Q J Med 1999; 92: 697-705
© 1999 Association of Physicians
Reviews |
The management of vasovagal syncope
From the Cardiovascular Investigation Unit, Department of Geriatric Medicine, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Dr S.W. Parry, Cardiovascular Investigation Unit, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP. e-mail: S.W. Parry{at}ncl.ac.uk
 |
Introduction |
|---|
 Top Introduction Symptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
Syncope, defined as transient loss of consciousness with loss of postural tone but with spontaneous recovery,1 accounts for 3% of Accident and Emergency attendances2 and 1% to 6% of hospital admissions annually,3 and has a prevalence of up to 23% in the institutionalized elderly.4 In last month's review,5 we described the head-up tilt-table test and its use in the diagnosis of the vasovagal syndrome, the commonest cause of syncope. This article aims to provide an overview of the management of the vasovagal syndrome, on the basis of current evidence and our experience in this field. Throughout the article, the terms `vasovagal syncope' and `vasovagal syndrome' will be used interchangeably.
|
Symptoms of the vasovagal syndrome |
|---|
|
TopIntroductionSymptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
Syncope is the most common presenting symptom of the vasovagal syndrome, though patients may present with pre-syncope and dizziness without loss of consciousness. A prodromal syndrome of variable duration is common, with light-headedness, weakness, a sensation of air-hunger or hyperventilation, detachment from surroundings, palpitations, blurring of vision and visual field disturbance, nausea, diaphoresis and ultimately pre-syncope or syncope being reported by the majority of patients.6–8 Recovery is usually prompt with the assumption of the supine position, but some subjects experience nausea, dizziness and diaphoresis for a variable period following an episode.6 Elderly subjects may experience little or no prodrome,7–9 and not infrequently present with serious injury following an unheralded syncopal event. Indeed, syncope may overlap with unexplained falls in older patients,10 with some elderly subjects recalling only the index fall rather than the syncopal attack precipitating it.10
|
Diagnosis of vasovagal syncope |
|---|
|
TopIntroductionSymptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
In many cases, a diagnosis can be made from history alone,6 particularly if a witness account is available. However, there are a subset of patients who require further investigation to determine a cause of symptoms because they are atypical, because comorbidity suggests another probable cause of syncope, or because a clear attributable diagnosis is necessary for social or other reasons. Clinical examination and cardiovascular and neurological investigations are generally helpful only in differentiating other causes of syncope, and the ultimate diagnosis is based on head-up tilt-table testing, as described last month.5
|
Treatment of vasovagal syncope |
|---|
|
TopIntroductionSymptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
The multiple treatments promoted for the vasovagal syndrome are a powerful indicator both of the complexity of the disease and the lack of a single, well-evaluated therapeutic option for its management. The following section will explain some of the methodological difficulties associated with the evaluation of interventions in vasovagal syncope, before going on to discuss the rationale and evidence for the various pharmacological and pacing therapies, and finally recommendations for treatment.
Methodological problems in the evaluation of therapies for vasovagal syncope
Definitive guidelines on therapy for the vasovagal syndrome are hampered by a dearth of randomized controlled trials, the numerous therapeutic approaches explored, and the small numbers of subjects studied. The multiple tilt protocols used at different laboratories serve to cloud the issue further. More specifically, the evaluation of therapeutic interventions in vasovagal syncope is troubled by three major methodological difficulties peculiar to this issue, namely the variable reproducibility of the head-up tilt table test, the beneficial effect of diagnosis on syncope recurrence and the tendency for vasovagal syncope to ameliorate with time.
Head-up tilt-table test reproducibility
The medium- to long-term reproducibility of positive responses to tilt-table testing varies from 62% to 85% of subjects,11–14 though one-day reproducibility may be as low as 35%.15 Such variability in concordance raises grave doubts regarding the utility of a negative second tilt-test one or more days after initial testing on therapy as a primary outcome measure, a frequent, and in our view, mistaken investigational approach. Symptom recurrence is a far more robust outcome measure in this context.
Placebo effect and efficacy of diagnosis in reducing rate of syncope recurrence
Many patients with vasovagal syncope experience dramatic resolution or diminution of symptoms following a positive head-up tilt-table test. This has been attributed by some to a powerful placebo effect,16 although a more likely explanation is that recurrent episodes are avoided or ameliorated by counselling regarding the avoidance of precipitating situations and recognition of premonitory symptoms to allow the patient to abort an imminent attack.17,18 Both aspects complicate therapy evaluation, particularly as there are few double-blind randomized controlled trials in this area which include a placebo arm (see Table 1
).
|
Amelioration of vasovagal syncope with time
Several studies suggest that the course of vasovagal syncope is benign, with progressive alleviation of symptoms over time,16–19 although whether this is due to the effects of counselling (as outlined above) or to the natural history of the disorder is unclear. Whichever explanation is correct, with the exception of a few randomized controlled trials, most studies have yet to account for this.
