Repeated tilt testing in patients with tilt-positive neurally mediated syncope

Transcription

1 Europace (25) 7, 628e633 Repeated tilt testing in patients with tilt-positive neurally mediated syncope Hugo Ector a, *, Rik Willems a, Hein Heidbüchel a, Tony Reybrouck b,c a Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium b Department of Cardiovascular Rehabilitation, University Hospital Gasthuisberg, Leuven, Belgium c Department of Rehabilitation Sciences, University of Leuven, Leuven, Belgium Submitted 4 February 25, and accepted after revision 25 June 25 Available online 8 September 25 KEYWORDS syncope; tilt test; orthostatic intolerance; tilt training Abstract In this study we have included 222 patients with apparent neurally mediated syncope and with a positive diagnostic tilt test. The mean age was 33.4 G 21.2 years (median 25.3): there were 17 men (median age 25.3) and 115 women (median age 22.6). The age difference between males and females was statistically significant (P Z.2). The response to the diagnostic tilt test was: type 1 (mixed) in 74 patients; type 2A (cardioinhibitory and bradycardia) in 6; type 2B (cardioinhibitory and asystole) in 61; type 3 (vasodepressor) in 81. In all 222 patients the diagnostic tilt test was positive after 19 G 11 min (mean G SD), median time: 18 min. For the four types of syncope, the duration in minutes of the diagnostic tilt test was: type 1 (mixed) 19.5 G 11.4; type 2A (cardioinhibitory) 24.8 G 13.6; type 2B (cardioinhibitory and asystole) 14.7 G 1.2; type 3 (vasodepressor) 21.6 G A significant difference was found between type 2B and type 3 responses (P Z.2). Between males and females no significant differences in the duration of the diagnostic tilt test were found, neither for all responses, nor for the four subtypes. A type 2B (cardioinhibitory and asystole) response occurred in 61 patients. The duration of asystole was 12.8 G 1.6 s (mean G SD; median 9, minimum 3, maximum 6). The head-up tilt test was repeated day after day: one session per day. The response became negative at the second session in 119 patients (54%); at session 3 in 47 (21%); at session 4 in 3 (13%); at session 5 in 15 (7%); at session 6 in 6 (3%); at session 7 in 2 (1%); at session 8 in 3 (1%). For all 222 patients the mean number of sessions in order to obtain a negative tilt test was 2.9 (SD 1.3; median 2). * Corresponding author. Department of Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3 Leuven, Belgium. Tel.: C ; fax: C address: hugo.ector@med.kuleuven.ac.be (H. Ector) /$3 ª 25 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:1.116/j.eupc

2 Repeated tilt testing in neurally mediated syncope 629 Only 25% of patients remained tilt-positive for three or more sessions. A negative tilt test was ultimately obtained in every patient. Follow-up data are available for 22/222 patients. The time span between the first and last tilt test was 11.1 G 1 months (median 8.8). Of these 22 patients, 163 remained free of any event (8.7%). ª 25 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Introduction For patients with suspected neurally mediated syncope, head-up tilt testing is the gold standard to confirm the diagnosis of neurally mediated syncope [1e5]. In a consensus document of the American College of Cardiology (ACC) and a task force report of the European Society of Cardiology (ESC) the key guidelines for the diagnosis and treatment of syncope have been described [4,5]. A new classification of positive responses to tilt testing has recently been introduced [6]. A possible therapeutic impact of repeated tilt testing (tilt training) has been implied [7e9]. Today, tilt training has emerged as a treatment option for recurrent neurally mediated syncope [1e15]. The purpose of the present study was to analyse the response to repeated tilt testing in the different types of neurally mediated syncope. Methods The inclusion criteria were twofold: (i) a clinical diagnosis of neurally mediated syncope, after exclusion of other causes of syncope; (ii) a positive head-up tilt test. We have used the tilt test protocol as recommended by the ESC task force report [5]: a supine pre-tilt phase of at least 5 min when no venous cannulation is performed, and at least 2 min when cannulation is undertaken, a tilt angle of 6, a passive phase of a minimum of 2 min and a maximum of 45 min. For avoiding false positive diagnoses, we did not use pharmacological provocation [16,17]. Tilt sessions were continued until syncope, or until symptoms of severe orthostatic intolerance. Tilt tests were repeated until we obtained a negative tilt test in two consecutive sessions. After the in-hospital tilt training sessions, the patients were instructed to continue this programme of orthostatic training at home by standing every day for one or two 3-min periods against a wall, with their feet 15e3 cm away from the wall. They were followed in the outpatient clinic