(Chest. 2003;124:813-818.)
© 2003
American College of Chest Physicians
Cardiac Arrhythmia Monitoring During Bronchial Provocation Test With Methacholine*
Mario Malerba, MD;
Alessandro Radaeli, MD;
Antonio Politi, MD;
Luigi Ceriani, MD;
Roberto Zulli, MD and
Vittorio Grassi, MD
* From the Department of Internal Medicine, University of Brescia, Brescia, Italy.
Correspondence to: Mario Malerba, MD, Dipartimento di Medicina Interna, Università di Brescia, 1° Divisione di Medicina, Spedali Civili, p.le Spedali Civili, 25100 Brescia, Italy; e-mail: malerba{at}master.cci.unibs.it
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Abstract
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Study objectives: During a bronchial provocation test (BPT), the performance of maximal inspiratory-expiratory maneuvers, causing abrupt and marked shifts in intrathoracic pressure, may increase the risk of cardiac arrhythmias. Moreover, the inhalation of methacholine (MCh), a cholinergic agonist agent, could favor the development of unwelcome cardiovascular events, namely, cardiac arrhythmias.
Subjects and methods: We studied the number and severity of cardiac arrhythmias by ECG-Holter monitoring before, during, and after BPTs with MCh challenge in a group of 46 consecutive nonselected subjects (28 men and 18 women) with clinical indications for BPT, without preexisting cardiovascular diseases, and not receiving arrhythmogenic drugs. The subjects performed a routine pulmonary function test (PFT), followed by BPT, during ECG-Holter monitoring. Determination of the serum potassium concentration, a baseline arterial blood gas analysis, and monitoring of oxyhemoglobin saturation also were performed.
Results: We found no significant increase in the number of supraventricular and ventricular arrhythmias during the performance of PFTs and of BPTs with MCh in the subjects, either with or without bronchial hyperresponsiveness (BHR). However, during the performance of BPTs, we observed a significant reduction in mean heart rate.
Conclusions: Our results indicate that the performance of PFTs and BPTs with MCh does not increase the cardiac arrhythmogenic risk in subjects without cardiovascular diseases, as well as in those with BHR, suggesting that these tests are safe to perform in most subjects.
Key Words: arrhythmias • bronchial hyperresponsiveness • bronchial provocation test • methacholine • pulmonary function tests
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Introduction
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Bronchial provocation tests (BPTs) are useful to assess bronchial hyperresponsiveness (BHR), the hallmark of asthma. Methacholine (MCh) is the inhaled bronchoconstrictor agent that is most used for BPT (MCh challenge).1
2
3
Breathing normally exerts an influence on cardiac rhythm by changes in vagal tone and shifts in intrathoracic pressure (ie, respiratory sinus arrhythmia).4
5
6
7
8
9
Adequate expiratory FVC maneuvers require vigorous respiratory efforts that cause rapid changes in intrathoracic pressure, enhanced vagal tone, and changes in oxygen saturation and hyperventilation,10
and that could heighten myocardial arrhythmogenicity.8
9
11
12
13
14
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Data from the literature regarding the frequency of cardiac arrhythmias during pulmonary function tests (PFTs) are contradictory. Montenegro et al11
and Kamaroulias16
assessed a significant increase in arrhythmias during PFTs, whereas Fields et al17
found a reduction in cardiac ectopy during expiratory FVC maneuvers. During BPTs, which are usually performed by measuring sequential change in FEV1, a great number of FVC maneuvers are performed, producing high cardiopulmonary stress that is enhanced by MCh challenge. MCh is an analog of acetylcholine with a long-term effect that produces parasympathomimetic effects such as vasodilatation, negative chronotropism, and inotropism when absorbed by the systemic route. Several studies18
19
20
21
22
on animals have shown MCh to have arrhythmogenic and coronary vasospastic effects. There are no reports in the literature concerning the risk of cardiac arrhythmias during BPTs with MCh challenge. Therefore, the purpose of this study was to assess the number and severity of cardiac arrhythmias as well as any abnormal change in cardiac activity by ECG-Holter monitoring before, during, and after BPTs with MCh in subjects with clinical indications for BPTs and without preexisting cardiovascular diseases.
