Manual of Cardiovascular Medicine

I.Introduction. Syncope is a common medical problem with an occurrence of 3.0% in men and 3.5% in women in the general population. It accounts for approximately 1% of emergency room visits and 6% of medical admissions. It is defined as a sudden and transient loss of consciousness accompanied by loss of postural tone with ultimate complete recovery. It has a bimodal presentation with peak incidence at 20 and 80 years of age. The recurrence rate and prognosis of syncope is mainly dictated by the underlying causative mechanism.

II.Etiology and pathophysiology. Syncope is ultimately caused by a transient interruption or reduction of cerebral blood flow. Cessation of brain blood flow for at least 6 to 8 seconds is enough to cause syncope, and reduction in systolic blood pressure (SBP) to less than 60 mm Hg is also associated with syncope. Prompt identification of the specific cause behind the episode can help minimize expensive evaluations and guide therapy to prevent recurrences and decrease morbidity. Based on the underlying pathophysiology, syncope is classified into reflex-mediated syncope, orthostatic hypotension (OH), and cardiac syncope (Table 32.1).

TABLE 32.1 Cardiovascular Causes of Syncope

Neurally mediated (vasovagal)

Situational

Micturition

Defecation

Postprandial

Swallowing

Coughing

Sneezing

Glossopharyngeal neuralgia

Orthostatic syncope

Carotid sinus syncope

Cardioinhibitory

Vasodepressor

Mixed

Mechanical

Aortic stenosis

Hypertrophic cardiomyopathy

Atrial myxoma

Mitral stenosis

Pulmonic stenosis

Pulmonary hypertension or embolism

Myocardial infarction

Cardiac tamponade

Electrical

Second- and third-degree AV block

SSS

SVT

Torsade de pointes

Pacemaker malfunction

AV, atrioventricular block; SSS, sick sinus syndrome; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

A.Reflex-mediated syncope is responsible for two-thirds of all syncopal events. It results from an exaggerated or inappropriate reflex, which causes unopposed parasympathetic tone leading to inappropriate vasodilation (vasodepressive effect) and/or bradycardia (cardioinhibitory effect). This group can be subclassified into the following:

B.Vasovagal syncope (“common faint”) is the most common cause of syncope irrespective of age, gender, or comorbidities. It is usually triggered by prolonged sitting or standing, emotional stress, or hot environments. Orthostatic stress is thought to be central in the development of vasovagal syncope causing a decrease in preload. A ventricular contraction on a less than full left ventricle leads to the activation of ventricular mechanoreceptors, which results in an increased parasympathetic tone ultimately causing syncope via sudden bradycardia and/or hypotension. Other potential mechanisms include release of endogenous opioids or nitric oxide and primary central nervous system activation.

C.Situational syncope is usually associated with distension of hollow viscera (micturition, defecation, cough, postexercise, and trumpet playing) which triggers a vagally mediated reflex that causes syncope via vasodilation and bradycardia.

D.Carotid sinus syncope causes less than 1% of syncope; yet it accounts for 25% to 50% of unexplained syncope events in patients over 50 years. Hypersensitivity of carotid baroreceptors is important in this situation because their activation, with or without obvious triggers (shaving, swimming, turning head, or wearing a tight collar), leads to syncope via bradycardia (70% of cases), hypotension (10%), or a mixed response in the rest of cases.

E.OH accounts for 10% of all syncope episodes, but is the most common cause of syncope in the elderly. It is characterized by an impaired sympathetic tone leading to insufficient peripheral vasoconstriction during gravitational stress, especially during position changes. Inappropriate drop in blood pressure with orthostatic stress defines OH. The following are the most common forms of OH:

1.Classic OH is defined by a decrease in SBP exceeding 20 mm Hg; and diastolic pressure (DBP) drops of at least 10 mm Hg within 3 minutes of standing.

2.Initial OH is characterized by a brief (<30 seconds) but exaggerated drop in blood pressure of more than 40 mm Hg with rapid normalization afterwards.

3.Delayed OH, common in the elderly, presents as a slow progressive decline in blood pressure with prolonged standing. The lack of bradycardia sets orthostatic episodes apart from reflex-mediated hypotension.

Common causes of OH include dysautonomic syndromes, volume depletion, medications, diabetes mellitus, alcohol abuse, infection, and varicose veins.

4.Dysautonomic syndromes are divided into two categories. Primary autonomic failure includes pure autonomic failure (i.e., Bradbury–Eggleston syndrome) and multisystem atrophy (i.e., Shy–Drager syndrome). Secondary causes include amyloidosis, Parkinson disease, Lewy body dementia, tabes dorsalis, and multiple sclerosis.

