- Email: [email protected]
Panel consensus
Panel Consensus PUTTING IT TOGETHER: A NEW TREATMENT ALGORITHM FOR VASOVAGAL SYNCOPE AND RELATED DISORDERS Daniel M. Bloomfield, MD, Robert Sheldon, MD, PhD, Blair P. Grubb, MD, Hugh Calkins, MD, and Richard Sutton,
DScMed
The consensus process that culminated in this symposium established an algorithm to guide the diagnosis and treatment of patients with vasovagal syncope and related disorders. In some patients, the hemodynamic response to standing may identify an abnormality— postural orthostatic tachycardia syndrome or orthostatic hypotension—that can often be treated without further testing. When the response to standing is normal, tilttable testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment. In some patients, however, the diagnosis is clear from the history, and tilt-table testing may not be necessary. Not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt. In evaluating the results of tilt-table testing, an important consider-
ation is the distinction between vasovagal syncope and the dysautonomic response to tilt characterized by a gradual and progressive decrease in blood pressure that leads to syncope. Current practice patterns suggest that  blockers, fludrocortisone, and midodrine, are commonly used to treat patients with vasovagal syncope, and patients with the dysautonomic response are generally treated with fludrocortisone and midodrine. Permanent pacing with specialized pacing algorithms should be considered for patients with frequent vasovagal syncope that is refractory to medical therapy. The guidelines proposed here are an amalgam of clinical experience, expert opinion, and research evidence; however, they do not suggest a standard of care for all patients. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:33Q–39Q
he diagnosis and treatment of vasovagal syncope has undergone a dramatic transformation since the T advent of tilt-table testing in 1986. Tilt-table testing
hypotension, in some cases, the hypotension is secondary to some other process such as tachyarrhythmia or bradyarrhythmia. For the purposes of this symposium, we assumed that other causes of syncope have been appropriately excluded and the likely diagnosis is vasovagal syncope. We included patients with conditions considered to be dysautonomic responses to upright posture: orthostatic hypotension and postural orthostatic tachycardia syndrome (POTS). These dysautonomias are often diagnosed at the same time that the diagnosis of vasovagal syncope is being considered and when other causes of syncope have been excluded.
1
not only significantly reduced the numbers of patients with unexplained syncope, but it defined a population by an objective finding during provocative testing that enabled researchers to study the mechanism of vasovagal syncope and evaluate the efficacy of different treatments. Many small, uncontrolled studies of ⬎10 types of drugs have been published. These are reviewed elsewhere in this symposium. Recently, the results of several randomized clinical trials have also been reported.2–7 At present, there is no published consensus on the treatment of patients with vasovagal syncope. The consensus process that culminated in this symposium resulted in an algorithm to guide diagnosis and treatment of patients with vasovagal syncope and related disorders (Figure 1). The focus of this symposium is on patients in whom a primary abnormality in blood pressure regulation results in hypotension and loss of consciousness. Although many cases of syncope result from From Columbia University, College of Physicians and Surgeons, New York, New York, USA; Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada; Medical College of Ohio, Toledo, Ohio, USA; Johns Hopkins University Medical School, Baltimore, Maryland, USA; and Royal Brompton Hospital, London, United Kingdom. This article may contain discussion of off-label or investigational uses (not yet approved by the FDA) of various therapeutic agents. Please refer to the box provided on page 2Q of this supplement for a disclosure of such agents. Address for reprints: Daniel M. Bloomfield, MD, College of Physicians and Surgeons, Columbia University, Division of Cardiology, PH 342, 630 West 168th Street, New York, New York 10032. ©1999 by Excerpta Medica, Inc. All rights reserved.
PATHOPHYSIOLOGIES OF VASOVAGAL SYNCOPE AND THE DYSAUTONOMIC RESPONSE
One of the most important diagnostic considerations in this symposium is the distinction between vasovagal syncope and the dysautonomic response to upright posture. These types of orthostatic intolerance are discussed in more detail in “Pathophysiology and Differential Diagnosis of Neurocardiogenic Syncope” in this supplement and in the literature.8 –11 These disorders can be distinguished based on the cardiovascular and autonomic responses to upright posture. In both, the provocative stimulus is venous pooling in the lower extremities and in the splanchnic vasculature while upright, which requires a compensatory response. In vasovagal syncope, the initial cardiovascular response to upright posture appears relatively normal, and syncope occurs after an abrupt decrease in blood pressure, sometimes accompanied by a marked decrease in heart rate after a delayed period of head-up tilt. In a few large series of patients undergoing tilttable testing, the mean time to syncope was ⬃25 0002-9149/99/$20.00 PII S0002-9149(99)00694-3
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FIGURE 1. Vasovagal syncope and related disorders: a suggested algorithm for the diagnosis and treatment of vasovagal syncope and related disorders. 䊚 1999, Professional Postgraduate Services姞, a division of Physicians World Communications Group. All rights reserved.
minutes with a standard deviation of 10 minutes.12,13 The abrupt decrease in blood pressure is thought to be caused by the Bezold–Jarisch reflex and likely represents a hypersensitive response to an otherwise normal stimulus. The triggering mechanism in vasovagal syncope is conjectured to result from a relatively central hypovolemia that occurs because of blood pooling in the lower extremities. The afferent end of this reflex may be mediated by left ventricular mechanoreceptors that are activated during vigorous contraction around an underfilled chamber, similar to severe hemorrhage. Information from these mechanoreceptors travels along vagal C fibers to the brain stem, which mediates the efferent response—primarily the withdrawal of sympathetic vasomotor tone and often a vagally mediated bradycardia.14 This proposed mechanism remains a matter of debate and has been reviewed elsewhere in this supplement and in the literature.9 The dysautonomic response occurs when the autonomic nervous system appears to be failing. Patients are unable to compensate for the acute decrease in venous return that occurs with upright posture. When this failure to compensate becomes severe, frank orthostatic hypotension occurs. However, if frank orthostatic hypotension does not develop immediately after assuming upright posture, patients with a failing autonomic nervous system may demonstrate a progressive type of orthostatic hypotension after prolonged periods of head-up tilt: As blood continues to pool in the lower extremities with prolonged periods of upright posture, blood pressure continues to decrease. This has been described as delayed or progressive orthostatic intolerance15 or a dysautonomic response to upright posture.8 This distinction in the mechanism of vasovagal syncope and the dysautonomic response to upright posture has important implications for treatment selection, and the treatment algorithm we have proposed takes this distinction into consideration. Before initiating treatment, it is useful to consider a series of key questions that will help focus the approach to therapy: Who needs treatment? What are the initial approaches to treatment? When should therapy be tailored for specific patients? And once treatment is initiated, how do we assess its efficacy?
WHO NEEDS TREATMENT? The decision to treat patients with vasovagal syncope or orthostatic intolerance must take into consideration their quality of life. Patients with recurrent syncope have a quality of life similar to that of patients with debilitating disorders such as severe rheumatoid arthritis or chronic low-back pain.16 Moreover, the reduction in quality of life is proportional to the frequency of syncopal episodes—patients with more frequent recurrent syncope have a poorer quality of life.17 One study has demonstrated that treating patients with vasovagal syncope improves quality of life to normal values.18 Patients with recurrent syncope: Often, patients present after 1 or 2 syncopal episodes and do not require treatment beyond education and counseling. Existing data, however, allow us to identify patients
who are likely to experience recurrent syncope. Factors associated with an increased risk of developing recurrent syncope include the absolute number of prior syncopal episodes,19 –21 the frequency of historical syncope,20 and syncope recurrence after a tilttable test.22 The probability of recurrent syncope increases significantly when the number of prior episodes increases from 1 to 3. In addition, patients who experience frequent spells over a short period of time are at greater risk of developing recurrent syncope than those who experience a similar number of episodes over a longer period of time. Two recent, randomized, controlled trials demonstrated the effectiveness of this risk stratification. The Vasovagal Pacemaker Study,5 which enrolled patients with a history of ⱖ6 syncopal episodes, reported that 70% of patients randomized to best medical therapy had recurrent syncope in 1 year. The European Vasovagal Syncope International Study3 of etilefrine required patients to have fainted at least 3 times in 2 years. Investigators reported that 24% of subjects in the placebo arm had recurrent syncope after 1 year— approximately the same rate of recurrence that would be expected in an unselected population. It is important to note that the occurrence of an asystolic pause during tilt-table testing, although quite dramatic, is not associated with an increased risk for syncope recurrence.23 These data allow clinicians to make reasonable estimates of the likelihood of recurrent syncope that can guide their decision of which patients to treat. At-risk patients: There are patients, regardless of the number or frequency of prior syncopal episodes, who should be treated because syncope puts them at high risk for developing trauma. These are patients who develop syncope without a warning or prodromal symptoms and patients who develop syncope while driving without enough warning to safely stop their vehicle. In addition, patients who work as pilots, truck drivers, roofers, etc., are placed at high risk for injury as a result of vasovagal syncope. For these patients, even a single syncopal episode can result in significant trauma, thus warranting a more aggressive approach to treatment. Finally, some physicians would treat patients with observed seizure-like activity during a syncopal episode, although there are no data available to document that these patients are at higher risk for injury.
WHAT ARE THE INITIAL APPROACHES TO TREATMENT?
Educate patients: The majority of patients with vasovagal syncope do not require specific pharmacologic treatment. Teaching the patient about the pathophysiology of vasovagal syncope and ways to avoid syncopal episodes may be extremely effective in preventing recurrence. Several studies have demonstrated that the probability of having recurrent syncope is significantly diminished after a tilt-table test, presumably because of the counseling and education that occurs after the test is completed.19 –21 Assess medications: Another important approach is thorough assessment of medications and other medical problems that might be contributing to syncope. In
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some patients, medications can be adjusted to reduce the risk of developing syncope. This is especially true for patients taking peripherally active ␣ antagonists, which are known to cause orthostatic hypotension and syncope and can be substituted with antihypertensives that are less potent vasodilators and may be less likely to cause syncope. Nitrates are another drug class that can cause syncope24 and can often be discontinued. Patients with Parkinson’s disease, for example, might be taking medications that lower blood pressure and can cause syncope or recurrent lightheadedness; however, stopping anti-Parkinsonian medications will significantly reduce their quality of life. It may be preferable to support their blood pressure with agents such as fludrocortisone or midodrine, which will allow them to continue their anti-Parkinsonian medications. Assess volume status: One of the first approaches to treatment is assessing volume status and salt intake. Although many patients adhere to the American Heart Association’s recommendation of a low-salt diet, this guideline might make some individuals more likely to develop vasovagal syncope. Increasing their salt intake might be sufficient to prevent recurrent syncope. Normotensive patients with vasovagal syncope should increase their dietary salt. Some patients will have difficulty increasing their dietary salt intake (because they don’t like the taste or because someone else in their household is hypertensive), in which case salt tablets can be given as a supplement.
WHEN SHOULD THERAPY BE TAILORED FOR SPECIFIC PATIENTS? Although tilt-table testing provides information that may suggest a specific line of therapy, in many patients it is reasonable to start empiric therapy without tilt-table testing. Patients with suspected vasovagal syncope might receive  blockers or fludrocortisone, and patients with suspected orthostatic intolerance might receive fludrocortisone or midodrine. As with any disorder, however, treatment choices should be tailored for individual patients. In particular, if patients are being treated for concomitant diseases, the physician must take into account any number of safety considerations. For example, use of fludrocortisone can exacerbate migraine headaches and can diminish the effects of oral antidiabetic agents and insulin,  blockers can cause or exacerbate asthma, and midodrine is contraindicated in patients with acute renal disease. If empiric therapy is ineffective, the results of tilt-table tests may allow the physician to tailor therapy to specific patient characteristics as outlined in the treatment algorithm.
HOW DO WE ASSESS THE EFFICACY OF TREATMENT?
Evaluate symptom reduction: For the majority of patients, the assessment of treatment efficacy should emphasize reduction of symptoms. This does not require the total prevention of all episodes of syncope and near-syncope. In many patients, treatment will convert recurrent syncope to recurrent near-syncope, which may significantly improve quality of life. In 36Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
patients at high risk for trauma, treatment might result in episodes that include enough warning to avoid syncope, trauma from a fall, or both. Tilt-table tests are not good predictors of efficacy:
Given the physiologic links between clinical vasovagal syncope and syncope induced by tilt-table testing, it would be tempting to propose that follow-up tilttable tests would be useful in determining the efficacy of treatment. Patients with positive tilt-table tests in the drug-free state, who then have negative tilt results on therapy, could be sent home on a therapy predicted to be effective. Several small, randomized, controlled studies tested this approach and, unfortunately, were unable to demonstrate that follow-up tilt testing predicts treatment efficacy.25–27 This approach to treatment and assessment of treatment efficacy, however, has not been tested in an adequately powered and structured study. Given the lack of evidence, the best method of assessing treatment efficacy is to evaluate the effect of treatment on the frequency of spontaneous syncopal and presyncopal episodes and quality of life. Assess medication side effects: The assessment of treatment efficacy must also include a careful evaluation of treatment side effects. Treatments associated with significant side effects may prevent syncope but still result in a quality of life that is the same or even worse than it was before treatment. A more detailed discussion of the side effects of various medications can be found in “Pharmacologic Approaches to Therapy for Vasovagal Syncope” in this supplement.28 Duration of treatment: Deciding how long to treat patients can be difficult. Most patients who are not at high risk for injury should be treated for a defined period of time—12 months is reasonable—and then attempts should be made to stop or taper treatment. Many patients will not have recurrent symptoms after treatment is stopped. In patients with high-risk syncope associated with injury, the decision is more difficult and must be individualized.
