QJM: An International Journal of Medicine, 2016, 767–773

doi: 10.1093/qjmed/hcw089
Advance Access Publication Date: 23 June 2016
Review – Sir William Osler Medicine Masterclass

REVIEW – SIR WILLIAM OSLER MEDICINE MASTERCLASS

The management of vasovagal syncope

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R.A. Kenny and T. McNicholas
From the Mercers Institute, St James’s Hospital, Dublin, Ireland
Address correspondence to Professor Rose Anne Kenny, The Irish Longitudinal Study on Ageing (TILDA), Lincoln Gate, Trinity College Dublin, Dublin 2,
Ireland. email: [email protected]

Abstract
Vasovagal syncope, or the “common faint”, is the most common cause of syncope. Although it is considered a benign
condition, there is a significant economic burden and significant impact on quality of life in patients with recurrent syncope,
particularly in older adults. Typical vasovagal syncope usually occurs in young adults, and can often be diagnosed on the
basis of history, in the absence of structural heart disease. Atypical vasovagal syncope, which is more common in older
adults, can be more difficult to diagnose, however. In atypical vasovagal syncope, there is often a short or absent prodrome,
and amnesia for loss of consciousness is common and it can, therefore, often be misdiagnosed, for example as falls. A more
standardized approach to the diagnosis and management of patients presenting with syncope or unexplained falls is
required, and it is anticipated that the number of Syncope Units will increase. Treatment of vasovagal syncope is largely
conservative; however, medical or device therapy may be required when syncope is severe and refractory to conservative
treatment, as there is significant impact on quality of life and it can be associated with injury. The aim of this article is to
provide an overview of the diagnosis and management of vasovagal syncope.

Introduction The lifetime cumulative incidence of syncope in women is

Syncope is a transient loss of consciousness (TLOC) due to tran- higher than in men, ranging from 5% aged 20–29 and up to 50%
sient global cerebral hypoperfusion characterized by rapid of women aged over 80.2 The age distribution is bimodal, peek-
onset, short duration and spontaneous and complete recovery.1 ing in teenagers and the elderly. The true incidence of syncope
It is classified into three groups: reflex syncope, syncope due to is difficult to ascertain due to variation in definition, differences
orthostatic hypotension (OH) and cardiac syncope. Vasovagal in population prevalence and underreporting. Reflex syncope is
syncope (VVS) is a type of reflex syncope mediated by emotional the most common cause of syncope both in the GP setting and
or orthostatic stress and is typically preceded by a prodrome of in the Emergency Department. It is the commonest cause of
autonomic activation, (such as sweating, pallor and nausea).1 syncope in youth, whereas multiple causes are often present in
In reflex syncope, cardiovascular reflexes that control the older adults and the history may be unreliable.2 Healthcare
circulation become intermittently inappropriate resulting in costs associated with syncope are comparable with healthcare
hypotension and/or bradycardia. It is usually classified based costs associated with other chronic conditions including
on the efferent pathway most involved, i.e. sympathetic (hypo- asthma, HIV and COPD.2 There is also a significant impact
tension or “vasodepressor”) or parasympathetic (bradycardia or on quality of life, particularly in older adults, and syncope in
“cardioinhibitory”). It may also be classified according to the later life may be associated with cognitive impairment.3 While
trigger i.e. micturition, defecation, cough or swallow syncope.1 typical VVS in youth is a benign condition, VVS starting in old
Classification of syncope based on the underlying pathophysio- age may have more serious underlying causes and
logical process is described in Figure 1.1 consequences.4

Submitted: 13 May 2016; Revised: 18 May 2016

C The Author 2016. Published by Oxford University Press on behalf of the Association of Physicians.
V
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Figure 1. Pathophysiological basis of Classification of Reflex Syncope.1 ANF, autonomic nervous function; ANS, autonomic nervous system; BP, blood pressure; low
periph. Resist, low peripheral resistance; OH, orthostatic hypotension.

