Quality of life measurements and bronchodilator responsiveness in prescribing nebulizer therapy in COPD

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1 Chronic Respiratory Disease 2008; 5: ORIGINAL PAPER Quality of life measurements and bronchodilator responsiveness in prescribing nebulizer therapy in COPD C Brophy 1, JA Kastelik 1, E Gardiner 2 and MA Greenstone 1 1 Medical Chest Unit, Castle Hill Hospital, Castle Road, Cottingham Hull, East Yorkshire HU16 5JQ; and 2 Department of Clinical Psychology, Hertford Building, West Campus University of Hull HU6 7RX, UK Nebulized bronchodilators are widely regarded as the optimal treatment for maintenance therapy in patients with severe chronic obstructive pulmonary disease (COPD). The aim of the study was to assess whether detailed physiological, functional and quality of life-related measurements can assist in determining the requirement for nebulized bronchodilator therapy in patients with moderate to severe COPD. This was an unblinded, randomized, crossover study that compared intermediate (120 mcg ipratropium bromide and 600 mcg of salbutamol using metered dose inhaler (MDI) and spacer) and high dose (nebulized 500 mcg ipratropium bromide and 2.5 mg salbutamol) bronchodilator therapy, on physiological, functional and quality of life-related measurements in patients with COPD. A total of 25 patients (12 female), mean (SD) age 68 (7) years, FEV 1 45 (10) % predicted completed the study. There was no statistically significant difference between the treatments in the pre- and post-bronchodilator lung function values, six-minute walk distance, breathlessness score or quality of life questionnaires. Fifteen patients preferred bronchodilator therapy with nebulizer and 10 with MDI and spacer. In 20 patients at least one positive response in quality of life score, lung function or six-minute walk, was observed on the preferred treatment. Only a proportion of patients with moderate or severe COPD prefer nebulized bronchodilator therapy. This study found that none of the parameters singly or in combination were consistently predictive of patients preference for nebulized bronchodilator therapy. Therefore, we suggest that clinicians institute a trial of stepping up to an intermediate dose of bronchodilators prior to introducing nebulized therapy. Chronic Respiratory Disease 2008; 5: Key words: bronchodilators; COPD; nebulizers Introduction Despite conflicting evidence of efficacy domiciliary nebulized bronchodilator therapy is commonly used in the management of patients with severe but stable chronic obstructive pulmonary disease (COPD). Thus approximately nebulizer compressors have been estimated to be in domiciliary use in the United Kingdom (UK). 1 The provision of nebulizers however, is variable both in the UK and other European countries. 2,3 This may be related to a number of factors including local funding priorities, patient and physician expectations and differing expert opinion on the efficacy of stepping up bronchodilator therapy dose with a suitable device as compared to nebulized treatment. 4 Correspondence: Dr Jack A Kastelik, Medical Chest Unit, Castle Hill Hospital, Castle Road, Cottingham Hull, East Yorkshire HU16 5JQ, UK. j.a.kastelik@hull.ac.uk The current British and European guidelines recommend nebulizer use in patients requiring high doses of inhaled bronchodilator or in patients who are unable to use other devices. 5 7 Several reports have highlighted the inability of laboratory-based single dose reversibility studies to predict the response to domiciliary nebulized therapy Thus existing recommendations suggest using objective PEF assessment and subjective individual self-reporting over a trial period to determine suitability for longer-term therapy. 6 More recently published National Institute for Clinical Health and Excellence (NICE) COPD guidelines recommend that nebulized bronchodilator therapy should not be prescribed without assessment for a reduction in symptoms, an increase in the ability to undertake activities of daily living, an increase in exercise capacity or an improvement in lung function. 7 This study set out to confirm the reported poor predictive capacity of one-off reversibility testing, to explore whether duration of response, functional SAGE Publications 2008 Los Angeles, London, New Delhi and Singapore /

