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Definition

Syncope is an abrupt loss of consciousness with a concomitant loss of postural tone. Presyncope, also called near syncope, is the prodrome of syncope, but without loss of consciousness. Syncope is part of a broader clinical network of symptoms that is best described as postural intolerance, which is a constellation of symptoms that occur in the upright posture including dizziness, lightheadedness, tremulousness, sweating, nausea, and palpitations. These symptoms improve with the assumption of a recumbent posture.

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Prevalence and Incidence

Syncope accounts for 3% of emergency room visits and 1% to 6% of hospital admissions.¹ It happens to men and women of all ages, but it increases in prevalence with age. In our syncope clinic from 1997 to 2007, we treated more women than men; it is unclear if this was due to a higher prevalence in women or to a higher tendency for women to seek medical assistance for this condition. Figure 1 shows the number of tests we performed, broken down by gender.

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Pathophysiology and Natural History

The autonomic nervous system is vital for maintaining internal homeostasis, including regulation of blood pressure (BP), heart rate, fluid and electrolyte balance, and body temperature.

The hemodynamic response to standing exemplifies the interaction between the circulatory and autonomic nervous systems. When standing, initially the force of gravity pools blood in the distensible veins below heart level. Increased capillary pressure follows, and plasma is lost to interstitial fluid due to ultrafiltration. It is estimated that plasma volume decreases by 15% within 20 minutes of standing. Pooling of blood in the veins decreases venous return to the heart, with subsequent reduction of cardiac output, which in turn, triggers compensatory mechanisms to prevent the fall of arterial pressure.

Normally the physiologic response to standing is gravitational blood pooling in the lower extremities, leading to reduced venous return to the heart. The mean arterial BP and stroke volume decrease, which deactivates strategically located mechanoreceptors that will initiate neural reflexes. These reflexes increase sympathetic outflow, decrease parasympathetic responses, and lead to tachycardia and vasoconstriction. In addition, unloading of the low pressure cardiopulmonary receptors play a role in regulating the release of arginine vasopressin (AVP). The reduction in effective plasma volume and renal blood flow stimulate the postural responses of the renin- angiotensin-aldosterone (RAA) system. Compensatory mechanisms include: increased sympathetic outflow leading to arteriolar vasoconstriction, venoconstriction, and increase in heart rate; increased catecholamine concentration in the plasma and urine; and rise in plasma epinephrine originating from the adrenal medulla.

The autonomic supply to the cardiovascular system is coordinated at the central autonomic network (CAN) in the brainstem. The autonomic nervous system counterbalances postural stressors to maintain mean arterial pressure. During orthostasis, the initial reduction of cardiac filling and stroke volume is sensed by pressure receptors in the heart, carotid sinuses, and aortic arch, which send impulses to the CAN. This initiates sympathetic vasomotor outflow to vascular beds in the skeletal muscles and cutaneous vasculature. Norepinephrine is released, causing vasoconstriction, venoconstriction, and increased heart rate and contractility.

Decreased atrial stretch during postural stress causes increased secretion of AVP and decreased secretion of A-type atrial natriuretic peptide (ANP). This antinatriuresis helps increase extra cellular fluid (ECF) volume and compensates for cardiac filling.

Orthostasis leads to a reflexive decrease of renal blood flow followed by decreased glomerular filtration of sodium. Decreases in renal blood flow and renal perfusion pressure stimulate the RAA system to enhance vasoconstriction.

Sympathetic stimulation plays a major role in the immediate response to upright posture. It maintains mean arterial pressure via constriction of several vascular beds. Venoconstriction causes c orrection of orthostasis by increasing cardiac filling for a given amount of gravitational pooling of blood. Increased cardiac inotropic function augments stroke volume for cardiac filling. Increased heart rate augments cardiac output for stroke volume. Leg pumping of skeletal muscles enhances venous return to the heart. The venoarterial reflex augments arterial vasoconstriction in response to venous distention.

On the other hand, the RAA system plays a minor role in the immediate constrictive response to orthostasis, and its effects are relatively late. In the absence of sympathetic postganglionic outflow, like that seen in cases of spinal cord injury and quadriplegia, orthostatic hypotension occurs despite marked stimulation of the RAA system.

Not every fall in BP leads to brain hypoxia. Syncope or presyncope occurs as a result of brain hypoxia, which is usually secondary to a reduction of cerebral perfusion pressure. This is because the cerebral circulation is autoregulated so brain perfusion is maintained in the face of significant changes in BP. Cerebral autoregulation allows regional cerebral blood flow to remain constant over a range of perfusion pressure (50-140 mm Hg).

