Effects of Adding Hypertonic Saline Solutions and/or Etilefrine to Standard Diuretics Therapy in Hepatic Ascites

Hepatic Ascites Clinical Trial

Official title:

Effects of Adding Hypertonic Saline Solutions and/or Etilefrine to Standard Diuretics Therapy in Egyptian Cirrhotic Patients With Ascites

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04785755
• Other study ID #: ascites of liver cirrhosis
• Status: Completed
• Phase: Phase 2
• Start date: November 30, 2017
• Est. completion date: April 30, 2020

Study information

• Verified date: March 2021
• Source: Tanta University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This work aimed to evaluate and compare the impact of adding hypertonic saline solution (HSS) infusion and/or etilefrine to oral diuretics therapy on clinical outcomes, renal and systemic hemodynamics, metabolic and inflammatory pathways by estimating the changes in selected biological markers in cirrhotic patients with ascites. Also, the trial aims to assess the safety and tolerability of such treatment regimens.

Description:

This comparative, randomized, prospective controlled clinical trial was conducted on 90 cirrhotic patients with ascites who were admitted to the Hepatology Department of National Liver Institute, Menoufiya University. The study was approved by the Institution Review Board (IRB) of the National Liver Institute (NLI), Menoufiya University, Egypt with NLI/IRB protocol number: 00131/2017. Informed consent was obtained from all patients who participated in the study.

Patients were randomized into four groups:

Group I: (n=15) received oral standard diuretic therapy (furosemide 40 mg plus spironolactone 100 mg with dose increase in 40 mg :100 mg ratio).

Group II: (n=25) received (150 ml,1.4% - 4.6%) of hypertonic saline solution (HSS) plus standard diuretics therapy.

Group III: (n=25) received etilefrine 5 mg tablets 3 times daily plus standard diuretics therapy.

Group IV: (n=25) received (150 ml, 1.4% - 4.6%) of HSS and etilefrine 5 mg tablets 3 times daily plus standard diuretics therapy.

Time frame:

Oral standard diuretics therapy administered for 38 days. Etilefrine tablets administered for 38 days. Infusion of HSS administered for eight days. Diuretics dosage reassessed according to blood pressure, diuresis, serum sodium, and serum potassium levels.

All blood and urine samples were collected and measured as follows:

1. At baseline before initiation of any treatment (first measurement)

2. Eight days after treatment with studied medications (second measurement).

3. One month after the second measurement (third measurement).

Samples collection:

Venous blood samples were drawn from enrolled patients in the morning before treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement). Blood samples were centrifuged and the resulting supernatant was frozen at -80 C until all samples were collected. 24-hr urine was collected in the morning from 7 am to 7 am of the next day before initiation of treatment, after eight days of treatment, and after a month from the second measurement to assess diuresis and urinary creatinine, urinary Na, and urinary K, also hepatic and renal functions, complete blood count, serum levels of c-reactive protein, interleukin-6, aldosterone, and leptin were measured at baseline, after eight days and, after a month from the second measurement.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 90
• Est. completion date: April 30, 2020
• Est. primary completion date: March 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 65 Years

Eligibility

Inclusion Criteria:

• All cirrhotic patients with ascites grade I- III.

• Patients ages from 25 -65 years.

Exclusion Criteria:

• Non-cirrhotic ascites.

• Congestive heart failure.

• Acute renal failure.

• Hepatocellular carcinoma.

• All Cancer types.

• Arterial hypertension.

• Acute infection.

Related Conditions & MeSH terms

• Ascites
• Hepatic Ascites

Intervention

Drug:
• Oral standard diuretics therapy
Oral standard diuretics therapy (furosemide 40 mg tablet plus spironolactone 100 mg tablet with a dose increase in 40 mg:100 mg ratio) given once daily in the morning for 38 days (from the first day of the study to the end of the study).
• Hypertonic saline solution
Hypertonic saline solution (150ml, 1.4% - 4.6%) infused slowly over one hour peripherally once daily from the first day of the study for eight days.
• Etilefrine
Etilefrine 5 mg tablet given by mouth three times daily for 38 days (from the first day of the study to the end of the study).

Locations

Country	Name	City	State
Egypt	National liver institute- menoufiya university	Shibin Al Kawm	Menoufiya

Sponsors (1)

Lead Sponsor	Collaborator
Hala Abd EL-Tawab Ibrahim Radwan

Country where clinical trial is conducted

Egypt, 

References & Publications (22)

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Gauthier A, Levy VG, Quinton A, Michel H, Rueff B, Descos L, Durbec JP, Fermanian J, Lancrenon S. Salt or no salt in the treatment of cirrhotic ascites: a randomised study. Gut. 1986 Jun;27(6):705-9. — View Citation

Gu XB, Yang XJ, Zhu HY, Xu BY. Effect of a diet with unrestricted sodium on ascites in patients with hepatic cirrhosis. Gut Liver. 2012 Jul;6(3):355-61. doi: 10.5009/gnl.2012.6.3.355. Epub 2012 Jul 12. — View Citation