2 14 performance or domiciliary measurements gave any extra useful information, and to determine whether commonly used quality of life measurements could reflect improvements in symptoms. If so, it would then argue for the routine use of such measurements in nebulizer assessment but, if negative, would suggest that other methods need to be developed. Methods Subjects We recruited patients referred for assessment for nebulized bronchodilator therapy by respiratory physicians in our institution, and who remained symptomatic despite treatment with bronchodilators delivered by metered dose inhaler (MDI). Patients were required to have a clinical diagnosis of COPD, FEV 1 60% predicted, FEV 1 to FVC ratio of 50% and with 15% and 200-mLs increase in FEV 1 from the baseline 30 min after inhalation of salbutamol 200 g. Patients with a history of asthma, those with a recent (within 1-month) infective exacerbation and those receiving long acting inhaled 2 -agonist bronchodilators were excluded from the study. In addition, patients were excluded if they had history of ischaemic heart disease or cardiac arrhythmia. The protocol was approved by the local research ethics committee, and written informed consent was obtained. Study design This was an unblinded, randomized, crossover study to compare the effects of intermediate and high-dose bronchodilator therapy on physiological, functional and quality of life-related measurements in patients with COPD. The study consisted of four clinic visits over a six-week period (Figure 1). Following an initial screening to assess eligibility, patients entered a two-week run in period. During this period, patients received four times daily 40 mcg of ipratropium bromide and 200 mcg of salbutamol as Combivent (Boehringer Ingelheim; Berks UK) via a hand held MDI. Afterwards, patients were randomized to receive either 3 weeks of intermediate or high-dose bronchodilator therapy in a crossover manner. Randomization was by sealed envelopes. The intermediate dose bronchodilator therapy consisted of 120 mcg ipratropium bromide and 600 mcg of salbutamol, as Combivent, via MDI with a large volume spacer four times daily using a single puff and tidal breathing technique. The high-dose bronchodilator therapy (consisting of 2.5 mg salbutamol and 500 g ipratropium bromide as a preservative-free Figure 1 STUDY PLAN. Initial assessment and reversibility testing was made at visit 1, week 0. Following two weeks treatment with low dose bronchodilator treatment, a full assessment occurred at the end of week 2, visit 2. Patients were then randomised to intermediate dose treatment via a spacer or to nebuliser for a further three weeks. After full assessment at visit 3, week 5, crossover occurred to the alternate treatment. Reassessment occurred at visit 4, week 8. isotonic Combivent nebulizer solution) was administered using LifeCare nebulizer (Medic Aid; Bognor Regis, UK) with either Portaneb (Medic Aid; Bognor Regis, UK) or Aquilon (AFP Medical Ltd; Rugby, UK) compressors four times daily. All patients received salbutamol MDI and were instructed to use it when required for symptom relief. Patients were allowed to use inhaled corticosteroids and/or theophyllines during the run in period, and throughout the entire study. If an exacerbation occurred during the study, antibiotics and/or corticosteroids were prescribed at the discretion of the primary investigator (CB). All new treatment was given for the first time in clinic, and patients inhaler, spacer and nebulizer techniques were checked at each visit. During all the visits spirometry with reversibility to bronchodilator and a six-minute walk was performed, Hospital Anxiety and Depression (HAD) score 11 were measured, and the Chronic Respiratory Disease Questionnaire (CRDQ) 12 and the SF-36 questionnaire 13 were administered. However, as it is recognized that there may be a learning effect, two six-minute walks were performed at baseline (clinic visit 1). At visits 2 (week 2), 3 (week 5) and 4 (week 8) comprehensive pulmonary function tests were performed using Jaeger Compact Lab (Jaeger Toennies GmbH; Hochberg, Germany), (static and dynamic lung volumes, vital capacity (VC)), accessible alveolar volume by helium dilution (Va), FEV 1, FVC, maximal expiratory flow at 25% of VC (MEF 25 ) and maximal expiratory flow at 50% of VC (MEF 50 ), total lung capacity (TLC) (using a gas dilution method), residual volume (RV), PEF, carbon monoxide transfer factor) and a six-minute walk test were performed prior to and 60 min after administration of their current medication dose. Flow-volume loops were repeated 5, 15, 30, 60, 90, 120, 150, 180, Chronic Respiratory Disease

