Clinical trial NCT02602210: Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis
Official title: Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Liver Cirrhosis
Keywords: cirrhosis
liver
corticosteroids
hypotension
sepsis
cortisol
Lead sponsor: Universitaire Ziekenhuizen KU Leuven
Sponsor class: OTHER
First posted: 2015-11-11
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* All patients with known or recently diagnosed cirrhosis who

  1. are admitted to the ICU because of persistent hypotension or
  2. 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

Primary outcomes:
measure: Patient survival at 28 days analysed from the day of randomisation
timeFrame: 28days
Secondary outcomes:
measure: patient survival at 90 days analysed from the day of randomization
timeFrame: 90 days
measure: ICU and hospital mortality
timeFrame: from the date of randomisation until ICU discharge or hospital mortality, whichever came first, up to day 90
measure: reversal of shock
timeFrame: up to day 90
measure: reversal of organ failures
timeFrame: up to 90 days
measure: vasopressor doses
timeFrame: up to 90 days
measure: vasopressor-free days
timeFrame: up to 90 days
measure: mechanical ventilation-free days
timeFrame: up to 90 days
measure: need for and duration of renal replacement therapy
timeFrame: up to 90 days
measure: ICU and hospital length-of-stay
timeFrame: up to 90 days
measure: acquirement of new infections
timeFrame: up to 90 days
measure: shock relapse
timeFrame: during tapering period until 3 days after end of study drug
measure: clinically important bleeding
timeFrame: up to 90 days
measure: glycemic control
timeFrame: during ICU stay, up to 10 days
measure: episode of hyper- (> 180 mg/dl) or hypoglycemia (< 60 mg/dl)
timeFrame: during study treatment period, up to 10 days
measure: new shock episode
timeFrame: during study treatment period, up to 13 days
measure: impact of coagulopathy
timeFrame: during ICU stay up to 10 days
measure: incidence of ICU-acquired weakness
timeFrame: during ICU stay, up to 90 days
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
state: Vlaams Brabant
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine
city: Copenhagen
country: Denmark
facility: Rigshospitalet, University of Copenhagen
city: Hamburg
country: Germany
facility: University Medical Center Hamburg-Eppendorf
city: Turin
country: Italy
facility: San Giovanni Battista Hospital
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: London
country: United Kingdom
facility: King's College Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Philippe Meersseman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Alexander Wilmer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hosp Clinic, Barcelona, Spain
name: Javier Fernandez, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References: