Pathophysiology and Management of Neurocardiogenic Syncope

Nandini Nair MD, PhD; Farooq A. Padder, MD, MRCP; Bharat K. Kantharia MD, MRCP

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ABSTRACT

Objective: To discuss the physiologic mechanisms underlying neurocardiogenic syncope in the context of several different management strategies.

Pathophysiology: Neurocardiogenic syncope or the “common faint” is variously called neurally mediated hypotension, vasovagal syncope, or vasodepressor syncope. It is the most common type of syncope. The pathophysiology of neurocardiogenic syncope is complex and not completely elucidated. Individuals susceptible to neurocardiogenic syncope are unable to maintain the adaptive neurocardiovascular responses to upright posture for prolonged periods. These patients tend to have a modest reduction in central blood volume, which is aggravated by upright posture. It is often noted in individuals receiving sympathetic blocking agents and vasodilator drugs for hypertension, elderly patients receiving tranquilizers, patients with anemia, and individuals with transient reductions in blood volume such as those that occur after a brisk diuresis or blood donation. The classic syncopal episode often is preceded by a constellation of prodromal symptoms several seconds before the event that may include nausea, headache, diaphoresis, dizziness, chest pain, palpitations, dyspnea, and paresthesia.

Management: Head-up tilt testing has become the diagnostic study of choice for the identification of patients with neurocardiogenic syncope. Therapeutic options include general measures such as volume expansion; pharmacologic approaches such as beta-adrenergic receptor blockade, anticholinergic agents, selective serotonin reuptake inhibitors, methylxanthines, and alpha agonists; and invasive methods such as placement of a dual-chamber cardiac pacemaker.

INTRODUCTION

Syncope is defined as a sudden and transient loss of consciousness. The incidence of syncope is 3.0% in men and 3.5% in women in the general population, according to 26-year surveillance data from the Framingham study; and the incidence increases with age [1]. Individuals with significant cardiac dysfunction are at higher risk of sudden death in the presence of syncope. Syncope has been classified into 3 broad categories: cardiac, noncardiac, and of undetermined cause (Table).

                               Table. Classification of the Causes of Syncope  

The relative incidence of these categories varies with the clinical site from which the patients are selected. In the emergency department, noncardiac syncope is the most common diagnosis; however, the most common diagnosis for patients admitted to hospitals is cardiac syncope [2]. Sudden transient loss or impairment of consciousness occurs under a wide variety of circumstances. Noncardiac syncope could be caused by neurocardiogenic reactions, orthostatic hypotension, hypothermia, cerebrovascular conditions, seizure disorders, carotid sinus hypersensitivity, situational factors (cough, swallowing, micturition, defecation, diver’s and postprandial states), metabolic conditions (hypoxia, hypoglycemia, hyperventilation, panic attacks), or drugs. Common disorders associated with cardiac syncope may be divided into 2 major types: abnormalities of the left side of the heart such as aortic stenosis, hypertrophic cardiomyopathy, prosthetic valve malfunction, mitral stenosis, and (rarely) atrial myxomas, and abnormalities of the right side of the heart such as Eisenmenger syndrome, Tetralogy of Fallot, pulmonary embolism, pulmonary stenosis, primary pulmonary hypertension, and cardiac tamponade. Cardiac arrhythmias including sinoatrial disease, atrioventricular block, supraventricular tachycardia, and ventricular tachycardia are the major causes of cardiac syncope.

PATHOPHYSIOLOGY

Neurocardiogenic syncope or the “common faint”—also called neurally mediated hypotension, vasovagal syncope, or vasodepressor syncope—is one of the most common types of syncope. It is considered to be the end result of abnormal interactions of complex neurocardiovascular mechanisms responsible for maintaining systemic and cerebral perfusion [3-5]. In its classic form, neurocardiogenic syncope consistsof a constellation of symptoms such as hypotension, bradycardia, pallor, and diaphoresis.

The pathophysiology of neurocardiogenic syncope is complex and not completely understood. In healthy individuals, upright posture causes venous pooling and a transient decrease in arterial pressure, resulting in an unloading of baroreceptors. Reflex augmentation of sympathetic activity and parasympathetic withdrawal result in peripheral arterial vasoconstriction, venoconstriction, and an increase in heart rate and contractility. Neuroendocrine systems such as renin-angiotensin and vasopressin may be important modulators of homeostasis during prolonged periods of orthostatic stress [6]. Individuals susceptible to neurocardiogenic syncope are unable to maintain the adaptive neurocardiovascular responses to upright posture for prolonged periods. These patients tend to have a modest reduction in central blood volume, which is aggravated by upright posture. Increases in circulating catecholamines and cardiac adrenergic tone in response to orthostatic stress result in increased myocardial contractility [7]. Studies in animal models suggest that, under these conditions, cardiopulmonary mechanoreceptors are activated, resulting in increased neural traffic across afferent C fibers leading to the central nervous system vasomotor center; this in turn results in reflex paradoxical vasodilation called the  “vasodepressor response” and bradycardia termed the “cardioinhibitory response” [7]. The final result is hypotension, cerebral hypoperfusion, cerebral hypoxia, and syncope. This paradoxical reflex is believed to be a variant of the Bezold-Jarisch reflex and also has been documented during nitrate therapy for acute myocardial ischemia and during acute hemorrhagic syndromes [8].

Neurocardiogenic reaction may be the ultimate cause of most types of syncope. It often is noted in individuals receiving sympathetic blocking agents and vasodilator drugs for hypertension, elderly patients receiving tranquilizers, patients with anemia, and individuals with transient reductions in blood volume such as those that occur after a brisk diuresis or blood donation. Neurocardiogenic syncope  complicates acute febrile infections and is noted in patients who are recumbent for prolonged periods of time (eg, in cases of chronic illness). Even healthy individuals on prolonged bed rest have a propensity for fainting, especially when they arise abruptly from a sitting or supine position. Neuro-cardiogenic syncope probably is the most frequent cause of cardiovascular collapse during dental procedures [9]. Neurocardiogenic syncope also has been noted after strenuous exercise and during rapid acceleration in air flight, particularly when centrifugal force is applied in the upright position. An unusual type of neurocardiogenic syncope may occur in pregnancy; it is observed when a patient in the supine position assumes a lateral decubitus or upright posture.

Situations that decrease central venous volume or increase cardiovascular adrenergic tone are particularly important in the aggravation of neurocardiogenic syncope. The postprandial state, exertion in warm environments, prolonged upright posture, sodium restriction or diuretic use, and emotional or stressful situations are a few important triggers. A relationship between chronic fatigue syndrome and neurocardiogenic syncope has been suggested [10].

The classic syncopal episode often is preceded by a constellation of prodromal symptoms several seconds before the event that may include nausea, headache, diaphoresis, dizziness, chest pain, palpitations, dyspnea, and paresthesia. These symptoms may persist anywhere from a few minutes to several hours after the syncopal episode has resolved. However, syncope experienced while supine should prompt an aggressive search for etiologies other than neurocardiogenic syncope.

During the syncopal episode, patients typically appear pale and diaphoretic, with a slow, diminished pulse. Seizure-like activity also has been noted during asystolic periods. The classic syncopal spell resolves spontaneously once the patient is in the supine position, but may recur if the patient stands or sits upright soon after the initial spell. Prolonged periods of confusion or bladder/bowel incontinence after the syncopal event are not usual, and other etiologies should be considered if these conditions are present.

PROGNOSIS

Neurocardiogenic syncope may occur as a single isolated event or as a cluster of spells over weeks to months, or it may be a recurrent lifetime problem. The overall prognosis in patients with neurocardiogenic syncope is good compared with that in patients with cardiac syncope. A malignant form of neurocardiogenic syncope has been reported in a small subset of patients, many of whom have underlying structural heart disease [11,12] This form of syncope is characterized by profound periods of asystole (>5 seconds) (Figure 1) with sudden loss of consciousness, potentially leading to severe trauma and a theoretically increased risk of ischemia- or bradycardia-mediated ventricular tachyarrhythmias. Despite such concerns in this population, the prognosis remains excellent [13,14].

Figure 1. Electrocardiographic tracings in a patient with malignant neurocardiogenic syncope

DIAGNOSIS

The head-up tilt (HUT) test is a common tool used in the evaluation of recurrent syncope with no identifiable cause [15]. The HUT test, which induces orthostatic stress, is the diagnostic study of choice for identifying patients with neurocardiogenic syncope. The sensitivity and specificity of the HUT test have been estimated in the range of 67% to 83% and 75% to 100%, respectively [16]. The sensitivity is increased by provocation with low doses of isoproterenol and vasodilating agents such as  nitroglycerin [17]. However, increasing doses of these agents leads to an increased number of false-positive tests.18 The sensitivity, specificity, and reproducibility of HUT testing depend to a large extent on the patient population studied and the HUT protocol used. The sensitivity of HUT testing at an angle of 60° to 90° for a time period of 20 to 60 minutes has been found to range from 20% to 74%. Longer durations of HUT testing (45 to 60 minutes) lead to improved sensitivity without a significant increase in false-positive responses. Recent studies suggest that the optimal HUT angle should be between 60° and 80°. Tilt angles less than 45° sacrifice sensitivity, whereas angles greater than 80° can result in more false-positive results [18,19]. High-dose intravenous isoproterenol, intravenous adenosine, and sublingual nitroglycerin during HUT testing all have been shown to increase sensitivity with some reduction in specificity and significant reduction in the time required to perform the test [20-22]. On average, 63% of patients who received HUT testing after a negative electrophysiologic study were found to have a positive HUT response, suggesting that a significant proportion of patients with unexplained syncope have neurocardiogenic syncope [22].

MANAGEMENT

The management of recurrent neurocardiogenic syncope is challenging. Patients should be taught to recognize premonitory symptoms and, if they are present, to assume a recumbent position to maintain cerebral perfusion. It has been suggested that tilt training may improve outcome [23]. First-line therapy Includes counseling the patient to avoid dehydration, prolonged periods of standing motionless, and situations known to trigger syncope. Increased salt intake, if not contraindicated, may be helpful.

The severity and frequency of recurrence of neurocardiogenic syncope are extremely variable. Hence, its pharmacologic management must be highly individualized. Patients with infrequent, nearsyncopal spells may respond to nonpharmacologic measures alone. Frequent syncopal spells, especially if they result in trauma, usually necessitate pharmacologic interventions; if these spells are refractory, nonmedical interventions like cardiac pacing may be required.

Pharmacologic approaches include beta-adrenergic receptor blockade, anticholinergic agents, selective serotonin reuptake inhibitors (SSRIs), methylxanthines, and alpha agonists. A progressive approach to pharmacologic therapy is advisable, starting with low initial doses that are gradually up-titrated until the frequency and severity of spells are diminished. This approach is important because these patients seem to be more prone to adverse reactions than the general population. If one class of drug is ineffective, a combination of drugs (each acting on different

factors responsible for the neurocardiogenic syncope) may be beneficial. The HUT test may be used for monitoring therapeutic efficacy. However, because it has been observed that the incidence of positive HUT tests decreases significantly over time regardless of the intervention, the HUT test should not be used as the single method of assessing therapeutic efficacy [24,25].

A large proportion of patients with neurocardiogenic syncope show evidence of mild reduction in central plasma volume, and plasma volume expansion can prevent recurrence. Simple measures such as liberalizing salt and fluid intake may suffice [26]. Custom-fitted, counterpressure support garments that extend from the ankle to the waist are useful in highly motivated individuals.

PHARMACOTHERAPY

Mineralocorticoids — In some instances, fludrocortisone acetate may be helpful in augmenting salt retention and volume expansion. The initial dose is 0.1 mg daily; this may be increased by increments of 0.1 mg every week. The maintenance dose varies from 0.1 to 1.0 mg daily [27]. Possible side effects include recumbent hypertension, fluid retention, congestive heart failure, and hypokalemia.

Beta-Adrenergic Blockers —  Increased adrenergic stimulation with resultant activation of cardiac mechanoreceptors is believed to be an important mechanism in the pathophysiologic cascade that culminates in neurocardiogenic syncope. The negative inotropic effect of beta blockers may theoretically prevent activation of the ventricular mechanoreceptors or block the peripheral vasodilator effects of beta-adrenergic receptor stimulation. Because administration of isoproterenol increases the likelihood of a positive HUT test in patients with presumed vasodepressor syncope, beta blockers were logically proposed as treatment for that condition [18]. Hence, beta blockers are the ideal choice for first-line therapy. Several studies have shown the efficacy of various beta blockers, including atenolol and pindolol, in the treatment of neurocardiogenic syncope [27-32]. In our experience, oral administration of pindolol, a nonselective beta blocker with intrinsic sympathetic activity, resulted in definite symptomatic improvement and stabilization of heart rate and blood pressure during HUT testing. The effect of pindolol can be seen within a few hours (N. Nair, MD, PhD; B. K. Kantharia, MD, MRCP; S. P. Kutalek, MD, unpublished data).

Anticholinergic Drugs —  During neurocardiogenic syncope, certain subsets of patients experience profound bradycardia that can aggravate the hypotension associated with vasodilation. In these patients, the bradycardia can be controlled with atropine or propantheline bromide [33]. The profound bradyarrhythmias are primarily observed in the young and in individuals who are otherwise “very healthy” [33]. Another agent that is useful in certain groups of patients with recurrent neurocardiogenic syncope is scopolamine in its transdermal form. The mechanism of action is poorly understood, but is presumed to be related to its anticholinergic actions as well as its depressant effect on central nervous system transmission to the autonomic nervous system [33]. Disopyramide, a Vaughn-Williams class 1A antiarrhythmic drug, has known anticholinergic and negative inotropic properties. These properties, which are considered undesirable effects of disopyramide in the therapy of tachyarrhythmias, may prevent the activation of cardiopulmonary mechanoreceptors and the neurogenic reflex observed in neurocardiogenic syncope. Disopyramide has been shown to prevent tilt-induced syncope and to prevent spontaneous syncopal spells. Disopyramide, however, must be used with caution because of its potential for causing proarrhythmia. In addition, disopyramide’s noncardiovascular side effects such as dry mouth, urinary hesitancy and retention, constipation, blurred vision, and closed-angle glaucoma may be intolerable for some patients.

Selective Serotonin Reuptake Inhibitors — Serotonin is a neurotransmitter that plays a major role in central regulation of heart rate and blood pressure. Activation of cerebral serotonin receptors results in a depressor effect, principally through sympathetic inhibition. Hence, SSRIs have been investigated for the prevention of neurocardiogenic syncope in patients who are refractory to other conventional pharmacologic treatments [34-38]. Nonrandomized studies suggest that the SSRIs fluoxetine hydrochloride (Prozac) and sertraline hydrochloride (Zoloft) both may be beneficial in the prevention of neurocardiogenic syncope after 4 to 6 weeks of therapy. These agents are estimated to be effective in approximately 55% of patients with severe, recurrent neurocardiogenic syncope [34]. Additionally, in 1 study the recurrence rate in patients treated with paroxetine was 18% versus 53% in patients receiving placebo, a difference that is significant [39].

Methylxanthines — Adenosine appears to be an important mediator of hypotension and bradycardia in certain subsets of patients with vasodepressor syncope. Adenosine receptor blockade with methylxanthines may hypothetically prevent the vasodepressor spell. Methylxanthines such as theophylline appear to have 3 different pharmacologic effects that may have therapeutic benefit. In low concentrations, methylxanthines are potent adenosine receptor antagonists. At higher serum concentrations, theophylline acts as a phosphodiesterase inhibitor and a calcium transport inhibitor, both of which may be important in maintaining peripheral vascular tone. Clinical studies have shown that theophylline can prevent recurrences of syncope in more than 70% of patients [40]. Even low doses of theophylline (6-12 mg/kg per day) appear to have a beneficial effect in those patients who cannot tolerate higher doses. Unfortunately, side effects such as nervousness, anxiety, and gastrointestinal abnormalities limit the usefulness of theophylline in this setting.

