Treatment of respiratory failure in COPD

Patients with advanced COPD and acute or chronic respiratory failure are at high risk for death. Beyond pharmacological treatment, supplemental oxygen and mechanical ventilation are major treatment options. This review describes the physiological concepts underlying respiratory failure and its therapy, as well as important treatment outcomes. The rationale for the controlled supply of oxygen in acute hypoxic respiratory failure is undisputed. There is also a clear survival benefit from long-term oxygen therapy in patients with chronic hypoxia, while in mild, nocturnal, or exercise-induced hypoxemia such long-term benefits appear questionable. Furthermore, much evidence supports the use of non-invasive positive pressure ventilation in acute hypercapnic respiratory failure. It application reduces intubation and mortality rates, and the duration of intensive care unit or hospital stays, particularly in the presence of mild to moderate respiratory acidosis. COPD with chronic hypercapnic respiratory failure became a major indication for domiciliary mechanical ventilation, based on pathophysiological reasoning and on data regarding symptoms and quality of life. Still, however, its relevance for long-term survival has to be substantiated in prospective controlled studies. Such studies might preferentially recruit patients with repeated hypercapnic decompensation or a high risk for death, while ensuring effective ventilation and the patients’ adherence to therapy

Aging and induced senescence as factors in the pathogenesis of lung emphysema

SummaryClassically, the development of emphysema in chronic obstructive pulmonary disease is believed to involve inflammation induced by cigarette smoke and leukocyte activation, including oxidant-antioxidant and protease-antiprotease imbalances. While there is substantial evidence for this, additional aspects have been suggested by a number of clinical and experimental observations.Smokers exhibit signs of premature aging, particularly obvious in the skin. The link between aging and chronic disease is well-known, e.g., for the brain and musculoskeletal or cardiovascular system, as well as the clinical link between malnutrition and emphysema, and the experimental link to caloric restriction. Interestingly, this intervention also increases lifespan, in parallel with alterations in metabolism, oxidant burden and endocrine signaling.Of special interest is the observation that, even in the absence of an inflammatory environment, lung fibroblasts from patients with emphysema show persistent alterations, possibly based on epigenetic mechanisms. The importance of these mechanisms for cellular reprogramming and response patterns, individual risk profile and therapeutic options is becoming increasingly recognized. The same applies to cellular senescence. Recent findings from patients and experimental models open novel views into the arena of gene-environment interactions, including the role of systemic alterations, cellular stress, telomeres, CDK inhibitors such as p16, p21, pRb, PI3K, mTOR, FOXO transcription factors, histone modifications, and sirtuins.This article aims to outline this emerging picture and to stimulate the identification of challenging questions. Such insights also bear implications for the long-term course of the disease in relation to existing or future therapies and the exploration of potential lung regeneration

Long-Term Efficacy of Pulmonary Rehabilitation in Patients with Occupational Respiratory Diseases

Background: Pulmonary rehabilitation is a well-recognized treatment option in chronic obstructive lung disease improving exercise performance, respiratory symptoms and quality of life. In occupational respiratory diseases, which can be rather cost-intensive due to the compensation needs, very little information is available. Objectives: This study aims at the evaluation of the usefulness of pulmonary rehabilitation in patients with occupational respiratory diseases, partly involving complex alterations of lung function and of the sustainability of effects. Methods: We studied 263 patients with occupational respiratory diseases (asthma, silicosis, asbestosis, chronic obstructive pulmonary disease) using a 4-week inpatient rehabilitation program and follow-up examinations 3 and 12 months later. The outcomes evaluated were lung function, 6-min walking distance (6MWD), maximum exercise capacity (Wmax), skeletal muscle strength, respiratory symptoms, exacerbations and associated medical consultations, quality of life (SF-36, SGRQ), anxiety/depression (HADS) and Medical Research Council and Baseline and Transition Dyspnea Index scores. Results: Compared to baseline, there were significant (p < 0.05) improvements in 6MWD, Wmax and muscle strength immediately after rehabilitation, and these were maintained over 12 months (p < 0.05). Effects were less pronounced in asbestosis. Overall, a significant reduction in the rate of exacerbations by 35%, antibiotic therapy by 27% and use of health care services by 17% occurred within 12 months after rehabilitation. No changes were seen in the questionnaire outcomes. Conclusions: Pulmonary rehabilitation is effective even in the complex settings of occupational respiratory diseases, providing sustained improvement of functional capacity and reducing health care utilization. Copyright (C) 2012 S. Karger AG, Base

Acute and Chronic Effects of Smoking on Inflammation Markers in Exhaled Breath Condensate in Current Smokers

Background: Long-term cigarette smoking is associated with pulmonary inflammation, but the acute effects of smoking have been less well studied. Analysis of the exhaled breath condensate (EBC) can provide noninvasive markers that might be indicative of inflammation. Objectives: The aim of the study was to determine whether the pH, electrical conductivity and the levels of ammonium and interleukin 8 (IL-8) of EBC were altered in smokers and whether they changed after smoking a single cigarette. Methods: We included 19 healthy nonsmokers (controls), 29 asymptomatic smokers, 10 patients with stable chronic obstructive pulmonary disease (COPD) {[}Global Initiative for Chronic Obstructive Lung Disease stages (GOLD) stages II-III], and 10 patients with exacerbated COPD. In 13 smokers, EBC was also analyzed before and after smoking. EBC was obtained during 10 min tidal breathing with a cooled RTube (TM). pH was determined after deaeration with argon. Results: Acute smoking did not alter the pH or ammonium and IL-8 levels, but raised conductivity. As in COPD patients, the pH was significantly decreased in chronic smokers with a history of at least 10 pack-years compared to controls. Conclusions: EBC can be used to detect the acute and chronic effects of smoking. The increased conductivity of EBC after smoking suggests acute inflammatory effects. The reduced pH in chronic smokers shows cigarette-induced inflammation. Copyright (C) 2009 S. Karger AG, Base

Independent Information of Nonspecific Biomarkers in Exhaled Breath Condensate

Background: Exhaled breath condensate (EBC) has been used for diagnosing and monitoring respiratory disorders. For clinical purposes the assessment of easy-to-obtain nonspecific markers seems particularly interesting. Objectives: As these measures are related to each other, our objective was to extract the independent information in global EBC markers across a range of respiratory disorders. Methods: EBC was collected from patients with asthma (n = 18), chronic obstructive pulmonary disease (n = 17), and cystic fibrosis (n = 46), as well as from lung transplant (LTX) recipients (n = 14) and healthy controls (n = 26). Samples were assessed for electrical conductivity, ammonia, pH, and nitrite/nitrate. pH was measured after both deaeration with argon and CO(2) standardization. Additionally, the fraction of exhaled nitric oxide (FE(NO)) was assessed. Factor analysis was applied to identify major factors concerning these measures. Results: Three independent factors were detected; the first comprised conductivity, ammonia, and pH, especially when standardized using CO(2), the second nitrite/nitrate, and the third FE(NO). Conductivity and ammonia were highly correlated (r = 0.968; p < 0.001). FE(NO) provided independent information mainly in asthma. The nonspecific EBC markers showed considerable overlap between patient groups and healthy subjects. However, conductivity, ammonia, pH standardized for CO(2) and nitrite/nitrate were increased in LTX recipients compared to healthy controls (p < 0.05 each). Conclusions: A panel of nonspecific easy-to-obtain exhaled breath markers could be reduced to 3 independent factors. The information content of conductivity, ammonia, and pH after CO(2) equilibration appeared to be similar, while FE(NO) was independent. The increased levels of these biomarkers in LTX might indicate a potential for their use in these patients. Copyright (C) 2010 S. Karger AG, Base

Mental health, serum biomarkers and survival in severe COPD: a pilot study

Background: Chronic obstructive pulmonary disease (COPD) impairs physical status and impacts on mental health. This prospective study was designed to assess associations between mental health and systemic biomarkers, and their combined relationship with long-term survival in stable severe COPD. Methods: Forty-five patients with severe but stable COPD (forced expiratory volume in 1 s of 29.8 (quartiles: 22.6;41.4) % predicted) were assessed using the Hospital Anxiety and Depression Scale (HADS), the Patient Health Questionnaire (PHQ), St. George's Respiratory Questionnaire and the State-Trait Anxiety Inventory (STAI). The following serum biomarkers were measured: 25-OH-cholecalciferol, C-reactive protein, erythrocyte sedimentation rate, leucocyte number, serum amyloid-A (SA-A), N-terminal pro-brain natriuretic peptide, troponin I, glycosylated haemoglobin, haemoglobin (Hb), haematocrit (Hc), creatinine and thyroid-stimulating hormone. Patients were followed-up for 36 months. Associations between aspects of mental health and biomarkers, and their utility as predictors of 3-year survival were evaluated by regression analyses. Results: The prevalence of anxiety (HADS-A: 89.9 %), depression (HADS-D: 58.8 %;PHQ: 60.6 %), somatisation (PHQ-15: 81.8 %) and psychosocial stress (PHQ-stress: 60.6 %) was high. There was a significant positive association between the leucocyte count and SA-A level with STAI-trait anxiety (p = 0.03 and p = 0.005, respectively), and between leucocytes and PHQ-stress (p = 0.043). Hb and Hc were significantly negatively associated with HADS-depression (p = 0.041 and p = 0.031, respectively). Univariate Cox regression analyses revealed that leucocyte count (hazard ratio (HR) 2.976, 95 % CI 1.059-8.358;p = 0.038), and stress (HR 4.922, 95 % CI 1.06-22.848;p = 0.042) were linked to long-term survival. In multivariate Cox regression analyses, including known risk factors for survival in COPD, PHQ-stress (HR 45.63, 95 % CI 1.72-1,208.48;p = 0.022) remained significantly associated with survival. Conclusion: In this pilot study different dimensions of mental health were correlated to serum biomarkers, probably reflecting systemic effects of COPD. While leucocyte number and PHQ-stress were associated with long-term survival in univariate analyses, PHQ-stress remained in multivariate analyses as independent prognostic factor

Reference values of impulse oscillometric lung function indices in adults of advanced age.

Impulse oscillometry (IOS) is a non-demanding lung function test. Its diagnostic use may be particularly useful in patients of advanced age with physical or mental limitations unable to perform spirometry. Only few reference equations are available for Caucasians, none of them covering the old age. Here, we provide reference equations up to advanced age and compare them with currently available equations. IOS was performed in a population-based sample of 1990 subjects, aged 45-91 years, from KORA cohorts (Augsburg, Germany). From those, 397 never-smoking, lung healthy subjects with normal spirometry were identified and sex-specific quantile regression models with age, height and body weight as predictors for respiratory system impedance, resistance, reactance, and other parameters of IOS applied. Women (n = 243) showed higher resistance values than men (n = 154), while reactance at low frequencies (up to 20 Hz) was lower (p<0.05). A significant age dependency was observed for the difference between resistance values at 5 Hz and 20 Hz (R5-R20), the integrated area of low-frequency reactance (AX), and resonant frequency (Fres) in both sexes whereas reactance at 5 Hz (X5) was age dependent only in females. In the healthy subjects (n = 397), mean differences between observed values and predictions for resistance (5 Hz and 20 Hz) and reactance (5 Hz) ranged between -1% and 5% when using the present model. In contrast, differences based on the currently applied equations (Vogel & Smidt 1994) ranged between -34% and 76%. Regarding our equations the indices were beyond the limits of normal in 8.1% to 18.6% of the entire KORA cohort (n = 1990), and in 0.7% to 9.4% with the currently applied equations. Our study provides up-to-date reference equations for IOS in Caucasians aged 45 to 85 years. We suggest the use of the present equations particularly in advanced age in order to detect airway dysfunction

Diagnostic accuracy of FeNO [fractional exhaled nitric oxide] and asthma symptoms increased when evaluated with a superior reference standard

