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Provocation of Neurocardiogenic Syncope During Head-up Tilt Testing in Children: Comparison Between Isoproterenol and Nitroglycerin

^a Departments of Child Health
^b Cardiology, University of Ioannina, Ioannina, Greece
^c Department of Pediatrics, University Hospital of Ioannina, Ioannina, Greece

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVE. Although nitroglycerin- and isoproterenol-augmented tilt tests are of equal value in the diagnosis of neurocardiogenic syncope in adults, no data exist in children. We compared the sensitivity and specificity of the 2 tests in a pediatric population.

PATITENS AND METHODS. We studied 85 patients (33 boys; mean age: 11.6 ± 2.9 years). Of them, 56 had a diagnostic history of neurocardiogenic syncope, whereas 29 served as controls. After a negative passive phase, they were randomly assigned to either intravenous isoproterenol or sublingual nitroglycerin, and tilt was continued for 20 minutes.

RESULTS. Sensitivity was 0.78 for the isoproterenol test and 0.79 for the nitroglycerin test, but specificity was significantly higher for isoproterenol test compared with nitroglycerin test. In patients with a positive test, the duration of the recovery period was significantly longer after nitroglycerin (8.4 ± 2.7 minutes) than after isoproterenol (5.1 ± 1.6 minutes).

CONCLUSIONS. Nitroglycerin- and isoproterenol-augmented tilt tests are associated with equal sensitivity in the diagnosis of neurocardiogenic syncope in children and adolescents. However, nitroglycerin results in more false-positive tests and produces more prolonged vasovagal symptoms. Our data do not support the routine use of nitroglycerin in the evaluation of syncope in this age group.

Key Words: neurocardiogenic syncope • tilt test • children • isoproterenol • nitroglycerin

Abbreviations: CI—confidence interval

Syncope is a common clinical problem in children and adolescents, affecting 15% of individuals before adulthood.¹ With the exception of a minority of pediatric patients with congenital heart disease or primary electrical disease, the most likely cause is neurocardiogenic syncope.^1,2 Although frequently benign, this condition may lead to injury and may cause distress in the family.

After the first reports in the early 1990s,^3–5 tilt test has gained considerable value in the diagnostic evaluation of children with syncope.^6,7 The specificity of tilt test is satisfactory, but concern has been raised with respect to its low sensitivity.^5,8,9 As a result, isoproterenol is now used as part of the tilt protocol in the majority of centers,^10,11 but its use requires venous cannulation, which may interfere with the diagnostic accuracy of the test.¹² Data in children, as well as clinical experience, indicate that such observations may apply to an even larger extent in pediatric patients.¹³ Furthermore, the use of intravenous isoproterenol is associated with a low but definite risk for induction of serious ventricular arrhythmias,⁸ restricting the use of tilt test to centers with emergency resuscitation equipment.

Data in adults have shown that head-up tilt test augmented by sublingual nitroglycerin results in a comparable diagnostic yield with isoproterenol-augmented test but may overcome some of the limitations of isoproterenol infusion.^14–18 However, very few data exist with respect to the use of sublingual nitroglycerin in children.¹⁹ Thus, the purpose of the present study was first to compare the sensitivity and specificity of nitroglycerin-augmented versus isoproterenol-augmented head-up tilt test in children and adolescents and, second, to assess the safety of sublingual nitroglycerin in this population.

	PATIENTS AND METHODS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Study Population
The study complies with the Declaration of Helsinki, and the research protocol was approved by the Institutional Ethics Committee. Consecutive children and adolescents (up to the age of 18 years) admitted to our hospital (between January 2002 and October 2005) for evaluation of syncope or presyncope were prospectively evaluated for eligibility to participate in the study. Syncope was defined as a transient loss of consciousness and presyncope as any of the various premonitory signs of an imminent syncope. In addition, consecutive patients referred for evaluation of episodes of dizziness, thought to be of psychosomatic origin, were also included in the study and formed the control group.

