Showing papers in "American Journal of Respiratory and Critical Care Medicine in 2002"
TL;DR: Evidence from methodologically strong cohort studies indicates that undiagnosed obstructive sleep apnea, with or without symptoms, is independently associated with increased likelihood of hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life.
Abstract: Population-based epidemiologic studies have uncovered the high prevalence and wide severity spectrum of undiagnosed obstructive sleep apnea, and have consistently found that even mild obstructive sleep apnea is associated with significant morbidity. Evidence from methodologically strong cohort studies indicates that undiagnosed obstructive sleep apnea, with or without symptoms, is independently associated with increased likelihood of hypertension, cardiovascular disease, stroke, daytime sleepiness, motor vehicle accidents, and diminished quality of life. Strategies to decrease the high prevalence and associated morbidity of obstructive sleep apnea are critically needed. The reduction or elimination of risk factors through public health initiatives with clinical support holds promise. Potentially modifiable risk factors considered in this review include overweight and obesity, alcohol, smoking, nasal congestion, and estrogen depletion in menopause. Data suggest that obstructive sleep apnea is associated with all these factors, but at present the only intervention strategy supported with adequate evidence is weight loss. A focus on weight control is especially important given the expanding epidemic of overweight and obesity in the United States. Primary care providers will be central to clinical approaches for addressing the burden and the development of cost-effective case-finding strategies and feasible treatment for mild obstructive sleep apnea warrants high priority.
4,086 citations
TL;DR: The Diagnostic Process Is Dynamic Clinical Evaluation Radiological Evaluation Role of Surgical Lung Biopsy Unclassifiable Interstitial Pneumonia Bronchoalveolar Lavage Fluid Evaluation Idiopathic Pulmonary Fibrosis.
Abstract: Executive Summary Objectives Participants Evidence Validation Key Messages Introduction Rationale for a Change in the Approach to Classification of Idiopathic Interstitial Pneumonias Development of a New Classification of Idiopathic Interstitial Pneumonia Current Classification of IIP New ATS/ERS Classification Principles Guiding the Assessment of Patients with Idiopathic Interstitial Pneumonias The Diagnostic Process Is Dynamic Clinical Evaluation Radiological Evaluation Role of Surgical Lung Biopsy Unclassifiable Interstitial Pneumonia Bronchoalveolar Lavage Fluid Evaluation Idiopathic Pulmonary Fibrosis Clinical Features Radiologic Features Histologic Features IPF: Areas of Uncertainty Nonspecific Interstitial Pneumonia Clinical Features Radiologic Features Histologic Features NSIP: Areas of Uncertainty Cryptogenic Organizing Pneumonia Clinical Features Radiologic Features Histologic Features COP: Areas of Uncertainty Acute Interstitial Pneumonia Clinical Features Radiologic Features Histologic Features AIP: Areas of Uncertainty Respiratory Bronchiolitis-Associated Interstitial Lung Disease Clinical Features Radiologic Features Histologic Features RB-ILD: Areas of Uncertainty Desquamative Interstitial Pneumonia Clinical Features Radiologic Features Histologic Features DIP: Areas of Uncertainty Lymphoid Interstitial Pneumonia Clinical Features Radiologic Features Histologic Features LIP: Areas of Uncertainty References Appendix
3,591 citations
TL;DR: RASS has high reliability and validity in medical and surgical, ventilated and nonventilated, and sedated and nonsedated adult ICU patients and is described as logical, easy to administer, and readily recalled.
Abstract: Sedative medications are widely used in intensive care unit (ICU) patients. Structured assessment of sedation and agitation is useful to titrate sedative medications and to evaluate agitated behavior, yet existing sedation scales have limitations. We measured inter-rater reliability and validity of a new 10-level (+4 “combative” to −5 “unarousable”) scale, the Richmond Agitation–Sedation Scale (RASS), in two phases. In phase 1, we demonstrated excellent (r = 0.956, lower 90% confidence limit = 0.948; κ = 0.73, 95% confidence interval = 0.71, 0.75) inter-rater reliability among five investigators (two physicians, two nurses, and one pharmacist) in adult ICU patient encounters (n = 192). Robust inter-rater reliability (r = 0.922–0.983) (κ = 0.64–0.82) was demonstrated for patients from medical, surgical, cardiac surgery, coronary, and neuroscience ICUs, patients with and without mechanical ventilation, and patients with and without sedative medications. In validity testing, RASS correlated highly (r = 0.93)...
2,784 citations
TL;DR: Appropriate antimicrobial treatment of patients with VAP significantly improves outcome, more rapid identification of infected patients and accurate selection of antimicrobial agents represent important clinical goals.
Abstract: Ventilator-associated pneumonia (VAP) continues to complicate the course of 8 to 28% of patients receiving mechanical ventilation (MV). In contrast to infections of more frequently involved organs (e.g., urinary tract and skin), for which mortality is low, ranging from 1 to 4%, the mortality rate for VAP ranges from 24 to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens. The predominant organisms responsible for infection are Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacteriaceae, but etiologic agents widely differ according to the population of patients in an intensive care unit, duration of hospital stay, and prior antimicrobial therapy. Because appropriate antimicrobial treatment of patients with VAP significantly improves outcome, more rapid identification of infected patients and accurate selection of antimicrobial agents represent important clinical goals. Our personal bias is that using bronchoscopic techniques to obtain protected brush and bronchoalveolar lavage specimens from the affected area in the lung permits physicians to devise a therapeutic strategy that is superior to one based only on clinical evaluation. When fiberoptic bronchoscopy is not available to physicians treating patients clinically suspected of having VAP, we recommend using either a simplified nonbronchoscopic diagnostic procedure or following a strategy in which decisions regarding antibiotic therapy are based on a clinical score constructed from seven variables. Selection of the initial antimicrobial therapy should be based on predominant flora responsible for VAP at each institution, clinical setting, information provided by direct examination of pulmonary secretions, and intrinsic antibacterial activities of antimicrobial agents and their pharmacokinetic characteristics. Further trials will be needed to clarify the optimal duration of treatment and the circumstances in which monotherapy can be safely used.
2,535 citations
TL;DR: Chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension and significantly improved indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics.
Abstract: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective. However, this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis, thromboembolism, or syncope. Treprostinil, a stable prostacyclin analogue, can be administered by a continuous subcutaneous infusion, avoiding these risks. We conducted a 12-week, double-blind, placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension, either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts. Exercise capacity improved with treprostinil and was unchanged with placebo; the between treatment group difference in median six-minute walking distance was 16 m (p = 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology. Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. The most common side effect attributed to treprostinil was infusion site pain (85%) leading to premature discontinuation from the study in 8% of patients. Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage. We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension.
1,340 citations
TL;DR: In conclusion, microvascular blood flow alterations are frequent in patients with sepsis and are more severe in Patients with a worse outcome.
Abstract: Microvascular blood flow alterations are frequent in animal models of sepsis and may impair tissue oxygenation. We hypothesized that alterations of the microcirculation are present in patients with sepsis. We used an orthogonal polarization spectral imaging technique to investigate the sublingual microcirculation in 10 healthy volunteers, 16 patients before cardiac surgery, 10 acutely ill patients without sepsis (intensive care unit control subjects), and 50 patients with severe sepsis. The effects of topical application of acetylcholine (10(-2) M) were tested in 11 patients with sepsis. In each subject, five to seven sublingual areas were recorded and analyzed semiquantitatively. Data were analyzed with nonparametric tests and are presented as medians (25th-75th percentiles). No significant difference in microvascular blood flow was observed between healthy volunteers and patients before cardiac surgery or intensive care unit control subjects. The density of all vessels was significantly reduced in patients with severe sepsis (4.5 [4.2-5.2] versus 5.4 [5.4-6.3]/mm in volunteers, p < 0.01). The proportion of perfused small (< 20 microm) vessels was reduced in patients with sepsis (48 [33-61] versus 90 [89-92]% in volunteers, p < 0.001). These alterations were more severe in nonsurvivors. The topical application of acetylcholine totally reversed these alterations. In conclusion, microvascular blood flow alterations are frequent in patients with sepsis and are more severe in patients with a worse outcome.
1,304 citations
TL;DR: The findings suggest that OSA is independently associated with insulin resistance, and its role in the atherogenic potential of sleep disordered breathing is worthy of further exploration.
Abstract: Epidemiological studies have implicated obstructive sleep apnea (OSA) as an independent comorbid factor in cardiovascular and cerebrovascular diseases. It is postulated that recurrent episodes of occlusion of upper airways during sleep result in pathophysiological changes that may predispose to vascular diseases. Insulin resistance is a known risk factor for atherosclerosis, and we postulate that OSA represents a stress that promotes insulin resistance, hence atherogenesis. This study investigated the relationship between sleep-disordered breathing and insulin resistance, indicated by fasting serum insulin level and insulin resistance index based on the homeostasis model assessment method (HOMA-IR). A total of 270 consecutive subjects (197 male) who were referred for polysomnography and who did not have known diabetes mellitus were included, and 185 were documented to have OSA defined as an apnea–hypopnea index (AHI) ⩾ 5. OSA subjects were more insulin resistant, as indicated by higher levels of fasting s...
1,188 citations
TL;DR: Increasing AHI was associated with worsening insulin resistance independent of obesity and Multivariable linear regression analyses revealed that sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.
