Supplemental Corticosteroids in Cirrhotic Hypotensive Patients With Suspicion of Sepsis (SCOTCH;)

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.

Study Overview

• Status: Terminated
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Hydrocortisone; Drug: NaCL 0.9%

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 Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • Universitaire Ziekenhuizen Leuven
• Czechia
  • Prague, Czechia
    • Institute for Clinical and Experimental Medicine
• Denmark
  • Copenhagen, Denmark
    • Rigshospitalet, University of Copenhagen
• Germany
  • Hamburg, Germany
    • University Medical Center Hamburg-Eppendorf
• Italy
  • Turin, Italy
    • San Giovanni Battista Hospital
• Spain
  • Barcelona, Spain
    • Hospital Clinic Barcelona
  • Madrid, Spain
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain
    • Hospital Universitario Ramon y Cajal
• United Kingdom
  • London, United Kingdom
    • King's College Hospital
  • Plymouth, United Kingdom
    • Derriford Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: group A; Group A: treated with intravenous hydrocortisone in addition to standard therapy (= treatment group)	Drug: Hydrocortisone; 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.; Other Names: solucortef
Placebo Comparator: group B; Group B: IV treatment with NaCL 0.9% in addition to standard therapy (= placebo group)	Drug: NaCL 0.9%; IV bolus of 50 ml NaCL 0.9%; followed by continuous IV infusion of NaCL 0.9%; Other Names: sodium chloride

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Alexander Wilmer, MD, PhD, Universitaire Ziekenhuizen KU Leuven; Principal Investigator: Philippe Meersseman, MD, Universitaire Ziekenhuizen KU Leuven; Principal Investigator: Javier Fernandez, MD,PhD, Hosp Clinic, Barcelona, Spain

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): December 31, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: September 22, 2015
• First Submitted That Met QC Criteria: November 9, 2015
• First Posted (Estimate): November 11, 2015

Study Record Updates

• Last Update Posted (Actual): January 22, 2021
• Last Update Submitted That Met QC Criteria: January 19, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: sepsis; cirrhosis; liver; cortisol; corticosteroids; hypotension
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Liver Diseases; Fibrosis; Sepsis; Liver Cirrhosis; Anti-Inflammatory Agents; Hydrocortisone; Hydrocortisone hemisuccinate
• Other Study ID Numbers: SCOTCH-SCotCHIS in the UK