidemiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controleRESUMO
Lung transplantation has become a standard treatment for patients with a broad spectrum of end stage lung diseases. Despite this success, many patients die on the waiting list while waiting for appropriate lungs to become available. This review describes the current strategies aimed at addressing this shortage of lungs, as well as summarizing potential future directions in the field. They include efforts to: 1) increase the number of organ donors by legislative action, and education of the public; 2) optimize the management of deceased, potential organ donors; 3) implement optimal criteria to determine organs suitable for transplantation; 4) use ex vivo reconditioning of lungs; and 5) develop xenotransplantation.
Assuntos
Transplante de Pulmão/estatística & dados numéricos , Obtenção de Tecidos e Órgãos/métodos , Animais , Humanos , Legislação Médica , Respiração Artificial , Doadores de Tecidos , Transplante Heterólogo , Listas de EsperaRESUMO
BACKGROUND: Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma-derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats. METHODS: Forty-eight hours after induction of S. pneumoniae pneumonia rats were subjected to mechanical ventilation (tidal volume 12 mL kg(-1), positive end-expiratory pressure 0 cmH(2)O and inspired oxygen fraction 40%). Rats were randomized to systemic treatment with AT (250 IU administered intravenously (i.v.) before the start of mechanical ventilation) or placebo (saline). Non-ventilated, non-infected rats and non-ventilated rats with pneumonia served as controls. The primary endpoints were pulmonary coagulation and inflammation in bronchoalveolar lavage fluid (BALF). RESULTS: Pneumonia was characterized by local activation of coagulation and inhibition of fibrinolysis, resulting in increased levels of fibrin degradation products and fibrin deposition in the lung. Mechanical ventilation exaggerated pulmonary coagulopathy and inflammation. Systemic administration of AT led to supra-normal BALF levels of AT and decreased ventilator-associated activation of coagulation. AT neither affected pulmonary inflammation nor bacterial outgrowth from the lungs or blood. CONCLUSIONS: Plasma-derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats.
Assuntos
Anticoagulantes/farmacologia , Proteínas Antitrombina/farmacologia , Transtornos da Coagulação Sanguínea/prevenção & controle , Coagulação Sanguínea/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pneumonia Pneumocócica/tratamento farmacológico , Respiração Artificial/efeitos adversos , Lesão Pulmonar Induzida por Ventilação Mecânica/tratamento farmacológico , Animais , Transtornos da Coagulação Sanguínea/sangue , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/imunologia , Transtornos da Coagulação Sanguínea/microbiologia , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinólise/efeitos dos fármacos , Humanos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Masculino , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/microbiologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Lesão Pulmonar Induzida por Ventilação Mecânica/sangue , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/imunologiaRESUMO
Unequivocal evidence from both experimental and clinical research has shown that mechanical ventilation can damage the lungs and initiate an inflammatory response, possibly contributing to extrapulmonary organ dysfunction. This type of injury, referred to as ventilator-induced lung injury (VILI), resembles the syndromes of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). VILI can trigger a complex array of inflammatory mediators, resulting in a local and systemic inflammatory response. Substances produced in the lungs can be translocated into the systemic circulation as a result of injury to the pulmonary epithelium and to the capillary endothelium. This type of injury forms the basis for the use of low tidal volumes (5-7 mL/kg of predicted body weight) during mechanical ventilation of patients with ALI/ARDS. The recognition of VILI has prompted a number of investigators to suggest that ALI/ARDS may be, in part, a product of our efforts to mechanically ventilate patients rather than the progression of the underlying disease. On the other hand, current scientific evidence supports a link between VILI and the development of extrapulmonary organ dysfunction, similar to how most severe cases of sepsis are clinically manifested. In addition, functional genomics approaches using a gene array methodology to measure lung gene expression have identified differential patterns of gene expression in animal models of VILI, similar to those gene pathways activated during experimental and clinical sepsis. In this line of thought, we hypothesize that injurious mechanical ventilation could be responsible for the perpetuation and worsening of sepsis in some patients and for the development of a sepsis-like syndrome in others.
Assuntos
Respiração Artificial/efeitos adversos , Sepse/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/complicações , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologia , Humanos , Insuficiência de Múltiplos Órgãos/etiologia , Lesão Pulmonar Induzida por Ventilação Mecânica/fisiopatologiaRESUMO
The effects of the combination of a 'lowest' lung ventilation with extracorporeal elimination of carbon dioxide by interventional lung assist are described in a patient presenting with severe acute respiratory distress syndrome due to fulminant pneumonia. Reducing tidal volume to 3 ml.kg(-1) together with interventional lung assist resulted in a decrease in severe hypercapnia without alveolar collapse or hypoxaemia but with a decrease in serum levels of interleukin-6. This approach was applied for 12 days with recovery of the patient, without complications. Extracorporeal removal of carbon dioxide by interventional lung assist may be a useful tool to enable 'ultraprotective' ventilation in severe acute respiratory distress syndrome.