Abstract: Sleep-disordered breathing is a prevalent condition associated with impairment of daytime function and may predispose individuals to metabolic abnormalities independent of obesity. The primary objective of this study was to determine the metabolic consequences and community prevalence of sleep-disordered breathing in mildly obese, but otherwise healthy, individuals. One hundred and fifty healthy men, without diabetes or cardiopulmonary disease, were recruited from the community. Measurements included polysomnography, a multiple sleep latency test, an oral glucose tolerance test, determination of body fat by hydrodensitometry, and fasting insulin and lipids. The prevalence of sleep-disordered breathing, depending on the apnea-hypopnea index (AHI) cutoff, ranged from 40 to 60%. After adjusting for body mass index (BMI) and percent body fat, an AHI gt-or-equal, slanted 5 events/h was associated with an increased risk of having impaired or diabetic glucose tolerance (odds ratio, 2.15; 95% CI, 1.05-4.38). The impairment in glucose tolerance was related to the severity of oxygen desaturation (DeltaSa(O(2))) associated with sleep-disordered breathing. For a 4% decrease in oxygen saturation, the associated odds ratio for worsening glucose tolerance was 1.99 (95% CI, 1.11 to 3.56) after adjusting for percent body fat, BMI, and AHI. Multivariable linear regression analyses revealed that increasing AHI was associated with worsening insulin resistance independent of obesity. Thus, sleep-disordered breathing is a prevalent condition in mildly obese men and is independently associated with glucose intolerance and insulin resistance.
926 citations
TL;DR: One of the subunits of the phagocyte NAD PH oxidase is now recognized as a member of a family of NADPH oxidases, or NOX, present in cells other than phagocytes, present at the plasma membrane from resident plasma membrane and cytosolic protein components.
Abstract: Phagocytes such as neutrophils and macrophages produce reactive oxygen species (ROS) during phagocytosis or stimulation with a wide variety of agents through activation of nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase that is assembled at the plasma membrane from resident plasma membrane and cytosolic protein components. One of the subunits of the phagocyte NADPH oxidase is now recognized as a member of a family of NADPH oxidases, or NOX, present in cells other than phagocytes. Physiologic generation of ROS has been implicated in a variety of physiologic responses from transcriptional activation to cell proliferation and apoptosis. The increase in superoxide and hydrogen peroxide (H2O2) that results from stimulation of the NADPH oxidase is transient, in part due to the presence of the antioxidant enzymes, which return their concentrations to the prestimulation steady state level. Thus, the antioxidant enzymes may function in the “turn-off” phase of signal transduction by ROS. During ...
846 citations
TL;DR: It is concluded that the risk of developing CVD is increased in middle-aged OSA subjects independently of age, BMI, SBP, diastolic blood pressure, DBP, and smoking.
Abstract: The incidence of a cardiovascular disease (CVD) was explored in a consecutive sleep clinic cohort of 182 middle-aged men (mean age, 46.8 +/- 9.3; range, 30-69 years in 1991) with or without obstructive sleep apnea (OSA). All subjects were free of hypertension or other CVD, pulmonary disease, diabetes mellitus, psychiatric disorder, alcohol dependency, as well as malignancy at baseline. Data were collected via the Swedish Hospital Discharge Register covering a 7-year period before December 31, 1998, as well as questionnaires. Effectiveness of OSA treatment initiated during the period as well as age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) at baseline, and smoking habits were controlled. The incidence of at least one CVD was observed in 22 of 60 (36.7%) cases with OSA (overnight oxygen desaturations of 30 or more) compared with in 8 of 122 (6.6%) subjects without OSA (p < 0.001). In a multiple logistic regression model, significant predictors of CVD incidence were OSA at baseline (odds ratio [OR] 4.9; 95% confidence interval [CI], 1.8-13.6) and age (OR 23.4; 95% CI, 2.7-197.5) after adjustment for BMI, SBP, and DBP at baseline. In the OSA group, CVD incidence was observed in 21 of 37 (56.8%) incompletely treated cases compared with in 1 of 15 (6.7%) efficiently treated subjects (p < 0.001). In a multiple regression analysis, efficient treatment was associated with a significant risk reduction for CVD incidence (OR 0.1; 95% CI, 0.0-0.7) after adjustment for age and SBP at baseline in the OSA subjects. We conclude that the risk of developing CVD is increased in middle-aged OSA subjects independently of age, BMI, SBP, DBP, and smoking. Furthermore, efficient treatment of OSA reduces the excess CVD risk and may be considered also in relatively mild OSA without regard to daytime sleepiness.
811 citations
TL;DR: It is found that a reduction in midthigh muscle cross-sectional area obtained by CT scan is a better predictor of mortality than BMI, and MTCSA had a strong impact on mortality in patients with an FEV(1) < 50% predicted.
