Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis
Trial Snapshot
- Phase
- Phase 3
- Status
- Terminated
- Enrollment
- 100
- Locations
- 10
- Primary Endpoint
- Patient survival at 28 days analysed from the day of randomisation
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
group A
Group A: treated with intravenous hydrocortisone in addition to standard therapy (= treatment group)
Intervention: Hydrocortisone (Drug)
group B
Group B: IV treatment with NaCL 0.9% in addition to standard therapy (= placebo group)
Intervention: NaCL 0.9% (Drug)
Outcomes
Primary Outcomes
Patient survival at 28 days analysed from the day of randomisation
Time Frame: 28days
survival status
Secondary Outcomes
- reversal of shock(up to day 90)
- mechanical ventilation-free days(up to 90 days)
- shock relapse(during tapering period until 3 days after end of study drug)
- patient survival at 90 days analysed from the day of randomization(90 days)
- episode of hyper- (> 180 mg/dl) or hypoglycemia (< 60 mg/dl)(during study treatment period, up to 10 days)
- acquirement of new infections(up to 90 days)
- ICU and hospital mortality(from the date of randomisation until ICU discharge or hospital mortality, whichever came first, up to day 90)
- vasopressor doses(up to 90 days)
- vasopressor-free days(up to 90 days)
- need for and duration of renal replacement therapy(up to 90 days)
- new shock episode(during study treatment period, up to 13 days)
- reversal of organ failures(up to 90 days)
- ICU and hospital length-of-stay(up to 90 days)
- impact of coagulopathy(during ICU stay up to 10 days)
- clinically important bleeding(up to 90 days)
- glycemic control(during ICU stay, up to 10 days)
- incidence of ICU-acquired weakness(during ICU stay, up to 90 days)