Reflex syncope in adults and adolescents: Treatment

INTRODUCTION — Syncope is a clinical syndrome in which transient loss of consciousness (TLOC) is caused by a period of inadequate cerebral blood flow, caused most often by an abrupt drop of systemic blood pressure. Reflex syncope (previously termed neurally mediated syncope) is a condition in which a reflex response causes vasodilatation and/or bradycardia. The heart rate slowing may or may not be profound but results in a heart rate that is slower than appropriate for the falling blood pressure, leading to systemic hypotension and cerebral hypoperfusion with TLOC. Types of reflex syncope include vasovagal syncope (eg, cough syncope, deglutition syncope, and others), situational syncope, carotid sinus syncope, and some cases without apparent triggers (table 1). Vasovagal syncope is by far the most common type of syncope across all age groups.

The treatment of patients with reflex syncope is reviewed here, focusing on preventive measures.

Related issues are discussed separately:

●(See "Syncope in adults: Epidemiology, pathogenesis, and etiologies" and "Syncope in adults: Clinical manifestations and initial diagnostic evaluation" and "Syncope in adults: Management and prognosis".)

●(See "Reflex syncope in adults and adolescents: Clinical presentation and diagnostic evaluation".)

IMMEDIATE MANAGEMENT — The immediate management of syncope to minimize the duration of loss of consciousness and reduce the risk of injury is discussed separately. (See "Syncope in adults: Management and prognosis", section on 'Immediate (emergency) treatment of syncopal patients'.)

GENERAL MEASURES — Therapy for patients with reflex syncope is primarily aimed at patients with recurrent episodes. These are primarily vasovagal faints (eg, with venipuncture) but may also be due to recurrent situational reflex faints, especially cough syncope. No therapy has been proven consistently effective for preventing vasovagal syncope recurrences. However, the measures discussed herein are undertaken to reduce the risk of syncope and/or the risk of injury from syncope.

Treat predisposing conditions — Medical conditions that may increase the risk of syncope (eg, volume depletion that predisposes to vasovagal syncope, pulmonary disease for cough syncope, or esophageal disease in deglutition syncope) should be identified and treated.

Of particular importance, medications that may induce volume depletion (eg, vasodilators, diuretics) should be minimized or avoided to the extent that alternative therapies are available [1,2].

Patient education — Patients should be provided with education regarding the nature, risks, and prognosis of reflex syncope [1,2].

Trigger avoidance — Patients should be advised to take steps to avoid known trigger events. Preventive steps include assuming a protected posture (eg, sitting to avoid prolonged standing), smoking cessation and cough suppression to avoid cough syncope, stool softeners to avoid defecation syncope, avoidance of excessive fluid intake (especially alcohol) prior to bedtime to diminish risk of postmicturition syncope, and avoidance of large gulps of cold drinks or boluses of food to avoid swallow syncope. Other steps that may be helpful include consuming small meals and reducing carbohydrates in the diet. (See "Treatment of orthostatic and postprandial hypotension".)

Recognizing symptoms and taking action — Patients should be educated to recognize early symptoms and take action to avert syncope and reduce the risk of injury. If the symptoms are mild, the patient may perform a physical counterpressure maneuver while moving safely to a seated or supine position, which should terminate the episode. If the symptoms are severe, the patient should move directly to a supine position. In either case, they should remain in a safe, gravitationally neutral position long enough to be sure that all of the warning symptoms have subsided. Arising too soon may trigger a symptom recurrence.

●Counterpressure maneuvers – Patients with vasovagal syncope and prodromal symptoms should be taught how to perform physical counterpressure maneuvers. The rationale for these maneuvers is to reduce venous pooling and thus improve cardiac output. The patient should undertake these maneuvers upon first recognition of premonitory symptoms [1-3] and then assume a supine position. These maneuvers may abort a syncope episode or at least delay it long enough for the patient to move to a safe protected position [4]. While isometric activity may offset a syncopal response, release of this activity may be associated with precipitous decline in heart rate and blood pressure.

