Corticosteroids for treating severe sepsis and septic shock

(Review)

Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2010, Issue 12
http://www.thecochranelibrary.com

Corticosteroids for treating severe sepsis and septic shock (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Corticosteroids for treating severe sepsis and septic shock (Review) i

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Corticosteroids for treating severe sepsis and septic shock

Djillali Annane1 , Eric Bellissant2 , Pierre Edouard Bollaert3 , Josef Briegel4 , Didier Keh5, Yizhak Kupfer6
1 Critical Care Department, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris, Garches, France. 2 Centre
d’Investigation Clinique INSERM 0203, Hôpital Pontchaillou, Rennes, France. 3 Intensive Care Unit, Hôpital Central, Nancy, France.
4 Klinik für Anaesthesiologie, Klinikum der Universitaet, Munich, Germany. 5 University Clinic of Anesthesiology and Intensive Care

Medicine CCM/CVK, Charité-Campus Virchow Clinic, Charité Universitätsmedizin Berlin, Berlin, Germany. 6 Division of Pulmonary
and Critical Care Medicine, Maimonides Medical Center, New York, USA

Contact address: Djillali Annane, Critical Care Department, Hôpital Raymond Poincaré, Assistance Publique - Hôpitaux de Paris,
104. Boulevard Raymond Poincaré, Garches, Ile de France, 92380, France. djillali.annane@rpc.ap-hop-paris.fr.

Editorial group: Cochrane Anaesthesia Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2010.
Review content assessed as up-to-date: 31 October 2010.

Citation: Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for treating severe sepsis and septic shock.
Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD002243. DOI: 10.1002/14651858.CD002243.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
Background
Sepsis may be complicated by impaired corticosteroid production. Giving corticosteroids may benefit patients.
Objectives
To examine the effects of corticosteroids on death at one month in sepsis.
Search strategy
We searched CENTRAL (The Cochrane Library Issue 3, 2009), MEDLINE (October 2009), EMBASE (October 2009), LILACS
(October 2009), reference lists of articles, and also contacted trial authors.
Selection criteria
We included randomized and quasi-randomized controlled trials of corticosteroids versus placebo or supportive treatment in severe
sepsis and septic shock.
Data collection and analysis
All review authors agreed the eligibility of trials. One review author extracted data, which was checked by the other review authors
and the primary author of the paper whenever possible. We obtained some missing data from the trial authors. We assessed the
methodological quality of the trials.
Main results
We identified 25 trials, of which 20 (17 randomized and three quasi-randomized trials) could be pooled in a meta-analysis.
Corticosteroids did not change 28-day mortality (20 trials, n = 2138, relative risk (RR) 0.87, 95% confidence interval (CI) 0.74 to 1.01;
random-effects model). There was significant heterogeneity that was partly related to the dosing strategy. Treatment with a long course
of low dose corticosteroids significantly reduced 28-day mortality (RR 0.84, 95% CI 0.72 to 0.97; P = 0.02), increased the proportion
of shock reversal by day seven (six trials, n = 965, RR 1.35, 95% CI 1.16 to 1.57; random-effects model) and day 28 (six trials, n =
Corticosteroids for treating severe sepsis and septic shock (Review) 1
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
952, RR 1.12, 95% CI 1.02 to 1.23), reduced the sepsis-related organ failure assessment (SOFA) score by day seven (five trials, n =
916, RR -1.47, (95% CI -2.01 to -0.92), and survivors’ length of stay in the intensive care unit (eight trials, n= 622, RR -4.49, 95%
CI -7.04 to -1.94), without inducing gastroduodenal bleeding (13 trials, n = 1594, RR 11.12, 95% CI 0.81 to 1.53), superinfection
(14 trials, n = 1917, RR 1.01, 95% CI 0.82 to 1.25), or neuromuscular weakness (three trials, n = 811, RR 0.63, 95% CI 0.12 to
3.35). Corticosteroid increased the risk of hyperglycaemia (nine trials, n = 1434, RR 1.16, 95% 1.07 to 1.25) and hypernatraemia
(three trials, n= 805, RR 1.61, 95% CI 1.26 to 2.06).
Authors’ conclusions
Overall, corticosteroids did not change mortality in severe sepsis and septic shock. A long course of low dose corticosteroids reduced
28-day mortality without inducing major complications; metabolic disorders were increased.

