By definition, syncope is a

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1 Approach to the Patient with Syncope: History and Physical Examination Are Key Nora Goldschlager, MD CARDIOLOGY ABSTRACT Syncope, the transient loss of consciousness that occurs due to inadequate cerebral perfusion, has many underlying etiologies, both cardiac and noncardiac. Common conditions, such as vasovagal syncope, carotid sinus syndrome, orthostatic hypotension, and primary autonomic nervous system failure, are discussed. The cardiac causes, however, are responsible for the significant morbidity and mortality observed in all age groups and populations. Syncope accounts for 3% to 5% of emergency department visits and up to 6% of hospital visits annually in the United States. A detailed history and physical examination are key in determining the cause and planning the subsequent management of syncope. It is critical to distinguish between true syncope and other conditions that may be misdiagnosed as syncope, such as seizures and other neuropsychiatric episodes. Differential diagnosis via selection of appropriate diagnostic tests and management of the common causes of syncope, including those in special populations, such as athletes and the elderly, are the focus of this review. (Adv Stud Med. 2003;3(5): ) By definition, syncope is a symptom, not a disease. Finding the cause of this symptom, which can present in myriad conditions, is a challenge to the clinician. Syncope refers to a transient loss of consciousness and of postural tone at the same time. Both events occur together when the brain fails to receive sufficient perfusion and, hence, insufficient oxygen and glucose. The constellation of other symptoms that may or may not accompany syncope is fundamental in guiding the clinician as to its underlying etiology. Although syncope is usually brief in duration with spontaneous recovery, patients and their families may be legitimately anxious about its occurrence because it may herald a condition that can be associated with serious morbidity or sudden death. Even if it occurs as a result of a benign process, unpredictable loss of consciousness can be the cause of other trauma as a result of falls, motor vehicle accidents, and similar events. In addition, the search for answers as to what precipitated the syncopal event may require lengthy, costly, and sometimes invasive diagnostic workups that fail to lead to a definitive diagnosis in 30% to 40% of patients. 1,2 EPIDEMIOLOGY AND PATHOPHYSIOLOGY EPIDEMIOLOGY: A PERVASIVE PROBLEM Data from the Framingham study (n = 5209 community-dwelling men and women) indicate that at least 3% of the population will have a syncopal event within a 26-year period, and that 30% will have more than one event. 3 Prognosis is not necessarily malign or benign if syncope recurs. As individuals age, prevalence increases; the Dr Goldschlager is Professor of Clinical Medicine, University of California at San Francisco, and Director, Coronary Care Unit, Electrocardiography, and Pacemaker Labs, San Francisco General Hospital, San Francisco, California. Dr Goldschlager reports she receives honoraria from Guidant Corporation; Medtronic, Inc; Siemens Pacesetter, Inc; Pfizer, Inc; and Wyeth. Off-Label Product Discussion: The author of this article does not include information on off-label use of products. Correspondence to: Nora Goldschlager, MD, San Francisco General Hospital, 1001 Potrero Avenue, 5G1, San Francisco, CA Advanced Studies in Medicine 265

2 CARDIOLOGY annual incidence of syncope in the elderly is approximately 6%. 4 Furthermore, in the United States, 3% to 5% of emergency department visits and up to 6% of hospital admissions annually are for patients who receive a diagnosis of syncope. 1 In total, approximately 1 million patients are evaluated for syncope each year in the United States. 5 These statistics probably underestimate the actual incidence because many individuals who experience a solitary episode of syncope do not seek medical attention. It is safe to say that syncope is very common, crosses all age groups, and has varying significance depending on the age of the patient. Figure 1. Real or Apparent Transient Loss of Consciousness Reprinted with permission from Task Force on Syncope, European Society of Cardiology. Eur Heart J. 2001;22: Copyright 2001 with permission from Elsevier. PHYSIOLOGY AND PATHOPHYSIOLOGY Neurological and cardiovascular functions maintain consciousness and the ability to stand upright. Upright posture causes pooling of blood in the lower extremities due to gravity. With upright stance, output to the brain decreases and muscle stretch decreases. The body detects these changes to blood pressure and compensates via the baroreceptors, which are sensitive to stretch. Baroreceptors are located in the carotid sinuses, aortic arch, great veins, right atrium, and both ventricles of the heart. Depending on the degree of stretch sensed by the body s receptors, sensory impulses are conducted to the vasomotor center in the medulla and then to the hypothalamus. The sympathetic and parasympathetic branches of the autonomic nervous system mediate these responses back to the heart and blood vessels. (Arterial baroreceptors respond to increases in blood pressure; cardiopulmonary baroreceptors mediate changes in blood volume.) If blood pressure or volume is low, the sympathetic nervous system responds by increasing cardiac output (increased heart rate and stroke volume) as well as by causing selective vasoconstriction at the arteriolar level. Blood pressure rises due to these conditions of increased peripheral resistance, and eventually, a negative feedback loop returns the body to baseline status. 6 Chemoreceptors that regulate cerebral vasodilatation (depending on ph, and on concentrations of oxygen and carbon dioxide) and renal and endocrine system functions also play a role in maintaining adequate circulation and, hence, cerebral perfusion. Syncope results when blood flow to the brain is inadequate to sustain consciousness. Cessation of perfusion for as few as 6 or 8 seconds has been shown to cause loss of consciousness. 7 Inadequate perfusion may be a result of decreased cardiac output (due to hypovolemia, structural defects in the heart, such as valvular heart disease, or arrhythmias), cerebrovascular atherosclerosis, or a neurally mediated decrease in heart rate, blood pressure, or both. Vasodilation decreases total peripheral vascular resistance, another major mechanism in fainting that may occur in reflex syncope, hyperthermia, and with certain medications. Syncope may be caused by malfunctioning of the body s normal protective mechanisms, autonomic nervous system responses, cardiovascular disease, or outside influences (such as medications or blood loss from trauma). However, a variety of conditions that range from epilepsy to metabolic states, such as hypoglycemia, may at first appear to be syncope. These conditions must be ruled out in the diagnostic workup to distinguish true syncope. ARRIVING AT A DIAGNOSIS: WHAT SYNCOPE IS AND WHAT IT IS NOT The European Society of Cardiology s Task Force on Syncope has classified transient unconscious states (Figure 1). In addition, eliciting a good history from patients is essential to determine whether true loss of consciousness occurred or the patient experienced near-syncope (presyncope), dizziness, vertigo, or a drop attack (a fall without loss of consciousness). 8 Several studies have compared various investigations that aimed at diagnosing syncope.the clear outcome of these meta-analyses has been that patient history and physical examination are key to 266 Vol. 3, No. 5 May 2003

3 SYNCOPE determining whether syncope did occur and determining the cause of documented syncopal events. 1,2 The Eastbourne Syncope Assessment Study performed a retrospective analysis of 1334 cases coded as syncope in a hospital in the United Kingdom during Of these patients, it was established that 660 patients (mean age, 64 years) had suffered an episode of syncope, and 40% of those had experienced recurrent syncope. In 61% of cases, the diagnosis could be made on the basis of a detailed history and physical examination alone. In the Eastbourne protocol, physical examination included lying and standing blood pressures, 12-lead electrocardiogram (ECG), complete blood count, plasma glucose, urea, and electrolyte studies. If this protocol failed to determine a cause, investigators found that 7-day external cardiac event recorders activated by the patient and tilt testing were 5 times more likely to diagnose syncope compared with Holter monitoring; they were 50 times more likely to diagnose the problem compared with echocardiography and computed axial tomography (CT) scan. Electroencephalography (EEG), chest radiography, electrophysiologic studies, and coronary angiography yielded extremely little information in patients without focal neurologic or cardiac signs following the taking of history and a physical examination. Kapoor arrived at similar findings in a US population of 433 patients with syncope. 2 The results showed that history, physical examination, and ECG most frequently determined the cause of syncope, when a cause could be determined (cause was undetermined 41% of the time). When these steps alone did not make the cause of syncope evident, they frequently led clinicians toward a probable diagnosis and selection of more extensive noninvasive and/or invasive diagnostic testing. For example, an abnormal ECG might direct a clinician toward event monitoring, cardiac catheterization, radionuclide studies, stress testing, and/or electrophysiologic testing. Signs and symptoms suggestive of seizure activity might indicate EEG or CT scanning, whereas a vasovagal presentation might result in headupright tilt table testing. In 1997, Linzer et al reviewed the literature that covered diagnostic testing for syncope. 9 The investigators included studies conducted in at least 10 patients with syncope or near-syncope beginning in Again, this meta-analysis confirmed history, physical examination, and ECG to have the highest yield and to be the most cost effective. 9 CLUES FROM THE HISTORY Asking the right questions is crucial in evaluating patients with syncope (Table 1). First, the patient and any witnesses should be asked to report what happened. Sudden and complete loss of consciousness without any warning or finding the patient in the supine position suggests a cardiac cause, whereas the presence of a prodrome may incline the clinician toward either a seizure (not syncope) or a vasovagal event, depending on the accompanying prodromal symptoms. If the patient reports feeling flushed, diaphoretic, nauseated, and/or weak and dizzy prior to loss of consciousness, or if the environment was somehow emotionally or physically uncomfortable, a vasovagal episode is the likely cause. In contrast, if the prodrome included an aura, the clinician should proceed with a workup for seizure. The patient should be asked questions regarding any precipitating factors. For example, a sudden change of posture (from lying to standing) may cause syncope in persons with orthostatic hypotension, whereas exercise-induced syncope may occur in the presence of certain cardiac conditions. In elderly patients with carotid sinus syn- Table 1. Clues to the Etiology of Syncope from the Physical Examination Questions about circumstances immediately prior to attack Position (supine, sitting, or standing) Activity (rest, change in posture, during or after exercise, during or immediately after urination, defecation, cough, or swallowing) Predisposing factors (eg, crowded or warm places, prolonged standing, postprandial period) and precipitating events (eg, fear, intense pain, neck movements) Questions about onset of attack Nausea, vomiting, abdominal discomfort, feeling of cold, sweating, aura, pain in neck or shoulders, blurred vision Questions about attack (eyewitness) Way of falling (slumping or keeling over), skin color (pallor, cyanosis, flushing), duration of loss of consciousness, breathing pattern (snoring), movements (tonic, clonic, tonic-clonic or minimal myoclonus, automatism) and their duration, onset of movement in relation to fall, tongue biting Questions about end of attack Nausea, vomiting, sweating, feeling of cold, confusion, muscle aches, skin color, injury, chest pain, palpitations, urinary or fecal incontinence Questions about background Family history of sudden death, congenital arrhythmogenic heart disease or fainting Previous cardiac disease Neurological history (parkinsonism, epilepsy, narcolepsy) Metabolic disorders (diabetes, etc) Medication (antihypertensives, antianginal agents, antidepressants, antiarrhythmic agents, diuretics, and QT-interval prolonging agents) (In case of recurrent syncope) Information on recurrences, such as time from first syncopal episode and the number of episodes Reprinted with permission from Task Force on Syncope, European Society of Cardiology. Eur Heart J. 2001;22: Copyright 2001 with permission from Elsevier. Advanced Studies in Medicine 267

4 CARDIOLOGY drome, turning the head or performing a Valsalva maneuver may cause syncope. Next, a history of medication use should be obtained. Table 2 lists some drugs that may cause syncope and the mechanisms by which they act. 10,11 The patient should be asked about other medical conditions he or she may have, such as diabetes, epilepsy, or narcolepsy. Family history of sudden death should also be determined, because certain genetically based cardiac anomalies may present with syncope or sudden death. Finally, how an attack ends may be just as significant as how it begins. The patient or witnesses should be questioned as to how the patient behaved when regaining consciousness. Prolonged Table 2. Categories of Drugs that May Cause Syncope Agents that cause hypotension Antihypertensive agents Diuretics Nitrates Agents that influence cardiac output Beta blocking agents Digitalis Agents that prolong QT interval Antianginal agents (Bepridil) Antiarrhythmic agents (Amiodarone, disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol) Anesthetics/antiasthmatics (Adrenaline, epinephrine) Antibiotics (Azithromycin, clarithromycin, erythromycin, fluconazole, gatifloxacin, itraconazole, ketoconazole, moxifloxacin, sparfloxacin, trimethoprim) Antihistamines (Astemizole, clemastine fumarate, diphenhydramine hydrochloride) Antihyperlipidemics (Cholestyramine, colestipol hydrochloride) Anti-infectives (Pentamidine) Calcium channel blocking agents Central nervous system drugs (eg, antidepressants and antipsychotics) (Chlorpromazine, haloperidol, mesoridazine, tricyclic antidepressants, thioridazine) Toxins (eg, arsenic, organophosphate insecticides) Miscellaneous (Anabolic steroids, cocaine, ipecac, liquid protein diets, sumatriptan) Miscellaneous agents known to cause cardiac arrest/arrhythmias (Chinese herbs [eg, glycyrrhiza glabra, aconite alkaloids, ephedra alkaloids]) Agents associated with altered sensorium (Alcohol, cocaine) Data from Goldschlager et al 10 and Morag et al. 11 confusion, sleepiness, or incontinence mandates a neurologic evaluation for seizures. Table 3 lists various cardiac and noncardiac causes of syncope, along with common signs and symptoms. 7,8 CLUES FROM THE PHYSICAL EXAMINATION AND LABORATORY EVALUATION A thorough cardiac examination (including 12- lead ECG) and neurological and psychiatric examinations add probably the most vital pieces to the syncope puzzle that physical examination can provide (Table 4). Detection of a heart murmur or gallop, abnormal rhythm, carotid bruit, focal neurologic sign, or an evaluation that mental status is impaired will separate those patients requiring more extensive cardiovascular or neurological testing. In these cases, echocardiography, stress testing, cardiac catheterization, external or implantable devices for event monitoring, and electrophysiologic testing are the cardiac tests that may be required to rule out a structural anomaly, coronary artery disease (CAD), or arrhythmia. Conventional Holter monitoring is not recommended because of the extremely low yield and questionable accuracy obtained from such shortterm recording. 7 CT scan, magnetic resonance imaging (MRI) and/or EEG should be used only when seizure disorder or stroke is suspected, because it is extremely rare for seizures or cerebrovascular attacks to present as syncope. Although carotid Doppler ultrasonography has been suggested, no studies confirm its value, and carotid artery transient ischemic attacks (TIAs), like cerebrovascular attacks, are not associated with loss of consciousness. 7 Carotid sinus syndrome may best be evaluated by performing carotid sinus massage in the appropriate candidates. Head-upright tilt table testing with or without administering medication to augment the effects of gravity may achieve reproducible vasovagal syncope. Finally, standard blood tests should be employed when a metabolic cause is suspected (eg, by obtaining plasma glucose levels in the case of possible diabetes, electrolytes for dehydration, or a complete blood count for hemorrhage). Abnormal metabolic states more often cause confusion, dizziness, or lightheadedness rather than true loss of consciousness. CAUSES OF SYNCOPE When the syncopal episode is transient or from a reversible cause, no further workup is necessary. However, once it has been established that an episode is truly syncope, further evaluation is needed to differentiate the underlying etiology (Figure 2), because more significant findings mandate referral to a cardiac electrophysiologist (Table 5). 268 Vol. 3, No. 5 May 2003

5 SYNCOPE The principle distinction that will guide management of syncope is whether the cause of the syncope is cardiac or noncardiac. Although cardiac syncope is more serious, because it includes organic heart disease (eg, aortic stenosis, pulmonary hypertension, pulmonary embolism, or myocardial infarction [MI]) and arrhythmias, it is less common compared with noncardiac syncope. The cause of syncope was unknown in 34% of cases studied by Linzer et al; the cause unknown category was larger than the cardiac or noncardiac cause categories. 9 NONCARDIAC CAUSES Linzer et al reported that neurally mediated syncope (including vasovagal syncope, situational syncope, and carotid sinus syncope) is the most common etiology. 9 Other noncardiac causes of syncope include orthostatic hypotension, neurological disease, medication-induced syncope, and psychiatric disorders. As with Linzer et al, Kapoor s study of 433 hospitalized patients failed to determine a cause in the majority of cases (41%); noncardiac causes (ie, vasovagal, carotid sinus syndrome, situational, drugrelated, orthostatic, and psychiatric) were the cause in 33%, and the remaining 25% had cardiac conditions. 2 The following sections discuss the most common categories of syncope, including specific indications of any specialized testing, as well as management for both noncardiac and cardiac causes of syncope. In general, EEGs, MRIs, and CT scans should be reserved for patients with focal neurologic signs and symptoms as opposed to those in whom syncope is the more likely scenario. NEURALLY MEDIATED SYNCOPE Vasovagal Syncope. Vasovagal or neurocardiogenic syncope (the common fainting spell) is by far the most common type of syncope, diagnosed in 40% of outpatient cases. 5 It is also the most enigmatic. Difficult to diagnose, vasovagal syncope often costs thousands of dollars per patient for unnecessary diagnostic tests without the physician being able to fully elucidate the specific underlying mechanism or mechanisms. Excessive venous pooling, which decreases venous return to the right side of the heart, is often thought to initiate the Bezold-Jarisch reflex (Figure 3), one proposed trigger for syncope. Instead of the normal physiologic compensation that vasoconstriction and tachycardia would accomplish, there is a paradoxical parasympathetic response and a withdrawal of sympathetic tone that lead to vasodilatation, bradycardia, hypotension, and loss of consciousness. 5 Other triggers may include serotonin, adenosine, opioids, beta-endorphins, and emotional stress that elicit responses from the higher central nervous system. 5 Whatever the mechanism, vasovagal syncope generally does not confer great risk of mortality, 12 although it may sometimes confer risk of injury from first fainting and then falling. When vasovagal syncope occurs as a 1-time or rare event and doesn t result in damage, treatment is generally not necessary Table 3. Clinical Features Suggestive of Specific Causes of Syncope Symptom or Finding Episodes occur after sudden unexpected pain, fear, or unpleasant sight, sound, or smell Episodes occur after prolonged standing at attention Episodes occur in a well-trained athlete without heart disease after exertion Episodes occur during or immediately after micturition, cough, swallowing, or defecation Syncope is accompanied by throat or facial pain (glossopharyngeal or trigeminal neuralgia) Episodes occur with head rotation or pressure on carotid sinus (eg, due to tumors, shaving, or tight collars) Episodes occur immediately on standing Patient takes medications that may lead to a long QT interval or orthostasis and bradycardia Syncope is associated with headaches Syncope is associated with vertigo, dysarthria, or diplopia Episodes occur with arm exercise Patient is confused after episode, or loss of consciousness lasts longer than 5 min Differences are found in blood pressure or pulse between the 2 arms Syncope and murmur occur with changes of position (from sitting to lying, bending, turning over in bed) Syncope occurs with exertion Patient has a family history of sudden death Patient has a brief loss of consciousness with no prodrome and has heart disease Patient has frequent syncope with somatic symptoms but no heart disease Diagnosis to Consider Vasovagal attack Vasovagal attack Vasovagal attack Situational syncope Neurally mediated syncope with neuralgia Carotid-sinus syncope Orthostatic hypotension Drug-induced syncope Migraines, seizures Transient ischemic attack, subclavian steal, basilar migraine Subclavian steal Seizure Subclavian steal or aortic dissection Atrial myxoma or thrombus Aortic stenosis, pulmonary hypertension, mitral stenosis, hypertrophic cardiomyopathy, coronary artery disease Long QT syndrome, Brugada syndrome Arrhythmias Psychiatric illness Reprinted with permission from Kapoor. N Engl J Med. 2000;343: Copyright 2000 Massachusetts Medical Society. All rights reserved. Advanced Studies in Medicine 269

6 CARDIOLOGY beyond reassuring the patient and educating him or her to avoid potential triggers or circumstances that may cause a recurrence (Sidebar, page 273). Treatment with pharmacotherapy and/or an implantable pacemaker must be carefully individualized and monitored. Although a variety of medications, including anticholinergic agents (scopolamine), centrally acting agents (serotonergic reuptake inhibitors), vasoconstrictors (alphaadrenergic agonists), and negative inotropic agents (disopyramide) have been tried in the treatment of syncope, pharmacotherapy is often unnecessary and may be ineffective. 5,7 Furthermore, if carotid sinus syndrome is the cause rather than vasovagal syncope, use of beta blocking agents may exacerbate the problem by causing bradycardia. The use of the antiarrhythmic medication disopyramide also may be dangerous in vasovagal syncope, because it may precipitate life-threatening ventricular tachyarrhythmias, urinary obstruction, or glaucoma. 10 Cardiac pacing may be advisable if the patient has recurrent attacks or has experienced severe physical injury from an episode, and if head-upright tilt table testing has documented severe bradycardia or asystole. 7 Permanent dual-chamber pacemakers designed to detect sudden falls in cardiac rate may then be implanted. In patients with significant bradycardia as a cause of neurocardiogenic syncope, these devices may convert sudden syncope without prodrome into a more gradual, symptomatic event for which the patient can take anticipatory measures. 10 It is important to rule out cardiac causes, especially in an older patient, but clinicians should also remember that vasovagal syncope can present for the first time at an Table 4. Clues to the Etiology of Syncope from Physical Examination and 12-Lead Electrocardiography Physical Examination Finding Possible Causes Orthostatic hypotension Dehydration, medications (eg, antihypertensives, diuretics) Ventricular asystole and/or hypotension during carotid Carotid sinus hypersensitivity sinus massage Displaced or abnormal left ventricular impulse, S 3 gallop, murmurs Ventricular tachycardia of mitral regurgitation suggesting myocardial dysfunction Sustained apical impulse, S 4 gallop indicating left Need for atrioventricular synchrony to preserve optimal ventricular hypertrophy cardiac output Ejection murmurs (aortic stenosis, hypertrophic Left ventricular outflow tract obstruction obstructive cardiomyopathy) Right ventricular lift, loud P 2, prominent A-wave in jugular Left ventricular underfilling, with reduced stroke volume venous pulse, right ventricular S 2 and S 4 gallops suggesting pulmonary hypertension 12-Lead Electrocardiography Finding Long QT interval Previous myocardial infarction Atrioventricular conduction delay or block, bundle branch block, fascicle block Ventricular hypertrophy Epsilon wave Right ventricular conduction delay with ST-segment elevation in precordial leads, typically V 1 through V 3 Atrial and ventricular ectopy Bradycardia Ventricular preexcitation Reprinted with permission from Goldschlager et al. Arch Intern Med. 2003;163: Possible Causes Torsade de pointes ventricular tachycardia Ventricular tachycardia Bradycardia Need for atrioventricular synchrony Arrhythmogenic right ventricular dysplasia Brugada syndrome Nonspecific; may indicate presence of a substrate for more sustained rhythm disturbance Nonspecific; may indicate conduction system disease Wolff-Parkinson-White syndrome 270 Vol. 3, No. 5 May 2003

7 SYNCOPE older age. The scenario that precipitated the fainting spell may differ from that in a younger person, but the diagnosis may be the same. Tilt table testing now offers a fairly inexpensive, safe, and noninvasive method for diagnosing vasovagal syncope. Patients undergo constant ECG and blood pressure monitoring as the technician shifts them from the supine position (after 10 to 20 minutes) to an angle of 80 that is maintained for a period of approximately 30 to 45 minutes or until symptoms are reproduced. To enhance response, various challenging medications, such as isoproterenol or sublingual nitroglycerin, may also be used if the initial phase of the test is negative. Sensitivity and specificity are reported to range between 80% to 90%, on average, for the reproduction of symptoms. A positive test is characterized by a sudden drop in blood pressure, pulse, and the occurrence of syncope. 13 Tilt table testing should be performed to document the response in individuals with recurrent syncope that appears to be vasovagal, and in those who have experienced or may experience syncope in a high-risk situation. It should not be performed in patients believed to have obstructive cardiac disease. 5 Guidelines for the use of tilt table testing have been issued by the American College of Cardiology and the North American Society of Pacing and Electrophysiology. 14 Carotid Sinus Syndrome. Hypersensitivity of the carotid sinus is another potential cause of neurally mediated syncope. It is responsible for 10% to 20% of presyncopal and syncopal spells, especially in elderly patients with atherosclerosis. 11 This syndrome may be diagnosed by performing carotid sinus massage. The patient is attached to a beat-to-beat blood pressure device and cardiac monitor. Massage is applied to the area of the maximal carotid pulse on one side of the neck at the level of the thyroid cartilage for 3 to 5 seconds. The clinician is looking for either a 3-second interval of asystole (cardioinhibitory response), a 50-mm Hg decrease in blood pressure (vasodepressor response), both parameters, and/or syncope for a confirmed diagnosis. The main risk associated with this procedure is the possibility of precipitating a TIA or cerebrovascular attack in individuals with carotid artery disease. However, the complication rate for carotid sinus massage is extremely low (<1%). Carotid sinus massage is generally avoided in patients with a previous history of cerebrovascular attack, TIA, carotid endarterectomy, and/or in those with carotid bruits. Patients with carotid sinus syndrome should avoid pressure to the carotid sinus, such as that which can occur with head turning, tight collars, and Valsalva maneuvers. Medications that may Figure 2. Approach to the Patient with Syncope *Syncope after recent head trauma, seizures, headache, or new neurologic abnormality: refer to neurologist. Atrioventricular block, ventricular tachycardia, supraventricular tachyarrhythmias including atrial fibrillation and flutter, sinus bradycardia, myocardial infarction, ectopy, QT interval 0.50 sec or longer (receiving/not receiving QT-prolonging drugs), arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, Wolff-Parkinson-White syndrome, and Brugada syndrome. ECG = electrocardiogram; BBB = bundle branch block; LVEF = left ventricular ejection fraction; RX = treatment as appropriate. Adapted with permission from Goldschlager et al. Arch Intern Med. 2003;163: Table 5. Indications to Refer to a Cardiac Electrophysiologist 1. Neurocardiogenic (including vasovagal) syncope, especially if refractory to avoidance of triggers and drug therapy or associated with prolonged pauses in cardiac rhythm 2. Arrhythmia identified during evaluation, including ventricular tachycardia due to any cause; bradyarrhythmia, such as sinus bradycardia or atrioventricular block not clearly caused by drug therapy that can be withheld or changed; supraventricular tachycardia, especially in the presence of Wolff-Parkinson-White conduction 3. Congenital long QT syndrome diagnosed or suspected from the electrocardiogram 4. Brugada syndrome diagnosed or suspected from the electrocardiogram 5. Structural heart disease, such as dilated or hypertrophic cardiomyopathy; suspected arrhythmogenic right ventricular dysplasia; or coronary artery anomaly identified during evaluation 6. Syncope in athletes 7. Syncope during exercise 8. Origin of syncope remains unknown and prolonged arrhythmia monitoring by means of an implantable loop recorder is being considered Reprinted with permission from Goldschlager et al. Arch Intern Med. 2003;163: Advanced Studies in Medicine 271

8 CARDIOLOGY precipitate bradycardia and/or hypotension should also be avoided. 10,11 Treatment for this syndrome is the implantation of a cardiac pacemaker to manage the bradycardia when a cardioinhibitory rather than a vasodepressor component is documented to be primary. 10,11 Kenny et al randomized 175 patients older than 50 years with cardioinhibitory carotid sinus hypersensitivity who had experienced nonaccidental falls (with or without syncope) to 2 groups in the Syncope and Falls in the Elderly: Pacing and Carotid Sinus Evaluation (SAFE PACE) trial. 15 One group had dual-chamber pacemakers implanted (n = 87), and the control group (n = 88) received standard therapy. Paced subjects experienced significantly fewer falls and syncopal events compared with control subjects (odds ratio, 0.42; 95% confidence interval [CI], ). Falls were reduced by two thirds and injuries by 70%, and syncopal events were nearly one half as common (n = 28 in paced patients; n = 47 in controls). Situational Syncope. Like vasovagal syncope, situational syncope is vagally mediated. However, in situational syncope, which is seen most often in the elderly, a specific situation consistently triggers a loss of consciousness. Common triggers include cough, swallowing, shaving, micturition, and defecation. Wherever possible, treatment is aimed at avoiding or Figure 3. Autonomic Nervous System Regulation of Cardiovascular Hemodynamic Responses Midbrain Medulla Nucleus tractus solitarius Nucleus ambiguus Ventrolateral medulla Spinal cord Intermediolateral cell column Higher Center Hypothalamus Amygdala Paraventricular cortex Insular cortex Anterior cingulate cortex (Glossopharyngeal) Afferents (Vagus) Heart Rate Parasympathetic efferents (vagus) Sympathetic efferents Vascular tone Mechanoreceptors and Baroreceptors Carotid sinus Aortic arch Heart Lung (cardiopulmonary) Reprinted with permission from Fenton et al. Ann Intern Med. 2000;133: lessening exposure to the situation. For example, patients with chronic obstructive pulmonary disease or asthma may suffer from cough syncope. Cough suppression and smoking cessation may be beneficial. Advising individuals to sit during and for a few minutes after urinating and defecating may also help to prevent loss of consciousness. OTHER NONCARDIAC CAUSES Orthostatic Hypotension. Orthostatic hypotension is defined as a drop in systolic blood pressure of 20 mm Hg, or a decrease of systolic blood pressure to <90 mm Hg, after the patient has been standing for 1 to 3 minutes following a period of having been supine for 5 minutes. It may also be indicated by a decline in diastolic blood pressure of at least 10 mm Hg after 3 minutes, or by a slower, steadier drop over a longer period (10 to 15 minutes). 10 A variety of acute and chronic etiologies have been implicated in orthostatic hypotension. Volume depletion, such as that which occurs with trauma, gastrointestinal bleeding, or dehydration, may cause orthostatic changes. Replacement of fluids and electrolytes will reverse orthostatic hypotension in these situations. In more chronic cases and especially in the elderly, failure of the autonomic system may be due to medications the patient is taking (Table 2). Diuretics, vasodilators, and alcohol are among the most common offenders. Whenever possible, these substances should be discontinued. Compression hosiery may also be of some use in patients who can wear them without discomfort. 4,7 Patients with orthostatic hypotension should be counseled to change positions slowly (eg, when getting out of bed for the first time in the morning). These patients should also be cautioned to avoid environments with high temperatures, such as saunas or Jacuzzis, and to make lifestyle changes that include changing the water temperature for baths and showers from hot to warm and avoiding heavy meals, excessive exertion, and alcohol. Restricting intake of salt and increasing fluids may also be helpful in selected patients. For example, salt intake may be detrimental in elderly patients, particularly those with hypertension or heart failure. Autonomic Nervous System Failure. When there is symptomatic evidence of a failure of the autonomic nervous system (ANS), it is sometimes necessary to consider a neurological evaluation of syncope. Orthostatic hypotension was discussed previously. Other situations result from serious degenerative diseases that cause primary failure of the ANS. The main etiologies are Parkinson s disease or atrophy of multiple systems (formerly including 272 Vol. 3, No. 5 May 2003

9 SYNCOPE Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar degeneration). This is a progressive disorder characterized by orthostatic hypotension along with other symptoms of ANS failure, such as ataxia and parkinsonism. Failure of the ANS may also be secondary to certain illnesses (eg, diabetes or liver or kidney failure) or due to certain drugs (monoamine oxidase inhibitors and tricyclic antidepressants, phenothiazines, antihistamines, or levodopa) or alcohol use. Although a neurological workup is not necessary in all cases of syncope, it is imperative in the syncopal patient who is taking these medications or demonstrates signs and symptoms of autonomic failure (eg, difficulty urinating, impotence), diabetes, or Parkinson s disease. Cerebrovascular Events. Vascular or subclavian steal syndrome is a rare cerebrovascular cause of syncope that occurs when the circulation to the arm is blocked due to stenosis or occlusion of the subclavian artery. Blood flow is essentially stolen by the vertebral artery. If there are excessive demands on the extremity (eg, during exercise), there may be insufficient perfusion to the brain stem, resulting in loss of consciousness. The diagnosis, which is most common in middle-aged men, is suggested by the circumstances surrounding the symptoms, and can be confirmed via Doppler ultrasonography. On physical examination, there is a discrepancy in blood pressure between the upper and lower extremities. Treatment is the use of revascularization techniques. Some types of basilar artery or complicated migraine headaches may have syncope as a component, although the patient s loss of consciousness may last for too long to be considered syncope, and the constellation of other symptoms may help the clinician differentiate migraine from syncope. These migraines generally occur in young adults. TIAs and cerebrovascular attacks rarely cause syncope as a primary symptom. Both are much more likely to present with complete or partial weakness or paralysis, slurred speech, abnormal eye movements or vision disturbances, altered mental status, and severe headache. It is generally not necessary to obtain expensive or invasive radiologic testing to rule out a TIA or cerebrovascular attack when syncope occurs. Epilepsy. Syncope has sometimes been misdiagnosed as epilepsy because both involve loss of consciousness. Because cardiovascular causes of syncope may result in cerebral hypoperfusion and seizurelike movements, these syncopal events may be particularly difficult to differentiate from true epilepsy. Zaidi et al investigated a population of 74 subjects who had been given a presumptive diagnosis of epilepsy, but who had presented with atypical seizures or convulsions that were resistant to treatment. 16 All of the study participants had experienced multiple episodes of seizures over a prolonged period of time (median, 25 incidents over 60 months). Subjects underwent 80 head-upright tilt table testing and carotid sinus massage with simultaneous EEG, ECG, and blood pressure monitoring. A select group of 10 patients in whom a cardiac cause was strongly suspected also had loop recorders implanted for long-term continuous ECG monitoring. Nineteen patients (25.7%) had positive headupright tilt table tests, 7 patients (9.5%) had significant pauses with carotid sinus massage, and 2 patients had prolonged bradycardia (diagnosed via loop recorder). Many of these patients had seizurelike activity during the course of their syncopal episodes, but their EEGs were normal. Two subjects were determined to have psychogenic seizures. Of the 74 subjects in this study, 31 (41.9%) were found to have convulsive syncope from vasovagal, cardiac, or psychogenic causes rather than from epilepsy. A careful history taken from the patient and eyewitnesses to the event is instrumental in arriving at a proper diagnosis. Clinicians should determine whether the individual experienced aura, whether the movements were tonic-clonic in nature, and whether there was a postictal state marked by sleepiness or confusion. Although movements may occur during syncope, they are generally not synchronous and they occur after the person falls down. Such movements contrast with what occurs in epilepsy, in which the Counseling Patients for Avoidance of Neurally Mediated Syncope Avoid environments that may trigger a fainting spell, such as hot, crowded rooms or the need for prolonged standing. Avoid stressful events that predispose some individuals to fainting, such as venipuncture or other exposure to blood, pain, fear, or highly emotional settings. Avoid dehydration. Be certain that proper attire, ventilation, and adequate fluids and salt intake are available during exertion, as with sports participation. Be aware of and attempt to minimize situations that trigger syncope, such as coughing or wearing tight collars. Discontinue medications, such as vasodilators, that increase susceptibility to fainting spells. Be aware of warning signs, such as feeling nauseated, sweaty, dizzy, or lightheaded, and sit or lie down to attempt to prevent loss of consciousness. Your healthcare provider may prescribe salt tablets or medications, such as fludrocortisone, midodrine, propranolol or other beta blocking agents, or anticholinergic agents for severe or recurrent episodes. He or she may also refer you to an electrophysiologist who may recommend implantation of a pacemaker in certain circumstances after the appropriate diagnostic tests have been performed. Advanced Studies in Medicine 273

10 CARDIOLOGY forceful and synchronous movements may precede collapse and may continue while the person is on the ground. Persons experiencing syncope will be upright prior to losing consciousness (except in the case of a cardiac arrhythmia, which may occur in other positions), and they are limp in muscle tone. By contrast, a seizure may occur in any position, and muscle tone is rigid. Incontinence and tongue biting also suggest seizure activity rather than syncope. However, because it is sometimes difficult for a lay person to differentiate a seizure from a syncopal episode (Table 3), patients with seizures that do not seem to respond to adequate doses of pharmacotherapy should be evaluated to rule out syncope (particularly cardiac syncope) as the true etiology. Psychogenic Episodes. Certain psychiatric conditions, including anxiety, depression, and panic attacks, may cause syncope-like symptoms, although there may not be definite loss of consciousness. Psychogenic seizures (pseudoepilepsy), hyperventilation syndrome, cataplexy (marked by sudden loss of muscle control [drop attacks] triggered by laughter or another emotion), narcolepsy, and somatization disorder may all need to be considered in differentiating syncope from other similar conditions. A psychiatric evaluation and the appropriate treatment should then be initiated when there are symptoms suggestive of one of these etiologies. CARDIAC CAUSES In 1990, Kapoor determined that, in his population of 433 patients with syncope, those with a cardiac cause had a much poorer prognosis than those in whom a noncardiac cause was found. After 1 year, patients with a cardiac cause had an 18% to 33% mortality rate compared with 0% to 12% in those with noncardiac causes and 6% in patients with syncope of undetermined etiology. At 5 years, patients with a cardiac cause had a mortality rate of 50.5% compared with 30% in patients with noncardiac causes and 24.1% in people for whom a cause of syncope could not be determined (P <.001). Cox regression analyses were performed because patients with a cardiac cause of syncope were older and tended to have preexisting cardiac disorders and risk factors. Despite these factors, the results of these analyses supported the fact that a cardiac cause of syncope was an independent predictor of mortality, especially sudden death. 2 Although this study is somewhat dated, and today we have more sophisticated tools at our disposal (such as electrophysiologic testing, event monitoring, implantable loop recorders, and more advanced echocardiography), it stresses the vital importance of excluding a cardiac cause of syncope. A study published by Soteriades et al in 2002 evaluated the incidence, specific causes, and prognosis of syncope among the 7814 men and women who participated in the Framingham Heart Study between 1971 and The findings suggested that individuals found to have a cardiac cause for their syncope were a high-risk group, predisposed to greater morbidity and mortality. After adjustment for other variables, the hazard ratios related to syncope from any cause were 1.31 (95% CI, 1.14 to 1.51) for death from any cause, 1.27 (95% CI, 0.99 to 1.64) for MI or death from CAD, and 1.06 (95% CI, 0.77 to 1.45) for stroke. Corresponding hazard ratios for cardiac syncope were 2.01 (95% CI, 1.48 to 2.73), 2.66 (95% CI, 1.69 to 4.19) for MI/CAD, and 2.01 (95% CI, 1.06 to 3.80) for stroke. Overall probability of survival of participants with syncope from cardiac causes was lower than that of participants without syncope (P <.001). 