Fletcher C, Peto R.
The natural history of chronic airflow obstruction.
Br Med J 1977 Jun 25; 1 (6077): 1645-8.
Ver Abstract                    Texto Completo

A prospective epidemiological study of the early stages of the development of chronic obstructive pulmonary disease was performed on London working men. The findings showed that forced expiratory volume in one second (FEV1) falls gradually over a lifetime, but in most non-smokers and many smokers clinically significant airflow obstruction never develops. In susceptible people, however, smoking causes irreversible obstructive changes. If a susceptible smoker stops smoking he will not recover his lung function, but the average further rates of loss of FEV1 will revert to normal. Therefore, severe or fatal obstructive lung disease could be prevented by screening smokers' lung function in early middle age if those with reduced function could be induced to stop smoking. Infective processes and chronic mucus hypersecretion do not cause chronic airflow obstruction to progress more rapidly. There are thus two largely unrelated disease processes, chronic airflow obstruction and the hypersecretory disorder (including infective processes).

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Pérez-Padilla R, Regalado J, Vedal S, Pare P, Chapela R, Sansores R et al.
Exposure to biomass smoke and chronic airway disease in Mexican women. A case-control study.
Am J Respir Crit Care Med 1996 Sep; 154 (3 Pt 1): 701-6.
Ver Abstract                    Texto Completo

A case-control study was performed in women older than 40 yr of age to evaluate the risk of cooking with traditional wood stoves for chronic bronchitis and chronic airway obstruction (CAO). The subjects were recruited from patients attending a referral chest hospital in Mexico City. We selected 127 patients with chronic bronchitis or CAO, of which 63 had chronic bronchitis alone, 23 had CAO alone (FEV1 less than 75% of predicted), and 41 had both chronic bronchitis and CAO (cases). Four control groups were selected: 83 patients with pulmonary tuberculosis, 100 patients with interstitial lung diseases, 97 patients with ear, nose and throat ailments, and 95 healthy visitors to the hospital (controls). Exposure to wood smoke, assessed as any or none, and as hour-years (years of exposure multiplied by average hours of exposure per day) was significantly higher in cases than in controls. Crude odds ratios for wood smoke exposure were 3.9 (95% CI, 2.0 to 7.6) for chronic bronchitis only, 9.7 (95% CI, 3.7 to 27) for CAO plus chronic bronchitis, and 1.8 (95% CI, 0.7 to 4.7) for CAO only. Differences in exposure to wood smoke persisted after adjusting by stratification and logistic regression for age, income, education, smoking, place of residence, and place of birth. Risk of chronic bronchitis alone and chronic bronchitis with CAO increased linearly with hour-years of cooking with a wood stove; odds ratios for exposure to more than 200 hour-years compared with nonexposed were 15.0 (95% CI, 5.6 to 40) for chronic bronchitis only and 75 (95% CI, 18 to 306) for chronic bronchitis with CAO. The findings support a causal role of domestic wood smoke exposure in chronic bronchitis and chronic airflow obstruction.

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Orozco-Levi M, Garcia-Aymerich J, Villar J, Ramírez-Sarmiento A, Antó JM, Gea J.
Wood smoke exposure and risk of chronic obstructive pulmonary disease.
Eur Respir J 2006 Mar; 27 (3): 542-6.
Ver Abstract                    Texto Completo

It was hypothesised that wood smoke exposure could be a risk factor for chronic obstructive pulmonary disease (COPD) in Spain. The present study was designed as a case-control study of 120 females requiring hospitalisation during 2001-2003 at Hospital del Mar (Barcelona, Spain). Cases were recruited from hospital records as females who had been admitted for an exacerbation of COPD. Controls were obtained from pulmonary function test laboratory consultations prior to a surgical intervention. All patients answered a standardised questionnaire. Exposure to wood or charcoal smoke was strongly associated with COPD after adjusting for age and smoking. The association between length of exposure and COPD suggested a dose-response pattern. Intensity of exposure in both summer and winter was also related to COPD. Wood or charcoal alone independently increased risk of COPD (odds ratio (OR) 1.8 and 1.5, respectively), but only the combination of both was statistically significant (OR 4.5). In conclusion, the present study shows a strong association between wood or charcoal smoke exposure and chronic obstructive pulmonary disease, supporting its existence not only in developing countries, but also in European countries, such as Spain. Further studies assessing whether this association also exists in other European societies are warranted.

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Alpha-1-Antitrypsin Deficiency Registry Study Group.
Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin.
Am J Respir Crit Care Med 1998 Jul; 158 (1): 49-59.
Ver Abstract                    Texto Completo

Subjects >= 18 yr of age with serum alpha1-antitrypsin (alpha1-AT) levels <= 11 microM or a ZZ genotype were followed for 3.5 to 7 yr with spirometry measurements every 6 to 12 mo as part of a National Heart, Lung, and Blood Institute Registry of Patients with Severe Deficiency of Alpha-1-Antitrypsin. Among all 1,129 enrollees, 5-yr mortality was 19% (95% CI: 16 to 21%). In multivariate analyses of 1, 048 subjects who had been contacted >= 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0. 43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV1 measurements >= 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups (p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.

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GOLD executive committee.
Global Initiative for Chronic Obstructive Pulmonary Disease.
2006
Ver Abstract                    Texto Completo

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) works with health care professionals and public health officials around the world to raise awareness of Chronic Obstructive Pulmonary Disease (COPD) and to improve prevention and treatment of this lung disease. Through the development of evidence-based guidelines for COPD management, and events such as the annual celebration of World COPD Day, GOLD is working to improve the lives of people with COPD in every corner of the globe. GOLD was launched in 1997 in collaboration with the National Heart, Lung, and Blood Institute, National Institutes of Health, USA, and the World Health Organization. GOLD’s program is determined and its guidelines for COPD care are shaped by committees made up of leading experts from around the world.

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Celli BR, MacNee W.
Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
Eur Respir J 2004 Jun; 23 (6): 932-46.
Ver Abstract                    Texto Completo

The Standards for the Diagnosis and Treatment of Patients with COPD document 2004 updates the position papers on chronic obstructive pulmonary disease (COPD) published by the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 1995 1, 2. Both societies felt the need to update the previous documents due to the following. 1) The prevalence and overall importance of COPD as a health problem is increasing. 2) There have been enough advances in the field to require an update, especially adapted to the particular needs of the ATS/ERS constituency. 3) It allows for the creation of a "live" modular document based on the web; it should provide healthcare professionals and patients with a user friendly and reliable authoritative source of information. 4) The care of COPD should be comprehensive, is often multidisciplinary and rapidly changing. 5) Both the ATS and the ERS acknowledge the recent dissemination of the Global Initiative of Obstructive Lung Disease (GOLD) 3 as a major worldwide contribution to the battle against COPD. However, some specific requirements of the members of both societies require adaptation of the broad GOLD initiative. Those requirements include specific recommendations on oxygen therapy, pulmonary rehabilitation, noninvasive ventilation, surgery in and for COPD, sleep, air travel, and end-of-life. In addition, special emphasis has been placed on issues related to the habit of smoking and its control.

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Finkelstein R, Fraser RS, Ghezzo H, Cosio MG.
Alveolar inflammation and its relation to emphysema in smokers.
Am J Respir Crit Care Med 1995 Nov; 152 (5 Pt 1): 1666-72.
Ver Abstract                    Texto Completo

The prevalent theory in the pathogenesis of emphysema proposes that increased numbers of activated neutrophils and/or alveolar macrophages produce large amounts of proteases, an activity that cannot be regulated by alpha 1-antiproteases, resulting in lung destruction. However, the cells in the lung parenchyma of smokers have not been properly identified. We characterized and quantitated the inflammatory cell load in the lungs of smokers and correlated these findings with the degree of lung destruction. Twenty-one patients, six nonsmokers and 15 smokers, undergoing lung resection were studied. Lungs or lobes were fixed and stained for light microscopy and neutrophil identification and immunohistochemically stained for identification of lymphocytes and macrophages. By point counting, we determined the extent of emphysema by the volume density of the lung parenchyma (Vvalv), and the different cell numbers per cubic millimeter in all lungs. In nonsmokers Vvalv was greater than in smokers. The number of neutrophils/mm3 of lung correlated directly with the Vvalv, (r = 0.71, p < 0.01), whereas the number of alveolar macrophages (r = -0.70) and T-lymphocytes (r = -0.78) correlated negatively with the Vvalv. The number of T-lymphocytes correlated negatively with the number of neutrophils (r = -0.58) and positively with the numbers of alveolar macrophages (r = 0.77). Our data suggest that as long as the inflammatory reaction is predominantly of neutrophils there is no destruction of the lung. However, the extent of lung destruction becomes evident, and its extent is directly related to the number of alveolar macrophages and T-lymphocytes/mm3. We conclude that the T-lymphocyte might be importantly implicated in the pathogenesis of emphysema in smokers.

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Peinado VI, Barberá JA, Abate P, Ramírez J, Roca J, Santos S et al.
Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1999 May; 159 (5 Pt 1): 1605-11.
Ver Abstract                    Texto Completo

Endothelial dysfunction and intimal thickening have been shown in pulmonary arteries (PA) of patients with mild chronic obstructive pulmonary disease (COPD). To investigate whether an inflammatory process related to tobacco smoking might be involved in the development of pulmonary vascular abnormalities in COPD, we characterized the inflammatory cell infiltrate and the endothelium-dependent relaxation in PA of 39 patients who underwent lung resection, divided into three groups: "nonsmokers" (n = 7); "smokers," with normal lung function (n = 12); and "COPD" (n = 20). Endothelium-dependent relaxation was assessed in vitro by exposing PA rings to adenosine diphosphate (ADP). Inflammatory cell types were identified by immunohistochemistry. PA of COPD patients developed lower relaxation in response to ADP than nonsmokers and smokers. The number of inflammatory cells was increased in PA of COPD compared with the other two groups. This cell infiltrate was largely constituted by T lymphocytes. The CD8(+) T-cell subset was increased in both smokers and COPD compared with nonsmokers, yielding a reduction of the CD4(+)/CD8(+) ratio. The intensity of the inflammatory infiltrate correlated with both the endothelium-dependent relaxation and the intimal thickness. We conclude that cigarette smoking induces a CD8(+) T-lymphocyte infiltrate in PA, which is associated with the impairment of the vessel's structure and function, suggesting the potential involvement of an inflammatory process in the pathogenesis of pulmonary vascular abnormalities in the early stage of COPD.

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Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L et al.
The nature of small-airway obstruction in chronic obstructive pulmonary disease.
N Engl J Med 2004 Jun 24; 350 (26): 2645-53.
Ver Abstract                    Texto Completo

Chronic obstructive pulmonary disease (COPD) is a major public health problem associated with long-term exposure to toxic gases and particles. We examined the evolution of the pathological effects of airway obstruction in patients with COPD. METHODS: The small airways were assessed in surgically resected lung tissue from 159 patients--39 with stage 0 (at risk), 39 with stage 1, 22 with stage 2, 16 with stage 3, and 43 with stage 4 (very severe) COPD, according to the classification of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). RESULTS: The progression of COPD was strongly associated with an increase in the volume of tissue in the wall (P<0.001) and the accumulation of inflammatory mucous exudates in the lumen (P<0.001) of the small airways. The percentage of the airways that contained polymorphonuclear neutrophils (P<0.001), macrophages (P<0.001), CD4 cells (P=0.02), CD8 cells (P=0.038), B cells (P<0.001), and lymphoid aggregates containing follicles (P=0.003) and the absolute volume of B cells (P=0.03) and CD8 cells (P=0.02) also increased as COPD progressed. CONCLUSIONS: Progression of COPD is associated with the accumulation of inflammatory mucous exudates in the lumen and infiltration of the wall by innate and adaptive inflammatory immune cells that form lymphoid follicles. These changes are coupled to a repair or remodeling process that thickens the walls of these airways. Copyright 2004 Massachusetts Medical Society.

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Agusti AG, Noguera A, Sauleda J, Sala F, Pons J, Busquets X.
Systemic effects of chronic obstructive pulmonary disease.
Eur Respir J 2003; 21(2):347-360.
Ver Abstract                    Texto Completo

Chronic obstructive pulmonary disease (COPD) is characterised by an inappropriate/excessive inflammatory response of the lungs to respiratory pollutants, mainly tobacco smoking. Recently, besides the typical pulmonary pathology of COPD (i.e. chronic bronchitis and emphysema), several effects occurring outside the lungs have been described, the so-called systemic effects of COPD. These effects are clinically relevant because they modify and can help in the classification and management of the disease. The present review discusses the following systemic effects of chronic obstructive pulmonary disease: 1) systemic inflammation; 2) nutritional abnormalities and weight loss; 3) skeletal muscle dysfunction; and 4) other potential systemic effects. For each of these, the potential mechanisms and clinical implications are discussed and areas requiring further research are highlighted.

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Gan WQ, Man SF, Senthilselvan A, Sin DD.
Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis.
Thorax 2004; 59(7):574-580.
Ver Abstract                    Texto Completo

BACKGROUND: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD. METHODS: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV(1)) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-alpha (TNF-alpha), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model. RESULTS: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-alpha levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)). CONCLUSIONS: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.

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Sobradillo V, Miravitlles M, Jiménez-Ruiz CA, Gabriel R, Viejo JL, Masa JF et al.
Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation.
Arch Bronconeumol 1999 Apr; 35 (4): 159-66.
Ver Abstract                    Texto Completo

The prevalence of chronic respiratory symptoms and chronic airflow limitation (CAFL) was determined in a multicentric epidemiological study carried out in seven different areas of Spain. Based on a target population of 236,412 persons, a random census sample of 4,035 individuals between 40 and 69 years of age was chosen. Subjects answered several questionnaires and performed spirometric tests followed by a bronchodilation test if bronchial obstruction was detected. Respiratory symptoms were reported by 48% of the population (95% CI: 46.4-49.5%) with greater frequency of symptoms among men than women (55.2% versus 41%, p < 0.001). The following levels of prevalence of chronic symptoms were found: cough, 13.5% (95% CI: 12.5-14.6%); expectoration, 10.7% (95% CI: 9.7-11.6%); dyspnea after one flight of stairs, 10.4% (95% CI: 9.5-11.4%); and wheezing, 40.2% (95% CI: 38.7-41.7%). The prevalence of chronic bronchitis (CB) was 4.8% (95% CI: 4.1-5.4%) and was more frequent among men than among women (8.3% and 1.4%, respectively; p < 0.001). Asthma had been diagnosed previously in 4.9% (95% CI: 4.2-5.5%), more often in women than in men (5.8% and 3.8%, respectively; p < 0.003). CAFL was found in 10.6% (95% CI: 9.6-11.5%), 15.8% in men and 5.5% in women (p < 0.001). All respiratory symptoms except asthma were more frequent among smokers than among ex-smokers, and in turn were more common among ex-smokers than non-smokers. The frequency of symptoms increased in accordance with accumulated smoking. The prevalence of CB and CAFL was vastly different from one region to another. Multivariate analysis showed that factors associated independently with the appearance of CB were smoking, age over 60 years, male sex and having worked in industry. In conclusion, respiratory symptoms, including CB and CAFL, are common in the Spanish population. Smoking and amount of smoking are directly related to the frequency of such symptoms. Substantial differences were found in the prevalence of CB and CAFL among the regions where the study was performed.

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Peña VS, Miravitlles M, Gabriel R, Jiménez-Ruiz CA, Villasante C, Masa JF et al.
Geographic variations in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study.
Chest 2000 Oct; 118 (4): 981-9.
Ver Abstract                    Texto Completo

OBJECTIVES: To ascertain the prevalence, diagnostic level, and treatment of COPD in Spain through a multicenter study comprising seven different geographic areas. Design and participants: This is an epidemiologic, multicenter, population-based study conducted in seven areas of Spain. A total of 4,035 men and women (age range, 40 to 69 years) who were randomly selected from a target population of 236,412 subjects participated in the study. INTERVENTIONS: Eligible subjects answered the European Commission for Steel and Coal questionnaire. Spirometry was performed, followed by a bronchodilator test when bronchial obstruction was present. RESULTS: The prevalence of COPD was 9.1% (95% confidence interval [CI], 8.1 to 10.2%), 15% in smokers (95% CI, 12.8 to 17.1%), 12.8% in ex-smokers (95% CI, 10.7 to 14.8%), and 4.1% in nonsmokers (95% CI, 3.3 to 5.1%). The prevalence in men was 14.3% (95% CI, 12.8 to 15. 9%) and 3.9% in women (95% CI, 3.1 to 4.8%). Marked differences were observed between sexes in smoking; the percentage of nonsmokers was 23% in men and 76.3% in women (p<0.0001). The prevalence of COPD varied among the areas, ranging from 4.9% (95% CI, 3.2 to 7.0%) in the area of the lowest prevalence to 18% (95% CI, 14.8 to 21.2%) in the area of the highest. There was no previous diagnosis of COPD in 78.2% of cases (284 of 363). Only 49.3% of patients with severe COPD, 11.8% of patients with moderate COPD, and 10% of patients with mild COPD were receiving some kind of treatment for COPD. Multivariate analysis showed that individuals had a higher probability of having received a previous diagnosis of COPD if they lived in urban areas, were of male gender, were > 60 years old, had higher educational levels, had > 15 pack-year smoking history, or had symptoms of chronic bronchitis. CONCLUSIONS: COPD is a very frequent disease in Spain, and presents significant geographic variations and a very low level of previous diagnosis and treatment, even in the most advanced cases.

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Menezes AM, Pérez-Padilla R, Jardim JR, Muiño A, López MV, Valdivia G et al.
Chronic obstructive pulmonary disease in five Latin American cities (the PLATINO study): a prevalence study.
Lancet 2005 Nov 26; 366 (9500): 1875-81.
Ver Abstract                    Texto Completo

BACKGROUND: Both the prevalence and mortality attributable to chronic obstructive pulmonary disease (COPD) seem to be increasing in low-income and middle-income countries, but few data are available. The aim of the PLATINO study, launched in 2002, was to describe the epidemiology of COPD in five major Latin American cities: Sao Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay), and Caracas (Venezuela). METHODS: A two-stage sampling strategy was used in the five areas to obtain probability samples of adults aged 40 years or older. These individuals were invited to answer a questionnaire and undergo anthropometry, followed by prebronchodilator and postbronchodilator spirometry. We defined COPD as a ratio less than 0.7 of postbronchodilator forced expiratory volume in the first second over forced vital capacity. FINDINGS: Complete information, including spirometry, was obtained from 963 people in Sao Paulo, 1173 in Santiago, 1000 in Mexico City, 885 in Montevideo, and 1294 in Caracas. Crude rates of COPD ranged from 7.8% (78 of 1000; 95% CI 5.9-9.7) in Mexico City to 19.7% (174 of 885; 17.2-22.2) in Montevideo. After adjustment for key risk factors, the prevalence of COPD in Mexico City remained significantly lower than that in other cities. INTERPRETATION: These results suggest that COPD is a greater health problem in Latin America than previously realised. Altitude may explain part of the difference in prevalence. Given the high rates of tobacco use in the region, increasing public awareness of the burden of COPD is important.

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García-Río F, Pino JM, Dorgham A, Alonso A, Villamor J.
Spirometric reference equations for European females and males aged 65-85 yrs.
Eur Respir J 2004 Sep; 24 (3): 397-405.
Ver Abstract                    Texto Completo

The aim of this study was to describe spirometric reference equations for healthy never-smoking European adults aged 65-85 yrs and to compare the predicted values of this sample with those from other studies including middle-aged and/or older adults. Reference equations and normal ranges for forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory volume in six seconds (FEV6), FEV1/FVC ratio and FEV1/FEV6 ratio were derived from a healthy subgroup of 458 subjects aged 65-85 yrs. Spirometry examinations followed the 1994 American Thoracic Society recommendations and the quality of the data was continuously monitored and maintained. Reference values and lower limits of normal were derived using a piecewise polynomial model with age and height as predictors. The reference values of FEV1 and FVC from the present study were higher than those given by prediction equations from the European Community for Coal and Steel. By contrast, use of prediction equations from Caucasian-American elderly subjects (Cardiovascular Health Study) consistently overpredicted FVC and FEV1 in females by 8.5 and 2.1%, respectively. In males, equations from the Cardiovascular Health Study overpredicted FVC by 2.8%, whilst underpredicting FEV1 by 2.5%. In conclusion, these results underscore the importance of using prediction equations appropriate to the origin, age and height characteristics of the subjects being studied.

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Anthonisen NR, Wright EC, Hodgkin JE.
Prognosis in chronic obstructive pulmonary disease.
Am Rev Respir Dis 1986 Jan; 133 (1): 14-20.
Ver Abstract                    Texto Completo

We recruited 985 patients with COPD but without hypoxemia or other serious disease, treated them in a standard fashion, and followed them closely for nearly 3 yr. At the time of recruitment the patients were carefully characterized as to symptom severity, lung function, exercise tolerance, and quality of life, and studies of lung function were repeated during follow-up. Overall mortality was 23% in 3 yr of follow-up. Patient age and the initial value of the FEV1 were the most accurate predictors of death; when FEV1 before bronchodilator was used, the response to bronchodilators was directly related to survival, but this relationship became nonsignificant when postbronchodilator FEV1 was used as a primary predictor. After adjustment for age and FEV1, mortality was related positively to TLC, resting heart rate, and perceived physical disability, and related negatively to exercise tolerance. These relationships, though significant, were relatively weak. When standardized for age and FEV1, mortality in the present series was less than that of a previous series (4), and the same as that of hypoxemic patients with COPD who received continuous home O2 therapy. Changes in FEV1 with time averaged -44 ml/yr, but the standard deviation was large. Patients with low initial values of FEV1 showed relatively little further decline, probably indicating a survivor effect. In patients with well-preserved initial FEV1, rate of decline correlated negatively with bronchodilator response, symptomatic wheezing, and psychological disturbances.

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Casanova C, Cote C, de Torres JP, Aguirre-Jaime A, Marin JM, Pinto-Plata V et al.
Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2005 Mar 15; 171 (6): 591-7.
Ver Abstract                    Texto Completo

Static lung hyperinflation has important clinical consequences in patients with chronic obstructive pulmonary disease. We analyzed the power of lung hyperinflation as measured by the inspiratory capacity-to-total lung capacity ratio (IC/TLC) to predict mortality in a cohort of 689 patients with chronic obstructive pulmonary disease (95% males; FEV(1), 1.17 L) with a mean follow-up of 34 months. We also compared the predictive value of IC/TLC with that of the BODE (body mass index, airflow obstruction, dyspnea, exercise performance) Index. Subjects who died (183; 27%) were older; had lower body mass index, FEV(1), and IC/TLC ratio; walked less in the 6-minute walking distance; and had more dyspnea, a higher BODE Index, and comorbidity (p < 0.001). On the basis of logistic regression analysis, IC/TLC was found to be a good and independent predictor of all-cause and respiratory mortality. On the basis of receiver operating characteristic Type II curves, IC/TLC compared favorably with FEV(1) and predicted mortality independently of the BODE Index. We conclude that IC/TLC is an independent risk factor for mortality in subjects with chronic obstructive pulmonary disease. We propose that this ratio be considered in the assessment of patients with chronic obstructive pulmonary disease.

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Costello R, Deegan P, Fitzpatrick M, McNicholas WT.
Reversible hypercapnia in chronic obstructive pulmonary disease: a distinct pattern of respiratory failure with a favorable prognosis.
Am J Med 1997 Mar; 102 (3): 239-44.
Ver Abstract                    Texto Completo

PURPOSE: Hypercapnia is regarded as a poor prognostic indicator in chronic obstructive pulmonary disease (COPD), but many patients hospitalized with hypercapnia associated with an acute exacerbation of COPD revert to normocapnia during recovery. We wished to determine if this reversible hypercapnia represents a distinct pattern of respiratory failure in COPD, or simply a stage in the progression to chronic hypercapnia. We therefore compared the long-term clinical progression and survival of COPD patients with reversible hypercapnic respiratory failure (defined as type 2.1) to those with normocapnic (PaCO2 < 50 mm Hg; type 1) and also to those patients with chronic hypercapnic (PaCO2 > 50 mm Hg) respiratory failure (defined as type 2.2). PATIENTS AND METHODS: We prospectively followed for 5 years a cohort of 85 patients who had been admitted as emergencies during a 1-year period to the respiratory unit of a University teaching hospital with an exacerbation of COPD complicated by respiratory failure (PaO2 < 60 mm Hg). The main long-term outcome measures were survival and blood gas changes. RESULTS: Sixty-eight (80%) patients survived the initial admission, and 17 (27%) survived 5 years. PaCO2 rose substantially more during exacerbations in type 2.1 patients (mean 15.8 mm Hg), compared with type 2.2 (mean 6.8 mm Hg) and type 1 patients (mean 1.5 mm Hg). We analyzed 149 subsequent admissions among the survivors over the following 5 years. Type 2.1 patients had a better 5-year survival (28%) than type 2.2 (11% survival; P < 0.05), and similar to type 1 patients (33% 5-year survival). Only 24% of reversible hypercapnic patients developed chronic hypercapnia during long-term followup. CONCLUSIONS: The data support reversible hypercapnia being a distinct manifestation of respiratory failure in COPD, with a similar prognosis to that of normocapnic respiratory failure.

