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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Critically ill cirrhotic - Defined as a cirrhotic patient who presents with at least one organ failure, defined by SOFA score WITH 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).

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

Conditions
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Septic Shock, Cirrhosis, Liver

Intervention / Treatment
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* Drug: Terlipressin
* Drug: vasopressin


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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 |
| --- | --- |
| Experimental: Terlipressin<br>Terlipressin 1mg/24 hours | Drug: Terlipressin<br>* 1mg/24 hour and titrate according to MAP<br>|
| Active Comparator: Vasopressin<br>Vasopressin 0.03 U/hour | Drug: vasopressin<br>* 0.03 U/hour and titrate according to MAP<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Mortality at day 28 |  | Day 28 | 
| Days of mechanical ventilation |  | Day 28 | 
| 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 |