Sepsis, Sepsis and Septic Shock, Sepsis at Intensive Care Unit, Sepsis - to Reduce Mortality in the Intensive Care Unit, Septic Shock
Conditions
Keywords
Fludrocortisone, Septic shock, Sepsis, hydrocortisone, intensive care unit, pilot
Brief summary
Sepsis is a life-threatening condition caused by the body's dysregulated response to an infection. While corticosteroids are known to help stabilize blood pressure in septic shock, their ability to reduce mortality is still debated. Recent analyses suggest that combining fludrocortisone with hydrocortisone may be more effective at saving lives than hydrocortisone alone. To test this hypothesis, a large, definitive international trial is needed. However, this research proposal is for a smaller pilot study (Phase II) involving 32 critically ill patients. The primary goal of this pilot is to determine the feasibility of conducting the subsequent large-scale trial that would compare hydrocortisone alone against the combination therapy and potentially change medical practice.
Detailed description
Design: Pilot, multicenter, randomized, double-blind, placebo-controlled trial on use of adjunctive fludrocortisone in critically ill patients with septic shock. Objective: Determine feasibility of conducting a large, international, multicenter, double-blind, randomized, placebo controlled efficacy trial of adjunctive fludrocortisone to improve septic shock mortality. Setting: 6 intensive care units (ICU) in Hong Kong, Australia and Singapore. Participants: 32 adult participants with suspected or confirmed septic shock within 24 hours of onset of shock and mechanical ventilation. Exclusion criteria are pregnancy, limitation of therapy, prescribed fludrocortisone for other medical condition, fludrocortisone cannot be administered within 24 hours of shock onset. Interventions: Enteral 100 mcg fludrocortisone daily or placebo for up to 7 days or until death or discharge from ICU, whichever comes first. Main outcome measures: Primary outcome is fulfillment of all pre-specified endpoints of feasibility criteria: protocol deviation \<15%, lost of concealment \<10%, drop out rate \<10% and missing data \<10%. Secondary outcomes include monthly recruitment rate, time to resolution of shock, 28-day mortality, days alive and free from organ support, severe electrolyte abnormality. Data analysis: Each feasibility criterion will be assessed amongst all study participants. Intention to treat analysis will be used to calculate differences in secondary outcomes between treatment groups. Expected results: Feasibility criteria will be met and demonstrate potential to scale-up to a large, international, multicenter, double-blind, randomized, placebo-controlled trial of adjunctive fludrocortisone to improve septic shock mortality.
Interventions
DRUGFludrocortisone 100 mcg daily
Patients will be given enteral fludrocortisone 100 mcg daily for 7 days or until discharge from ICU or death, whichever comes first. All patients will be treated with 7 days of intravenous hydrocortisone 50 mg every 6 hours for 7 days from randomization or until discharge from ICU or death, whichever comes first.
DRUGPlacebo
Patients will be given an enteral placebo tablet for 7 days or until discharge from ICU or death, whichever comes first. All patients will be treated with 7 days of intravenous hydrocortisone 50 mg every 6 hours for 7 days from randomization or until discharge from ICU or death, whichever comes first.
Sponsors
Chinese University of Hong Kong
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Pilot, multicenter, randomized, double-blind, placebo-controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. suspected or confirmed adult sepsis as defined by ≥ 2 increase in Sequential Organ Failure Assessment (SOFA) score due to infection 2. ≥0.25 μg/kg/min of noradrenaline infusion or vasoactive-inotropic score (VIS) ≥25 to maintain mean arterial pressure (MAP) ≥65 mmHg for at least 1 hour 3. onset of septic shock within 24 hours 4. shock due to infection with no other proven or apparent cause 5. hypoperfusion defined as arterial or venous lactate concentration \>2.0 mmol/L 6. mechanical ventilation
Exclusion criteria
1. fludrocortisone cannot be administered within 24 hours of onset of septic shock 2. death is deemed imminent or inevitable by treating clinicians 3. limitation of therapy 4. an underlying disease process with a life expectancy of less than 90 days 5. pregnancy (confirmed or suspected) 6. receiving immunomodulatory agents including hydrocortisone \> 300mg/day 7. enteral medication cannot be administered 8. prescribed fludrocortisone for other medical condition 9. contraindication to hydrocortisone or fludrocortisone
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Protocol deviations < 15% | End of study approximately 20 months | Defined as \<15% of recruited subjects that had at least one protocol deviation during the duration of intervention |
| Number of Lost of concealment < 10% | End of study approximately 20 months | Defined as \<10% of recruited subjects that lost blinding of allocations to either the patient, clinical or trial statistician |
| Number of Drop out < 10% | End of study approximately 20 months | Defined as \<10% of recruited subjects who drop out of the study after recruitment |
| Number of Missing data < 10% | End of study approximately 20 months | Defined as \<10% of data with missing values for each data category including lost to follow up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Monthly Recruitment | End of study approximately 20 months | Defined as the number of patients recruited per month across all study sites. In addition, screening and exclusion of subjects will be reported to inform the recruitment process and target study population of a future definitive trial. |
| Time to resolution of shock | Until patient discharge from ICU | Defined as time from randomization to attainment of a clinician-prescribed MAP target of \>24 hours without use of vasopressor or inotropes |
| 28-day mortality | First 28 days after enrollment | Defined as mortality in the first 28 days after randomization |
| Days alive and vasopressor-free until day 28 | First 28 days after enrollment | Defined as days alive without need for vasopressors or inotropes in the first 28 days after randomization |
| Days alive and ventilator-free until day 28 | First 28 days after enrollment | Defined as days alive without mechanical ventilation in the first 28 days after randomization |
| Days alive and dialysis-free until day 28 | First 28 days after enrollment | Defined as days alive without any forms of renal replacement therapy in the first 28 days after randomization |
| Days alive and free from organ support | First 28 days after enrollment | Defined as days alive without need for mechanical ventilation, vasopressors or dialysis in the first 28 days after randomization |
| Number of new onset infections | First 28 days after enrollment | Defined as new nosocomial infection 2 days after randomization until the first 28 days after randomization |
| Severe electrolyte abnormality | First 7 days after enrollment | Defined as plasma sodium ≥ 155 mmol/L or potassium ≤ 2.5 mmol/L during the first 7 days after randomization |
Countries
Hong Kong
Contacts
CONTACTLowell Ling, MBBS
Outcome results
None listed