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Background The efficacy of permanent cardiac pacing in patients with neurocardiogenic (or vasovagal) syncope associated with bradycardia or asystole is not clear. We compared the efficacy of cardiac pacing with that of oral drug therapy in the prevention of hypotension and syncope during head-up tilt testing.
Methods Among 70 patients with a history of syncope in whom hypotension and syncope could be provoked during head-up tilt testing, 22 had bradycardia (a heart rate <60 beats per minute, with a decline in the rate by at least 20 beats per minute) or asystole along with hypotension during testing. There were 9 men and 13 women, with a mean (±SD) age of 41 ±17 years. Head-up tilt testing was repeated during atrioventricular sequential pacing (in 20 patients with sinus rhythm) or ventricular pacing (in 2 patients with atrial fibrillation). Regardless of the results obtained during artificial pacing, all the patients subsequently had upright-tilt testing repeated during therapy with oral metroprolol, theophylline, or disopyramide.
Results During the initial tilt test, 6 patients had asystole and 16 had bradycardia along with hypotension. Despite artificial pacing, the mean arterial pressure during head-up tilt testing still fell significantly, from 97 ±19 to 57 ±19 mm Hg (P<0.001); 5 patients had syncope, and 15 had presyncope. By contrast, 19 patients who later received only medical therapy (metoprolol in 10, theophylline in 3, and disopyramide in 6), 2 patients who received both metoprolol and atrioventricular sequential pacing, and 1 patient who received only atrioventricular sequential pacing had negative head-up tilt tests. After a median follow-up of 16 months, 18 of the 19 patients who were treated with drugs alone (94 percent) remained free of recurrent syncope or presyncope, whereas the patient treated only with a permanent dual-chamber pacemaker had recurrent syncope.
Conclusions In patients with neurocardiogenic syncope associated with bradycardia or asystole, drug therapy is often effective in preventing syncope, whereas artificial pacing is not.
Because hypotension in patients with neurocardiogenic syncope is frequently accompanied by bradycardia, the implantation of a permanent pacemaker would appear to be an appropriate treatment. No studies have yet demonstrated the efficacy of cardiac pacing, however, in preventing hypotension and syncope in such patients. Therefore, we designed this study to assess the efficacy of atrioventricular sequential pacing in preventing hypotension induced by head-up tilt testing in patients with neurocardiogenic syncope.
Methods
Population of Patients
From October 1989 through March 1991, 70 patients with a history of recurrent syncope were found to have abnormal responses to head-up tilt testing. Among these patients, 22 had bradycardia or asystole during testing, and they form the basis of this report. Our definition of bradycardia had two components: a sinus rate below 60 beats per minute at the termination of the head-up tilt test, and a decline in the heart rate during the test by at least 20 beats per minute from the base-line value. The mean (±SD) age of the patients was 41 ±17 years (range, 14 to 73); 9 were male, and 13 were female. All the patients had had at least two episodes of frank syncope during the year before they were studied. Eighteen of the 22 had also had recurrent episodes of presyncope. A comprehensive physical examination, a neurologic evaluation, surface electrocardiography, and an electrophysiologic evaluation did not identify the cause of syncope in these patients.
Three patients had documented asystole (for periods ranging from 5.5 to 22 seconds), and three patients had sinus bradycardia and syncope while they were monitored in the hospital to determine a cause for their previous episodes of syncope. Three of these six patients continued to have recurrent syncope despite the implantation of ventricular-demand pacemakers at other institutions. Twenty of the 22 patients had no underlying structural heart disease, and the remaining 2 had coronary artery disease. The underlying rhythm was sinus rhythm in 20 patients and atrial fibrillation in 2.
Head-up Tilt Testing
After informed consent was obtained, head-up tilt testing was performed with the patient in a nonsedated, postabsorptive state. Under local anesthesia, multipolar electrode catheters were inserted percutaneously through the antecubital and femoral veins and were positioned high in the right atrium and the right ventricular apex with use of fluoroscopic guidance. Arterial blood pressure was monitored with an intraarterial cannula inserted percutaneously into a brachial or femoral artery. Readings from three surface electrocardiographic leads (I, II, and V1), a blood-pressure tracing, and a time line were displayed simultaneously on a multichannel oscilloscope. Hard copies were produced at a photographic-paper speed of 25 mm per second.
After the heart rate and blood pressure were measured at base line with the patient in the supine position, the patient was positioned upright on the tilt table at an angle of 70 degrees for a maximum of 15 minutes, with a footboard used to bear the patient's weight. If the head-up tilt test was negative at base line, the patient was returned to the supine position for five minutes, after which intravenous isoproterenol was infused at a rate of 1 µg per minute. The infusion rate was gradually increased until the average heart rate was increased by at least 20 percent. Head-up tilt testing was then repeated as described above. In three patients who had ventricular-demand pacemakers, base-line head-up tilt testing was also performed at the previously programmed rate of 50 beats per minute and again after the pacemaker was programmed to the lowest rate (30 beats per minute), in order to evaluate the response of the intrinsic heart rate during the test. Finally, after the patient had been returned to the supine position for five minutes, head-up tilt testing was repeated after atrioventricular sequential pacing in the 20 patients with sinus rhythm, and after ventricular pacing in the 2 patients with atrial fibrillation, at a pacing rate approximately 20 percent higher than the resting heart rate. Pacing was started with the patient still in the supine position for one minute before the test, and it was continued throughout head-up tilt testing. A pacing rate approximately 20 percent higher than the resting heart rate was chosen in order to avoid competition with the sinus rhythm and to have a standard pacing protocol for all patients.
All the patients were subsequently evaluated with head-up tilt testing while they were receiving oral 
-adrenergic-receptor blockers, after a period equivalent to at least five half-lives of the drug. Twenty-one patients received 50 mg of metoprolol twice daily, and one patient who weighed 46 kg received 25 mg of metoprolol twice daily. Patients who continued to have positive responses to the head-up tilt test while receiving metoprolol were subsequently tested while receiving theophylline (200 mg twice daily). If patients continued to have abnormal responses to the tilt test while receiving theophylline, they were tested while receiving an extended-release preparation of disopyramide (150 mg twice daily). In patients receiving theophylline or disopyramide, testing was performed after a period equivalent to at least five half-lives of the drug, just as it was for metoprolol.
Definitions and Diagnostic Criteria
Syncope was defined as a transient loss of consciousness not compatible with other altered states of consciousness in the history of the patient in question2. Presyncope was defined as any of various premonitory signs and symptoms of imminent syncope (e.g., severe weakness or lightheadedness). A positive response to tilt testing alone or in conjunction with an infusion of isoproterenol was defined as one in which arterial hypotension and bradycardia or asystole were found to be sufficiently severe to have caused syncope or presyncope. A patient's response to head-up tilt testing during artificial pacing was defined as positive if the arterial hypotension was sufficiently severe to have caused syncope or presyncope.
Statistical Analysis
Data are expressed as means ±SD. The results were analyzed by the SAS system (SAS Institute, Cary, N.C.)15. A paired t-test was used to compare changes in heart rate and blood pressure at base line and during artificial pacing. A two-tailed P value of less than 0.05 was considered to indicate significance.
Results
Initial Head-up Tilt Testing
Twenty-one patients had abnormal responses to head-up tilt testing at base line while receiving no medications; of these patients, 18 had syncope, and 3 had presyncope. The mean time before the occurrence of a positive response was 7 ±3 minutes (range, 2 to 13). The remaining patient had an infusion of isoproterenol; six minutes into the test, hypotension and bradycardia developed, along with presyncope. The clinical symptoms were reproduced in all patients during head-up tilt testing, and there were no complications.
The changes in mean arterial pressure and heart rate during head-up tilt testing at base line are shown in Figure 1. The mean arterial pressure declined from 98 ±15 to 37 ±14 mm Hg (P<0.001). Six patients, including two with atrial fibrillation, had asystole. The other 16 patients (1 of whom had an infusion of isoproterenol) had bradycardia (heart rate, 39 ±10 beats per minute; range, 21 to 58). The underlying rhythm at the time of the bradycardia was sinus bradycardia in 14 patients, sinus rhythm with 2:1 atrioventricular-nodal block in 1, and junctional escape rhythm in the remaining patient. The heart rate and mean arterial pressure became normal in all patients after they returned to the supine position.
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A beat-to-beat analysis of all tracings made during head-up tilt testing showed that in 17 patients the mean arterial pressure started to decline much earlier than the heart rate, by a mean of 42 ±29 seconds (range, 10 to 120) (Figure 2). In the remaining five patients, the changes in arterial pressure and heart rate occurred simultaneously or within five seconds of each other. In 19 patients, the onset of hypotension was associated with prodromal symptoms of warmth, dizziness, or nausea. In the remaining three patients, syncope occurred abruptly during tilt testing without any premonitory symptoms.
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Eighteen patients with sinus rhythm continued to have positive responses to the head-up tilt test during atrioventricular sequential pacing, and two patients with atrial fibrillation had positive responses during ventricular pacing (Figure 3 and Figure 4). One patient felt extremely dizzy despite a decrease in mean arterial pressure of only 20 mm Hg. The head-up tilt test was negative in the remaining patient during artificial pacing. The mean arterial pressure during artificial pacing declined significantly, from 97 ±19 to 57 ±19 mm Hg (P<0.001). These changes in mean arterial pressure were less marked, however, than those that occurred during head-up tilt testing at base line (mean decline, 41 ±19 mm Hg vs. 59 ±16 mm Hg, respectively; P = 0.005). Fifteen patients had presyncope during temporary pacing, and five patients had syncope.
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Oral therapy with metoprolol, theophylline, or disopyramide resulted in negative head-up tilt testing in 10, 3, and 6 patients, respectively. Two patients had negative tests during atrioventricular sequential pacing while they were receiving metoprolol after drug therapy alone had been unsuccessful; they were then treated successfully with metoprolol and a permanent dual-chamber pacemaker. The remaining patient who had a negative head-up tilt test during temporary pacing received a permanent dual-chamber pacemaker as the sole therapy.
Two patients had recurrent syncope after discontinuing metoprolol because they were extremely tired. Both were successfully treated with disopyramide. One patient with a negative head-up tilt test during atrioventricular sequential pacing, who was subsequently treated with a permanent dual-chamber pacemaker, had recurrent syncope. He was free of syncope, however, for six months after the addition of theophylline. During a median follow-up of 16 months, 18 of the 19 patients (94 percent) who were treated with drugs alone remained free of recurrent syncope or presyncope, whereas the remaining patient, who had had frequent episodes of syncope before treatment, had only two episodes of presyncope during follow-up.
Discussion
Several studies have shown that -adrenergic-receptor blockers, theophylline, and disopyramide are effective in the long-term treatment of patients with neurocardiogenic (vasovagal) syncope16,17,18. The role of therapy with a permanent pacemaker in these patients is controversial, however19. A recent report advocates the use of permanent pacemakers in patients who have a history of syncope and previously documented transient bradycardia20. Head-up tilt testing was, however, not performed in these patients in order to exclude the possibility of neurocardiogenic syncope. In our series, atrioventricular sequential pacing (for the patients with sinus rhythm) or ventricular pacing (for the patients with atrial fibrillation) did not prevent hypotension and syncope or presyncope during head-up tilt testing in the patients who had syncope in addition to asystole or bradycardia. Such patients may have a potential for serious injury. On the other hand, the implantation of a permanent pacemaker is not without complications, may be associated with psychological sequelae, particularly in younger patients, and is costly. Therefore, it is imperative that an appropriate therapeutic strategy be implemented that will prevent incapacitating and potentially serious symptoms in these patients.
In the vast majority of our patients, the onset of bradycardia was consistently preceded by hypotension. The underlying mechanisms of the tilt-induced hypotension in patients with neurocardiogenic syncope are not clearly understood. When a person is in the upright position, the arterial pressure is normally maintained by a baroreceptor-reflex-mediated increase in sympathetic outflow that causes enhanced cardiac contractility, heart rate, and peripheral vasoconstriction11. In susceptible people, activation of the left ventricular mechanoreceptors due to increased cardiac contractility could override the baroreceptor reflex, resulting in peripheral vasodilatation, hypotension, and bradycardia owing to the diminution of sympathetic tone and enhancement of parasympathetic activity8,9,10,11,12,13,14. In a previous report from our laboratory, we showed that an increase in myocardial contractility and a decrease in left ventricular end-systolic dimensions occurred two to four minutes before the onset of syncope21. Furthermore, in a series of experiments, sequential measurements of catecholamine levels suggested that despite a substantial fall in arterial pressure at the time of tilt-induced syncope, norepinephrine levels failed to increase, whereas epinephrine levels increased severalfold22. These observations and the lack of efficacy of pacing in patients with bradycardia or asystole suggest that even in patients with a cardioinhibitory response, hypotension is predominantly due to vasodepression, whereas vagally mediated bradycardia may play only a secondary part in the pathogenesis of neurocardiogenic syncope.
The exact mechanisms by which -adrenergic-receptor blocking agents, disopyramide, and theophylline prevent neurocardiogenic syncope are unclear. Several experiments in animals10,23 have suggested that -blockers can lower the discharge frequency of mechanoreceptors. This phenomenon has been attributed to the negative myocardial inotropic effect. Furthermore, -blockade, by allowing unopposed activation of alpha receptors, can also have a peripheral vasoconstrictive effect. Negative myocardial inotropic, anticholinergic, and peripheral vasoconstrictive effects are known properties of disopyramide that could account for its efficacy in preventing neurocardiogenic syncope24. Adenosine, an endogenous nucleoside, is known to cause presynaptic inhibition of the release of transmitters from peripheral adrenergic nerves25. Theophylline may act by blocking the uptake of adenosine.
Because of the design of our study, ascertaining whether some of the medically treated patients in our series may actually have had spontaneous remission of their syncope is not possible. Although this seems unlikely because of the excellent response to medical therapy in highly symptomatic patients, further studies with a placebo control group are needed to clarify the issue.
The magnitude of hypotension was significantly less during artificial pacing than during base-line tilt testing, and only five patients continued to have syncope with pacing. Therefore, one could argue that the implantation of a permanent pacemaker may be beneficial in some patients with neurocardiogenic syncope. Although this argument cannot be dismissed, the majority of the patients in this series did not have recurrent syncope while they were receiving medical therapy alone. Thus, in marked contrast to a previous report,19 our results suggest that the vast majority of patients with neurocardiogenic syncope can be effectively treated with medical therapy alone. However, the mean age of the patients in the previous study (68 years) was higher than that of our patients. Because it may reduce the severity of attacks, pacemaker therapy could be considered in patients who are not appropriate candidates for medical therapy because of unacceptable side effects.
We are indebted to Alfred J. Anderson, Barbara Alexander, and Brian Miller for their assistance in the preparation of the manuscript.
Source Information
Presented in part at the 64th Annual Scientific Sessions of the American Heart Association, November 11-14, 1991.
From the Sinai Samaritan Medical Center, 945 N. 12th St., Milwaukee, WI 53233, where reprint requests should be addressed to Dr. Sra.
References
-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coll Cardiol 1992;19:402-408. [Abstract]
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Related Letters:
Treatment of Neurocardiogenic Syncope
van Lieshout J. J., Jellema W. T., Wieling W., Fitzpatrick A. P., Papa L. J., Sra J. S.
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Full Text
N Engl J Med 1993;
329:969-970, Sep 23, 1993.
Correspondence
This article has been cited by other articles:
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