Annane D, Renault A, Brun-Buisson C et al.
The hypothalamus-pituitary-adrenal access is crucial to the physiological stress response. However, exogenous use of steroids in critically ill patients remains controversial.
A previous multi-centre multi-national trial including 3658 patients (ADRENAL) found that in patients with septic shock on mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (This was despite the Hydrocortisone group having reduced time to resolution of shock, reduced duration of ICU, reduced time to cessation of mechanical ventilation and a reduction in the use of blood transfusion.) Whilst there are signals for improved cardiovascular parameters, this did not translate to clear mortality benefits.
Aim of Study
In critically ill patients with septic shock, does the combination of hydrocortisone plus fludrocortisone therapy reduce 90-day mortality?
Design and Location
- Multi-centre, Randomised, placebo-controlled trial
- Double blinded
- 34 centres – 34 French ICUs
- September 2008 – June 2015
The study initially also included drotrecogin alfa (DAA) – a form of human activated protein C – but this was removed partway through trial as showed no evidence for benefit in sepsis. The trial was suspended twice relating to DAA: October 2011 – May 2012 (DAA withdrawal) and July 2014 – October 2014 (request of data and safety monitoring board to check the quality of the trial agents and the distribution of the serious adverse events RE DAA).
Initial design of 4 parallel groups to evaluate benefits/risks of steroids and drotrecogin alfa (DAA) in a 2 by 2 factorial design
- Original =4 groups
- Group 1: Corticosteroids placebo + DAA placebo
- Group 2: Corticosteroids + DAA placebo
- Group 3: Corticosteroids placebo + DAA
- Group 4: Corticosteroids + DAA
- When drotrecogin alfa was withdrawn from the market, the trial was continued with 2 parallel groups: Group 1 and 3, Group 2 and 4 combined
- Randomised by permuted blocks of 8 not disclosed to the operators
Population: 1671 patients screened; 1241 randomised into 4 groups
- Inclusion: Intensive care patients with indisputable or probable septic shock for <24 h
- SOFA Sequential organ failure assessment of 3 or 4
- Norad, adrenaline, or any other vasopressor at a dose of ≥0.25 μg per kilogram of body weight per minute or ≥1 mg per hour
- septic shock >24 hours – risk of confounding variable
- High risk of bleeding – as DAA increases bleeding risk
- Pregnancy or lactation
- Underlying condition which would limit short-term survival – patients with a survival prognosis of < 28 days because of pre-existing co-morbidity non-related to sepsis, HIV + patients with CD4 recent rate ≤ 50/mm , patients on chronic dialysis and patients undergoing bone marrow transplant or lung, liver, pancreas, small bowel transplantation, and patients with acute clinical pancreatitis without a proven source of infection
- DAA allergy
- Previous treatment with corticosteroids
- Hydrocortisone 50mg IV bolus every 6 hours
- Fludrocortisone 50 mcg tablet once in the morning
- Administered for 7 days without tapering
Control: Placebo drug – similar in appearance and manufactured for the trial
Other Management common to both groups:
- Before randomisation, plasma total cortisol levels measured before, 30 and 60 minutes after IV bolus of 250 mcg of corticotrophin (Synacthen)
- Other interventions were harmonised across centres according to 2008 Surviving Sepsis Campaign guidelines
- National guidelines for the prevention of superinfection were followed
- Primary outcome– 90-day all-cause mortality.
- Secondary outcomes included – mortality (at ICU discharge, at hospital discharge, at day 28, at day 180); number of days alive and free of vasopressors, mechanical ventilation, or organ failure.
- Safety outcomes included superinfection up to day 180, gastrointestinal bleeding up to day 28, episodes of hyperglycemia up to day 7, and neurologic sequelae (cognitive impairment and muscle weakness) at the time of ICU and hospital discharge, day 90, and day 180. All adverse events were recorded according to Medical Dictionary for Regulatory Activities classification (Appendix.
- Baseline characteristics were similar between intervention vs placebo group
- Patients were more likely admitted for medical than surgical reasons, & had more likely community than hospital acquired sepsis (lung sepsis predominated)
- Patients had high severity of illness scores (SAPSII and SOFA scores), high lactate levels (4.2-4.4 on admission), and a high degree of vasopressor dependency (mean dose of norepinephrine > 1μg/kg/minute).
- The initial antimicrobial treatment was judged adequate (by the steering committee, according to the site of infection and the sensitivity of the pathogens) in 96.2% of the patients who received placebo and 96.9% of those who received corticosteroids.
- There was some imbalance between the two groups in the distribution of pathogens, with slightly more viral infections in the hydrocortisone-plus-fludrocortisone group than in placebo.
- Intention to treat analysis
- Sample size calculation was based on an anticipated 90-day mortality of 45% among pts with septic shock (based on Annane et al 2007 paper)
- According to the 2-by-2 factorial design with a two-sided formulation, 320 patients were needed in each group (i.e., a total of 1280 patients) to detect an absolute difference of 10 percentage points in 90-day mortality (α=0.05 and power at 95%) between either DAA (activated) or corticosteroids and placebo. (Owing to the withdrawal of DAA from the market in 2011, the trial continued with two parallel groups and was underpowered to assess the effect of drotrecogin alfa (activated)).
- The sponsor terminated the trial when the expiration dates of the trial agents were reached and 1241 patients (97% of the expected sample size) had been enrolled.
Primary outcome: Significant reduction in 90 day mortality in intervention compared to control group
- Intervention group: 264 of 614 (43.0%) patients had died
- Control group: 308 of 627 (49.1%) patients had died
- Relative Risk (RR): 0.88 (95% CI 0.78 to 0.99; P=0.03)
- Absolute Risk Reduction (ARR): 6.1% (95% CI 0.6% to 11.7%; P=0.03)
- Number Needed to Treat (NNT): 17
- Fragility Index (FI): 3
Secondary outcome: Intervention vs control group- significantly in favour of intervention group
- All cause mortality at ICU discharge 35% vs 41% (RR 0.86; 95% CI 0.75–0.99; P=0.04)
- All cause mortality at hospital discharge 39% vs 45% (RR 0.86; 95% CI 0.76–0.98; P=0.02)
- All cause mortality at 180 days 47% vs 52% (RR 0.89; 95% CI 0.79–0.99; P=0.04)
- days pts were alive + free from vasopressors up to 28 days mean 17+/-11 vs 15+/-11 (P<0.001)
- Organ-failure-free days up to day 28 mean 14+/-11 vs 12+/-11 (P=0.003)
- % of pts weaned from vasopressors at 28 days (P<0.001)
- % of pts weaned from mechanical ventilation at 28 days (P=0.006)
- % of pts with SOFA score below 6 at day 28 P<0.001
No significant difference between groups for:
- All cause mortality at 28 days 34% vs 39% (RR 0.87; 95% CI 0.75–1.01; P=0.06)
- % of pts from whom care was withheld or withdrawn 10.4% vs 9.7%, (P=0.69)
- No of days that pts were alive and free from mechanical ventilation up to 28 days mean 11+/-11 vs 10+/-11, (P=0.07)
Serious Adverse Events:
No significant difference of serious adverse events overall: 53.1% vs 58%, P=0.08
- NO significant increased risk of gastroduodenal bleeding (RR 88; 95% CI, 0.58 to 1.34; P=0.56),
- NO significant increased risk of superinfection (RR 09; 95% CI, 0.92 to 1.30; P=0.30).
- INCREASED risk of hyperglycemia in hydrocort group (RR, 1.07; 95% CI, 1.03 to 1.12; P=0.002).
In critically ill patients with septic shock, the addition of hydrocortisone and fludrocortisone compared to placebo was associated with a significant improvement in mortality at 90 days.
Cochrane systematic review of 33 trials looking at steroids in sepsis- also Annane et al.
Reports 2 of 33 trials were powered to address the effects of a long (≥5 days) course of low-dose corticosteroids on mortality.
- (Ger-Inf-05), in which patients received hydrocortisone plus fludrocortisone or matching placebos for 7 days, showed an absolute difference of 6 percentage points in 28-day mortality in favor of hydrocortisone plus fludrocortisone.
- (Corticosteroid Therapy of Septic Shock [CORTICUS]) showed no significant survival benefit from an 11-day course of hydrocortisone alone.
- A third more recent trial involving 380 adults with severe sepsis (Hydrocortisone for Prevention of Septic Shock [HYPRESS]), hydrocortisone alone failed to prevent septic shock. That trial was not powered to address the effects of hydrocortisone on mortality and excluded patients with shock.
The author reports two main differences between trials that showed a survival benefit from corticosteroid therapy (APROCCHSS and Ger-Inf-05) and those that did not (CORTICUS and HYPRESS).
- In APROCCHSS and Ger-Inf-05 trials, fludrocortisone (enteral, no parenteral formulation) was added to hydrocortisone to provide additional mineralocorticoid potency
- In APROCCHSS and Ger-Inf-05, Patients selected high risk of death most in need of adjunct therapy – i.e. septic shock whose condition did not improve after initial resuscitation according to the 6-hour bundle of care outlined in the Surviving Sepsis Campaign guidelines. Implying this strategy may be beneficial in adults with septic shock and persistent vasopressor dependency and organ failures.
- Randomised controlled trial – reduced bias, relatively good blinding/ placebo
- Multi-centre, relatively big study
- Analysis appeared appropriate, applied Intention to treat
- Appropriate primary outcome, and relatively good breadth of secondary outcomes
- Appropriateness of antibiotic therapy recorded
- The trial was initially designed and powered with DAA being part of the therapy. The withdrawal of DAA has impacted aspects of this trial including statistical power calculation
Statistical analysis published in supplementary material suggest no interaction with DAA + other Rx
- Following from this powering, The Fragility Index for several of the outcomes (including primary outcome) in favour of intervention is in single figures
- Outcome of Synacthen test conducted pre-randomisation was not mentioned or discussed in main paper: NB Results discussed in supplementary material section: there was no difference between responders and non-responders in those from which the Synacthen test was actually conducted
- Use of Surviving Sepsis Guidelines from 2008 which has since been updated
- Very sick patient population – the high doses of vasopressors used in the trial population may limit external validity
- Not all secondary endpoints included in original trial protocol reported on in final manuscript – lots of iterations/changes to protocol
- The addition of fludrocortisone and its effect is less well investigated compared to hydrocortisone by itself. It is not my current practice to administer this drug for refractory septic shock
- Primary and secondary outcomes, including safety profile, shows a trend in favour of the corticosteroid group (consistent with the findings of the ADRENAL trial)
Summary by Dr K Townsend. Journal Club Meeting 06 June 2019.