Patients with structural heart disease, long QT or Brugada syndrome, or those on medication known to affect heart rate or to cause orthostatic hypotension were excluded. For inclusion in the study, the following criteria were fulfilled: (1) the patients and their guardians were willing to participate and gave informed consent; (2) the patients had a diagnostic history of neurocardiogenic syncope or a history suggestive of psychosomatic symptoms, nonindicative of vasovagal origin; (3) the index episode of syncope, presyncope, or vague "dizziness" had occurred during the preceding month before evaluation; and (4) all other possible causes of loss of consciousness were excluded. In particular, physical examination, 12-lead electrocardiogram, 24-hour Holter monitoring, and two-dimensional and Doppler echocardiography were normal in all of the patients. In addition, fasting blood glucose and/or glucose tolerance test were normal, and neurologic evaluation, electroencephalogram, or MRI were unrevealing in all of the participants.

During baseline evaluation, all of the children were hospitalized in the Department of Pediatrics of the University Hospital of Ioannina. The history of the episode was obtained in detail and independently by 4 experienced physicians of different specialties, that is, a pediatric cardiologist (Dr Vlahos), a cardiologist (Dr Katsouras), a pediatrician (Dr Tzoufi or Sionti), and a cardiologist/electrophysiologist (Dr Kolettis). The history of the index episode was taken from the child, the guardians, and from witnesses, if feasible. Subsequently, all of the cases were reviewed by all of the authors, and the symptoms were classified, by consensus, into 2 main categories: diagnostic of neurocardiogenic syncope^20,21 or clearly atypical symptoms.²² Accordingly, cases in the former category formed the patient group, and cases in the latter category formed the control group. Patients with an equivocal history that could not be classified into either category were excluded from the study. As a result, the control group consisted of normal children and adolescents, based on history, physical examination, and laboratory tests (as outlined above). The criteria used to classify the episode of loss of consciousness as indicative of neurocardiogenic syncope have been described previously in detail.^20,21 In brief, they include the short duration of the episode, the presence of triggering factors (such as pain, medical or dental procedure, sight of blood, or unpleasant odors) or provocative situations (such as prolonged standing or warm environment), and the presence of symptoms and signs of autonomic dysfunction, such as pallor, nausea, or sweating. The severity of symptoms was classified according to the frequency of syncopal episodes during the preceding 2 years, the absence of prodromes, or the occurrence of serious trauma, injury, or seizure-like events during spontaneous episodes.

Head-up Tilt Test Protocol
The end point of the head-up tilt test was the induction of syncope or presyncope, reproducing the symptoms leading to the index hospitalization. All of the patients were tested in the morning (between 10:00 AM and 12:00 PM) after an overnight fast in a quiet, dimly lit room, at a comfortable temperature. Atropine and resuscitation equipment were available for immediate use. A peripheral venous cannulation was performed a minimum of 1 hour before the test. Heart rhythm was monitored continuously, and blood pressure was recorded every 2 minutes (or every 30 seconds if symptoms were reported) using an automatic sphygmomanometer. The patients were placed in the supine position for 10 minutes for baseline electrocardiogram and blood pressure recordings and were subsequently tilted to a head-up position at 85° for 20 minutes on a table with foot-plate support. This protocol is relatively short and convenient and is associated with satisfactory sensitivity and specificity rates.^5,23,24

If no symptoms occurred after this passive (unmedicated) phase, the patients were randomly assigned to either sublingual nitroglycerin or to intravenous isoproterenol, and tilting continued for another 20 minutes. Simple randomization was performed in a 1-to-1 fashion by a custom lottery draw. Isoproterenol was administered intravenously in escalating doses every 2 minutes, ranging from 0.02 to 0.08 µg/kg, for 20 minutes, targeting at a heart rate of 150 beats per minute. Nitroglycerin was administered sublingually as a spray, at a dose of 400 µg. A positive test in normal control subjects was defined as false-positive, and a positive test in the patients' group was defined as true-positive. To investigate the possible relationship between nitroglycerin dosage and body weight, we compared the body weight between children who had a false-positive versus those who had a true-positive result after nitroglycerin administration. We used previously published definitions,²⁵ with slight modifications: if the patient developed presyncope or syncope at any stage, associated with a sudden fall in systolic blood pressure (of >40 mmHg) and/or a sudden drop in heart rate (to <50 beats per minute), the test was considered positive, and the patient was returned to the supine position immediately. The time of onset of symptoms after the test initiation or after medication administration was recorded. In patients with a positive tilt test, the duration of the observation period until full recovery was also recorded. The type of abnormal response was classified as mainly vasodilatory, cardioinhibitory, or mixed, according to previously published criteria.²⁶ If there were no changes in blood pressure or heart rate, the test was considered negative.