3 210 and 240 min post dosing with bronchodilator in order to measure the area under the curve (AUC) of time and response. Measurements were performed according to American Thoracic Society guidelines. 14 The highest values of FEV 1 and FVC measurements were retained. Patients were required to refrain from taking short acting inhaled bronchodilators for 4 h and oral theophyllines for 24 h before clinic visits. They were allowed one cup of tea, coffee or xanthine-containing drink from 4 h before and during the visit. The AUC for the FEV 1 from both time 0 and 30 min post bronchodilator at each visit were calculated. In addition, between the study visits, morning and evening PEF, and breathlessness scores on a sevenpoint Likert scale based on the dyspnoea CRDQ rating 12 were recorded by the patients daily. PEF were performed using a mini Wright meter (Clement Clarke International Ltd; Harlow, UK). Patients were requested to record the best of three efforts. During the protocol stage of this study, we defined a positive clinical response between the end of treatment periods as one of the following: increase 4 in the physical function (this component consists of the dyspnoea and fatigue scores) score of the CRDQ, 12 increase 0.3 in dyspnoea scores, increase 15% of PEF over the last seven days of the treatment period, 10,15 increase 200-mL in FEV 1 from baseline until 240 min post-bronchodilator, 16 10% difference between baseline and 60 min post-bronchodilator of RV/TLC ratio, 30 metres difference in six-minute walk distance. 17 Preferred treatment of the individual patients was taken to indicate subjective benefit from the mode of therapy given. The patients preference was assessed qualitatively during the final visit. Statistical analysis Analysis was performed using SPSS, version 7.5 (SPSS Inc; Chicago, IL, USA) software. Characteristics of the subjects are reported with the use of descriptive statistics. Modelling assumptions, such as normality, were checked by residual plots for all variables. The data for PEF, percent predicted FEV 1, the change in RV, TLC, RV/TLC ratio, MEF 25 and MEF 50 six-minute walk, HAD, CRDQ, and the SF-36 scores were expressed as mean (SD). The comparisons of the data between the treatment periods were performed using analyses of variance (ANOVA). A P 0.05 was regarded as statistically significant. The final cohort size of 25 was sufficient to give an 80% chance of detecting a mean difference of 10 in the physical function dimension of the SF-36, and four in the physical function dimension of the CRDQ between treatments. Results A total of 28 patients were entered into the study and underwent a baseline assessment. Three patients treated with oral steroids were withdrawn, while others who suffered exacerbations continued in the study but had the next visit postponed until they were considered to be stable when the domiciliary PEF and laboratory FEV 1 were similar to that during the baseline assessments. Twenty-five patients (12 female) completed the study. Patient characteristics are described in Table 1. Examination of the profile plots for the primary and secondary variables during the three treatment periods revealed no evidence of either a carry-over or direct treatment effect. No important period effects were noted. All patients preferred high or intermediate doses of bronchodilator regimens compared with standard low dose delivered with MDI alone. There was no statistically significant difference between the treatments in the pre-and post-bronchodilator lung function values, sixminute walk distance and domiciliary PEF and breathlessness score measurements. Similarly, health-related quality of life questionnaires did not discriminate between the treatments (Table 2). There were no significant differences between each visit for any of the SF-36 scores. The AUC of FEV 1 was similar for the two treatments both from time 0 and 30 min post-bronchodilator. There were no significant differences in MEF 25 and MEF 50 at baseline and post-bronchodilator for both treatments. Baseline HAD scores approached threshold levels for clinically relevant anxiety and depression but did not change with treatment. The only variable that was predictive of patients preference was that of RV/TLC ratio at 60 min post bronchodilator (P 0.05). Fifteen patients preferred bronchodilator therapy with nebulizer and 10 with MDI and spacer. In 20 patients at least one positive response in CRDQ, breathlessness scores, PEF measurements, FEV 1 values, RV/TLC ratio or six-minute walk, was observed on the preferred treatment. Table 3 summarizes those parameters that improved on the preferred treatment. None of the parameters singly or in combination were consistently predictive of patients preference. Table 1 Patient characteristics Number of patients 25 Female/Male 12/13 Age (yrs) 68 (7) FEV 1 (% predicted) 45 (10) FEV 1 /FVC 36 (5) % Increase in FEV 1 to bronchodilator (ml) 146 (69) RV/TLC (%) 62 (9) Maximum PEF diurnal variability (%) 12 (19) Data expressed as mean (SD). 15