Conservative advice and withdrawal of culprit medications
As mentioned above, the provision of the diagnosis of vasovagal syncope, coupled with reassurance of its benign course and counselling regarding recognition of prodromal symptoms and subsequent manoeuvres to abort attacks, are central to the management of this disorder. The avoidance of precipitating factors, such as prolonged standing or sitting, excess alcohol intake and exercising after large meals or in a hot environment should be emphasized, although one report noted an improvement in orthostatic tolerance and blood volumes following exercise training.20 Stratagems to increase blood volume by increasing fluid and salt intake may also be helpful, as one of the main triggers for vasovagal syncope (and the pathophysiological cornerstone of the head-up tilt-table test) is venous pooling in the lower limbs and relative central hypovolaemia.5 A recent uncontrolled, retrospective report found that oral fluid therapy (1920 ml on rising followed by sufficient non-caffeinated fluids to keep urine clear) significantly reduced the number of syncopal episodes in a cohort of adolescent sufferers (mean age 14.7 years),21 while El-Sayed and Hainsworth elegantly demonstrated the utility of salt therapy in a small (20 subjects) randomized placebo-controlled study.22 Patients with vasovagal syncope diagnosed by lower-body negative pressure (LBNP) tilt underwent plasma volume measurements, 24-h urinary sodium, tilt- and baroreceptor sensitivity testing before and 8 weeks after treatment with 120 mmol salt or placebo daily. Plasma volume and orthostatic tolerance (assessed as time to onset of syncope during LBNP tilt) increased while baroreceptor sensitivity decreased in 8/10 of the salt treatment group but in only 3/10 of the placebo group, with the main determinant of response to salt treatment being 24-h urinary sodium excretion of <170 mmol.22 While this study did not assess symptomatic outcome, a retrospective study in adolescents found that a positive response to normal saline challenge during tilt testing (i.e. prevention of syncope following 10 ml/kg saline bolus) predicted symptomatic benefit from salt therapy with or without fludrocortisone treatment.23 Further minimization of relative hypovolaemia may be achieved by withdrawal of culprit medications. Nitrates and other vasodilators and diuretics are particularly implicated in older patients, and may either cause vasovagal syncope de novo or uncover a previously latent tendency to the disorder. Complete resolution of symptoms may ensue following discontinuation of therapy with these agents. Finally, venous pooling may be minimized by compression hosiery,9 though these are often poorly tolerated, particularly in older subjects.
Pharmacological treatment of vasovagal syncope
Beta blockers
These are the most commonly prescribed drugs in vasovagal syncope and will be discussed in depth.
Beta-adrenergic receptor antagonists have been used for several years in the management of the vasovagal syndrome. Their action is thought to be manifold, with the primary therapeutic benefit being a reduction in myocardial inotropy, which prevents the stimulation of left ventricular mechanoreceptors culminating in the Bezold-Jarisch–type reflex thought to be responsible for the vasovagal episode.24–26 A further benefit may include modification of the increases in circulating epinephrine27–29 and heart rate29 found prior to sympathetic withdrawal30 and syncope in many patients.
From a high-sensitivity Medline search,31 along with scrutiny of non-Medline-listed journals, we were able to identify only six randomized controlled trials of ß-blocker therapy in the treatment of vasovagal syncope,16,32–36 only two of which were placebo-controlled and blinded.32,36 None reported power calculations to ensure adequate numbers of participants, the maximum being 48 subjects,35 the minimum 13.36 While symptoms during follow-up were reported in several of the trials,33,35 the primary outcome measure in all six studies was repeat tilt on medication from 7 days34 to 6 months35 on therapy. Metoprolol was found to be superior to clonidine33 and verapamil,34 while atenolol was superior to placebo,32 but no more effective than fludrocortisone35 in reducing the number of positive tilt tests on therapy. In addition, there were no syncopal episodes during a short 15-day follow-up period on metoprolol.33 Unfortunately, the placebo-controlled study of Mahanonda et al.32 suffers from a host of methodological problems, not least of which were the loose inclusion criteria for the study, which allowed the enrolment of 23 (55%) subjects with precipitating factors including neck movements, cough, and postural change, in whom alternative causes of symptoms which may be exacerbated or improved by ß-blockers (such as carotid sinus syndrome and orthostatic hypotension) had not been excluded. The trials of Fitzpatrick et al.36 and Brignole et al.16 used a variety of pharmacological therapies which included atenolol,16,36 scopolamine,36 clonidine,36 cafedrine,16 domperidone16 and dihydroergotamine,16 and found no differences between placebo and treatment arms,16,36 although few firm conclusions can be drawn because of the small numbers of patients and the even smaller number on each treatment.
Several reports have provided positive evidence for the benefits of ß-blockade in the vasovagal syndrome, though the methodological confounders discussed above are of course pertinent here. Metoprolol,30,37–42 pindolol,42 propranolol,43,44 esmolol,40,41 betaxolol,45 and atenolol46–48 have all shown benefit in uncontrolled studies, though again negative repeat tilt testing was the main outcome measure in the majority of these. Two reports show no benefit,49,50 with one describing worsening of symptoms on atenolol treatment.50
Thus, while the evidence for the use of ß-blockers is scant and of dubious quality, the attractiveness of the pathophysiological rationale for their use, as well as their relative tolerability, ensures that these agents continue to be widely prescribed in the vasovagal syndrome.