PLAIN LANGUAGE SUMMARY

A long course (five days or more) of a low dose of corticosteroids may be considered as an adjunct therapy in patients with
septic shock.
Septic shock is the most severe form of infection. It may also interfere with the production of corticosteroids, a key hormone for host
defence against infection. This review showed that corticosteroids did not impact on mortality overall. However, the trials conducted
after the scientific community agreed upon a consensual definition of sepsis, in 1992, suggested that a low dose of corticosteroids for
five days or more improved the survival of patients in septic shock without causing harm They did develop some metabolic disorders.
Trials performed before 1992 showed no benefit from a short course of high dose corticosteroids.

Corticosteroids for treating severe sepsis and septic shock (Review) 2

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Corticosteroids for treating severe sepsis and septic shock (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

long course low dose corticosteroids compared to placebo or standard therapy for severe sepsis and septic shock

Patient or population: patients with severe sepsis and septic shock

Settings: in patient
Intervention: long course low dose corticosteroids
Comparison: placebo or standard therapy

Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

placebo or standard long course low dose

therapy corticosteroids

All-cause mortality Medium risk population RR 0.84 1228 ⊕⊕⊕ Meta-analysis of all
Follow-up: 28 days (0.72 to 0.97)1 (12 studies) moderate2,3 doses/duration of corti-
costeroids showed non-
significant decrease in
45 per 100 38 per 100 mortality, RR 0.87 (0.74,
(32 to 44) 1.01)

Intensive care unit mor- Medium risk population RR 0.81 1082 ⊕⊕⊕
tality (0.63 to 1.04) (8 studies) moderate2
37 per 100 30 per 100
(23 to 38)

Number of patients with Medium risk population RR 1.35 965 ⊕⊕⊕

shock reversal (1.16 to 1.57) (6 studies) moderate4
Follow-up: 7 days 50 per 100 68 per 100
(58 to 79)
3
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Corticosteroids for treating severe sepsis and septic shock (Review)

SOFA score The mean sofa score The mean SOFA score 916 ⊕⊕⊕
Scale from: 0 to 24 (most ranged across control in the intervention groups (5 studies) moderate2
abnormal). groups from was
Follow-up: 7 days 2 to 9.5 1.47 lower
(2.01 to 0.92 lower)

Length of ICU stay The mean length of icu The mean Length of ICU 622 ⊕⊕⊕
stay ranged across con- stay in the intervention (8 studies) moderate2
trol groups from groups was
11 to 38 days 4.49 lower
(7.04 to 1.94 lower)

Number of patients with Medium risk population RR 1.01 1917 ⊕⊕⊕

adverse events (0.82 to 1.25) (14 studies) moderate2,4
superinfections 16 per 100 16 per 100
(13 to 20)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio;

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Metaregression analysis also showed evidence for a dose and duration response: longer duration and low dose are associated with
better treatment response
2 Different definitions of sepsis, concomitant therapies, and baseline risk of death; and some inconsistency with large trials showing