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Etiology

In stratifying the etiology of syncope, prospective studies have found that neurally mediated causes account for the largest percentage of events (38%-56%). Cardiovascular causes, separated into cardiac causes (11%-23%) and postural hypotension (2%-24%), account for a smaller percentage of cases. Undetermined causes occur in 14% to 18% of events.

Poor prognosis was reported in syncope patients with underlying heart disease. The etiologies of syncope can be subdivided into those occurring in patients with or without structural heart disease. Hospital admission criteria following emergency department evaluation for a syncope event have been extensively discussed, and decision making about prevention of serious outcomes is critical.^2,3

Presence of Structural Heart Disease

In patients with structural heart disease, syncope can occur secondary to bradyarrhythmias, tachyarrhythmias, or arrhythmias secondary to medication and electrolyte abnormalities. Cardiac left ventricular outflow obstruction (including aortic stenosis or hypertrophic cardiomyopathy) or right ventricular obstruction (including pulmonary embolus or pulmonary hypertension) can cause syncope. Other cardiac structural abnormalities, such as mitral stenosis, atrial myxoma, or dissecting aortic aneurysm, can also lead to syncope. Finally, the syndromes that accompany cardiac events including myocardial ischemia or infarction, cardiac tamponade, or subclavian steal syndrome can include syncope.

Absence of Structural Heart Disease

In the absence of structural heart disease, neurally mediated mechanisms, postural hypotension, postural orthostatic tachycardia syndrome (POTS), metabolic or neurologic abnormalities, and psychogenic causes should be considered as a possible etiology of a syncopal event. For practical purposes, syncope in the absence of heart disease may be grouped into events where the BP declines steadily, those where BP drops only at the endpoint, and those where BP response to upright posture remains normal.

Neurally Mediated Mechanisms

Neurocardiogenic Syncope. Also known as vasovagal syncope and vasodepressor syncope, neurocardiogenic syncope is commonly described using the Bezold-Jarisch reflex model.² A reduction in ventricular preload stimulates mechanoreceptors in the inferoposterior part of the left ventricle, leading to a vigorous contraction. This causes an increased afferent discharge of the unmyelinated C fibers from the ventricular mechanoreceptors. The central nervous system responds with reflex sympathetic withdrawal and increased parasympathetic output. These signals cause vasodilation, hypotension, and bradycardia in the vasovagal type, but only vasodilation occurs in the vasodepressor type.

Other potential mechanisms include involvement of central serotoninergic pathways and release of endogenous opioids or catecholamines. Of importance is the report of a monitored vasovagal event in a heart transplant patient.⁴

Carotid Sinus Syncope. Some patients have hypersensitive carotid sinus baroreceptors leading to vagal overstimulation and syncope. The underlying mechanism for hypersensitivity is not known, but it is commonly associated with ischemic heart disease, aging, and hypertension.⁵

Situational Syncope. Situational syncope includes cough, laughter, deglutition, micturition, and defecation syncope. The underlying mechanisms of these events are likely similar to that of neurocardiogenic syncope. Some other situational events may be related to human fear circuitry and sociogenic pseudoneurologic symptoms.^6-8

Postural Hypotension

Postural hypotension is defined as a drop in systolic BP of at least 20 mm Hg accompanied by a drop in diastolic BP of at least 10 mm Hg with upright posture. It is caused by deviation from the normal physiologic response to upright posture, which leads to postural decline of BP or postural hypotension.

About 16% to 18% patients older than 65 years have postural hypotension, and 2% of these are symptomatic. The value of the clinical history is limited in diagnosing the cause of syncope in older patients (≥65 years) as compared to younger patients (<65 years).⁹

Possible causes of postural hypotension include hypovolemia, autonomic insufficiency, medications or toxins (tricyclic antidepressants, vasodilators, angiotensin-converting enzyme inhibitors, ganglionic blockers, alcohol), metabolic or endocrine causes (Addison’s disease, pheochromocytoma, systemic mastocytosis, carcinoid syndrome), or vascular insufficiency (varicose veins, arteriovenous malformations).

Autonomic dysfunction (Box 1) is a disorder of postganglionic noradrenergic transmission. The central nervous system does not appropriately activate efferent sympathetic fibers. Mechanisms of dysfunction include subnormal norepinephrine release, impaired vasoconstriction, and reduced vascular volume from urinary sodium wasting. Autonomic dysfunction is classified as primary or secondary.

