Midodrine May Be Comparable to Albumin for PICD Prevention in ACLF

Neil Osterweil

November 17, 2022

WASHINGTON, DC — For patients with acute-on-chronic liver failure (ACLF) undergoing modest-volume paracentesis for ascites, oral midodrine may be an alternative to intravenous albumin for preventing paracentesis-induced circulatory dysfunction (PICD), according to the results of a randomized controlled trial.

Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases.

Midodrine may be a safer and cost-effective option for these patients, said Sharma, of the Department of Hepatology and Liver Transplantation, AIG Hospitals, Hyderabad, India.

But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.

PICD Common in ACLF

PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.

The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Sharma noted.

Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.

In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).

In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Sharma said.

Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.

Study Details

Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.

They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.

They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.

The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.

Patients' mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.

The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.

The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.

Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.

Complications and Costs

PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.

No cases of hypertension or urinary retention arose in either group.

Grade I/II hepatic encephalopathy occurred 2 to 3 days after paracentesis in three patients on albumin and in two patients on midodrine.

Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.

At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.

Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.

A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.

More Data Needed

Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.

Sarin also emphasized that albumin is "mandatory" for protecting patients who require large-volume paracentesis, and that it would be "unethical" not to use it in that clinical situation.

The study was internally supported. Sharma and Sarin have disclosed no relevant financial relationships.

The Liver Meeting 2022: American Association for the Study of Liver Diseases (AASLD): Abstract 117. Presented November 7, 2022.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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