THE TREATMENT ALGORITHM The treatment algorithm was designed to mirror the process by which we make treatment decisions for patients with vasovagal syncope or syncope that results from autonomic dysfunction. These guidelines have been developed to supplement clinical judgment and do not suggest a standard of care for all patients. The algorithm has 2 primary decision points. The first is based on a patient’s hemodynamic response to standing, a simple maneuver that should be done as part of the initial evaluation. Assuming the hemodynamic response to standing is normal, the second decision is whether treatment choices will be made empirically or if tilt-table testing will guide therapy. Although tilt-table testing offers a great deal of information about a patient’s hemodynamic and autonomic responses to prolonged orthostatic stress, the information may not be necessary to initiate therapy. In addition, tilt-table testing may not be available in certain areas. For those patients with presumed vasovagal syncope who are being treated empirically, the algorithm distinguishes treatment based on whether the
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patient is normotensive at rest or has resting hypertension. For patients who undergo tilt-table testing, the algorithm distinguishes those with a dysautonomic response to head-up tilt from those with vasovagal syncope. Hemomodynamic response to standing: After a detailed history, the physical examination of a patient with unexplained syncope should include orthostatic vital signs. Two abnormalities are worthy of discussion: POTS and orthostatic hypotension. POTS: POTS is defined as an excessive increase in heart rate (⬎30 beats/min or a heart rate ⬎120 beats/ min) in the first few minutes after assuming upright posture.29,30 This tachycardia may be associated with mild orthostatic hypotension, although some patients with POTS develop syncope. Symptoms may include orthostatic lightheadedness, dizziness, exercise intolerance, fatigue, and near-syncope. The pathophysiology of POTS is not well understood, but the syndrome most likely is represented by a heterogeneous group of patients with autonomic dysfunction. Several different pathophysiologic mechanisms have been proposed, including -receptor hypersensitivity,31 decreased plasma volume,32,33 inappropriate venous pooling,34 and dysautonomia.35,36 The patient’s volume status should be assessed because hypovolemia can present with a tachycardic response to head-up tilt. Given the heterogeneity, the best therapy for patients with POTS is empiric. Beta blockers, salt and fludrocortisone, and midodrine are reasonable treatments. Orthostatic hypotension: Orthostatic hypotension is defined as a 20 mm Hg decrease in systolic blood pressure or a decrease in systolic blood pressure to values ⬍90 mm Hg, or a 10 mm Hg decrease in diastolic blood pressure within 3 minutes of assuming upright posture. Patients with significant decreases in blood pressure will experience lightheadedness, suggesting that orthostatic hypotension may be responsible for their syncopal or near-syncopal episodes. In some patients, however, there will be a significant but asymptomatic decrease in blood pressure after standing. Although it is difficult to attribute this type of asymptomatic orthostatic hypotension to the cause of a patient’s syncopal episode, the abnormality should be further evaluated with tilt-table testing. Some of these patients demonstrate a dysautonomic response to head-up tilt with a progressive decrease in blood pressure resulting in frank hypotension and syncope. The treatment of orthostatic hypotension is limited primarily to 2 approaches: volume expansion therapy with salt and fludrocortisone and vasoconstrictor therapy with midodrine. Midodrine is the only drug approved by the US Food and Drug Administration (FDA) for treatment of symptomatic orthostatic hypotension. All patients with orthostatic hypotension require a careful assessment of volume status. If the patient continues to have symptomatic orthostatic hypotension after volume repletion with salt, fludrocortisone or midodrine may be necessary to prevent a symptomatic decrease in blood pressure. Whereas fludrocortisone may be effective in some patients with mild orthostatic hypotension, it is often ineffective or
associated with side effects, principally edema, in patients with severe orthostatic hypotension. Midodrine has been shown in placebo-controlled clinical trials to be safe and effective in increasing standing blood pressure and reducing symptoms in patients with orthostatic hypotension.37,38 Who needs a tilt-table test? In patients with a normal response to standing up, tilt-table testing may be an effective method of making the diagnosis of vasovagal syncope or a related orthostatic intolerance that can cause syncope.39 The indications for tilt-table testing are discussed in “Indications, Methodology, and Classification of Results of Tilt-Table Testing” in this supplement.40 Not all patients with unexplained syncope, however, require tilt-table testing to make the diagnosis of vasovagal syncope. Some patients present with classic prodromal symptoms that strongly suggest the diagnosis of vasovagal syncope. The decision to treat these patients and the choice of therapy can be made without tilt-table testing. Treatment options: Three agents are widely used to treat patients with vasovagal syncope:  blockers, fludrocortisone, and midodrine. Each is designed to prevent afferent triggering of the Bezold–Jarisch reflex. Beta blockers are thought to blunt the welldocumented release of epinephrine that enhances the inotropic state. Fludrocortisone results in plasma volume expansion that diminishes the relatively central hypovolemia that occurs with upright posture, and thus reduces the reflex increase in sympathetic drive and the possibility of an intense contraction of a relatively underfilled chamber. Midodrine is an ␣1 agonist thought to prevent vasovagal syncope by increasing venous vasomotor tone, thereby limiting the amount of venous pooling when upright.2 As with fludrocortisone, the reduction in venous pooling diminishes the relative central hypovolemia during upright posture. Interestingly, another ␣1 agonist, etilefrine, did not prevent recurrent vasovagal syncope in a randomized, placebo-controlled trial.3 It is important to note that none of these widely used treatments has been tested in appropriately powered randomized clinical trials. Empiric therapy: The empiric treatment of vasovagal syncope depends in part on whether the patient is hypertensive. In the absence of hypertension,  blockers or fludrocortisone might be used as first-line therapy. However, there is only 1 placebo-controlled trial of  blockers (although there are a number of uncontrolled trials), and there are no controlled trials of fludrocortisone. Despite this relative lack of solid evidence, there is ample clinical experience supporting the use of these agents. Deciding which class of treatment to use depends on a number of subtle characteristics in the patient’s history. If the history suggests increased adrenergic drive before the syncopal episode,  blockers may be preferable. If, however, the syncopal events appear to have occurred when the patient was relatively hypovolemic, fludrocortisone might be preferred as firstline therapy. If a patient does describe symptoms that
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suggest increased adrenergic drive, it is important to distinguish whether the adrenergic drive is primary or secondary to hypovolemia. In many patients,  blockers or fludrocortisone will be effective; if one agent does not work or is contraindicated, the other may be effective. The combination of  blockers and fludrocortisone can also be effective therapy. If  blockers, fludrocortisone, or their combination are not effective or well tolerated, empiric therapy with midodrine might be initiated as monotherapy or in combination with fludrocortisone. Although midodrine is a newer drug, evidence supporting its use is relatively strong. It has been shown to reduce the frequency of syncopal and near-syncopal episodes in patients with frequent vasovagal syncope in a randomized, double-blind, placebo-controlled, crossover trial.2 Midodrine was also reported to be effective in an uncontrolled trial in which 9 of 11 patients had recurrent vasovagal syncope that was refractory to multiple other drugs.41 Many patients with recurrent vasovagal syncope can be effectively treated with  blockers, fludrocortisone, or midodrine. If a patient fails all of them, however, vasovagal syncope may not be the cause of their symptoms and we would recommend a repeat evaluation that includes tilt-table testing. For hypertensive patients with presumed vasovagal syncope,  blockers might be used as first-line therapy because they can help reduce hypertension while preventing syncope recurrence. Potent vasodilators might make some hypertensive patients vulnerable to vasovagal syncope and switching to  blockers might be effective. If  blockers are not effective or not tolerated, hypertensive patients become more difficult to treat. Because they have been associated with the development of hypertension, fludrocortisone or midodrine are contraindicated in hypertensive patients. Alternatives include clonidine, disopyramide, and serotonin reuptake inhibitors. Importantly, a welldone randomized clinical trial recently demonstrated that the serotonin reuptake inhibitor paroxetine may be useful in preventing vasovagal syncope.6 Tilt-table testing can be useful in hypertensive patients because they may develop orthostatic hypotension or a dysautonomic response to upright posture (progressive orthostatic hypotension), which is demonstrable during prolonged tilt. Pacing is a reasonable consideration in hypertensive patients, although the data supporting the use of pacing is based on patients who had some degree of bradycardia during tilt-induced syncopal collapse.5 Tilt-guided therapy: Tilt-table testing allows the physician to observe the evolution of syncopal collapse due to orthostatic stress. The most important distinction to make during tilt-table testing is whether the syncopal collapse pattern is consistent with a vasovagal response or a dysautonomic response. This distinction is easily made by examining the time course and pattern of the decrease in blood pressure as discussed in more detail elsewhere in this supplement. Vasovagal response: The vasovagal response occurs after some period of hemodynamic stability, in38Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
dicating relatively normal autonomic nervous system function followed by reflex-mediated vasodepression and bradycardia. Treatments are designed to prevent the triggering of the reflex. Beta blockers, fludrocortisone, and midodrine might prevent the afferent triggering of the Bezold–Jarisch reflex. Either  blockers or fludrocortisone may be used as first-line treatment because of dosing convenience and physicians’ large experience with them. If either agent is ineffective or not tolerated, midodrine can be substituted. The choice between  blockers or fludrocortisone as firstline therapy may depend on whether the heart rate increases in the minute or two before the decrease in blood pressure that results in syncopal collapse. If it does, use of  blockers makes sense. In patients whose heart rate is relatively constant before the decrease in blood pressure, fludrocortisone is often used first. Relatively few patients continue to have recurrent syncope after education, reassurance, and treatment with ⱖ1 of these agents. In patients with recurrent syncope, despite optimal use of these treatments, a number of alternatives may be considered, including other drugs and permanent pacing. The use of pacemakers to treat vasovagal syncope is now supported by a randomized, controlled trial5 and is discussed at greater length in “The Role of Pacing in the Treatment of Vasovagal Syncope” in this supplement.42 Generally, pacemakers should be reserved for patients who continue to have recurrent syncope despite the use of multiple medications. In patients for whom permanent pacing is not an option, several other agents have been shown to prevent vasovagal syncope. Paroxetine was recently shown to be effective in a well-done randomized, placebo-controlled clinical trial. Other agents, such as disopyramide, theophylline, transdermal scopolamine, and clonidine, have been used to treat vasovagal syncope based on data from uncontrolled studies. Each of these drugs may have a role in selected patients. Dysautonomic response: The dysautonomic response is characterized by a gradual and progressive decrease in blood pressure without a significant increase in heart rate, suggesting that the autonomic nervous system is failing. This response has multiple etiologies, including Parkinsons’s disease, multisystem atrophy, and pure autonomic failure, a review of which is presented in this supplement.11 Treatment of patients with a dysautonomic response is aimed at minimizing the orthostatic challenge and supporting the failing system. This can be accomplished with fludrocortisone or midodrine. Some patients with a dysautonomic response will have mild-to-moderate supine hypertension, and while upright, their blood pressure will decrease into the normal range within the first few minutes and then progressively decrease to hypotensive levels at which syncope may occur. Treatment with fludrocortisone may exacerbate supine hypertension. Midodrine, because it is short acting, can be given during daylight hours when most patients are either sitting or standing. To avoid nocturnal supine hypertension, the final dose of midodrine should be given in the late afternoon.
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CONCLUSION
15. Streeten DHP, Anderson GH. Delayed orthostatic intolerance. Arch Intern
The focus of this symposium was on patients in whom a primary abnormality in blood pressure regulation results in hypotension and loss of consciousness. Although the most common abnormality is vasovagal syncope, it is also important to consider other disorders in autonomic function including orthostatic hypotension, POTS, and the dysautonomic response to prolonged head-up tilt. This symposium established an algorithm to guide diagnosis and treatment of patients with these disorders, and our conclusions are: (1) the hemodynamic response to standing should be part of the routine evaluation of all patients with unexplained syncope; (2) tilt-table testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment for patients whose diagnosis is not clear from their history or who do not respond appropriately to therapy; (3) not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt; (4) limited data from appropriately powered, randomized clinical trials are available to guide the treatment of patients with vasovagal syncope or the other disorders of autonomic function; and finally (5) the guidelines outlined here represent but one approach to a complex disorder. They are intended to be flexible and not to supersede the discretion of experienced clinicians—in the end, treatment must be tailored to the needs of individual patients. 1. Kenny RA, Bayliss J, Ingram A, Sutton R. Head-up tilt: a useful test for
investigating unexplained syncope. Lancet 1986;1:1352–1355. 2. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the management
of neurocardiogenic syncope. Heart 1998;79:45– 49. 3. Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, Moya A.
Effect of etilefrine in preventing syncopal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial: The Vasovagal Syncope International Study. Circulation 1999;99:1452–1457. 4. Mahanonda N, Bhuripanyo K, Kangkagate C, Wansanit K, Kulchot B, Nademanee K, Chaithiraphan S. Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J 1995;130:1250 –1253. 5. Connolly SJ, Sheldon R, Roberts RS, Gent M. The North American Vasovagal Pacemaker Study (VPS): a randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll Cardiol 1999;33:16 –20. 6. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33:1227–1230. 7. Zeng C, Zhu Z, Liu G, Hu W, Wang X, Yang C, Wang H, He D, Tan J. Randomized, double-blind, placebo-controlled trial of oral enalapril in patients with neurally mediated syncope. Am Heart J 1998;136:852– 858. 8. Grubb BP, Karas B. Clinical disorders of the autonomic nervous system associated with orthostatic intolerance: an overview of classification, clinical evaluation, and management. PACE Pacing Clin Electrophysiol 1999;22:798 – 810. 9. Benditt DG. Neurally mediated syncopal syndromes: pathophysiological concepts and clinical evaluation. PACE Pacing Clin Electrophysiol 1997;20:572– 584. 10. Sutton R, Petersen ME. The economics of treating vasovagal syncope. PACE Pacing Clin Electrophysiol 1997;20:849 – 850. 11. Grubb PB. Pathophysiology and differential diagnosis of neurocardiogenic syncope: a brief review. Am J Cardiol 1999;84:3Q–9Q. 12. Bloomfield D, Maurer M, Bigger JTJ. Effects of age on outcome of tilt-table testing. Am J Cardiol 1999;83:1055–1058. 13. Fitzpatrick AP, Theodorakis G, Vardas P, Sutton R. Methodology of head-up tilt testing in patients with unexplained syncope. J Am Coll Cardiol 1991;17: 125–130. 14. Oberg B, Thoren PN. Increased activity in left ventricular receptors during hemorrhage or occlusion of caval veins in the cat—a possible cause of the vasovagal reaction. Acta Physiol Scand 1972;85:164 –173.
Med 1992;152:1066 –1072. 16. Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB.
Impairment of physical and psychosocial function in recurrent syncope. J Clin Epidemiol 1991;44:1037–1043. 17. Rose S, Koshman ML, McDonald S, Sheldon R. Health-related quality of life in patients with neuromediated syncope. (Abstr.) Can J Cardiol 1996;12:131E. 18. Sheldon R, Koshman ML, Wilson W, Kieser T, Rose S. Effect of dualchamber pacing with automatic rate-drop sensing on recurrent neurally mediated syncope. Am J Cardiol 1998;81:158 –162. 19. Grimm W, Degenhardt M, Hoffman J, Menz V, Wirths A, Maisch B. Syncope recurrence can better be predicted by history than by head-up tilt testing in untreated patients with suspected neurally mediated syncope. Eur Heart J 1997;18:1465–1469. 20. Natale A, Geiger MJ, Maglio C, Newby KH, Dhala A, Akhtar M, Sra J. Recurrence of neurocardiogenic syncope without pharmacologic interventions. Am J Cardiol 1996;77:1001–1003. 21. Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Risk factors for syncope recurrence after a positive tilt-table test in patients with syncope. Circulation 1996;93:973–981. 22. Malik P, Koshman ML, Sheldon R. Timing of first recurrence of syncope predicts syncopal frequency after a positive tilt table test result. J Am Coll Cardiol 1997;29:1284 –1289. 23. Brignole M, Menozzi C, Gianfranchi L, Bottoni N, Lolli G. The clinical and prognostic significance of the asystolic response during the head-up tilt test. Eur J Pacing Electrophysiol 1992;2:109 –113. 24. Davidson E, Fuchs J, Rotenberg Z, Weinberger I, Agmon J. Drug-related syncope. Clin Cardiol 1989;12:577–580. 25. Morillo CA, Leitch JW, Yee R, Klein GJ. A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally-mediated syncope induced by head-up tilt. J Am Coll Cardiol 1993;22:1843–1848. 26. Brignole M, Menozzi C, Gianfranchi L, Lolli G, Bottoni N, Oddone D. A controlled trial of acute and long term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 1992;70:339 –342. 27. Moya A, Permanyer-Miralda G, Sagrista-Sauleda J, Carne X, Rius T, Mont L, Soler-Soler J. Limitations of head-up tilt test for evaluating the efficacy of therapeutic interventions in patients with vasovagal syncope: results of a controlled study of etilefrine versus placebo. J Am Coll Cardiol 1995;25:65– 69. 28. Calkins H. Pharmacologic approaches to therapy for vasovagal syncope. Am J Cardiol 1999;84:20Q–25Q. 29. Grubb BP, Kosinski DJ, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing. PACE Pacing Clin Electrophysiol 1997;20:2205–2212. 30. Narkiewicz K, Somers VK. Chronic orthostatic intolerance: part of a spectrum of dysfunction in orthostatic cardiovascular homeostasis? (Editorial.) Circulation 1998;98:2105–2107. 31. Frohlich ED, Tarazi RC, Dustan HP. Hyperdynamic beta-adrenergic circulatory state. Increased beta-receptor responsiveness. Arch Intern Med 1969;123:1–7. 32. Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann Intern Med 1986;104:298 –303. 33. Hoeldtke RD, Davis KM. The orthostatic tachycardia syndrome: evaluation of autonomic function and treatment with octreotide and ergot alkaloids. J Clin Endocrinol Metab 1991;73:132–139. 34. Streeten DH, Anderson GHJ, Richardson R, Thomas FD. Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: evidence for excessive venous pooling. J Lab Clin Med 1988;111:326 –335. 35. Low PA, Opfer-Gehrking TL, Textor SC, Schondorf R, Suarez GA, Fealey RD, Camilleri M. Comparison of the postural tachycardia syndrome (POTS) with orthostatic hypotension due to autonomic failure. J Auton Nerv Syst 1994;50: 181–188. 36. Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993;43:132–137. 37. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan CH, Rubin M, Fouad-Tarazi FM. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med 1993;95:38 – 48. 38. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension: a randomized, doubleblind multicenter study. Midodrine Study Group. JAMA 1997;277:1046 –1051. 39. Benditt DG, Ferguson DW, Grubb BP, Kapoor WN, Kugler J, Lerman BB, Maloney JD, Raviele A, Ross B, Sutton R, Wolk MJ, Wood DL. Tilt table testing for assessing syncope: American College of Cardiology. J Am Coll Cardiol 1996;28:263–275. 40. Sutton R, Bloomfield DM. Indications, methodology, and classification of results: What do tilt-table tests tell us? Am J Cardiol 1999;84:10Q–19Q. 41. Sra J, Maglio C, Biehl M, Dhala A, Blanck Z, Deshpande S, Jazayeri MR, Akhtar M. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 1997;8:42– 46. 42. Sheldon R. The role of pacing in the treatment of vasovagal syncope. Am J Cardiol 1999;84:26Q–32Q.
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DScMed
The consensus process that culminated in this symposium established an algorithm to guide the diagnosis and treatment of patients with vasovagal syncope and related disorders. In some patients, the hemodynamic response to standing may identify an abnormality— postural orthostatic tachycardia syndrome or orthostatic hypotension—that can often be treated without further testing. When the response to standing is normal, tilttable testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment. In some patients, however, the diagnosis is clear from the history, and tilt-table testing may not be necessary. Not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt. In evaluating the results of tilt-table testing, an important consider-
ation is the distinction between vasovagal syncope and the dysautonomic response to tilt characterized by a gradual and progressive decrease in blood pressure that leads to syncope. Current practice patterns suggest that  blockers, fludrocortisone, and midodrine, are commonly used to treat patients with vasovagal syncope, and patients with the dysautonomic response are generally treated with fludrocortisone and midodrine. Permanent pacing with specialized pacing algorithms should be considered for patients with frequent vasovagal syncope that is refractory to medical therapy. The guidelines proposed here are an amalgam of clinical experience, expert opinion, and research evidence; however, they do not suggest a standard of care for all patients. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:33Q–39Q
he diagnosis and treatment of vasovagal syncope has undergone a dramatic transformation since the T advent of tilt-table testing in 1986. Tilt-table testing
hypotension, in some cases, the hypotension is secondary to some other process such as tachyarrhythmia or bradyarrhythmia. For the purposes of this symposium, we assumed that other causes of syncope have been appropriately excluded and the likely diagnosis is vasovagal syncope. We included patients with conditions considered to be dysautonomic responses to upright posture: orthostatic hypotension and postural orthostatic tachycardia syndrome (POTS). These dysautonomias are often diagnosed at the same time that the diagnosis of vasovagal syncope is being considered and when other causes of syncope have been excluded.
1
not only significantly reduced the numbers of patients with unexplained syncope, but it defined a population by an objective finding during provocative testing that enabled researchers to study the mechanism of vasovagal syncope and evaluate the efficacy of different treatments. Many small, uncontrolled studies of ⬎10 types of drugs have been published. These are reviewed elsewhere in this symposium. Recently, the results of several randomized clinical trials have also been reported.2–7 At present, there is no published consensus on the treatment of patients with vasovagal syncope. The consensus process that culminated in this symposium resulted in an algorithm to guide diagnosis and treatment of patients with vasovagal syncope and related disorders (Figure 1). The focus of this symposium is on patients in whom a primary abnormality in blood pressure regulation results in hypotension and loss of consciousness. Although many cases of syncope result from From Columbia University, College of Physicians and Surgeons, New York, New York, USA; Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada; Medical College of Ohio, Toledo, Ohio, USA; Johns Hopkins University Medical School, Baltimore, Maryland, USA; and Royal Brompton Hospital, London, United Kingdom. This article may contain discussion of off-label or investigational uses (not yet approved by the FDA) of various therapeutic agents. Please refer to the box provided on page 2Q of this supplement for a disclosure of such agents. Address for reprints: Daniel M. Bloomfield, MD, College of Physicians and Surgeons, Columbia University, Division of Cardiology, PH 342, 630 West 168th Street, New York, New York 10032. ©1999 by Excerpta Medica, Inc. All rights reserved.
PATHOPHYSIOLOGIES OF VASOVAGAL SYNCOPE AND THE DYSAUTONOMIC RESPONSE
One of the most important diagnostic considerations in this symposium is the distinction between vasovagal syncope and the dysautonomic response to upright posture. These types of orthostatic intolerance are discussed in more detail in “Pathophysiology and Differential Diagnosis of Neurocardiogenic Syncope” in this supplement and in the literature.8 –11 These disorders can be distinguished based on the cardiovascular and autonomic responses to upright posture. In both, the provocative stimulus is venous pooling in the lower extremities and in the splanchnic vasculature while upright, which requires a compensatory response. In vasovagal syncope, the initial cardiovascular response to upright posture appears relatively normal, and syncope occurs after an abrupt decrease in blood pressure, sometimes accompanied by a marked decrease in heart rate after a delayed period of head-up tilt. In a few large series of patients undergoing tilttable testing, the mean time to syncope was ⬃25 0002-9149/99/$20.00 PII S0002-9149(99)00694-3
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FIGURE 1. Vasovagal syncope and related disorders: a suggested algorithm for the diagnosis and treatment of vasovagal syncope and related disorders. 䊚 1999, Professional Postgraduate Services姞, a division of Physicians World Communications Group. All rights reserved.
minutes with a standard deviation of 10 minutes.12,13 The abrupt decrease in blood pressure is thought to be caused by the Bezold–Jarisch reflex and likely represents a hypersensitive response to an otherwise normal stimulus. The triggering mechanism in vasovagal syncope is conjectured to result from a relatively central hypovolemia that occurs because of blood pooling in the lower extremities. The afferent end of this reflex may be mediated by left ventricular mechanoreceptors that are activated during vigorous contraction around an underfilled chamber, similar to severe hemorrhage. Information from these mechanoreceptors travels along vagal C fibers to the brain stem, which mediates the efferent response—primarily the withdrawal of sympathetic vasomotor tone and often a vagally mediated bradycardia.14 This proposed mechanism remains a matter of debate and has been reviewed elsewhere in this supplement and in the literature.9 The dysautonomic response occurs when the autonomic nervous system appears to be failing. Patients are unable to compensate for the acute decrease in venous return that occurs with upright posture. When this failure to compensate becomes severe, frank orthostatic hypotension occurs. However, if frank orthostatic hypotension does not develop immediately after assuming upright posture, patients with a failing autonomic nervous system may demonstrate a progressive type of orthostatic hypotension after prolonged periods of head-up tilt: As blood continues to pool in the lower extremities with prolonged periods of upright posture, blood pressure continues to decrease. This has been described as delayed or progressive orthostatic intolerance15 or a dysautonomic response to upright posture.8 This distinction in the mechanism of vasovagal syncope and the dysautonomic response to upright posture has important implications for treatment selection, and the treatment algorithm we have proposed takes this distinction into consideration. Before initiating treatment, it is useful to consider a series of key questions that will help focus the approach to therapy: Who needs treatment? What are the initial approaches to treatment? When should therapy be tailored for specific patients? And once treatment is initiated, how do we assess its efficacy?
WHO NEEDS TREATMENT? The decision to treat patients with vasovagal syncope or orthostatic intolerance must take into consideration their quality of life. Patients with recurrent syncope have a quality of life similar to that of patients with debilitating disorders such as severe rheumatoid arthritis or chronic low-back pain.16 Moreover, the reduction in quality of life is proportional to the frequency of syncopal episodes—patients with more frequent recurrent syncope have a poorer quality of life.17 One study has demonstrated that treating patients with vasovagal syncope improves quality of life to normal values.18 Patients with recurrent syncope: Often, patients present after 1 or 2 syncopal episodes and do not require treatment beyond education and counseling. Existing data, however, allow us to identify patients
who are likely to experience recurrent syncope. Factors associated with an increased risk of developing recurrent syncope include the absolute number of prior syncopal episodes,19 –21 the frequency of historical syncope,20 and syncope recurrence after a tilttable test.22 The probability of recurrent syncope increases significantly when the number of prior episodes increases from 1 to 3. In addition, patients who experience frequent spells over a short period of time are at greater risk of developing recurrent syncope than those who experience a similar number of episodes over a longer period of time. Two recent, randomized, controlled trials demonstrated the effectiveness of this risk stratification. The Vasovagal Pacemaker Study,5 which enrolled patients with a history of ⱖ6 syncopal episodes, reported that 70% of patients randomized to best medical therapy had recurrent syncope in 1 year. The European Vasovagal Syncope International Study3 of etilefrine required patients to have fainted at least 3 times in 2 years. Investigators reported that 24% of subjects in the placebo arm had recurrent syncope after 1 year— approximately the same rate of recurrence that would be expected in an unselected population. It is important to note that the occurrence of an asystolic pause during tilt-table testing, although quite dramatic, is not associated with an increased risk for syncope recurrence.23 These data allow clinicians to make reasonable estimates of the likelihood of recurrent syncope that can guide their decision of which patients to treat. At-risk patients: There are patients, regardless of the number or frequency of prior syncopal episodes, who should be treated because syncope puts them at high risk for developing trauma. These are patients who develop syncope without a warning or prodromal symptoms and patients who develop syncope while driving without enough warning to safely stop their vehicle. In addition, patients who work as pilots, truck drivers, roofers, etc., are placed at high risk for injury as a result of vasovagal syncope. For these patients, even a single syncopal episode can result in significant trauma, thus warranting a more aggressive approach to treatment. Finally, some physicians would treat patients with observed seizure-like activity during a syncopal episode, although there are no data available to document that these patients are at higher risk for injury.
WHAT ARE THE INITIAL APPROACHES TO TREATMENT?
Educate patients: The majority of patients with vasovagal syncope do not require specific pharmacologic treatment. Teaching the patient about the pathophysiology of vasovagal syncope and ways to avoid syncopal episodes may be extremely effective in preventing recurrence. Several studies have demonstrated that the probability of having recurrent syncope is significantly diminished after a tilt-table test, presumably because of the counseling and education that occurs after the test is completed.19 –21 Assess medications: Another important approach is thorough assessment of medications and other medical problems that might be contributing to syncope. In
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some patients, medications can be adjusted to reduce the risk of developing syncope. This is especially true for patients taking peripherally active ␣ antagonists, which are known to cause orthostatic hypotension and syncope and can be substituted with antihypertensives that are less potent vasodilators and may be less likely to cause syncope. Nitrates are another drug class that can cause syncope24 and can often be discontinued. Patients with Parkinson’s disease, for example, might be taking medications that lower blood pressure and can cause syncope or recurrent lightheadedness; however, stopping anti-Parkinsonian medications will significantly reduce their quality of life. It may be preferable to support their blood pressure with agents such as fludrocortisone or midodrine, which will allow them to continue their anti-Parkinsonian medications. Assess volume status: One of the first approaches to treatment is assessing volume status and salt intake. Although many patients adhere to the American Heart Association’s recommendation of a low-salt diet, this guideline might make some individuals more likely to develop vasovagal syncope. Increasing their salt intake might be sufficient to prevent recurrent syncope. Normotensive patients with vasovagal syncope should increase their dietary salt. Some patients will have difficulty increasing their dietary salt intake (because they don’t like the taste or because someone else in their household is hypertensive), in which case salt tablets can be given as a supplement.
WHEN SHOULD THERAPY BE TAILORED FOR SPECIFIC PATIENTS? Although tilt-table testing provides information that may suggest a specific line of therapy, in many patients it is reasonable to start empiric therapy without tilt-table testing. Patients with suspected vasovagal syncope might receive  blockers or fludrocortisone, and patients with suspected orthostatic intolerance might receive fludrocortisone or midodrine. As with any disorder, however, treatment choices should be tailored for individual patients. In particular, if patients are being treated for concomitant diseases, the physician must take into account any number of safety considerations. For example, use of fludrocortisone can exacerbate migraine headaches and can diminish the effects of oral antidiabetic agents and insulin,  blockers can cause or exacerbate asthma, and midodrine is contraindicated in patients with acute renal disease. If empiric therapy is ineffective, the results of tilt-table tests may allow the physician to tailor therapy to specific patient characteristics as outlined in the treatment algorithm.