Objectives: The objective of the study is to determine the impact of changing reference standards (RS), namely spirometry vs. whole-body plethysmography (WBP), on estimation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and clinical signs and symptoms (CSS) as index tests regarding asthma diagnosis. Study Design and Setting: This was a diagnostic study conducted in 393 patients attending a private practice of pneumologists with complaints suspicious of asthma. First, the index tests were compared with the diagnostic results of spirometry in terms of forced expiratory volume in the first second (FEV1) responsiveness. Second, the index tests were compared with the results of WBP in terms of specific airway resistance and FEV1 responsiveness. Areas under the curve (AUC) were compared with a generalized estimating equation approach based on binary logistic regression. Results: FeNO values and CSS ‘wheezing’ and ‘allergic rhinitis’ showed higher specificities (P < 0.001) and sensitivities (not significant) when evaluated with WBP; also, Youden indices increased in these CSS (P < 0.05). AUC of FeNO in combination with ‘wheezing’ and ‘allergic rhinitis’ when WBP was used as RS (AUC = 0.724; 95% confidence interval 0.672 to 0.776) was higher compared with spirometry as RS (AUC = 0.654; 95% confidence interval 0.585 to 0.722) (P < 0.001). Conclusion: In case of asthma, superior RS led to more favorable assessment of index tests. FeNO measurement might have been underestimated in some previous studies

Comparison of two devices and two breathing patterns for exhaled breath condensate sampling.

Analysis of exhaled breath condensate (EBC) is a noninvasive method to access the epithelial lining fluid of the lungs. Due to standardization problems the method has not entered clinical practice. The aim of the study was to assess the comparability for two commercially available devices in healthy controls. In addition, we assessed different breathing patterns in healthy controls with protein markers to analyze the source of the EBC. EBC was collected from ten subjects using the RTube and ECoScreen Turbo in a randomized crossover design, twice with every device--once in tidal breathing and once in hyperventilation. EBC conductivity, pH, surfactant protein A, Clara cell secretory protein and total protein were assessed. Bland-Altman plots were constructed to display the influence of different devices or breathing patterns and the intra-class correlation coefficient (ICC) was calculated. The volatile organic compound profile was measured using the electronic nose Cyranose 320. For the analysis of these data, the linear discriminant analysis, the Mahalanobis distances and the cross-validation values (CVV) were calculated. Neither the device nor the breathing pattern significantly altered EBC pH or conductivity. ICCs ranged from 0.61 to 0.92 demonstrating moderate to very good agreement. Protein measurements were greatly influenced by breathing pattern, the device used, and the way in which the results were reported. The electronic nose could distinguish between different breathing patterns and devices, resulting in Mahalanobis distances greater than 2 and CVVs ranging from 64% to 87%. EBC pH and (to a lesser extent) EBC conductivity are stable parameters that are not influenced by either the device or the breathing patterns. Protein measurements remain uncertain due to problems of standardization. We conclude that the influence of the breathing maneuver translates into the necessity to keep the volume of ventilated air constant in further studies

Uric acid, lung function, physical capacity and exacerbation frequency in patients with COPD: a multi-dimensional approach

Background: Recent investigations showed single associations between uric acid levels, functional parameters, exacerbations and mortality in COPD patients. The aim of this study was to describe the role of uric acid within the network of multiple relationships between function, exacerbation and comorbidities. Methods: We used baseline data from the German COPD cohort COSYCONET which were evaluated by standard multiple regression analyses as well as path analysis to quantify the network of relations between parameters, particularly uric acid. Results: Data from 1966 patients were analyzed. Uric acid was significantly associated with reduced FEV1, reduced 6-MWD, higher burden of exacerbations (GOLD criteria) and cardiovascular comorbidities, in addition to risk factors such as BMI and packyears. These associations remained significant after taking into account their multiple interdependences. Compared to uric acid levels the diagnosis of hyperuricemia and its medication played a minor role. Conclusion: Within the limits of a cross-sectional approach, our results strongly suggest that uric acid is a biomarker of high impact in COPD and plays a genuine role for relevant outcomes such as physical capacity and exacerbations. These findings suggest that more attention should be paid to uric acid in the evaluation of COPD disease status