Pathophysiology usually occurs in young subjects and episodes may be isolated

or infrequent, or may occur in clusters.
Assumption of the upright position leads to pooling of up to 1 l
Typical episodes occur when upright, during prolonged
of blood in the lower limbs and splanchnic area. This leads to a
standing or after exercise. Episodes are triggered by fasting, de-
reduction in venous return, ventricular preload and cardiac out-
hydration, alcohol, hot rooms, hot showers/baths and queuing.
put. Consequent reduction in distension of the baroreceptors re-
There is often a positive family history of fainting or low blood
sults in attenuated baroreflex signals to the cardiovascular
pressure and the patient may also have diagnosis of irritable
centre in the brain stem. This triggers parasympathetic inhib-
bowel syndrome, restless legs, Raynaud’s phenomenon and
ition and sympathetic activation, leading to an increase in heart
chronic fibromyalgia. Previous studies have shown that younger
rate and total peripheral resistance.5 However, after an interval
patients with recurrent VVS may also have symptoms consist-
of time upright, the Bezold–Jarisch reflex occurs with conse-
ent with chronic fatigue syndrome and there may be an overlap
quent vasodepression and/or bradycardia. Most therapies are
in some patients between POTS symptoms and VVS.7 Because
focused on maneuvers which attenuate peripheral pooling and
VVS can be triggered by emotion, cognitive behavioral therapy
increase intravascular volume, modification of medications
and similar strategies to modify emotional triggers are of bene-
which contribute to hypotension or bradycardia and raising
fit. Symptoms may occur for the first time after stressful life
awareness of prodromal symptoms.
events or periods of emotional strain, and this history should
Animal models for VVS are not available to inform studies
unmask this.
because VVS requires bipedalism, which requires the systolic
VVS can occur when supine or seated, possibly in as many
blood pressure at the level of the heart be sufficient to overcome
as 10% of events. VVS is classified as “severe” if events are
a 30 mmHg hydrostatic burden. This together with the fact that
atypical (i.e. supine/seated/no prodrome/no triggers), associ-
the volume of blood required by the human brain is much
ated with injury, frequent or associated with hospital admis-
higher than that required by animals (20% of cardiac output) is
sions. Multiple attributable causes may be present, rising
thought to have led to the development of VVS in humans, to
with age.
protect cerebral function.6
Atypical VVS can be diagnosed in subjects with T-LOC not
preceded by any trigger, but who have a positive response to tilt
testing, with no evidence of competing diagnosis.8 Atypical VVS
Clinical presentation is often observed in older patients, who often experience a
VVS is typically characterized by precipitating triggers such as shorter or no prodrome. Amnesia for loss of consciousness in
emotional or orthostatic stress and prodromal symptoms due VVS occurs in 20% of young adults and up to 50% of older pa-
to activation of the autonomic system, e.g. awareness of fast tients.9 Focal neurology has also been reported with syncope,
heart rate, sweating, pallor or symptoms of cerebral hypoperfu- with a recent study reporting one in twenty individuals with
sion such as dizziness, loss of vision and heightened awareness syncope/presyncope having co-existent focal neurology that
of senses, particularly auditory. The duration is short, with does not progress to a persistent deficit.10 If patients have am-
prompt recovery on assuming the supine position. Typical VVS nesia for loss of consciousness and if no collateral witness of
 R.A. Kenny and T. McNicholas | 769

syncope is available, VVS may be misdiagnosed as falls, TIA or Jarisch reflex, increasing parasympathetic activity and reducing
stroke, or seizures.8–10 sympathetic activity, leading to reflex bradycardia, vasodilation
While familial aggregation studies have consistently shown and hypotension. A positive test demonstrates a hypotensive
a familial link in patients with VVS, no clear genetic profiles for susceptibility, which plays a role in causing syncope irrespect-
VVS have been described,11,12 this is compounded by the lack of ive of its etiology.18 A recent meta-analysis of studies compar-
clarity for diagnostic sub types and heterogeneity of reflex syn- ing HUT outcomes between patients with syncope of unknown
copal syndromes. origin and control subjects without previous syncope demon-
strated good overall ability of HUT to discriminate between
symptomatic patients and asymptomatic controls.19 Despite
Investigations and diagnosis limitations, including lack of reproducibility and multiple differ-
ent tilt protocols, HUT remains an important part of the work
Initial investigations include a comprehensive history and
up for VVS. It is particularly useful for diagnosing atypical VVS,
physical exam, electrocardiograph (ECG) and orthostatic blood
distinguishing syncope from seizures, diagnosing psychogenic
pressure measurements, such as lying and standing blood pres-
pseudo-syncope, diagnosing orthostatic hypotension (OH) and

