Discussion

Vasovagal syncope is common both in childhood and adulthood, and it is usually considered as benign symptom. The pathophysiological mechanism is not clear; however, a sudden sympathetic suppression resulting in vasodilation, hypotension, and/or bradycardia is considered to be the cause. The diagnosis is based entirely on clinical signs and symptoms. ^{Reference Driscoll, Jacobsen, Porter and Wollan10–Reference Wieling, Jardine and de Lange12}

The starting treatment of vasovagal syncope is providing adequate information about the factors triggering syncope, patient’s awareness of prodromal symptoms, and avoiding prolonged standing, rapid change of position, hot environments, and dehydration. Moreover, non-pharmacological treatment methods such as increased fluid and salt intake, physical exercise, counter pressure manoeuvres are administered. ^{Reference Wang, Li, Liao, Tian, Huang and Dong13} However, syncope episodes continue in many patients despite the treatment. Furthermore, additional treatment approaches are required when frequent recurrences impair the quality of life and the risk of traumatic injury increases. In studies conducted with adults in this patient group, it has been suggested that treatment methods such as atenolol, paroxetine, midodrine, disopyramide, and permanent cardiac pacing are partially beneficial in reducing and preventing vasovagal syncope recurrences. ^{Reference Mahanonda, Bhuripanjo and Kangkate14–Reference Connolly, Sheldon and Roberts17} There are limited numbers of studies on pharmacological treatment in refractory vasovagal syncope in childhood. Salim et al ^{Reference Salim and Di Sessa18} compared fludrocortisone and sodium intake with placebo group, and it was suggested that the placebo group had better results in terms of symptom recurrence (symptoms recurred in 10 of 18 children receiving fludrocortisone and sodium and in 5 of 14 children receiving placebo). In a prospective, randomised study, ^{Reference Zhang, Jin, Wang, Chen, Tang and Du19} a group receiving metoprolol was compared with a group receiving conventional treatment which includes increasing water and salt intake, not standing too long without moving, and avoiding stressful situations which previously caused syncope. During 22 ± 10 months of follow-up, it was identified that the recurrence of vasovagal syncope was similar in children and adolescents receiving metoprolol to the patients receiving conventional treatment (43 versus. 29%, respectively, p = 0.695).

In a study where children with recurrent vasovagal syncope received midodrine, midodrine was used as a first line therapy for recurrent syncope episodes. A total of 26 children were followed for 6 months. During the follow-up period, syncope recurrence rate was 22% in the Group 1 (receiving midodrine) and 80% in the Group 2 (receiving only conventional non-pharmacological treatment). It was reported that both effectivity rate observed with the tilt test and the rate of remaining syncope free were significantly higher in the patients receiving midodrine treatment than those receiving conventional treatment (p = 0.03 and p = 0.023, respectively) despite a low dose level of 2.5 mg/day as the starting dose of midodrine treatment was administered to the patients included in the study. ^{Reference Qingyou, Junbao and Chaoshu20} However, this study was conducted on those who were hospitalised for syncope, agreed to take tilt tests, and had “positive” tilt table test results. According to current American Heart Association and European Society of Cardiology guidelines, ^{Reference Brignole, Moya and de Lange3,Reference Shen, Sheldon and Benditt21} tilt tests are no longer required to diagnose simple vasovagal syncope. This new requirement is the result of a high incidence of “false negatives”. The use of tilt table test in the diagnosis of vasovagal syncope should be considered to those patients who have a very typical history of vasovagal syncope, but do not faint during orthostatic testing, and those patients who do not have a vasovagal history, but faint during orthostatic testing and have false positive results. Similarly, there is no point in evaluating the effectiveness of a treatment for the same reasons. We did not use tilt table tests in the present study. Other tests for aetiology were performed and the diagnosis of vasovagal syncope was made through medical history and elimination of other diseases.

Midodrine is a peripheral vasoconstrictor alpha-agonist which increases peripheral vascular resistance and reduces venous pooling. Midodrine, following oral administration, is rapidly metabolised to the active matter desglymidodrine. Its effects on alpha adrenergic receptors on the veins results vasoconstriction. Desglymidodrin passes poorly through the blood–brain barrier, and therefore has little or no effect on the central nervous system. Midodrine has little cardiostimulatory or arrhythmic effect on normal hearts when compared to beta-adrenergic receptors that predominantly mediate cardiac inotropic effects. ^{Reference Ward, Gray and Gilroy15,Reference Sra, Maglio and Biehl23–Reference Kaufmann, Saadia and Voustianiouk26}

Properties of midodrine are ideal for improving the response to orthostatic stress as all acute and chronic orthostatic intolerance forms are primarily related to decreased vasoconstriction and/or increased venous pooling. Therefore, it creates a tendency to treat or prevent hypotension with increased blood volume. The administration of midodrine increases systolic and diastolic blood pressure in patients with decreased blood pressure. It was suggested in a series of studies conducted in adults with orthostatic hypotension, paroxysmal orthostatic tachycardia, and vasovagal syncope that midodrine had a beneficial effect. ^{Reference Sra, Maglio and Biehl23–Reference Kaufmann, Saadia and Voustianiouk26}

In clinical practice, the first intervention for vasovagal syncope is non-pharmacological methods. ^{Reference Brignole, Moya and de Lange3,Reference Shen, Sheldon and Benditt21,Reference Sanatani, Chau and Fournier22} In the present study, pharmacological treatment was administered only when patients had at least three syncope recurrences after utilising non-pharmacological treatments such as aggressive fluid and salt intake, using counterpressure manoeuvres, and exercise. It was shown that administering midodrine was safe and effective in the treatment of children with vasovagal syncope who did not benefit from traditional non-pharmacological treatment. It prevented syncope recurrence in 87.5% of patients in the first 6 months, and it was successful with a rate of 96% in remaining patients with dose escalation in 1 year follow-up.

Mitro et al reported in their study on 41 adults with recurrent vasovagal syncope episodes and a positive tilt table test result that 38 of 39 patients (97%) with negative repeated tilt table test remained free of syncope recurrence during 19 ± 9 months of follow-up in patients who received midodrine. Effective midodrine dose was 5 mg/day in 25 patients and 10 mg/day in 16 patients. ^{Reference Mitro, Trejbal and Rybar6} In our study, effective midodrine dose was 5 mg/day in 21 patients and 7.5 mg/day in 3 patients. Moreover, similar to the results of the study by Mitro et al, 23 of 24 patients (96%) remained free of syncope recurrence. Sra et al ^{Reference Sra, Maglio and Biehl23} administered midodrine to 11 adult patients diagnosed with vasovagal syncope resistant to other medications. They reported that symptoms completely disappeared with a dose of 7.5 mg/day in five patients (46%). There was significant improvement in four patients, one patient discontinued the treatment due to its side effects, and one patient still had syncope episodes despite midodrine treatment. Ward et al ^{Reference Ward, Gray and Gilroy15} performed a double-blind, placebo-controlled trial in 16 tilt positive patients with frequent syncope episodes. They reported that 14 of 16 patients receiving placebo and only 6 of 16 patients receiving midodrine had positive repeated tilt table test results. They also suggested that midodrine treatment caused a significant increase in the number of symptom-free days.

Unlike these studies, in a randomised double-blind crossover study ^{Reference Romme, van Dijk and Go-Schon27} (STAND Trial) conducted in the Netherlands on midodrine efficacy in adult patients with recurrent vasovagal syncope episodes resistant to non-pharmacological treatment, a total of 28 patients alternately received placebo and midodrine treatments for 3 months. Unlike previous studies using the head-up tilt test, it was aimed to measure the efficacy by recording recurrent syncope and presyncope episodes in daily life. There was no dose adjustment in patients with recurring episodes, and the patients received a fixed dose of midodrine 5 mg BID. Researchers stated that there was no statistically significant difference between additional midodrine and placebo treatment in terms of syncopal recurrence, and that the efficacy of midodrine treatment was much less than expected in patients who did not respond to non-pharmacological treatment. Therefore, they did not recommend administering midodrine as routine additional treatment in those patients. They explained the different results from previous studies which investigated midodrine efficacy without a control group, decreases in symptom frequency could be expected in patients with vasovagal syncope regardless of treatment, and thus, placebo-controlled studies should be conducted to investigate whether midodrine treatment had therapeutic effect on the expected decrease in the frequency of recurrence following the diagnosis. However, they did not make any dose adjustments in patients with recurring episodes, and the patients received a fixed dose of midodrine 5 mg BID in the study. We suggest that syncope recurrences may be prevented with increasing dose escalation in some of patients and this may affect the results of the study. Moreover, the study was valuable in that it was randomised and double-blind; however, it was conducted in an adult population. There is limited study on vasovagal syncope mechanism in paediatric age, especially in adolescence, and different results may be obtained compared to adulthood.

Midodrine is considered quite safe in terms of side effects. In previous studies, it was reported that supine hypertension, headache, pilomotor reactions, and gastrointestinal symptoms were rare. In the STAND Trial ^{Reference Romme, van Dijk and Go-Schon27} conducted in the Netherlands, when the patients were compared in terms of side effects, those who received placebo reported more side effects than those who received midodrine treatment, which is quite interesting (headache, cold sensations, and nausea in those receiving midodrine; headache and fatigue/loss of energy in those receiving placebo, 57 versus. 48%). Midodrine is actually a “prodrug” converted into desglymidodrine which is an active metabolite with high bioavailability. This offers several advantages. As a prodrug, it enters into the system as a partially active agent and minimises the possibility of gastrointestinal side effects. As midodrine does not pass through the blood–brain barrier, it does not have any stimulant effect on the central nervous system. Therefore, it does not have a potential for abuse. ^{Reference Grubb, Karas, Kosinski and Boehm25,Reference Kaufmann, Saadia and Voustianiouk26} In the present study, there was no side effect other than mild headache in 2/24 patients.