non-significant results.
3
Funnel plot showed asymmetry which may be consistent with publication bias but not downgraded.
4 Studies from both short and long dose corticosteroids.
4
BACKGROUND
Sepsis is present when a site of infection is apparent in a patient and
there is evidence of body-wide, systemic inflammation. Systemic
inflammation is usually defined by two or more criteria. These are
fever or low body temperature, an increase or decrease in white
blood cells, an increase in the heart rate, and rapid breathing (
ACCP/SCCM 1992; Bone 1991). Septic shock is when sepsis is
combined with organ dysfunction or hypoperfusion and a fall in
systemic blood pressure that does not improve even when health
staff give intravenous fluids. The current incidence of severe sepsis
in industrialised countries ranges from 50 to 100 cases per 100,000
population, with a short term mortality of 20% to 50% (Annane
2003; Finfer 2004; Martin 2003; Padkin 2003; The EPISPESIS
group 2004). People usually die from hypotension or progressive
multiple organ failure (Annane 2005; Parrillo 1993).
Researchers have explored the biological mechanisms of shock
for potential interventions. Corticosteroids have been a partic-
ular focus because of their influence on the immune response.
In sepsis, the hypothalamic-pituitary gland hormonal pathway to
the adrenal glands stimulates corticosteroid production (Chrousos
1995). These hormones affect inflammation through the white
blood cells, cytokines (proteins that influence the immune re-
sponse), and nitric oxide production. In septic shock, cytokines
may suppress the cortisol response to adrenocorticotropin hor-
mone (Hotta 1986; Jaattela 1991). This causes poor adrenal ac-
tivity in almost half of patients (Annane 2000; Lipiner 2007;
Rothwell 1991) and body tissues possibly become resistant to cor-
ticosteroids (Meduri 1998a) through fewer corticosteroid recep-
tors or receptors with lower affinity (Barnes 1995; Huang 1987;
Molijn 1995). Early studies demonstrated that a pharmacological
dose of corticosteroids prolonged survival in septic animals (Fabian
1982). More recent studies in rodents demonstrated that lower
dose of corticosteroids, for example 0.1 mg/kg of dexamethasone,
also improved haemodynamic and organ function, modulated the
inflammatory response favourably, and prolonged survival (Heller
2003; Tsao 2004; Vachharajani 2006). LIkewise, in healthy vol-
unteers challenged with endotoxin, a low dose of corticosteroids,
for example 10 mg of prednisolone, blocked the release of pro-in-
flammatory cytokines, prevented endothelial cell and neutrophil
activation, and inhibited the acute phase response without altering
the coagulation and fibrinolysis balance (de Kruif 2007). Studies
in patients with septic shock showed that a short course of corti-
costeroids may result in a rebound in the systemic inflammatory
response (Briegel 1994; Keh 2003). In addition, it is now recog-
nized that increased pro-inflammatory cytokine release can be sus-
tained for more than a week in patients with severe sepsis (Kellum
2007). Finally, a recent randomized controlled study in 82 patients
with septic shock compared a seven-day to a three-day course of
200 mg/day hydrocortisone (Huh 2007). This study found lower
mortality in patients treated for seven days (32% versus 24%). For
these reasons, we would anticipate that corticosteroid treatment
is of benefit in human septic shock and that a different dose or
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
duration of steroid may differentially affect the patient response
to treatment.
Initial research used high doses of corticosteroids, usually given as
a single bolus, in an attempt to block any potential burst in pro-
inflammatory cytokines. A systematic review and meta-analysis of
trials of corticosteroids in sepsis or septic shock included 10 ran-
domized and placebo controlled trials with a total of 1329 patients
(Lefering 1995). The result showed no significant difference in ab-
solute mortality rate, but there was significant heterogeneity across
the trials. The various subgroup analyses included whether or not
the infection was related to Gram-negative bacteria, and compared
low and normal doses of corticosteroids. Another systematic re-
view and meta-analysis of trials of corticosteroids in sepsis or sep-
tic shock included nine randomized and placebo controlled trials
accounting for 1232 patients (Cronin 1995). The authors did not
include one unpublished study (Rogers 1970) since they could
not clarify whether the treatment was allocated in a random order
or not. This systematic review showed no significant difference in
relative risk of death, but there was significant heterogeneity across
the trials. These systematic reviews did not show any significant
increase in gastrointestinal bleeding or superinfection associated
with corticosteroids.
As a result of these reviews, most clinicians will not recommend
the use of high doses of corticosteroids in severe sepsis. However,
the reviews covered a period from 1966 to 1993 and did not ex-
clude a possible benefit of a lower dose (≤ 300 mg of hydrocor-
tisone or equivalent per day) and longer duration (≥ 5 days) of
treatment, as observed in more recent randomized, placebo con-
trolled trials (Annane 2002; Bollaert 1998; Briegel 1999; Chawla
1999; Cicarelli 2007; Confalonieri 2005; Huh 2007; Keh 2003;
Mikami 2007; Oppert 2005; Rinaldi 2006; Tandan 2005; Yildiz
2002). In these trials, the major expectations for corticosteroids
were a reduction in shock duration and improvement in survival
with no increase in adverse events. A recent multicentre trial con-
firmed that corticosteroids reduced shock duration in septic shock
patients but failed to demonstrate any survival benefit and sug-
gested an increased risk of superinfections (Sprung 2008). There-
after, recent international guidelines suggest using corticosteroids
only in septic shock patients who are poorly responsive to fluid
replacement and vasopressors (Dellinger 2008).
We therefore aim to systematically review the effects of corticos-