Disopyramide and other anti-cholinergics
Disopyramide is a type IA anti-arrhythmic agent with anti-cholinergic and negative inotropic effects. It was thus postulated that the drug would prevent vasovagal syncope through a combination of diminishing left ventricular contraction (see above) and the exertion of a vagolytic effect, preventing the bradycardic/asystolic component of the attack. Uncontrolled studies showed great promise,51–53 but the only placebo-controlled, randomized trial of disopyramide showed no benefit, either during repeat tilt testing or during an average 29 months of follow-up.54 Its use cannot therefore be recommended.
More potent anti-cholinergics including propantheline bromide55 and transdermal scopolamine56,57 have both shown promise in small-scale uncontrolled series, but there is insufficient hard evidence of efficacy to advocate their routine use in the vasovagal syndrome.
Midodrine and other 
-adrenergic agonists
Midodrine is a powerful -agonist and vasoconstrictor, exhibiting 80% of norepinephrine-induced contraction of human peripheral veins.58 It is used in the management of orthostatic hypotension,59 and has recently received attention in the treatment of vasovagal syncope,60–63 in which it is thought to exert systemic pressor effects while impeding orthostatic blood pooling via peripheral venoconstriction.60 Only one randomized double-blind placebo-controlled study has been reported to date,60 with the midodrine-treated patients experiencing significantly less syncopal episodes and a better quality of life than those on placebo.60 Positive experiences with the drug in case reports61,62 and a series of eleven patients refractory to `usual measures'63 further suggest benefit with this agent. Midodrine is generally well tolerated, but its main side-effects (supine systolic hypertension, urinary frequency and urgency, piloerection, worsening of angina and cerebrovascular disease) necessitate discontinuation in up to 25% of older subjects after a year's treatment.64 It is currently available in the UK on a named patient basis only.
Uncontrolled studies using ephedrine,65,66 pseudephedrine,67 dextro-amphetamine,68 methylphenidate69 and etilefrine70 all showed benefit in this disorder, but the small numbers of patients and methodologies preclude any firm conclusions, particularly as the only randomized controlled study (using etilefrine) found no benefits over placebo.54
Fludrocortisone
Fludrocortisone is a synthetic mineralocorticoid which acts on the distal tubules of the kidney to retain sodium and hence expand blood volume and prevent relative central hypovolaemia.71 It also increases pressor sensitivity to circulating catecholamines.71 The only randomized trial of its use in vasovagal syncope was in adolescents, and showed equal benefit with atenolol, though there was no placebo arm to the study.35 Uncontrolled studies provide further modest evidence of efficacy and tolerability, though again only small numbers of patients have been studied.47,56,57 The most common side effects include hypertension, hypokalaemia and symptomatic fluid retention, and cardiac failure.
Theophylline
Theophylline is a methylxanthine with several pharmacological modes of action depending on serum concentration, one of which includes antagonism of adenosine receptors shown to mediate vasodilatation.73 Only two small uncontrolled reports have been published, both of which show modest benefit with theophylline, albeit with minimal follow-up.66,74
Selective serotonin reuptake inhibitors (SSRIs)
While there is undoubtedly central serotonergic neuronal involvement in blood pressure regulation, the exact mechanism and mode of action remains uncertain. In animal models, 5HT2 receptor agonism raises blood pressure,75 while 5HT1A receptor stimulation decreases blood pressure.76 Experimental studies in vasovagal syncope using clomipramine (which enhances central serotonergic activity) show a higher responsiveness of central serotonergic mechanisms in vasovagal subjects than in normal controls.77 The theoretical tenets of treatment with SSRIs are thus uncertain, as reflected in the paucity of studies on these agents in vasovagal syncope. Case reports and small series from one unit claim benefit,78–80 though a recent case series showed exacerbation of symptoms in three patients.81 A more recent randomized placebo-controlled study on 68 patients with refractory vasovagal syncope demonstrated a negative one-month tilt test in 61.8% of patients on paroxetine and 38.2% of placebo-treated controls (p<0.001), while 17.6% of the paroxetine group reported syncope during a mean of 25.4 months of follow-up vs. 52.9% of controls (p<0.0001)97 SSRIs thus have a role in patients with refractory symptoms, and in others where depressive symptoms would prompt pharmacological intervention.
Enalapril
Angiotensin-converting-enzyme inhibitors (ACEI) were until recently avoided in vasovagal syncope because of concerns regarding exacerbation of hypotension, but a recent double-blind, randomized, placebo-controlled trial in 24 elderly patients with vasovagal syncope showed that none of the enalapril-treated group (n=12) had a second positive tilt test after one week, compared to 10 who were syncopal in the placebo group.82 The enalapril-treated group also had lower plasma catecholamine concentrations, prompting the hypothesis that the ACEI blunted the triggering effects of the catecholamine surge prior to syncope.82 Further work is awaited with interest.
