Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease

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1 et al. DOI: /j x British Journal of Clinical Pharmacology Effects of rac-albuterol on arterial blood gases in patients with stable hypercapnic chronic obstructive pulmonary disease Christopher I. Whale, Milind P. Sovani, Kevin Mortimer, Janet Oborne, Sue Cooper, Timothy W. Harrison & Anne E. Tattersfield Division of Respiratory Medicine, University of Nottingham, Nottingham City Hospital, Nottingham NG5 1PB, UK Correspondence Dr Christopher I. Whale, Division of Respiratory Medicine, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK. Tel: + 44 (0) Fax: + 44 (0) chris.whale@nottingham.ac.uk Key words albuterol, COPD, hypercapnia, salbutamol Received 4 August 2005 Accepted 24 November 2005 Published OnlineEarly 18 April 2006 Aims Many patients with chronic obstructive pulmonary disease (COPD) are treated with high dose β 2 -adrenoceptor agonists, which can increase ventilation/perfusion mismatching, and tremor and cardiac output, thereby increasing oxygen uptake and carbon dioxide output (VCO 2 ). Patients with severe COPD and hypercapnia may be unable to increase ventilation in response to increased VCO 2, in which case arterial carbon dioxide tension (P a CO 2 ) may rise. Our aim was to determine whether high dose nebulized rac-albuterol could increase P a CO 2 in patients with COPD, limited bronchodilator reversibilty and hypercapnia. Methods We compared 10 mg and 400 µg rac-albuterol, given in two doses 1 h apart on nonconsecutive days, in a double-blind randomized crossover study in 14 patients with severe COPD. P a CO 2, arterial oxygen tension (P a O 2 ) and heart rate were measured over 120 min and change from baseline was plotted against time to obtain an area under the curve. Results Mean P a CO 2 fell slightly over 120 min, with no difference between treatments (0.03 kpa h 1 (95% confidence interval 0.02, 0.04)) and only three subjects had an increase in P a CO 2 after high dose rac-albuterol. High dose rac-albuterol caused a greater fall in P a O 2 [0.1 kpa h 1 (95% confidence interval 0, 0.2)] and increase in heart rate than the low dose, although the differences were small. Conclusions Under stable conditions most subjects with severe COPD and hypercapnia will have a fall in P a CO 2 and P a O 2 following 10 mg rac-albuterol, suggesting that they maintain capacity to respond to any increase in VCO 2 and prevent a rise in P a CO 2. Introduction Acute exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of hospital admissions [1] and patients with hypercapnia have particularly high mortality rates [2]. The response of these patients to treatment has been little studied and guidelines have been unable to provide clear dose recommendations for bronchodilator treatment. Patients with severe COPD have a limited ability to bronchodilate and the adverse effects following high doses of β 2 -adrenoceptor agonists can outweigh the benefit [3] The Authors Br J Clin Pharmacol 62: Journal compilation 2006 Blackwell Publishing Ltd

2 C. I. Whale et al. Potential problems with high dose β-adrenoceptor agonists in patients with severe COPD include an increase in ventilation/perfusion mismatching and an increase in carbon dioxide output (VCO 2 ). Carbon dioxide output may rise by over 25% [4 6] and has been attributed to an increase in CO 2 production as tremor increases, and a reduction in CO 2 stores as cardiac output increases [6 8]. The normal response to an increase in CO 2 flux to the lungs would be to increase ventilation, but patients with severe COPD and limited reversibility may not have the capacity to do this, particularly during an acute exacerbation, in which case the P a CO 2 would rise and may worsen acidosis. Due to the difficulties of studying patients in a controlled manner during an acute exacerbation, we have initially examined the effect of high dose nebulized rac-albuterol in patients with severe stable COPD and chronic hypercapnia. We chose to give a low dose of rac-albuterol as the control rather than normal saline to reduce the possibility that patients would require treatment to relieve breathlessness during the study and to avoid bronchoconstriction from normal saline [9]. We report the changes in arterial blood gas tensions from a crossover study in which 14 patients with stable COPD, documented hypercapnia and limited reversibility received 10 mg or 400 µg nebulized rac-albuterol on separate days, both given in two doses 1 h apart. Methods Subjects Patients aged years with a clinical diagnosis of COPD were recruited if they had a forced expiratory volume in 1 s (FEV 1 ) below 50% predicted and a FEV 1 / forced vital capacity (FVC) ratio of less than 70%. Ten minutes after inhaling 200 µg rac-albuterol, all subjects had an increase in FEV 1 of not more than 200 ml and 15%. Subjects were required to have had an arterial carbon dioxide tension (P a CO 2 ) of greater than 6 kpa on two occasions when clinically stable or have developed hypercapnia (P a CO 2 > 6 kpa) during assessment for long-term oxygen. Exclusion criteria were other causes of ventilatory failure, an additional unstable medical condition, an acute exacerbation of COPD requiring oral corticosteroids within the last 4 weeks and regular medication with a β 2 -adrenoceptor antagonist or anticoagulant. Nottingham City Hospital Research Ethics Committee approved the study and written informed consent was obtained at least 24 h before the first study day. Measurements P a CO 2, P a O 2 and ph were measured using standard electrodes on a blood gas analyser (Rapidlab 840, Bayer, Leverkusen, Germany) that was calibrated daily. Heart rate, oxygen saturation and blood pressure were recorded on a central monitor (Dynascope DS-5100E, Fukuda Denshi, Tokyo, Japan), attached to a three-lead electrocardiograph, an oximeter sensor (Nellcor, Pleasanton, USA) and a diaphragm transducer and amplifier to measure blood pressure. Study design and methods This was a randomized, double-blind, crossover study performed on two nonconsecutive days, not more than 5 days apart. Subjects were required to withhold shortacting bronchodilators for at least 10 h, and theophylline, tiotropium and long-acting β 2 -adrenoceptor agonists for at least 24 h before each study day; inhaled and oral corticosteroids and nonpulmonary medications were taken as usual. Subjects using home oxygen discontinued this 30 min before leaving home. After an early breakfast without caffeine-containing beverages, subjects came to the hospital by taxi, were escorted to the laboratory by wheelchair and rested in a reclining chair for 10 min. Three chest leads and the fingertip pulse oximeter were attached and Alan s test performed on the radial and ulnar arteries to confirm the adequacy of local circulation. A cannula (FloSwitch, Becton Dickinson, Swindon, UK) was inserted into the radial artery under local anaesthetic and attached to the transducer. Two 1 ml blood samples were taken sequentially from the arterial cannula to measure ph, P a O 2 and P a CO 2 (mean value recorded) and repeated at 10-min intervals until consecutive mean P a O 2 and P a CO 2 readings were within 0.5 kpa. Consecutive heart rate readings also had to be within five beats min 1, without an increase in rate. Baseline values for all variables were taken as the mean of the last two results. On each day the patient was given rac-albuterol sulphate (Steri-Neb, Baker Norton, London, UK), either two doses of 5 mg in 2.5 ml or two doses of 200 µg diluted to 2.5 ml with normal saline, with the order determined by computer-generated random sequence. The first dose was delivered over 6 min via a nebulizer (IEC 601 1, Medic-Aid, Pagham, UK) driven by air at 5 l min 1. Duplicate 1 ml samples of arterial blood were taken 10, 15, 20, 30, 45 and 60 min after starting drug delivery to determine P a CO 2 and P a O 2 and followed at each time point by heart rate, blood pressure and oxygen saturation measurements in that order. Sixty minutes after starting the first nebulization the second identical dose of rac-albuterol was delivered and the measurements repeated over the next hour. Subjects received the alternative dose of rac-albuterol on the second study day, using an identical protocol, :2 Br J Clin Pharmacol

