Efficacy and Safety of Vasopressin Versus Terlipressin as a Second Vasopressor in Critically Ill Cirrhotics With Septic Shock- the VITEL-C Trial

Efficacy and Safety of Vasopressin Versus Terlipressin as a Second Vasopressor in Critically Ill Cirrhotics With Septic Shock- the VITEL-C Trial.

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response. A Subset of sepsis is septic shock which has almost 4-6 times the mortality when compared to sepsis. Septic shock has underlying cellular and metabolic abnormalities in addition to circulatory dysfunction. The circulatory dysfunction in sepsis is in the form of severe vasodilatation with high cardiac index. Cirrhosis is a state of hyperdynamic circulation. The mortality of septic shock in these group of patients is still higher.

At the onset of septic shock there is initially an increased secretion of Arginine vasopressin. However, this initial rise is short lasting, and the vasopressin levels come back to normal or low serum levels with continued hypotension. However, even normal levels are too low for the degree of hypotension in septic shock. This causes a relative deficiency of vasopressin in septic shock. The exact time when this fall happens is not known and it is likely to be variable. Vasopressin was therefore tried as an agent in septic shock. Terlipressin is a synthetic analogue of vasopressin. It has a greater selectivity for the V1 receptor. Terlipressin is also shown to be effective in septic shock in cirrhotics3. Other vasoactive agents are not preferred in cirrhotics - dopamine due to high risk of arrhythmias and dobutamine as baseline cardiac output of cirrhotics is high which further increases in sepsis and dobutamine would further add to it. However, it may be given in myocardial dysfunction. Noradrenaline is recommended as the first vasopressor to be started in general in septic shock population. No study has compared the effectiveness of vasopressin and Terlipressin when added to noradrenaline in patients with cirrhosis. Acute kidney injury is a very common complication of septic shock in cirrhotics.

Study Overview

• Status: Not yet recruiting
• Conditions: Septic Shock; Cirrhosis, Liver
• Intervention / Treatment: Drug: Terlipressin; Drug: vasopressin

Detailed Description

Hypothesis: We hypothesise that vasopressin would be non-inferior to terlipressin as a second vasopressor in critically ill cirrhotics with septic shock and would have lesser adverse effects when compared to terlipressin.

Aim: To compare the efficacy of adding continuous infusion of terlipressin versus vasopressin to noradrenaline in causing improvement in systemic hemodynamics and microcirculation.

Methodology:

Study population:

1. Critically ill cirrhotic - Defined as a cirrhotic patient who presents with at least one organ failure, defined by SOFA score WITH
2. septic shock - Defined as a patient in septic shock after initial fluid resuscitation and antibiotic administration, requiring a noradrenaline of at least 2.6mcg/min to maintain a MAP more than 65mmHg.

Study design: Prospective open label randomised controlled study. The study will be conducted in Department of Hepatology ILBS- intensive care unit.

Study period: 1 year

Sample size: Based on the previous studies it is assumed that terlipressin + noradrenaline group would give a response rate of 93%, it was assumed that vasopressin and noradrenaline would give a response rate 15% less than the terlipressin and noradrenaline group and a response rate of 78% was assumed. Further considering an alpha error of 5% and power 95% with a non-inferiority margin of 10% we need to enroll 82 cases Assuming a 10% dropout rate we need to enroll 90 cases with 45 in each arm. However, we decided to enroll 100 cases randomized into 2 groups, 50 each by block randomization method by taking a block size of 10

Patients will be evaluated in the Emergency Room. Detailed history and clinical examination and investigation accordingly will be sent when septic shock is clinically suspected

Fluid Resuscitation Initially a 16G peripheral line will be placed. CVP line and arterial line preferably in the radial artery will be placed as soon as possible.

5% albumin will be used as the resuscitation fluids according to the FRISC protocol.

Fluid response will be assessed at the end of 1 hour

Antibiotics Antibiotics will be given according to the institutional policy

Vasopressors Noradrenaline will be started at a dose of 0.05mcg/kg/min and titrated. All the infusions will be given via central line placed in the jugular, subclavian or femoral vein by a critical care expert under USG guidance.

Intervention:Patients after screening for all exclusion criteria will be randomised into 2 arms (group-1, Terlipressin arm) and (group-2, Vasopressin arm) in a ratio 1:1

• STATISTICAL ANALYSIS: Continuous data- Student's t test
• Nonparametric analysis- Mann Whitney test
• Survival outcome By Kaplan-Meier method curve.
• For all tests, p≤ 0.05 will be considered statistically significant.
• Analysis will be performed using SPSS.
• The analysis will be done with intention to treat and per protocol analysis if applicable.

Stopping rule: Side effects or toxicities that are severe -arrhythmia, AMI, Cardiomyopathy (defined later) Cyanosis.

• Suspicion or confirmed bowel ischemia.
• Patient unwilling for further hospital stay.
• Study unrelated complication here the drug effects could not be assessed (massive
• GI bleed uncontrolled, bowel perforation or any surgical intervention).

