© 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.
SYNCOPE
Paradoxical effect of isoprenaline infusion
Cardiology, CHU Brabois Rue du Morvan 54511, 54500 Vandoeuvre-les-Nancy, France
Manuscript submitted 9 October 2003. Accepted after revision 30 June 2005.
*Corresponding author. Tel.: +33 383153142; fax: +33 383154226. E-mail address: b.brembilla-perrot{at}chu-nancy.fr
Abstract
BACKGROUND: Isoprenaline (isoproterenol) is a beta-adrenergic drug, used to increase the heart rate and, during electrophysiological study, to facilitate the induction of supraventricular (SVT) and ventricular tachycardias (VT). Decrease in heart rate during isoprenaline infusion is a rare phenomenon. The purpose of the study was to evaluate the incidence, the possible mechanisms, and the significance of a paradoxical bradycardia induced by isoprenaline infusion.
METHODS: Electrophysiological study was performed for the evaluation of tachycardias (n = 551) or dizziness/syncope (n = 214) in 765 patients aged from 15 to 85 years. The study was negative in the basal state, and was repeated after isoprenaline infusion (2–4 µg/min).
RESULTS: In 714 patients, this perfusion increased the heart rate to 100–140 bpm. A bradycardia was noted in 51 patients (7%). Two bradyarrhythmias were noted: (1) sinus or junctional bradycardia (cycle length – 10%) occurred in 43 patients, aged 15–70 years, generally studied for unexplained syncope (n = 37); a young age (40 ± 16 years), syncope (n = 37) and absence of heart disease (n = 27) were more frequent than that in patients without isoprenaline-induced sinus or junctional bradycardia; another arrhythmia (SVT or VT) was induced in seven patients with syncope, five with heart disease and two without; six young patients (<50 years) had no syncope and were studied for SVT or VT; (2) eight patients, aged 65 ± 11 years, developed second-degree atrioventricular (AV) block which was supraHisian (n = 4) or infraHisian (n = 4); they were studied for exercise-related syncope; they had no signs of myocardial ischaemia and AV block was reproduced by ajmaline testing: isoprenaline revealed organic conduction disturbance.
CONCLUSION: The occurrence of paradoxical bradycardia was a rare finding during isoprenaline infusion (7%); sinus or junctional bradycardia was a sign of hypervagotonia, but was without clinical significance in 35% of these patients. The development of second-degree AV block was always pathological and associated with AV conduction disturbances, which occurred spontaneously during exercise. Isoprenaline infusion appeared to be a simple means to detect organic AV conduction disturbance in patients complaining of exercise or stress-related dizziness/syncope and unable to perform exercise test.
Key Words: isoproterenol, isoprenaline, bradycardia
Isoprenaline (isoproterenol) is a beta-adrenergic drug, which is used to increase the heart rate[1]
and, during electrophysiological study, to facilitate the induction of supraventricular and ventricular tachycardias[2–6]. Isoprenaline is known to accelerate the sinus node and to enhance AV nodal conduction; the drug has no effect on His-Purkinje conduction time[7]. Paradoxical bradycardia is an unusual phenomenon.
The purpose of the study was to evaluate the incidence, the possible significance of paradoxical bradycardia induced by isoprenaline infusion and to look for its clinical application.
Population
The study population is issued from a consecutive group of 765 patients in whom isoprenaline infusion was used during electrophysiological study. These studies were performed between the years 1985 and 2000. The patients were aged from 15 to 85 years (mean 62 ± 5).
Three hundred and sixty-three patients had underlying heart disease, idiopathic dilated cardiomyopathy (133), previous myocardial infarction (101), right ventricular dysplasia (58), hypertrophic cardiomyopathy (29), valvular heart disease (29) and various heart diseases (13).
Electrophysiological study was performed for the evaluation of tachycardias (n = 364), to detect a risk of sudden death (n = 187) or to elucidate the cause of unexplained dizziness or syncope (n = 214).
Isoprenaline infusion was used in the case of negativity of a classical electrophysiological study in the control state, when symptoms occurred during or after stress or exercise or when heart disease classically associated with a risk of arrhythmias in adrenergic situation was noted.
In 51 patients, a paradoxical bradycardia occurred during isoprenaline infusion and was reproducibly induced by isoprenaline.
These 51 consecutive patients represent the study population. Clinical data of this study group and those of the entire population are reported in Table 1.
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Methods
Personal and family clinical history, list of drugs taken at the time of syncope or tachycardias and clinical examination were initially noted.
The following non-invasive studies were performed: surface ECG, 24 h Holter monitoring (Elatec, Ela Medical, France) and transthoracic 2D echocardiogram were recorded; in patients with ischaemic heart disease, thallium exercise scintigraphy was performed.
In patients with unexplained syncope, head-up tilt test without provocative drugs was performed since 1994. Isoprenaline infusion was not used for this test.
A complete electrophysiological study was performed and the protocol was previously reported[8]. The patients were in a fasting non-sedated state and informed and written consent was obtained. All antiarrhythmic drugs, digoxin, beta blockers and all drugs having an effect on cardiac electrophysiological properties were stopped for at least five half-lives.
