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Administer Low-Dose Steroids by a Standard Policy

Related Measures

Low-Dose Steroid Administration

Background

Intravenous corticosteroids (hydrocortisone 200 to 300 mg/day, for 7 days in three or four divided doses or by continuous infusion) are recommended in patients with septic shock who despite adequate fluid replacement require vasopressor therapy to maintain adequate blood pressure.

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 have failed to improve outcome, 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 evoked a corticosteroid renaissance, and a current discussion of which patients may profit from this approach.

In the context of corticosteroid therapy in severe sepsis or 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 to 300 mg of hydrocortisone or equivalent administered for 5 to 7 days or longer. (3–8)

Choice of Steroid

Hydrocortisone is preferred to other glucocorticoids in patients with septic shock.
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. [4–6,8,9,10]  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 methylprednisolone (or dexamethasone) does not.

Role of Corticotropin Stimulation Testing

The use of a 250-μg ACTH stimulation test to identify responders (> 9 μg/dL increase in cortisol 30 to 60 minutes post-ACTH administration) and to discontinue therapy in these patients is optional. Clinicians should not wait for ACTH stimulation results to administer corticosteroids.

The key point is, whether patients without RAI should be excluded from low-dose corticosteroid therapy.  First, as mentioned above, response to corticosteroids may be less effective or even not effective in some responders, but current data do not provide sufficient evidence that low doses of corticosteroids are indeed harmful in patients without RAI. Second, a consensus concerning reference values for baseline and stimulated cortisol concentrations is missing (see above).  Third, patients with adequate adrenocortical function may also respond to low-dose corticosteroids.

Mineralocorticoid Supplementation

The use of fludrocortisone in addition to low-dose steroids in patients with septic shock is considered optional.

One reasonable argument for supplementation is the improved survival observed in patients treated with low-dose hydrocortisone plus fludrocortisone (4), but a comparative study between hydrocortisone alone and hydrocortisone plus fludrocortisone has not been performed. As noted by the authors, fludrocortisone was supplemented to cover possible absolute primary adrenal insufficiency, which is rare (0 to 3 percent) in septic shock. (11)

Adrenal Insufficiency

Different mechanisms and reasons provide the rationale for the use of low-dose corticosteroids in patients with septic shock: relative adrenal insufficiency (RAI), peripheral steroid resistance, effects on the vascular tone and immune response, and prolongation of survival time. Absolute adrenal insufficiency is rare in critically ill patients (0 to 3 percent). (11)  RAI is considerably more common, especially in patients with septic shock.

In refractory septic shock, prevalence of RAI may be as high as 50 to 75 percent. (12)  An absolute incremental increase of < 9 μg/dL, 30 or 60 minutes after 250 μg of corticotropin stimulation, was found as the best cut-off value to discriminate between adequate adrenal response (responders) and RAI (nonresponders). (12–13)

In a large series of patients, basal cortisol of 34 μg/dL and incremental increase of 9 μg/dL after stimulation were best cut-off points to discriminate between survivors and nonsurvivors, and these were independent predictors of death. (12)  In general, the higher basal plasma cortisol and the weaker cortisol response to corticotropin, the higher was the risk of death.  Combining both cut points, a three-level prognostic classification was proposed in which mortality was best in patients (26 percent) with basal cortisol of < 34 μg/dL and > 9 μg/dL increase after stimulation and worst in patients (82 percent) with basal cortisol of > 34 μg/dL and < 9 μg/dL increase after stimulation.

Shock Reversal

Low-dose corticosteroids promote shock reversal.  Effects of corticosteroids on vascular tone have been recognized for decades, long before the discovery of glucocorticoids as anti-inflammatory drugs. (19)  Postulated mechanisms are numerous and cover signal transduction; prostaglandin metabolism; sodium and calcium transport; and modulation of adreno-, angiotensin-, endothelin-, and mineralocorticoid receptors; and inhibition of cyclooxegenase-2. (14,15)  In patients with septic shock, low-dose hydrocortisone significantly reduced nitrite/nitrate plasma concentrations, indicating inhibition of nitric oxide formation. (16)  Numerous randomized, controlled trials with low-dose corticosteroids in patients with septic shock con-firm shock reversal and reduction of vasopressor support within a few days after initiation of therapy in most patients. (3–7,9,16)  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). In a recent crossover study in septic shock patients, mean arterial pressure and systemic vascular resistance increased during low dose hydrocortisone treatment, and heart rate, cardiac index, and norepinephrine requirement decreased significantly. (16)

Immunologic and Anti-Inflammatory Effects

In septic shock, immune effects of corticosteroids may depend on preexisting conditions and, perhaps most importantly, on dosage and timing. Evidence of possible beneficial effects of corticosteroids in infection includes a decline of both, pro-inflammatory and anti-inflammatory markers of inflammation (interleukin-6, interleukin-8, interleukin-10, soluble tumor necrosis factor receptors), but an increase in other pro-inflammatory mediators (e.g., interleukin-12). (16)  In the same trial, low-dose hydrocortisone neither induced immunoparalysis nor affected innate immune responses such as respiratory burst and phagocyte function. Attenuation of a broad spectrum of the inflammatory response without causing immunosuppression might be a promising therapeutic approach that goes far beyond hemodynamic stabilization. 

Prolonged Survival

Low-dose corticosteroids improve survival in septic shock. In a recent French, multiple-center, randomized, controlled trial in 300 patients with severe volume and catecholamine refractory septic shock, the main prospectively defined outcome measure was 28-day survival in patients with RAI. (4)  Patients received either 50 mg of hydrocortisone every 6 hrs and 50 μg of fludrocortisone once daily or placebo over a total period of 7 days. Mortality distribution analysis revealed a significantly increased survival time of verum-treated patients in nonresponders (hazard ratio, 0.67; 95 percent CI, 0.47– 0.95; p = .02) and pooled patient data (hazard ratio, 0.71; 95 percent CI, 0.53– 0.97; p = .03) but not in responders.  This study demonstrated for the first time that low doses of hydrocortisone reduced risk of death in septic shock patients with RAI.  A recent critical statistical review stressed the point that the data gave only enough evidence to conclude that corticosteroids prolonged time until death in patients with septic shock, but there was no statistically significant effect on mortality. (17)

Decreased Mortality

Preliminary data from a Cochrane meta-analysis considering 15 randomized controlled trials of low- and high-dose corticosteroids in 2,022 patients with septic shock give further evidence. (18)  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 = .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 = .01), whereas high-dose trials did not (relative risk, 0.99; 95 percent CI, 0.83–1.17; p = .9) (Fig. 1). 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.

References

  1. Lefering R, Neugebauer EA. Steroid controversy in sepsis and septic shock: A meta-analysis. Crit Care Med. 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. Crit Care Med. 1995;23:1430–1439.
  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. JAMA. 2002;288:862–871.
  5. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med. 1998;26:645-650.
  6. Chawla K, Kupfer Y, Goldman I, et al. Hydrocortisone reverses refractory septic shock. Crit Care Med 1999;27(1S):33A.
  7. Yildiz O, Doganay M, Aygen B, et al. Physiological-dose steroid therapy in sepsis. Crit 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. Crit Care Med. 1999;27:723–732.
  9. 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. Intens Care Med. 2000;26:1747–1755.
  10. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet. 1991;337:582–583.
  11. Matot I, Sprung CL. Corticosteroids in septic shock: Resurrection of the last rites? Crit Care Med. 1998;26:627–629.
  12. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA. 2000;283:1038–1045.
  13. Moran JL, Chapman MJ, O’Fathartaigh MS, et al. Hypocortisolaemia and adrenocortical responsiveness at onset of septic shock. Intens Care Med. 1994;20:489–495.
  14. Walker BR, Williams BC. Corticosteroids and vascular tone: Mapping the messenger maze. Clin Sci. 1992;82:597–605.
  15. Ullian ME. The role of corticosteroids in the regulation of vascular tone. Cardio Res. 1999;41:55–64.
  16. 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. AJRCCM. 2003;167:512–520.
  17. Rubenfeld GD. When survival is not the same as mortality. Critical Care Alert. 2003;10:113–115.
  18. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating severe sepsis and septic shock. Cochrane Database Systematic Review. 2005;1:CD002243.
  19. Perla D, Marmorston J. Suprarenal cortical hormone and salt in the treatment of pneumonia and other severe infections. Endocrinology. 1940;27:367–374.

Content adapted extensively from

  • Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign Guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873.
  • Keh D, Sprung CL. Use of corticosteroid therapy in patients with sepsis and septic shock: An evidence-based review. Crit Care Med. 2004;32[Suppl.]:S527–S533.

Tips

  • Use the Interim Low-Dose Glucorticoid Policy until your institution is able to devise an appropriate policy.
  • Create a standardized ICU policy protocol that governs the use of low-dose steroids in septic shock. 
  • Use a sufficient dose of glucocorticoid for efficacy, for example, dexamethasone 4 mg IV every 8 hours, hydrocortisone 50 mg IV every 6 hours, methylprednisolone 15 mg IV every 8 hours.
  • Resist deferring the use of low-dose steroids for fear of worsening infection.
  • An ACTH stimulation test can be used to shorten recommended 5-7 days that the patient remains on low-dose steroids, but delay in treatment should not occur while awaiting the test.