Research Article

Midodrine in patients with cirrhosis and refractory or recurrent ascites: A randomized pilot study
Virendra Singh1,, Sahdeb P. Dhungana2, Baljinder Singh3, Rajesh Vijayverghia4, Chander K. Nain5, Navneet Sharma2, Ashish Bhalla2, Pramod K. Gupta6
Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India; 2Department of Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India; 3Department of Nuclear Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India; 4Department of Cardiology, Postgraduate Institute of Medical Education & Research, Chandigarh, India; 5Department of Gastroenterology, Postgraduate Institute of Medical Education & Research, Chandigarh, India; 6 Department of Biostatistics, Postgraduate Institute of Medical Education & Research, Chandigarh, India
1

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 signicant 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 signicant 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 ltration rate and model for end-stage liver disease (MELD) score. Midodrine plus standard medical therapy was signicantly 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 signicantly higher than the midodrine group (p <0.046). There was no signicant 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. 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction Ascites is the most common complication of cirrhosis. Refractory ascites develops in approximately 510% of all cases of ascites and 50% of such patients die within 6 months of its development [1]. Portal hypertension and splanchnic vasodilatation are major factors in the development of ascites [2,3]. Splanchnic arterial vasodilatation causes more marked arterial underlling and the sodium retaining mechanisms become permanently activated [4]. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, liver transplantation, transjugular intrahepatic portosystemic shunt (TIPS), and peritoneovenous shunt [59]. Several studies have evaluated the efcacy of various vasopressors in patients with hepatorenal syndrome (HRS) [1013]. Vasopressors have also been used for the prevention of post-paracentesis circulatory dysfunction with variable results [1418]. Recently, various vasoconstrictors have been used in nonazotemic cirrhotic patients with ascites and showed an improvement in circulatory and renal function and sodium excretion [1921]. Midodrine, an oral a1-adrenergic agonist along with octreotide and albumin, has been shown to better control ascites in a short term pilot study in patients with refractory ascites [22]. There are no reports of long term use of midodrine in patients with cirrhosis and ascites. Therefore, we plan to study the role of long term administration of midodrine in patients with cirrhosis with refractory or recurrent ascites in a pilot study.

Materials and methods

A total of 59 patients with cirrhosis and refractory or recurrent ascites were evaluated for inclusion in the study between December 2007 and June 2009. Nineteen of 59 screened patients were excluded during the screening period for various reasons (spontaneous bacterial peritonitis in 6, encephalopathy in 6, acute renal failure in 3, hepatorenal syndrome in 1, and gastrointestinal bleeding in 3 patients). Therefore, 40 patients with cirrhosis and refractory or recurrent ascites [23] with stable renal function (creatinine level <1.5 for at least 7 days) attending the Hepatology Department of a tertiary centre were prospectively included in this study. The study was approved by the Institute Ethics Committee. Written informed consent was taken. Diagnosis of cirrhosis was based on clinical, laboratory, and ultrasonographic ndings with or without liver biopsy [24]. Inclusion

Keywords: Ascites; Cirrhosis; Hemodynamics; Splanchnic vasodilatation; Vasopressors. Received 20 December 2010; received in revised form 6 April 2011; accepted 24 April 2011; available online 13 July 2011 Corresponding author. Address: Professor, Department of Hepatology, PGIMER, Chandigarh 160 012, India. Fax: +91 172 2744401. E-mail address: virendrasingh100@hotmail.com (V. Singh).

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criteria were presence of refractory or recurrent ascites; patients less than 70 years of age; absence of gastrointestinal bleeding, hepatorenal syndrome, hepatic encephalopathy of grade 2 or higher or infection within 1 month preceding the study or during the study, presence of diabetes, intrinsic renal or cardiovascular disease or arterial hypertension on history and physical examination, abnormal urine analysis, chest radiograph, or electrocardiogram, presence of hepatocellular carcinoma or portal vein thrombosis, no treatment with drugs with known effects on systemic and renal hemodynamics within 7 days before inclusion. These patients were randomized to either the standard medical therapy arm or standard medical therapy with midodrine arm. A computer made the randomization code with 40 envelopes, with half for standard medical therapy and half for standard medical therapy with midodrine. Patients and investigators were blinded to the treatment assignments. These patients were on low sodium diet (2 g/day) for at least 7 days before inclusion in the study. A combination of loop diuretic (furosemide 40160 mg/day) and a distal acting diuretic (spironolactone 100400 mg/day) was given with dose escalation by one step at a time. Large volume paracentesis (LVP) was performed along with intravenous albumin (8 g/L ascites removed) using standard clinical methodology wherever required. Subjects randomized to midodrine were prescribed oral midodrine 7.5 mg every 8 h and was stopped whenever the end points were achieved. Refractory ascites was dened as ascites that cannot be mobilized or the early recurrence of which cannot be satisfactorily prevented by lack of response to sodium restricted diet and high-dose diuretic treatment (400 mg/day of spironolactone and 160 mg/day furosamide) or development of diuretic-induced complications that preclude the use of an effective diuretic dosage [23,25]. Recurrent ascites was dened as tense ascites that recurred on at least at three occasions within a 12-month period despite standard treatment [23]. The standard medical treatment was dened by restriction of sodium, treatment with diuretics and repeated LVP as needed. A combination of a loop-acting diuretic (furosemide, 40160 mg/day) and a distal-acting diuretic (spironolactone, 100400 mg/day) was given with dose escalation by one step at a time permitted for a >10 lb weight gain. Repeat LVP with infusion of albumin was performed in both arms for tense, symptomatic ascites with weight gain >10 lb from immediately previous nadir weight despite maximal diuretic therapy or inability to use an effective dose of diuretics due to diuretic-related side effects. On day of admission, baseline workup, including body weight, blood pressure, heart rate, electrocardiogram, systemic vascular resistance (SVR), liver function tests, and renal function tests, was obtained. Glomerular ltration rate (GFR) was estimated by using CockcroftGault equation [26]. SVR was measured as mean arterial pressure/cardiac output (MAP/CO) [20]. CO was evaluated by recording the diastolic mitral ow [27] with duplex-Doppler apparatus (Vivid Five, Vingmed Technology, Japan). These clinical and biochemical parameters were assessed in all patients at baseline and at 1, 3, and 6 month interval. Along with that, arterial blood sample was collected after overnight fast and bed rest at least for 8 h in supine position for plasma renin activity and plasma aldosterone concentration. Blood samples were taken from the radial artery, put into chilled ethylenediaminetetraacetic acid tubes, centrifuged at 2500 rpm for 10 min at 3 C and stored at 80 C. Patients were followed up at weekly interval for 1 month, then at monthly interval till death or termination of the study. All patients were instructed to come for paracentesis when become symptomatic.

Table 1. Baseline clinical, biochemical and hormonal variables of patients in two study groups.

Variables Age (years) Sex Male Female Etiology 1. Alcoholic 2. Others HCV related HBV related Autoimmune Recurrent ascites Refractory ascites Weight (kg) Mean arterial pressure (mmHg) MELD score Cardiac output (L/min) Systemic vascular resistance (dynes/s/cm5) GFR (ml/min) 24 hr urine output (ml/24 hr) Serum bilirubin (mg/dl) Serum albumin (g/dl) Prothrombin time (INR) Serum sodium (meq/L) Serum creatinine (mg/dl) Urinary sodium excretion (meq/24 hr) Plasma renin activity (ng/ml/h) Plasma aldosterone concentration (pg/ml)

Standard medical therapy group (n = 20) 47.6 11.033 20 (100%) 0 12 (60%) 8 3 (15%) 5 (25%) 0 14 (70%) 6 (30%) 64.43 12.15 83.59 11.44 14.85 4.68 5.81 1.8 1247.0 390.5 92.22 25.3 1381.2 636.8 2.73 1.40 2.71 0.57 1.25 0.46 134.15 5.5 1.03 0.31 70.47 30.24 13.12 3.88 1545.3 630.9

Midodrine group (n = 20) 45.6 10.049 17 (85%) 3 (15%)

p value 0.553 0.231

0.307 17 (85%) 3 1 (5%) 1 (5%) 1 (5%) 14 (70%) 6 (30%) 68.45 18.70 85.6 10.7 12.9 3.13 5.68 1.66 1297.5 377.4 115.5 57.06 1235 665.1 2.5 1.0 2.84 0.79 1.328 0.2 134.6 10.57 0.86 0.27 73.14 35.63 13.73 4.41 1601.5 789.7 0.658 0.704 0.140 0.650 0.820 0.239 0.680 0.556 0.471 0.084 0.867 0.074 0.671 0.645 0.805 0.634

Data are mean SD or number (%) of patients; MELD, model for end-stage liver disease; GFR, glomerular ltration rate.

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Blood sample was also collected for plasma renin activity and plasma aldosterone concentration at 1 month. Plasma renin activity was measured by radioimmunoassay using Gamma Coat 125I RIA plasma renin activity kit (Immunotech SA, France). Plasma aldosterone concentration was measured by radioimmunoassay using RIA aldosterone kit (Immunotech SA, France). Outcome measures The primary end point of the study was control of ascites. Secondary end points include frequency of worsening encephalopathy, liver and renal function, and frequency of other complications of cirrhosis (e.g. variceal hemorrhage or development of hepatorenal syndrome) and 3 months of midodrine therapy. Complete response was dened as the elimination of ascites; a partial response as the presence of ascites not requiring paracentesis and absence of a response was dened as the persistence of ascites requiring paracentesis [28]. Statistical analysis Data were analyzed using SPSS for MS-Windows (version 13.0, SPSS Inc., Chicago, IL, USA). The baseline patient characteristics (clinical as well as biochemical) were compared between two groups by using unpaired t test or Chi-square test. Intragroup comparisons were done using paired t test. Two-factor repeated-measures ANOVA was used for analysis. The rst factor analyzed the nature of treatment (midodrine or standard medical therapy) and the second factor analyzed the rep-

Table 2. Clinical and laboratory parameters before and after 1, 3, and 6 months of therapy.

Variables Baseline 1 Weight (kg) Mean arterial pressure (mmHg) MELD score Cardiac output (L/min) Systemic vascular resistance (dynes/s/ cm5) Heart rate (beat/min) Serum sodium (meq/L) Serum creatinine (mg/dl) Glomerular rate (ml/min) Urine output (ml/day) Urinary sodium excretion (meq/24 hr) Plasma renin activity (ng/ml/hr) Plasma aldosterone (pg/ml) 1381.2 636.8 70.47 30.24 1496.8 549.6 68.75 18.93 64.43 12.15 83.59 11.44 65.5 10.79 83.01 8.50

Standard medical therapy group Month 3 69.12 9.84 82.61 8.63 6 67.7 10.74 79.24 7.52 1 0.142 p value B vs. 3 0.185 6 0.973 68.45 18.70 85.60 10.70 Baseline 1 67.15 19.78 92.88 7.91

Midodrine group Month 3 68.06 19.47 85.75 9.167 6 1 p value B vs. 3 0.091 6 0.001

60.6 0.330 25.06 79.92 9.01 0.001

0.710

0.997

0.570

0.989

0.336

14.8 4.6 5.81 1.82 1247.0 390.5

16.1 5.6 5.69 1.55 1232.8 302.9

17.3 4.3 5.53 0.54 1196.3 119.2

19.5 5.1 5.43 0.76 1171.7 103.8

0.003

0.002

0.001

12.9 3.13 5.68 1.66 1297.5 377.4

13.9 4.1 5.33 1.37 1329.9 274.9

13.5 3.3 5.25 1.62 1443.7 498.0

14.5 3.7 6.03 0.40 1028.8 69.0

0.10

0.065

0.06

0.632

0.590

0.108

0.210

0.012

0.066

0.819

0.976

0.098

0.647

0.026

0.680

89.87 11.75 134.15 5.5

94.56 12.67 131.93 5.421

104.57 16.39 127.62 4.62

101.8 9.28 131.25 3.4

0.246 0.030

0.198 0.001

0.263 0.611

94.2 15.01 134.6 10.57

92.4 13.3 132.75 4.435

93.86 12.59 133.2 4.056

90.4 8.98 134.57 6.29

0.601 0.432

0.864 0.355

0.465 0.897

1.03 0.310 92.22 25.3

1.01 0.227 88.36 23.64

1.3 0.54 99.15 39.97

1.08 0.25 103.4 32.9

0.952

0.123

0.163

0.85 0.272 115.5 57.06

0.84 0.205 113.08 48.8

0.91 0.241 100.2 42.97

0.90 0.952 0.524 69.67 0.755 30.06

0.115

0.717

0.648

0.825

0.941

0.161

0.376

1531 497.8 71.0 15.67

1340 378.15 57.0 18.02

0.343

0.297

0.852

1235 1830 665.12 564.84 73.14 35.63 93.21 32.19

1933 599.6 96.07 33.03

1775 0.001 650.0 72.4 0.003 15.38

0.001

0.649

0.798

0.638

0.216

0.019

0.464

13.12 3.88

14.75 3.48

0.079

13.73 4.41

9.66 2.51

0.002

1545.3 630.9

1440.59 497.3

0.776

1601.5 789.7

921.5 547.8

0.008

Data are mean SD; B, baseline.

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25 Plasma renin activity (ng/ml/h)
Before After

20

15

10

5 1 5 9 13 17 21 25 29 33 37 41 1-20: midodrine group 21-40: SMT group

Fig. 1. Individual changes in plasma renin activity before and after 1 month of therapy (120: midodrine group, 2140: standard medical therapy group).

etition of measures (i.e. at baseline and on 1/3/6 months). The results were reported as mean values SD. p <0.05 was taken as signicant. Since we conducted a pilot study, no power calculation was performed.

Results The demographic prole, clinical and laboratory parameters were similar between standard medical therapy and midodrine groups (Table 1). Twenty-eight patients had recurrent and 12 refractory ascites. Four patients did not respond to sodium-restricted diet and high-dose diuretic treatment. Eight patients stopped these medications due to side-effects. Baseline body weight did not differ signicantly between two groups (p = 0.658). In both treatment groups, no signicant difference in weight was noted at 1 and 3 months (Table 2). Body weight signicantly decreased in

4000 Plasma aldosterone (pg/ml)

Before After

3000

2000

1000

0 1 5 9 13 17 21 25 29 33 37 41 1-20: midodrine group 21-40: SMT group

Fig. 2. Individual changes in plasma aldosterone concentration before and after 1 month of therapy (120: midodrine group, 2140: standard medical therapy group).

the midodrine group at 6 months (p = 0.001; Table 2) but not in the standard medical therapy group (p = 0.973). Baseline mean arterial pressure did not differ between standard medical therapy and midodrine groups (p = 0.704). Signicant increase in mean arterial pressure was noted in the midodrine group at 1 month (p = 0.001) but it did not change signicantly in the standard medical therapy group (p = 0.710). The changes in values after treatment at 3 and 6 months were not signicant in both groups. Baseline cardiac output did not differ between standard medical therapy and midodrine groups (p = 0.65). It signicantly decreased in the midodrine group at 3 months after treatment (p = 0.012) but no signicant change was noted in either group at 1 month and 6 months after therapy. The systemic vascular resistance increased signicantly at 3 months after therapy in the midodrine group (p = 0.026); however, it did not change signicantly in the standard medical therapy group at 3 months and in either group at 1 months and 6 months after therapy (Table 2). Baseline urine output did not differ between standard medical therapy and midodrine groups (p = 0.680). The urine output was signicantly higher in the midodrine group after treatment (p = 0.001) but not in the standard medical therapy group (Table 2). Baseline urinary sodium excretion was comparable in both standard medical therapy and midodrine groups (p = 0.671). Urinary sodium excretion signicantly increased in the midodrine group after treatment at 1 month (p = 0.003) and 3 months (p = 0.019) but not so in the standard medical therapy group. Baseline serum sodium values were similar in both groups (p = 0.867). They decreased signicantly in the standard medical therapy group after treatment at 1 month (p = 0.03) and 3 months (p = 0.001, Table 2). However, no signicant change in serum sodium values was noted in the midodrine group after treatment. Baseline values for serum creatinine and glomerular ltration rate between standard medical therapy and midodrine groups were similar. There was no signicant change in these variables in either group after treatment. Baseline values for plasma renin activity were similar in both treatment groups (p = 0.645). Plasma renin activity signicantly decreased at 1 month (p = 0.002, Table 2 and Fig. 1) in the midodrine group but did not differ signicantly in the standard medical therapy group (p = 0.079, Table 2 and Fig. 1). Baseline plasma aldosterone concentrations did not differ between the midodrine group and the standard medical therapy group (p = 0.805). Plasma aldosterone concentrations decreased signicantly at 1 month from baseline value in the midodrine group (p = 0.008; Table 2 and Fig. 2) but there was no signicant change in the standard medical therapy group (p = 0.776; Table 2 and Fig. 2). There was signicant change in rate of response to treatment in the midodrine group at 3 months (p = 0.013) although no change was noted at 1 month and 6 months after therapy (Table 3). There was no signicant change in rate of response to treatment in the standard medical therapy group at anytime. Baseline MELD scores were similar in both treatment groups (p = 0.140). MELD score signicantly increased at 1, 3, and 6 months from baseline in the standard medical therapy group but did not differ signicantly from baseline in the midodrine group (Table 2). Pain abdomen was noted in 6 patients in the midodrine group and 4 patients in the standard medical therapy group which was mild and subsided on its own.

