Download Acute Electrophysiologic Effects of Inhaled Salbutamol in Humans*

Acute Electrophysiologic Effects of
Inhaled Salbutamol in Humans*
Eleftherios M. Kallergis, MD; Emmanuel G. Manios, MD;
Emmanuel M. Kanoupakis, MD; Sophia E. Schiza, MD;
Hercules E. Mavrakis, MD; Nikolaos K. Klapsinos, MD; and
Panos E. Vardas, MD, PhD
Study objectives: Although inhaled ␤2-agonists are in widespread use, several reports question
their potential arrhythmogenic effects. The purpose of this study was to evaluate the cardiac
electrophysiologic effects of a single, regular dose of an inhaled ␤2-agonist in humans.
Design: Prospective study.
Setting: Tertiary referral center.
Patients: Six patients with bronchial asthma and 12 patients with mild COPD.
Interventions: All patients underwent an electrophysiologic study before and after the administration of salbutamol solution (5 mg in a single dose).
Measurements and results: Sinus cycle length, sinus node recovery time (SNRT), interval from the
earliest reproducible rapid deflection of the atrial electrogram in the His bundle recording to the
onset of the His deflection (AH), interval from the His deflection to the onset of ventricular
depolarization (HV), Wenckebach cycle length (WCL), atrial effective refractory period (AERP),
and ventricular effective refractory period (VERP) were evaluated just before and 30 min after
the scheduled intervention. Salbutamol, a selective ␤2-agonist, administered by nebulizer had
significant electrophysiologic effects on the atrium, nodes, and ventricle. The AH length
decreased from 86.1 ⴞ 19.5 ms at baseline to 78.8 ⴞ 18.4 ms (p < 0.001), and the WCL decreased
from 354.4 ⴞ 44.2 to 336.6 ⴞ 41.7 ms (p ⴝ 0.001). Salbutamol significantly decreased the AERP
and VERP too while leaving the HV unchanged. Additionally, inhaled salbutamol increased heart
rate (from 75.5 ⴞ 12.8 beats/min at baseline to 93.1 ⴞ 16 beats/min, p < 0.001) and shortened the
SNRT (from 1,073.5 ⴞ 178.7 to 925.2 ⴞ 204.9 ms, p ⴝ 0.001).
Conclusion: Inhaled salbutamol results in significant changes of cardiac electrophysiologic
properties. Salbutamol enhances atrioventricular (AV) nodal conduction and decreases AV nodal,
atrial, and ventricular refractoriness in addition to its positive chronotropic effects. These
alterations could contribute to the generation of spontaneous arrhythmias.
(CHEST 2005; 127:2057–2063)
Key words: ␤2-agonist; electrophysiologic effects; refractory period; salbutamol
Abbreviations: AERP ⫽ atrial effective refractory period; AH ⫽ interval from the earliest reproducible rapid
deflection of the atrial electrogram in the His bundle recording to the onset of the His deflection; AV ⫽ atrioventricular;
ERP ⫽ effective refractory period; HV ⫽ interval from the His deflection to the onset of ventricular depolarization;
SCL ⫽ sinus cycle length; SNRT ⫽ sinus node recovery time; VERP ⫽ ventricular effective refractory period;
WCL ⫽ Wenckebach cycle length
autonomic nervous system and especially its
T hesympathetic
component play an important role in
the development of cardiac arrhythmias.1–3 The in*Departments of Cardiology and Pneumonology, University Hospital of Heraklion, Crete, Greece.
Manuscript received November 13, 2004; revision accepted
December 1, 2004.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Panos Vardas, MD, PhD, Department of
Cardiology, Heraklion University Hospital, 71000, Voutes,
Heraklion-Crete, Greece; e-mail: [email protected]
creased sympathetic activity and the consequent
enhanced catecholamine release result in the activation of myocardial adrenergic receptors, which mediate its arrhythmogenic effects.1– 4
Until recently it was believed that all myocardial
␤-receptors belonged to the ␤1 subtype. Now it has
become clear that the atrial and ventricular myocardium consist of both ␤1- and ␤2-adrenergic receptors.5– 8 It has been demonstrated that ␤2-adrenergic
receptors constitute 20 to 40% of the total number of
␤-receptors in the human heart and play a significant
role in physiologic and pathologic conditions.7,8
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CHEST / 127 / 6 / JUNE, 2005
2057
Inhaled ␤2-adrenoceptor agonists are the most
effective known bronchodilators. Apart from their
therapeutic benefits, inhaled ␤2-agonists have been
associated with adverse cardiac events such as cardiac arrest and acute cardiac death.9 –15 Although the
cause and underlying mechanism are unclear, arrhythmias could be a contributory factor.