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Patients and Methods
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Patients
We have enrolled a group of 46 consecutive subjects (28 men and 18 women; mean [± SD] age, 39.7 ± 18.8 years) who were referred to our Pulmonary Function Laboratory in the Department of Internal Medicine (Brescia, Italy) to perform a BPT with MCh in order to assess BHR. Exclusion criteria included conditions that could enhance myocardial arrhythmogenicity, as follows: cardiac diseases; hyperthyroidism; chronic hypoxemic diseases; and the use of medications known to be potentially arrhythmogenic. Moreover, the following conditions were considered contraindications for BPTs: moderate and severe airflow obstruction (ie, FEV1 < 60% predicted or < 1.5 L); recent (ie, < 3 months) myocardial infarction or stroke; recent respiratory tract infections (ie, < 2 weeks); uncontrolled hypertension; pregnancy; epilepsy; and aortic aneurysm. Subjects gave their written informed consent to participate in the study, which was conducted in accordance with the Helsinki Declaration.
ECG-Holter Monitoring
All subjects underwent a baseline 12-lead ECG. A continuous ECG according to the Holter method was recorded before, during PFTs and BPTs, and after BPTs. Continuous ECG recording was performed with the use of two positive electrodes (leads V5 and II) and a cassette recorder (model 445-B; Del Mar Avionics; Irvine, CA). ECG recording time was divided into the following four study periods: rest period was defined as the 30-min period prior to performing the baseline PFT; the baseline PFT period was defined as the 30-min period during which the PFT was performed; the BPT period was defined as the 30-min period during which the BPT was performed; and the post-BPT period was designated as the 30-min interval after the completion of the BPT. The ECG recordings were analyzed (Trendsetter 775; Del Mar Avionics) for the following parameters: heart rate; supraventricular ectopic beats (SVEBs); ventricular ectopic beats (VEBs); and ventricular repolarization abnormalities (ie, ST-segment depression or elevation, and T-wave inversion). Myocardial ischemia was assessed in presence of ST-segment depression or elevation (defined as a 
1-mm ST-segment deviation occurring 80 ms after the J point, and lasting for 60 s), and/or in the appearance of T-wave inversion. Atrial tachycardia, atrial flutter, atrial fibrillation, junctional tachycardia, multiform VEBs, paired VEBs, ventricular tachycardia, and ventricular fibrillation for the purposes of analysis were arbitrarily grouped as complex arrhythmias.
PFTs
Dynamic lung volumes were measured using a pneumotachograph (1070 MGC; Spirometer CAD/Net System; St. Paul, MN) in accordance with American Thoracic Society (ATS) standard procedure.23
The flow-volume loop was also obtained by performing a maximal inspiration to total lung capacity (TLC), followed by a rapid, forceful expiration to residual volume, then the loop was completed by an inspiration back to TLC. Predicted values were used in accordance with the European Community for Coal and Steel.24
BHR
A BPT with MCh challenge was performed in accordance with ATS guidelines.25
MCh was freshly dissolved in distilled water to obtain solutions of a given concentration, which were inhaled using a dosimeter (Mefar; Bovezzo, Italy) that was set to deliver 10 µL per breath of each solution. In this way, we were able to administer an exact amount of MCh at each step of the challenge procedure. A doubling-dose protocol was used starting from an initial dose of 20 µg. The subject, wearing a nose clip, consumed each dose by slowly inhaling from end-tidal lung volume to TLC through a mouthpiece, which was connected to the dosimeter. Each dose was given at 3-min intervals, and after 90 s FEV1 was measured. The inhalation of the diluent was performed first, and the best postdiluent FEV1 value was used as the baseline value for analysis. The challenge was stopped when the inhaled dose of MCh caused a > 20% FEV1 fall from the post-saline solution FEV1 value. The exact cumulative dose corresponding to a 20% fall in FEV1 was calculated for all subjects with a positive challenge test using linear interpolation between log doses from the cumulative dose-response curve. Hyperresponsiveness was defined as the occurrence of a cumulative dose of inhaled MCh corresponding to a 20% fall in FEV1 of < 1,600 µg.