Postural Orthostatic Tachycardia Syndrome

POTS^10,11 is defined by excessive heart rate increments upon upright posture. A person with POTS experiences heart rates that increase 30 beats or more per minute—and that can increase to 120 beats or more per minute—upon standing. These heart rate increases usually occur within 10 minutes of rising. We have described early versus late POTS (accentuated postural tachycardia).¹¹

A variety of circulatory and autonomic neural abnormalities occur in association with POTS and can cause accentuated postural tachycardia including hypovolemia, augmentation of postural venous pooling, β-adrenergic hypersensitivity, hyperbradykininemia, and autonomic imbalance. In a substantial number of patients, no definite cause is found. The literature describes this condition as associated with mitral valve prolapse, basilar migraine, chronic fatigue syndrome, and neurocardiogenic (vasovagal) syncope.

Metabolic and Neurologic Conditions

Metabolic disorders include hyperventilation, hypoglycemia, or hypoxia. Neurologic conditions may be due to vertebral-basilar insufficiency or migraine.¹²

Psychogenic Conditions

Psychogenic causes of syncope include anxiety or panic disorder. Cerebral blood flow velocity by ultrasonography of the middle cerebral artery has been assessed in patients with orthostatic intolerance during head-up tilt or during the Valsalva procedure.¹²

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Complications and Outcome

The 1-year mortality was 18% to 33% in patients with a cardiac-caused syncope, 0% to 12% for syncope of noncardiac causes, and 6% with syncope of unknown cause.¹³

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Signs and Symptoms

Symptoms of postural intolerance are related to brain anoxia or hypoxia resulting from a reduction of BP. Lightheadedness, dizziness, imbalance, tunnel vision, blurriness, spotted visual field, and headache are symptoms related to brain hypoxia. These symptoms may be aborted by assuming a sitting or supine posture. The occurrence and severity of symptoms are influenced not only by the quantitative drop of BP but also by the rapidity of BP decline. However, in elderly patients with chronic postural hypotension, BP can fall extensively without symptoms, possibly due to adaptive mechanisms affecting cerebral autoregulation. Other symptoms of orthostatic intolerance depend on the underlying etiology including palpitations, chest pain or fatigue. Box 2 lists clinical features suggesting specific etiologies.

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Diagnosis

History

A detailed history from patients and witnesses and a comprehensive physical examination identifies a cause for syncope in up to 50% of cases. It is important to remember conditions simulating syncope such as epileptic seizures, hypoglycemia, or vestibular dysfunction. In a thorough history, questions should cover the event, the week to month before the event, and what happened after the event.

Physical Examination

Careful, comprehensive physical examination is essential. Blood pressure should be checked for both arms and in the supine and standing positions. Signs to look for in the physical examination include dehydration, facial flushing, carotid bruits, cardiac murmurs, abdominal masses, varicose veins, and signs of endocrine disorders in skin, eyes, and thyroid.

Laboratory Testing

Blood work is useful if metabolic disturbance or anemia is suspected, but in general, it has low diagnostic yield.

Electrocardiographic Testing

Although the electrocardiogram (ECG) is often normal on presentation, it is an essential part of the initial evaluation of syncope. Only 5% of initial ECGs are diagnostic. Another 5% suggest an underlying diagnosis. Box 3 lists the European Society of Cardiology Task Force ECG abnormalities, which might suggest an arrhythmia as the etiology of a syncopal event. During the tilt test, T wave changes are common as heart rate increases, and progressive shortening of the PR interval has been observed before cardioinhibitory syncope, but the clinical significance is as yet unclear.^14,15

Holter monitoring has low diagnostic yield, about 2%, in studies of an unselected syncope population. Symptoms and a recorded arrhythmia are often not correlated. Prolonged Holter monitoring of 48 to 72 hours detects more arrhythmias, but not necessarily correlating with symptoms. A negative Holter monitor recording does not exclude arrhythmia as a cause of syncope, because events may be infrequent and sporadic. Patients with a high pretest probability are those with an abnormal resting ECG or evidence of structural heart disease. In these patients, further evaluation maybe necessary, even if the Holter study is negative. The yield of 24-hour Holter monitoring was found to improve when restricted to high-risk patients.¹⁶ One-month external loop recorders were found to add to the diagnostic yield and considered a help in offsetting the cost.¹⁷

Event monitors are diagnostically useful, especially in patients with infrequent episodes or symptoms. Transtelephonic event recorders are activated by the patient, who starts recording when symptoms occur. This event can be stored and transmitted at a later time. A continuous loop event monitor can record up to a few minutes of ECG recording retrospectively when activated by the patient, in addition to recording prospectively. An implantable loop recorder is useful in patients with unexplained syncope and very infrequent events. This device has a life span of 1 to 2 years. It is activated automatically by a rapid heart rate or by the patient or family members applying a magnet.¹⁷

A signal-averaged ECG can be used to determine late ventricular potentials, which act as a substrate for ventricular arrhythmias. This test has a sensitivity of 63% to 89% and a specificity of 89% to 100% for predicting ventricular tachycardia in patients with syncope. This is a useful screening test if ventricular tachycardia is the only concern, but it does not provide additional information that would be obtained during an electrophysiology study.

Imaging

Cerebral imaging is helpful if a neurologic cause is suspected. Evaluation with echocardiography is a Class I recommendation from the American College of Cardiology and American Heart Association (ACC/AHA) if there is clinical suspicious of structural heart disease, and it is a Class IIb recommendation if there in no evidence of heart disease clinically.

Procedural Tests

Stress testing is appropriate in patients with a history of exercise-related arrhythmia or syncope. Stress testing should be avoided in severe patients with symptomatic aortic stenosis and in patients with hypertrophic cardiomyopathy and severe outflow tract obstruction.

Electrophysiology testing has a low yield in patients with a normal ECG, no evidence of structural heart disease, and ejection fraction greater than 40%. Predictors of positive findings include ejection fraction less than 40%, male sex, bundle branch block, history of myocardial infarction, injury, and nonsustained ventricular tachycardia. Overall diagnostic yield is 50% in patients with organic heart disease and 10% in patients without structural heart disease. Electrophysiologic testing is a class I recommendation by the ACC/AHA guidelines for patients with suspected heart disease and unexplained syncope. Criteria for a positive electrophysiology test are listed in  Box 4.

Other, more specialized syncope evaluations include an assessment of global autonomic function. This entails a number of maneuvers, pressor testing, Valsalva maneuver, phenylephrine test, and amyl nitrite inhalation. These are performed while heart rate variability and BP are monitored.

Tilt Table Testing

The tilt table test is a provocative test that moves a patient from a supine to an upright position using a tilt table. It is used to examine autonomic neural regulation of cardiovascular orthostatic responses.¹⁸ Indications for the tilt test are shown in Box 5. Figure 2 shows a tilt table laboratory. Evaluations of the tilt test procedure have shown sensitivity of 32% to 85%, specificity of 75% to 93%, reproducibility of 62% to 85%, and false negative rate of 14%.

Normally, in response to the tilt procedure, a patient experiences gravitational blood pooling in the lower extremities and reduced venous return to the heart, resulting in a decreased mean arterial BP and stroke volume, which leads to deactivation of various mechanoreceptors and activation of renin-angiotensin system (RAS). This leads to an increase in sympathetic outflow, withdrawal of parasympathetic responses, and tachycardia and vasoconstriction.

Susceptible patients can experience vigorous cardiac contractions with relative central hypovolemia due to peripheral blood pooling.¹⁹ This leads to secondary reflex sympathetic withdrawal and increased vagal output, resulting in bradycardia or hypotension, or both, with symptoms.

During the tilt table procedure, the patient is monitored with continuous ECG recording and an automatic sphygmomanometer or beat-by-beat finger arterial pressure recording. The patient is tilted from the supine position to 70 degrees (range, 60-80 degrees) over a period of 45 minutes. Procedure end-points are induction of syncope or presyncope in association with hypotension or bradycardia; change in BP, heart rate, and symptoms; or completion of planned tilt duration.

Various BP and heart rate response patterns to the tilt procedure are recognized, and they reflect the underlying pathophysiologic determinants. Additional testing may be planned according to the tilt response pattern, such as hemodynamic evaluation, blood volume, and autonomic reflex testing. The role of blood volume determination was enhanced by research findings.²⁰ Pharmacophysiologic interventions help differentiation of preganglionic from postganglionic lesions.²¹

Relative contraindications to the tilt test include severe left ventricular outflow tract obstruction, critical mitral stenosis, critical proximal coronary artery stenosis or active angina, and critical cerebrovascular stenosis. Limitations of the head-up tilt test include inability to stand because of leg weakness or pain or because of severe back pain; unstable medical conditions; nability to obtain BP because of incompressible arm arteries, bilateral arm arteriovenous fistulas, or bilateral subclavian artery stenosis; and inability to secure intravenous access.

