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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: At baseline before initiation of any treatment (first measurement) Eight days after treatment with studied medications (second measurement). 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.

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

Conditions
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Hepatic Ascites

Intervention / Treatment
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* Drug: Oral standard diuretics therapy
* Drug: Hypertonic saline solution
* Drug: Etilefrine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group I<br>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<br>* 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).<br>* Other names: Furosemide (lasix®), Spironolactone (Aldactone®);|
| Experimental: Group II<br>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<br>* 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).<br>* Other names: Furosemide (lasix®), Spironolactone (Aldactone®);Drug: Hypertonic saline solution<br>* 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.<br>* Other names: prepared from sodium chloride 0.9% intravenous solution and sodium chloride 3% intravenous solution (, Egypt Otsuka Pharmaceutical Co.).;|
| Experimental: Group III<br>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<br>* 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).<br>* Other names: Furosemide (lasix®), Spironolactone (Aldactone®);Drug: Etilefrine<br>* 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).<br>* Other names: (Vascon®);|
| Experimental: Group IV<br>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<br>* 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).<br>* Other names: Furosemide (lasix®), Spironolactone (Aldactone®);Drug: Hypertonic saline solution<br>* 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.<br>* Other names: prepared from sodium chloride 0.9% intravenous solution and sodium chloride 3% intravenous solution (, Egypt Otsuka Pharmaceutical Co.).;Drug: Etilefrine<br>* 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).<br>* Other names: (Vascon®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ascites, Hypertonic saline, Etilefrine, Aldosterone, Leptin.