The electrophysiological protocol included assessment of sinoatrial conduction time, sinus node recovery time, atrioventricular node conduction using measurement of AH, HV intervals and intraatrial conduction time, and atrial pacing at progressively faster rates until atrioventricular block occurred.
Programmed atrial stimulation was systematically performed during sinus rhythm and atrial pacing at two cycle lengths, 600 and 400 ms, using one and then two extrastimuli. Right ventricular pacing was performed at an incremental rate up to 200 bpm. Right ventricular premature stimulation using a single premature ventricular extrastimulus (S2) and double ventricular extrastimuli (S2 and S3) was introduced during sinus rhythm and during paced cycle lengths (600 and 400 ms), at the right ventricular apex initially and subsequently at the right ventricular outflow tract. Then, a third extrastimulus was added and programmed stimulation was repeated in both sites of the right ventricle.
Carotid sinus massage was performed except in patients with known carotid atherosclerosis. The study remained negative in the basal state in these patients.
Also, the study was repeated after isoprenaline infusion: a dose of 2–4 µg/min was infused to decrease the sinus cycle length by at least 15% and the infusion was continued until the completion of atrial and ventricular stimulation for 15–25 min.
In the case of isoprenaline-induced bradycardia, the infusion was stopped until recovery of basal cycle length; a second infusion of isoprenaline was attempted.
Arterial blood pressure was continuously monitored by an external sphygmomanometer (Baxter, Japan).
Definitions
Abnormal electrophysiological findings at the end of the study were categorized as sinus node dysfunction, inducible supraventricular tachyarrhythmias (SVT), AV node dysfunction, inducible ventricular tachyarrhythmia (VT) or hypervagotonia. The criteria are detailed in a recent study[9]. Hypervagotonia was diagnosed when asystole with an RR interval of >3000 ms was provoked by right or left carotid sinus massage.
Statistical analysis of the data was expressed as mean ± standard deviation. Statistical analysis was performed with the Student's t paired test for quantitative data, with the chi square test for discrete variables and ordinal tests. A P value < 0.05 was considered as significant.
Results
Incidence of isoprenaline-induced bradycardia (Table 1)
In most of the patients (n = 714), the isoprenaline perfusion increased the heart rate to 100–140 bpm and this rate was maintained during completion of the electrophysiological study.
In 51 patients (7%), a paradoxical bradycardia was noted during isoprenaline infusion. The bradycardia was related to sinus or junctional bradycardia (generally <65/min or basal cycle length – 15%) in 43 patients and to second-degree AV block in eight other patients. These 51 consecutive patients represent the study population.
Analysis of the bradycardia
1 – Sinus or junctional bradycardia developed in 43 patients, 14 women, 29 men, aged 15–70 years (mean 40 ± 16), after a short period of 5 s to 3 min of increasing heart rate (Fig. 1):
- In 11 patients, the bradycardia was not considered as specific, because another arrhythmia was induced: one patient with syncope and idiopathic dilated cardiomyopathy also had inducible sustained ventricular tachycardia during isoprenaline infusion; in four patients with syncope and without heart disease, the following arrhythmias were also induced: polymorphic ventricular tachycardia, paroxysmal junctional tachycardia, atrial tachycardia and monomorphic ventricular tachycardia were considered as the possible cause of syncope; six young patients (<50 years) had no dizziness or syncope and were studied for ventricular or supraventricular tachycardia.
- In two patients, isoprenaline-induced bradycardia was responsible for the spontaneous occurrence of atrial fibrillation (Fig. 2); these patients had syncope and one of them had hypertrophic cardiomyopathy. The mechanism of atrial fibrillation was considered as a vagal-induced arrhythmia.
- In remaining 30 patients, bradycardia was considered as a sign of hypervagotonia: the patients were studied for syncope; heart disease was present in eight patients (hypertrophic cardiomyopathy four, sequelae of myocardial infarction three and idiopathic dilated cardiomyopathy one), but they had no other cause of syncope; 22 patients had no heart disease. Head-up tilt test was positive in 15 of them and carotid sinus massage was positive in five other patients. Electrophysiological study was performed either to exclude ventricular tachycardia in patients with heart disease or because the patients had repeated syncope and had a job with a risk of accident (e.g. bus driver or roofer). In the remaining 10 patients, tilt test or carotid sinus massage was negative.
- The isoprenaline infusion-induced bradycardia was reproducible: in each patient, isoprenaline infusion was stopped; when sinus rate and arterial blood pressure had recovered, isoprenaline infusion was reinitiated; similar effects on sinus rate were noted.
