The venous system is the main determinant of hypotension in patients with vasovagal syncope

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1 Europace (2006) 8, doi: /europace/eul095 The venous system is the main determinant of hypotension in patients with vasovagal syncope Giuseppe Fucà 1, Maurizio Dinelli 1, Paolo Suzzani 2, Salvatore Scarfò 3, Fabio Tassinari 1, and Paolo Alboni 1 * 1 Division of Cardiology, Ospedale Civile, Cento (Fe), Italy; 2 SEDA, Milano, Italy; and 3 Division of Cardiology, Ospedale del Delta, Lagosanto (Fe), Italy Received 30 May 2005; accepted after revision 27 March 2006; online publish-ahead-of-print 17 August 2006 KEYWORDS Syncope; Haemodynamics; Tilt test Introduction The haemodynamics of vasovagal syncope (VVS) should be investigated during spontaneous episodes but, for obvious reasons, adequate haemodynamic study is practically impossible. Several observations suggest that the hypotension and bradycardia induced by tilt testing (TT) are similar to the spontaneous episodes, 1 4 and tilt-induced syncope is accepted as a model for this condition. 5 It has been widely demonstrated that VVS is secondary to a fall in blood pressure (BP), usually followed by bradycardia due to withdrawal of sympathetic tone; 6 11 however, the genesis of VVS remains unclear. Blood pressure is dependent on total peripheral resistance (TPR) and cardiac output (CO); the latter on stroke volume (SV) and heart rate (HR). In patients with normal hearts, without systolic dysfunction, SV and CO are mainly determined by venous return, whereas the arterial response is mainly manifest as * Corresponding author. Tel: þ ; fax: þ address: p.alboni@ausl.fe.it Aims In patients with vasovagal syncope (VVS), a neural reflex appears the main determinant of hypotension leading to loss of consciousness; whether hypotension is mainly due to involvement of the arterial system or the venous system remains a debated issue. The aim of the present study was to assess which of these two systems is responsible for the fall in blood pressure (BP) in patients with VVS; to this end, a haemodynamic study was carried out not only before and during loss of consciousness but also during the recovery phase. Methods and results Beat-to-beat recordings of heart rate (HR), BP (volume-clamp method) and stroke volume (SV) (modelflow method), cardiac output (CO), and total peripheral resistance (TPR) were made at rest, during unmedicated tilt testing (TT) and recovery from loss of consciousness in 18 patients with a history of syncope (age years) and positive response to TT. Blood pressure showed a significant fall during prodromal symptoms and a further fall at the beginning of loss of consciousness, together with a fall in SV, CO, and HR, and a slight, but significant, increase in TPR. At the beginning of recovery, BP showed a significant increase and a further increase 5 min later, together with an increase in SV, CO, and HR without significant changes in TPR. Conclusion These results suggest that in VVS the fall in BP is mainly caused by reduced venous return to the heart. The arterial system does not appear to be the main determinant of the fall of BP; however, the system appears unable to make the appropriate compensatory changes. TPR. Certain data suggest that the fall in BP could be related to an impairment of venous return due to inadequate venoconstrictive response during orthostatic or mental stress; other data suggest that the fall in BP could be secondary to inadequate arterial vasoconstriction during orthostatic or physical stress The aim of the present study was to assess whether the fall in BP responsible for the loss of consciousness is mainly due to an inadequate compensatory response of the venous system or the arterial system; to this end, a haemodynamic study was carried out in patients with tilt-induced syncope not only before and during loss of consciousness but also during the recovery phase. Methods Patients referred for the evaluation of syncope were regarded as candidates for the present study if they (i) were aged 18 years; (ii) did not show any sign of cardiological or neurological disease, or arterial hypertension; (iii) had negative carotid sinus massage (not induction of syncope or presyncope during supine or standing & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 840 G. Fucà et al. position); (iv) had syncope of unknown origin after the first evaluation; 26 (v) developed syncope associated with hypotension and/ or bradycardia after at least 5 min of unmedicated TT. We selected this time to ensure that we could separate the haemodynamic adjustments during the first 2 min of TT 27 from those that occurred during the minutes before loss of consciousness. From January 2004 to March 2005, 181 patients underwent TT in the out patient clinic and 22 met the eligibility criteria. The study was approved by the Ethics Committee of Cento Hospital. Tilt test protocol The test was always performed in the morning in a quiet room (temperature of C) after overnight fasting without any medication. The procedure was carried out by means of an electronically controlled tilt table with a footboard for weight-bearing. No patient was taking cardioactive medication at the time of the study. After 15 min supine control phase, patients were tilted upright at 608 for 30 min or until syncope, at which time they were immediately tilted back to the horizontal and recorded for a further 15 min. The test was considered positive when it induced syncope associated with hypotension with or without bradycardia. Haemodynamic recording To assess haemodynamic values, Finometer (Finapress Medical Systems, Anhem, The Netherlands) was used; it is a non-invasive monitor to measure beat-to-beat HR and BP by means of the volume-clamp method and the physical criteria developed by Wesseling et al. 28 In addition, the device includes a method (modelflow) to compute aortic flow, SV, CO, and TPR beat-to-beat from an arterial pressure using a three-element model of the arterial input impedance. 29 Total peripheral resistance, expressed in resistance units, was calculated as the quotient of the mean BP and CO. Beat-to-beat registration was made; however, the values of haemodynamic variables were reported as the average of four consecutive cycles just before tilt, after 3 and 5 min of tilt, then, at 5 min intervals, at the beginning of prodromal signs and symptoms as previously described, 30 at the beginning of loss of consciousness, at the beginning of recovery, and 5 and 15 min thereafter. The data from each subject were reviewed manually to remove artefacts. Definitions Syncope was defined as transient loss of consciousness due to diminished cerebral perfusion with inability to maintain postural tone and with spontaneous recovery. Statistical analysis Statistical evaluation of the data was achieved by using paired Student s t-test and the analysis of variance as applicable. Results are expressed as mean + standard deviation. Results Of the 22 patients who met eligibility criteria, four were excluded for technical reasons. The age of the remaining 18 patients was years; 10 were males. The number of spontaneous episodes of syncope was During TT, prodromal symptoms occurred in 17 patients after min and loss of consciousness in all patients after min. The syncopal phase 31 was type 1 (mixed) in 10 patients, type 2A (cardioinhibition without asystole) in four patients, type 2B (cardioinhibition with asystole) in one patient and type 3 (vasodepressor) in three patients. The behaviour of haemodynamic variables is reported in Figures 1 5 and the mean values in Table 1. Figure 1 Systolic, diastolic and mean BP, HR, and SV show a significant decrease at the beginning of the prodrome and a further decrease at the beginning of loss of consciousness. At the beginning of recovery, these variables increase significantly.

3 Venous system: the main determinant of hypotension 841 Figure 2 Cardiac output shows a significant decrease at the beginning of the prodrome and a further decrease at the beginning of loss of consciousness; at the beginning of recovery, this variable increases significantly. Total peripheral resistance remains rather constant, showing a slight but significant increase only before loss of consciousness. Figure 3 From the last scheduled measurement before prodromal symptoms to the beginning of loss of consciousness, SV decreases in all patients and increases in almost all patients at the beginning of recovery.

4 842 G. Fucà et al. Figure 4 In almost all patients, cardiac output decreases from the last scheduled measurement before prodromal symptoms to the beginning of loss of consciousness and increases at the beginning of recovery. Figure 5 Total peripheral resistance shows small changes, with the exception of two older patients showing a marked increase before loss of consciousness.

