US Pharm. 2011;36(1):HS2-HS11.
Syncope is a transient loss of consciousness associated with a loss of postural tone due to decreased cerebral perfusion. Onset is sudden, rapid, and usually followed by a prompt and complete spontaneous recovery.1-3 It is a common and potentially disabling incident that may be associated with a risk of sudden death.4,5 In 30% of patients, recurrent syncopal episodes have been reported, which may lead to increased morbidity (i.e., lacerations, contusions, fractures, and organ damage due to trauma).6,7
Syncope accounts for 1% to 6% of hospital admissions and 3% of emergency departments visits.8 Its overall incidence is estimated to be 3.3% in younger adults and is reported to increase with age, up to 6% in long-term health care institutions.6,9 The loss of consciousness experienced is frequently precipitated by factors such as pain, exercise, stressors, sudden changes in body position, micturition, defecation, heat, dehydration, sweating, and exhaustion. In addition, numerous cardiac, neurologic, psychiatric, metabolic, and pulmonary disorders can contribute to a syncopal episode.1,10 Patients frequently report a prodromal state of lightheadedness, headache, nausea, warmth, sweating, weakness, and/or visual disturbances.2,11 Prognosis is highly dependent on etiology. Noncardiac causes of syncope are associated with a mortality of 5% to 10%, while cardiac causes have an annual mortality of 20% to 30%.12 Therefore, timely identification of the underlying cause(s) of this disorder is important for appropriate management and evaluation of sudden cardiac death risk.
Neurocardiogenic syncope is the most common type of syncope among children and adults, accounting for up to 50% of cases.13,14 It is usually characterized by a presyncopal warning period of warmth, weakness, diaphoresis, nausea, lightheadedness, dizziness, and/or visual disturbances. Neurocardiogenic syncope is a self-limiting condition caused by an abnormal or exaggerated autonomic response to certain stimuli. Further classifications of this particular type of syncope include situational, carotid sinus, and vasovagal syncope.
Situational syncope refers to neurally mediated syncope commonly associated with cough, micturition, and defecation. Carotid sinus syncope is defined as syncope due to the manipulation of the carotid sinuses (i.e., rotation/turning of the head or pressure placed on the carotid sinuses) that may be reproduced by carotid sinus massage.
Vasovagal syncope is responsible for the majority of neurocardiogenic cases; therefore, it is commonly used synonymously with the term neurocardiogenic syncope. It is often precipitated by emotional situations, pain, blood loss, dehydration, or standing for prolonged periods of time. Although the exact mechanism of this type of syncope is not fully understood, it is believed to occur as a result of reflex-mediated changes in vascular tone and/or heart rate.15,16 Excessive peripheral venous pooling (mainly in the lower extremities) leads to a sudden decrease in peripheral venous return. Stimulation of the vagal efferent fibers ultimately occurs causing a vasodepressor and/or cardioinhibitory response, in addition to sympathetic withdrawal.11,15,16 Transient hypotension results from the peripheral vasodilatation and bradycardia, yielding a reduction in cerebral blood flow and loss of consciousness, which usually lasts for seconds and is followed by recovery with no memory loss or sensory disturbances. Other proposed mechanisms of vasovagal syncope involve serotonin, vasopressin, endorphin, and epinephrine pathways.10
Prompt identification of the underlying cause of a syncopal episode is essential in determining prognosis and management strategies. Thorough histories and physical examinations are necessary to rule out any cardiac, neurologic, or other etiologies. In most cases (up to 50%), patients who experience syncope have no exact cause despite comprehensive evaluation. However, it is believed that 50% to 66% of these patients actually experience neurocardiogenic syncope.10,12
Electrocardiograms (ECGs) and electroencephalograms may be used upon initial presentation postsyncope in order to exclude cardiac and neurologic causes (i.e., arrhythmias and seizures). A Holter monitor may also be used for 24 to 48 hours to continuously monitor and assess the rhythm and rate of the heart. This device records data without patient activation. A continuous-loop event monitor is sometimes worn intermittently for a period of 30 days to continuously record data; however, data are recorded only when the device is prompted by the patient when experiencing symptoms of palpitations or syncope. In certain patients, usually those with recurrent syncope, subcutaneous implanted recorders may be used to maintain ECG data for long-term evaluation of rare events commonly missed by short-term monitoring and data assessment.11
A head-upright, tilt-table test is also frequently used to aid in establishing a diagnosis of neurocardiogenic syncope when history, physical examination, and other measures fail to provide adequate information regarding the etiology of syncope. This test is performed using an angle of 60 to 80 degrees with or without pharmacologic stressors such as isoproterenol, nitrates, or adenosine (which are believed to increase the diagnostic yield). An individual with normal autonomic function will be able to tolerate the test with no sudden decreases in heart rate and/or blood pressure. The test has a relatively high sensitivity, low specificity, and lack of reproducibility, limiting its usefulness. It should be noted that the results of the tilt-table test do not necessarily guide or provide management strategies for neurocardiogenic syncope.11,13,17
The management of neurocardiogenic syncope, particularly recurrent episodes of the vasovagal type, may be difficult due its unclear etiology. Several nonpharmacologic and pharmacologic treatment options have been proposed to decrease the incidence of syncope and potential consequences (i.e., falls, injuries, and other trauma).
Prior to the utilization of pharmacologic agents, nonpharmacologic interventions should be considered for all patients who experience vasovagal syncope. Educating patients is key to early identification and prevention of syncopal episodes. Review with patients the aforementioned warning signs and symptoms, as well as teach them how to avoid precipitating factors, if possible. If warning signs and symptoms are experienced, recommending that one tighten and relax the arm and leg muscles may help in the prevention of an event by positively influencing venous return when sitting. When standing, the patient should assume the supine position and elevate the legs to increase venous blood return. In a study conducted by Krediet et al, 21 male patients aged 17 to 74 years were evaluated after tensing their leg muscles and crossing their legs for 30 seconds immediately before a tilt-table–induced syncopal episode.18 When the instructed exercises were performed, warning signs and symptoms disappeared in all patients. In follow-up interviews, 13 of the patients reported subsequent alleviation of symptoms with the maneuver.
Increasing fluid and salt intake has also been shown to prevent and decrease the number of syncopal episodes. In a study by El-Sayd and Hainsworth, 21 patients with histories of syncope and no cardiovascular or neurologic diseases were randomly assigned to receive 120 mmol salt or placebo for 8 weeks.19 Of those who received salt, 70% reported an improvement in orthostatic intolerance as compared to 30% of those receiving placebo.
In addition, the use of waist-high support stockings with a minimum of 30 mmHg ankle counterpressure may help decrease and prevent syncopal episodes.1,10 Medication reviews should also be performed in order to recognize, reduce, or withdraw those that can precipitate a syncopal event. Specifically, the discontinuation of angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, long-acting nitrates, and diuretics in patients experiencing vasovagal syncope has been associated with a reduction of positive tilt-table test results.20
A number of pharmacologic agents have shown some promise in the management of neurocardiogenic syncope; however, none currently possesses approval for this indication by the FDA. Some of the more common pharmacologic agents used in the management and prevention of this condition include beta-adrenergic receptor blockers (beta-blockers), selective serotonin reuptake inhibitors (SSRIs), mineralocorticoids, and vasoconstrictors (TABLE 1). Reports of success with these agents are mixed due to the lack of available data with consistent methodologies, trial populations, and optimal design. Other pharmacologic agents being studied for their potential benefits in the treatment of vasovagal syncope include theophylline, scopolamine, and methylphenidate.15
Beta-Blockers: These agents were among the first to be evaluated for their potential role in the management of vasovagal syncope. They have been administered acutely by IV, as well as orally for chronic use.15 Their proposed mechanism involves counteracting the increase in serum epinephrine that takes place before a syncopal episode.11,15 Beta-blockers are believed to affect the Bezold-Jarisch reflex as well, which involves cardiovascular and neurologic responses. Additionally, it has been proposed that agents of this class may provide beneficial effects by inhibiting myocardial contractility. However, beta-blockers may also worsen syncope because of their ability to induce orthostatic hypotension in some patients.17
Several studies have been conducted to determine beta-blocker effectiveness in the treatment of neurocardiogenic syncope. To date, no conclusive evidence exists to favor any one beta-blocker in the treatment of neurocardiogenic syncope. Nonetheless, cardioselectivity is believed to be essential when considering the selection of an agent in order to prevent certain side effects and events. The beta-blockers most commonly studied include metoprolol, pindolol, and atenolol.21
In a study by Mahanonda et al, both atenolol 50 and 100 mg were proven to be effective in patients with unexplained syncope and a positive upright tilt-table test.22 However, the study failed to determine the length of therapy needed and any long-term benefits.
Madrid et al also conducted a small study comparing atenolol to placebo in patients with histories of vasovagal syncope.21 This randomized, double-blind, placebo-controlled trial included follow-up assessment at 1 year. No statistical differences were reported between the atenolol and placebo groups. The authors concluded that the somewhat benign nature of neurocardiogenic syncope may give patients a false sense of drug efficacy and resolution of symptoms.
Sheldon et al performed a nonrandomized trial using several beta-blockers for syncope recurrence.23 Depending on individual precautions and/or contraindications, patients were assigned to receive atenolol, metoprolol, propranolol, nadolol, timolol, or pindolol. The authors reported recurrence in 17 of the 52 patients who received beta-blocker therapy and in 28 of the 101 patients who were not given any medication. It was concluded that beta-blockers did not exhibit a significant effect in preventing the recurrence of syncope after a positive isoproterenol tilt test. It should be noted that patients were not treated with the maximal dose of the selected beta-blocker, but with doses similar to those found in previous studies.
In a study by Flevari et al, investigators prospectively randomized patients into a propranolol, nadolol, or placebo group.24 After a short assessment period of 3 months, the authors determined that propranolol, nadolol, and placebo were all equally effective in the treatment of vasovagal syncope.
In the Prevention of Syncope Trial (POST), a total of 208 patients were randomized to receive either metoprolol 25 to 200 mg or placebo.25 A focus of this study was the influence of age on the potential effects of beta-blocker therapy in the treatment of syncope. No significant difference in the number of syncopal episodes was reported between the groups. Therefore, no benefits of beta-blocker therapy for individuals under the age of 42 years were reported nor were any significant trends observed for patients over the age of 42 years.
Selective Serotonin Reuptake Inhibitors: SSRIs, such as sertraline, fluoxetine, and paroxetine, have been evaluated and thought to be beneficial in the treatment of vasovagal syncope. Serotonin has been thought to inhibit sympathetic neural outflow while increasing adrenal sympathetic stimulation. There are three main serotonin (5-hydroxytryptamine [5-HT]) receptors—5-HT1, 5-HT2, and 5-HT3. The inhibition is found to be beneficial in treatment only with the reuptake at 5-HT1 and 5-HT2 receptors. Inhibition of the 5-HT3 receptors has actually been associated with causing vasovagal syncope.26
The first trial to evaluate this class of medication in syncope was completed by Grubb et al.27 It aimed to evaluate the effects of fluoxetine as compared to placebo. Although this study was relatively small, the authors concluded that in the treatment of tilt-table–induced syncope, fluoxetine 20 mg may be an effective option for patients unresponsive to other therapies.
In a subsequent study conducted by Di Girolamo et al, the use of paroxetine in patients who had a positive tilt-table test was investigated in a randomized, double-blind, placebo-controlled approach.26 Patients in the study had failed on previous therapies, which were discontinued before initiating paroxetine. Prior to treatment, the placebo group reported an average of 7.2 syncopal episodes, while the paroxetine group reported an average of 8.1 episodes. Recurrence of spontaneous syncope during the 2-year follow-up was reported to be 17.6% in the paroxetine group as compared to 52.9% in the placebo group. Only one patient in this study requested treatment discontinuation due to side effects.
A few years later, Theodorakis et al conducted a study comparing fluoxetine 20 mg daily to propranolol 10 to 40 mg three times daily and placebo.28 Out of 94 total patients evaluated in this trial over a 6-month period, 13 experienced syncope: 3 in the fluoxetine group, 5 in the propranolol group, and 5 in the placebo group. No significant differences were noted between the groups; therefore, the authors were unable to conclude whether there was any advantage to using fluoxetine over the other agents for syncope.
Fludrocortisone: Volume imbalances, as seen in dehydrated patients and those with electrolyte imbalances, may greatly influence the number of syncopal events patients experience. Fludrocortisone is a synthetic mineralocorticoid that increases sodium and fluid retention. It is frequently used in patients with no underlying cardiovascular diseases. It has been studied in both pediatric and geriatric populations.
In a trial by Scott et al, 59 patients (mean age, 13 years) were randomized to receive either atenolol 25 to 50 mg or fludrocortisone 0.3 mg for 7 days followed by 0.1 mg daily.29 The authors reported no difference in efficacy between the two groups. Of the 59 patients, 7 in the atenolol group reported adverse events (i.e., depression, suicidal ideation, increased irritability, headache, or hypotension) as opposed to 3 in the fludrocortisone group (i.e., facial swelling, bloating, or insomnia).