Assuntos
Oxigenação por Membrana Extracorpórea/métodos , Hipercapnia/terapia , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/terapia , Dióxido de Carbono/sangue , Humanos , Hipercapnia/sangue , Hipercapnia/etiologia , Masculino , Pessoa de Meia-Idade , Oxigênio/sangue , Pressão Parcial , Síndrome do Desconforto Respiratório/sangue , Volume de Ventilação PulmonarRESUMO
Pneumonia, the main cause of acute lung injury, is characterised by a local pro-inflammatory response and coagulopathy. Mechanical ventilation (MV) is often required. However, MV can lead to additional injury: so-called ventilator-induced lung injury (VILI). Therefore, the current authors investigated the effect of VILI on alveolar fibrin turnover in Streptococcus pneumoniae pneumonia. Pneumonia was induced in rats, followed 48 h later by either lung-protective MV (lower tidal volumes (LV(T)) and positive end-expiratory pressure (PEEP)) or MV causing VILI (high tidal volumes (HV(T)) and zero end-expiratory pressure (ZEEP)) for 3 h. Nonventilated pneumonia rats and healthy rats served as controls. Thrombin-antithrombin complexes (TATc), as a measure for coagulation, and plasminogen activator activity, as a measure of fibrinolysis, were determined in bronchoalveolar lavage fluid (BALF) and serum. Pneumonia was characterised by local (BALF) activation of coagulation, resulting in elevated TATc levels and attenuation of fibrinolysis compared with healthy controls. LV(T)-PEEP did not influence alveolar coagulation or fibrinolysis. HV(T)-ZEEP did intensify the local procoagulant response: TATc levels rose significantly and levels of the main inhibitor of fibrinolysis, plasminogen activator inhibitor-1, increased significantly. HV(T)-ZEEP also resulted in systemic elevation of TATc compared with LV(T)-PEEP. Mechanical ventilation causing ventilator-induced lung injury increases pulmonary coagulopathy in an animal model of Streptococcus pneumoniae pneumonia and results in systemic coagulopathy.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Pneumonia Bacteriana/terapia , Streptococcus pneumoniae/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/diagnóstico , Animais , Antitrombinas/química , Transtornos da Coagulação Sanguínea/complicações , Líquido da Lavagem Broncoalveolar , Modelos Animais de Doenças , Fibrinólise , Lipopolissacarídeos/metabolismo , Masculino , Pneumonia Bacteriana/complicações , Troca Gasosa Pulmonar , Ratos , Ratos Sprague-Dawley , Trombina/química , Lesão Pulmonar Induzida por Ventilação Mecânica/etiologiaRESUMO
BACKGROUND: Different levels of positive end-expiratory pressure (PEEP) with and without a recruitment maneuver (RM) may have a significant impact on ventilator-induced lung injury but this issue has not been well addressed. METHODS: Anesthetized rats received hydrochloric acid (HCl, pH 1.5) aspiration, followed by mechanical ventilation with a tidal volume of 6 ml/kg. The animals were randomized into four groups of 10 each: (1) high PEEP at 6 cm H(2)O with an RM by applying peak airway pressure at 30 cm H(2)O for 10 s every 15 min; (2) low PEEP at 2 cm H(2)O with RM; (3) high PEEP alone; and (4) low PEEP alone. RESULTS: The mean arterial pressure and the amounts of fluid infused were similar in the four groups. Application of the higher PEEP improved oxygenation compared with the lower PEEP groups (P<0.05). The lung compliance was better reserved, and the systemic cytokine responses and lung wet to dry ratio were lower in the high PEEP than in the low PEEP group for a given RM (P<0.05). CONCLUSIONS: The use of a combination of periodic RM and the higher PEEP had an additive effect in improving oxygenation and pulmonary mechanics and attenuation of inflammation.
