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

NCT04785755 | Completed Phase 2

• 1 other identifier: ascites of liver cirrhosis
• Study Type: interventional
• Target: 90
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hepatic Ascites

Keywords

Ascites, Hypertonic saline, Etilefrine, Aldosterone, Leptin.

Outcome Measures

Primary Outcomes (8)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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)

• 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 Outcomes (12)

• Evaluate the effect of adding HSS infusion and/or etilefrine to oral diuretics therapy on prothrombin concentration in cirrhotic patients with ascites.

  38 days (from the first day of the study to the end of the study)

• 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.

  38 days (from the first day of the study to the end of the study)

• 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.

  38 days (from the first day of the study to the end of the study)

• 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.

  38 days (from the first day of the study to the end of the study)

• 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.

  38 days (from the first day of the study to the end of the study)

Other Outcomes (2)

• Safety of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy in cirrhotic patients with ascites.

  38 days (from the start of the study to the end of the study).

• Tolerability of adding HSS infusion and/or etilefrine to the standard oral diuretics therapy in cirrhotic patients with ascites.

  38 days (from the start of the study to the end of the study).

Study Arms (4)

Group I

ACTIVE COMPARATOR

The control group (n=15) received oral standard diuretic 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).

Drug: Oral standard diuretics therapy

Group II

EXPERIMENTAL

The hypertonic saline solution (HSS) group (n=25) received oral standard diuretic 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 start of the study to the end of the study) with 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.

Drug: Oral standard diuretics therapy; Drug: Hypertonic saline solution

Group III

EXPERIMENTAL

The etilefrine group (n=25) received oral standard diuretic 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), and 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).

Drug: Oral standard diuretics therapy; Drug: Etilefrine

Group IV

EXPERIMENTAL

The hypertonic saline solution (HSS) + Etilefrine group (n=25) received oral standard diuretic therapy (furosemide 40 mg tablet plus spironolactone 100 mg tablet with a dose increase in 40 mg100mg ratio) given once daily in the morning for 38 days (from the first day of the study to the end of the study), with 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, and 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).

Drug: Oral standard diuretics therapy; Drug: Hypertonic saline solution; Drug: Etilefrine

Interventions

Oral standard diuretics therapy DRUG

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).

Also known as: Furosemide (lasix®), Spironolactone (Aldactone®)

Group I; Group II; Group III; Group IV

Hypertonic saline solution DRUG

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.

Also known as: prepared from sodium chloride 0.9% intravenous solution and sodium chloride 3% intravenous solution (, Egypt Otsuka Pharmaceutical Co.).

Group II; Group IV

Etilefrine DRUG

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).

Also known as: (Vascon®)

Group III; Group IV

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All cirrhotic patients with ascites grade I- III.
• Patients ages from 25 -65 years.

You may not qualify if:

• Non-cirrhotic ascites.
• Congestive heart failure.
• Acute renal failure.
• Hepatocellular carcinoma.
• All Cancer types.
• Arterial hypertension.
• Acute infection.

Sponsors & Collaborators

• Hala Abd EL-Tawab Ibrahim Radwan: lead

Study Sites (1)

National liver institute- menoufiya university

Shibīn al Kawm, Monufia Governorate, 32511, Egypt

Location

Related Publications (22)

• Reynolds TB. Ascites. Clin Liver Dis. 2000 Feb;4(1):151-68, vii. doi: 10.1016/s1089-3261(05)70101-x.

  PMID: 11232182 RESULT

• 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.

  PMID: 22844565 RESULT

• 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. Liver Int. 2015 May;35(5):1508-15. doi: 10.1111/liv.12583. Epub 2014 May 21.

  PMID: 24811138 RESULT

• 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.

  PMID: 19602136 RESULT

• Eghtesad S, Poustchi H, Malekzadeh R. Malnutrition in liver cirrhosis:the influence of protein and sodium. Middle East J Dig Dis. 2013 Apr;5(2):65-75.

  PMID: 24829672 RESULT

• Arroyo V, Fernandez J. Relationship between systemic hemodynamics, renal dysfunction, and fluid retention in cirrhosis. Clin Liver Dis (Hoboken). 2013 Jun 21;2(3):120-122. doi: 10.1002/cld.185. eCollection 2013 Jun. No abstract available.

  PMID: 30992841 RESULT

• 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.

  PMID: 26630543 RESULT

• 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. Epub 2011 Jul 13.

  PMID: 21749847 RESULT

• Hatanaka E, Shimomi FM, Curi R, Campa A. Sodium chloride inhibits cytokine production by lipopolysaccharide-stimulated human neutrophils and mononuclear cells. Shock. 2007 Jan;27(1):32-5. doi: 10.1097/01.shk.0000238061.69579.a5.

  PMID: 17172977 RESULT

• Kolsen-Petersen JA. Immune effect of hypertonic saline: fact or fiction? Acta Anaesthesiol Scand. 2004 Jul;48(6):667-78. doi: 10.1111/j.1399-6576.2004.00396.x.

  PMID: 15196097 RESULT

• Perez-Perez A, Vilarino-Garcia T, Fernandez-Riejos P, Martin-Gonzalez J, Segura-Egea JJ, Sanchez-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.2017.03.001. Epub 2017 Mar 4.

  PMID: 28285098 RESULT

• Buechler C, Haberl EM, Rein-Fischboeck L, Aslanidis C. Adipokines in Liver Cirrhosis. Int J Mol Sci. 2017 Jun 29;18(7):1392. doi: 10.3390/ijms18071392.

  PMID: 28661458 RESULT

• 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. doi: 10.1136/gut.19.6.549.

  PMID: 680588 RESULT

• Lafreniere G, Beliveau P, Begin JY, Simonyan D, Cote 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(8):685-692. doi: 10.4330/wjc.v9.i8.685.

  PMID: 28932357 RESULT

• Henriksen JH, Fuglsang S, Bendtsen F, Moller S. Arterial hypertension in cirrhosis: arterial compliance, volume distribution, and central haemodynamics. Gut. 2006 Mar;55(3):380-7. doi: 10.1136/gut.2005.064329.

  PMID: 16474108 RESULT

• 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.

  PMID: 27991854 RESULT

• Drazner MH, Palmer BF. Hypertonic saline: a novel therapy for advanced heart failure? Am Heart J. 2003 Mar;145(3):377-9. doi: 10.1067/mhj.2003.165. No abstract available.

  PMID: 12660656 RESULT

• 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 in Cirrhotic Subjects with Refractory Ascites. PLoS One. 2016 Dec 12;11(12):e0165443. doi: 10.1371/journal.pone.0165443. eCollection 2016.

  PMID: 27941973 RESULT

• 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):295-301. doi: 10.1016/j.cardfail.2014.01.012. Epub 2014 Jan 22.

  PMID: 24462960 RESULT

• 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.

  PMID: 29608812 RESULT

• 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 solution (HSS) and after a saline loading. Nutr Metab Cardiovasc Dis. 2011 May;21(5):372-9. doi: 10.1016/j.numecd.2009.10.014. Epub 2010 Mar 25.

  PMID: 20346637 RESULT

• 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. doi: 10.1136/gut.27.6.705.

  PMID: 3522371 RESULT

MeSH Terms

Conditions

Ascites

Interventions

Furosemide; Spironolactone; Saline Solution, Hypertonic; Sodium Chloride; Etilefrine

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Sulfanilamides; Sulfonamides; Amides; Organic Chemicals; Aniline Compounds; Amines; Sulfones; Sulfur Compounds; Lactones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hypertonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Phenylephrine; Ethanolamines; Amino Alcohols; Alcohols

Study Officials

• Gamal A Badra, professor

  national liver institute / menoufiya university

  STUDY DIRECTOR

• Sahar El-Haggar, professor

  Tanta University

  STUDY DIRECTOR

• hala El said, professor

  national liver institute / menoufiya university

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: clinical pharmacy master degree, pharm D

Study Record Dates

• First Submitted: February 26, 2021
• First Posted: March 8, 2021
• Study Start: November 30, 2017
• Primary Completion: March 21, 2020
• Study Completion: April 30, 2020
• Last Updated: March 8, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

EG (1)