teroids in patients with severe sepsis and septic shock.
OBJECTIVES
To examine the effects of corticosteroids on death at one month
in patients with severe sepsis and septic shock, and to examine
whether dose and duration of corticosteroids influence patient
responses to this treatment.
5
METHODS
Criteria for considering studies for this review
Types of studies
We included randomized or quasi-randomized controlled trials
with or without blinding.
Types of participants
We included children and adults with septic shock defined by the
following criteria (ACCP/SCCM 1992).
1. Documented infection defined as culture or Gram stain of
blood, sputum, urine, or normally sterile body fluid that is
positive for a pathogenic microorganism; or a focus of infection
identified by visual inspection (e.g. ruptured bowel with the
presence of free air or bowel contents in the abdomen found at
the time of surgery; wound with purulent drainage).
2. At least two symptoms of a systemic inflammatory response
syndrome, such as fever (body temperature > 38 °C) or
hypothermia (< 36 °C), tachycardia (> 90 beats per minute),
tachypnoea (> 20 breaths per minute), or hyperventilation
(arterial carbon dioxide tension (PaCO2 ) < 32 mm Hg), and
abnormal white blood cell count (> 12,000 cells/ml or < 4000
cells/ml), or more than 10% immature band of neutrophils.
3. At least one sign of organ dysfunction, that is metabolic
acidosis, arterial hypoxaemia (arterial oxygen tension [PaO2 ]:
fractional inspired oxygen [FiO2 ] < 250 mm Hg), oliguria (< 30
ml/h for at least 3 h), coagulopathy, or encephalopathy.
4. Hypotension (persisting systolic arterial pressure below 90
mm Hg) that is refractory to fluid resuscitation and which needs
vasopressor support, that is more than 5 µg/kg of body weight
per minute of dopamine or any dose of either epinephrine or
norepinephrine).
We included data from trials of sepsis, sepsis syndrome, or acute
respiratory distress syndrome if separate data were available for pa-
tients with septic shock, or when contact with the authors resulted
in provision of the data.
Types of interventions
Intervention
Intravenous treatment with any type of corticosteroid preparation
(for example cortisone, hydrocortisone, methylprednisolone, be-
tamethasone, or dexamethasone).
Low dose corticosteroid was defined by a total dose per day of 300
mg or less of hydrocortisone (or equivalent); otherwise it would
be considered to be a high dose of corticosteroid. A long course
for the intervention was defined by a full dose treatment duration
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
of five days or more; otherwise it was considered as short course
treatment.
Control
Standard therapy (which may have included antibiotics, fluid re-
placement, inotropic or vasopressor therapy, mechanical ventila-
tion, renal replacement therapy) or placebo.
Types of outcome measures
Primary outcomes
• The 28-day all-cause mortality
Indeed, this was the primary outcome measure in most of the
randomized controlled trials on sepsis that have been conducted in
the past 15 years (Annane 2009b). Most of the studies performed
before 1992 looked at 14-day or hospital mortality rates. We used
these data to compute the pooled analysis on 28-day mortality,
unless actual 28-day mortality rates could be obtained from studies
authors.
Secondary outcomes
• Intensive care unit mortality
• Hospital mortality
• Number of patients with shock reversal (as defined by stable
haemodynamic status for at least 24 hours after withdrawal of
vasopressor therapy) at day 7 and at day 28
• Number of organ dysfunction-free days (as defined in
individual studies)
• Length of stay in the intensive care unit (for all patients and
for survivors only)
• Length of hospital stay (for all patients and for survivors
only)
• Adverse events (i.e. gastrointestinal bleeding and
superinfection or any other adverse effects or complications of
corticosteroid treatment)
Search methods for identification of studies
We attempted to identify all relevant studies regardless of language
or publication status (published, unpublished, in press, and in
progress).
Electronic searches
We originally searched the Cochrane Infectious Diseases Group
Trials Register for relevant trials (to August 2003) using the search
terms: ’sepsis’; and ’septic shock’. Full details of the Cochrane In-
fectious Diseases Group’s methods and the journals they hand-
search are published in The Cochrane Library in the section on
Cochrane Review Groups.
6
In this updated version, we searched the Cochrane Central Register
of Controlled Trials (CENTRAL) (The Cochrane Library 2009,
Issue 3) using the search terms: ’sepsis’; ’septic shock’; ’steroids’;
and ’corticosteroids’ (for detailed search strategy see Appendix 1).
We also searched (up to Octobre 2009) MEDLINE, EMBASE
and LILACS using the topic search terms in combination with the
search strategy for identifying trials developed by The Cochrane
Collaboration (Higgins 2005). (For detailed search strategy see
Appendix 2 (MEDLINE), Appendix 3 (EMBASE) and Appendix
4 (LILACS))
Searching other resources
We checked the reference lists of all trials identified by the above
methods, and contacted authors to identify any additional pub-
lished or unpublished data. We also searched the proceedings of
the annual meetings of major critical care medicine symposia, that
is Society of Critical Care Medicine, American Thoracic Society,
the International Symposium on Intensive Care and Emergency
Medicine, the American College of Chest Physicians, and Euro-
pean Society of Intensive Care Medicine (1998 to 2009).
Finally, we searched for ongoing randomized controlled trials
(October2009) in the metaRegister of Controlled Trials using
the search terms: ’septic shock’; ’sepsis’; steroids’; ’corticosteroids’;
’adrenal cortex hormones’; and ’glucocorticoids’ (www.controlled-
trials.com/mrct/active).
Data collection and analysis
Study selection
All review authors checked the titles and abstracts identified with
the search strategy. All authors examined in full any trial that po-
tentially met the inclusion criteria. Whenever possible, one author
was blinded to the journal in which the paper was published, the
authors, the institution, and the magnitude and direction of the re-
sults. Five authors (Djillali Annane, Pierre Edouard Bollaert, Josef
Briegel, Didier Keh, and Yizhak Kupfer) evaluated all the trials.
We decided which trials fitted the inclusion criteria and graded
their methodological quality. We resolved any disagreement be-
tween the five authors by discussion with the sixth author (Eric
Bellissant) until a consensus was reached. One author (Djillali An-
nane) contacted study authors for clarification, where necessary.
Assessment of methodological quality
We graded generation of allocation sequence and allocation con-
cealment as adequate, unclear, or inadequate according to Juni
2001. We described the method for blinding as double blind
(method described and placebo(s) or dummy technique meant nei-
ther the participant nor the care provider or assessor knew which
treatment was given); single blind (participant or the care provider
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
or assessor was aware of the treatment given); and open (all parties
were aware of the treatment). We described, whenever possible,
who among patients, care-givers, data collectors, outcome asses-
sors, and data analysts remained blinded (Devereaux 2001). We
considered loss to follow up as adequate (90% or more of the par-
ticipants randomized were included in the analysis), unclear (not
reported), or inadequate (< 90% participants randomized into the
trial were included in the analysis). We resolved any disagreements
between the five authors by discussion with the sixth author (Eric
Bellissant) until a consensus was reached. We contacted study au-
thors for clarification, where necessary.
Data extraction
DA drew up a standard data extraction form and four other au-
thors (PEB, JB, DK, YK) amended and validated the design of the
form prior to data abstraction. Four authors (DA, PEB, JB, DK)
independently extracted data and DA systematically contacted the
authors of the trials to provide missing data where possible. DA
entered (DA secretary independently reentered all data to achieve
a double entry) the data into the computer and five authors (EB,
PEB, JB, DK, YK) checked the accuracy of data that were entered
using the original articles.
Data analyses
1. We performed intention-to-treat analyses. We performed all
statistical calculations using RevMan 5 or STATA/IC version
10.0 (Stata Corp, College Station, Texas) as appropriate.
2. We calculated a weighted treatment effect across trials. We
expressed the results as RRs with 95% confidence intervals (CI)
for dichotomous outcomes, and mean differences (MD, 95%
CI) for continuous outcomes. We considered methods based on
the random-effects model for all analyses. Indeed, we suspected
that we would observe heterogeneity across the studies as they
were conducted over a wide period of time (almost half a century
between the first and the last trials) and the rationale on which
the studies were designed varied greatly over time, with marked
differences in treatment strategies between studies conducted
prior to and after the early 90s.
3. To identify potential sources of heterogeneity (when I2 ≥
20%), we a priori sought to conduct a subgroup analysis based
on ’dose and duration’, that is long course (at least five days) of
low dose (< 300 mg/day of hydrocortisone or equivalent). This
subgroup analysis allowed the evaluation of a strategy based on
new developments in the understanding of the role of
corticosteroids in host response to sepsis, tested in trials
performed after 1992 (Annane 2002; Bollaert 1998; Briegel
1999; Chawla 1999; Cicarelli 2007; Confalonieri 2005; Huh
2007; Keh 2003; Meduri 1998b; Mikami 2007; Oppert 2005;
Rinaldi 2006; Sprung 2008; Tandan 2005; Yildiz 2002). Older
trials used a short course (one to four bolus doses within 24
hours) of high dose corticosteroids (more than 300 mg of
7
hydrocortisone or equivalent) as an anti-inflammatory approach,
while the most recent trials used low dose corticosteroids for a
long period of time (at least five days) as a hormonal replacement
strategy. To further explore the putative interaction between
steroid dose and duration and the magnitude of effect, we
considered performing a meta-regression analysis using 28-day
all-cause mortality as the dependent variable, and dosage and
duration of corticosteroids as predictors. The meta-regression
analyses were computed using STATA/IC version 10.0 (Stata
Corp, College Station, Texas). We also a priori tested the
interaction between baseline severity of illness and the
magnitude of effect in a meta-regression analysis using mortality
rates in controls as the predictors.
4. We conducted sensitivity analyses for generation of
allocation sequence, concealment of allocation, and blinding.
5. We sought evidence of publication bias using the funnel
plot method. We computed, using STATA/IC version 10.0
(Stata Corp, College Station, Texas), a contour enhance funnel
plot (Peters 2008). This graphical analysis used the log of the RR
and the standard error of the RR. Contours illustrating the
statistical significance of the study effect estimates were plotted
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
from a two-tailed test.
6. We assessed the validity of the subgroup analysis (dose and
duration) on the basis of the following criteria: (1) subgroup
comparisons within studies rather than between studies; (2)
hypothesis preceded the analysis; (3) one of very few hypotheses;
(4) large and consistent difference across studies; and (5) external
evidence to support the results (Guyatt 2008b). When subgroup
analyses met these criteria and were found to be statistically
significant, we applied Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) criteria to
evaluate the quality of evidence (Guyatt 2008a).
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies; Characteristics of ongoing studies.
Our search results are detailed in Figure 1 .
8
 Figure 1. Search flow diagram