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2 – Atrioventricular (AV) block occurred in eight patients, two women and six men, aged from 39 to 75 years (mean 65 ± 11) and explained the bradycardia; these patients were significantly older (P < 0.05) than the patients who developed sinus or junctional bradycardia. Spontaneous second-degree supraHisian AV block developed in four patients; infraHisian AV block developed either spontaneously in two patients or occurred during atrial pacing at a rate <160 bpm in two patients (Fig. 3). All patients were studied for exercise or stress-related syncope. They had normal AV conduction in the basal state. Heart disease was present in two patients, one with ischaemic heart disease and one with idiopathic dilated cardiomyopathy. Another patient, aged 70 years, had syncope and Wolff–Parkinson–White syndrome; the preexcitation was related to an accessory pathway with a long refractory period and was without clinical significance; syncope was due to infraHisian AV conduction disturbances. After ajmaline injection, preexcitation disappeared and complete infraHisian third-degree AV block developed. Second-degree AV block was reproduced during exercise and at maximum exercise in three patients who were capable of performing the test.
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Similar second or third-degree AV block, was reproduced by 1 mg/kg ajmaline infusion, in six patients without heart disease.
Analysis of the predictive factors for the isoprenaline-related sinus or junctional bradycardia
Table 1 indicated that a young age, the presence of syncope and the absence of heart disease were significant predictors of bradycardia development during isoprenaline infusion. Among the patients with heart disease, the incidence of isoprenaline-induced bradycardia was significantly more frequent in patients with hypertrophic cardiomyopathy (17%) than in patients with old myocardial infarction (3%) (P < 0.05), or those with idiopathic dilated cardiomyopathy (1.5%) (P < 0.001) or those with other heart diseases (0%). Female sex tended to be more frequent in patients who developed paradoxical bradycardia during isoprenaline infusion, but the difference was not statistically significant. Table 2 confirms that isoprenaline-induced bradycardia is more frequent in patients studied under 40 years than in those over 40 years, but these patients had less associated heart disease, and were studied more frequently for syncope.
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Discussion
Usually, isoprenaline is used to increase the heart rate and to enhance sinoatrial and atrioventricular conduction 1–7,10 such as dobutamine. Paradoxical bradycardia has been reported with dobutamine[11–13] and occurs in 8% of patients during dobutamine stress testing[11], principally in old women with a history of hypertension and relatively high left ventricular ejection fraction[14] or in patients with coronary artery disease[12]; it can be prevented by early administration of atropine[14]. Paradoxical bradycardia during isoprenaline infusion occurred with the same incidence in our study and was relatively infrequent (7%). To our knowledge isoprenaline-induced bradycardia has never been described during electrophysiological study in the supine position, except for atrioventricular block.
Several mechanisms could explain the paradoxical bradycardia during isoprenaline infusion:
- A neurally mediated vagal reflex with hypervagotonia secondary to beta-stimulation is the most probable explanation[15]. It is noted either in patients with latent hypervagotonia revealed by the test or in young asymptomatic patients. This is believed to result from activation of the cardioinhibitory reflex (Bezold-Jarisch reflex) through left ventricular sensory receptors[14]. Isoprenaline infusion is currently used during head-up tilt test to provoke a vasovagal response[15–17]. However, the specificity of bradycardia-induced isoprenaline infusion during head-up tilt test is controversial[18]. In the present study, the occurrence of isoprenaline infusion-related bradycardia was considered as being without clinical significance in only 13 of 765 patients (2%). In other patients, the bradycardia was correlated with symptoms suggestive of hypervagotonia or was useful to induce vagally mediated atrial fibrillation.
- The occurrence of AV conduction disturbance has a different mechanism. The normal effect of isoprenaline on sinus and atrioventricular nodes with shortening of refractory periods and acceleration of conduction is sinus tachycardia, best conduction in the AV node and the provocation of intra or infraHisian conduction disturbances[19] which were masked in the control state by the presence of conduction abnormalities at a higher level. Advanced organic damage to the AV node and sinus tachycardia could explain the occurrence of second-degree supraHisian AV block during isoprenaline infusion. All patients with AV conduction disturbances were older than patients with hypervagotonia and had clinical signs of exercise or stress-related dizziness/syncope. Provocation of myocardial ischaemia and induction of ischaemic atrioventricular block[13] could be another mechanism, which has been reported in studies with dobutamine. In the present study, there were no signs of ischaemia and syncope disappeared after pacemaker implantation.
Limitations of the study: the neurocardiogenic cause for sinus or junctional bradycardia after isoprenaline is only speculative. This is a retrospective study. Bradycardia is infrequent; a prospective study using repeat isoprenaline infusion after atropine could be useful to understand the mechanism of bradycardia.
In conclusion, the occurrence of paradoxical bradycardia was a rare finding during isoprenaline infusion (7%). It can be without clinical significance in asymptomatic patients, but was rare (2% of tests). In the remaining patients, sinus or junctional bradycardia was associated with hypervagotonia and principally was noted in young patients, those with syncope, and those without heart disease, except in those with hypertrophic cardiomyopathy. The development of second-degree AV block was pathological and a sign of organic AV conduction disturbances. Isoprenaline infusion was a simple means to detect organic AV conduction disturbance especially in patients complaining of exercise-related dizziness/syncope, but unable to perform an exercise test.
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