Corresponding Bundle Item:

Low-dose steroids administered for septic shock in accordance with a standardized ICU policy.

Related Measures

Low-Dose Steroid Administration

Background:

Intravenous corticosteroids (hydrocortisone 200–300 mg/day, for 7 days in three or four divided doses or by continuous infusion) are suggested for adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy. We believe hospitals should strive to develop a standardized policy in their ICU for the administration of steroids in accordance with the available evidence for use.

For decades, the rationale for the use of glucocorticoids in sepsis trials has been the fundamental role that they play in the stress response to infection and the anti-inflammatory effects that they exert.  Randomized, controlled, high-dose glucocorticoid trials failed to improve outcomes, leading to skepticism and the avoidance of using any glucocorticoids in septic patients by most intensive care unit physicians. However, recent randomized, controlled trials with low doses of hydrocortisone in septic shock have evoked a renewed interest.

In the context of corticosteroid therapy for septic shock, high doses of glucocorticoids mainly refer to 30 mg/kg methylprednisolone or equivalent steroid preparations administered up to four times during a short course of 1 or 2 days. [1,2]  Recent low-dose glucocorticoid trials refer to a daily dose of 200–300 mg of hydrocortisone or equivalent administered for 5 to 7 days or longer. [3–8]

Possible Decreased Mortality:

Preliminary data from a 2005 Cochrane meta-analysis considering 15 randomized controlled trials of low- and high-dose corticosteroids in 2,022 patients with septic shock summarizes available evidence on the use of steroids in septic shock. [9] Pooled 28-day all-cause mortality did not differ between placebo and verum (relative risk, 0.98; 95 percent CI, 0.87–1.10; p=0.7). Subgroup analysis of five trials [3–7] with low-dose corticosteroids reduced 28-day all-cause mortality significantly (relative risk, 0.8; 95 percent CI, 0.67– 0.95; p=0.01), whereas high-dose trials did not (relative risk, 0.99; 95 percent CI, 0.83–1.17; p=0.9). The number needed to treat with low-dose corticosteroids to save one additional life was nine (95 percent CI, 5–33). In addition, low-dose corticosteroids significantly reduced intensive care unit and hospital all-cause mortality and significantly increased the number of patients with shock reversal on day 7 and day 28. 

These data stand in contrast to results from a large European trial, CORTICUS, which failed to show a mortality benefit from administration of low-dose steroids in septic shock. [12] In this multicenter, randomized, double-blind, placebo-controlled trial, 251 patients were assigned to receive 50 mg of intravenous hydrocortisone and 248 patients to receive placebo every 6 hours for 5 days; the dose was then tapered during a 6-day period. At 28 days, the primary outcome was death among patients who did not have a response to a corticotropin test. Of the 499 patients in the study, 233 (46.7 percent) did not have a response to corticotropin (125 in the hydrocortisone group and 108 in the placebo group). At 28 days, there was no significant difference in mortality between patients in the two study groups who did not have a response to corticotropin (39.2 percent in the hydrocortisone group and 36.1 percent in the placebo group, p=0.69) or between those who had a response to corticotropin (28.8 percent in the hydrocortisone group and 28.7 percent in the placebo group, p=1.00). At 28 days, 86 of 251 patients in the hydrocortisone group (34.3 percent) and 78 of 248 patients in the placebo group (31.5 percent) had died (p=0.51). Possible interpretations and concerns about CORTICUS are detailed below.

Earlier Shock Reversal:

Low-dose corticosteroids promote more rapid shock reversal than when they are not administered to patients with septic shock. Numerous randomized, controlled trials with low-dose corticosteroids in patients with septic shock confirm shock reversal and reduction of vasopressor support within a few days after initiation of therapy in most patients. [3–7] The median time to cessation of vasopressors decreased in one study from 13 to 4 days [5] and, in the other study, from 7 to 3 days. [8] CORTICUS, although finding no overall decreased mortality from low-dose steroid administration, confirmed the finding of more rapid shock reversal. [12]

Choice of Steroid:

Hydrocortisone is preferred to other glucocorticoids in patients with septic shock in most clinical trials.

Although a comparative study of different corticosteroids has not been performed in patients with septic shock, there are several reasons why hydrocortisone is preferred. First, most of the experience with low-dose corticosteroid treatment in septic shock has been with the use of hydrocortisone. [4–6,8,10,11] Second, hydrocortisone is the synthetic equivalent to the physiologic final active cortisol. Therefore, treatment with hydrocortisone directly replaces cortisol, independent of metabolic transformation. Third, hydrocortisone has intrinsic mineralocorticoid activity, whereas dexamethasone does not.