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Naeije R.
Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease.
Proc Am Thorac Soc 2005; 2 (1): 20-2.
Ver Abstract                    Texto Completo

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). The increase in pulmonary artery pressures is often mild to moderate. However, 5-10% of patients with advanced COPD may suffer from severe pulmonary hypertension and present with a progressively downhill clinical course because of right heart failure added to ventilatory handicap. The prevalence of clinically significant severe pulmonary hypertension in COPD is roughly estimated to be of 1-2/1,000. The cause of pulmonary hypertension in COPD is generally assumed to be hypoxic pulmonary vasoconstriction leading to permanent medial hypertrophy. However, recent pathologic studies point rather at extensive remodeling of all layers of the pulmonary arterial walls. These aspects account for minimal reversibility with supplemental oxygen. There may be a case for pharmacologic treatment of pulmonary hypertension in selected patients with advanced COPD and right heart failure. However, it will be a challenge for randomized controlled trials to overcome the difficulties of the diagnosis of right ventricular failure and the definition of a relevant primary endpoint in pulmonary hypertensive patients with COPD.

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Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T.
Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status.
Am J Respir Crit Care Med 2003 Feb 15; 167 (4): 544-9.
Ver Abstract                    Texto Completo

In this study, we analyzed the relationships of exercise capacity and health status to mortality in patients with chronic obstructive pulmonary disease (COPD). We recruited 150 male outpatients with stable COPD with a mean postbronchodilator FEV1 at 47.4% of predicted. Their pulmonary function, progressive cycle ergometry, and health status using the Chronic Respiratory Disease Questionnaire, the St. George's Respiratory Questionnaire (SGRQ), and the Breathing Problems Questionnaire were measured at entry. Among 144 patients who were available for the 5-year follow-up, 31 had died. Univariate Cox proportional hazards analysis revealed that the SGRQ total score and the Breathing Problems Questionnaire were significantly correlated with mortality; however, with the Chronic Respiratory Disease Questionnaire, the total score was not significantly correlated. Multivariate Cox proportional hazards analysis revealed that the peak oxygen uptake and the SGRQ total score were both predictive of mortality, independent of FEV1 and age. Stepwise Cox proportional hazards analysis revealed that the peak oxygen uptake was the most significant predictor of mortality. We found that exercise capacity and health status were significantly correlated with mortality, although different health status measures had different abilities to predict mortality. These results will have a potentially great impact on the multidimensional evaluation of disease severity in COPD.

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Domingo-Salvany A, Lamarca R, Ferrer M, García-Aymerich J, Alonso J, Félez M et al.
Health-related quality of life and mortality in male patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2002 Sep 1; 166 (5): 680-5.
Ver Abstract                    Texto Completo

To assess whether generic and specific health-related quality of life (HRQL) are independently associated with total and specific mortality in patients with chronic obstructive pulmonary disease (COPD), we followed until 1999 a cohort of 321 male patients with COPD, recruited in 1993-1994 at outpatient respiratory clinics. Baseline characteristics recorded under stable clinical conditions included forced spirometry, arterial blood gas tensions, dyspnea scales, 11 comorbid conditions, St. George's Respiratory Questionnaire (SGRQ), and SF-36 Health Survey. Vital status was assessed through reinterviews, the Mortality Register, and clinical records. Subjects who died (106) were older (69.8 versus 62.5 years) (p < 0.001), had lower body mass index (BMI) (25.4 versus 27.1) (p < 0.01), were more impaired in the clinical characteristics studied (%FEV(1), 34.0 versus 51.0) (p < 0.001), and had long-term oxygen therapy more frequently (31% versus 7%) (p < 0.001). Survival was shorter when worse HRQL was reported. SGRQ total and SF-36 physical summary scores were independently associated with total and respiratory mortality in Cox models, including age, FEV(1), and BMI. The total mortality-standardized hazard ratios for both HRQL measures were 1.3, whereas those for FEV(1) were 1.6. HRQL measures provide independent and relevant information on the health status of male patients with COPD. Their use should be considered for a more thorough evaluation and staging of patients with COPD.

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Garcia-Aymerich J, Farrero E, Félez MA, Izquierdo J, Marrades RM, Antó JM.
Risk factors of readmission to hospital for a COPD exacerbation: a prospective study.
Thorax 2003 Feb; 58 (2): 100-5.
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BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are a leading cause of admission to hospital among men in many countries, although the factors causing exacerbations are largely unknown. The association between readmission for a COPD exacerbation and a wide range of modifiable potential risk factors, after adjusting for sociodemographic and clinical factors, has been assessed. METHODS: Three hundred and forty patients with COPD recruited during an admission for an exacerbation in four tertiary hospitals in the Barcelona area of Spain were followed for a mean period of 1.1 years. Information on potential risk factors, including clinical and functional status, medical care and prescriptions, medication adherence, lifestyle, health status, and social support, was collected at the recruitment admission. A Cox's proportional hazards model was used to obtain independent relative risks of readmission for COPD. RESULTS: During the follow up period 63% of patients were readmitted at least once, and 29% died. The final multivariate model showed the following risk (or protective) factors: > or =3 admissions for COPD in the year before recruitment (hazard ratio (HR)=1.66, 95% CI 1.16 to 2.39), forced expiratory volume in 1 second (FEV(1)) percentage predicted (0.97, 95% CI 0.96 to 0.99), oxygen tension (0.88, 95% CI 0.79 to 0.98), higher levels of usual physical activity (0.54, 95% CI 0.34 to 0.86), and taking anticholinergic drugs (1.81, 95% 1.11 to 2.94). Exposure to passive smoking was also related to an increased risk of readmission with COPD after adjustment for clinical factors (1.63, 95% CI 1.04 to 2.57) but did not remain in the final model. CONCLUSIONS: This is the first study to show a strong association between usual physical activity and reduced risk of readmission to hospital with COPD, which is potentially relevant for rehabilitation and other therapeutic strategies.

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Nishimura K, Izumi T, Tsukino M, Oga T.
Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD.
Chest 2002 May; 121 (5): 1434-40.
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BACKGROUND: FEV(1) is regarded as the most significant correlate of survival in COPD and is used as a measure of disease severity in the staging of COPD. Recently, however, the categorization of patients with COPD on the basis of the level of dyspnea has similarly been reported to be useful in the prediction of health-related quality of life and improvement in exercise performance after pulmonary rehabilitation. Study objectives: We compared the effects of the level of dyspnea and disease severity, as evaluated by airway obstruction, on the 5-year survival rate of patients with COPD. DESIGN AND METHODS: A total of 227 patients with COPD were enrolled in a 5-year, prospective, multicenter study in the Kansai area of Japan, involving 20 divisions of respiratory medicine from various university and city hospitals. RESULTS: After 5 years, 183 patients were available for the follow-up examination (follow-up rate, 81%). The 5-year cumulative survival rate among patients with COPD was 73%. The effect of disease staging, based on the American Thoracic Society (ATS) guideline as evaluated by the percentage of predicted FEV(1), on the 5-year survival rate was not significant (p = 0.08). However, the level of dyspnea was significantly correlated to the 5-year survival rate (p < 0.001). The Cox proportional hazards model revealed that the level of dyspnea had a more significant effect on survival than disease severity based on FEV(1). CONCLUSIONS: The categorization of patients with COPD on the basis of the level of dyspnea was more discriminating than staging of disease severity using the ATS guideline with respect to 5-year survival. Dyspnea should be included as one of the variables, in addition to airway obstruction, for evaluating patients with COPD in terms of mortality.

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Soler-Cataluña JJ, Martínez-García MA, Román-Sánchez P, Salcedo E, Navarro M, Ochando R.
Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
Thorax 2005 Nov; 60 (11): 925-31.
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BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often present with severe acute exacerbations requiring hospital treatment. However, little is known about the prognostic consequences of these exacerbations. A study was undertaken to investigate whether severe acute exacerbations of COPD exert a direct effect on mortality. METHODS: Multivariate techniques were used to analyse the prognostic influence of acute exacerbations of COPD treated in hospital (visits to the emergency service and admissions), patient age, smoking, body mass index, co-morbidity, long term oxygen therapy, forced spirometric parameters, and arterial blood gas tensions in a prospective cohort of 304 men with COPD followed up for 5 years. The mean (SD) age of the patients was 71 (9) years and forced expiratory volume in 1 second was 46 (17)%. RESULTS: Only older age (hazard ratio (HR) 5.28, 95% CI 1.75 to 15.93), arterial carbon dioxide tension (HR 1.07, 95% CI 1.02 to 1.12), and acute exacerbations of COPD were found to be independent indicators of a poor prognosis. The patients with the greatest mortality risk were those with three or more acute COPD exacerbations (HR 4.13, 95% CI 1.80 to 9.41). CONCLUSIONS: This study shows for the first time that severe acute exacerbations of COPD have an independent negative impact on patient prognosis. Mortality increases with the frequency of severe exacerbations, particularly if these require admission to hospital.

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Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T et al.
Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City Heart Study.
Am J Respir Crit Care Med 2006 Jan 1; 173 (1): 79-83.
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RATIONALE: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight(2)). OBJECTIVES: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD. METHODS: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account. MAIN RESULTS: The mean FFMI was 16.0 kg/m(2) for women and 18.7 kg/m(2) for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI. CONCLUSIONS: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.

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Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA et al.
The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease.
N Engl J Med 2004 Mar 4; 350 (10): 1005-12.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by an incompletely reversible limitation in airflow. A physiological variable--the forced expiratory volume in one second (FEV1)--is often used to grade the severity of COPD. However, patients with COPD have systemic manifestations that are not reflected by the FEV1. We hypothesized that a multidimensional grading system that assessed the respiratory and systemic expressions of COPD would better categorize and predict outcome in these patients. METHODS: We first evaluated 207 patients and found that four factors predicted the risk of death in this cohort: the body-mass index (B), the degree of airflow obstruction (O) and dyspnea (D), and exercise capacity (E), measured by the six-minute-walk test. We used these variables to construct the BODE index, a multidimensional 10-point scale in which higher scores indicate a higher risk of death. We then prospectively validated the index in a cohort of 625 patients, with death from any cause and from respiratory causes as the outcome variables. RESULTS: There were 25 deaths among the first 207 patients and 162 deaths (26 percent) in the validation cohort. Sixty-one percent of the deaths in the validation cohort were due to respiratory insufficiency, 14 percent to myocardial infarction, 12 percent to lung cancer, and 13 percent to other causes. Patients with higher BODE scores were at higher risk for death; the hazard ratio for death from any cause per one-point increase in the BODE score was 1.34 (95 percent confidence interval, 1.26 to 1.42; P<0.001), and the hazard ratio for death from respiratory causes was 1.62 (95 percent confidence interval, 1.48 to 1.77; P<0.001). The C statistic for the ability of the BODE index to predict the risk of death was larger than that for the FEV1 (0.74 vs. 0.65). CONCLUSIONS: The BODE index, a simple multidimensional grading system, is better than the FEV1 at predicting the risk of death from any cause and from respiratory causes among patients with COPD.

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Kesten S, Chapman KR.
Physician perceptions and management of COPD.
Chest 1993 Jul; 104 (1): 254-8.
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To assess awareness and understanding of obstructive airway diseases by primary-care physicians, the authors surveyed a randomly selected population of 75 primary care practitioners. During one-on-one interviews, physicians were presented with a standardized case scenario and a subsequent series of open-ended questions concerning asthma and COPD. Each respondent was presented in randomized fashion with one of two versions of a case description of a hypothetical 52-year-old male smoker with a recent upper respiratory tract infection and persistent productive cough. The only difference between case descriptions was that one included explicit reference to an earlier tentative diagnosis of chronic bronchitis (CB version); the other description made no specific mention of this diagnostic term (NCB version). Chest radiographs were requested by 80 percent of physicians and sputum cultures by 50 percent, these percentages not differing significantly between CB and NCB groups. Spirometry was requested less often than either of the foregoing tests (21 percent). The CB group requested spirometry significantly more often than the NCB group (38 percent vs 5 percent, p < 0.05). The most frequently mentioned primary diagnosis was bronchitis/pneumonia (33 percent), followed by bronchitis (28 percent) and chronic bronchitis (16 percent), all of which were similar in both groups. However, the diagnostic term "COPD" was the primary diagnosis in 16 percent of the CB group, compared with 8 percent in the NCB group (p > 0.05). Oral antibiotics were the most frequently chosen first-line drug therapy (63 percent). In subsequent questions concerning the management of obstructive airway diseases, primary practitioners distinguished COPD from asthma conceptually, but their prescribed therapy for the two disorders was less distinct. beta 2-agonists were selected most frequently and similarly as initial therapy for both disorders (53 percent). Minor differences between first-line therapeutic choices included nonsignificant trends toward the more frequent mention of anticholinergic bronchodilators for COPD than for asthma (10 percent vs 0 percent) and the more frequent selection of inhaled corticosteroids for asthma (12 percent vs 5 percent). The authors conclude that to the extent that questionnaire responses reflect actual practice, primary care practitioners (1) have a low index of suspicion for obstructive airway disease, (2) markedly underutilized spirometry as a screening tool, (3) consider beta 2-agonists first-line therapy for COPD and asthma, and (4) despite considering COPD and asthma different disease processes, choose similar medications for each disorder.

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Schols AM, Slangen J, Volovics L, Wouters EF.
Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1998 Jun; 157 (6 Pt 1): 1791-7.
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The objective of the study was to further unravel the prognostic significance of body weight changes in patients with COPD. Two survival analyses were performed: (1) a retrospective study, including 400 patients with COPD none of whom had received nutritional therapy; (2) a post hoc analysis of a prospective study, including 203 patients with COPD who had participated in a randomized placebo-controlled trial. There was no overlap between the patient groups. Baseline characteristics of all patients were collected on admission to a pulmonary rehabilitation center in stable clinical condition. In the prospective randomized placebo-controlled trial, the physiologic effects of nutritional therapy alone (n = 71) or in combination with anabolic steroid treatment (n = 67) after 8 wk was studied in patients with COPD prestratified into a depleted group and a nondepleted group. Mortality was assessed as overall mortality. The Cox proportional hazards model was used to quantify the relationship between the baseline variables age, sex, spirometry, arterial blood gases, body mass index (BMI), smoking, and subsequent overall mortality. Additionally, the influence of treatment response on mortality was investigated in the prospective study. The retrospective study revealed that low BMI (p < 0.001), age (p < 0.0001) and low PaO2 (p < 0.05) were significant independent predictors of increased mortality. After stratification of the group into BMI quintiles a threshold value of 25 kg/m2 was identified below which the mortality risk was clearly increased. In the prospective study, weight gain (> 2 kg/8 wk) in depleted and nondepleted patients with COPD, as well as increase in maximal inspiratory mouth pressure during the 8-wk treatment, were significant predictors of survival. On Cox regression analysis weight change entered as a time-dependent covariate remained an independent predictor of mortality in addition to all variables that were entered in the retrospective study. The combined results of the two survival analyses provide evidence to support the hypothesis that body weight has an independent effect on survival in COPD. Moreover the negative effect of low body weight can be reversed by appropriate therapy in some of the patients with COPD.

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Thurlbeck WM, Simon G.
Radiographic appearance of the chest in emphysema.
AJR Am J Roentgenol 1978 Mar; 130 (3): 429-40.
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Accuracy of the radiologic diagnosis of emphysema was assessed in 696 patients from whose lungs paper-mounted whole-lung sections had been made. Emphysema was diagnosed radiographically primarily on the basis of arterial deficiency. In addition, lung length, lung width, size of the retrosternal space, heart size, and diaphragm position were recorded from the chest films. Recognition of emphysema was poor when radiographs of inadequate quality were included (anteroposterior films or films from patients with acute or chronic lung disease). When these films were excluded, only occasional radiographs from patients without emphysema or with mild emphysema were thought to have emphysema radiologically. Of the patients with moderately severe and severe emphysema, 41% were diagnosed as having emphysema, as were two-thirds of those with the most severe grade of emphysema. For a given grade of emphysema, the radiologic diagnosis of emphysema was made more frequently when patients had severe chronic airflow obstruction. Emphysema was usually most severe in the zones of the lung in which emphysema was radiologically apparent. Centrilobular emphysema was usually present when emphysema was diagnosed radiologically in the upper zones of the lung, and panacinar emphysema was usually present when emphysema was diagnosed in the lower zones. Lung length and the size of the retrosternal space increased, the level of the diaphragm lowered, heart size decreased, and lung width was unchanged as emphysema became more severe. Lung length and diaphragm level were the most discriminating measurements, followed by size of the retrosternal space. No combination of radiologic variables was found that recognized emphysema better than the subjective diagnosis of emphysema based on arterial deficiency. Radiologic lung dimensions are related to stature; for given stature these measurements are larger in men and women.

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Klein JS, Gamsu G, Webb WR, Golden JA, Muller NL.
High-resolution CT diagnosis of emphysema in symptomatic patients with normal chest radiographs and isolated low diffusing capacity.
Radiology 1992 Mar; 182 (3): 817-21.
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To determine the prevalence of "nonobstructive" (impairment of gas transfer) emphysema in a select population of smokers with dyspnea, a retrospective study of patients with emphysema evident at high-resolution computed tomography (HRCT) was undertaken. Four hundred seventy HRCT studies were reviewed. In 47 cases, centrilobular emphysema was the dominant or sole parenchymal abnormality. Concomitant chest radiographs were available in 41 of these cases; 16 of the 41 lacked radiographic findings of emphysema. Among these 16 patients, pulmonary function testing revealed 10 to have normal flow rates (ratio of forced expiratory volume in 1 second to forced vital capacity and forced expiratory volume in 1 second greater than 80% predicted) and impaired gas transfer (single-breath carbon monoxide diffusing capacity [DLCOSB] less than 80% predicted). With the exclusion of one patient with congestive heart failure from the group of 10, the severity of emphysema at HRCT correlated inversely with DLCOSB (r = -.643). These results indicate that HRCT allows detection of emphysema in symptomatic patients when chest radiographs and pulmonary function tests are nondiagnostic.

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Guell R, Casan P, Sangenis M, Santis J, Morante F, Borras JM et al.
The Spanish translation and evaluation of a quality-of-life questionnaire in patients with chronic obstructive pulmonary disease.
Arch Bronconeumol 1995 May; 31 (5): 202-10.
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The Chronic Respiratory Disease Questionnaire (CRDQ), proposed by Guyatt et al, is a specific instrument used to assess quality of life in patients with chronic obstructive pulmonary disease (COPD). Our aim was to translate the questionnaire and validate it so that it could then be used as a measurement instrument in programs of respiratory rehabilitation. Sixty-five patients with COPD who were candidates for breathing therapy were enrolled in the study. Mean age was 64 +/- 7 years and all had severe air flow limitation, with FEV1 33 +/- 13% over reference values but not respiratory failure (pO2 70 +/- 10 mmHg). The questionnaire was subjected to a process of translation/back translation and disagreements over wording were discussed by a panel of bilingual speakers and the author himself. The validation process involved the following steps: 1) a comprehension study with a group of 5 patients, which revealed no special difficulties; 2) analysis of internal consistency or reliability by way of Crombach's alpha coefficient, which gave and overall score of 0.92 and area scores of 0.51 for dyspnea, 0.8 for fatigue, 0.86 for emotional factors and 0.84 for disease control, and 3) analysis of correlation between various lung function parameters and exercise test results (6 min of increasing effort and a stationary cycle), which showed weak but statistically significant correlations that were comparable to those found by the author of the original CRDQ.

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Ferrer M, Alonso J, Prieto L, Plaza V, Monsó E, Marrades R et al.
Validity and reliability of the St George's Respiratory Questionnaire after adaptation to a different language and culture: the Spanish example.
Eur Respir J 1996 Jun; 9 (6): 1160-6.
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We describe the adaptation into Spanish of the St George's Respiratory Questionnaire (SGRQ), a self-administered questionnaire developed by Jones et al. (1991) covering three domains of health in airways disease patients: symptoms, activity and impacts. For the adaptation, the forward and back-translation method by bilinguals was used, together with professional committee and lay panel. Once tested for feasibility and comprehension, 318 male chronic obstructive pulmonary disease (COPD) patients with a wide range of disease severity completed the Spanish version of the SGRQ. The clinical status of the patients was evaluated concurrently with the measurement of health status. Lung function was assessed in the 2 months before or after the questionnaire administration. The Spanish version of the SGRQ was acceptable and easy to understand. Cronbach's alpha reliability coefficient was 0.94 for the overall scale and 0.72 for "Symptoms", 0.89 for "Activity", and 0.89 for "Impacts" subscales. Correlation coefficients between the overall score and dyspnoea and % forced expiratory volume in one second (FEV1) were 0.59 and -0.45, respectively, and these correlations were higher than those observed between the clinical variables and the Nottingham Health Profile, a generic measure of health-related quality of life. Results of the study suggest that the Spanish version of the SGRQ is conceptually equivalent to the original, and similarly reliable and valid. Although further studies should complete the adaptation work, results suggest that the SGRQ may already be used in Spain and in international studies involving Spanish respiratory patients. According to the present approach, it appears to be feasible to adapt a specific questionnaire on health-related quality of life in respiratory disease to another language and culture.

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Vidal R, Blanco I, Casas F, Jardí R, Miravitlles M, Comité del Registro Nacional de Pacientes con Déficit de Alfa-1-Antitripsina.
Diagnóstico y tratamiento del déficit de alfa-1-antitripsina: Normativa SEPAR.
Arch Bronconeumol 2006 Dic; 42 (12): 645-59.
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El déficit de alfa-1-antitripsina (DAAT) es la enfermedad congénita potencialmente mortal más frecuente en la edad adulta. A pesar de ello, continúa siendo una enfermedad infradiagnosticada y cuando se llega al diagnóstico se suele hacer en fases muy avanzadas de la enfermedad pulmonar. Por este motivo es importante llamar la atención de los médicos que atienden pacientes con enfermedad pulmonar obstructiva crónica (EPOC) acerca de las recomendaciones de la OMS y de las sociedades científicas ATS/ERS, que indican de forma categórica que se debe realizar la cuantificación sérica de la alfa-1-antitripsina (AAT) a todos los pacientes con EPOC dentro del esquema diagnóstico habitual de esta enfermedad. También es importante señalar cuándo y cómo deben realizarse otras técnicas diagnósticas de laboratorio, como la determinación del fenotipo o del genotipo. Por último, los detalles referentes a la administración del tratamiento sustitutivo con AAT intravenosa deben actualizarse y ponerse al alcance de los médicos que tratan a estos pacientes. Con estos objetivos, un grupo de trabajo de la SEPAR ha desarrollado esta normativa sobre el diagnóstico y el tratamiento del DAAT. En este documento se detalla la importancia epidemiológica de la enfermedad, con especial referencia a los resultados de estudios realizados en España, las características clínicas de los pacientes con DAAT, las pautas actuales de diagnóstico clínico y de laboratorio y las indicaciones del tratamiento sustitutivo. Esperamos que sirvan de apoyo a los médicos clínicos que atienden a pacientes con EPOC y que puedan solucionar las dudas más frecuentes que se plantean al afrontar la atención a los individuos con sospecha o confirmación de un DAAT.

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Hardie JA, Buist AS, Vollmer WM, Ellingsen I, Bakke PS, Morkve O.
Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers.
Eur Respir J 2002 Nov; 20 (5): 1117-22.
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The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined stage I chronic obstructive pulmonary disease (COPD) as forced expiratory volume in one second/forced vital capacity (FEV1/FVC)% <70% and a FEV1% predicted of >80%. Stage 2 has been defined as FEV1/FVC <70% and a FEV1% pred of <80%. The authors examined the extent of COPD misdiagnosis using this definition in healthy, never-smoker, asymptomatic adults aged >70 yrs in Bergen, Norway. A respiratory questionnaire was mailed to a random sample of 2,871 persons aged >70 yrs. In a random, well-defined subgroup of 208 never-smoker respondents with no current respiratory disease and significant dyspnoea or heart disease/hypertension complicated with dyspnoea, 71 were able to perform an acceptable spirometry. Approximately 35% of these healthy, elderly never-smokers had an FEV1/FVC% of <70% and would be classified as having at least a stage 1 COPD. This percentage increased with age and in those aged >80 yrs approximately 50% would be classified as having COPD and approximately one-third would have an FEV1 of <80% pred (stage 2 COPD). The estimated 5th percentile of FEV1 was consistently <80% pred. The Global Initiative for Chronic Obstructive Lung Disease criteria will probably lead to a significant degree of over-diagnosis of chronic obstructive pulmonary disease in those aged >70 yrs. The criteria used to define the various stages of chronic obstructive pulmonary disease need to be age-specific.

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Casas A, Vilaro J, Rabinovich R, Mayer A, Barbera JA, Rodriguez-Roisin R et al.
Encouraged 6-min walking test indicates maximum sustainable exercise in COPD patients.
Chest 2005 Jul; 128 (1): 55-61.
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STUDY OBJECTIVES: In patients with moderate-to-severe COPD, an encouraged 6-min walking test (6MWT) is a high-intensity submaximal exercise protocol that shows an oxygen uptake (Vo(2)) plateau after the third minute of the test. This last feature prompted the hypothesis that self-paced walking speed is set to achieve "maximal" sustainable Vo(2), namely "critical power" or "critical speed." PATIENTS AND METHODS: Eight patients with moderate-to-severe COPD (mean age, 68 +/- 7 years [+/- SD]; FEV(1), 50 +/- 13% predicted; Pao(2), 69 +/- 8 mm Hg) underwent the following tests on different days in order: (1) encouraged 6MWT; (2) standard incremental shuttle test to identify peak walking speed; (3) four different high-intensity, constant walking speed tests to exhaustion to calculate critical walking speed; and (4) timed walking test at critical walking speed (CWS) to examine sustainability of the exercise. RESULTS: 6MWT and CWS showed similar results (mean of last 3 min): Vo(2) (1,605 +/- 304 mL/min vs 1,584 +/- 319 mL/min), minute ventilation (47 +/- 12 L/min vs 48 +/- 11 L/min), respiratory exchange ratio (0.89 +/- 0.1 vs 0.90 +/- 0.1), heart rate (130 +/- 18 beats/min vs 131 +/- 16 beats/min), Borg dyspnea score (5.4 +/- 1.3 vs 5.5 +/- 2.4), and walking speed (1.49 +/- 0.1 m/s vs 1.44 +/- 0.1 m/s, respectively). CONCLUSION: This study supports that 6MWT indicates maximum sustainable exercise that might be related with its predictive value in COPD patients.