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Table 3. Rates of response in two groups at various intervals.

Duration At month 1

No. of patients Midodrine group (n = 18) Standard medical therapy group (n = 17) Midodrine group (n = 16) Standard medical therapy group (n = 16) Midodrine group (n = 12) Standard medical therapy group (n = 5)

Response Complete Partial None Complete Partial None Complete Partial None

Midodrine group N (%) 2 (11.1) 15 (83.3) 1 (5.6) 5 (31.3) 10 (62.5) 1 (6.3) 5 (41.7) 7 (58.3) 0

Standard medical therapy group N (%) 0 (0) 14 (82.4) 3 (17.6) 1 (6.3) 7 (43.8) 8 (50) 1 (20) 4 (80) 0

p value 0.222

At month 3

0.013

At month 6

0.395

Median survival was 90 days (range: 30365) in the standard medical therapy group and 365 days (range: 30365) in the midodrine group. The mortality rate in the standard medical therapy group was signicantly higher than the midodrine group (p <0.046) as shown by KaplanMeier survival curve (Fig. 3). Follow up Fifteen patients in the standard medical therapy group (upper gastrointestinal bleeding in 2, sepsis in 4, encephalopathy in 4, hepatorenal syndrome in 2, and alcoholic hepatitis in 3 patients) and 8 patients in the midodrine group (upper gastrointestinal bleeding in 1, sepsis in 3, encephalopathy in 3, and alcoholic hepatitis in 1) died during follow-up period.

Discussion Splanchnic vasodilation plays a major role in the development of ascites and hepatorenal syndrome. The therapeutic options available for patients with refractory ascites are serial therapeutic paracentesis, TIPS, peritoneovenous shunts, and liver transplantation. Currently, the rst line approach to refractory ascites is

1.0 Cumulative survival 0.8 0.6 0.4 0.2 0.0 0 100 200 Survival Group

Midodrine group Standard medical therapy group

300

Days from randomization

0 30 45 60 90 180 210 300 330 Standard medical therapy 20 16 16 14 9 5 5 5 5 Midodrine 20 17 16 16 13 12 12 12 12

Fig. 3. The hazard of mortality in the two treatment arms is shown in the form of a KaplanMeier curve. The mortality rate in the standard medical therapy group was signicantly higher than the midodrine group (p <0.046). The number of patients at risk in each arm is shown below the gure.

