Sage Journals: Discover world-class research

Abstract

Syncope is a symptom that is commonly encountered in the practice and may point to a cardiac or neurological diagnosis. The evaluation of syncope rests on a thorough clinical evaluation, aided by electrocardiogram (ECG) findings, followed by risk stratification of the particular case. Once high-risk factors have been ruled out, the patient can be further diagnosed as having a reflex syncope (RS), orthostatic hypotension, or cardiac syncope based on specific clues. If the initial evaluation is not confirmatory various diagnostic tests may be used to guide further management (eg, long-term ECG monitoring, tilt table testing, etc). The management should be based on the overall profile of the patient and not only on any single test. In this review, we discuss the evaluation of a patient with RS and give an overview of treatments available for the patients.

Keywords

Reflex syncope clinical evaluation tilt table testing implantable loop recorder pacemaker

Abbreviations

AMI: Acute myocardial infarction

ARVC: Arrhythmogenic Right Ventricular Cardiomyopathy

AV: Atrioventricular

BP: Blood pressure

BrS: Brugada syndrome

CHF: Congestive heart failure

CLS: Closed-loop stimulation

CPM: Counterpressure maneuverers

CSM: Carotid sinus massage

CSS: Carotid sinus stimulation

ED: Emergency department

ELR: External loop recorder

EPS: Electrophysiological study

ILR: Implantable loop recorder

ISSUE: International study on syncope of unexplained etiology

LOC: Loss of consciousness

LQTS: Long QT Syndrome

LVOTO: Left ventricular outflow tract obstruction

NT-TLOC: Non-traumatic transient loss of consciousness

OH: Orthostatic hypotension

POTS: Postural orthostatic tachycardia syndrome

RS: Reflex syncope

SCD: Sudden cardiac death

TLOC: Transient Loss of Consciousness Úfter Sudden cardiac death

TT: Tilt training

TTT: Tilt table testing

UI: Urinary incontinence

VASIS: Vasovagal syncope international study

Introduction

One of the most challenging symptoms to evaluate, encountered by the medical practitioners, is syncope (pronounced “sing-kuh-pee”). Syncope is a syndrome in which there is a total loss of consciousness due to cerebral hypoperfusion, characterized by a rapid onset, short duration, and spontaneous complete recovery.^{1
2
3} Syncope can be caused due to traumatic head injury which is outside the scope of this article. Most of the syncope seen in clinical practice is non-traumatic. Nontraumatic transient loss of consciousness (NT-TLOC)is defined as a real or apparent loss of consciousness (LOC), with loss of awareness for a short duration.³ A clear and detailed history taking and a focused clinical examination for specific causes of syncope do lead to the diagnosis of the etiology in the majority of the cases. In a patient with NT-TLOC, one needs to rule out epileptic seizures, psychogenic LOC (pseudo-seizure), and other vascular causes (eg, subclavian steal syndrome, subarachnoid hemorrhage, etc), based on clinical and investigational clues, to come to the diagnosis of syncope.⁴ The important thing to remember is—syncope is not a complete diagnosis but just the presenting symptom and identifying the underlying cause is important.²

The causes of syncope can be broadly classified into reflex syncope (RS) (neurally mediated), syncope due to orthostatic hypotension (OH), and cardiac syncope, as per the European Practice Guidelines (Figure 1).³ RS is the most common cause of syncope irrespective of age or clinical setting.^{3
5
6} The epidemiological studies have shown that RS is common in the younger population, whereas cardiovascular causes are common in older individuals.⁵ Syncope is considered to be due to cerebral hypoperfusion with a combination of multiple central as well as peripheral mechanisms.^{3
7}

Figure 1.

Abbreviations. AMI, acute myocardial infarction; LVOTO, left ventricular outflow tract obstruction; OH, orthostatic hypotension.

Since the frequency and severity of syncope vary in the patients with RS, there is a myriad of treatment options available ranging from lifestyle management to cardiac ganglion ablation.⁷ In this review, we will give a brief overview of the evaluation and treatment of RS.

Clinical Evaluation and Approach to Symptoms

The evaluation can be divided into 3 phases: history, examination, and investigations.

History

The most important component of the evaluation of a suspected case of syncope is history taking.⁸ The goal of history taking would be as follows: (a) To establish the etiology of syncope with certainty and differentiate it from epileptic or nonepileptic seizure. (b) Clues to suggest the probable etiology of the syncope like RS.⁸

To establish the etiology of syncope with certainty and to differentiate it from epileptic seizure or pseudosyncope (Table 1).

Table 1.

Differentiation of Syncope From Epileptic and Psychogenic LOC/syncope.

Parameter		Syncope^{9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25}	Epileptic Seizure^{21 22 23 24 26 27 28 29 30 31 32 33 34}	Psychogenic LOC (Pseudo-seizure)^{27 35 36 37 38 39}
Trigger before the attack	Situations	Prolonged standing, noxious stimuli, etc	Flashing lights/startle/sleep deprivation	For seeking attention for something
At the onset of attack		Change in vision/nausea, vomiting, pallor/	Ictal cry/rising sensation from abdomen/aura	NA
During the attack	Fall	Flaccid	Stiff	Any type
	Movements	Begin after the fall or LOC/asynchronous/fewer movements	Begin before or after the fall/synchronous/many movements	Pelvic thrusting/repeated waxing and waning in intensity
	Duration of LOC	Short	Few minutes	Can be prolonged
	UI	Less common	More common	Variable
After the attack	Clear-headed	Common	Very rare	Variable
Background history		Change in medications/OI/DM	h/o epilepsy or neurological disease	h/o earlier traumatizing events

Abbreviations. LOC, loss of consciousness; OI, orthostatic intolerance; UI, urinary incontinence.

The goal should be in eliciting the history of sudden or gradual transient loss of consciousness (TLOC) with total recovery after a few seconds/minutes from the patient or bystanders. The following questions will be required to get clues regarding differentiation of syncope from epileptic seizure or nonepileptic seizure:

What was the body habitus?—supine/sitting/standing

What was the activity?—meal, exercise, and so on.

Were there any precipitating factors?—warm crowded place, fear, pain, cough, and so on.

What were the historical details from the eyewitness with regard to the event? —duration, associated body movements, tongue bite, post-event confusion, and so on.

What is the background history?—frequency, h/o sudden cardiac arrest, neurological disease, diabetes mellitus, vasoactive medications, and so on. What was the body habitus?—supine/sitting/standing.

There is a definite value for the video evidence of the event, so the relatives may be asked to record an episode if it occurs in the future again.

2. Is it a reflex-mediated syncope (RS) or syncope due to orthostatic hypotension or cardiac etiology?

Once it is confirmed that the patient has syncope and not any other cause of NT-TLOC, we need to look for the clues to diagnose RS and differentiate it from syncope due to OH and cardiac causes. Table 2 provides a few clues to the diagnosis of the specific type of syncope.^{2
3}

Table 2.

Clues for the Cause of Syncope.

