Resph'atory Medicine (1992) 86, 33-38
Simplifying the assessment of patients with chronic airflow limitation for home nebulizer therapy J. M. GOLDMAN*, C. TEALE AND M. F. MUERS
Regional Respiratory Unit, Killingbeck Hospital, York Road, Leeds LS14 6UQ, U.K.
One-hundred nebulizer trials were performed in 98 adult patients with chronic airflow limitation who had rcmained symptomatic despite regular use of bronchodilators by metered dose or dry powder inhalation. Mean baseline FEV~ was 0.9 (SD = 0"41) I, FVC - 2 . 0 (0"74) 1 and P E F R 169 (77) I min-t. After laboratory measurements of reversibility to inhaled salbutamol (5 mg) and ipratropium bromide (0-5 mg), patients were supplied with a compressor and a peak flow meter to make twice daily measurements at home for 3 weeks. They nebulized normal saline, salbutamol (5 mg) and salbutamol (5 mg) ipratropium (0'5 mg) mixture 6-hourly, each for 1 week. A positive nebulizer trial was defined as a 15% increase in mean P E F R over a week on an active treatment compared to the week on saline. Twenty-eight patients had positive trials based on these criteria. Of these nine responded to both active treatments and 16 to the salbutamol/ipratropium mixture. Although no laboratory measurements predicted a positive domiciliary trial, the patients' subjective assessment of benefit had a 93% sensitivity and 87% negative predictive value. We conclude that an appropriate protocol for assessing the value of long-term nebulized bronchodilators is for patients to measure their P E F R during a week of nebulized saline and a week of nebulized ~-agonist/ipratropium mixture. Those with an increase of 15% in mean P E F R in the week on active treatment and who experienced subjective benefit should be supplied with a compressor. Had we conducted our 100 trials in this way we would have started 25 of our 98 patients on long-term home nebulized bronchodilators.
Introduction Long-term domiciliary nebulized bronchodilators have been shown to produce symptomatic benefit and objective improvement in lung function in patients with chronic airflow limitation (1-3). Home nebulizer therapy is becoming increasingly common (4) and its expense cannot be overlooked as a years supply of bronchodilator drugs costs over £1000 (5). The potential benefits of this treatment are significant for patients with chronic lung disease in whom there are few other effective therapeutic options. It must, therefore, be the aim of the physician to identify those patients who will benefit from long-term fiebulized bronchodilators. At present there is little evidence to indicate how this can be best achieved in normal clinical practice, though it has been suggested that laboratory assessment might be sufficient (6,7). Two studies, each including 20 patients have shown that laboratory measurements of reversibility to bronchodilators do not predict which patients will benefit from domiciliary nebulizer therapy when this Received 28 January 1991 and accepted in revised form 12 June 1991. *To whom correspondence should be addressed at: Box MS98, Leeds General Infirmary, Great George Street, Leeds LSI 3EX, U.K. 0954-61 I 1/92/010033 + 06 $03.00/0
is assessed by home peak flow rate recordings made over a number of weeks (1,8). We have tested this hypothesis in clinical practice by performing 100 nebulizer trials which included short-term laboratorybased reversibility studies and long-term home-based measurements. We have analysed the results of these trials with the aim of devising a simple method of assessing response to home nebulizer therapy which will provide adequate information and can be easily applied by practising clinicians.
Methods One-hundred nebulizer trials were performed on 98 patients presenting consecutively to an out-patient respiratory service. Patients were referred for a nebulizer trial if they had clinical evidence of chronic airflow limitation and remained symptomatic on therapy including regular doses of bronchodilators as a dry powder or metered dose inhaler (minimum of ! mg salbutamol daily by aerosol or equivalent). All patients had evidence of severe airflow obstruction on spirometry with forced expiratory volume in 1 s (FEV~) less than 50 % predicted and FEV Jforced vital © 1992 Bailli6re Tindall