As sufficient data do not exist concerning the
cardiac electrophysiologic effects of ␤2-agonists, particularly the inhaled ␤2-agonists, we planned to
investigate the electrophysiologic characteristics of
salbutamol, one of the most effective selective ␤2agonists, administered by nebulization and thus provide a further insight into the possible arrhythmogenic effects of inhaled ␤2-agonists.
Materials and Methods
period (ERP) determinations at each cycle length. The AERP
and VERP were defined as the longest S1៮S2 coupling interval
that failed to result in atrial and ventricular capture, respectively.
All intracardiac recordings were stored on an optical disk (EP
Lab; Quinton; Washington, DC).
Measurements of Conduction Intervals: An electrode catheter
(USCI) was advanced into the right atrium and across the
tricuspid valve until it was clearly in the right ventricle. The
catheter was then withdrawn across the tricuspid orifice with
fluoroscopic monitoring until the His bundle potential was
recorded. The interval from the earliest reproducible rapid
deflection of the atrial electrogram in the His bundle recording to
the onset of the His deflection (AH) and the interval from the His
deflection to the onset of ventricular depolarization (HV) were
measured during the electrophysiologic study (Fig 1), according
to the standard method.17 The sinus node recovery time (SNRT)
and corrected SNRT were determined after 60 s of atrial pacing
at a cycle length of 500 ms, according to the standard method.18
A 500-ms cycle length was used to avoid interference with high
sinus node activity, as caused by salbutamol administration. The
Wenckebach cycle length (WCL) was determined by atrial pacing
and was used as an indirect reflection of atrioventricular (AV)
nodal refractoriness.
Patient Selection
The ethics committee of our institution approved the study.
This investigation conforms to the principles outlined in the
Declaration of Helsinki. Signed informed written consent was
obtained from all subjects before their participation in the study.
In the present study, 18 patients were enrolled. All patients
had mild COPD with postbronchodilator FEV1/FVC ratio
ⱕ 70% and FEV1 ⱖ 80% of predicted normal value, or mild
persistent bronchial asthma with FEV1 ⱖ 80% of the predicted
normal value and ⱖ 15% reversibility 15 min after inhalation of a
single dose of salbutamol.16
All patients were ⬎ 18 years of age, with no history of
myocardial infarction, unstable angina, heart failure, or known
severe arrhythmias. The patients were clinically stable during the
4 weeks preceding the intervention, with no upper or lower
respiratory tract infections. Oral and inhaled corticosteroids and
oral bronchodilators were discontinued for at least 1 month prior
to the study. Inhaled short- and long-acting bronchodilator agents
were not permitted for at least 12 h and 24 h prior to the study,
respectively. Patients were asked to avoid smoking and drinks
containing any form of caffeine before the study.
Measured Variables
Effective Refractory Period Assessment: A 6F quadripolar
catheter (USCI; Norcross, GA) was inserted via the right femoral
vein and advanced to the right atrial appendage under fluoroscopic guidance for the atrial effective refractory period (AERP)
assessment. After stable placement, the AERP was assessed by
the incremental method at two basic cycle lengths (500 ms and
400 ms). Eight-beat stimulation trains at twice the diastolic
threshold were used, with a 2-s pause between them. A starting
coupling interval of 150 ms was selected for the extra stimulus
and was increased initially in 10-ms steps. When atrial capture
was noted, stimulation was repeated, starting from a coupling
interval 20 ms lower than that where atrial capture occurred and
increased in steps of 2 ms.