4 16 Table 2 Lung function measurements and quality of life assessment during treatment periods Variable Treatment 1 Treatment 2 Treatment 3 Baseline FEV 1 (L) 0.88 (0.34) 0.87 (0.33) 0.89 (0.28) FEV 1 post-bronchodilator (L) 1.06 (0.38) 1.08 (0.37) 1.08 (0.35) Baseline FVC (L) 2.44 (0.76) 2.49 (0.75) 2.54 (0.80) FVC post-bronchodilator (L) 2.97 (0.92) 3.13 (0.81) 3.03 (0.91) Baseline RV/TLC 62 (9) 60 (9) 58 (7) RV/TLC post-bronchodilator 56 (10) 55 (9) 52 (8) Baseline IC (L) 1.33 (0.56) 1.50 (0.53) 1.50 (0.47) IC post-bronchodilator (L) 1.69 (0.65) 1.82 (0.62) 1.90 (0.66)* Baseline MEF (0.36) 0.67 (0.35) 0.66 (0.29) MEF 25 post-bronchodilator 0.85 (040) 0.86 (0.44) 0.85 (0.35) Baseline MEF (0.14) 0.32 (0.12) 0.39 (0.35) MEF 50 post-bronchodilator 0.39 (0.13) 0.39 (0.16) 0.38 (0.12) Six minute walk distance (m) 272 (96) 290 (102) 278 (92) Borg score 3.6 (1.8) 4.1 (2.4) 3.9 (2.7) PEF (ml/s) 155 (65) 153 (60) 159 (63) Breathlessness score 3.6 (1.2) 3.5 (1.2) 3.7 (1.1) HAD Anxiety 7.2 (3.8) 7.4 (4.2) 7.7 (4.9) HAD Depression 6.9 (3.1) 7.1 (3.6) 7.2 (3.8) CRDQ Fatigue 14.4 (5.2) 14.1 (6.0) 14.2 (5.2) CRDQ Mastery (4.8) (4.6) (4.8) CRDQ Emotional function (8.6) (9.9) (9.8) CRDQ Dyspnoea (3.7) (4.6) (5.3) Treatment 1 indicates period on low dose of bronchodilators delivered with MDI. Treatment 2 indicates period on intermediate dose of bronchodilators via MDI with spacer. Treatment 3 indicates period on high dose of nebulized bronchodilators. Data is expressed as mean (SD). *Significant difference between treatment 1 and treatment 3 (P 0.043). Discussion This study in patients with moderately severe COPD found no significant differences in lung function, sixminute walking distance, breathlessness or quality of life between intermediate-dose bronchodilator by MDI/spacer and high-dose nebulized bronchodilator therapy. These findings confirm those of previous studies, which have consequently urged caution in prescribing long-term nebulizer therapy in COPD, in preference to other devices more suitable for lower doses of bronchodilators In addition, we confirmed that Table 3 Performed tests and a number of patients with a positive tests when on preferred treatment Performed tests 15% increase of domiciliary PEF measurements ml increase of FEV 1 from baseline at 4 h post-bronchodilator 12 15% ( 200 ml) increase of FEV 1 15 min post-bronchodilator from baseline 0 30 meters increase in six-minute walk 2 Improvement in breathlessness score 4 10% decrease (from the baseline) in RV/TLC ratio 6 4 increase in physical function of CRDQ score 4 At least one positive test 20 Number of patients with a positive test on the preferred treatment a single laboratory reversibility measurement was not able to predict the results of a longer trial with different delivery devices, and that domiciliary PEF assessment did not reflect a patient s treatment preference. We found that the predefined PEF criteria for a clinically relevant response to treatment was satisfied in fewer cases than for the FEV 1 criteria, and agreed with patient preference in fewer cases (Table 3: 4 PEF, 12 FEV 1 ). While this is in contrast to previous reports suggesting that PEF are more reliable than laboratory spirometry, we defined improvement in FEV 1 as being at any time over the 4-h study period, rather than only at the expected time of peak bronchodilatation. 22,23 However, our findings are consistent with the current recommendation that FEV 1 is the variable of choice to monitor COPD patients. 5 Despite the lack of benefit in any variable for the group, all patients expressed a preference for either the intermediate-dose or high-dose bronchodilator regimens. However, most parameters (spirometry, PEF, six-minute walk, quality of life questionnaires or symptom scores) failed to predict treatment preference. The only measurement that reflected patient s preference was the RV/TLC 60 min post-bronchodilator (box-plot and logistic regression; P-value 0.05). This measurement (which is indicative of the degree of gas trapping) may reflect the type of functional benefit, which results from bronchodilators more closely than PEF or spirometry. Recent work has Chronic Respiratory Disease