RS		OH		Cardiac
Long history with age <40 years		After standing	Abrupt	Structural heart disease*
No cardiac disease			Delayed	Family history of SCD
Specific background	With head rotation or tight collars/shaving/neck tumor	Temporal relationship to starting hypotensive medication		Preceded by palpitation
	Prolonged standing or hot-crowded places	Hot-crowded places		Syncope while supine/sleep
	Post-meal/exertion	Post exertion		During exertion
	Post voiding, swallowing, etc.	Diabetes mellitus		ECG changes* s/o arrhythmia (tachy or brady) or specific clues, eg, LQTS
	Unexpected sight, smell, or pain	Autonomic neuropathy

Note: *May be present, not always. Clues in bold are more indicative of the respective diagnoses.

Abbreviations. ECG, electrocardiogram; LQTS, long QT syndrome; OH, orthostatic hypotension; RS, reflex syncope; SCD, sudden cardiac death.

Examination

The physical examination should be focused to rule out or confirm the suspected cause of syncope. In particular, evidence of bradycardia, OH, and ejection systolic murmur should be looked out for to rule out organic causes of syncope.⁴⁰

Certain diagnostic clinical tests may aid in the diagnosis of the specific cause of syncope.

1 Active standing test^{41
42}

This test is used to diagnose different types of orthostatic intolerance.³ The resting blood pressure (BP) of the patient should be measured in the supine position. Then the patient is made to stand without support and continuous BP monitoring is done. BP should be noted at 1-min and 3-min intervals, if continuous monitoring is not possible. The definition used for the abnormal test is—“abnormal BP fall is defined as a progressive and sustained fall in systolic BP from the baseline value ≥20 mmHg or diastolic BP ≥10 mmHg, or a decrease in systolic BP to <90 mmHg.” The test can classify OH into classical (within 30 s-3 min) and delayed OH (after 3 min).⁴³ The sensitivity, specificity, and accuracy of the active standing test were found to be 58.8, 63.3, and 60.9, respectively.⁴⁴

2. Carotid sinus stimulation⁴⁵

This test is useful in the diagnosis of carotid sinus syndrome (CSS). Carotid sinus stimulation can be performed with mechanical stimulation (carotid sinus massage [CSM]) or pharmacological stimulation (with nitroprusside and phenylephrine injections). CSM is performed by giving 5-s gentle pressure over the carotid sinus on one side with continuous heart rate and BP monitoring, in supine as well as 60^o upright position. Carotid sinus hypersensitivity is considered to be present if CSM elicits asystole ≥3 s (cardio inhibition) and/or a fall in systolic BP >50 mmHg (vasodepression).⁶ Reproduction of spontaneous syncope is considered as a relatively specific diagnostic sign for CSS.⁴⁶ Three forms of CSS may be diagnosed based on associated asystole ≥3 s or hypotension (any drop in systolic BP).

Vasodepressor: Syncope + Fall in Systolic BP + No Asystole ≥3 s

Cardioinhibitory: Syncope + No Fall in Systolic BP + Asystole ≥3 s (sometime ≥ 6 s)

Mixed: Syncope + Fall in Systolic BP (present/absent) + Asystole ≥3 s ↓ Atropine for the elimination of asystole ↓ Symptoms persist

The sensitivity and specificity of CSM to diagnose CSS were found to be 74% and 100%, respectively, in the supine position. The sensitivity increases to 100% if the test is performed in the upright position.⁴⁷

3. Clinical autonomic function tests

Valsalva maneuver

During the maneuver, the patient is asked to conduct a maximally forced expiration for 15 s against a closed glottis, that is, with a closed nose/mouth, or into a closed system with 40 mmHg resistance.⁶

Traditionally, the Valsalva ratio (ratio of maximum heart rate during expiration and minimum heart rate within 30 s after maximum heart rate) has been used to evaluate the autonomic function but it may give erroneous readings in the patients who have inadequate expiratory efforts, square wave BP response, and blunted phase IV overshoot.⁴⁸ Therefore, the common findings used are:

Absence of BP overshoot or heart rate increase: r/o autonomic dysfunction^{49
50}

Pronounced BP fall with a normal chronotropic response: r/o situational syncope⁵¹

Deep breathing

The patient is asked to breathe deeply at 6/min under continuous heart rate and BP monitoring.^6
52 Blunted or abolished heart rate variability during deep breathing (expiratory/inspiratory [E/I] index), that is, <15 bpm in healthy individuals of >50 years of age, is considered abnormal. A parasympathetic dysfunction should be ruled out in these patients.^48
50

Investigations

The investigations should be tailored as per the presenting complaints of the patients. Electrocardiogram (ECG) is considered an emergency investigation when the diagnosis of cardiac syncope is to be confirmed.

Resting ECG (12 lead)

Used to rule out serious cardiac conditions (eg, acute coronary syndrome, heart blocks, pulmonary embolism, etc) or certain specific ECG characteristics (eg, long QT syndrome, short QT syndrome, Brugada syndrome, preexcitation syndrome, etc).

Long-term ECG monitoring

Holter (24 h or 3 days)—will be useful for daily syncopal events, with normal/unclear presenting ECG.

External loop recorder (3-30 days)—for a less frequent event and implantable loop recorder (ILR) (up to 3 years)—for infrequent events only in the patients with high suspicion of arrhythmic cause.

A major limitation with Holter monitoring is frequent noncompliance with keeping a log of symptoms and event markers (from the patient’s side), which may cause errors in the interpretation of Holter findings as symptom-event correlation becomes difficult.⁵³

The significant pause detected on long-term monitoring is traditionally considered to be ≥3 s, which has been included as an indication for permanent pacing in the American and European guidelines. This is based on observational evidence with low specificity, which has been challenged by recent studies.^54
55 Most of these studies concluded that the follow-up was not sufficient enough to decide on the benefit of permanent pacing.⁵⁶

ECG recordings on ILR were analyzed on follow-up in the first international study on syncope of uncertain etiology (ISSUE) study which has divided the findings into—Type 1 (asystole ≥3 s) [IA: sinus arrest, IB: sinus bradycardia with AV block, IC: AV block]; Type 2 (bradycardia) [2A: decreased HR >30%, 2B: HR <40 bpm for >10 s]; Type 3 (no/slight rhythm variation) [3A: none/<10% HR variation, 3B increase 10-30% and HR <120 or decrease 10-30% and HR >40 bpm]; Type 4 (tachycardia, ie, increase in HR >30% or >120 bpm) [4A: progressive sinus tachycardia, 4B: atrial fibrillation, 4C: supraventricular tachycardia (non-sinus), 4D: ventricular tachycardia].⁵⁷ A series of studies was carried out to define the need and clinical significance of ILR in patients with suspected RS.^{57
58
59} These studies have defined cardioinhibitory responses based on the international study on syncope of uncertain etiology (ISSUE) classification as type 1 (asystole) or 2 (bradycardia).⁵⁷

Mobile phone-based monitoring

The use of mobile phones and different apps focusing on cardiovascular disease (eg, atrial fibrillation) has increased tremendously over the last few years.⁶⁰ Mobile phone-based plethysmography and handheld ECG recorders with external sensors have been used for monitoring cardiac rhythm.⁶¹ The study comparing various applications (apps) used for this purpose showed that there is wide variability in quality, functionality, and adherence to self-management behaviors in these apps.⁶² Further studies are warranted in order to use these mobile phone applications for large-scale screening of heart rhythm abnormalities. Artificial intelligence and its subfields (ie, machine learning and deep learning) have found their utility in the monitoring of heart rhythm, diagnosis of certain conditions, and correlation of ECG findings with imaging (eg, left ventricular ejection fraction).^{63
64
65}