Permanent pacemaker therapy for vasovagal syncope
Vasovagal syncope has cardio-inhibitory, mixed and vasodepressor components, classified into four sub-types (VASIS Types I, IIa, IIb and III) depending on the relative contribution of each59 with Types IIa and IIb representing the cardio-inhibitory sub-types (Table 2). Permanent pacemaker implantation has been proposed as a therapeutic option particularly in the so-called `malignant vasovagal syndrome', where there is a predominant asystolic/bradycardic component (VASIS Types IIa and IIb) in association with unheralded, injurious, disablingly frequent syncope.83,84 Concerns remain over this course of action for several reasons, including the paucity of well-conducted studies, the profound placebo effect of pacemaker implantation, the benign nature of the syndrome, the problems associated with implanting a life-long foreign device in otherwise well (and often young) subjects, and the inability of pacing therapy to counter the vasodepressor component of the vasovagal response.
|
Most of the evidence to date has been based on small retrospective series,86 case reports78,87 and uncontrolled trials,88,89 all of which showed dramatic resolution of symptoms with pacing. One small trial of pacing therapy versus conventional drug treatment (but no placebo) found no fall in number of syncopal episodes post-pacing intervention,90 while a study of tilt responses with dual-chamber pacemaker implanted and switched on and off in separate studies (within individual subjects) found no difference in the time to syncope.91 A recent randomized controlled trial of pacing in vasovagal syncope was stopped at 54 out of the planned 284 patients enrolled92 because of the dramatic benefit seen in the pacing arm of the study group, though the small numbers used and the use of time to first syncope as the primary outcome measure are controversial.
Despite this confusion, `neurally mediated syncope with significant bradycardia reproduced by a head-up tilt'93 remains an American College of Cardiology/American Heart Association Guidelines indication for pacing,93 but should be reserved for selected patients as described above. The results of ongoing European and Canadian randomized controlled trials are awaited.
Miscellaneous
Biofeedback-assisted relaxation has been shown to help improve symptoms in several patients with syncopal disorders and concomitant headache,94 though this technique has not been formally evaluated in purely vasovagal subjects. A recent retrospective uncontrolled report noted resolution of symptoms in subjects undergoing repeated tilt testing (to syncope) and subsequent `tilt training' at home by standing against a wall for 30 min daily.95 Further studies are needed before this practice is widely adopted.
|
Management of vasovagal syncope: recommendations |
|---|
|
TopIntroductionSymptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
Recommendations based on the scant evidence available and our experience are summarised in Figure 1
. The following are intended as a guide only, and drug doses, cautions, contra-indications should be observed as per usual practice. Patient education, conservative advice and withdrawal of culprit medications should be the primary therapeutic intervention, and should be reviewed and reinforced at all stages of management. Salt doses should be 120 mmol daily, while ß-blockade may be achieved with metoprolol (50 mg bd or atenolol 25 mg bd increased as appropriate). Fludrocortisone dosage should commence at 50 mcg daily increasing to a maximum 400 mcg daily, with monitoring of blood pressure and serum potassium. Midodrine should be prescribed in specialist centres only, beginning at 2.5 mg bd or tds to a maximum of 40 mg qds, with monitoring of supine blood pressure and routine haematological and biochemical indices. The last dose should be given no later than early evening to prevent nocturnal systolic hypertension. SSRIs previously reported on include paroxetine sertraline and fluoxetine, and should be commenced at the lowest dose possible. Enalapril, scopolamine patches and theophylline should be prescribed as per the manufacturers' recommended doses. Permanent pacing therapy may be reserved for patients with serious injuries, frequent and unheralded syncope who have reproducible, prolonged asystole or bradycardia on tilt-table testing who have failed medical therapy. The choice of device should be dual-chamber, preferably with a rate drop response or similar algorithm. Such devices detect relative drops in heart rate as well as absolute levels of bradycardia/asystole, and intervene at a pre-programmable higher initial rate (usually 90–110 beats per minute) in an attempt to counter the vasodepressor component of the response.96
|
|
References |
|---|
|
TopIntroductionSymptoms of the vasovagal...Diagnosis of vasovagal syncopeTreatment of vasovagal syncopeManagement of vasovagal syncope:...References |
|---|
1. Lipsitz LA. Syncope in the elderly. Ann Intern Med 1983; 99:92–105.
2. Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982; 73:15–23.[Web of Science][Medline]
3. Kapoor WN. Diagnostic evaluation of syncope. Am J Med 1991; 90:91–106.[Web of Science][Medline]
4.
Lipsitz LA, Wei JY, Rowe JW. Syncope in an elderly, institutionalised population: prevalence, incidence, and associated risk. Q J Med 1985; 55:45–54.
5.
Parry SW, Kenny RA. Tilt table testing in the diagnosis of unexplained syncope. Q J Med 1999; 92:623–9.
6. Calkins H, Yu Shyr MS, Frumin H, Schork A, Morady F. The value of the clinical history in the differentiation of syncope due to ventricular tachycardia, atrioventricular block and neurocardiogenic syncope. Am J Med 1995; 98:365–73.[Web of Science][Medline]
7. Sutton R. Vasovagal syncope: clinical features, epidemiology and natural history. In: Blanc JJ, Benditt D, Sutton R eds. Neurally Mediated Syncope: Pathophysiology, Investigations, and Treatment. The Bakken Research Center Series, Vol 10. Armonk NY, Futura, 1996:71–6.
8. Kenny RA. Introduction. In: Kenny RA, ed. Syncope in the Older Patient: Causes, Investigations and Consequences of Syncope and Falls. London, Chapman & Hall, 1996:1–14.
