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Effects of Inhaled Albuterol and Ipratropium Bromide on Autonomic Control of the Cardiovascular System* A. Joel Dagnone, BSc; and Joel L. Parlow, MD, MSc Study objective: Systemic administration of P-agonist and anticholinergic drugs markedly impair normal autonomic heart rate control. The purpose of this study was to quantify and compare the effects of therapeutic doses of inhaled albuterol and ipratropium on autonomic control of the cardiovascular system. Design: Randomized, double-blind, placebo-controlled, crossover design study. Setting: Tertiary-care hospital. Subjects: Twelve healthy male volunteers. Interventions: Subjects self-administered four puffs through a spacer device from one of three identical inhalers containing albuterol (100 |xg per puff), ipratropium (20 [ig per puff), or placebo in three different testing sessions. Measurements: ECG and noninvasive continuous BP traces were recorded at baseline and from 45 to 75 min after administration of the drug. Autonomic control of the cardiovascular system was quantified by analysis of spontaneous baroreflex sensitivity and power spectral analysis of heart variability. Results: Neither albuterol nor ipratropium caused a significant alteration in baroreflex sensitivity, normalized low-power frequency, or normalized high-power frequency. No adverse effects were reported by subjects. Conclusions: Inhalation of four puffs of albuterol (400 (xg) or ipratropium (80 juig) does not alter the autonomic control of the cardiovascular system in young, healthy male subjects. rate (CHEST 1997; 111:1514-18) Key words: albuterol; baroreflex; bronchodilators; heart rate; heart rate variability; thetic nervous system; sympathetic nervous system ipratropium bromide; parasympa¬ Abbreviations: BRS=baroreflex sensitivity; HRV= heart rate variability'; PNS=parasympathetic nervous system; RR interval=time between two successive R waves of ECG (heart period); SNS=sympathetic nervous system A Ibuterol (salbutamol), a P2-receptor agonist, and -^¦^the anticholinergic ipratropium bromide are two commonly used drugs in the treatment of reactive airway disease. In addition to their local bronchodi¬ lating effects, inhaled albuterol and ipratropium are also capable of causing untoward systemic effects. The use of inhaled P2-agonists has been associated with tachycardia, tremor, arrhythmias, and increased risk of death from asthma.1-2 Similarly, the use of high doses of inhaled ipratropium has been associ*From the of Anaesthesia, Queen's University, Department Canada. Kingston, Ontario, an MRC/PMAC Supported by Studentship.received October Health Research Foundation 17, 1996; revision accepted January Manuscript MD, Department of Anaesthe¬ Reprint requests: Joel L. Parlow, sia, Queen's University, 76 Stuart St, Kingston Out, K7L 2V7 Canada 6, 1997. ated with tachycardia and headache, suggesting a degree of systemic absorption.34 Past investigators have studied changes in heart rate and blood pressure (BP) to measure the cardio¬ vascular effects of albuterol and ipratropium.5-6 However, these measures may be insensitive to the more subtle effects these drugs exert on the auto¬ nervous system and its control over the car¬ diovascular system. Furthermore, heart rate and BP are influenced by changes in inherent autonomic nervous system activity, thus confounding the inter¬ pretation of the cardiovascular effects using these markers.7 Recently, a number of noninvasive meth¬ ods have been developed to quantify the autonomic control of the cardiovascular system. Spontaneous baroreflex sensitivity (BRS) represents an index of nomic beat-by-beat parasympathetic nervous system (PNS) control of heart rate.8-9 Spectral analysis of heart rate variability (HRV) allows the quantification of the 1514 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20383/ on 05/05/2017 Clinical Investigations relative influence of the PNS and sympathetic ner¬ system (SNS) input on the heart.1011 Impairment of autonomic control of heart rate is strongly associated with adverse outcome following of myocardial ischemia or infarction.1214 episodes Since many patients with chronic obstructive lung disease have coexisting ischemic heart disease, pres¬ ervation of autonomic control of the heart may be an important goal in the treatment of these patients during periods of stress, hypoxemia, and acidosis, which may accompany exacerbations of their pulmo¬ nary disease. Since systemic