The Journal of Pediatrics
Volume 149, Issue 6 , Pages 740-742, December 2006

Midodrine for the treatment of vasovagal syncope (simple FAINT)

  • Julian M. Stewart, MD, PhD

      Affiliations

    • Corresponding Author InformationReprint requests: Julian M. Stewart MD, PhD, Professor of Pediatrics and Physiology, Research Division and Hypotension Laboratory, New York Medical College, Suite 3050, 19 Bradhurst Avenue, Hawthorne, NY 10532

Center for Hypotension Department of Pediatrics and Physiology New York Medical College Valhalla, NY

Article Outline

Abbreviations: POST, Prevention of Syncope Trials

 

Midodrine may be the ideal drug for all forms of orthostatic hypotension associated with normal blood volume. After oral administration, midodrine is metabolized by deglycination to the active product desglymidodrine, an alpha-1–adrenergic agonist.1 It exerts its effects on alpha-adrenergic receptors of the arteriolar and venular vasculature, producing vasoconstriction and venoconstriction, respectively. This increases blood pressure through a combination of increased ventricular afterload and enhanced preload (venous return).2 Desglymidodrine crosses the blood-brain barrier poorly and thus exerts little effect on the central nervous system. Because cardiac inotropic effects are mediated predominantly by beta-adrenergic receptors, midodrine has little cardiostimulatory or arrhythmic effects in normal hearts, but must be used with caution in ischemic or myopathic hearts, in which cardiogenic alpha-adrenergic effects have been demonstrated.3 In addition, alpha-1–adrenergic stimulation can produce smooth muscle contraction within the coronary arteries.4

See related article, p 777

Midodrine’s properties are ideal for improving the response to orthostatic stress, because essentially all forms of acute and chronic orthostatic intolerance are associated with decreased vasoconstriction and/or increased venous pooling. Thus, along with increasing blood volume, midodrine affords a system-wide capability of correcting or preventing hypotension. Indeed, its first Food and Drug Administration–approved use has been in treating neurogenic orthostatic hypotension.5, 6 Administration of midodrine increases standing, sitting, and supine systolic and diastolic blood pressure in patients with reduced blood pressure of diverse etiologies. It should not be given if the patient is planning to remain supine, because supine hypertension will result.7 The plasma levels of the prodrug peak after about 1/2 hour and decline with a half-life of approximately 25 minutes, whereas the metabolite reaches peak blood concentrations about 1 to 2 hours after administration and has a half-life of about 3 to 4 hours. Its short duration is both bane and boon—bane in that frequent dosing is required (typically every 4 hours, with the last dose given at least 4 hours before bedtime), boon because side effects such as piloerection, pruritus, paraesthesias, urinary retention, and chills, should they occur, are short-lived.

Furthermore, midodrine has been extensively studied in numerous investigations large and small, blinded and placebo-controlled, and has demonstrated clinical efficacy. These include the initial studies of true orthostatic hypotension8 with autonomic failure,6, 9 studies of orthostatic intolerance related to space flight,10, 11 and a larger group of studies dealing with vasovagal or neurogenic syncope.12, 13, 14, 15 However, until now no such study has been performed in pediatric patients with vasovagal syncope.

In this issue of The Journal, Qingyou et al16 have performed this task in their nicely crafted study using low-dose midodrine to treat simple vasovagal faint. The results in 26 children (10 boys, 16 girls; ranging from 6 to 16 years old) are compelling. Subjects were studied after being withdrawn from medications. After an initial 60-degree upright tilt table test confirmed simple faint, the subjects were evenly divided among those receiving conventional therapy comprising training in aversive physical maneuvers and salt and water loading and those receiving midodrine in addition to conventional therapy. The midodrine group received a rather small starting dose of midodrine, only 1.25 mg given twice a day. Both groups underwent retilting; if fainting continued within the drug treatment group, then the midodrine dose was increased to 2.5 mg twice a day, still a rather small dose. Those receiving the large dose were tilted a third time. During a 6-month follow-up period, the midodrine dose seems to have been effective in preventing recurrent syncope in 80% of the midodrine-treated patients, compared with 20% of the non–midodrine-treated patients, with no significant alterations in heart rate, blood pressure, or physical activities. These results are most important in highlighting the utility of rather small doses in children that are well tolerated, free of side effects, and apparently efficacious in twice-daily doses.

The results must be interpreted with care, however. Studies were performed in a select population; the results are strictly applicable only to a highly select group of patients: those who are hospitalized for syncope, who agree to undergo tilt tests, and who have “positive” tilt test results. Current American Heart Association guidelines17 no longer require tilt testing to diagnose simple faint. Part of this new requirement relates to a high incidence of “false negatives”—patients who have a history highly consistent with vasovagal faint but who fail to faint during orthostatic testing—as well as “false positives”-patients who have no history of vasovagal faint but who faint during orthostatic testing, particularly in young persons.18, 19

The study was neither blinded nor placebo-controlled. The best and most complete studies of simple faint, such as the Prevention of Syncope Trials (POST,)20 used placebo control and a double-blind design. In the POST study, the expected utility of standard beta-1 blockade with metoprolol was shown to be similar to that of placebo. In fact, no large study using placebo control and a double-blind design has demonstrated effective medical therapy for syncope in young patients, although further studies are currently underway (eg, POST-II). The placebo effect per se remains unstudied in the pediatric age group. The placebo effect as studied in adults21 is often quite large, leading me to speculate that placebo might be the best and safest form of initial therapy, nocebo effects22 notwithstanding. This is potentially as large as the medication effect detected here, but perhaps not. Nevertheless, in the absence of a placebo control arm, the current knowledge base remains incomplete.

Caveats notwithstanding, I now personally endorse the informed use of low-dose midodrine as a first-line therapy for vasovagal syncope in children and propose a large-scale double-blind, placebo-controlled study of the efficacy of midodrine (and perhaps other medications) to treat vasovagal syncope in children.

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References 

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PII: S0022-3476(06)00785-2

doi:10.1016/j.jpeds.2006.08.026

Refers to article:

  • The efficacy of midodrine hydrochloride in the treatment of children with vasovagal syncope

    Zhang Qingyou, Du Junbao, Tang Chaoshu
    The Journal of Pediatrics December 2006 (Vol. 149, Issue 6, Pages 777-780)

The Journal of Pediatrics
Volume 149, Issue 6 , Pages 740-742, December 2006

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