Tilt table testing

Tilt table testing (TTT) has been considered complementary to clinical examination since its inception in 1986.⁶⁶ The test typically carried out after 2 to 4 h fasting that involves ≥20 min supine phase (post-venous cannulation) followed by ≥20 min of tilt (60-80^o) (passive phase) with or without the use of a provocative agent (nitroglycerine, isoproterenol, or clomipramine) for 5 to 20 min (active phase) if the first phase of the test is negative.^{67
68
69
70} TTT is considered to be positive only if there is syncope during the testing.³ The response can be mixed (type 1), cardioinhibition without asystole (type 2A), or cardioinhibition with asystole (type 2B), and vasodepressor (type 3) as per the new Vasovagal Syncope International Study (VASIS) classification.⁷¹ Cardioinhibitory response means that HR falls to less than 40 bpm for more than 10 s but asystole >3 s doesn’t occur (BP falls before HR fall) (Type 2A) or asystole occurs for >3 s (BP falls with or before HR fall) (Type 2B). The positivity rate of TTT depends upon the indication for the test and provocative agent used—highest for vasovagal or emotional syncope with clomipramine (>90%), around 50% for atypical syncope (without classical features of vasovagal syncope⁷²) with nitroglycerine, and lowest ≤30% for unexplained syncope.^{73
74} The sensitivity and specificity of TTT with the use of isoproterenol or sublingual nitrate have been reported to be similar (sensitivity: 61-69%; specificity: 92-94%).^{68
69}

Recently, there have been contrasting publications regarding the usefulness of TTT. One of these has advocated the abolishment of the test in view of no additional diagnostic benefit, high false positivity rates, use of active standing test instead of TTT in the patients with OH or postural orthostatic tachycardia syndrome, and no mortality benefit.⁷⁵ The other has highlighted the benefits of TTT as an ancillary test in the evaluation of suspected syncope and reiterated that it should be used as a part of the diagnostic workup, not as a standalone to draw any conclusions.⁷⁶ We propose that TTT may play a role in cases where the history is not diagnostic, provided the more serious causes like cardiac syncope are ruled out.

24-h ambulatory BP monitoring

24-h ambulatory BP monitoring is recommended for the diagnosis and management of hypertension, as per the recent guidelines.⁷⁷ This can help in the diagnosis of OH based on nocturnal “non-dipping” (decrease in BP of less than 10% during night-time) or “reverse-dipping” (increase in BP at night) patterns.⁷⁸

Echocardiogram—resting and exercise

Echocardiography is useful to rule out underlying structural heart disease which can present with syncope viz. left ventricular outflow tract obstruction (ie, aortic stenosis or hypertrophic cardiomyopathy), obstructive masses, pericardial tamponade, aortic dissection.^{79
80
81
82
83
84} In the cases where resting echocardiography is normal but there is high clinical suspicion, a stress echocardiogram may help in the confirmation of the level of obstruction in the patients with hypertrophic cardiomyopathy.^{85
86}

Electrophysiological Study

The group of patients in which there is suspicion of cardiac syncope based on ECG changes (eg, sinus pauses, bifascicular blocks, etc) or history of acute myocardial infarction/low ejection fraction, electrophysiological study may aid in deciding the further course of action (eg, need for a pacemaker in a patient with bifascicular block and pharmacological challenge [≥80% positive predictive value] or need for implantable cardioverter-defibrillator in patients with low ejection fraction [yield of 42% in whom VT was inducible], etc).^{3
87
88
89}

Evaluation Algorithm

For any patient presenting with syncope, the most important part of the evaluation is the history of the event. Physical examination and ECG may help in confirmation of the diagnosis and to rule out causes for severe syncope in the emergency setting. The risk factors that may guide the decision regarding admission are given in Table 3. Figure 2 gives the proposed evaluation algorithm for these patients.

Table 3.

High-Risk Factors Which Warrant Admission.

High-risk factors in history	History of structural heart disease Old history of myocardial infarction
Syncope related	Syncope during exercise Syncope associated with head/body injury
Examination related	Slow or fast heart rate Low blood pressure Ejection systolic murmur
ECG	Ischemic changes on ECG Prolonged QTc, Brugada pattern Bradyarrhythmias or tachyarrhythmias Bundle branch blocks

Figure 2.

Note: ^aMay not be possible on out-patient basis.

Treatment

Overall management depends upon the predictability and frequency of the symptoms. Patients may be classified into 2 groups:

Group I: Unpredictable or high-symptom-frequency of syncope ↓ will need specific therapy.

Group II: Predictable or low-symptom-frequency of syncope ↓ education/reassurance may be enough.

The treatment should start with the education of the patient and relatives regarding the cause of syncope and then further treatment may be required in cases where there are high-risk ECG features, recurrence of symptoms, or nonresponse to conservative management.

The various treatment modalities used are:

Education and lifestyle modification

This forms the cornerstone of the treatment of RS, but its long-term effects have not been evaluated with randomized studies.³ The main components are:

Reassurance about the benign nature of the disease

Education regarding triggers/precipitants

Early recognition of prodrome (if any)

Increased oral fluids (2-3 L/day³)

Salt supplementation⁹⁰): 10 gm/day³ or 6-10 gm/day^{91
92}

Reduction of hypotensive drug therapy ⁹³

The patients with hypotensive susceptibility (HS) may be helped with the reduction of hypotensive therapy targeting a systolic BP of 140 mmHg to reduce symptoms.³

Physical counterpressure maneuvers

Isometric muscle exercises and counterpressure maneuvers viz. leg crossing, hand gripping, and hand tensing may help reduce syncopal episodes.^{94
95} They need to be taught and should be employed when the patient recognizes the prodrome.⁶ These maneuvers may help prevent and/or abort an episode of RS or orthostatic fainting. Leg crossing is done with maximum tensing of the leg, abdominal, and buttock muscles for the maximum tolerated time or until the disappearance of symptoms. Hand gripping means squeezing a rubber ball or similar soft object in the dominant hand for the maximum tolerated time or until the disappearance of symptoms. Arm tensing consists of maximum tolerated isometric contraction of the 2 arms achieved by gripping 1 hand with the other and at the same time abducting for the maximum tolerated time or until the disappearance of symptoms.⁶

Tilt training (orthostatic training) and yoga therapy

In patients with RS which is triggered by orthostatic stress, the prescription of a prolonged period of enforced upright posture is called tilt training.⁹⁶ The training is generally started in a hospital setting with 10- to 50-min sessions based on the prodromal symptoms and then home training is advised.⁹⁷ The hospital training generally is similar to the protocol used for diagnostic TTT. After discharge, the patient is advised to continue the training with feet 15-cm away from the wall with upper back resting on the wall for increasing time starting from 15 min based on the symptoms.⁹⁸ There is conflicting evidence regarding the use of tilt training, with a few studies showing benefit^{96
99
100
101}, while the others reporting no benefit.^{102
103
104} Zeng et al⁹⁹ studied 125 consecutive patients with positive TTT; they found that there was no recurrence of syncope in 72.6% of patients undergoing orthostatic training (OT), as against 36.1% in patients without any treatment, at 1-year follow-up and as against a placebo-controlled trial demonstrated a positive trend in terms of the benefit of home OT (20% vs 50%, P = 0.2) but it did not reach statistical significance level.¹⁰⁴ The contrasting results of the studies may be due to the non-uniformity of methods and variable compliance of the patients with tilt training.

The use of yoga for the treatment of RS has been recently studied in a randomized study by Shenthar et al.¹⁰⁵ The yoga module described in the trial consisted of warmup, asanas (yoga postures), pranayama (breathing exercises), dhyana (meditation), and deep relaxation technique with each session of 60 min at least 5 times/week for 12 months. At 12 months follow-up, there was a significant reduction in syncope recurrence in the yoga therapy group as against conventional conservative therapy (without yoga) (3.8 ± 3.2 episodes vs 1.1 ± 0.8, P < 0.001).

Pharmacological therapy (Figure 4)

Fludrocortisone¹⁰⁶

These work by the mechanism: increasing renal sodium reabsorption ↓ expansion of plasma volume↓ reducing orthostatic component of the syncope

Alpha agonists—these act by peripheral vasoconstriction (increasing peripheral resistance).

Beta-blockers have been tried in the past for the treatment of RS, presumed to be acting by decreasing the ventricular mechanoreceptor activation by their negative inotropic effect. There was no benefit in the treatment of RS in the randomized trials.^{107
108} Moreover, if the patient has underlying borderline or low heart rate, these may worsen the condition. The latest ESC guidelines have given class III indication for the use of beta-blockers in the treatment of RS.³

There is recruitment going on for the trial COMFORTS (comparison of outcomes with Midrodrine and Fludrocortisone for objective recurrence in treating syncope) [NCT04595942] which will give us a better picture regarding the benefit of pharmacological therapy in RS.¹⁰⁹

Table 4.

Pharmacological Agents Useful in the Management of RS.

Group	Drug	Dose	Indication	Outcome in RS
Mineralocorticoid	Fludrocortisone	0.05-0.2 mg OD	Recurrent syncope with low-normal BP without comorbidities like HTN	Marginal nonsignificant benefit; more benefit if a dose of 0.2 mg OD was given (randomized study)¹⁰⁶
Alpha agonist	Etilefrine	25 mg	Recurrent vasovagal syncope	No benefit on 1 year follow-up in terms of syncope recurrence and time to first syncope¹¹⁰
Alpha agonist	Midodrine	2.5-10 mg TDS	Recurrent vasovagal syncope and/or orthostatic symptoms	There are mixed data regarding benefits. Overall, low evidence of benefit based on small nonrandomized studies¹¹¹

Abbreviations. HTN, hypertension; OD, once a day; TDS, thrice a day.

Pacing (with or without counteracting HS)

A pacemaker may be indicated in a specific subset of the patients with RS. A small subset of patients has a predominant cardioinhibitory response (VASIS type 2 or ISSUE type 1 or 2) on TTT or long-term ECG monitoring (eg, ILR) with or without HS, which is common in the elderly population.^{5
57
71} These patients may be treated with the conservative line of management, along with medications, at the initial presentation but may require additional treatment if¹¹²:

Recurrent symptoms are not responding to medications

Very short prodrome

Syncope during high-risk activities, for example, driving, machine operations, flying, etc.

The benefit of pacing in this particular subset is based on the rationale—pacing may be able to modulate RS episodes if acted sufficiently early at a rate higher than lower pacing rate and with atrioventricular (AV) sequential pacing.¹¹³ Early studies have used cardioinhibitory response on TTT to decide on the need for pacing.^{114
115} Few of the nonblinded studies were positive but the metanalysis by Sud et al¹¹⁶ including both blinded and nonblinded studies found that there was no benefit of pacing based solely on TTT response and the benefit shown in nonblinded studies was an “expectation effect.” The most convincing evidence regarding this was provided by the ISSUE-3 study, in which all the patients had undergone ILR implantation and found that pacing in the patients with syncope with ≥3 s or without syncope with ≥ 6s pause reduced recurrent syncope over 2 years follow-up.⁵⁹

Since the earliest evidence of the usefulness of pacing in RS, it tried to use various specific algorithms which may help the patients with recurrent syncope like rate-drop response (RDR) algorithm and closed-loop-stimulation (CLS) pacing.^{117
118
119
120} RDR algorithm detects a sudden decrease in heart rate and increases the rate of pacing so that the syncopal event can be avoided. The detection portion of the algorithm has a programmable “heart rate change-time duration” window which is helpful in the detection of imminent RS (based on decreasing heart rate) and triggers AV sequential pacing at a programmable rate.¹¹⁷ In the ISSUE-3 study, all the patients receiving pacemakers had an RDR algorithm and it showed 57% relative risk reduction in syncope recurrence.⁵⁹ The main issue with the RDR algorithm is that it takes time to respond in an episode of RS.¹²¹

CLS is the proprietary algorithm of Biotronik (Berlin, Germany), which detects right ventricular (RV) impedance as an indirect measure of RV contractility and uses it to counteract RS events.¹²² RV lead constantly measures impedance, which is dependent on the amount of myocardium interfering with the lead tip. In diastole, there is maximum blood in RV so impedance is low. In contrast, in systole, when there is minimum blood pool in RV, the amount of myocardium interfering with lead tip is highest and so is the impedance. This high impedance triggers pacing at the CLS intervention rate (programmable). This beat-to-beat monitoring of RV impedance can detect inotropic changes early in an RS event. The response time is relatively fast for the CLS algorithm.¹²³ An elegant study has recently been done to evaluate the benefit of the CLS algorithm in 127 patients aged 40 years and older with at least 2 episodes of unpredictable severe syncope in last year and a systolic pause of >3 s induced by TTT. The syncope recurrence, at 11.2 months of median follow-up, was reduced by 77% with the use of the CLS algorithm (16% vs 53%, P = .00005) as compared to the control population (with ODO pacing mode).¹²⁰

The patients who have mixed or hypotensive responses on TTT (type 1/3) are suspected of having HS.¹²⁴ These patients may require the measures to counteract HS like discontinuation/reduction in hypotensive drugs, optimal salt/fluid intake, use of medications (eg, fludrocortisone/midodrine), and so on.³

We propose an algorithm based on the European Society of Cardiology (ESC) guidelines to decide on pacing in patients with RS (Figure 3).

Figure 3.

Abbreviations. CLS, closed loop stimulation; CPM, counterpressure maneuvers; CSS, carotid sinus stimulation; ILR, implantable loop recorder; PPI-DDD, dual-chambered pacemaker; TT, tilt training; TTT, tilt table testing.

Management of situational syncope

Common precipitants associated with syncope are micturition, gastrointestinal stimulation (swallowing and defecation), cough, sneeze, laughing, and so on. The easiest way to avoid these episodes is to educate the patient regarding the events and if possible avoid the specific situations which may induce symptoms, but it may not be possible always. In all these patients, the addition of salt and water in the diet, an inclination of the head end of the bed by 10 degrees, and avoiding a sudden change of posture may avoid precipitation of the symptoms.¹²⁵ For micturition syncope, patients are advised to do an intermittent voiding and avoid sudden bladder emptying of the bladder.¹²⁶ For gastrointestinal-related syncope and cough/sneeze-related syncope, the underlying cause of difficulty in swallowing/defecation has to be determined for the definitive management of the patient.^{127
128}

New emerging therapies: still need more robust trials to evaluate their effectiveness.