administration of P-ag¬ onist and anticholinergic drugs markedly impairs normal autonomic heart rate control,915 it would be important to determine whether inhalation of these agents causes a similar effect. The purpose of this study was to quantify and compare the effects of doses of inhaled albuterol and ipra¬ therapeutic on autonomic control of the cardiovascular tropium vous system. Oscillometric BP (Dinamap; Critikon; Petersboro, Ontario), peak expiratory flow (Mini-Wright Peak Flow Meter; Airmed; London), and respiratory rate were assessed prior to all interven¬ Monitoring consisted of lead II ECG (Tektronix; Beaverton, Ore) and noninvasive continuous BP by the volume clamp method (Finapres 2300; Ohmeda; Englewood, Colo). Respiratory tions. rate was paced by a metronome at each subject's natural with a minimum of 12 breaths/min.23 BP and respiratoiy ECG traces were recorded for 12 min at baseline, and for the period from 45 to 75 min after administration to reflect the time of peak serum levels and peak improvement in pulmonary function after albuterol and ipratropium.31718'24 The data from 45 to 60 min (time 1) and 60 to 75 min (time 2) after drug rate administration were compared the period of peak effect. so as to ensure sampling during Data Analysis Continuous ECG and BP traces were digitized by a 12-bit analog-digital converter at a sampling rate of 1,000 Hz (CIO DAS-16) and stored on computer. During digitization, systolic and diastolic BP time two R and between successive waves of ECG (RR intervals) were measured and recorded for every heart beat. Data for each study period were placed in coded files and analyzed by an investigator blinded as to study condition. Cardiac was calculated using the spontaneous baroreflex method, which identifies series of spontaneously occurring increases and decreases in BP that are accompanied by appropriate baroreflexmediated responses in RR interval. Detailed descriptions of the method have been published previously.925 For each of the hemodynamic recordings, the computer software selected all sequences of three or more successive heart beats in which there were concordant increases or decreases in systolic BP and RR intervals. The systolic pressure and RR interval points for these sequences were plotted on an x-y curve, and linear regression was applied to each of the sequences. An average regression slope of all sequences detected during each recording period was thereby calculated. This slope represents the cardiac BRS (ms/mm Hg) for any study condition and has been shown to correlate with values obtained by the vasoactive method.9 Spectral analysis was carried out using methods published previously.1026 For each study period, a time series of 512 consecutive RR intervals (representing approximately 8 to 10 min) was selected from stationary7 data free from artifact. A fast Fourier transformation was applied to the time series to generate a power spectral curve. This power spectrum describes the frequency distribution of the variability of RR intervals (heart rate) in units of ms2/Hz. The absolute power of RR interval variability7 is calculated as the integration of the area under the curve over any given frequency range. Spectral power was calculated over the low (0 to 0.15) and high (0.15 to 0.50 Hz) frequency ranges. When normalized to total power (0 to 0.50 Hz), these values yield indicators of SNS and PNS influence on the heart, respectively.11-27 Continuous data were analyzed statistically by repeated mea¬ sures of variance on two factors (time and drug), with p<0.05 considered significant. BRS Materials and Methods Subjects Following approval by the Queen's University Research Ethics Board, 12 healthy male volunteers, aged 18 to 27 years, were studied in a randomized, double-blind, placebo-controlled, cross¬ over design study. A minimum sample size of 11 subjects was determined to be necessary to detect a decrease in BRS of 40% with a power of 0.80 and alpha error of 0.05. Subjects were excluded from the study if they had documented history, symp¬ toms, or physical signs of respiratory or cardiovascular disease, diabetes, allergy to study drugs, or smoking, or had used any medications acting on the respiratory, cardiovascular, or nervous systems. Women were not studied owing to the variation in hormonal effects on the autonomic system during different times in the menstrual cycle.16 Written informed consent was obtained from all subjects. Testing was performed between 7 and 11:30 am, with subjects having abstained from caffeine-containing beverages and alcohol for 12 h and having avoided strenuous exercise for 24 h prior to each study period. Procedure Each volunteer attended three testing sessions separated by at least 48 h to eliminate the possibility of carryover effects from the previous test. Subjects were studied in a semireclining position in a quiet, dimly lit room. An instruction period preceded the first session to familiarize subjects with the use of inhalers. Subjects self-administered four puffs from one of three identical metereddose inhalers, containing albuterol (100 fxg per puff), ipratropium (20 fxg per puff), or placebo. These doses are at the high end of the therapeutic range and have been shown to be clinically efficacious and equipotent.3-17'19 Single repeated puffs separated by 30 s were administered.20 A spacer device was used toas maximize and standardize drug delivery to the lower airways much as possible.2122 The order of administration of test drugs was randomized and subjects were blinded to the test drug received. Subjects were questioned before and after each testing session to identify any side effects from the test drugs. Results Baseline measures of BP, RR interval, respiratory rate, and peak flow were similar between study sessions, and there were no significant effects of either drug on these parameters (Table 1). The top CHEST/111 /6/JUNE, 1997 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20383/ on 05/05/2017 1515 Table 1.Hemodynamic and Respiratory Values* Albuterol Placebo Study Systolic RR Baseline Session BP, mm Hg119±13 interval, ms1,034±148 Respiratory7 rate, breaths/min13±1 Peak 610±63 flow'L/min Drug 125±12 113±10 1,096±174 1,066±142 13±1 606±62 Ipratropium Baselii 12±1 12±1 12±1 12±1 615±48 Drug Baseline Drug 123±9 119±11 120±12 1,045±120 1,079±164 633±56 613±63 629±66 1,150±150 *Mean±SD; p>0.05 for all conditions. of Figure 1 illustrates the mean spontaneous panel BRS for all 12 subjects. There was no statistical difference among the three different baseline mea¬ sures. Neither albuterol nor ipratropium caused a significant alteration in BRS at either time 1 (45 to 60 min) or time 2 (60 to 75 min). The middle and lower panels of Figure 1 repre¬ high- and low-power activity of all 12 subjects, normalized to total power of HRV. There was no statistical difference between the baseline measures. Neither albuterol nor ipratropium caused a signifi¬ cant change in normalized low- or high-frequency power at either time 1 or time 2. All subjects cooperated well and mastered the administration of the test drugs. No subjects re¬ ported adverse side effects such as palpitations, sent headache, or tremors. Discussion The aim of this study was to evaluate and quantify the effects of two commonly used asthma drugs on autonomic nervous system control of the cardiovas¬ cular system. Previous studies have generally focused on gross heart rate and BP changes when examining the cardiovascular effects of these drugs.56 However, alterations in the balance of parasympathetic and sympathetic control of the heart rate may exist in the absence of gross effects on heart rate and BP.7 We have shown that inhalation of single, high therapeu¬ tic doses of albuterol or ipratropium does not result in significant impairment of PNS-mediated barore¬ flex control of heart rate. In addition, PNS and SNS modulation of heart rate were not altered. In addi¬ tion, no unpleasant systemic effects were reported. The importance of parasympathetic control of the heart has been elucidated by a number of different studies. Reduced parasympathetic activity is associ¬ ated with arrhythmias and sudden cardiac death after episodes of myocardial ischemia.1428 Diabetic pa¬ tients with evidence of vagal impairment are at increased perioperative risk for cardiovascular insta¬ bility.29 In animals with experimentally induced myocardial infarction, increased sympathetic activity and impairment of parasympathetic activity are as¬ sociated with fatal arrhythmias during periods of myocardial ischemia.1213 The association of sudden death from asthma with regular (32-agonist use raises concerns about the effects of these drugs on the cardiovascular and autonomic nervous systems.1-2 In individuals with cardiopulmonary disease, who char¬ acteristically exhibit preexisting decrease of PNS control,30 further impairment could make these in¬ dividuals more vulnerable to stresses such as hypox¬ emia and