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Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS et al.
Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study.
JAMA 1994 Nov 16; 272 (19): 1497-505.
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OBJECTIVE--To determine whether a program incorporating smoking intervention and use of an inhaled bronchodilator can slow the rate of decline in forced expiratory volume in 1 second (FEV1) in smokers aged 35 to 60 years who have mild obstructive pulmonary disease. DESIGN--Randomized clinical trial. Participants randomized with equal probability to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention. SETTING--Ten clinical centers in the United States and Canada. PARTICIPANTS--A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease. INTERVENTIONS--Smoking intervention: intensive 12-session smoking cessation program combining behavior modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Bronchodilator: ipratropium bromide prescribed three times daily (two puffs per time) from a metered-dose inhaler. MAIN OUTCOME MEASURES--Rate of change and cumulative change in FEV1 over a 5-year period. RESULTS--Participants in the two smoking intervention groups showed significantly smaller declines in FEV1 than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The small noncumulative benefit associated with use of the active bronchodilator vanished after the bronchodilator was discontinued at the end of the study. CONCLUSIONS--An aggressive smoking intervention program significantly reduces the age-related decline in FEV1 in middle-aged smokers with mild airways obstruction. Use of an inhaled anticholinergic bronchodilator results in a relatively small improvement in FEV1 that appears to be reversed after the drug is discontinued. Use of the bronchodilator did not influence the long-term decline of FEV1.

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Silagy C, Lancaster T, Stead L, Mant D, Fowler G.
Nicotine replacement therapy for smoking cessation (Cochrane Review).
Cochrane Database Syst Rev 2004; (3): CD000146.
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BACKGROUND: The aim of nicotine replacement therapy (NRT) is to replace nicotine from cigarettes. This reduces withdrawal symptoms associated with smoking cessation thus helping resist the urge to smoke cigarettes. OBJECTIVES: The aims of this review were:to determine the effectiveness of the different forms of NRT (chewing gum, transdermal patches, nasal spray, inhalers and tablets) in achieving abstinence from cigarettes, or a sustained reduction in amount smoked; to determine whether the effect is influenced by the clinical setting in which the smoker is recruited and treated, the dosage and form of the NRT used, or the intensity of additional advice and support offered to the smoker; to determine whether combinations of NRT are more effective than one type alone; to determine its effectiveness compared to other pharmacotherapies. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group trials register in March 2004. SELECTION CRITERIA: Randomized trials in which NRT was compared to placebo or to no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow up of less than six months. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose, duration and form of nicotine therapy, the outcome measures, method of randomization, and completeness of follow up.The main outcome measure was abstinence from smoking after at least six months of follow up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. For each study we calculated summary odds ratios. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed effect model. MAIN RESULTS: We identified 123 trials; 103 contributing to the primary comparison between NRT and a placebo or non-NRT control group.The odds ratio (OR) for abstinence with NRT compared to control was 1.77 (95% confidence intervals (CI): 1.66 to 1.88). The ORs for the different forms of NRT were 1.66 (95% CI: 1.52 to 1.81) for gum, 1.81 (95% CI: 1.63 to 2.02) for patches, 2.35 (95% CI: 1.63 to 3.38) for nasal spray, 2.14 (95% CI: 1.44 to 3.18) for inhaled nicotine and 2.05 (95% CI: 1.62 to 2.59) for nicotine sublingual tablet/lozenge. These odds were largely independent of the duration of therapy, the intensity of additional support provided or the setting in which the NRT was offered. In highly dependent smokers there was a significant benefit of 4 mg gum compared with 2 mg gum (OR 2.20, 95% CI: 1.85 to 3.25). There was weak evidence that combinations of forms of NRT are more effective. Higher doses of nicotine patch may produce small increases in quit rates. Only one study directly compared NRT to another pharmacotherapy. In this study quit rates with bupropion were higher than with nicotine patch or placebo. REVIEWERS' CONCLUSIONS: All of the commercially available forms of NRT (gum, transdermal patch, nasal spray, inhaler and sublingual tablets/lozenges) are effective as part of a strategy to promote smoking cessation. They increase the odds of quitting approximately 1.5 to 2 fold regardless of setting.The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the smoker. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT.

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Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR et al.
A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.
N Engl J Med 1999 Mar 4; 340 (9): 685-91.
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BACKGROUND AND METHODS: Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8. RESULTS: The abstinence rates at 12 months were 15.6 percent in the placebo group, as compared with 16.4 percent in the nicotine-patch group, 30.3 percent in the bupropion group (P<0.001), and 35.5 percent in the group given bupropion and the nicotine patch (P<0.001). By week 7, subjects in the placebo group had gained an average of 2.1 kg, as compared with a gain of 1.6 kg in the nicotine-patch group, a gain of 1.7 kg in the bupropion group, and a gain of 1.1 kg in the combined-treatment group (P<0.05). Weight gain at seven weeks was significantly less in the combined-treatment group than in the bupropion group and the placebo group (P<0.05 for both comparisons). A total of 311 subjects (34.8 percent) discontinued one or both medications. Seventy-nine subjects stopped treatment because of adverse events: 6 in the placebo group (3.8 percent), 16 in the nicotine-patch group (6.6 percent), 29 in the bupropion group (11.9 percent), and 28 in the combined-treatment group (11.4 percent). The most common adverse events were insomnia and headache. CONCLUSIONS: Treatment with sustained-release bupropion alone or in combination with a nicotine patch resulted in significantly higher long-term rates of smoking cessation than use of either the nicotine patch alone or placebo. Abstinence rates were higher with combination therapy than with bupropion alone, but the difference was not statistically significant.

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Cahill K, Stead L, Lancaster T.
Nicotine receptor partial agonists for smoking cessation.
Cochrane Database Syst Rev 2007 Jan 24; (1): CD006103.
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BACKGROUND: Nicotine receptor partial agonists may help smokers to quit by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). Varenicline was developed as a nicotine receptor partial agonist from cytisine, a drug widely used in central and eastern Europe for smoking cessation. The first trial reports of varenicline were released in 2006, and further trials are underway. OBJECTIVES: The primary objective of this review is to assess the efficacy and tolerability of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group's specialised register for trials, using the terms ('varenicline' or 'cytisine' or 'Tabex' or 'nicotine receptor partial agonist') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, PsycINFO and CINAHL using MeSH terms and free text, and we contacted authors of trial reports for additional information where necessary. The last search was in October 2006. SELECTION CRITERIA: We included randomized controlled trials which compared the treatment drug with placebo. We also included comparisons with bupropion where available. We excluded trials which did not report a minimum follow-up period of six months from start of treatment. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, and completeness of follow up.The main outcome measured was abstinence from smoking after at least six months from the beginning of treatment. We used the most rigorous definition of abstinence, and preferred biochemically validated rates where they were reported. Where appropriate we performed meta-analysis using the Mantel-Haenszel fixed-effect model. MAIN RESULTS: We found five trials of varenicline compared with placebo for smoking cessation; three of these also included a bupropion experimental arm. We also found one relapse prevention trial, comparing varenicline with placebo. The six trials covered 4924 participants, 2451 of whom used varenicline. We identified one trial of cytisine (Tabex) for inclusion.The pooled odds ratio (OR) for continuous abstinence at 12 months for varenicline versus placebo was 3.22 (95% confidence interval [CI] 2.43 to 4.27). The pooled OR for varenicline versus bupropion was 1.66 (95% CI 1.28 to 2.16). The main adverse effect of varenicline was nausea, which was mostly at mild to moderate levels and usually subsided over time. The two trials which tested the use of varenicline beyond the 12-week standard regimen found the drug to be well-tolerated and effective during long-term use.The one cytisine trial included in this review found that more participants taking cytisine stopped smoking compared with placebo at two-year follow up, with an OR of 1.77 (95% CI 1.30 to 2.40). AUTHORS' CONCLUSIONS: Varenicline increased the odds of successful long-term smoking cessation approximately threefold compared with pharmacologically unassisted quit attempts.In trials reported so far, more participants quit successfully with varenicline than with bupropion. The effectiveness of varenicline as an aid to relapse prevention has not been clearly established. The main adverse effect of varenciline is nausea, but this is mostly at mild to moderate levels and tends to reduce with habituation.There is a need for independent trials of varenicline versus placebo, to test the early findings. There is also a need for direct comparisons with nicotine replacement therapy, and for further trials with bupropion, to establish the relative efficacy of the treatments.Cytisine may also increase the chances of quitting, but the evidence at present is inconclusive.

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Jiménez-Ruiz CA, Solano S, González de Vega M, Ruiz MJ, Flórez S, Ramos A et al.
Normativa para el tratamiento del tabaquismo.
Arch Bronconeumol 1999; 35 (10): 499-506.
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[No hay abstract disponible]

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Nichol KL, Baken L, Nelson A.
Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease.
Ann Intern Med 1999 Mar 2; 130 (5): 397-403.
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BACKGROUND: Influenza vaccine is underused in groups targeted for vaccination. OBJECTIVE: To define the effects of influenza and the benefits of influenza vaccination in elderly persons with chronic lung disease. DESIGN: Retrospective, multiseason cohort study. SETTING: Large managed care organization. PATIENTS: All elderly members of a managed care organization who had a previous diagnosis of chronic lung disease. MEASUREMENTS: Outcomes in vaccinated and unvaccinated persons for the 1993-1994, 1994-1995, and 1995-1996 influenza seasons were compared after adjustment for baseline demographic and health characteristics. All data were obtained from administrative databases. RESULTS: Vaccination rates were greater than 70% for each season. Among unvaccinated persons, hospitalization rates for pneumonia and influenza were twice as high in the influenza seasons as they were in the interim (noninfluenza) periods. Influenza vaccination was associated with fewer hospitalizations for pneumonia and influenza (adjusted risk ratio, 0.48 [95% CI, 0.28 to 0.82]) and with lower risk for death (adjusted odds ratio, 0.30 [CI, 0.21 to 0.43]) during the influenza seasons. It was also associated with fewer outpatient visits for pneumonia and influenza and for all respiratory conditions. CONCLUSIONS: For elderly persons with chronic lung disease, influenza is associated with significant adverse health effects and influenza vaccination is associated with substantial health benefits, including fewer outpatient visits, fewer hospitalizations, and fewer deaths. Health care providers should take advantage of all opportunities to immunize these high-risk patients.

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Ortqvist A, Hedlund J, Burman LA, Elbel E, Hofer M, Leinonen M et al.
Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group.
Lancet 1998 Feb 7; 351 (9100): 399-403.
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BACKGROUND: We assessed the effectiveness of a 23-valent pneumococcal vaccine in the prevention of pneumococcal pneumonia and of pneumonia overall in non-immunocompromised middle-aged and elderly people. METHODS: The prospective, multicentre, double-blind, randomised, placebo-controlled trial was carried out across departments of infectious diseases at six tertiary-care or university hospitals in Sweden. 691 non-immunocompromised patients aged 50-85 years who had been treated as inpatients for community-acquired pneumonia (CAP) were randomly assigned either 23-valent pneumococcal capsular polysaccharide vaccine or placebo (sodium chloride). We used Cox regression models to estimate the relative risks of pneumonia overall and pneumococcal pneumonia for the placebo group compared with the vaccine group. FINDINGS: 63 (19%) of 339 patients in the vaccine group and 57 (16%) of 352 patients in the placebo group developed a new pneumonia, corresponding to a relative risk over time for the placebo group compared with the vaccine group of 0.83 (95% CI 0.58-1.12, p=0.31). Pneumococcal pneumonia was diagnosed in 16 (4.5%) patients in the placebo group and in 19 (5.6%) in the vaccine group, corresponding to a relative risk for the placebo group of 0.78 (95% CI 0.40-1.51, p=0.45). We found no difference in the death rate between the two study groups. INTERPRETATION: The 23-valent pneumococcal polysaccharide vaccine did not prevent pneumonia overall or pneumococcal pneumonia in middle-aged and elderly individuals.

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Alfageme I, Vazquez R, Reyes N, Muñoz J, Fernández A, Hernández M et al.
Clinical efficacy of anti-pneumococcal vaccination in patients with COPD.
Thorax 2006 Mar; 61 (3): 189-95.
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BACKGROUND: A study was undertaken to evaluate the clinical efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV) in immunocompetent patients with chronic obstructive pulmonary disease (COPD). METHODS: A randomised controlled trial was carried out in 596 patients with COPD of mean (SD) age 65.8 (9.7) years, 298 of whom received PPV. The main outcome was radiographically proven community acquired pneumonia (CAP) of pneumococcal or unknown aetiology after a mean period of 979 days (range 20-1454). RESULTS: There were 58 first episodes of CAP caused by pneumococcus or of unknown aetiology, 25 in the intervention group and 33 in the non-intervention group. Kaplan-Meier survival curves for CAP did not show significant differences between the intervention and non-intervention arms (log rank test = 1.15, p = 0.28) in the whole group of patients. The efficacy of PPV in all patients was 24% (95% CI -24 to 54; p = 0.333). In the subgroup aged <65 years the efficacy of PPV was 76% (95% CI 20 to 93; p = 0.013), while in those with severe functional obstruction (forced expiratory volume in 1 second <40%) it was 48% (95% CI -7 to 80; p = 0.076). In younger patients with severe airflow obstruction the efficacy was 91% (95% CI 35 to 99; p = 0.002). There were only five cases of non-bacteraemic pneumococcal CAP, all in the non-intervention group (log rank test = 5.03; p = 0.025). Multivariate analysis gave a hazard ratio for unknown and pneumococcal CAP in the vaccinated group, adjusted for age, of 0.20 (95% CI 0.06 to 0.68; p = 0.01). CONCLUSIONS: PPV is effective in preventing CAP in patients with COPD aged less than 65 years and in those with severe airflow obstruction. No differences were found among the other groups of patients with COPD.

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Prieto A, Reyes E, Bernstein ED, Martínez B, Monserrat J, Izquierdo JL et al.
Defective natural killer and phagocytic activities in chronic obstructive pulmonary disease are restored by glycophosphopeptical (inmunoferón).
Am J Respir Crit Care Med 2001 Jun; 163 (7): 1578-83.
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We have investigated both modifications in natural (innate) immunity caused by chronic obstructive pulmonary disease (COPD) and the effects of a glycophosphopeptical immunomodulator (Inmunoferon) treatment on COPD-associated immunoalterations. In a double-blinded clinical trial, 60 patients with COPD received glycophosphopeptical or placebo during 90 consecutive days at oral doses of 3 g/d. Fifty-six sex- and age-matched healthy control subjects were included as a reference group for immunologic parameters. Peripheral blood natural killer (PBNK) cell cytotoxic activity and phagocytic activity of peripheral monocytes/macrophages (Mo/Ma) and polymorphonuclear (PMN) cells were assessed at baseline and then again at the end of treatments. We found both PBNK activity and phagocytic activity to be significantly decreased in patients with COPD compared with levels in healthy volunteers. The treatment with glycophosphopeptical provoked significant stimulatory effects on PBNK cytotoxic activity. This stimulation was not mediated by an increase in CD3(-)CD56(+) NK cells. Further, glycophosphopeptical significantly increased the percentage of monocytes and PMNs that phagocytize Escherichia coli in vitro, as well as increased phagocytic indices. We conclude that peripheral blood cells of patients with COPD show clear defects in natural immunity that are partially rescued by glycophosphopeptical.

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Collet JP, Shapiro P, Ernst P, Renzi T, Ducruet T, Robinson A.
Effects of an immunostimulating agent on acute exacerbations and hospitalizations in patients with chronic obstructive pulmonary disease. The PARI-IS Study Steering Committee and Research Group.
Am J Respir Crit Care Med 1997 Dec; 156 (6): 1719-24.
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The PARI-IS Study is a double-blind placebo-controlled randomized clinical trial to study the effect of an immunostimulating agent to prevent acute respiratory exacerbation in patients with COPD. Three hundred eighty-one ambulatory patients (190 placebo and 191 immunostimulant) were followed at home for 6 mo by experienced research nurses. The risk of having at least one episode of acute exacerbation (primary outcome) was similar in the two groups (p = 0.872). In contrast, the total number of days of hospitalization for a respiratory problem was 55% less in the group treated with OM-85 BV (287 d) than in the group treated with placebo (642 d). Patients treated with OM-85 BV spent an average of 1.5 d in hospital compared with 3.4 d for patients treated with placebo (p = 0.037). The risk of being hospitalized for a respiratory problem was 30% lower in the treated group (16.2%) than in the placebo group (23.2%); p = 0.089. Eight deaths were observed: two in patients treated with OM-85 BV and six in patients treated with placebo (p = 0.153). During the course of the study dyspnea improved slightly in patients treated with OM-85 BV, whereas it deteriorated slightly in patients receiving placebo (p = 0.028). These results suggest that this immunostimulating agent may be beneficial for patients with COPD by reducing the likelihood of severe respiratory events leading to hospitalization.

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Calverley PM.
Breathlessness during exercise in COPD: how do the drugs work?
Thorax 2004 Jun; 59 (6): 455-7.
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The inability to exercise because of distressing breathlessness is one of the most frequent problems experienced by patients with chronic obstructive pulmonary disease (COPD)1 and is a major determinant of impaired quality of life.2 Our understanding of why this occurs and how best to treat it has improved significantly in the last decade. At one level the problem appears relatively straightforward. Exercise invariably involves an increase in whole body oxygen consumption and carbon dioxide production, which requires an appropriate rise in alveolar ventilation if arterial carbon dioxide tension is to remain constant. In patients with COPD the ability to increase minute ventilation is restricted as is the capacity to empty their lungs quickly, hence exercise limitation occurs at a lower workload than in age matched healthy subjects. Although there is much truth in this simple scheme, it does not do justice to the many complex adaptive responses that patients use to cope with their chronic airflow obstruction, nor does it explain the variability seen in both the duration of exercise and the intensity of breathlessness in patients with apparently similar levels of airflow obstruction.

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COMBIVENT Inhalation Aerosol Study Group.
In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85-day multicenter trial.
Chest 1994 May; 105 (5): 1411-9.
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Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) is available widely throughout the world except in North America. Previous studies have yielded conflicting results regarding the advantages of combining anticholinergic therapy with sympathomimetic therapy in COPD. We report the results of a 12-week prospective, double-blind, parallel-group evaluation of the use of the following: albuterol, a beta-adrenergic agent; ipratropium, an anticholinergic agent; or a combination of the two, administered by metered-dose inhaler to patients with moderately severe stable COPD. Following baseline studies, 534 patients were given one of the three test bronchodilator preparations to be used at home four times daily in addition to oral theophylline and corticosteroids as required. The doses of the latter two drugs were kept stable. Subjects were tested on days 1, 29, 57, and 85. Analysis of 1-s forced expiratory volume (FEV1) curves on those test days indicated that the combination was superior to either single agent alone in peak effect, in the effect during the first 4 h after dosing, and in the total area under the curve of the FEV1 response. The mean peak percent increases in FEV1 over baseline on the four test days were 31 to 33 percent for the combination, 24 to 25 percent for ipratropium, and 24 to 27 percent for albuterol. The differences between the combination and its components were statistically significant on all test days. The AUC0-4 means for the combination were 21 to 44 percent greater than the ipratropium means and 30 to 46 percent greater than the albuterol means. Similar changes were noted in the forced vital capacity curves. Symptom scores did not change over time and did not differ among the treatment groups. We conclude that the combination of ipratropium and albuterol, when given by metered-dose inhaler to patients with COPD, is more effective than either of the two agents alone. The advantage of the combination is apparent primarily during the first 4 h after administration. The availability of combination therapy by metered-dose inhaler should help to improve patient compliance.

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Boyd G, Morice AH, Pounsford JC, Siebert M, Peslis N, Crawford C.
An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD).
Eur Respir J 1997 Apr; 10 (4): 815-21.
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The objectives of this study were to compare the efficacy and safety of salmeterol xinafoate (50 and 100 microg b.i.d.) with that of placebo, when added to existing therapy, in the treatment of patients with chronic obstructive pulmonary disease (COPD). Six hundred and seventy four patients were randomized to receive either salmeterol 50 microg b.i.d., salmeterol 100 microg b.i.d., or placebo treatment for a period of 16 weeks. The results showed a significant improvement in daily symptom scores noted for patients taking either 50 microg (p=0.043) or 100 microg b.i.d. salmeterol (p=0.01) compared with placebo, with a corresponding decrease in additional daytime salbutamol requirements for both salmeterol groups. The same pattern was reflected for night-time symptoms and additional salbutamol use. During treatment, forced expiratory volume in one second (FEV1) measurements improved significantly in each salmeterol group, with up to a 7% improvement observed at the end of the study. Although no difference was observed between treatment groups for the distance walked in 6 min, patients treated with salmeterol 50 microg b.i.d. were significantly less breathless than those treated with placebo after their 6 min walk, after 8 weeks (p=0.024) and 16 weeks (p=0.004) of therapy. Adverse events were similar in all three groups except for tremor, which was significantly higher in the 100 microg b.i.d. salmeterol group (p=0.005) compared both with 50 microg b.i.d. salmeterol and placebo. Salmeterol offered further positive improvement to the effect of therapy in patients with chronic obstructive pulmonary disease when added to their existing regimens. This clinical improvement was similar both with 50 and 100 microg b.i.d. dosage, although the group receiving 50 microg b.i.d. tolerated the drug better than those receiving 100 microg b.i.d. salmeterol.

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Aalbers R, Ayres J, Backer V, Decramer M, Lier PA, Magyar P et al.
Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial.
Eur Respir J 2002 May; 19 (5): 936-43.
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The aim of this study was to investigate formoterol, an inhaled long-acting beta2-agonist, in patients with chronic obstructive pulmonary disease (COPD). Six-hundred and ninety-two COPD patients, mean baseline forced expiratory volume in one second (FEV1) 54%, FEV1/forced vital capacity 75% of predicted, reversibility 6.4% pred, were treated with formoterol (4.5, 9 or 18 microg b.i.d.) or placebo via Turbuhaler for 12 weeks. Symptoms were recorded daily. Spirometry and the incremental shuttle walking test (SWT) were performed at clinic visits. Compared with placebo, 18 microg b.i.d. formoterol reduced the mean total symptom score by 13% and increased the percentage of nights without awakenings by 15%. Formoterol (9 and 18 microg b.i.d.) significantly reduced symptom scores for breathlessness (-7% and -9%, respectively) and chest tightness (-11% and -8%, respectively), reduced the need for rescue medication (-25% and -18%, respectively), and increased symptom-free days (71% and 86%, respectively). FEV1 improved significantly after all three doses of formoterol (versus placebo). No differences were found between groups in SWT walking distance. No unexpected adverse events were seen. In conclusion, 9 and 18 microg b.i.d. formoterol reduced symptoms and increased the number of symptom-free days in a dose-dependent manner in chronic obstructive pulmonary disease patients. Formoterol improved lung function at a dose of 4.5 microg b.i.d. and higher.

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Jones PW, Bosh TK.
Quality of life changes in COPD patients treated with salmeterol.
Am J Respir Crit Care Med 1997 Apr; 155 (4): 1283-9.
Ver Abstract                    Texto Completo

Changes in health-related quality of life (HRQoL) were evaluated in patients with chronic obstructive pulmonary disease (COPD) following treatment with placebo, salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler. Patients completed the disease-specific St. George's Respiratory Questionnaire (SGRQ) and the Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 16 wk of treatment. Data from 283 patients (95 patients in the placebo group and 94 in each salmeterol group) were available for HRQoL analysis. Apart from a small difference in ages, all treatment groups were well matched at baseline in terms of forced expiratory volume in one second (FEV1) and HRQoL scores. Compared with placebo, salmeterol 50 microg twice a day was associated with significant improvements in SGRQ "Total" and "Impacts" scores which exceeded the threshold for a clinically significant change. This was not seen with salmeterol 100 microg twice a day. Changes in SGRQ and SF-36 scores correlated. They also showed a weak but significant relationship with FEV1. This study has shown that a modest change in lung function may be associated with clinically significant gain in health and well-being in COPD patients.

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O'Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B et al.
Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD.
Eur Respir J 2004 Jun; 23 (6): 832-40.
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The aim of this study was to test the hypothesis that use of tiotropium, a new long-acting anticholinergic bronchodilator, would be associated with sustained reduction in lung hyperinflation and, thereby, would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease. A randomised, double-blind, placebo-controlled, parallel-group study was conducted in 187 patients (forced expiratory volume in one second 44 +/- 13% pred): 96 patients received 18 microg tiotropium and 91 patients received placebo once daily for 42 days. Spirometry, plethysmographic lung volumes, cycle exercise endurance and exertional dyspnoea intensity at 75% of each patient's maximal work capacity were compared. On day 42, the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to placebo: vital capacity and inspiratory capacity (IC) increased, with inverse decreases in residual volume and functional residual capacity. Tiotropium increased post-dose exercise endurance time by 105 +/- 40 s (21%) as compared to placebo on day 42. At a standardised time near end-exercise (isotime), IC, tidal volume and minute ventilation all increased, whilst dyspnoea decreased by 0.9 +/- 0.3 Borg scale units. In conclusion, the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise. Resultant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance.