Assuntos
Respiração com Pressão Positiva/métodos , Síndrome do Desconforto Respiratório/fisiopatologia , Ventiladores Mecânicos/efeitos adversos , Animais , Gasometria , Pressão Sanguínea , Citocinas/sangue , Modelos Animais de Doenças , Ácido Clorídrico , Pulmão/fisiopatologia , Complacência Pulmonar , Oxigênio/sangue , Ratos , Ratos Sprague-Dawley , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/induzido quimicamente , Testes de Função Respiratória , Volume de Ventilação PulmonarRESUMO
Recent evidence suggests that alveolar epithelial cells (AECs) may contribute to the development, propagation, and resolution of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Proinflammatory cytokines, pathogen products, and injurious mechanical ventilation are important contributors of excessive inflammatory responses in the lung. In the present study, we used cDNA microarrays to define the gene expression patterns of A549 cells (an AEC line) in the early stages of three models of pulmonary parenchymal cell activation: cells treated with tumor necrosis factor-alpha (TNFalpha) (20 ng/ml), lipopolysaccharide (LPS, 1 microg/ml), or cyclic stretch (20% elongation) for either 1 h or 4 h. Differential gene expression profiles were determined by gene array analysis. TNFalpha induced an inflammatory response pattern, including induction of genes for chemokines, inflammatory mediators, and cell surface membrane proteins. TNFalpha also increased genes related to pro- and anti-apoptotic proteins, signal transduction proteins, and transcriptional factors. TNFalpha further induced a group of genes that may form a negative feedback loop to silence the NFkappaB pathway. Stimulation of AECs with mechanical stretch changed cell morphology and activated Src protein tyrosine kinase. The combination of TNFalpha plus stretch enhanced or attenuated expression of multiple genes. LPS decreased microfilament polymerization but had less impact on NFkappaB translocation and gene expression. Results from this study indicate that AECs can tailor their response to different stimuli or/and combination of stimuli and subsequently play an important role in acute inflammatory responses in the lung.
Assuntos
DNA Complementar/genética , Células Epiteliais/química , Células Epiteliais/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/fisiologia , Lipopolissacarídeos/imunologia , Análise em Microsséries/métodos , Alvéolos Pulmonares/citologia , Estresse Mecânico , Fator de Necrose Tumoral alfa/imunologia , Apoptose/genética , Linhagem Celular , Retroalimentação Fisiológica/genética , Perfilação da Expressão Gênica/estatística & dados numéricos , Humanos , Inflamação/genética , Análise em Microsséries/estatística & dados numéricos , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/estatística & dados numéricosRESUMO
To date, the only therapeutic option that has convincingly been shown to decrease mortality in acute respiratory distress syndrome (ARDS) has been to use a lung-protective strategy that minimises the iatrogenic consequences of providing adequate life support through the use of mechanical ventilation. In terms of the pharmacological options for ARDS, no single drug or treatment has been shown to be the magic bullet in this disease. The search for novel therapies and pharmacological agents is active and relentless. Important pathophysiological areas of focus are preventative therapy, supportive care and treatment of the underlying inflammatory process. In this paper we will review current and experimental approaches to the management of ARDS. In addition, the pathophysiological basis for their putative modes of action, the current state of the literature and the potential for future clinical development will be discussed.
Assuntos
Síndrome do Desconforto Respiratório/tratamento farmacológico , Doença Aguda , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Movimento Celular/efeitos dos fármacos , Fator 7 de Crescimento de Fibroblastos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Interleucina-10/metabolismo , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ventilação Pulmonar/efeitos dos fármacos , Síndrome do Desconforto Respiratório/complicações , Síndrome do Desconforto Respiratório/fisiopatologia , Trombose/etiologia , Trombose/prevenção & controle , Vasodilatadores/uso terapêuticoAssuntos
Recém-Nascido Prematuro/crescimento & desenvolvimento , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologia , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso/crescimento & desenvolvimento , Pulmão/crescimento & desenvolvimento , Pulmão/fisiopatologia , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Fatores de TempoRESUMO
Studies of the antimicrobial activity of neutrophil defensins have mostly been carried out in microbiological media, and their effects on the host defense in physiological conditions are unclear. We examined 1) the antibacterial activity of defensins in physiological media with and without lung tissue present, 2) the effect of defensins on hydrogen peroxide (H(2)O(2)) production by lung tissue that had been exposed to bacteria, and 3) the effect of diphenyleneiodonium (DPI), an inhibitor of reactive oxygen species formation, on the antibacterial activity of defensins in the presence of lung tissue. Defensins were incubated with Escherichia coli or Pseudomonas aeruginosa in the absence or presence of primary cultured mouse lung explants. Defensins reduced bacterial counts by approximately 65-fold and approximately 25-fold, respectively, at 48 h; bacterial counts were further decreased by approximately 600-fold and approximately 12,000-fold, respectively, in the presence of lung tissue. Defensins induced H(2)O(2) production by lung tissue, and the rate of killing of E. coli by defensins was reduced by approximately 2,500-fold in the presence of 10 microM DPI. We conclude that defensins exert a significant antimicrobial effect under physiological conditions and that this effect is enhanced in the presence of lung tissue by a mechanism that involves the production of reactive oxygen species.