A normal response to the tilt test is a 10 to 15 beat/min increase in heart rate or a 10% to 15% rise from baseline, a 0 to 10 mm Hg decrease in systolic BP, and a 5 to 10 mm Hg increase in diastolic BP.

Induced abnormal hemodynamic patterns during tilt testing are listed in Box 6.

If the tilt test is negative and the patient’s history suggests a neurocardiogenic etiology of syncope, the patient is subjected to the isoproterenol tilt test. The addition of isoproterenol increases the sensitivity of the tilt test for the diagnosis of vasovagal syncope at the expense of a reduction in the specificity of the test for the same diagnosis.²²

A genetic component in vasovagal syndrome has been considered but is not proved. Pediatric drop attacks with abrupt loss of muscle tone have been described in association with a specific genetic syndrome.²³ Clinical genetic tests to determine patients at high risk for pediatric sudden cardiac death can lead to more aggressive and specific treatment.

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Treatment

Managing the Acute Episode

Family members should learn to recognize early symptoms. They may notice pallor, sweating, lack of concentration, disorientation, and nausea, which suggest postural hypotension and brain hypoperfusion. Convulsions suggest prolonged or severe brain hypoperfusion. Shakiness, which can accompany hyperadrenergic activity, can simulate seizure. The duration of loss of consciousness as well as the position of the patient during loss of consciousness is important information. Urinary incontinence and tongue biting during a spell favor a seizure event.

Helping the patient sit or lie down quickly and raising the legs above the heart level permit faster recovery in patients with a typical reflex postural hypotension event. Physicians should check the pulse for amplitude and rhythm. When a patient recovers the acute event, ambulation should be resumed with care because recurrence of hypotension may be inevitable at this stage due to circulatory instability. Oral hydration with salty fluids usually is helpful in the early recovery phase if the patient has no known previous history of heart disease. Serious arrhythmogenic events, coronary insufficiency syndromes, pulmonary embolism, strokes or transient ischemic attacks, and blood loss must be recognized for proper immediate medical care. Injuries sustained during a sudden fall require immediate attention.

Admission is necessary for syncope that may be secondary to coronary events, pulmonary embolization, stroke, unstable arrhythmias, and syncope-related injuries. Hospital admission is necessary for status epilepticus, need for detoxication, severe dehydration, or hypertensive crises, which may be part of the autonomic failure syndromes or a complication of the treatment given for syncope.

In patients with syncope secondary to structural heart disease, the underlying causes should be treated. Situational syncope is managed with avoidance of triggers and assumption of a supine position with legs raised at the onset of symptoms.

Some patients continue to have recurrent syncope despite treatment, and the etiology of syncope remains uncertain. Such patients require more specialized laboratory workup to determine the predisposing neurocirculatory factors. In some patients, ambulatory monitoring procedures have proved valuable in determining the heart rate events before and during an episode of syncope or orthostatic intolerance. Patients who have multiple or serious comorbid conditions require special treatment programs that can be monitored in a specialized syncope clinic. See Table 1 for the guidelines for syncope treatment based on pathophysiology.

Pharmacologic Treatment

Anticholinergic Agents

Hyoscyamine is used in patients with neurocardiogenic syndrome who have supine bradycardia and evidence of heightened vagal modulation of heart. Disopyramide possesses a vagolytic effect in addition to its class IA antiarrhythmic action It is rarely used to treat simple syncope without arrhythmias. It requires hospitalization and monitoring of QT interval during the initiation of treatment.

Beta Blockers

Either cardioselective or non-cardioselective beta-blockers can be used to treat syncope and orthostatic intolerance.

Calcium Channel Blockers

Non-dihydropyridine calcium channel blockers have been used to slow heart rate and prevent orthostatic tachycardia in patients who cannot tolerate beta-blockers. Verapamil has been used instead of beta-blockers in asthmatic patients.

Fludrohydrocortisone

Fludrohydrocortisone is a synthetic selective mineralocorticoid when used in small doses; it retains salt and water and promotes plasma volume expansion.

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (Paroxetine; Sertraline) can be effective in treating resistant cases of neurocardiogenic syncope.

Vasoconstrictors

Midodrine is an α-adrenergic agonist used for the treatment of autonomic insufficiency and neurocardiogenic syncope. It has been used in combination with beta-blockers and with fludrohydrocortisone. Due to its effect of increasing afterload, it is not advised in hypertension, heart failure, active coronary artery disease, peripheral vascular disease.

Other vasoconstrictors used in the past are sometimes used in the present era such as ephedrine, IM dihydroergotamine, or intra-nasal desmopressin. Other medications tried include ibuprofen with meals, caffeine, and octreotide.

Nonpharmacologic Treatment

Treatment of the individual causes of syncope can be tailored according to the individual diagnosis: neurocardiogenic syncope, carotid sinus syncope, postural hypotension, autonomic failure, and POTS.

Permanent cardiac pacemakers have been tried, but they are rarely used now to treat a vasovagal event. Permanent cardiac pacing is the treatment of choice for the carotid hypersensitivity syndrome.

Compression support stockings help dimish venous pooling. An abdominal binder and small frequent meals are advised in patients with postprandial hypotension.

Physical countermaneuvers and simple postural maneuvers are easy to teach to patients and may be useful in mild orthostatic symptoms, at the very onset of orthostatic symptoms until other interventions are started. During these maneuvers patient should avoid Valsalva straining.

Patients should avoid the triggers such as heat, prolonged standing, decongestants, excess caffeine, large meals, and alcohol. Elevation the head of the bed by 6 to 8 inches can help patients with supine hypertension and postural hypotension.

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Follow-up

Patients with syncope of unknown etiology and without underlying structural heart disease have a favorable outcome compared with those having organic heart disease. These patients should be followed regularly.

Response to treatment can be assessed by noting a patient’s overall improvement of symptoms, standing time, the number of syncopal episodes in a predefined period, the extent of drop in BP during standing, and time to drop in BP during standing.

Patients with syncope and underlying structural heart disease need regular and close follow-up due to increased risk of sudden death. Attention should be paid to potential side effects of therapy, such as supine hypertension in susceptible patients taking midodrine and hypokalemia in patients taking fludrocortisone. Pacemakers and implantable cardiac defibrillators should be checked routinely.

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Prevention and Screening

Recurrence of syncopal episodes may be prevented by patient education and treatment. Patients need to be aware of triggers that can predispose to or precipitate syncopal spells and orthostatic intolerance. There is no definite procedure for screening of subjects for syncope. Practice guidelines are included in the references.

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Summary

• Syncope is a part of a broader network of symptoms that is best described as postural intolerance.
• The interaction between the circulatory system and the autonomic nervous system is crucial to understanding the pathophysiology of syncope.
• Syncope or presyncope occurs as a result of brain anoxia, which is usually secondary to reduction of cerebral perfusion pressure and failure of cerebral circulatory autoregulation.
• The tilt test is an important screening test in the evaluation of postural intolerance and syncope.
• Procedural testing other than the tilt test is also used for determining the cause of syncope.

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Suggested Readings

• Biaggioni I: The sympathetic nervous system and blood volume regulation: Lessons from autonomic failure patients. Am J Med Sci 2007;1(334):61-64.
• Blanc J-J, L’Her C, Touiza A, et al: Prospective evaluation and outcome of patients admitted for syncope over a 1-year period. Eur Heart J 2002;23:815-820.
• Chapleau MW, Lu J, Hajduczok G, Abboud FM: Mechanism of baroreceptor adaptation in dogs: Attenuation of adaptation by the K⁺ channel blocker 4-aminopyridine. J. Physiology [London] 1993;462:291-306.
• Goldschlager N, Epstein AE, Grubb BP, et al; Practice Guidelines Subcommittee, North American Society of Pacing and Electrophysiology: Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med 2003;163:151-162.
• Grubb BP, Gerard G, Rousch K, et al: Differentiation of convulsive syncope and epilepsy with head up tilt table testing. Ann Int Med 1991;115:871-876.
• Ibrahim MH, Tarazi RC, Dustan HP, et al: Idiopathic orthostatic hypotension: Circulatory dynamics in chronic autonomic insufficiency. Am J Cardiol 1974;34: 288-294.
• Lipsitz LA, Wei JY, Rowe JW: Syncope in an elderly, institutionalized population: Prevalence, incidence, and associated risk. Q J Med 1985;55:45-55.
• Mathias CJ: Role of autonomic evaluation in the diagnosis and management of syncope. Clin Autonom Res 2004;14(Suppl 1):45-54.
• Raj S, Robertson D: Blood volume perturbations in the postural tachycardia syndrome. Am J Med Sci 2005;1(334):57-60.
• Tarazi RC, Fouad FM: Circulatory dynamics in autonomic failure. In Bannister R (ed): Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford: Oxford University Press, 1983, pp 96-114.

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