serial LVP up to every 2 weeks. Vasopressors have been used in patients with HRS [1013] as well as for the prevention of post-paracentesis circulatory dysfunction with variable results [1418]. It is possible that vasoconstrictors may reverse some of the pathogenic events that result in increased renal sodium retention and refractoriness to diuretic therapy. Midodrine is a potent and selective, peripherally acting oral alpha adrenergic receptor agonist with little effect on the beta-adrenergic receptors in the heart [29]. Midodrine has been used to improve renal haemodynamics in cirrhotics with ascites [30]. In these patients, it increases effective arterial blood volume by causing splanchnic vasoconstriction and improves renal perfusion and glomerular ltration [30]. Midodrine, along with octreotide and albumin, has been shown to better control ascites in a short term pilot study in patients with refractory ascites [22]. There are no reports of long-term use of midodrine in patients with cirrhosis and ascites. Therefore, the aim of the present study was to study the role of long-term administration of midodrine in patients with cirrhosis with refractory or recurrent ascites. In our study, we compared the changes in systemic haemodynamics (mean arterial pressure, heart rate, and cardiac output), renal haemodynamics and function (glomerular ltration rate, urinary sodium excretion, 24 h urinary output), and vasoactive systems (plasma renin activity and plasma aldosterone) in patients with cirrhosis with refractory or recurrent ascites after long-term administration of midodrine. In a recent study, combination of octreotide plus midodrine administered to 13 nonazotemic cirrhotic patients with ascites for 11 days signicantly decreased cardiac index and heart rate and increased mean arterial pressure, systemic vascular resistance and glomerular ltration rate [19]. In another study, administration of midodrine for 7 days to patients with cirrhosis and ascites was associated with an improvement in circulatory and renal function and sodium excretion in non-azotemic patients with cirrhosis and ascites [20]. In another study, a single dose of terlipressin showed marked benecial effects on renal function in patients with and without refractory ascites [21]. In another recent study, midodrine along with octreotide and albumin given for 1 month to 8 patients with cirrhosis and refractory ascites was associated with a trend towards a reduction in the volume of ascites removed by paracentesis [22]. Similarly, our study showed signicant increase in mean arterial pressure in midodrine group at 1 month after treatment but it did not change signicantly in standard medical therapy group (Table 2). Cardiac output signicantly decreased in midodrine group at 3 months after treatment but

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no signicant change was noted in either group at 1 month and 6 months after therapy (Table 2). Systemic vascular resistance increased signicantly at 3 months after therapy in midodrine group (Table 2). The urine output was signicantly higher in the midodrine group after treatment (Table 2). In a previous study by our group [17] midodrine resulted in signicantly more 24 h urine output and sodium excretion. In the present study, urinary sodium signicantly increased in the midodrine group after treatment at 1 month and 3 months but not in the standard medical therapy group (Table 2). Serum sodium decreased signicantly in the standard medical therapy group after treatment at 1 month and 3 months (Table 2). However, no signicant changes in serum sodium values were noted in the midodrine group after treatment. Hyponatremia is a frequent complication of diuretic therapy in these patients [23,31]. Midodrine therapy was effective in suppressing the renin angiotensinaldosterone axis as evidenced by signicant decrease in plasma renin activity and plasma aldosterone concentration noted after 1 month of therapy which was not observed in the standard medical therapy group (Table 2). Previous studies also showed suppression of activity of the reninangiotensin system in patients with ascites after use of vasoconstrictors [2022]. No signicant differences between standard medical therapy and midodrine groups were observed between values for serum creatinine and glomerular ltration rates after treatment. There are variable reports of renal function abnormalities after vasopressor therapy in these patients [1921]. There was a signicant deterioration in the MELD score during treatment as well as on follow-up in the standard medical therapy group and not in the midodrine group. Earlier studies evaluating midodrine [20] or midodrine plus octreotide [19] in nonazotemic cirrhotics did not show a signicant change in hepatic function. However, in a recent pilot study, there was a signicant deterioration in the MELD score during treatment with midodrine [22]. Rates of response to treatment (measured as need for large volume paracentesis and reduction of ascites) with standard medical therapy or midodrine therapy were measured. There was a significant change in the rate of response to treatment in the midodrine group at 3 months although no change was observed at 1 month and 6 months after therapy (Table 3). There was a higher survival in the midodrine group at the end of follow-up. There are no studies in literature on the long-term use of midodrine in patients with cirrhosis with refractory or recurrent ascites. During treatment with midodrine, pain abdomen was present in 6 patients. However, all episodes were mild and did not require discontinuation of therapy. Other studies have demonstrated no serious side effects with midodrine [20,32]. In conclusion, the results of this randomized pilot study suggest that long-term midodrine plus standard medical therapy improves systemic hemodynamics and better controls ascites without any renal or hepatic dysfunction in nonazotemic patients with refractory or recurrent ascites with cirrhosis as compared to standard medical therapy alone. References
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Conict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conict of interest with respect to this manuscript.

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