Effect of Midodrine in Non-azotemic Liver Cirrhosis Patients with Refractory or Recurrent Ascites

INTRODUCTION

The most common sequelae of cirrhosis are ascites, hepatorenal syndrome, hepatic encephalopathy (HE), and upper gastrointestinal hemorrhage. Development of ascites predicts poor prognosis and lower standard of living (quality of life).^[1] Such patients with ascites become more vulnerable to complications from bacterial peritonitis, hyponatremia, and hepatic hydrothorax and need diuretic therapy.^[2] The prognosis worsens when ascites become resistant to therapy. Without a liver transplant, about 40–60% of patients are able to survive for two years.^[3] Ascites progress to refractory ascites in about 5–10%, and within 6 months, the mortality rate is 50%. According to the International Ascites Club, refractory ascites cannot be mobilized or recur following large-volume paracentesis and cannot be adequately controlled by medical treatment.^[4] Recurrent ascites are defined by frequent hospital admissions (more than three times per year) brought by the reaccumulation of ascites.^[5]

Clinically, ascites can be classified as (1) diuretic-resistant ascites, which are unresponsive to the maximum tolerable dose of DT (400 mg/day of spironolactone and 160 mg/day of furosemide) and (2) diuretic-intractable ascites, which occurs when complications (e.g., hepatic encephalopathy, renal dysfunction or electrolyte abnormalities) prevent the use of diuretics at the therapeutically effective dose.^[6]

Liver cirrhosis leads to restricted portal flow (in refractory ascites), causing portal hypertension. It is considered the first phase. Nitric oxide and other local vasodilators are released, which causes the splanchnic vessels to dilate.^[7] Splanchnic arterial vasodilation reduces the amount of arterial blood in individuals with severe cirrhosis, making it challenging to maintain blood pressure. Associated neurohumoral activation and circulatory dysfunction^[8] are reported. Vasoconstrictors and anti-natriuretic factors, such as the sympathetic nervous system and the renin-angiotensin-aldosterone system, are activated to compensate for this condition, leading to salt and water retention.^[8] Vasodilation of the vessels and portal hypertension influence the permeability and pressure of the intestinal capillaries, which causes retained fluid in the abdominal cavity. Refractory ascites can develop for a variety of reasons, including markedly impaired renal excretion of free water, renal vasoconstriction, and sodium reabsorption.^[9]

Options for refractory ascites are serial therapeutic paracentesis large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunt (TIPS), peritoneovenous shunt, and liver transplantation.^[10] Liver transplantation is the most successful treatment option but not always feasible due to its economic viability and lack of donors. In addition, some ascite patients are contraindicated for liver transplantation. As a result, non-transplant treatment alternatives for ascites that are refractory and recurring are currently receiving more attention.

It was reported that several vasoconstrictors, after administration to non-azotemic cirrhotic patients with ascites, circulatory, renal, and sodium excretion functions improved.^[11,12] Specifically, midodrine, an oral a1-adrenergic agonist combined with octreotide and albumin, improved ascites control in individuals with refractory ascites.^[13] Desglymidodrine (1 receptor agonist) is the active metabolite of midodrine, which raises blood pressure and causes an increase in vascular tone. It has no neural (diffuses weakly across the blood-brain barrier) or cardiac effects. It improves systemic and renal hemodynamics by reducing mesenteric vasodilatation in cirrhotic patients.^[14]

There is a paucity of studies to evaluate the efficacy of midodrine in the management of refractory and recurrent ascites. So, this study was conducted to study the effect of midodrine in patients with liver cirrhosis with refractory or recurrent ascites.

MATERIAL AND METHODS

This is a facility-based open-label parallel design randomized controlled trial conducted in RIMS, Imphal, from 1st January 2021 to 1st July 2022. All patients with non-azotemic liver cirrhosis with refractory or recurrent ascites patients attending medicine outpatient department (OPD), liver clinic, and those admitted in the medicine ward, RIMS, Imphal, were enrolled. The census sampling method was used for data collection.

