The Use of Human Albumin for the Treatment of Ascites in Patients With Hepatic Cirrhosis: a Multicenter, Open-label Randomized Clinical Trial

Background.

Ascites is the most frequent complication of liver cirrhosis and carries a significant worsening of the prognosis. Medical treatment of uncomplicated ascites is based on diuretics associated to a mild reduction of dietary sodium intake. Approximately 10% of patients per year develop refractory ascites, as defined by the International Ascites Club, because of either the lack of response to medical treatment or the onset of diuretic-induced complications that preclude the use of an effective dosage. Refractory ascites is associated with an increased incidence of severe complications of cirrhosis, such as hepatorenal syndromes (HRS), hyponatremia, spontaneous bacterial peritonitis (SBP), and umbilical hernia rupture and strangulation. Thus, the overall probability of survival of patients with refractory ascites is very poor, being approximately 30% at 2 years. Furthermore, the development of refractory ascites greatly deteriorates the patient's quality of life and substantially raises health costs, due to the frequent need for hospitalization and invasive procedures. Repeated large-volume paracentesis is the most widely accepted therapy for refractory ascites, although early recurrence of fluid accumulation occurs almost invariably. Transjugular intrahepatic portosystemic shunt (TIPS) is usually effective in preventing recurrence, but this procedure can be performed safely only in selected patients. Finally, refractory ascites represents an indication for liver transplantation in patients with no other contraindications.

Renal sodium retention and ascites formation are the consequence of portal hypertension and effective hypovolemia. The background of effective hypovolemia in advanced cirrhosis is represented by arteriolar vasodilation, which mainly occurs in the splanchnic circulatory area and evokes the compensatory activation of neuro-humoral systems able to promote vasoconstriction and renal retention of sodium and water.

Based on the above pathophysiological considerations, the preservation of the central blood volume represents a major purpose in the management of patients with advanced cirrhosis. Albumin constitutes approximately half of the proteins in the plasma of healthy individuals, and is responsible for about 70% of the plasma oncotic pressure. It plays, therefore, a pivotal role in modulating the distribution of fluid between compartments. However, albumin carries other biological properties, such as molecule and drug transport, free radical scavenging, and anti-inflammatory activity, which can be relevant under several circumstances and diseases. Finally, several controlled and/or randomized studies have shown that albumin administration is effective to prevent the circulatory dysfunction after large-volume paracentesis and renal failure after SBP, and to treat HRS when given together with vasoconstrictors. Furthermore, it is currently believed that its capacity to expand central blood volume in cirrhosis is superior to that of several plasma-expanders. In contrast, the chronic use of albumin to treat ascites is still debated, due to the lack of definitive scientific evidence supporting its clinical benefits. Thus, the absence of large multicenter randomized studies together with the high cost of the human albumin explains why albumin infusion is not usually included among the therapeutic options for difficult-to-treat ascites.

Objectives.