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