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

  1. Peter C. Minneci, MD;
  2. Katherine J. Deans, MD;
  3. Steven M. Banks, PhD;
  4. Peter Q. Eichacker, MD; and
  5. Charles Natanson, MD
  1. From the Clinical Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and Massachusetts General Hospital, Boston, Massachusetts.
    1. Figure 1.
      View larger version:
      Figure 1. Flow diagram of the published articles evaluated for inclusion in this meta-analysis.
    2. Figure 2. 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 . Meta-analysis of all 13 trials demonstrated variability (I = 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 (  = 0.02). In the 4 trials published after 1997 (1 study did not report mortality data ), the effect of steroids on the relative survival benefit was consistently beneficial (I = 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 (I = 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 , which was a statistically significant outlier, yields a homogeneous group of 8 trials with a consistent harmful effect of steroids on survival (I = 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 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:
      Figure 2. 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 . Meta-analysis of all 13 trials demonstrated variability (I = 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 (  = 0.02). In the 4 trials published after 1997 (1 study did not report mortality data ), the effect of steroids on the relative survival benefit was consistently beneficial (I = 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 (I = 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 , which was a statistically significant outlier, yields a homogeneous group of 8 trials with a consistent harmful effect of steroids on survival (I = 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 had methodologic differences, including being performed by 1 investigator over an 8-year period and enrolling patients both prospectively and retrospectively. VA = Veterans Administration. Effects of steroids on survival in previous and recent sepsis trials.(40)2P[33]22(16)(17-19, 35-39)2(16)
    3. Figure 3. The relationship between the dose of steroids administered in the first 24 hours after enrollment in a sepsis trial and relative survival benefit ( ) is presented. There is a linear relationship (that is, the relative survival benefit decreases with high-dose steroids but increases with lower doses) (  = 0.02). One study ( ) was overly influential in our regression analysis, was a statistical outlier (  = 0.001) compared with the other trials, and was therefore excluded . 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:
      Figure 3. The relationship between the dose of steroids administered in the first 24 hours after enrollment in a sepsis trial and relative survival benefit ( ) is presented. There is a linear relationship (that is, the relative survival benefit decreases with high-dose steroids but increases with lower doses) (  = 0.02). One study ( ) was overly influential in our regression analysis, was a statistical outlier (  = 0.001) compared with the other trials, and was therefore excluded . This study was performed a decade before all of the other trials, included children, and had a high percentage of patients with meningitis. Effects of steroid dose on survival.black circlesPwhite circleP(35)
    4. Figure 4. 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 (I = 0%;  > 0.2).
      View larger version:
      Figure 4. 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 (I = 0%;  > 0.2). Effects of steroids on shock reversal.2P

    Responses to this article

    • Corticosteroids in sepsis: should therapy be based on response to ACTH testing?
      • Katherine J Deans and
      • Charles Natanson and Peter C. Minneci
      Ann Intern Med published online October 26, 2009
    • Controversy due to heterogeneous mortality results among patients with normal adrenal responsiveness
      • Robert G Badgett
      Ann Intern Med published online October 26, 2009
    • Corticosteroids for septic shock: - a question of interpretation.
      • David W Noble
      Ann Intern Med published online October 26, 2009
    • Low dose steroids stabilizes patient in sepsis.
      • Enrique J. Sánchez-Delgado, and
      • Marvin Mayorga, Erwin Plata, Josè A. Montiel, Daniel Meneses
      Ann Intern Med published online October 26, 2009

    Summary for Patients

    • Summaries for Patients:Low Doses of Steroids Improve Survival in Patients with Septic Shock Ann Intern Med July 6, 2004 141:I-64
    « Previous | Next Article »Table of Contents

    This Article

    1. Ann Intern Med July 6, 2004 vol. 141 no. 1 47-56
    1. AbstractFREE
    2. » Figures
    3. Full Text
    4. Full Text (PDF)
      1. Summary for Patients

    Current Issue

    1. November 17, 2009, 151 (10)
    1. Alert me to current issues