Ascites-derived pancreatic ductal adenocarcinoma primary cell cultures as a platform for personalised medicine.

BACKGROUND: Challenges in developing drugs for pancreatic ductal adenocarcinoma (PDAC) include obtaining metastatic cancer tissue for research and validating biomarkers predicative for personalised therapeutic decisions. We have recently developed a novel therapeutic model for PDAC to address these challenges based on the isolation of viable PDAC cells derived from ascites fluid. METHODS: Ascites fluid was obtained from PDAC patients undergoing palliative paracentesis. Ascites-derived PDAC primary cells were isolated, cultured and characterised in ovo and in vitro. RESULTS: We successfully established ascites-derived primary cell cultures within 2-7 days from 92% (93 out of 101) of the ascites fluid samples obtained (from 36 different patients). Homogeneous epithelial PDAC-enriched cell cultures were identified and characterised. We observed a wide range in doubling times and migration properties among the different patient-derived cell cultures. The diverse nature of each individual patient's cell cultures was further demonstrated by differences in therapeutic susceptibility and resistance. The tumorigenicity and invasiveness of the cells were demonstrated in vivo using chicken chorioallantoic membrane grafts. CONCLUSIONS: We have developed a unique ascites-derived PDAC primary cell culture model. This model has the potential to study signalling pathways in PDAC progression and to evaluate targeted therapies for the individual patient expeditiously, thereby supporting personalised treatment decisions.

Ambulatory transcutaneous carbon dioxide monitoring for children with neuromuscular disease.

OBJECTIVE: Early screening and diagnosis of nocturnal hypoventilation can slow progression to diurnal hypercapnia and mortality in children with neuromuscular disease (NMD). However, gold standard, laboratory-based polysomnography (PSG) testing is a limited resource. Therefore, we evaluated the diagnostic accuracy of ambulatory transcutaneous carbon dioxide (tcCO2) monitoring used in the home compared to PSG in children with NMD. METHODS: Prospective, cross-sectional study in children 0-18 years old with a confirmed diagnosis of NMD and a clinically indicated need for PSG. Ambulatory tcCO2 was assessed by a respiratory therapist in participant's homes. Demographics, and PSG (including tcCO2). RESULTS: We enrolled 39 children with NMD; 3 had unusable ambulatory tcCO2 data because of failure of drift correction on the machine (n = 2) or an air bubble (n = 1). The remaining 36 patients aged 11 months to 16 years (median (IQR) 12.5 years (6.0-15.8)) had ambulatory tcCO2 and outpatient level 1 PSG data. Ambulatory tcCO2 monitoring had a sensitivity of 20.0% (95% confidence interval [CI] 0.5-71.6%) and a specificity of 93.5% (95% CI 78.6-99.2%). Almost all children and/or parents (34/36, 94%) preferred ambulatory monitoring over in-hospital PSG. CONCLUSIONS: Ambulatory transcutaneous carbon dioxide monitoring was not sufficiently accurate as a clinical tool for the diagnosis of nocturnal hypoventilation our cohort of children with neuromuscular disease despite being preferred over PSG by both children and parents.

Rapid in vivo testing of drug response in multiple myeloma made possible by xenograft to turkey embryos.

BACKGROUND: The best current xenograft model of multiple myeloma (MM) in immune-deficient non-obese diabetic/severe-combined immunodeficient mice is costly, animal maintenance is complex and several weeks are required to establish engraftment and study drug efficacy. More practical in vivo models may reduce time and drug development cost. We recently described a rapid low-cost xenograft model of human blood malignancies in pre-immune turkey. Here, we report application of this system for studying MM growth and the preclinical assessment of anticancer therapies. METHODS: Cell lines and MM patient cells were injected intravenously into embryonic veins on embryonic day 11 (E11). Engraftment of human cells in haematopoietic organs was detected by quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry and circulating free light chain. RESULTS: Engraftment was detected after 1 week in all embryos injected with cell lines and in 50% of those injected with patient cells. Injection of bortezomib or lenalinomide 48 h after cell injection at therapeutic levels that were not toxic to the bone marrow dramatically reduced MM engraftment. CONCLUSION: The turkey embryo provides a practical, xenograft system to study MM and demonstrates the utility of this model for rapid and affordable testing therapeutics in vivo. With further development, this model may enable rapid, inexpensive personalised drug screening.

