Thorax 2001;56:713–720 713 Alternative methods for assessing bronchodilator Thorax: first published as 10.1136/thx.56.9.713 on 1 September 2001. Downloaded from reversibility in chronic obstructive pulmonary disease J Hadcroft, P M A Calverley Abstract Chronic obstructive pulmonary disease Background—Bronchodilator reversibil- (COPD) is characterised by airflow limitation ity testing is recommended in all patients which varies little over several months of with chronic obstructive pulmonary dis- observation or after treatment.12 The assess- ease (COPD) but does not predict im- ment of airflow limitation usually relies on provements in breathlessness or exercise spirometric testing and, in particular, the performance. Two alternative ways of forced expiratory volume in 1 second (FEV1) assessing lung mechanics—measurement which is the usual outcome measure in of end expiratory lung volume (EELV) diagnostic bronchodilator reversibility testing.3 using the inspiratory capacity manoeuvre Although useful diagnostically and prognosti- and application of negative expiratory cally,4 spirometric abnormalities are poor pressure (NEP) during tidal breathing to descriptors of the severity of breathlessness in detect tidal airflow limitation—do relate 5 COPD. Likewise, significant changes in FEV1 to the degree of breathlessness in COPD. after inhaled bronchodilators are not necessary Their usefulness as end points in broncho- for improvement in exercise performance or dilator reversibility testing has not been dyspnoea to occur.5–7 Two alternative tech- examined. niques of measuring lung mechanics relatively Methods—We studied 20 patients with easily are now available. Both are better corre- clinically stable COPD (mean age 69.9 lates of breathlessness than FEV , but their (1.5) years, 15 men, forced expiratory vol- 1 reproducibility and sensitivity to change in ume in one second (FEV ) 29.5 (1.6)% pre- 1 response to bronchodilator drugs has not been dicted) with tidal flow limitation as assessed—an important consideration if they assessed by their maximum flow-volume loop. Spirometric parameters, slow vital are to be of practical value. The application of negative expiratory pres- capacity (SVC), inspiratory capacity (IC), http://thorax.bmj.com/ and NEP were measured seated, before sure during tidal breathing (the NEP tech- and after nebulised saline, and at intervals nique) is a simple and rapid way of assessing after 5 mg nebulised salbutamol and the presence of flow limitation during tidal res- 500 µg nebulised ipratropium bromide. piration which overcomes the problems of gas The patients attended twice and the treat- compression artefacts and variations in the 8 ment order was randomised. preceding volume history of the manoeuvre. The degree of tidal flow limitation correlates Results—Mean FEV1, FVC, SVC, and IC were unchanged after saline but the with the severity of everyday breathlessness 9 degree of tidal flow limitation varied. using the MRC scale. One study has reported on September 25, 2021 by guest. Protected copyright. FEV1 improved significantly after salbuta- that tidal flow limitation was unchanged after a mol and ipratropium (0.11 (0.02) l and moderate (400 µg) dose of inhaled salbutamol 0.09 (0.02) l, respectively) as did the other in patients with resting flow limitation,10 but lung volumes with further significant the eVects of higher doses of this drug or other increases after the combination. Tidal bronchodilators have not been examined. volume and mean expiratory flow in- Pulmonary hyperinflation during spontane- creased significantly after all bronchodi- ous breathing is common in advanced COPD, Department of lators but breathlessness fell significantly relates well to the intensity of dyspnoea during Medicine, University only after the combination treatment. The exercise,11 and can be reproducibly detected of Liverpool, initial NEP score was unrelated to subse- using the inspiratory capacity manoeuvre.12 University Hospital quent changes in lung volume. Inhaled â agonists and anticholinergic agents Aintree, Liverpool Conclusions—NEP is not an appropriate L9 7AL, UK reduce exercise induced dynamic hyperinfla- 67 J Hadcroft measurement of acute bronchodilator re- tion. Measurements of expired lung volume P M A Calverley sponsiveness. Changes in IC were signifi- such as the forced and relaxed vital capacities cantly larger than those in FEV1 and may also improve after bronchodilators, suggesting Correspondence to: be more easily detected. However, our Professor P M A Calverley a fall in residual volume, but how these changes [email protected] data showed no evidence for separation of relate to those in inspiratory capacity (IC) is “reversible” and “irreversible” groups less certain. Received 8 August 2000 whatever