Abstract: This study was undertaken to test the hypothesis that a reduction in midthigh muscle cross-sectional area obtained by CT scan (MTCSACT) is a better predictor of mortality in chronic obstructive pulmonary disease (COPD) than low body mass index (BMI). We also wished to evaluate whether anthropometric measurements could be used to estimate MTCSACT. One hundred forty-two patients with COPD (age = 65 ± 9 years, mean ± SD, 26 F, BMI = 26 ± 6 kg/m2, FEV1 = 42 ± 16% predicted) were recruited from September 1995 to April 2000 with a mean follow-up of 41 ± 18 months. The primary end-point was all-cause mortality during the study period. A Cox proportional hazards regression model was used to predict mortality using the following independent variables: age, sex, daily use of corticosteroid, FEV1, DlCO, BMI, thigh circumference, MTCSACT, peak exercise workrate, PaO2, and PaCO2. Only MTCSACT and FEV1 were found to be significant predictors of mortality (p = 0.0008 and p = 0.01, respectively). A second analysis was al...
TL;DR: It is concluded that NSIP is the histopathologic pattern in most patients with FASSc, however, outcome is linked more strongly to disease severity at presentation and serial DL(CO) trends than to histopathological findings.
Abstract: Fibrosing alveolitis associated with systemic sclerosis (FASSc) has a better prognosis than idiopathic pulmonary fibrosis. In view of recent reports that idiopathic nonspecific interstitial pneumonia (NSIP) has a better prognosis than idiopathic usual interstitial pneumonia (UIP), we classified histologic appearances of surgical lung biopsies performed in 80 patients with FASSc. NSIP (n = 62, 77.5%), subcategorized as cellular NSIP (n = 15) and fibrotic NSIP (n = 47) was much more prevalent than UIP (n = 6), end-stage lung disease (ESL, n = 6), or other patterns (n = 6). There were 25 deaths (NSIP 16/62, 26%; UIP/ESL 6/12, 50%). Five-year survival differed little between NSIP (91%) and UIP/ESL (82%); mortality was associated with lower initial carbon monoxide diffusing capacity (DL(CO)) and FVC levels (p = 0.004 and p = 0.007, respectively). Survival and serial FVC and DL(CO) trends did not differ between cellular and fibrotic NSIP. Increased mortality in NSIP was associated with lower initial DL(CO) levels (p = 0.04), higher BAL eosinophil levels (p = 0.03), and deterioration in DL(CO) levels during the next 3 years (p < 0.005). We conclude that NSIP is the histopathologic pattern in most patients with FASSc. However, outcome is linked more strongly to disease severity at presentation and serial DL(CO) trends than to histopathologic findings.
TL;DR: It is found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects.
Abstract: Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free radicals and adhesion molecules were implicated in the pathogenesis of atherosclerosis leading to cardiovascular disorders. Therefore, we investigated the link between CD15, CD11c, CD11b, and CD64 expression on leukocytes and their ability to generate reactive oxygen species (ROS) in patients with OSA and control volunteers. We also studied the effects of hypoxia in vitro on monocytes from control subjects and the ability of monocytes from both groups to adhere to human endothelial cells in culture. The effect of nasal continuous positive airway pressure (nCPAP) treatment was studied as well. We found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Furthermore, nCPAP treatment was associated with downregulation of CD15 and CD11c monocyte expression and decreased basal ROS production in CD11c+ monocytes. Monocyte adherence to endothelial cells decreased as well. Our findings provide one of the possible mechanisms for explaining the high rate of cardiovascular morbidity in patients with sleep apnea.
TL;DR: Differences in lung function between treatment groups persisted; smoking intervention participants had less decline in FEV(1) than usual care participants and smoking habits by original LHS treatment groups tended to converge.
Abstract: Eleven years after Lung Health Study (LHS) entry, we performed spirometry in 774% of surviving participants who enrolled in a long-term follow-up study Those not enrolling tended to be younger male heavy smokers who continued to smoke during the LHS Their initial LHS lung function, after adjustment for these factors, did not differ from that of enrollees Smoking habits by original LHS treatment groups (smoking intervention vs usual care) tended to converge, but 93% of participants who were abstinent throughout the LHS were still abstinent at 11 years Differences in lung function between treatment groups persisted; smoking intervention participants had less decline in FEV(1) than usual care participants Men who quit at the beginning of the LHS had an FEV(1) rate of decline of 302 ml/year, whereas women who quit declined at 215 ml/year Men continuing to smoke throughout the 11 years declined by 661 ml/year, and women continuing to smoke declined by 542 ml/year When decline in FEV(1) was expressed as a percentage of predicted normal value, no significant sex-based difference was apparent among continuing smokers At 11 years, 38% of continuing smokers had an FEV(1) less than 60% of the predicted normal value compared with 10% of sustained quitters
TL;DR: Positive associations with air pollutants are indicated for wheezing, physician-diagnosed asthma, ear/nose/throat infections, and flu/serious colds, but no associations were observed for the other health outcomes analyzed.
