The foundation for treatment of most NMRS syndromes is patient education.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Provide patients with advice on physical techniques to abort imminent NMRS or prevent recurrence.
There is insufficient evidence to support the use of most pharmacologic treatments for NMRS. Several drugs have been proposed, but there are few randomized clinical trials to rely on.[58]Jacobus JR, Johannes BR, Catherine NB, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004194.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004194.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/21975744?tool=bestpractice.com
Consequently no agent, except perhaps midodrine, can be strongly recommended in the treatment of neurally mediated faints.[59]Izcovich A, González Malla C, Manzotti M, et al. Midodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review. Neurology. 2014 Sep 23;83(13):1170-7.
http://www.ncbi.nlm.nih.gov/pubmed/25150287?tool=bestpractice.com
Patient education
Patient education is an important factor in treatment for all types of NMRS.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Inform patients that although NMRS is rarely life-threatening, these types of faints tend to recur and injury can result if preventive measures are not taken.[2]Brignole M, Moya A, de Lange FJ, et al; ESC Scientific Document Group. 2018 ESC guidelines for the diagnosis and management of syncope. Eur Heart J. 2018 Jun 1;39(21):1883-948.
https://academic.oup.com/eurheartj/article/39/21/1883/4939241
http://www.ncbi.nlm.nih.gov/pubmed/29562304?tool=bestpractice.com
Patients need to recognize and respond to warning symptoms, and may benefit from knowledge of basic pathophysiology; such understanding reduces injury risk and may ultimately enhance treatment compliance. Educate patients on the avoidance of triggers such as prolonged standing, warm environments, and coping with dental and medical settings.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Medications that cause hypotension may be reduced or withdrawn where appropriate and safe.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Patients susceptible to recurrent vasovagal faints should learn techniques for both aborting attacks and reducing susceptibility to future episodes (e.g., physical maneuvers, hydration with electrolyte-rich fluids). These patients should also be taught the value and possible risks of increased salt intake. In situational faints, inform patients of the potential for ameliorating or entirely avoiding triggers. For instance, suppression by smoking cessation in cough syncope, and sitting to void in micturition syncope. In some cases, desensitization techniques (e.g., syncope associated with fear of air flight) may help. Those with carotid sinus syndrome (CSS) should avoid wearing tight collars or neckties, although cardiac pacing is also usually recommended.
Physical techniques
1. Physical counter-pressure maneuvers (PCM)
PCM are advocated to abort imminent NMRS or orthostatic faints when warning symptoms are first recognized. Useful techniques include squatting, arm tensing, leg crossing, and leg crossing with tensing of the lower body muscles.[60]Krediet CT, van Dijk N, Linzer M, et al. Management of vasovagal syncope: controlling or aborting faints by leg crossing and muscle tensing. Circulation. 2002 Sep 24;106(13):1684-9.
https://www.ahajournals.org/doi/10.1161/01.CIR.0000030939.12646.8F
http://www.ncbi.nlm.nih.gov/pubmed/12270863?tool=bestpractice.com
[61]Brignole M, Croci F, Menozzi C, et al. Isometric arm counter-pressure maneuvers to abort impending vasovagal syncope. J Am Coll Cardiol. 2002 Dec 4;40(11):2053-9.
https://www.jacc.org/doi/10.1016/S0735-1097%2802%2902683-9
http://www.ncbi.nlm.nih.gov/pubmed/12475469?tool=bestpractice.com
In the Physical Counterpressure Manoeuvres Trial, physical maneuvers reduced total burden and recurrence rate of syncopal events.[62]van Dijk N, Quartieri F, Blanc JJ, et al; PC-Trial Investigators. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol. 2006 Oct 17;48(8):1652-7.
https://www.jacc.org/doi/10.1016/j.jacc.2006.06.059
http://www.ncbi.nlm.nih.gov/pubmed/17045903?tool=bestpractice.com
Consequently, PCM should be an essential part of the treatment strategy for vasovagal faints. Data are lacking for the role of PCM in patients with situational faints or carotid sinus syncope, but may have been used in selected cases.
2. Tilt training (standing training)
The principal goal of tilt training (more accurately termed standing training) is to enhance the neurovascular response to orthostatic stress.[63]Ector H, Reybrouck T, Heidbüchel H, et al. Tilt training: a new treatment for recurrent neurocardiogenic syncope and severe orthostatic intolerance. Pacing Clin Electrophysiol. 1998 Jan;21(1 Pt 2):193-6.
http://www.ncbi.nlm.nih.gov/pubmed/9474671?tool=bestpractice.com
The favored method entails standing training (usually at home) for progressively longer periods of time over 10-12 weeks. The recommended starting duration is 3-5 minutes twice daily; standing duration is then gradually lengthened every 3 or 4 days to 30-40 minutes twice daily.
The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) advise that the usefulness of orthostatic training is uncertain in patients with frequent vasovagal syncope.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Nonrandomized studies suggest that standing training reduces susceptibility to reflex syncope if undertaken consistently.[64]Di Girolamo E, Di Iorio C, Leonzio L, et al. Usefulness of a tilt training program for the prevention of refractory neurocardiogenic syncope in adolescents: a controlled study. Circulation. 1999 Oct 26;100(17):1798-801.
https://www.ahajournals.org/doi/10.1161/01.CIR.100.17.1798
http://www.ncbi.nlm.nih.gov/pubmed/10534467?tool=bestpractice.com
[65]Reybrouck T, Heidbüchel H, Van De Werf F, et al. Long-term follow-up results of tilt training therapy in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol. 2002 Oct;25(10):1441-6.
http://www.ncbi.nlm.nih.gov/pubmed/12418741?tool=bestpractice.com
[66]Kinay O, Yazici M, Nazli C, et al. Tilt training for recurrent neurocardiogenic syncope: effectiveness, patient compliance, and scheduling the frequency of training sessions. Jpn Heart J. 2004 Sep;45(5):833-43.
http://www.ncbi.nlm.nih.gov/pubmed/15557724?tool=bestpractice.com
However, compliance is often a problem because the process is time consuming and boring.[13]Runser LA, Gauer RL, Houser A. Syncope: evaluation and differential diagnosis. Am Fam Physician. 2017 Mar 1;95(5):303-12.
https://www.aafp.org/pubs/afp/issues/2017/0301/p303.html
http://www.ncbi.nlm.nih.gov/pubmed/28290647?tool=bestpractice.com
Randomized controlled trials have been less encouraging, suggesting that the method may not be as effective as originally thought; further study is needed.[67]On YK, Park J, Huh J, et al. Is home orthostatic self-training effective in preventing neurally mediated syncope? Pacing Clin Electrophysiol. 2007 May;30(5):638-43.
http://www.ncbi.nlm.nih.gov/pubmed/17461874?tool=bestpractice.com
[68]Gurevitz O, Barsheshet A, Bar-Lev D, et al. Tilt training: does it have a role in preventing vasovagal syncope? Pacing Clin Electrophysiol. 2007 Dec;30(12):1499-505.
http://www.ncbi.nlm.nih.gov/pubmed/18070305?tool=bestpractice.com
Pharmacotherapy
Volume expansion is an essential recommendation for most patients who require medical therapy for vasovagal faints, but evidence is limited.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
[27]Sandhu RK, Raj SR, Manlucu J, et al; Primary Writing Committee. Canadian Cardiovascular Society clinical practice update on the assessment and management of syncope. Can J Cardiol. 2020 Aug;36(8):1167-77.
https://www.onlinecjc.ca/article/S0828-282X(19)31549-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/32624296?tool=bestpractice.com
Conventional approaches include increased dietary salt and electrolyte-rich sports drinks. The primary safety concern is initiation of hypertension. Fortunately, this is rare in younger patients, but it is a concern in older patients. Contraindications to increased salt and fluid intake include history of hypertension, renal disease, heart failure, or cardiac dysfunction.
If a prescription drug is needed for volume expansion, fludrocortisone can be used.[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com
Adverse effects include hypertension and hypokalemia. However, clinical evidence for the efficacy of fludrocortisone is weak.[69]Scott WA, Pongiglione G, Bromberg BI, et al. Randomized comparison of atenolol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol. 1995 Aug 15;76(5):400-2.
http://www.ncbi.nlm.nih.gov/pubmed/7639169?tool=bestpractice.com
[70]Salim MA, Di Sessa TG. Effectiveness of fludrocortisone and salt in preventing syncope recurrence in children: a double-blind, placebo-controlled, randomized trial. J Am Coll Cardiol. 2005 Feb 15;45(4):484-8.
