Adjunctive Corticosteroid Treatment in Critically Ill Patients With Septic Shock (ADRENAL)

Venkatesh B, Finfer S and Cohen J et al.

The New England Journal of Medicine published online first 19th January 2018

DOI: 10.1056/NEJMoa1705835

 

Aim of Study

To assess whether the use of hydrocortisone, compared with placebo reduced 90 day mortality, in critically ill patients with septic shock.

Design and Location

• Randomised, double-blinded, placebo controlled trial
• Stratified according to participating site and medical vs surgical admission
• Intention to treat analysis
• Sample size calculation
  • 3800 patients will provide 90% power to detect a 5% absolute risk reduction, from a baseline mortality rate of 33%, with a false positive rate of 5%; allowing for a 1% rate of withdrawal/loss to follow-up

• 69 medical–surgical ICUs
  • Australia (45 sites), UK (12), New Zealand (8), Saudi Arabia (3), and Denmark (1)
• March 2013 – April 2017

Methodology

Population

• Inclusion criteria: Adult patients with septic shock requiring vasopressors and mechanical ventilation
  • Documented or strong suspicion of infection
  • 2 of the 4 SIRS criteria
  • Mechanical ventilation, including non-invasive ventilation (CPAP, bilevel)
  • Vasopressors/inotropes for ≥4 hours to maintain systolic BP >90mmHg, or MAP >60mmHg, or a MAP target set by treating physician
• Exclusion criteria:
  • Met all inclusion criteria >24 hours ago
  • Clinicians expects to prescribe systemic corticosteroids for another indication
  • Treated with etomidate or amphotericin B
  • Cerebral malaria or strongloides infection
  • Death deemed inevitable or imminent, or death from underlying disease likely within 90 days
• Trial included 3658 patients out of 3800 patients who were randomised
  • 142 (3.7%) patients withdrew/did not have consent/lost to follow-up
• Baseline characteristics were similar: hydrocortisone vs placebo group:
  • Mean age, Male sex, Surgical admission, APACHE score, Timing from shock to onset of resolution, Vasoactive drugs administered, Use RRT, Mechanical ventilation, Use of Antimicrobial agent, Site of infection (predominantly pulmonary/abdominal)

Intervention : Hydrocortisone

• 200mg/day, given as continuous infusion for 7 days or until ICU discharge
• Assigned trial regimen received in 99.8% of patients
• Infusion continued for median 5.1 days

Control: Placebo

• Infusion given as per intervention group
• Assigned trial regimen received in 99.7% of patients
• Infusion continued for median 5.6 days

Management common to both groups

• All other aspects of the patients’ care were conducted at the discretion of the treating clinicians
• Between days 1-14 post randomisation, 7.4% of patients in the hydrocortisone group and 8.8% in the placebo group received open-label glucocorticoids, P=0.13

Statistics

Primary-outcome

• Result presented as the odds ratio for death, with corresponding 95% Cis
• Analyzed with logistic-regression model with adjustment for stratification variables, with admission type (medical or surgical) as a fixed effect and trial site as a random effect.
• Sensitivity analyses performed by adding covariates; Sex, age, APACHE II score, assessed on a scale from 0-71, the time from the onset of shock to randomization, use of RRT in the 24 hours before randomization

Secondary Outcomes

• Binary outcomes analysed with logistic regression and continuous outcomes with linear regression, with adjustment for stratification variables
• Post-hoc Holm–Bonferroni procedure was applied to control for multiple testing
• Rate of death in a time-to-event analysis was reported with the use of Kaplan–Meier plots
• Differences in survival and time to event (e.g. resolution of shock, cessation of ventilation, ICU or hospital discharge) tested using Cox proportional-hazards model
• Proportion of patients who had adverse events and serious adverse events compared using Fisher’s exact test.

Results

Primary Outcome

• Primary outcome: no statistical difference in 90 day mortality
  • 511 of 1832 patients (27.9%) in the hydrocortisone had died vs 526 of 1826 (28.8%) in the placebo group
    • Odds ratio (OR), 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50
    • Absolute risk reduction (ARR) 0.91%; 95% CI -2.01% to 3.83%; P=0.56 (Fisher’s exact)

Secondary Outcomes

Hydrocortisone vs placebo group

• Significantly reduced:
  • Median days to resolution of shock
    • 3 vs 4 days (Hazard ratio [HR] 1.32; 95% C.I. 1.23-1.41, P=<0.001)
  • Median time to cessation of initial mechanical ventilation
    • 6 vs. 7 days (HR 1.13; 95% C.I. 1.05-1.22, P=<0.001)
  • Median time to discharge from the ICU
    • 10 vs. 12 days (HR 1.14, 95% C.I. 1.06-1.23, P=<0.001)
  • Use of blood transfusion
    • 0% vs. 41.7% (OR 0.82; 95% C.I. 0.72-0.94, P=0.004)
  • No significant difference in: 28 day mortality, Recurrence of shock, No. of days alive and outside of the ICU, Median days to discharge from the hospital, No. of days alive and outside of the hospital, No. of days alive and free of mechanical ventilation, Use of renal replacement therapy, New-onset bacteraemia or fungemia
• Sub-group analysis – no difference in primary outcome
  • Medical vs. surgical admission; norepinephrine <15 vs. ≥15μg/min; primary site of sepsis pulmonary vs. non-pulmonary; male vs. female; APACHE II <25 vs. ≥25; duration of shock

• Adverse events
  • Number of patients with adverse events – significantly greater in hydrocortisone group
    • 21 (1.1%) vs. 6 (0.3%), p=0.009
    • Hyperglycaemia: 6 vs. 3, Hypernatraemia: 3 vs. 0, Encephalopathy: 3 vs. 0
  • Serious adverse events
    • 4 events in the hydrocortisone group: 2 myopathy, 1 ischaemic bowel, 1 circulatory shock
    • 2 events in the placebo group: 1 bleeding, 1 abdominal-wound dehiscence
      • Mortality by region
    • Australia: 25.1% vs. 27.6% (median APACHE II Score 23)
    • United Kingdom: 35.3% vs. 31.7% (median APACHE II Score 25)

Conclusions/Discussions

• Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo
• In mechanically ventilated patients with septic shock, low dose hydrocortisone administered via an infusion for up to 7 days does not reduce or increase mortality at 90 days
• Secondary outcomes demonstrated that patients in the hydrocortisone group had a reduced time to resolution of shock, reduced duration of ICU but not hospital stay, reduced time to cessation of mechanical ventilation and a reduction in the use of blood transfusion. Adverse events were low, but significantly increased in the hydrocortisone group.

Stated Limitations from the Study

• Greater rate of withdrawal/loss to follow up than anticipated
• 7.4% in intervention group and 8.8% of patients in placebo group received open-label steroids
• Use of antibiotic therapy was recorded, appropriate choice based on microbiology analyses was not
• Long-term neuromuscular weakness as an adverse event was not assessed
• A number of patients remained on vasopressors when the trial intervention completed

Discussion from Journal Club Meeting (?Change of Practice)

• Is hydrocortisone use in septic shock cost-effective – reduces initial period of mechanical ventilation but not cumulative ventilated time. Reduced ICU stay but overall length of hospital stay.
• Potential benefit of set dose continuous infusion over intermittent dosing
• Consider whether continuous infusion offers practical and clinical benefit over tapering regimen
• Need for robust monitoring of attributable adverse effects – many potential confounders

Summary by Dr R Simper. Journal Club 08 February 2018.