Abstract: Despite the important contribution of traffic sources to urban air quality, relatively few studies have evaluated the effects of traffic-related air pollution on health, such as its influence on the development of asthma and other childhood respiratory diseases. We examined the relationship between traffic-related air pollution and the development of asthmatic/allergic symptoms and respiratory infections in a birth cohort (n ∼ 4,000) study in The Netherlands. A validated model was used to assign outdoor concentrations of traffic-related air pollutants (nitrogen dioxide, particulate matter less than 2.5 μm in aerodynamic diameter, and “soot”) at the home of each subject of the cohort. Questionnaire-derived data on wheezing, dry nighttime cough, ear, nose, and throat infections, skin rash, and physician-diagnosed asthma, bronchitis, influenza, and eczema at 2 years of age were analyzed in relation to air pollutants. Adjusted odds ratios for wheezing, physician-diagnosed asthma, ear/nose/throat infections, a...
TL;DR: Low-radiation-dose spiral computed tomography and sputum cytology in screening for lung cancer in 1,520 individuals aged 50 yr or older who had smoked 20 pack-years or more is evaluated.
Abstract: Studies suggest that screening with spiral computed tomography can detect lung cancers at a smaller size and earlier stage than chest radiography can. To evaluate low-radiation-dose spiral computed tomography and sputum cytology in screening for lung cancer, we enrolled 1,520 individuals aged 50 yr or older who had smoked 20 pack-years or more in a prospective cohort study. One year after baseline scanning, 2,244 uncalcified lung nodules were identified in 1,000 participants (66%). Twenty-five cases of lung cancer were diagnosed (22 prevalence, 3 incidence). Computed tomography alone detected 23 cases; sputum cytology alone detected 2 cases. Cell types were: squamous cell, 6; adenocarcinoma or bronchioalveolar, 15; large cell, 1; small cell, 3. Twenty-two patients underwent curative surgical resection. Seven benign nodules were resected. The mean size of the non-small cell cancers detected by computed tomography was 17 mm (median, 13 mm). The postsurgical stage was IA, 13; IB, 1; IIA, 5; IIB, 1; IIIA, 2; limited, 3. Twelve (57%) of the 21 non-small cell cancers detected by computed tomography were stage IA at diagnosis. Computed tomography can detect early-stage lung cancers. The rate of benign nodule detection is high.
TL;DR: There has been rapid progress toward elucidation of the molecular mechanisms underlying both the congenital and acquired forms of pulmonary alveolar proteinosis, following serendipitous discoveries in gene-targeted mice lacking granulocyte-macrophage colony-stimulating factor.
Abstract: Pulmonary alveolar proteinosis is a rare clinical syndrome that was first described in 1958. Subsequently, over 240 case reports and small series have described at least 410 cases in the literature. Characterized by the alveolar accumulation of surfactant components with minimal interstitial inflammation or fibrosis, pulmonary alveolar proteinosis has a variable clinical course ranging from spontaneous resolution to death with pneumonia or respiratory failure. The most effective proven treatment—whole lung lavage—was described soon after the first recognition of this disease. In the last 8 years, there has been rapid progress toward elucidation of the molecular mechanisms underlying both the congenital and acquired forms of pulmonary alveolar proteinosis, following serendipitous discoveries in gene-targeted mice lacking granulocyte-macrophage colony-stimulating factor (GM-CSF). Impairment of surfactant clearance by alveolar macrophages as a result of inhibition of the action of GM-CSF by blocking autoanti...
TL;DR: It is shown that an SFTPC mutation segregates with the pulmonary fibrosis phenotype in this kindred and may cause type II cellular injury.
Abstract: Familial pulmonary fibrosis is a heterogeneous group of interstitial lung diseases of unknown cause that is associated with multiple pathologic subsets Mutations in the surfactant protein C (SP-C) gene (SFTPC) are associated with familial desquamative and nonspecific interstitial pneumonitis Genetic studies in familial usual interstitial pneumonitis have been inconclusive Using a candidate gene approach, we found a heterozygous exon 5 + 128 T→A transversion of SFTPC in a large familial pulmonary fibrosis kindred, including adults with usual interstitial pneumonitis and children with cellular nonspecific interstitial pneumonitis The mutation is predicted to substitute a glutamine for a conserved leucine residue and may hinder processing of SP-C precursor protein SP-C precursor protein displayed aberrant subcellular localization by immunostaining Electron microscopy of affected lung revealed alveolar type II cell atypia, with numerous abnormal lamellar bodies Mouse lung epithelial cells transfected w
TL;DR: It is concluded that high-frequency oscillation is a safe and effective mode of ventilation for the treatment of acute respiratory distress syndrome in adults.