with control tilt tests. For the classification of positive responses to tilt testing, we have adopted the definitions of the ESC task force report [5]: type 1 (mixed type), type 2A (cardioinhibition without asystole), type 2B (cardioinhibition with asystole) and type 3 (vasodepressor response). Statistics Statistical calculations and graphical figures were performed with SPSS for Windows standard version For age, the duration of the diagnostic test, and the number of the first negative tilt test, we have calculated the mean G standard deviation (SD) and the median. Logistic regression was used for analysing a possible correlation between: (i) outcome and the first negative tilt test; (ii) outcome and duration of the first diagnostic tilt test; (iii) duration of diagnostic tilt test and the first negative session. Scatter plots give all individual values for the age at the time of the first tilt test (Fig. 1), for the duration of this test (Fig. 1), and for the duration of asystole in seconds in type 2B cardioinhibitory syncope (Fig. 3). Fig. 2 gives the mean duration of the diagnostic test versus gender and type of positive response. Results In this study we have included 222 patients with apparent neurally mediated syncope and with a positive diagnostic tilt test. The mean age was 33.4 G 21.2 years (median 25.3): 17 men (38.5 G 22.4 years; median 25.3) and 115 women (28.6 G 18.8 years; median 22.6). The age difference between males and females was statistically significant (P Z.2). The age of all individuals is represented in Fig. 1. There was a great variation in the number of syncopal episodes before the diagnostic tilt test (Table 1).

3 63 H. Ector et al. Duration in Minutes Diagnostic Tilt Test: 222 Patients Age in years at the time of first tilt test The 222 patients underwent a total of 1469 tilt tests: 949 training sessions and 52 follow-up sessions. The response to the diagnostic tilt test was: type 1 (mixed) in 74 patients; type 2A (cardioinhibitory) in 6; type 2B (cardioinhibitory and asystole) in 61; and type 3 (vasodepressor) in 81. The mean (Gstandard deviation) duration in minutes of the diagnostic tilt test was: all tests: 19 G 11 (median 18); type 1 (mixed type) 19.5 G 11.4 (median 2); type 2A (cardioinhibitory) 24.8 G 13.6 (median 21); type 2B (cardioinhibitory and asystole) 14.7 G 1.2 (median 12); type 3 (vasodepressor) 21.6 G 11.1(median 2). The difference between type 2B and type 3 9 Gender FEMALE MALE Figure 1 The diagnostic tilt tests in 222 patients. The x-axis gives the age in years for all patients. The y-axis gives the duration in minutes until the occurrence of syncope. 5 Duration of Diagnostic Test Asystole: Duration in Seconds Cardioinhibitory Response with Asystole Type 2B: 61 patients Patient Age responses was statistically significant (Fig. 2: P Z.2). Between males and females there were no significant differences in the duration of the diagnostic tilt test, neither for all responses, nor for the four subtypes. Figs. 1 and 2 illustrate the duration of the diagnostic tilt test. A type 2B (cardioinhibitory and asystole) response occurred in 61 patients. The duration of asystole amounted to 12.8 G 1.6 s (median 9, minimum 3, maximum 6). In men the duration of asystole averaged 13.5 G 11.9 (median 9) s and in women 11.8 G 8.8 (median 9). Fig. 3 shows the individual episodes of asystole for all 61 type 2B responses. No difference for the duration of asystole was found between male and female patients. The head-up tilt test was repeated day after day: one session per day. The response became negative at the second session in 119 patients (54%); at session 3 in 47 (21%); at session 4 in Gender FEMALE MALE Figure 3 Details of cardioinhibitory responses with asystole in 61 patients. Duration of asystolic response in seconds versus patient age. Mean +- 2 SE Minutes N = MX 2A CI 2B CI 3 VD Positive Response to Tilt Test 45 Gender MALE FEMALE Figure 2 Duration of the diagnostic tilt test versus the different types of positive responses: 1 MX Z mixed; 2A CI Z cardioinhibitory with bradycardia; 2B CI Z cardioinhibitory with asystole; 3 VD Z vasodepressor. Table 1 Clinical spectrum of 222 patients: number (No) of syncopal episodes and numbers of patients Syncope: No No of patients Syncope: No e e2 per day e4 per day e1 per day e2 per week e4 per week e2 per month e4 per year 2 1e15 13 Near-syncope 3 No of patients