Intervention

The clinically confirmed and diagnosed cases of non-azotemic liver cirrhosis with refractory or recurrent ascites cases were divided into 2 groups as shown in Flow chart 1.

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Flow chart 1:

Depicts the participants’ recruitment and study procedure.

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Group A: patients in SMT [low sodium diet + diuretic therapy (loop diuretic in a dose 40–160 mg/day and distal acting diuretic in a dose100–400 mg/day)] + LVP as needed.

Group B: patients in SMT and midodrine tolerable dose for one month.

RESULTS

The present study enrolled 40 non-azotemic liver cirrhosis with refractory or recurrent ascites patients, and the mean (SD) age in years in the intervention group (midodrine group) was 46.9(±10.34) years and in the control group was 49.85(±12.57) years. Between the two groups, baseline socio-demographic and clinical characteristics were given in Table 2, baseline clinical characteristics between the two groups were given in Table 3, and baseline biochemical characteristics between the two groups were given in Table 4. The majority of them were males (15,75%) and (14,70%) in the intervention group and control group, respectively. The distribution of baseline co-morbidities between the groups was almost similar in both groups. Most of the patients were chronic alcoholics (90%), whereas the distribution of tobacco usage and IV drugs at the baseline was similar and comparable. The hemoglobin percentage in the study was less than normal and was around 8.9 gm/dl in the midodrine group and 8.4 gm/dl in the SMT group. Total leucocyte count was around 8.4(±2.62) thousand and 8.85(±3.6) thousand in the midodrine group and SMT group, respectively, and the values are within the normal range. Platelet count was similar in both groups but was less than the normal range. Random blood sugar was 114(±35.7) mg/dl in the midodrine group and 136.55(±50.4) mg/dl in the SMT group; there was no significant difference between the groups. Baseline total bilirubin values were very high, 8.9(±1.29) in the midodrine group and 8.4(±1.35) in the control group. The serum albumin was 2.9(±0.85 g/dl) and 2.75(±0.71) g/dl in the midodrine group and SMT group, respectively, and there was no significant difference between the groups. The mean distribution of LFT parameters among two treatment groups. The mean serum glutamic oxaloacetic transaminase (SGOT) among the midodrine group was 114.5 u/l, and the SMT group was 136.55 u/l. The mean serum glutamic pyruvic transaminase (SGPT) level among the midodrine group was 39.75 u/l, and among the SMT group was 49.4 u/l. The mean ALP level among the midodrine group was 122.95 u/l, and among the SMT was 173.15 u/l. The mean GGT level among the midodrine group was 111.4 u/l, and among the SMT was 169.7 u/l. The mean serum globulin among the midodrine group was 3.05 g/dl, and the SMT group was 3.65 g/dl.

Among the two groups, blood urea was 39.80(16.4) and 47.65(18.8) in the midodrine group and SMT group, respectively, but there is no significant difference between the groups. Serum creatinine was slightly elevated in both the groups and there was no significant difference between the groups. Serum sodium was slightly decreased in both groups.

Clinical parameters before and after one month of therapy among groups are shown in Table 5. A comparison of outcome variables after one month of therapy across groups was given in Table 6. MELD score was 24.60(5.10) and 25.35(4.8) in the midodrine group and SMT group, respectively, and there was no significant difference between the groups (p- 0.640), but after one month of treatment, there was a significant decrease in MELD scores in midodrine group, but there is no much difference in the SMT group compared to baseline.

GFR increased in both groups but was significantly increased only among the midodrine group (p=0.003). Baseline urine output in the midodrine group was 1105(395.30) ml/24 hr, and in the SMT group was 1008(386.91), and the values were similar and were comparable. Urine output was significantly higher in the midodrine group after the treatment compared with the control group after one month of treatment (p-value 0.006). Among the midodrine group, there is a significant decrease in body weight (p=0.000) after the treatment, whereas in the SMT group, there is a slight increase in body weight, but it is not significant (p=0.230).