Low-adenosine syncope

Some patients affected with recurrent syncope have a very short duration prodrome (<5 s) with a structurally normal heart and normal ECG. This particular population has been found to have low plasma adenosine levels and is susceptible to even a small increase in adenosine, which may act on the A1 receptor located in the AV node and sinus node, which may lead to heart block.¹²⁹ The most common mode of presentation is paroxysmal AV block, some patients may present with symptomatic bradycardia.¹³⁰ In the recent case series of 16 patients, it was found that use of theophylline (adenosine receptor blocker) in this specific type of syncope helps in the reduction of syncope (2.6 syncope/year vs 0.4 syncope/year; P = .005)^{131
132}

b. Low-norepinephrine syncope

RS is associated with the sudden withdrawal of sympathetic activity and release of epinephrine from the adrenal medulla as a “fight” response. Similarly, in the nerve endings of the cardiac sympathetic nervous system (SNS), there is an increase in norepinephrine levels.¹³³ This is associated with increased serum levels of metabolic by-products of norepinephrine (ie, dihydroxy phenyl glycol or DHPG).¹³⁴ With the use of norepinephrine reuptake transporter inhibitors (ie, reboxetine, sibutramine), there is a decreased peripheral (adrenal medulla) adrenaline secretion, increased local norepinephrine concentration (in cardiac SNS), and decreased DHPG levels (indicating decreased degradation of norepinephrine).¹³⁵ This correction of the catecholamine milieu has been found to be beneficial in improving orthostatic tolerance in the patients presenting with recurrent syncope with a positive TTT (TTT duration 35 ± 1 min vs 29 ± 2 min, P = .001).¹³⁴ These medications are found to increase BP and HR in all the subjects due to locally increased norepinephrine concentration, hence it has been advised to be given to the patients with low baseline levels of norepinephrine.³

c. Cardioneuroablation (CNA)

RS may be very rapid in some patients which may not provide enough time for the use of any other management modalities like counterpressure maneuvers or pacing to abort a particular episode.¹³⁶ Catheter ablation to attenuate vagal activity on sinus and AV node has evolved as one of the treatment modalities in a subgroup of patients not responsive to other treatments.^{136
137
138} This technique of treatment of bradyarrhythmia is termed CNA. In this technique, ganglionated plexi (GPs) are targeted systematically—left-sided plexi first, aorto-superior vena cava (Ao-SVC) GP (for tackling atrial vagal innervations), posteromedial left GP (in case of AV block as the presenting feature), and an additional right-sided ablation if left-sided ablation was not sufficient.¹³⁸ This has recently been compared with conventional management without the use of CNA in the propensity-matched patient subset (recurrent syncope with VASIS-type 2B response or >3 s asystole), which showed that CNA caused a significant reduction in syncope recurrence (4-year syncope free rate—CNA: 0.86 vs conventional therapy: 0.50).¹³⁹ Also, the same group has recently shown that CNA reduces QTc through neuromodulation which is not noted in the patients treated with pacemaker implantation for RS.¹⁴⁰

Concluding Remarks

Syncope needs meticulous evaluation on the part of the physician. The diagnosis of RS centers around the history and examination of the episode. The other diagnostic modalities can help in the confirmation of the diagnosis and in deciding the treatment of the condition. The management of RS may be conservative if the episodes are infrequent or may require additional management in case of recurrence.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ORCID iDs

Ameya Udyavar

Saurabh Deshpande

References

Kapoor

WN.

Current evaluation and management of syncope. Circulation . 2002;106(13):1606-1609.

Benditt

DG.

Syncope: an overview of diagnosis and treatment. Revista Uruguaya de Cardiología . 2011;26:55-70.

Brignole

, Moya

, de Lange

, . 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J . 2018;39(21):1883-1948.

Silva

, Godinho

, Freitas

Transient loss of consciousness assessment in a university hospital: from diagnosis to prognosis. Porto Biomed J . 2016;1(3):118-123.

Aydin

, Salukhe

, Wilke

, Willems

Management and therapy of vasovagal syncope: a review. World J Cardiol . 2010;2(10):308-315.

Brignole

, Moya

, de Lange

, . Practical instructions for the 2018 ESC Guidelines for the diagnosis and management of syncope. Eur Heart J . 2018;39(21):e43-e80.

Gampa

, Upadhyay

GA.

Treatment of neurocardiogenic syncope: from conservative to cutting-edge. J Innov Card Rhythm Manag . 2018;9(7):3221-3231.

Sutton

, van Dijk

, Wieling

Clinical history in management of suspected syncope: a powerful diagnostic tool. Cardiol J . 2014;21(6):651-657.

Ganzeboom

, Colman

, Reitsma

, Shen

, Wieling

Prevalence and triggers of syncope in medical students. Am J Cardiol . 2003;91(8):1006-1008, a8.

10.

Berecki-Gisolf

, Sheldon

, Wieling

, . Identifying cardiac syncope based on clinical history: a literature-based model tested in four independent datasets. PLoS One . 2013;8(9):e75255.

11.

Busweiler

, Jardine

, Frampton

, Wieling

Sleep syncope: important clinical associations with phobia and vagotonia. Sleep Med . 2010;11(9):929-933.

12.

Khadilkar

, Yadav

, Jagiasi

Are syncopes in sitting and supine positions different? Body positions and syncope: a study of 111 patients. Neurol India . 2013;61(3):239-243.

13.

Sakakibara

, Hattori

, Kita

, Yamanishi

, Yasuda

Urodynamic and cardiovascular measurements in patients with micturition syncope. Clin Auton Res . 1997;7(5):219-221.

14.

Kapoor

, Peterson

, syncope.

Karpf M. Defecation

A symptom with multiple etiologies. Arch Intern Med . 1986;146(12):2377-2379.

15.

Benditt

, Samniah

, Pham

, . Effect of cough on heart rate and blood pressure in patients with "cough syncope". Heart Rhythm . 2005;2(8):807-813.

16.

Dicpinigaitis

, Lim

, Farmakidis

Cough syncope. Respir Med . 2014;108(2):244-251.

17.

Omi

, Murata

, Yaegashi

, Inomata

, Fujioka

, Muramoto

Swallow syncope, a case report and review of the literature. Cardiology . 2006;105(2):75-79.

18.

Sarzi Braga

, Manni

, Pedretti

RF.

Laughter-induced syncope. Lancet . 2005;366(9483):426.

19.

Mündel

, Perry

, Ainslie

, . Postexercise orthostatic intolerance: influence of exercise intensity. Exp Physiol . 2015;100(8):915-925.

20.

Halliwill

, Sieck

, Romero

, Buck

, Ely

MR.

Blood pressure regulation X: what happens when the muscle pump is lost? Post-exercise hypotension and syncope. Eur J Appl Physiol . 2014;114(3):561-578.

21.

Sheldon

, Rose

, Ritchie

, . Historical criteria that distinguish syncope from seizures. J Am Coll Cardiol . 2002;40(1):142-148.

22.

Lempert

, Bauer

, Schmidt

Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol . 1994;36(2):233-237.

23.

Brigo

, Bongiovanni

, Nardone

Lateral tongue biting versus biting at the tip of the tongue in differentiating between epileptic seizures and syncope. Seizure . 2013;22(9):801.

24.

