To Assess the Efficacy of Midodrine in Prevention of Cirrhosis Related Complications in Children Awaiting Liver Transplantation.
Condition: Cirrhosis, Liver
MeSH terms: Liver Cirrhosis; Fibrosis
Study type: Interventional

Summary: 
      Children with cirrhosis awaiting transplantation are more proned to develop various
      complications. The pathogenesis of cirrhotic complications (ascites, hyponatremia, acute
      kidney injury) includes release of vasodilatory molecules like nitric oxide, damage
      associated molecular pathogens (DAMPs) and pattern associated molecular pathogens (PAMPs)
      secondary to bacterial translocation, which causes splanchnic bed vasodilation resulting in
      activation of renin-angiotensin and aldosterone axis(RAAS) causing sodium and water retention
      and renal vasoconstriction [1].

      The development of complications in these children may result in death or may preclude them
      from reaching upto liver transplantation [2].

      Midodrine is an α1 adrenergic receptor agonist, which increases vascular tone causing rise in
      the blood pressure, thereby improving renal perfusion and causes RAAS deactivation. The
      effects of midodrine is documented in reduction of refractory ascites, hepatorenal syndrome
      and hyponatremia[2-4].

      One group will receive only standard medical therapy and other group will receive midodrine
      and standard medical therapy for 6 months. Mean arterial pressure will be monitored at every
      OPD visit. At the end of 12 weeks, and 24 weeks, plasma renin activity, incidence of
      complications related to cirrhosis like new onset ascites, increase in grade of ascites,
      hyponatremia, acute kidney injury and spontaneous bacterial peritonitis will be assessed.
      Also the transplant free survival and need for albumin transfusion will be compared between
      the two groups.

      In case of liver transplantation or death before 6 months, midodrine will be stopped
    

Detailed description: 
      Aim: To determine the efficacy of midodrine in preventing development of complications in
      children with cirrhosis awaiting liver transplantation

      Primary Objective:

      1) To compare incidence of complications (Acute kidney injury, New onset ascites or increase
      in grade of ascites, Spontaneous bacterial peritonitis, Hyponatremia, Hepatic encephalopathy)
      of cirrhosis in patients receiving midodrine (at a dose of 0.25 - 0.5mg/kg/day) and standard
      medical therapy versus standard medical therapy alone for 6 months

      Secondary Objectives:

        -  Frequency of development of new onset ascites or increase in grade of ascites by 6
           months

        -  Change in serum sodium from baseline to 6 months

        -  Change in Mean arterial pressure (MAP) at 1 week and then 2 weekly till the end of the
           study

        -  Plasma renin activity at baseline, at 12 weeks and 24 weeks

        -  Frequency of development of SBP over 6 months

        -  Change in eGFR from baseline to 6 months

        -  Frequency of developing AKI by 6 months

        -  Frequency of development of Hepatic encephalopathy by 6 months

        -  Proportion of patients developing hypertension at 6 months

        -  Frequency of development of drug related adverse effects by 6 months

        -  Requirement of albumin infusion in 2 groups

        -  Transplant free survival

      Methodology:

        -  Study population :Children and Adolescents of age group upto 18 years with cirrhosis and
           PELD/ MELDNa score more than 14, on waitlist for liver transplantation following up in
           the Pediatric Hepatology Department

        -  Study design: Open label RCT (computer based randomization - block randomization with
           block size of 4)

        -  Study period: 6 months weeks for each patient; The study will be conducted between
           January 2022 and July 2023

        -  Sample size:

        -  Pilot study - 10 patients in each group
    

Intervention name(s): Midodrine Oral Tablet; Standard Medical Treatment
Intervention type(s): Drug; Other
Intervention description(s): Midodrine starting at 0.25mg/kg/day in 2-3 divided doses, increased to 0.5mg/kg/day after 7 days if MAP does not increase by >10% ; Midodrine dosage will be decreased by 25% in case of arterial hypertension (>95th centile BP for the age). Also Standard medical therapy as per departmental protocol will be continued; Albumin infusion 1g/kg/day - maximum 20gm/day and repeat till serum albumin reaches 2.8g/dl If serum albumin is < 2.8g/dl SBP - Day 1 and Day 3
For Ascites :
Restriction of sodium to < 2meq/kg/day A combination of a distal-acting diuretic (spironolactone, 3-6 mg/ kg/day) and loop-acting diuretic (furosemide,0.5- 2 mg/kg per day) was given with dose escalation by one step at a time if there is no decrease in weight (by ≥ 0.5 %/day) after 5-7 days Therapeutic paracentesis (>50ml/kg) with infusion of albumin (8 g/L) performed for tense, symptomatic ascites
For Spontaneous Bacterial Peritonitis :
IV antibiotics for 7 days Albumin Infusion on Day 1 and Day 3
Intervention MeSH terms: Midodrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment