ADRENAL

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Venkatesh B, et al. "Adjunctive glucocorticoid therapy in patients with septic shock". New England Journal of Medicine. 2018. Epub 2018-01-19:1-12.
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Clinical Question

In patients with septic shock requiring ventilatory and vasopressor support, does a continuous week-long infusion of hydrocortisone 200 mg/day improve mortality at 90 days when compared to placebo?

Bottom Line

In patients with septic shock on mechanical ventilation and receiving vasopressors, a week of hydrocortisone 200 mg/day did not reduce 90 day mortality but may be associated with time until reversal of shock, time to extubation, length of ICU stay, and blood transfusion.

Major Points

Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock. The Annane Trial in 2002 with 299 patients demonstrated a short-term mortality benefit with IV hydrocortisone and fludrocortisone among patients with evidence of adrenal insufficiency on ACTH stimulation testing. CORTICUS with 499 patients in 2008 investigated hydrocortisone in patients with and without adrenal insufficiency and found a faster reversal of shock but no benefit in either subgroup with suggestion of increased infection rates in patients receiving hydrocortisone. HYPRESS in 2016 with 380 patients showed no difference in mortality but showed decrease time to reversal of shock.

Published in 2018, the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial randomized 3800 patients from 69 international sites with septic shock on vasopressors and mechanical ventilation to hydrocortisone 200 mg/day continuous infusion or placebo. There was no difference at the primary outcome of death from any cause at 90 days, nor were any difference found in any of the six prespecified subgroups. The hydrocortisone group had faster time to reversal of shock, shorter time to discharge from the ICU, time to extubation, and decreased number of blood transfusion. These additional outcomes may best be regarded as hypothesis-generating.

The 2016 Surviving Sepsis Campaign severe sepsis and septic shock[1] suggests using IV hydrocortisone if hemodynamics cannot be stabilized using fluids and vasopressors. This recommendation was made before the release of the large ADRENAL trial and may lead to re-evaluation of this recommendation. This trial likely puts to rest steroids for all-comers in sepsis, however, does not settle if steroids would be beneficial in patients that are non-responders to initial fluid resuscitation and vasopressor administration, as recommended in the guidelines.

Guidelines

As of February 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=3,658 patients with septic shock requiring vasopressors and mechanical ventilation
    • Hydrocortisone (n=1,832)
    • Placebo (n=1,826)
  • Setting: Australia (45 sites), UK (12), New Zealand (8), Saudi Arabia (3), and Denmark (1)
  • Enrollment: 2013-2017
  • Follow-up: 90 days
  • Analysis: Intention-to-treat
  • Primary Outcome: 90-day mortality

Population

Inclusion Criteria

  • Age ≥18 years
  • Mechanical ventilation
  • Strong clinical suspicion of infection
  • ≥2 SIRS criteria [2]
    • Note: Alignment between participants and newer SEPSIS-3 definitions are presented in the supplementary appendix in Table S2c on page 11.[3]
  • Continuous vasopressors/inotropes for SBP >90mmHg or MAP >60mmHg for ≥4 hours

Exclusion Criteria

  • Receiving systemic corticosteroids for indication other than septic shock
  • Received etomidate
  • Receiving amphotericin B for systemic fungal infection
  • Documented cerebral malaria
  • Documented strongyloides infection
  • Life expectancy ≤90 days from pre-existing disease
  • Treatment limitations in place (e.g., DNR)
  • Met all inclusion criteria for longer than 24 hours