In order to evaluate the ventricular effective refractory period
(VERP), the same catheter (USCI) was advanced in the right
ventricular apex. The VERP was assessed by the incremental
method in steps of 2 ms at two basic cycle lengths (500 ms and
400 ms) as has been described above.
A 2-min interval was allowed between effective refractory
Figure 1. ECG lead V1 and His bundle electrogram (HBE)
recorded simultaneously from the same patient before (top, A)
and after (bottom, B) salbutamol inhalation are shown. Salbutamol decreased SCL (CL) from 813 to 662 ms and AH interval
from 74 to 60 ms. HV interval remained practically unchanged
(54 ms and 55 ms, respectively).
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Clinical Investigations
Study Design
All patients underwent the aforementioned stimulation protocol at the beginning of our study. Subsequently, salbutamol
solution (5 mg in a single dose) with an ECONOneb nebulizer
(Medix Limited; Lutterworth, UK) was administered. The nebulizer is driven by compressed air and is reported to produce a
mass median particle diameter of 3.5 ␮m with an average of 84%
particles ⬍ 5 ␮m. According to our protocol, all baseline electrophysiologic measurements were repeated 30 min after salbutamol inhalation when all potential changes were expected to be
maximal.11,19
ECG leads I, II, and V1, systolic and diastolic BPs, as well as
the RR interval were recorded in all patients. Venous blood was
obtained for measurement of baseline plasma potassium and
glucose concentrations.
Statistical Analysis
Data are presented as mean ⫾ SD. The statistical differences
of paired data were evaluated by paired t test or one-way,
repeated-measures analysis of variance followed by contrasts for
mean values comparison. A p value ⬍ 0.05 was considered
significant.
Results
Patients
The patient population included 11 men and 7
women between 44 years and 71 years of age (mean,
57 ⫾ 4 years). Six patients had bronchial asthma, and
the remaining 12 patients had mild COPD. Nine
patients also had arterial hypertension and were
receiving an angiotensin-converting enzyme inhibitor drug regimen. No patients were receiving administered ␤-blockers. All patients were evaluated with
lung function tests at the beginning of the study. All
subjects had normal left ventricular function as
assessed by two-dimensional echocardiography.
Table 1—Blood Test Results and Clinical and
Demographic Characteristics of the Patient
Population*
Variables
Data
Age, yr
Male/female gender
Pulmonary disease
COPD
Bronchial asthma
Cardiovascular disease
Hypertension
None
Pao2, mm Hg
Paco2, mm Hg
HCO3, mm Hg
pH
K⫹, mEq/L
Na⫹, mEq/L
Systolic BP, mm Hg
Diastolic BP, mm Hg
57 ⫾ 4
11/7
12
6
9
9
88.3 ⫾ 8.3
39.2 ⫾ 2.4
24.8 ⫾ 1.4
7.4 ⫾ 0.02
4.2 ⫾ 0.2
140.2 ⫾ 1.9
137.7 ⫾ 14.1
86.3 ⫾ 5.08
*Values are expressed as mean ⫾ SD or No.
mol resulted in shortening of the sinus cycle length
(SCL) and the SNRT. The SCL shortened from
817.7 ⫾ 147.4 ms at baseline to 665.5 ⫾ 131.2 ms
(p ⬍ 0.001), and the SNRT decreased (Fig 2) from
1,073.5 ⫾ 178.7 to 925.2 ⫾ 204.9 ms (p ⫽ 0.001).
In addition, salbutamol enhanced AV nodal conduction and decreased AV nodal refractoriness. The
WCL was used as an indirect reflection of AV nodal
refractoriness because our ability to determine the
actual AV nodal ERP was limited by atrial tissue
refractoriness. In response to inhaled salbutamol, the
AH interval decreased from 86.1 ⫾ 19.5 ms at baseline to 78.8 ⫾ 18.4 ms (p ⬍ 0.001), and the WCL
decreased from 354.4 ⫾ 44.2 to 336.6 ⫾ 41.7 ms
(p ⫽ 0.001). According to our results, salbutamol
Physiologic Parameters
Serum electrolytes, glucose concentration, and
arterial blood gases were measured throughout the
study. In all patients, blood pH values, Pao2, Paco2,
K⫹, Na⫹, and glucose levels were within normal
range (Table 1). There were no significant changes in
these parameters after the administration of salbutamol. Furthermore, no significant changes in systolic
and diastolic arterial BPs (Table 1) were detected.