Benbadis

, Wolgamuth

, Goren

, Brener

, Fouad-Tarazi

Value of tongue biting in the diagnosis of seizures. Arch Intern Med . 1995;155(21):2346-2349.

25.

Wijkman

, Länne

, Östgren

, Nystrom

FH.

Diastolic orthostatic hypertension and cardiovascular prognosis in type 2 diabetes: a prospective cohort study. Cardiovasc Diabetol . 2016;15(1):83.

26.

Carreño

, Fernández

Sleep-related epilepsy. Curr Treat Options Neurol . 2016;18(5):23.

27.

Perez

, LaFrance

Nonepileptic seizures: an updated review. CNS Spectr . 2016;21(3):239-246.

28.

Kasteleijn-Nolst Trenité

, Verrotti

, Di Fonzo

, . Headache, epilepsy and photosensitivity: how are they connected. J Headache Pain . 2010;11(6):469-476.

29.

Verrotti

, Beccaria

, Fiori

, Montagnini

, Capovilla

Photosensitivity: epidemiology, genetics, clinical manifestations, assessment, and management. Epileptic Disord . 2012;14(4):349-362.

30.

Elzawahry

, Do

, Lin

, Benbadis

SR.

The diagnostic utility of the ictal cry. Epilepsy Behav . 2010;18(3):306-307.

31.

Kuan

, Shih

, Chen

, . Abdominal auras in patients with mesial temporal sclerosis. Epilepsy Behav . 2012;25(3):386-390.

32.

Rossetti

, Kaplan

PW.

Seizure semiology: an overview of the 'inverse problem'. Eur Neurol . 2010;63(1):3-10.

33.

Pan

, Wang

, Li

, Liu

Factors influencing the duration of generalized tonic-clonic seizure. Seizure . 2016;34:44-47.

34.

Lamberts

, Sander

, Thijs

RD.

Postictal sleep: syncope or seizure? Seizure . 2011;20(4):350-351.

35.

Herskovitz

Psychogenic nonepileptic seizure patterns in patients with epilepsy. Psychosomatics . 2015;56(1):78-84.

36.

Szabó

, Siegler

, Zubek

, . A detailed semiologic analysis of childhood psychogenic nonepileptic seizures. Epilepsia . 2012;53(3):565-570.

37.

Tannemaat

, van Niekerk

, Reijntjes

, Thijs

, Sutton

, van Dijk

JG.

The semiology of tilt-induced psychogenic pseudosyncope. Neurology . 2013;81(8):752-758.

38.

Geyer

, Payne

, Drury

The value of pelvic thrusting in the diagnosis of seizures and pseudoseizures. Neurology . 2000;54(1):227-229.

39.

Saygi

, Katz

, Marks

, Spencer

SS.

Frontal lobe partial seizures and psychogenic seizures: comparison of clinical and ictal characteristics. Neurology . 1992;42(7):1274-1277.

40.

Arthur

, Kaye

GC.

Important points in the clinical evaluation of patients with syncope. Postgrad Med J . 2001;77(904):99.

41.

Ricci

, De Caterina

, Fedorowski

Orthostatic hypotension: epidemiology, prognosis, and treatment. J Am Coll Cardiol . 2015;66(7):848-860.

42.

Naschitz

, Rosner

Orthostatic hypotension: framework of the syndrome. Postgrad Med J . 2007;83(983):568-574.

43.

Torabi

, Ricci

, Hamrefors

, Sutton

, Fedorowski

Classical and delayed orthostatic hypotension in patients with unexplained syncope and severe orthostatic intolerance. Front Cardiovasc Med . 2020;7:21.

44.

Carmody

, Finucane

, Nolan

, . A machine learning framework to detect syncope using the active stand. medRxiv . 2020. DOI:10.1101/2020.12.07.20245159.

45.

Morillo

, Camacho

, Wood

, Gilligan

, Ellenbogen

KA.

Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope. J Am Coll Cardiol . 1999;34(5):1587-1594.

46.

Kerr

, Pearce

, Brayne

, Davis

, Kenny

RA.

Carotid sinus hypersensitivity in asymptomatic older persons: implications for diagnosis of syncope and falls. Arch Intern Med . 2006;166(5):515-520.

47.

Parry

, Richardson

, O'Shea

, Sen

, Kenny

RA.

Diagnosis of carotid sinus hypersensitivity in older adults: carotid sinus massage in the upright position is essential. Heart . 2000;83(1):22-23.

48.

Jones

, Gibbons

CH.

The role of autonomic testing in syncope. Auton Neurosci . 2014;184:40-45.

49.

Fanciulli

, Strano

, Ndayisaba

, . Detecting nocturnal hypertension in Parkinson’s disease and multiple system atrophy: proposal of a decision-support algorithm. J Neurol . 2014;261(7):1291-1299.

50.

Baschieri

, Calandra-Buonaura

, Doria

, . Cardiovascular autonomic testing performed with a new integrated instrumental approach is useful in differentiating MSA-P from PD at an early stage. Parkinsonism Relat Disord . 2015;21(5):477-482.

51.

Kim

, Frishman

WH.

Laughter-induced syncope. Cardiol Rev . 2012;20(4):194-196.

52.

Allan

, Johns

, Doshi

, Anne Kenny

, Newton

JL.

Abnormalities of sympathetic and parasympathetic autonomic function in subjects with defaecation syncope. EP Europace . 2004;6(3):192-198.

53.

Zimetbaum

, Goldman

Ambulatory arrhythmia monitoring. Circulation . 2010;122(16):1629-1636.

54.

Ector

, Rolies

, De Geest

Dynamic electrocardiography and ventricular pauses of 3 seconds and more: etiology and therapeutic implications. Pacing Clin Electrophysiol . 1983;6(3 Pt 1):548-551.

55.

Saba

, Donahue

, Panotopoulos

, Ibrahim

, Abi-Samra

FM.

Long-term mortality in patients with pauses in ventricular electrical activity. Pacing Clin Electrophysiol . 2005;28(11):1203-1237.

56.

Liu

, Lin

, Chang

, . Intermediate pause at daytime is associated with increased cardiovascular risk and mortality: an 8-year cohort study. J Am Heart Assoc . 2018;7(12):e009034.

57.

Brignole

, Moya

, Menozzi

, Garcia-Civera

, Sutton

Proposed electrocardiographic classification of spontaneous syncope documented by an implantable loop recorder. EP Europace . 2005;7(1):14-18.

58.

Brignole

, Sutton

, Menozzi

, . Early application of an implantable loop recorder allows effective specific therapy in patients with recurrent suspected neurally mediated syncope. Eur Heart J . 2006;27(9):1085-1092.

59.

Brignole

, Menozzi

, Moya

, . Pacemaker therapy in patients with neurally mediated syncope and documented asystole. Circulation . 2012;125(21):2566-2571.

60.

Moerenhout

, Devisch

, Cornelis

GC.

E-health beyond technology: analyzing the paradigm shift that lies beneath. Med Health Care Philos . 2018;21(1):31-41.

61.

KHC

, White

, Tipoe

, . The current state of mobile phone apps for monitoring heart rate, heart rate variability, and atrial fibrillation: narrative review. JMIR Mhealth Uhealth . 2019;7(2):e11606.

62.

Turchioe

, Jimenez

, Isaac

, Alshalabi

, Slotwiner

, Creber

RM.

Review of mobile applications for the detection and management of atrial fibrillation. Heart Rhythm O2 . 2020;1(1):35-43.

63.

Lyon

, Mincholé

, Martínez

, Laguna

, Rodriguez

Computational techniques for ECG analysis and interpretation in light of their contribution to medical advances. J R Soc Interface . 2018;15(138):20170821.

64.

Hannun

, Rajpurkar

, Haghpanahi

, . Cardiologist-level arrhythmia detection and classification in ambulatory electrocardiograms using a deep neural network. Nat Med . 2019;25(1):65-69.

65.

Attia

, Kapa

, Lopez-Jimenez

, . Screening for cardiac contractile dysfunction using an artificial intelligence–enabled electrocardiogram. Nat Med . 2019;25(1):70-74.

66.

Kenny

, Ingram

, Bayliss

, Sutton

Head-up tilt: a useful test for investigating unexplained syncope. Lancet . 1986;1(8494):1352-1355.

67.

Benditt

, Ferguson

, Grubb

, . Tilt table testing for assessing syncope. J Am Coll Cardiol. 1996;28(1):263-275.

68.

Morillo

, Klein

, Zandri

, Yee

Diagnostic accuracy of a low-dose isoproterenol head-up tilt protocol. Am Heart J . 1995;129(5):901-906.

69.

Bartoletti

, Alboni

, Ammirati

, . ‘The Italian Protocol’: a simplified head-up tilt testing potentiated with oral nitroglycerin to assess patients with unexplained syncope. Europace . 2000;2(4):339-342.

70.

Zyśko

, Fedorowski

, Nilsson

, . Tilt testing results are influenced by tilt protocol. Europace . 2016;18(7):1108-1112.

71.

Brignole

, Menozzi

, Del Rosso

, . New classification of haemodynamics of vasovagal syncope: beyond the VASIS classification: analysis of the pre-syncopal phase of the tilt test without and with nitroglycerin challenge. EP Europace . 2000;2(1):66-76.

72.

Alboni

The different clinical presentations of vasovagal syncope. Heart . 2015;101(9):674.

73.

Furukawa

, Maggi

, Solano

, Croci

, Brignole

Effect of clinical triggers on positive responses to tilt-table testing potentiated with nitroglycerin or clomipramine. Am J Cardiol . 2011;107(11):1693-1697.

74.

Raviele

, Menozzi

, Brignole

, . Value of head-up tilt testing potentiated with sublingual nitroglycerin to assess the origin of unexplained syncope. Am J Cardiol . 1995;76(4):267-272.

75.

Kulkarni

, Mody

, Levine

BD.

Abolish the tilt table test for the workup of syncope!

Circulation . 2020;141(5):335-337.

76.

Chrysant

SG.

The tilt table test is useful for the diagnosis of vasovagal syncope and should not be abolished. J Clin Hypertens . 2020;22(4):686-689.

77.

Williams

, Mancia

, Spiering

, . 2018 ESC/ESH Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). Eur Heart J . 2018;39(33):3021-3104.

78.

Voichanski

, Grossman

, Leibowitz

, . Orthostatic hypotension is associated with nocturnal change in systolic blood pressure. Am J Hypertens . 2012;25(2):159-164.

79.

Høegholm

, Clementsen

, Mortensen

SA.

Syncope due to right atrial thromboembolism: diagnostic importance of two-dimensional echocardiography. Acta Cardiol . 1987;42(6):469-473.

80.

Goliasch

, Kammerlander

, Nitsche

, . Syncope: the underestimated threat in severe aortic stenosis. JACC Cardiovasc Imaging . 2019;12(2):225-232.

81.

Williams

, Frenneaux

Syncope in hypertrophic cardiomyopathy: mechanisms and consequences for treatment. EP Europace . 2007;9(9):817-822.

82.

Saseedharan

, Kulkarni

, Pandit

, Karnad

Unusual presentation of pericardial effusion. Indian J Crit Care Med . 2012;16(4):219-221.

83.

Babs Animashaun

, Akinseye

, Akinboboye

OO.

Right atrial myxoma and syncope. Am J Case Rep . 2015;16:645-647.

84.

Nallamothu

, Mehta

, Saint

, . Syncope in acute aortic dissection: diagnostic, prognostic, and clinical implications. Am J Med . 2002;113(6):468-471.

85.

Ommen

, Mital

, Burke

, . 2020 AHA/ACC guideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy. Circulation . 2020;142(25):e558-e631.

86.

Shah

, Esteban

, Thaman

, . Prevalence of exercise-induced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy. Heart . 2008;94(10):1288-1294.

87.

Bergfeldt

, Edvardsson

, Rosenqvist

, Vallin

, Edhag

Atrioventricular block progression in patients with bifascicular block assessed by repeated electrocardiography and a bradycardia-detecting pacemaker. Am J Cardiol . 1994;74(11):1129-1132.

88.

Al-Khatib

, Stevenson

, Ackerman

, . 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation . 2018;138(13):e272-e391.

89.

Click

, Gersh

, Sugrue

, . Role of invasive electrophysiologic testing in patients with symptomatic bundle branch block. Am J Cardiol . 1987;59(8):817-823.

90.

Loughlin

, Judge

, Gorey

, . Increased salt intake for orthostatic intolerance syndromes: a systematic review and meta-analysis. Am J Med . 2020;133(12):1471-1478.e4.

91.

Shen

, Sheldon

, Benditt

, . 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines and the heart rhythm society. J Am Coll Cardiol . 2017;70(5):e39-e110.

92.

Shibao

, Lipsitz

, Biaggioni

ASH position paper: evaluation and treatment of orthostatic hypotension. J Clin Hypertens (Greenwich) . 2013;15(3):147-153.

93.

Solari

, Tesi

, Unterhuber

, . Stop vasodepressor drugs in reflex syncope: a randomised controlled trial. Heart . 2017;103(6):449-455.

94.

van Dijk

, Quartieri

, Blanc

, . Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol . 2006;48(8):1652-1657.

95.

Krediet

, van Dijk

, Linzer

, van Lieshout

, Wieling

Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation . 2002;106(13):1684-1689.

96.

Jang

, Yim

, Lee

, Park

, Kim

, On

YK.

Prognosis after tilt training in patients with recurrent vasovagal syncope. Int J Cardiol . 2013;168(4):4264-4265.

97.

Di Girolamo

, Di Iorio

, Leonzio

, Sabatini

, Barsotti

Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents. Circulation . 1999;100(17):1798-1801.

98.

Kinay

, Yazici

, Nazli

, . Tilt training for recurrent neurocardiogenic syncope: effectiveness, patient compliance, and scheduling the frequency of training sessions. Jpn Heart J . 2004;45(5):833-843.

99.

Zeng

, Ge

, Zhang

, Wang

, Guo

The effect of orthostatic training in the prevention of vasovagal syncope and its influencing factors. Int Heart J . 2008;49(6):707-712.

100.

Sinam

, Gangwar

, Banavalikar

, . A randomized trial of yoga therapy for reflex syncope. Eur Heart J . 2019;40(Supplement_1):ehz746.0108.

101.

Gunda

, Kanmanthareddy

, Atkins

, . Role of yoga as an adjunctive therapy in patients with neurocardiogenic syncope: a pilot study. J Interv Card Electrophysiol . 2015;43(2):105-110.