3 How rac-albuterol effects arterial blood gases in hypercapnic COPD patients except that the cannula was placed in the contralateral radial artery. The primary endpoint was the difference in change in P a CO 2 between two doses of rac-albuterol. Fourteen patients provided >95% power to find a mean difference of 0.05 kpa h 1, assuming a standard deviation of 0.02 kpa h 1. Secondary outcome measures were differences between doses for change in P a O 2 and heart rate. Analysis Change in mean P a CO 2, P a O 2 and heart rate for each dose of rac-albuterol was plotted against time and area under the time-response curves (AUC for min) calculated by trapezoid integration. t-tests were conducted to exclude carry-over and period effects between baseline readings [10] and paired t-tests to determine differences between doses. Within subject change in P a CO 2 (AUC) following high dose rac-albuterol was related to change in P a O 2 (AUC) and heart rate (AUC) and baseline measures using Pearson s correlation. Analyses were carried out using the statistical software program, SPSS version 11 (SPSS inc, Chicago, USA), with statistical significance accepted at P < Results Of 15 subjects who agreed to participate, one was withdrawn after the first study day following a fall at home. Mean demographic data for the 14 patients (three women) who completed the study is found in Table 1. Twelve patients had had a P a CO 2 above 6 kpa on two occasions and two had developed hypercapnia in response to oxygen (2 l min 1 ) during assessment for long-term domiciliary treatment. Table 1 Mean (SD) baseline data for the 14 subjects Baseline P a O 2 showed a positive correlation with FEV 1 (r = 0.6, P = 0.02) and a negative correlation with baseline P a CO 2 (r = 0.6, P = 0.02). There was no carry-over or period effect for the two study treatments. Mean changes with rac-albuterol Mean P a CO 2 for the 14 patients fell gradually over the study period following both doses of rac-albuterol, but with no difference between doses for P a CO 2 AUC (Table 2). The mean fall after 120 min was 0.32 and 0.29 kpa for the high and low doses of rac-albuterol, respectively (Figure 1). There was a progressive fall in mean P a O 2 following both doses of rac-albuterol, with a significant difference between doses (mean difference in P a O 2 AUC 0.1 kpa h 1 ; 95% confidence interval (CI) 0, 0.2, P = 0.04). The reduction at 120 min was 0.57 and 0.24 kpa for the high and low doses, respectively (Figure 1). There was a greater rise in mean heart rate with the high dose compared with the low dose (mean difference in heart rate AUC 1.1 beats min 1 h; 95% CI 0.4, 1.8, P = 0.005); the heart rate increase at 120 min in the two groups was 4.9 and 1.1 beats min 1 (Figure 1). Within subject changes with high dose rac-albuterol The change from baseline P a CO min after high dose rac-albuterol ranged from +0.8 kpa to 0.82 kpa (Figure 2), with 11 of the 14 subjects showing a fall in P a CO 2. Patients showing a rise in P a CO 2 were more likely to have a lower baseline P a CO 2 and a smaller rise in heart rate with rac-albuterol, i.e. P a CO 2 AUC showed a negative correlation with baseline P a CO 2 (r = 0.6, P = 0.04) and heart rate AUC (r = 0.6, P = 0.02). There was no significant correlation between P a CO 2 AUC and P a O 2 AUC (r = 0.2, P = 0.44) or other baseline measures (P a O 2 r = 0, FEV 1 r = 0.4, reversibility r = 0). Age (years) 66 (7) FEV 1 (l) 0.71 (0.3) BMI (kg m 2 ) 28 (6) Cigarette consumption (pack years) 53 (34) Reversibility (ml) 109 (57) P a CO 2 (kpa) 7.9 (1.0) P a O 2 (kpa) 7.2 (1.3) Number of subjects taking respiratory medication Short-acting β 2 -adrenoceptor agonists 13 Long-acting β 2 -adrenoceptor agonists 9 Inhaled corticosteroids 9 Short-acting antimuscarinics 9 Long-acting antimuscarinic 0 Oral theophylline 2 Home oxygen 8 Table 2 Between dose comparisons of mean AUC for P a CO 2, P a O 2 and heart rate over 2 h P a CO 2 AUC Difference (high vs. low) 0.03 kpa h 1 (95% CI 0.02, 0.04), P = 0.57 P a O 2 AUC Difference (high vs low) 0.1 kpa h 1 (95% CI 0, 0.2), P = 0.04 Heart rate AUC Difference (high vs. low) 1.1 beats min 1 h (95% CI 0.4, 1.8), P = Br J Clin Pharmacol 62:2 155

4 C. I. Whale et al. Beats/min 8 4 Heart rate 11 P a CO 2 P a O 2 0 kpa P a CO kpa P a O ST DOSE 2 ND DOSE Time (mins) Figure 1 Mean change in heart rate, arterial carbon dioxide (P a CO 2 ) and oxygen (P a O 2 ) tension over 120 min after high ( ) and low dose ( ) nebulized rac-albuterol (n = 14) Patients with the largest falls in PaO 2 had higher baseline FEV 1 and P a O 2 values and a greater rise in heart rate, i.e. P a O 2 AUC showed a negative correlation with FEV 1 (r = 0.6, P = 0.04), baseline P a O 2 (r = 0.7, P = 0.01) and heart rate AUC (r = 0.53, P = 0.05). Discussion We examined the effects of high and low dose nebulized rac-albuterol on arterial blood gas tensions in patients with stable COPD who had limited bronchodilator reversibility and either resting hypercapnia or a raised P a CO 2 in response to oxygen therapy. The higher dose of rac-albuterol produced a greater fall in mean P a O 2 and increase in heart rate. However, the differences between doses were small. Neither dose of rac-albuterol caused a rise in mean P a CO 2, although three subjects showed a small increase in P a CO 2 with high dose rac-albuterol. 5 Figure 2 The effect of high dose rac-albuterol on P a CO 2 and P a O 2 for each patient (n = 14), comparing baseline reading with the reading at 120 min postdose Baseline 120 mins Baseline 120 mins β-adrenoceptor agonists have reduced P a O 2 in previous studies in patients with less severe COPD and the changes were attributed to an increase in ventilation/ perfusion mismatching [11 13]. Although these studies have not shown a rise in P a CO 2, other studies have documented an acute increase in CO 2 output of over 25% in response to modest rac-albuterol doses in normal subjects and patients with asthma [5, 6]. This increase in VCO 2 has been attributed to increased CO 2 flux to the lungs, due to increased cardiac output, and increased CO 2 production as metabolic rate and skeletal muscle tremor increase. We hypothesized that P a CO 2 might rise following higher doses of rac-albuterol in patients with severe COPD, hypercapnia and limited bronchodilator reversibility due to an inability to increase ventilation in :2 Br J Clin Pharmacol

5 How rac-albuterol effects arterial blood gases in hypercapnic COPD patients response to an increase in VCO 2. We initially chose to test the hypothesis on patients with severe COPD in a stable condition in whom hypercapnia may suggest limited ability to further increase ventilation. The mean P a CO 2 in our patients fell after high dose rac-albuterol, suggesting that either VCO 2 did not rise for most subjects or that ventilation increased appropriately in response to an increase in VCO 2 despite severe airflow obstruction and hypercapnia. We did not measure VCO 2 as it was important that patients were as relaxed as possible. All but one of our subjects was taking regular β 2 -adrenoceptor agonists and they may therefore have developed tolerance, thus reducing the increase in tremor and cardiac output following rac-albuterol. Tolerance has been shown for the increase in CO 2 production with β-adrenoceptor agonists in normal subjects [14] and it would also explain the relatively small increase in heart rate following rac-albuterol in our study. There was some variation in change in P a CO 2 in response to the high dose of rac-albuterol and a rise in P a CO 2 was seen in three of the 14 subjects. Contrary to expectations, patients showing a rise in P a CO 2 were more likely to have had low baseline P a CO 2 values and a smaller increase in heart rate. This could reflect relaxation during the study although we tried to ensure that subjects were relaxed and baseline measurements stable before giving rac-albuterol. Nevertheless patients who were less relaxed would have a lower P a CO 2 and higher heart rate prior to treatment, and these would tend to increase and decrease, respectively, during the study. We also considered whether rac-albuterol might potentiate the effects of hypoxaemia on chemoreceptor stimulation and ventilation, as there is putative evidence of β- adrenoceptors on central chemoreceptors [15, 16]. However, change in P a CO 2 did not correlate with either baseline P a O 2 or change in P a O 2, which may reflect differences between patients in their ability to increase ventilation, in the extent to which tolerance to β 2 -adrenoceptor agonists had developed and/or the presence of different β 2 -adrenoceptor polymorphisms within the group. Whatever the mechanism behind these changes, our findings confirm that 10 mg nebulized rac-albuterol reduces P a O 2 and suggest that an increase in P a CO 2 following a high dose of rac-albuterol is uncommon in patients with stable severe COPD who take β-adrenoceptor agonists regularly. Whether an increase would occur more often during an acute exacerbation of COPD when patients are less able to increase ventilation is uncertain. 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