Head-upright Tilt Table Testing in Evaluation of Recurrent, Unexplained Syncope Blair P. Grubb, MD*, Edward Orecchio, MDt, and Thaddeus W. Kurczynski, MD, PhDt
Recurrent syncope is one of the most common problems referred to the pediatric neurologist for evaluation. Traditional evaluations are time consuming and expensive, and leave 40% of patients without a precise diagnosis. Vasovagai syncope has been believed to be a common cause of syncope; however, no reliable diagnostic modality has been available to confirm this theory. Head-upright tilt table testing has recently emerged as a useful tool in the evaluation and management of recurrent, unexplained syncope. In this review, we present the pathophysiologic mechanisms of vasovagal syncope and relate them to the reflexes triggered during head-upright tilt table testing. Additionally, we review the clinical data on the uses of this test in unexplained syncope, suggest a practical testing protocol, and elaborate potential therapeutic modalities that can be employed to prevent further episodes. Head-upright tilt table testing will likely become a standard test employed by both adult and child neurologists. Grubb BP, Orecchio E, Kurczynski TW. Head-upright tilt table testing in evaluation of recurrent, unexplained syncope. Pediatr Neurol 1992;8:423-7.
Introduction Recurrent, unexplained syncope is a major problem in the United States accounting for up to 6% of all hospital admissions [1] and up to 3-4% of all emergency room visits [2]. The precise incidence of recurrent syncope in children and adolescents is not known but is presumed to be at nearly equivalent proportions [3]. The classic diagnostic workup of syncope in the child or adolescent is frequently both expensive and unrewarding [4]. Recent studies suggested that over 40% of patients with recurrent syncope are never given a definitive diagnosis [5] and many of these individuals continue to experience syncopal episodes [6]. The cost of an evaluation in older patients often averages about $2,563 per patient in the United States, or roughly $23,855 per patient with syncope of a discernable cause [4,7]. The usual diagnostic evaluations -cranial computed tomography, Holter monitoring, elec-
From the *ElectrophysiologySection; Division of Cardiology; Department of Medicine; and tDivision of Pediatric Neurology; Departments of Pediatrics and Neurology; Medical College of Ohio; Toledo, Ohio.
troencephalography (EEG), glucose tolerance testing, and, in some cases, intracardiac electrophysiologic studiesare frequently unrevealing in both children and adults [4,5]. These unexplained, recurrent syncopal episodes can produce extreme stress in affected individuals and their families. A recent report suggested that the degree of functional impairment caused by recurrent syncope is comparable to that of chronic rheumatoid arthritis and similar to other chronic disabling disorders [8]. Bodily injuries, which may include fractures of the nose, ribs, hip, and legs as well as subdural hematomas, also can occur in a child or adolescent who has syncope [9]. In many of these individuals with recurrent idiopathic syncope, the postulated mechanism has been vasovagalmediated episodes of hypotension and bradycardia [4]; however, until recently, no effective clinical laboratory method has been available for reproducing these syncopal episodes and thereby confirming the diagnosis [10]. In order to determine the susceptibility of patients with recurrent idiopathic syncope to these vasovagal episodes, it has been suggested that a strong orthostatic stimulus, such as prolonged passive upright posture, could be employed [10]. Investigators have reported that headupright tilt table testing may indeed be useful in revealing a predisposition to vasovagal-mediated hypotension and bradycardia (neuroregulatory dysfunction) as a cause of syncope [10-12]. This review examines the physiologic and pathophysiologic concepts upon which tilt table testing is based, considers its use in the evaluation of recurrent syncope and in the differentiation of convulsive syncope from epilepsy, suggests a practical testing protocol, and discusses potential therapies that may be useful in preventing recurrent syncopal episodes.
Pathophysiologic Aspects Over the last 50 years, investigators have elaborated on the responses of normal subjects to the assumption of upright posture [13-15]. At first, these studies focused principally on the body's response to rapid changes in posture [16], while later inquiries elaborated on how the body reacts to higher degrees of stress imposed by aerospace travel [17]. From these investigations, it has been
Communications should be addressed to: Dr. Grubb; Division of Cardiology;Medical Collegeof Ohio; 3000 Arlington Avenue;P.O. Box 10008; Toledo,OH 43699. Received March 5, 1992; acceptedJune 8, 1992.
Grubb et ai: Tilt TableTestingand Syncope 423
determined that when an individual assumes an uptight posture, a resultant gravity-mediated increase in peripheral venous pooling occurs [ 18], which is then compensated for by a reflex-mediated augmentation in both heart rate and peripheral vasoconstriction [19]. Normally, this process results in a relatively gradual decrease in venous return to the heart, causing the cardiac mechanoreceptors (C fibers) located in the base of both the right and left ventricles to reduce their output resulting in reflex sympathetic stimulation [20]; therefore, in response to upright posture, the normal individual exhibits an increase in heart rate, unchanged or slightly decreased systolic blood pressure, and a mild increase in diastolic blood pressure [21 ]. In those individuals who experience vasovagal syncope, however, it is postulated that a rapid reduction in peripheral venous return to the heart allows for very vigorous contractions of a nearly "empty" right ventricle to occur [22]. This sudden increase in ventricular inotropy results in activation of a large number of cardiac mechanoreceptors resulting in a paroxysmal increase in afferent neural output [23]. The medulla, and in particular the nucleus tractus solitarius, appears to be the principal site where these signals interact [24]. It is currently believed that this surge in normal input to the brainstem somehow mimics the conditions usually observed in hypertension [25] which then provokes an apparent "paradoxical" reflex decrease in heart rate and an increase in peripheral vascular dilatation [26]. This process results in sudden hypotension and bradycardia which, if sufficiently profound, may result in cerebral hypoxia and subsequent loss of consciousness [27]. The responses of the cerebral vasculature during vasovagal syncope have also been evaluated [28]. Until recently, it was believed that cerebral autoregulation occurred solely on a local cerebral arterial level (the myogenic theory) [29]. With changes in systemic arterial pressure, the cerebral arterioles were believed to dilate as the systemic pressure decreased and constrict as it increased thereby maintaining a relatively constant cerebral blood flow [30]. To evaluate this finding, Grubb et al. performed transcranial doppler sonography on 30 patients undergoing head-upright tilt table testing [28]. Of these patients, 20 experienced vasovagal syncope during the study, at which time transcranial Doppler sonography revealed evidence of intense cerebral vasoconstriction which occurred with sudden, profound hypotension. Nelson et al. reported identical findings using a rabbit model [31]. This response of the cerebral vasculature is paradoxical and suggests that sudden changes in cerebral vascular resistance (arteriolar vasoconstriction) may play an important role in producing vasovagal-mediated syncope [28]. H e a d - u p r i g h t Tilt T a b l e Testing
Head-upright tilt table testing has been proposed as a means of provoking episodes of vasovagal syncope in
424 PEDIATRIC NEUROLOGY Vol. 8 No. 6
