Oral midodrine for prophylaxis against post-spinal anesthesia hypotension during hip arthroplasty in elderly population: a randomized controlled trial.

BACKGROUND: We aimed to evaluate the efficacy of midodrine as a prophylaxis against post-spinal hypotension in elderly patients undergoing hip arthroplasty. METHODS: This randomized controlled trial included elderly patients undergoing hip arthroplasty under spinal anesthesia. Ninety minutes before the procedure, patients were randomized to receive either 5-mg midodrine or placebo (metoclopramide). After spinal anesthesia, mean arterial pressure (MAP) and heart rate were monitored every 2 min for 20 min then every 5 min until the end of the procedure. Post-spinal hypotension (MAP < 80% baseline) was treated with 10 mg ephedrine. The primary outcome was intraoperative ephedrine consumption. Secondary outcomes were the incidence of post-spinal hypotension, bradycardia, and hypertension (MAP increased by > 20% of the baseline reading). RESULTS: We analyzed 29 patients in the midodrine group and 27 in the control group. The intraoperative ephedrine consumption was lower in the midodrine group than in the control group (median [quartiles]: 10 [0, 30] mg versus 30 [20, 43] mg, respectively, P-value: 0.002); and the incidence of intraoperative hypotension was lower in the midodrine group than that in the control group. The incidence of hypertension and bradycardia were comparable between the two groups. CONCLUSION: The use of 5 mg oral midodrine decreased the vasopressor requirements and incidence of hypotension after spinal anesthesia for hip surgery in elderly patients. CLINICAL TRIAL REGISTRATION: This study was registered on September 22, 2022 at clinicaltrials.gov registry, NCT05548985, URL: https://classic. CLINICALTRIALS: gov/ct2/show/NCT05548985 .

Serum uric acid predicts therapeutic response to midodrine hydrochloride in children with vasovagal syncope: a pilot study.

Serum uric acid (UA) level has been proven to be related to several cardiovascular and metabolic diseases. In the present study, we examined if baseline serum UA level could predict the therapeutic efficacy of midodrine hydrochloride on vasovagal syncope (VVS) in children. The pediatric VVS patients who received midodrine hydrochloride from November 2008 to October 2022 were enrolled. After a median treatment duration of 3 months, the therapeutic effect was evaluated. According to the patients' responses to midodrine hydrochloride, which was determined by the recurrence of syncope, they were divided into effective and ineffective groups. The baseline variables were explored using univariable and multivariate logistic analysis. The predictive efficacy was assessed by receiver operating characteristic curve (ROC), precision-recall curve (PR), Hosmer-Lemeshow test, calibration curve, and decision curve analysis (DCA). Totally, 53 participants were included in the study. Among the 51 patients who were successfully followed up, 29 (56.9%) responded to midodrine hydrochloride (effective group), and the other 22 (43.1%) failed to respond to midodrine hydrochloride (ineffective group). The participants in effective group had lower baseline serum UA level than those in ineffective group (276.5 ± 73 µmol/L vs. 332.7 ± 56 µmol/L, p = 0.004). Multivariable logistic analysis showed that serum UA was associated with the therapeutic response (odds ratio (OR): 0.985, 95% confidence interval (CI): 0.974-0.997, p = 0.01). ROC analysis indicated that using baseline serum UA < 299 µmol/L as a threshold value yielded a sensitivity of 77.3% and a specificity of 79.3% in predicting the treatment response to midodrine hydrochloride. The area under the PR curve was 0.833. Hosmer-Lemeshow test yielded a p value of 0.58, and calibration plot indicated that the model was well-fitted. DCA demonstrated that treatment decision depending on the baseline serum UA level resulted in a favorable net benefit.   Conclusion: This pilot study suggested that the baseline serum UA level could be taken as a predictor of therapeutic effect of midodrine hydrochloride on VVS in children. What is Known: • Empirical and unselected use of midodrine hydrochloride has an unfavorable therapeutic effect on VVS in children. Serum uric acid (UA) is closely linked to cardiovascular events. What is New: • A low baseline serum UA level successfully predicts the therapeutic effectiveness of midodrine hydrochloride on VVS in children.

Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients.

OBJECTIVE: To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary- and quaternary-care university teaching hospital. PARTICIPANTS: Included patients who received at least 4 consecutive doses of droxidopa or atomoxetine and remained on concurrent midodrine. Patients were excluded if they received study medication before admission, had clinical deterioration after study medication initiation requiring additional vasoactives/escalation of IV vasoactive dosage for at least 12 hours, had a diagnosis of hepatorenal syndrome, were prisoners, or were pregnant. INTERVENTIONS: Droxidopa, atomoxetine, or both. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to discontinuation of IV vasoactive agents after initiation of study medication, analyzed using a Kaplan-Meier estimate with the Wilcoxon method, censoring death within 24 hours of the last dose of study medication. No adjustment for repetitive analyses was made, as the analysis was hypothesis-generating. Of the 72 charts reviewed, 45 patients met inclusion criteria (18 atomoxetine, 17 droxidopa, and 10 both). There were no differences in median time to discontinuation of IV vasoactive agents (21.9 days v 8.0 days v 13.9 days, respectively; p = 0.259) or ICU or hospital length of stay between groups. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% v 76.5%) than atomoxetine alone (44.4%, p = 0.028). CONCLUSIONS: Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.

Pharmacologic prevention of recurrent vasovagal syncope: A systematic review and network meta-analysis of randomized controlled trials.

Vasovagal syncope (VVS) is a transient loss of consciousness that currently imposes a high burden on health care systems with limited evidence of the comparative efficacy of available pharmacologic interventions. This study aims to compare all pharmacologic therapies suggested in randomized controlled trials (RCTs) through systematic review and network meta-analysis. A systematic search in PubMed, Embase, Web of Science, and Cochrane Library was conducted to identify RCTs evaluating pharmacologic therapies for patients with VVS. The primary outcome was spontaneous VVS recurrence. The secondary outcome was a positive head-up tilt test (HUTT) after receiving intervention, regarded as a lower level of evidence. Pooled risk ratio (RR) with 95% confidence interval (CI) was calculated using random-effect network meta-analysis. Pairwise meta-analysis for comparison with placebo was also performed when applicable. The surface under the cumulative ranking curve analysis was conducted to rank the treatments for each outcome. Twenty-eight studies with 1744 patients allocated to different medications or placebo were included. Network meta-analysis of the reduction in the primary outcome showed efficacy for midodrine (RR 0.55; 95% CI 0.35-0.85) and fluoxetine (especially in patients with concomitant anxiety) (RR 0.36; 95% CI 0.16-0.84). In addition, midodrine and atomoxetine were superior to other treatment options, considering positive HUTT (RR 0.37; 95% CI 0.23-0.59; and RR 0.49; 95% CI 0.28-0.86, respectively). Overall, midodrine was the only agent shown to reduce spontaneous syncopal events. Fluoxetine also seems to be beneficial but should be studied further in RCTs. Our network meta-analysis did not find evidence of the efficacy of any other medication.

Current approach to the treatment of vasovagal syncope in adults.

Vasovagal syncope (VVS) is the most common cause of transient loss of consciousness. Although not associated with mortality, it causes injuries, reduces quality of life, and is associated with anxiety and depression. The European and North American cardiac societies recently published syncope clinical practice guidelines. Most patients with VVS do well after specialist evaluation, reassurance and education. Adequate hydration, increased salt intake when not contraindicated, and careful withdrawal of diuretics and specific hypotension-inducing drugs are a reasonable initial strategy. Physical counterpressure maneuvers might be helpful but can be of limited efficacy in older patients and those with short or no prodromes. Orthostatic training lacks long term efficacy and is troubled by non-compliance. Yoga might be helpful, although the biomedical mechanism is unknown. Almost a third of VVS patients continue to faint despite these conservative measures. Metoprolol was not helpful in a pivotal randomized clinical trial. Fludrocortisone and midodrine significantly reduce syncope recurrences with tolerable side effects, when titrated to target doses. Pacing therapy with specialized sensors appears promising in carefully selected population who have not responded conservative measures. Cardioneuroablation may be helpful but has not been studied in a formal clinical trial.

