What They Did:
- International, pragmatic, double-blind, parallel-group randomized, controlled trial of 3800 patients with septic shock undergoing mechanical ventilation
- Hydrocortisone infusion (at a dose of 200mg/day) or placebo for 7 days or until death or discharge from ICU
- ADRENAL = ADjunctive corticosteroid tREatment iN criticAlly ilL patients with septic shock
- Tried to answer the question of whether hydrocortisone therapy reduces mortality in patients admitted to the ICU with septic shock
Outcomes:
- Primary: 90 day mortality
- Secondary:
- 28 day mortality
- Time to resolution of shock
- Recurrence of shock
- Length of ICU stay
- Length of hospital stay
- Frequency and duration of mechanical ventilation
- Frequency and duration of treatment with renal-replacement therapy
- Incidence of new-onset bacteremia or fungemia between 2 and 14 days after randomization
- Blood transfusion requirements
Inclusion:
- Adults (≥18 years of age) undergoing mechanical ventilation with strong clinical suspicion of infection, who fulfilled 2 or more criteria of SIRS
- Continuous vasopressors or inotropes to maintain a SBP >90mmHg or mean MAP >60mmHg, or MAP target set by the treating physician for maintain perfusion
- Administration of vasopressors or inotropes for ≥4 hours and present at time of randomization
Exclusion:
- Receiving systemic corticosteroids for an indication other than septic shock
- Received Etomidate
- Patients receiving treatment with Amphotericin B for systemic fungal infections at time of randomizations
- Patients with documented cerebral malaria
- Patients with documented strongyloides infection
- Considered to suffer death within 90 days from pre-existing disease
- Treatment limitations in place (i.e. DNR)
- Met all inclusion criteria for >24hours
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%
- Death from Any Cause at 90 Days (Primary Outcome):
- Hydrocortisone Group: 27.9%
- Placebo Group: 28.8%
- OR 0.95, 95% CI 0.82 – 1.10; p = 0.50
- 7% of patients received open label steroids, but after doing a post hoc analysis of the primary outcome excluding these patients there is still no difference in mortality OR 0.96, 95% CI 0.82 – 1.12; p = 0.59
- No difference in mortality across 6 pre-specified subgroups as well:
- 3658 patients were included in the primary outcome
- Median Time to Shock Reversal
- Hydrocortisone Group: 3 Days (Range 2 – 5)
- Placebo Group: 4 Days (Range 2 – 9)
- HR 1.32, 95% CI 1.23 – 1.41; p <0.001
- No Statistical Difference in:
- Mortality at 28 days
- Rate of recurrence of shock
- Number of days alive and out of the ICU
- Number of days alive and out of the hospital
- Recurrence of mechanical ventilation
- Rate of renal replacement therapy
- Incidence of new-onset bacteremia or fungemia
- Adverse Events
- Total of 33 adverse events
- Hydrocortisone Group: 1% (24 events)
- Placebo Group: 0.3% (3 events)
- P = 0.009
- Hyperglycemia
- Hydrocortisone: 6 Events
- Placebo 3 Events
- Serious Adverse Events
- Hydrocortisone Group: 4 Events
- Placebo Group: 2 Events
Strengths:
- International, pragmatic, double-blind, parallel-group randomized, controlled trial increases the validity of the results
- Primary outcome clinically important and patient centered
- Largest patient populations of patients in septic shock to be included in a trial answering the question of adjunctive corticosteroids in septic shock (i.e. 3800 patients)
- Annane Trial [2]: 3.5 years to enroll 299 patients
- CORTICUS Trial [3]: 3.5 years to enroll 499 patients
- VASST Trial: 5 years to enroll 778 patients
- APROCCHS Trial: 6.9 years to enroll 1241 patients
- ADRENAL Trial: 4.1 years to enroll 3800 patients
- Before the trial was even completed the trial protocol and statistical analysis plan was published to help reduce bias in results
- Neither Pfizer (which supplies hydrocortisone) or Radpharm Scientific (which supplied placebo) had any input into the design or conduct of the study, data collection, statistical analysis, or writing the manuscript
- Randomizations concealed using a password-protected, encrypted, web-based interface
- Patients, treating physicians, and trial personnel were blinded in regards to hydrocortisone vs placebo was completed by use of identical, masked vials
