RESUMO
BACKGROUND: Tidal expiratory flow limitation (EFLT) is common among COPD patients. Whether EFLT changes during sleep and can be abolished during home ventilation is not known. METHODS: COPD patients considered for noninvasive ventilation used a ventilator which measured within-breath reactance change at 5 Hz (∆Xrs) and adjusted EPAP settings to abolish EFLT. Participants flow limited (∆Xrs > 2.8) when supine underwent polysomnography (PSG) and were offered home ventilation for 2 weeks. The EPAP pressure that abolished EFLT was measured and compared to that during supine wakefulness. Ventilator adherence and subjective patient perceptions were obtained after home use. RESULTS: Of 26 patients with supine EFLT, 15 completed overnight PSG and 10 the home study. In single night and 2-week home studies, EFLT within and between participants was highly variable. This was unrelated to sleep stage or body position with only 14.6% of sleep time spent within 1 cmH2O of the awake screening pressure. Over 2 weeks, mean EPAP was almost half the mean maximum EPAP (11.7 vs 6.4 cmH2O respectively). Group mean ∆Xrs was ≤ 2.8 for 77.3% of their home use with a mean time to abolish new EFLT of 5.91 min. Adherence to the ventilator varied between 71 and 100% in prior NIV users and 36-100% for naïve users with most users rating therapy as comfortable. CONCLUSIONS: Tidal expiratory flow limitation varies significant during sleep in COPD patients. This can be controlled by auto-titrating the amount of EPAP delivered. This approach appears to be practical and well tolerated by patients. TRIAL REGISTRATION: The trial was retrospectively registered at CT.gov NCT04725500.
Assuntos
Expiração/fisiologia , Ventilação não Invasiva/métodos , Polissonografia/métodos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/terapia , Volume de Ventilação Pulmonar/fisiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Estudos RetrospectivosRESUMO
Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Variantes Farmacogenômicos/genética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Negro ou Afro-Americano/genética , Idoso , Caderinas/genética , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , América do Norte , Testes Farmacogenômicos , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Sarcoglicanas/genética , Índice de Gravidade de Doença , Espirometria , Resultado do Tratamento , População Branca/genéticaRESUMO
BACKGROUND: In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery. METHODS: This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L). DISCUSSION: The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT01325883 - 29(th) March 2011.
Assuntos
Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Procedimentos Cirúrgicos do Sistema Digestório/mortalidade , Neoplasias Gastrointestinais/terapia , Aptidão Física/fisiologia , Inglaterra , Teste de Esforço/métodos , Feminino , Neoplasias Gastrointestinais/mortalidade , Neoplasias Gastrointestinais/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Qualidade de Vida , Análise de Sobrevida , Resultado do Tratamento , País de GalesRESUMO
We investigated the impact of season relative to other determinants of chronic obstructive pulmonary disease (COPD) exacerbation frequency in a long-term international study of patients with forced expiratory volume in 1 s (FEV(1)) <60% predicted. COPD exacerbations were defined by worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate) or hospital admission (severe). Seasonality effect was calculated as the proportion of patients experiencing an exacerbation each month. Exacerbations in the northern and southern regions showed an almost two-fold increase in the winter months. No seasonal pattern occurred in the tropics. Overall, 38% of exacerbations were treated with antibiotics only, 19% with systemic corticosteroids only and 43% with both, while 20% required hospital admission irrespective of the season. Exacerbation frequency was associated with older age, lower body mass index, lower FEV(1) % pred and history of prior exacerbations. Females and patients with worse baseline breathlessness, assessed using the Medical Research Council (MRC) dyspnoea scale, exacerbated more often (rate ratio (RR) for male versus female 0.7, 95% CI 0.7-0.8 (p<0.001); RR for MRC dyspnoea score 3 versus 1 and 2 combined 1.1, 95% CI 1.1-1.2 (p<0.001)). The effect of season was independent of these risk factors. COPD exacerbations and hospitalisations were more frequent in winter.
Assuntos
Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Pneumologia/métodos , Corticosteroides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Doença Pulmonar Obstrutiva Crônica/terapia , Risco , Estações do Ano , Resultado do TratamentoRESUMO
The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting ß(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 µg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Corticosteroides/administração & dosagem , Idoso , Broncodilatadores/administração & dosagem , Ciclopropanos/administração & dosagem , Dispneia/metabolismo , Feminino , Humanos , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Placebos , Análise de RegressãoRESUMO
Lack of reproducibility of findings has been a criticism of genetic association studies on complex diseases, such as chronic obstructive pulmonary disease (COPD). We selected 257 polymorphisms of 16 genes with reported or potential relationships to COPD and genotyped these variants in a case-control study that included 953 COPD cases and 956 control subjects. We explored the association of these polymorphisms to three COPD phenotypes: a COPD binary phenotype and two quantitative traits (post-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted and FEV1/forced vital capacity (FVC)). The polymorphisms significantly associated to these phenotypes in this first study were tested in a second, family-based study that included 635 pedigrees with 1,910 individuals. Significant associations to the binary COPD phenotype in both populations were seen for STAT1 (rs13010343) and NFKBIB/SIRT2 (rs2241704) (p<0.05). Single-nucleotide polymorphisms rs17467825 and rs1155563 of the GC gene were significantly associated with FEV1 % predicted and FEV1/FVC, respectively, in both populations (p<0.05). This study has replicated associations to COPD phenotypes in the STAT1, NFKBIB/SIRT2 and GC genes in two independent populations, the associations of the former two genes representing novel findings.
Assuntos
Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/genética , Fator de Transcrição STAT1/genética , Sirtuína 2/genética , Proteína de Ligação a Vitamina D/genética , Idoso , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Testes de Função Respiratória/estatística & dados numéricos , Fumar/epidemiologiaRESUMO
The TOwards a Revolution in COPD Health (TORCH) study was a 3-yr multicentre trial of 6,112 patients randomised to salmeterol (Salm), fluticasone propionate (FP), a Salm/FP combination (SFC) or placebo (P). Here the cost-effectiveness of treatments evaluated in the TORCH study is assessed. For four regions, 3-yr all-cause hospitalisation, medication and outpatient care costs were calculated. The sample was restricted to the 21 countries (n = 4,237) in which European quality of life five-dimension (EQ-5D) data were collected in order to estimate the number of quality-adjusted life years (QALYs). Regression models were fitted to survival, study medication cost, other medication cost and EQ-5D data in order to estimate total cost, number of QALYs and cost per QALY, adjusted for missing data and region. SFC had a trial-wide estimate of cost per QALY of 43,600 US dollars (USD) compared with P (95% confidence interval 21,400-123,500 USD). Estimates for Salm versus P (197,000 USD) and FP versus P (78,000 USD) were less favourable. The US estimates were greater than those from other regions; for SFC versus P, the cost per QALY was 77,100 (46,200-241,700) USD compared to 24,200 (15,200-56,100) USD in Western Europe. Compared with P, SFC has a lower incremental cost-effectiveness ratio than either FP or Salm used alone, and is, therefore, preferred to these monotherapies on the grounds of cost-effectiveness.
Assuntos
Corticosteroides/economia , Albuterol/análogos & derivados , Androstadienos/economia , Broncodilatadores/economia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/economia , Administração por Inalação , Corticosteroides/administração & dosagem , Idoso , Albuterol/administração & dosagem , Albuterol/economia , Androstadienos/administração & dosagem , Broncodilatadores/administração & dosagem , Análise Custo-Benefício , Combinação de Medicamentos , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Xinafoato de SalmeterolRESUMO
INTRODUCTION: Oral mucolytics are now recommended in some treatment guidelines for the management of chronic obstructive pulmonary disease (COPD). This article reviews the evidence for their use and their possible benefits. SOURCES OF DATA: The review is based upon peer reviewed publications relating to the use of mucolytics in COPD cited in PubMed. AREAS OF AGREEMENT: Much of the published evidence is of somewhat poor quality and many studies include patients with both chronic bronchitis and COPD. Mucolytics reduce exacerbations by up to 0.8 exacerbations per year, but have little additional benefit in those on standard maximum therapy. AREAS OF CONTROVERSY: Data that mucolytics improve symptoms, alter mucus or impact health-related quality of life in COPD patients receiving other standard therapy are unconvincing. In those on little or no other treatment, they may reduce exacerbation rate. GROWING POINTS: The use of mucolytics to treat acute exacerbations is promising. AREAS TIMELY FOR DEVELOPING RESEARCH: Head-to-head trials of mucolytics versus long-acting bronchodilators and/or inhaled corticosteroids are lacking. Even in patients with severe COPD who remain symptomatic despite maximal inhaled therapy the role of mucolytics remains unproven.
Assuntos
Expectorantes/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração Oral , Humanos , Resultado do TratamentoRESUMO
Dyspnoea, usually defined as an uncomfortable awareness of breathing, is one of the most frequent and distressing symptoms experienced by patients with lung disease. Idiopathic hyperventilation (IHV) has unknown aetiology and little is known about the mechanisms that cause the characteristic sustained hypocapnia and chronic dyspnoea. We have shown in IHV and other chronic respiratory disorders that air hunger is the dominant sensation during exercise, while resting breathlessness is characterised by an affective component. The increased drive to breathe in IHV, and indeed dyspnoea in all chronic respiratory disorders, might be better understood if the central mechanisms of dyspnoea were known. The aim of the present study was to characterise the cortical processing of respiratory-related sensory inputs in patients with IHV. Four patients with IHV were studied with ethical approval. Respiratory stimulation was produced using transient occlusion of inspiration (TIO) during spontaneous breathing (delivered in early inspiration with duration c. 300 ms; this is well tolerated) while BOLD fMRI was performed on a 3 Tesla Siemens Trio. TIO was associated with significant activation in sensorimotor and pre-motor cortical areas and the cerebellum, notably the anterior insula, an area previously associated with breathlessness in healthy volunteers. These preliminary observations on the pattern of brain activity in response to respiratory stimulation support the hypothesis that breathlessness in IHV may reflect inappropriate cortical processing of respiratory-related sensory inputs.
Assuntos
Encéfalo/fisiologia , Hiperventilação/fisiopatologia , Respiração , Humanos , Inalação/fisiologia , Imageamento por Ressonância MagnéticaRESUMO
RATIONALE: Hyperglycaemia predicts a poor outcome in Intensive Care Unit (ICU) patients. Whether this is true for respiratory failure necessitating non-invasive ventilation (NIV) is not known. OBJECTIVES: To determine whether hyperglycaemia within 24 h of admission independently predicts outcome of NIV during acute decompensated ventilatory failure complicating chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: Patients with COPD presenting with acute hypercapnic respiratory failure at University Hospital Aintree between June 2006 and September 2007 and receiving NIV within 24 h of admission were studied prospectively. Random blood glucose levels were measured before NIV administration. RESULTS: 88 patients (mean baseline pH 7.25, PaCO(2) 10.20 kPa, and PaO(2) 8.19 kPa) met the inclusion criteria, with NIV normalising arterial pH off therapy in 79 (90%). After multivariate logistic regression, the following predicted outcome: baseline respiratory rate (OR 0.91; 95% CI 0.84 to 0.99), random glucose > or = 7 mmol/l (OR 0.07; 95% CI 0.007 to 0.63) and admission APACHE II (Acute Physiology and Chronic Health Evaluation II) score (OR 0.75; 95% CI 0.62 to 0.90). The combination of baseline respiratory rate (RR) <30 breaths/min and random glucose <7 mmol/l increased prediction of NIV success to 97%, whilst use of all three factors was 100% predictive. CONCLUSIONS: In acute decompensated ventilatory failure complicating COPD, hyperglycaemia upon presentation was associated with a poor outcome. Baseline RR and hyperglycaemia are as good at predicting clinical outcomes as the APACHE II score. Combining these variables increases predictive accuracy, providing a simple method of early risk stratification.
Assuntos
Glicemia/metabolismo , Hiperglicemia/etiologia , Respiração com Pressão Positiva , Doença Pulmonar Obstrutiva Crônica/terapia , Doença Aguda , Idoso , Gasometria , Cuidados Críticos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hipercapnia/etiologia , Masculino , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/sangue , Insuficiência Respiratória/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Little is known about adherence to inhaled medication in chronic obstructive pulmonary disease (COPD) and the impact on mortality and morbidity. METHODS: Data on drug adherence from a randomised double-blind trial comparing inhaled salmeterol 50 microg + fluticasone propionate 500 microg twice daily with placebo and each drug individually in 6112 patients with moderate to severe COPD over 3 years in the TORCH study were used. All-cause mortality and exacerbations leading to hospital admission were primary and secondary end points. The study of adherence was not specified a priori as an ancillary study. RESULTS: Of the 4880 patients (79.8%) with good adherence defined as >80% use of study medication, 11.3% died compared with 26.4% of the 1232 patients (20.2%) with poor adherence. The annual rates of hospital admission for exacerbations were 0.15 and 0.27, respectively. The association between adherence and mortality remained unchanged and statistically significant after adjusting for other factors related to prognosis (hazard ratio 0.40 (95% CI 0.35 to 0.46), p<0.001). The association was even stronger when analysing on-treatment deaths only. Similarly, the association between adherence and hospital admission remained unchanged and significant in a multivariate analysis (rate ratio 0.58 (95% CI 0.44 to 0.73, p<0.001). The association between increased adherence and improved mortality and reduction in hospital admission was independent of study treatment. The effect of treatment was more pronounced in patients with good adherence than in those with poor adherence. CONCLUSION: Adherence to inhaled medication is significantly associated with reduced risk of death and admission to hospital due to exacerbations in COPD. Further research is needed to understand these strong associations.
Assuntos
Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Broncodilatadores/administração & dosagem , Hospitalização/estatística & dados numéricos , Adesão à Medicação , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuterol/administração & dosagem , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Métodos Epidemiológicos , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Xinafoato de SalmeterolRESUMO
Paradoxical inward displacement of the costal margin during inspiration is observed in many chronic obstructive pulmonary disease patients at rest but its importance is unclear. The current authors studied 20 patients (forced expiratory volume in one second 32.6+/-11.7, functional residual capacity 186+/-32% predicted) and 10 healthy controls at rest and during symptom-limited incremental exercise. With optoelectronic plethysmography, the phase shift between pulmonary and abdominal ribcage volumes and the percentage of inspiratory time the ribcage compartments moved in opposite directions were quantified, using control data to define the normal range of movement. Eight patients showed lower ribcage inspiratory paradox at rest (P+), while 12 patients did not (P-). This was unrelated to resting lung function or exercise tolerance. Total end-expiratory chest wall volume (EEV(cw)) increased immediately when exercise began in P+ patients, but later in exercise in P- patients. This difference in EEV(cw) was mainly due to a greater increase of end-expiratory pulmonary ribcage volume in P+ patients. During exercise, dyspnoea increased similarly in the two groups, while leg effort increased more markedly in the patients without paradox. In conclusion, lower ribcage paradox at rest is reproducible and associated with early-onset hyperinflation of the chest wall and predominant dyspnoea at end-exercise. When paradox is absent, the sense of leg effort becomes a more important symptom limiting exercise.
Assuntos
Exercício Físico/fisiologia , Movimento/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Mecânica Respiratória/fisiologia , Descanso/fisiologia , Parede Torácica/fisiopatologia , Idoso , Estudos de Casos e Controles , Dispneia/etiologia , Dispneia/fisiopatologia , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Pletismografia , Doença Pulmonar Obstrutiva Crônica/complicações , Reprodutibilidade dos TestesRESUMO
Bronchodilator drugs produce variable improvements in forced expiratory volume in 1 s (FEV(1)), but larger changes in end-expiratory lung volume (EELV) in chronic obstructive pulmonary disease (COPD), which were suggested to be related to the presence of expiratory flow limitation (EFL) at rest. We tested this concept in 42 COPD patients (FEV(1) 42.3+/-13.8% predicted) during spontaneous breathing before and after 5 mg nebulised salbutamol. EFL was detected by within-breath changes in respiratory system reactance measured by a multifrequency forced oscillation method, while changes in EELV were assessed by inspiratory capacity (IC). Bronchodilation (BD) increased IC (from 1.8+/-0.5 to 2.1+/-0.6 L, p<0.001) and reduced inspiration resistance ((insp)) at 5 Hz (from 5.1+/-1.6 to 4.2+/-1.5 cmH(2)OxsxL(-1), p<0.001). (insp) identified BD responders with a discriminative power of 80.1%. In total, 20 patients were flow-limited before BD. They showed worse spirometry and higher residual volume, but significant improvements in IC were seen in all patients irrespective of flow limitation. Changes in (insp) were confined to flow-limited patients, as were reactance changes. BD reduced the degree of heterogeneity in the respiratory system, a change best seen with inspiratory values. BD has complex effects on lung mechanics in COPD, and EFL affects both this and the response of some respiratory variables to treatment. However, changes in EELV are consistently seen, irrespective of the presence of flow limitation at rest.
Assuntos
Albuterol/uso terapêutico , Broncodilatadores/uso terapêutico , Volume Expiratório Forçado/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Mecânica Respiratória/efeitos dos fármacos , Albuterol/administração & dosagem , Broncodilatadores/administração & dosagem , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Capacidade Inspiratória , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Oscilometria , Pletismografia , Valor Preditivo dos Testes , Descanso , Processamento de Sinais Assistido por Computador , Espirometria , Volume de Ventilação PulmonarRESUMO
The TORCH (Towards a Revolution in COPD Health) trial has highlighted some important issues in the design and analysis of long term trials in chronic obstructive pulmonary disease. These include collection of off-treatment exacerbation data, analysis of exacerbation rates and the effect of inclusion of patients receiving inhaled corticosteroids (ICS) prior to randomisation. When effective medications are available to patients who withdraw, inclusion of off-treatment data can mask important treatment effects on exacerbation rates. Analysis of on-treatment data avoids this bias but it needs to be combined with careful analysis of withdrawal patterns across treatments. The negative binomial model is currently the best approach to statistical analysis of exacerbation rates, while analysis of time to exacerbation can supplement this approach. In the TORCH trial, exacerbation rates were higher among patients with previous use of ICS compared to those with no prior use on all study treatments. Retrospective subgroup analysis suggests ICS reduced exacerbation rates compared with placebo, regardless of prior use of ICS before entry to the study. Factorial analysis provides an alternative analysis for trials with combinations of treatments, but assumes no interaction between treatments, an assumption which cannot be verified by a significance test. No definitive conclusions can yet be drawn on whether ICS treatment has an effect on mortality.
Assuntos
Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Albuterol/administração & dosagem , Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Broncodilatadores/administração & dosagem , Quimioterapia Combinada , Fluticasona , Humanos , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Xinafoato de Salmeterol , Fatores de Tempo , Resultado do TratamentoRESUMO
Inhaled corticosteroids (ICS) are important in reducing exacerbation frequency associated with chronic obstructive pulmonary disease (COPD). However, little is known about the risk of associated infections. In a post hoc analysis of the TOwards a Revolution in COPD Health (TORCH) study, we analysed and identified potential risk factors for adverse event reports of pneumonia in this randomised, double-blind trial comparing twice-daily inhaled salmeterol (SAL) 50 microg, fluticasone propionate (FP) 500 microg, and the combination (SFC) with placebo in 6,184 patients with moderate-to-severe COPD over 3 yrs. Despite a higher withdrawal rate in the placebo arm, after adjusting for time on treatment, a greater rate of pneumonia was reported in the FP and SFC treatment arms (84 and 88 per 1,000 treatment-yrs, respectively) compared with SAL and placebo (52 and 52 per 1,000 treatment-yrs, respectively). Risk factors for pneumonia were age > or =55 yrs, forced expiratory volume in 1 s <50% predicted, COPD exacerbations in the year prior to the study, worse Medical Research Council dyspnoea scores and body mass index <25 kg.m(-2). No increase in pneumonia deaths with SFC was observed; this could not be concluded for FP. Despite the benefits of ICS-containing regimens in COPD management, healthcare providers should remain vigilant regarding the possible development of pneumonia as a complication in COPD patients receiving such therapies.
Assuntos
Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Broncodilatadores/administração & dosagem , Pneumonia/epidemiologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Idoso , Albuterol/administração & dosagem , Estudos de Coortes , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fluticasona , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico , Doença Pulmonar Obstrutiva Crônica/complicações , Fatores de Risco , Xinafoato de SalmeterolRESUMO
BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) walk less than healthy older people and their self-reported activity predicts exacerbation risk. The relationship between lower limb activity and total daily activity is not known, nor are there any data which relate objectively assessed daily activity to laboratory assessments made before and after rehabilitation. METHODS: Lower limb activity was measured by leg actigraphy over 3 days in 45 patients with moderate to severe COPD and 18 controls of similar age. Thirty-three patients with COPD entered an 8-week rehabilitation programme in which the change in leg activity was measured and related to other outcomes. RESULTS: In patients with COPD the mean level of activity measured by whole body and leg activity monitors was closely related (r = 0.92; p<0.001), but leg activity was consistently reduced compared with controls of similar age (p = 0.001). Mean leg activity, mean intensity of leg activity and the time that patients spent mobile at home were all related to forced expiratory volume in 1 s (FEV(1)) (r = 0.57, p = 0.001; r = 0.5, p = 0.003; and r = 0.51, p = 0.002, respectively), but intensity of activity and time spent mobile were not related. Subjects completing pulmonary rehabilitation showed significant improvements in mean activity (p = 0.001) and spent more time moving (p = 0.014). These changes were unrelated to improvement in muscle strength or walking distance but correlated with baseline FEV(1) (r = 0.8, p<0.001). CONCLUSIONS: Total daily activity in patients with COPD is closely related to leg activity which is reduced compared with controls of similar age. Individuals differ in the time spent mobile during the day, but subjective and objectively assessed activity improves after rehabilitation and is predicted by FEV(1). The change in activity is unrelated to improvements in corridor walking and health status.