102.

, Park

, Huh

, Soo Kim

Is home orthostatic self-training effective in preventing neurally mediated syncope? Pacing Clin Electrophysiol . 2007;30(5):638-643.

103.

Duygu

, Zoghi

, Turk

, . The role of tilt training in preventing recurrent syncope in patients with vasovagal syncope: a prospective and randomized study. Pacing Clin Electrophysiol . 2008;31(5):592-596.

104.

Tan

, Newton

, Chadwick

, Gray

, Nath

, Parry

SW.

Home orthostatic training in vasovagal syncope modifies autonomic tone: results of a randomized, placebo-controlled pilot study. Europace . 2010;12(2):240-246.

105.

Shenthar

, Gangwar

, Banavalikar

, Benditt

, Lakkireddy

, Padmanabhan

A randomized study of yoga therapy for the prevention of recurrent reflex vasovagal syncope. Europace . 2021;23(9):1479-1486.

106.

Sheldon

, Raj

, Rose

, . Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol . 2016;68(1):1-9.

107.

Madrid

, Ortega

, Rebollo

, . Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective, double-blind, randomized and placebo-controlled study. J Am Coll Cardiol . 2001;37(2):554-559.

108.

Sheldon

, Connolly

, Rose

, . Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation . 2006;113(9):1164-1170.

109.

Aminorroaya

, Tavolinejad

, Sadeghian

, . Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): rationale and design for a multi-center randomized controlled trial. Am Heart J . 2021;237:5-12.

110.

Raviele

, Brignole

, Sutton

, . Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The vasovagal syncope international study. Circulation . 1999;99(11):1452-1457.

111.

Izcovich

, González Malla

, Manzotti

, Catalano

, Guyatt

Midodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review. Neurology . 2014;83(13):1170-1177.

112.

Brignole

Diagnosis and treatment of syncope. Heart . 2007;93(1):130-136.

113.

Gopinathannair

, Salgado

, Olshansky

Pacing for vasovagal syncope. Arrhythm Electrophysiol Rev . 2018;7(2):95-102.

114.

Connolly

, Sheldon

, Thorpe

, . Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA . 2003;289(17):2224-2229.

115.

Raviele

, Giada

, Menozzi

, . A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE). Eur Heart J . 2004;25(19):1741-1748.

116.

Sud

, Massel

, Klein

, . The expectation effect and cardiac pacing for refractory vasovagal syncope. Am J Med . 2007;120(1):54-62.

117.

Benditt

, Sutton

, Gammage

, . "Rate-drop response" cardiac pacing for vasovagal syncope. rate-drop response investigators group. J Interv Card Electrophysiol . 1999;3(1):27-33.

118.

Occhetta

, Bortnik

, Audoglio

, Vassanelli

Closed loop stimulation in prevention of vasovagal syncope. Inotropy Controlled Pacing in Vasovagal Syncope (INVASY): a multicentre randomized, single blind, controlled study. Europace . 2004;6(6):538-547.

119.

Baron-Esquivias

, Morillo

, Moya-Mitjans

, . Dual-chamber pacing with closed loop stimulation in recurrent reflex vasovagal syncope: the SPAIN study. J Am Coll Cardiol . 2017;70(14):1720-1728.

120.

Brignole

, Russo

, Arabia

, . Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. Eur Heart J . 2020;42(5):508-516.

121.

Connolly

, Sheldon

, Roberts

, Gent

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(1):16-20.

122.

Akella

, Olshansky

, Lakkireddy

, Gopinathannair

Pacing therapies for vasovagal syncope. J Atr Fibrillation . 2020;13(1):2406.

123.

Kanjwal

, Karabin

, Kanjwal

, Grubb

Preliminary observations on the use of closed-loop cardiac pacing in patients with refractory neurocardiogenic syncope. J Int Card Electrophysiol . 2009;27:69-73.

124.

Sutton

, Brignole

Twenty-eight years of research permit reinterpretation of tilt-testing: hypotensive susceptibility rather than diagnosis. Eur Heart J . 2014;35(33):2211-2212.

125.

Sari

, L1sabay

, Syncope:

SelÁuki D. Micturition

Report of Two Cases. J Psychiatr Neurol Sci . 2013;26:219-222.

126.

Brignole

, Alboni

, Benditt

, . Guidelines on management (diagnosis and treatment) of syncope–update 2004. Europace . 2004;6(6):467-537.

127.

Chhetri

, Khan

, Nixon

Swallow syncope unravelled by fizzy drink challenge. Int J Med . 2016;109(5):341-342.

128.

Tigga

MP.

An unusual case of defecation syncope. J Midlife Health . 2019;10(2):99-100.

129.

Deharo

, Brignole

, Guieu

Adenosine hypersensitivity and atrioventricular block. Herzschrittmacherther Elektrophysiol . 2018;29(2):166-170.

130.

Aste

, Brignole

Syncope and paroxysmal atrioventricular block. J Arrhythm . 2017;33(6):562-567.

131.

Brignole

, Solari

, Iori

, Bottoni

, Guieu

, Deharo

JC.

Efficacy of theophylline in patients affected by low adenosine syncope. Heart Rhythm . 2016;13(5):1151-1154.

132.

Brignole

, Iori

, Solari

, . Efficacy of theophylline in patients with syncope without prodromes with normal heart and normal ECG. Int J Cardiol . 2019;289:70-73.

133.

Mosqueda-Garcia

, Furlan

, Fernandez-Violante

, . Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J Clin Invest . 1997;99(11):2736-2744.

134.

Schroeder

, Birkenfeld

, Mayer

, . Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. J Am Coll Cardiol . 2006;48(3):516-522.

135.

Esler

, Wallin

, Dorward

, . Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol Regul Integr Comp Physiol . 1991;260(4):R817-R23.

136.

Scanavacca

, Hachul

Ganglionated plexi ablation to treat patients with refractory neurally mediated syncope and severe vagal-induced bradycardia. Arq Bras Cardiol . 2019;112(6):709-712.

137.

, Wei

, Upadhyay

, Tung

Catheter-based cardio-neural ablation for refractory vasovagal syncope: first U.S. report. JACC: Case Rep . 2020;2(8):1161-1165.

138.

Aksu

, Guler

, Bozyel

, Yalin

Vagal responses during cardioneuroablation on different ganglionated plexi: is there any role of ablation strategy? Int J Cardiol . 2020;304:50-55.

139.

Aksu

, Padmanabhan

, Shenthar

, . The benefit of cardioneuroablation to reduce syncope recurrence in vasovagal syncope patients: a case-control study. J Interv Card Electrophysiol . 2021. doi: 10.1007/s10840-020-00938-0.

140.

Aksu

, Turagam

, Gautam

, . Effects of permanent cardiac pacing on ventricular repolarization when compared to cardioneuroablation. J Electrocardiol . 2021;67:13-18.

Evaluation and Management of Reflex Vasovagal Syncope—A Review

Abstract

Keywords

Abbreviations

Introduction

Clinical Evaluation and Approach to Symptoms

History

Differentiation of Syncope From Epileptic and Psychogenic LOC/syncope.

Clues for the Cause of Syncope.

Examination

Investigations

Evaluation Algorithm

High-Risk Factors Which Warrant Admission.

Treatment

Pharmacological Agents Useful in the Management of RS.

Concluding Remarks

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iDs

References