Double-blinded, placebo-controlled crossover trial to determine the effects of midodrine on blood pressure during cognitive testing in persons with SCI.

STUDY DESIGN: Clinical trial. OBJECTIVES: Individuals with spinal cord injury (SCI) above T6 experience impaired descending cortical control of the autonomic nervous system, which predisposes them to hypotension. However, treatment of hypotension is uncommon in the SCI population because there are few safe and effective pharmacological options available. The primary aim of this investigation was to test the efficacy of a single dose of midodrine (10 mg), compared with placebo, to increase and normalize systolic blood pressure (SBP) between 110 and 120 mmHg during cognitive testing in hypotensive individuals with SCI. Secondary aims were to determine the effects of midodrine on cerebral blood flow velocity (CBFv) and global cognitive function. SETTING: United States clinical research laboratory. METHODS: Forty-one healthy hypotensive individuals with chronic (≥1-year post injury) SCI participated in this 2-day study. Seated SBP, CBFv, and cognitive performance were monitored before and after administration of identical encapsulated tablets, containing either midodrine or placebo. RESULTS: Compared with placebo, midodrine increased SBP (4 ± 13 vs. 18 ± 24 mmHg, respectively; p < 0.05); however, responses varied widely with midodrine (-15.7 to +68.6 mmHg). Further, the proportion of SBP recordings within the normotensive range did not improve during cognitive testing with midodrine compared with placebo. Although higher SBP was associated with higher CBFv (p = 0.02), global cognitive function was not improved with midodrine. CONCLUSIONS: The findings indicate that midodrine increases SBP and may be beneficial in some hypotensive patients with SCI; however, large heterogeneity of responses to midodrine suggests careful monitoring of patients following administration. CLINICAL TRIALS REGISTRATION: NCT02307565.

Continuation of Newly Initiated Midodrine Therapy After Intensive Care and Hospital Discharge: A Single-Center Retrospective Study.

OBJECTIVES: Midodrine is an α1-agonist approved for orthostatic hypotension. Recently, it has received attention as an oral vasopressor to facilitate ICU discharge. The purpose of this study was to identify the incidence of continuation of newly initiated midodrine upon ICU and hospital discharge and identify risk factors associated with its occurrence. DESIGN: Single-center retrospective study. SETTING: ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. PATIENTS: Adult patients admitted to any ICU who received new midodrine for hypotension and survived to discharge. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During the study period, 1,010 patients were newly started on midodrine and survived to ICU discharge. Midodrine was continued in 67% (672/1,010) of patients at ICU discharge. Admission to cardiovascular surgery ICU and mixed medical/surgical ICU was a risk factor for midodrine continuation at ICU discharge (odds ratio, 3.94 [2.50-6.21] and 2.03 [1.29-3.20], respectively). At hospital discharge, 34% (311/909) of patients were continued on midodrine therapy. History of congestive heart failure predicted midodrine continuation at hospital discharge (odds ratio, 1.49 [1.05-2.12]). Hypertension and use of mechanical ventilation were associated with a decreased odds of midodrine prescription at both ICU and hospital discharge. Of those discharged from the ICU or hospital on midodrine, 50% were concomitantly prescribed antihypertensives. Discharge from the ICU on midodrine was associated with a significantly shorter ICU length of stay (7.5 ± 8.9 vs 10.6 ± 13.4 d) and reduced risk of in-hospital mortality (hazard ratio, 0.47 [95% CI, 0.32-0.70]; p < 0.001), despite no difference in baseline severity of illness scores. In contrast, patients discharged from the hospital on midodrine had a higher risk of 1-year mortality (hazard ratio, 1.60 [95% CI, 1.26-2.04]; p < 0.001). CONCLUSIONS: This study established a high prevalence of midodrine continuation in transitions of care. The risks and benefits of this practice remain unclear. Future studies should explore the impact of this practice on patient outcomes and resource utilization. These insights could be used to model interventions for proper tapering, discontinuation, or follow-up of new start midodrine.

Pediatric intradialytic hypotension: recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup.

Intradialytic hypotension (IDH) is a common adverse event resulting in premature interruption of hemodialysis, and consequently, inadequate fluid and solute removal. IDH occurs in response to the reduction in blood volume during ultrafiltration and subsequent poor compensatory mechanisms due to abnormal cardiac function or autonomic or baroreceptor failure. Pediatric patients are inherently at risk for IDH due to the added difficulty of determining and attaining an accurate dry weight. While frequent blood pressure monitoring, dialysate sodium profiling, ultrafiltration-guided blood volume monitoring, dialysate cooling, hemodiafiltration, and intradialytic mannitol and midodrine have been used to prevent IDH, they have not been extensively studied in pediatric population. Lack of large-scale studies on IDH in children makes it difficult to develop evidence-based management guidelines. Here, we aim to review IDH preventative strategies in the pediatric population and outlay recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup. Without strong evidence in the literature, our recommendations from the expert panel reflect expert opinion and serve as a valuable guide.

Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial.

BACKGROUND & AIMS: Patients with decompensated cirrhosis on the waiting list for liver transplantation (LT) commonly develop complications that may preclude them from reaching LT. Circulatory dysfunction leading to effective arterial hypovolemia and activation of vasoconstrictor systems is a key factor in the pathophysiology of complications of cirrhosis. The aim of this study was to investigate whether treatment with midodrine, an alpha-adrenergic vasoconstrictor, together with intravenous albumin improves circulatory dysfunction and prevents complications of cirrhosis in patients awaiting LT. METHODS: A multicenter, randomized, double-blind, placebo-controlled trial (NCT00839358) was conducted, including 196 consecutive patients with cirrhosis and ascites awaiting LT. Patients were randomly assigned to receive midodrine (15-30 mg/day) and albumin (40 g/15 days) or matching placebos for one year, until LT or drop-off from inclusion on the waiting list. The primary endpoint was incidence of any complication (renal failure, hyponatremia, infections, hepatic encephalopathy or gastrointestinal bleeding). Secondary endpoints were mortality, activity of endogenous vasoconstrictor systems and plasma cytokine levels. RESULTS: There were no significant differences between both groups in the probability of developing complications of cirrhosis during follow-up (p = 0.402) or one-year mortality (p = 0.527). Treatment with midodrine and albumin was associated with a slight but significant decrease in plasma renin activity and aldosterone compared to placebo (renin -4.3 vs. 0.1 ng/ml.h, p < 0.001; aldosterone -38 vs. 6 ng/dl, p = 0.02, at week 48 vs. baseline). Plasma norepinephrine only decreased slightly at week 4. Neither arterial pressure nor plasma cytokine levels changed significantly. CONCLUSIONS: In patients with cirrhosis awaiting LT, treatment with midodrine and albumin, at the doses used in this study, slightly suppressed the activity of vasoconstrictor systems, but did not prevent complications of cirrhosis or improve survival. LAY SUMMARY: Patients with cirrhosis who are on the liver transplant waiting list often develop complications which prevent them from receiving a transplant. Circulatory dysfunction is a key factor behind a number of complications. This study was aimed at investigating whether treating patients with midodrine (a vasoconstrictor) and albumin would improve circulatory dysfunction and prevent complications. This combined treatment, at least at the doses administered in this study, did not prevent the complications of cirrhosis or improve the survival of these patients.

The Impact of Midodrine on Outcomes in Patients with Intradialytic Hypotension.

BACKGROUND: Intradialytic hypotension (IDH) is a frequent complication of hemodialysis, and is associated with significant morbidity and mortality. Off-label use of the alpha-1 andrenergic receptor agonist midodrine to reduce the frequency and severity of IDH is common. However, limited data exist to support this practice. This study sought to examine real-world efficacy of midodrine with respect to relevant clinical and hemodynamic outcomes. METHODS: Here, we compared a variety of clinical and hemodynamic outcomes among adult patients who were prescribed midodrine (n = 1,046) and matched controls (n = 2,037), all of whom were receiving in-center hemodialysis treatment at dialysis facilities in the United States (July 2015 - September 2016). Mortality, all-cause hospitalization, cardiovascular hospitalization, and hemodynamic outcomes were considered from the month following the initiation of midodrine (or corresponding month for controls) until censoring for discontinuation of dialysis, transplant, loss to follow-up, or study end (September 30, 2016). Rate outcomes were compared using Poisson models and quantitative outcomes using linear mixed models; all models were adjusted for imbalanced patient characteristics. RESULTS: Compared to non-use, midodrine use was associated with higher rates of death (adjusted incidence rate ratio 1.37, 95% CI 1.15-1.62), all-cause hospitalization (1.31, 1.19-1.43) and cardiovascular hospitalization (1.41, 1.17-1.71). During follow-up, midodrine use tended to be associated with lower pre-dialysis systolic blood pressure (SBP), lower nadir SBP, greater fall in SBP during dialysis, and a greater proportion of treatments affected by IDH. CONCLUSION: Although residual confounding may have influenced the results, the associations observed here are not consistent with a potent beneficial effect of midodrine with respect to either clinical or hemodynamic outcomes.

Pharmacological Therapies for Hepatorenal Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Hepatorenal syndrome (HRS) is a serious complication of advanced chronic liver disease. Different pharmacological therapies have variable efficacy. We performed a systematic review and meta-analysis to compare the efficacy of various drugs in the treatment of HRS. STUDY: Randomized controlled trials comparing active drug with placebo or comparing 2 different drugs were included in this analysis. Primary study outcome was reversal of HRS. Secondary outcomes were HRS relapse and patient survival. Subgroup analysis was performed on patients with type 1 HRS. RESULTS: Thirteen randomized controlled trial were eligible for analysis. Terlipressin plus albumin was more efficacious than placebo plus albumin (odds ratio=4.72; 95% confidence interval, 1.72-12.93; P=0.003) or midodrine plus albumin and octreotide (odds ratio=5.94; 95% confidence interval, 1.69-20.85; P=0.005), for HRS reversal. However, no significant difference was noted comparing terlipressin plus albumin versus noradrenaline plus albumin, octreotide plus albumin versus placebo plus albumin or noradrenaline plus albumin versus midodrine plus albumin and octreotide. None of the comparisons showed difference on HRS relapse or patient survival. Subgroup analysis revealed that terlipressin was more effective than placebo for type 1 HRS reversal, but no significant differences were noted between any other comparisons, and none of the comparisons showed difference on HRS relapse or patient survival. CONCLUSIONS: Intravenous infusion of terlipressin is the most effective medical therapy for reversing HRS. Intravenous infusion of noradrenaline is an acceptable alternative. Studies are needed as basis for developing pharmacological strategies to reduce relapse of HRS and improve patient survival.

The Treatment of Primary Orthostatic Hypotension.

OBJECTIVE: To review the efficacy and safety of pharmacological and nonpharmacological strategies used to treat primary orthostatic hypotension (OH). DATA SOURCES: A literature review using PubMed and MEDLINE databases searching hypotension, non-pharmacological therapy, midodrine, droxidopa, pyridostigmine, fludrocortisone, atomoxetine, pseudoephedrine, and octreotide was performed. STUDY SELECTION AND DATA EXTRACTION: Randomized or observational studies, cohorts, case series, or case reports written in English between January 1970 and November 2016 that assessed primary OH treatment in adult patients were evaluated. DATA SYNTHESIS: Based on the chosen criteria, it was found that OH patients make up approximately 15% of all syncope patients, predominantly as a result of cardiovascular or neurological insults, or offending medication. Nonpharmacological strategies are the primary treatment, such as discontinuing offending medications, switching medication administration to bedtime, avoiding large carbohydrate-rich meals, limiting alcohol, maintaining adequate hydration, adding salt to diet, and so on. If these fail, pharmacotherapy can help ameliorate symptoms, including midodrine, droxidopa, fludrocortisone, pyridostigmine, atomoxetine, sympathomimetic agents, and octreotide. CONCLUSIONS: Midodrine and droxidopa possess the most evidence with respect to increasing blood pressure and alleviating symptoms. Pyridostigmine and fludrocortisone can be used in patients who fail to respond to these agents. Emerging evidence with low-dose atomoxetine is promising, especially in those with central autonomic failure, and may prove to be a viable alternative treatment option. Data surrounding other therapies such as sympathomimetic agents or octreotide are minimal. Medication management of primary OH should be guided by patient-specific factors, such as tolerability, adverse effects, and drug-drug and drug-disease interactions.

Midodrine as adjunctive support for treatment of refractory hypotension in the intensive care unit: a multicenter, randomized, placebo controlled trial (the MIDAS trial).

BACKGROUND: Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital. METHODS: The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration. DISCUSSION: Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine. TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

Ejaculation and sperm characteristics in men with cauda equina and conus medullaris syndromes.

STUDY DESIGN: Retrospective. OBJECTIVES: The objective of the study was to describe the type of ejaculation in patients with cauda equina (CE) and conus medullaris (CM) lesions, and to analyse sperm quality. SETTING: France. METHODS: One hundred sixty-six patients with CE and CM lesions were included. Diagnosis was based on clinical (no motor responses, sensation or sacral reflexes) and urodynamic assessments (no detrusor activity). Vibromassage (VM) was used to induce ejaculation according to the recommendations for patients with spinal cord injury. If ejaculation did not occur, oral midodrine was administered in progressive doses. Retrograde ejaculation was systematically sought. Sperm parameters were analysed according to World Health Organisation recommendations (2010). RESULTS: Eighty-nine patients were included. Eleven ejaculated on the first VM trial (four anterograde (AE), six retrograde (RE) and one antero-retrograde (ARE)). Five patients continued trials of VM alone, two of whom ejaculated following a mean 1.9 trials (one RE, one ARE). Twenty-six patients underwent trials of VM+ midodrine, 18 of whom ejaculated following a mean 4.4 trials with a mean dose of 22.5 g of midodrine (2 AE, 13 RE and 5 ARE). Fifty-three ejaculates from 26 patients were analysed. Sperm concentration was low in 90.6% of samples; total necrospermia was found in 65% and asthenospermia in 95% of samples. CONCLUSION: Ejaculation is difficult to induce using VM in patients with CE and CM lesions, and requires high doses of midodrine. Sperm counts were generally low, and asthenospermia and necrospermia were found in the majority of specimens. Cryopreservation of sperm should be systematic in case of medically assisted procreation.

Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial.

UNLABELLED: Hepatorenal syndrome (HRS), a serious complication of cirrhosis, is associated with high mortality without treatment. Terlipressin with albumin is effective in the reversal of HRS. Where terlipressin is not available, as in the United States, midodrine and octreotide with albumin are used as an alternative treatment of HRS. The aim was to compare the effectiveness of terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of HRS in a randomized controlled trial. Twenty-seven patients were randomized to receive terlipressin with albumin (TERLI group) and 22 to receive midodrine and octreotide plus albumin (MID/OCT group). The TERLI group received terlipressin by intravenous infusion, initially 3 mg/24 hours, progressively increased to 12 mg/24 hours if there was no response. The MID/OCT group received midodrine orally at an initial dose of 7.5 mg thrice daily, with the dose increased to a maximum of 12.5 mg thrice daily, together with octreotide subcutaneously: initial dose 100 µg thrice daily and up to 200 µg thrice daily. Both groups received albumin intravenously 1 g/kg of body weight on day 1 and 20-40 g/day thereafter. There was a significantly higher rate of recovery of renal function in the TERLI group (19/27, 70.4%) compared to the MID/OCT group (6/21, 28.6%), P = 0.01. Improvement in renal function and lower baseline Model for End-Stage Liver Disease score were associated with better survival. CONCLUSION: Terlipressin plus albumin is significantly more effective than midodrine and octreotide plus albumin in improving renal function in patients with HRS.

Dose-dependency of clonidine's effects in ascitic cirrhotic rats: comparison with α1-adrenergic agonist midodrine.