Heart rate increased in response to salbutamol from
75.5 ⫾ 12.8 beats/min at baseline to 93.1 ⫾ 16 beats/
min (p ⬍ 0.001).
Electrophysiologic Data
Salbutamol inhalation produced significant changes
in the cardiac electrophysiologic properties (Table 2;
Fig 1, 2). On the part of sinus node function, salbuta-
Table 2—Electrophysiologic Effects of Salbutamol*
Variables
Baseline
Salbutamol
p Value
SCL, ms
SNRT500, ms
CSNRT500, ms
WCL, ms
AH, ms
HV, ms
AERP500, ms
AERP400, ms
VERP500, ms
VERP400, ms
817.7 ⫾ 147.4
1073.5 ⫾ 178.7
253.4 ⫾ 156.2
354.4 ⫾ 44.2
86.1 ⫾ 19.5
47.1 ⫾ 8.2
220.6 ⫾ 26.4
215.5 ⫾ 22.1
230.8 ⫾ 18.6
220.4 ⫾ 15.2
665.5 ⫾ 131.2
925.2 ⫾ 204.9
253 ⫾ 96.5
336.6 ⫾ 41.7
78.8 ⫾ 18.4
46.2 ⫾ 8.1
204.2 ⫾ 22.6
200.2 ⫾ 24.4
221.7 ⫾ 16.9
209.7 ⫾ 13.7
⬍ 0.001
0.001
NS
0.001
⬍ 0.001
NS
⬍ 0.001
⬍ 0.001
⬍ 0.001
⬍ 0.001
*Values are expressed as mean ⫾ SD. SNRT500 ⫽ SNRT at a drive
cycle length of 500 ms; CSNRT500 ⫽ corrected SNRT at a drive
cycle length of 500 ms; AERP500 ⫽ AERP determined at 500 ms;
AERP400 ⫽ AERP determined at 400 ms; VERP500 ⫽ VERP determined at 500 ms; VERP400 ⫽ AERP determined at 400 ms;
NS ⫽ not significant.
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CHEST / 127 / 6 / JUNE, 2005
2059
Figure 2. Effects of salbutamol on SNRT at the drive cycle length of 500 ms in the patient population.
Values were obtained just before (䡺) and 30 min after (f) salbutamol inhalation.
had greater effects on sinus node parameters than
AV node parameters. We observed a decrease of
18.6% in SCL and of 13.8% in SNRT vs a decrease
in AH of 8.3% and in WCL of 5.01%.
Finally, salbutamol significantly decreased myocardial tissue refractoriness. The AERP (at a drive
cycle length of 500 ms) decreased from 220.6 ⫾ 26.4
to 204.2 ⫾ 22.6 ms. A similar reduction was observed when the AERP was determined at a drive
cycle length of 400 ms (Table 2). Although the VERP
(both at 500 ms and at 400 ms) decreased too (Table
2), the effects of salbutamol on VERP were less
pronounced than those on AERP. In particular,
AERP decreased by approximately 7% while VERP
decreased by approximately 4%. No effect on HisPurkinje conduction was found.
Discussion
Despite the widespread use of ␤2-agonists, their
safety has been questioned. Several studies9 –15 have
reported an increased incidence of cardiac arrhythmias in patients treated with these agents, and other
studies13–15 found an increased cardiovascular death
with the use of oral and nebulized ␤2-agonists.9 –15
Although no causal relationship has been demon-
strated, the possible arrhythmogenic effects of these
drugs place them under considerable suspicion.
Clarifying the effects of ␤2-agonists on myocardial
conduction and refractoriness could provide a significant insight into the potential arrhythmogenic role
of these agents. This study is the first to evaluate the
cardiac electrophysiologic effects of a single, regular
dose of an inhaled ␤2-agonist in humans. Salbutamol
was selected, as it is one of the most widely used
inhaled ␤2-agonists and would ensure improved correlation with standard clinical practice. The main
finding of this study is that the inhalation of a
standard dose of the ␤2-agonist salbutamol results in
significant changes of cardiac electrophysiologic
properties.