34
J. M. Goldman et al.
capacity (FVC) ratio less than 60%. The working diagnosis was chronic obstructive lung disease in 73 patients and chronic asthma in 25 patients. Each patient attended the lung function unit for baseline measurements. They refrained from taking inhaled bronchodilators for 8 h and theophyllines for 24 h prior to each laboratory visit. At the initial visit spirometry (dry wedge spirometer, Vitalograph) and peak expiratory flow rate (PEFR) (Wright mini-peak flow meter, Airmed U.K. Ltd) were measured. The best of three measurements were recorded at time zero and at 10 min, and the highest values were taken as the baseline measurements. Reversibility to salbutamol (5 mg) nebulized (Micro neb III, Lifecare driven by oxygen at 101 min-~) was assessed by performing spirometry and peak flow recordings 20 min after administration of the drug. The changes in FEV~, FVC and P E F R were expressed as a percentage of the baseline measurement and as absolute values. Reversibility to ipratropium bromide 0-5 mg was assessed in the same way 1 h after administration. Patients made an assessment of their degree of breathlessness using a visual analogue scale (VAS). For a 3-week period, each patient was loaned a compressor (Medix traveller, Airmed Ltd), a nebulizer (Micro neb III, Lifecare) and a peak flow meter. Throughout the study they recorded the best of three PEFR readings (before nebulizer treatment) on waking and at 1800 h. They continued to take their usual inhaled bronchodilator on an 'as required' basis and other therapies remained unchanged. They used the nebulizer 6-hourly for the 3-week study period and then returned it to the laboratory. In the first week of the study patients nebulized normal saline (supplied in 100 ml bottles with needles and syringes for dispensing), in the second week salbutamol 5 mg (nebules) and in the third week a mixture of salbutamol 5 mg and preservative-free ipratropium bromide 0-5 mg (nebules). Patients were not informed directly of the nature of each solution but there was no attempt to make the study double-blind. At the end of each week patients attended the laboratory for a further assessment. Spirometry and P E F R was measured as described for the baseline visit, a VAS score of breathlessness for the previous week was recorded as was the patients' subjective assessment of their symptoms expressed as "better', 'worse' or 'the same'. At the end of the study mean P E F R for each week of treatment was calculated and the mean for each active treatment week was expressed as a percentage of the mean for the saline treatment week. Studies in which there was a 15% rise in mean peak flow on active treatment were classified as positive and the patient
was commenced on long-term domiciliary nebulizer therapy using the preferred treatment (2). A variety of parameters were assessed for their ability to predict a positive trial. We have expressed the value of such tests in terms of their sensitivity, specificity, positive and negative predictive values. Paired Student's t-tests were used to compare different therapies. Sensitivity is defined as the ability of a positive result in a test to predict correctly a positive outcome, i.e. the number of true-positive tests expressed as a proportion o f the number of true-positive plus false-negative tests. Specificity is defined as the ability of a negative result in a test to correctly predict a negative outcome, i.e. the number of true-negative tests expressed as a proportion of true-negative plus false-positive tests. The positive predictive value is the proportion of positive tests that will correctly predict the outcome, i.e. true-positive as a proportion of truepositive plus false-positive tests. The negative predictive value is the proportion of negative tests that will correctly predict the outcome, i.e. true-negative as a proportion of true-negative plus false-negative tests. Results
Fifty-five men and 43 women with a mean age of 66 (range 35-84) years were studied. Two studies were repeated. Seventeen patients were current smokers and six had never smoked. Baseline lung function tests demonstrated a mean FEV~ of 0'9 (SD =0"41) I, FVC2"0 (0-74) 1 and P E F R l 6 9 (77)lmin -I. Onehundred studies were performed of which 90 were suitable for analysis. Three patients died, one in hospital with cor pulmonale and two at home due to myocardial infarction (it is possible that these home deaths were nebulizer related, but we feel this is less likely as both occurred in the third week of the trial and we would have expected any cardiac dysrhythmia to [lave presented sooner). Three patients made inadequate P E F R recordings for analysis, and four developed acute exacerbations of their conditions requiring steroid therapy. Two patients were studied twice, one was negative on both occasions and the second was void on the first occasion because of a chest infection and positive on the second occasion. Three patients complained of tremor whilst nebulizing salbutamol and one of sickness during the week of nebulized salbutamol/ipratropium mixture, but all completed the trial. The mean P E F R over a week on nebulized saline was 177 (74)lmin -I (am 170, pm 1841rain -~) over a week on salbutamol 223 (76)lmin -~ (am214, pm2321min -~) and over a week of salbutamol/ ipratropium mixture 233 (75) I rain- t (am 225, pm 241
Simplifying assessment.for home nebulizers
35
Table 1 Reliability of a variety of methods for predicting the results of trials of nebulized domiciliary bronchodilators. Results are expressed as the sensitivity, specificity,and positive and negative predictive value (PV) of each test
Test
Sensitivity (%)
Specificity (%)
Positive PV (%)
Negative PV (%)
Single laboratory measures of reversibility to either salbutamol 5 mg or ipratropium 0-5 mg FEV~+ 15% and + 200 ml FEV E+20% and +400 ml FEV, + 10% FVC+ 15% and +350 ml FVC + 20% and + 700 ml
29 21 68 29 14
80 90 52 73 87
40 60 38 31 31
71 70 78 69 69
Weekly laboratory measures of reversibility FEV I+ 15% PEFR+ 15%
27 57
80 74
47 55
68 75
Patient assessment
93
42
49
87
Imin-~). There was no significant difference between baseline PEFR and PEFR on nebulized saline. The increase in PEFR on both nebulized salbutamol and nebulized salbutamol/ipratropium mixture when compared to nebulized saline and to baseline PEFR was highly significant (P
Simplifying the assessment of patients with chronic airflow limitation for home nebulizer therapy J. M. GOLDMAN*, C. TEALE AND M. F. MUERS
Regional Respiratory Unit, Killingbeck Hospital, York Road, Leeds LS14 6UQ, U.K.
One-hundred nebulizer trials were performed in 98 adult patients with chronic airflow limitation who had rcmained symptomatic despite regular use of bronchodilators by metered dose or dry powder inhalation. Mean baseline FEV~ was 0.9 (SD = 0"41) I, FVC - 2 . 0 (0"74) 1 and P E F R 169 (77) I min-t. After laboratory measurements of reversibility to inhaled salbutamol (5 mg) and ipratropium bromide (0-5 mg), patients were supplied with a compressor and a peak flow meter to make twice daily measurements at home for 3 weeks. They nebulized normal saline, salbutamol (5 mg) and salbutamol (5 mg) ipratropium (0'5 mg) mixture 6-hourly, each for 1 week. A positive nebulizer trial was defined as a 15% increase in mean P E F R over a week on an active treatment compared to the week on saline. Twenty-eight patients had positive trials based on these criteria. Of these nine responded to both active treatments and 16 to the salbutamol/ipratropium mixture. Although no laboratory measurements predicted a positive domiciliary trial, the patients' subjective assessment of benefit had a 93% sensitivity and 87% negative predictive value. We conclude that an appropriate protocol for assessing the value of long-term nebulized bronchodilators is for patients to measure their P E F R during a week of nebulized saline and a week of nebulized ~-agonist/ipratropium mixture. Those with an increase of 15% in mean P E F R in the week on active treatment and who experienced subjective benefit should be supplied with a compressor. Had we conducted our 100 trials in this way we would have started 25 of our 98 patients on long-term home nebulized bronchodilators.
Introduction Long-term domiciliary nebulized bronchodilators have been shown to produce symptomatic benefit and objective improvement in lung function in patients with chronic airflow limitation (1-3). Home nebulizer therapy is becoming increasingly common (4) and its expense cannot be overlooked as a years supply of bronchodilator drugs costs over £1000 (5). The potential benefits of this treatment are significant for patients with chronic lung disease in whom there are few other effective therapeutic options. It must, therefore, be the aim of the physician to identify those patients who will benefit from long-term fiebulized bronchodilators. At present there is little evidence to indicate how this can be best achieved in normal clinical practice, though it has been suggested that laboratory assessment might be sufficient (6,7). Two studies, each including 20 patients have shown that laboratory measurements of reversibility to bronchodilators do not predict which patients will benefit from domiciliary nebulizer therapy when this Received 28 January 1991 and accepted in revised form 12 June 1991. *To whom correspondence should be addressed at: Box MS98, Leeds General Infirmary, Great George Street, Leeds LSI 3EX, U.K. 0954-61 I 1/92/010033 + 06 $03.00/0
is assessed by home peak flow rate recordings made over a number of weeks (1,8). We have tested this hypothesis in clinical practice by performing 100 nebulizer trials which included short-term laboratorybased reversibility studies and long-term home-based measurements. We have analysed the results of these trials with the aim of devising a simple method of assessing response to home nebulizer therapy which will provide adequate information and can be easily applied by practising clinicians.
Methods One-hundred nebulizer trials were performed on 98 patients presenting consecutively to an out-patient respiratory service. Patients were referred for a nebulizer trial if they had clinical evidence of chronic airflow limitation and remained symptomatic on therapy including regular doses of bronchodilators as a dry powder or metered dose inhaler (minimum of ! mg salbutamol daily by aerosol or equivalent). All patients had evidence of severe airflow obstruction on spirometry with forced expiratory volume in 1 s (FEV~) less than 50 % predicted and FEV Jforced vital © 1992 Bailli6re Tindall