F.Cardiac syncope is the second most common cause of syncope responsible for 10% to 20% of all syncope episodes. It carries a high rate of recurrence and a poor prognosis.

1.Arrhythmia induced is the most common form of cardiac syncope and the main cause of syncope in patients with known cardiac disease. The arrhythmic heart rate is the main factor leading to syncope in close interplay with the type of arrhythmia, cardiac preload, left ventricular function, and vascular adaptation. Commonly identified rhythms include sick sinus syndrome, atrioventricular block (AV block), and ventricular tachycardia (VT), and less common but important potential causes include supraventricular tachycardia (SVT) and torsade de pointes. Specific syndromes with known electrophysiologic abnormalities may be involved and should be sought in the appropriate circumstances such as Wolff–Parkinson–White syndrome, arrhythmogenic right ventricular dysplasia, long QT syndrome, and Brugada syndrome.

2.Mechanical cardiac syncope frequently occurs with exertion and arises from left ventricular outflow obstruction, as seen in aortic stenosis or hypertrophic obstructive cardiomyopathy (HOCM). Right ventricular outflow obstruction such as pulmonic stenosis may also result in syncope. Typically, exertion leads to a drop in peripheral vascular resistance, and hypotension develops given the inability to increase flow because of fixed cardiac output in the setting of mechanical obstruction. Arrhythmias and altered baroreceptors response also play a role in syncope in patients with an obvious mechanical cause. Myocardial ischemia, pulmonary embolism, and cardiac tamponade should be kept in mind as potential causes of syncope. Up to 7% of patients older than 65 years with myocardial ischemia may present with syncope.

G.Unexplained etiology. Up to half of patients with syncope have no identifiable cause after initial presentation. Asystole has been identified as an underlying mechanism in 50% of patients over 40 years of age with no structural heart disease and normal electrocardiogram (ECG) presenting with recurrent syncope. A new classification has been proposed for unexplained and/or recurrent syncope using precipitating mechanism (bradycardia or asystole, tachycardia or none to minimal rhythm variation) rather than the underlying etiology. Recent evidence revealed higher diagnostic yields when identifying mechanism of syncope via ECG monitoring compared with conventional assessment. This classification aims to promote an early use of ECG monitoring during workup of unexplained syncope to allow prompt use of ECG-tailored therapy in selected cases to ultimately improve treatment efficacy.

III.Clinical presentation. A thorough history and physical examination can provide a clue to the diagnosis in up to 50% of cases. The most important aspects of history taking during syncope evaluation are as follows (Table 32.2):

TABLE 32.2 Clinical Features Suggesting Specific Causes
Symptoms or Finding	Diagnostic Consideration
After sudden unexpected pain, unpleasant sight, sound, or smell	Vasovagal syncope
During or immediately after micturition, cough, swallow, or defecation	Situational syncope
With neuralgia (glossopharyngeal or trigeminal)	Bradycardia or vasodepressor
Upon standing	OH
Taking hypotensive medication	Drug-induced syncope
Symptoms within 1 h after meals	Postprandial hypotension
Prolonged standing at attention	Vasovagal
Well-trained athlete after exertion	Vasovagal
Changing position (from sitting to lying, bending, turning over in bed)	Atrial myxoma, thrombus
Syncope with exertion	Aortic stenosis, pulmonary hypertension, mitral stenosis, HOCM, coronary artery disease
With head rotation, pressure on carotid sinus associated with vertigo, dysarthria, diplopia with arm exercise	Carotid sinus syncope TIA, stroke, subclavian steal syndrome

HOCM, hypertrophic obstructive cardiomyopathy; OH, orthostatic hypotension; TIA, transient ischemic attack.

A.Pertinent medical history. The initial approach should focus on

1.Patient age as young patients are more likely to have reflex-mediated syncope, whereas the elderly commonly present with carotid hypersensitivity or OH

2.Comorbidities with special attention to history of heart disease, such as valvular stenosis, cardiomyopathy, or myocardial infarction. The presence of any of these may suggest more malignant causes such as VT.

3.Family history looking for syncope and/or sudden cardiac death in family members

4.Medications review for their potential causative role or interaction with other medications

5.Circumstances before syncope; whether there is association with any particular activity, exertion, or change in position; and the frequency of occurrence

a.Syncope during exercise suggests cardiac etiology. Similarly, noise and strong emotion are known triggers of long QT-related syncope.

b.An event after exertion in young athletes or syncope triggered by pain, prolonged standing, and hot or crowded environments is indicative of vasovagal syncope.

c.Situational syncope presents during urination, defecation, cough, postexercise, and trumpet playing.

d.Carotid syncope is triggered by shaving, swimming, head turning, or neck extension.

