Hypotension and Syncope

HUGH CALKINS
DOUGLAS P. ZIPES

Syncope is a sudden transient loss of consciousness and postural tone with spontaneous recovery. Loss of consciousness results from a reduction of blood flow to the reticular activating system located in the brain stem and does not require electrical or chemical therapy for reversal. The metabolism of the brain, in contrast to that of many other organs, is exquisitely dependent on perfusion. Consequently, cessation of cerebral blood flow leads to loss of consciousness within approximately 10 seconds. Syncope is an important clinical problem because it is common, is costly, is often disabling, may cause injury, and may be the only warning sign before sudden cardiac death.[1] [2] [3] [4] [14A] [21A] [21B] [28A] Patients with syncope account for 1 percent of hospital admissions and 3 percent of emergency department visits.[1] Elderly persons have a 6 percent annual incidence of syncope. Surveys of young adults have revealed that up to 50 percent report a prior episode of loss of consciousness, most of which are isolated events that never come to medical attention. The annual cost of evaluating and treating patients with syncope has been estimated to be $800 million dollars.[2] Patients who experience syncope also report a markedly reduced quality of life, similar to that experienced by patients with chronic diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease.[3]
CLASSIFICATION OF THE CAUSES OF SYNCOPE
The causes of syncope can be classified into four primary groups: vascular, cardiac, neurologic/cerebrovascular, and metabolic/miscellaneous (Table 27-1) . Vascular causes of syncope can be further subdivided into anatomical, orthostatic, and reflex-mediated causes. A similar approach to subclassification of the causes of syncope can be applied to the other three diagnostic groups. The probable cause of syncope can be identified in approximately 75 percent of patients.[5] [6]
Vascular Causes of Syncope
Vascular causes of syncope, particularly reflex-mediated syncope and orthostatic hypotension, are by far the most common causes of syncope, accounting for at least one third of all syncopal episodes. In contrast, subclavian steal syndrome is an exceedingly uncommon cause of syncope, accounting for less than 0.1 percent of syncopal episodes.
Orthostatic Hypotension
When a person stands, 500 to 800 ml of blood is displaced to the abdomen and lower extremities, resulting in an abrupt drop in venous return to the heart. This leads to a decrease in cardiac output and stimulation of aortic, carotid, and cardiopulmonary baroreceptors that trigger a reflex increase in sympathetic outflow. As a result, heart rate, cardiac contractility, and vascular resistance increase to maintain a stable systemic blood pressure on standing.[7] Orthostatic hypotension, which is defined as a 20-mm Hg drop in systolic blood pressure or a 10-mm Hg drop in diastolic blood pressure within 3 minutes of standing, results from a defect in any portion of this blood pressure control system.[8] Orthostatic hypotension may be asymptomatic or may be associated with symptoms such as lightheadedness, dizziness, blurred vision, weakness, palpitations, tremulousness, and syncope. These symptoms are often worse immediately on arising in the morning and/or after meals or exercise. Syncope that occurs after meals, particularly in the elderly, may result from a redistribution of blood to the gut. A decline in systolic blood pressure of about 20 mm Hg approximately 1 hour after eating has been reported in up to one third of elderly nursing home residents.[9] Although usually asymptomatic, it may result in lightheadedness or syncope.
Drugs that either cause volume depletion or result in vasodilation are the most common cause of orthostatic hypotension (Table 27-2) . Elderly patients are particularly susceptible to the hypotensive effects of drugs because of reduced baroreceptor sensitivity, decreased cerebral blood flow, renal sodium wasting, and an impaired thirst mechanism that develops with aging.[10] Orthostatic hypotension may also result from neurogenic causes, which can be subclassified into primary and secondary autonomic failure.[8] [11] Primary causes are generally idiopathic, whereas secondary causes are associated with a known biochemical or structural anomaly or are seen as part of a particular disease or syndrome. There are three types of primary autonomic failure. Pure autonomic failure (Bradbury-Eggleston syndrome) is an idiopathic sporadic disorder characterized by orthostatic hypotension, usually in conjunction with evidence of more widespread autonomic failure such as disturbances in bowel, bladder, thermoregulatory, and sexual function. Patients with pure autonomic failure have reduced supine plasma norepinephrine levels. Multiple system atrophy (Shy-Drager syndrome) is a sporadic, progressive, adultonset disorder characterized by autonomic dysfunction, parkinsonism, and ataxia in any combination. The third type of primary autonomic failure is Parkinson's disease with autonomic failure. A small subset of patients with Parkinson's disease may also develop autonomic failure, including orthostatic hypotension. In addition to these forms of chronic autonomic failure is a rare acute panautonomic neuropathy.[12] This generally presents in young people and results in a widespread severe sympathetic and parasympathetic failure with orthostatic hypotension, loss of sweating, disruption of bladder and bowel function, fixed heart rate, and fixed dilated pupils.
Postural orthostatic tachycardia syndrome (POTS) is a milder form of chronic autonomic failure and orthostatic intolerance characterized by the presence of symptoms of orthostatic intolerance, a 28-beats/min or greater increase in heart rate, and the absence of a significant change in blood pressure within 5 minutes of standing or upright tilt.[13] [14] POTS appears to result from a failure of the peripheral vasculature to appropriately vasoconstrict under orthostatic

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ETIOLOGIES OF SYNCOPE
Vascular
Anatomical
Subclavian steal
Orthostatic
Drug-induced
Hypovolemia
Primary disorders of autonomic failure
Pure autonomic failure (Bradbury-Eggleston syndrome)
Multiple system atrophy (Shy-Drager syndrome)
Parkinson's disease with autonomic failure
Secondary neurogenic
Postprandial (in the elderly)
Postural orthostatic tachycardia syndrome (POTS)
Reflex-mediated
Neurally mediated syncope/vasovagal syncope
Carotid sinus hypersensitivity
Situational (cough, defecation, micturition, swallow)
Glossopharyngeal syncope
Trigeminal neuralgia


Cardiac
Anatomical
Aortic dissection
Aortic stenosis
Atrial myxoma
Cardiac tamponade
Hypertrophic cardiomyopathy
Mitral stenosis
Myocardial ischemia/infarction
Pulmonary embolism
Pulmonary hypertension
Arrhythmias
Bradyarrhythmias
Atrioventricular block
Pacemaker malfunction
Sinus node dysfunction/bradycardia
Tachyarrhythmias
Supraventricular tachycardia
Ventricular tachycardia
Torsades de pointes/long QT syndrome


Neurological/Cerebrovascular
Arnold Chiari malformation
Migraine
Seizures (partial complex, temporal lobe)
Transient ischemic attack/vertebrobasilar insufficiency/cerebrovascular accident


Metabolic/Miscellaneous
Metabolic
Hyperventilation (hypocapnea)
Hypoglycemia
Hypoxemia
Drugs/alcohol
Miscellaneous
Psychogenic syncope
Hysterical
Panic disorder
Anxiety disorder
Cerebral syncope
Hemorrhage
Unknown


stress. POTS may also be associated with syncope due to neurally mediated hypotension (see later). In some patients, the postural orthostatic tachycardia syndrome may result from an abnormality in the clearance of norepinephrine from the synaptic cleft.[14A] Approximately 90 percent of norepinephrine that is released into the synaptic cleft is cleared by uptake into the neuron by the norepinephrine transporter. A recent report identified a mutation in the norepinephrine transporter gene in a family with several affected family members.[14A]
REFLEX-MEDIATED SYNCOPE.
There are many reflex-mediated

AUSES OF ORTHOSTATIC HYPOTENSION
Drugs
Diuretics
Alpha-adrenergic blocking drugs
Terazosin (Hytrin), labetalol
Adrenergic neuron blocking drugs
Guanethidine
Angiotensin-converting enzyme inhibitors
Antidepressants
Monoamine oxidase inhibitors
Alcohol
Diuretics
Ganglion-blocking drugs
Hexamethonium, mecamylamine
Tranquilizers
Phenothiazines, barbiturates
Vasodilators
Prazosin, hydralazine, calcium channel blockers
Centrally acting hypotensive drugs
Methyldopa, clonidine


Primary Disorders of Autonomic Failures
Pure autonomic failure (Bradbury-Eggleston syndrome)
Multiple system atrophy (Shy-Drager syndrome)
Parkinson's disease with autonomic failure


Secondary Neurogenic
Aging
Autoimmune disease
Guillain-Barre syndrome, mixed connective tissue disease, rheumatoid arthritis
Eaton-Lambert syndrome, systemic lupus erythematosus
Carcinomatosis autonomic neuropathy
Central brain lesions
Multiple sclerosis, Wernicke's encephalopathy
Vascular lesions or tumors involving the hypothalmus and midbrain
Dopamine beta-hydroxylase deficiency
Familial hyperbradykinism
General medical disorders
Diabetes, amyloid, alcoholism, renal failure
Hereditary sensory neuropathies, dominant or recessive
Infections of the nervous system
Human immunodeficiency virus infection, Chagas' disease, botulism, syphillis, botulism
Metabolic disease
Vitamin B12 deficiency, porphyria, Fabry's disease, Tangier disease
Spinal cord lesions
Adapted from Bannister SR (ed): Autonomic Failure. 2nd ed. Oxford, Oxford University Press, 1988, p 8.


syncopal syndromes (see Table 27-1) . In each case, the reflex is composed of a trigger (the afferent limb) and a response (the efferent limb). This group of reflex-mediated syncopal syndromes has in common the response limb of the reflex, which consists of increased vagal tone and a withdrawal of peripheral sympathetic tone and leads to bradycardia, vasodilation, and, ultimately, hypotension, presyncope, or syncope. What distinguishes these causes of syncope are the specific triggers. For example, micturition syncope results from activation of mechanoreceptors in the bladder; defecation syncope results from neural inputs from gut wall tension receptors; and swallowing syncope results from afferent neural impulses arising from the upper gastrointestinal tract. The two most common types of reflex-mediated syncope, carotid sinus hypersensitivity and neurally mediated hypotension, are discussed later.
The termneurally mediated hypotension/syncope (also known as neurocardiogenic, vasodepressor, and vasovagal syncope and as "fainting") has been used to describe a common abnormality of blood pressure regulation characterized by the abrupt onset of hypotension with or without

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bradycardia. Triggers associated with the development of neurally mediated syncope are those that either reduce ventricular filling or increase catecholamine secretion. These include the sight of blood, pain, prolonged standing, a warm environment or hot shower, and stressful situations. Under these types of situations, patients with this condition develop severe lightheadedness and/or syncope. It has been proposed that these clinical phenomena result from a paradoxical reflex that is initiated when ventricular preload is reduced by venous pooling. This leads to a reduction in cardiac output and blood pressure, which is sensed by arterial baroreceptors. The resultant increased catecholamine levels, combined with reduced venous filling, leads to a vigorously contracting volume-depleted ventricle. The heart itself is involved in this reflex by virtue of the presence of mechanoreceptors, or C-fibers, consisting of nonmyelinated fibers found in the atria, ventricles, and the pulmonary artery.[15] [16] [17] [18] [19] It has been proposed that vigorous contraction of a volume-depleted ventricle leads to activation of these receptors in susceptible individuals. These afferent C-fibers project centrally to the dorsal vagal nucleus of the medulla, leading to a "paradoxic" withdrawal of peripheral sympathetic tone and an increase in vagal tone, which, in turn, causes vasodilation and bradycardia. The ultimate clinical consequences are syncope or presyncope. Not all neurally mediated syncope results from activation of mechanoreceptors. In humans, it is well known that the sight of blood or extreme emotion can trigger syncope. These observations suggest that higher neural centers can also participate in the pathophysiology of vasovagal syncope. In addition, central mechanisms can contribute to the production of neurally mediated syncope.[18] [20]
Syncope due to carotid sinus hypersensitivity results from stimulation of carotid sinus baroreceptors, which are located in the internal carotid artery above the bifurcation of the common carotid artery. This condition is diagnosed by applying gentle pressure over the carotid pulsation just below the angle of the jaw, where the carotid bifurcation is located. Pressure should be applied unilaterally for approximately 5 seconds, after first listening for a carotid bruit. It has recently been reported that the sensitivity of diagnosing carotid sinus hypersensitivity can be increased, with no change in specificity, by performing carotid sinus massage during 60- or 70-degree upright tilt.[21A] [21B] The normal response to carotid sinus massage is a transient decrease in the sinus rate and/or slowing of atrioventricular (AV) conduction. Three types of abnormal responses have been described: (1) the cardioinhibitory response, characterized by marked bradycardia (>3-second pause); (2) the vasodepressor type, characterized by a 50-mm Hg fall in the systolic blood pressure in the absence of bradycardia; and (3) the mixed response. Carotid sinus hypersensitivity is commonly detected in patients with syncope. One study reported the presence of carotid sinus hypersensitivity in 65 of 279 patients (23 percent) who presented to the emergency department with falls.[21] It is important to recognize that carotid sinus hypersensitivity is also commonly observed in asymptomatic elderly patients, with carotid sinus hypersensitivity identified in one study in more than one third of asymptomatic patients undergoing cardiac catheterization for coronary artery disease. Because of this, the diagnosis of carotid sinus hypersensitivity should be approached cautiously after excluding alternative causes of syncope.
Cardiac Causes of Syncope
Cardiac causes of syncope, particularly tachyarrhythmias and bradyarrhythmias, are the second most common causes, accounting for 10 to 20 percent of syncopal episodes. Ventricular tachycardia is the most common tachyarrhythmia that can cause syncope. Supraventricular arrhythmias can also cause syncope, although the great majority of patients with supraventricular arrhythmias present with less severe symptoms such as palpitations, dyspnea, and lightheadedness. Bradyarrhythmias that can result in syncope include sick sinus syndrome as well as AV block. Anatomical causes of syncope result from obstruction to blood flow, such as a massive pulmonary embolus, an atrial myxoma, and/or aortic stenosis.
Neurological Causes of Syncope
Neurological causes of syncope, including migraines, seizures, Arnold Chiari malformations, and transient ischemic attacks, are surprisingly uncommon causes of syncope, accounting for less than 10 percent of all cases of syncope. The majority of patients in whom a "neurological" cause of syncope is established are found in fact to have had a seizure rather than true syncope.[5]
Metabolic/Miscellaneous Causes of Syncope
Metabolic causes of syncope are rare, accounting for less than 5 percent of syncopal episodes. The most common metabolic causes of syncope are hypoglycemia, hypoxia, and hyperventilation. The establishment of hypoglycemia as the cause of syncope requires demonstration of hypoglycemia during the syncopal episode. Although the mechanism of hyperventilation-induced syncope has been generally considered to be due to a reduction in cerebral blood flow, a recent study demonstrated that hyperventilation alone was not sufficient to cause syncope. This suggests that hyperventilation-induced syncope may also have a psychological component.[22] Psychiatric disorders may also cause syncope. It has been reported that up to 25 percent of patients with syncope of unknown origin may have psychiatric disorders for which syncope is one of the presenting symptoms.[23] Cerebral syncope is a rare, recently described cause of syncope resulting from cerebral vasoconstriction induced by orthostatic stress.[24]
Relationship Between Prognoses and the Cause of Syncope
The prognosis of patients with syncope varies greatly with diagnosis. Syncope of unknown origin or syncope due to a noncardiac etiology (including reflex mediated syncope) is generally associated with a benign prognosis. In contrast, syncope due to a cardiac cause is associated with a 30 percent mortality at 1 year.
DIAGNOSTIC TESTS
Identification of the precise cause of syncope is often challenging. Because syncope usually occurs sporadically and infrequently, it is extremely difficult to either examine a patient or obtain an electrocardiogram (ECG) during an episode of syncope. For this reason, the primary goal in the evaluation of a patient with syncope is to arrive at a presumptive determination of the cause of syncope.
History and Physical Examination
The history and physical examination is the most important component of the evaluation of a patient with syncope.[5] [25] [26] [27] In one prospective series of 433 patients a diagnosis was established based on the history and physical examination in 144 patients, representing 58 percent of those patients in whom a diagnosis was established.[5] When taking a clinical history, particular attention should then be focused on (1) determining if the patient experienced true syncope as compared with a transient alteration in consciousness without loss of postural tone; (2) determining if the patient has a history of cardiac disease or if a family history of cardiac disease, syncope, or sudden death exists;