5 Venous system: the main determinant of hypotension 843 Table 1 The variations of each haemodynamic variable during tilt and the level of significance, by using the analysis of variance, are shown Supine 5 min Before prodrome Beginning Syncope Recovery 5 min post of prodrome recovery 15 min post recovery P-value Systolic BP (mmhg) ,0.001 Diastolic BP (mmhg) ,0.001 Mean BP (mmhg) ,0.001 Heart rate (beats/min) ,0.001 Stroke volume (ml) ,0.001 Cardiac output (L/min) ,0.001 Total peripherial resistance (U) NS Data are reported as mean value + SD. Early tilt test After 3 min of tilt, systolic and mean BP and TPR did not change significantly in comparison with the values recorded in the supine position; diastolic BP and HR increased significantly (P, 0.05 and P, 0.001, respectively) and SV and CO decreased significantly (P, 0.001). The haemodynamic variables did not show significant differences between the third and the fifth minutes of tilt, apart from SV, which decreased significantly (P, 0.05). From the fifth minute of tilt to the last scheduled measurement before prodromal symptoms systolic, diastolic and mean BP and TPR did not change significantly; HR increased (P, 0.05), whereas SV and CO decreased significantly (P, and P ¼ 0.003, respectively). Prodromal symptoms and loss of consciousness From the last scheduled measurement before prodromal symptoms to the beginning of the prodrome, all the variables decreased (systolic, diastolic and mean BP P, 0.001, HR P ¼ 0.004, SV P ¼ 0.004, and CO P, 0.001) with the exception of TPR, which did not change significantly. From the beginning of the prodrome to the beginning of loss of consciousness, all the variables showed a further decrease (systolic BP P, 0.001, diastolic and mean BP P ¼ 0.001, HR P ¼ 0.006, SV P, 0.001, and CO P ¼ 0.002) with the exception of TPR, which increased significantly (P, 0.05). This variable increased markedly in two old patients (75 and 76 years old) with high baseline values (Figure 5). From the last scheduled measurement before prodromal symptoms to the beginning of loss of consciousness, SV decreased in all patients (10%), CO decreased in 17 patients and increased in one; in this patient (21 years old), hypotension was caused by a fall in TPR (from 1.1 to 0.3 U). Total peripheral resistance increased in 10 patients, decreased in five, and remained unchanged in three. Recovery From the beginning of loss of consciousness to the beginning of recovery, systolic, diastolic, and mean BP, HR, SV, and CO increased significantly (P, 0.001, P, 0.001, P, 0.001, P ¼ 0.001, P, 0.001, and P, 0.001, respectively), whereas TPR did not change significantly. At the fifth minute of recovery, all the variables showed a further significant increase with the exception of HR and TPR, which did not change significantly. After 15 min of recovery, the values of all the variables returned to baseline (pre-tilt) values. Discussion Main findings The main finding of the present study is that the fall in BP during both prodromal symptoms and loss of consciousness appears to be due to the marked reduction in SV and CO, as the calculated TPR showed a slight but significant increase at the beginning of prodrome. Similarly, the increase in BP during the recovery phase is associated with a marked increase in SV and CO, without significant changes in calculated TPR. These data suggest that the fall in BP during orthostatic syncope and the subsequent rise after tilting back to the horizontal are mainly dependent on the venous system. Only in one young patient (5%) hypotension appeared secondary to a fall in TPR, as CO increased during loss of consciousness. The fall in CO before loss of consciousness is partly secondary to the reduction in HR, and the rise in CO at the beginning of recovery is partly secondary to the increase in HR. However, it should be pointed out that before loss of consciousness SV decreases in spite of the decrease in HR, and at the beginning of recovery SV increases in spite of the increase in HR. That seems to strengthen the role of the venous return in the genesis of hypotension in VVS patients. In humans, orthostatic stress normally evokes compensatory vasoconstriction; when this compensatory mechanism fails within the venous system, venoconstriction is inadequate, leading to reduced venous return to the heart and, ultimately, to a fall in BP. It is well known that VVS is reversed more rapidly by laying the patient down and raising the legs but, to our knowledge, the haemodynamics of the recovery phase has not been thoroughly investigated and, consequently, the haemodynamic behaviour of this phase has not been sufficiently taken into account in the analysis of the determinants of hypotension. Some authors 23,32 have reported, even during invasive investigation, 32 a decrease in TPR just before loss of consciousness during TT; this suggests a reduction of the arterial tone and therefore a role of the arterial system in the genesis of hypotension. On the contrary, we have observed a slight but significant increase in calculated TPR at the

