Takashi Hajiro

Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease

BACKGROUND The effects of theophylline or anticholinergic agents on exercise capacity in patients with chronic obstructive pulmonary disease (COPD) remain controversial. The aim of the present study was to compare the effect of an oral theophylline with an inhaled anticholinergic agent and to examine the effects of combined therapy on exercise performance using progressive cycle ergometry. METHODS Twenty one men with stable COPD and a mean (SD) forced expiratory volume in one second (FEV1) of 1.00 (0.40) l were studied. Theophylline (600 or 800 mg daily), ipratropium bromide (160 μg), a combination of both drugs, and placebo were given in a randomised, double blind, four period crossover design study. Spirometric data, pulse rate, and blood pressure were assessed before and at 90 and 120 minutes after inhalation. Symptom limited progressive cycle ergometer exercise tests (20 watts/min) were performed 90 minutes after each inhalation, and dyspnoea was measured during exercise using the Borg scale. RESULTS The mean (SD) serum theophylline concentration was 18.3 (6.3) μg/ml, and seven patients had side effects during treatment with theophylline. Theophylline and ipratropium bromide produced greater increases in FEV1, maximal oxygen consumption, maximal minute ventilation, and several dyspnoea ratios than placebo. There were no differences between theophylline and ipratropium bromide except in maximal heart rate. A combination of both drugs produced greater improvements in pulmonary function and exercise capacity than either drug alone. CONCLUSIONS Both high dose theophylline and high dose ipratropium bromide improved exercise capacity in patients with stable COPD. Although data based on short term effects cannot be directly applied to long term therapy, theophylline added to an inhaled anticholinergic agent may have beneficial effects on exercise capacity in patients with COPD.

Predictive properties of different multidimensional staging systems in patients with chronic obstructive pulmonary disease.

Background Chronic obstructive pulmonary disease (COPD) is considered to be a respiratory disease with systemic manifestations. Some multidimensional staging systems, not based solely on the level of airflow limitation, have been developed; however, these systems have rarely been compared. Methods We previously recruited 150 male outpatients with COPD for an analysis of factors related to mortality. For this report, we examined the discriminative and prognostic predictive properties of three COPD multidimensional measurements. These indices were the modified BODE (mBODE), which includes body mass index, airflow obstruction, dyspnea, and exercise capacity; the ADO, composed of age, dyspnea, and airflow obstruction; and the modified DOSE (mDOSE), comprising dyspnea, airflow obstruction, smoking status, and exacerbation frequency. Results Among these indices, the frequency distribution of the mBODE index was the most widely and normally distributed. Univariate Cox proportional hazards analyses revealed that the scores on three indices were significantly predictive of 5-year mortality of COPD (P < 0.001). The scores on the mBODE and ADO indices were more significantly predictive of mortality than forced expiratory volume in 1 second, the Medical Research Council dyspnea score, and the St. George’s Respiratory Questionnaire total score. However, peak oxygen uptake on progressive cycle ergometry was more significantly related to mortality than the scores on the three indices (P < 0.0001). Conclusion The multidimensional staging systems using the mBODE, ADO, and mDOSE indices were significant predictors of mortality in COPD patients, although exercise capacity had a more significant relationship with mortality than those indices. The mBODE index was superior to the others for its discriminative property. Further discussion of the definition of disease severity is necessary to promote concrete multidimensional staging systems as a new disease severity index in guidelines for the management of COPD.

A comparison of the responsiveness of different generic health status measures in patients with asthma

Generic health status has been recommended to be measured separately from disease-specific health status, because they can yield complementary information. In particular, generic health status can provide comprehensive health ratings across various disorders. However, the weakness with generic measures is that they may be less responsive to clinical changes than disease-specific ones. Therefore, when using generic health status as an endpoint in clinical trials, the instrument to be used is a problem with respect to responsiveness. In the present study, we investigated and compared the responsiveness of health status measures during asthma treatment using three different generic instruments: the Medical Outcomes Study Short Form 36-items Health Survey (SF-36), the Nottingham Health Profile (NHP) and the EQ5D (EuroQoL), as well as one disease-specific instrument, the Asthma Quality of Life Questionnaire (AQLQ). Fifty-four new patients with asthma who consulted our clinic were recruited. The health status measurements were performed on the initial visit, and at 3 and 6 months. All subscales of the SF-36 showed a significant improvement during the first 6 months. Each dimension of the EQ5D showed stronger ceiling effects than the SF-36. With respect to the responsiveness indices, the SF-36 was regarded as more responsive than the NHP or EQ5D utility. The changes in the SF-36 had a weak to moderate correlation with the changes in the AQLQ. In conclusion, the SF-36 had a higher responsiveness for asthma as a generic measure than the NHP or EQ5D, and evaluated different aspects from the AQLQ. The SF-36 can be used effectively in asthma clinical trials.

Health‐Related Quality of Life in Stable Asthma: What Are Remaining Quality of Life Problems in Patients with Well‐Controlled Asthma?

We purposed to examine the distribution of the disturbances in the health‐related quality of life (HRQoL) and to determine the relationship between HRQoL and various clinical parameters in patients with well‐controlled asthma according to the guidelines. We enrolled 162 patients with stable asthma, and 113 were defined as well‐controlled. HRQoL was measured by the Living with Asthma Questionnaire (LWAQ), the St. Georges Respiratory Questionnaire (SGRQ), and the short‐form 36 health survey questionnaire (SF‐36), dyspnea by the Medical Research Council (MRC), and psychological status by the Hospital Anxiety and Depression Scale (HADS). In both stable and well‐controlled patients, the frequency distributions showed that the scores on the Avoidance, Distress, and Preoccupation constructs on the LWAQ were widely distributed, whereas the scores on the Vitality and General Health scales on the SF‐36 were normally distributed. In patients with well‐controlled asthma, the HADS had mild to moderate correlations with all questionnaires. Multiple regression analysis showed that the Anxiety, the MRC scale and the treatment steps accounted for 44% of the variance in the Avoidance on the LWAQ. These results suggest that domains of psychological well‐being may continue to be affected even though the asthma patients are well‐controlled by guideline criteria.

Comparison of the Bronchodilator Effects of Salbutamol Delivered via a Metered-Dose Inhaler with Spacer, a Dry-Powder Inhaler, and a Jet Nebulizer in Patients with Chronic Obstructive Pulmonary Disease

The aim of this study was to compare the bronchodilator effects of salbutamol delivered via three different devices: a dry-powder inhaler (DPI), a metered-dose inhaler (MDI) with a large-volume spacer and a jet nebulizer (NEB) in patients with stable chronic obstructive pulmonary disease (COPD). Ten male patients with stable COPD [age: 67.2 ± 3.8 years, forced expiratory volume in 1 s (FEV1): 1.56 ± 0.32 liters] were studied in a randomized, double-blind and crossover manner. Each patient received 200 or 1,000 µg salbutamol via an MDI with an InspirEaseTM spacer, a RotahalerTM, or a DeVilbiss 646TM nebulizer (NEB), or matching placebo on 7 separate days. Spirometry was performed before and 15, 30, 60, 90, 120, and 240 min after inhalation. With the 200-µg dose, only DPI produced a small but greater response in maximum FEV1 and in area under the time-response curve (AUC-FEV1) compared with placebo. With the 1,000-µg dose, DPI and MDI produced equally greater improvements in both maximum FEV1 and AUC–FEV1 than NEB. An equal bronchodilating effect can be obtained using either DPI or MDI with a spacer device, whereas the NEB was less effective when the same dose was administered.

A comparison of two simple measures to evaluate the health status of asthmatics : the Asthma Bother Profile and the Airways Questionnaire 20

Simple and concise measures for health status are desirable in clinical practice. The Asthma Bother Profile (ABP), which consists of 23 items, has been developed to assess how much asthma bothers patients. The Airways Questionnaire 20 (AQ20) is a simple instrument which consists of 20 items. The purpose of this study was to investigate how the ABP and AQ20 evaluate the health status of patients with asthma. A total of 166 patients with chronic asthma (age: 48 ± 16 yr, 77 males) completed pulmonary function testing, measurement of airway hyperresponsiveness, dyspnea rating, assessments of their anxiety and depression (HADS; Hospital Anxiety and Depression Scale), and assessments of their health status. The health status was assessed using the ABP, AQ20, the short‐form 36 health survey questionnaire (SF‐36), the Living With Asthma Questionnaire (LWAQ) and the Asthma Quality of Life Questionnaire (AQLQ). The Japanese version of the ABP included only 15 ‘bother’ items out of the original 23 items due to cultural differences. The scores on the ABP were widely distributed, whereas the scores on the AQ20 were skewed towards the milder end of the scale. The ABP had a strong correlation with the Avoidance and Distress constructs on the LWAQ, and Anxiety and Depression on the HADS (Rs = 0.56 ∼ 0.79), and its strongest correlation with the General Health (Rs = − 0.64) scale among the 8 subscales on the SF‐36. The AQ20 had a less significant correlation with the LWAQ, AQLQ, and SF‐36 than the ABP. The ABP and AQ20 were short and simple to complete, and both measures could easily be used in clinical practice. The ABP can evaluate patients more specifically with respect to distress and bother than the AQ20.

Change in Generic and Disease-Specific Health-Related Quality of Life during a One-Year Period in Patients with Newly Detected Chronic Obstructive Pulmonary Disease

Background: Although the health-related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD) has been assessed by generic or disease-specific HRQoL measures, the responsiveness of the generic HRQoL measures is generally weak. Objectives: To investigate the responses generated by generic and disease-specific HRQoL questionnaires, we prospectively followed the clinical course of patients with newly detected COPD after the initiation of treatment. Methods: A prospective, longitudinal study with a 1-year follow-up was designed. The forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), the Nottingham Health Profile (NHP) as a generic HRQoL measure, and the Chronic Respiratory Disease Questionnaire (CRQ) as a disease-specific HRQoL measure were measured at baseline and at 3, 6, and 12 months after the initiation of standard treatment. Results: Eighty-two patients completed the study. The FEV1, FVC, and NHP and CRQ scores improved significantly during the first 3 months (p < 0.05). During the last 6 months, although the FEV1 declined (p < 0.05), the HRQoL assessed by the NHP and CRQ remained elevated. Except for the score on the social isolation section of the NHP at 12 months, all HRQoL scores at 6 and 12 months were significantly improved compared to baseline (p < 0.05). Conclusion: In new patients with COPD, the NHP as well as the CRQ was able to detect changes in the HRQoL associated with effective medical interventions. The influence of the changes in airflow limitation on the HRQoL was weak.

Comparison of health-related quality of life measurements using a single value in patients with asthma and chronic obstructive pulmonary disease.

Three methods have been developed to measure health-related quality of life (HRQoL) expressed as a single value: the global rating scale, the total score obtained from disease-specific instruments, and the preference-based utility index. We compared these different single HRQoL measurements in patients with asthma and chronic obstructive pulmonary disease (COPD). We recruited 167 patients with asthma and 161 patients with COPD. The global rating HRQoL was assessed by the Hyland scale. The total HRQoL was assessed by the Living With Asthma Questionnaire in asthma and the St. Georges Respiratory Questionnaire in COPD. The Quality of Well-being (QWB) scale was used for the utility measurement derived from the Medical Outcome Study Short-form 36. The inter-relationships between these three HRQoL values were weak to moderate in asthma and moderate in COPD. In asthma, the Hyland scale was weakly correlated with the total HRQoL (Spearmans rank correlation coefficients [Rs] = −0.20) and moderately with the QWB score (Rs = −0.43). In the stepwise multiple regression analyses, anxiety on the Hospital Anxiety and Depression scale and the dyspnea score tended to correlate more significantly with the single HRQoL values in both asthma and COPD than physiological measurements such as the forced expiratory volume in one second. The Hyland scale was less correlated with existing parameters (cumulative coefficient determination [R2] = 0.04) than the total HRQoL (cumulative R2 = 0.47) and the QWB scale (cumulative R2 = 0.49) in asthma. The single HRQoL values from the Hyland scale, the total HRQoL and the QWB scale evaluated different aspects of asthma and COPD. The psychological status and dyspnea contributed more significantly to the single HRQoL values in these two disorders than the physiological measurements. In asthma, the Hyland scale was especially different from the other single HRQoL scales and should be evaluated separately from the multi-item HRQoL assessments.

Changes in indices of airway hyperresponsiveness during one year of treatment with inhaled corticosteroids in patients with asthma.

We analyzed the changes in indices of airway hyperresponsiveness, including hypersensitivity and hyperreactivity, during one year of treatment with inhaled corticosteroids. We then investigated on which of them the inhaled corticosteroids had a primary effect. Fifty outpatients with asthma were recruited and treated with inhaled beclomethasone dipropionate. They underwent bronchoprovocation tests on the initial visit and at 3, 6, and 12 months. The dose of methacholine required to produce a 20% fall in the forced expiratory volume in 1 second (PD20-FEV1) was measured to evaluate airway hypersensitivity. A relatively novel index, the percent change in the forced vital capacity (ΔFVC%) at the PD20-FEV1, was assessed as a marker of airway hyperreactivity. PD20-FEV1 and ΔFVC% were assumed to indicate the horizontal shift of the dose-response curve and the vertical change in the maximal response plateau, respectively. Log(PD20-FEV1) and ΔFVC% continued to improve throughout the year (p < 0.001 and p = 0.002, respectively). Log(PD20-FEV1) improved significantly at the 3-month evaluation (p < 0.001), and ΔFVC% improved at the 6-month evaluation (p = 0.012). Log(PD20-FEV1) had no or weak relationships with ΔFVC% at all evaluation points. In conclusion, inhaled corticosteroids continued not only to reverse the leftward shift of the curve, but also to restore the plateau. Furthermore, their effect was reflected primarily by the former rather than the latter. They should be followed separately to examine how much airway inflammation is reduced.

Possible Maximal Change in the SF-36 of Outpatients with Chronic Obstructive Pulmonary Disease and Asthma

The purpose of the present study was to investigate the responsiveness of the Short Form‐36 (SF‐36) in patients with chronic obstructive pulmonary disease (COPD) and asthma. We studied patients with COPD and asthma who attended our outpatient clinic. In the first cross‐sectional study, we compared the differences in the SF‐36 scores between pretreatment patients (152 with COPD and 174 with asthma) who visited the clinic for the first time and in‐treatment patients (123 with COPD and 151 with asthma) who had received treatment for > 6 months. The differences in each scale of the SF‐36 ranged from 6.9 to 14.4 in COPD patients and from 7.0 to 28.3 in asthma patients. In the second longitudinal study, patients who visited for the first time were enrolled, and the initial, and, 3‐, 6‐, and 12‐month evaluations of the SF‐36 were studied. A total of 136 COPD patients and 136 asthma patients were enrolled consecutively, and 100 patients with COPD and 66 patients with asthma completed the year‐long examinations. In COPD patients, except for bodily pain, the scores in all scales of the SF‐36 improved significantly during the first 3 or 6 months. In patients with asthma, all scale scores of the SF‐36 improved significantly during the first 3 months. Maximal changes in the SF‐36 scores were observed at 6 or 12 months. Longitudinal maximal changes in each scale approached or exceeded the possible maximal changes, which were derived from the differences in the scores between pretreatment patients and in‐treatment patients in the first cross‐sectional study. Improvements in the SF‐36 scores showed moderate to strong negative correlations with their baseline scores in patients with COPD and asthma. In conclusion, the SF‐36 shows sufficient responsiveness in the assessment of the health status of patients with COPD and asthma, but these responses are strongly influenced by their baseline values.