ADRENAL – Corticosteroids in Septic Shock

Background

During physiological stress, hypotension, or severe infection, the hypothalamic-pituitary-adrenal (HPA) axis is activated. The hypothalamus secretes corticotrophin-releasing hormone (CRH) stimulating the release of adrenocorticotrophin hormone (ACTH) from the anterior pituitary. This results in cortisol secretion from the adrenal glands, and as a result, serum cortisol increases.

Endogenous cortisol is thought to have many benefits in physiologic stress¹. These benefits include such physiologic changes as: increased sensitivity to adrenergic receptors and decreased pro-inflammatory response.

Randomized clinical trials (RCTs) looking at the effectiveness of adjunctive corticosteroids in the treatment of septic shock have yielded conflicting results (Annane 2002, Sprung 2008). The current surviving sepsis guidelines recommend the addition of hydrocortisone in patients with fluid and vasopressor refractory septic shock (Level 2C). Further high-quality data is needed on the subject to help elucidate the role of corticosteroids in septic shock.

Primary Results

• 3800 patients from 69 medical-surgical ICUs underwent randomization
• 3658 patients were included in the primary outcome
  • 1832 patients in the hydrocortisone group
  • 1826 patients in the placebo group
• Admission type breakdown:
  • Non-operative (Medical) ≈ 68%
  • Operative (Surgical) ≈ 32%
• All patients had similar baseline therapy:
  • Mechanical Ventilation ≈ 100%
  • Inotropes/Vasopressors ≈ 100%
  • Antimicrobials ≈ 98%

Critical Results

• 90-day Mortality (primary outcome)
  • No statistically significant difference
  • Hydrocortisone group: 27.9% (511/1832) vs Placebo group: 28.8% (526/1826)
  • Odds ratio (OR), 0.95 (95% CI 0.82 to 1.10)
  • Absolute risk reduction (ARR) 0.91% (95% CI -2.01% to 3.83%)
• Adverse Events
  • All adverse events significantly greater in hydrocortisone group: 21 (1.1%) vs. 6 (0.3%), p=0.009
    • Hyperglycemia: 6 vs. 3
    • Hypernatremia: 3 vs. 0
    • Encephalopathy: 3 vs. 0
  • Serious adverse events
    • Hydrocortisone: n = 4
      • 2 myopathy, 1 ischemic bowel, 1 circulatory shock
    • Placebo: n = 2
      • 1 bleeding, 1 abdominal-wound dehiscence

Secondary outcomes:

Significant Reduction in Steroid Group

• 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: 37.0% vs. 41.7% (OR 0.82; 95% C.I. 0.72-0.94, P=0.004

No significant difference in:

• 28 day mortality: 22.3% vs 24.3%
• Recurrence of shock: 19.7% vs 18.4%
• Use of renal replacement therapy: 30.6% vs. 32.7%
• Number of days alive and outside of the ICU: 58 vs 43
• Median days to discharge from the hospital: 39 vs 43
• Number of days alive and outside of the hospital: 40 vs 38
• Number of days alive and free of mechanical ventilation: 61 vs 59
• New-onset bacteremia or fungemia: 14.1% vs 14.1%

Strengths

• Multicenter, multinational increasing external validity
• Largest study to date, investigating steroids in septic shock
• Primary outcome clinically important and patient centered
• Trial protocol and statistical analysis plan were published in advance of the trial start
• Randomization was appropriately performed and concealed
• Baseline patient characteristics were similar
• Loss to follow up was minimal (0.7%)

Limitations

• Patients receiving etomidate were excluded. This may reduce generalizability as this is a commonly used induction agent in rapid sequence intubations during septic shock.
• The time from ICU admission to randomization was prolonged (longer than 24 hours). This is a clinically long amount of time in the treatment of septic shock.
• Microbiology analysis was not included
• A noted secondary outcome of hyponatremia was documented however the amount and type of intravenous fluids were not included.
• Around 8% of the patient received open label steroids; which create bias

Author's Conclusions

“Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.”

Our Conclusions

Although the use of „stress dose steroids“ in Sepsis provides no overall improvement in 90 day mortality there are significant findings illuminated by this study that can change clinical practice. Patient’s who received stress dose steroids spent less days in the ICU, less time on the ventilator and had lower amount of blood transfusions. These benefits in secondary outcomes need further exploration.

Potential Impact To Current Practice

This study doesn’t change the overall management of sepsis and septic shock. With patient’s in extremis who are not improving with basic management of  their infection the addition of stress dose steroids may prove beneficial as it has been shown to decrease ICU stay, time of ventilation and possible lower their chances of receiving additional blood products.

Bottom Line

Hydrocortisone use does not change mortality in septic shock patients, however there is possible benefit in decreasing morbidity based on secondary outcomes.

Read More

REBEL EM: The ADRENAL Trial: Steroids in Septic Shock

EM Nerd: The Case of the Relative Insufficiency

EM Lit of Note: The Definitive Word on Steroids in Septic Shock

The Bottom Line: ADRENAL

Critical Care Reviews: ADRENAL Trial Results

References

Annane D et al. Effect of Treatment with low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patient with Septic Shock. JAMA 2002. PMID: 12186604

Sprung CL et al. Hydrocortisone Therapy for Patients with Septic Shock. The CORTICUS Trial. NEJM 2008. PMID: 18184957