Abstract: Observational studies of high-frequency oscillatory ventilation in adults with the acute respiratory distress syndrome have demonstrated improvements in oxygenation. We designed a multicenter, randomized, controlled trial comparing the safety and effectiveness of high-frequency oscillatory ventilation with conventional ventilation in adults with acute respiratory distress syndrome; 148 adults with acute respiratory distress syndrome (Pa O2 /fraction of inspired oxygen � 200 mm Hg on 10 or more cm H 2 O positive end-expiratory pressure) were randomized to high-frequency oscillatory ventilation (n � 75) or conventional ventilation (n � 73). Applied mean airway pressure was significantly higher in the highfrequency oscillation group compared with the conventional ventilation group throughout the first 72 hours (p � 0.0001). The high-frequency oscillation group showed early (less than 16 hours) improvement in Pa O2 /fraction of inspired oxygen compared with the conventional ventilation group (p � 0.008); however, this difference did not persist beyond 24 hours. Oxygenation index decreased similarly over the first 72 hours in both groups. Thirty-day mortality was 37% in the high-frequency oscillation group and was 52% in the conventional ventilation group (p � 0.102). The percentage of patients alive without mechanical ventilation at Day 30 was 36% and 31% in the high-frequency oscillation and conventional ventilation groups, respectively (p � 0.686). There were no significant differences in hemodynamic variables, oxygenation failure, ventilation failure, barotraumas, or mucus plugging between treatment groups. We conclude that high-frequency oscillation is a safe and effective mode of ventilation for the treatment of acute respiratory distress syndrome in adults.
TL;DR: It is concluded that in the hospitalized elderly, CAP is a common and frequently fatal disease that often requires intensive care unit admission and mechanical ventilation and consumes considerable health care resources.
Abstract: Community-acquired pneumonia (CAP) is a frequent cause of hospital admission and death among elderly patients, but there is little information on age- and sex-specific incidence, patterns of care (intensive care unit admission and mechanical ventilation), resource use (length of stay and hospital costs), and outcome (mortality). We conducted an observational cohort study of all Medicare recipients, aged 65 years or older, hospitalized in nonfederal U.S. hospitals in 1997, who met ICD-9-CM-based criteria for CAP. We identified 623,718 hospital admissions for CAP (18.3 per 1,000 population > or = 65 years), of which 26,476 (4.3%) were from nursing homes and of which 66,045 (10.6%) died. The incidence rose five-fold and mortality doubled as age increased from 65-69 to older than 90 years. Men had a higher mortality, both unadjusted (odds ratio [OR]: 1.21 [95% CI: 1.19-1.23]) and adjusted for age, location before admission, underlying comorbidity, and microbiologic etiology (OR: 1.15 [95% CI: 1.13-1.17]). Mean hospital length of stay and costs per hospital admission were 7.6 days and $6,949. For those admitted to the intensive care unit (22.4%) and for those receiving mechanical ventilation (7.2%), mean length of stay and costs were 11.3 days and $14,294, and 15.7 days and $23,961, respectively. Overall hospital costs were $4.4 billion (6.3% of the expenditure in the elderly for acute hospital care), of which $2.1 billion was incurred by cases managed in intensive care units. We conclude that in the hospitalized elderly, CAP is a common and frequently fatal disease that often requires intensive care unit admission and mechanical ventilation and consumes considerable health care resources. The sex differences are of concern and require further investigation.
TL;DR: When all participants were considered and smoking status considered as a time-dependent covariate, smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary artery disease.
Abstract: This report deals with deaths and hospitalizations during the 5-year Lung Health Study, as documented by examination of appropriate records. There were 149 deaths (2.5%) during the study, caused largely by lung cancer and cardiovascular disease, particularly coronary heart disease. A total of 12.8% of participants were hospitalized, with cancer, cardiovascular disease, and nonmalignant respiratory disease accounting for 75% of hospitalizations. There were no significant differences among the original treatment groups for all-cause mortality, lung cancer, or hospitalizations for respiratory disease. Deaths and hospitalizations for cardiovascular disease and coronary artery disease were more common in the smoking intervention plus Atrovent inhaler (SI-A) group, which received ipratropium bromide, than in the smoking intervention plus placebo inhaler (SI-P) group, which received placebo, and the differences approached statistical significance. However, we were unable to find a dose effect, in that differences were not related to self-reported inhaler compliance. In the SI-A group, nine participants were hospitalized for supraventricular tachycardia as compared with two in the SI-P group, and SI-A participants with this condition were unusually compliant with their inhaled medication. When all participants were considered and smoking status considered as a time-dependent covariate, smoking cessation was associated with significant reductions in fatal or nonfatal cardiovascular disease and coronary artery disease.
TL;DR: Diminished regional and often unilateral gray matter loss was apparent in multiple sites of the brain in patients with OSA, including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum, which suggests onset of neural deficits early in the OSA syndrome.