Utilidad de la midodrina para controlar el síncope vasovagal: ¿la recomienda la evidencia? / Usefulness of Midodrine for the Control of Recurrent Vasovagal Syncope: Does the Evidence Recommend it? / Utilidade da midodrina no controle da síncope vasovagal: as evidencias a recomendam?

Introducción:El síncope vasovagal es la principal causa de pérdida transitoria de la conciencia, y es un motivo de consulta cada vez más frecuente en pediatría y medicina del adulto. La midodrina es un agonista de los recepto-res alfa, de acción periférica, empleada principalmente en el manejo de la hipotensión ortostática; sin embargo, también se ha evaluado en el síncope vasovagal, con resultados prometedores.Objetivo:Analizar la evidencia más reciente sobre la utilidad de la midodrina para el control y la prevención del síncope vasovagal.Materiales y métodos: Se realizó una búsqueda bibliográfica utilizando términos de búsqueda como Vasovagal Syncope y Midodrine, así como sinónimos, que se combinaron con operadores booleanos, en cinco bases de datos, hasta octubre del 2022. Se incluyeron estudios originales, revisiones sistemáticas y metanálisis, publicados tanto en inglés como en español.Resultados:Ensayos controlados aleatorizados y revisiones sistemáticas y metanálisis difieren ligeramente entre resultados, pero estos demuestran un efecto global protector. La evidencia más reciente y completa indica que utilizar este agente reduce significativamente la positividad al realizar la prueba de la mesa inclinada y que previene la aparición de episodios sincopales.Conclusiones:Aunque la evidencia actual sobre la eficacia de la midodrina respecto a la prevención y control del síncope vasovagal es limitada, se observa un efecto protector significativo, porque disminuye el riesgo de sufrir un episodio sincopal, aproximadamente hasta en un 50 %.Palabras clave: midodrina; síncope vasovagal; síncope; adrenérgicos; medicina basada en la evidencia

Introduction: Vasovagal syncope is the main cause of transient loss of consciousness, being an in-creasingly frequent reason for consultation in pediatrics and adult medicine. Midodrine, a periphe-rally acting alpha-receptor agonist, is mainly used in the management of orthostatic hypotension. However, it has also been evaluated in vasovagal syncope, with promising results. Objective: To analyze the most recent evidence on the usefulness of midodrine for the control and prevention of vasovagal syncope. Materials and Methods: A literature search was performed using search terms such as "Vasovagal Syncope" and "Midodrine," as well as synonyms, which were combined with Boolean operators, in 5 databases until October 2022. Original studies, systematic reviews and meta-analyses, published in both English and Spanish, were included. Results: Randomized controlled trials and systematic reviews and meta-analyses differ slightly between results, but these demonstrate an overall protective effect. The most recent and complete evidence shows that using this agent significantly reduces the probability of positivity when performing the tilt table test and prevents the occurrence of syncopal episodes. Conclusions: Although current evidence on the efficacy of midodrine with respect to the prevention and control of vasovagal syncope is limited, a significant protective effect is observed, reducing the risk of suffering syncopal episode by approximately up to 50%

Introdução: a síncope vasovagal é a principal causa de perda transitória de consciência e é um motivo cada vez mais comum de consulta em pediatria e medicina de adultos. A midodrina é um agonista do receptor alfa de ação periférica usado principalmente no tratamento da hipotensão ortostática; no entanto, ela também foi avaliada na síncope vasovagal, com resultados promissores. Objetivo: Revisar as evidências mais recentes sobre a utilidade da midodrina para o controle e a pre-venção da síncope vasovagal. Materiais e métodos: Foi realizada uma pesquisa na literatura usando termos de pesquisa como Va-sovagal, Syncope e Medodrine, bem como sinônimos, que foram combinados com operadores boo-leanos, em cinco bancos de dados, até outubro de 2022. Foram incluídos estudos originais, revisões sistemáticas e metanálises, publicados em inglês e espanhol. Resultados: Os ensaios clínicos randomizados, as revisões sistemáticas e as metanálises diferem ligei-ramente entre os resultados, mas demonstram um efeito protetor geral. As evidências mais recentes e abrangentes indicam que o uso desse agente reduz significativamente a positividade no teste de inclinação da mesa e evita a ocorrência de episódios de síncope. Conclusões: Embora as evidências atuais sobre a eficácia da midodrina em relação à prevenção e ao controle da síncope vasovagal sejam limitadas, observa-se um efeito protetor significativo, pois ela diminui o risco de sofrer um episódio sincopal em aproximadamente 50%

Neurogenic orthostatic hypotension after treatment with sorafenib.

A man in his 70s with a history of fatigue, abdominal pain, and a palpable abdominal mass was found to have a peritoneal desmoid tumour. One year after diagnosis, he was prescribed sorafenib to limit tumour growth. Two months later, he developed dyspnoea on exertion and lower extremity weakness and was reported to have supine hypertension and orthostatic hypotension. On formal autonomic testing, he was noted to have severely impaired sympathetic responses and marked orthostatic hypotension without appropriate chronotropic response. A decision to hold sorafenib was made, and treatment was started with graduated compression stockings, liberal fluid and sodium intake, and midodrine. The patient had a modest and gradual improvement in his symptoms. To our knowledge, this is the first reported case of orthostatic hypotension related to sorafenib or any vascular endothelial growth factor inhibitors.

[A 10-year retrospective analysis of spectrums and treatment options of orthostatic intolerance and sitting intolerance in children].

OBJECTIVE: To analyze the disease spectrums underlying orthostatic intolerance (OI) and sitting intolerance (SI) in Chinese children, and to understand the clinical empirical treatment options. METHODS: The medical records including history, physical examination, laboratory examination, and imagological examination of children were retrospectively studied in Peking University First Hospital from 2012 to 2021. All the children who met the diagnostic criteria of OI and SI were enrolled in the study. The disease spectrums underlying OI and SI and treatment options during the last 10 years were analyzed. RESULTS: A total of 2 110 cases of OI and SI patients were collected in the last 10 years, including 943 males (44.69%) and 1 167 females (55.31%) aged 4－18 years, with an average of (11.34±2.84) years. The overall case number was in an increasing trend over the year. In the OI spectrum, postural tachycardia syndrome (POTS) accounted for 826 cases (39.15%), followed by vasovagal syncope (VVS) (634 cases, 30.05%). The highest proportion of SI spectrum was sitting tachycardia (STS) (8 cases, 0.38%), followed by sitting hypertension (SHT) (2 cases, 0.09%). The most common comorbidity of OI and SI was POTS coexisting with STS (36 cases, 1.71%). The highest proportion of treatment options was autonomic nerve function exercise (757 cases, 35.88%), followed by oral rehydration salts (ORS) (687 cases, 32.56%), metoprolol (307 cases, 14.55%), midodrine (142 cases, 6.73%), ORS plus metoprolol (138 cases, 6.54%), and ORS plus midodrine (79 cases, 3.74%). The patients with POTS coexisting with VVS were more likely to receive pharmacological intervention than the patients with POTS and the patients with VVS (41.95% vs. 30.51% vs. 28.08%, χ2= 20.319, P < 0.01), but there was no significant difference in the proportion of treatment options between the patients with POTS and the patients with VVS. CONCLUSION: POTS and VVS in children are the main underlying diseases of OI, while SI is a new disease discovered recently. The number of children with OI and SI showed an increasing trend. The main treatment methods are autonomic nerve function exercise and ORS. Children with VVS coexisting with POTS were more likely to take pharmacological treatments than those with VVS or POTS only.

Therapeutic effects of silodosin and urapidil on underactive bladder associated with diabetic cystopathy.

OBJECTIVES: Pharmacological treatment options for underactive bladder (UAB) syndrome are limited. Urapidil is the only alpha1 -adrenoceptor (AR) antagonist that can be used for urinary disorders in women in some countries. However, no studies have directly verified the effects of alpha1 -AR antagonists on the female urethra and UAB-like dysfunctions. We investigated the effects of silodosin (alpha1A -AR antagonist) and urapidil (nonselective alpha1 -AR antagonist) on the voiding function in female rats with diabetes mellitus (DM). METHODS: Changes in intraurethral pressure (IUP) induced by midodrine (alpha1 -AR agonist) and mean blood pressure (MBP) were continuously measured in normal female rats to verify the pharmacological profiles of the drugs. To establish a DM model, rats were administered streptozotocin (STZ; 50 mg/kg, intravenous). Eight weeks after STZ administration, drugs were subcutaneously delivered through an osmotic pump. Four weeks after drug administration, emptied bladder blood flow (BBF), intravesical pressure, and the micturition volume were measured. RESULTS: Both silodosin and urapidil inhibited the midodrine-induced increase in IUP and decreased MBP in a dose-dependent manner. Silodosin had a more substantial effect on the lower urinary tract than on MBP. Twelve weeks after STZ administration, DM rats exhibited UAB-like dysfunction (increased bladder capacity/bladder weight and residual volume and decreased bladder voided efficiency) and decreased BBF. Both drug treatments controlled this dysfunction. CONCLUSIONS: Alpha1 -AR antagonists induced dose-dependent urethral relaxation in female rats. These drugs ameliorated UAB-like dysfunction in STZ-induced DM rats. In addition, alpha1A -AR antagonists such as silodosin, which have limited effects on blood pressure, appear to be useful for treating UAB.

Efficacy of Preoperative Oral Midodrine in Preventing Hypotension After Spinal Anesthesia in Young Adults: A Randomized Controlled Trial.

BACKGROUND: Midodrine was effectively used for prophylaxis against hypotensive syndromes such as postural hypotension and intradialytic hypotension, and during the recovery phase of septic shock. In our study, we aimed to assess the efficacy of prophylactic administration of midodrine tablets before spinal anesthesia in reducing the occurrence of hypotension. METHODS: This randomized placebo-controlled study embraced 67 patients aged 18 to 40 years undergoing elective knee surgery under spinal anesthesia. Patients were randomized to midodrine group (given 10-mg tablets of midodrine) or placebo group (given placebo tablets), and tablets were administered 1 hour before spinal anesthesia (intrathecal injection of 12.5-mg 0.5% hyperbaric bupivacaine and 15-µg fentanyl). The primary outcome was the occurrence of hypotension, defined as a systolic blood pressure <90 mm Hg or <80% of baseline. Secondary outcomes were hemodynamic characteristics (mean arterial pressure [MAP] and heart rate [HR]) after spinal anesthesia, ephedrine dose, and occurrence of complications including bradycardia, vasovagal attacks, reactive hypertension nausea, vomiting, and shivering. RESULTS: The number of patients who became hypotensive after spinal anesthesia was 5 (14.7%) in midodrine group versus 14 (42.4%) in the placebo group; relative risk (95% confidence interval) was 0.35 (0.14-0.85) ( P = .021). The median (interquartile range) total dose of ephedrine was significantly lower in midodrine group 0 (0-10) mg than in placebo group (0 (0-15) mg; the Hodges-Lehmann median difference (95% confidence interval) was 0 (0-5) mg ( P = .015). For MAP data, the group × time interaction was significant ( P = .038), and the MAP was significantly lower in the placebo group than in the midodrine group after intrathecal injection at 2 minutes ( P = .047), 10 minutes ( P = .045), 15 minutes ( P < .001), 20 minutes ( P = .007), 30 minutes ( P =.013), 45 minutes ( P = .029), 60 minutes ( P = .029), and at the end of surgery ( P < .001). For HR data, the group × time interaction was nonsignificant ( P = .807), and the difference in means (95% confidence interval) between groups collapsing over time was -1.4 (-3.1 to 0.2) beats/min ( P = .096). There was no significant difference between the 2 groups regarding the occurrence of complications. CONCLUSIONS: Prophylactic administration of 10-mg midodrine tablets before spinal anesthesia is an effective method in the prevention of hypotension in young adult patients undergoing elective orthopedic knee surgery.

