Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis

Study Overview
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Brief Summary
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The main goal of the study is to investigate the clinical relevance, efficacy and safety of treating hypotensive cirrhotic patients with suspicion of sepsis and on vasopressors with low-dose hydrocortisone in order to reverse hemodynamic instability and organ failure and to decrease mortality.

Detailed Description
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Ample evidence suggests that a significant number of patients (52-77%) with chronic liver disease develop adrenal insufficiency in case of concomitant sepsis. This condition impairs hemodynamic integrity and probably worsens often encountered multiorgan failure. Different groups suggested that treating those patients with corticosteroids gives a faster reversal of hemodynamic instability and even lowers mortality compared to historical controls. However, most of the published data are retrospective and comprise small groups of patients. These data raise the possibility that corticosteroids at stress doses may be beneficial in hypotensive cirrhotics admitted to the ICU but as yet this has not been subjected to a large-scale multicentre randomized controlled clinical trial. The study will be a double-blind, randomized, placebo-controlled, multicenter trial, involving tertiary intensive care units with expertise in management of patients with decompensated cirrhosis. Patients who satisfy inclusion criteria and do not present any of the exclusion criteria at ICU admission will be randomized into two groups: Group A: treated with intravenous hydrocortisone in addition to standard therapy (= treatment group) Group B: placebo (NaCl 0.9%) treatment in addition to standard treatment (= placebo group) If, after adequate fluid resuscitation, patients are still on norepinephrine at a dose of at least 0,1 mcg/kg/min for at least 4 hours, the patient can be randomized. Study drug can be started immediately after randomization but no later than 24 h after initiation of norepinephrine. Patients will receive an intravenous bolus of 50 ml of normal saline (placebo) or an intravenous bolus of 50 ml of normal saline containing 100 mg of hydrocortisone (double-blind) that will be followed by a continuous intravenous infusion of the study drug (hydrocortisone) or placebo. Treatment with study drug (hydrocortisone or placebo) at initial rate will be maintained until the start of day 4 and gradually discontinued (reduction of infusion rate with 0.5 ml/h/d) when 1) patients do not require vasoactive drugs anymore to maintain MAP(mean arterial pressure) > 60 mmHg or > 65 mmHg if associated with signs of hypoperfusion in spite of ongoing adequate fluid resuscitation or 2) in any case after a 7-day treatment period. Investigators, treating physicians, nurses and patients will be blinded to the intervention.

Official Title
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Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis

Conditions
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Liver Cirrhosis

Intervention / Treatment
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* Drug: Hydrocortisone
* Drug: NaCL 0.9%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All patients with known or recently diagnosed cirrhosis who are admitted to the ICU because of persistent hypotension or develop persistent hypotension while admitted to the ICU, secondary to proven or suspected infection, in both cases despite adequate fluid resuscitation and with persistent need for low-dose norepinephrine to maintain a mean arterial blood pressure > 60 mmHg or > 65 mmHg if accompanied by signs of hypoperfusion, are eligible for study entry. The diagnosis of cirrhosis is preferably made by histology or based on imaging and laboratory findings. Exclusion Criteria: Age < 18 or ≥ 80 years Patients receiving any vasopressor medication for more than 24 h prior to administration of study drug. Terlipressin initiated for treatment of hepatorenal syndrome or variceal bleeding is allowed Patients with known hypoadrenalism Active GI bleeding (unless controlled for >72 hours) or hemorrhagic shock. Cardiogenic shock or severe cardiac dysfunction (CI <2 l/min/ m2) Active uncontrolled hepatitis B infection HIV infection Evidence of current malignancy (except hepatocellular carcinoma within transplant criteria or non-melanocytic skin cancer) Therapy with any corticosteroid (oral or intravenous) in the last 3 months Patients who received etomidate within the past 3 days Severe acute alcoholic hepatitis (biopsy proven) Chronic hemodialysis Severe chronic heart disease (NYHA class III or IV) Severe chronic obstructive pulmonary disease (GOLD III or IV) Severe psychiatric disorder Child-Pugh score C14 -15 SOFA score > 16 points at inclusion Pregnant or breastfeeding women Contraindications for systemic steroids Refusal to consent Patients who cannot provide prior informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: group A<br>Group A: treated with intravenous hydrocortisone in addition to standard therapy (= treatment group) | Drug: Hydrocortisone<br>* IV bolus of 100 mg hydrocortisone in 50ml NaCl 0.9% (sodium chloride); followed by continuous IV infusion of 200 mg hydrocortisone in 50 ml NaCl 0.9% at a rate of 2 ml/h until the start of day 4.Reduction of infusion rate with 0.5 ml/h/day.<br>* Other names: solucortef;|
| Placebo Comparator: group B<br>Group B: IV treatment with NaCL 0.9% in addition to standard therapy (= placebo group) | Drug: NaCL 0.9%<br>* IV bolus of 50 ml NaCL 0.9%; followed by continuous IV infusion of NaCL 0.9%<br>* Other names: sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient survival at 28 days analysed from the day of randomisation | survival status | 28days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| patient survival at 90 days analysed from the day of randomization | survival status | 90 days | 
| ICU and hospital mortality | mortality | from the date of randomisation until ICU discharge or hospital mortality, whichever came first, up to day 90 | 
| reversal of shock | time in days from start of placebo or active medication to resolution of shock as defined as cessation of continuous vasopressor medication (for > 24 hours) | up to day 90 | 
| reversal of organ failures | measured with SOFA-score and CLIF (Chronic Liver Failure Consortium)-SOFA score | up to 90 days | 
| vasopressor doses | administration of vasopressor | up to 90 days | 
| vasopressor-free days | days without vasopression | up to 90 days | 
| mechanical ventilation-free days | days without mechanical ventilation | up to 90 days | 
| need for and duration of renal replacement therapy | days of renal replacement therapy | up to 90 days | 
| ICU and hospital length-of-stay | days of ICU stay , days of hospital stay | up to 90 days | 
| acquirement of new infections | bacterial and/or fungal: defined according to CDC (Centers for Diseases Control) criteria (pneumonia, bacteremia, spontaneous bacterial peritonitis, catheter-related bloodstream infections, skin infections and others) | up to 90 days | 
| shock relapse | defined as hypotension recurrence during the tapering period or within 3 days of total discontinuation of study drug | during tapering period until 3 days after end of study drug | 
| clinically important bleeding | defined as new melena, new haematemesis or unexplained fall in haemoglobin > 2g/dl (not related to volume expansion). The presence of 'coffee ground' aspirate from nasogastric aspirate will not be considered active GI bleeding. | up to 90 days | 
| glycemic control | measured as units of insulin required to attain glycemic levels between 80 - 140 mg/dl | during ICU stay, up to 10 days | 
| episode of hyper- (> 180 mg/dl) or hypoglycemia (< 60 mg/dl) | number of episodes of hypo- hyperglycemia | during study treatment period, up to 10 days | 
| new shock episode | hypotension recurrence with need for vasopressor therapy after 3 days of total discontinuation of study drug | during study treatment period, up to 13 days | 
| impact of coagulopathy | assessed by disseminated intravascular coagulopathy (DIC)-score | during ICU stay up to 10 days | 
| incidence of ICU-acquired weakness | occurrence of IC acquired weakness | during ICU stay, up to 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, liver, corticosteroids, hypotension, sepsis, cortisol