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Effect of Acute Alterations in Inspired Oxygen Tension on Methacholine

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Effect of Acute Alterations in Inspired Oxygen Tension on Methacholine Thorax 1997;52:453±457 453 EVect of acute alterations in inspired oxygen Thorax: first published as 10.1136/thx.52.5.453 on 1 May 1997. Downloaded from tension on methacholine induced bronchoconstriction in patients with asthma Kenneth D Dagg, Lorna J Thomson, Robert A Clayton, Scott G Ramsay, Neil C Thomson Abstract mild to moderate patients with stable Background ± Recent in vitro and in vivo asthma. studies in animals have suggested that am- (Thorax 1997;52:453±457) bient oxygen tension may in¯uence airway responsiveness to bronchoconstrictor Keywords: hyperoxia, hypoxia, bronchoconstriction, stimuli. These observations may have rel- methacholine, asthma. evance to the management of acute ex- acerbations of asthma. The present studies were designed to examine the in¯uence Little is known about the eVect of acute alter- of inspired oxygen tension (Fio2 1.0, 0.21, ations in oxygen tension on the responsiveness 0.15) on methacholine induced broncho- of the airways to bronchoconstrictor stimuli. constriction in patients with asthma. Recent in vitro and in vivo studies in animals Methods ± In a dual study two groups of suggest that hypoxia potentiates and hyperoxia asthmatic patients performed metha- attenuates the airway constrictor response to choline inhalation challenges breathing certain stimuli.12 Similar in vivo studies in man, 3±5 either air (Fio2 0.21) or a hypoxic gas mix- however, have produced con¯icting ®ndings. ture (Fio2 0.15) in study 1 and air (Fio2 If airway responsiveness is increased by a fall 0.21) or hyperoxia (Fio2 1.0) in study 2. in oxygen tension during acute exacerbations The gases were administered through a of asthma, then the administration of high closed breathing circuit in a randomised concentrations of inspired oxygen may act to http://thorax.bmj.com/ double blind fashion. The PC20 values reduce this eVect. (dose of methacholine causing a 20% fall The present studies were designed to in- in forced expiratory volume in one second vestigate the eVect of acute hypoxia and (FEV1)) were calculated after each metha- hyperoxia on methacholine induced broncho- choline challenge by linear interpolation constriction in patients with asthma. from the logarithmic dose response curve. Plasma catecholamine levels were meas- ured before and after methacholine chal- Methods lenges as well as heart rate, oxygen patients on September 25, 2021 by guest. Protected copyright. Department of saturation, and percentage end tidal car- Study 1 Respiratory Medicine, bon dioxide levels. Eleven mild asthmatic patients (®ve men) of West Glasgow Results ± The geometric mean PC20 value mean (SD) age 42 (12) years were recruited Hospitals University for methacholine was signi®cantly lower NHS Trust, Glasgow into the study (table 1). All were receiving G12 0YN, UK on the hypoxic study day than on the nor- inhaled b2 agonists as required, 10 were re- KDDagg moxic day in study 1 (mean diVerence in ceiving regular inhaled corticosteroids, two L J Thomson PC values 2.88 mg/ml (95% CI 1.4 to 5.3); R A Clayton 20 were taking regular inhaled salmeterol, and one S G Ramsay p<0.05), but there was no signi®cant a long acting oral theophylline. N C Thomson diVerence in the geometric mean PC20 Correspondence to: value for methacholine between the hyper- Dr K D Dagg. oxic and normoxic study days in study 2 Study 2 Received 11 July 1996 (mean diVerence in PC20 values 1.45 mg/ Fourteen adult mild asthmatic patients (®ve Returned to authors ml (95% CI 0.83 to 2.51)). 16 September 1996 men) of mean (SD) age 36 (9.2) years were Revised version received Conclusions ± Acute hypoxia potentiates recruited into the study (table 1). All were 7 January 1997 methacholine induced bronchoconstric- Accepted for publication taking inhaled b2 agonists on an as required 9 January 1997 tion and acute hyperoxia has no eVect in basis, 10 were receiving regular inhaled cortico- steroids, two were taking regular oral theo- phyllines, and one inhaled salmeterol. Table 1 Patient characteristics In both studies on each study day inhaled b2 agonists were discontinued for eight hours, No. of Mean (SD) Mean (SD) FEV1 Geometric mean (range) salmeterol for 24 hours, and oral theophyllines patients age (years) PC20 methacholine (mg/ml) Litres % predicted for 48 hours prior to attendance. Patients were Study 1 11 42 (12) 2.76 (0.49) 86 (7.7) 1.13 (0.04±7.90) asked to continue their inhaled corticosteroids Study 2 14 36 (9.2) 2.80 (0.60) 90 (8.6) 0.84 (0.04±7.90) as usual. They were asked to refrain from caVeine containing products for eight hours FEV1=forced expiratory volume in one second; PC20 methacholine=concentration of metha- choline provoking a fall in FEV1 of 20%. before each study day. All patients had been 454 Dagg, Thomson, Clayton, Ramsay, Thomson stable for a period of two months before