4 Repeated tilt testing in neurally mediated syncope 631 (13%); at session 5 in 15 (7%); at session 6 in 6 (3%); at session 7 in 2 (1%); and at session 8 in 3 (1%). Only 25% of patients remained tilt-positive for three or more sessions. A negative response to repeated tilt testing was ultimately obtained in every patient. For all 222 patients the mean number of sessions to achieve the first negative tilt test was reached after 2.9 (SD 1.3; median 2) sessions. We did not find significant differences between the different types of tilt responses. With repeated tilt testing a negative response was found for type 1 (mixed type) after 2.9 G 1.3 (median 2) sessions, for type 2A (cardioinhibitory) after 2.8 G 1.2 (median 2.5) sessions, for type 2B (cardioinhibitory with asystole) after 2.7 G 1.2 sessions (median 2.5) and, for type 3 (vasodepressor) after 3.1 G 1.4 (median 3) sessions. We did not find a correlation between the first negative session and the duration of the diagnostic test. During subsequent tilt tests, a change in the type of syncope was found in only two patients. In these two patients, from session 1 to 2, the type of syncope changed from type 1 to type 2B. There was a gradual increase in the duration of the tilt training sessions: 22.7 G 14.1 (median 21.2) min for session 1, 35.5 G 15.3 (median 45) min for session 2, 38.9 G 13.7 (median 45) min for session 3, and 4.7 G 12.2 (median 45) min for session 4. Differences were significant for session 1 versus 2, 3 and 4 (P! 1); session 2 versus 3 (P!.1); session 2 versus 4 (P!.1). Between session 3 and 4, the difference was not significant. To analyse whether the response to tilt training was influenced by age, we compared a subgroup of patients!3 years of age (N Z 156) with a group of patients O65 years of age (N Z 32). The mean value for the first negative tilt test was 2.8 sessions for the younger age group versus 3.4 sessions for the older group (P Z.2). Follow-up data are available for 22/222 patients. Twenty patients refused the proposed control tilt tests. The time span between the first and the last tilt test was 11.1 G 1.2 months (median 8.85, interquartile range 13.9). Of the 22 patients with adequate follow-up, 163 remained free of any event (8.7%). Frank syncope recurred in 27 (13.4%), syncope after stopping tilt training in 5 (2.5%), a single syncope after a specific trigger in 7 (3.5%). We did not find a correlation between outcome and a first negative session, or between outcome and duration of the diagnostic test. During follow-up after the training sessions, 25 control tilt tests were positive in 23 patients. Five of these patients had experienced recurrence of frank syncope, one presented with syncope after stopping tilt training, 17 patients had not had recurrence of syncope. Discussion Neurally mediated syncope is the result of an excessive, abnormal, autonomic reflex activity. In a substantial number of patients with neurally mediated syncope, subnormal orthostatic tolerance can be documented by a head-up tilt test. The results of this study illustrate that repeated tilt testing can restore normal orthostatic tolerance. A negative response to tilt testing was ultimately obtained in every patient. A therapeutic impact of a tilt test was implied in some early reports [7e9]. In a study not specifically designed to determine the reproducibility of acute serial head-up tilt testing, Morillo et al. [8] observed a striking reduction in the incidence of positive responses both in treated (disopyramide) and not actively treated (placebo) patients. Sheldon et al. [9] were surprised by the apparent reduction in the risk of a recurrence of syncope after a positive tilt-table test. Morillo and Sheldon concluded that the clinical encounter and the tilt test are themselves interventions. A case report from Hoeldtke et al. [7] describes a patient with severe orthostatic hypotension. He failed multiple therapeutic trials, experienced recurrent syncope, and became bedridden. A combination of potent vasoconstrictor drugs initially failed to stabilize his walking blood pressure, yet made it possible for him to perform isometric exercises on a tilt table. By combining pressor drug therapy with tilt table conditioning, his orthostatic intolerance gradually improved and he regained the capacity to walk. Recent reports advocate the therapeutic effect of repeated tilt testing which is sustained by continued standing training at home [1e15]. As early as 194, for the treatment of orthostatic hypotension and orthostatic tachycardia, MacLean and Allen had proposed a treatment with the head-up bed: the patient should sleep in a bed with the head elevated 18 inches (45 cm) [18]. This technique can be considered as an alternative form of orthostatic training. We admit that, in combination with tilt training, we also have prescribed sleeping in a head-up bed for some severe cases of recurrent and malignant syncope. Many reports have raised concerns about poor reproducibility of head-up tilt testing [4,19e27]. However, the knowledge that repeated tilt testing and continued standing training are themselves

