Original Article Hydrocortisone Therapy for Patients with Septic
Shock
Charles L. Sprung, M.D., Djillali Annane, M.D., Ph.D., Didier Keh, M.D., Rui Moreno, M.D., Ph.D., Mervyn Singer, M.D., F.R.C.P., Klaus Freivogel, Ph.D., Yoram G.
Weiss, M.D., Julie Benbenishty, R.N., Armin Kalenka, M.D., Helmuth Forst, M.D., Ph.D., Pierre-Francois Laterre, M.D., Konrad Reinhart, M.D., Brian H. Cuthbertson,
M.D., Didier Payen, M.D., Ph.D., Josef Briegel, M.D., Ph.D., for the CORTICUS Study Group
N Engl J MedVolume 358(2):111-124
January 10, 2008
In the beginning……
Cortisol response to corticotropin and survival in septic shock.
Lancet, 1991
Rothwell PM, Udwadia ZF, Lawler PG.
Intensive Therapy Unit, South Cleveland Hospital, Middlesbrough, UK.
Corticotropin stimulation tests were used to assess adrenocortical function in 32 patients with septic shock. 13 patients had a poor cortisol response (rise less
than 250 nmol/l) to corticotropin, all of whom died. However, there were only 6 deaths among the 19 patients with adequate responses (p less than 0.001). These results suggest that some patients with septic shock may have relative
adrenocortical insufficiency.
A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock
RC Bone, CJ Fisher, TP Clemmer, GJ Slotman, CA Metz, and RA Balk
N Engl J MedVolume 317:653-658September 10, 1987
Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. The Veterans Administration Systemic Sepsis Cooperative Study Group
Annane et al , JAMA 2000
• STIM +
• Basal <34 mg/dL
• Stim > 9mg/dL
• Mortality 74%
• STIM –
• Basal >34 mg/dL
• Stim <9mg/dL
• Mortality 18%
Study, year Study design InterventionOutcome measured
Results Comments
Annane, 2002
RCT(300 pts, all ventilated)
hydrocortisone (50 mg q 6 hrs) &fludrocortisone (50 mcg qd)
mortality
Overall: steroid group 55% placebo 61% (P =.09) Adrenal normal: steroid group 61% placebo 53% (P =.02)Adrenal insufficient: steroid group 53% placebo 63% (P =.02)
First study with sufficient power.
Cotreated with fludrocortisone.
76% with adrenal insuff (<9mcg cortisol increase after corticotropin test).
Bollaert, 1998
RCT(41 patients requiring pressors >48 hrs)
hydrocortisone 100 mg tid x5d
mortality
steroids: 32% placebo: 63% (insig)Adrenal normal (n=29): steroids 33% placebo 64%Adrenal insufficient (n=12): steroids 25% placebo 63%
Introduced role of corticotropin testing - which did not predict response to steroids.
29% were adrenal insufficient (<6mcg cortisol increase after corticotropin test)
Cronin, 1995
Systematic review of RCTs(730 patients with septic shock in 6 studies)
varying regimens mortality RR=1.07 (95% CI 0.91, 1.26) Much heterogeneity
Study Overview
• The benefit of adjuvant use of corticosteroids in patients with septic shock remains controversial
• In this international, multicenter, double-blind, placebo-controlled trial, adjunctive therapy with hydrocortisone in nearly 500 patients with septic shock was not found to be clinically helpful
• This lack of benefit was also found in a subgroup of patients who did not have a response to a corticotropin test
Enrollment and Outcomes
Sprung CL et al. N Engl J Med 2008;358:111-124
Demographic Characteristics of the Patients, According to Subgroup
Sprung CL et al. N Engl J Med 2008;358:111-124
Clinical Characteristics of the Patients at Baseline, According to Subgroup
Sprung CL et al. N Engl J Med 2008;358:111-124
Kaplan-Meier Curves for Survival at 28 Days
Sprung CL et al. N Engl J Med 2008;358:111-124
Outcomes According to Subgroup
Sprung CL et al. N Engl J Med 2008;358:111-124
Kaplan-Meier Curves for the Time to Reversal of Shock
Sprung CL et al. N Engl J Med 2008;358:111-124
Adverse Events (Per-Protocol Population)
Sprung CL et al. N Engl J Med 2008;358:111-124
Annane et al JAMA, 2002
• Use of Fludrocortisone
• Overall Mortality
• Stim results
• Etomidate
• Tapering steroids
Conclusion
• Hydrocortisone did not improve survival or reversal of shock in patients with septic shock, either overall or in patients who did not have a response to corticotropin, although hydrocortisone hastened reversal of shock in patients in whom shock was reversed