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 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 200–300 mg of hydrocortisone or equivalent administered for 5–7 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 30–60 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 (0–3 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 (0–3 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 50–75 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:

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Content adapted extensively from:

• 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.
• 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.