BACKGROUND & AIMS: Sympathetic nervous system (SNS) activation decreases response to diuretics, but both α1-adrenoceptor agonists and sympatholytic α2-adrenoceptor agonists are recommended in the management of ascitic cirrhosis. We intend to compare the effects of increasing doses of clonidine (α2-agonist) vs. midodrine (α1-agonist) in advanced cirrhosis. METHODS: Renal function, mean arterial pressure (MAP), and hormonal status were measured in rats with ascitic cirrhosis due to 13-week CCl(4) administration (groups G1-G5), in control rats (Gc), and in rats with ascitic cirrhosis untreated (G6) or treated with daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+) -canrenoate during the 11(th) -13(th) weeks of CCl(4)) (G7). G1-G5 cirrhotic rats received daily, during the 11(th)-13(th) CCl(4) weeks: clonidine 0.3 µg only (G1), diuretics + clonidine 0.2 (G2), 0.5 (G3) or 1 µg (G4), and diuretics + midodrine 1 mg/kg b.w. (G5). RESULTS: Cirrhotic rats in G1 or G2 had higher glomerular filtration rate, renal plasma flow and natriuresis than cirrhotic rats treated with diuretics (G7) (all P < 0.05). The addition of clonidine 0.2 µg to diuretics (G2 vs. G7) reduced serum norepinephrine (169 ± 71 ng/L vs. 523 ± 88 ng/L) and plasma renin activity (12 ± 3 ng/ml/h vs. 25 ± 5 ng/ml/h) (all P < 0.05). Midodrine did not improve the renal performance in ascitic rats treated with diuretics. In comparison to absolute cirrhotic controls (G6), MAP was lower in G4 and higher in G5 (all P < 0.05). CONCLUSION: Low-dose α2-agonists improve natriuresis and reduce SNS function and hyper-aldosteronism without affecting arterial pressure in experimental ascitic cirrhosis treated with diuretics.

Midodrine for the weaning of vasopressor infusions.

WHAT IS KNOWN AND OBJECTIVE: Midodrine, an orally available α1-agonist indicated for the treatment of orthostatic hypotension, has been used at our institution as an adjunctive treatment to provide haemodynamic support to facilitate intravenous (IV) vasopressor weaning. Limited published data exist for this off-label use; thus, the objective of this study was to evaluate outcomes in patients who received midodrine for IV vasopressor weaning compared to control patients. METHODS: This retrospective comparison included adult ICU patients admitted to our institution from January 2007 to March 2012. The primary outcome was the time to IV vasopressor discontinuation after midodrine initiation. Secondary outcomes included a comparison between midodrine and control patients of the time from IV vasopressor discontinuation to ICU discharge, hospital and ICU length of stay (LOS), and the number of ICU readmissions. RESULTS AND DISCUSSION: The analysis included 188 patients (94 midodrine and 94 control). Patients discontinued IV vasopressors a median of 1·2 days (IQR 0·5-2·8) after midodrine initiation. ICU discharge occurred sooner after IV vasopressor discontinuation (0·8 vs. 1·5 days, P = 0·01), and 96% of patients remained off IV vasopressors after midodrine treatment. Hospital LOS was longer in midodrine patients (P < 0·01), but there were no differences in ICU LOS or readmissions. Adverse event rates after midodrine use were consistent with those observed in other studies. WHAT IS NEW AND CONCLUSION: Midodrine may serve as a useful adjunct to wean IV vasopressors in difficult-to-wean patients. Further studies are needed to assess the efficacy and safety of midodrine for this indication.

Oral Midodrine Hydrochloride for Prevention of Orthostatic Hypotension during Early Mobilization after Hip Arthroplasty: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Early postoperative mobilization is essential for rapid recovery but may be impaired by orthostatic intolerance (OI) and orthostatic hypotension (OH), which are highly prevalent after major surgery. Pathogenic mechanisms include an insufficient postoperative vasopressor response. The oral α-1 agonist midodrine hydrochloride increases vascular resistance, and the authors hypothesized that midodrine would reduce the prevalence of OH during mobilization 6 h after total hip arthroplasty relative to placebo. METHODS: This double-blind, randomized trial allocated 120 patients 18 yr or older and scheduled for total hip arthroplasty under spinal anesthesia to either 5 mg midodrine hydrochloride or placebo orally 1 h before mobilization at 6 and 24 h postoperatively. The primary outcome was the prevalence of OH (decrease in systolic or diastolic arterial pressures of > 20 or 10 mmHg, respectively) during mobilization 6 h after surgery. Secondary outcomes were OI and hemodynamic responses to mobilization at 6 and 24 h. RESULTS: At 6 h, 14 (25%; 95% CI, 14 to 38%) versus 23 (39.7%; 95% CI, 27 to 53%) patients had OH in the midodrine and placebo group, respectively, relative risk 0.63 (0.36 to 1.10; P = 0.095), whereas OI was present in 15 (25.0%; 15 to 38%) versus 22 (37.3%; 25 to 51%) patients, relative risk 0.68 (0.39 to 1.18; P = 0.165). At 24 h, OI and OH prevalence did not differ between groups. CONCLUSIONS: Preemptive use of oral 5 mg midodrine did not significantly reduce the prevalence of OH during early postoperative mobilization compared with placebo. However, further studies on dose and timing are warranted since midodrine is effective in chronic OH conditions.

