Shock Syndromes I

iv.

The Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial

randomized 1241 patients to hydrocortisone and fludrocortisone or placebo within 24 hours of

shock onset. Patients were also randomized to drotrecogin alfa (activated) in a 2 x 2 factorial

design, but after the drug was withdrawn from the market, the study was continued with only the

corticosteroid randomization. Patients in the hydrocortisone and fludrocortisone group had lower

90-day mortality than those receiving placebo (43.0% vs. 49.1%; RR 0.88; 95% CI, 0.78–0.99;

p=0.03). In addition, patients randomized to the corticosteroid arm had increased vasopressor-

free days (16 vs. 11 days; p<0.001) and organ failure–free days (14 vs. 13 days; p=0.003).

These studies differed in the patient populations evaluated, with patients more severely ill

demonstrating a mortality benefit from corticosteroids. When this question was specifically

evaluated in the ADRENAL trial, there was no heterogeneity of effect by subgroup, suggesting

severity of illness did not influence the outcome.

vi.

Other notable differences between studies that may account for the disparate results are the

drug regimens used and the timing of therapy initiation.

Two meta-analyses that included these four studies found that corticosteroids had no mortality

benefit (RR 0.96; 95% CI, 0.91–1.02 in one meta-analysis and RR 0.93; 95% CI 0.84–1.03 in another

meta-analysis).

In meta-analyses, corticosteroid administration has consistently been associated with improvements

in shock reversal and a higher incidence of adverse effects (particularly hypernatremia and

hyperglycemia).

A recent evaluation using the Premier Healthcare Database evaluated the addition of fludrocortisone

to hydrocortisone compared with hydrocortisone alone in patients with septic shock and found

lower rates of the primary composite outcome of in-hospital death or discharge to hospice (47.2%

vs. 50.8%; adjusted risk difference: –3.7% 95% confidence –4.2% to –3.1%) in the group of

patients who received fludrocortisone. Additional data are needed to confirm the findings from

this retrospective evaluation and definitively determine if the addition of fludrocortisone to the

standard regimen of hydrocortisone is necessary.

Medicine suggest using corticosteroids in patients with septic shock. These guidelines further state

that if hydrocortisone is indicated, a dose of less than 400 mg/day for 3 days or more at full dose

is suggested.

The SSC guidelines suggest using hydrocortisone in patients with septic shock and an ongoing

requirement for vasopressor therapy at a dose of 200 mg/day given as either 50 mg intravenously

every 6 hours or a continuous infusion. The guidelines note the suggestion that hydrocortisone be

initiated when norepinephrine or epinephrine doses exceed 0.25 mcg/kg/minute at least 4 hours

after initiation.

Although two of the randomized controlled trials mentioned earlier used fludrocortisone,

the SSC guidelines recommend hydrocortisone alone. This is likely because of the COIITSS

study, a 2 x 2 factorial trial that compared hydrocortisone in combination with fludrocortisone

with hydrocortisone alone. No difference in the primary outcome of in-hospital death (42.9%

hydrocortisone and fludrocortisone vs. 45.8% hydrocortisone alone) or other clinical outcomes was

detected between treatment arms.

the ACTH test should not be used to identify patients for corticosteroid administration.