Examples of counterpressure maneuvers include:

•Leg-crossing with simultaneous tensing of leg, abdominal, and buttock muscles (very effective).

•Handgrip, which consists of maximum grip on a rubber ball or similar object (effectiveness is limited by hand strength).

•Arm tensing, which involves gripping one hand with the other while simultaneously abducting both arms (effectiveness is limited by arm strength).

The efficacy of these maneuvers was evaluated in a randomized trial of 223 patients with recurrent vasovagal syncope and recognizable prodromal symptoms [5]. Patients were randomly assigned to lifestyle modification (eg, avoidance of triggers, increasing fluid and salt intake, lying down at the onset of prodromal symptoms), or lifestyle modification plus physical counterpressure maneuvers. Over a mean follow-up of 14 months, patients assigned to counterpressure maneuvers were significantly less likely to have recurrent syncope compared with those assigned to lifestyle modification alone (32 versus 51 percent).

●Supine position – Patients should be advised to assume the supine position with legs raised at the onset of severe symptoms or immediately after performing a counterpressure maneuver, whenever feasible. Assuming a seated or squatting position may also prove effective.

Volume support — Patients with recurrent reflex syncope should receive counseling on steps to optimize and maintain intravascular volume, similar to the regimens for orthostatic hypotension (see "Treatment of orthostatic and postprandial hypotension") [1,2,6]. These include:

●Increase fluid intake – A reasonable regimen is ingesting 500 mL of fluid upon waking with a daily target of 1.5 to 3 L. The fluid may be a low-carbohydrate electrolyte-containing drink or water. Patients can conserve resources by adding electrolyte powder to water.

●Liberalizing salt intake – Unless there is a contraindication, a typical target dose is 6 to 10 g of sodium daily. This may be achieved by high sodium-containing food, drink, or salt tablets. Salt tablets are often poorly tolerated from a gastrointestinal perspective, and electrolyte caplets (available on various websites) may be preferred.

●Compression stockings and binders – Compression undergarments may help support intravascular volume. Many options may be found on the internet.

•Compression type "bicycling" shorts are relatively easy to put on and focus on the major muscle groups in the buttocks, thighs, and, to some extent, the abdomen.

•Compression vests or abdominal binders that compress the splanchnic may be helpful as the splanchnic bed is a large, highly compliant vascular bed that can sequester large volumes of blood, but use of these garments may be limited by discomfort. They are only infrequently needed.

•Compression (or support) stockings should extend to the waist as the leg muscles have limited blood volume. However, these stockings are poorly tolerated by many patients. Many individuals find these stockings difficult to put on and take off (especially for older patients) and too hot to wear on warm days. They may be contraindicated for patients with evidence of leg ischemia due to peripheral vascular disease or with extensive lower extremity skin lesions. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Contraindications'.)

Counseling on risk — Patients should be reassured about the benign nature of reflex syncope but, nevertheless, warned about potential for injury due to collapse. While mortality risk is very low, injury and accidents are a concern. The risk of injury is highest in patients who have recurrent syncope, are older adults/frail and at risk of fall-induced injury, or who are active in high-risk settings (eg, commercial vehicle driver, pilot, individuals working on ladders) and wish to continue these activities. Patients with recurrent episodes may require restriction of activities until therapy is shown to be effective. Practitioners should consult local regulations advising patients regarding driving or flying. (See 'Driving restrictions' below.)

Driving restrictions — Although vasovagal syncope generally has a benign prognosis from a mortality perspective, a frequent concern is the potential for accidents and injury, particularly during certain activities such as driving. Clinicians should be familiar with local driving restrictions and reporting requirements for patients with conditions that could impair safe motor vehicle operation. The applicable local laws and regulations vary widely [7,8]. Insurance companies may decline accident coverage for individuals who are restricted from driving.