HOW DO WE ASSESS THE EFFICACY OF TREATMENT?
Evaluate symptom reduction: For the majority of patients, the assessment of treatment efficacy should emphasize reduction of symptoms. This does not require the total prevention of all episodes of syncope and near-syncope. In many patients, treatment will convert recurrent syncope to recurrent near-syncope, which may significantly improve quality of life. In 36Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
patients at high risk for trauma, treatment might result in episodes that include enough warning to avoid syncope, trauma from a fall, or both. Tilt-table tests are not good predictors of efficacy:
Given the physiologic links between clinical vasovagal syncope and syncope induced by tilt-table testing, it would be tempting to propose that follow-up tilttable tests would be useful in determining the efficacy of treatment. Patients with positive tilt-table tests in the drug-free state, who then have negative tilt results on therapy, could be sent home on a therapy predicted to be effective. Several small, randomized, controlled studies tested this approach and, unfortunately, were unable to demonstrate that follow-up tilt testing predicts treatment efficacy.25–27 This approach to treatment and assessment of treatment efficacy, however, has not been tested in an adequately powered and structured study. Given the lack of evidence, the best method of assessing treatment efficacy is to evaluate the effect of treatment on the frequency of spontaneous syncopal and presyncopal episodes and quality of life. Assess medication side effects: The assessment of treatment efficacy must also include a careful evaluation of treatment side effects. Treatments associated with significant side effects may prevent syncope but still result in a quality of life that is the same or even worse than it was before treatment. A more detailed discussion of the side effects of various medications can be found in “Pharmacologic Approaches to Therapy for Vasovagal Syncope” in this supplement.28 Duration of treatment: Deciding how long to treat patients can be difficult. Most patients who are not at high risk for injury should be treated for a defined period of time—12 months is reasonable—and then attempts should be made to stop or taper treatment. Many patients will not have recurrent symptoms after treatment is stopped. In patients with high-risk syncope associated with injury, the decision is more difficult and must be individualized.
THE TREATMENT ALGORITHM The treatment algorithm was designed to mirror the process by which we make treatment decisions for patients with vasovagal syncope or syncope that results from autonomic dysfunction. These guidelines have been developed to supplement clinical judgment and do not suggest a standard of care for all patients. The algorithm has 2 primary decision points. The first is based on a patient’s hemodynamic response to standing, a simple maneuver that should be done as part of the initial evaluation. Assuming the hemodynamic response to standing is normal, the second decision is whether treatment choices will be made empirically or if tilt-table testing will guide therapy. Although tilt-table testing offers a great deal of information about a patient’s hemodynamic and autonomic responses to prolonged orthostatic stress, the information may not be necessary to initiate therapy. In addition, tilt-table testing may not be available in certain areas. For those patients with presumed vasovagal syncope who are being treated empirically, the algorithm distinguishes treatment based on whether the
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patient is normotensive at rest or has resting hypertension. For patients who undergo tilt-table testing, the algorithm distinguishes those with a dysautonomic response to head-up tilt from those with vasovagal syncope. Hemomodynamic response to standing: After a detailed history, the physical examination of a patient with unexplained syncope should include orthostatic vital signs. Two abnormalities are worthy of discussion: POTS and orthostatic hypotension. POTS: POTS is defined as an excessive increase in heart rate (⬎30 beats/min or a heart rate ⬎120 beats/ min) in the first few minutes after assuming upright posture.29,30 This tachycardia may be associated with mild orthostatic hypotension, although some patients with POTS develop syncope. Symptoms may include orthostatic lightheadedness, dizziness, exercise intolerance, fatigue, and near-syncope. The pathophysiology of POTS is not well understood, but the syndrome most likely is represented by a heterogeneous group of patients with autonomic dysfunction. Several different pathophysiologic mechanisms have been proposed, including -receptor hypersensitivity,31 decreased plasma volume,32,33 inappropriate venous pooling,34 and dysautonomia.35,36 The patient’s volume status should be assessed because hypovolemia can present with a tachycardic response to head-up tilt. Given the heterogeneity, the best therapy for patients with POTS is empiric. Beta blockers, salt and fludrocortisone, and midodrine are reasonable treatments. Orthostatic hypotension: Orthostatic hypotension is defined as a 20 mm Hg decrease in systolic blood pressure or a decrease in systolic blood pressure to values ⬍90 mm Hg, or a 10 mm Hg decrease in diastolic blood pressure within 3 minutes of assuming upright posture. Patients with significant decreases in blood pressure will experience lightheadedness, suggesting that orthostatic hypotension may be responsible for their syncopal or near-syncopal episodes. In some patients, however, there will be a significant but asymptomatic decrease in blood pressure after standing. Although it is difficult to attribute this type of asymptomatic orthostatic hypotension to the cause of a patient’s syncopal episode, the abnormality should be further evaluated with tilt-table testing. Some of these patients demonstrate a dysautonomic response to head-up tilt with a progressive decrease in blood pressure resulting in frank hypotension and syncope. The treatment of orthostatic hypotension is limited primarily to 2 approaches: volume expansion therapy with salt and fludrocortisone and vasoconstrictor therapy with midodrine. Midodrine is the only drug approved by the US Food and Drug Administration (FDA) for treatment of symptomatic orthostatic hypotension. All patients with orthostatic hypotension require a careful assessment of volume status. If the patient continues to have symptomatic orthostatic hypotension after volume repletion with salt, fludrocortisone or midodrine may be necessary to prevent a symptomatic decrease in blood pressure. Whereas fludrocortisone may be effective in some patients with mild orthostatic hypotension, it is often ineffective or
associated with side effects, principally edema, in patients with severe orthostatic hypotension. Midodrine has been shown in placebo-controlled clinical trials to be safe and effective in increasing standing blood pressure and reducing symptoms in patients with orthostatic hypotension.37,38 Who needs a tilt-table test? In patients with a normal response to standing up, tilt-table testing may be an effective method of making the diagnosis of vasovagal syncope or a related orthostatic intolerance that can cause syncope.39 The indications for tilt-table testing are discussed in “Indications, Methodology, and Classification of Results of Tilt-Table Testing” in this supplement.40 Not all patients with unexplained syncope, however, require tilt-table testing to make the diagnosis of vasovagal syncope. Some patients present with classic prodromal symptoms that strongly suggest the diagnosis of vasovagal syncope. The decision to treat these patients and the choice of therapy can be made without tilt-table testing. Treatment options: Three agents are widely used to treat patients with vasovagal syncope:  blockers, fludrocortisone, and midodrine. Each is designed to prevent afferent triggering of the Bezold–Jarisch reflex. Beta blockers are thought to blunt the welldocumented release of epinephrine that enhances the inotropic state. Fludrocortisone results in plasma volume expansion that diminishes the relatively central hypovolemia that occurs with upright posture, and thus reduces the reflex increase in sympathetic drive and the possibility of an intense contraction of a relatively underfilled chamber. Midodrine is an ␣1 agonist thought to prevent vasovagal syncope by increasing venous vasomotor tone, thereby limiting the amount of venous pooling when upright.2 As with fludrocortisone, the reduction in venous pooling diminishes the relative central hypovolemia during upright posture. Interestingly, another ␣1 agonist, etilefrine, did not prevent recurrent vasovagal syncope in a randomized, placebo-controlled trial.3 It is important to note that none of these widely used treatments has been tested in appropriately powered randomized clinical trials. Empiric therapy: The empiric treatment of vasovagal syncope depends in part on whether the patient is hypertensive. In the absence of hypertension,  blockers or fludrocortisone might be used as first-line therapy. However, there is only 1 placebo-controlled trial of  blockers (although there are a number of uncontrolled trials), and there are no controlled trials of fludrocortisone. Despite this relative lack of solid evidence, there is ample clinical experience supporting the use of these agents. Deciding which class of treatment to use depends on a number of subtle characteristics in the patient’s history. If the history suggests increased adrenergic drive before the syncopal episode,  blockers may be preferable. If, however, the syncopal events appear to have occurred when the patient was relatively hypovolemic, fludrocortisone might be preferred as firstline therapy. If a patient does describe symptoms that