We found that inhalation of a single regular dose
of salbutamol significantly enhanced AV nodal conduction, as reflected by shortening of the AH interval and decreased atrial and ventricular refractoriness without any remarkable effect on His-Purkinje
conduction. The refractoriness of the AV node was
also decreased, as indicated by shortening of the
atrial pacing cycle length that resulted in AV node
Wenckebach block. In addition, inhaled salbutamol
produced a significant increase in heart rate and
shortened the SNRT.
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Clinical Investigations
However, our findings cannot be interpreted on
the basis of changes in heart rate. Since all refractory
periods were determined at the same drive cycle
length (both 500 ms and 400 ms), the observed
changes in refractory periods are independent of the
underlying heart rate and indicate the effects of
salbutamol on myocardial conduction and refractoriness. Moreover, we found a shortening of the AH
interval after the inhalation of salbutamol, which
seems to be due to the effect of the drug, as the AH
interval normally decreases with a sympathetic
driven heart rate increase.
The above electrophysiologic effects of salbutamol
are in accordance with the known cellular effects of
the ␤-adrenergic stimulation (shortening of the action potential duration in the nodes and in atrial and
ventricular muscle, increase in upstroke velocity of
the action potential in the AV node, and no effect on
the upstroke velocity of the action potential in the
His-Purkinje system or ventricular myocardium).20
Therefore, our findings could be explained by a
direct activation of ␤2-adrenergic receptors.
It has indeed been increasingly recognized that
␤1- and ␤2-adrenergic receptors coexist in the human heart.5– 8,21–23 ␤2-adrenergic receptors constitute 20 to 30% and 30 to 40% of the total number of
␤-adrenergic receptors in human ventricles and
atria, respectively.8 In addition, salbutamol, a selective ␤2-agonist, would not be expected to stimulate
␤1-adrenergic receptors under the conditions applied. Furthermore, salbutamol in our study produced a greater proportional decrease in atrial tissue
refractoriness compared with the ventricular tissue
refractoriness. These differential effects on atrial and
ventricular refractoriness could be explained by the
different density of ␤2-adrenergic receptors in atrial
and ventricular myocardium,8 suggesting that the
effects of salbutamol were mediated by direct activation of these receptors.
The activation of prejunctional ␤2-adrenoceptors
leading to an enhanced noradrenaline release and
indirect stimulation of ␤1-adrenergic receptors is
also unlikely. The intracoronary infusion of salbutamol caused significant changes on temporal dispersion of cardiac repolarization, and no blunting of
these effects in patients receiving the ␤1-selective
adrenergic receptor antagonist, atenolol, was noted
in one study.24 In another study,25 intracoronary
injection of salbutamol caused increases in heart rate
that were not affected by the ␤1-adrenoceptor antagonist practolol but were blocked by the nonselective ␤-adrenoceptor antagonist propranolol.
Reflex release of catecholamines secondary to
␤2-adrenergic receptor-mediated peripheral vasodilatation is not likely to influence our findings, as no
measurable changes to systolic or to diastolic BP
were observed. Moreover, in heart transplant recipients after pretreatment with the ␤1-adrenoceptor
antagonist bisoprolol, isoprenaline is found to increase heart rate under conditions where it acts
solely via ␤2-adrenergic receptors, an effect that
cannot be due to any reflex mechanisms since the
transplanted human heart is a denervated organ.26
The results of our study demonstrate that salbutamol, a selective ␤2-agonist, administered by nebulizer has significant electrophysiologic effects on the
atrium, nodes, and ventricle. The dosages administered reflected the regular recommended clinical
dose, emphasizing that our findings are of particular
importance since there is significant correlation with
the everyday clinical practice. Larger doses of salbutamol, such as those used in asthmatic exacerbations,
could have led to even more pronounced changes in
myocardial conduction and refractoriness.
Comparison With Other Studies
Existing data on the effects of ␤2-agonists, especially those administered in an inhaled form, on
myocardial electrophysiologic properties are rare. In
a previous experimental study,27 inhaled metaproterenol, a ␤2-agonist, resulted in significant enhancement of AV node conduction and a decrease of
cardiac tissue refractoriness in dogs. In a more
recent human study,28 salbutamol produced similar
effects but was administered IV. In general, our
findings are in agreement with the results of the
above-mentioned studies.
There are, however, some significant differences.
First, our study is the first to evaluate the effects of
an inhaled, selective ␤2-agonist on AV node conduction and myocardial tissue refractoriness in humans.
Secondly, the administration mode of salbutamol
correlates well with everyday clinical conditions. In
addition, unlike the study by Insulander et al,28 we
found no measurable changes in systolic or diastolic
BP after the administration of salbutamol, suggesting
that no reflex mechanism influenced our findings.
This could be explained by the fact that inhaled
salbutamol has significantly fewer systemic effects
than salbutamol one.19 Especially, in our study the
proportional decrease of atrial refractory period after
salbutamol inhalation was greater than the ventricular refractory period decrease, which is consistent
with the different density of ␤2-adrenergic receptors
in atrial and ventricular myocardium.8 Finally, salbutamol in our study produced more evident changes
on the sinus node electrophysiologic properties compared with AV node. This finding is in contrast with
the results of Insulander et al,28 but confers with the
recently published study by Rodefeld et al,29 which
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CHEST / 127 / 6 / JUNE, 2005
2061
shows that ␤2-adrenoceptor density is about 2.5-fold
higher in the human sinoatrial node than in the right
atrial myocardium.
Clinical Implications
The cardiac effects of ␤2-agonists include tachycardia, atrial and ventricular ectopic complexes, as
well as atrial and ventricular arrhythmias.9 –13 Our
study allows us to speculate that the shortening of
the cardiac tissue refractoriness may facilitate the
induction of such arrhythmias and could explain the
increased incidence of arrhythmias in certain patients receiving ␤2-agonists. It is well known that the
decrease in tissue refractoriness predisposes reentrant and triggered arrhythmias. This could be particularly important in certain clinical conditions, such
as heart failure. The down-regulation of the ␤1receptors in chronic heart failure results in relative
up-regulation of the cardiac ␤2-receptors.30,31 As a
consequence, ␤2-agonists may produce significantly
greater cardiac electrophysiologic changes in patients with compromised cardiac function, predisposing to atrial and ventricular arrhythmias. There is
evidence that salbutamol increases the episodes of
ventricular tachycardia in patients with heart failure32 and that ␤2-receptor antagonists protect
against ventricular fibrillation in animals shown to be
susceptible to malignant arrhythmias.4 Furthermore,
the decreases of AV node conduction time and
refractoriness produced by salbutamol could result
in an increase of the ventricular response during
certain supraventricular arrhythmias such as atrial
flutter and fibrillation.
Study Limitations
The design of our study does not allow as to
evaluate the role of the ␤- adrenergic system in
mediating the electrophysiologic effects of salbutamol. Moreover, there are no selective ␤2-receptor
antagonists available for use in vivo that would
permit us to estimate the selectivity of the action of
salbutamol. In any case, salbutamol is a selective
␤2-agonist; as noted previously, our findings seem to
be independent of any reflex mechanism.
The results of our study refer to the acute effects
of inhaled salbutamol. Although our study assessed
the short-term effects, as opposed to the long-term
effects, the existing evidence of down-regulation of
extrapulmonary ␤2-receptors (including cardiac receptors) after prolonged administration of ␤2-agonists33 suggests that the effects are likely to be more
marked in patients who are not receiving these
agents continuously.
Conclusion
We have demonstrated that inhaled salbutamol
results in significant changes in cardiac electrophysiologic properties. These effects seem to be due to
␤2-adrenergic stimulation and could explain the increased incidence of arrhythmias in some patients
treated with these agents, especially in certain clinical conditions, such as heart failure. Care must be
taken before extrapolating our findings to all human
subjects, and further studies are required to clarify to
what extent the electrophysiologic effects of salbutamol contribute to the generation of spontaneous
arrhythmias.
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