Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies.
OBJECTIVE
Low-dose steroids have shown contradictory results in trials and three recent meta-analyses. We aimed to assess the efficacy and safety of low-dose steroids for severe sepsis and septic shock by Bayesian methodology.


METHODS
Randomized trials from three published meta-analyses were reviewed and entered in both classic and Bayesian databases to estimate relative risk reduction (RRR) for 28-day mortality, and relative risk increase (RRI) for shock reversal and side effects.


RESULTS
In septic shock trials only (Marik meta-analysis; N = 965), the probability that low-dose steroids decrease mortality by more than 15% (i.e., RRR > 15%) was 0.41 (0.24 for RRR > 20% and 0.14 for RRR > 25%). For severe sepsis and septic shock trials combined, the results were as follows: (1) for the Annane meta-analysis (N = 1,228), the probabilities were 0.57 (RRR > 15%), 0.32 (RRR > 20%), and 0.13 (RRR > 25%); (2) for the Minneci meta-analysis (N = 1,171), the probability was 0.57 to achieve mortality RRR > 15%, 0.32 (RRR > 20%), and 0.14 (RRR > 25%). The removal of the Sprung trial from each analysis did not change the overall results. The probability of achieving shock reversal ranged from 65 to 92%. The probability of developing steroid-induced side effects was as follows: for gastrointestinal bleeding (N = 924), there was a 0.73 probability of steroids causing an RRI > 1%, 0.70 for RRI > 2%, and 0.67 for RRI > 5%; for superinfections (N = 964), probabilities were 0.81 (RRI > 1%), 0.76 (RRI > 2%), and 0.70 (RRI > 5%); and for hyperglycemia (N = 540), 0.99 (RRI > 1%), 0.97 (RRI > 2%), and 0.94 (RRI > 5%).


CONCLUSIONS
Based on clinically meaningful thresholds (RRR > 15-25%) for mortality reduction in severe sepsis or septic shock, the Bayesian approach to all three meta-analyses consistently showed that low-dose steroids were not associated with survival benefits. The probabilities of developing steroid-induced side effects (superinfections, bleeding, and hyperglycemia) were high for all analyses.
Department of Medicine, University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, 68198, USA. akalil@unmc.edu
Andre C
AC
Kalil
Junfeng
J
Sun
D001499:Bayes Theorem; D002986:Clinical Trials as Topic; D006801:Humans; D015201:Meta-Analysis as Topic; D016017:Odds Ratio; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic; D015203:Reproducibility of Results; D018570:Risk Assessment; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D013256:Steroids / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D014481:United States / Q000453:epidemiology
D013256:Steroids
Crit Care Med. 2006 Sep;34(9):2334-9
16850006
N Engl J Med. 2008 Jan 10;358(2):111-24
18184957
Lancet. 1991 Dec 21-28;338(8782-8783):1557-8
1720856
N Engl J Med. 2001 Mar 8;344(10):699-709
11236773
Crit Care Med. 2004 Jan;32(1):21-30
14707556
PLoS One. 2008 May 28;3(5):e2291
18509455
Am J Respir Crit Care Med. 2002 Nov 1;166(9):1197-205
12403688
Cardiovasc Res. 1994 Jan;28(1):34-9
7509259
Sao Paulo Med J. 2006 Mar 2;124(2):90-5
16878192
Am J Respir Crit Care Med. 2009 Nov 1;180(9):861-6
19696442
N Engl J Med. 2008 May 8;358(19):2068-9; author reply 2070-1
18467974
Ann Surg. 1976 Sep;184(3):333-41
786190
Crit Care Med. 1998 Apr;26(4):645-50
9559600
N Engl J Med. 1987 Sep 10;317(11):659-65
2888017
J Natl Cancer Inst. 1959 Apr;22(4):719-48
13655060
Crit Care Med. 2008 Jun;36(6):1937-49
18496365
Control Clin Trials. 1986 Sep;7(3):177-88
3802833
Crit Care Med. 2005 Nov;33(11):2457-64
16276166
Intensive Care Med. 2010 Feb;36(2):222-31
20069275
Crit Care Med. 1993 Sep;21(9):1287-95
8370291
Crit Care Med. 2009 Jan;37(1):385-6; author reply 386-7
19112330
JAMA. 2009 Oct 21;302(15):1643-4; author reply 1644-5
19843894
Health Technol Assess. 2000;4(38):1-130
11134920
Crit Care Med. 2008 Jun;36(6):1987-9
18520670
Clin Microbiol Infect. 2009 Apr;15(4):308-18
19416302
Crit Care Med. 2009 Feb;37(2):463-70
19114915
Intensive Care Med. 2008 Oct;34(10):1804-11
18504550
Crit Care Med. 1999 Apr;27(4):723-32
10321661
Crit Care Med. 2004 Jan;32(1):1-12
14707554
ACP J Club. 2008 Jun 17;148(4):6
18588257
Clin Chem Lab Med. 2005;43(3):259-68
15843228
Am J Respir Crit Care Med. 1999 Aug;160(2):458-65
10430714
JAMA. 2002 Aug 21;288(7):862-71
12186604
N Engl J Med. 2008 May 8;358(19):2068; author reply 2070-1
18463386
Chest. 2007 Apr;131(4):954-63
17426195
Intensive Care Med. 2008 Mar;34(3):568-77
17992512
N Engl J Med. 2008 May 8;358(19):2069; author reply 2070-1
18467975
JAMA. 2009 Jun 10;301(22):2362-75
19509383
Crit Care Med. 2008 Aug;36(8):2489-90; author reply 2490
18664828
Am J Respir Crit Care Med. 2005 Feb 1;171(3):242-8
15557131
N Engl J Med. 1984 Nov 1;311(18):1137-43
6384785
Crit Care. 2002 Jun;6(3):251-9
12133187
Crit Care Med. 1995 Aug;23(8):1430-9
7634816