acidosis, which might accompany exacer¬ bations of their respiratory disease. Alternatively, these individuals may have already adapted to the decreased parasympathetic influence on their heart, making a further reduction in parasympathetic tone inconsequential. Most previous studies examining the effects of albuterol and ipratropium on the cardiovascular sys¬ tem have focused on heart rate and BP changes, which may ignore the more subtle effects these drugs have on cardiovascular stability. IV and oral administration of both bronchodilators causes doseincreases in heart rate,18 while large dependent doses of albuterol (400 to 1,200 |xg), but not ipra¬ tropium (up to 280 jug), administered via a metereddose inhaler have been shown to cause tachycar¬ dia.331 One recent study examined the effect of ipratropium on respiratory sinus arrhythmia, a non¬ specific indicator of PNS modulation of heart rate, showing no effect in asthmatic subjects.32 These investigators used a low therapeutic dose of ipra¬ tropium (40 jjig) without a spacer device. In addition, the subjects were not standardized with respect to their disease severity, and it has been shown that the amount of inhaled drug that reaches the terminal airways depends on the severity and type of respira¬ tory disease, lung volumes, and utilization of a spacer device.3-22-33 In the present study, the drug amounts adminis¬ tered were chosen to reflect the high end of recom¬ mended clinical doses and equipotency.3-17-19 Larger doses of albuterol or ipratropium, such as those used in asthmatic exacerbations, might have produced significant changes in autonomic control of the heart. 1516 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20383/ on 05/05/2017 Clinical Investigations pilot studies conducted by the present authors, doses of inhaled albuterol (1,200 |mg) extremelyinhigh 60. resulted an increase in heart rate and systolic BP, ¦o- Placebo and decreased BRS and high-frequency HRV. No Albuterol 50. similar changes occurred when high doses of ipra¬ tropium (240 jULg) were inhaled. The data sampling Ipratropium times 40-^ (45 to 75 min) used in this study were chosen to reflect the peak serum level of the drug and the time of maximal bronchodilation.1718'24-33 It is thus 30. that data collection sooner following drug unlikely administration would have yielded different results. 20. Healthy, young male volunteers were studied to elucidate pure drug effects without the difficulties in 10for confounding factors such as age, standardizing Baseline Time 1 Time 2 of menstrual timing cycle, severity of underlying disease, and concurrent drug use.16 34 Future studies are required to clarify the autonomic effects of these agents in other study populations, including women Power and High Frequency pregnancy, the aged, and individuals with un¬ derlying respiratory and cardiovascular disease. 0.8. In Baroreflex Sensitivity *- £ E I i Q. 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Inhalation anti-asthma therapy with spacers: tech¬ nical aspects. Monaldi Arch Chest Dis 1994; 49:258-64 of morbidity in asth¬ Cunningham SJ, Craina EF. Reduction matic children given spacer device. Chest 1994; 106:753-57 Patwardhan AR, Evans JM, Bruce EN, et al. Voluntary7 control of breathing does not alter vagal modulation of heart J Appl Physiol 1995; 78:2087-94 SR, McKenzie WrN, Copeland C, et al. A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease. Arch Intern Med 1989; Heart J 1987; 58:592-97 31 Amoroso P, Wilson SR, Moxham J, et al. Acute effects of inhaled salbutamol on the metabolic rate of normal subject. Thorax 1993; 48:882-85 32 Lehrer PM, Hochron SM, Rausch L, et al. Effects of aerosol ipratropium bromide on cardiac vagal tone. Chest 1994; 105:1701-04 33 Hochhaus G, Mollmann H. mol, and fenoterol. Int J rate. 34 Ebert TJ, Morgan BJ, Barney JA, et al. Effects of aging on baroreflex regulation of sympathetic activity in humans. Am J Physiol 1992; 263:H798-803 B i C A K COIUCE OF mc II K ST C I N II Pharmacol Ther Toxicol 1992; 30:342-62 149:544-47 i» Pharmacokinetic/pharmacodyterbutaline, salbuta¬ b-2-agonists Clin namic characteristics of the 24 Braun A I! E Burgos LG, Ebert TJ, Asiddao CB, et al. Increased intraop¬ Y 8 I A .H Moving Toward the Future with Patient-Centered Care * October 26 30, 1997 . New Orleans? Louisiana - FOR INFORMATION CALL: 1-800-343-ACCP or 847-498-1 400 1518 Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20383/ on 05/05/2017 Clinical Investigations