susceptible individuals by initiating the reflex sequence just described [ 10]. This response is accomplished by exposing the individual to strong orthostatic stress, such as that provided by prolonged, passive upright posture, in order to produce maximal venous pooling [25]. Early studies utilizing this technique demonstrated that ~yncope only rarely occurs in normal subjects during upright tilt [1[]. Shvartz and Myerstein reported only 3 syncopal episodes among 36 control subjects who underwent tih testing at an angle of 70 ° for 20 min [32]. In a similar study, Vogt reported only 2 syncopal episodes following 64 trials of head-up tilt at 70 ° for 20 rain among 9 male volunteers [33]. Extensive studies by Sheldon and Killman [34] and Fitzpatrick et al. [35] demonstrated an incidence of syncope in normal volunteers of 7-13%. The responses of patients with a history of vasovagal syncope are markedly distinct. In the initial observations by Kenny et al., 10 of 15 patients (67%) with unexplained syncope had positive tests at approximately 29 _+ 19 min into upright-tilt [10]. Abi-Samra et al. reproduced syncopal episodes in 63 of 154 patients with recurrent idiopathic syncope with head-upright tilt table testing [361]. Strasburg et al. evaluated 40 patients with recurrent, unexplained syncope by means of a 60 ° head-upright tilt maintained for 60 min; 10 controls with no history of syncope were also studied [37]. Syncope was provoked in 15 patients (38%) after a mean tilt time of 42 + 12 min; no control subject experienced syncope during tilt. A similar study by Raviele et al. evaluated 30 patients with recurrent syncope with a 60 ° tilt for 60 rain [38]. Fifteen patients (50%) had syncopal episodes reproduced, while 8 concomitant controls had no symptoms. A number of investigators utilized low-level graded isoproterenol infusions as a provocative agent during headupright tilt table testing [39]. This technique was based on observations that sympathetic adrenal activity increases markedly just prior to the onset of syncope [40,41 ]. This approach was first reported by Almquist et al. during an evaluation of 24 patients with recurrent, unexplained syncope [42]. Following the initial head-upright tilt table test, only 5 patients experienced syncope; however, when the tilt was repeated in conjunction with a low-level isoproterenol infusion an additional 9 patients had positive tests. A subsequent study by Chen et al. confirmed these findings and addressed the issue of reproducibility [43 I. Twenty-three patients with recurrent idiopathic syncope were evaluated with two consecutive head-upright tilt table tests which were performed both in the baseline state and during a graded isoproterenol infusion. A second tilt-table study then was conducted under identical conditions, utilizing an identical amount of isoproterenol (if any) as the initial tilt. Of these 23 patients, 15 (65%) developed syncope during the initial tilt. These results then were reproduced, either positive or negative studies, in 20 of 23 patients (87%) during the second tilt. A similar study by Sheldon et al. reported that isoproterenol tilt table tests had an 85-90% symptomatic reproducibility [44].
Tilt Table Testing in Pediatric Patients Several studies have investigated the use of headupright tilt table testing in the evaluation of children and adolescents with recurrent, unexplained syncope. Thilenius et al. reported the ability to reproduce clinical syncopal episodes in 26 of 35 pediatric patients with recurrent, unexplained syncope using head-upright tilt table testing [45]. Lerman-Sagie et al. evoked positive responses in 6 of 14 children during tilt testing [46], while Ross et al. evaluated 104 pediatric patients with recurrent idiopathic syncope and was able to provoke syncope in 47 (45%) [47]. Pongiglione et al. evaluated the use of tilt table testing combined with graded isoproterenol infusions, and were able to reproduce syncope in 16 of 20 young patients (80%) with recurrent idiopathic syncope [48]. A recent study by Grubb et al. reported similar findings [49].
Head-upright Tilt Table Testing in Differentiation of Convulsive Syncope from Epilepsy One of the disorders most commonly confused with epilepsy is vasovagal syncope [50]. Over the years, investigators have reported that severe vasovagal episodes may be accompanied by tonic-clonic seizure-like movements (convulsive syncope) [51]. A recent study by Grubb et al. tested the hypothesis that in some patients with recurrent idiopathic seizures, their episodes may be secondary to vasovagal syncope rather than epilepsy, and head-upright tilt table testing may be useful in identifying these individuals [52]. Fifteen patients with a history of recurrent, generalized seizures of unknown origin, with normal EEGs who continued to experience seizure-like episodes despite adequate doses of antiseizure medications were studied. Head-upright tilt table testing, both baseline and in conjunction with a graded isoproterenol infusion, was performed in the fasting, drug-free state. Vasovagal syncope associated with tonic-clonic seizure activity (convulsive syncope) occurred in 6 patients (40%) during the initial tilt and in 4 additional patients (27%) during tilt combined with a graded isoproterenol infusion (total positive patients: 67%). A second drug-free tilt table study was performed in 5 patients under identical conditions as the first, this time with continuous EEG recording. Each of these patients had convulsive syncopal episodes reproduced during which EEG revealed diffuse slowing indicative of cerebral hypoxia rather than the hypersynchronous spike-and-wave activity observed in epileptic seizures [50]. Jaeger et al. reported comparable results with headupright tilt table testing in 16 children with recurrent seizure-like episodes who had convulsive syncope during ocular compression testing [53]. These findings suggest that head-upright tilt table testing may prove useful in the differentiation of convulsive syncope from epilepsy in patients with recurrent idiopathic seizures [52,53].
Testing Protocols The optimal protocol to be utilized during head-upright tilt table testing has yet to be identified; therefore, a variety
of different methods is utilized. Many physiologic studies have suggested that a minimum angle of 60 ° should be employed, while the maximum angle should not exceed 80 ° [15]. Fitzpatrick et al. suggested that, when used alone, tilting at 60 ° for 45 min has a 75% yield [35]. Benditt et al. recently proposed a standardization scheme to optimize results while creating a greater uniformity of research data [54]. In our laboratory, tilt table testing is usually performed in the morning following an overnight fast. Cardioactive (or antiseizure) medications are discontinued for 5 half-lives prior to the study. An intravenous line is established, and the patient is connected to a standard electrocardiographic monitor for continuous evaluation of heart rate and rhythm. A standard sphygmomanometer is used to measure blood pressure. Respiratory rate is measured every 3 min by direct observation. The patient then is placed on a tilt table with a foot board made for weight bearing. After a 20 min rest, baseline heart rate and blood pressure measurements are determined, and the patient then is positioned at an angle 80 ° from horizontal for up to 30 min. Blood pressure is measured every 3 min, and electrocardiographic monitoring is performed continuously (Fig 1). If syncope (hypotension and bradycardia with resultant loss of consciousness) were to develop during the tilt, the patient would be lowered to the supine position and the study concluded. If no syncope were to occur, the patient would be lowered to the supine position for 10 min and an intravenous infusion of isoproterenol begun at 1 ~tg/min (for those children weighing less than 50 kg, 0.015 ~tg/kg/min is employed). Upright tilt table testing then is performed as previously described for 15 min. When negative, the patient is returned to the supine position, the isoproterenol infusion is increased to 2 ~tg/min (or 0.03 ~tg/kg/min), and head-upright tilt table testing is repeated. If again negative, a third tilt would be performed at 3 ktg/min. We successfully used this technique with children as young as 3 years (although with this age group, we found it useful to have a parent present during the test). If the patient were evaluated for convulsive syncope, tilt table testing would be performed along with continuous EEG recording.
Therapy A variety of therapeutic modalities has been employed to help prevent recurrent, severe syncopal episodes. Betal adrenergic blocking agents have been successfully employed to prevent further syncopal episodes [25]. Although the precise mechanism is unknown, they presumably exert negative inotropic actions that decrease the force of ventricular contraction and thereby reduce the degree of mechanoreceptor activation [42,55]. Sra et al. recently reported that intravenous esmolol can be used during tilt table testing to predict the efficacy of oral beta-blocking agents in preventing vasovagal syncope [56]. In our laboratory, patients with positive tilt studies are given 510 mg of intravenous metoprolol and testing is repeated after 15 min. Transdermal scopolamine has been reported
Grubbet al: TiRTableTestingand Syncope 425
I
Recent studies by both Grubb et al. [621 and Gamache et al. [63] documented that a therapy effecti,.e in pt'eventing syncope during repeated tilt testing, in patienls with an initially positive tilt study, appears to be predictive of longterm efficacy in preventing long-term syncope recurrence. Traditionally, the evaluation of recurrent syncope has been frustrating, time consuming, expensive, and frequently unrewarding. The emergence of head-upright lilt table testing has dramatically altered this situation, allowing a simple, safe, inexpensive, and effective technique for determining susceptibility to vasovagal-mediated syncope and evaluating the efficacy of proposed therapies; however, the precise sensitivity and specificity of the technique has not been defined and the optimal test protocol used in pediatric patients has not been determined. In addition, double-blind, prospective evaluations of potential therapies still need to be performed. Despite these limitations, head-upright tilt table studies will likely become a commonly used modality in the neurologist's diagnostic armamentarium.
NPO IVLine Supine 20 min 80* Tilt 30 Minutes
t
I
I
Study ~ (~ End
Supine10 min Then
Tilt15min ~ (~ End Study
References Supine10 min Then
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I
Ire Infusion3/~g/min 1 Supine10mln Then
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~
~ End synm,~ O No Syncope
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ISO = Isopl~erenol
Figure 1. Medical College of Ohio pediatric tilt test protocol.
to be effective in a number of individuals, an effect attributed to its reduction of the high vagal tone produced during these episodes [36,57]; however, some investigators suggested that the agent may act centrally as well [58]. Milstein et al. reported that disopyramide, an antiarrhythmic with both negative inotropic and vagolytic properties, was highly effective in preventing recurrent syncope [59]. Flurohydrocortisone has been utilized to achieve volume expansion and has been used as either primary or adjuvant therapy; it appears to be particularly helpful in treating children with recurrent syncope [45,47,49]. In patients who demonstrate prolonged episodes of asystole- the malignant vasovagal syndrome- permanent pacemaker insertion may be necessary when pharmacotherapy proves ineffective [60,61].
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[1] Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of con~iousness. Am J Med 1982;73:15-23. [2] Gendelman HE, Linzer M, Gabelman M, Smoller J. Syncope in a general hospital patient population. NY State J Med 1983;83:1161-5. [3] Ross BA. Evaluation and treatment of syncope in children. Heart House Learn Center Highlights 1990;5:7-10. [4] Hannon D, Ross B. Head-up tilt testing in children who faint. J Pediatr 1991;118:731-2. [5] Kapoor W. Diagnostic evaluation of syncope. Am J Med 1991; 90:91-106. [6] Kapoor W, Karpf M, Wieand S, Peterson JR, Levey GS. A prospective evaluation and follow up of patients with syncope. N Engl J Med 1983;309:197-204. [7] Kapoor W, Karpf M, Maher Y, Miller R, Levey GS. Syncope of unknown origin: The need for a more cost-effective approach to its diagnostic evaluation. JAMA 1982;247:2687-91. [8] Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. Impairment of physical and psychomotor health in recurrent syncope. Clin Res 1990;38:698A. [9] Silverstein MD, Singer DE, Mulley A, Thibault GE, Barnett GO. Patients with syncope admitted to medical intensive care units. JAMA 1982;248:1185-9. [10] Kenny RA, lngram A, Bayliss J, Sutton R. Head-up tilt: A useful tool for investigating unexplained syncope. Lancet 1986;2: 1352-4. [11] Fitzpatrick A, Sutton R. Tilting toward a diagnosis in unexplained recurrent syncope. Lancet 1989;1:658-60. [12] Grossi D, Nozzoli C, Roca M, Santostasi R, Simone E Headup tilt test for triggering and diagnosing syncope. Funct Neurol 1987; 11:457-63. [13] Barach JH, Marks WL. Effects of changes in posture without active muscular exertion on the arterial and venous pressures. Arch Intern Med 1913;11:485-9. [14] Asmussen E, Christensen EH, Neilson M. The regulation of the circulation in different postures. Surgery 1940;8:604-8. [15] Hellebrandt FA, Franseen EB. Physiological study of the vertical stance in man. Physiol Rev 1943;23:220-5. [16] Allen SC, Taylor CL, Hall VE. A study of orthostatic inefficiency by the tilt board method. Am J Physiol 1945;I 43:11-6. [17] Abeimen WH, Fareeduddin K. Circulatory response to upright tilt in patients with heart disease. Aerosp Med 1967;38:60-5.
[18] Lagerof H, Eliasch H, Werkol L. Orthostatic changes of the pulmonary and peripheral circulation in man. Scand J Clin Lab Invest 1951;3:85. [19] Bie E Secher N, Astrup A, Warberg J. Cardiovascular and endocrine responses to head-upright tilt and vasopressin infusion in humans. Am J Physiol 1986;251:732-41. [20] Thoren P. Role of cardiac vagal C fibers in cardiovascular control. Rev Physiol Biochem Pharmacol 1979;86: 1-94. [21] Pelletier CL, Shepherd JT. Circulatory reflexes from mechanoreceptors in the cardiothoracic area. Circ Res 1973;33:131-8. [22] Streeten D, Anderson G, Richardson R, Thomas D. Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: Evidence for excessive venous pooling. J Lab Clin Med 1988;111:326-35. [23] Sander-Jensen K, Secher N, Astrup A, et al. Hypotension induced by passive head-up tilt: Endocrine and circulatory mechanisms. Am J Physiol 1986;251:742-8. [24] Coleridge HM, Coleridge JC. Cardiovascular afferents involved in regulation of peripheral vessels. Annu Rev Physiol 1980;42: 413-27. [25] Milstein S, Reyes W, Benditt D. Upright body tilt for evaluation of patients with recurrent syncope. PACE 1989;12:117-24. [26] Mark AL. The Bezold-Jarish reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1983;1:90-102. [27] Gliek C, Yu PN. Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 1963;34:42-7. [28] Grubb BE Gerard G, Roush K, et ai. Cerebral vasoconstriction during upright tilt induced syncope: A paradoxic and unexpected response. Circulation 1991 ;84:1157-64. [29] Hansson L. Arterial hypotension and its consequences for the cerebral circulation. Acta Med Scand 1979;628:17-20. [30] Strandgeard S, Olesen J, Skinhei E, Lasson N. Autoregulation of the brain circulation on severe arterial hypertension. Br Med J 1973; 1:507-10. [31] Nelson ILl, Perry S, Hames TK, Pichard JD. Transcranial doppler ultrasound studies of cerebral autoregulation and subarachnoid hemorrhage in the rabbit. J Neurosurg 1990;73:601-8. [32] Shvartz E, Myerstein N. Tilt tolerance in young men and women. Aerosp Med 1970;41:253-6. [33] Vogt FB. Tilt table and plasma volume changes with short term deconditioning experiments. Aerosp Med 1967;38:564. [34] Sheldon R, Killman S. Methodology of isoproterenol tilt table testing in patients with syncope. J Am Coil Cardiol 1992;19:773-9. [35] Fitzpatrick A, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt table testing in patients with unexplained syncope. J Am Coil Cardiol 1991;17:125-30. [36] Abi-Samra E Maloney J, Fouad FM, Castle L. The usefulness of head-up tilt table testing and hemodynamic investigations in the work-up of syncope of unknown origin. PACE 1987; 10:406. [37] Strasburg B, Rechavia E, Sagie A, et al. The head-up tilt table test in syncope of unknown origin. Am Heart J 1989;118:923-7. [38] Raviele A, Gasparini G, DiPede E Delise E Bono A, Piccolo E. Usefulness of head-up tilt table test in evaluating patients with syncope of unknown origin and negative electrophysiologic study. Am J Cardiol 1990;65:1322-7. [39] Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol induction of vasodepressor-type reaction in vasodepressor prone persons. Am J Cardiol 1989;63:50-65. [40] Chosy J J, Graham DT. Catecholamines in vasovagal fainting. J Psychosom Med 1984;46:95-9. [41] Wallin BG, Sundlof G. Sympathetic outflow in muscles during vasovagal syncope. J Auton Nerv Syst 1982;6:287-91. [42] AImquist A, Goldenburg I, Milstein S, et al. Provocation of hradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 1980;32:346-51.
[43] Chert XC, Chen MY, Remole S, et al. Reproducibility of upright tilt table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease. Am J Cardiol 1992;69: 755-60. [44] Sheldon R, Splawinski J, Killman S. Reproducibility of isoproterenol tilt table tests in patients with syncope. Am J Cardiol 1992; 69:1300-5. [45] Thilenius OG, Quinones JA, Husayni TS, Novak J. Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics 1991;87:334-8. [46] Lerman-Sagie T, Rechavia E, Strausberg B, Sagie A, Blieden L, Mimouni M. Head-up tilt for the evaluation of syncope of unknown origin in children. J Pediatr 1991;118:676-9. [47] Ross B, Hughes S, Anderson E, Gillette E Abnormal responses to orthostatic testing in children and adolescents with recurrent unexplained syncope. Am Heart J 1991;122:748-54. [48] Pongiglione G, Fish FA, Strasburger JF, Benson DW. Heart rate and blood pressure response to upright tilt in young patients with unexplained syncope. J Am Coll Cardiol 1990; 16:165-70. [49] Grubb BE Temesy-Armos E Moore J, Wolfe D, Hahn H, Elliott L. Utility of head-upright tilt table testing in the diagnosis and management of recurrent syncope in children and adolescents. PACE 1992;15:742-7. [50] Engle J. Differential diagnosis of seizures. In: Engle J, ed. Seizures and epilepsy. Philadelphia: FA Davis, 1989;340-1. [51] Stephenson JBE Reflex anoxic seizures: Non-epileptic vagal attacks. Arch Dis Child 1978;53:193-200. [52] Grubb BE Gerard G, Roush K, et al. Convulsive syncope and epilepsy: Differentiation with head-up tilt testing. Ann Intern Med 1991;115:871-6. [53] Jaeger E Schneider L, Maloney J, Cruse R, Fouad-Tarazi FM. Vasovagal syncope: Diagnostic role of head-up tilt test in patients with a positive ocular compression test. PACE 199l;13:1416-23. [54] Benditt D, Remole S, Balin S, Dunnigan A, Asso A, Milstein S. Tilt table testing for evaluation of neurally-mediated (cardioneurogenic) syncope: Rationale and proposed protocols. PACE 1991;14: 1528-37. [551 Thames M. Effect of d- and l-propranolol on the discharge of cardiac vagal C fibers. Am J Physiol 1980;238:H465-7. [56] Sra J, Murthy V, Jazayeri M, et al. U ~ of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coil Cardiol 1992;19:402-8. [57] Jaeger FJ, Fouad-Tarazi FM; Abi-Samra FM, Cruse RF, Castle LW, Maloney JD. Transdermal scopolamine for treatment of vasovagal syncope. Clin Res 1987;35:832. [58] Vybiral T, Byrg R, Maddens M, et al. Effects of transdermal scopolamine on heart rate variability in normal subjects. Am J Cardiol 1990;65:604-8. [59] Milstein S, Buetikofer J, Dunnigan A, Benditt D, Garnick C, Reyes W. Usefulness of disopyramide for prevention of upright tilt induced hypotension-bradycardia. Am J Cardiol 1990;65:1339-44. [60] Sapire DW, Casta A, Safley W, O'Riordan AC, Balsara RK. Vasovagal syncope in children requiring pacemaker implantation. Am Heart J 1983;65:1339-44. [61] Grubb BP, Temesy-Armos E Wolfe D, Moore J, Hahn H, Elliott L. The use of head upright tilt table testing in the evaluation and management of the malignant vasovagal syndrome. Am J Cardiol 1992; 69:904-8. [62] Gruhb BE Temesy-Armos E Hahn H, Elliott L. Utility of upright tilt table testing in the evaluation and management of syncope of unknown origin. Am J Med 1991;90:6-10. [63] Gamache C, Janosiki D, Redd R, Bjerregaard E Long term outcome of head-up tilt guided therapy in patients with neurally mediated syncope. PACE 1991;14:663.