6.Prodrome with diaphoresis, warmth, nausea, abdominal discomfort, or ear ringing is common in vasovagal syncope (except in in elderly patients), whereas none or short prodrome with palpitations suggests cardiac syncope. Seizures are typically preceded by an aura.

7.The syncopal event provides useful information to differentiate syncope from other causes of loss of consciousness, so an effort must be made to contact witnesses.

a.Syncope is a transient loss of consciousness (<30 seconds). Vasovagal syncope might present with generalized pallor, whereas cardiac syncope could reveal cyanosis.

b.Occasionally, syncope is accompanied by mild muscular jerking (convulsive syncope) as a result of cerebral anoxia. The evaluating physician must make every effort to distinguish this from seizure and pseudoseizure.

8.Recovery postsyncope with persistent somnolence, fatigue, and nausea from minutes to hours is suggestive of vasovagal syncope, whereas fast recovery is seen after tachycardia or bradycardia. Seizures commonly present with prolonged (hours) confusion and transient focal neurologic deficits.

B.Physical findings. The physical examination is important, especially when the patient is unable to describe the event and no witnesses are available, because certain findings on examination can direct the physician in the diagnostic evaluation. A comprehensive examination includes

1.Blood pressure measurement in both arms

2.Orthostatic vital signs should be serially checked immediately upon standing and after 3 and 5 minutes of orthostatic stress. SBP drop of over 20 mm Hg or to less than 90 mm Hg and DBP decreases over 10 mm Hg are diagnostic for OH.

3.Evaluation for the presence of carotid bruit and assessment of the carotid upstroke

4.Carotid sinus massage testing should be considered in patients over 40 years of age with syncope of unknown etiology after initial assessment. Massage is performed on one side followed by contralateral side for 5 to 10 seconds under continuous ECG and beat-to-beat blood pressure monitoring. A diagnosis of carotid sinus hypersensitivity is made when massage elicits an asystolic sinus pause >3 seconds or drop in SBP over 50 mm Hg. Carotid sinus syndrome is made only when symptoms accompanies carotid hypersensitivity. Contraindications include carotid bruits, significant carotid stenosis, or myocardial infarction or stroke within 3 months.

5.Cardiac examination evaluating heart rhythm, heart rate, extra heart sounds (such as S₃, S₄, or tumor plop), and murmurs

6.Peripheral pulses for evidence of peripheral vascular disease and entities such as subclavian steal; and dermatologic clues that may suggest collagen vascular disease or vasculitis

7.Neurologic examination for focal neurologic deficits

IV.Management. The initial management of syncope includes a thorough history, physical examination, and an ECG. The following systematic stepwise assessment is recommended (Fig. 32.1):

FIGURE 32.1 Schematic algorithm for the evaluation of patients presenting with syncope. ECG, electrocardiogram; EGSYS, Evaluation of Guidelines in Syncope Study; ELR, external loop recorder; HCT: hematocrit; EPS, electrophysiologic study; ICD: implantable cardiac defibrillator; ILR, implantable loop recorder; LHC, left heart catheterization; T-LOC, transient loss of consciousness.

A.Determine likelihood of syncope versus nonsyncopal event (stroke, transient ischemic attacks, normal pressure hydrocephalus, seizures, metabolic causes, and psychogenic). Syncope is highly likely when there is complete loss of consciousness of rapid onset and short duration accompanied by loss of postural tone followed by complete recovery. If one or more of these criteria are absent, nonsyncopal causes must be ruled out before proceeding with syncopal assessment.

B.Identify specific cause of syncope (Table 32.3). The most important goal during this step is to rule out structural heart disease. A single ECG offers the possible diagnosis in approximately 5% of cases. The following ECG findings are suggestive of heart-related syncope:

TABLE 32.3 Causes of Syncope in the Evaluation of Guidelines in Syncope Study 2 Trial
Neurally Mediated	OH	Cardiac Arrhythmia	Structural Cardiopulmonary	Nonsyncopal
•Vasovagal	•Drug induced	•Brady	•AMI	•Metabolic
•Carotid sinus	•ANS failure	•Sick sinus	•Aortic stenosis	•Epilepsy
•Situational	•Primary	•AV block	•HOCM	•Intoxications
•Cough	•Secondary	•Tachy	•Pulmonary HTN	•Drop attacks
•Micturition	•Volume depletion	•VT	•Others	•Psychogenic
•Defecation		•SVT		•TIA
•Swallow		•Inherited		•Falls
•Others
66%	10%	11%	5%	6%

Unknown cause: 2%.

AMI, acute myocardial infarction; ANS, autonomic nervous system; AV, atrioventricular; HOCM, hypertrophic obstructive cardiomyopathy; HTN, hypertension; OH, orthostatic hypotension; SVT, supraventricular tachycardia; TIA, transient ischemic attack; VT, ventricular tachycardia.

Adapted from Brignole M. Diagnosis and treatment of syncope. Heart. 2007;93(1):130–136. With permission from BMJ Publishing Group Ltd.

1.Persistent sinus bradycardia <40 beats/min or sinus pauses >3 seconds

2.Mobitz II second or complete heart block

3.Bifascicular block or alternating left and right bundle branch block (RBBB)

4.Preexcited or wide QRS complexes

5.Rapid paroxysmal SVT

6.VT or nonsustained polymorphic VT with abnormal QT interval

7.RBBB with ST elevation in leads V1 to V3 (Brugada syndrome)

8.Inverted T-waves in precordial leads with epsilon waves and ventricular late potentials (arrhythmogenic right ventricular dysplasia)

9.Ischemia signs with or without myocardial infarction

C.Risk-stratify syncope events of unknown etiology. The main goal is to identify those with unexplained syncope at higher risk of cardiovascular event or cardiac sudden death. A number of validated risk scoring systems exist including San Francisco Syncope Rule, Evaluation of Guidelines in Syncope Study (EGSYS) score, and Osservatorio Epidemiologico sulla Sincope nel Lazio score. The following are the main high-risk features:

1.Severe structural or coronary artery disease (e.g., heart failure, low ejection fraction, or previous myocardial infarction) is the major predictor of VT and death.

2.ECG findings suggestive of cardiac syncope as described before

3.Severe anemia (hematocrit < 30%) and electrolyte abnormality

D.Assess need for hospital admission. It is recommended to admit only cases of syncope with suspicion for cardiac etiology or syncope of uncertain etiology at an increased risk of major cardiovascular events or death.

A genuine effort must be made to accurately follow this stepwise assessment and to pursue hospital admission and/or further testing only in appropriately selected patients. Besides standardization of assessment, the use of EGSYS-2 online interactive decision-making software and utilization of syncope units are the only interventions known to further improve the diagnostic yield and rate of hospitalization and/or testing.

E.Need for further testing. Additional testing is generally not needed when an underlying cause for syncope has been identified by initial assessment. Further workup is recommended when there is a suggestion of cardiac cause or uncertain etiology. Investigations should be individualized to be cost-effective (Fig. 32.1).

1.Echocardiography is recommended when structural cardiac disease is suspected. It is useful in diagnosing valve pathology and myocardial processes that may contribute to syncope (i.e., aortic stenosis and cardiac tumors). It has a low diagnostic yield in the absence of clinical, physical, or ECG findings, suggesting a cardiac abnormality.

2.Stress testing is recommended in patients with exertional syncope or with presentation suggestive of coronary artery disease. In addition to ischemia assessment, stress test helps in the detection of exertional arrhythmias.

3.Patients with pacemakers should undergo pacemaker interrogation for possible malfunction (battery depletion, lead malfunction, lead dislodgement, or R-on-T phenomenon).

4.Tilt table testing works via orthostatic stress induced by upright position with or without chemical stimulation which provokes a reflex-mediated syncope. Isoproterenol is needed in >50% of cases to trigger the reflex but at the expense of a higher false-positive rate. The following are indications for tilt testing:

a.Single unexplained syncope at increased risk of traumatic injury or with occupational hazard during subsequent events (e.g., driver, pilot)

b.Unexplained recurrent syncope in patients with no heart disease or in those with heart disease after ruling out a cardiac cause

c.Also used to differentiate vasovagal syncope from OH

A positive test is defined by hypotension and/or relative or absolute bradycardia. Bradycardia (cardioinhibitory response) translates into a higher risk of subsequent asystolic syncope. Tilt table testing has a sensitivity of 70% and specificity of 35% to 92% with isoproterenol. The sensitivity increases with higher angle of tilt and longer duration. It appears that tilt table testing, when used in the appropriate setting, is beneficial in diagnosing previously unexplained syncope.