9. Grubb BP, Samoil D. Neurocardiogenic syncope. In: Kenny RA, ed. Syncope in the Older Patient: Causes, Investigations and Consequences of Syncope and Falls. London, Chapman & Hall, 1996:91–106.
10.
Shaw FE, Kenny RA. The overlap between falls and syncope in the elderly. Postgrad Med J 1997; 73:635–9.
11. Raviele A, Gasparini G, DiPede F, 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; 65:1322–7.[Web of Science][Medline]
12. Petersen MEV, Price D, Williams T, Jensen N, Riff K, Sutton R. Short AV interval VDD pacing does not prevent tilt induced vasovagal syncope in patients with cardioinhibitory vasovagal syndrome. Pacing Clin Electrophysiol 1994; 17:882–91.[Medline]
13. 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; 72:469–71.[Web of Science][Medline]
14. Sheldon R, Splawinski J, Killam S. Reproducibility of upright tilt-table tests in patients with syncope. Am J Cardiol 1992; 69:1300–5.[Web of Science][Medline]
15. Brooks R, Ruskin JN, Powell AC, Newell J, Garan H, McGovern BA. Prospective evaluation of day-to-day reproducibility of upright tilt-table testing in unexplained syncope. Am J Cardiol 1993; 72:1289–92.
16. Brignole M, Menozzi C, Gianfranchi L, Lolli G, Bottoni N, Oddone D. A controlled trial of acute and long-term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 1992; 70:339–42.[Web of Science][Medline]
17. Natale A, Geiger MJ, Maglio C, Newby KH, Dhala A, Akhtar M, Sra J. Recurrence of neurocardiogenic syncope without pharmacologic interventions. Am J Cardiol 1996; 77:1001–3.[Web of Science][Medline]
18. Aurora Ruiz G, Peralta A, Gonzalez-Zuegaray J, Duce E. Evolution of patients with clinical neurocardiogenic (vasovagal) syncope not subjected to specific treatment. Am Heart J 1995; 130:345–50.[Web of Science][Medline]
19. Morillo CA, Leitch JW, Yee R, Klein GJ. A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by head-up tilt. J Am Coll Cardiol 1993; 22:1843–8.[Abstract]
20.
Mtinangi BL, Hainsworth R. Increased orthostatic tolerance following moderate exercise training in patients with unexplained syncope. Heart 1998; 80:596–600.
21.
Youoszai AK, Franklin WH, Chan DP, Cassidy SC, Allen HD. Oral fluid therapy. A promising treatment for vasodepressor syncope. Arch Pediatr Adolesc Med 1998; 152:165–8.
22.
El-Sayed H, Hainsworth R. Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope. Heart 1996; 75:134–40.
23. Mangru NN, Young M-L, Mas MS, Chandar JS, Pearse LA, Wolff GS. Usefulness of tilt table test with normal saline infusion in management of neurocardiac syncope in children. Am Heart J 1996; 131:953–5.[Web of Science][Medline]
24. Oberg B, Thoren P. Increased activity in left ventricular receptors during haemorrhage or occlusion of caval veins in the cat. A possible cause of the vasovagal reaction. Acta Physiol Scand 1972; 85:164–73.[Web of Science][Medline]
25. Shalev Y, Gal R, Tchou PJ, Anderson AJ, Avitall B, Akhtar M, 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; 18:746–51.[Abstract]
26. Parry SW, Kenny RA. Tilt table testing. In: Malik M, ed. Clinical Guide to Cardiac Autonomic Tests. Amsterdam, Kluwer Academic Publishers, 1998;67–99.
27. Sra JS, Murthy V, Natale A, Jazayeri MR, Dhala A, Deshpaned S, Sheth M, Akhtar M. Circulatory and catecholamine changes during head-up tilt testing in neurocardiogenic (vasovagal) syncope. Am J Cardiol 1994; 73:33–7.[Web of Science][Medline]
28. Jardine DL, Melton IC, Crozier IG, Bennett SI, Donald RA, Ikram H. Neurohormonal response to head-up tilt and its role in vasovagal syncope. Am J Cardiol 1997; 79:1302–6.[Web of Science][Medline]
29. Wallin BG, Sundlof G. Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst 1982; 6:287–91.[Web of Science][Medline]
30. Klingheben T, Kalusche D, Li Y-G, Schopperl M, Hohnloser SH. Changes in plasma epinephrine concentration and in heart rate during head-up tilt testing in patients with neurocardiogenic syncope. J Cardiovasc Electrophysiol 1996; 7:802–8.[Web of Science][Medline]
31. Sackett DL, Richardson WS, Rosenburg W, Haynes RB. Evidence Based Medicine. How to Teach and Practice EBM. London, Churchill Livingston, 1997, Chapter 2, Pp 37–78.
32. Mahanonda N, Bhuripanyo K, Kangkagate C, Wansanit K, Kulchot B, Nademanee K, Chaithiraphan S. Randomized double blind, placebo controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J 1995; 130:1250–3.[Web of Science][Medline]
33.
Biffi M, Boriani G, Sabbatini P, Bronzetti G, Frabetti L, Zannoli R, Branzi A, Magnani B. Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine. Heart 1997; 77:268–72.
34. Jhamb DK, Singh B, Sharda B, Kaul U, Goel P, Talwar KK, Wasir HS. Comparative study of the efficacy of metoprolol and verapamil in patients with syncope and positive head-up tilt test response. Am Heart J 1996; 132:608–11.[Web of Science][Medline]
35. Scott WA, Pongiglione G, Bromberg BI, Schaffer MS, Deal BJ, Fish FA, Macdonald D. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol 1995; 76:400–2.[Web of Science][Medline]
36. Fitzpatrick AP, Ahmed R, Williams S, Travill C, Sutton R. A randomised trial of medical therapy for vasodepressor vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 1991; 1:99–102.
37.
O'Marcaigh AS, MacLellan-Tobert SG, Porter CJ. Tilt table testing and oral metoprolol therapy in young patients with unexplained syncope. Pediatrics 1994; 93:278–83.
38. Muller G, Deal BJ, Strasburger JF, Benson DW. Usefulness of metoprolol for unexplained syncope and positive response to tilt testing in young persons. Am J Cardiol 1993; 71:592–5.[Web of Science][Medline]
39. Abe H, Kobayashi H, Nakashima Y, Izume F, Kuroiwa A. Effects of beta-adrenergic blockade on vasodepressor reaction in patients with vasodepressor syncope. Am Heart J 1994; 128:911–18.[Web of Science][Medline]
40. Natale A, Newby KH, Dhala A, Akhtar M, Sra J. Response to beta-blockers in patients with neurocardiogenic syncope: how to predict beneficial effects. J Cardiovasc Electrophysiol 1996; 7:1154–8.[Web of Science][Medline]
41. Sra JS, Murthy VS, Jazayeri MR, Shen Y-H, Troup PJ, Avitall B, Akhtar M. Use of intravenous esmolol to predict efficacy of oral beta-adrenergic blocker therapy in patients with neurocardiogenic syncope. J Am Coll Cardiol 1992; 19:402–8.[Abstract]
42. Cohen MV, Snow JS, Grasso V, Lehnert L, Goldner BG, Jadonath RL, Cohen TJ. Efficacy of pindolol for treatment of vasovagal syncope. Am Heart J 1995; 130:786–90.[Web of Science][Medline]
43. Leor J, Rotstein Z, Vered Z, Kaplinsky E, Truman S, Eldar M. Absence of tachycardia during tilt test predicts failure of beta-blocker therapy in patients with neurocardiogenic syncope. Am Heart J 1994; 127:1539–43.[Web of Science][Medline]
44.
Theodorakis GN, Kremastinos DT, Stefanakis GS, Iliodromitis GK, Avrambos GT, Livanis EG, Karavolias GK, Toutouzas PK. The effectiveness of betablockade and its influence on heart rate variability in vasovagal patients. Eur Heart J 1993; 14:1499–507.
45. Abi-Samra FM, Davison NM, Gohn DC, Vincent KA. Longterm effectiveness of beta blockers for the treatment of recurrent vasodepressor syncope. J Am Coll Cardiol 1992; 19:821–1:339A.
46. Blanc JJ, Corbel C, Mansourati J, Genet L. Evaluation of betablocker therapy in vasovagal syncope reproduced by the head-up tilt test. Arch Mal Coeur 1991; 84:1453–7.
47. Deal BJ, Strieper M, Scagliotti D, Julse E, Auld D, Campbell R, Strasburger JF, Benson DW. The medical therapy of cardioinhibitory syncope in pediatric patients. Pacing Clin Electrophysiol 1997; 20:1759–61.[Medline]
48. Lippman N, Stein KM, Lerman BB. Differential therapeutic responses of patients with isoproterenol-dependent and isoproterenol-independent vasodepressor syncope. Am Heart J 1994; 128:1110–16.[Web of Science][Medline]
49. Linzer M, Wang P, Mandalakas N, Comegno A, Butts L, Colburn C, Clyne C, Estes III NAM. Beta blockade is not effective in treating generally mediated syncope. J Am Coll Cardiol 1992; 19:821–3:339A.
50.
Rashtian MY, Bhandari AK. Worsening of neurocardiogenic syncope by beta-blockers. Ann Intern Med 1993; 119:955–6.
51. Milstein S, Buetikofer J, Dunnigan A, Benditt DG, Gornick C, Reyes WJ. Usefulness of disopyramide for prevention of upright tilt-induced hypotension-bradycardia. Am J Cardiol 1990; 65:1339–44.[Web of Science][Medline]
52. Sra JS, Anderson AJ, Sheikh SH, Avitall B, Tchou PJ, Troup PJ, Gilbert CJ, Akhtar M, Jazayeri MR. Unexplained syncope evaluated by electrophysiologic studies and head-up tilt testing. Ann Intern Med 1991; 114:1013–19.