outcome measure was adopted. The major diagnostic diYculties with spiro- Returned to authors (Thorax 2001;56:713–720) 1 November 2000 metric based reversibility testing occur in Revised version received patients with a low baseline FEV where 1 June 2001 Keywords: chronic obstructive pulmonary disease; 1 Accepted for publication bronchodilator; reversibility; end expiratory lung vol- changes after the bronchodilator drug fall 4 June 2001 ume; flow limitation within the spontaneous reproducibility of the www.thoraxjnl.com 714 Hadcroft, Calverley measurement.13 In these individuals hyperinfla- in response to the question: “How breathless Thorax: first published as 10.1136/thx.56.9.713 on 1 September 2001. Downloaded from tion is present at rest and tidal flow limitation is are you feeling?” Each patient received 2.5 ml more likely to be present when the subject is normal saline via a wet nebuliser (Sidestream seated,8 increasing the chance of a positive sig- Disposable Nebuliser, MedicAid Ltd, UK) at nal using these variables after a bronchodilator flow rate of 5 l/min for 5 minutes. After 15 test. Our previous studies have suggested that minutes’ rest this assessment protocol was acute bronchodilator responsiveness in COPD repeated. Patients in group A were then given is a continuous variable.14 We hypothesised that 5 mg salbutamol via the nebuliser at the same changes in the degree of hyperinflation and in flow rate as the saline. After a further 15 min- tidal flow limitation would be as reproducible utes all measurements were repeated. Group A as those in FEV1 and would separate potential subjects finally received 500 µg ipratropium responder groups for future treatment trials. To bromide nebulised as before and then repeated test this, we have conducted a single blind ran- their measurements 45 minutes later. Patients domised placebo controlled trial of nebulised â in Group B received saline, followed by agonists and anticholinergic drugs measuring nebulised ipratropium with measurements both pulmonary hyperinflation and tidal flow made after 45 minutes, then nebulised salbuta- limitation in a group of patients with more mol with final measurements made 15 minutes severe COPD than reported previously. Addi- after this. tionally, we have measured the relaxed or On the second day the same protocol was “slow” vital capacity to assess whether this followed but the order of the bronchodilators more readily available measurement showed was reversed. equivalent sensitivity to change after active drugs to those seen with the newer measure- PHYSIOLOGICAL MEASUREMENTS ments of resting lung mechanics. Spirometry FEV1 and forced vital capacity (FVC) were Methods measured using a 1 litre dry rolling seal spiro- SUBJECTS meter (MedGraphics, Minnesota, USA), the Twenty patients (15 men) with severe COPD best FEV1 and FVC values from reproducible participated in the study. All had been cigarette measurements being reported as recom- smokers of >20 pack years, had a clinical mended by the ATS.18 19 Normal values were course consistent with the disease, and met the those of the ECSC.20 At the time of their first BTS criteria for diagnosis and classification of visit a maximum flow-volume manoeuvre was disease severity.15 None had clinical or radio- recorded after a period of quiet breathing and graphic evidence of bronchial asthma, bron- with the equipment software a tidal loop was chiectasis, or neoplasia, nor of significant positioned relative to the maximal loop using cardiovascular/neuromuscular disease which the IC manoeuvre. The resulting plot was would aVect their resting sensation of breath- printed to determine whether the resting tidal http://thorax.bmj.com/ lessness or their pulmonary function results. loop exceeded the maximum flow-volume All had been free of respiratory tract infection envelope. for at least 4 weeks. Short acting inhaled bron- chodilators were omitted for 6 hours, long act- Inspiratory capacity/slow vital capacity ing inhaled bronchodilators were omitted for These were measured using the same spiro- 12 hours, and oral theophyllines were omitted meter as above. After four normal tidal breaths for 24 hours prior to testing and caVeinated the patient inhaled to total lung capacity beverages were avoided for 6 hours. All were (TLC) from their spontaneous end expiratory lung volume (EELV), paused for 1 second, recruited from the respiratory outpatient clin- on September 25, 2021 by guest. Protected copyright. ics of the University Hospital Aintree and gave then exhaled slowly to functional residual their informed consent to the study which was capacity. This manoeuvre was repeated until approved by our institutional ethics committee. two values corresponded to within 5% of each other. PROTOCOL Thoracic gas volume/total lung