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Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S.
Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD.
Chest 2005 Mar; 127 (3): 809-17.
Ver Abstract                    Texto Completo

STUDY OBJECTIVES: Pulmonary rehabilitation (PR) improves exercise tolerance in COPD patients. Tiotropium is a once-daily, inhaled anticholinergic bronchodilator that provides sustained 24-h improvements in airflow and lung hyperinflation reduction. We hypothesized that ventilatory mechanics improvements from tiotropium would permit enhanced ability to train muscles of ambulation and therefore augment exercise tolerance benefits of PR. DESIGN: In a randomized, double-blind, placebo-controlled trial (tiotropium, n = 47; placebo, n = 44), tiotropium (18 microg qd) was administered to COPD patients participating in 8 weeks of PR (treadmill training three times a week; >/= 30 min per session) at 17 sites. Study drug was administered 5 weeks prior to, 8 weeks during, and 12 weeks following PR. The primary end point was treadmill walking (0% incline) endurance time at 80% of maximum speed attained in an initial incremental test. The transition dyspnea index (TDI), St. George's respiratory questionnaire (SGRQ), and rescue albuterol use were secondary end points. PARTICIPANTS: Mean age of the 93 participants was 67 years, 57% were men, and mean FEV(1) was 0.88 L (34% predicted). RESULTS: Mean endurance time differences (tiotropium minus placebo) prior to PR, at the end of PR, and 12 weeks after PR were 1.65 min (p = 0.183), 5.35 min (p = 0.025), and 6.60 min (p = 0.018), respectively. Mean TDI focal scores at the end of PR were 1.75 for tiotropium and 0.91 for placebo (p > 0.05). At 12 weeks after PR, TDI focal scores were 1.75 for tiotropium and 0.08 for placebo (p < 0.05). Relative to placebo, tiotropium improved SGRQ total scores by 3.86 at the end of PR and 4.44 at 12 weeks after PR (p > 0.05). Mean albuterol use declined following PR plus tiotropium, compared to PR alone (p </= 0.05 for 17 of 25 weeks). CONCLUSIONS: Tiotropium in combination with PR improved endurance of a constant work rate treadmill task and produced clinically meaningful improvements in dyspnea and health status compared to PR alone. Improvements with tiotropium were sustained for 3 months following PR completion.

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Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J et al.
Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD.
Chest 2002 Apr; 121 (4): 1058-69.
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STUDY OBJECTIVE: To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD. DESIGN: A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations. SETTING: Eighty-one centers worldwide. PATIENTS: Eight hundred fifty-four patients with symptomatic COPD. INTERVENTION: Comparison of twice-daily inhaled formoterol dry powder (12 or 24 microg), PL, and THEO (individualized doses) over 12 months. MEASUREMENTS AND RESULTS: Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV(1) measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 microg, was significantly more effective than that with THEO (p < or = 0.026). Formoterol significantly reduced the percentage of "bad days" (i.e., days with at least two individual symptom scores > or = 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p < or = 0.035 vs. PL and THEO), and the use of salbutamol rescue medication (p < or = 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p < or = 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol. CONCLUSIONS: Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.

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Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A et al.
Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial.
Lancet 2003 Feb 8; 361 (9356): 449-56.
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BACKGROUND: Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease (COPD), whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status. We postulated that a combination of these treatments would be better than each component used alone. METHODS: 1465 patients with COPD were recruited from outpatient departments in 25 countries. They were treated in a randomised, double-blind, parallel-group, placebo-controlled study with either 50 microg salmeterol twice daily (n=372), 500 microg fluticasone twice daily (n=374), 50 microg salmeterol and 500 microg fluticasone twice daily (n=358), or placebo (n=361) for 12 months. The primary outcome was the pretreatment forced expiratory volume in 1s (FEV1) after 12 months treatment' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h. Secondary outcomes were other lung function measurements, symptoms and rescue treatment use, the number of exacerbations, patient withdrawals, and disease-specific health status. We assessed adverse events, serum cortisol concentrations, skin bruising, and electrocardiograms. Analysis was as predefined in the study protocol. FINDINGS: All active treatments improved lung function, symptoms, and health status and reduced use of rescue medication and frequency of exacerbations. Combination therapy improved pretreatment FEV1 significantly more than did placebo (treatment difference 133 mL, 95% CI 105-161, p<0.0001), salmeterol (73 mL, 46-101, p<0.0001), or fluticasone alone (95 mL, 67-122, p<0.0001). Combination treatment produced a clinically significant improvement in health status and the greatest reduction in daily symptoms. All treatments were well tolerated with no difference in the frequency of adverse events, bruising, or clinically significant falls in serum cortisol concentration. INTERPRETATION: Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function, with no greater risk of side-effects than that with use of either component alone, this combination treatment should be considered for patients with COPD.

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Dusser D, Bravo ML, Iacono P.
The effect of tiotropium on exacerbations and airflow in patients with COPD.
Eur Respir J 2006 Mar; 27 (3): 547-55.
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This randomised, double-blind, parallel-group, 1-yr study compared the effect of tiotropium 18 microg once daily (n=500) and placebo (n=510) on exacerbations, associated health resource use (HRU) and airflow limitation in chronic obstructive pulmonary disease (COPD) patients. The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40, the mean weekly morning peak expiratory flow (PEF) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second (FEV1) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days, reduced the proportion of patients experiencing more than one exacerbation by 17%, and decreased the number of exacerbations by 35% and exacerbation days by 37% versus placebo. Tiotropium also decreased HRU versus placebo, as indicated by the significant reductions in the use of concomitant respiratory medications, antibiotics and oral steroids, and the number of unscheduled physician contacts. Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study. At the end of the study, tiotropium significantly improved trough (pre-dose) FEV1, forced vital capacity, slow vital capacity and inspiratory capacity versus placebo. In conclusion, tiotropium reduced exacerbations and associated health resource use, and improved airflow over 1 yr in chronic obstructive pulmonary disease patients.

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Aaron SD, Vandemheen KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R et al.
Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
Ann Intern Med 2007 Apr 17; 146 (8): 545-55.
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BACKGROUND: Treatment of moderate or severe chronic obstructive pulmonary disease (COPD) with combinations of inhaled corticosteroids, long-acting beta-agonists, and long-acting anticholinergic bronchodilators is common but unstudied. OBJECTIVE: To determine whether combining tiotropium with salmeterol or fluticasone-salmeterol improves clinical outcomes in adults with moderate to severe COPD compared with tiotropium alone. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from October 2003 to January 2006. SETTING: 27 academic and community medical centers in Canada. PATIENTS: 449 patients with moderate or severe COPD. INTERVENTION: 1 year of treatment with tiotropium plus placebo, tiotropium plus salmeterol, or tiotropium plus fluticasone-salmeterol. MEASUREMENTS: The primary end point was the proportion of patients who experienced an exacerbation of COPD that required treatment with systemic steroids or antibiotics. RESULTS: The proportion of patients in the tiotropium plus placebo group who experienced an exacerbation (62.8%) did not differ from that in the tiotropium plus salmeterol group (64.8%; difference, -2.0 percentage points [95% CI, -12.8 to 8.8 percentage points]) or in the tiotropium plus fluticasone-salmeterol group (60.0%; difference, 2.8 percentage points [CI, -8.2 to 13.8 percentage points]). In sensitivity analyses, the point estimates and 95% confidence bounds shifted in the direction favoring tiotropium plus salmeterol and tiotropium plus fluticasone-salmeterol. Tiotropium plus fluticasone-salmeterol improved lung function (P = 0.049) and disease-specific quality of life (P = 0.01) and reduced the number of hospitalizations for COPD exacerbation (incidence rate ratio, 0.53 [CI, 0.33 to 0.86]) and all-cause hospitalizations (incidence rate ratio, 0.67 [CI, 0.45 to 0.99]) compared with tiotropium plus placebo. In contrast, tiotropium plus salmeterol did not statistically improve lung function or hospitalization rates compared with tiotropium plus placebo. LIMITATIONS: More than 40% of patients who received tiotropium plus placebo and tiotropium plus salmeterol discontinued therapy prematurely, and many crossed over to treatment with open-label inhaled steroids or long-acting beta-agonists. CONCLUSIONS: Addition of fluticasone-salmeterol to tiotropium therapy did not statistically influence rates of COPD exacerbation but did improve lung function, quality of life, and hospitalization rates in patients with moderate to severe COPD. International Standard Randomised Controlled Trial registration number: ISRCTN29870041.

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van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B et al.
Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.
Eur Respir J 2005 Aug; 26 (2): 214-22.
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This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

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Ram FS, Jones PW, Castro AA, De Brito JA, Atallah AN, Lacasse Y et al.
Oral theophylline for chronic obstructive pulmonary disease (Cochrane Review).
Cochrane Database Syst Rev 2002; (4): CD003902.
Ver Abstract                    Texto Completo

BACKGROUND: Oral theophylline has, for many years, been used as a bronchodilator in patients with COPD. Despite the introduction of new drugs, and its narrow therapeutic index, theophylline is still recommended for COPD treatment. OBJECTIVES: To determine the effectiveness of oral theophylline when compared to placebo in patients with stable COPD. SEARCH STRATEGY: The Cochrane Airways Review Group and Cochrane Controlled Clinical Registers were searched. SELECTION CRITERIA: All studies were randomised controlled trials (RCTs). DATA COLLECTION AND ANALYSIS: Data were independently abstracted and the methodological quality assessed by two reviewers. MAIN RESULTS: Twenty RCTs met the inclusion criteria. Concomitant therapy varied from none to any other bronchodilator plus corticosteroid (oral and inhaled). The following outcomes were significantly different when compared to placebo. FEV1 improved with treatment: Weighted Mean Difference (WMD) 100 ml; 95% Confidence Interval (95%CI) 40, 160 ml. Similarly for FVC: WMD 210 ml 95%CI 100, 320. Two studies reported an improvement in VO2max; WMD 195 ml/min, 95%CI 113,27). At rest, PaO2 and PaCO2 both improved with treatment (WMD 3.2 mmHg; 95%CI = 1.2, 5., and WMD -2.4 mmHg; 95%CI = -3.5, -1.2, respectively). Walking distance tests did not improve (4 studies, Standardised Mean Difference 0.30, 95%CI -0.01, 0.62), neither did Visual Analogue Score for breathlessness isn two small studies (WMD 3.6, 95%CI -4.6, 11.8). The Relative Risk (RR) of nausea was greater with theophylline (RR 7.7; 95%CI 1.5, 39.9). However, patients' preference for theophylline was greater than that for placebo (RR 2.27; 95%CI = 1.26, 4.11). Very few patient withdrew from these studies for any reason. REVIEWER'S CONCLUSIONS: Theophylline has a modest effect on FEV1 and FVC and slightly improves arterial blood gas tensions in moderate to severe COPD. These benefits were seen in patients receiving a variety of different concomitant therapies. Improvement in exercise performance depended on the method of testing. There was a very low dropout rate in the studies that could be included in this review, which suggests that recruited patients may have been known by the investigators to be theophylline tolerant. This may limit the generalisability of these studies.

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Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K.
Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial.
Lancet 1999 May 29; 353 (9167): 1819-23.
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BACKGROUND: Little is known about the long-term efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease (COPD). We investigated the efficacy of inhaled budesonide on decline in lung function and respiratory symptoms in a 3-year placebo-controlled study of patients with COPD. METHODS: We used a parallel-group, randomised, double-blind, placebo-controlled design in a singlecentre study, nested in a continuing epidemiological survey (the Copenhagen City Heart Study). Inclusion criteria were as follows: no asthma; a ratio of forced expiratory volume in 1 s (FEV1) and vital capacity of 0.7 or less; FEV1 which showed no response (<15% change) to 1 mg inhaled terbutaline or prednisolone 37.5 mg orally once daily for 10 days. 290 patients were randomly assigned budesonide, 800 microg plus 400 microg daily for 6 months followed by 400 microg twice daily for 30 months, or placebo for 36 months. The mean age of the participants was 59 years and the mean FEV1 2.37 L or 86% of predicted. The main outcome measure was rate of FEV1 decline. Analyses were by intention to treat. FINDINGS: The crude rates of FEV1 decline were slightly smaller than expected (placebo group 41.8 mL per year, budesonide group 45.1 mL per year). The estimated rates of decline from the regression model did not differ significantly (49.1 mL vs 46.0 mL per year; difference 3.1 mL per year [95% CI -12.8 to 19.0]; p=0.7). Before the study, the minimum relevant difference was defined as 20 mL per year; this difference was outside the 95% CI. No effect of inhaled budesonide was seen on respiratory symptoms. 316 exacerbations occurred during the study period, 155 in the budesonide group and 161 in the placebo group. Treatment was well tolerated. INTERPRETATION: Inhaled budesonide was of no clinical benefit in COPD patients recruited from the general population by screening. We question the role of long-term inhaled corticosteroids in the treatment of mild to moderate COPD.

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Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB et al.
Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease.
N Engl J Med 1999 Jun 24; 340 (25): 1948-53.
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BACKGROUND: Although patients with chronic obstructive pulmonary disease (COPD) should stop smoking, some do not. In a double-blind, placebo-controlled study, we evaluated the effect of the inhaled glucocorticoid budesonide in patients with mild COPD who continued smoking. After a six-month run-in period, we randomly assigned 1277 subjects (mean age, 52 years; mean forced expiratory volume in one second [FEV1], 77 percent of the predicted value; 73 percent men) to twice-daily treatment with 400 microg of budesonide or placebo, inhaled from a dry-powder inhaler, for three years. RESULTS: Of the 1277 subjects, 912 (71 percent) completed the study. Among these subjects, the median decline in the FEV1 after the use of a bronchodilator over the three-year period was 140 ml in the budesonide group and 180 ml in the placebo group (P=0.05), or 4.3 percent and 5.3 percent of the predicted value, respectively. During the first six months of the study, the FEV1 improved at the rate of 17 ml per year in the budesonide group, as compared with a decline of 81 ml per year in the placebo group (P<0.001). From nine months to the end of treatment, the FEV1 declined at similar rates in the two groups (P=0.39). Ten percent of the subjects in the budesonide group and 4 percent of those in the placebo group had skin bruising (P<0.001). Newly diagnosed hypertension, bone fractures, postcapsular cataracts, myopathy, and diabetes occurred in less than 5 percent of the subjects, and the diagnoses were equally distributed between the groups. CONCLUSIONS: In patients with mild COPD who continue smoking, the use of inhaled budesonide is associated with a small one-time improvement in lung function but does not appreciably affect the long-term progressive decline.

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Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA, Maslen TK.
Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial.
BMJ 2000 May 13; 320 (7245): 1297-303.
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OBJECTIVES: To determine the effect of long term inhaled corticosteroids on lung function, exacerbations, and health status in patients with moderate to severe chronic obstructive pulmonary disease. DESIGN: Double blind, placebo controlled study. SETTING: Eighteen UK hospitals. Participants: 751 men and women aged between 40 and 75 years with mean forced expiratory volume in one second (FEV(1)) 50% of predicted normal. Interventions: Inhaled fluticasone propionate 500 microgram twice daily from a metered dose inhaler or identical placebo. Main outcome measures: Efficacy measures: rate of decline in FEV(1) after the bronchodilator and in health status, frequency of exacerbations, respiratory withdrawals. Safety measures: morning serum cortisol concentration, incidence of adverse events. RESULTS: There was no significant difference in the annual rate of decline in FEV(1 )(P=0.16). Mean FEV(1) after bronchodilator remained significantly higher throughout the study with fluticasone propionate compared with placebo (P<0.001). Median exacerbation rate was reduced by 25% from 1.32 a year on placebo to 0.99 a year on with fluticasone propionate (P=0.026). Health status deteriorated by 3.2 units a year on placebo and 2.0 units a year on fluticasone propionate (P=0.0043). Withdrawals because of respiratory disease not related to malignancy were higher in the placebo group (25% v 19%, P=0.034). CONCLUSIONS: Fluticasone propionate 500 microgram twice daily did not affect the rate of decline in FEV(1) but did produce a small increase in FEV(1). Patients on fluticasone propionate had fewer exacerbations and a slower decline in health status. These improvements in clinical outcomes support the use of this treatment in patients with moderate to severe chronic obstructive pulmonary disease.

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Altose MD, Redline S, Deitz CD, Quinlan KJ, The Lung Health Study Research Group.
Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease.
N Engl J Med 2000 Dec 28; 343 (26): 1902-9.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) results from a progressive decline in lung function, which is thought to be the consequence of airway inflammation. We hypothesized that antiinflammatory therapy with inhaled corticosteroids would slow this decline. METHODS: We enrolled 1116 persons with COPD whose forced expiratory volume in one second (FEV1) was 30 to 90 percent of the predicted value in a 10-center, placebo-controlled, randomized trial of inhaled triamcinolone acetonide administered at a dose of 600 microg twice daily. The primary outcome measure was the rate of decline in FEV1 after the administration of a bronchodilator. The secondary outcome measures included respiratory symptoms, use of health care services, and airway reactivity. In a substudy of 412 participants, we measured bone density in the lumbar spine and femur at base line and one and three years after the beginning of treatment. RESULTS: The mean duration of follow-up was 40 months. The rate of decline in the FEV1 after bronchodilator use was similar in the 559 participants in the triamcinolone group and the 557 participants in the placebo group (44.2+/-2.9 vs. 47.0+/-3.0 ml per year, P= 0.50). Members of the triamcinolone group had fewer respiratory symptoms during the course of the study (21.1 per 100 person-years vs. 28.2 per 100 person-years, P=0.005) and had fewer visits to a physician because of a respiratory illness (1.2 per 100 person-years vs. 2.1 per 100 person-years, P=0.03). Those taking triamcinolone also had lower airway reactivity in response to methacholine challenge at 9 months and 33 months (P=0.02 for both comparisons). After three years, the bone density of the lumbar spine and the femur was significantly lower in the triamcinolone group (P < or = 0.007). CONCLUSIONS: Inhaled triamcinolone does not slow the rate of decline in lung function in people with COPD, but it improves airway reactivity and respiratory symptoms and decreases the use of health care services for respiratory problems. These benefits should be weighed against the potential long-term adverse effects of triamcinolone on bone mineral density.

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Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW et al.
Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
N Engl J Med 2007 Feb 22; 356 (8): 775-89.
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BACKGROUND: Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease (COPD), but their effect on survival is unknown. METHODS: We conducted a randomized, double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily (combination regimen), administered with a single inhaler, with placebo, salmeterol alone, or fluticasone propionate alone for a period of 3 years. The primary outcome was death from any cause for the comparison between the combination regimen and placebo; the frequency of exacerbations, health status, and spirometric values were also assessed. RESULTS: Of 6112 patients in the efficacy population, 875 died within 3 years after the start of the study treatment. All-cause mortality rates were 12.6% in the combination-therapy group, 15.2% in the placebo group, 13.5% in the salmeterol group, and 16.0% in the fluticasone group. The hazard ratio for death in the combination-therapy group, as compared with the placebo group, was 0.825 (95% confidence interval [CI], 0.681 to 1.002; P=0.052, adjusted for the interim analyses), corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5%. The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo. As compared with placebo, the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values (P<0.001 for all comparisons with placebo). There was no difference in the incidence of ocular or bone side effects. The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate (19.6% in the combination-therapy group and 18.3% in the fluticasone group) than in the placebo group (12.3%, P<0.001 for comparisons between these treatments and placebo). CONCLUSIONS: The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients.

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Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S et al.
Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease.
Eur Respir J 2003 Jan; 21 (1): 74-81.
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The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo, budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). In a 12-month, randomised, double-blind, placebo-controlled, parallel-group study in 812 adults (mean age 64 yrs, mean forced expiratory volume in one second (FEV1) 36% predicted normal), patients received two inhalations twice daily of either budesonide/formoterol (Symbicort) 160/4.5 microg (delivered dose), budesonide 200 microg (metered dose), formoterol 4.5 microg or placebo. Severe exacerbations and FEV1 (primary variables), peak expiratory flow (PEF), COPD symptoms, health-related quality of life (HRQL), mild exacerbations, use of reliever beta2-agonist and safety variables were recorded. Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24% versus placebo and 23% versus formoterol. FEV1 increased by 15% versus placebo and 9% versus budesonide. Morning PEF improved significantly on day 1 versus placebo and budesonide; after 1 week, morning PEF was improved versus placebo, budesonide and formoterol. Improvements in morning and evening PEF versus comparators were maintained over 12 months. Budesonide/formoterol decreased all symptom scores and use of reliever beta2-agonists significantly versus placebo and budesonide, and improved HRQL versus placebo. All treatments were well tolerated. These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease.

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Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H.
Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease.
Eur Respir J 2003 Dec; 22 (6): 912-9.
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Lung function in chronic obstructive pulmonary disease (COPD) can be improved acutely by oral corticosteroids and bronchodilators. Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown. COPD patients (n=1,022, mean prebronchodilator forced expiratory volume in one second (FEV1) 36% predicted) initially received formoterol (9 microg b.i.d.) and oral prednisolone (30 mg o.d.) for 2 weeks. After this time, patients were randomised to b.i.d. inhaled budesonide/formoterol 320/9 microg, budesonide 400 microg, formoterol 9 microg or placebo for 12 months. Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George's Respiratory Questionnaire (SGRQ) by 4.5 units after run-in. Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide, formoterol or placebo. Budesonide/formoterol patients had a prolonged time to first exacerbation (254 versus 96 days) and maintained higher FEV1 (99% versus 87% of baseline), both primary variables versus placebo. They had fewer exacerbations (1.38 versus 1.80 exacerbations per patient per year), had higher prebronchodilator peak expiratory flow, and showed clinically relevant improvements in SGRQ versus placebo (-7.5 units). Budesonide/formoterol was more effective than either monocomponent in both primary variables. Budesonide/formoterol in a single inhaler (Symbicort) maintains the benefit of treatment optimisation, stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo.

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van der Valk P, Monninkhof E, van der Palen J, Zielhuis G, van Herwaarden C.
Effect of discontinuation of inhaled corticosteroids in patients with chronic obstructive pulmonary disease: the COPE study.
Am J Respir Crit Care Med 2002 Nov 15; 166 (10): 1358-63.
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The aim of this double-blind single center study (the COPE study) was to investigate the effect of discontinuation of the inhaled corticosteroid fluticasone propionate (FP) on exacerbations and health-related quality of life in patients with chronic obstructive pulmonary disease. After 4 months of treatment with FP (1,000 microg/day), 244 patients were randomized to either continue FP or to receive placebo for 6 months: 123 patients continued FP (FP group), and 121 received placebo (placebo group). In the FP group, 58 (47%) patients developed at least one exacerbation compared with 69 (57%) in the placebo group. The hazard ratio of a first exacerbation in the placebo group compared with the FP group was 1.5 (95% confidence interval [CI] 1.1-2.1). In the placebo group 26 patients (21.5%) experienced rapid recurrent exacerbations and were subsequently unblinded and prescribed FP compared with 6 patients (4.9%) in the FP group (relative risk = 4.4; 95% CI 1.9-10.3). Over a 6-month period, a significant difference in favor of the FP group was observed in the total score (+2.48 95% CI 0.37-4.58), activity domain (+4.64 95% CI 1.60-7.68), and symptom domain (+4.58 95% CI 1.05-8.10) of the St. George's Respiratory Questionnaire. This study indicates that discontinuation of FP in patients with chronic obstructive pulmonary disease is associated with a more rapid onset and higher recurrence-risk of exacerbations and a significant deterioration in aspects of Health-Related Quality of Life.

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Wouters EF, Postma DS, Fokkens B, Hop WC, Prins J, Kuipers AF et al.
Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial.
Thorax 2005 Jun; 60 (6): 480-7.
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BACKGROUND: Guidelines recommend inhaled corticosteroids (ICS) as maintenance treatment for patients with chronic obstructive pulmonary disease (COPD) with a post-bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and frequent exacerbations, although they have only a small preventive effect on the accelerated decline in lung function. Combined treatment with ICS and long acting beta2 agonists (LABA) may provide benefit to the stability of COPD, but it is unknown if withdrawal of ICS will result in disease deterioration. METHODS: The effects of 1 year withdrawal of the ICS fluticasone propionate (FP) after a 3 month run-in treatment period with FP combined with the LABA salmeterol (S) (500 microg FP + 50 microg S twice daily; SFC) were investigated in patients with COPD in a randomised, double blind study. 497 patients were enrolled from 39 centres throughout the Netherlands; 373 were randomised and 293 completed the study. RESULTS: The drop out rate after randomisation was similar in the two groups. Withdrawal of FP resulted in a sustained decrease in FEV1: mean (SE) change from baseline -4.4 (0.9)% (S) v -0.1 (0.9)% (SFC); adjusted difference 4.1 (95% CI 1.6 to 6.6) percentage points (p<0.001). Corresponding figures for the FEV1/FVC ratio were -3.7 (0.8)% (S) v 0.0 (0.8)% (SFC) (p = 0.002). The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups, respectively (adjusted rate ratio 1.2; 95% CI 0.9 to 1.5; p = 0.15). The mean annual incidence rate of mild exacerbations was 1.3 (S) v 0.6 (SFC), p = 0.020. An immediate and sustained increase in dyspnoea score (scale 0-4; mean difference between groups 0.17 (0.04), p<0.001) and in the percentage of disturbed nights (6 (2) percentage points, p<0.001) occurred after withdrawal of fluticasone. CONCLUSIONS: Withdrawal of FP in COPD patients using SFC resulted in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights. This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration, even under treatment with a LABA.