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DIFFERENTIATING SYNCOPE DUE TO NEURALLY MEDIATED HYPOTENSION, ARRHYTHMIAS, AND SEIZURES

NEURALLY MEDIATED HYPOTENSION
ARRHYTHMIAS
SEIZURE
Demographics/Clinical Setting
Female>male gender
Younger age (<55 yr)
More episodes (>2)
Standing, warm room, emotional upset
Male>female gender
Older age (>54 yr)
Fewer episodes (<3)
Any setting
Younger age (<45 yr)
Any setting


Premonitory Symptoms
Longer duration (>5 sec)
Palpitations
Blurred vision
Nausea
Warmth
Diaphoresis
Lightheadedness
Shorter duration (<6 sec)
Palpitations less common
Sudden onset or brief aura
(deja vu, olfactory, gustatory, visual)


Observations During the Event
Pallor
Diaphoretic
Dilated pupils
Slow pulse, low blood pressure
Incontinence may occur
Brief clonic movements may occur
Blue, not pale
Incontinence can occur
Brief clonic movements can occur
Blue face, no pallor
Frothing at the mouth
Prolonged syncope (duration >5 minutes)
Tongue biting
Horizontal eye deviation
Elevated pulse and blood pressure
Incontinence more likely*
Tonic clonic movements if grand mal


Residual Symptoms
Residual symptoms common
Prolonged fatigue common (>90%)
Oriented
Residual symptoms uncommon (unless prolonged unconsciousness)
Oriented
Residual symptoms common
Aching muscles
Disoriented
Fatigue
Headache
Slow recovery