No Role for Corticotropin Stimulation Testing:

The use of a 250-μg ACTH stimulation test to identify responders (> 9 μg/dL increase in cortisol 30–60 minutes post-ACTH administration) and to discontinue therapy in these patients is no longer recommended. Clinicians should not wait for results of ACTH stimulation to administer corticosteroids. See Grading the Evidence below for a more detailed explanation and rationale. 

Grading the Evidence: [See Ranking the Evidence]

The Grade 2 suggestions below are weaker recommendations for care based on a number of qualitative considerations. “B” level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert opinion.

• The 2008 Surviving Sepsis Campaign Guidelines suggest intravenous hydrocortisone be given only to adult septic shock patients after blood pressure is identified to be poorly responsive to fluid resuscitation and vasopressor therapy (Evidence Grade 2C).

Rationale: One French multi-center, randomized, controlled trial (RCT) of patients in vasopressor-unresponsive septic shock (hypotension despite fluid resuscitation and vasopressors) showed a significant shock reversal and reduction of mortality rate in patients with relative adrenal insufficiency (defined as post-adrenocorticotropic hormone [ACTH] cortisol increase 9 µg/dL or less). [4] Two additional smaller RCTs also showed significant effects on shock reversal with steroid therapy. [3,5] However, a large European multicenter trial (CORTICUS) failed to show a mortality benefit with steroid therapy of septic shock. [11] CORTICUS did show a faster resolution of septic shock in patients who received steroids. The use of the ACTH test (responders and nonresponders) did not predict the faster resolution of shock. Importantly, unlike the French trial, which only enrolled shock patients with blood pressure unresponsive to vasopressor therapy, the CORTICUS study included patients with septic shock, regardless of how the blood pressure responded to vasopressors. Although corticosteroids do appear to promote shock reversal, the lack of a clear improvement in mortality ― coupled with known side effects of steroids such as increased risk of infection and myopathy ― generally tempered enthusiasm for their broad use. Thus, there was broad agreement that the recommendation should be downgraded from the previous 2004 Surviving Sepsis Campaign Guidelines (Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Guidelines for management of severe sepsis and septic shock. Critical Care Medicine. 2004;32:858-873.). 

• The Surviving Sepsis Campaign suggests the ACTH stimulation test not be used to identify the subset of adults with septic shock who should receive hydrocortisone (Grade 2B).

Rationale: Although one study suggested those who did not respond to ACTH with a brisk surge in cortisol (failure to achieve or > 9 µg/dL increase in cortisol 30-60 minutes post-ACTH administration) were more likely to benefit from steroids than those who did respond, the overall trial population appeared to benefit regardless of ACTH result, and the observation of a potential interaction between steroid use and ACTH test was not statistically significant. [4] Furthermore, there was no evidence of this distinction between responders and nonresponders in a more recent multicenter trial. [12] Commonly used cortisol immunoassays measure total cortisol (protein-bound and free) while free cortisol is the pertinent measurement. The relationship between free and total cortisol varies with serum protein concentration. When compared to a reference method (mass spectrometry), cortisol immunoassays may over- or underestimate the actual cortisol level, affecting the assignment of patients to responders or nonresponders. [13] Although the clinical significance is not clear, it is now recognized that etomidate, when used for induction for intubation, will suppress the HPA axis. [14] 

• The Surviving Sepsis Campaign suggests that patients with septic shock should not receive dexamethasone if hydrocortisone is available (Grade 2B).

Rationale: Although often proposed for use until an ACTH stimulation test can be administered, we no longer suggest an ACTH test in this clinical situation. Furthermore, dexamethasone can lead to immediate and prolonged suppression of the HPA axis after administration. [15]

• The Surviving Sepsis Campaign suggests the daily addition of oral fludrocortisone (50 µg) if hydrocortisone is not available and the steroid that is substituted has no significant mineralocorticoid activity. Fludrocortisone is considered optional if hydrocortisone is used (Grade 2C).

Rationale: One study added 50 μg of fludrocortisone orally. [4] Since hydrocortisone has intrinsic mineralcorticoid activity, there is controversy as to whether fludrocortisone should be added.

• The Surviving Sepsis Campaign suggests clinicians wean the patient from steroid therapy when vasopressors are no longer required (Grade 2D).

Rationale: There has been no comparative study between a fixed duration and clinically guided regimen, or between tapering and abrupt cessation of steroids. Three RCTs used a fixed duration protocol for treatment [3,5,12], and in two RCTs [3,16] therapy was decreased after shock resolution. In four RCTs steroids were tapered over several days [3,5,12,16], and in two RCTs [4,7] steroids were withdrawn abruptly. One cross-over study showed hemodynamic and immunologic rebound effects after abrupt cessation of corticosteroids. [16] It remains uncertain whether outcome is affected by tapering of steroids or not.