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• India
  • Delhi
    • New Delhi, Delhi, India, 110070
      • Institute of Liver & Biliary Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-70yrs
2. An informed consent from the patient or relative

Exclusion Criteria:

1. Age <18 years and > 70 years
2. Stroke
3. Severe sepsis requiring higher dose of noradrenaline (>1mcg/Kg/min)
4. Myocardial dysfunction, Coronary artery disease, Arrhythmias
5. Peripheral Vascular disease
6. Gut Paralysis
7. Acute on chronic liver failure (ACLF)
8. Hepato-cellular carcinoma (HCC), intrahepatic or extrahepatic malignancy
9. Complete portal vein thrombosis
10. Hepatic vein outflow tract obstruction (HVOTO)
11. Pregnancy
12. Patients with Pa02/FiO2 ratio <150
13. CKD
14. COPD
15. Severe coagulopathy - platelets <20,000 and INR > 4
16. Active Bleed or DIC
17. Patients already on terlipressin or vasopressin in the last 48 hours
18. Extremely moribund patients with an expected life expectancy of less than 24 hours
19. Failure to give informed consent from family members.
20. Patient enrolled in other clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Terlipressin; Terlipressin 1mg/24 hours	Drug: Terlipressin; 1mg/24 hour and titrate according to MAP
Active Comparator: Vasopressin; Vasopressin 0.03 U/hour	Drug: vasopressin; 0.03 U/hour and titrate according to MAP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in systemic hemodynamics at 6 hours after randomization	Improvement in systemic hemodynamics defined as discontinuation of noradrenaline infusion OR reversal of shock	6 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Days of mechanical ventilation		Day 28
Mortality at day 28		Day 28
Reduction in dose of noradrenaline at the end of 6 hours		6 hours
Amount of noradrenaline requirements between in each arm at the end of 6 hours		6 hours
Improvement in Systemic Vascular Resistance (SVR) by 10% or above 500 at 6 hours	Systemic Vascular Resistance will be measured by using pulmonary thermodilution	6 hours
Improvement in SVR by 10% or above 500 at 12 hours		12 hours
Improvement in SVR by 10% or above 500 at 48 hours		48 hours
Decrease in Cardiac output by 10% or less than 6L after 6 hours of randomization	Cardiac output will be measured by using pulmonary thermodilution	6 hour of randomization
KDIGO criteria - increase in urine output in 6 hours		6 hour
KDIGO criteria - increase in urine output in 12 hours.		12 hour
KDIGO criteria - increase in urine output in 24 hours		24 hour
KDIGO criteria - increase in urine output in 48 hours.		48 hour
improvement in serum creatinine in 24 (Improvement in KDIGO stage at 24)		24 hour
Improvement in serum creatinine in 48 hours (Improvement in KDIGO stage at 48 hours)		48 hour
Need of Renal Replacement Therapy		Day 28
Improvement in microcirculation as measured by improvement in lactate		6 hours
Improvement in microcirculation as measured by improvement in capillary refill time at 6 hours		6 hours
Improvement in microcirculation as measured by Near IR spectroscopy ina subset of patients whenever feasible		6 hours
Improvement in microcirculation as measured by improvement in lactate		24 hours
Improvement in microcirculation as measured by improvement in capillary refill time at 24 hours.		24 hours
Improvement in microcirculation as measured by Near IR spectroscopy ina subset of patients whenever feasible		24 hours
Improvement in microcirculation as measured by improvement in lactate		48 hours
Improvement in microcirculation as measured by improvement in capillary refill time at 48 hours.		48 hours
Improvement in microcirculation as measured by Near IR spectroscopy ina subset of patients whenever feasible		48 hours
Improvement in renal resistive index at 24 hours		24 hours
Improvement in renal resistive index at 48 hours		48 hours
Incidence of adverse effects till 48 hours after randomization including incidence of rebound hypertension		48 hours
Days of Intensive Care Unit stay.		Day 28
Endothelial function will be measured in a subset of patients	Endothelial function will be assessed from a change in endothelin-1 and von Willebrand Factor (vWF) levels in a subset of patients whereever feasible	48 hours
Coagulation function will measure in a subset of patients	Coagulation function will be measured by change in rotational thromboelastometry test	48 hours

Collaborators and Investigators

• Sponsor: Institute of Liver and Biliary Sciences, India

Study record dates

Study Major Dates

• Study Start (Anticipated): April 5, 2022
• Primary Completion (Anticipated): March 31, 2023
• Study Completion (Anticipated): March 31, 2023

Study Registration Dates

• First Submitted: March 7, 2022
• First Submitted That Met QC Criteria: March 30, 2022
• First Posted (Actual): April 7, 2022

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: March 30, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Liver Diseases; Sepsis; Fibrosis; Shock, Septic; Shock; Liver Cirrhosis; Physiological Effects of Drugs; Antihypertensive Agents; Natriuretic Agents; Hemostatics; Coagulants; Vasoconstrictor Agents; Antidiuretic Agents; Vasopressins; Arginine Vasopressin; Terlipressin
• Other Study ID Numbers: ILBS-Cirrhosis-48

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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