Hussain et al later studied the tolerance of fludrocortisone in the elderly,30 since this population may often receive fludrocortisone for the treatment of hypotensive disorders, including neurocardiogenic syncope. The authors concluded that during prolonged treatment, this agent is poorly tolerated even at low doses. Adverse events included systolic hypertension, hypokalemia, cardiac failure, and even death. Fludrocortisone may be a better option for younger individuals with no cardiac histories or autonomic failures.10,15
Disopyramide: This medication, used in the treatment of arrhythmias, is yet another potentially useful agent in the treatment of vasovagal syncope. The benefits of this medication are believed to be due to its ability to decrease cardiac contractility and manage heart rate. However, there are certain possible side effects that may limit its use such as drug-induced QT interval prolongation, urinary tract obstruction, and glaucoma. Two small trials have found disopyramide to be effective when used at high trough concentrations, but this increases the consequential anticholinergic potential.17
Kelly et al measured disopyramide concentrations in 15 patients to determine whether or not blood levels correlated with the efficacy of the drug.31 Initial doses were titrated from 450 to 600 mg/day to a final dose of 450 to 1,200 mg/day, depending on blood levels. The average disopyramide concentration in patients who were positive for the tilt-table test was significantly lower than in those who had negative tests. The authors concluded that higher blood levels may be needed to achieve successful treatment of syncope.
Midodrine: This alpha1-adrenergic agonist is used in the treatment of symptomatic orthostatic hypotension. It is known to cause arteriolar constriction and decrease venous pooling.15 Initial unlabeled doses used for vasovagal syncope are 2.5 to 5 mg three times daily. Nausea, headache, and systolic hypertension have been reported in withdrawal of therapy and thought to be mild and infrequent.32
In a study conducted by Sra et al, a total of 11 patients (mean age, 34 years) with recurrent vasovagal syncope despite treatment with conventional medications were evaluated and followed-up for an average of 17 weeks on midodrine.33 One patient discontinued treatment due to headache and hypertension. Of the remaining patients, 5 remained asymptomatic during follow-up and 4 reported improvement in symptoms during that time period compared to a baseline period of time prior to the trial.
In another trial, Ward et al sought to determine the benefit of midodrine on the frequency of neurocardiogenic symptoms and head-up, tilt-table–test responses.34 Sixteen patients (mean age, 56 years) with histories of frequent hypotensive symptoms were evaluated monthly in this randomized, double-blind, placebo-controlled study. Patients who received midodrine had significantly more asymptomatic days (7.3 more symptom-free days) than those who received placebo. Quality-of-life measures also showed more improvement in the midodrine group. In addition, 14 patients who received placebo experienced tilt-table–induced syncope as compared to the 6 patients who received midodrine. The authors concluded that midodrine may be recommended for the treatment of neurocardiogenic syncope in patients with frequent symptoms.
Neurocardiogenic syncope is a disorder that requires careful evaluation, diagnosis, and management. It is essential to rule out any underlying cardiac, neurologic, or other organ system causes in order to minimize the risk of serious complications (i.e., risk of sudden death). Patients should be counseled on sodium-appropriate diets, adequate hydration, maintenance of blood volume, and the warning signs of syncope. Pharmacologic treatment may be considered on an individualized basis. No medication classes are without certain side effects and risks. Therefore, a thorough history, physical examination, and diagnostic screening should be performed for all patients before selecting an appropriate management strategy to prevent or limit recurrent syncopal episodes and their potential consequences, thereby improving quality of life.
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27. Grubb BP, Wolfe DA, Samoil D, et al. Usefulness of fluoxetine hydrochloride for prevention of resistance upright tilt induced syncope. Pacing Clin Electrophysiol. 1993;16:458-464.
28. Theodorakis GN, Leftheriotis D, Livanis E, et al. Fluoxetine vs. propranolol in the treatment of vasovagal syncope: a prospective, randomized, placebo-controlled study. Europace. 2006;8:193-198.
29. Scott W, Pongiglione G, Bromberg B, et al. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol. 1995:76:400-402.
30. Hussain RM, McIntosh S, Lawson J, et al. Fludrocortisone in the treatment of hypotensive disorders in the elderly. Heart. 1996;76:507-509.
31. Kelly PA, Mann DE, Adler SW, et al. Low dose disopyramide often fails to prevent neurogenic syncope during head-up tilt testing. Pacing Clin Electrophysiol. 1994;17:573-576.
32. Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol. 2001;12:935-938.
33. Sra J, Maglio C, Biehl M, et al. Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol. 1997;8:42-46.
34. Ward C, Gray J, Gilroy J, Kenny R. Midodrine: a role in the management of neurocardiogenic syncope. Heart. 1998;79:45-49.
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