Norepinephrine Infusion Versus Midodrine & Octreotide in Patients With Hepatorenal Syndrome Type 1.

Pros & Cons of Norepinephrine Infusion Versus Midodrine & Octreotide in Patients With Hepatorenal Syndrome Type 1 in Intensive Care Unit.

This study aimed to investigate the efficacy of midodrine plus octreotide versus norepinephrine and to determine the predictive factors of response in patients with HRS-AKI.

Study Overview

• Status: Completed
• Conditions: Renal Impairment in Hepatorenal Syndrome
• Intervention / Treatment: Drug: norepinephrine versus midodrine & octreotide

Detailed Description

Both sexes aged 18 years or older having cirrhosis, ascites, and a diagnosis of HRS-AKI based on the 2015 International Club of Ascites (ICA) diagnostic criteria [2] were eligible for participation.

Screening and eligibility criteria were verified upon admission to the ICU. A diagnosis of AKI was established through comparing sCr value at time of ICU admission to that recorded in the patient's file. Patients who meet all other diagnostic criteria of HRS-AKI provided by the previous definition [2] were enrolled in the study. Qualified patients were subjected to baseline assessments after informed consent signature. It included vital sign measurements, presence of comorbidities, height and weight, Child-Pugh score and Sequential Organ Failure Assessment (SOFA) score. Vital signs, Blood urea nitrogen, sCr, serum sodium, serum albumin, total bilirubin, and complete blood count with differential were measured at baseline and at daily basis throughout the study period. Patients were randomized in a 1:1 ratio to receive either continuous infusion of norepinephrine in an initial dose of 0.5mg/h (Maximum 3 mg/h or oral midodrine 5mg three times/day (Maximum 12.5mg three times/day) plus octreotide 100μg/6h as subcutaneous injection (Maximum 200 μg/6h). Duration of treatment was allowed to extend to a maximum of 10 days. Administration of albumin at doses of 20 to 40 gm/day was recommended, as clinically indicated, for all patients in both study arms as per current ICA guidelines.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • NHTMRI

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients that will be included in the study have cirrhosis as diagnosed by clinical, biochemical, and ultrasound findings, with HRS type 1, the absence of bacterial infections; however, patients with bacterial infections could be included in the study if renal failure persisted after infection resolution by clinical, laboratory indices up to 48 hours.

Exclusion Criteria:

• Patients will be excluded if there are advanced cardiovascular diseases due to poor prognosis or any extrahepatic disease that could affect the short-term prognosis, the presence of advanced hepatocellular carcinoma or presence of contraindication to norepinephrine as hypotension due to blood volume deficits except emergency measure, mesenteric or peripheral vascular thrombosis unless there is life-saving procedure, profound hypoxia or hypercarbia.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: norepinephrine; norepinephrine continuous intravenous infusion in a dose of 0.05-0.3ug/Kg/min. average7-10 days to keep mean arterial pressure ≥ 80-100mmHg & continued either until HRS reversal or for maximum 10 days.	Drug: norepinephrine versus midodrine & octreotide; either intravenous infusion (IVi) norepinephrine in a dose of 0.05-0.3ug/Kg/min. to keep mean arterial pressure ≥ 80-100mmHg & continued either until HRS reversal or for maximum 10 days or oral midodrine 5mg three times/day & can be increased every 24h up to 12.5mg three times daily plus octreotide 100ug/ 6h subcutaneous & if needed increased to 200ug/6h.
Active Comparator: midodrine & octreotide; midodrine 5mg three times/day orally & can be increased every 24h up to 12.5mg three times daily plus octreotide 100ug/ 6h subcutaneous & if needed increased to 200ug/6hS.C. for 7-10 days	Drug: norepinephrine versus midodrine & octreotide; either intravenous infusion (IVi) norepinephrine in a dose of 0.05-0.3ug/Kg/min. to keep mean arterial pressure ≥ 80-100mmHg & continued either until HRS reversal or for maximum 10 days or oral midodrine 5mg three times/day & can be increased every 24h up to 12.5mg three times daily plus octreotide 100ug/ 6h subcutaneous & if needed increased to 200ug/6h.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the proportion of patients achieved full response	defined as return of sCr to a value within 0.3 mg/dl of the baseline value	within10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the proportion of patients achieved partial response	defined as a regression of at least one AKI stage with a fall in the sCr value to ≥0.3 mg/dl above the baseline value	within 10 days
Incidence of HRS reversal	defined as at least one sCr value of ≤ 1.5 mg/dl while on treatment	within 10 days
incidence of HRS-AKI relapse	relapse of HRS-AKI after cessation of treatment	30 days
overall survival	patients who are survived	30 days
adverse events experienced throughout the study period in both treatment groups.	The incidence of hepatic encephalopathy episodes, bacterial infections, gastrointestinal bleeding, myocardial infarction, arrhythmia, circulatory overload and arterial hypertension was assessed at the end of the study. The need for mechanical ventilation and the need for dialysis.	within 10 days

Collaborators and Investigators

• Sponsor: National Hepatology & Tropical Medicine Research Institute

Publications and helpful links

General Publications

• El-Desoki Mahmoud EI, Abdelaziz DH, Abd-Elsalam S, Mansour NO. Norepinephrine is More Effective Than Midodrine/Octreotide in Patients With Hepatorenal Syndrome-Acute Kidney Injury: A Randomized Controlled Trial. Front Pharmacol. 2021 Jul 2;12:675948. doi: 10.3389/fphar.2021.675948. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2018
• Primary Completion (Actual): April 20, 2020
• Study Completion (Actual): July 10, 2020

Study Registration Dates

• First Submitted: January 3, 2018
• First Submitted That Met QC Criteria: February 27, 2018
• First Posted (Actual): March 6, 2018

Study Record Updates

• Last Update Posted (Actual): February 23, 2021
• Last Update Submitted That Met QC Criteria: February 21, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Syndrome; Renal Insufficiency; Hepatorenal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antineoplastic Agents; Gastrointestinal Agents; Antineoplastic Agents, Hormonal; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Adrenergic alpha-1 Receptor Agonists; Octreotide; Norepinephrine; Midodrine
• Other Study ID Numbers: NHTMRI-2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Time Frame: 6 - 12 months
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No