6 844 G. Fucà et al. beginning of prodromal symptoms (Figures 2 and 5). There is not a clear explanation for the different behaviour of TPR observed by us and these authors; however, examination of the behaviour of TPR in these studies 23,32 reveals that it does not fall below the pre-tilt values at any time during the entire TT, not even during loss of consciousness. This suggests that a reduction in arterial tone is not the main determinant of the hypotension that leads to loss of consciousness. The increase in calculated TPR we observed just before loss of consciousness could be an attempt of arterial system to counteract reduction in SV that follows a decrease in venous return; however, the arterial system appears unable to make the appropriate compensatory vasoconstriction. In this regard, an increase in calculated TPR just before tilt-induced syncope has recently been reported after nitroglycerine administration. 33 These results suggest that the withdrawal of sympathetic tone, which appears responsible for the vascular changes preceding loss of consciousness, as shown by Wallin et al., 6 mainly affects the venous and, to a lesser extent, the arterial system. Previous studies Impaired venoconstriction has been suggested as an underlying cause of the fall in BP A greater increase in calf and in splanchnic blood volume has been observed during TT in patients with a positive response than in control subjects 13,19 as an expression of reduced venoconstrictive response. During physical exercise, splenic volume is reported to decrease to a lesser degree in patients with VVS than in control subjects, 16 and, during mental stress, a lower forearm venoconstrictive response has been observed in VVS patients than in controls. 15 During the first and intermediate phases of TT, the reduction or the rate of reduction in SV or end-diastolic volume has been seen to be greater in patients with positive TT than in controls. 11,12,14,17,18 In the studies by de Jong-de Vos van Steenwijk et al. 21 and Novak et al., 23 a decrease in SV and CO was not observed in patients with positive TT before loss of consciousness, and hypotension appeared secondary to a fall in calculated TPR. However, the former study investigated paediatric subjects without a history of spontaneous syncope, who might show a different haemodynamic behaviour. In the latter study, SV and CO were measured by using thoracic impedance, which Marik et al. 34 defined as unreliable to measure these variables. The reduction in SV that we and other authors 11,17,32,35 observed before loss of consciousness might be related not only to a reduced venous return but also to an impairment of myocardial contractility. In this regard, the literature offers rather contrasting data. Some authors 36,37 have reported a fall of dp/dt max or peak endocardial acceleration just before loss of consciousness; others 38,39 have not observed this fall. In most studies, 12,32,40 left ventricular ejection fraction or fractional shortening increased before tilt-induced syncope; in others, 14,17 a decrease or a nonsignificant change has been reported. On the basis of the present knowledge, there is no evidence for left ventricular systolic dysfunction before loss of consciousness. Some authors 20,22,24,25 have reported a smaller increase in calculated TPR during the initial phase of TT or during lower body negative pressure in patients with positive TT than in control subjects. For this reason, they suggest a role of the arterial system in the genesis of the fall in BP. However, these results do not enable us to understand whether the impaired arterial vasoconstriction is the main determinant of hypotension. Study limitations Tilt-induced syncope may not be the physiological equivalent of VVS, which can be triggered by a variety of stimuli other than orthostatic stress. 