https://www.jacc.org/doi/10.1016/j.jacc.2004.11.033
http://www.ncbi.nlm.nih.gov/pubmed/15708690?tool=bestpractice.com
The Second Prevention of Syncope Trial (POST II) reported a nonsignificant decrease in episodes of vasovagal syncope in the fludrocortisone group compared with placebo.[71]Sheldon R, Morillo CA, Krahn A, et al. A randomized clinical trial of fludrocortisone for the prevention of vasovagal syncope (POST II). Paper presented at: Canadian Cardiovascular Congress 2011. Vancouver, Canada. Abstract 903. Can J Cardiol. 2011 Sep 1;27(suppl 5):S335-6.
https://www.onlinecjc.ca/article/S0828-282X(11)01050-6/fulltext
Among other drugs suggested for preventing vasovagal faints, beta-blockers remain widely used despite absence of strong supporting evidence. Beta-blockers were initially advocated to prevent reflex syncope by diminishing the impact of the adrenergic surge that commonly precedes and may be part of the vasovagal trigger. The positive supportive evidence is derived largely from small observational studies and one single small randomized controlled trial.[72]Mahanonda N, Bhuripanyo K, Kangkagate C, et al. 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 Dec;130(6):1250-3.
http://www.ncbi.nlm.nih.gov/pubmed/7484777?tool=bestpractice.com
One large randomized controlled trial (POST I) showed no statistically significant benefit with beta-blockers in patients of all age ranges.[73]Sheldon R, Connolly S, Rose S, et al; POST Investigators. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation. 2006 Mar 7;113(9):1164-70.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.105.535161
http://www.ncbi.nlm.nih.gov/pubmed/16505178?tool=bestpractice.com
Vaso- and venoconstrictors have also been of interest for preventing faints associated with orthostatic intolerance. Midodrine is the principal drug in this class used for this indication. While midodrine has been studied most extensively in patients with orthostatic hypotension, research suggests it is also effective in vasovagal syncope.[74]Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med. 1993 Jul;95(1):38-48.
http://www.ncbi.nlm.nih.gov/pubmed/7687093?tool=bestpractice.com
[75]Ward CR, Gray JC, Gilroy JJ, et al. Midodrine: a role in the management of neurocardiogenic syncope. Heart. 1998 Jan;79(1):45-9.
https://heart.bmj.com/content/79/1/45
http://www.ncbi.nlm.nih.gov/pubmed/9505918?tool=bestpractice.com
[76]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 Aug;12(8):935-8.
http://www.ncbi.nlm.nih.gov/pubmed/11513446?tool=bestpractice.com
In one multicenter randomized controlled trial (POST IV), midodrine reduced the recurrence of syncope compared with placebo in healthy, younger patients.[77]Sheldon R, Faris P, Tang A, et al; POST 4 investigators. Midodrine for the prevention of vasovagal syncope: a randomized clinical trial. Ann Intern Med. 2021 Oct;174(10):1349-56.
http://www.ncbi.nlm.nih.gov/pubmed/34339231?tool=bestpractice.com
Methylphenidate has also been proposed for midodrine-intolerant patients, although its value has not been established.[78]Grubb BP, Kosinski D, Mouhaffel A, et al. A. The use of methylphenidate in the treatment of refractory neurocardiogenic syncope. Pacing Clin Electrophysiol. 1996 May;19(5):836-40.
http://www.ncbi.nlm.nih.gov/pubmed/8734752?tool=bestpractice.com
Etilephrine, which is a modest alpha- and beta-agonist, was found to be ineffective at preventing vasovagal faints in the Vasovagal International Study.[79]Sutton R, Brignole M, Menozzi C, et al; the Vasovagal Syncope International Study (VASIS) Investigators. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope. Pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000 Jul 18;102(3):294-9.
https://www.ahajournals.org/doi/10.1161/01.CIR.102.3.294
http://www.ncbi.nlm.nih.gov/pubmed/10899092?tool=bestpractice.com
Several other drug classes have been advocated but remain of uncertain value at best. The most important among these are the selective serotonin-reuptake inhibitors (SSRIs).[80]Grubb BP, Wolfe DA, Samoil D, et al. Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt induced syncope. Pacing Clin Electrophysiol. 1993 Mar;16(3 Pt 1):458-64.
http://www.ncbi.nlm.nih.gov/pubmed/7681197?tool=bestpractice.com
SSRI pretreatment is thought to blunt a hypothesized hypersensitive serotonin response in the central nervous system that may contribute to triggering NMRS. However, clinical trial results have been mixed.
Disopyramide, pure anticholinergics (e.g., scopolamine), and theophylline were also advocated in the past, but the evidence is unconvincing.
Data are lacking for the role of volume expansion, fludrocortisone, and midodrine in patients with situational faints or carotid sinus syncope, but may have been used in selected cases.
Cardiac pacing
Cardiac pacing may play a role in the treatment of carotid sinus syndrome with documented bradycardia to prevent bradycardia-induced faint. However, patients may remain symptomatic because of persistent vasodepressor response.
The usefulness of pacing in patients with refractory vasovagal syncope is less certain. Intuitively, it was thought that preventing severe bradycardia (cardioinhibitory syncope) by pacing would be desirable. Three unblinded trials showed efficacy for pacing, whereas two subsequent trials that used pacemakers in both treatment arms did not show benefit.[42]Raviele A, Giada F, Menozzi C, et al; Vasovagal Syncope and Pacing Trial Investigators. A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The Vasovagal Syncope and Pacing Trial (SYNPACE). Eur Heart J. 2004 Oct;25(19):1741-8.
https://academic.oup.com/eurheartj/article/25/19/1741/528715
http://www.ncbi.nlm.nih.gov/pubmed/15451153?tool=bestpractice.com
[79]Sutton R, Brignole M, Menozzi C, et al; the Vasovagal Syncope International Study (VASIS) Investigators. Dual-chamber pacing in the treatment of neurally mediated tilt-positive cardioinhibitory syncope. Pacemaker versus no therapy: a multicenter randomized study. Circulation. 2000 Jul 18;102(3):294-9.
https://www.ahajournals.org/doi/10.1161/01.CIR.102.3.294
http://www.ncbi.nlm.nih.gov/pubmed/10899092?tool=bestpractice.com
[81]Ammirati F, Colivicchi F, Santini M; Syncope Diagnosis and Treatment Study Investigators. Permanent cardiac pacing versus medical treatment for the prevention of recurrent vasovagal syncope: a multicenter, randomized, controlled trial. Circulation. 2001 Jul 3;104(1):52-7.
https://www.ahajournals.org/doi/10.1161/hc2601.091708
http://www.ncbi.nlm.nih.gov/pubmed/11435337?tool=bestpractice.com
[82]Connolly SJ, Sheldon R, Roberts RS, et al. 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 Jan;33(1):16-20.
https://www.jacc.org/doi/10.1016/S0735-1097%2898%2900549-X
http://www.ncbi.nlm.nih.gov/pubmed/9935002?tool=bestpractice.com
[83]Connolly SJ, Sheldon R, Thorpe KE, et al; VPS II Investigators. Pacemaker therapy for prevention of syncope in patients with recurrent severe vasovagal syncope. Second Vasovagal Pacemaker Study (VPS II): a randomized trial. JAMA. 2003 May 7;289(17):2224-9.
https://jamanetwork.com/journals/jama/fullarticle/196492
http://www.ncbi.nlm.nih.gov/pubmed/12734133?tool=bestpractice.com
In a randomized crossover study of otherwise healthy patients with refractory vasovagal syncope, dual-chamber closed-loop stimulation (CLS on) reduced syncope recurrence compared with regular pacing (CLS off).[84]Russo V, Rago A, Papa AA, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study. Heart. 2013 Nov;99(21):1609-13.
http://www.ncbi.nlm.nih.gov/pubmed/23723446?tool=bestpractice.com
However, a systematic review found insufficient evidence to support the use of pacemaker treatments.[58]Jacobus JR, Johannes BR, Catherine NB, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD004194.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004194.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/21975744?tool=bestpractice.com
The ACC/AHA/HRS guidelines recommend consideration of dual-chamber pacing in a narrow group of patients who are "40 years of age or older with recurrent vasovagal syncope and prolonged spontaneous pauses".[1]Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines, and the Heart Rhythm Society. Heart Rhythm. 2017 Aug;14(8):e155-217.
https://www.heartrhythmjournal.com/article/S1547-5271(17)30297-7/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/28286247?tool=bestpractice.com