Grubb et al: Tilt Table Testing and Syncope 427
Recurrent syncope is one of the most common problems referred to the pediatric neurologist for evaluation. Traditional evaluations are time consuming and expensive, and leave 40% of patients without a precise diagnosis. Vasovagai syncope has been believed to be a common cause of syncope; however, no reliable diagnostic modality has been available to confirm this theory. Head-upright tilt table testing has recently emerged as a useful tool in the evaluation and management of recurrent, unexplained syncope. In this review, we present the pathophysiologic mechanisms of vasovagal syncope and relate them to the reflexes triggered during head-upright tilt table testing. Additionally, we review the clinical data on the uses of this test in unexplained syncope, suggest a practical testing protocol, and elaborate potential therapeutic modalities that can be employed to prevent further episodes. Head-upright tilt table testing will likely become a standard test employed by both adult and child neurologists. Grubb BP, Orecchio E, Kurczynski TW. Head-upright tilt table testing in evaluation of recurrent, unexplained syncope. Pediatr Neurol 1992;8:423-7.
Introduction Recurrent, unexplained syncope is a major problem in the United States accounting for up to 6% of all hospital admissions [1] and up to 3-4% of all emergency room visits [2]. The precise incidence of recurrent syncope in children and adolescents is not known but is presumed to be at nearly equivalent proportions [3]. The classic diagnostic workup of syncope in the child or adolescent is frequently both expensive and unrewarding [4]. Recent studies suggested that over 40% of patients with recurrent syncope are never given a definitive diagnosis [5] and many of these individuals continue to experience syncopal episodes [6]. The cost of an evaluation in older patients often averages about $2,563 per patient in the United States, or roughly $23,855 per patient with syncope of a discernable cause [4,7]. The usual diagnostic evaluations -cranial computed tomography, Holter monitoring, elec-
From the *ElectrophysiologySection; Division of Cardiology; Department of Medicine; and tDivision of Pediatric Neurology; Departments of Pediatrics and Neurology; Medical College of Ohio; Toledo, Ohio.
troencephalography (EEG), glucose tolerance testing, and, in some cases, intracardiac electrophysiologic studiesare frequently unrevealing in both children and adults [4,5]. These unexplained, recurrent syncopal episodes can produce extreme stress in affected individuals and their families. A recent report suggested that the degree of functional impairment caused by recurrent syncope is comparable to that of chronic rheumatoid arthritis and similar to other chronic disabling disorders [8]. Bodily injuries, which may include fractures of the nose, ribs, hip, and legs as well as subdural hematomas, also can occur in a child or adolescent who has syncope [9]. In many of these individuals with recurrent idiopathic syncope, the postulated mechanism has been vasovagalmediated episodes of hypotension and bradycardia [4]; however, until recently, no effective clinical laboratory method has been available for reproducing these syncopal episodes and thereby confirming the diagnosis [10]. In order to determine the susceptibility of patients with recurrent idiopathic syncope to these vasovagal episodes, it has been suggested that a strong orthostatic stimulus, such as prolonged passive upright posture, could be employed [10]. Investigators have reported that headupright tilt table testing may indeed be useful in revealing a predisposition to vasovagal-mediated hypotension and bradycardia (neuroregulatory dysfunction) as a cause of syncope [10-12]. This review examines the physiologic and pathophysiologic concepts upon which tilt table testing is based, considers its use in the evaluation of recurrent syncope and in the differentiation of convulsive syncope from epilepsy, suggests a practical testing protocol, and discusses potential therapies that may be useful in preventing recurrent syncopal episodes.
Pathophysiologic Aspects Over the last 50 years, investigators have elaborated on the responses of normal subjects to the assumption of upright posture [13-15]. At first, these studies focused principally on the body's response to rapid changes in posture [16], while later inquiries elaborated on how the body reacts to higher degrees of stress imposed by aerospace travel [17]. From these investigations, it has been
Communications should be addressed to: Dr. Grubb; Division of Cardiology;Medical Collegeof Ohio; 3000 Arlington Avenue;P.O. Box 10008; Toledo,OH 43699. Received March 5, 1992; acceptedJune 8, 1992.
Grubb et ai: Tilt TableTestingand Syncope 423
determined that when an individual assumes an uptight posture, a resultant gravity-mediated increase in peripheral venous pooling occurs [ 18], which is then compensated for by a reflex-mediated augmentation in both heart rate and peripheral vasoconstriction [19]. Normally, this process results in a relatively gradual decrease in venous return to the heart, causing the cardiac mechanoreceptors (C fibers) located in the base of both the right and left ventricles to reduce their output resulting in reflex sympathetic stimulation [20]; therefore, in response to upright posture, the normal individual exhibits an increase in heart rate, unchanged or slightly decreased systolic blood pressure, and a mild increase in diastolic blood pressure [21 ]. In those individuals who experience vasovagal syncope, however, it is postulated that a rapid reduction in peripheral venous return to the heart allows for very vigorous contractions of a nearly "empty" right ventricle to occur [22]. This sudden increase in ventricular inotropy results in activation of a large number of cardiac mechanoreceptors resulting in a paroxysmal increase in afferent neural output [23]. The medulla, and in particular the nucleus tractus solitarius, appears to be the principal site where these signals interact [24]. It is currently believed that this surge in normal input to the brainstem somehow mimics the conditions usually observed in hypertension [25] which then provokes an apparent "paradoxical" reflex decrease in heart rate and an increase in peripheral vascular dilatation [26]. This process results in sudden hypotension and bradycardia which, if sufficiently profound, may result in cerebral hypoxia and subsequent loss of consciousness [27]. The responses of the cerebral vasculature during vasovagal syncope have also been evaluated [28]. Until recently, it was believed that cerebral autoregulation occurred solely on a local cerebral arterial level (the myogenic theory) [29]. With changes in systemic arterial pressure, the cerebral arterioles were believed to dilate as the systemic pressure decreased and constrict as it increased thereby maintaining a relatively constant cerebral blood flow [30]. To evaluate this finding, Grubb et al. performed transcranial doppler sonography on 30 patients undergoing head-upright tilt table testing [28]. Of these patients, 20 experienced vasovagal syncope during the study, at which time transcranial Doppler sonography revealed evidence of intense cerebral vasoconstriction which occurred with sudden, profound hypotension. Nelson et al. reported identical findings using a rabbit model [31]. This response of the cerebral vasculature is paradoxical and suggests that sudden changes in cerebral vascular resistance (arteriolar vasoconstriction) may play an important role in producing vasovagal-mediated syncope [28]. H e a d - u p r i g h t Tilt T a b l e Testing
Head-upright tilt table testing has been proposed as a means of provoking episodes of vasovagal syncope in
424 PEDIATRIC NEUROLOGY Vol. 8 No. 6
susceptible individuals by initiating the reflex sequence just described [ 10]. This response is accomplished by exposing the individual to strong orthostatic stress, such as that provided by prolonged, passive upright posture, in order to produce maximal venous pooling [25]. Early studies utilizing this technique demonstrated that ~yncope only rarely occurs in normal subjects during upright tilt [1[]. Shvartz and Myerstein reported only 3 syncopal episodes among 36 control subjects who underwent tih testing at an angle of 70 ° for 20 min [32]. In a similar study, Vogt reported only 2 syncopal episodes following 64 trials of head-up tilt at 70 ° for 20 rain among 9 male volunteers [33]. Extensive studies by Sheldon and Killman [34] and Fitzpatrick et al. [35] demonstrated an incidence of syncope in normal volunteers of 7-13%. The responses of patients with a history of vasovagal syncope are markedly distinct. In the initial observations by Kenny et al., 10 of 15 patients (67%) with unexplained syncope had positive tests at approximately 29 _+ 19 min into upright-tilt [10]. Abi-Samra et al. reproduced syncopal episodes in 63 of 154 patients with recurrent idiopathic syncope with head-upright tilt table testing [361]. Strasburg et al. evaluated 40 patients with recurrent, unexplained syncope by means of a 60 ° head-upright tilt maintained for 60 min; 10 controls with no history of syncope were also studied [37]. Syncope was provoked in 15 patients (38%) after a mean tilt time of 42 + 12 min; no control subject experienced syncope during tilt. A similar study by Raviele et al. evaluated 30 patients with recurrent syncope with a 60 ° tilt for 60 rain [38]. Fifteen patients (50%) had syncopal episodes reproduced, while 8 concomitant controls had no symptoms. A number of investigators utilized low-level graded isoproterenol infusions as a provocative agent during headupright tilt table testing [39]. This technique was based on observations that sympathetic adrenal activity increases markedly just prior to the onset of syncope [40,41 ]. This approach was first reported by Almquist et al. during an evaluation of 24 patients with recurrent, unexplained syncope [42]. Following the initial head-upright tilt table test, only 5 patients experienced syncope; however, when the tilt was repeated in conjunction with a low-level isoproterenol infusion an additional 9 patients had positive tests. A subsequent study by Chen et al. confirmed these findings and addressed the issue of reproducibility [43 I. Twenty-three patients with recurrent idiopathic syncope were evaluated with two consecutive head-upright tilt table tests which were performed both in the baseline state and during a graded isoproterenol infusion. A second tilt-table study then was conducted under identical conditions, utilizing an identical amount of isoproterenol (if any) as the initial tilt. Of these 23 patients, 15 (65%) developed syncope during the initial tilt. These results then were reproduced, either positive or negative studies, in 20 of 23 patients (87%) during the second tilt. A similar study by Sheldon et al. reported that isoproterenol tilt table tests had an 85-90% symptomatic reproducibility [44].
Tilt Table Testing in Pediatric Patients Several studies have investigated the use of headupright tilt table testing in the evaluation of children and adolescents with recurrent, unexplained syncope. Thilenius et al. reported the ability to reproduce clinical syncopal episodes in 26 of 35 pediatric patients with recurrent, unexplained syncope using head-upright tilt table testing [45]. Lerman-Sagie et al. evoked positive responses in 6 of 14 children during tilt testing [46], while Ross et al. evaluated 104 pediatric patients with recurrent idiopathic syncope and was able to provoke syncope in 47 (45%) [47]. Pongiglione et al. evaluated the use of tilt table testing combined with graded isoproterenol infusions, and were able to reproduce syncope in 16 of 20 young patients (80%) with recurrent idiopathic syncope [48]. A recent study by Grubb et al. reported similar findings [49].
Head-upright Tilt Table Testing in Differentiation of Convulsive Syncope from Epilepsy One of the disorders most commonly confused with epilepsy is vasovagal syncope [50]. Over the years, investigators have reported that severe vasovagal episodes may be accompanied by tonic-clonic seizure-like movements (convulsive syncope) [51]. A recent study by Grubb et al. tested the hypothesis that in some patients with recurrent idiopathic seizures, their episodes may be secondary to vasovagal syncope rather than epilepsy, and head-upright tilt table testing may be useful in identifying these individuals [52]. Fifteen patients with a history of recurrent, generalized seizures of unknown origin, with normal EEGs who continued to experience seizure-like episodes despite adequate doses of antiseizure medications were studied. Head-upright tilt table testing, both baseline and in conjunction with a graded isoproterenol infusion, was performed in the fasting, drug-free state. Vasovagal syncope associated with tonic-clonic seizure activity (convulsive syncope) occurred in 6 patients (40%) during the initial tilt and in 4 additional patients (27%) during tilt combined with a graded isoproterenol infusion (total positive patients: 67%). A second drug-free tilt table study was performed in 5 patients under identical conditions as the first, this time with continuous EEG recording. Each of these patients had convulsive syncopal episodes reproduced during which EEG revealed diffuse slowing indicative of cerebral hypoxia rather than the hypersynchronous spike-and-wave activity observed in epileptic seizures [50]. Jaeger et al. reported comparable results with headupright tilt table testing in 16 children with recurrent seizure-like episodes who had convulsive syncope during ocular compression testing [53]. These findings suggest that head-upright tilt table testing may prove useful in the differentiation of convulsive syncope from epilepsy in patients with recurrent idiopathic seizures [52,53].
Testing Protocols The optimal protocol to be utilized during head-upright tilt table testing has yet to be identified; therefore, a variety
of different methods is utilized. Many physiologic studies have suggested that a minimum angle of 60 ° should be employed, while the maximum angle should not exceed 80 ° [15]. Fitzpatrick et al. suggested that, when used alone, tilting at 60 ° for 45 min has a 75% yield [35]. Benditt et al. recently proposed a standardization scheme to optimize results while creating a greater uniformity of research data [54]. In our laboratory, tilt table testing is usually performed in the morning following an overnight fast. Cardioactive (or antiseizure) medications are discontinued for 5 half-lives prior to the study. An intravenous line is established, and the patient is connected to a standard electrocardiographic monitor for continuous evaluation of heart rate and rhythm. A standard sphygmomanometer is used to measure blood pressure. Respiratory rate is measured every 3 min by direct observation. The patient then is placed on a tilt table with a foot board made for weight bearing. After a 20 min rest, baseline heart rate and blood pressure measurements are determined, and the patient then is positioned at an angle 80 ° from horizontal for up to 30 min. Blood pressure is measured every 3 min, and electrocardiographic monitoring is performed continuously (Fig 1). If syncope (hypotension and bradycardia with resultant loss of consciousness) were to develop during the tilt, the patient would be lowered to the supine position and the study concluded. If no syncope were to occur, the patient would be lowered to the supine position for 10 min and an intravenous infusion of isoproterenol begun at 1 ~tg/min (for those children weighing less than 50 kg, 0.015 ~tg/kg/min is employed). Upright tilt table testing then is performed as previously described for 15 min. When negative, the patient is returned to the supine position, the isoproterenol infusion is increased to 2 ~tg/min (or 0.03 ~tg/kg/min), and head-upright tilt table testing is repeated. If again negative, a third tilt would be performed at 3 ktg/min. We successfully used this technique with children as young as 3 years (although with this age group, we found it useful to have a parent present during the test). If the patient were evaluated for convulsive syncope, tilt table testing would be performed along with continuous EEG recording.