53. Kelly PA, Mann DE, Adler SW, Fuenzalida CE, Reiter MJ. Low dose disopyramide often fails to prevent neurogenic syncope during head-up tilt testing. Pacing Clin Electrophysiol 1994; 17:573–6.[Medline]
54. Moya A, Permanyer-Miralda G, Sagrista-Salueda J, Carne X, Rius T, Mont L, Soler-Soler J. Limitations of head-up tilt test for evaluating the efficacy of therapeutic interventions in patients with vasovagal syncope: results of a controlled study of etilefrine versus placebo. J Am Coll Cardiol 1995; 25:65–9.[Abstract]
55. Yu JCL, Sung RJ. Clinical efficacy of propantheline bromide in neurocardiogenic syncope: pharmacodynamic implications. Cardiovasc Drugs Ther 1996; 10:687–92.
56. Abi-Samra F, Maloney JD, Fouad-Tarazi FM, Castle LW. The usefulness of head-up tilt testing and hemodynamic investigations in the work-up of syncope of unknown origin. Pacing Clin Electrophysiol 1988; 11:1202–14.[Medline]
57. Grubb BP, Temesy-Armos P, 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.[Web of Science][Medline]
58. Thulesius O, Gjores JE, Berlin E. Vasoconstrictor effect of midodrine, ST-1059, noradrenaline, etilefrine and dihydroergotamine on isolated human veins. Eur J Clin Pharmacol 1979; 16:423–4.[Web of Science][Medline]
59. McTavish D, Goa KL. Midodrine: a review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders. Drugs 1989; 38:757–7.[Web of Science][Medline]
60.
Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management of neurocardiogenic syncope. Heart 1998; 79:45–9.
61. Koyama S, Matsubara T, Aizawa Y, Ohshima M, Yamaguchi T, Yamazaki Y, Igarashi Y, Tamura Y, Yamazoe M, Izumi T, et al. A case of vasovagal syncope with convulsions—the effects of midodrine hydrochloride. Jap Circulation J 1992; 56(9):950–4.
62. Ward C, Kenny RA. Observations on midodrine in a case of vasodepressor neurogenic syncope. Clin Auton Res 1995; 5:257–60.[Web of Science][Medline]
63. Sra J, Maglio C, Biehl M, Dhala A, Blanck Z, Deshpande S, Jazayeri MR, Akhtar M. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997; 8:42–6.[Web of Science][Medline]
64. Lawson J, Ross R, Graham L, Kenny RA. Midodrine in the treatment of hypotensive disorders (abstract). Clin Auton Res 1998; 8:71.
65. Janosik D, Holt D, Fredman C, Bjerregaard P. Efficacy of oral ephedrine sulfate in preventing neurocardiogenic syncope (abstract). Circulation 1991; 84(Suppl II):II–234.
66. Natale A, Sra J, Dhala A, Wase A, Jazayeri M, Deshpande S, Blanck Z, Akhtar M. Efficacy of different treatment strategies for neurocardiogenic syncope. Pacing Clin Electrophysiol 1995; 18(4 Pt 1):655–62.[Medline]
67. Streiper MJ, Campbell RM. Efficacy of alpha-adrenergic agonist therapy for prevention of pediatric neurocardiogenic syncope. J Am Coll Cardiol 1993; 22:594–7.[Abstract]
68. Susmano A, Volgman AS, Buckingham TA. Beneficial effects of dextroamphetamine in the treatment of vasovagal syncope. Pacing Clin Electrophysiol 1993; 16:1235–9.[Medline]
69. Grubb BP, Kosinski D, Mouhaffel A, Pothoulakis A. The use of methylphenidate in the treatment of refractory neurocardiogenic syncope. Pacing Clin Electrophysiol 1996; 19:836–40.[Medline]
70. Raviele A, Gasparini G, DiPede F, 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; 65:1322–7.
71. Bannister R, Mathias CJ. Management of postural hypotension in autonomic failure. In: Bannister R, ed. Autonomic Nervous System: A Testbook of Clinical Disorders of the Autonomic Nervous System. London, Oxford University Press, 1993:589–90.
72.
Hussain RM, McIntosh SJ, Lawson J, Kenny RA. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart 1996; 76:507–9.
73. Rall TW. Evolution of the mechanisms of action of methylxanthines from calcium mobilizers to antagonists of adenosine receptors. Pharmacologist 1982; 24:277–87.
74.
Nelson DS, Stanley M, Love CJ, Coyne KS, Schaal SF. The autonomic and hemodynamic effects of oral theophylline in patients with vasodepressor syncope. Arch Intern Med 1991; 151:2425–9.
75. Dabire H. Central 5-hydroxytryptamine (5-HT) receptors in blood pressure regulation. Therapie 1991; 46:421–9.[Web of Science][Medline]
76. Dabire H, Cherqui C, Fournier B, Schmitt H. Comparison of effects of some 5-HT1 agonists on blood pressure and heart rate of normotensive anaesthetized rats. Eur J Pharmacol 1987; 140:259–66.[Web of Science][Medline]
77.
Theodorakis GN, Markianos M, Livanis EG, Zarvalis E, Flevari P, Kremastinos DT. Central serotonergic responsiveness in neurocardiogenic syncope. A clomipramine challenge test. Circulation 1998; 98:2724–30.