5 632 H. Ector et al. a treatment has opened a new therapeutic approach for patients with frequent syncope [1e15]. An indirect physiological explanation for this type of therapy comes from studies on cardiovascular deconditioning in individuals exposed to prolonged spaceflight. In space, development of orthostatic intolerance is well known [28,29]. When astronauts return to Earth, about half experience symptoms of orthostatic intolerance [3]. Crew members exposed to 1e2 weeks of microgravity are sometimes orthostatically intolerant for several hours after landing. However, cosmonauts exposed to many months of microgravity sometimes require several days after return to Earth before they are able to stand and walk unaided [31,32]. The vascular baroreflex dysfunction after spaceflight can be compared with the syndrome of neurally mediated syncope. In astronauts microgravity has desensitized the normal baroreflex activity. Standing training will finally correct the situation. In neurally mediated syncope, a sudden, temporary imbalance occurs between gravitational stress and orthostatic tolerance. Return to a supine position restores the abnormal reflex activity. In cases with prodromal warning symptoms, physical manoeuvres such as isometric arm counterpressure [33], squatting, bending forward, abdominal compression and leg-crossing [34] are reported to abort impending syncope. In a recent report standing training was considered not to be effective in reducing tilt testing positivity [35]. In this study, only a minority of the patients performed all the programmed sessions. Patients were instructed to start standing training at home. There was no initial repeated tilt table testing. The rationale for our initial in-hospital tilt testing is that for heavily symptomatic patients, it restores orthostatic tolerance in a few days. It adds to the motivation to continue standing training at home. In our setting, the initial in-hospital phase is facilitated by the fact that a significant number of patients had been admitted as emergencies. Nowadays, in some cases, we also prescribe immediate out-of-hospital standing training, provided that adequate supervision by a well informed family member is available. We concur with our colleagues [35] that tilt training appears to be a feasible treatment, only for highly motivated patients. In our patient population 2/ 222 patients refused the proposed follow-up tilt tests. In a long-term follow-up [11] the experience is that patients adapt the standing training schedule to their own needs. Some will intensify standing training by increasing the number of sessions or by increasing the duration of sessions. Others will reduce the standing training programme and resume it when symptoms recur. In conclusion, this study shows that in tiltpositive patients with neurally mediated syncope, repeated tilt testing leads to a negative tilt response in every patient and in all types of collapse pattern. Although orthostatic tolerance can vary under the influence of external triggers, repeated tilt testing and prolonged standing training are able to restore baroreflex activity to a level which prevents syncope. References [1] Kenny RA, Ingram A, Bayliss J, Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lancet 1986;1:1352e5. [2] Fitzpatrick A, Sutton R. Tilting towards a diagnosis in recurrent unexplained syncope. Lancet 1989;1:658e6. [3] Fitzpatrick A, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol 1991;17:125e3. [4] Benditt DG, Ferguson DW, Grubb BP, et al. Tilt table testing for assessing syncope. ACC expert consensus document. J Am Coll Cardiol 1996;28:263e75. [5] Brignole M, Alboni P, Benditt D, et al. Guidelines on management (diagnosis and treatment) of syncope e update 24. Europace 24;6:467e537. [6] Brignole M, Menozzi C, Del Rosso A, et al. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Vasovagal Syncope International Study. Europace 2;2: 66e76. [7] Hoeldtke RD, Cavanaugh ST, Hughes JD. Treatment of orthostatic hypotension: interaction of pressor drugs and tilt table conditioning. Arch Phys Med Rehabil 1988;69: 895e8. [8] Morillo CA, Leitch JW, Yee R, Klein GJ. A placebocontrolled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by headup tilt. J Am Coll Cardiol 1993;22:1843e8. [9] Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 1996;93:973e81. [1] Ector H, Reybrouck T, Heidbüchel H, Gewillig M, Van de Werf F. Tilt training: a new treatment for recurrent neurocardiogenic syncope and severe orthostatic intolerance. Pacing Clin Electrophysiol 1998;21:193e6. [11] Reybrouck T, Heidbüchel H, Van de Werf F, Ector H. Longterm follow-up results of tilt training therapy in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol 22;25:1441e6. [12] Di Girolamo E, Di Iorio C, Leonzio L, Sabatini P, Barsotti A. Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents. A controlled study. Circulation 1999;1:1798e81. [13] Abe H, Kondo S, Kohshi K, Nakashima Y. Usefulness of orthostatic self-training for the prevention of neurocardiogenic syncope. Pacing Clin Electrophysiol 22;25: 1454e8. [14] Hachul D, Gardenghi G, Rondon MU, et al. The role of physical training in the management of recurrent neurally mediated syncope. Eur Heart J 24;25:351 [Abstract supplement].

