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(Circulation. 1999;100:1798-1801.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Cardiosurgical Department, Cardiologic Division, C.C.U. "SS. Annunziata" Hospital, School of Cardiology "G. D'Annunzio" University, Chieti, Italy.
Correspondence to Enrico Di Girolamo, MD, Cardiosurgical Department, Via F. Molino, 35, 66013 Chieti, Italy. E-mail edgirol{at}tin.it
| Abstract |
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Methods and ResultsForty-seven consecutive adolescents (18 male and 29 female, mean age 16.0±2.2 years) with recurrent syncope and positive head-up tilt test refractory to previous traditional therapies were distributed between 2 groups, depending on their consent (24 patients) or refusal (controls, 23 patients) to enter the program. Orthostatic training was started, in the presence of a family member, with a series of 5 in-hospital sessions. The 24 patients and their relatives were then instructed to perform the tilt training at home by standing against a wall twice a day for a planned duration of up to 40 minutes, depending on the in-hospital orthostatic tolerance. Head-up tilt response was reevaluated after 1 month, and the clinical effect was noted over a mean follow-up of 18.2±5.3 months (range 15 to 23); 26.1% of patients in the control group and 95.8% of patients in the training group became tilt-negative (P<0.0001). Spontaneous syncope was observed in 56.5% versus 0% in the control and training group, respectively (P<0.0001).
ConclusionsOrthostatic training was found to significantly improve symptoms of adolescents with neurocardiogenic syncope unresponsive to or intolerant of traditional medications. Twice-a-day training sessions of 40 minutes were well accepted by patients.
Key Words: syncope baroreceptors nervous system, autonomic reflex
| Introduction |
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| Methods |
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Baseline Head-Up Tilt Test
Patients underwent head-up tilt test between 10 AM
and 12 AM, after a 12-hour fasting period. After baseline
blood pressure and heart rate values measurement, each patient was
tilted to 60° for up to 45 minutes.17 If syncope
developed during the tilt, the patient was immediately lowered to the
supine position and the study ended. If no symptoms developed, the test
was prolonged for up to 20 minutes after 5 mg sublingual isosorbide
dinitrate (Carvasin, Wyeth) administration.18 Blood
pressure was recorded by an automatic sphygmomanometer on the right
arm while heart rate was monitored by a 12-channel ECG. A positive
head-up tilt test was defined as the provocation of hypotension,
bradycardia, or both, associated with a loss of consciousness that
reproduced the patients' clinical episodes.19 The study
was performed according to the guidelines of the institutional
committee on human research. All patients (ie, their parents) were
informed about the study and signed a consent form.
Previous Therapies
In each of the 47 patients, traditional therapies were either
ineffectual or poorly tolerated. Failure was defined as the clinical
recurrence of syncope. Patients were unresponsive to or
intolerant of 75 mg daily etilefrine (19 patients), 80 mg daily
propranolol (15 patients), and either etilefrine or
propranolol (11 patients). The other patients underwent 0.2
mg daily fludrocortisone (1 patient) or 20 mg daily paroxetine (1
patient) after unsuccessful etilefrine and propranolol
therapy. Medications were all discontinued in both control and placebo
groups before the study started.
Tilt Training Program
After diagnostic head-up tilt, the pathophysiology
of neurocardiogenic syncope and the end points of the program were
explained to each of the patients. Patients were then distributed
between 2 follow-up groups, depending on their consent (24 patients) or
refusal (no compliance; controls, 23 patients) to enter the
program.
Orthostatic training was then started with a series of 5 in-hospital sessions for a planned duration of between 10 and 50 minutes (once a day for 5 days), with an increase of test duration of 10 minutes per day. If syncope developed during the test, the patient was immediately lowered to the supine position and the study ended. A family member participated in all the in-hospital head-up tilt sessions. At hospital discharge, the 24 patients and their relatives were instructed to perform the tilt training at home by standing against a wall (with the united ankles 15 cm from the wall)16 twice a day for a planned duration of up to 40 minutes, depending on the orthostatic tolerance during in-hospital tilting. The sessions were performed in a comfortable and safe environment to avoid the risk of physical trauma, and were completed under the supervision of a family member.16 One month after the initiation of the tilt training program, the response to head-up tilt test was reevaluated in the same laboratory at approximately the same time of day using the same protocol of baseline test. None of the patients in either the control or training groups were given instructions about increasing their salt intake as a protective measure to avoid symptoms. Patients or their relatives were seen or contacted by telephone every month, and recurrence of spontaneous syncope was evaluated over a mean period of 18.2±5.3 months. Each of the 47 patients had a follow-up of at least 15 months (range 15 to 23).
Statistical Analysis
Results are expressed as mean±SD. Patients were classified as
positive or negative for both the head-up tilt study and their clinical
course on the basis of whether or not their symptoms occurred. The
response rate of the 2 groups was compared by
2 test, whereas other continuous data were
expressed as mean±SD and compared by Student's t test.
P<0.05 was considered significant. For multiple statistical
comparisons to baseline, P<0.025 was considered
significant.
| Results |
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Head-Up Tilt Test Reevaluation
At tilt test repeat, acute tilt-induced syncope was observed in
73.9% (18 patients) versus 4.2% (1 patient) in the control and tilt
training group, respectively (P<0.0001). However, the
patient in the training group reported a significant increase of test
duration, with a mean delay of symptoms onset of up to 52 minutes
(P<0.001), and nitrate challenge was required to provoke
syncope (Table 2
).
