The management of vasovagal syncope
Introduction
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.4In 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
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.6Elderly 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,10with some elderly subjects recalling only the index fall rather than the syncopal attack precipitating it.10
Diagnosis of vasovagal syncope
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
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
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.
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.
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.
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).
View this table:
Table 1
Randomized controlled trials of therapeutic interventions in vasovagal syncope
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).
View this table:
Table 1
Randomized controlled trials of therapeutic interventions in vasovagal syncope
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.
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 novoor 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.
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 novoor 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–,29and heart rate29 found prior to sympathetic withdrawal30 and syncope in many patients.
From a high-sensitivity Medline search,31along with scrutiny of non-Medline-listed journals, we were able to identify only six randomized controlled trials of β-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 days34to 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.33Unfortunately, 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 β-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,36clonidine,36 cafedrine,16 domperidone16and 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 β-blockade in the vasovagal syndrome, though the methodological confounders discussed above are of course pertinent here. Metoprolol,30,37–,42 pindolol,42propranolol,43,,44 esmolol,40,,41betaxolol,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,,50with one describing worsening of symptoms on atenolol treatment.50
Thus, while the evidence for the use of β-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.
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–,29and heart rate29 found prior to sympathetic withdrawal30 and syncope in many patients.
From a high-sensitivity Medline search,31along with scrutiny of non-Medline-listed journals, we were able to identify only six randomized controlled trials of β-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 days34to 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.33Unfortunately, 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 β-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,36clonidine,36 cafedrine,16 domperidone16and 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 β-blockade in the vasovagal syndrome, though the methodological confounders discussed above are of course pertinent here. Metoprolol,30,37–,42 pindolol,42propranolol,43,,44 esmolol,40,,41betaxolol,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,,50with one describing worsening of symptoms on atenolol treatment.50
Thus, while the evidence for the use of β-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.
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.
Midodrine and other α-adrenergic agonists
Midodrine is a powerful α-agonist and vasoconstrictor, exhibiting 80% of norepinephrine-induced contraction of human peripheral veins.58 It is used in the management of orthostatic hypotension,59and 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.60Only one randomized double-blind placebo-controlled study has been reported to date,60with 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,,66pseudephedrine,67 dextro-amphetamine,68methylphenidate69 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
Midodrine is a powerful α-agonist and vasoconstrictor, exhibiting 80% of norepinephrine-induced contraction of human peripheral veins.58 It is used in the management of orthostatic hypotension,59and 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.60Only one randomized double-blind placebo-controlled study has been reported to date,60with 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,,66pseudephedrine,67 dextro-amphetamine,68methylphenidate69 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.
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
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.76Experimental 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.
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.76Experimental 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.82Further work is awaited with interest.
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.82Further 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,,84Concerns 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.
View this table:
Table 2
Classification of head-up tilt-table-induced vasovagal syncope
Most of the evidence to date has been based on small retrospective series,86 case reports78,,87 and uncontrolled trials,88,,89all 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.
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,,84Concerns 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.
View this table:
Table 2
Classification of head-up tilt-table-induced vasovagal syncope
Most of the evidence to date has been based on small retrospective series,86 case reports78,,87 and uncontrolled trials,88,,89all 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.95Further studies are needed before this practice is widely adopted.
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.95Further studies are needed before this practice is widely adopted.
Management of vasovagal syncope: recommendations
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 β-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
Figure 1.
Algorithm for the management of vasovagal syncope.
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 β-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
Figure 1.
Algorithm for the management of vasovagal syncope.
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