Assuntos
Defensinas/farmacologia , Pulmão/efeitos dos fármacos , Neutrófilos/imunologia , Animais , Antibacterianos/farmacologia , Contagem de Colônia Microbiana , Técnicas de Cultura , Fibrose Cística/metabolismo , Defensinas/isolamento & purificação , Eletroforese em Gel de Poliacrilamida , Inibidores Enzimáticos/farmacologia , Escherichia coli/fisiologia , Humanos , Peróxido de Hidrogênio/metabolismo , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Oniocompostos/farmacologia , Oxidantes/biossíntese , Pseudomonas aeruginosa/fisiologiaRESUMO
This study compared pathophysiological and biochemical indexes of acute lung injury in a saline-lavaged rabbit model with different ventilatory strategies: a control group consisting of moderate tidal volume (V(T)) (10-12 ml/kg) and low positive end-expiratory pressure (PEEP) (4-5 cmH(2)O); and three protective groups: 1) low V(T) (5-6 ml/kg) high PEEP, 2-3 cmH(2)O greater than the lower inflection point; 2) low V(T) (5-6 ml/kg), high PEEP (8-10 cmH(2)O); and 3) high-frequency oscillatory ventilation (HFOV). The strategy using PEEP > inflection point resulted in hypotension and barotrauma. HFOV attenuated the decrease in pulmonary compliance, the lung inflammation assessed by polymorphonuclear leukocyte infiltration and tumor necrosis factor-alpha concentration in the alveolar space, and pathological changes of the small airways and alveoli. Conventional mechanical ventilation using lung protection strategies (low V(T) high PEEP) only attenuated the decrease in oxygenation and pulmonary compliance. Therefore, HFOV may be a preferable option as a lung protection strategy.
Assuntos
Ventilação de Alta Frequência , Pulmão/fisiologia , Animais , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Pulmão/citologia , Complacência Pulmonar/fisiologia , Masculino , Neutrófilos/fisiologia , Respiração com Pressão Positiva , Alvéolos Pulmonares/patologia , Troca Gasosa Pulmonar/fisiologia , Coelhos , Testes de Função Respiratória , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
Mechanical ventilation of the lung is an essential but potentially harmful therapeutic intervention for patients with acute respiratory distress syndrome. The objective of the current study was to establish and characterize an isolated mouse lung model to study the harmful effects of mechanical ventilation. Lungs were isolated from BalbC mice and randomized to either a nonventilated group, a conventionally ventilated group (tidal volume 7 mL x kg(-1), 4 cm positive endexpiratory pressure (PEEP)) or an injuriously ventilated group (20 mL x kg(-1), 0 cm PEEP). Lungs were subsequently analysed for lung compliance, morphology, surfactant composition and inflammatory cytokines. Injurious ventilation resulted in significant lung dysfunction, which was associated with a significant increase in pulmonary surfactant, and surfactant small aggregates compared to the other two groups. Injurious ventilation also led to a significantly increased concentration of interleukin-6 and tumour necrosis factor-a in the lavage. It was concluded that the injurious effects of mechanical ventilation can effectively be studied in isolated mouse lung, which offers the potential of studying genetically altered animals. It was also concluded that in this model, the lung injury is, in part, mediated by the surfactant system and the release of inflammatory mediators.
Assuntos
Interleucina-6/biossíntese , Pulmão/imunologia , Pulmão/patologia , Respiração com Pressão Positiva , Surfactantes Pulmonares/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Animais , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
As in other areas of medicine, the specialty of critical care medicine, which has made important contributions in the pathophysiology of critical illness, is facing challenges that must be recognized and addressed in the current century. In this review, we argue that the skill set required to adequately treat critically ill patients will also require knowledge of molecular biology for better diagnosis and treatment. The foundations of molecular biology and genetics are essential for the understanding of the mechanisms of disease. Incorporating molecular biology techniques in the research arsenal of the intensivist will provide the opportunity to dissect out and define the reversible and irreversible intracellular processes giving rise to the major causes of mortality in intensive care units. Two historical paradigms, the cardiopulmonary resuscitation and polymerase chain reaction, summarize how critical care medicine began, and how it could mature in the years to come.