Baseline Characteristics

Hydrocortisone group displayed

  • Demographics: Age 62 years, male sex 60%
  • Anthropomorphics: Weight 86 kg
  • Critical care details: Medical admission 69%, surgical admission 31%
    • APACHE II score: Median 24, score of ≥25 46%
  • Therapy at baseline: Mechanical ventilation 99.8%, antimicrobial therapy 98%, RRT 12%
    • Inotropes/vasopressors 99.5%
      • Norepinepherine: 98%
      • Vasopressin: 15%
      • Epinepherine: 7%
      • Other: 8%
  • Physiological parameters: MAP 72 mm Hg, CVP 12 mm Hg, HR 96 BPM
  • Labs: Highest lactate 34 mg/dL, highest bilirubin 1.7 mg/dL, highest creatinine 2.2 mg/dL, lowest PaO2:FIO2 165, highest WBC count 17 cells/10-9/L
  • Primary site of infection: Pulmonary 34%, abdominal 26%, blood 17%, skin/soft tissue 7%, urinary 8%, other 8%
  • Time from ICU admission to randomization: 26 hours
  • Time from shock onset to randomization: 21 hours

Interventions

  • Participants were randomized to a group:
    • Hydrocortisone - Continuous infusion of hydrocortisone 200 mg IV daily for 7 days or ICU discharge or death
    • Placebo

Outcomes

Comparisons are hydrocortisone vs. placebo

Primary Outcomes

Death from Any Cause at 90 Days
27.9% vs. 28.8% (OR 0.95; 95% CI 0.82–1.10; P=0.50)

Secondary Outcomes

28-day mortality
22.3% vs. 24.3% (OR 0.89; 95% CI 0.76-1.03; P=0.13)
Median time to shock reversal, days (IQR)
3 (2-5) vs. 4 (2-9) (HR 1.32; 95% CI 1.23–1.41; P<0.001)
Recurrence of shock
19.7% vs. 18.4% (OR 1.07; 95% CI 0.94-1.22; P=0.32)
Median time to discharge, days (IQR)
From ICU: 10 (5-30) vs. 12 (6-42) (HR 1.14; 95% CI 1.06-1.23; P<0.001)
From the hospital: 39 (19-NA) vs 43 (19-NA) (HR 1.06; 95% CI 0.98-1.15; P=0.13)
Duration of initial mechanical ventilation, days (IQR)
6 (3-18) vs. 7 (3-24) (HR 1.13; 95% CI 1.05-1.22; P<0.001)
Days alive and free from mechanical ventilation
61.2 vs. 59.1 days (Mean absolute difference 2.18, 95% CI -0.11 to 4.46; P=0.06)
Frequency of RRT
30.6% vs. 32.7% (OR 0.94; 95% CI 0.86-1.03; P=0.18)
Days alive and free from RRT
42.6 vs. 40.4 days (Mean absolute difference 2.37, 95% CI -2.00 to 6.75; P=0.29)
Incident new-onset bacteremia or fungemia
14.1% vs. 14.1% (OR 1.00; 95% CI 0.86-1.16; P=0.96)
Blood transfusion
37.0% vs. 41.7% (OR 0.82; 95% CI 0.72-0.94; P=0.004)

Subgroup Analysis

There were no significant differences between subgroups when stratified by sex, admission type, catecholamine dose, site of sepsis, APACHE II score, or time from shock onset to randomization.

Adverse Events

Total patients with adverse event
21 vs. 6

Criticisms

  • Adverse events were recorded based on clinical judgement and were not centrally adjudicated. Similarly, appropriateness of antimicrobials was not centrally adjudicated.
  • The trial excluded those who had received etomidate, an anesthetic with some adrenal suppression. This limits generalizability.
  • Long-term neuromuscular weakness not assessed.
  • Cost analysis not performed.
  • ACTH stimulation testing was not performed.
  • Prior trials used bolus doses of corticosteroids. Given importance of rapid reversal of shock, is unclear if a slower infusion may have delayed onset of action of the medication and, thus, attenuated any true association between the intervention and primary outcome. The authors note that they chose an infusion over bolus dosing because of theoretical safety benefits (lower hyperglycemia and impacts on the inflammatory response).

Funding

  • National Health and Medical Research Council of Australia

Further Reading

  1. Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." Critical Care Medicine. 2017;45(3)1-67.
  2. Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992. 101:1644-55.
  3. Supplementary appendix