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sure measurements or Active Stand, which may reveal ten-
Postural Orthostatic Tachycardia Syndrome (POTS), and in high-
dency towards orthostatic intolerance.1 A detailed history
risk situations such as serious injury and occupational implica-
including a collateral history, in the absence of structural heart
tions. HUT enables witness by medical professionals of symp-
disease, will enable a diagnosis in a majority of cases. Based on
toms, thus patients can be reassured with objective measures of
the history and initial investigations, further investigations
hemodynamics and given biofeedback, training of physical
may be warranted such as Tilt Table testing. Diagnostic scores
counter maneuvers and other methods to prevent events.20
have been introduced to aid with the diagnosis; however, they
Figure 2 shows an example of the Finometer (Finapres
have low specificity, potentially misdiagnosing cardiac syncope
Medical Systems) output for a cardioinhibitory tilt test and
as VVS. The most widely used is the Calgary Syncope Symptom
Figure 3 shows an example of the Finometer output for a vaso-
Score, which is applicable to patients without a history of car-
depressor tilt test.
diomyopathy or myocardial infarction13. However, the specifity
of this score has since been found to be low14. Despite this, they
do serve as a reminder of the importance of history in diagnos- External monitoring
ing VVS.
Because of a lack of reliable long term monitoring technologies
Patients who require further assessment should be referred
for BP, the vasodepressor component of VVS is difficult to cap-
to a Syncope Unit. The EHRA task force recently published
ture during real time. Cardiac monitoring may detect bradycar-
guidelines on Syncope Units (SU), including referral pathways,
dia/asystole. If patients have syncopal episodes with no sign of
necessary skills, staffing and equipment.15 The SU features a
bradycardia/asystole, a diagnosis of vasodepressor subtype can
standardized approach to diagnosis of TLOC, with dedicated
be made by exclusion. Rebound sinus tachycardia may be evi-
staff and access to appropriate diagnostics and therapies.
dent during heart rate recording in these patients.
Evidence for benefits of SU include reduced health care costs,
Twenty-four hours holter monitoring is unlikely to be of
reduced length of stay, higher diagnostic rates and reduced re-
benefit because of the short duration of monitoring.1 External
admission rates in hospitals with SUs.15
loop recorders may be more useful as they allow for activation
In the Cardiac Arrest Survivors with Preserved Ejection
during symptoms and longer duration of monitoring. However,
Fraction Registry (CASPER), 35% of patients (without evidence of
patients are unlikely to comply for more than a few weeks. VVS
structural heart disease) had experienced syncope before their
events tend to cluster and this is unlikely to be picked up on
index cardiac arrest event.16 Some “Red Flags” to be considered
short duration monitoring. More prolonged monitoring is often
in evaluating patients presenting with syncope are listed in
required.
Table 1.

Internal loop recorders (ILRs)

Head up tilt table testing (HUT)
The ILR is an implantable subcutaneous device, which sits in
HUT allows reproduction of neurally mediated symptoms in the the chest wall and monitors heart rate continuously. It is pre-
laboratory setting. It was introduced into clinical practice in programmed to retain abnormal rates and rhythms. ILRs allow
1986 and has been the commonest provocative test used in prolonged cardiac monitoring, increasing the likelihood of
diagnosing VVS since this time.17 HUT augments the Bezold– achieving symptom-rhythm correlation in patients with syn-
cope. ILRs are used in patients with recurrent unexplained syn-
Table 1. Red flags. cope, or in high-risk patients in whom comprehensive
evaluation did not reveal an underlying cause. The
ECG abnormalities International Study on Syncope of Uncertain Etiology (ISSUE)
Syncope in patients with established heart disease trials have demonstrated a role for early ILR implantation in un-
Family history of sudden unexplained death,
explained syncope. They demonstrated that early ILR applica-
or sudden cardiac death
tion, with PPM therapy delayed until documentation of syncope
Supine/seated syncope
allows a safe, specific and effective therapy in patients with
Syncope while driving
syncope.21 In The recent Falls and Unexplained Syncope in the
Palpitations preceding syncope
Emergency Department (FUSE) study in which patients over 50
Syncope during exercise
Chest pain/shortness of breath
with unexplained recurrent falls and normal initial cardiac
Anaemia, electrolyte imbalances evaluation had ILR implanted, demonstrated 20% of patients
Stokes–Adams attacks—short TLOC without warning had underlying cardiac arrhythmias which was attributable as
the cause of their fall.22
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Figure 2. Finometer output for Cardioinhibitory Positive Tilt Test. An example of a finometer output for a cardioinhibitory positive tilt test, with reduction in HR preced-
ing reduction in blood pressure. SYS, systolic blood pressure; DIA, diastolic blood pressure; HR, heart rate; CO, cardiac output; TPR, total peripheral resistance.