34
J. M. Goldman et al.
capacity (FVC) ratio less than 60%. The working diagnosis was chronic obstructive lung disease in 73 patients and chronic asthma in 25 patients. Each patient attended the lung function unit for baseline measurements. They refrained from taking inhaled bronchodilators for 8 h and theophyllines for 24 h prior to each laboratory visit. At the initial visit spirometry (dry wedge spirometer, Vitalograph) and peak expiratory flow rate (PEFR) (Wright mini-peak flow meter, Airmed U.K. Ltd) were measured. The best of three measurements were recorded at time zero and at 10 min, and the highest values were taken as the baseline measurements. Reversibility to salbutamol (5 mg) nebulized (Micro neb III, Lifecare driven by oxygen at 101 min-~) was assessed by performing spirometry and peak flow recordings 20 min after administration of the drug. The changes in FEV~, FVC and P E F R were expressed as a percentage of the baseline measurement and as absolute values. Reversibility to ipratropium bromide 0-5 mg was assessed in the same way 1 h after administration. Patients made an assessment of their degree of breathlessness using a visual analogue scale (VAS). For a 3-week period, each patient was loaned a compressor (Medix traveller, Airmed Ltd), a nebulizer (Micro neb III, Lifecare) and a peak flow meter. Throughout the study they recorded the best of three PEFR readings (before nebulizer treatment) on waking and at 1800 h. They continued to take their usual inhaled bronchodilator on an 'as required' basis and other therapies remained unchanged. They used the nebulizer 6-hourly for the 3-week study period and then returned it to the laboratory. In the first week of the study patients nebulized normal saline (supplied in 100 ml bottles with needles and syringes for dispensing), in the second week salbutamol 5 mg (nebules) and in the third week a mixture of salbutamol 5 mg and preservative-free ipratropium bromide 0-5 mg (nebules). Patients were not informed directly of the nature of each solution but there was no attempt to make the study double-blind. At the end of each week patients attended the laboratory for a further assessment. Spirometry and P E F R was measured as described for the baseline visit, a VAS score of breathlessness for the previous week was recorded as was the patients' subjective assessment of their symptoms expressed as "better', 'worse' or 'the same'. At the end of the study mean P E F R for each week of treatment was calculated and the mean for each active treatment week was expressed as a percentage of the mean for the saline treatment week. Studies in which there was a 15% rise in mean peak flow on active treatment were classified as positive and the patient
was commenced on long-term domiciliary nebulizer therapy using the preferred treatment (2). A variety of parameters were assessed for their ability to predict a positive trial. We have expressed the value of such tests in terms of their sensitivity, specificity, positive and negative predictive values. Paired Student's t-tests were used to compare different therapies. Sensitivity is defined as the ability of a positive result in a test to predict correctly a positive outcome, i.e. the number of true-positive tests expressed as a proportion o f the number of true-positive plus false-negative tests. Specificity is defined as the ability of a negative result in a test to correctly predict a negative outcome, i.e. the number of true-negative tests expressed as a proportion of true-negative plus false-positive tests. The positive predictive value is the proportion of positive tests that will correctly predict the outcome, i.e. true-positive as a proportion of truepositive plus false-positive tests. The negative predictive value is the proportion of negative tests that will correctly predict the outcome, i.e. true-negative as a proportion of true-negative plus false-negative tests. Results
Fifty-five men and 43 women with a mean age of 66 (range 35-84) years were studied. Two studies were repeated. Seventeen patients were current smokers and six had never smoked. Baseline lung function tests demonstrated a mean FEV~ of 0'9 (SD =0"41) I, FVC2"0 (0-74) 1 and P E F R l 6 9 (77)lmin -I. Onehundred studies were performed of which 90 were suitable for analysis. Three patients died, one in hospital with cor pulmonale and two at home due to myocardial infarction (it is possible that these home deaths were nebulizer related, but we feel this is less likely as both occurred in the third week of the trial and we would have expected any cardiac dysrhythmia to [lave presented sooner). Three patients made inadequate P E F R recordings for analysis, and four developed acute exacerbations of their conditions requiring steroid therapy. Two patients were studied twice, one was negative on both occasions and the second was void on the first occasion because of a chest infection and positive on the second occasion. Three patients complained of tremor whilst nebulizing salbutamol and one of sickness during the week of nebulized salbutamol/ipratropium mixture, but all completed the trial. The mean P E F R over a week on nebulized saline was 177 (74)lmin -I (am 170, pm 1841rain -~) over a week on salbutamol 223 (76)lmin -~ (am214, pm2321min -~) and over a week of salbutamol/ ipratropium mixture 233 (75) I rain- t (am 225, pm 241
Simplifying assessment.for home nebulizers
35
Table 1 Reliability of a variety of methods for predicting the results of trials of nebulized domiciliary bronchodilators. Results are expressed as the sensitivity, specificity,and positive and negative predictive value (PV) of each test
Test
Sensitivity (%)
Specificity (%)
Positive PV (%)
Negative PV (%)
Single laboratory measures of reversibility to either salbutamol 5 mg or ipratropium 0-5 mg FEV~+ 15% and + 200 ml FEV E+20% and +400 ml FEV, + 10% FVC+ 15% and +350 ml FVC + 20% and + 700 ml
29 21 68 29 14
80 90 52 73 87
40 60 38 31 31
71 70 78 69 69
Weekly laboratory measures of reversibility FEV I+ 15% PEFR+ 15%
27 57
80 74
47 55
68 75
Patient assessment
93
42
49
87
Imin-~). There was no significant difference between baseline PEFR and PEFR on nebulized saline. The increase in PEFR on both nebulized salbutamol and nebulized salbutamol/ipratropium mixture when compared to nebulized saline and to baseline PEFR was highly significant (P