Management and Follow-up
All of the children were followed up at the outpatient clinic, irrespective of the outcome of the test. Particular attention was given to confirm the initial diagnosis regarding the presence or absence of neurocardiogenic syncope. In cases of neurocardiogenic syncope, standard treatment was recommended, including instructions on appropriate postural maneuvers and on adequate food, water, and salt consumption. Tilt training was recommended in the majority of cases, whereas pharmacologic treatment was reserved for children with severe or recurrent symptoms.

Statistical Analysis
Continuous variables are reported as median value and range (with mean value ±1 SD). They were compared using Student's unpaired t test, or with 1-way analysis of variance, followed by Tukey's multiple comparison test, as appropriate. The presence or absence of the disease was defined based on the expert panel consensus, and all of the test results were classified as positive or negative. Sensitivity and specificity were calculated separately for isoproterenol- and nitroglycerin-augmented tilt test and were compared using the Yates corrected ² test. Subgroup analysis was performed, and the effects of gender and age (dichotomized as above or below the median value) were examined. Statistical significance was defined as an value of .05. All of the statistics were performed using Statistica 6 (StatSoft Inc, Tulsa, OK).

	RESULTS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
A total of 129 children (56 boys; mean age: 11.7 ± 2.5 years) was initially included in the study. Of these, 76 patients had a history diagnostic of neurocardiogenic syncope, and 29 children were thought to have clearly atypical symptoms and formed the control group. The remaining 24 children could not be classified into any category and were excluded from further analysis. The median age of patients with neurocardiogenic syncope was 12 years (range: 5–18 years), and the median body weight was 36 kg (range: 18–50 kg). The respective figures for the control group were 12 years (range: 6–17 years) and 35 kg (range: 20–46 kg). All of the demographics and clinical characteristics of patients and control subjects are shown in Table 1. No significant differences were found between the 2 groups regarding age and gender.

View larger version (15K): [in this window] [in a new window]   FIGURE 1 Age (A), body weight (B), and time to syncope (C) in true-positive and false-positive results after isoproterenol and after nitroglycerin administration. a Significant difference.

Safety of Isoproterenol or Nitroglycerin Administration and Duration of the Recovery Period
Seizure-like events during induced syncope were observed in 2 (10.0%) children during the unmedicated phase, in 1 (5.5%) child after isoproterenol challenge, and in 2 (9.0%) children after nitroglycerin challenge. These percentages did not differ significantly between the 3 groups.

No ventricular arrhythmias were observed after isoproterenol administration. Apart from palpitations, reported in 19 patients (47.5%), no untoward symptoms were recorded. Atropine was required in 1 patient with positive tilt test after isoproterenol infusion. In this patient, atrioventricular block leading to symptomatic bradycardia persisted after placement in the supine position.