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Sin DD, Tu JV.
Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2001 Aug 15; 164 (4): 580-4.
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There is considerable controversy concerning the utility of inhaled corticosteroids for the long-term treatment of patients with COPD. Recent studies have suggested that although inhaled corticosteroids do not alter the rate of decline in lung function, they may reduce airway hyperresponsiveness, decrease the frequency of exacerbations, and slow the rate of decline in the patients' health status. The relationship between inhaled corticosteroids and subsequent risk of hospitalization or mortality remains unknown. We therefore conducted a population-based cohort study using administrative databases in Ontario, Canada (n = 22,620) to determine the association between inhaled corticosteroid therapy and the combined risk of repeat hospitalization and all-cause mortality in elderly patients with COPD. Patients who received inhaled corticosteroid therapy postdischarge (within 90 d) had 24% fewer repeat hospitalizations for COPD (95% confidence interval [CI], 22 to 35%) and were 29% less likely to experience mortality (95% CI, 22 to 35%) during 1 yr of follow-up after adjustment for various confounding factors. This cohort study has suggested that inhaled corticosteroid therapy is associated with reduced COPD-related morbidity and mortality in elderly patients. Although not definitive, because of the observational nature of these findings, these data provide a compelling rationale for a large randomized trial to determine the effect of inhaled corticosteroids on COPD-related morbidity and mortality.

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Soriano JB, Vestbo J, Pride NB, Kiri V, Maden C, Maier WC.
Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice.
Eur Respir J 2002 Oct; 20 (4): 819-25.
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Despite substantial evidence regarding the benefits of combined use of inhaled corticosteroids and long-acting beta2-agonists in asthma, such evidence remains limited for chronic obstructive pulmonary disease (COPD). Observational data may provide an insight into the expected survival in clinical trials of fluticasone propionate (FP) and salmeterol in COPD. Newly physician-diagnosed COPD patients identified in primary care during 1990-1999 aged > or = 50 yrs, of both sexes and with regular prescriptions of respiratory drugs were identified in the UK General Practice Research Database. Three-year survival in 1,045 COPD patients treated with FP and salmeterol was compared with that in 3,620 COPD patients who regularly used other bronchodilators but not inhaled corticosteroids or long-acting beta2-agonists. Standard methods of survival analysis were used, including adjustment for possible confounders. Survival at year 3 was significantly greater in FP and/or salmeterol users (78.6%) than in the reference group (63.6%). After adjusting for confounders, the survival advantage observed was highest in combined users of FP and salmeterol (hazard ratio (HR) 0.48 (95% confidence interval 0.31-0.73)), followed by users of FP alone (HR 0.62 (0.45-0.85)) and regular users of salmeterol alone (HR 0.79 (0.58-1.07)) versus the reference group. Mortality decreased with increasing number of prescriptions of FP and/or salmeterol. In conclusion, regular use of fluticasone propionate alone or in combination with salmeterol is associated with increased survival of chronic obstructive pulmonary disease patients managed in primary care.

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Kiri VA, Pride NB, Soriano JB, Vestbo J.
Inhaled corticosteroids in chronic obstructive pulmonary disease: results from two observational designs free of immortal time bias.
Am J Respir Crit Care Med 2005 Aug 15; 172 (4): 460-4.
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RATIONALE: Recent cohort studies in chronic obstructive pulmonary disease (COPD) have questioned the validity of previously reported associations between inhaled corticosteroids (ICS) and reductions in mortality and rehospitalization in observational studies. Using time-dependent versions of statistical survival models, these studies have suggested immortal time bias as responsible for the proposed beneficial association. OBJECTIVES: We explored the extent of this bias in a study of patients with COPD monitored for a year from COPD discharge with two designs free of any immortal time bias in the General Practice Research Database in the United Kingdom. METHODS: In Design 1, we used only patients whose treatment status was defined on the same day of discharge to obtain a matched cohort based on propensity scores, which were derived from the patient-level baseline characteristics. In Design 2, we identified all in the study cohort who experienced death or rehospitalization and then matched each case to up to four noncases by randomly sampling from the cohort risk sets without regard to treatment status. MEASUREMENTS AND MAIN RESULTS: The propensity scores matched cohort analysis of 786 patients without a wait time found a significant risk reduction associated with use of ICS: hazard ratio, 0.69 (95% confidence interval, 0.52-0.93). The matched nested case-control analysis of 2,222 patients, designed without regard to exposure status and hence free of immortal time bias, gave a similar association with exposure to ICS in the last 6-month period: hazard ratio, 0.71 (0.56-0.90). CONCLUSIONS: We conclude that immortal time bias cannot account for the risk reduction associated with ICS exposure in observational studies.

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Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW.
Bronchodilator reversibility testing in chronic obstructive pulmonary disease.
Thorax 2003 Aug; 58 (8): 659-64.
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BACKGROUND: A limited or absent bronchodilator response is used to classify chronic obstructive pulmonary disease (COPD) and can determine the treatment offered. The reliability of the recommended response criteria and their relationship to disease progression has not been established. METHODS: 660 patients meeting European Respiratory Society (ERS) diagnostic criteria for irreversible COPD were studied. Spirometric parameters were measured on three occasions before and after salbutamol and ipratropium bromide sequentially or in combination over 2 months. Responses were classified using the American Thoracic Society/GOLD (ATS) and ERS criteria. Patients were followed for 3 years with post-bronchodilator FEV(1) and exacerbation history recorded 3 monthly and health status 6 monthly. RESULTS: FEV(1) increased significantly with each bronchodilator, a response that was normally distributed. Mean post-bronchodilator FEV(1) was reproducible between visits (intraclass correlation 0.93). The absolute change in FEV(1) was independent of the pre-bronchodilator value but the percentage change correlated with pre-bronchodilator FEV(1) (r=-0.44; p<0.0001). Using ATS criteria, 52.1% of patients changed responder status between visits compared with 38.2% using ERS criteria. Smoking status, atopy, and withdrawing inhaled corticosteroids were unrelated to bronchodilator response, as was the rate of decline in FEV(1), decline in health status, and exacerbation rate. CONCLUSION: In moderate to severe COPD bronchodilator responsiveness is a continuous variable. Classifying patients as "responders" and "non-responders" can be misleading and does not predict disease progression.

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Burge PS, Calverley PM, Jones PW, Spencer S, Anderson JA.
Prednisolone response in patients with chronic obstructive pulmonary disease: results from the ISOLDE study.
Thorax 2003 Aug; 58 (8): 654-8.
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BACKGROUND: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV(1)) after prednisolone, and whether the prednisolone response predicts 3 year changes in FEV(1), health status, or number of exacerbations during placebo or fluticasone propionate treatment. METHODS: Oral prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV(1) after prednisolone were investigated using multiple regression. The response to prednisolone was entered into separate mixed effects models of decline in FEV(1) and health status during the 3 years of the study. RESULTS: The post-bronchodilator FEV(1) increased by a mean 60 ml (CI 46 to 74) after prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV(1) after prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV(1) after prednisolone and the response to inhaled bronchodilators, baseline FEV(1), atopic status, age, or sex. The response to prednisolone, however expressed, was unrelated to the subsequent change in FEV(1) over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent prednisolone response. The significant effect of treatment on decline in health status was not predicted by the prednisolone response. CONCLUSION: Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV(1) response to prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.

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Poole PJ, Black PN.
Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease (Cochrane Review).
Cochrane Database Syst Rev 2006 Jul 19; 3: CD001287.
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BACKGROUND: Individuals with chronic bronchitis or chronic obstructive pulmonary disease (COPD) may suffer recurrent exacerbations with an increase in volume and/or purulence of sputum. Because of the personal and healthcare costs associated with exacerbations, any therapy that reduces the number of exacerbations is useful. There is a marked difference between countries in terms of prescribing of mucolytics depending on whether or not they are perceived to be effective. OBJECTIVES: To assess the effects of oral mucolytics in adults with stable chronic bronchitis or COPD. SEARCH STRATEGY: We have searched the Cochrane Airways Group Specialised Register and reference lists of articles on four separate occasions, the most recent being in June 2005. This is the third major update. SELECTION CRITERIA: Randomised trials that compared oral mucolytic therapy with placebo for at least two months in adults with chronic bronchitis or COPD. Studies of people with asthma and cystic fibrosis were excluded. DATA COLLECTION AND ANALYSIS: One reviewer extracted data. Study authors and drug companies were contacted for missing information. MAIN RESULTS: Twenty six trials were included (7335 participants). Compared with placebo, there was a significant reduction in the number of exacerbations per patient with oral mucolytics (weighted mean difference (WMD) -0.05 per month, 95% confidence interval -0.05, -0.04). Using the annualised rate of exacerbations in the control patients of 2.6 per year, this is a 20% reduction. The number of days of disability also fell (WMD -0.56, 95% confidence interval -0.77, -0.35). A recent study has shown that the benefit may apply only to those patients not already receiving inhaled corticosteroids. The number of patients who remained exacerbation-free was greater in the mucolytic group (OR 2.13 (95% CI 1.86 to 2.42)). There was no difference in lung function or in adverse effects reported between the treatments. AUTHORS' CONCLUSIONS: In subjects with chronic bronchitis or COPD, treatment with mucolytics was associated with a small reduction in acute exacerbations and a reduction in total number of days of disability. Benefit may be greater in individuals who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations with COPD. They should be considered for use, through the winter months at least, in patients with moderate or severe COPD in whom inhaled corticosteroids (ICS) are not prescribed.

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Decramer M, Rutten-van Molken M, Dekhuijzen PN, Troosters T, van Herwaarden C, Pellegrino R et al.
Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.
Lancet 2005 Apr 30-May 6; 365 (9470): 1552-60.
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BACKGROUND: Increased oxidative stress is important in the pathogenesis of chronic obstructive pulmonary disease (COPD). We postulated that treatment with the antioxidant N-acetylcysteine would reduce the rate of lung-function decline, reduce yearly exacerbation rate, and improve outcomes. METHODS: In a randomised placebo-controlled study in 50 centres, 523 patients with COPD were randomly assigned to 600 mg daily N-acetylcysteine or placebo. Patients were followed for 3 years. Primary outcomes were yearly reduction in forced expiratory volume in 1 s (FEV1) and the number of exacerbations per year. Analysis was by intention to treat. FINDINGS: The yearly rate of decline in FEV1 did not differ between patients assigned N-acetylcysteine and those assigned placebo (54 mL [SE 6] vs 47 mL [6]; difference in slope between groups 8 mL [9]; 95% CI -25 to 10). The number of exacerbations per year did not differ between groups (1.25 [SD 1.35] vs 1.29 [SD 1.46]; hazard ratio 0.99 [95% CI 0.89-1.10, p=0.85]). Subgroup analysis suggested that the exacerbation rate might be reduced with N acetylcysteine in patients not treated with inhaled corticosteroids and secondary analysis was suggestive of an effect on hyperinflation. INTERPRETATION: N-acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD.

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Rabe KF, Bateman ED, O'Donnell D, Witte S, Bredenbroker D, Bethke TD.
Roflumilast--an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial.
Lancet 2005 Aug 13-19; 366 (9485): 563-71.
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BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. METHODS: This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an outpatient setting. 1411 patients with COPD were randomly assigned roflumilast 250 microg (n=576), roflumilast 500 microg (n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1 and health-related quality of life. Secondary outcomes included other lung function parameters and COPD exacerbations. Analyses were by intention to treat. FINDINGS: 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the roflumilast 250 microg group, and 124 (22%) from the roflumilast 500 microg group. Postbronchodilator FEV1 at the end of treatment significantly improved with roflumilast 250 microg (by 74 mL [SD 18]) and roflumilast 500 microg (by 97 mL [18]) compared with placebo (p<0.0001). Improvement in health-related quality of life was greater with roflumilast 250 microg (-3.4 units [0.6]) and roflumilast 500 microg (-3.5 units [0.6]) than with placebo (-1.8 units [0.8]), although the differences between treatment groups were not significant. The mean numbers of exacerbations per patient were 1.13 (2.37), 1.03 (2.33), and 0.75 (1.89) with placebo, roflumilast 250 microg, and roflumilast 500 microg, respectively. Most adverse events were mild to moderate in intensity and resolved during the study. INTERPRETATION: Roflumilast is a promising candidate for anti-inflammatory COPD treatment because it improved lung function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect on health-related quality of life.

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Medical Research Council Working Party.
Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema.
Lancet 1981 Mar 28; 317 (8222): 681-6.
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A controlled trial of long term domiciliary oxygen therapy has been carried out in three centres in the U.K. The 87 patients, all under 70 years of age, who took part had chronic bronchitis or emphysema with irreversible airways obstruction, severe arterial hypoxaemia, carbon dioxide retention, and a history of congestive heart failure. The patients were randomised to oxygen therapy (treated) or no oxygen (controls). Oxygen was given by nasal prongs for at least 15 h daily, usually at 2 1/min. The two groups were well matched, both clinically and in terms of lung function and other laboratory findings. 19 of the 42 oxygen treated patients died in the five years of survival follow-up compared with 30 out of 45 controls: in the 66 men in this trial the survival advantage of oxygen did not emerge until 500 days had elapsed. Survival for the 12 female controls was surprisingly poor, 8 of them being dead at 3 years. Mortality was not easy to predict, though a summation of arterial carbon dioxide tension and red cell mass was helpful. Neither time spent in hospital because of exacerbations of respiratory failure nor work attendance were affected by oxygen therapy, but these patients were very ill at the start of the trial and many had already retired on grounds of age or ill-health. Physiological measurements suggested that oxygen did not slow the progress of respiratory failure in those who died early. However, in longer term survivors on oxygen, arterial oxygenation did seem to stop deterioration.

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Nocturnal Oxygen Therapy Trial Group.
Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial.
Ann Intern Med 1980 Sep; 93 (3): 391-8.
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At six centers, 203 patients with hypoxemic chronic obstructive lung disease were randomly allocated to either continuous oxygen (O2) therapy or 12-hour nocturnal O2 therapy and followed for at least 12 months (mean, 19.3 months). The two groups were initially well matched in terms of physiological and neuropsychological function. Compliance with each oxygen regimen was good. Overall mortality in the nocturnal O2 therapy group was 1.94 times that in the continuous O2 therapy group (P = 0.01). This trend was striking in patients with carbon dioxide retention and also present in patients with relatively poor lung function, low mean nocturnal oxygen saturation, more severe brain dysfunction, and prominent mood disturbances. Continuous O2 therapy also appeared to benefit patients with low mean pulmonary artery pressure and pulmonary vascular resistance and those with relatively well-preserved exercise capacity. We conclude that in hypoxemic chronic obstructive lung disease, continuous O2 therapy is associated with a lower mortality than is nocturnal O2 therapy. The reason for this difference is not clear.

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Gorecka D, Gorzelak K, Sliwinski P, Tobiasz M, Zielinski J.
Effect of long-term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia.
Thorax 1997 Aug; 52 (8): 674-9.
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BACKGROUND: To date only two controlled studies have been published on the effects of domiciliary oxygen treatment on survival in patients with chronic obstructive pulmonary disease (COPD) with advanced respiratory failure. The survival in such patients despite oxygen treatment remains poor. The prescription of long term oxygen therapy (LTOT) in less severe disease remains controversial. The aim of this study was to evaluate the rationale for prescribing oxygen to patients with COPD with moderate hypoxaemia. METHODS: One hundred and thirty five patients with COPD, with PaO2 7.4-8.7 kPa (56-65 mmHg) and advanced airflow limitation (mean (SD) forced expiratory volume in one second (FEV1) 0.83 (0.28) 1), were randomly allocated to a control (n = 67) and LTOT (n = 68) group. The patients were followed every three months for at least three years or until death. RESULTS: The cumulative survival rate was 88% at one year, 77% at two years, and 66% at three years. No significant differences were found in survival rates between patients treated with LTOT and controls, nor did longer oxygen use (over 15 hours per day) improve survival. Younger age, better spirometric values, and higher body mass index predicted better survival. CONCLUSIONS: Domiciliary oxygen treatment does not prolong survival in patients with COPD with moderate hypoxaemia. Airway limitation seems to determine survival in this group of patients.

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McDonald CF, Blyth CM, Lazarus MD, Marschner I, Barter CE.
Exertional oxygen of limited benefit in patients with chronic obstructive pulmonary disease and mild hypoxemia.
Am J Respir Crit Care Med 1995 Nov; 152 (5 Pt 1): 1616-9.
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It is unclear whether short-term benefits from supplemental oxygen translate into improved quality of life in patients with severe COPD. In a 12 wk double-blind randomized crossover study, we assessed the effects of supplemental air and oxygen on exercise performance (step tests and 6 min walking distance [6MWD]) initially and after two 6 wk periods at home using exertional cylinder air or oxygen. We measured quality of life at baseline and after the two 6 wk domiciliary periods. The 26 patients (24 males) had a mean age of 73 +/- 6 yr; mean FEV1, 0.9 +/- 0.4 L; mean DLCO, 10.6 +/- 2.4 ml/min/mm Hg; mean resting PO2, 69 +/- 8.5 (range 58 to 82) mm Hg; mean PCO2, 41 +/- 3.3 mm Hg; and mean resting SaO2, 94 +/- 2.1 (mean +/- SD). Laboratory tests were performed breathing intranasal air or oxygen at 4 L/min, and measurements were made of SaO2 and Borg dysnea scores. Supplemental oxygen increased 6MWD and steps by small, statistically significant increments acutely at baseline and after 6 and 12 wk, without corresponding falls in Borg score. Degree of desaturation at baseline did not correlate with increase in 6MWD or steps achieved at baseline or at 6 or 12 wk, nor with the domiciliary gas used. There was no difference in 6MWD or steps achieved while breathing supplemental oxygen after 6 wk of domiciliary oxygen compared with domiciliary air. Small improvements in quality of life indices were found after domiciliary oxygen, and mastery also improved after domiciliary air. There were no differences in quality of life, however, when domiciliary oxygen was compared with domiciliary air. Although oxygen supplementation induced small acute increments in laboratory exercise performance, such improvements had little impact on the patients' daily lives.

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Fletcher EC, Luckett RA, Goodnight-White S, Miller CC, Qian W, Costarangos-Galarza C.
A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg.
Am Rev Respir Dis 1992 May; 145 (5): 1070-6.
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The efficacy of nasal oxygen during sleep was evaluated in patients with COPD, episodic rapid eye movement sleep desaturation, and a daytime PaO2 greater than 60 mm Hg. The double-blind, randomized 3-yr trial used nasal oxygen versus room air in two groups of nocturnal sleep desaturating subjects. The setting was the outpatient chest clinic of a Veterans Affairs Medical Center. There were 51 patients with moderate to severe COPD, daytime PaO2 greater than or equal to 60 mm Hg: 38 with proven REM sleep desaturation and 13 without desaturation. Nocturnal oxygen at 3 L/min was delivered by concentrator to 19 desaturating subjects, and room air at 3 L/min was delivered by defective concentrator to the remaining 19 desaturating subjects. There was no gas therapy for the 13 nondesaturating subjects. The nocturnal desaturator group who received supplemental oxygen during sleep over 36 months showed a significant downward trend in pulmonary artery pressure (-3.7 mm Hg) compared with desaturating patients treated with room air (+3.9 mm Hg). Nonvascular parameters of hypoxia, such as hemoglobin and red blood cell mass, did not differ between the sham- and oxygen-treated groups. Mortality was decidedly higher in the desaturating patients compared with non-desaturating subjects, but there was no significant difference between oxygen- and sham-treated desaturating subjects. We conclude that nasal supplemental oxygen used during sleep to reverse episodic desaturation in COPD patients whose daytime PaO2 is above 60 mm Hg has a beneficial effect in reducing pulmonary artery pressure.

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Sánchez L, Cornudella R, Estopá R, Molinos L, Servera E.
Normativa para la indicación y empleo de la oxigenoterapia continuada domiciliaria (OCD).
Arch Bronconeumol 1998; 34 (2): 87-94.
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La oxigenoterapia continua domiciliaria (OCD) ha supuesto un importante adelanto en el tratamiento de la enfermedad pulmonar obstructiva crónica (EPOC) toda vez que en sus fases más evolucionadas constituye la causa más frecuente de insuficiencia respiratoria crónica (IRC). Los efectos beneficiosos inducidos por esta modalidad terapéutica, con escasos y poco significativos efectos colaterales, justifican su empleo cada vez más frecuente; no obstante, su elevado coste junto con la incomodidad y problemática psíquica que para algunos enfermos y sus familiares más allegados supone la administración de oxígeno en el domicilio, imponen la exigencia de una cuidadosa indicación y empleo. Para ello resulta imprescindible un correcto conocimiento de los efectos y objetivos que se persiguen con la administración de oxígeno, así como un cierto hábito en el manejo de las técnicas comúnmente utilizadas en el seguimiento y control de los pacientes con insuficiencia respiratoria, lo que no resulta fácil concebir si no es bajo las directrices de un servicio de neumología.

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García F, Borderías L, Casanova C, Celli BR, Escarrabill J, González N et al.
Patología respiratoria y vuelos en avión.
Arch Bronconeumol 2007; 43 (2): 101-25.
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A lo largo de las últimas décadas, se ha experimentado un incremento progresivo del número de personas que utilizan aviones para sus desplazamientos. Según datos de la International Civil Aviation Organization, en 2000 volaron 1.647 millones de personas y, pese a los problemas derivados de los conflictos de seguridad y del síndrome respiratorio agudo grave (SARS), se prevé que el número de pasajeros experimente un incremento anual del 4,4% hasta el año 2015 . En los aeropuertos gestionados por Aeropuertos Españoles y Navegación Aérea (AENA), se realizaron más de dos millones de operaciones de tráfico aéreo durante 2005, lo que supone el embarque de 179 millones de pasajeros . Estas cifras representan un incremento del 29% en el número de pasajeros desde 2000, con un incremento anual del 6%. Por otra parte, los avances alcanzados en el control y tratamiento de muchos trastornos respiratorios crónicos han favorecido un cambio en el estilo de vida de los enfermos. De tal forma, que se plantea la realización de actividades de ocio o profesionales que hace años no eran asumibles. En este documento, se intentará definir unas pautas de evaluación para enfermos respiratorios crónicos que pretenden viajar en avión, adaptadas a las características de nuestro entorno y a las últimas evidencias disponibles. También se tratará de establecer recomendaciones específicas para las enfermedades respiratorias más habituales.

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Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Anto JM.
Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study.
Thorax 2006 Sep; 61 (9): 772-8.
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BACKGROUND: Information about the influence of regular physical activity on the course of chronic obstructive pulmonary disease (COPD) is scarce. A study was undertaken to examine the association between regular physical activity and both hospital admissions for COPD and all-cause and specific mortality in COPD subjects. METHODS: From a population-based sample recruited in Copenhagen in 1981-3 and 1991-4, 2386 individuals with COPD (according to lung function tests) were identified and followed until 2000. Self-reported regular physical activity at baseline was classified into four categories (very low, low, moderate, and high). Dates and causes of hospital admissions and mortality were obtained from Danish registers. Adjusted associations between physical activity and hospital admissions for COPD and mortality were obtained using negative binomial and Cox regression models, respectively. RESULTS: After adjustment for relevant confounders, subjects reporting low, moderate or high physical activity had a lower risk of hospital admission for COPD during the follow up period than those who reported very low physical activity (incidence rate ratio 0.72, 95% confidence interval (CI) 0.53 to 0.97). Low, moderate and high levels of regular physical activity were associated with an adjusted lower risk of all-cause mortality (hazard ratio (HR) 0.76, 95% CI 0.65 to 0.90) and respiratory mortality (HR 0.70, 95% CI 0.48 to 1.02). No effect modification was found for sex, age group, COPD severity, or a background of ischaemic heart disease. CONCLUSIONS: Subjects with COPD who perform some level of regular physical activity have a lower risk of both COPD admissions and mortality. The recommendation that COPD patients be encouraged to maintain or increase their levels of regular physical activity should be considered in future COPD guidelines, since it is likely to result in a relevant public health benefit.

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Lacasse Y, Wong E, Guyatt GH, King D, Cook DJ, Goldstein RS.
Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease.
Lancet 1996 Oct 26; 348 (9035): 1115-9.
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BACKGROUND: Respiratory rehabilitation is increasingly recognised as an important part of the management of patients with chronic obstructive pulmonary disease (COPD). The widespread application of such programmes should be preceded by evidence of directly attributable improvements in function. We assessed the effect of respiratory rehabilitation on exercise capacity and health-related quality of life (HRQL) in patients with COPD. METHODS: We carried out a meta-analysis of randomised controlled trials of respiratory rehabilitation in patients with COPD that assessed functional or maximal exercise capacity, HRQL, or both. Respiratory rehabilitation was defined as exercise training (for at least 4 weeks) with or without education, psychological support, or both. The most commonly used measure for HRQL was the chronic respiratory questionnaire, in which responses were presented on a 7-point scale. The control groups received no rehabilitation. Within each trial and for each outcome an effect size was calculated; the effect sizes were then pooled by a random-effects model. The overall effect of treatment was compared with its minimum clinically important difference (MCID)--defined as the smallest difference perceived as important by the average patient. FINDINGS: We included 14 trials. Significant improvements were found for all the outcomes. For two important features of HRQL, dyspnoea and mastery, the overall treatment effect was larger than the MCID: 1.0 (95% CI 0.6-1.5) and 0.8 (0.5-1.2), respectively, compared with an MCID of 0.5. For functional exercise capacity (6-min walk test), the overall effect was 55.7 m (27.8-92.8), and for maximum exercise capacity (incremental cycle ergometer test), 8.3 W (2.8-16.5). Functional exercise capacity showed heterogeneity that could not be explained by the sensitivity analyses. INTERPRETATION: Respiratory rehabilitation relieves dyspnoea and improves the control over COPD. These improvements are clinically important. The value of the improvement in exercise capacity is not clear. Respiratory rehabilitation is an effective part of care in patients with COPD.