Abstract: Obstructive sleep apnea (OSA) is characterized by repeated occurrences of hypoxic, hypercapnic, and transient blood pressure elevation episodes that may damage or alter neural structures. Underdeveloped structures or pre-existing damage in brain areas may also contribute to the genesis of the syndrome. Brain morphology in 21 patients with OSA and in 21 control subjects was assessed using high-resolution T1-weighted magnetic resonance imaging. Three-dimensional brain images were obtained with voxels of approximately 1 mm3. Images were spatially normalized and segmented into gray matter, white matter, and cerebrospinal fluid. For each segment, regional volumetric differences were determined relative to age, handedness, and group (patients with OSA versus control subjects), using voxel-based morphometry, with OSA effects weighted by disease severity. A significant age effect on total gray matter was found in control subjects but not in patients with OSA. Diminished regional and often unilateral gray matter l...
TL;DR: Clinical prediction rules for severe CAP do not appear adequately robust to guide clinical care at the current time, and ICU use for CAP is common and expensive but admission rates are variable.
Abstract: Despite careful evaluation of changes in hospital care for community-acquired pneumonia (CAP), little is known about intensive care unit (ICU) use in the treatment of this disease. There are criteria that define CAP as “severe,” but evaluation of their predictive value is limited. We compared characteristics, course, and outcome of inpatients who did (n = 170) and did not (n = 1,169) receive ICU care in the Pneumonia Patient Outcomes Research Team prospective cohort. We also assessed the predictive characteristics of four prediction rules (the original and revised American Thoracic Society criteria, the British Thoracic Society criteria, and the Pneumonia Severity Index [PSI]) for ICU admission, mechanical ventilation, medical complications, and death (as proxies for severe CAP). ICU patients were more likely to be admitted from home and had more comorbid conditions. Reasons for ICU admission included respiratory failure (57%), hemodynamic monitoring (32%), and shock (16%). ICU patients incurred longer ho...
TL;DR: It is concluded that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo.
Abstract: This randomized controlled trial examined the benefits of combining an inhaled corticosteroid, fluticasone propionate (F), with an inhaled long-acting beta(2)-agonist, salmeterol (S), to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease (COPD). A total of 691 patients with COPD received the combination of F and S (FSC), S (50 mcg), F (500 mcg), or placebo twice daily via the Diskus device for 24 weeks. A significantly greater increase in predose FEV(1) at the endpoint was observed after FSC (156 ml) compared with S (107 ml, p = 0.012) and placebo (-4 ml, p < 0.0001). A significantly greater increase in 2-hour postdose FEV(1) at the endpoint was observed after treatment with FSC (261 ml) compared with F (138 ml, p < 0.001) and placebo (28 ml, p < 0.001). There were greater improvements in the Transition Dyspnea Index with FSC (2.1) compared with F (1.3, p = 0.033), S (0.9, p < 0.001), and placebo (0.4, p < 0.0001). The incidence of adverse effects (except for an increase in oral candidiasis with FSC and F) was similar among the treatment groups. We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo.
TL;DR: In this article, endothelin-1 (ET1) levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome), and further hypothesized that ET1 levels would be associated with concurrent severity of PH.
Abstract: Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH). Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH.Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure.Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33...
TL;DR: The elevated levels of 4-HNE may play a role in the signaling events in lung inflammation leading to the imbalance of the expression of both proinflammatory mediators and protective antioxidant genes in COPD.
Abstract: Cigarette smoking results in oxidative stress and inflammation in the lungs, which are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). 4-Hydroxy-2-nonenal (4-HNE), a highly reactive diffusible product of lipid peroxidation, is a key mediator of oxidant-induced cell signaling and apoptosis. 4-HNE has a high affinity toward cysteine, histidine, and lysine groups and forms direct protein adducts. We investigated the presence of 4-HNE-modified proteins in lung tissue obtained from subjects with and without COPD. We studied 23 current or ex-smokers with similar smoking histories with COPD (n = 11; FEV(1) 84% predicted) who had undergone lung resection. As 4-HNE and transforming growth factor-beta(1) (TGF-beta(1)) can modulate gamma-glutamylcysteine synthetase (gamma-GCS) mRNA levels in lung cells, we assessed the relations between 4-HNE-modified protein levels, FEV(1), gamma-GCS, and TGF-beta(1). 4-HNE-modified protein levels were elevated in airway and alveolar epithelial cells, endothelial cells, and neutrophils in subjects with COPD, compared with the levels in subjects without COPD (p < 0.01). We also observed a significant inverse correlation between the levels of 4-HNE adducts in alveolar epithelium, airway endothelium, and neutrophils and FEV(1) (p < 0.05) and a positive correlation between 4-HNE adducts and TGF-beta(1) protein and mRNA as well as gamma-GCS mRNA levels in airway and alveolar epithelium (p < 0.01). The elevated levels of 4-HNE may play a role in the signaling events in lung inflammation leading to the imbalance of the expression of both proinflammatory mediators and protective antioxidant genes in COPD.
TL;DR: In patients with COPD and bronchiectasis, the values of pH were significantly correlated with both sputum neutrophilia and oxidative stress, and in patients with moderate asthma, a significant correlation was observed between pH andSputum eosinophilia, total nitrate/nitrite, and oxidative Stress.
Abstract: Endogenous airway acidification, as assessed by pH in expired breath condensate, has been implicated in asthma pathophysiology. We measured pH in breath condensate of patients with inflammatory airway diseases in stable condition and examined its relationship with the inflammatory process (as assessed by differential cell counts in induced sputum), oxidative stress (as assessed by H2O2 and 8-isoprostane), and nitric oxide metabolism (as assessed by total nitrate/nitrite). We studied 40 patients with bronchial asthma (20 with moderate disease, forced expiratory volume in 1 second 60 [10]% SD predicted), 20 patients with bronchiectasis, 20 patients with chronic obstructive pulmonary disease (COPD), and 10 normal subjects. Mean (95% confidence intervals) pH values were significantly lower in patients with COPD and bronchiectasis compared with patients with asthma and control subjects (7.16, 7.09–7.23 and 7.11, 7.04–7.19 versus 7.43, 7.35–7.52 and 7.57, 7.51–7.64, respectively, p < 0.0001). Patients with mode...
TL;DR: Although the incidences of ALI and ARDS are higher and the mortality rates are lower than those reported from studies in other countries, multicenter international studies are required to exclude methodological differences as the cause for this finding.
Abstract: To determine the incidence and 28-d mortality rate for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) using the 1994 American-European Consensus Conference definitions, we prospectively screened every admission to all 21 adult intensive care units in the States of South Australia, Western Australia, and Tasmania (total population older than 15 yr of age estimated as 2,941,137), between October 1 and November 30, 1999. A total of 1,977 admissions were screened of which 168 developed ALI and 148 developed ARDS, which represents a first incidence of 34 and 28 cases per 100,000 per annum, respectively. The respective 28-d mortality rates were 32% and 34%. The most common predisposing factors for ALI were nonpulmonary sepsis (31%) and pneumonia (28%). Although the incidences of ALI and ARDS are higher and the mortality rates are lower than those reported from studies in other countries, multicenter international studies are required to exclude methodological differences as the cause for this finding.
TL;DR: Levels of sTNF-R55, sT NF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with CopD after smoking cessation.
Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by significant chronic inflammation in the pulmonary compartment as well as in the circulation. This study aimed to elucidate the relationship between local and systemic inflammation in smoking-induced COPD by assessing levels of soluble (s) tumor necrosis factor (TNF) receptors, TNF-alpha, and interleukin-8 (IL-8) in induced sputum and in plasma. Sputum induction was performed in 18 subjects with COPD (FEV(1) 56% predicted) and 17 healthy smokers (FEV(1) 99% predicted). Patients with COPD showed significantly higher percentages of neutrophils and levels of sTNF-R55 and IL-8 in sputum as compared with control subjects, whereas sputum sTNF-R75 levels tended to be higher in COPD. Sputum TNF-alpha levels were similar in both groups. When comparing sTNF receptors in sputum and plasma, no direct correlations were found despite elevation of circulating sTNF-R75 levels in patients with COPD. In addition, sputum sTNF receptors were inversely related to the FEV(1) in patients with COPD, whereas circulating sTNF receptors were not, suggesting different regulation of inflammation in the pulmonary and systemic compartment. When subjects were divided according to their current smoking status, levels of sTNF-R55, sTNF-R75, and IL-8 in sputum were significantly elevated in ex-smoking versus currently smoking patients with COPD, suggesting ongoing inflammation in airways and circulation of patients with COPD after smoking cessation.
TL;DR: Data suggest that relative to healthy subjects, patients with moderate-to-severe airways obstruction receive an increased dose from ultrafine particle exposure.
Abstract: Numerous epidemiologic studies have shown associations between exposure to particulate air pollution and acute increases in morbidity and mortality, particularly in persons with chronic obstructive pulmonary disease. The dosimetry of ultrafine particles in the human lung is poorly characterized. We studied the deposition and clearance of an ultrafine technetium-99m–labeled aerosol in 10 patients with chronic obstructive pulmonary disease and in 9 healthy subjects. Particle retention was followed for 2 hours after inhalation and again at 24 hours by γ scintigraphy. Central-to-peripheral ratios indexed airway deposition. Particle accumulation in the liver was examined by quantifying activity below the right lung. The dose rate for an aerosol exposure of 10 μg/m3 was calculated. Patients had a significantly greater dose rate than healthy subjects (2.9 ± 1.0 versus 1.9 ± 0.4 μg/h, p = 0.02). Central-to-peripheral ratios were slightly greater in patients than in healthy subjects (1.11 ± 0.10 versus 1.01 ± 0.11...