Head-up tilt test with clomipramine challenge in vasovagal syndrome—a new tilt testing protocol

G.N. Theodorakis, E.G. Livanis, D. Leftheriotis, P. Flevari, M. Markianos* and D.Th. Kremastinos

Onassis Cardiac Surgery Center, 2nd Department of Cardiology and Laboratory of Neurochemistry, Eginition Hospital, Athens University Medical School, 356 Syngrou Avenue, Athens 17674, Greece

* Corresponding author. Tel.: +30-210-9493-372; fax: +30-210-9493-373
E-mail address: elbee{at}ath.forthnet.gr

Received 8 November 2002; accepted 20 November 2002


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Purpose The aim of the study was to randomly compare clomipramine, used as a challenge-agent during head-up tilt test, with isoproterenol, used in the conventional test, in patients with vasovagal syndrome.

Subjects and methods The serotonergic re-uptake inhibitor clomipramine was infused (5mg in 5min) at the start of head-up tilt test (Clom-HUT) in 126 patients (mean age 41±16 years) with positive history of recurrent neurocardiogenic syncope, and in 54 healthy control subjects (mean age 46±15 years). All subjects had also been tested with a conventional 60° head-up tilt test (Con-HUT) for 30min and, if negative, isoproterenol infusion was performed at the end of the test. The two tests were performed in a random order with a 24-h interval between them.

Results Fifty-two of the 126 patients (41%) and two of the 54 controls had a positive response to Con-HUT. In the Clom-HUT the proportion of patients who experienceda positive response increased to 83% (105 subjects), while this happened only tofour control subjects. The predictive accuracy of Clom-HUT increased compared to Con-HUT from 58 to 86%, respectively.

Conclusion The results indicate an increased responsiveness of central serotonergic neural system in subjects with vasovagal syndrome, the activation of which leads to sympathetic withdrawal. The use of clomipramine infusion during tilt test seems to improve considerably its diagnostic value.

Key Words: Head-up tilt test • Neurocardiogenic syncope • Central serotonergic activity • Clomipramine challenge


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
The clinical tool of choice for the diagnosis of neurocardiogenic syncope is head-up tilt testing with or without drugs.1,2 Despite the widespread acceptance of tilt testing as a diagnostic procedure, many questions concerning the precise pathophysiology of neurally mediated syncope and the most optimal provocative agent during tiltingremain unanswered. Although central nervoussystem seems to participate in the pathogenesis of neurocardiogenic syncope, no centrally acting drugs have been used as challenge agents during head-up tilt testing. In a recent study, we have reported that a high proportion of patients with history of neurocardiogenic syncope had a positive response to head-up tilting, when clomipramine (a serotonin re-uptake inhibitor) was infused as a drug-challenge.3 This finding was in accordance to our previous observations, regarding the increase in plasma prolactin and cortisol, following a vasovagal reaction during head-up tilt test, which suggests the participation of central serotonergic activation.4 We have also reported that patients with neurocardiogenic syncope had higher prolactin and cortisol responses to clomipramine infusion compared to normal subjects, indicating a more sensitive central serotonergic system.5 The purpose of the present study was to evaluate the diagnostic utility of clomipramine tilt test in patients with recurrent vasovagal syncope. For this reason, we assessed the sensitivity, specificity and positive rate of clomipramine test and we compared them with those of the conventional tilt test with or without isoproterenol infusion.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
The study population consisted of 153 subjects. One hundred and twenty six of them (mean age 41±16 years, 60 males) had a positive history of neurocardiogenic syncope (patient group). We considered as a positive history of recurrent neurocardiogenic syncope the presence of two or more syncopal spells in association with symptoms of autonomic dysfunction such as pallor, nausea or sweating. The mean number of syncopal episodes during the last 6 months was 3.7±2. All patients with positive history were followed-up in the outpatient clinic for the evaluation of their syncopal episodes. A thorough clinical evaluation, 12-lead electrocardiography (ECG), echocardiography and electrophysiologic study, when needed, ruled out any structural heart disease, while neurologic diagnostic procedures (electroencephalography, computed tomography scan), performed when clinically indicated, ruled out any neurological disease in patients withneurocardiogenic syncope.