After BPTs, the subjects with a fall in FEV1 of at least 10% from baseline received albuterol, 200 µg.25
We performed spirometry after the bronchodilator test at the end of the post-BPT period to document the recovery of the FEV1 baseline value.
Serum Potassium and Arterial Blood Gas Monitoring
Biochemical data obtained on the day of testing included the following: serum potassium concentration at rest and after BPT period to verify electrolytic alterations; baseline arterial blood gas analysis to exclude hypoxemia; and monitoring of oxyhemoglobin saturation by ear oximeter probe (Biox 3700 Pulse Oxymeter; Ohmeda; Helsinki, Finland) during rest, the baseline PFT period, the BPT period, and the post-BPT period.
Statistical Analysis
All data are expressed as the frequency or mean and SD or 95% confidence intervals (CIs). Data analysis was performed by analysis of variance with repeated measures. 
2 analysis, Fisher exact test, and Friedman test were used to analyze nonparametric variables. The power of the study to a detect heart rate difference of 3 beats/min was 80%. A p value of < 0.05 was considered to be statistically significant.
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Results
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The demographic, biochemical, and respiratory characteristics of the 46 subjects studied are listed in Table 1
. Among the subjects performing BPTs with MCh, 30 were hyperreactive (65.2%). Since at the end of the MCh challenge all nonhyperreactive subjects showed a fall in FEV1 between 10% and 15% from baseline, they were given, as hyperreactive subjects, albuterol, 200 µg, after undergoing the BPT.
We found no abnormalities in baseline arterial blood gas levels and serum potassium concentrations. The potassium concentration, which was rechecked after the test, did not differ from basal values. In all subjects oxyhemoglobin saturation was always > 97% before, during, and after the test (Table 1)
.
Holter monitoring observed isolated SVEBs in five subjects at rest, in two subjects during the baseline PFT period, in two subjects during the BPT, and in three subjects in the post-BPT period. Higher frequencies of SVEBs (ie, > 30 SVEBs per hour) were not observed. Among subjects with isolated VEBs four had them at rest, six had them during the baseline PFT period, two had them during the BPT, and seven had them during the post-BPT period. Higher frequencies of VEBs (ie, > 30 VEBs per hour) were not observed. The mean values of SVEBs and VEBs registered during the four study periods are reported in Table 2
. The statistical analysis that was performed did not show any difference in the incidence of SVEBs and VEBs during the four study periods, and the same results were observed by comparing hyperreactive and nonhyperreactive subjects. However, we noticed that SVEBs and VEBs were not enhanced after the MCh inhalation challenge. We did not observe any change in ST segments and T waves during the four study periods.
The mean heart rate of subjects studied in the four study periods is reported in Figure 1
. The mean (± 95% CI) heart rate that was registered at rest was 79.5 ± 4.1 beats/min, during baseline PFT period it was 81.8 ± 4.5 beats/min, during the BPT period it was 77.2 ± 4.0 beats/min, and during the post-BPT period it was 77.7 ± 3.8 beats/min. Although these changes were always within the normal heart rate range, statistical analysis demonstrated that the mean heart rate during the baseline PFT period (p < 0.01) was significantly higher than the one observed at rest. Moreover, during the BPT period a significant decrease (p < 0.01) in mean heart rate was registered compared to the one observed at rest conditions and during the baseline PFT period (Fig 1)
. The same results were observed considering hyperreactive and nonhyperreactive subjects separately.