Corticosteroids for treating severe sepsis and septic shock (Review) 9

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The search strategy yielded 35 randomized controlled trials that
evaluated corticosteroids in severe sepsis or septic shock. Of these,
we excluded 10 (see Characteristics of excluded studies). We in-
cluded the remaining 25 trials and have described them below (see
Characteristics of included studies).
We identified nine additional randomized trials of prolonged
treatment with a low dose of corticosteroids from trials registries
(but these nine studies were not included in the analysis, see
Characteristics of ongoing studies). One of these trials was to com-
pare hydrocortisone alone to the combination of hydrocortisone
and fludrocortisone but this trial did not start due to lack of fund-
ing (NCT00368381 2008). One of the trials has a 2 x 2 factorial
design to also allow evaluation of the effects of the recombinant
activated protein C (NCT00625209 2008). The trials included
only adults except one trial evaluating treatment with hydrocorti-
sone in children with severe sepsis (NCT00732277 2008).
Source of information
In addition to the extracted data from the publications, we ob-
tained unpublished information from 15 trials by contacting the
primary authors (Annane 2002; Annane 2010; Bollaert 1998;
Briegel 1999; Chawla 1999; Cicarelli 2007; Confalonieri 2005;
Keh 2003; Meduri 2007; Oppert 2005; Rinaldi 2006; Sprung
1984; Sprung 2008; Tandan 2005; Yildiz 2002) (Appendix 5).
In one case, contact with the authors did not allow provision of
additional information (Luce 1988). For one trial we could use
only published data.
Trial centres
Seven trials were multicentre trials (that is more than two centres) (
Annane 2002; Annane 2010; Bone 1987; CSG 1963; Confalonieri
2005; Sprung 2008; VASSCSG 1987).
Age of participants
One study enrolled both children and adults (CSG 1963). Another
trial included only children (Slusher 1996). All remaining trials
included only adults.
Description of participants
Eight trials included both severe sepsis and septic shock patients
(Bone 1987; Klastersky 1971; Lucas 1984; Luce 1988; Slusher
1996; VASSCSG 1987; Wagner 1955; Yildiz 2002) and only one
study provided separate data for septic shock (Bone 1987). Two
trials included patients with severe sepsis (Confalonieri 2005;
Rinaldi 2006).The remaining trials focused only on septic shock
patients treated by a vasopressor. Two trials included only septic
shock patients with adrenal insufficiency as defined by a cortisol
increment of less than 9 µg/dl after a corticotropin bolus (Huh
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2007; Tandan 2005). In five trials, a short corticotropin test was
systematically performed at baseline (Annane 2002; Annane 2010;
Bollaert 1998; Oppert 2005; Sprung 2008).
Control
Two studies did not use a placebo and corticosteroid therapy was
compared to standard therapy, that is antibiotics, fluid resuscita-
tion, and vasopressor when needed (Lucas 1984; Rinaldi 2006).
In one study a placebo was used in one centre only (Sprung 1984).
In another trial (Wagner 1955), a placebo was available only at the
end of the study. Thereafter, in the first 85 patients, corticosteroid
therapy was compared to standard therapy, that is antibiotics, fluid
resuscitation, and vasopressor when needed, and to a placebo in
the last 28 patients. In one trial that compared hydrocortisone to
hydrocortisone plus fludrocortisone did not use a placebo of flu-
drocortisone for technical reasons (Annane 2010). In the remain-
ing trials, the corticosteroid therapy was compared to a placebo.