Stimulation of Alpha-1-Adrenergic Receptor Ameliorates Obesity-Induced Cataracts by Activating Glycolysis and Inhibiting Cataract-Inducing Factors.

BACKGROUND: Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts. METHODS: To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity. RESULTS: Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5'-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase. CONCLUSION: The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.

Midodrine for the prevention of vasovagal syncope: a systematic review and meta-analysis.

AIMS: Vasovagal syncope (VVS) is a common clinical condition that lacks effective medical therapies despite being associated with significant morbidity. Current guidelines suggest that midodrine, a prodrug for an α1-adrenergic receptor agonist, might suppress VVS but supporting studies have utilized heterogeneous methods and yielded inconsistent results. To evaluate the efficacy of midodrine to prevent syncope in patients with recurrent VVS by conducting a systematic review and meta-analysis of published studies. METHODS AND RESULTS: Relevant randomized controlled trials were identified from the MEDLINE, Embase, CENTRAL, and CINAHL databases without language restriction from inception to June 2021. All studies were conducted in clinical syncope populations and compared the benefit of midodrine vs. placebo or non-pharmacological standard care. Weighted relative risks (RRs) were estimated using random effects meta-analysis techniques. Seven studies (n = 315) met inclusion criteria. Patients were 33 ± 17 years of age and 31% male. Midodrine was found to substantially reduce the likelihood of positive head-up-tilt (HUT) test outcomes [RR = 0.37 (0.23-0.59), P < 0.001]. In contrast, the pooled results of single- and double-blind clinical trials (I2 = 54%) suggested a more modest benefit from midodrine for the prevention of clinical syncope [RR = 0.51 (0.33-0.79), P = 0.003]. The two rigorous double-blind, randomized, placebo-controlled clinical trials included 179 VVS patients with minimal between-study heterogeneity (I2 = 0%) and reported a risk reduction with midodrine [RR = 0.71 (0.53-0.95), P = 0.02]. CONCLUSIONS: Midodrine is effective in preventing syncope induced by HUT testing and less, but still significant, RR reduction in randomized, double-blinded clinical trials.

Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial.

BACKGROUND: Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. OBJECTIVE: To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). SETTING: 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. PATIENTS: Patients with recurrent vasovagal syncope and no serious comorbid conditions. INTERVENTION: Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. MEASUREMENTS: The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. RESULTS: The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. LIMITATION: Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. CONCLUSION: Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial.

BACKGROUND: The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions. METHODS: In this open-label multi-center randomized controlled trial, we are going to randomize 1375 patients with VVS who had ≥2 syncopal episodes in the last year into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or no medication. All patients will be recommended to drink 2 to 3 liters of fluids per day, consume 10 grams of NaCl per day, and practice counter-pressure maneuvers. In medication arms, patients will start on 5 mg of midodrine TDS or 0.05 mg of fludrocortisone BD. After one week the dosage will be up-titrated to midodrine 30 mg/day and fludrocortisone 0.2 mg/day. Patient tolerance will be the principal guide to dosage adjustments. We will follow-up the patients on 3, 6, 9, and 12 months after randomization. The primary outcome is the time to first syncopal episode. Secondary outcomes include the recurrence rate of VVS, time interval between first and second episodes, changes in quality of life (QoL), and major and minor adverse drug reactions. QoL will be examined by the 36-Item Short Form Survey questionnaire at enrollment and 12 months after randomization. CONCLUSION: The COMFORTS trial is the first study that aims to make a head-to-head comparison between midodrine and fludrocortisone, against a background of lifestyle modifications for preventing recurrences of VVS and improving QoL in patients with VVS.