6 Repeated tilt testing in neurally mediated syncope 633 [15] Gajek J, Zysko D, Mazurek W. Tilt training in patients with vasovagal syncope. Eur Heart J 24;25:352 [Abstract supplement]. [16] Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing with isoproterenol. A nonspecific test. Ann Intern Med 1992;116:358e63. [17] Kapoor WN, Smith MA, Miller NL. Upright tilt testing in evaluating syncope: a comprehensive literature review. Am J Med 1994;97:78e88. [18] MacLean AR, Allen EV. Orthostatic hypotension and orthostatic tachycardia. Treatment with the head-up bed. JAMA 194;115:2162e7. [19] Brooks R, Ruskin JN, Powell A, Garan H, McGovern BA. Prospective evaluation of day-to-day reproducibility of upright tilt-table testing in unexplained syncope. Am J Cardiol 1993;71:1289e992. [2] Grubb BP, Wolfe D, Temesy-Armos P, Hahn H, Elliott L. Reproducibility of head upright tilt table test results in patients with syncope. Pacing Clin Electrophysiol 1992;15: 1477e81. [21] Fish FA, Strassburger JF, Benson W. Reproducibility of a symptomatic response to upright tilt in young patients with unexplained syncope. Am J Cardiol 1992;7:65e9. [22] Blanc JJ, Mansourati J, Maheu B, Boughaleb D, Genet L. Reproducibility of a positive passive upright tilt test at a seven-day interval in patients with syncope. Am J Cardiol 1993;72:469e71. [23] Sagrista-Sauleda J, Romero B, Permanyer-Miralda G, Moya A, Soler-Soler J. Reproducibility of sequential head-up tilt testing in patients with recent syncope, normal ECG and no structural heart disease. Eur Heart J 22;23:176e13. [24] Foglia-Manzillo G, Romano M, Corrado G, et al. Reproducibility of asystole during head-up tilt testing in patients with neurally mediated syncope. Europace 22;4:365e7. [25] Levine MM. Neurally mediated syncope in children: results of tilt testing, treatment, and long-term follow-up. Pediatr Cardiol 1999;2:331e5. [26] Kochiadakis GE, Kanoupakis EM, Rombola AT, Igoumenidis NE, Chlouverakis GI, Vardas PE. Reproducibility of tilt table testing in patients with vasovagal syncope and its relation to variations in autonomic nervous system activity. Pacing Clin Electrophysiol 1998;21:169e76. [27] Folino AF, Buja G, Martini B, Bassan L, Nava A. Upright tilt test: correlation between results. Pacing Clin Electrophysiol 1996;19:1582e7. [28] Wieling W, Halliwill JR, Karemaker JM. Orthostatic intolerance after space flight. J Physiol 22;538:1. [29] Levine BD, Pawelczyk JA, Ertl AC, et al. Human muscle sympathetic neural and haemodynamic responses to tilt following spaceflight. J Physiol 22;538:331e4. [3] Hargens AR, Watenpaugh DE. Cardiovascular adaptation to spaceflight. Med Sci Sports Exerc 1996;28:977e82. [31] Garshnek V. Long-duration Soviet manned space flight: the development and implementation of postflight recovery measures. In: Lorr DB, Garshnek V, Cadoux C, editors. Working in orbit and beyond: the challenges for space medicine. San Diego: Univelt, Inc; p. 127e32. [32] Buckey JC, Lane LD, Levine D, et al. Orthostatic intolerance after spaceflight. J Appl Physiol 1996;81:7e18. [33] Brignole M, Croci F, Menozzi C, et al. Isometric arm counter-pressure, maneuvers to abort impending vasovagal syncope. J Am Coll Cardiol 22;4:253e9. [34] Wieling W, van Lieshout JJ, van Leeuwen AM. Physical manoeuvres that reduce postural hypotension in autonomic failure. Clin Auton Res 1993;3:57e65. [35] Foglia-Manzillo G, Giada F, Gaggioli G, et al. Efficacy of tilt training in the treatment of neurally mediated syncope. Europace 24;6:199e24.