41 After calibration, the tracking of changes in SV and CO with modelflow vs. thermodilution-based estimate changes compared within 5 + 2% during prolonged TT. 42 However, if absolute values are not required, the modelflow method gives reliable trend data, and changes in these haemodynamic variables can be tracked from an arterial pressure waveform. A complex mixture of inter-related factors (i.e. endocrine, physical, interactions between pre-load and afterload, etc.) can affect CO and, at present, distinguishing one from another is not possible, which can undermine the reliability of the conclusions. Total peripheral resistance is always calculated as the quotient of mean BP and CO. We cannot be sure that this quotient, measured by means of any invasive or non-invasive method, is a true expression of the arterial tone. Moreover, even if the arterial tone is much higher than the venous tone, the estimated TPR does not allow us to differentiate the venous contribution from that of the arterial system. It must also be pointed out that in the clinical setting it is not possible to dissociate completely pre-load and afterload as both condition SV. The beginning of prodromal symptoms we recorded could not be very precise, above all in old patients. Conclusion The results of the present study add further support to the notion that VVS is mainly related to an impaired venoconstrictive response, leading to reduced venous return to the heart. This is suggested by the haemodynamic behaviour before tilt-induced syncope and, above all, by the behaviour during the recovery phase. The arterial system appears to be the main determinant of the fall in BP in very few patients, and in the others this system is unable to make the appropriate compensatory changes. Our results, together with those obtained in paediatric subjects, 21 suggest that the behaviour of calculated TPR just before loss of consciousness could be different in young and old subjects; however, that requires further investigation. References 1. Almquist A, Goldenberg IF, Milstein S et al. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 1989;320: Fitzpatrick A, Sutton R. Tiltings towards a diagnosis in recurrent unexplained syncope. Lancet 1989;1: 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: Raviele A, Gasparini G, Pede FD, Delise P, Bonso A, Piccolo E. Usefulness of head-up tilt test in evaluating patients with syncope of unknown origin and negative electrophysiologic study. Am J Cardiol 1990;65:

7 Venous system: the main determinant of hypotension Grubb BP, Kosinski D. Tilt table testing: concepts and limitations. Pacing Clin Electrophysiol 1997;20: Wallin BG, Sundlöf G. Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst 1982;6: Van Lieshout JJ, Wieling W, Karemaker JM, Eckberg DL. The vasovagal response. Clin Sci (Lond) 1991;81: Smith M, Ellenbogen KA, Eckberg DL. Sympathoinhibition and hypotension in carotid sinus hypersensitivity. Clin Auton Res 1992;2: Dietz NM, Halliwill JR, Spielmann JM et al. Sympathetic withdrawal and forearm vasodilation during vasovagal syncope. J Appl Physiol 1997;82: Mosqueda-Garcia R, Furlan R, Fernandez-Violante R et al. Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J Clin Invest 1997;99: Jardine DL, Melton IC, Crozier IG et al. Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope. Am J Physiol Heart Circ Physiol 2002;282:H Shalev Y, Rami G, Tchou PJ et al. Echocardiographic demonstration of decreased left ventricular dimensions and vigorous myocardial contraction during syncope induced by head-up tilt. J Am Coll Cardiol 1991;18: Hargreaves AD, Muir AL. Lack of variation in venous tone potentiates vasovagal syncope. Br Heart J 1992;67: Mizumaki K, Fujiki A, Tani M, Shimono M, Hayashi H, Inoue H. Left ventricular dimensions and autonomic balance during head-up tilt differ between patients with isoproterenol-dependent and isoproterenolindependent neurally mediated syncope. J Am Coll Cardiol 1995;26: Manyari DE, Rose S, Tyberg JV, Sheldon RS. Abnormal reflex venous function in patients with vasovagal syncope. J Am Coll Cardiol 1996;27: Thompson HL, Atherton JJ, Khafagi FA, Frenneaux MP. Failure of reflex venoconstriction during exercise in patients with vasovagal syncope. Circulation 1996;93: Yamanouchi Y, Jaalouk S, Shehadeh AA, Jaeger F, Goren