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Figure 1. Mean heart rate in the four study periods. Values are given as the mean ± 95% CI. * = p < 0.01 (vs rest period, BPT period, and post-BPT period); ** = p < 0.001 (vs rest period and baseline PFT period).
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In brief, we observed that the number of atrial and ventricular ectopies occurring during the test periods was the same as that observed at rest and during the poststudy periods. We found a significant increase in heart rate during the execution of the baseline PFT, whereas we observed a significant reduction in mean heart rate (within normal values) during the BPT with MCh challenge.
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Discussion
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It is well-known that breathing normally has an influence on cardiac rhythm by means of changes in vagal tone and intrathoracic pressure. The performance of adequate FVC maneuvers requires vigorous inspiratory-expiratory efforts. The relationship between the development of cardiac arrhythmias and the performance of spirometry seldom has been investigated.11
16
17
It is noteworthy that the BPT requires a great number of vigorous sequential FVC maneuvers and that the inhalation of doubling doses of MCh, inducing cough and bronchoconstriction, may affect myocardial oxygenation and vagal tone with arrhythmogenic and coronary vasospastic effects. Because there are no specific reports in the literature, we investigated the incidence and severity of arrhythmias during BPTs with MCh. Although this test is widely used, it is unclear whether silent and important cardiac events may occur during the performance of the test as supposed on the basis of pathophysiologic factors. Current guidelines are not exhaustive on this topic, likely because of the lack of studies.25
Subjects with cardiopulmonary diseases were not included in the population studied to avoid confounding factors since myocardial arrhythmogenity could be enhanced in these diseases. Moreover, according to ATS guidelines, moderate and severe airway obstruction and cardiovascular problems are contraindications for performing a BPT. Therefore, the cohort studied is probably representative of the population that more frequently undergoes BPT. Holter monitoring showed that the frequency of cardiac ectopy was not increased during the performance of the baseline PFT and the BPT. The number of subjects with SVEBs and VEBs occurring during the baseline PFT period and the BPT period were not different than those found during the rest period and the post-BPT period. The mean number of SVEBs and VEBs observed during the four study periods remains relatively unchanged. Complex arrhythmias or ventricular repolarization abnormalities were not observed in any of the study periods.
The present study excludes the conclusion that routine PFTs, and in particular BPTs, are significant risk factors for supraventricular and ventricular arrhythmias. Therefore, our data, confirming the results of Fields et al17
about baseline PFTs, show no further arrhythmogenic risk during a BPT with MCh.
Heart rate analysis found that mean heart rate was higher during the baseline PFT than at rest (p < 0.01), whereas a significant decrease (p < 0.01) in mean heart rate during the BPT compared to at rest and during the baseline PFT was observed. These findings might suggest the presence of a tachycardia-inducing effect during the PFT and a bradycardia-inducing effect during BPT that is produced by a MCh systemic effect.13
14
15
16
17
To clarify the influence of MCh on heart activity, we analyzed the relationship between the inhaled dose of MCh and heart rate, hypothesizing that the subjects who received higher doses of MCh would show greater reductions in heart rate. However, no significant negative effect on heart rate was observed with progressively increasing doses of MCh, suggesting that the MCh-related reduction in heart rate is not dose-dependent.
In conclusion, our results show that either routine PFT or BPT with MCh does not entail an increased cardiac arrhythmogenic risk in subjects without preexisting cardiovascular diseases, as well as in those with BHR, suggesting that these procedures are safe to perform in the vast majority of subjects.
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Footnotes
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Abbreviations: ATS = American Thoracic Society; BHR = bronchial hyperresponsiveness; BPT = bronchial provocation test; CI = confidence interval; MCh = methacholine; PFT = pulmonary function test; SVEB = supraventricular ectopic beat; TLC = total lung capacity; VEB = ventricular ectopic beat
Received for publication September 16, 2002.
Accepted for publication February 26, 2003.
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References
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Abstract
Introduction