Corticosteroid dose and treatment course
Twelve trials tested the effects of a long course (> 5 days) with
low dose hydrocortisone (Annane 2002; Annane 2010; Bollaert
1998; Briegel 1999; Chawla 1999; Confalonieri 2005; Huh 2007;
Oppert 2005; Rinaldi 2006; Sprung 2008; Tandan 2005; Wagner
1955), one trial tested prednisolone (Yildiz 2002), and one trial
tested the effects of dexamethasone (Cicarelli 2007). In six trials
(Annane 2002; Bollaert 1998; Huh 2007; Oppert 2005; Sprung
2008; Tandan 2005) the effects of corticosteroids were analysed
in patients with adrenal insufficiency. In one trial (Huh 2007)
the authors compared hydrocortisone 50 mg intravenously every
six hours when given for three days versus seven days. Another
trial compared a seven-day treatment with hydrocortisone to a
seven-day treatment with the combination of hydrocortisone plus
fludrocortisone (Annane 2010).
Seven trials tested the effects of a short course with a large dose
of methylprednisolone (Bone 1987; Luce 1988; Schumer 1976;
Sprung 1984; VASSCSG 1987), of dexamethasone (Lucas 1984;
Schumer 1976; Sprung 1984), or of betamethasone (Klastersky
1971).
Outcomes
Thirteen trials explicitly reported 28-day mortality rates (Annane
2002; Annane 2010; Bollaert 1998; Briegel 1999; Chawla 1999;
Cicarelli 2007; Confalonieri 2005; Huh 2007; Klastersky 1971;
Oppert 2005; Sprung 2008; Tandan 2005; Yildiz 2002). For three
trials contact with the primary author of the paper allowed record-
ing of 28-day mortality rates (Meduri 2007; Rinaldi 2006; Sprung
10
1984). Three trials reported only 14-day mortality rates (Bone
1987; Lucas 1984; VASSCSG 1987). Five trials reported only
hospital mortality rates (CSG 1963; Luce 1988; Schumer 1976;
Slusher 1996; Wagner 1955;). One trial reported only two deaths
among 113 patients during hospital stay (Wagner 1955) and one
trial did not report mortality rates (Keh 2003).
Seven trials explicitly reported the intensive care unit (ICU) mor-
tality rate (Annane 2002; Annane 2010; Bollaert 1998; Briegel
1999; Confalonieri 2005; Meduri 2007; Sprung 2008) and the
primary author of two additional trials provided this outcome
(Chawla 1999; Rinaldi 2006). Hospital mortality rates were avail-
able for 16 trials (Annane 2002; Annane 2010; Bollaert 1998;
Briegel 1999; Chawla 1999; Confalonieri 2005; Klastersky 1971;
Lucas 1984; Luce 1988; Meduri 2007; Rinaldi 2006; Schumer
1976; Sprung 1984; Sprung 2008; Wagner 1955; Yildiz 2002).
Eight trials reported the rate of shock reversal at day seven
(Annane 2002; Bone 1987; Bollaert 1998; Briegel 1999; Chawla
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1999; Oppert 2005; Sprung 1984; Sprung 2008) and eight tri-
als (Annane 2002; Bollaert 1998; Briegel 1999; Chawla 1999;
Huh 2007; Sprung 2008; Tandan 2005) the rate of shock rever-
sal at day 28. Five trials reported the numbers of organ dysfunc-
tion at seven days, that is SOFA score (Annane 2002; Cicarelli
2007; Oppert 2005; Rinaldi 2006; Sprung 2008). The length of
ICU stay was reported in 10 trials (Annane 2002; Annane 2010;
Bollaert 1998; Briegel 1999; Chawla 1999; Confalonieri 2005;
Huh 2007; Meduri 2007; Rinaldi 2006; Sprung 2008) and the
length of hospital stay in nine trials (Annane 2002; Annane 2010;
Bollaert 1998; Chawla 1999; Confalonieri 2005; Meduri 2007;
Slusher 1996; Sprung 2008; Yildiz 2002).
Risk of bias in included studies
The detailed methodological quality of individual trials are re-
ported in the risk of bias tables, Figure 2, and in Appendix 6.
11
 Figure 2. Methodological quality summary: review authors’ judgements about each methodological quality
item for each included study.

