Download Ipratropium Bromide on Autonomic

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
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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
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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
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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.
References
0.6-J
1 Suissa S, Blais
use
+¦»
o
L, Ernst P. Patterns of increasing beta-agonist
or near-fatal asthma. Eur Respir J
and the risk of fatal
1994; 7:1602-09
H
2
0.4-
if
3
0.2-
Baseline
Time 1
Time 2
Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists
and the risk of death and near death from asthma. N Engl
} Med 1992; 326:501-06
Pakes GE, Brogden RN, Heel RC, et al. Ipratropium bro¬
mide: a review of its pharmacological properties and thera¬
peutic efficacy in asthma and chronic bronchitis. Drugs 1980;
20:237-66
Hemodynamic and non-bronchial effects of
Bremner P, Burgess D, Purdie G, et al. The extrapulmonary
effects of inhaled hexoprenaline and salbutamol in healthy
4 Anderson WM.
5
ipratropium bromide. Am J Med 1986; 81:45-53
individuals. Eur J Clin Pharmacol 1993; 45:37-9
6 Ashutosh K, Dev G, Steele D. Nonbronchodilator effects of
Low Frequency Power
I
pirbuterol and ipratropium in chronic obstructive pulmonary
disease. Chest 1995; 107:173-78
7 Corea L, Bentivoglio M, Verdecchia P, et al. Noninvasive
assessment of chronotropic and inotropic response to prefer¬
ential beta-1 and beta-2 adrenoceptor stimulation. Clin Phar¬
75
8 Bertinieri
0.8.
CL 0.6-
macol Ther 1984; 35:776-81
!
G, Di Rienzo M, Cavallazzi A, et al. A new
analysis of the arterial baroreflex. J Hypertens
approach
1985; 3:S79-81
Parlow JL, Viale JP,
to
o
0.4.
0.2-
Baseline
Figure 1.
Time 1
Time 2
and normalized ratios of
(top panel) and
SpontaneousofBRS
bottom
for
low
HRV
(middle
power
panels)
high and albuterol,
and ipratropium treatment. Data were col¬
placebo,
lected at baseline, and at time 1 (45 to 60 min) and time 2 (60 to
75 min) after drug administration. Data are expressed as mean±
SEM, n 12 subjects, p>0.05 for all treatments vs respective
baseline.
=
Annat G, et al. Spontaneous cardiac
baroreflex activity in humans: comparison with pharmacolog¬
ical responses. Hypertension 1995; 25:1058-68
10 Pomeranz B, Macauley RJB, Caudill MA, et al. Assessment of
autonomic function in humans by heart rate spectral analysis.
9
Am J Physiol 1985; 248:H151-53
11 Akselrod S, Gordon D, Madwed
JB,
et
al.
regulation: investigation by spectral analysis.
1985; 249:H867-75
Hemodynamic
Am J Physiol
PJ, Vanoli E, Stramba-Badiale M, et al. Autonomic
mechanisms and sudden death. Circulation 1988; 78:969-79
13 Schwartz PJ, La Rovere MT, Vanoli E. Autonomic nervous
system and sudden cardiac death. Circulation 1992; 85(suppl
12 Schwartz
lj:I77-91
CHEST/111 /6/JUNE, 1997
Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/20383/ on 05/05/2017
1517
25 Blaber AP, Yamamoto Y, Hughson RL. Change in phase
relationship between SBP and R-R interval during lower body
negative pressure. Am J Physiol 1995; 268:1688-93
26 Yamamoto Y, Hughson RL, Peterson JC. Autonomic control
of heart rate during exercise studied by heart rate variability
analysis. J Appl Physiol 1991; 71:1136-42
spectral
27 Montano N, Ruscone TG, Porta A, et al. Power spectrum
analysis of heart rate variability to assess the changes in
sympathovagal balance during graded orthostatic tilt. Circu¬
lation 1994; 90:1826-31
28 La Rovere MT, Specchia G, Mortara A, et al. Baroreflex
Bigger JT, La Rovere MT, Steinman RC, et al. Comparison of
baroreflex sensitivity and heart period variability after myo¬
cardial infarction. J Am Coll Cardiol 1989; 14:1511-18
15 Hosomi H, Kawada M, Yoshida H, et al. Alpha-agonist
modifies baroreflex vasoconstriction by a postjunctional
mechanism in dogs. Clin Exp Pharmacol Physiol 1989; 15:
14
71-9
16 Sato
N, Miyake S, Akatsu J, et al. Power spectral analysis of
heart rate variability in healthy young women during the
normal menstrual cycle. Psychosom Med 1995; 57:331-35
17 Ensing K, deZeeuw RA, Nossent GD, et al. Pharmacokinetics
of ipratropium bromide after single dose inhalation and oral
and intravenous administration. Eur J Clin Pharmacol 1989;
36:189-94
18 Price AH, Clissold SP. Salbutamol in the 1980's: a reappraisal
of its clinical efficacy. Drugs 1989; 38:77-122
19 Braun SR, Levy SF, Grossman J. Comparison of ipratropium
20
21
22
23
sensitivity, clinical correlates, and cardiovascular mortality
among patients with a first myocardial infarction. Circulation
1988; 78:816-24
29
morbidity in diabetics with autonomic
neuropathy. Anesthesiology 1989; 70:591-97
30 Airaksinen KEJ, Ikaheimo MJ, Linnaluoto MK, et al. Im¬
paired vagal heart rate control in coronary artery disease. Br
erative cardiovascular
bromide and albuterol in chronic obstructive pulmonary
disease: a three center study. Am J Med 1991; 91:28-32
Rau JL, Restrepo RD, Deshpande V. Inhalation of single vs
multiple metered-dose bronchodilator actuations from reser¬
voir devices: an in vitro study. Chest 1996; 109:969-74
Zanon P. 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
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.H
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