The HYPRESS Trial: Early Steroids to Prevent Septic Shock

Background: The most recent surviving sepsis campaign recommends the use of hydrocortisone in patients with refractory septic shock (i.e. vasopressor dependent). However, the use of hydrocortisone in severe sepsis without shock still remains a very controversial topic. Recommendations for hydrocortisone are mostly based on 2 randomized clinical trials (i.e. Annane et al [2] and CORTICUS [3]), but subsequent meta-analyses had more mixed results. Shock reversal was consistently improved irrespective of disease severity; however, mortality outcomes were not as consistent. Therefore, it has been hypothesized that early hydrocortisone administration could prevent shock by attenuating patient’s inflammatory response.

What Article are we Reviewing:

Keh D et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA 2016. [Epub ahead of print] PMID: 27695824

What They Did:

Determine if use of hydrocortisone in patients with severe sepsis prevents development of septic shock

Double-blind, randomized clinical trial

Study performed in 34 intermediate and intensive care units in Germany

Included 380 patients with severe sepsis not in septic shock

Patients randomized to continuous infusion of hydrocortisone 200mg for 5 days followed by a tapering dose until day 11 vs placebo

Main exclusion criteria was septic shock

Patients not excluded for use of etomidate within 72 hours before enrollment

Study Medications:

Medications administered as IV bolus of 50mg, followed by a 24hr continuous infusion of 200mg for 5days, 100mg on days 6 and 7, 50mg on days 8 and 9, and 25mg on days 10 and 11

Outcomes:

Primary: Development of septic shock within 14 days

Development of septic shock within 14 days Secondary: Time until septic shock Mortality in the ICU or hospital Survival up to 180 days Development of secondary infections Weaning failure Muscle weakness Hyperglycemia (Blood glucose >150 mg/dL)



Results:

Intention to Treat Analysis

Strengths:

This is a multicenter study

Blinding of Medications: Medication delivered in boxes, containing 17 brown glass vials containing 100mg of lyophilized hydrocortisone or same amount of lyophilized mannitol as placebo

Treatment arms were comparable regarding age, type of admission to the ICU, severity of disease or organ dysfunction, use of etomidate within 72hors before randomization, initial treatment, and vital signs within 6 hrs after diagnosis of severe sepsis

Limitations:

The rate of septic shock in the placebo group of 23% (95% CI 17 – 30%) was lower than the originally presumed sample size calculation of 40%. This study assumed 40% of patients in the placebo group would have septic shock, which the study did not meet.

Patients who developed septic shock early may have been missed due to the time taken to get informed consent. This means some patients may have not been enrolled due to the exclusion criteria of septic shock

Patients with data from corticotropin levels was only 206 patients, making sample size and event rates very small

Delirium data should be viewed with caution due to exclusion of patients with incomplete data sets, only 1 daily assessment in most patients, and interrater reliability not being assessed

Discussion:

Use of hydrocortisone was more associated with development of hyperglycemia, while there was no benefit in mortality

Author Conclusion: “Among adults with severe sepsis not in septic shock, use of hydrocortisone compared with placebo did not reduce the risk of septic shock within 14 days. These finding do not support the use of hydrocortisone in these patients.”

Clinical Take Home Point: The use of hydrocortisone in adults with severe sepsis not in septic shock, did not reduce the risk of septic shock within 14 days, but the results of this study should be interpreted with caution as this study was underpowered to detect this outcome (i.e. An inconclusive study)

References:

Keh D et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized clinical Trial. JAMA 2016. [Epub ahead of print] PMID: 27695824 Annane D et al. Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock. JAMA 2002; 288 (7): 862 – 871. PMID: 12186604 Sprung CL et al CORTICUS Study Group. Hydrocortisone Therapy for Patients with Septic Shock. NEJM 2008. 358 (2); 111 – 124. PMID: 18184957

For More Thoughts on This Topic Checkout:

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami)