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Slyvka Nataliia Oleksiivna, PhD, professor's assistant, Higher State Educational Establishment of Ukraine "Bukovinian State Medical University", Chernivtsi, Ukraine
E-mail: slyvkanataliia@gmail.com
ADVANTAGES OF TERLIPRESSIN VERSUS DOPAMINE IN THE TREATMENT OF HEPATORENAL SYNDROME
Abstract. This research is aimed to compare the efficacy of vasoconstrictors used for the treatment of hepatorenal syndrome, such as dopamine and terlipressin. The study enrolled 92 patients, which were divided into 2 groups and examined in the dynamics of treatment. The results have shown that dopamine administration in "renal doses" did not lead to any improvement in kidney function - rates of GFR, serum urea and creatinine, serum ions didn't change significantly (p > 0.05) and didn't increase patients survival, despite the obvious temporary improvement of the hemodynamics and dieresis. Terlipressin has demonstrated much better correction ofkidney function and decreased the mortality rate (p > 0.05). Thus, terlipressin can be considered as the treatment of choice for patients with hepatorenal syndrome.
Keywords: hepatorenal syndrome, alcoholic liver cirrhosis, terlipressin, dopamine.
Introduction. The number of patients with Changes of blood circulation manifest with the alcoholic liver cirrhosis (ALC) remains consis- hyperdynamic syndrome because ofvasodilation in
tently high now days. One of the most dangerous complication of ALC is the hepatorenal syndrome (HRS) - renal dysfunction along with the increase of intoxication and a deterioration of patients survival prognosis [1].
HRS develops in patients with ALC, severe liver failure and portal hypertension. HRS manifests with the impaired renal function, arterial circulation failure and high activity of the endogenous vasoactive system. Pronounced vasoconstriction in kidneys, leading to the decrease of glomerular filtration rate (GFR) is the main pathophysiological mechanism of HRS. Arterial vasodilation prevails in the extra-hepatic blood flow, leading to the reduction of total vascular resistance and arterial hypotension [2].
The pathogenesis of HRS is not clearly understood yet, but there are evidences of hemodynamic disturbances leading to the decrease in renal blood flow, activation of sympathetic nervous system and increased synthesis of humoral and renal vasoactive mediators [7].
most patients with ALC and HRS [1]. The circulatory disorders in HRS are explained with an increase of deposition ofblood in the internal organs associated with severe peripheral vasodilation [6].
To maintain effective kidney blood supply the systolic blood pressure (sBP) has to exceed 85 mm Hg. It is possible to achieve this range by means of volume expanders and vasopressors, such as vasopressin, or-nipressin, octreotide, terlipressin or dopamine [9].
The use of dopamine in patients with HRS is based on its ability to inhibit the synthesis of aldosterone, to increase the renal blood flow and GFR.The clinical studies in patients with ALC and HRS have shown that low doses of dopamine (1.5 mcg/kg/min) lead to an increase in renal blood flow by 31% with unchanged GFR. Opinions about the effectiveness of dopamine in patients with HRS are controversial. It is reported that low-dosage of dopamine doesn't increase the diuresis and doesn't decrease serum creatinine level in patients with ALC and HRS [7].
There are also positive effects of dopamine to renal function. At the same time, it is noted that the effect of dopamine is short-lived and manifests itself only during the first week since the onset of treatment [10].
Terlipressin is a synthetic analogue of vasopressin (H-triglycyl-8-lysine), which has a longer half-life and more favorable safety profile as compared to ornipres-sin. The use ofterlipressin in combination with albumin can reduce the activity ofrenin-angiotensin system, increase sBP, improve the systemic blood flow, and normalize level ofthe serum creatinine and GFR[3; 9; 10].
Material and methods. This study analyzes the results of a comprehensive examination of 92 patients (64 men and 28 women) with ALC and HRS in the dynamics of treatment. The age of patients ranged from 28 to 73 years, the majority of them were between 41-60 years.
HRS was diagnosed by the criteria of EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis [4; 5]:
1. Liver cirrhosis with ascites.
2. Serum creatinine concentration more than 133 mmol/l (1,5 mg/dl).
3. Absence of positive dynamics in the level of serum creatinine (<133 mmol/l) for 2 days after discontinuation of diuretics and volume expansion with albumin (1 g/kg body weight, maximum 100 g/kg).
4. No signs of shock.
5. No history of administration of nephrotoxic drugs.
6. No history of parenchymal kidney disease, manifested by proteinuria more than 500 mg/day, hematuria more than 50 cells in the high power field and/or changes during ultrasound examination.
All enrolled patients with ALC and HRS were prescribed albumin (Albumin-Biopharm 20%; OOO Biopharma Plasma Ukraine) intravenously (i/v), 1 g/kg per day on the first day of treatment and 20-40 g/day - in the next few days. They were divided into two groups: Group 1 (control group) (n = 27) - received dopamine (Dopamine-Darnytsa, 5 mg/ml) in
the "renal dose" - 5 mg/kg/min for 7 days; Group 2 (study group) (n = 23) received terlipressin (Remestip 0.1mg/ml, Ferring-Lechyam a.s., Czech Republic) was initially administered at the dose of 3 mg/24 hours by continuous intravenous administration for 7 days. The response to treatment was evaluated every 48 hours, in case if serum creatinine decreased by less than 25% from baseline, the dose was gradually increased to 12 mg/24 hours.
The risk of short term mortality (within the first 29 days) was prognosed by MELD score (Model for End-Stage Liver Disease) [8]. MELD score uses the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR) to predict survival. It is calculated according to the following formula:
MELD = 3.78 x ln[serum bilirubin (mg/dL)] + + 11.2 x ln[lNR] + 9.57 x ln [serum creatinine (mg/dL)] + 6.43
In interpreting the MELD score in hospitalized patients, the 3 month observed mortality is: 40 or more - 71.3% observed mortality; 30-39-52.6% observed mortality; 20-29-19.6% observed mortality; 10-19-6.0% observed mortality; < 9-1.9% observed mortality [8].
Statistical processing of the study results was carried out using the program package STATISTICA 15.0. To assess the difference between groups, Student's t-test for independent samples was used. To measure the degree of linear dependence between the values of the indices in the groups, the Pearson correlation coefficient (r) was used for parametric values, and the chi-square criteria (x2) for nonpara-metric ones. The assessment of patients' survival was performed using the Kaplan Meier method. The statistics are given in the format M±a. The level p <0.05 was accepted as statistically significant.
Results. Symptoms of chronic hepatic and acute renal failure prevailed in all patients before the treatment has started. Initially, patients of both groups were noted the tendency to hypotonia and tachycardia, which is typical for patients with ALC and HRS.
In patients of Group 1 the symptoms of liver failure were combined with the symptoms of renal failure: low GFR, oligouria, edema, ascites, hyperkalemia, hyponatremia, high levels of serum urea and creatinine. Administration of dopamine at a dose of 5 mg/kg/min was accompanied by an increase of sBP, on the 7-8th day it was 84.7 ± 9.2 mm Hg. (p < 0.05) in comparison with the initial level) and reached normal values, while an unreliable increase in the heart rate was recorded. These results can be considered as a hemodynamic stabilization in patients with ALC and HRS. However, sBP has decreased to the baseline values by the 30th day (dopamine was administered only for the first seven days). On the 7-8th day, the examined parameters did not differ from the initial values, the amount of diuresis also did not increase. Thus, dopamine administration in "renal doses" did not lead to any improvement in kidney function - rates of GFR, serum urea and creatinine, serum ions didn't change significantly (p < 0.05). By the 30th day, a progressive hyperkalemia along with increase of serum creatinine and urea were observed. The diuresis rate also did not increase.
In Group 2 the terlipressin therapy has significantly improved the indicators of water-electrolyte metabolism and toxins elimination. On the 7-8th day, a significant decrease of serum urea and creatinine occurred in comparison with the initial values up to 17.5 ± 1.9 mmol/l and 165.6 ± 18.9 mmol/l (p <
< 0.05). At the same time, an increase sodium ions and a decrease ofpotassium were observed (p < 0.05). A positive phenomenon was also an increase of the volume of diuresis, observed on the 7-8th day in patients of the Group 2. The clinical effects of the terlipressin therapy were to reduce the degree of overhydration and the symptoms of ascites.
In Group 1 within the first 7-8 days of treatment 5 patients died, and another 18 died by the 30th day - the mortality rate composed 21.8% and 78.3% respectively. Mortality in this group corresponded to the predicted level by MELD score before the start of treatment. In Group 2 within the first 7-8 days of treatment 2 patients died, and another 11 died by the 30th day - the mortality rate composed 7.4% and 40.7% respectively, which was much less than in Group 1 (p < 0.05) and less, than the level predicted by MELD score before the start of treatment. The results indicate that the inclusion of dopamine in the therapy of patients with HRS does not reduce their mortality.
Conclusions. The results of the study show that vasopressor therapy according to the scheme of terlipressin + albumin is more effective compared to the scheme of dopamine + albumin - both for the normalization of kidney function, and for the survival of patients with hepatorenal syndrome on the background of alcoholic liver cirrhosis. Thus, terlipressin in combination with albumin can be considered as the treatment of choice for such patients.
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