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Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K et al.
Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial.
Lancet 2000 Jan 29; 355 (9201): 362-8.
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BACKGROUND: Pulmonary rehabilitation seems to be an effective intervention in patients with chronic obstructive pulmonary disease. We undertook a randomised controlled trial to assess the effect of outpatient pulmonary rehabilitation on use of health care and patients' wellbeing over 1 year. METHODS: 200 patients with disabling chronic lung disease (the majority with chronic obstructive pulmonary disease) were randomly assigned a 6-week multidisciplinary rehabilitation programme (18 visits) or standard medical management. Use of health services was assessed from hospital and general-practice records. Analysis was by intention to treat. FINDINGS: There was no difference between the rehabilitation (n=99) and control (n=101) groups in the number of patients admitted to hospital (40 vs 41) but the number of days these patients spent in hospital differed significantly (mean 10.4 [SD 9.7] vs 21.0 [20.7], p=0.022). The rehabilitation group had more primary-care consultations at the general-practitioner's premises than did the control group (8.6 [6.8] vs 7.3 [8.3], p=0.033) but fewer primary-care home visits (1.5 [2.8] vs 2.8 [4.6], p=0.037). Compared with control, the rehabilitation group also showed greater improvements in walking ability and in general and disease-specific health status. INTERPRETATION: For patients chronically disabled by obstructive pulmonary disease, an intensive, multidisciplinary, outpatient programme of rehabilitation is an effective intervention, in the short term and the long term, that decreases use of health services.

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Cote CG, Celli BR.
Pulmonary rehabilitation and the BODE index in COPD.
Eur Respir J 2005 Oct; 26 (4): 630-6.
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The BODE index, which integrates body mass index, airflow limitation (forced expiratory volume in one second), dyspnoea and 6-min walk distance, predicts mortality in chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation (PR) improves some components of BODE. It was hypothesised that changes in BODE may reflect the effects of PR. To test this, participation in PR was offered to 246 patients (BODE quartiles 2-4). The patients were divided as follows: no PR (130 who declined rehabilitation or who dropped out from PR), and PR (116 who completed PR). BODE was determined at entry, after PR, and at 1 and 2 yrs. Other outcomes were: length of stay (LOS) for respiratory-related hospitalisations and mortality. At entry, the two groups had similar age and comorbidity but different BODE. After PR, the BODE improved by 19% and returned to baseline after 2 yrs. The BODE worsened in the no PR group by 4% at 12 months and 18% at 2 yrs. Respiratory mortality at 2 yrs for PR was 7%, compared with 39% for no PR. LOS at 1 yr for COPD decreased 20% in PR, while it increased 25% in no PR. In conclusion, pulmonary rehabilitation participation improves BODE and is associated with better outcomes. The BODE index change after pulmonary rehabilitation provides valuable prognostic information.

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Hernández MT, Rubio TM, Ruiz FO, Riera HS, Gil RS, Gómez JC.
Results of a home-based training program for patients with COPD.
Chest 2000 Jul; 118 (1): 106-14.
Ver Abstract                    Texto Completo

OBJECTIVES: To have a group of COPD patients undergo a simple program of home-based exercise training, using the shuttle walking test (SWT) to standardize the intensity of training. METHODS: Sixty patients participated, randomly distributed into two groups (rehabilitation and control) of 30 patients each. The following evaluations were carried out at baseline and at 12 weeks: (1) pulmonary function studies; (2) SWT; (3) submaximal intensity resistance test; (4) cycle ergometer test; (5) quality of life; and (6) dyspnea. The rehabilitation group underwent a lower-extremity training program. Walking was selected as the type of exercise. The intensity of training was set at 70% of the maximum speed attained on the SWT. Divided sessions were held, lasting 1 h, 6 days/wk, at home, with a checkup every 2 weeks. The duration of the program was 12 weeks. RESULTS: The following patients completed the study: 20 patients (66.6%) from the rehabilitation group (mean [+/- SD]) age, 64.3 +/- 8.3 years; mean FEV(1), 41.7 +/- 15.6% of predicted); and 17 patients (56.6%) from the control group (mean age, 63.1 +/- 6.9 years; mean FEV(1), 40 +/- 16.4% of predicted). We found no changes in pulmonary function or effort parameters (SWT or cycle ergometer) in the rehabilitation group at 12 weeks. A twofold increase (1,274 +/- 980 to 2,651 +/- 2,056 m; p < 0.001) was achieved in the submaximal intensity resistance test, with less dyspnea at the conclusion of the test (p = 0.05). Significant improvement also was achieved in basal dyspnea and, both statistically and clinically, in the quality of life. Significant changes were not achieved in the control group patients. CONCLUSIONS: A simple home-based program of exercise training achieved improvement in exercise tolerance, posteffort dyspnea, basal dyspnea, and quality of life in COPD patients.

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Puente-Maestu L, Sánz ML, Sanz P, Ruíz de Ona JM, Rodríguez-Hermosa JL, Whipp BJ.
Effects of two types of training on pulmonary and cardiac responses to moderate exercise in patients with COPD.
Eur Respir J 2000 Jun; 15 (6): 1026-32.
Ver Abstract                    Texto Completo

The effects of two 8-week programmes of exercise reconditioning on the time constants (tau) of the pulmonary gas exchange, ventilatory and heart rate responses to moderate intensity exercise in patients with chronic obstructive pulmonary disease (COPD) were studied. Thirty-five subjects (mean+/-SD 64+/-5 yrs; forced expiratory volume in one second (FEV1) 1.09+/-0.17 L; 41+/-6.2% predicted) were randomly assigned either to supervised (s) training on a treadmill, 4 days x week(-1) (group S; n=21) or self-monitored (SM) walking 3 or 4 km in 1 h 4 days x week(-l) (group SM; n=20). The different levels of supervision resulted in a different estimated intensity of training (35+/-10 W in the SM group and 70+/-22 W in the S group). The kinetics were evaluated with a constant-load exercise test on a cycle-ergometer at a work rate corresponding to 80% the highest oxygen consumption (V'O2) that can be achieved without blood lactic acidosis (V'O2,LAT) or 50% of V'O2,max, if maximum oxygen consumption V'O2,LAT was not found. Mean endurance time at a work rate equivalent to 70% of the pretraining V'O2,max increased by 493+/-281 s in the S group and 254+/-283 s in the SM group (p<0.001). Mean tauV'O2 decreased from 83+/-17 s to 67+/-11 s (p<0.0001) in the S group and from 84+/-12 to 79+/-16 (p=0.04) in the SM group. Mean tau for carbon dioxide output minute ventilation and heart rate were also speeded after training, again more markedly in the S group. In the S group there was a significant correlation between the decrease in tauV'O2 and the increase in endurance time (r=-0.56, SEM=0.21). It is concluded that training speeds the kinetic response of oxygen consumption, carbon dioxide production, minute ventilation and heart rate to moderate exercise and that the effect is greater after supervised, more intense training.

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De Lucas P, Güell R, Sobradillo V.
Normativa sobre rehabilitación respiratoria.
Arch Bronconeumol 2000 May 1; 36 (5): 257-74.
Ver Abstract                    Texto Completo

La rehabilitación respiratoria comienza a practicarse a finales del siglo pasado para tratar a los pacientes tuberculosos, pero su desarrollo científico ha tenido lugar en los últimos treinta años1. Aunque la rehabilitación es ampliamente aceptada en diversas áreas de la medicina, como en el tratamiento de las enfermedades neuromusculares y esqueléticas agudas o crónicas, la rehabilitación respiratoria continúa siendo mucho más debatida, fundamentalmente porque se ha equiparado su efectividad a la mejoría en los parámetros rutinarios de laboratorio. Se olvida que en el paciente respiratorio crónico la valoración de la mejoría va más allá de la práctica de unas pruebas de función respiratoria, de manera que debe evaluarse la capacidad del individuo para realizar las actividades de su vida diaria. En los últimos años, la existencia de nuevas herramientas de estudio, como los cuestionarios de calidad de vida o las escalas de disnea, han permitido demostrar la efectividad de los programas de rehabilitación respiratoria sobre el control de los síntomas, el manejo de la enfermedad y sobre la capacidad de ejercicio2,3. De todas formas, en la rehabilitación respiratoria quedan todavía diversos aspectos no bien conocidos, especialmente en lo referente al mantenimiento de los efectos beneficiosos a largo plazo y al conocimiento de qué componentes de los programas son los responsables de los beneficios que se obtienen. Se han utilizado diversas definiciones de la rehabilitación respiratoria, aunque todas tienen como objetivo común que el paciente consiga la máxima capacidad funcional a través de programas multidisciplinarios. La más reciente de la American Thoracic Society (ATS) define la rehabilitación respiratoria como "una prestación continua y multidimensional de servicios dirigidos a las personas con enfermedades respiratorias y sus familias, generalmente realizadas por un equipo multidisciplinario de especialistas, con el objetivo de mejorar y mantener al individuo en el máximo grado de independencia y funcionamiento en su comunidad". En general, los pacientes que con mayor frecuencia se incluyen en los programas de rehabilitación respiratoria son los que padecen enfermedad pulmonar obstructiva crónica (EPOC) y enfermedades que provocan restricción de la función ventilatoria.

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Nici L, Donner C, Wouters E, Zuwallack R, Ambrosino N, Bourbeau J et al.
American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation.
Am J Respir Crit Care Med 2006 Jun 15; 173 (12): 1390-413.
Ver Abstract                    Texto Completo

Since the last statements on pulmonary rehabilitation by the American Thoracic Society (ATS; 1999) and the European Respiratory Society (ERS; 1997), there have been numerous scientific advances both in our understanding of the systemic effects of chronic respiratory disease as well as the changes induced by the process of pulmonary rehabilitation. Evidence-based support for pulmonary rehabilitation in the management of patients with chronic respiratory disease has grown tremendously, and this comprehensive intervention has been clearly demonstrated to reduce dyspnea, increase exercise performance, and improve health-related quality of life (HRQL). Furthermore, an emerging literature is beginning to reveal its effectiveness in reducing health care costs. The impressive rise in interest in pulmonary rehabilitation is likely related to both a substantial increase in the number of patients being referred as well as the establishment of its scientific basis by the use of well-designed clinical trials that use valid, reproducible, and interpretable outcome measures. Advances in our understanding of the pathophysiology of chronic respiratory conditions are extending the scope and applicability of pulmonary rehabilitation.

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Güell R, Casan P, Belda J, Sangenis M, Morante F, Guyatt GH et al.
Long-term effects of outpatient rehabilitation of COPD: A randomized trial.
Chest 2000 Apr; 117 (4): 976-83.
Ver Abstract                    Texto Completo

OBJECTIVE: To examine the short- and long-term effects of an outpatient pulmonary rehabilitation program for COPD patients on dyspnea, exercise, health-related quality of life, and hospitalization rate. SETTING: Secondary-care respiratory clinic in Barcelona. METHODS: We conducted a randomized controlled trial with blinding of outcome assessment and follow-up at 3, 6, 9, 12, 18, and 24 months. Sixty patients with moderate to severe COPD (age 65 +/- 7 years; FEV(1) 35 +/- 14%) were recruited. Thirty patients randomized to rehabilitation received 3 months of outpatient breathing retraining and chest physiotherapy, 3 months of daily supervised exercise, and 6 months of weekly supervised breathing exercises. Thirty patients randomized to the control group received standard care. RESULTS: We found significant differences between groups in perception of dyspnea (p < 0.0001), in 6-min walking test distance (p < 0.0001), and in day-to-day dyspnea, fatigue, and emotional function measured by the Chronic Respiratory Questionnaire (p < 0. 01). The improvements were evident at the third month and continued with somewhat diminished magnitude in the second year of follow-up. The PR group experienced a significant (p < 0.0001) reduction in exacerbations, but not the number of hospitalizations. The number of patients needed to treat to achieve significant benefit in health-related quality of life for a 2-year period was approximately three. CONCLUSION: Outpatient rehabilitation programs can achieve worthwhile benefits that persist for a period of 2 years.

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Velloso M, Stella SG, Cendon S, Silva AC, Jardim JR.
Metabolic and ventilatory parameters of four activities of daily living accomplished with arms in COPD patients.
Chest 2003 Apr; 123 (4): 1047-53.
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STUDY OBJECTIVE: The upper limbs are involved in the activities of daily living (ADLs). Normal subjects usually perform such activities without noticing the energy cost, but patients with COPD report tiredness when performing them. This study was designed to assess the metabolic and ventilatory demands in patients with COPD during the performance of four ADLs involving the upper limbs. DESIGN: The patients were tested on two different days. Oxygen uptake (O(2)), carbon dioxide output (CO(2)), minute ventilation (E), and heart rate were measured while performing four ADLs for 5 min each: sweeping, erasing a blackboard, lifting pots, and replacing lamps. PARTICIPANTS: Ten normal, young, male subjects (mean age, 27.9 years) were selected for testing the reproducibility of the methods, and 9 male patients with COPD (FEV(1), 32.5%; mean age, 58.9 years) entered the study. MEASUREMENTS AND RESULTS: The tests were reproducible for both groups. Patients with COPD presented a significant increase (p < 0.05) in O(2) (mean, 50.2% of maximum O(2)) and in E (mean, 55.7% of maximum voluntary ventilation [MVV]) in relation to initial resting conditions for all four activities. CONCLUSIONS: We conclude that when performing these four activities, patients with moderate-to-severe COPD present a high O(2), which may explain the tiredness reported by them during simple activities involving the upper limbs; the high E/MVV may be associated to dyspnea.

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Lotters F, van Tol B, Kwakkel G, Gosselink R.
Effects of controlled inspiratory muscle training in patients with COPD: a meta-analysis.
Eur Respir J 2002 Sep; 20 (3): 570-6.
Ver Abstract                    Texto Completo

The purpose of this meta-analysis is to review studies investigating the efficacy of inspiratory muscle training (IMT) in chronic obstructive pulmonary disease (COPD) patients and to find out whether patient characteristics influence the efficacy of IMT. A systematic literature search was performed using the Medline and Embase databases. On the basis of a methodological framework, a critical review was performed and summary effect-sizes were calculated by applying fixed and random effects models. Both IMT alone and IMT as adjunct to general exercise reconditioning significantly increased inspiratory muscle strength and endurance. A significant effect was found for dyspnoea at rest and during exercise. Improved functional exercise capacity tended to be an additional effect of IMT alone and as an adjunct to general exercise reconditioning, but this trend did not reach statistical significance. No significant correlations were found for training effects with patient characteristics. However, subgroup analysis in IMT plus exercise training revealed that patients with inspiratory muscle weakness improved significantly more compared to patients without inspiratory muscle weakness. From this review it is concluded that inspiratory muscle training is an important addition to a pulmonary rehabilitation programme directed at chronic obstructive pulmonary disease patients with inspiratory muscle weakness. The effect on exercise performance is still to be determined.

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Ortega F, Toral J, Cejudo P, Villagomez R, Sánchez H, Castillo J et al.
Comparison of effects of strength and endurance training in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 2002 Sep 1; 166 (5): 669-74.
Ver Abstract                    Texto Completo

We determined the effect of different exercise training modalities in patients with chronic obstructive pulmonary disease, including strength training (n = 17), endurance training (n = 16), and combined strength and endurance (n = 14) (half of the endurance and half of the strengthening exercises). Data were compared at baseline, the end of the 12-week exercise-training program, and 12 weeks later. Improvement in the walking distance was only significant in the strength group. Increases in submaximal exercise capacity for the endurance group were significantly higher than those observed in the strength group but were of similar magnitude than those in the combined training modality, which in turn were significantly higher than for the strength group. Increases in the strength of the muscle groups measured in five weight lifting exercises were significantly higher in the strength group than in the endurance group but were of similar magnitude than in the combined training group, which again showed significantly higher increases than subjects in the endurance group. Any training modality showed significant improvements of the breathlessness score and the dyspnea dimension of the chronic respiratory questionnaire. In conclusion, the combination of strength and endurance training seems an adequate training strategy for chronic obstructive pulmonary disease patients.

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Spruit MA, Gosselink R, Troosters T, De Paepe K, Decramer M.
Resistance versus endurance training in patients with COPD and peripheral muscle weakness.
Eur Respir J 2002 Jun; 19 (6): 1072-8.
Ver Abstract                    Texto Completo

The effects of endurance training on exercise capacity and health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD) patients have been studied thoroughly, while resistance training has been rarely evaluated. This study investigated the effects of resistance training in comparison with endurance training in patients with moderate to severe COPD and peripheral muscle weakness (isometric knee extension peak torque <75% predicted). Forty-eight patients (age 64+/-8 yrs, forced expiratory volume in one second 38+/-17% pred) were randomly assigned to resistance training (RT, n=24) or endurance training (ET, n=24). The former consisted of dynamic strengthening exercises. The latter consisted of walking, cycling and arm cranking. Respiratory and peripheral muscle force, exercise capacity, and HRQL were re-evaluated in all patients who completed the 12-week rehabilitation (RT n=14, ET n=16). Statistically significant increases in knee extension peak torque (RT 20+/-21%, ET 42+/-21%), maximal knee flexion force (RT 31+/-39%, ET 28+/-37%), elbow flexion force (RT 24+/-19%, ET 33+/-25%), 6-min walking distance (6MWD) (RT 79+/-74 m, ET 95+/-57 m), maximum workload (RT 15+/-16 Watt, ET 14+/-13 Watt) and HRQL (RT 16+/-25 points, ET 16+/-15 points) were observed. No significant differences in changes in HRQL and 6MWD were seen between the two treatments. Resistance training and endurance training have similar effects on peripheral muscle force, exercise capacity and health-related quality of life in chronic obstructive pulmonary disease patients with peripheral muscle weakness.

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Casanova C, Celli BR, Tost L, Soriano E, Abreu J, Velasco V et al.
Long-term controlled trial of nocturnal nasal positive pressure ventilation in patients with severe COPD.
Chest 2000 Dec; 118 (6): 1582-90.
Ver Abstract                    Texto Completo

STUDY OBJECTIVES: To determine the 1-year efficacy of noninvasive positive pressure ventilation (NPPV) added to long-term oxygen therapy (LTOT) in patients with stable severe COPD. PATIENT SELECTION AND METHODS: We prospectively randomized 52 patients with severe COPD (FEV(1) < 45%) to either NPPV plus "standard care" (96% patients with LTOT) or to standard care alone (93% patients with LTOT). The outcomes measured included the following: rate of acute COPD exacerbations; hospital admissions; intubations; and mortality at 3 months, 6 months, and 12 months. The patients were also evaluated at 3 months and 6 months for dyspnea using the Medical Research Council and Borg scales, gas exchange, hematocrit, pulmonary function, cardiac function with echocardiogram, and neuropsychological performance. RESULTS: One-year survival was similar in both groups (78%). The number of acute exacerbations was similar at all time points in patients receiving NPPV, compared with control subjects. The number of hospital admissions was decreased at 3 months in the NPPV group (5% vs 15% of patients, p < 0.05), but this difference was not seen at 6 months (18% vs 19%, respectively). The only beneficial differences were observed in the Borg dyspnea rating, which dropped from 6 to 5 (p < 0.039), and in one of the neuropsychological tests (psychomotor coordination) for the NPPV group at 6 months. CONCLUSIONS: Our study indicates that over 1 year, NPPV does not affect the natural course of the disease and is of marginal benefit in outpatients with severe COPD who are in stable condition.

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Clini E, Sturani C, Rossi A, Viaggi S, Corrado A, Donner CF et al.
The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients.
Eur Respir J 2002 Sep; 20 (3): 529-38.
Ver Abstract                    Texto Completo

Chronic obstructive pulmonary disease (COPD) patients with chronic ventilatory failure (CVF) are more likely to develop exacerbations, which are an important determinant of health-related quality of life (HRQL). Long-term noninvasive positive-pressure ventilation (NPPV) has been proposed in addition to long-term oxygen therapy (LTOT) to treat CVF but little information is available on its effects on HRQL and resource consumption. Therefore, the current authors undertook a 2-yr multicentric, prospective, randomised, controlled trial to assess the effect of NPPV+ LTOT on: 1) severity of hypercapnia; 2) use of healthcare resources, and 3) HRQL, in comparison with LTOT alone. One hundred and twenty-two stable hypercapnic COPD patients on LTOT for > or = 6 months were consecutively enrolled. After inclusion and 1-month run-in, 90 patients were randomly assigned to NPPV+LTOT (n=43) or to LTOT alone (n=47). Arterial blood gases, hospital and intensive care unit (ICU) admissions, total hospital and ICU length of stay and HRQL were primary outcome measures; survival and drop-out rates, symptoms (dyspnoea and sleep quality) and exercise tolerance were secondary outcome measures. Follow-up was performed at 3-month intervals up to 2 yrs. Lung function, inspiratory muscle function, exercise tolerance and sleep quality score did not change over time in either group. By contrast the carbon dioxide tension in arterial blood on usual oxygen, resting dyspnoea and HRQL, as assessed by the Maugeri Foundation Respiratory Failure Questionnaire, changed differently over time in the two groups in favour of NPPV+LTOT. Hospital admissions were not different between groups during the follow-up. Nevertheless, overall hospital admissions showed a different trend to change in the NPPV+LTOT (decreasing by 45%) as compared with the LTOT group (increasing by 27%) when comparing the follow-up with the follow-back periods. ICU stay decreased over time by 75% and 20% in the NPPV+LTOT and LTOT groups, respectively. Survival was similar. Compared with long-term oxygen therapy alone, the addition of noninvasive positive-pressure ventilation to long-term oxygen therapy in stable chronic obstructive pulmonary disease patients with chronic ventilatory failure: 1) slightly decreased the trend to carbon dioxide retention in patients receiving oxygen at home and 2) improved dyspnoea and health-related quality of life. The results of this study show some significant benefits with the use of nocturnal, home noninvasive positive-pressure ventilation in patients with chronic ventilatory failure due to advanced chronic obstructive pulmonary disease patients. Further work is required to evaluate the effect of noninvasive positive-pressure ventilation on reducing the frequency and severity of chronic obstructive pulmonary disease exacerbation.

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Wijkstra PJ, Lacasse Y, Guyatt GH, Casanova C, Gay PC, Meecham Jones J et al.
A meta-analysis of nocturnal noninvasive positive pressure ventilation in patients with stable COPD.
Chest 2003 Jul; 124 (1): 337-43.
Ver Abstract                    Texto Completo

STUDY OBJECTIVES: The potential benefits of noninvasive positive pressure ventilation (NIPPV) for patients with COPD remains inconclusive, as most studies have included only a small number of patients. We therefore undertook a meta-analysis of randomized controlled trials (RCTs) that compared nocturnal NIPPV with conventional management in patients with COPD and stable respiratory failure. DESIGN: RCTs were identified from several sources, such as MEDLINE, EMBASE, and CINAHL. In addition, records were identified through hand searching of abstracts from meetings of the American Thoracic Society, the American College of Chest Physicians, and the European Respiratory Society. PATIENTS: Patients with COPD according to the definition of the American Thoracic Society. INTERVENTIONS: NIPPV applied via a nasal or facemask for at least 5 h/d for at least 3 weeks. Patients in the actively treated group continued to receive the usual management for COPD. The control group received the same management as the study group but did not receive NIPPV. Measurements and results: PaCO(2), PaO(2), 6-min walking distance (6MWD), respiratory muscle function, FEV(1), vital capacity, and sleep efficiency (time asleep as a percentage of total time in bed) were used as outcome measures. The publications were reduced to 10 potentially eligible articles from 164 publications retrieved from computer searches and 8 further abstracts. Four trials were finally included in the meta-analysis. The only outcome for which the confidence intervals excluded zero was maximal inspiratory pressure (PImax). The confidence intervals for the other outcomes included zero. The mean treatment effects for FEV(1) and PImax were small, whereas it was moderate for the 6MWD. Small negative effects were found for the outcomes of vital capacity, PaCO(2), and sleep efficiency. CONCLUSIONS: This meta-analysis of 3 months of NIPPV in patients with stable COPD showed that ventilatory support did not improve lung function, gas exchange, or sleep efficiency. The high upper limit of the confidence interval for the 6MWD suggested that some people do improve their walking distance. The small overall sample size precluded a clear clinical direction regarding the effects of NIPPV in patients with COPD.

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Simonds AK.
Ethics and decision making in end stage lung disease.
Thorax 2003 Mar; 58 (3): 272-7.
Ver Abstract                    Texto Completo

Most physicians believe they do more good than harm, and these duties of helping and not harming the patient are rooted in the Hippocratic oath, the good Samaritan tradition, and the Order of the Knight Hospitallers founded in the 11th century to care for pilgrims and those wounded in the Crusades.(1) In recent times the simple principles of beneficence and non-maleficence have been augmented and sometimes challenged by a rising awareness of patient/consumer rights, and the public expectation of greater involvement in medical, social and scientific affairs which affect them. In a publicly funded healthcare system in which rationing (explicit or otherwise) is inevitable, the additional concepts of utility and distributive justice can easily come into conflict with the individual's right to autonomy. Possible treatment options for end stage lung disease include transplantation and long term invasive ventilation which are challenging in resource terms. Other interventions such as pulmonary rehabilitation and palliative care are relatively low cost but not uniformly accessible.

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Lynn J, Goldstein NE.
Advance care planning for fatal chronic illness: avoiding commonplace errors and unwarranted suffering.
Ann Intern Med 2003 May 20; 138 (10): 812-8.
Ver Abstract                    Texto Completo

Patients with eventually fatal illnesses often receive routine treatments in response to health problems rather than treatments arising from planning that incorporates the patient's situation and preferences. This paper considers the case of an elderly man with advanced lung disease who had mechanical ventilation and aggressive intensive care, in part because his nursing home clinicians did not complete an advance care plan and his do-not-resuscitate order did not accompany him to the hospital. The errors that led to his hospitalization and his unwanted treatment there demonstrate how the ordinary lack of advance care planning is deleterious for patients who are nearing the end of life. We discuss serious, recurring, and generally unnoticed errors in planning for care near the end of life and possible steps toward improvement. Repairing these shortcomings will require quality improvement and system redesign efforts, methods familiar from patient safety initiatives. Reliable improvement will also require making it unacceptable for clinicians to fail to plan ahead for care during fatal chronic illness.

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Rodriguez-Roisin R.
Toward a consensus definition for COPD exacerbations.
Chest 2000 May; 117 (5 Suppl 2): 398S-401S.
Ver Abstract                    Texto Completo

In patients with COPD, an acute worsening of respiratory symptoms is often described as an exacerbation. Exacerbations are associated with a significant increase in mortality, hospitalization, and health-care utilization, but there is currently no widely accepted definition of what constitutes an exacerbation of COPD. This paper summarizes the discussions of the workshop, "COPD: Working Towards a Greater Understanding," in which the participants proposed the following working definition of an exacerbation of COPD: a sustained worsening of the patient's condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD.

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Tashkin DP, Detels R, Simmons M, Liu H, Coulson AH, Sayre J et al.
The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second.
Am J Respir Crit Care Med 1994 May; 149 (5): 1209-17.
Ver Abstract                    Texto Completo

We assessed the relative impact of residential exposure to community air pollution and habitual cigarette smoking on lung function by comparing the annualized rate of change in forced expiratory volume in 1 s (FEV1) in current, former, and never-smokers 25 to 59 yr of age residing in three demographically similar areas of the Southern California air basin who had been chronically exposed to (1) moderate levels of photochemical oxidants and very low levels of other pollutants (Lancaster); (2) very high levels of photochemical oxidants, sulfates, and particulate matter (Glendora); and (3) high levels of sulfates, oxides of nitrogen, and probably hydrocarbons (Long Beach), together with moderate levels of sulfur dioxide. Of the 621 to 763 nonsmokers, 317 to 479 former smokers and 472 to 691 continuing smokers residing in the three areas who were studied initially, 53 to 64, 49 to 59, and 43 to 54%, respectively, were retested. For male residents, area of residence and smoking category each had highly significant effects on FEV1 decline (two-way ANCOVA; p < 0.001) without significant interaction (p > 0.4). After adjustment for baseline FEV1, age, height, and a history of allergy, the mean decline in FEV1 attributable to living in Long Beach compared with living in Lancaster was 23.6 ml/yr, which was 71% of the rate of decline in FEV1 (33.3 ml/yr), attributable to smoking > 1 pack of cigarettes per day. For female residents, a significant interaction was noted between area and smoking (p < 0.05).

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Postma DS.
When can an exacerbation of COPD be treated at home?
Lancet 1998 Jun 20; 351 (9119): 1827-8.
Ver Abstract                    Texto Completo

[No hay abstract disponible]

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Pérez-Trallero E, García-de-la-Fuente C, García-Rey C, Baquero F, Aguilar L, Dal-Ré R et al.
Geographical and ecological analysis of resistance, coresistance, and coupled resistance to antimicrobials in respiratory pathogenic bacteria in Spain.
Antimicrob Agents Chemother 2005 May; 49 (5): 1965-72.
Ver Abstract                    Texto Completo

A multicenter susceptibility surveillance (the S.A.U.C.E. project) including 2,721 Streptococcus pneumoniae, 3,174 Streptococcus pyogenes, and 2,645 Haemophilus influenzae consecutive isolates was carried out in 25 hospitals all over Spain from November 2001 to October 2002 to evaluate the current epidemiology of resistance of the main bacteria involved in community-acquired respiratory tract infections. Susceptibility testing was performed in a single centralized laboratory by a broth microdilution method. The prevalence of resistant S. pneumoniae strains was 0.4% for cefotaxime, 4.4% for amoxicillin and amoxicillin-clavulanic acid, 25.6% for cefuroxime-axetil, 34.5% for erythromycin, clarithromycin, and azithromycin, and 36.0% for cefaclor. Phenotypes of resistance to erythromycin were MLS(B) (macrolide-lincosamide-streptogramin B) in 89.9% (gene ermB) and M (macrolide) in 9.7% of cases (gene mefA). No strain harbored both genes simultaneously. Serotypes 19, 6, 23, 14, and 3 were the most prevalent, accounting for 54.6% of the total isolates. Resistance to macrolides seems to be the most alarming point, since among penicillin-susceptible isolates it reached 15.1% compared to 55.8% among penicillin-resistant strains. Geographically, a number of regions had rates of erythromycin resistance above 40% (even higher in children). Resistance to erythromycin was also high in S. pyogenes isolates: mean regional 33.2%, beta-lactamase-producing H. influenzae were 20%, whereas 4.4% had a beta-lactamase-negative, ampicillin-resistant phenotype. We highlight the importance of different geographical frequencies of coresistance (associations of resistance to different drugs within the same species) and coupled resistance (association of resistance between different species) probably resulting from different local coselective events.

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Wood-Baker R, Walters EH, Gibson P.
Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease (Cochrane Review).
Cochrane Database Syst Rev 2001; (2): CD001288.
Ver Abstract                    Texto Completo

BACKGROUND: Systemic corticosteroids are widely used in the management of patients with acute exacerbations of COPD, in combination with other treatments. OBJECTIVES: To determine the effect of corticosteroids, administered either parenterally or orally, on the outcome in patients with acute exacerbations of COPD. SEARCH STRATEGY: An initial search was carried out using the Cochrane Airways Group COPD RCT register with additional studies sought in the bibliographies of randomised controlled trials and review articles. Authors of identified randomised controlled trials were contacted for other published and unpublished studies. SELECTION CRITERIA: Randomised controlled trials comparing corticosteroids, administered either parenterally or orally, with appropriate placebo. Other interventions were standardised e.g. bronchodilators, antibiotics. Clinical studies of acute asthma were excluded. DATA COLLECTION AND ANALYSIS: Data was extracted by one of the reviewers and sent to authors for verification. All trials were combined using Review Manager (version 4.1) for analysis. MAIN RESULTS: We have identified 7 studies that fulfilled the inclusion criteria. Outcomes were varied and few were common to all studies. The most commonly reported outcome, the FEV1 between 6 - 72 hours after treatment, showed a significant treatment benefit for corticosteroid over placebo treatment, weighted mean difference 120 ml 95% confidence intervals: 5, 190 ml. There were significantly fewer treatment failures in patients given corticosteroid treatment, but the number of studies reporting this outcome was smaller and there was significant heterogeneity between them. There was an increased likelihood of an adverse drug reaction with corticosteroid treatment. REVIEWER'S CONCLUSIONS: Treatment with oral or parenteral corticosteroids increases the rate of lung function improvement over the first 72 hours of an exacerbation of chronic obstructive pulmonary disease, but at a significantly increased risk of an adverse drug reaction. There is no evidence that this benefit is maintained after 72 hours, or that other outcomes are improved.

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Ram FS, Wedzicha JA, Wright J, Greenstone M.
Hospital at home for acute exacerbations of chronic obstructive pulmonary disease (Cochrane Review).
Cochrane Database Syst Rev 2003; (4): CD003573.
Ver Abstract                    Texto Completo

BACKGROUND: Hospital at home schemes are a recently adopted method of service delivery for the management of acute exacerbations of chronic obstructive pulmonary disease aimed at reducing demand for acute hospital in-patient beds and promoting a patient centered approach through admission avoidance. However, evidence in support of such a service is contradictory. OBJECTIVES: To evaluate the efficacy of "hospital at home" compared to hospital inpatient care in acute exacerbations of chronic obstructive pulmonary disease. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials; electronically available databases e.g. MEDLINE (1966-current), EMBASE (1980-current), PubMed, ClincalTrials, Science Citation Index and on-line individual respiratory journals; bibliographies of included trials were all searched and contact with authors was made to obtain studies. The most recent searches were carried out in August 2003. SELECTION CRITERIA: Only randomised controlled trials were considered where patients presented to the emergency department with an exacerbation of their chronic obstructive pulmonary disease. Studies must not have recruited patients that are usually deemed obligatory admissions. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected articles for inclusion, evaluated methodological quality of the studies and abstracted data. MAIN RESULTS: Seven studies with 754 patients were included in the review. Studies provided data on hospital readmission and mortality both of which were not significantly different when the two study groups were compared (RR 0.89; 95%CI 0.72 to 1.12 & RR 0.61; 95%CI 0.36 to 1.05, respectively). Both the patients and the carers preferred hospital at home schemes to inpatient care (RR 1.53; 95%CI 1.23 to 1.90). Other reported outcomes included few studies. REVIEWER'S CONCLUSIONS: This review has shown that one in four carefully selected patients presenting to hospital emergency departments with acute exacerbations of chronic obstructive pulmonary disease can be safely and successfully treated at home with support from respiratory nurses. This review found no evidence of significant differences between "hospital at home" patients and hospital inpatients for readmission rates and mortality at two to three months after the initial exacerbation. Both the patients and carers preferred "hospital at home" schemes to inpatient care.

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Skwarska E, Cohen G, Skwarski KM, Lamb C, Bushell D, Parker S et al.
Randomised controlled trial of supported discharge in patients with exacerbations of chronic obstructive pulmonary disease.
Thorax 2000 Nov; 55 (11): 907-12.
Ver Abstract                    Texto Completo

BACKGROUND: A randomised trial was performed on patients presenting to hospital with an exacerbation of chronic obstructive pulmonary disease (COPD) to compare outcomes in those managed at home with support with those admitted to hospital in the standard manner. METHODS: Over an 18 month period all patients presenting to the Royal Infirmary of Edinburgh on weekdays (n=718) with a diagnosis of an exacerbation of COPD were assessed for inclusion in the trial. Patients with impaired level of consciousness, acute confusion, acute changes on radiography, or an arterial pH of <7.35 or with other serious medical or social reasons for admission were excluded. Patients randomised to home support were discharged with an appropriate treatment package (antibiotics, corticosteroids, nebulised bronchodilators and, if necessary, home oxygen). They were visited by a nurse the following day and thereafter at intervals of 2-3 days until recovery when they were discharged from follow up. Parallel observations were made on patients allocated to normal hospital admission up to the point of discharge. Patients in both groups were assessed at home eight weeks after the initial assessment. RESULTS: Among weekday patients 353 (50%) were considered obligatory admissions, 140 (19%) were admitted because of co-morbidity, 17 (2%) because of poor social circumstances, and 24 (3%) did not consent to the trial. The remaining 184 (26%) were randomised (2:1) either to home support or to a standard hospital admission. The median time to discharge was 7 days for the home support group and 5 days for the admitted group (p<0.01); 25% of the home support group and 34% of the admitted group were readmitted before the final assessment at eight weeks (p>0.05). There were no significant differences between the groups in attendances by GPs and carers or in health status measured eight weeks after the initial assessment. Satisfaction with the service was good. The mean total health service cost per patient was estimated as 877 pounds sterling for the home support group and 1753 pounds sterling for the admitted group. CONCLUSIONS: This study shows that home supported discharge is a well tolerated, safe, and economic alternative to hospital admission for a proportion of patients referred to hospital for admission for an exacerbation of COPD.

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Casas A, Troosters T, Garcia-Aymerich J, Roca J, Hernández C, Alonso A et al.
Integrated care prevents hospitalisations for exacerbations in COPD patients.
Eur Respir J 2006 Jul; 28 (1): 123-30.
Ver Abstract                    Texto Completo

Hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations have a major impact on the disease evolution and costs. The current authors postulated that a simple and well-standardised, low-intensity integrated care intervention can be effective to prevent such hospitalisations. Therefore, 155 exacerbated COPD patients (17% females) were recruited after hospital discharge from centres in Barcelona (Spain) and Leuven (Belgium). They were randomly assigned to either integrated care (IC; n = 65; age mean+/-sd 70+/-9 yrs; forced expiratory volume in one second (FEV(1)) 1.1+/-0.5 L, 43% predicted) or usual care (UC; n = 90; age 72+/-9 yrs; FEV(1) 1.1+/-0.05 L, 41% pred). The IC intervention consisted of an individually tailored care plan upon discharge shared with the primary care team, as well as accessibility to a specialised nurse case manager through a web-based call centre. After 12 months' follow-up, IC showed a lower hospitalisation rate (1.5+/-2.6 versus 2.1+/-3.1) and a higher percentage of patients without re-admissions (49 versus 31%) than UC without differences in mortality (19 versus 16%, respectively). In conclusion, this trial demonstrates that a standardised integrated care intervention, based on shared care arrangements among different levels of the system with support of information technologies, effectively prevents hospitalisations for exacerbations in chronic obstructive pulmonary disease patients.

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Sala E, Alegre L, Carrera M, Ibars M, Orriols FJ, Blanco ML et al.
Supported discharge shortens hospital stay in patients hospitalized because of an exacerbation of COPD.
Eur Respir J 2001 Jun; 17 (6): 1138-42.
Ver Abstract                    Texto Completo

This prospective, controlled, but not formally randomized study investigates the feasibility and efficiency of an alternative to standard hospitalization for patients with exacerbated chronic obstructive pulmonary disease (COPD), based upon supported discharge with nurse supervision at home. Over a 12-month period, emergency physicians, not directly involved in the study, admitted 205 patients with exacerbated COPD to the authors' respiratory unit. Patients were included in the supported discharge group (n=105) if they voluntarily chose to participate in the programme and lived in the city of Palma de Mallorca (where adequate home support could be provided). Patients not fulfilling these criteria (mainly residents outside the city) served as controls (n=100). Inpatient treatment was standardized in all patients and included oxygen therapy, bronchodilators, antibiotics and steroids. Both groups were comparable in terms of age (mean +/- SD: 70 +/- 10 versus 65 +/- 11 yr for supported discharge and control group, respectively), severity of airflow obstruction (forced expiratory volume in one second 45 +/- 18% reference versus 46 +/- 19% ref.), comorbidity and socioeconomic status. Length of hospital stay (LOS) in the supported discharge group was shorter (5.9 +/- 2.8 versus 8.0 +/- 5.1 days, p < 0.001). After discharge, a respiratory nurse visited supported discharge patients at home during 7.3 +/- 3.8 days. Only one patient (1%) required hospital readmission during this period of time. The reduced LOS resulted in a lower utilization of hospital beds at any given point in time throughout the study period. Within the framework and potential limitations of this study, the results indicate that the supported discharge programme in Spain: 1) allows a significant reduction in the length of hospital stay of patients hospitalized because of an exacerbation of chronic obstructive pulmonary disease; 2) does not result in an inappropriately increased rate of hospital readmissions; and 3) reduces the utilization of hospital resources.

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Murata GH, Gorby MS, Chick TW, Halperin AK.
Use of emergency medical services by patients with decompensated obstructive lung disease.
Ann Emerg Med 1989 May; 18 (5): 501-6.
Ver Abstract                    Texto Completo

Little information is available about the risk of relapse when patients with decompensated obstructive lung disease are treated in an emergency department for dyspnea. The purpose of our study was to determine if the risk of relapse was related to the severity and type of airway obstruction or to the time and duration of treatment. Over a period of 29 months, 496 patients with decompensated chronic obstructive pulmonary disease (COPD), asthma, or both were seen in the ED of the Albuquerque Veterans Administration Medical Center. Of 868 visits in which patients were treated and released, 244 (28.1%) were followed by a relapse within 14 days. Those who relapsed had a slightly higher one-second forced expiratory volume at baseline than those who did not (50.1 +/- 22.2% versus 45.5 +/- 20.6% predicted, P = .054). For 94 patients (group 1), asthma was the exclusive clinical diagnosis, and all available pulmonary function tests showed a bronchodilator response. For 268 patients (group 2), COPD was the exclusive diagnosis, and all tests showed no bronchodilator response. One hundred thirty-four patients (group 3) were either diagnosed as having both disorders or had varying bronchodilator response on sequential testing. The risk of relapse for group 3 patients (35.6%) was higher than for those in groups 2 (23.1%, P less than .001) or 1 (19.7%, P = .001). The frequency of relapse was higher for nighttime than daytime visits (36.1% versus 24.5%, P = .006) and for weekend than weekday visits (33.6% versus 26.6%, P = .049). Prognosis did not vary with the season or duration of treatment.

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Chu CM, Chan VL, Lin AW, Wong IW, Leung WS, Lai CK.
Readmission rates and life threatening events in COPD survivors treated with non-invasive ventilation for acute hypercapnic respiratory failure.
Thorax 2004 Dec; 59 (12): 1020-5.
Ver Abstract                    Texto Completo

BACKGROUND: Non-invasive ventilation (NIV) has been shown to reduce intubation and in-hospital mortality in patients with chronic obstructive pulmonary disease (COPD) and acute hypercapnic respiratory failure (AHRF). However, little information exists on the outcomes following discharge. A study was undertaken to examine the rates of readmission, recurrent AHRF, and death following discharge and the risk factors associated with them. METHODS: A cohort of COPD patients with AHRF who survived after treatment with NIV in a respiratory high dependency unit was prospectively followed from July 2001 to October 2002. The times to readmission, first recurrent AHRF, and death were recorded and analysed against potential risk factors collected during the index admission. RESULTS: One hundred and ten patients (87 men) of mean (SD) age 73.2 (7.6) years survived AHRF after NIV during the study period. One year after discharge 79.9% had been readmitted, 63.3% had another life threatening event, and 49.1% had died. Survivors spent a median of 12% of the subsequent year in hospital. The number of days in hospital in the previous year (p = 0.016) and a low Katz score (p = 0.018) predicted early readmission; home oxygen use (p = 0.002), APACHE II score (p = 0.006), and a lower body mass index (p = 0.041) predicted early recurrent AHRF or death; the MRC dyspnoea score (p<0.001) predicted early death. CONCLUSIONS: COPD patients with AHRF who survive following treatment with NIV have a high risk of readmission and life threatening events. Further studies are urgently needed to devise strategies to reduce readmission and life threatening events in this group of patients.

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Rosell A, Monso E, Soler N, Torres F, Angrill J, Riise G et al.
Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease.
Arch Intern Med 2005 Apr 25; 165 (8): 891-7.
Ver Abstract                    Texto Completo

BACKGROUND: The culture of bronchial secretions from the lower airway has been reported to be positive for potentially pathogenic microorganisms (PPMs) in patients with stable chronic obstructive pulmonary disease (COPD), but the determinants and effects of this bacterial load in the airway are not established. METHODS: To determine the bronchial microbial pattern in COPD and its relationship with exacerbation, we pooled analysis of crude data from studies that used protected specimen brush sampling, with age, sex, smoking, lung function, and microbiologic features of the lower airway as independent variables and exacerbation as the outcome, using logistic regression modeling. RESULTS: Of 337 study participants, 70 were healthy, 181 had stable COPD, and 86 had exacerbated COPD. Differences in the microbial characteristics in the participating laboratories were not statistically significant. A cutoff point of 10(2) colony-forming units (CFU) per milliliter or greater for the identification of abnormal positive culture results for PPMs was defined using the 95th percentile in the pooled analysis of healthy individuals. Bronchial colonization of 10(2) CFU/mL or greater by PPMs was found in 53 patients with stable COPD (29%) and in 46 patients with exacerbated COPD (54%) (P<.001, chi(2) test), with a predominance of Haemophilus influenzae and Pseudomonas aeruginosa. Higher microbial loads were associated with exacerbation and showed a statistically significant dose-response relationship after adjustment for covariates (odds ratio, 3.62; 95% confidence interval, 1.47-8.90), but P aeruginosa persisted as a statistically significant risk factor after adjustment for microbial load (odds ratio, 11.12; 95% confidence interval, 1.17-105.82). CONCLUSIONS: One quarter of the patients with COPD are colonized by PPMs during their stable periods. Exacerbation is associated with the overgrowth of PPMs and with the appearance of P aeruginosa in the lower airway, which is associated with exacerbation symptoms independent of load.

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Barberà JA, Roca J, Ferrer A, Félez MA, Díaz O, Roger N et al.
Mechanisms of worsening gas exchange during acute exacerbations of chronic obstructive pulmonary disease.
Eur Respir J 1997 Jun; 10 (6): 1285-91.
Ver Abstract                    Texto Completo

This study was undertaken to investigate the mechanisms that determine abnormal gas exchange during acute exacerbations of chronic obstructive pulmonary disease (COPD). Thirteen COPD patients, hospitalized because of an exacerbation, were studied after admission and 38+/-10 (+/-SD) days after discharge, once they were clinically stable. Measurements included forced spirometry, arterial blood gas values, minute ventilation (V'E), cardiac output (Q'), oxygen consumption (V'O2), and ventilation/perfusion (V'A/Q') relationships, assessed by the inert gas technique. Exacerbations were characterized by very severe airflow obstruction (forced expiratory volume in one second (FEV1) 0.74+/-0.17 vs 0.91+/-0.19 L, during exacerbation and stable conditions, respectively; p=0.01), severe hypoxaemia (ratio between arterial oxygen tension and inspired oxygen fraction (Pa,O2/FI,O2) 32.7+/-7.7 vs 37.6+/-6.9 kPa (245+/-58 vs 282+/-52 mmHg); p=0.01) and hypercapnia (arterial carbon dioxide tension (Pa,CO2) 6.8+/-1.6 vs 5.9+/-0.8 kPa (51+/-12 vs 44+/-6 mmHg); p=0.04). V'A/Q' inequality increased during exacerbation (log SD Q', 1.10+/-0.29 vs 0.96+/-0.27; normal < or = 0.6; p=0.04) as a result of greater perfusion in poorly-ventilated alveoli. Shunt was almost negligible on both measurements. V'E remained essentially unchanged during exacerbation (10.5+/-2.2 vs 9.2+/-1.8 L x min(-1); p=0.1), whereas both Q' (6.1+/-2.4 vs 5.1+/-1.7 L x min(-1); p=0.05) and V'O2 (300+/-49 vs 248+/-59 mL x min(-1); p=0.03) increased significantly. Worsening of hypoxaemia was explained mainly by the increase both in V'A/Q' inequality and V'O2, whereas the increase in Q' partially counterbalanced the effect of greater V'O2 on mixed venous oxygen tension (PV,O2). We conclude that worsening of gas exchange during exacerbations of chronic obstructive pulmonary disease is primarily produced by increased ventilation/perfusion inequality, and that this effect is amplified by the decrease of mixed venous oxygen tension that results from greater oxygen consumption, presumably because of increased work of the respiratory muscles.

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Aubier M, Murciano D, Milic-Emili J, Touaty E, Daghfous J, Pariente R et al.
Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure.
Am Rev Respir Dis 1980 Nov; 122 (5): 747-54.
Ver Abstract                    Texto Completo

The effects of the administration of 100% oxygen on minute ventilation (VE) and arterial blood gases were studied in patients with chronic obstructive pulmonary disease during acute respiratory failure. The administration of O2 resulted in an early decrease in VE, which averaged 18% +/- 2 SE of the control VE, and was due to a decrease in both tidal volume (VT) and respiratory frequency (f). This was followed by a slow increase in VE, such that after 15 min of breathing O2, VE rose to 93 +/- 6% of the control room air value, with both VT and f similar to control values. Despite the small difference between VE while breathing room air and that at the fifteenth minute of O2 inhalation, PaCO2 increased by 23 +/- 5 mmHg, and no significant correlation was found between the changes in VE and PaCO2. By the fifteenth minute of O2 inhalation the PaO2 averaged 225 +/- 23 mmHg, and it was concluded that despite the removal of the hypoxic stimulus of O2 inhalation, the activity of the respiratory muscles remained great enough to maintain VE at nearly the same degree as that while breathing room air. Consequently, the changes in PaCO2 after the administration of O2 were mainly due to increased inhomogeneity of VA/Q distribution within the lungs.

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Moloney ED, Kiely JL, McNicholas WT.
Controlled oxygen therapy and carbon dioxide retention during exacerbations of chronic obstructive pulmonary disease.
Lancet 2001 Feb 17; 357 (9255): 526-8.
Ver Abstract                    Texto Completo

Hypoxaemic patients with exacerbations of chronic obstructive pulmonary disease (COPD) are at some risk of carbon dioxide (CO2) retention during oxygen therapy. We quantified the risk of CO2 retention with oxygen therapy in COPD in 24 consecutive patients presenting to the accident and emergency department with acute exacerbations associated with hypercapnic respiratory failure (partial arterial pressure of oxygen [PaO2] < 8 kPa and partial pressure of CO2 [PaCO2] > or = 6.5 kPa). Only three patients developed clinically important CO2 retention (defined as a rise in PaCO2 > 1 kPa) with controlled oxygen therapy (24-40% by Venturi mask to maintain the oxygen saturation at 91-92%). These patients presented with more severe hypercapnia, but all three required only low-flow oxygen (24-28%). These findings suggest only a small risk of aggravating hypercapnia with controlled oxygen supplementation.