Therapy A variety of therapeutic modalities has been employed to help prevent recurrent, severe syncopal episodes. Betal adrenergic blocking agents have been successfully employed to prevent further syncopal episodes [25]. Although the precise mechanism is unknown, they presumably exert negative inotropic actions that decrease the force of ventricular contraction and thereby reduce the degree of mechanoreceptor activation [42,55]. Sra et al. recently reported that intravenous esmolol can be used during tilt table testing to predict the efficacy of oral beta-blocking agents in preventing vasovagal syncope [56]. In our laboratory, patients with positive tilt studies are given 510 mg of intravenous metoprolol and testing is repeated after 15 min. Transdermal scopolamine has been reported
Grubbet al: TiRTableTestingand Syncope 425
I
Recent studies by both Grubb et al. [621 and Gamache et al. [63] documented that a therapy effecti,.e in pt'eventing syncope during repeated tilt testing, in patienls with an initially positive tilt study, appears to be predictive of longterm efficacy in preventing long-term syncope recurrence. Traditionally, the evaluation of recurrent syncope has been frustrating, time consuming, expensive, and frequently unrewarding. The emergence of head-upright lilt table testing has dramatically altered this situation, allowing a simple, safe, inexpensive, and effective technique for determining susceptibility to vasovagal-mediated syncope and evaluating the efficacy of proposed therapies; however, the precise sensitivity and specificity of the technique has not been defined and the optimal test protocol used in pediatric patients has not been determined. In addition, double-blind, prospective evaluations of potential therapies still need to be performed. Despite these limitations, head-upright tilt table studies will likely become a commonly used modality in the neurologist's diagnostic armamentarium.
NPO IVLine Supine 20 min 80* Tilt 30 Minutes
t
I
I
Study ~ (~ End
Supine10 min Then
Tilt15min ~ (~ End Study
References Supine10 min Then
Tilt15rain ~ ~ End Study
I
Ire Infusion3/~g/min 1 Supine10mln Then
Tilt15rain I
~
~ End synm,~ O No Syncope
nN~d~S~uT~S E t
Study
ISO = Isopl~erenol
Figure 1. Medical College of Ohio pediatric tilt test protocol.
to be effective in a number of individuals, an effect attributed to its reduction of the high vagal tone produced during these episodes [36,57]; however, some investigators suggested that the agent may act centrally as well [58]. Milstein et al. reported that disopyramide, an antiarrhythmic with both negative inotropic and vagolytic properties, was highly effective in preventing recurrent syncope [59]. Flurohydrocortisone has been utilized to achieve volume expansion and has been used as either primary or adjuvant therapy; it appears to be particularly helpful in treating children with recurrent syncope [45,47,49]. In patients who demonstrate prolonged episodes of asystole- the malignant vasovagal syndrome- permanent pacemaker insertion may be necessary when pharmacotherapy proves ineffective [60,61].
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[1] Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of con~iousness. Am J Med 1982;73:15-23. [2] Gendelman HE, Linzer M, Gabelman M, Smoller J. Syncope in a general hospital patient population. NY State J Med 1983;83:1161-5. [3] Ross BA. Evaluation and treatment of syncope in children. Heart House Learn Center Highlights 1990;5:7-10. [4] Hannon D, Ross B. Head-up tilt testing in children who faint. J Pediatr 1991;118:731-2. [5] Kapoor W. Diagnostic evaluation of syncope. Am J Med 1991; 90:91-106. [6] Kapoor W, Karpf M, Wieand S, Peterson JR, Levey GS. A prospective evaluation and follow up of patients with syncope. N Engl J Med 1983;309:197-204. [7] Kapoor W, Karpf M, Maher Y, Miller R, Levey GS. Syncope of unknown origin: The need for a more cost-effective approach to its diagnostic evaluation. JAMA 1982;247:2687-91. [8] Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. Impairment of physical and psychomotor health in recurrent syncope. Clin Res 1990;38:698A. [9] Silverstein MD, Singer DE, Mulley A, Thibault GE, Barnett GO. Patients with syncope admitted to medical intensive care units. JAMA 1982;248:1185-9. [10] Kenny RA, lngram A, Bayliss J, Sutton R. Head-up tilt: A useful tool for investigating unexplained syncope. Lancet 1986;2: 1352-4. [11] Fitzpatrick A, Sutton R. Tilting toward a diagnosis in unexplained recurrent syncope. Lancet 1989;1:658-60. [12] Grossi D, Nozzoli C, Roca M, Santostasi R, Simone E Headup tilt test for triggering and diagnosing syncope. Funct Neurol 1987; 11:457-63. [13] Barach JH, Marks WL. Effects of changes in posture without active muscular exertion on the arterial and venous pressures. Arch Intern Med 1913;11:485-9. [14] Asmussen E, Christensen EH, Neilson M. The regulation of the circulation in different postures. Surgery 1940;8:604-8. [15] Hellebrandt FA, Franseen EB. Physiological study of the vertical stance in man. Physiol Rev 1943;23:220-5. [16] Allen SC, Taylor CL, Hall VE. A study of orthostatic inefficiency by the tilt board method. Am J Physiol 1945;I 43:11-6. [17] Abeimen WH, Fareeduddin K. Circulatory response to upright tilt in patients with heart disease. Aerosp Med 1967;38:60-5.
[18] Lagerof H, Eliasch H, Werkol L. Orthostatic changes of the pulmonary and peripheral circulation in man. Scand J Clin Lab Invest 1951;3:85. [19] Bie E Secher N, Astrup A, Warberg J. Cardiovascular and endocrine responses to head-upright tilt and vasopressin infusion in humans. Am J Physiol 1986;251:732-41. [20] Thoren P. Role of cardiac vagal C fibers in cardiovascular control. Rev Physiol Biochem Pharmacol 1979;86: 1-94. [21] Pelletier CL, Shepherd JT. Circulatory reflexes from mechanoreceptors in the cardiothoracic area. Circ Res 1973;33:131-8. [22] Streeten D, Anderson G, Richardson R, Thomas D. Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: Evidence for excessive venous pooling. J Lab Clin Med 1988;111:326-35. [23] Sander-Jensen K, Secher N, Astrup A, et al. Hypotension induced by passive head-up tilt: Endocrine and circulatory mechanisms. Am J Physiol 1986;251:742-8. [24] Coleridge HM, Coleridge JC. Cardiovascular afferents involved in regulation of peripheral vessels. Annu Rev Physiol 1980;42: 413-27. [25] Milstein S, Reyes W, Benditt D. Upright body tilt for evaluation of patients with recurrent syncope. PACE 1989;12:117-24. [26] Mark AL. The Bezold-Jarish reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1983;1:90-102. [27] Gliek C, Yu PN. Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 1963;34:42-7. [28] Grubb BE Gerard G, Roush K, et ai. Cerebral vasoconstriction during upright tilt induced syncope: A paradoxic and unexpected response. Circulation 1991 ;84:1157-64. [29] Hansson L. Arterial hypotension and its consequences for the cerebral circulation. Acta Med Scand 1979;628:17-20. [30] Strandgeard S, Olesen J, Skinhei E, Lasson N. Autoregulation of the brain circulation on severe arterial hypertension. Br Med J 1973; 1:507-10. [31] Nelson ILl, Perry S, Hames TK, Pichard JD. Transcranial doppler ultrasound studies of cerebral autoregulation and subarachnoid hemorrhage in the rabbit. J Neurosurg 1990;73:601-8. [32] Shvartz E, Myerstein N. Tilt tolerance in young men and women. Aerosp Med 1970;41:253-6. [33] Vogt FB. Tilt table and plasma volume changes with short term deconditioning experiments. Aerosp Med 1967;38:564. [34] Sheldon R, Killman S. Methodology of isoproterenol tilt table testing in patients with syncope. J Am Coil Cardiol 1992;19:773-9. [35] Fitzpatrick A, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt table testing in patients with unexplained syncope. J Am Coil Cardiol 1991;17:125-30. [36] Abi-Samra E Maloney J, Fouad FM, Castle L. The usefulness of head-up tilt table testing and hemodynamic investigations in the work-up of syncope of unknown origin. PACE 1987; 10:406. [37] Strasburg B, Rechavia E, Sagie A, et al. The head-up tilt table test in syncope of unknown origin. Am Heart J 1989;118:923-7. [38] Raviele A, Gasparini G, DiPede E Delise E Bono A, Piccolo E. Usefulness of head-up tilt table test in evaluating patients with syncope of unknown origin and negative electrophysiologic study. Am J Cardiol 1990;65:1322-7. [39] Waxman MB, Yao L, Cameron DA, Wald RW, Roseman J. Isoproterenol induction of vasodepressor-type reaction in vasodepressor prone persons. Am J Cardiol 1989;63:50-65. [40] Chosy J J, Graham DT. Catecholamines in vasovagal fainting. J Psychosom Med 1984;46:95-9. [41] Wallin BG, Sundlof G. Sympathetic outflow in muscles during vasovagal syncope. J Auton Nerv Syst 1982;6:287-91. [42] AImquist A, Goldenburg I, Milstein S, et al. Provocation of hradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 1980;32:346-51.
[43] Chert XC, Chen MY, Remole S, et al. Reproducibility of upright tilt table testing for eliciting susceptibility to neurally mediated syncope in patients without structural heart disease. Am J Cardiol 1992;69: 755-60. [44] Sheldon R, Splawinski J, Killman S. Reproducibility of isoproterenol tilt table tests in patients with syncope. Am J Cardiol 1992; 69:1300-5. [45] Thilenius OG, Quinones JA, Husayni TS, Novak J. Tilt test for diagnosis of unexplained syncope in pediatric patients. Pediatrics 1991;87:334-8. [46] Lerman-Sagie T, Rechavia E, Strausberg B, Sagie A, Blieden L, Mimouni M. Head-up tilt for the evaluation of syncope of unknown origin in children. J Pediatr 1991;118:676-9. [47] Ross B, Hughes S, Anderson E, Gillette E Abnormal responses to orthostatic testing in children and adolescents with recurrent unexplained syncope. Am Heart J 1991;122:748-54. [48] Pongiglione G, Fish FA, Strasburger JF, Benson DW. Heart rate and blood pressure response to upright tilt in young patients with unexplained syncope. J Am Coll Cardiol 1990; 16:165-70. [49] Grubb BE Temesy-Armos E Moore J, Wolfe D, Hahn H, Elliott L. Utility of head-upright tilt table testing in the diagnosis and management of recurrent syncope in children and adolescents. PACE 1992;15:742-7. [50] Engle J. Differential diagnosis of seizures. In: Engle J, ed. Seizures and epilepsy. Philadelphia: FA Davis, 1989;340-1. [51] Stephenson JBE Reflex anoxic seizures: Non-epileptic vagal attacks. Arch Dis Child 1978;53:193-200. [52] Grubb BE Gerard G, Roush K, et al. Convulsive syncope and epilepsy: Differentiation with head-up tilt testing. Ann Intern Med 1991;115:871-6. [53] Jaeger E Schneider L, Maloney J, Cruse R, Fouad-Tarazi FM. Vasovagal syncope: Diagnostic role of head-up tilt test in patients with a positive ocular compression test. PACE 199l;13:1416-23. [54] Benditt D, Remole S, Balin S, Dunnigan A, Asso A, Milstein S. Tilt table testing for evaluation of neurally-mediated (cardioneurogenic) syncope: Rationale and proposed protocols. PACE 1991;14: 1528-37. [551 Thames M. Effect of d- and l-propranolol on the discharge of cardiac vagal C fibers. Am J Physiol 1980;238:H465-7. [56] Sra J, Murthy V, Jazayeri M, et al. U ~ of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coil Cardiol 1992;19:402-8. [57] Jaeger FJ, Fouad-Tarazi FM; Abi-Samra FM, Cruse RF, Castle LW, Maloney JD. Transdermal scopolamine for treatment of vasovagal syncope. Clin Res 1987;35:832. [58] Vybiral T, Byrg R, Maddens M, et al. Effects of transdermal scopolamine on heart rate variability in normal subjects. Am J Cardiol 1990;65:604-8. [59] Milstein S, Buetikofer J, Dunnigan A, Benditt D, Garnick C, Reyes W. Usefulness of disopyramide for prevention of upright tilt induced hypotension-bradycardia. Am J Cardiol 1990;65:1339-44. [60] Sapire DW, Casta A, Safley W, O'Riordan AC, Balsara RK. Vasovagal syncope in children requiring pacemaker implantation. Am Heart J 1983;65:1339-44. [61] Grubb BP, Temesy-Armos E Wolfe D, Moore J, Hahn H, Elliott L. The use of head upright tilt table testing in the evaluation and management of the malignant vasovagal syndrome. Am J Cardiol 1992; 69:904-8. [62] Gruhb BE Temesy-Armos E Hahn H, Elliott L. Utility of upright tilt table testing in the evaluation and management of syncope of unknown origin. Am J Med 1991;90:6-10. [63] Gamache C, Janosiki D, Redd R, Bjerregaard E Long term outcome of head-up tilt guided therapy in patients with neurally mediated syncope. PACE 1991;14:663.
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