- Primary outcome examined in 6 pre-specified subgroups to ensure no subgroup would benefit from hydrocortisone therapy
- Two interim analyses were performed by an independent statistician when 950 patients (25% of enrollment) and 2500 patients (66% of enrollment) could be assessed with regard to the primary outcome
- Baseline characteristics of patients were similar. In other words one patient population was not sicker than the other
- Very few patients lost to follow up (28 patients or 0.7% of study population) increasing the validity of the results
- Results verified in 5 different hospital systems which increases external validity to general practice
Limitations:
- Patients receiving etomidate were excluded from this study. However many providers may still be using etomidate for RSI in septic patients
- Adverse events were recorded based on clinician judgment as being related to the trial regimen, but this judgment was not adjudicated
- Data was not collected on all secondary infections
- The appropriateness of antibiotic therapy was also not adjudicated
- Rates of recurrent ventilation was used as a surrogate for myopathy but long-term neuromuscular weakness was not assessed
- A detailed cost-benefit analysis was not done
- Unclear what amount of fluids patients got in each arm of the study as too much fluid has been associated with increased mortality
- It’s possible that there is a significant difference for a smaller but still clinically relevant outcome (i.e. the 0.9% difference could be real if a larger group was recruited and, across large number of patients may still be important)
- Management outside of steroids at discretion of treating physician, although according to the authors management followed EBM guidelines for sepsis
Discussion:
- This trial was different than many other trials trying to answer this question as they used a hydrocortisone infusion of 200mg/day instead of bolus dosing
- No corticotropin testing was performed due to the controversial nature of this tests results in critically ill patients
- Breakdown of 90 day mortality by region enrolled (Majority of enrollment came out of Australia ≈ 70%)
- Majority of infection sites were:
- Pulmonary: 33.8% Hydrocortisone group and 36.5% Placebo group
- Abdominal: 25.9% Hydrocortisone group and 25.2% Placebo group
- Some interesting points to consider (And I am not sure we have the answers to these questions):
- Is infusion better than bolus?
- Is the appropriate duration 7 days?
Author Conclusion: “Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo.”
Clinical Take Home Point: In patients with septic shock, admitted to the ICU on mechanical ventilation and requiring ≥4 hours of vasopressors/inotropes, hydrocortisone infusion (200mg/d) compared to placebo, does not make a difference in 90 day mortality, however there were some improved secondary outcomes including: shock reversal, ventilator free days, LOS in the ICU, and fewer blood transfusions required (the last one is hypothesis generating as stated by the authors).
References:
- Venkatesh B et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. NEJM 2018. [Epub Ahead of Print]
- 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
For More Thoughts on This Topic Checkout:
- Ryan Radecki at EM Literature of Note: The Definitive Word on Steroids in Septic Shock
- David Slessor at The Bottom Line: Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock
- Rory Spiegel at EMNerd(EMCrit): The Case of the Relative Insufficiency
- Dan Horner at St. Emlyn’s Blog: The End of the ‘Roid?’
- Josh Farkas at PulmCrit (EMCrit): Metabolic Sepsis Resuscitation – Strike Hard, Strike Fast, No Remorse
- Mike Winters at Resuscitation: Episode 89 – Steroids in Septic Shock? Do We Finally Have the Answer?
- Ken Milne at The SGEM: SGEM #208 – It Makes No Difference – Glucocorticoids for the Treatment of Septic Shock
- Rob Macsweeney at Critical Care Reviews (Fast Forward to 1:01):
Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami)
The post The ADRENAL Trial: Steroids in Septic Shock appeared first on REBEL EM - Emergency Medicine Blog.