78. Kosinski DJ, Grubb BP, Elliott L, Dubois B. Treatment of malignant neurocardiogenic syncope with dual chamber cardiac pacing and fluoxetine hydrochloride. Pacing Clin Electrophysiol 1995; 18:1455–7.[Medline]
79. Grubb BP, Samoil D, Kosinski D, Kip K, Brewster P. Use of sertraline hydrochloride in the treatment of refractory neurocardiogenic syncope in children and adolescents. J Am Coll Cardiol 1994; 24:490–4.[Abstract]
80. Grubb BP, Wolfe DA, Samoil D, Temesy-Armos P, Hahn H, Elliot L. Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt induced syncope. Pacing Clin Electrophysiol 1993; 16:458–64.[Medline]
81. Tandan T, Giuffre M, Sheldon R. Exacerbations of neurally mediated syncope associated with sertraline. Lancet 1997; 349:1145–6.[Web of Science][Medline]
82. Zeng C-Y, Zhu Z, Liu G, Wang X, He D, Wang H, Yang C, Tan J. Inhibitory effect of enalapril on neurally mediated syncope in elderly patients. J Cardiovasc Pharmacol 1998; 31:638–42.[Web of Science][Medline]
83. Fitzpatrick A, Sutton R. Tilting toward a diagnosis in unexplained recurrent syncope. Lancet 1989; 1:658–60.[Web of Science][Medline]
84. Sutton R. Vasovagal syndrome—could it be malignant? Eur J Cardiac Pacing Electrophysiol 1992; 2:89.
85. Sutton R, Petersen M, Brignole M, Raviele A, Menozzi C, Giani P. Proposed classification for tilt induced vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 1992; 2:180–3.
86.
Petersen MEV, Chamberlain-Webber R, Fitzpatrick AP, Ingram A, Williams T, Sutton R. Permanent pacing for cardioinhibitory malignant vasovagal syndrome. Br Heart J 1994; 71:274–81.
87. Grubb BP, Temesy-Armos P, Moore J, Wolfe D, Hahn H, Elliot L. Head-upright tilt-table testing in evaluation and management of the malignant vasovagal syndrome. Am J Cardiol 1992; 69:904–8.[Web of Science][Medline]
88. Fitzpatrick AP, Theodorakis G, Ahmed R, Williams T, Sutton R. Dual chamber pacing aborts vasovagal syncope induced by head up 60 degree tilt. Pacing Clin Electrophysiol, 1991; 14:13–19.[Medline]
89. Samoil D, Grubb BP, Brewster P, Moore J, Temesy-Armos P. Comparison of single and dual chamber pacing techniques in prevention of head up tilt induced vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 1993; 1:36–41.
90.
Sra JS, Jazayeri MR, Avitall B, Dhala A, Deshpande S, Blanck Z, Akhtar M. Comparison of cardiac pacing in drug therapy in the treatment of neurocardiogenic (vasovagal) syncope with bradycardia or asystole. N Engl J Med 1993; 328:1085–90.
91. El-Bedawi KM, Wahba MMAE, Hainsworth R. Cardiac pacing does not improve orthostatic tolerance in patients with vasovagal syncope. Clin Auton Res 1994; 4:233–7.[Medline]
92.
Connolly SJ, Sheldon R, Roberts RS, Gent M and the Vasovagal Pacemaker Study Investigators. The North American Vasovagal Pacemaker Study (VPS). A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 1999; 33:16–20.
93.
ACC/AHA Task Force Report. ACC/AHA Guidelines for implantation of cardiac pacemakers and antiarrhythmia devices. A report of the American College of Cardiology/American Heart Association Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (Committee on Pacemaker Implantation). J Am Coll Cardiol 1998; 31:1175–209.
94. McGrady A, Bush EG, Grubb BP. Outcome of biofeedback-assisted relaxation of neurocardiogenic syncope and headache. Appl Physiol Biofeedback 1997; 22:63–72.
95. Ector H, Reybrouck T, Heidbuchel H, Gewillig M, Van de Werf F. Tilt training: a new treatment for recurrent neurocardiogenic syncope and severe orthostatic intolerance. Pacing Clin Electrophysiol 1998; 21:193–6.[Medline]
96. Benditt DG, Sutton R, Gammage MD, Markowitz T, Gorski J, Nygaard GA, Fetter J and the International Rate-Drop Investigators Group. Clinical experience with Thera DR Rate-Drop Response pacing algorithm in carotid sinus syndrome and vasovagal syncope. Pacing Clin Electrophysiol 1997; 20:832–9.[Medline]
97.
Di Girolamo E, Di Lorio C, Sabatini P, Leonzio L, Barcone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo controlled study. J Am Coll Cardiol 1999; 33:1227–30.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. G. Benditt and J. T. Nguyen Syncope: therapeutic approaches. J. Am. Coll. Cardiol., May 12, 2009; 53(19): 1741 - 1751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. P. Grubb Neurocardiogenic Syncope N. Engl. J. Med., March 10, 2005; 352(10): 1004 - 1010. [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Jones, J. P. Moyers, J. T. Rogers, R. M. Rodriguez, Y. C. G. Lee, and R. W. Light Ultrasound-Guided Thoracentesis: Is It a Safer Method? Chest, February 1, 2003; 123(2): 418 - 423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E M Smith IF IT'S NOT EPILEPSY . . . J. Neurol. Neurosurg. Psychiatry, June 1, 2001; 70(suppl_2): ii9 - ii14. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||