A group of 54 subjects (mean age 46±15 years, 24 males) with non-specific symptoms, without history of syncopal attacks in their medical records or any evidence of structural heart disease served as the control group.

2.2. Protocol
All patients were tested without any medical treatment for at least 1 week. They all underwent two consecutive head-up tilt tests with a 24-h interval between the tests. One conventional tilt test was performed using the protocol currently used forthe evaluation of neurocardiogenic syncope in our Cardiology Clinic6 (Con-HUT), and the other test included intravenous clomipramine administration (Clom-HUT). Both tests were performed sequentially, in a random order. All tilt table tests were performed between 8.00 and 13.00h, after the subjects had been in a fasting state for at least 12h. Subjects were connected to a standard ECG monitor for continuous observation of heart rate and rhythm. Arterial blood pressure was also continuously monitored by a Finapress non-invasive blood pressure system. An automatic arterial blood pressure sphygmomanometer was also used toconfirm the blood pressure measures every 5min throughout the test and continuously during symptoms. Thirty minutes before the test, a venous cannula was inserted into a forearm vein.

During Con-HUT the subjects were placed in the supine position for 10min for baseline ECG and blood pressure recordings and then tilted to a head-up position at 60° for 30min on a foot plate support (passive phase). If a positive response to head-up tilt test occurred during the initial upright tilt, patients were returned to the supine position and the test was terminated. If the 30min period of passive tilt test was completed without a positive response, patients were returned to the supine position for 10min and upright tilting was repeated for 15min with intravenous infusion of isoproterenol (infusion rate 2µg/min, increased until the heart rate reached the target of 130beats/min).

Clom-HUT was sequentially performed, either as the first or the second test. In this test, all subjects underwent a tilt test at 60° for 20min, after a 10-min rest in the supine position. At the start of the tilt test, 5mg of clomipramine were intravenously administered over the first 5min.

2.3. Definitions
A test was regarded as positive if it succeeded in reproducing the patient's syncope or presyncope, associated with an abrupt fall in blood pressure (systolic blood pressure <80mmHg) and/or concomitant bradycardia (heart rate <50beats/min). The test was regarded as negative if it was completed without any symptoms. Positive responses were classified into vasodepressor (defined ashypotension without significant bradycardia),cardioinhibitory (bradycardia without associated hypotension) and mixed type (hypotension followed by bradycardia).

The positive rate of head-up tilt testing was defined as the proportion of patients with unexplained syncope who had a positive test result with reproduction of spontaneous symptoms. The specificity of head-up tilt testing was defined as the proportion of control subjects who had a negative test. The predictive accuracy of head-up tilt testing was defined as the value obtained by dividing the sum of true positive and true negative responses by the total number of patients and control subjects studied multiplying by 100.

All subjects were informed about the experimental nature of the study and gave their written consent. The Ethics Committee of the Hospitalapproved the study protocol.

2.4. Statistical analysis
Statistical analysis was performed using Student's t-test. Categoric variables were compared bychi-square test. A value of was considered significant.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
3.1. Con-HUT
Fifty-two of the 126 (41%) subjects in the patient group had a positive response during Con-HUT (34 during passive tilt test and 18 during tilt testing with isoproterenol). The mean time to syncope was 15±10min (minimum 2min and maximum 30min) during the passive tilt test and 5±2min during tilt test with isoproterenol (minimum 3min, maximum 12min). The type of the positive response was cardioinhibitory in 14 (27%) patients, vasodepressor in 12 (23%) and mixed in the remaining 26 (50%) patients. Two out of the 54 control subjects had a positive Con-HUT (specificity 96%) of mixed type. The predictive accuracy of the test was 58%.

Out of 52 patients with positive Con-HUT 27 (43%) had a positive response when the test was performed first in the randomization and theremaining 25 (40%) when the test was performed as the second one (Table 1).


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Table 1 Positive rate and specificity of Clom-HUT and Con-HUT

 
3.2. Clom-HUT
One hundred and five of the 126 (83%) subjectsin the patient group had a positive response to Clom-HUT. The mean time to syncope in a positive Clom-HUT was 9±3min (minimum 5min and maximum 17min). The type of the positive response was cardioinhibitory in 21 (20%) patients, vasodepressor in 41 (39%) and mixed in the remaining 43 (41%) patients.

Four of the 54 subjects in the control group had a positive Clom-HUT of vasodepressor type (specificity 93%). The predictive accuracy of the test was 86%. In 51 (81%) positive patients with positive response the test was performed first and in the remaining 54 (86%) it was the second test inthe randomized order (Table 1).

3.3. Comparison between the two test responses
The comparison of the results of the two tests inthe patient group is shown in Table 2. The cardioinhibitory response was 27% in Con-HUT versus 20% in Clom-HUT, which was not significantly different . The mixed type of response was notdifferent between the two tests as well. The vasodepressive reaction was more frequentin Clom-HUT than in Con-HUT, (39 versus 23%, respectively, ) as shown in Table 3.


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Table 2 Comparison of the responses to Con-HUT and Clom-HUT

 

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Table 3 Comparison between positive HUTs

 
3.4. Complications during tests
During passive head-up tilting no complication was observed and patients did not complain of any discomfort. Four out of 92 patients who underwent tilting with isoproterenol infusion experienceddyspnea and chest discomfort during isoproterenol administration. Seven patients experienced nausea and vomiting during clomipramine infusion. Four of them had a positive response to Clom-HUT a few minutes later, while in the remaining three patients these symptoms were diminished and they continued tilting until the test was completed. Following Clom-HUT, two patients reported dizziness and headache in the afternoon of the same day. No statistically significant difference was found between complications observed during Con-HUT and Clom-HUT (chi-square, ).


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
This study shows that clomipramine administration during head-up tilt testing is a promising technique, because the positive rate of the test might be increased compared to the Con-HUT which is currently approved by the European Task Force for Syncope.17 Moreover, this could be achieved without a loss of specificity and without the needfor prolonged titration and time-consuming procedures. The mean time until a positive response was reduced from 15±10min in the passive tilt test to 9±3min in the clomipramine test. In addition, there was no need for isoproterenol infusion. The duration of a negative Con-HUT was 55min, while that of Clom-HUT was 20min only.

The positive response during the passive phaseof Con-HUT was 27%. This rate was increased to41% when tilting was combined with isoproterenol infusion. These findings are almost in agreement with those reported by Raviele et al.8 and somewhat lower than those reported by other investigators.9–11 This disparity could be attributed to some small differences in the tilt test protocol and the lower dose of the administeredisoproterenol.

Regarding Clom-HUT, the positive response increased to 83%, which is in agreement with our previous preliminary study.3 In that study, Con-HUT had been performed first and Clom-HUT had been performed 24h later. However, the positive response and the specificity of Clom-HUT (80 and 95%, respectively) are comparable to those of the present study when both tests were performed in a random order (83 and 96%, respectively).

Clomipramine seems to be superior to other drugs like nitroglycerin or adenosine that have been used to provoke syncope during head-up tilt testing. Raviele et al.8 have compared the positive response and predictive accuracy of sublingualnitroglycerin test and low-dose isoproterenol test in patients with unexplained syncope. It has been reported that both tests are equivalent in regard to the positive response (49 versus 41%) for evaluating unexplained syncope. In the same study, the predictive accuracy was found to be 62% with sublingual nitroglycerin and 55% with isoproterenol provocation. In our study, the predictive accuracy of clomipramine tilt test and basic tilt test was found to be 86 and 58%, respectively. Regarding positive response following isoproterenol challenge to tilt test with isoproterenol challenge, ourresults are similar to those reported by otherinvestigators.12,13

Adenosine has also been used to provoke syncope, administered either in the supine position or during tilt testing. Injection of adenosine in supine position and interpretation of the results is based on the duration of cardiac pause. A value between 6 and 10s is defined as positive response. In patients with history of unexplained syncope, the adenosine test is abnormal in 28–41%.14,15 When adenosine is administered during tilt testing, the positive responses are limited to no more than 20% of the cases.16–19 These results show that adenosine isnot superior to currently used isoproterenol ornitroglycerin.7

The concordant response between the two tests was also high, reaching the 94% of Con-HUT positive cases. In the patient group, 49 of the 52 subjects (94%) with a positive Con-HUT reproduced a positive response with Clom-HUT as well. This means that clomipramine tilt test can be used as a single test instead of performing more than one drug challenges. Some studies comparing low dose of isoproterenol and sublingual nitroglycerin during tilt testing have found a significant discordantresponse suggesting both tests to be used ascomplementary tests.8,12,13

4.1. Central serotonergic activity and syncope
The central nervous system plays a major role in the homeostasis of the cardiovascular system. Medullary nuclei contain the major excitatory (pressor) and inhibitory (depressor) regions.20 The functional role of the nucleus tractus solitarius and other brain stem nuclei are quite significant in the cardiovascular control of peripheral vascular resistance and heart rate. Serotonergic receptors are found in the nucleus tractus solitarious, in the raphe nuclei and within the ventrolateral area.21–23

In human subjects, drugs that enhance central serotonergic activity, such as clomipramine, fenfluramine, or 5-hydroxytryptophan, have been shown to increase the plasma levels of prolactin and cortisol and have been used as a probe to assess the reactivity of the system.24–28 Acute clomipramine administration blocks the re-uptake of the serotonin (5-HT) in the synapse space and increases stimulation of 5-HT receptors. Hypothalamic pituitary–adrenal axis hormones and prolactinsecretion are in part regulated via 5-HT inputs, and their responses to acute administration of 5-HT agents are mediated, at least in part, by 5-HT mechanisms.29,30 Clomipramine readily penetrates the blood–brain barrier and following a single parenteral dose, its maximum concentration in the brain is 10 times higher than that in plasma. It has been proven that as low as 10mg of clomipramine administered intravenously leads to an increase in plasma prolactin and cortisol concentrations, suggesting that even small doses comprise a useful probe for serotonergic activity in humans. Approximately 2h after the administration of clomipramine, its plasma concentration is practically not detected.31 Additionally, intravenous administering of a low dose of clomipramine, and thereby avoiding the ‘first pass effect’ of hepatic metabolism, minimizes its effect on norepinephrine,providing relative specificity for serotonergic activity.24 In our study, we administrated only 5mg intravenously, because we assumed that the increase of the serotonin in the central nervoussystem, along with the orthostatic stress, wouldbe sufficient to provoke syncope in patients with neurocardiogenic syncope. The nausea and vomiting observed in some of our patients could be attributed to clomipramine's side effects, since almost half of them had a negative response to HUT.

In a previous study, we have shown that plasma levels of cortisol and prolactin increased during the tilt test in subjects who developed syncope.4 In another study, we found that after an intravenous infusion of 25mg of clomipramine in the supine position, patients with a history of recurrentneurocardiogenic syncope had higher cortisol and prolactin plasma levels than normal controls, indicating an increased responsiveness of the central serotonergic system to this agent.5 Since central serotonergic system is, in part, a regulator of heart rate and blood pressure homeostasis, syncopedevelopment is also dependent on the feedback of peripheral and cortical inputs. From the present study, it is concluded that the enhancement of serotonergic activity in susceptible subjects could increase the diagnostic yield of tilt testing inindividuals with history of neurocardiogenicsyncope.

Another interesting point of our study is the higher rate of vasodepressor response to HUT observed during Clom-HUT, indicating that serotonergic stimulation interferes mainly with vascular resistance mechanisms, presumably by stimulating post-synaptic 5-HT4receptors.20


    5. Conclusion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
In conclusion, the results of our study show that central serotonergic activation with clomipramine infusion during head-up tilt testing can reliably reproduce syncope probably by enhancing serotonergic activity in the central nervous system. The head-up tilt testing with clomipramine may prove to be a valuable, time-saving test for the evaluation of patients with neurocardiogenic syncope.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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