When MAP was compared before and after the treatment in two groups, there was a significant increase in MAP among the midodrine group, but there was an increase in MAP among the control group, which was not significant. After one month of treatment with midodrine compared to baseline, there is no significant increase in MAP among the control group.

DISCUSSION

Ascites occur in nearly 50% of cirrhotic patients at least within 10 years period^[28], and refractory ascites occur in 5–10% of cases.^[29] In cirrhosis, splanchnic arterial vasodilatation is predominant; therefore, arterial vasoconstrictors could be a treatment option.^[30] Vasoconstrictors (noradrenaline, terlipressin, octreotide, and midodrine) are useful in the treatment of HRS. Midodrine hydrochloride increases effective arterial blood volume by causing splanchnic vasoconstriction and improves renal perfusion and glomerular filtration through selective a1-adrenergic agonist action.^[30] Moreover, midodrine prevents dialysis-induced hypotension and improves systolic blood pressure due to its effects on autonomic nerves. No side effects, such as an increase in the volume of fluid filtered by dialysis or a change in body weight in these patients. Midodrine, along with octreotide, increases MAP, renal plasma flow, GFR, urine volume, and urine salt levels, with non-azotemic and decreases recurrence of hydrothorax and mild ascites. Midodrine has also been used for the treatment of autonomic dysfunction, such as postural orthostatic tachycardia syndrome.

A total of 40 non-azotemic liver cirrhosis with refractory or recurrent ascites were enrolled in the study and were equally randomized into the midodrine group (n=20) and SMT group (n=20). The mean (SD) age in years in the intervention group (midodrine group) was 46.9(±10.34) years, and in the control group was 49.85(±12.57) years, which was similar to the sample size of 39 and 40 used in Singh V et al.^[29] and Kalambokis G et al.^[11], respectively.

In the present study, the mean age of the study participants was 48.5 years, which was comparable with the studies by Singh V et al.^[29] (47 years) and Kalambokis G et al.^[11] (52 years). The majority of the study participants were males in our study and other studies as well.^[29,11]

There was a comparison of MAP, body weight, MELD scores, 24-hour urine output, and glomerular filtration rate among the groups after one-month treatment of midodrine and SMT.

In a study by Kalambokis G et al.^[11], a combination of midodrine and octreotide administered to 13 non-azotemic cirrhotic patients with ascites for 11 days significantly decreased cardiac index and heart rate and increased MAP, systemic vascular resistance, and GFR. Similarly, our study showed a significant increase in MAP in the midodrine group one month after treatment, but it did not change significantly in the SMT group, which was consistent with the findings by Tandon et al.^[13] and Singh et al.^[14]

In the present study, the baseline 24-hour urine output was 1105 ml and 1008 ml among the midodrine and SMT groups, respectively. After one month of treatment, in the midodrine group, there was a significant increase in urine output, while there was no significant increase in the SMT group. Similar results were observed in the Singh V et al. study.^[14] The present study showed a significant increase in GFR in the midodrine group after one month of treatment, whereas in the SMT group, there was no significant increase in GFR, which was consistent with the study by Singh et al.^[14]

Our study showed a significant decrease in body weight in the midodrine group, whereas, in the SMT group, there was no significant decrease in body weight, which might be explained by the decrease in fluid accumulation by midodrine. This finding was at par with that of Ali et al. study.^[31]

There was a significant decrease in MELD score in the midodrine group after one month of treatment but not in the SMT group, which was similar to the study by Tandon P et al.,^[13] whereas Kalambokis G et al.^[11] reported no significant decrease in MELD score.

CONCLUSION

The results of this randomized controlled trial suggest that adding midodrine drug to the SMT improves the systemic hemodynamics in non-azotemic cirrhotic patients with ascites, and it is also effective in lowering the body weights of the patients by decreasing fluid accumulation.