Guo TT, Yang Y, Song Y, Ren Y, Liu ZX, Cheng G. Effects of midodrine in patients with ascites due to cirrhosis: Systematic review and meta-analysis. J Dig Dis. 2016 Jan;17(1):11-9. doi: 10.1111/1751-2980.12304. Review. — View Citation

Haberl J, Zollner G, Fickert P, Stadlbauer V. To salt or not to salt?-That is the question in cirrhosis. Liver Int. 2018 Jul;38(7):1148-1159. doi: 10.1111/liv.13750. Epub 2018 May 16. Review. — View Citation

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Henriksen JH, Fuglsang S, Bendtsen F, Møller S. Arterial hypertension in cirrhosis: arterial compliance, volume distribution, and central haemodynamics. Gut. 2006 Mar;55(3):380-7. — View Citation

Kølsen-Petersen JA. Immune effect of hypertonic saline: fact or fiction? Acta Anaesthesiol Scand. 2004 Jul;48(6):667-78. Review. — View Citation

Lafrenière G, Béliveau P, Bégin JY, Simonyan D, Côté S, Gaudreault V, Israeli Z, Lavi S, Bagur R. Effects of hypertonic saline solution on body weight and serum creatinine in patients with acute decompensated heart failure. World J Cardiol. 2017 Aug 26;9( — View Citation

Li H, Guo Z, Yang X, Sun D. Mean arterial pressure drop is an independent risk factor of death in patients with HBV-related cirrhosis ascites. Turk J Gastroenterol. 2017 Jan;28(1):26-30. doi: 10.5152/tjg.2016.0412. Epub 2016 Dec 19. — View Citation

Morando F, Rosi S, Gola E, Nardi M, Piano S, Fasolato S, Stanco M, Cavallin M, Romano A, Sticca A, Caregaro L, Gatta A, Angeli P. Adherence to a moderate sodium restriction diet in outpatients with cirrhosis and ascites: a real-life cross-sectional study. — View Citation

Okuhara Y, Hirotani S, Naito Y, Nakabo A, Iwasaku T, Eguchi A, Morisawa D, Ando T, Sawada H, Manabe E, Masuyama T. Intravenous salt supplementation with low-dose furosemide for treatment of acute decompensated heart failure. J Card Fail. 2014 May;20(5):29 — View Citation

Pérez-Pérez A, Vilariño-García T, Fernández-Riejos P, Martín-González J, Segura-Egea JJ, Sánchez-Margalet V. Role of leptin as a link between metabolism and the immune system. Cytokine Growth Factor Rev. 2017 Jun;35:71-84. doi: 10.1016/j.cytogfr.2017.03.0 — View Citation

Reynolds TB, Lieberman FL, Goodman AR. Advantages of treatment of ascites without sodium restriction and without complete removal of excess fluid. Gut. 1978 Jun;19(6):549-53. — View Citation

Reynolds TB. Ascites. Clin Liver Dis. 2000 Feb;4(1):151-68, vii. Review. — View Citation

Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic indicator of mortality among patients hospitalized with cirrhosis and portal hypertension. Liver Int. 2009 Oct;29(9):1396-402. doi: 10.1111/j.1478-3231.2009.02077.x. Epub 2009 Jul 7. — View Citation

Singh V, Dhungana SP, Singh B, Vijayverghia R, Nain CK, Sharma N, Bhalla A, Gupta PK. Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. J Hepatol. 2012 Feb;56(2):348-54. doi: 10.1016/j.jhep.2011.04.027. Ep — View Citation

Tuttolomondo A, Di Raimondo D, Bellia C, Clemente G, Pecoraro R, Maida C, Simonetta I, Vassallo V, Di Bona D, Gulotta E, Ciaccio M, Pinto A. Immune-Inflammatory and Metabolic Effects of High Dose Furosemide plus Hypertonic Saline Solution (HSS) Treatment — View Citation

Tuttolomondo A, Pinto A, Di Raimondo D, Corrao S, Di Sciacca R, Scaglione R, Caruso C, Licata G. Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy in cirrhotic patients with ascites.	Assessed by the number of patients who developed any new episodes of spontaneous bacterial peritonitis (SBP), new onset of hepatic encephalopathy (HE), the incidence of gastrointestinal bleeding, the incidence of hepatorenal syndrome (HRS), or renal impairment (increase in serum creatinine > 50% above the baseline. All assessments of enrolled patients were reported in the safety sheets.	38 days (from the start of the study to the end of the study).
Other	Tolerability of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy in cirrhotic patients with ascites.	Assessed by the number of patients who developed any unwanted side effects were reported from the treatment regimen as osmotic demyelination syndrome (ODS), vein extravasation, hypokalemia, acute hypotension, and laboratory abnormalities. All assessments of enrolled patients were reported in tolerability sheets.	38 days (from the start of the study to the end of the study).
Primary	Evaluate and compare the impact of adding hypertonic saline solution (HSS) infusion and/or etilefrine to oral standard diuretics therapy on the inflammatory pathway in cirrhotic patients with ascites.	By measuring the final change in serum interleukin-6 (pg/ml) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Primary	Evaluate and compare the impact of adding HSS infusion and/or etilefrine to oral standard diuretics therapy on the serum C-reactive protein in cirrhotic patients with ascites.	By measuring the final change in serum C-reactive protein (mg/L) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Primary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral standard diuretics therapy on the metabolic pathway in cirrhotic patients with ascites.	By measuring the final change in serum leptin (pg/ml) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Primary	Evaluate and compare the impact of adding HSS solution infusion and/or etilefrine to oral standard diuretics therapy on the renal hemodynamics in cirrhotic patients with ascites.	By measuring the final change in plasma aldosterone (pg/ml) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Primary	Evaluate and compare the impact of adding HSS infusion and/or etilefrine to oral diuretics therapy on the diuresis of cirrhotic patients with ascites.	By measuring the final change in 24-hour urine output (ml/24 hr) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). 24-hr urine was collected in the morning from 7 am to 7 am of the next day before treatment (first collection), after eight days of treatment (second collection), and after a month from the second collection for assessing diuresis.	38 days (from the first day of the study to the end of the study)
Primary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on the systemic hemodynamic of cirrhotic patients with ascites.	By measuring the effects of the treatments on mean arterial pressure (MAP) in patients with ascites. Systolic blood pressure (mmHg) and diastolic blood pressure (mmHg) were measured using a sphygmomanometer to calculate MAP first on day one of the treatments (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement). Final changes in MAP (mmHg) were calculated from the first day of the study to the end of the study (study duration 38 days)	38 days (from the first day of the study to the end of the study)
Primary	Evaluate the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on serum sodium (Na) concentration in cirrhotic patients with ascites.	By measuring the final change in serum Na concentration (mEq/L) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Primary	Evaluate the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on serum creatinine concentration in cirrhotic patients with ascites.	By measuring the final change in serum creatinine concentration (mg/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on prothrombin concentration in cirrhotic patients with ascites.	By measuring the final change in prothrombin concentration (%) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on the model of end-stage liver disease (MELD score)in cirrhotic patients with ascites.	By calculating the final change in MELD score in patients with ascites to assess the severity of liver disease for transplant planning, from the first day of the study to the end of the study (study duration 38 days). MELD score calculation depends on serum creatinine, serum bilirubin, prothrombin time, and the score calculated by a suitable online medical calculator. All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on the model of end-stage liver disease depending on sodium (MELD score-Na)in cirrhotic patients with ascites.	By calculating the final change in MELD-Na score in patients with ascites from the first day of the study to the end of the study (study duration 38 days). MELD-Na score calculation depends on serum creatinine, serum bilirubin, serum Na, prothrombin time, and the score calculated by a suitable online medical calculator. All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on Child-Pugh score in cirrhotic patients with ascites.	By calculating the final change in Child-Pugh score in patients with ascites to assess the prognosis in liver cirrhosis from the first day of the study to the end of the study (study duration 38 days). Child-Pugh score calculation depends on serum albumin, serum bilirubin, prothrombin time, ascites, and encephalopathy grades. The score was calculated by a suitable online medical calculator. All blood samples were collected for measuring from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on the bodyweight in cirrhotic patients with ascites.	By calculating the final change in the patients' weight (kg) from the first day of the study to the end of the study (study duration 38 days). All enrolled patients were weighed by suitable weight scale on the morning of the first day of the study (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on urinary sodium excretion in cirrhotic patients with ascites.	By measuring the final change in urinary Na concentration (mEq/24 hr) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). Urinary Na concentration was measured from a 24-hr urine collection sample. 24-hr urine was collected in the morning from 7 am to 7 am of the next day before initiation of the treatment (first measurement), after eight days of the treatment (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on urinary creatinine excretion in cirrhotic patients with ascites.	By measuring the final change in urinary creatinine concentration (mg/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). 24-hr urine collected in the morning from 7 AM to 7 AM of the next day before initiation of the study to measure urinary creatinine concentration (first measurement), after eight days of treatment (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on serum alanine aminotransferase enzyme (ALT) in cirrhotic patients with ascites.	By measuring the final change in serum ALT (U/L) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on serum albumin in cirrhotic patients with ascites.	By measuring the final change in serum albumin (mg/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on serum total bilirubin in cirrhotic patients with ascites.	By measuring the final change in serum total bilirubin (mg/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on serum blood urea nitrogen (BUN) in cirrhotic patients with ascites.	By measuring the final change in serum BUN (mg/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)
Secondary	Evaluate and compare the effect of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy on hemoglobin concentration in cirrhotic patients with ascites.	By measuring the final change in hemoglobin concentration (gm/dl) in patients with ascites from the first day of the study to the end of the study (study duration 38 days). All blood samples were collected from enrolled patients in the morning on the first day of treatment (first measurement), after eight days (second measurement), and after a month from the second measurement (third measurement).	38 days (from the first day of the study to the end of the study)