5 17 shown that while body plethysmography data may not detect significant changes to nebulized salbutamol, there is a subgroup of patients who show a reduction in RV. 24 Other evidence of a reduction in gas trapping is the finding of increased mean inspiratory capacity at 60 min post-nebulizer compared to the value post-mdi and the lowest RV/TLC being on nebulizer. However, in our study only six patients had a difference of 10% between baseline and 60 min post-bronchodilator RV/TLC values, so that we cannot advocate this as a means of predicting preference in individual patients, although it does hint at one of the possible mechanisms by which an individual might experience symptomatic benefit. The reasons for a stated preference where no clinically significant improvement in quantitative physiological parameters was found might be relief of symptoms 8, or increased sense of well-being. Our results show that relief of symptoms as measured by domiciliary breathing score did not help to identify the reason for preference but did not assess other possible benefits such as facilitation of expectoration. Similarly, the physical function component of the CRDQ, which has been reported to define a clinically relevant treatment effect 12 concurred with treatment preference in only four of our patients. No single criterion reflected preference in even half the patient group. Patients were often unable to define precisely the advantage of one treatment modality over another, but mentioned a variety of benefits, which appeared collectively to comprise worthwhile improvement. The fact that a clinically relevant response in at least one of the predefined variables agreed with preference in 20 of the 25 patients suggests that the benefits rated as important by patients differ and are a combination of symptomatic, functional and quality of life improvements. Overall, the range of measurements (be they symptomatic or physiological) was helpful in clarifying potential reasons for a particular patient preference, even though the changes varied across the patient group. One limitation of this study is that it was not placebo-controlled, therefore it is possible that the researchers and patients expectations about the treatment may have influenced responses. Although there was no formal measure of preconceptions about treatment, many patients expressed disappointment with the lack of marked difference between the two trial treatments. We believe this reflects the wide spread belief in primary care and by non-respiratory physicians that nebulizer therapy is the gold standard treatment for severe COPD. The extended trial period and the use of domiciliary measures and quality of life scores enabled patients to gauge for themselves the effects of each treatment trial. The assessment phases replicated the clinical situation and, because we were aware that the investigators views might influence responses, we used multiple objective measures. We have not studied the exacerbation rates of patients taking the treatment issued at the end of trial but our impression is that some patients like nebulized treatment because they had received it previously in hospital during exacerbations and it might allow them to deal with their subsequent mild exacerbations at home without requiring admission. It is unlikely that this affects the natural history of COPD but it might be a further indication for considering long-term domiciliary use. Although a practice six-minute walk was performed at the baseline visit our protocol did not require this at subsequent visits and we acknowledge that a slightly better walking distance might have been achieved by repeating a practice walk. Our data confirm that patients with severe COPD are physically limited, have a poor quality of life and suffer intrusive symptoms. It is perhaps not surprising that small improvements in any one of these areas of limitation might translate into positive benefit for an individual. Despite performing a wide range of frequently complicated and time-consuming tests we were unable to show that any of the parameters singly or in combination could consistently predict patients preference for nebulized bronchodilator therapy. However, as a proportion of our patients with moderate and severe COPD preferred an intermediate dose using MDI and spacer to nebulized bronchodilator therapy; it may be appropriate to suggest a trial with intermediate dose of bronchodilators prior to introducing nebulized bronchodilator therapy. Acknowledgement We would like to thank Dr Josephine C Ojoo for her help in reviewing the manuscript. References 1. Brandli O. Maintenance and servicing of nebulisers. 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