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Physicians Should Administer Low-Dose Corticosteroids Selectively to Septic Patients until an Ongoing Trial Is Completed

John M. Luce, MD
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From University of California, San Francisco, San Francisco General Hospital.


Potential Financial Conflicts of Interest: None disclosed.

Current Author Address: John M. Luce, MD, Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, 1001 Potrero Avenue, Room 5 K1, San Francisco, CA 94110; e-mail, john.luce@sfdph.org.


Ann Intern Med. 2004;141(1):70-72. doi:10.7326/0003-4819-141-1-200407060-00019
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Most physicians prefer administering therapies that have a physiologic rationale and proven benefit. We urgently need beneficial therapies for sepsis severe enough to cause shock, which is responsible for approximately 400 000 intensive care unit admissions and 200 000 deaths each year in the United States (1). In this issue, a meta-analysis by Minneci and colleagues (2) from the National Institutes of Health (NIH) concludes that low but not high doses of corticosteroids reduce mortality from septic shock and that we should administer these agents to all patients who have vasopressor-dependent sepsis. How the investigators reached these conclusions and why I agree with the first but not the second of them are the subjects of this editorial.

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Should corticotropin stimulation testing guide steroid therapy in septic shock?
Posted on July 13, 2004
Peter C. Minneci
Critical Care Medicine Department, National Institutes of Health
Conflict of Interest: None Declared

Letter to the Editor

The accompanying editorial to our meta-analysis examining the clinical trials of low dose steroid therapy in sepsis raises concerns about our recommendation to administer low dose glucocorticoids to all patients with vasopressor-dependent septic shock. (1, 2) In Dr. Luce's commentary, he concludes that the results of the clinical sepsis trials of low dose steroids only support administering steroids to patients with "proven adrenal insufficiency". (1) As cited by Dr. Luce, a recent report by Hamrahian and colleagues demonstrated that in critically ill patients, variations in total serum cortisol measurements may be explained by differences in the concentration of serum binding proteins, and only free serum cortisol measurements accurately reflect adrenal function in these patients. (3) In light of these findings, the division of patients into subgroups based on the results of corticotropin stimulation testing using total serum cortisol measurements may be inappropriate. Furthermore, this data supports evaluating the overall effects of steroids in each of the clinical sepsis trials rather than focusing on subgroup analyses based on corticotropin stimulation tests using total serum cortisol measurements.

Each of the five low dose steroid trials analyzed in our meta- analysis demonstrates a beneficial effect of steroids on mortality and/or shock reversal. (2, 4-8) The marked consistency of the results of these five sepsis trials of low dose steroid therapy (I2 = 0), while unusual in sepsis research, provides substantial evidence of the effectiveness of this therapy. This is even more remarkable given that the studies were relatively small and performed in different medical centers. Moreover, even though one of the five studies was much larger than the rest, it was not excessively influential on the overall results. (4) In fact, when this larger study is removed from the analysis, there is still a significant beneficial effect of low dose steroids on survival (relative survival benefit = 1.36; 95% CI 1.04 "“ 1.79; p = 0.03). With regards to Dr. Luce's concerns, our meta-analysis reveals that steroids had consistent beneficial effects on both survival and shock reversal when patients were divided into either responders or nonresponders. In fact, the overall effects of steroids on these subgroups are indistinguishable in the three trials that reported this subdivision (Table 1). (4, 5, 8)

We believe that our meta-analysis reveals a consistent and overall statistically significant beneficial effect of steroids on survival and shock reversal regardless of corticotropin stimulation testing results; therefore, we recommended "that unless further clinical sepsis trials demonstrate that responders do not benefit from therapy, steroids should be considered for all patients with vasopressor-dependent septic shock". (2) As Dr. Luce discussed, there is an ongoing randomized controlled trial in which 800 patients will be randomized to receive low dose steroid therapy or placebo (CORTICUS). Given the results of our meta-analysis, and the insight provided by Hamrahian et al., we feel that an interim analysis should be performed by the CORTICUS data safety and monitoring board to evaluate whether the trial should: continue in its current form, be altered to evaluate only the subgroup of responders for which there is no conclusive data on outcome, accept a higher p-value for benefit if the results are consistent with the previous studies, or be discontinued. Such an interim analysis may prevent the inadvertent withholding of a beneficial therapy to critically ill patients in septic shock.

Table 1: Overall Effects of Low Dose Steroids Based on Corticotropin Stimulation Testing Results

Percent (event #/total n)

Non-Responders Responders

Outcome Control Steroid p-value Control Steroid p-value

Mortality 63 (83/132) 51 (63/123) 0.05 57 (32/56) 49 (34/69) 0.44

Shock reversal 39 (48/123) 53 (63/118) 0.03 44 (20/45) 56 (30/54) 0.26

References: 1. Luce JM. Physicians should administer low-dose corticosteroids selectively to septic patients until an ongoing trial is completed. Ann Intern Med. 2004;141(1):70-2. 2. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta- analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141(1):47-56. 3. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350(16):1629-38. 4. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. 5. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26(4):645-50. 6. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: a prospective, randomized, double- blind, single-center study. Crit Care Med. 1999;27(4):723-32. 7. Chawla K, Kupfer Y, Goldman I. Hydrocorticsone reverses refractory septic shock. Crit Care Med. 1999;27(1 (Suppl.)):A33. 8. Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care. 2002;6(3):251-9.

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