Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose

BACKGROUND: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied. PURPOSE: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials. DATA SOURCES: Systematic MEDLINE search for studies published between 1988 and 2003. STUDY SELECTION: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements. DATA EXTRACTION: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes. DATA SYNTHESIS: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, 95% CI, 1.01 to 1.50; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 CI, 1.29 to 2.26; P < 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 CI, 0.82 to 0.97; P = 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; P = 0.02), for longer courses (6 days vs. 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; P = 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02). LIMITATIONS: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results. CONCLUSIONS: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.