Assuntos
Cuidados Críticos/tendências , Estado Terminal , HumanosRESUMO
STUDY OBJECTIVES: The fractional concentration of exhaled nitric oxide (FENO) is a marker of asthmatic airway inflammation. We determined the dose response and the reproducibility of the FENO fall following inhaled beclomethasone dipropionate (iBDP) therapy in nonsteroid-treated asthmatic patients. STUDY DESIGN: Study A: For four 1-week periods (period 1 to period 4), the following regimens were administered in sequential order to 15 nonsteroid-treated asthmatic patients: period 1, placebo; period 2, 100 microg/d of iBDP; period 3, 400 microg/D of iBDP; and period 4, 800 microg/d of iBDP. Spirometry, FENO, and provocative concentration of methacholine resulting in a 20% fall in FEV(1) (PC(20)) were measured at each of five visits (visit 1 to visit 5). Study B: During four periods, 12 nonsteroid-treated asthmatic patients received placebo treatment for 7 days (period 1), 200 microg/d of iBDP for 14 days (period 2), washout on placebo treatment until the FENO was within 15% of baseline (period 3), and 200 microg/d of iBDP for 14 days (period 4). RESULTS: Study A: Mean FEV(1) rose progressively from 3.10 L (visit 1) to 3.41 L (visit 5; p = 0.001). All iBDP doses caused a significant FEV(1) rise compared to placebo treatment, but with no significant separation of doses using FEV(1). FENO geometric mean (95% confidence limits) fell progressively from 103.5 parts per billion (ppb) (78.5 to 136.7) to 37.4 ppb (29.1 to 48.0) from visit 1 to visit 5 (p = 0.001). All doses of iBDP resulted in a significant change in FENO from placebo treatment, but with significant separation of only the 100-microg and 800-microg doses by FENO. Geometric mean (95% confidence limits) PC(20) rose progressively from 0.01 mg/mL (0.00 to 0.19) to 0.48 mg/mL (0.01 to 8.1) from visit 1 to visit 5 (p = 0.002). All doses of iBDP resulted in a significant change in PC(20) from baseline or placebo treatment, but with no significant separation of active iBDP doses using PC(20). Study B: FENO fell from 111.56 ppb (80.3 to 155.1) to 66.3 ppb (49.2 to 89.5; p < 0.001) from period 1 to period 2, and from 110.2 ppb (79.3 to 153.1) to 61.7 ppb (42.9 to 88.8; p < 0.001) from period 3 to period 4. There were no significant differences between FENO in period 1 and period 3 (p = 0.83) or between period 2 and period 4 (p = 0.220). CONCLUSIONS: FENO was superior to FEV(1) and PC(20) in separating doses of iBDP. The fall in FENO after two identical administrations of iBDP separated by placebo washout was highly reproducible.
Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Beclometasona/administração & dosagem , Óxido Nítrico/metabolismo , Administração por Inalação , Adolescente , Adulto , Asma/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Estudos Prospectivos , Reprodutibilidade dos TestesRESUMO
Our laboratory has previously shown decreased mortality rates and the attenuation of lung injury in rats exposed to heat stress (H) 18 h prior to induction of sepsis. In the present study, we examined the hypothesis that heat stress would protect lungs against ventilator-induced lung injury. Male Sprague-Dawley rats were anesthetized and randomly allocated to receive either sham treatment or exposure to heat (rectal temperature 41 degrees C, for 15 min). The lungs were harvested 18 h later, a pressure-volume (P- V) curve was constructed, and the lungs were either lavaged for cytokine and surfactant analyses (preventilation data) or were mechanically ventilated with VT 40 ml/kg in a warmed, humidified chamber. After 2 h of mechanical ventilation, another P-V curve was constructed and the lungs were lavaged for cytokine and surfactant analyses (postventilation data). Mechanical ventilation in control lungs produced a 47% decrease in chord compliance, an increase in lung lavage levels of tumor necrosis factor (TNF)-alpha (722 +/- 306 pg/ml), interleukin (IL)-1beta (902 +/- 322 pg/ml), and macrophage inflammatory protein-2 (MIP-2) (363 +/- 104 pg/ml) as compared with low levels of cytokines detected in preventilation data, and no change in percentage of surfactant large aggregates (LA). In contrast, in mechanically ventilated lungs from animals that were exposed to heat stress we observed a smaller decrease in chord compliance (17%), a significant attenuation in cytokine levels (TNF-alpha 233 +/- 119 pg/ml; IL-1beta 124 +/- 53 pg/ml; MIP-2 73 +/- 52 pg/ml; p < 0.05) and a significant increase in percentage LA compared with control animals. We conclude that exposing animals to heat stress confers protection against the effects of an injurious form of mechanical ventilation, by a mechanism that may involve attenuation of cytokines and preservation of some surfactant properties.