H, Fouad-Tarazi FM. Changes in left ventricular volume during head-up tilt in patients with vasovagal syncope: an echocardiographic study. Am Heart J 1996;131: Liu JE, Hahn RT, Stein KM et al. Left ventricular geometry and function preceding neurally mediated syncope. Circulation 2000;101: Steward JM, McLeod KJ, Sanyal S, Herzberg G, Montgomery LD. Relation of postural vasovagal syncope to splanchnic hypervolemia in adolescents. Circulation 2004;110: Sneddon JF, Counihan PJ, Bashir Y, Haywood GA, Ward DE, Camm AJ. Impaired immediate vasoconstrictor responses in patients with recurrent neurally mediated syncope. Am J Cardiol 1993;71: de Jong-de Vos van Steenwijk CCE, Wieling W, Johannes JM, Harms MP, Kuis W, Wesseling KH. Incidence and hemodynamic characteristics of near-fainting in healthy 6- to 16-year old subjects. J Am Coll Cardiol 1995;25: Thomson HL, Lele SS, Atherton JJ, Wright KN, Stafford W, Frenneaux MP. Abnormal forearm vascular responses during dynamic leg exercise in patients with vasovagal syncope. Circulation 1995;92: Novak V, Honos G, Shondorf R. Is the heart empty at syncope? J Auton Nerv Syst 1996;60: Thomson HL, Wright K, Frenneaux M. Baroreflex sensitivity in patients with vasovagal syncope. Circulation 1997;95: Shen WK, Low PA, Rea RF, Lohse CM, Hodge DD, Hammil SC. Distinct hemodynamic profiles in patients with vasovagal syncope: a heterogeneous population. J Am Coll Cardiol 2000;35: Brignole M, Alboni P, Benditt DG et al. Guidelines on management (diagnosis and treatment) of syncope update Europace 2004; 6: Van Lieshout JJ, Wieling W, Karemaker JM, Secher NH. Syncope, cerebral perfusion and oxygenation. J Appl Physiol 2003;94: Wesseling KH, Settels JJ, van der Hoeven GMA, Nijboer JA, Butyn MWT, Dorlas JC. Effects of peripheral vasocostriction on the measurement of blood pressure in a finger. Cardiovasc Res 1985;19: Wesseling KH, Jansen JRC, Settels JJ et al. Computation of aortic flow from pressure in humans using a nonlinear, three-element model. J Appl Physiol 1993;74: Alboni P, Dinelli M, Gruppillo P et al. Haemodynamic changes early in prodromal symptoms of vasovagal syncope. Europace 2002;4: Brignole M, Menozzi C, Del Rosso A et al. New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification. Analysis of pre-syncopal phase of the tilt test without and with nitroglycerin challenge. Europace 2000;2: Fitzpatrick A, Williams T, Ahmed R, Lightman S, Bloom SR, Sutton R. Echocardiographic and endocrine changes during vasovagal syncope induced by prolonged head-up tilt. Eur J Card Pacing Electrophysiol 1992;2: Gisolf J, Westerhof BE, van Dijk N, Wesseling KH, Wieling W, Karemaker JM. Sublingual nitroglycerin used in routine tilt testing provokes a cardiac output-mediated vasovagal response. J Am Coll Cardiol 2004;44: Marik PE, Pendelton JE, Smith R. A comparison of hemodynamic parameters from transthoracic electrical bioimpedance with those parameters obtained by thermodilution and angiography. Crit Care Med 1997;25: Bergenwald L, Freyschuss U, Sjöstrand T. The mechanism of orthostatic and hemorrhagic fainting. Scand J Clin Lab Invest 1977;37: Petersen MEV, Wialliams TR, Erickson M, Sutton R. Right ventricular pressure, dp/dt, and preejection interval during tilt induced vasovagal syncope. Pacing Clin Electrophysiol 1997;20: Deharo JC, Peyre JP, Chalvidan T et al. Continuous monitoring of an endocardial index of myocardial contractility during head-up tilt test. Am Heart J 2000;139: Brignole M, Menozzi C, Corbucci G, Garberoglio B, Plicchi G. Detecting incipient vasovagal syncope: intraventricular acceleration. Pacing Clin Electrophysiol 1997;20: Mangin L, Kobeissi A, Lelouche D et al. Simultaneous analysis of heart rate variability and myocardial contractility during head-up tilt in patients with vasovagal syncope. J Cardiovasc Electrophysiol 2001;12: Hosaka H, Takase B, Kitumara K et al. Assessment of left ventricular volume by an ambulatory monitoring system during head-up tilt in patients with unexplained syncope: relation to autonomic activity assessed by heart rate variability. J Nucl Cardiol 2001;8: Benditt DG. Neurally mediated syncopal syndromes: pathophysiological concepts and clinical evaluation. Pacing Clin Electrophysiol 1997;20: Harms MPM, Wesseling KH, Pott F, Jenstrup M, Van Goudoever J, Secher NH, Van Lieshout JJ. Continuous stroke volume arterial pressure in humans under orthostatic stress. Clin Sci (Lond) 1999;97: