Comparison of Bolus Versus Continuous Infusion of Terlipressin Cirrhotic Patients With Septic Shock.

Methodology: * Study population: All the consecutive patients of cirrhosis admitted to Intensive care unit of Hepatology department of ILBS will be evaluated for inclusion * Study design: Prospective open label randomised controlled study -superiority trial. The study will be conducted in Department of Hepatology ILBS- intensive care unit. * Study period: 1 year from ethics approval (Feb 21- Jan 22) * Sample size: Assuming that the response rate is 90% in continuous and 80% in bolus , with α=5% β=80% and the superiority margin taken as 10%; then we need to enroll 141 cases in each arm, further taking 10% drop out rate, we need to randomise a total of 310 cases (155 in each arm). Randomisation will be done by block randomisation method by taking block size as 10. * Intervention: 250 patients after screening for all exclusion criteria randomised into 2 arms(group-1, Terlipressin bolus arm) and(group-2, Terlipressin continuous infusion arm) in a ratio 1:1. * 250 patients after screening for all exclusion criteria randomised into 2 arms(group-1, Terlipressin bolus arm) and(group-2, Terlipressin continuous infusion arm) in a ratio 1:1. * Monitoring and assessment Both the group will undergo assessment of cardiac function by measuring NT-Pro BNP, Troponin I, ANP and baseline transthoracic echocardiography (TTE), 30 minutes after the first bolus dose and after the starting of infusion, lastly at 72 hours. TTE will be performed to evaluate the cardiac function; Cardiac output (velocity time integral at aortic flow times the area of left ventricular outflow tract), LV ejection fraction by modified Simpson's method, LV diastolic function by E/E' measurement, right ventricular systolic function by fractional area change, tricuspid annular plane systolic excursion (TAPSE), and flattening of the interventricular septum. * USG Doppler will be performed in all the patients to assess the flow in renal, portal, hepatic veins and also permeability index, and extravascular lung volume. * The macro-hemodynamic parameters were MAP, heart rate, cardiac output, SVR index, global end diastolic volume, extravascular lung water, lung permeability index and hourly urine output. Global tissue perfusion adequacy and microcirculation assessment was done by * 1\. SVR index = MAP-CVP/CO \*80 ( 700 - 1500dynes/sec/cm-5 * 2\. Global EDV = combined end diastolic volume of all 4 chambers. * 3\. Lactate of Blood Gas preferably * 4\. Lactate clearance13 (defined by lactate baseline-lactate at time point/baseline lactate ×100) * 5\. Central venous O2 saturation (SCV02) with a target of SCVO2\>70% * In all patients, baseline endotoxin activity assay and blood sample will be stored for looking at the effect of therapy on cytokine profile (TNF alpha, IL6, IFN-gamma, and ADAMTS and vWillebrand factor). * Improvement in Endothelial dysfunction would be assessed by measuring the biomarkers such as Endotoxin, von willebrand factor and ADAMTS at three times At baseline (Hour 0), at 30 minutes after Terlipressin dose and at 72 hours. * Renal function would be measured by serum Renin, serum cystatin C, urine NGAL,eGFR, and improvement in AKI stage according to KDIGO criteria or requirement of dialysis. * For assessment of impact of coagulation, ROTEM would be performed at respective time. * Also the serum level of Noradrenaline and terlipressin will be assessed at starting and after 72 hours. STATISTICAL ANALYSIS: Continuous data- Student's t test * Non parametric 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. \- Adverse effects Severity of adverse events (CTACE Grade) GRADE-1 * Loose motion(2 -3 episodes) * Hyponatremia (135-130) GRADE-2 * Loose motion (4-6 episodes) * Abdominal pain * Hyponatremia (130-120) GRADE-3 * Loose motion (\> 6) * Bacterial infections * Chest pain * Circulatory overload * Hponatremia( \<120) GRADE-4 * Arrhythmia * Myocardial Infarction * Mesenteric ischemia * Livedo reticularis * Respiratory acidosis * Hepatic encephalopathy * Gastrointestinal bleeding * Peripheral cyanosis * Lactic acidosis * Bradycardia * Atrial fibrillation * Ventricular tachycardia GRADE-5 * Death * Stopping Rule: Side effects or toxicities that are severe -arrhythmia, AMI, Cardiomyopathy (defined later) Cyanosis and all orther grade IV adverse effects of Terlipressin. * 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).