Whole blood cytokine attenuation by cholinergic agonists ex vivo and relationship to vagus nerve activity in rheumatoid arthritis.

OBJECTIVE: The central nervous system regulates innate immunity in part via the cholinergic anti-inflammatory pathway, a neural circuit that transmits signals in the vagus nerve that suppress pro-inflammatory cytokine production by an alpha-7 nicotinic acetylcholine receptors (alpha7nAChR) dependent mechanism. Vagus nerve activity is significantly suppressed in patients with autoimmune diseases, including rheumatoid arthritis (RA). It has been suggested that stimulating the cholinergic anti-inflammatory pathway may be beneficial to patients, but it remains theoretically possible that chronic deficiencies in this pathway will render these approaches ineffective. METHODS: Here we addressed the hypothesis that inflammatory cells from RA patients can respond to cholinergic agonists with reduced cytokine production in the setting of reduced vagus nerve activity. RESULTS: Measurement of RR interval variability (heart rate variability, HRV), in RA patients (n = 13) and healthy controls (n = 10) revealed that vagus nerve activity was significantly depressed in patients. Whole blood cultures stimulated by exposure to endotoxin produced significantly less tumour necrosis factor in samples from RA patients as compared to healthy controls. Addition of cholinergic agonists (nicotine and GTS-21) to the stimulated whole blood cultures however significantly suppressed cytokine production to a similar extent in patients and healthy controls. CONCLUSION: These findings suggest that it is possible to pharmacologically target the alpha7nAChR dependent control of cytokine release in RA patients with suppressed vagus nerve activity. As alpha7nAChR agonists ameliorate the clinical course of collagen induced arthritis in animals, it may be possible in the future to explore whether alpha7nAChR agonists can improve clinical activity in RA patients.

Counting, analysing and reporting exacerbations of COPD in randomised controlled trials.

BACKGROUND: Clinical trials measure exacerbations of chronic obstructive pulmonary disease (COPD) inconsistently. A study was undertaken to determine if different methods for ascertaining and analysing COPD exacerbations lead to biased estimates of treatment effects. METHODS: Information on the methods used to count, analyse and report COPD exacerbation rates was abstracted from clinical trials of long-acting bronchodilators or long-acting bronchodilator/inhaled steroid combination products published between 2000 and 2006. Data from the Canadian Optimal Therapy of COPD Trial was used to illustrate how different analytical approaches can affect the estimate of exacerbation rates and their confidence intervals. RESULTS: 22 trials (17,156 patients) met the inclusion criteria and were reviewed. None of the trials adjudicated exacerbations or determined independence of events. 14/22 studies (64%) introduced selection bias by not analysing outcome data for subjects who prematurely stopped study medications. Only 31% of trials used time-weighted analyses to calculate the mean number of exacerbations/patient-year and only 15% accounted for between-subject variation. In the Canadian Optimal Therapy of COPD Trial the rate ratio for exacerbations/patient-year was 0.85 when all data were included in a time-weighted analysis, but was overestimated as 0.79 when data for those who prematurely stopped study medications were excluded and was further overestimated as 0.46 when a time-weighted analysis was not conducted; p values ranged from 0.03 to 0.24 depending on how exacerbations were determined and analysed. CONCLUSIONS: Clinical trials have used widely different methods to define and analyse COPD exacerbations and this can lead to biased estimates of treatment effects. Future trials should strive to include blinded adjudication and assessment of the independence of exacerbation events, and trials should report time-weighted intention-to-treat analyses with adjustments for between-subject variation in COPD exacerbations.

Anxiety and depression in end-stage COPD.

Although feelings of anxiety and depression are common in patients with chronic obstructive pulmonary disease (COPD), estimates of their prevalence vary considerably. This probably reflects the variety of scales and methods used to measure such symptoms. Regardless of whether anxiety and depression are considered separately or as a single construct, their impact on COPD patients is important. A heightened experience of dyspnoea is likely to be a contributing factor to anxiety. Feelings of depression may be precipitated by the loss and grief associated with the disability of COPD. Smoking has been associated with nicotine addiction, and the factors that contribute to smoking may also predispose to anxiety and depressive disorders. Randomised controlled trials indicate that exercise training and carefully selected pharmacological therapy are often effective in ameliorating anxiety and depression. Most medical illnesses are influenced by the psychological responses and coping mechanisms that patients use. However, anxiety and depression are associated with dyspnoea, fatigue and altered sleep, all of which also occur in COPD. An understanding of the psychological history and coping mechanisms of patients and the role of anxiety and depressive reactions to illness may enable clinicians to reduce these symptoms and improve quality of life among patients with chronic obstructive pulmonary disease.