Assuntos
Perna (Membro)/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Pessoas com Deficiência , Exercício Físico/fisiologia , Tolerância ao Exercício , Feminino , Volume Expiratório Forçado/fisiologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Doença Pulmonar Obstrutiva Crônica/reabilitação , Músculo Quadríceps/fisiologia , Fatores de Risco , Capacidade Vital/fisiologia , Caminhada/fisiologiaRESUMO
Access to comprehensive guidelines on the management of chronic obstructive pulmonary disease (COPD) is now available, and several treatment goals of therapy have been identified from these guidelines, which have since been studied in clinical trials. Drug therapy is a key component of an individual patient's management plan, particularly in more severe disease. During the past few years, a number of new drug treatments have become available, although these are not always appropriately prescribed; this is particularly the case for oxygen. For patients with a history of exacerbations, there is good evidence for the use of inhaled long-acting anticholinergic agents or combined inhaled steroids and long-acting beta-agonists. Evidence for prophylactic antibiotics and antioxidant agents is lacking. Nutritional and calorie supplementation have not been shown to improve exercise capacity. Statins may improve outcomes in COPD, but prospective trials are needed to confirm this. The evidence for the use of long-term oxygen therapy in hypoxaemic patients is robust. Ambulatory oxygen improves exercise capacity, but whether it is used appropriately is in doubt. Overall, short burst oxygen therapy does not offer a benefit and therefore cannot be recommended.
Assuntos
Oxigenoterapia , Doença Pulmonar Obstrutiva Crônica/terapia , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Terapia Combinada , Tolerância ao Exercício , Humanos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoRESUMO
Various statistical methods have been used to measure the impact of treatment on chronic obstructive pulmonary disease (COPD) exacerbations. Poisson regression has recently been recommended as the appropriate method but the model does not satisfactorily account for variability between patients. In contrast, use of a negative binomial model, which corresponds to assuming a separate Poisson parameter for each patient, offers a more appealing approach. The present paper reviews analysis methods, with particular focus on the negative binomial model. To illustrate the differences that arise from using different analysis methods, we have reanalysed data from two large studies which, among other objectives, investigated the effectiveness of inhaled corticosteroids in reducing COPD exacerbation rates. Using the negative binomial model to reanalyse data from the TRISTAN and ISOLDE studies, the overall estimates of exacerbation rates on each treatment arm are higher and the confidence intervals for comparisons between treatments are wider, but the overall conclusions of TRISTAN and ISOLDE regarding reduction of exacerbations remain unchanged. The negative binomial approach appears to provide a better fit to the distribution of the data than earlier methods and is currently the method of choice. Research needs to continue on further methods to improve the analysis of exacerbation data.
Assuntos
Doença Pulmonar Obstrutiva Crônica/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Interpretação Estatística de Dados , Humanos , Distribuição de Poisson , Doença Pulmonar Obstrutiva Crônica/complicaçõesRESUMO
The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.
Assuntos
Comitês Consultivos , Biomarcadores/sangue , Ensaios Clínicos como Assunto , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/mortalidade , Corticosteroides/uso terapêutico , Broncodilatadores/uso terapêutico , Feminino , Humanos , Masculino , Guias de Prática Clínica como Assunto , Prognóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Testes de Função Respiratória , Medição de Risco , Sociedades Médicas , Análise de Sobrevida , Resultado do TratamentoRESUMO
Chronic obstructive pulmonary disease (COPD) is now recognized as a major source of ill health around the world with an important impact on both developed and developing economies. The emphasis in research has shifted from a purely physiological focus that mainly considered how airway smooth muscle tone can be modulated to improve lung emptying. Although long-acting inhaled beta-agonist and antimuscarinic antagonists have improved clinical management for many symptomatic patents, there is increasing attention being paid to the inflammatory component of COPD in the airways and lung parenchyma and to its close association with other diseases, which cannot simply be attributed to their having a common risk factor such as tobacco smoking. This clinical review is intended to identify not only those areas where pharmacological treatment has been successful or has offered particular insights into COPD but also to consider where existing treatment is falling short and new opportunities exist to conduct original investigations. A picture of considerable complexity emerges with a range of clinical patterns leading to several common end points such as exacerbations, exercise impairment and mortality. Defining subsets of patients responsive to more specific interventions is the major challenge for the next decade in this field.