The Case

A 70-year-old man with a history of hypertension and type 2 diabetes presents to the emergency department from home with fever, cough, and shortness of breath for two days. He is a nonsmoker and was immunized against influenza in the fall. Vitals at triage are temperature 102.7°F, blood pressure 105/61 mmHg, heart rate 118 bpm, respiratory rate 22 bpm, and oxygen saturation 89% on room air. The chest X-ray confirms pneumonia. The nurses have already established two intravenous (IV) lines of normal saline and provided supplemental oxygen via nasal cannula that corrects his hypoxia. He is also receiving appropriate antibiotics. His blood pressure begins to drop but responds to IV fluids. You wonder if IV hydrocortisone would provide any additional benefit.

Background

The Surviving Sepsis Campaign recently published its 2016 guidelines. It continues to give a weak recommendation for the use of intravenous hydrocortisone at a dose of 200 mg per day in patients with refractory septic shock (ie, inadequate response to fluid resuscitation and vasopressor therapy); this is based on low-quality evidence. As stated by the campaign:

We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day (weak recommendation, low quality of evidence).

Clinical Question

In adult patients with severe sepsis, does the use of IV hydrocortisone prevent the development of septic shock?

Reference

Keh D, Trips E, Marx G, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis: the HYPRESS randomized clinical trial. JAMA. 2016;316(17):1775-1785.

• Population: Adult patients in intermediate care units or intensive care units.
  • Inclusion: Evidence of infection, at least two SIRS criteria, and organ dysfunction present for not longer than 48 hours.
  • Exclusion: Septic shock, younger than 18 years of age, hypersensitivity to hydrocortisone or mannitol, history of regularly on glucocorticoids, pregnant, breastfeeding, moribund, or had a do-not-resuscitate order.
• Intervention: 50 mg IV bolus of hydrocortisone, followed by a continuous infusion of 200 mg/24 hours for five days followed by dose tapering until day 11.
• Comparison: Placebo (mannitol).

• Outcome:
  • Primary: Development of septic shock (defined as hypotensive despite adequate fluid resuscitation or needing vasopressors for more than four hours) within 14 days.
  • Secondary: Time until septic shock or death (whichever came first); mortality in the ICU and hospital; mortality at 28, 90, and 180 days; duration of stay in the ICU and hospital; Sequential Organ Failure Assessment score; duration of mechanical ventilation; renal replacement therapy; and frequency of delirium.
  • Adverse Events: Development of secondary infections, weaning failure, muscle weakness, gastrointestinal bleeding, and hyperglycemia.

Authors’ Conclusions

“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 findings do not support the use of hydrocortisone in these patients.”

Key Results

In the study, 380 adult patients were randomized to receive hydrocortisone (n = 190) or placebo (n = 190). The mean age was 65 years, with 65 percent being male.

There was no statistical difference in developing septic shock within 14 days in the placebo arm versus the hydrocortisone arm (difference, −1.8%; 95% CI; −10.7% to 7.2%; P = .70). There was no statistical differences in mortality at 28, 90, or 180 days. More delirium was noted in the placebo arm versus the hydrocortisone arm. There was no statistical difference in adverse events except more episodes of hyperglycemia in the hydrocortisone arm versus the placebo arm (see Table 1).

(click for larger image)
Table 1: Key Results of the HYPRESS Trial

EBM Commentary

1) Power: One issue with the study is its power to detect a difference. It was designed to detect an absolute difference of 15 percent between the hydrocortisone group and placebo group with a significance level of 0.05 (P value) and power of 0.8. It only found a 1.8 percent difference favoring hydrocortisone that was not statistically significant. Perhaps, a larger sample size would have confirmed this difference. It also assumed 40 percent of the patients in the placebo group would have septic shock, but the observed rate was only 23 percent. As prevalence goes down, the required sample size goes up. In the end, this resulted in an underpowered study.

2) Measurement Bias: Another issue is measurement bias. Progression from severe sepsis to septic shock is not a very precise measure and exists on a continuum. It is somewhat subjective despite being based on quantitative measures.

3) Clinical Versus Statistical Significance: One of the most important problems with this study is the issue of clinical versus statistical significance. Even if the study was properly sized to detect a smaller difference that was statistically significant, it may not be clinically significant. Progression from severe sepsis to septic shock is a disease-oriented outcome, not a patient-oriented outcome like mortality.

This underpowered study failed to detect a statistical difference in a surrogate marker between IV hydrocortisone and placebo in adult patients with severe sepsis.

Bottom Line

The use of IV hydrocortisone cannot be recommended at this time to treat adult patients with severe sepsis in order to prevent septic shock.

Case Resolution

You choose not to start IV hydrocortisone but continue with IV fluids, IV antibiotics, and supplemental oxygen.

Thank you to Dr. Salim Rezaie from REBEL EM for his help with this review. Dr. Rezaie is an emergency physician from San Antonio, Texas.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.