Outcomes of Renal Function in Hepatorenal Syndrome (HRS) Determined By Comparison of Target Mean Arterial Pressure (MAP) of 65 - 70 Mmhg Versus ≥ 85 Mmhg

Comparing renal outcomes based on a Mean Arterail Pressure (MAP) of 65-7085mmhg versus a MAP of greater than or equal to 85mmhg

Study Overview

• Status: Completed
• Conditions: Hepatorenal Syndrome
• Intervention / Treatment: Drug: Norepinephrine (Levophed); Drug: Norepinephrine (Levophed)

Detailed Description

Main hypothesis:

The investigators propose that there will be no difference clinical outcomes as evidenced by a significant difference in urine output or change in creatinine between the MAP target ≥ 85mmhg and the MAP target of 65-70 mmhg.

Primary end point:

To determine if High MAP or Low MAP will provide the most optimal renal function. The primary endpoints will be 96h UOP and change in creatinine levels. UOP will be calculated as cc/24 hours. The investigators will compare the change in urinary output of day 1 versus day 4. Creatinine will be measured daily and the change from initiation to completion of the study will be recorded. The mean values of these will be compared.

Secondary end point:

To determine if High MAP or Low MAP will decrease the occurrence of cardiac events (arrhythmias and myocardial infarctions) and vascular events (limb or intestinal ischemia).

Study Design:

This is a prospective, unblinded, randomized, Two-arm treatment, pilot study. Patients will undergo block randomization to receive either a MAP ≥ 85mmhg or a MAP 65-70mmhg.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 1. Admission to intensive care unit (ICU) 2. Age >18 years old 3. Able to obtain informed consent obtained from the patient, from the patient's power of attorney, or from the next of kin 4. Must meet all major criteria based on the International Ascites Club definition and diagnostic criteria for Hepatorenal Syndrome:

  1. chronic or acute liver disease with advanced hepatic failure and portal hypertension;
  2. the serum creatinine is greater than 1. 5 mg/dL or 24 hour creatinine clearance of less than 40 ml/min;
  3. absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs;
  4. absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses;
  5. no sustained improvement in renal function defined as a decrease in serum creatinine to less than 1.5 mg/dL or increase in 24 hour creatinine clearance to 40 ml/min or more following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline;
  6. proteinuria less than 500 mg/dL;
  7. no ultrasonic evidence of obstructive uropathy or parenchymal renal disease. 5. In addition, patients must meet the definition of HRS type I or HRS type I
  1. -HRS I defined by a rapid deterioration in kidney function with the serum creatinine increasing by more than 100% from baseline to greater than 2.5mg/dl within a two week period.
  2. -HRS II defined as: patients with refractory ascites with either a steady but moderate degree of functional renal failure (≥ 1.5mg/dl) or deterioration in kidney function that does not fulfill the criteria for HRS type I

Exclusion Criteria:

• 1. pre-existing continuous renal replacement therapy cannot or those initiated on dialysis during their hospital stay.

  2. artificial liver support therapies 3. ongoing gastrointestinal bleeding 4. active surgical issues 5. pre-existing TIPS or TIPS placed during hospital stay 6. long standing hypertension 7. improvement in renal function after central blood volume expansion contraindications to norepinephrine (active myocardial event, ventricular arrhythmia, obstructive physiology, limb ischemia) 8. Pregnancy 9. Treating physicians refusing to enroll patient

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MAP 65-70; Goal MAP of 65-70	Drug: Norepinephrine (Levophed); Titrate norepinephrine to MAP 65-70; Drug: Norepinephrine (Levophed); Titrate norepinephrine to MAP 85 or greater
Active Comparator: MAP greater than or equal to 85	Drug: Norepinephrine (Levophed); Titrate norepinephrine to MAP 65-70; Drug: Norepinephrine (Levophed); Titrate norepinephrine to MAP 85 or greater

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urine output	To determine if High MAP or Low MAP will provide the most optimal renal function. The primary endpoints will be 96h UOP and change in creatinine levels. UOP will be calculated as cc/24 hours. We will compare the change in urinary output of day 1 versus day 4. Creatinine will be measured daily and the change from initiation to completion of the study will be recorded. The mean values of these will be compared.	2 years
serum creatinine		2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiac events	To determine if High MAP or Low MAP will decrease the occurrence of cardiac events (arrhythmias and myocardial infarctions) and vascular events (limb or intestinal ischemia).	2 years
ischemic events	To determine if High MAP or Low MAP will decrease the occurrence of cardiac events (arrhythmias and myocardial infarctions) and vascular events (limb or intestinal ischemia).	2 years

Collaborators and Investigators

• Sponsor: University of Louisville

Publications and helpful links

General Publications

• Varajic B, Cavallazzi R, Mann J, Furmanek S, Guardiola J, Saad M. High versus low mean arterial pressures in hepatorenal syndrome: A randomized controlled pilot trial. J Crit Care. 2019 Aug;52:186-192. doi: 10.1016/j.jcrc.2019.04.006. Epub 2019 Apr 15.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): January 11, 2018
• Study Completion (Actual): January 11, 2018

Study Registration Dates

• First Submitted: January 28, 2015
• First Submitted That Met QC Criteria: May 26, 2016
• First Posted (Estimate): June 2, 2016

Study Record Updates

• Last Update Posted (Actual): January 16, 2018
• Last Update Submitted That Met QC Criteria: January 11, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease; Liver Diseases; Syndrome; Hepatorenal Syndrome; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympathomimetics; Vasoconstrictor Agents; Norepinephrine
• Other Study ID Numbers: 14.1190