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Follow-Up
Before entering the protocol, the patients in the control group
had an overall mean of 7.9±3.2 yearly syncopal episodes and the
patients in the training group, 8.6±3.8 (P=0.499).
Spontaneous syncope recurrence during a 15-month follow-up was
56.5% (13 patients) versus 0% (0 patients) in the control and tilt
training group, respectively (P<0.0001) (Table 2
).
One patient (4.2%) in the training group experienced a promptly
reverted episode of presyncope, secondary to an obvious and avoidable
triggering situation (sauna session). No patients reported feeling
worse during follow-up. Twice daily orthostatic training
sessions of 40 minutes were well accepted by patients. Two patients
failed to comply with the training program after 18 and 20 months,
respectively, and syncope reappeared within 2 months (5 and 7
weeks).
| Discussion |
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In individuals prone to neurocardiogenic syncope, the assumption of passive upright posture leads to gravitationally mediated venous pooling of blood in the lower limbs. This downward displacement of intravascular volume leads to a relevant impairment of cardiac output, and arterial baroreceptor reflexes are activated, resulting in a reflex increase in sympathetic stimulation.4 5 6 7 The sympathetically mediated increase in contractility in a preload-reduced left ventricular cavity is believed to activate unmyelinated vagal C-fibers (ventricular mechanoreceptors). Stimulation of these receptors produces a large afferent signal to the brain stem, and inhibition of sympathetic outflow occurs.4 5 6 7
Several neurotransmitters are believed to facilitate vasovagal reactions by inhibiting the neuroadrenergic system. Catecholamines, opioid peptides, arginine-vasopressin, nitric oxide, adenosine, and serotonin have all been reported to play an important role in the modulation of central nervous blood pressure and heart rate regulation, thus fluctuations in central levels of some of these molecules are supposed to facilitate the pathogenesis of neurocardiogenic syncope.8 9 10 11 12 13 14
Several studies have been undertaken to evaluate the efficacy of pharmacological or electrical therapies on neurocardiogenic syncope, but a real gold standard of head-up tilt-guided therapy has not been established yet. Therapy has largely been empiric, based on the mechanism that is currently believed to be responsible for fainting.12 13 14 20 21 22 Nevertheless, irrespective of ß-blocking, vasoconstrictor, vagolytic, antipurinergic, negative inotropic, mineral corticoid, serotonin reuptake inhibiting, and cardiac pacing therapies, several patients continue to experience episodes of syncope (refractory syncope). Recently, midodrine has been indicated to be an effective treatment for neurocardiogenic syncope and, apart from ß-blockers, it is fast becoming the treatment of choice in these patients.23 Unfortunately, when the present study was designed these data were not available. Furthermore, young patients are notoriously difficult to treat and long-term drug administration is often poorly accepted by patients and their parents. In our series we studied 47 adolescents with recurrent syncope who had previous ineffectual or poorly tolerated ethylephrine, propranolol, fludrocortisone, or paroxetine therapies. The clinical recurrence of syncope, irrespective of therapy, encouraged patients (and their relatives) to agree to the training program.
All the patients who performed regular tilt training became asymptomatic during follow-up and only 1 patient (4.2%) experienced syncope during repeat head-up tilt test. Conversely, 56.5% of the patients in the control group still continued to experience syncope. The therapeutic effect of the training program seems to be time-dependent, because syncope reappeared within 2 months in the 2 patients who failed to comply with the proposed training program. These data conform to those reported by Ector et al.16
The mechanisms by which tilt training improves symptoms in adolescents with refractory neurocardiogenic syncope remains unclear. Morillo et al observed a reduction of acute tilt-induced syncope in patients subjected to multiple head-up tilt test to evaluate both reproducibility and therapy, and a reconditioning of baroreceptor or mechanoreceptor response was suggested to be responsible for this phenomenon.22 During peripheral venous pooling, an appropriate compensatory cardiopulmonary baroreceptor reflex-mediated sympathetic activity occurs.5 In patients prone to neurocardiogenic syncope, these compensatory mechanisms are followed by a paradoxic sympathetic withdrawal.5 We believe that the daily performance of orthostatic training may have a desensitizing effect on the cardiopulmonary receptors that are believed to trigger the neurocardiogenic reaction. Moreover, patients with recurrent syncope often suffer severe psychological burden; the information about the benignancy of the disorder associated with regained self-confidence of the patients may produce a powerful positive psychological impact,15 16 which may contribute to the therapeutic effects of orthostatic training.
Study Limitations
This study was not randomized. Selection of patients was based on
their consent or refusal to enter the training sessions. The
enthusiastic motivation of those who complied with the self-training
program may have represented a powerful placebo, thus
contributing to the positive therapeutic effects of the program.
Conclusions
The tilt training program was found to correct the excessive
autonomic reflex activity of neurocardiogenic syncope. We conclude that
a self-training program may represent an effective and well
accepted therapy in adolescents with recurrent neurocardiogenic syncope
who are unresponsive to or intolerant of traditional tilt-guided
medication. Major series and longer follow-up periods are needed to
resolve the question of the role of orthostatic training in
the prophylaxis of refractory neurocardiogenic syncope.
| Acknowledgments |
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Received April 7, 1999; revision received June 23, 1999; accepted July 2, 1999.
| References |
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