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Agustí AG, Carrera M, Barbé F, Muñoz A, Togores B.
Oxygen therapy during exacerbations of chronic obstructive pulmonary disease.
Eur Respir J 1999 Oct; 14 (4): 934-9.
Ver Abstract                    Texto Completo

Venturi masks (VMs) and nasal prongs (NPs) are widely used to treat acute respiratory failure (ARF) in chronic obstructive pulmonary disease (COPD). In this study, these devices were compared in terms of their potentiality to worsen respiratory acidosis and their capacity to maintain adequate (> 90%) arterial oxygenation (Sa,O2) through time (approximately 24 h). In a randomized cross-over study, 18 consecutive COPD patients who required hospitalization because of ARF were studied. After determining baseline arterial blood gas levels (on room air), patients were randomized to receive oxygen therapy through a VM or NPs at the lowest possible inspiratory oxygen fraction that resulted in an initial Sa,O2 of > or = 90%. Arterial blood gas levels were measured again 30 min later (on O2), and Sa,O2 recorded using a computer during the subsequent approximately 24 h. Patients were then crossed-over to receive O2 therapy by means of the alternative device (NPs or VM), and the same measurements obtained again in the same order. It was observed that both the VM and NPs improved arterial oxygen tension (p<0.0001) to the same extent (p=NS), without any significant effect upon arterial carbon dioxide tension or pH. However, despite this adequate initial oxygenation, Sa,O2 was < 90% for 3.7+/-3.8 h using the VM and for 5.4+/-5.9 h using NPs (p<0.05). Regression analysis showed that the degree of arterial hypoxaemia (p<0.05) and arterial hypercapnia (p<0.05) present before starting O2 therapy and, particularly, the initial Sa,O2 achieved after initiation of O2 therapy (p<0.0001) enabled the time (in h) that patients would be poorly oxygenated (Sa,O2 < 90%) on follow-up to be predicted. These findings suggest that, in order to maintain an adequate (> 90%) level of arterial oxygenation in patients with chronic obstructive pulmonary disease and moderate acute respiratory failure: 1) the initial arterial oxygen saturation on oxygen should be maximized whenever possible by increasing the inspiratory oxygen fraction; 2) this strategy seems feasible because neither the VM nor NPs worsen respiratory acidosis significantly; and 3) the Venturi mask (better than nasal prongs) should be recommended.

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Bone RC, Pierce AK, Johnson RL Jr.
Controlled oxygen administration in acute respiratory failure in chronic obstructive pulmonary disease: a reappraisal.
Am J Med 1978 Dec; 65 (6): 896-902.
Ver Abstract                    Texto Completo

Controlled oxygen therapy may aggravate carbon dioxide retention during acute exacerbations of chronic obstructive pulmonary disease (COPD). Of 50 consecutive patients with COPD and acute respiratory failure, 13 required intubation because of carbon dioxide narcosis. With discriminant analysis of their arterial oxygen tension (PaO2) and pH on admission, a diagram separated patients into those at high risk and those at low risk for carbon dioxide narcosis. This diagram was then used to predict carbon dioxide narcosis in 73 patients with COPD and acute respiratory failure who were treated with controlled oxygen. In 16 of these patients carbon dioxide narcosis developed. Thirteen (81 per cent) were predicted by the diagram to be at high risk for this complication. Only two (4 per cent) patients judged by the diagram to be at low risk for carbon dioxide narcosis required mechanical ventilation. Utilizing an oxygen tension (PO2), carbon dioxide tension (PCO2) diagram a patient's ventilatory response was compared to that of ambulatory patients with COPD. These data suggest that hypoxemia and acidosis are more discriminatory for "carbon dioxide narcosis" than hypercapnia.

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Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A et al.
Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 1995 Sep 28; 333 (13): 817-22.
Ver Abstract                    Texto Completo

BACKGROUND. In patients with acute exacerbations of chronic obstructive pulmonary disease, noninvasive ventilation may be used in an attempt to avoid endotracheal intubation and complications associated with mechanical ventilation. METHODS. We conducted a prospective, randomized study comparing noninvasive pressure-support ventilation delivered through a face mask with standard treatment in patients admitted to five intensive care units over a 15-month period. RESULTS. A total of 85 patients were recruited from a larger group of 275 patients with chronic obstructive pulmonary disease admitted to the intensive care units in the same period. A total of 42 were randomly assigned to standard therapy and 43 to noninvasive ventilation. The two groups had similar clinical characteristics on admission to the hospital. The use of noninvasive ventilation significantly reduced the need for endotracheal intubation (which was dictated by objective criteria): 11 of 43 patients (26 percent) in the noninvasive-ventilation group were intubated, as compared with 31 of 42 (74 percent) in the standard-treatment group (P < 0.001). In addition, the frequency of complications was significantly lower in the noninvasive-ventilation group (16 percent vs. 48 percent, P = 0.001), and the mean (+/- SD) hospital stay was significantly shorter for patients receiving noninvasive ventilation (23 +/- 17 days vs. 35 +/- 33 days, P = 0.005). The in-hospital mortality rate was also significantly reduced with noninvasive ventilation (4 of 43 patients, or 9 percent, in the noninvasive-ventilation group died in the hospital, as compared with 12 of 42, or 29 percent, in the standard-treatment group; P = 0.02). CONCLUSIONS. In selected patients with acute exacerbations of chronic obstructive pulmonary disease, noninvasive ventilation can reduce the need for endotracheal intubation, the length of the hospital stay, and the in-hospital mortality rate.

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Plant PK, Owen JL, Elliott MW.
Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial.
Lancet 2000 Jun 3; 355 (9219): 1931-5.
Ver Abstract                    Texto Completo

BACKGROUND: Within the intensive-care unit, non-invasive ventilation (NIV) can prevent the need for intubation and the mortality associated with severe episodes of chronic obstructive pulmonary disease (COPD). The aim of this study was to find whether the introduction of NIV, early after the admission on a general respiratory ward, was effective at reducing the need for intubation and the mortality associated with acute exacerbations of COPD. METHODS: We did a prospective multicentre randomised controlled study comparing NIV with standard therapy in patients with mild to moderate acidosis. NIV was administered on the ward with a simple non-invasive ventilator and a standardised predefined protocol. Patients were recruited from 14 UK hospitals over 22 months. FINDINGS: 236 patients were recruited, 118 received standard therapy alone and 118 additional NIV. The two groups had similar characteristics at enrolment. The use of NIV significantly reduced the need for intubation as defined by the failure criteria. 32/118 (27%) of the standard group failed compared with 18/118 (15%) of the NIV group (p=0.02). In-hospital mortality was also reduced by NIV, 24/118 (20%) died in the standard group compared with 12/118 (10%) in the NIV group (p=0.05). In both groups pH, PaCO2, and respiratory rate improved at 4 h (p<0.01). However, NIV led to a more rapid improvement in pH in the first hour (p=0.02) and a greater fall in respiratory rate at 4 h (p=0.035). The duration of breathlessness was also reduced by NIV (p=0.025). INTERPRETATION: The early use of NIV for mildly and moderately acidotic patients with COPD in the general ward setting leads to more rapid improvement of physiological variables, a reduction in the need for invasive mechanical ventilation (with objective criteria), and a reduction in in-hospital mortality.

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British Thoracic Society Standards of Care Committee.
Non-invasive ventilation in acute respiratory failure: BTS Guideline.
Thorax 2002 Mar; 57 (3): 192-211.
Ver Abstract                    Texto Completo

Non-invasive ventilation (NIV) refers to the provision of ventilatory support through the patient’s upper airway using a mask or similar device. This technique is distinguished from those which bypass the upper airway with a tracheal tube, laryngeal mask, or tracheostomy and are therefore considered invasive. In this document NIV refers to non-invasive positive pressure ventilation, and other less commonly used techniques such as external negative pressure or rocking beds will not be discussed. (NIPPV is an alternative abbreviation but it is more cumbersome and involves ambiguity as to whether "N" is for "non-invasive" or "nasal".). Continuous positive airway pressure (CPAP) in this document refers to the non-invasive application of positive airway pressure, again using a face or nasal mask rather than in conjunction with invasive techniques. Although it might be open to debate as to whether the use of non-invasive CPAP in acute respiratory failure constitutes ventilatory support, it is included in this document because of the confusion which commonly arises between NIV and CPAP in clinical practice. This document is aimed at those who wish to set up an acute NIV service. It is also intended to help those who are seeking to expand or consolidate existing facilities, particularly where purchasers require evidence of efficacy. The provision of long term NIV at home is not covered. NIV can be used as a treatment for breathlessness in the terminal stages of progressive neuromuscular disease, but this and other specialised applications will not be discussed further. Although NIV is being introduced into paediatric practice, the published evidence is not yet strong enough for recommendations to be made about its use in children.

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Esteban A, Anzueto A, Frutos F, Alia I, Brochard L, Stewart TE et al.
Characteristics and outcomes in adult patients receiving mechanical ventilation: a 28-day international study.
JAMA 2002 Jan 16; 287 (3): 345-55.
Ver Abstract                    Texto Completo

CONTEXT: The outcome of patients receiving mechanical ventilation for particular indications has been studied, but the outcome in a large number of unselected, heterogeneous patients has not been reported. OBJECTIVE: To determine the survival of patients receiving mechanical ventilation and the relative importance of factors influencing survival. DESIGN, SETTING, AND SUBJECTS: Prospective cohort of consecutive adult patients admitted to 361 intensive care units who received mechanical ventilation for more than 12 hours between March 1, 1998, and March 31, 1998. Data were collected on each patient at initiation of mechanical ventilation and daily throughout the course of mechanical ventilation for up to 28 days. MAIN OUTCOME MEASURE: All-cause mortality during intensive care unit stay. RESULTS: Of the 15 757 patients admitted, a total of 5183 (33%) received mechanical ventilation for a mean (SD) duration of 5.9 (7.2) days. The mean (SD) length of stay in the intensive care unit was 11.2 (13.7) days. Overall mortality rate in the intensive care unit was 30.7% (1590 patients) for the entire population, 52% (120) in patients who received ventilation because of acute respiratory distress syndrome, and 22% (115) in patients who received ventilation for an exacerbation of chronic obstructive pulmonary disease. Survival of unselected patients receiving mechanical ventilation for more than 12 hours was 69%. The main conditions independently associated with increased mortality were (1) factors present at the start of mechanical ventilation (odds ratio [OR], 2.98; 95% confidence interval [CI], 2.44-3.63; P<.001 for coma), (2) factors related to patient management (OR, 3.67; 95% CI, 2.02-6.66; P<.001 for plateau airway pressure >35 cm H(2)O), and (3) developments occurring over the course of mechanical ventilation (OR, 8.71; 95% CI, 5.44-13.94; P<.001 for ratio of PaO(2) to fraction of inspired oxygen <100). CONCLUSION: Survival among mechanically ventilated patients depends not only on the factors present at the start of mechanical ventilation, but also on the development of complications and patient management in the intensive care unit.

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Studer SM, Levy RD, McNeil K, Orens JB.
Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness.
Eur Respir J 2004 Oct; 24 (4): 674-85.
Ver Abstract                    Texto Completo

The success of lung transplantation has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. However, significant improvement for the overall outcomes of lung transplantation will only occur when better methods exist to prevent or effectively treat chronic rejection.

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Nava S, Ambrosino N, Clini E, Prato M, Orlando G, Vitacca M et al.
Noninvasive mechanical ventilation in the weaning of patients with respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial.
Ann Intern Med 1998 May 1; 128 (9): 721-8.
Ver Abstract                    Texto Completo

BACKGROUND: In patients with acute exacerbations of chronic obstructive pulmonary disease, mechanical ventilation is often needed. The rate of weaning failure is high in these patients, and prolonged mechanical ventilation increases intubation-associated complications. OBJECTIVE: To determine whether noninvasive ventilation improves the outcome of weaning from invasive mechanical ventilation. DESIGN: Multicenter, randomized trial. SETTING: Three respiratory intensive care units. PATIENTS: Intubated patients with chronic obstructive pulmonary disease and acute hypercapnic respiratory failure. INTERVENTION: A T-piece weaning trial was attempted 48 hours after intubation. If this failed, two methods of weaning were compared: 1) extubation and application of noninvasive pressure support ventilation by face mask and 2) invasive pressure support ventilation by an endotracheal tube. MEASUREMENTS: Arterial blood gases, duration of mechanical ventilation, time in the intensive care unit, occurrence of nosocomial pneumonia, and survival at 60 days. RESULTS: At admission, all patients had severe hypercapnic respiratory failure (mean pH, 7.18+/-0.06; mean PaCO2, 94.2+/-24.2 mm Hg), sensory impairment, and similar clinical characteristics. At 60 days, 22 of 25 patients (88%) who were ventilated noninvasively were successfully weaned compared with 17 of 25 patients (68%) who were ventilated invasively. The mean duration of mechanical ventilation was 16.6+/-11.8 days for the invasive ventilation group and 10.2+/-6.8 days for the noninvasive ventilation group (P = 0.021). Among patients who received noninvasive ventilation, the probability of survival and weaning during ventilation was higher (P = 0.002) and time in the intensive care unit was shorter (15.1+/-5.4 days compared with 24.0+/-13.7 days for patients who received invasive ventilation; P = 0.005). Survival rates at 60 days differed (92% for patients who received noninvasive ventilation and 72% for patients who received invasive ventilation; P = 0.009). None of the patients weaned noninvasively developed nosocomial pneumonia, whereas 7 patients weaned invasively did. CONCLUSIONS: Noninvasive pressure support ventilation during weaning reduces weaning time, shortens the time in the intensive care unit, decreases the incidence of nosocomial pneumonia, and improves 60-day survival rates.

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Maurer JR, Frost AE, Estenne M, Higenbottam T, Glanville AR.
International guidelines for the selection of lung transplant candidates. The International Society for Heart and Lung Transplantation, the American Thoracic Society, the American Society of Transplant Physicians, the European Respiratory Society.
Transplantation 1998 Oct 15; 66 (7): 951-6.
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[No hay abstract disponible]

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Varela A, Álvarez A, Román A, Ussetti P, Zurbano F.
Trasplante pulmonar: Normativa SEPAR.
Arch Bronconeumol 2001; 37 (8): 307-15.
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Con la perspectiva de 10 años de experiencia en trasplante pulmonar en nuestro país y con más de 500 trasplantes realizados, se pretende actualizar en esta Normativa los criterios de selección de los posibles candidatos, así como su seguimiento, tanto en el hospital trasplantador como en su lugar de origen. En la actualidad podemos decir que este tratamiento está aceptado y adaptado en nuestro medio, pudiéndose identificar a aquellos pacientes que van a poder beneficiarse de este procedimiento desde el punto de vista de función pulmonar y capacidad al ejercicio, calidad de vida y supervivencia. Por otra parte, el conocimiento de los factores de riesgo de mortalidad temprana, como son el fracaso primario del injerto y la infección, y tardía como el rechazo crónico (bronquiolitis), y de las infecciones permite tomar decisiones riesgo-beneficio de forma más selectiva. Es también importante el conocimiento de las posibles opciones terapéuticas en algunos pacientes bien seleccionados, como la reducción de volumen en el enfisema, el tratamiento vasodilatador en la hipertensión pulmonar o la tromboendarterectomía en la hipertensión pulmonar tromboembólica crónica. Por tanto, esta Normativa es el compendio de los conocimientos adquiridos durante estos años por clínicos y cirujanos, y debe servir para un mejor seguimiento de estos pacientes por parte de los médicos responsables de sus cuidados.

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Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A et al.
A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.
N Engl J Med 2003 May 22; 348 (21): 2059-73.
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BACKGROUND: Lung-volume-reduction surgery has been proposed as a palliative treatment for severe emphysema. Effects on mortality, the magnitude and durability of benefits, and criteria for the selection of patients have not been established. METHODS: A total of 1218 patients with severe emphysema underwent pulmonary rehabilitation and were randomly assigned to undergo lung-volume-reduction surgery or to receive continued medical treatment. RESULTS: Overall mortality was 0.11 death per person-year in both treatment groups (risk ratio for death in the surgery group, 1.01; P=0.90). After 24 months, exercise capacity had improved by more than 10 W in 15 percent of the patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). With the exclusion of a subgroup of 140 patients at high risk for death from surgery according to an interim analysis, overall mortality in the surgery group was 0.09 death per person-year, as compared with 0.10 death per person-year in the medical-therapy group (risk ratio, 0.89; P=0.31); exercise capacity after 24 months had improved by more than 10 W in 16 percent of patients in the surgery group, as compared with 3 percent of patients in the medical-therapy group (P<0.001). Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was lower in the surgery group than in the medical-therapy group (risk ratio for death, 0.47; P=0.005). Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was higher in the surgery group than in the medical-therapy group (risk ratio, 2.06; P=0.02). CONCLUSIONS: Overall, lung-volume-reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non-upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume-reduction surgery, because of increased mortality and negligible functional gain.

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National Emphysema Treatment Trial Research Group.
Patients at high risk of death after lung-volume-reduction surgery.
N Engl J Med 2001 Oct 11; 345 (15): 1075-83.
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BACKGROUND: Lung-volume-reduction surgery is a proposed treatment for emphysema, but optimal selection criteria have not been defined. The National Emphysema Treatment Trial is a randomized, multicenter clinical trial comparing lung-volume-reduction surgery with medical treatment. METHODS: After evaluation and pulmonary rehabilitation, we randomly assigned patients to undergo lung-volume-reduction surgery or receive medical treatment. Outcomes were monitored by an independent data and safety monitoring board. RESULTS: A total of 1033 patients had been randomized by June 2001. For 69 patients who had a forced expiratory volume in one second (FEV1) that was no more than 20 percent of their predicted value and either a homogeneous distribution of emphysema on computed tomography or a carbon monoxide diffusing capacity that was no more than 20 percent of their predicted value, the 30-day mortality rate after surgery was 16 percent (95 percent confidence interval, 8.2 to 26.7 percent), as compared with a rate of 0 percent among 70 medically treated patients (P<0.001). Among these high-risk patients, the overall mortality rate was higher in surgical patients than medical patients (0.43 deaths per person-year vs. 0.11 deaths per person-year; relative risk, 3.9; 95 percent confidence interval, 1.9 to 9.0). As compared with medically treated patients, survivors of surgery had small improvements at six months in the maximal workload (P= 0.06), the distance walked in six minutes (P=0.03), and FEV1 (P<0.001), but a similar health-related quality of life. The results of the analysis of functional outcomes for all patients, which accounted for deaths and missing data, did not favor either treatment. CONCLUSIONS: Caution is warranted in the use of lung-volume-reduction surgery in patients with emphysema who have a low FEV1 and either homogeneous emphysema or a very low carbon monoxide diffusing capacity. These patients are at high risk for death after surgery and also are unlikely to benefit from the surgery.

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Wan IY, Toma TP, Geddes DM, Snell G, Williams T, Venuta F et al.
Bronchoscopic lung volume reduction for end-stage emphysema: report on the first 98 patients.
Chest 2006 Mar; 129 (3): 518-26.
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OBJECTIVES: To report the first multicenter experience on the treatment of end-stage emphysema using an endobronchial valve (EBV) [Emphasys EBV; Emphasys Medical; Redwood City, CA]. DESIGN: Retrospective analysis from prospective multicenter registry. PATIENTS AND INTERVENTIONS: This is a study of the use of EBVs in the treatment of end-stage emphysema at nine centers in seven countries. Ninety-eight patients with mean FEV(1) of 0.9 +/- 0.3 L (30.1 +/- 10.7% of predicted) [+/- SD] and residual volume (RV) of 5.1 +/- 1.3 L (244.3 +/- 0.3% of predicted) were treated over a period of 20 months. Spirometry, plethysmography, and diffusing capacity of the lung for carbon monoxide (Dlco) and exercise tolerance testing were performed at 30 days and 90 days after the procedure. RESULTS: RV decreased by 4.9 +/- 17.4% (p = 0.025), FEV(1) increased by 10.7 +/- 26.2% (p = 0.007), FVC increased by 9.0 +/- 23.9% (p = 0.024), and 6-min walk distance increased by 23.0 + 55.3% (p = 0.001). There was a trend toward improvement in Dlco, but this did not reach statistical significance (17.2 +/- 52.0%, p = 0.063). Patients treated unilaterally showed a trend toward greater improvement than those treated bilaterally. A similar trend toward improvement was observed in patients who had one entire lobe treated compared to those with just one or two bronchopulmonary segments treated. Eight patients (8.2%) had serious complications in the first 90 days, including one death (1.0%). CONCLUSION: This multicenter analysis confirms that improvement in pulmonary function and exercise tolerance can be achieved in emphysematous patients using EBVs. Future efforts should be directed to determining how to select those patients who would benefit most from this procedure and the best endobronchial treatment strategy.

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Ingenito EP, Berger RL, Henderson AC, Reilly JJ, Tsai L, Hoffman A.
Bronchoscopic lung volume reduction using tissue engineering principles.
Am J Respir Crit Care Med 2003 Mar 1; 167 (5): 771-8.
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Bronchoscopic lung volume reduction (BLVR), a minimally invasive procedure based on tissue engineering principles, was performed in six sheep with papain-induced experimental emphysema (EMPH). Physiologic measurements, at baseline, after generation of EMPH, and at 3 and 9 weeks after BLVR, included lung volumes, diffusing capacity (DL(CO)), pressure-volume relationships for the lung and chest wall, pleural pressures generated during active respiratory muscle contraction, lung resistance and dynamic elastance. The animal model displayed hyperinflation (change in total lung capacity +8%; change in residual volume +66%), reduced DL(CO) (-21%), and elevated airway resistance (+76%) that resembled advanced human EMPH. BLVR was well tolerated without complications, and it reduced lung volumes (change in total lung capacity -16%; change in residual volume -55%) in a pattern that resulted in significant improvements in vital capacity (10%). At autopsy, well-organized, peripheral scars associated with tissue contraction were observed at 33 of the 36 (91%) treated sites. There was no evidence of infection, abscess, or granuloma formation, or allergic reaction. Scar tissue, generated by BLVR, replaced hyperinflated lung, reduced overall lung volume, and improved respiratory function safely and consistently. The BLVR technology employed in this study addresses the limitations identified in our prior attempt at BLVR therapy and appears safe and effective enough to justify a trial in humans.

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Snider GL.
Reduction pneumoplasty for giant bullous emphysema. Implications for surgical treatment of nonbullous emphysema.
Chest 1996 Feb; 109 (2): 540-8.
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A review of the literature on reduction pneumoplasty for giant bullous emphysema was undertaken to identify current criteria for this surgical treatment and in the hope of obtaining insights into evaluating reduction pneumoplasty for nonbullous emphysema. Twenty-two retrospective case series, published since 1950, were retrieved by a computer search of the literature and a search of the Index Medicus prior to 1966. Reduction pneumoplasty is most effective when bullae are larger than one third of a hemithorax with evidence of compression of adjacent lung tissue and an FEV1 of less than 50% predicted; the presence of emphysema in nonbullous lung and the amount of compression are best judged by CT. The rationale for reduction pneumoplasty for nonbullous emphysema is supported by the similar early functional changes after reduction pneumoplasty for bullous and nonbullous-improvement of blood gas values and lung mechanics. A single study showing that decline of lung function after surgery for bullous emphysema was less in those who stopped smoking than in those who continued to smoke supports the need for preoperative and maintained smoking cessation in patients receiving reduction pneumoplasty. After 4 decades, the duration of improvement in lung function, whether worsening of emphysema occurs in remaining lung, and late morbidity and mortality after reduction pneumoplasty for bullous emphysema are not well defined. A registry with an unoperated-on comparison group could more rapidly accumulate such data after reduction pneumoplasty for nonbullous emphysema.

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Varela-Simó G, Barberà-Mir JA, Cordovilla-Pérez R, Duque-Medina JL, López-Encuentra A, Puente-Maestu L.
Normativa sobre valoración del riesgo quirúrgico en el carcinoma broncogénico.
Arch Bronconeumol 2005; 41 (12): 686-697.
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La resección pulmonar sigue siendo el tratamiento de elección en el carcinoma broncogénico (CB) localizado. Debido a que muchos de los pacientes que desarrollan un CB presentan una importante comorbilidad, la resección pulmonar se asocia con un riesgo no despreciable de complicaciones y muerte operatoria. Por lo tanto, es muy conveniente que exista un amplio consenso entre profesionales acerca de cuáles son las principales variables asociadas con el riesgo quirúrgico y cuál es el estudio preoperatorio recomendable en cada caso. En esta normativa se han desarrollado algunos de los aspectos relacionados con la operabilidad, u operabilidad funcional del paciente, definida como su capacidad para tolerar una cirugía de resección pulmonar sin que representen un elevado riesgo de muerte o de secuela invalidante. La resecabilidad, u operabilidad oncológica, es la capacidad, evaluada preoperatoriamente, para resecar completamente todo el tejido tumoral del CB con un pronóstico de beneficio, demostrado o presumible. La metodología seguida para la redacción de esta normativa ha sido la de "consenso de expertos", puesto que la gran mayoría de las recomendaciones no pueden basarse en ensayos clínicos ni en otra metodología de investigación que permita un mayor grado de evidencia científica.

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