12 These significant findings show that it behooves the clinician to carefully evaluate patients for cardiac causes of syncope, treat them, and monitor them carefully to avert morbidity and mortality. ARRHYTHMIAS Arrhythmias are a primary cardiac cause of syncope. One potential mechanism (eg, in heart block) is the slow transmission of impulses through the heart. This eventually causes inadequate cerebral perfusion, thus causing syncope or presyncope. 7 These abnormal cardiac rhythms may arise as a result of structural defects in the heart, impeding the proper conduction of impulses. Some of these arrhythmias include ventricular tachycardia, supraventricular tachycardia, sinus node disease (manifested by sinus bradycardia or long sinus pauses), and heart block (complete atrioventricular block or Mobitz II). Electrophysiologic studies are generally the means of diagnosing arrhythmias in syncope of unclear etiology, although fortuitous timing via an ECG or Holter monitor may reveal these arrhythmias. For persons who have abnormally slow heart rates, permanent pacing is indicated and effective for symptoms. 7 Other arrhythmias, such as torsade de pointes (a polymorphic ventricular tachycardia associated with a prolonged QT interval or prominent U wave on ECG), may be congenital, but are frequently the result of certain medications. 17 Discontinuation of the suspect medication will cure the syncope. Ironically, some antiarrhythmic agents will cause torsade de pointes, as will certain psychoactive medications, antimicrobial drugs, and nonsedating antihistamines (Table 2). 7,10, Vol. 3, No. 5 May 2003

11 SYNCOPE Concomitant ingestion of grapefruit juice with these medications may interfere with the cytochrome P450-3A4 enzyme system, causing elevated levels of the drugs and increasing the risk of prolonged QT interval. Chinese herbs (glycyrrhiza glabra), aconite and ephedra alkaloids, and anabolic steroids in large doses may also precipitate ventricular arrhythmias and syncope. 10 STRUCTURAL CARDIAC AND CARDIOPULMONARY DISEASE Syncope also may occur in the midst of cardiac arrest secondary to MI or CAD. Less common causes of cardiac syncope include aortic stenosis, aortic dissection, pericardial tamponade, hypertrophic obstructive cardiomyopathy, atrial myxoma, mitral stenosis, pulmonary stenosis, pulmonary embolism, pulmonary hypertension, and permanent pacemaker malfunction. 4 Syncope in these cases may be arrhythmia associated, mediated by neurocardiac reflexes, or due to inadequate blood flow from a mechanical obstruction. SUMMARY AND TREATMENT Patients who have cardiac as opposed to noncardiac syncope generally have little prodrome. Whereas vasovagal syncope may be postural, and syncope secondary to a mechanical defect in the heart may be exertional or postexertional, arrhythmia-induced syncope is usually neither postural nor exertional, and comes on with very little warning. There is a sudden drop in cardiac output and cerebral blood flow in both types of cardiac syncope arrhythmia based and structurally based.treatment of the underlying arrhythmia, or of the structural cardiac or cardiopulmonary disease, is the goal in preventing recurrence of syncope in these patients. This may be accomplished via pharmacotherapy, surgery, or both, according to underlying etiology. Specific details of these treatments are beyond the scope of this article. The patient should be referred to a cardiologist for specific diagnostic testing and management (Table 5). Hospitalization may also be necessary in some instances. SPECIAL SITUATIONS: THE ATHLETE One in athletes, including 25 adolescents, die annually while engaging in exercise, including competitive sports. Syncope in athletes should therefore be carefully evaluated. It may be benign but may also signal serious potentially fatal cardiac pathology (Table 6). Risk varies according to age, sex, intensity of the activity, previous syncope, and/or known cardiac disease. 10 The nature and intensity of training can have a physiologic effect. Sympathetic activity and the baroreceptor reflex can be blunted in the athlete. Aerobic exercise increases oxygen uptake, heart rate, cardiac output, and vagal tone. Isometric exercise (eg, weight training) can increase blood pressure to very elevated levels (>350/150 mm Hg). 10 The clinician should consider a potentially lethal arrhythmia in any athlete who has an episode of syncope that is both quick in onset (no prodrome) and in recovery. A structural anomaly of the heart (aortic stenosis) or of a coronary blood vessel may be present. Clinicians should consider these possibilities if an athlete collapses shortly after beginning physical activity or with prolonged activity, although ischemia presenting as syncope in response to exercise is unusual. Because athletes sometimes develop physiologic left ventricular hypertrophy, it may be necessary to restrict exercise for several months in order to attempt to differentiate the athletic heart, which will regress, from hypertrophic cardiomyopathy, which will not. 10 Bikers and runners in particular may suffer from noncardiac causes of syncope, including dehydration, hypoglycemia, or a sudden fall in blood pressure at the end of their exercise session. Athletes may have vasovagal episodes from neurally mediated hypotension and bradycardia. Hyperventilation or Valsalva maneuvers induced in the process of exercising may also lead to syncope or presyncope. Supplements (eg, ephedra [mahuang], androgenic steroids, creatine) may cause potentially fatal arrhythmias in athletes who use these substances, which may be obtained over the counter. Both creatine and ephedra have been implicated in sudden deaths in athletes. 10 In light of more than 100 deaths linked to the use of ephedra, the US Food and Drug Administration (FDA) has issued a warning regard- Table 6. Factors to Consider in the Evaluation of Syncope in the Athlete High catechol levels Exposure to excessive heat or cold Hormonal shifts Mental stress Dehydration Exercise type (aerobic vs isometric) Hyperventilation Valsalva maneuvers (weight lifting) Substance abuse (cocaine, amphetamines) Supplements (steroids, ephedra, creatine) Advanced Studies in Medicine 275