Figure 3. Finometer output for vasodepressor positive tilt test. An example of a finometer output for a vasodepressor positive tilt test, with no significant reduction in
heart rate accompanying reduction in blood pressure. SYS, systolic blood pressure; DIA, diastolic blood pressure; HR, heart rate; CO, cardiac output; TPR, total periph-
eral resistance.
 R.A. Kenny and T. McNicholas | 771

A subtype of reflex syncope which has been recorded during While the overall results of the trial were disappointing, there
cardiac monitoring is vagally mediated AV block. This is defined was suggestion that bBlockers are effective in suppressing VVS
as a paroxysmal first-, second- or third degree AV block. It is dif- in patients older than 42 and a subsequent meta-analysis sup-
ferentiated from intrinsic AV block by a simultaneous sinus ports this.30,31 POST 5 is currently underway to assess the bene-
slowing. Syncope due to vagally mediated AV block should be fit of metoprolol in preventing VVS in older patients.32 Caution
managed as reflex syncope.23 should be exercised when using bBlockers as a recent study has
shown an association between orthostatic hypotension and
bBlockers.33
Treatment of vasovagal syncope
Non-pharmacological treatment Alpha agonists
The rationale for using a-agonists in prevention of VVS is that
First-line treatment for VVS is conservative, with lifestyle meas- stimulating a-adrenergic receptors increases peripheral vascu-
ures such as increasing fluid and salt intake and Physical lar tone. Midodrine is the most widely studied. The STAND trial
Counter Maneuvers (PCMs). Fluid intake should be increased by did not show a significant improvement in symptoms with