Sublingual nitroglycerin was generally well tolerated, and no serious adverse effects were noted. Of the 45 patients allocated sublingual nitroglycerin, 7 patients (15.5%) reported mild symptoms, such as headache, nausea, and vague malaise. In 2 of these patients, the result of the test had been classified as true-positive and in 2 as false-positive. These symptoms persisted, despite restoration of blood pressure and heart rate, after placement in the supine position. One patient required intravenous atropine, whereas the remaining 3 patients were managed with intravenous fluid administration. These symptoms resulted in significant differences in the duration of the recovery period of patients with a positive tilt test. In these patients, the duration of the recovery period showed a significant variance (F = 33.5; P < .0001). It was significantly longer in patients with nitroglycerin-augmented tilt test (8.4 ± 2.7 minutes) when compared with either the isoproterenol-augmented tilt test (5.1 ± 1.6 minutes; P < .001) or patients with a positive test during the passive, unmedicated phase (3.9 ± 1.0 minutes; P < .001). Three additional patients in the control group reported headache and malaise after a negative nitroglycerin-augmented tilt test. No action was taken, and all of the symptoms subsided within 15 minutes after placement in the supine position. The difference in the duration of the recovery period remained (P < .001) when isoproterenol- (5.1 ± 1.6 minutes) and nitroglycerin-augmented (8.0 ± 2.1 minutes) tests were directly compared in the patient group, that is, after exclusion of normal control subjects.

Time to Onset of Symptoms
The time to onset of symptoms after administration of medication was significantly shorter in children with a positive isoproterenol-augmented tilt test (6.8 ± 1.0 minutes) when compared with children with a positive nitroglycerin-augmented tilt test (8.3 ± 3.0 minutes; P = .046). A significantly longer time interval of symptom onset after nitroglycerin administration was found between false-positive (14.5 ± 3.6 minutes) and true-positive (7.4 ± 1.5 minutes; P < .0001) results. As a result, when only true-positive cases were included, the time to the onset of symptoms was similar after isoproterenol-augmented tilt tests (6.8 ± 1.0 minutes) and nitroglycerin-augmented tilt tests (7.4 ± 1.5 minutes; P = .16).

Management and Follow-up
Follow-up was available in 95 children. The mean duration of the follow-up period was 21 ± 12 months (median: 20 months). No child from the control group received any treatment. There was no difference in the initiation of outpatient management between the isoproterenol- and the nitroglycerin-augmented positive tilt test groups. All of the patients were managed conservatively with increased consumption of water and salt, tilt training, and medical treatment with fludrocortisone and/or propranolol. Specifically, medications were commenced in 7 children (35%) with a positive passive-phase test, in 5 children (21%) with a positive isoproterenol-augmented test, and in 6 children (18%) with a positive nitroglycerin-augmented tilt test. These percentages were comparable among the 3 groups. No patient required treatment with a selective serotonin reuptake inhibitor or implantation of a permanent pacemaker. During follow-up, symptoms recurred in 4 children (22%) with a positive passive-phase test, in 3 children (14%) with a positive isoproterenol-augmented test, and in 3 children (10%) with a positive nitroglycerin-augmented tilt test. These percentages were not statistically significantly different.

	DISCUSSION

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Although neurocardiogenic syncope is common in pediatric populations, controversy exists on the optimal diagnostic approach of such patients.^1,2 In this prospective, randomized study, we report on 76 patients, representing one of largest series published so far. Our data indicate that sublingual nitrates can be safely administered in children and adolescents. No significant adverse effects were noted in 45 patients, with an age range from 6 to 18 years, after sublingual nitroglycerin administration. These results are in accordance with the single published report on the use of sublingual nitrates in children.¹⁹ Dindar et al¹⁹ reported no significant adverse effects after sublingual isosorbide dinitrate administration in 25 children and adolescents, ranging from 9 to 18 years of age. However, in our study, prolonged symptoms after a positive test were observed in 16% of patients after nitroglycerin administration, requiring atropine or intravenous fluid administration. These symptoms, albeit mild, tended to be more common in the nitroglycerin group, resulting in a significantly more prolonged recovery period after a positive tilt test. In addition, mild symptoms, also requiring a prolonged observation period, were reported after negative nitroglycerin-augmented tests in 6% of cases. Thus, despite the evidence provided by adult studies^14,15 for a more simplified procedure after nitrate use, our results indicate that nitrates do not obviate the need for venous cannulation. Furthermore, nitrates result in a significant prolongation of the recovery period in positive, as well as in negative, tests.