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suggest increased adrenergic drive, it is important to distinguish whether the adrenergic drive is primary or secondary to hypovolemia. In many patients,  blockers or fludrocortisone will be effective; if one agent does not work or is contraindicated, the other may be effective. The combination of  blockers and fludrocortisone can also be effective therapy. If  blockers, fludrocortisone, or their combination are not effective or well tolerated, empiric therapy with midodrine might be initiated as monotherapy or in combination with fludrocortisone. Although midodrine is a newer drug, evidence supporting its use is relatively strong. It has been shown to reduce the frequency of syncopal and near-syncopal episodes in patients with frequent vasovagal syncope in a randomized, double-blind, placebo-controlled, crossover trial.2 Midodrine was also reported to be effective in an uncontrolled trial in which 9 of 11 patients had recurrent vasovagal syncope that was refractory to multiple other drugs.41 Many patients with recurrent vasovagal syncope can be effectively treated with  blockers, fludrocortisone, or midodrine. If a patient fails all of them, however, vasovagal syncope may not be the cause of their symptoms and we would recommend a repeat evaluation that includes tilt-table testing. For hypertensive patients with presumed vasovagal syncope,  blockers might be used as first-line therapy because they can help reduce hypertension while preventing syncope recurrence. Potent vasodilators might make some hypertensive patients vulnerable to vasovagal syncope and switching to  blockers might be effective. If  blockers are not effective or not tolerated, hypertensive patients become more difficult to treat. Because they have been associated with the development of hypertension, fludrocortisone or midodrine are contraindicated in hypertensive patients. Alternatives include clonidine, disopyramide, and serotonin reuptake inhibitors. Importantly, a welldone randomized clinical trial recently demonstrated that the serotonin reuptake inhibitor paroxetine may be useful in preventing vasovagal syncope.6 Tilt-table testing can be useful in hypertensive patients because they may develop orthostatic hypotension or a dysautonomic response to upright posture (progressive orthostatic hypotension), which is demonstrable during prolonged tilt. Pacing is a reasonable consideration in hypertensive patients, although the data supporting the use of pacing is based on patients who had some degree of bradycardia during tilt-induced syncopal collapse.5 Tilt-guided therapy: Tilt-table testing allows the physician to observe the evolution of syncopal collapse due to orthostatic stress. The most important distinction to make during tilt-table testing is whether the syncopal collapse pattern is consistent with a vasovagal response or a dysautonomic response. This distinction is easily made by examining the time course and pattern of the decrease in blood pressure as discussed in more detail elsewhere in this supplement. Vasovagal response: The vasovagal response occurs after some period of hemodynamic stability, in38Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
dicating relatively normal autonomic nervous system function followed by reflex-mediated vasodepression and bradycardia. Treatments are designed to prevent the triggering of the reflex. Beta blockers, fludrocortisone, and midodrine might prevent the afferent triggering of the Bezold–Jarisch reflex. Either  blockers or fludrocortisone may be used as first-line treatment because of dosing convenience and physicians’ large experience with them. If either agent is ineffective or not tolerated, midodrine can be substituted. The choice between  blockers or fludrocortisone as firstline therapy may depend on whether the heart rate increases in the minute or two before the decrease in blood pressure that results in syncopal collapse. If it does, use of  blockers makes sense. In patients whose heart rate is relatively constant before the decrease in blood pressure, fludrocortisone is often used first. Relatively few patients continue to have recurrent syncope after education, reassurance, and treatment with ⱖ1 of these agents. In patients with recurrent syncope, despite optimal use of these treatments, a number of alternatives may be considered, including other drugs and permanent pacing. The use of pacemakers to treat vasovagal syncope is now supported by a randomized, controlled trial5 and is discussed at greater length in “The Role of Pacing in the Treatment of Vasovagal Syncope” in this supplement.42 Generally, pacemakers should be reserved for patients who continue to have recurrent syncope despite the use of multiple medications. In patients for whom permanent pacing is not an option, several other agents have been shown to prevent vasovagal syncope. Paroxetine was recently shown to be effective in a well-done randomized, placebo-controlled clinical trial. Other agents, such as disopyramide, theophylline, transdermal scopolamine, and clonidine, have been used to treat vasovagal syncope based on data from uncontrolled studies. Each of these drugs may have a role in selected patients. Dysautonomic response: The dysautonomic response is characterized by a gradual and progressive decrease in blood pressure without a significant increase in heart rate, suggesting that the autonomic nervous system is failing. This response has multiple etiologies, including Parkinsons’s disease, multisystem atrophy, and pure autonomic failure, a review of which is presented in this supplement.11 Treatment of patients with a dysautonomic response is aimed at minimizing the orthostatic challenge and supporting the failing system. This can be accomplished with fludrocortisone or midodrine. Some patients with a dysautonomic response will have mild-to-moderate supine hypertension, and while upright, their blood pressure will decrease into the normal range within the first few minutes and then progressively decrease to hypotensive levels at which syncope may occur. Treatment with fludrocortisone may exacerbate supine hypertension. Midodrine, because it is short acting, can be given during daylight hours when most patients are either sitting or standing. To avoid nocturnal supine hypertension, the final dose of midodrine should be given in the late afternoon.
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CONCLUSION
15. Streeten DHP, Anderson GH. Delayed orthostatic intolerance. Arch Intern
The focus of this symposium was on patients in whom a primary abnormality in blood pressure regulation results in hypotension and loss of consciousness. Although the most common abnormality is vasovagal syncope, it is also important to consider other disorders in autonomic function including orthostatic hypotension, POTS, and the dysautonomic response to prolonged head-up tilt. This symposium established an algorithm to guide diagnosis and treatment of patients with these disorders, and our conclusions are: (1) the hemodynamic response to standing should be part of the routine evaluation of all patients with unexplained syncope; (2) tilt-table testing may be useful in making the diagnosis of vasovagal syncope and guiding treatment for patients whose diagnosis is not clear from their history or who do not respond appropriately to therapy; (3) not all patients with vasovagal syncope need to be treated, and many can be treated effectively with education, reassurance, and a simple increase in dietary salt; (4) limited data from appropriately powered, randomized clinical trials are available to guide the treatment of patients with vasovagal syncope or the other disorders of autonomic function; and finally (5) the guidelines outlined here represent but one approach to a complex disorder. They are intended to be flexible and not to supersede the discretion of experienced clinicians—in the end, treatment must be tailored to the needs of individual patients. 1. Kenny RA, Bayliss J, Ingram A, Sutton R. Head-up tilt: a useful test for
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A SYMPOSIUM: TREATMENT FOR PATIENTS WITH VASOVAGAL SYNCOPE
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