5.Electrocardiographic monitoring encompasses a variety of ECG-monitoring techniques with different recording times. It is indicated when there is suspicion for arrhythmia-induced syncope. Guidelines also recognize the early use of implantable loop recorders (ILRs) in the workup of unexplained and recurrent syncope with low risk for cardiovascular events. High-risk patients can be considered for ECG monitoring only after a complete comprehensive work fails to reveal a cardiac cause because a delay in diagnosis could pose harm to the patient. The main goal of this monitoring strategy is to detect a correlation between symptoms and the arrhythmia. Yet, certain rhythms are considered diagnostic even if asymptomatic:

a.Asystole > 3 seconds

b.SVT with rate higher than 160 beats/min for 32 or more beats

c.VT

d.Second-degree AV block (type II) or complete AV block, and runs of nonsustained ventricular tachycardia (NSVT) should be taken seriously

Even a normal cardiac rhythm during a syncopal episode helps exclude an arrhythmia-induced event suggesting a good prognosis. The main disadvantages of monitoring strategies include delayed diagnosis and variable diagnostic yield based on event frequency. Therefore, the selection of recording device is based on risk of cardiovascular event and frequency of symptoms.

a.In-hospital telemetry is the ECG monitoring of choice in patient with high risk for major cardiovascular events or sudden death requiring admission.

b.Holter monitor offers generally 24- to 48-hour monitoring with a diagnostic yield for arrhythmia of 24% and correlation of a cardiac arrhythmia with a syncopal spell of 4%. It can be considered when symptoms occur on a daily basis.

c.External loop recorders are capable of monitoring the heart’s electrical activity for up to 4 weeks, thus they are only indicated if symptoms frequency is greater than monthly. They continuously record and delete electrical activity in a loop until it is activated by the patient to record activity during symptoms. When activated by the patient, loop recorders permanently record the previous 5 to 15 minutes of rhythm data. The recorder can capture arrhythmias during a syncopal episode even if the patient activates it after regaining consciousness. Reported diagnostic yield is better than Holter monitoring (50% at 2 weeks and 90% at 4 weeks), but is significantly reduced by operator error.

d.ILRs offer a long recording time with battery life up to 3 years. They are implanted subcutaneously via a minor surgical procedure. They can be manually or automatically activated with wireless transmission. Early use of ILR enhances diagnostic yield and time to diagnosis in an unselected population with recurrent and unexplained syncopal events compared with conventional management. Pooled analysis from available studies revealed a diagnostic yield of 32% at 18 months. Reports suggest that diagnostic yield can increase up to 80% with extended monitoring for 2 years. Early ILR use also decreases the number of hospitalizations and testing without impact on mortality. ILR allows earlier initiation of ECG-targeted therapy with associated reduction of syncopal recurrences in selected cases (e.g., documented asystolic pauses). Nonetheless, no evidence exists to support the use of ILR as a first-line diagnostic tool in all patients with syncope. ILR is recommended during the following scenarios:

(1)Recurrent unexplained syncope at low risk for cardiovascular event or sudden death. In high-risk patients it may be used only after prompt cardiac evaluation failed to reveal the cause of the event.

(2)Patients with recurrent reflex-mediated syncope despite appropriate medical management when identification of underlying mechanism might change management. (e.g., identification of asystolic pauses)

(3)Other suggestions include differentiation of seizure from syncope when anticonvulsive therapy failed to control episodes.

e.Mobile cardiac outpatient telemetry (MCOT) provides continuous ambulatory ECG monitoring with continuous recording or 24-hour loop memory. MCOT offers live wireless reporting to a center, which is able to record the event and contact the patient and/or physician. Therefore, it provides higher diagnostic yield compared with patient-activated systems.

6.Signal-averaged electrocardiography (SAECG) is a collection of 100 to 300 single QRS complexes, which are amplified, filtered for noise, and averaged to determine the presence of late potentials. Late potentials seem to identify the presence of a reentrant substrate and may indicate an independent risk for the development of future life-threatening ventricular arrhythmias. SAECG is useful in predicting inducibility of ventricular arrhythmias by an electrophysiology study (EPS), especially in patients with ischemic heart disease with structurally normal hearts. SAECG may also be helpful in identifying patients with arrhythmogenic right ventricular dysplasia or infiltrative cardiomyopathies.

a.A positive SAECG finding suggests the need for further EP testing, especially in individuals with known heart disease.

b.The absence of late potentials has a high negative predictive value.

7.EPS in the assessment of syncope is mainly recommended in patients with coronary artery disease and syncope of suspected arrhythmic etiology with otherwise no indication for implantable cardiac defibrillator (ICD) implantation. Conversely, EPS is not indicated in patients with a structurally normal heart, normal ECG, and no palpitations preceding the syncope. Sensitivity and specificity of EPS are generally poor. EPS should also be considered in the following scenarios:

a.Uncertainty about the origin of wide QRS tachycardia, including bundle branch blocks after nonrevealing noninvasive cardiac testing

b.Patient with syncope at high risk of cardiovascular event or with occupational implications that could translate into harm if diagnosis is delayed

c.Known or suspected VT, especially to guide therapy

d.NSVT, mild-moderate left ventricular dysfunction, and late potentials on SAECG, used to stratify prognosis and guide therapy

e.Drug-refractory malignant VT in candidates for ablative therapy

Induced arrhythmia during EPS does not usually produce syncope in the laboratory; therefore, a cause-and-effect relationship often has to be assumed. EPS findings considered diagnostic in the cause of syncope include

a.Sustained monomorphic VT

b.Sinus bradycardia with corrected sinus node recovery time over 525 ms

c.Spontaneous or pacing-induced infranodal block or infrahisian block

d.Baseline His-ventricle (HV) interval >100 ms or significant prolongation after procainamide challenge

e.Paroxysmal SVT with symptomatic hypotension

The limitations and disadvantages of EPS are high cost, invasive nature, lower specificity if a more aggressive electrical stimulation protocol is used, and poor prediction of bradyarrhythmias.

8.Adenosine triphosphate (ATP) test has been suggested to aid in the diagnosis of unexplained syncope. Patients are injected with a 20-mg bolus of ATP and are kept in a supine position with continuous electrocardiographic monitoring. Asystole lasting >6 seconds or AV block lasting >10 seconds is considered abnormal. ATP test may be able to diagnose syncope caused by transient AV block. However, it has not been able to reproduce sinus arrest. This test remains in the investigational phase, and outcome data are not yet available.

V.Treatment. The treatment of syncope hinges on preventing recurrent episodes, decreasing physical harm from syncopal events, and lowering mortality. Therapy must be individualized to the underlying cause or mechanism.

A.Reflex-mediated syncope. The first step involves reassurance about the benign prognosis and patient education to avoid triggers. It should also include adjustment of medication regimen (e.g., chronic vasodilator therapy).

1.Nonpharmacologic treatment: may be sufficient for those with infrequent and predictable syncopal episodes

a.Blood volume expansion (probably helpful). All patients should be counseled to liberalize salt (10 g salt per day) and fluid intake (2 to 3 L/d) unless contraindicated (e.g., hypertension, heart failure).This increases orthostatic tolerance evidenced in the negativization of previously positive tilt test with intravenous fluid expansion. However, there exists no randomized trial assessing the impact of salt tablets in syncope prevention.

b.Exercise training (debatable effect) seems to increase blood pressure and orthostatic tolerance, but a small trial failed to detect reduction in syncopal recurrences.

c.Tilt training (debatable effect) exposes patients to progressively longer periods of upright posture in order to condition the neural and vascular systems to counter gravitational stress. In one small study on neutrally mediated syncope, tilt training resolved symptoms in 85% of patients during the period of training. However, four randomized trials reported no reduction in the rate of positive tilt test.

d.Counterpressure maneuvers (probably helpful) should be recommended in all patients with predictable episodes. They include isometric arm and leg exercises (e.g., crossing leg or hand grip) performed at the first sign of a syncopal episode. They raise peripheral vascular resistance and blood pressure and can prevent the syncopal spell. A recent trial reported a significant risk reduction of 36% in syncope recurrence when these measures were added to conventional therapy.

2.Medical therapy is recommended in patients with frequent and/or unpredictable syncopal episodes as an add-on regimen to lifestyles changes. The majority of long-term randomized studies have failed to show any benefit from most of the medications. These treatments are generally considered second line in reflex-mediated syncope.

a.α-Agonists (probably helpful): Guidelines favor use of midodrine as “pill in the pocket” strategy in anticipation of known syncope triggers over chronic use. Few small open label studies have reported that midodrine reduces symptoms and increases likelihood of tilt test negativization. Midodrine may decrease syncope recurrence based on one pediatric open label trial. Etilefrine consistently provides no benefit in the prevention of neuromediated syncope.

b.Fludrocortisone (debatable effect) in pediatric studies has shown inconsistent benefit with two trials actually reporting harm. No trial to date has assessed benefit in adult population, but results of Prevention of Syncope Trial (POST) II will further clarify the role of fludrocortisone in adults.

c.Selective serotonin reuptake inhibitor (SSRI) (probably helpful). Specifically paroxetine showed promising reduction of syncope recurrence in highly symptomatic patients. Results have not been confirmed by other trials. Conversely, fluoxetine provides no benefit compared with propranolol or placebo based on one small study.

d.β-blockers (probably unhelpful). Initial low-quality evidence showed inconsistent benefits, but POST I trial reported that metoprolol provides no benefit in the treatment of reflex-mediated syncope at moderate risk of recurrence.

3.Device therapy has been extensively studied in reflex-mediated syncope. Asystolic pauses are detected in a significant proportion of neuromediated syncope events, whereas carotid hypersensitivity is known to predict the occurrence of sinus pauses. A recent meta-analysis of randomized double-blind studies revealed no benefit of pacing in an unselected population with vasovagal syncope. Nonetheless, International Study on Syncope of Uncertain Etiology 3 trial reveals that pacing patients with vasovagal syncope with symptomatic asystolic pauses (>3 seconds) or asymptomatic pause (>6 seconds) provides a risk reduction in syncope recurrence (57%) at 2 years. Similarly, pacing is thought to be helpful for carotid syncope with bradycardia. In this setting, dual-chamber pacing is preferred over single ventricular lead pacing, whereas atrial pacing is not recommended.

B.Orthostatic hypotension. The management of OH benefits from education and lifestyle changes as outlined above. Emphasis must be made on discontinuation of potentially offending drugs, avoidance of sudden changes in position, liberalization of fluid and salt intake, utilization of counterpressure maneuver if events are predictable, and use of compression stocking to prevent orthostatic pooling of venous blood.

1.Contrary to reflex-mediated syncope, chronic use of midodrine (5 to 20 mg TID) is recommended in patients with OH that failed nonpharmacologic regimen.

2.Weaker evidence exists on fludrocortisone suggesting a decrease in symptoms and higher blood pressure. Additional treatment includes desmopressin in nocturnal polyuria, octreotide in postprandial hypotension, and erythropoietin in severe anemia.

C.Cardiac syncope. The management of cardiac syncope starts with the correction of electrolyte abnormalities (e.g., prolonged QT from hypomagnesaemia or hypocalcaemia). Further therapy depends on the underlying mechanism and/or cause of syncope as follows:

1.Symptomatic bradyarrhythmias and AV blocks require pacemaker implantation. Patients with an HV interval of >100 ms are at a high risk for progression to heart block and may benefit from a pacemaker. Single- and dual-chamber pacemakers decrease risk of recurrence and sudden death in patients with syncope caused by bradyarrhythmias.

2.Implantable defibrillators are the best option for patients with malignant or life-threatening ventricular arrhythmias, sustained monomorphic VT, and/or unexplained syncope in the setting of severe left ventricular dysfunction.

3.Antiarrhythmic therapy appears to decrease the frequency of syncope; however, it has not been shown to improve survival.

4.Patients with left or right heart outflow obstruction, such as HOCM, should be instructed to avoid exertional activities that precipitate syncope and should be considered for surgical repair.

5.Coronary revascularization is strongly indicated in patients with life-threatening arrhythmias (usually polymorphic VT) because of myocardial ischemia.

VI.Prognosis. Among all syncope cases presenting to ED, only 14% will have nonfatal severe outcome and 0.7% will die within a month. Reflex- and OH-mediated syncope are not associated with increased mortality, but harm may occur in association with a syncopal event. Conversely, patients with cardiac syncope or unknown etiology have higher rates of mortality and sudden death. Unexplained syncope has a mortality rate of 6% to 10% over 3 years and 24% over 5 years. Meanwhile, cardiac syncope confers mortality rate of 50% over 5 years and 30% in the first year after diagnosis.

Syncope presents usually as a single event with only 20% recurring. The best predictor of recurrence for vasovagal episode is the number of events in the prior year (e.g., 7%, 22%, and 69% for patients with 0, <2, or >6 syncopal episodes, respectively). Cardiac syncope has a higher risk of recurrence compared with other syncope etiologies.

VII.Postural Orthostatic Tachycardia Syndrome (POTS). This is a poorly understood syndrome characterized by exaggerated increase in heart rate with tilt and exercise. Patients may also feel fatigue, dyspnea, and lightheadedness on standing, but do not typically experience OH or syncope. Patients typically present at age 14 to 45 years and it predominantly affects females. They often have multisystem complaints such as fibromyalgia, chronic fatigue syndrome, sleep disorders, and gastrointestinal symptoms.

A.Etiology. POTS is thought to be a syndrome with multiple overlapping etiologies, with each etiology having varying importance in individual patients. There is also suggestion of different genetic forms of the disease.

1.Partial dysautonomia refers to autonomic impairment in some parts of the nervous system, with efforts by the still-functioning nervous system to compensate.

2.Increased sympathetic activity. Studies have shown that patients with POTS have elevated arterial norepinephrine levels and decreased norepinephrine clearance.

3.Hypovolemia. Studies have shown reduced blood volume and reduced erythrocyte volume. The cause of these findings is not clear, but some have postulated problems with the renin–angiotensin–aldosterone axis, possibly because of renal denervation.

4.Changes in venous function. Patients with POTS have been shown to have increased venous pooling and a decrease in stroke volume on standing.

5.Primary baroreflex abnormalities may also cause the increase in heart rate without change in blood pressure that is seen on standing.

In clinical practice, two main forms of the disease have been identified: the dysautonomic or peripheral form with inability to increase systemic vascular resistance with orthostatic stress and the hyperadrenergic or central form with abnormal biofeedback mechanism above the baroreceptor level.

B.Diagnosis. There are no established criteria for the diagnosis of POTS. The characteristic finding is an increase in heart rate of >30 beats/min or a rise in heart rate to >120 beats/min in the first 10 minutes of tilt as their diagnostic criterion. OH does not typically occur. It is important to rule out other conditions, such as autonomic neuropathy, central dysautonomia, dehydration, and medication effects.

C.Treatment. Because of the heterogeneous etiologies of POTS, treatment can be very challenging and often requires multiple attempts with different regimens. There are no large controlled studies of therapy.

1.Volume expansion using oral fluid intake, a high salt diet, and fludrocortisone may improve symptoms.

2.Adreno-receptor agonists such as midodrine may improve symptoms in patients with mainly peripheral autonomic denervation; studies have shown improvement in heart rate response and symptoms during tilt testing.

3.Patients with mainly hyperadrenergic symptoms may see improvement with β-blockers. In one placebo-controlled, randomized crossover study, low-dose propranolol (20 mg) improved tachycardia and reduced symptoms, but high-dose propranolol (80 mg) did not change or worsened symptoms.

4.Pyridostigmine, an acetylcholinesterase inhibitor, has been used to attenuate tachycardia.

5.Other centrally acting drugs, such as SSRIs, clonidine, methyldopa, and phenobarbital, have been used with some success, but experience with their use is very limited.

ACKNOWLEDGMENTS: The authors thank Drs. Kia Afshar, Salim H. Ahmed, Carlos Alves, Keith Ellis, and Vasant B. Patel for their contributions to earlier editions of this chapter.

Landmark Articles

Ammirati F, Colivicchi F, Santini M; for the Syncope Diagnosis and Treatment Study Investigators. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. Circulation. 2001;104:52–57.

Bardy GH, Lee KL, Mark DB, et al; for the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225–237.

Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patient with neurally-mediated syncope and documented asystole (ISSUE-3): a randomized trial. Circulation. 2012;125:2566–2571.

Farwell DJ, Freemantle N, Sulke AN. Use of implantable loop recorders in the diagnosis and management of syncope. Eur Heart J. 2004;25:1257–1263.

Sheldon R, Connolly S, Rose S, et al. Prevention of syncope trial (POST): a randomized, placebo controlled study of metoprolol in the prevention of vasovagal syncope. Circulation. 2006;113(9):1164–1170.

Key Reviews

Brignole M, Hamdan M. New concepts in the assessment of syncope. J Am Coll Cardiol. 2012;59:1583–1591.

Goldschlager N, Epstein AE, Grubb BP; for the practice outline subcommittee, NASPE. Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med. 2003;163:151–162.

Hanna E. Syncope: etiology and diagnostic approach. Cleve Clin J Med. 2014;81(12):755–766.

Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope. Eur Heart J. 2009;30:2631–2671.

Sklani P, Khan A, Klein G. Syncope. Circulation. 2013;127:1330–1339.

Strickberger SA, Benson DW, Biaggioni I, et al. AHA/ACCF scientific statement on the evaluation of syncope. J Am Coll Cardiol. 2006;47:473–484.

Relevant Book Chapter

Carlson MD, Grubb BP. Diagnosis and management of syncope. In: Fuster V, Walsh RA, Harrington RA, eds. Hurst’s The Heart. 13th ed. New York, NY: McGraw-Hill; 2011:chap 48.

Crawford MH. Syncope. In: Crawford MH, eds. Current Diagnosis & Treatment: Cardiology. 4th ed. New York, NY: McGraw-Hill; 2014:chap 16.

Calkins HG, Zipes DP. Hypotension and syncope. In: Mann DL, Zipes DP, Libby P, et al. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. Vol 40. 10th ed. Philadelphia, PA: Elsevier; 2015:861–871:chap 40.