The main purpose of our study was to compare the diagnostic value of nitroglycerin- with that of isoproterenol-augmented tilt test in a pediatric population. To our knowledge, such a comparison has not been performed previously. The 2 tilt test protocols were randomly used in 2 different groups with similar clinical characteristics. Apart from the medication used for syncope provocation, the tilting protocols were identical. We report almost equal sensitivity rates for isoproterenol- (78%) and for nitroglycerin-augmented (79%) tilt test. These values lie within the range reported for isoproterenol,^3,8,10,11 whereas the single previous study assessing nitrate-augmented tilt test in a pediatric population reported an almost identical sensitivity of 77.5%.¹⁹ However, we found significantly lower specificity rates for nitroglycerin- compared with isoproterenol-augmented tilt test. Subgroup analysis failed to show a significant impact of gender or age, but the relatively small number of patients in each group precludes firm conclusions.

The specificity of nitroglycerin-augmented tilt test reported in our study (67%) seems lower than the 91% reported by Dindar et al.¹⁹ We feel that this apparent difference reflects differences in the tilt test protocols. We used a steeper tilting angle (85°), with a longer (20-minute) duration of the medication phase, whereas Dindar et al¹⁹ used an angle of 70^o with a 15-minute duration of the medication phase. Both parameters have been shown to affect the false-positive rates of tilt tests by augmenting venous pooling in the lower extremities.^27,28 The synergistic effect of nitroglycerin, which acts via the same mechanism, may explain the increased incidence of false-positive nitroglycerin tests in our study. Our finding that all of these tests were vasodepressive and that they appeared later during tilt, reinforces this hypothesis. In contrast, our results indicate that the specificity of isoproterenol-augmented test may be less affected by tilting protocols.

The present report suggests that isoproterenol remains the agent of choice in the provocation of syncope during tilt test in children and adolescents. However, we would agree with the concept supported by Oraii et al,¹⁴ Raviele et al,¹⁵ and Natale et al²⁷ that the 2 tests are not mutually exclusive but complementary. This view is supported by the fact the 2 medications act through different mechanisms in provoking a vasovagal response in susceptible persons. We feel that further studies are required to test the nitroglycerin challenge after a negative isoproterenol-augmented tilt test.

Strengths and Limitations of Our Study
Our study is the first randomized, controlled trial directly comparing the use of isoproterenol and nitroglycerin for provocation of syncope during tilt test in a pediatric population of adequate size. Although our study may add to the current thinking on the diagnostic approaches of children with syncope, 2 limitations may be apparent. First, the selection of our control group might not be completely unbiased. However, we believe that the careful evaluation of symptoms by several investigators, independently and subsequently by consensus, compensates for any possible bias. In addition, our initial diagnosis was reconfirmed during the follow-up period, that is, no child in the control group developed any symptoms suggestive of neurocardiogenic syncope or presyncope. Moreover, the lack of clear-cut definitions of patient and control groups may be an inherent limitation of all of the studies evaluating the diagnostic value of the head-up tilt test, because there is no "gold standard" method to serve as a reference.²⁹ Second, the comparison of the 2 tilting protocols would have been more accurate if all of the patients had undergone the sublingual nitroglycerin and low-dose isoproterenol tests on separate days in a randomized fashion, as recommended previously by studies in adults.^14,15 However, we felt that such a protocol would have been difficult to apply in our population. Moreover, we believe that the adequate sample size of our study compensates, in part, for this limitation.

	CONCLUSIONS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Nitroglycerin- and isoproterenol-augmented tilt tests are associated with equal sensitivity in the diagnosis of neurocardiogenic syncope in children and adolescents. However, the nitroglycerin test is associated with lower specificity and produces more prolonged vasovagal symptoms, leading to an increased total duration of the test. Our data do not support the routine use of nitroglycerin in the evaluation of syncope in children and adolescents.

	FOOTNOTES

 
Accepted Aug 30, 2006.

Address correspondence to Antonios P. Vlahos, MD, Child Health Department, Pediatric Cardiology Division, University of Ioannina, 45110 Ioannina, Greece. E-mail: anvlahos{at}uoi.gr

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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