A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome.

POTS (postural tachycardia syndrome) is a chronic form of OI (orthostatic intolerance). Neuropathic POTS is characterized by decreased adrenergic vasoconstriction, whereas hyperadrenergic POTS exhibits increased adrenergic vasoconstriction. We hypothesized that midodrine, an α1-adrenergic receptor agonist, would increase CVR (calf vascular resistance), decrease C(v) (calf venous capacitance) and decrease orthostatic tachycardia in neuropathic POTS, but not alter haemodynamics in hyperadrenergic POTS. A total of 20 POTS patients (12 neuropathic and eight hyperadrenergic), ages 12-20 years, participated in this randomized placebo-controlled double-blind cross-over study. Of these subjects, 15 were female. POTS subjects received 2 weeks of treatment with midodrine or placebo, with increased dosing from 2.5 to 10 mg three times daily. Following a 7-day drug-washout period, subjects received the cross-over treatment. HR (heart rate), MAP (mean arterial pressure), Q(calf) (calf blood flow) and CVR were measured supine and during 35° HUT (head-up tilt). C(v) was measured supine. In neuropathic POTS, midodrine decreased supine HR, Q(calf) and C(v), while increasing MAP and CVR compared with placebo. During HUT, in neuropathic POTS, midodrine decreased HR, Q(calf) and C(v), while increasing MAP and CVR. In hyperadrenergic POTS, placebo and midodrine both decreased upright HR and increased supine CVR. Placebo also increased supine C(v), compared with midodrine in hyperadrenergic POTS. Therefore midodrine improved postural tachycardia in neuropathic POTS by increasing CVR and decreasing Q(calf) and C(v), whereas these effects were not seen in hyperadrenergic POTS patients who experienced a placebo effect. This suggests that midodrine is probably an effective treatment for neuropathic POTS, but not for hyperadrenergic POTS.

Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study.

BACKGROUND & AIMS: Splanchnic arterial vasodilatation plays an important role in cirrhotic ascites. The aim of this study was to evaluate the effects of long term administration of midodrine on systemic hemodynamics, renal function, and control of ascites in patients with cirrhosis and refractory or recurrent ascites. METHODS: Forty cirrhotic patients with refractory or recurrent ascites were prospectively studied after long term administration of midodrine plus standard medical therapy (n=20) or standard medical therapy alone (n=20) in a randomized controlled trial at a tertiary centre. RESULTS: A significant increase in urinary volume, urinary sodium excretion, mean arterial pressure, and decrease in plasma renin activity (p<0.05) was noted after 1 month of midodrine administration. There was also a significant decrease in cardiac output and an increase in systemic vascular resistance after midodrine therapy at 3 months (p<0.05). There was no change in glomerular filtration rate and model for end-stage liver disease (MELD) score. Midodrine plus standard medical therapy was significantly superior to standard medical therapy alone in the control of ascites (p=0.013) at 3 months. The mortality rate in the standard medical therapy group was significantly higher than the midodrine group (p<0.046). There was no significant difference in the frequency of various complications at the end of follow-up. CONCLUSIONS: The results of this randomized pilot study suggest that midodrine plus standard medical therapy improves the systemic hemodynamics without any renal or hepatic dysfunction in these patients and is superior to standard medical therapy alone for the control of ascites.

The combination of octreotide and midodrine is not superior to albumin in preventing recurrence of ascites after large-volume paracentesis.

BACKGROUND & AIMS: Large-volume paracentesis (LVP) is the treatment of choice for patients with cirrhosis and refractory ascites. However, LVP can lead to postparacentesis circulatory dysfunction (PCD), which is associated with faster ascites recurrence and renal failure. PCD results from vasodilatation, which reduces effective blood volume, and is prevented by intravenous administration of albumin. Vasoconstrictors could be used instead of albumin and, with longer use, prevent PCD and delay ascites recurrence. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial to compare albumin with the vasoconstrictor combination of octreotide and midodrine in patients with refractory ascites who underwent LVP. Patients in the albumin group received a single intravenous dose of albumin at the time of LVP plus placebos for midodrine and octreotide (n = 13). Patients in the vasoconstrictor group received saline solution (as a placebo for albumin), 10 mg of oral midodrine (3 times/day), and a monthly 20-mg intramuscular injection of long-acting octreotide (n = 12). Patients were followed up until recurrence of ascites. RESULTS: The median times to recurrence of ascites were 10 days in the albumin group and 8 days in the vasoconstrictor group (P = .318). There were no significant differences in PCD between the albumin group (18%) and the vasoconstrictor group (25%, P = .574). When ascites recurred, serum levels of creatinine were higher in the vasoconstrictor group (1.2 vs 0.9 mg/dL in the albumin group; P = .051). CONCLUSIONS: The combination of midodrine and octreotide after LVP is not superior to albumin in delaying recurrence of ascites or preventing PCD in patients with cirrhosis. Outcomes appear to be worse in patients given octreotide and midodrine. ClinicalTrials.gov number, NCT00108355.

Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.

BACKGROUND: The study was carried out to examine the effect of selective α1 adrenoceptor agonist midodrine hydrochloride vs. ß-adrenergic blockade metoprolol in the treatment of children with postural orthostatic tachycardia syndrome (POTS). METHODS AND RESULTS: Fifty-three children with POTS were divided into group I (midodrine hydrochloride plus conventional therapy), group II (metoprolol plus conventional therapy) and group III (conventional therapy). Standing test was conducted for all participants. The cure rate, improvement rate, effective rate and score of symptoms were compared among the 3 groups. A Kaplan-Meier survivorship curve was used to describe the proportion of symptom-free cases during a long term follow-up. The cure rate and effective rate at the end of short term follow-up in group I were significantly higher than those of group II and group III (68.42% vs. 42.11% vs. 20.00%, P<0.05; 89.47% vs. 57.89% vs. 53.33%, P<0.05). After treatment, the symptom score in group I was significantly lower than group II and group III, respectively (1.1±2.2 vs. 2.8±2.4 vs. 3.7±2.0, P<0.05), and it also had significant difference between group II and group III (P<0.05). The symptom recurrent rate in group I was significantly lower than that of group II and group III, respectively (P<0.05), but it did not differ between group II and group III (P>0.05). CONCLUSIONS: Midodrine hydrochloride is effective in the treatment of children with POTS.

Case report: severe myoclonus associated with oral midodrine treatment for hypotension.

RATIONALE: Midodrine is widely used in the treatment of hypotensive states, there have been no reports of myoclonus associated with midodrine use in hypotension with chronic kidney disease. PATIENT CONCERNS: We report a 58-year-old female patient with chronic kidney disease (CKD) presenting with involuntary tremor 2 h after taking midodrine, which became more frequent after 6 h. Brain CT and neurological examination did not yield findings of note. Blood chemistry showed serum albumin of 3.1 g/L, ALT of 19 U/L, AST of 22 U/L, SCr of 273.9 µmol/L, K of 2.94 mmol/L, Ca of 1.63 mmol/L, and Mg of 0.46 mmol/L. Her BP was maintained at 83-110/56-75 mmHg. Her urine volume was 600-1000 mL/d, and her heart rate was within a range of 90-100 beats/min. DIAGNOSIS: Chronic kidney disease (CKD), hypotension, metabolic acidosis, hypocalcemia, hypokalemia, and hypomagnesemia. INTERVENTIONS: Midodrine treatment was stopped and the patient was treated with intravascular rehydration and furosemide. Myoclonus ceased one day after midodrine withdrawal. LESSONS: Oral midodrine is widely used in the treatment of orthostatic hypotension, recurrent reflex syncope and dialysis-associated hypotension and the adverse effects are mostly mild. However, clinicians should be alert for midodrine-induced myoclonus, especially in patients with CKD.