The Grade 1 recommendations below are based on strong evidence for care based on a number of qualitative considerations. “B” level evidence generally derives from randomized control trials with certain limitations or very well-done observational or cohort studies. “C” level evidence reflects well-done observational or cohort studies with controls. “D” level evidence generally reflects case series data or expert opinion.

• The 2008 Surviving Sepsis Campaign Guidelines suggest doses of corticosteroids comparable to >300 mg hydrocortisone daily not be used in severe sepsis or septic shock for the purpose of treating septic shock (Grade 1A).

Rationale: Two randomized prospective clinical trials and a meta-analyses concluded that for therapy of severe sepsis or septic shock, high-dose corticosteroid therapy is ineffective or harmful. [2,18,19] Reasons to maintain higher doses of corticosteroid for medical conditions other than septic shock may exist.

• The Surviving Sepsis Campaign recommends that corticosteroids not be administered for the treatment of sepsis in the absence of shock. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress does steroids if the patient’s endocrine or corticosteroid administration history warrants (Grade 1D).

Rationale: No studies exist that specifically target severe sepsis in the absence of shock that offer support for use of stress doses of steroids in this patient population.  Steroids may be indicated in the presence of a prior history of steroid therapy or adrenal dysfunction. A recent preliminary study of stress dose level steroids in community-acquired pneumonia is encouraging but needs confirmation. [20]

References:

1. Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: A meta-analysis. Critical Care Medicine. 1995;23:1294–1303.
2. Cronin L, Cook DJ, Carlet J, et al. Corticosteroid treatment for sepsis: A critical appraisal and meta-analysis of the literature. Critical Care Medicine. 1995;23:1430–1439.DIV>
3. Briegel J, Kellermann W, Forst H, et al. Low-dose hydrocortisone infusion attenuates the systemic inflammatory response syndrome: The Phospholipase A2 Study Group. The Clinical Investigator. 1994;72:782–787.
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. Journal of the American Medical Association. 2002;288:862–871.
5. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Critical Care Medicine. 1998;26:645-650.
6. Chawla K, Kupfer Y, Goldman I, et al. Hydrocortisone reverses refractory septic shock. Critical Care Medicine. 1999;27(1S):33A.
7. Yildiz O, Doganay M, Aygen B, et al. Physiological-dose steroid therapy in sepsis. Critical Care. 2002;6:251–259.
8. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single-center study. Critical Care Medicine. 1999;27:723–732.
9. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Systematic Review. 2005;1:CD002243.
10. Oppert M, Reinicke A, Gräf KJ, et al. Plasma cortisol levels before and during “low-dose” hydrocortisone therapy and their relationship to hemodynamic improvement in patients with septic shock. Intensive Care Medicine. 2000;26:1747–1755.
11. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet. 1991;337:582–583.
12. Sprung CL, Annane D, Keh D, et al. CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. New England Journal of Medicine. 2008 Jan 10;358(2):111-124.
13. Briegel J, Vogeser M, Annane D, Keh D, Moreno R, Singer M, Weiss Y, Sprung CL. Measurement of cortisol in septic shock: Interlaboratory harmonization. American Journal of Respiratory and Critical Care Medicine. 2007;175:A436.
14. Allolio B, Dorr H, Stuttmann R, et al. Effect of a single bolus of etomidate upon eight major corticosteroid hormone and plasma ACTH. Clinical Ednocrinology. 1985;22:281-286.
15. Reincke M, Allolio B, Würth G, Winkelmann W. The hypothalamic-pituitary-adrenal axis in critical illness: Response to dexamethasone and corticotropin-releasing hormone. Journal of Clinical Endocrinology and Metabolism. 1993;77:151-156.
16. Oppert M, Schindler R, Husung C, et al. Low dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Critical Care Medicine. 2005;33:2457-2464.
17. Keh D, Boehnke T, Weber-Carstens S, et al. Immunologic and hemodynamic effects of “low-dose” hydrocortisone in septic shock: A double-blind, randomized, placebo-controlled, crossover study. American Journal of Respiratory and Critical Care Medicine. 2003;167:512–520.
18. Bone RC, Fisher CJ, Clemmer TP. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. New England Journal of Medicine. 1987;317:653-658.
19. The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect on high-dose glucocorticoid therapy on mortality in patients with clinical signs of sepsis. New England Journal of Medicine. 1987;317:659-665.
20. Confalonieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia. A preliminary randomized study. American Journal of Respiratory and Critical Care Medicine. 2005;171:242-248.

 

Content adapted extensively from:

• Dellinger, RP, Levy, MM, Carlet, JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Critical Care Medicine. 2008;36(1):296-327.
• Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review. Critical Care Medicine. 2004;32[Suppl.]:S527–S533.