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

View larger version (41K): [in a new window]   Figure 1. Flow diagram of the published articles evaluated for inclusion in this meta-analysis.

View larger version (27K): [in a new window]   Figure 2. Effects of steroids on survival in previous and recent sepsis trials. The relative survival benefits are shown with fixed-effects model and 95% CIs with glucocorticoid therapy in the sepsis trials. Both the fixed-effects estimate (to compare across studies) and the random-effects estimate (to generalize to other samples) of relative survival benefit are presented (40). Meta-analysis of all 13 trials demonstrated variability (I2 = 70%) with no overall improvement in relative survival benefit (fixed-effects estimate, 1.01 [95% CI, 0.94 to 1.09]; random-effects estimate, 1.04 [CI, 0.90 to 1.20]). The effect of steroids in the trials published before 1989 compared with those published after 1997 significantly differed (P = 0.02). In the 4 trials published after 1997 (1 study did not report mortality data [33]), the effect of steroids on the relative survival benefit was consistently beneficial (I2 = 0%) (fixed-effects estimate, 1.23 [CI, 1.01 to 1.50]; random-effects estimate, 1.19 [CI, 0.99 to 1.43]). The effects of steroids on the relative survival benefit in the 9 sepsis trials published before 1989 varied (I2 = 75%; fixed-effects estimate, 0.97 [CI, 0.89 to 1.04]; random-effects estimate, 0.97 [CI, 0.81 to 1.16]). Excluding 1 trial (16), which was a statistically significant outlier, yields a homogeneous group of 8 trials (17-19, 35-39) with a consistent harmful effect of steroids on survival (I2 = 14%; fixed-effects estimate, 0.89 [CI, 0.82 to 0.97]; random-effects estimate, 0.90 [CI, 0.80 to 1.02]). This excluded trial (16) had methodologic differences, including being performed by 1 investigator over an 8-year period and enrolling patients both prospectively and retrospectively. VA = Veterans Administration.

View larger version (22K): [in a new window]   Figure 3. Effects of steroid dose on survival. The relationship between the dose of steroids administered in the first 24 hours after enrollment in a sepsis trial and relative survival benefit (black circles) is presented. There is a linear relationship (that is, the relative survival benefit decreases with high-dose steroids but increases with lower doses) (P = 0.02). One study (white circle) was overly influential in our regression analysis, was a statistical outlier (P = 0.001) compared with the other trials, and was therefore excluded (35). This study was performed a decade before all of the other trials, included children, and had a high percentage of patients with meningitis.

View larger version (17K): [in a new window]   Figure 4. Effects of steroids on shock reversal. The relative benefit (95% CI) and the hazard ratio (with 95% CI) of shock reversal for the sepsis trials published after 1997 are presented. Of note, in 3 of the 4 studies, the discontinuation of vasopressor therapy with steroid treatment statistically significantly improved. In the fourth trial, the effect of steroid therapy on vasopressor discontinuation was similar to the effect in the other trials (I2 = 0%; P > 0.2).