Alpha Agonists — Alpha agonists may prevent neurocardiogenic syncope because of a potent vasoconstrictor effect that may reduce venous pooling and concomitant reflex arteriolar vasodilation. However, 2 doubleblind, randomized, placebo-controlled trials have yielded variable results. Etilefrine was not any more effective than placebo in the prevention of syncope. In contrast, the alpha-agonist midodrine reduced the incidence of HUT-induced syncope and improved quality of life compared with placebo [41,42].

Cardiac Pacing — Cardiac pacing is valuable in preventing bradycardia-induced hypotension and should be reserved for those patients who have documented episodes of prolonged bradycardia associated with syncope. Pacing may be especially beneficial in those rare patients with malignant neurocardiogenic syncope due to cardiac asystole. These patients typically require pharmacologic therapy in addition to cardiac pacing to prevent vasodepressor syncope [43-45]. Open-label studies show that permanent pacemaker therapy is associated with substantial improvement compared with medical therapy. The roles of specific pacemaker modes have not been determined, although rate-drop responsiveness has yielded the best results so far. Permanent cardiac pacing was evaluated in 3 historical studies that lasted several years. The frequency of syncope before and after pacing was compared in 77 patients who received pacemakers with rate hysteresis (37 patients), rate-drop responsiveness (28 patients), or rate smoothing (12 patients). Most patients either stopped fainting or had far fewer episodes of syncope after insertion of a permanent cardiac pacemaker [43,46,47]. Almost all the patients studied had a previous positive HUT test with induced bradycardia. Randomized trials of permanent pacing also showed a lower rate of recurrence of syncope [45,48,49]. Vasovagal Pacemaker Study I was the first randomized trial to show benefit from pacing. However, that study had several limitations. First, it was an open-label study, so a placebo effect may have been present. Second, the study patients were carefully selected, and as a result the conclusions could not be applied to a more general patient population with neurocardiogenic syncope. Finally, the medical therapy was not standardized [45]. In the Vasovagal Syncope International Study, the investigators randomly assigned 19 patients to receive a dual-chamber pacemaker with rate hysteresis and 23 patients to no pacemaker implant. They found that in a limited, select group of patients with tilt-positive cardioinhibitory syncope, DDI (chamber paced-dual, chamber sensed-dual, response to sensing-inhibited) pacing with hysteresis reduced the likelihood of syncope. The benefit of the therapy was maintained over the long term. Even in untreated patients, the rate of syncopal recurrence was low. The investigators also noted that a negative HUT test was not a useful way to evaluate the efficacy of therapy. However, because this was an open-label study, a placebo effect cannot be ruled out; it also used a highly selected group of patients [48]. The Syncope Diagnosis and Treatment Study was an open-label, randomized trial testing whether cardiac pacing or atenolol was better in preventing vasovagal syncope. This study compared the effects of permanent dual-chamber cardiac pacing with pharmacologic therapy in patients with recurrent vasovagal syncope. DDD (chamber paced-dual, chamber sensed-dual, response to sensing-dual) pacing with rate-drop response function was found to be more effective than beta blockade for the prevention of syncopal recurrences in highly symptomatic vasovagal fainters with relative bradycardia during tilt-induced syncope [49].

The results of several ongoing studies will be able to more clearly define the role of cardiac pacing in the treatment of syncope. However, until they are made available, the American College of Cardiology, American Heart Association, and North American Society of Pacing and Electrophysiology guidelines suggest a class IIa indication for significantly symptomatic and recurrent neurocardiogenic syncope associated with bradycardia documented spontaneously or at the time of HUT testing [50].

In conclusion, the diagnosis and management of neurocardiogenic syncope continue to remain challenging. Different combinations of treatment strategies tailored to individual situations are the key to success. A thorough understanding of the pathophysiology is imperative to designing successful treatment plans.

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