Oxygen therapy during exercise training in chronic obstructive pulmonary disease.

BACKGROUND: Exercise training within the context of pulmonary rehabilitation improves outcomes of exercise capacity, dyspnea and health-related quality of life in individuals with chronic obstructive pulmonary disease (COPD). Supplemental oxygen in comparison to placebo increases exercise capacity in patients performing single-assessment exercise tests. The addition of supplemental oxygen during exercise training may enable individuals with COPD to tolerate higher levels of activity with less exertional symptoms, ultimately improving quality of life. OBJECTIVES: To determine how supplemental oxygen in comparison to control (compressed air or room air) during the exercise-training component of a pulmonary rehabilitation program affects exercise capacity, dyspnea and health-related quality of life in individuals with COPD. SEARCH STRATEGY: All records in the Cochrane Airways Group Specialized Register of trials coded as 'COPD' were searched using the following terms: (oxygen* or O2*) AND (exercis* or train* or rehabilitat* or fitness* or physical* or activ* or endur* or exert* or walk* or cycle*). Searching the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE and CINAHL databases identified studies. The last search was carried out in June 2006. SELECTION CRITERIA: Only randomized controlled trials (RCTs) comparing oxygen-supplemented exercise training to non-supplemented exercise training (control group) were considered for inclusion. Participants were 18 years or older, diagnosed with COPD and did not meet criteria for long-term oxygen therapy. No studies with mixed populations (pulmonary fibrosis, cystic fibrosis, etc) were included. Exercise training was greater than or equal to three weeks in duration and included a minimum of two sessions a week. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review and extracted data. Weighted mean differences (WMD) with 95% confidence intervals (CI) were calculated using a random-effects model. Missing data were requested from authors of primary studies. MAIN RESULTS: Five RCTs met the inclusion criteria. The maximum number of studies compared in the meta-analysis was three (31 on oxygen versus 32 control participants), because all included studies did not measure the same outcomes. When two studies were pooled, statistically significant improvements of oxygen-supplemented exercise training were found in constant power exercise time, WMD 2.68 minutes (95% CI 0.07 to 5.28 minutes). Supplemental oxygen increased the average exercise time from 6 to 14 minutes; the control intervention increased average exercise time from 6 to 12 minutes. Constant power exercise end-of-test Borg score (on a scale from 1 to 10) also showed statistically significant improvements with oxygen-supplemented exercise training, WMD -1.22 units (95% CI -2.39 to -0.06). One study showed a significant improvement in the change of Borg score after the shuttle walk test, by -1.46 units (95% CI -2.72 to -0.19). There were no significant differences in maximal exercise outcomes, functional exercise outcomes (six-minute walk test), shuttle walk distance, health-related quality of life or oxygenation status. According to the GRADE system most outcomes were rated as low quality because they were limited by study quality. AUTHORS' CONCLUSIONS: This review provides little support for oxygen supplementation during exercise training for individuals with COPD, but the evidence is very limited. Studies with larger number of participants and strong design are required to permit strong conclusions, especially for functional outcomes such as symptom alleviation, health-related quality of life and ambulation.

Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. A Cochrane systematic review.

BACKGROUND: The widespread application of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function attributable to the programs. OBJECTIVES: To determine the impact of rehabilitation on health-related quality of life (QoL) and exercise capacity in patients with COPD. METHODS: We identified randomized controlled trials (RCTs) from the Cochrane Airways Group Specialised Register. We selected RCTs of rehabilitation in patients with COPD in which quality of life (QoL) and/or exercise capacity were measured. Rehabilitation was defined as exercise training for at least 4 weeks with or without education and/or psychological support. Control groups received conventional community care without rehabilitation. RESULTS: A total of 31 RCTs met the inclusion criteria. We found statistically significant improvements for all the outcomes. In 4 important domains of QoL (Chronic Respiratory Questionnaire scores for Dyspnea, Fatigue, Emotional function and Mastery), the effect was larger than the minimal clinically important difference. For exercise capacity, the effect was small and slightly below the threshold of clinical significance for the six-minute walking distance (WMD: 48 m; 95% CI: 32 to 65; n = 16 trials). CONCLUSIONS: Rehabilitation relieves dyspnea and fatigue, improves emotional function and enhances patients' control over their condition. These improvements are moderately large and clinically significant. Rehabilitation forms an important component of the management of COPD.

Perspectives that influence action plans for chronic obstructive pulmonary disease.

BACKGROUND: Prompt treatment of acute exacerbations (AEs) in chronic obstructive pulmonary disease (COPD) improves quality of life and reduces the use of health care resources. Although patient self-management through an individualized action plan (AP) can help with early initiation of therapy, its use is critically dependent on the patient recognizing the features of an exacerbation. OBJECTIVE: To describe COPD patients' experiences with AEs, as well as health care professionals' (HCPs') attitudes toward the provision of an AP as part of self-management education. METHODS: Thirty-two patients with moderate to severe COPD who recently experienced at least one AE, and 22 HCPs with experience in the management of COPD, were interviewed. RESULTS: The most common symptoms and signs associated with an AE were difficulty breathing (84%), fatigue (81%), cold symptoms (59%), changes in sputum colour (53%) or amount (47%), and cough (44%). The main precipitants identified were environmental triggers (47%), infective agents (31%), excessive activities (25%), emotional factors (16%) and changes in medications (9%). Strategies for dyspnea relief included increasing medications (72%), resting (56%), avoiding exposure to environmental triggers (41%) and performing breathing exercises (31%). Patients supported the use of an AP and recommended that it be individualized for symptoms and triggers, and that it should also include strategies for addressing anxiety and depression. HCPs also supported the use of an individualized AP and recommended that it be regularly revisited, depending on the patient's disease severity. CONCLUSIONS: Patients' experiences with AEs do not always conform to a standard medical definition. Therefore, an understanding of their experience is of value in the design of an individualized AP. HCPs support the use of an AP that emphasizes self-management of exacerbations as well as general COPD management.

Nutritional supplementation for stable chronic obstructive pulmonary disease.

BACKGROUND: Low body weight in patients with chronic obstructive pulmonary disease (COPD) is associated with an impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity and higher mortality rate when compared to adequately nourished individuals with this disease. Nutritional support may therefore be a useful part of their comprehensive care. OBJECTIVES: To conduct a systematic review of randomised controlled trials (RCTs) to clarify whether nutritional supplementation (caloric supplementation for at least 2 weeks) improved anthropometric measures, pulmonary function, respiratory muscle strength and functional exercise capacity in patients with stable COPD. SEARCH STRATEGY: Randomized controlled trials (RCTs) were identified from the Cochrane Airways Group register of RCTs, a hand-search of abstracts presented at international meetings and consultation with experts. Searches are current as of March 2004. SELECTION CRITERIA: Two reviewers independently selected trials for inclusion, assessed quality and extracted the data. DATA COLLECTION AND ANALYSIS: Within each trial and for each outcome, we calculated an effect size. The effect sizes were then pooled by a random-effects model. Homogeneity among the effect sizes was also tested. MAIN RESULTS: Eleven studies recruiting 352 participants met the inclusion criteria. Eight papers were considered as high quality. Two studies were double-blinded. For each of the outcomes studied, the effect of nutritional support was small: the 95% confidence intervals around the pooled effect sizes all included zero. The effect of nutritional support was homogeneous across studies. AUTHORS' CONCLUSIONS: Nutritional support had no significant effect on anthropometric measures, lung function or exercise capacity in patients with stable COPD.