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up to 2–2.5 l per day, and salt intake should be increased, if there midodrine34; however, a meta-analysis excluding the STAND
are no contraindications. The rationale for this is that sodium trial found midodrine to be effective.35 POST 4 is underway to
content determines the volume of the extracellular fluid vol- investigate the use of midodrine in VVS.32 It is frequently used
ume.20 In older patients, reduction or withdrawal of possible in practice for the treatment of refractory VVS in normotensive
culprit medications such as cardiovascular drugs or psycho- patients, with positive results often observed.
tropic drugs should be considered.1 Twenty-four hours ambula-
tory blood pressure may assist in diagnosing overall low BP, or
Anti-cholinergic medications
post-prandial hypotension, which can provide collateral evi-
It has been proposed that anti-cholinergic medications would
dence for the need to withdraw/modify medications.
prevent VVS by diminishing left ventricular contraction and
Orthostatic blood pressure measures may also be abnormal in
exerting a vagolytic effect, preventing bradycardia/asystole.
patients in whom medications are causal for VVS and provide
However, there is a lack of strong evidence for their use and
further collateral evidence for modification of CV drugs.24
side effects can be difficult to tolerate.29
Patients should be reassured of the benign course of the con-
dition, and counselled regarding recognition of prodromal
Somatostatin analogues
symptoms.25 PCMs, with isometric exercise of the large muscles
Octreotide has shown a benefit in small, non-randomized stud-
(e.g. leg crossing, tensing of leg, abdominal and buttock muscle
ies for the treatment of OH and POTS. However its use has not
and arm tensing) have been shown to induce a significant blood
been studied in patients with VVS without orthostasis.29
pressure increase during the prodromal phase of reflex syncope
on tilt tests, and avoiding or delaying TLOC.24,26 PCMs are only
Norepinephrine transporter (NET) inhibitors
effective in preventing VVS in patients who experience a pro-
NET inhibitors block the reuptake of norepinephrine in sympa-
drome. A recent study in ISSUE 3 showed many patients had
thetic neural synapses, leading to a selective increase in sympa-
syncope recurrence despite PCMs, perhaps because of older age
thetic tone during stress. Schroeder et al compared NET
and lack of sufficiently long prodrome.27 However, PCMs are
inhibitors with placebo in delaying the onset of presyncope dur-
risk free, low cost and should be used as first line treatment in
ing HUT.36 Results were promising but the significance of this is
patients with prodromal symptoms.1,28
debatable as it was performed on healthy volunteers. A small
Tilt training or home orthostatic training, with prolonged
study of sibutramine in preventing VVS showed a significant re-
periods in the upright position, is not currently recommended.
duction in VVS.37 However, sibutramine has been removed from
the market by the FDA due to increased cardiovascular risk.
Pharmacological treatment
In cases of severe VVS refractory to conservative measures, Pacemaker therapy
including reduction of culprit medications where possible,
VVS is often associated with a cardioinhibitory response, and,
pharmacological treatment may be required. Results from
therefore, pacemakers have been proposed as a potential treat-
randomized controlled trials have been disappointing; however,
ment in correctly selected patients, although there is still some
a number of medications are used in clinical practice.
debate regarding patients who will benefit from pacing inter-
vention.38 ISSUE 3 assessed the benefit of pacemaker therapy in
Fludrocortisone patients with VVS and documented asystole on ILR. There was
Fludrocortisone is frequently used in patients with OH, but is a reduction in syncope recurrence in the PPM ON group (2-year
less well studied in recurrent VVS without OH.29 The rationale recurrence rate of 57% in the PPM OFF group, and 25% in the
for its use is to enhance sodium and fluid retention. The PPM ON group).39 A sub-study of ISSUE 3 looking at the role of
Prevention of Syncope Trial II (POST II) is an ongoing random- tilt testing in predicting recurrences concluded that cardiac pac-
ized controlled trial assessing the effectiveness of fludrocorti- ing was effective in preventing the recurrence of syncope in pa-
sone in treating VVS.29 Despite the lack of published evidence, tients with VVS and documented asystole when tilt testing was
fludrocortisone has been used successfully in clinical practice negative, whereas pacemaker therapy showed no benefit in tilt
for treating refractory VVS. positive patients. The ISSUE trials were the first to include both
tilt positive and negative patients, and this result was unex-
Beta blockers pected.40 This may be because tilt positive patients may have a
Results from RCTs on the use of bBlockers in the prevention of predominantly vasodepressor response to VVS, whereas tilt
VVS have been disappointing. The Prevention of Syncope Trial negative patients may have a predominantly cardioinhibitory
(POST) assessed the effectiveness of metoprolol in treating VVS. response. The effectiveness of PPM therapy in tilt negative
 772 | QJM: An International Journal of Medicine, 2016, Vol. 109, No. 12

patients has been corroborated in the Syncope Unit Project 2 12. Klein KM, Berkovic SF. Genetics of vasovagal syncope. Auton
(SUP2). The syncope recurrence rates in SUP2 were lower in all Neurosci 2014; 184:60–5.
groups who received PPM therapy compared with controls; 13. Sheldon R, Rose S, Connolly S, Ritchie D, Koshman ML,
however, probability of recurrence was lowest in patients who Frenneaux M. Diagnostic criteria for vasovagal syncope based
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tients paced for intrinsic AV block.41 It is noteworthy that the 14. Romme JJ, van Dijk N, Boer KR, Bossuyt PM, Wieling W,
mean age in the SUP 2 population was over 70. Reitsma JB. Diagnosing vasovagal syncope based on quantita-
There have also been a number of studies investigating the tive history-taking: validation of the Calgary Syncope
use of closed loop stimulation (CLS) pacemakers in patients Symptom Score. Eur Heart J 2009; 30:2888–96.
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makers, determining the appropriate heart rate based on intra- Doherty C, et al. Syncope unit: rationale and requirement –
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reinterpretation of tilt-testing: hypotensive susceptibility ra-
While there has been significant progress in recent years, evi- ther than diagnosis. Eur Heart J 2014; 35:2211–2.
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Nonpharmacological treatment of reflex syncope. Clin Auton
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