Safety and Efficacy of Midodrine Hydrochloride in the Management of Refractory Ascites Due to Cirrhosis in Children

Ascites in liver cirrhosis is explained by increased production of vasoactive substances leading to renal vasoconstriction and salt and water retention. The retained water then accumulates in the peritoneal cavity under the effect of portal hypertension and low albumin. Refractory ascites is defined as ascites that cannot be mobilized or prevented from early recurrence after large-volume paracentesis despite medical therapy and dietary sodium restriction. Midodrine is an α1 receptor agonist that can improve systemic and renal hemodynamics in non-azotemic cirrhotic patients by counteracting mesenteric vasodilatation, which is accentuated in cirrhosis.

Ascites in liver cirrhosis is explained by increased production of vasoactive substances, such as nitric oxide, carbon monoxide, and endocannabinoids, which cause splanchnic vasodilatation, increased blood flow through this area, and a decrease in peripheral vascular resistance and the effective arterial volume with resulting reduction in renal blood flow with subsequent activation of rennin-angiotensin-aldosterone system which in turn leads to renal vasoconstriction and salt and water retention. The retained water then accumulates in the peritoneal cavity under the effect of portal hypertension and low albumin.

The International Ascites Club defines refractory ascites as ascites that cannot be mobilized or prevented from early recurrence after large-volume paracentesis despite medical therapy and dietary sodium restriction.

There are two varieties of refractory ascites: diuretic-resistant ascites that is unresponsive to the maximal tolerable dose of diuretic therapy and diuretic-intractable ascites when complications such as hepatic encephalopathy, renal dysfunction, or electrolyte abnormalities limit the use of diuretics in the effective therapeutic dose (Cárdenas and Arroyo, 2005)

The therapeutic options for refractory ascites are serial therapeutic paracentesis, transjugular intrahepatic portosystemic shunt, peritoneovenous shunt, and liver transplantation.

Midodrine is transformed into the active metabolite desglymidodrine, which is an α1 receptor agonist causing an increase in vascular tone and increase in blood pressure without β-adrenergic receptors stimulation so, it can improve systemic and renal hemodynamics in non-azotemic cirrhotic patients by counteracting mesenteric vasodilatation, which is accentuated in cirrhosis. It diffuses poorly across the blood-brain barrier with no central effects.

In a study included 600 adult patients with refractory ascites, midodrine was added to diuretic therapy and lead to enhancement of diuresis with the improvement of systemic, renal hemodynamics and short-term survival. Approximately, the only use of midodrine hydrochloride in children was in postural orthostatic tachycardia syndrome (POTS) which showed a good efficacy and safety profile.

Eligibility Criteria:
Inclusion Criteria:

* Children aged 7-18 years
* Both sexes
* Having refractory ascites (not responding to maximal dose of diuretics
* Diuretic-induced complications necessitate discontinuation of the drug

Exclusion Criteria:

* Non-cirrhotic causes of ascites
* Intrinsic renal disease ( e.g; polycystic kidney disease)
* Active gastrointestinal bleeding or the presence of risky varices
* Patients with Portal vein thrombosis and Budd-Chiari
* Cardiovascular disease
* Systemic hypertension or prehypertension
* Hyperthyroidism
* Patients with narrow-angle glucoma