Critical appraisal of clinical practice guidelines targeting chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is so prevalent that the endorsement of management strategies by professional organizations issuing clinical practice guidelines (CPGs) will likely influence the clinical and financial resources allocated to this condition. OBJECTIVES: To examine the content of and to critically appraise the CPGs targeting COPD. METHODS: We identified, through a MEDLINE search (from January 1990 to May 1999) and contacts with experts and professional organizations, the CPGs for the overall management of COPD. We assessed the guidelines according to an index of quality measuring 3 dimensions: the rigor of development, the context and content, and the extent to which the dissemination and implementation have been addressed. The recommendations were also examined and compared. RESULTS: Of the 15 CPGs we included, none was based on a systematic review of the literature. Two were independently reviewed before their release, 1 included strategies for dissemination and implementation, and 1 estimated the economic implications associated with its recommendations. The recommendations were often difficult to interpret (reviewers' agreement: kappa median, 0.41). When unanimity existed regarding the benefits of a given management modality (such as respiratory rehabilitation), discrepancies were often identified in the application of the recommendation. CONCLUSIONS: The methodological quality of CPGs targeting COPD is limited, and there are disparities among many of their recommendations. Despite there being several CPGs worldwide, there is a need for an evidence-based summary of the literature to serve as a resource for those who provide health care to individuals with COPD.

New chromogens for alkaline phosphatase histochemistry: salmon and magenta phosphate are useful for single- and double-label immunohistochemistry.

Two new substrate chromogens for alkaline phosphatase (ALP) detection have been recently synthesized for use in molecular biology research, salmon and magenta phosphate. We show here that these two chromogens have advantageous characteristics for immunocytochemistry as well. Their relatively delicate pink- and magenta-colored products do not mask the colors produced by other staining procedures. In addition, the reaction products of these substrates are insoluble in water, ethanol, and xylene, permitting the use of regressive hematoxylin staining procedures and coverslipping in permanent resin-based media. Most importantly, when these ALP substrates are used in double-label immunocytochemistry in combination with horseradish peroxidase-diaminobenzidine (HRP-DAB) and counterstained with hematoxylin, all three colors can be easily distinguished. An application using these substrates for simultaneous immunocytochemical detection of two monoclonal antibodies of different classes, in combination with hematoxylin staining, is illustrated.

Severe asthma: prevention is better than cure.

Asthmatic patients during sympton-free periods almost invariably have abnormalities in lung mechanics and gas exchange. Tentacious secretions and mucosal thickening exaggerate maldistribution of ventilation and cause flow limitation in small airways. Hence, the maximal expiratory flow volume loop in these patients will show impaired flow rates at low lung volumes and many will show a widened alveolar-arterial O2 tension difference. Preventive treatment should be aimed at reversing these abnormalities. The regular use of inhaled sympathomimetics and oral theophylline preparations is justified in the symptom-free patient whose history suggests that he is susceptible to acute exacerbations. Such patients commonly experience an improved sense of well-being, increased exercise tolerance, and a decrease in the frequency and severity of their acute episodes.

Cholestatic potentials of alpha-naphthylisothiocyanate (ANIT) and beta-naphthylisothiocyanate (BNIT) in the isolated perfused rat liver.

Previous studies in rats have shown that a single oral dose of alpha-naphthylisothiocyanate (ANIT), but not the regioisomer beta-naphthylisothiocyanate (BNIT), results in intrahepatic cholestasis. The present studies were designed to evaluate the intrinsic cholestatic potential of ANIT and BNIT in the isolated perfused rat liver. Livers from male Sprague-Dawley rats (300-450 g) were isolated and perfused with Krebs-Henseleit buffer supplemented with 50 microM taurocholate and ANIT or BNIT (0, 5, 15 or 50 microM). Rates of bile flow, bile acid uptake and bile acid excretion were monitored for up to 70 min. Permeability of tight junctions also was evaluated. At concentrations of 5 microM, neither ANIT nor BNIT altered hepatobiliary function or tight junction permeability. In contrast, perfusion with 50 microM ANIT or BNIT for 35 min resulted in decreases in bile flow rates of 19 +/- 8 and 13 +/- 4%, respectively. After 70 min of perfusion with ANIT or BNIT, rates of bile flow were decreased by 78 +/- 5 and 71 +/- 4%, respectively. Bile acid excretion also was decreased following perfusion with 50 microM ANIT or BNIT. Perfusion with 50 microM ANIT or BNIT decreased bile acid uptake by 51 +/- 13 and 46 +/- 6%, respectively, at 60 min. Bile/plasma (B/P) ratios of [3H]sucrose were not affected by ANIT or BNIT at any time during perfusion, indicating that changes in bile flow and bile acid excretion in the isolated perfused liver were not associated with increased hepatocyte tight junction permeability. These data demonstrate that the direct portal infusion of a 50 microM concentration of either ANIT or BNIT produced marked decreases in bile flow, indicating that these isomers have a comparable intrinsic cholestatic potential in the isolated perfused liver.

Assessing the minimal important difference in symptoms: a comparison of two techniques.

We have developed a method for estimating the minimally important difference (MID) for health status measures. Whereas the conventional approach requires patients to judge themselves relative to their memories, our method requires patients to judge themselves relative to others with the same condition. In this study we examined whether our method (based on between-patient differences) and the conventional method (based on within-patient changes) provides comparable estimates of the MID for one health status measure: the Chronic Respiratory Questionnaire. Patients with chronic obstructive pulmonary disease who were participating in a supervised respiratory rehabilitation program were included if they were in stable health (n = 112). Their mean score per question in the Chronic Respiratory Questionnaire was 4.5 (range, 1 to 7; where bigger values indicate better health). Our method estimated that the MID was 0.5 (95% confidence interval 0.4 to 0.7). This estimate was similar to the MID previously found using the conventional method. These observations support the role of the Chronic Respiratory Questionnaire for measuring patient's symptoms, the validity of our approach for assessing the MID, and an estimate on the order of 0.5 as the threshold for this particular health status measure.

Generic and specific measurement of health-related quality of life in a clinical trial of respiratory rehabilitation.

The purpose of this study was to compare the performance of measures of health-related quality of life in a randomized controlled trial of respiratory rehabilitation versus conventional community care for patients with chronic airflow limitation. The study included 89 stable patients with moderate to severe chronic airflow limitation with measurement of health status at 12, 18, and 24 weeks. Outcomes included two disease-specific (the Oxygen Cost Diagram and the Chronic Respiratory Questionnaire [CRQ]) measures, a generic health profile (the Sickness Impact Profile [SIP]), and two utility measures (the Standard Gamble and the Quality of Well-Being index [QWB]). Of the measures, only the four domains of the CRQ (dyspnea, fatigue, mastery, and emotional function) showed statistically significant differences (P < or = 0.05) between treatment and control groups. Correlation between change in the CRQ and change in other relevant measures, including the 6-minute walk test and global ratings of change in dyspnea, fatigue, and emotional function were generally weak to moderate (from 0.19 to 0.51). All correlations between change in the QWB, SIP, and Standard Gamble and other measures were very weak or weak (up to 0.30). Correlation between change in the three generic measures were all very weak (<0.15). The results suggest that unless investigators include responsive and valid disease-specific measures of health-related quality of life in controlled trials in chronic diseases, they risk misleading conclusions about the effect of treatments on health status.

An artifact induced by negative pressure ventilation.

This report draws attention to an artifact that influences the qualitative information gained from respiratory inductance plethysmography during negative pressure ventilation with a cuirass. This artifact may prevent identification of upper airway obstruction, a manageable complication of this mode of ventilation.

Proportional assist ventilation and exercise tolerance in subjects with COPD.

STUDY OBJECTIVE: This study determined whether proportional assist ventilation (PAV) applied during constant power submaximal exercise could enable individuals with severe but stable COPD to increase their exercise tolerance. DESIGN: Prospective controlled study having a randomized order of intervention. SETTING: Pulmonary function exercise laboratory. PARTICIPANTS: Ten subjects with severe stable COPD (mean [SD]: age=59 [6] years; FEV1=29 [7]% predicted; FEV1/FVC=33 [7]%; thoracic gas volume=201 [47]% predicted; diffusion of carbon monoxide=36 [10]% predicted; PaO2=76 [8] mm Hg; and PaCO2=41 [4] mm Hg). INTERVENTION: Each subject completed five sessions of cycling at 60 to 70% of their maximum power. The sessions differed only in the type of inspiratory assist: (1) baseline (airway pressure [Paw]=0 cm H2O); (2) proportional assist ventilation (PAV) (volume assist=6 [3] cm H2O/L, flow assist=3 [1] cm H2O/L/s); (3) continuous positive airway pressure (CPAP) (5 [2] cm H2O); (4) PAV+CPAP; and (5) sham (Paw=0 cm H2O). MEASUREMENTS AND RESULTS: Dyspnea was measured using a modified Borg scale. Subjects reached the same level of dyspnea during all sessions but only PAV+CPAP significantly (p<0.05) increased exercise tolerance (12.88 [8.74] min) vs the sham session (6.60 [3.12] min). Exercise time during the PAV and CPAP sessions was 7.10 [2.83] and 8.26 [5.54] min, respectively. Minute ventilation increased during exercise but only during PAV+CPAP was the end exercise minute ventilation greater than the unassisted baseline end exercise minute ventilation (36.2 [6.7] vs 26.6 [6.4] L/min, respectively; p<0.05). CONCLUSIONS: In this study, PAV+CPAP provided ventilatory assistance during cycle exercise sufficient to increase the endurance time. It is now appropriate to evaluate whether PAV+CPAP will facilitate exercise training.

The components of a respiratory rehabilitation program: a systematic overview.

OBJECTIVE: To determine the contribution of the various components of a rehabilitation program to the improvement of exercise capacity and health-related quality of life (HRQL) in patients with COPD. DATA SOURCES: MEDLINE (1966 to April 1996) was searched. Abstracts presented at international conferences were also hand searched for additional relevant trials. Bibliographies of the retrieved articles were reviewed. Experts in rehabilitation were consulted to uncover unpublished trials. STUDY SELECTION: Randomized controlled trials (RCTs) of exercise training, breathing exercises, education, and psychosocial support in patients with COPD were primarily included if (1) the treatment effect of a specific component of a rehabilitation program could be isolated, and (2) exercise capacity, HRQL, compliance with medical therapy, and/or knowledge about the disease were measured. DATA SYNTHESIS: A best-evidence synthesis was conducted; 22 RCTs contributed to the analysis. We found the following: (1) the patients exposed to interventions that included exercise training improved their functional exercise capacity and HRQL; (2) exercise training was muscle specific; (3) the evidence to support inspiratory muscle training and other breathing exercises as an adjunct to exercise training in COPD remains equivocal; (4) the contribution of education has not been well addressed; and (5) psychosocial support reduced dyspnea acutely and, when used as an adjunct to rehabilitation, promoted compliance with an exercise regimen and improved HRQL. CONCLUSION: Respiratory rehabilitation is likely to improve functional exercise capacity and HRQL if it includes exercise training and psychosocial support. Further research is required to better define the types and intensity of exercise as well as the influence of respiratory muscle training and patient education.

Trends in the epidemiology of COPD in Canada, 1980 to 1995. COPD and Rehabilitation Committee of the Canadian Thoracic Society.

PURPOSE: To describe trends in the epidemiology of COPD in Canada from 1980 to 1995, in terms of perceived prevalence, mortality, and hospital morbidity. DATA SOURCES: We limited the analysis to data related to chronic bronchitis, emphysema, or chronic airway obstruction not classified elsewhere, and excluded asthma (Ninth International Classification of Diseases, codes 490 to 492 and 496). The perceived prevalence rate of COPD was derived from the 1994-1995 National Health Survey. Mortality and hospital morbidity data (from 1980 to 1995) were obtained from the Health Statistics Division of Statistics Canada. RESULTS: From the National Health Survey, it was estimated that 750,000 Canadians had chronic bronchitis or emphysema diagnosed by a health professional. Prevalence rates were the following: ages 55 to 64 years, 4.6%; ages 65 to 74 years, 5.0%; > or =75 years, 6.8%. From 1980 to 1995, the total number of deaths from COPD increased from 4,438 to 8,583. Although the age-standardized mortality rate remained stable throughout this period in men (around 45/100,000 population), it doubled in women (8.3/100,000 in 1980 to 17.3/100,000 in 1995). There were 55,782 hospital separations in 1993-1994 with COPD as the primary discharge diagnosis (compared to 42,102 in 1981-1982). In people aged > or =65 years, the age-specific hospital separation rate increased over this period, especially in women > or =75 years (from 504/100,000 to 1,033/100,000). The average in-hospital length of stay was 9.6 days in 1981-1982 and 8.3 days in 1993-1994. CONCLUSION: COPD represents a major health issue in Canada and will likely remain so for decades. Physician and non-physician health professionals who provide health care, as well as those who fund it must actively encourage approaches for primary and secondary prevention of this condition as well as approaches shown to be effective in addressing its associated impairment, disability, and handicap.