entry FEV1 Thorax: first published as 10.1136/thx.52.5.453 on 1 May 1997. Downloaded from into the study with no signi®cant change in their FEV1 was measured using a dry wedge spir- asthma symptoms or medication. All patients ometer (Vitalograph S, Vitalograph, Buck- gave informed consent to the studies which ingham, UK) and the best of three attempts had the approval of the West ethics committee. was taken for analysis. Methacholine inhalation challenge Baseline FEV1 was measured by taking the study design best of three recordings. Thereafter a saline For both study 1 and study 2 patients attended inhalation was administered and then doubling the laboratory on three separate days at ap- doses of nebulised methacholine (acetyl-b- proximately the same time each day. Patients methylcholine chloride (Sigma Chemical Com- were excluded from the study if there was any pany, Dorset UK) made up in normal saline) signi®cant change in their asthma symptoms were administered at ®ve minute intervals. or medication between visits. The maximum Each concentration was given for two minutes period between each visit was seven days. Dur- via a MicroCirrus nebuliser. All challenge tests ing the initial screening visit each patient under- were performed by the same person throughout went a methacholine inhalation challenge test both studies. The nebuliser output for both to determine the PC20 ± that is, the con- gases in study 1 at a ¯ow rate of 7 l/min was centration of methacholine causing a 20% fall 0.13 ml/min, and in study 2 at a ¯ow rate of in forced expiratory volume in one second 6 l/min the nebuliser output was 0.12 ml/min (FEV1). On the subsequent two days, after for both gases. The FEV1 was measured at 0.5, 30 minutes of supine rest, the patients were 1.5, and three minutes after each inhalation commenced on a closed breathing circuit. Fol- until a fall in FEV1 of at least 20% was achieved lowing a 10 minute run-in period breathing air as determined by linear interpolation from the (Fio2 0.21) baseline measurements of FEV1, logarithmic dose-response curve. This result respiratory rate (RR), heart rate (HR), oxygen was then expressed as the methacholine PC20. saturation (Sao2%), inspired oxygen and car- All methacholine solutions were made up by bon dioxide levels (insp O2%, insp CO2%), the sterile unit of our pharmacy department. and expired oxygen and carbon dioxide levels (Peto2%, Petco2%) were made. Venous blood was also taken for assay of plasma ca- Oxygen breathing circuit techolamines. All gases were administered from J size cyl- In study 1 patients then received either air inders (3200 litre capacity, British Oxygen Cor- http://thorax.bmj.com/ (Fio2 0.21) or a hypoxic gas mixture (Fio2 poration Medical Gases) via a calibrated ¯ow 0.15) and in study 2 either air (Fio2 0.21) or head and a ®ve litre rebreathing bag. The oxygen (Fio2 1.0) for the remainder of the rebreathing bag was connected to an aircraft study day. All gases were administered in a face mask (Thomas Respiratory Systems, Lon- randomised double blind manner by a second don) via elephant tubing and a two way breath- person obscured from the vision of both the ing valve. patient and the doctor administering the methacholine challenge. The methacholine on September 25, 2021 by guest. Protected copyright. inhalation challenge was performed 10 minutes Plasma catecholamines after starting the study gas. All measurements, Five millilitre aliquots of venous blood were except venous blood sampling, were repeated collected into lithium heparin tubes, stored on before commencing the methacholine inhala- ice, and spun within 90 minutes. Adrenaline tion challenge. The study day was terminated and noradrenaline were later measured by 6 whenaPC20 value had been obtained and the radioenzymatic assay with both interassay and measurements made at baseline repeated. intra-assay variations of less than 10%. statistical analysis Statistical analysis was performed on an Apple measurements Mackintosh LC II computer using a Statview Heart rate, oxygen saturation, inspired and software package (Brainpower Inc, Calabasas). expired oxygen and carbon dioxide levels Data were analysed for treatment, period and Heart rate and oxygen saturation were meas- order eVects as a two period crossover clinical ured using a pulse oximetry probe (Datex Di- trial using the method described by Hills 7 vision of Instrumentarium Corp, Helsinki, and Armitage. The PC20 values were log- Finland). A side port on the face mask allowed arithmically transformed before analysis. A p continuous sampling of the inspired and ex- value of <0.05 was accepted as signi®cant. pired gases and monitoring of respiratory rate. The gases were analysed using an OSCARoxy TM multigas monitor (Datex Instrumentarium Results Corp, Helsinki, Finland). Recordings were There were no signi®cant diVerences in base- made every 10 seconds for one minute and line measurements between study days in either automatically printed by a Hewlett Packard study (table 2).
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