APROCCHSS

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock

Annane. NEJM 2018; 378: 809-818. DOI: 10.1056/NEJMoa1705716

Clinical Question

  • In critically ill patients with septic shock, does the combination of hydrocortisone plus fludrocortisone therapy reduce 90 day mortality?

Background

  • The use of steroids in critically ill patients continues to be controversial. Whilst there are signals for improved cardiovascular parameters, this did not translate to clear mortality benefits.
  • The most recent of these trials (ADRENAL, 2018), concluded that among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.

Design

  • Multi-centre
  • Randomised placebo controlled trial
  • Double blinded
  • Initially designed to have 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    • When drotrecogin alfa was withdrawn from the market, the trial was continued with 2 parallel groups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 combined
      • Group 2 and 4 combined
  • Randomised by permuted blocks of 8
  • Intention to treat analysis
  • Sample size calculation
    • Based on anticipated 90 day mortality of 45% among pts with septic shock
    • 320 pts required in each of the original 4 groups (1280 pts total) for 95% power to detect an absolute difference of 10% in 90 day mortality (α=0.05)

Setting

  • 34 French ICUs
  • September 2008 – June 2015
    • Trial suspended twice: 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)
  • 1671 patients screened; 1241 randomised into 4 groups

Population

  • Inclusion: Intensive care patients with indisputable or probable septic shock for less than 24 hours
    • Septic shocked defined as clinically or microbiologically documented infection
    • SOFA score of 3 or 4 for at least 2 organs and at least 6 hours in duration
    • Vasopressor therapy for at least 6 hours to maintain a systolic blood pressure of at least 90mmHg or a mean blood pressure of 65mmHg
  • Exclusion:
    • Presence of septic shock for more than 24 hours
    • High risk of bleeding
    • Pregnancy or lactation
    • Underlying condition which would limit short-term survival
    • Known hypersensitivity to drotrecogin alfa (later removed)
    • Previous treatment with corticosteroids
  • Baseline characteristics were similar: intervention vs placebo group
    • Mean age (years): 66 vs 66
    • Male sex (%): 65.5 vs 67.7
    • Medical admission (%): 82.4 vs 81
    • SOFA score: 12 vs 11
    • Site of infection (%)
      • Unknown: 1.8 vs 2.9
      • Lung: 60.7 vs 58.0
      • Abdomen: 12.1 vs 10.9
      • Urinary tract: 16.6 vs 18.8
    • Positive blood culture (%): 36.6 vs 36.6
    • Vasopressor administration
      • Epinephrine
        • Number of pts: 53 vs 58
        • Dose (mcg/kg/min): 2.31 vs 1.74
      • Norepinephrine
        • Number of pts: 534 vs 552
        • Dose (mcg/kg/min): 1.02 vs 1.14
    • Mechanical ventilation (%): 92.3 vs 91.3
    • RRT (%): 27.0 vs 28.1
    • % of pts who received DAA: 17.1 (105/614) vs 16.4 (103/627)

Intervention

  • Hydrocortisone
    • 50mg IV bolus every 6 hours
  • Fludrocortisone
    • 50 mcg tablet once in the morning
  • Administered for 7 days without tapering

Control

  • Placebo
    • Similar in appearance and manufactured for the trial

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

Outcome

  • 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)
      • No of days that pts were alive and 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
      • 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
      • Safety outcomes/Incidence of serious adverse events
        • 53.1% vs 58%, P=0.08

Authors’ Conclusions

  • 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.

Strengths

  • Randomised controlled trial
  • Multi-centre
  • Intention to treat analysis
  • Appropriate primary outcome
  • Appropriateness of antibiotic therapy recorded

Weaknesses

  • 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 and other treatments
    • 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
    • Results discussed in supplementary material section where there was no difference between responders and non-responders in those from which the Synacthen test was actually conducted
  • The trial was conducted using the 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

The Bottom Line

  • 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)
  • I will continue my current practice of using hydrocortisone IV (6 hourly) for refractory septic shock

External Links

Metadata

Summary author: Adrian Wong
Summary date: 15 March 2018
Peer-review editor: Segun Olusanya

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