Nonetheless, given the demands of daily life, it is recognized that adherence to clinician-advised driving restrictions may be low for patients who have been counseled to abstain from driving because of concerns about recurrent syncope [9]. Whether clinicians are legally obligated to report such patients to local authorities varies from region to region.

Yoga training — Some studies suggest that yoga training may reduce susceptibility to vasovagal syncope [10,11]. An open-label trial randomly assigned 49 patients with recurrent episodes to standard measures and 51 to guided yoga training. The mean number of syncopal episodes before the study was 6.36. There were fewer recurrent episodes in Group 2 compared with Group 1 at the third month (0.8 versus 1.8), at the sixth month (1.0 versus 3.4), and at the twelfth month (1.1 versus 3.8).

ADDITIONAL MEASURES

Approach to refractory recurrent syncope — For patients with recurrent syncope despite the general measures described above (see 'General measures' above), treatment is based upon the results of tilt testing and other clinical characteristics.

●For patients ≥40 years of age with recurrent syncope despite general measures, bradycardic or asystolic episodes (≥3 seconds if with syncope, ≥6 seconds if asymptomatic) documented by electrocardiographic monitoring and no major vasodepressor component on tilt testing [12,13], we suggest permanent cardiac pacing [1,2,14,15]. (See 'Pacemaker therapy' below and "Permanent cardiac pacing: Overview of devices and indications".)

●For patients with recurrent syncope despite general measures who do not have an indication for permanent cardiac pacing, we suggest treatment with fludrocortisone or midodrine. The choice of drug is based upon the patient’s clinical characteristics and preferences. Based on limited evidence, fludrocortisone may be preferred for patients with baseline systolic blood pressure <120 mmHg.

Pacemaker therapy

Rationale and limitations — Although there is usually a significant bradycardic response in vasovagal syncope, there has been uncertainty about the role of pacemakers because of the severe vasodepressor reactions often found in most episodes of reflex syncope. This is true even for those patients who have asystole during a tilt-table test [16]. Only in carotid sinus hypersensitivity does pacing seem to be consistently effective.

In vasovagal syncope, pacing may be useful if the patient does not exhibit a prominent vasodepressor response on tilt-table testing [13]. This finding suggests that recurrent vasovagal syncope is predominantly cardioinhibitory in nature and may thereby respond to pacing treatment. (See "Permanent cardiac pacing: Overview of devices and indications".)

In a patient with a mixed response (significant cardioinhibitory and vasodepressor components), dual-chamber permanent pacing may blunt the symptoms. However, many patients with recurrent vasovagal syncope experience a significant fall in blood pressure prior to any significant decline in heart rate, so pacemakers that sense only changes in heart rate cannot provide pacing in a timely manner [17].

Several algorithms (eg, rate-drop response, closed-loop stimulation [CLS]) have been included in pacemakers in an attempt to prevent vasovagal syncope:

●CLS – Dual-chamber permanent pacing with CLS has been the best-studied approach [18-20]. CLS uses a specialized assessment of cardiac contraction changes to intervene with pacing at an early stage of the evolving faint, thereby potentially interrupting its development. Pacemakers that offer CLS should eliminate most if not all symptoms in patients with a pure cardioinhibitory response [18,20].

●Rate-drop response – The rate-drop response provides a high pacing rate temporarily during a detected vasovagal event to help support the circulation; it is less well-studied than is CLS [21].

Efficacy of pacemaker therapy — Evidence from clinical trials suggests a limited role for pacemaker therapy in patients with vasovagal syncope [20-24]. Pacemaker therapy is not helpful as a routine treatment for all patients with vasovagal syncope, but some evidence suggests that pacemakers may be helpful in selected patients with recurrent syncope who have documented asystole ≥3 seconds with syncope or asystole ≥6 seconds without syncope [14]. Pacing effectiveness is limited if the hypotension is predominantly of vasodepressor origin or if bradycardia occurs only late during evolution of the vasovagal event when the hypotension is already severe.

A 2018 meta-analysis suggested that an insertable cardiac monitor (ICM; also referred to as implantable cardiac monitor or implantable loop recorder (see "Ambulatory ECG monitoring", section on 'Insertable cardiac monitor')) may be helpful in identifying patients with recurrent vasovagal syncope who have asystole and are likely to respond to pacemaker therapy [24]. Of 1046 patients with recurrent syncope who were studied by ICM, 201 patients were documented as having an asystolic event (mean duration 12.8 sec) and underwent pacemaker implantation. Follow-up was available in 60 percent of patients with asystolic events. Syncope recurred after pacing in 14.9 percent of patients with an actuarial rate of 13 percent at one year, 21 percent at two years, and 24 percent at three years. On multivariable analysis, positive tilt-test response was the only significant predictor of syncope recurrence (hazard ratio [HR] 4.3, 95% CI 1.4-13). A possible reason for the difference in results between this meta-analysis and earlier studies [22] is the use of ICM to identify candidates for pacing, in contrast to use of tilt testing as a criterion in earlier trials [23].

The above cited meta-analysis included the ISSUE-3 trial in which 511 patients aged ≥40 years with ≥3 syncopal episodes within the prior two years received an ICM [21]. Eighty-nine patients were identified with ≥3 seconds of asystole with syncope or ≥6 seconds of asystole without syncope; of these 89 patients, 77 received a dual-chamber pacemaker and were randomly assigned to having the pacing function programmed ON or OFF. The two-year estimated syncope recurrence rate was 25 percent (95% CI 13-45) with the pacing function ON and 57 percent (95% CI 40-74) with the pacing function OFF.

The later Biosync CLS trial found that pacemakers with a closed loop stimulation (CLS) function (see 'Rationale and limitations' above) reduced the risk of recurrence in selected individuals with reflex syncope identified by tilt test [20]. Patients aged 40 years or older with two or more episodes of unpredictable reflex syncope during the last year and tilt-induced syncope with an asystolic pause longer than 3 sec were randomly assigned to receive either an active (pacing ON; 63 patients) or an inactive (pacing OFF; 64 patients) dual-chamber pacemaker with CLS. After a median follow-up of 11.2 months, syncope occurred in fewer patients in the pacing group than in the control group (16 versus 53 percent; HR 0.23). Minor device-related adverse events were reported in 4 percent.

Drug therapy

Fludrocortisone — Fludrocortisone is a mineralocorticoid that retains salt in the body and thereby enhances fluid retention. It may be helpful when used along with augmented fluid and salt intake as a means of reducing susceptibility to reflex faints. The drug is typically administered as 0.1 to 0.2 mg daily and is well tolerated. It may, however, cause loss of potassium from the body, and this effect should be monitored, with dietary replacement provided as needed. Fludrocortisone should generally be avoided in patients with hypertension or heart failure. Fludrocortisone may also aggravate migraine susceptibility. In terms of dose, 0.2 mg daily is often needed, but over time (and especially if hypertension evolves) the dose can be reduced to 0.1 mg daily or even lower to 0.1 mg two to four times weekly.

In the POST2 Trial, fludrocortisone provided only modest benefit versus placebo [6]. In this trial, 210 patients (median age 30 years, median 15 syncopal spells over a median of 9 years) were randomly assigned to fludrocortisone or placebo. The baseline median systolic blood pressure was 112.5 mmHg. Ninety-six patients had one or more syncope recurrences, and 14 patients were lost to follow-up before syncope recurrence. The frequency of syncope in the fludrocortisone group was nominally but not significantly reduced (HR 0.69, 95% CI 0.46-1.03). In a multivariable model that adjusted for lifetime frequency of spells, fludrocortisone significantly reduced the likelihood of syncope (HR 0.63, 95% CI 0.42-0.94).

Fludrocortisone was not helpful in a small trial in children [25].

Midodrine — Midodrine is a prodrug; the active metabolite is an alpha-1-adrenergic agonist. Contraindications to midodrine therapy include hypertension and urinary retention. The usual starting dose for midodrine is 5 mg three times daily (morning, noon, and late afternoon). The dose range is 2.5 mg, twice daily, four hours apart to 10 mg, three times daily, four hours apart. Dosing within three to four hours of bedtime should be avoided due to potential detrimental impact on sleep. In some patients, 5 mg twice daily is adequate if the patient has had a more positive response to lifestyle-based therapies.

In general, therapy with midodrine should not be considered as a lifelong therapy; patients should be evaluated every three to six months with the goal of reducing or discontinuing the medication if reflex syncope has resolved.

Midodrine is used off-label in the management of reflex syncope, as a beneficial effect was suggested by two small randomized trials and a number of observational studies [26-30]. However, the efficacy of midodrine in reflex syncope is limited, and side effects (including supine hypertension) necessitate termination in a substantial number of cases [31].

The largest randomized trial included 133 patients (mean age 32 years; 73 percent female) with a median of six syncope episodes in the prior year [30]. The median baseline systolic blood pressure was 117 mmHg. The participants were randomly assigned to take midodrine or placebo with 12 months of follow-up. The recurrence of syncope was less frequent in the group receiving midodrine (42 versus 61 percent; relative risk 0.69, 95% CI 0.49-0.97). The number needed to treat to prevent syncope in one patient was 5.3. A subgroup analysis suggested that most of the benefit from midodrine was associated with a baseline systolic blood pressure >120 mmHg. Adverse effects were similar in the two groups.

TREATMENTS WITH UNCERTAIN BENEFIT

Orthostatic training — The efficacy of orthostatic training has not been established [15]. Four randomized controlled trials found that home orthostatic training in patients with syncope and positive tilt-table tests did not reduce tilt-positive responses or spontaneous syncopal events [32-35]. One of these studies suggested a possible benefit in the subset of patients with vasodepressor-type syncope [35].

Unproven drug therapies — A variety of medications other than midodrine and fludrocortisone have been used (sometimes in an off-label fashion) in the management of patients with vasovagal syncope [1,2]. None of these drugs are deemed to be consistently effective, and they should be used as a last resort. These medications, including serotonin reuptake inhibitors, anticholinergics (eg, disopyramide, scopolamine), theophylline, desmopressin, and erythropoietin, should only be used in patients who have ongoing issues in spite of reassurance, physical counterpressure maneuvers, and volume support with liberal sodium and fluid intake. The limited available evidence for these supplemental medications in all cases is largely based on small and/or uncontrolled series.

Beta blockers — The available evidence does not support efficacy of beta blockers for treatment of reflex syncope [2], although these drugs have been commonly used to treat this condition based on a proposed role of a catecholamine trigger for vasovagal events [36]. At least four randomized trials have failed to show a benefit compared with placebo [1,37-40] despite observational data that suggested a benefit [41-43].

The best data come from the POST trial, which enrolled 208 patients with recurrent syncope and an abnormal tilt-table test [39]. The patients were randomly assigned to treatment with placebo or metoprolol (titrated to 200 mg daily or the highest tolerated dose; average dose 122 mg daily). At one year, the rate of recurrent syncope was 36 percent in both groups, with no benefit in any prespecified subgroups.

Vasoconstrictors other than midodrine — There is insufficient evidence to support the use of vasoconstrictors other than midodrine to treat reflex syncope:

●Etilefrine – The alpha agonist etilefrine was ineffective in a placebo-controlled study of 126 patients [2,44].

●Droxidopa – This synthetic amino acid is converted in the body to norepinephrine and is approved by the US Food and Drug Administration for short-term use in adults with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure. This agent may be an alternative to midodrine, but supportive evidence for use to treat reflex syncope is lacking [45]. (See "Treatment of orthostatic and postprandial hypotension".)

●A preliminary report of seven patients refractory to all other medical therapies suggested benefit from methylphenidate [46]. This agent shares some properties with the amphetamines. It is a peripheral vasoconstrictor and stimulates the central nervous system.

Other drugs

●SSRIs – Small studies have suggested that selective serotonin reuptake inhibitors (SSRIs) such as sertraline, fluoxetine, or paroxetine may reduce symptoms in patients with vasovagal syncope [40,47,48]. However, a study found that paroxetine did not prevent a vasovagal reaction to carotid sinus massage and/or lower body negative pressure in healthy volunteers [49].

●Disopyramide – Disopyramide may be useful due to its negative inotropic (inhibition of myocardial mechanoreceptors) and anticholinergic properties [50]. However, despite apparent benefit in observational studies [50,51], a small controlled trial showed that the rate of recurrent syncope at 29 months was similar with disopyramide and placebo (27 versus 30 percent) [52]. Overall, the potential risks of disopyramide (a Class 1 antiarrhythmic drug that causes QT prolongation) outweigh a possible benefit.

●Theophylline – Small studies have suggested that theophylline may reduce the risk of recurrent reflex syncope [53]. Theophylline may helpful for patients with a mixed vasodepressor and bradycardic response with associated fatigue during the episodes, but data are lacking to support this clinical observation.

Ganglionic ablation — Radiofrequency ablation has been proposed as a means of reducing vagal inputs to the heart and diminishing susceptibility to reflex vasovagal faints. The methodologies and overall clinical experience remain in their infancy, although there has been increasing interest [54-56]. Use of this procedure should be restricted to prospective clinical trials [12].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Syncope".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Syncope (fainting) (The Basics)")

●Beyond the Basics topic (see "Patient education: Syncope (fainting) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Reflex syncope is a condition in which a reflex response causes vasodilatation and/or bradycardia (which may not be profound but is nevertheless slower than appropriate for the falling blood pressure), leading to systemic hypotension and cerebral hypoperfusion with transient loss of consciousness (TLOC). Types of reflex syncope include vasovagal syncope, situational syncope, carotid sinus syncope, and some cases without apparent triggers (table 1). Vasovagal syncope is the most common type of syncope. (See 'Introduction' above.)

●General measures – General measures for patients with recurrent reflex syncope include (see 'General measures' above):

•Treatment of predisposing conditions – This includes treatment of pulmonary disease for cough syncope. (See 'Treat predisposing conditions' above.)

•Patient education – This includes education on trigger avoidance, need for volume support with high daily fluid and salt intake (if not contraindicated), symptom recognition and appropriate action to avoid risk of injury, and applicable driving restrictions. Patients with vasovagal syncope and prodromal symptoms are counseled to use counterpressure maneuvers (eg, leg crossing) upon first recognition of premonitory symptoms and to move to a supine position as soon as feasible when symptoms develop. (See 'Patient education' above.)

•Driving restrictions – As the regulations and restrictions on driving differ widely depending upon local law, clinicians should become familiar with the pertinent local regulations. (See 'Driving restrictions' above.)

●Management of refractory recurrent syncope – For patients with recurrent syncope despite the general measures described above, treatment is based upon the results of tilt testing and other clinical characteristics. (See 'Approach to refractory recurrent syncope' above.)

•For bradycardic or asystolic episodes – For patients ≥40 years of age with recurrent syncope despite general measures, spontaneous bradycardic or asystolic episodes (≥3 seconds if with syncope, ≥6 seconds if asymptomatic) documented by ambulatory electrocardiographic monitoring and no major vasodepressor component (documented by tilt test), we suggest permanent cardiac pacing (Grade 2C). (See 'Pacemaker therapy' above.)

•For other types of episodes – For patients with recurrent syncope despite general measures who do not have an indication for permanent cardiac pacing, we suggest treatment with fludrocortisone or midodrine (Grade 2C). The choice of drug is based upon the patient’s clinical characteristics and preferences. Based on limited evidence, fludrocortisone may be preferred for patients with baseline systolic blood pressure <120 mmHg.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Brian Olshansky, MD, who contributed to earlier versions of this topic review.