Short summary

Cirrhosis and portal hypertension is associated to hyper-dynamic circulation leading to decreased renal perfusion and water retention. Terlipressin is a vasoconstrictor and the drug of choice to increase renal perfusion in patients with cirrhosis and renal failure. Dobutamine is a B1-adrenergic agonist that increases cardiac output, which is used for patients with acute cardiac and renal failure. In participants with cirrhosis and ascites we will evaluate the cardiovascular and renal effects of terlipressin and dobutamine separately and in a combination. 

Rationale

Patients with cirrhosis and portal hypertension have a hyper-dynamic circulation leading to decreased renal perfusion and water retention. This condition makes these patients vulnerable to an acute event causing decreased blood pressure which may lead to hepatorenal syndrome (HRS). According to current guidelines standard treatment of HRS is terlipressin and albumin. Even though HRS is managed according to the guidelines the 30-days-mortality is still around 40 percent. Terlipressin has beneficial effects on the renal function by increasing arterial blood pressure and systemic vascular resistance. At the same time, terlipressin a reduced heart rate and thus reduced cardiac output. A low cardiac output in patients with cirrhosis and ascites is associated with reduced renal perfusion and increased mortality. Dobutamine is a predominantly B1-adrenergic agonist that increases cardiac output.

Objectives:

To evaluate the cardiac and renal effects and safety of dobutamine alone and in combination with terlipressin in patients with cirrhosis and ascites.

The observation is going to run for four hours of three periods. Through the first period of one hour baseline values will be measured. During the second and the third period each of one and a half hour the participants will receive the study drugs.

To estimate the required number of patients, we chose a type one error of 0.05 and a type 2 error of 0.20. The standard deviation of the estimate of renal function in this type of patients is approximately 20%. A paired design requires eight participants in each arm for detecting a difference of 20% after the treatment, which is a clinically relevant difference. The project is registered in the European Clinical Trial Database. Indification: EudraCT 2012-002275-33/1. The project is monitored by the GCP-unit and approved by Danish Health Authority, Ethics Committee and the Danish Data Protection Agency. 

Description of the cohort

We plan to perform a 2:2:1 randomization of 25 patients with cirrhosis and ascites into three groups. Group A will receive dobutamine infusion in the second period followed by terlipressin in the third period. Group B will receive terlipressin in the second period and followed by dobutamine in the third period. Group C will receive saline as placebo in period B and C. 

Data and biological material

Baseline data registration: 

• Age, gender, weight, height
• Etiology and of staging of the liver disease (CHILD-PUGH + MELD)
• Medical history
• Medicine list

Baseline biochemical data

• Cardiac, liver, renal and coagulation biomarkers

Biological material

• Urine
• Blood samples from a peripheral vein

The biological material will be analyzed to calculate the primary outcome, glomerular filtration rate, using Chrome-EDTA clearance, which is a measurement of renal function. Secondary outcomes include electrolyte excretion, changes in endogen vasoactive substances and non-invasive assessment of cardiac output.

Collaborating researchers and departments

Cardiovascular and Renal Research, University of Southern Denmark

• Director of a research institute Boye L. Jensen