Corticosteroids for treating severe sepsis and septic shock (Review) 12

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Randomization
In three trials, we considered that the randomization (method of
generation of allocation sequence) was inappropriate to minimize
selection bias, that is based on hospital numbers in two trials (
Lucas 1984; Wagner 1955) and on a card system in one study
(Schumer 1976); the method for generation of allocation sequence
was judged inadequate. In four trials the method was unclear (
CSG 1963; Huh 2007; Klastersky 1971; Slusher 1996) and was
deemed adequate in the remaining trials. We judged the method
for allocation concealment to be adequate in all but eight trials. In
two trials assignment of treatment was based on hospital numbers
(Lucas 1984; Wagner 1955) and in one trial on unsealed envelopes
(Schumer 1976). In one trial, in one of the two participating
centres the investigators enrolling patients could have foreseen the
upcoming assignment as the local ethical committee refused to
accept blind allocation (Sprung 1984). In four trials the method
for allocation concealment was not reported (CSG 1963; Huh
2007; Klastersky 1971; Slusher 1996).
Blinding
In five trials, blinding was inadequate (Annane 2010; Lucas 1984;
Rinaldi 2006; Sprung 1984; Wagner 1955). In one study (Wagner
1955), blinding of treatment administration and of outcome as-
sessment was used only at the end of the study (for the last 28
patients among 113 patients). Two trials used open labelled treat-
ments (Annane 2010; Rinaldi 2006;). In another trial (Lucas
1984) the authors stated that “steroids were administered in a non
blinded manner, because a previous unpublished double-blind
study of steroid therapy for patients caused uniform defervescence
in the steroid-treated patients, thereby permitting an accurate pre-
diction of steroid supplementation by the nursing personnel”. In
the fifth trial (Sprung 1984), the local ethical committee of one
of the two centres did not permit double-blind allocation and ad-
ministration of treatment. Then, blinding was not possible for 40
out of the 59 patients included in the trial. The remaining trials
were deemed as appropriately double blinded. In three additional
trials the method for ensuring blinding was not reported (CSG
1963; Klastersky 1971; Schumer 1976).
Withdrawal
Eleven trials (Annane 2002; Annane 2010; Bollaert 1998; Briegel
1999; Keh 2003; Lucas 1984; Meduri 2007; Oppert 2005; Rinaldi
2006; Sprung 2008; VASSCSG 1987) explicitly provided the
number of, and reasons for, withdrawals or losses to follow up. In
one trial only 500 out of the 800 expected patients were recruited,
mainly due to a low recruitment rate after loss of equipoise among
investigators (Sprung 2008).
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Intention-to-treat analysis and adherence to the
protocol
Thirteen trials explicitly reported the use of intention-to-treat
analysis (as the primary analysis) and the number of, and rea-
sons for, non-adherence to the protocol (Annane 2002; Annane
2010; Bollaert 1998; Bone 1987; Briegel 1999; Chawla 1999;
Confalonieri 2005; Keh 2003; Meduri 2007; Oppert 2005;
Rinaldi 2006; Sprung 2008; VASSCSG 1987). One trial reported
only the use of intention-to-treat analysis (Luce 1988). The re-
maining trials provided no information about these criteria. How-
ever, the number of analysed participants matched the number
of randomized participants except for five of all the trials. In one
trial, 191 participants were randomized in the placebo group and
190 were analysed for the mortality outcome (Bone 1987). In two
trials (Annane 2002; Sprung 2008), one patient withdrew his or
her consent and 499/500 and 299/300 randomized patients were
analysed, respectively. In two trials, contact with the primary au-
thor allowed us to get information for patients who were dropped
out from the analysis (Oppert 2005; Rinaldi 2006). In the first
study, seven randomized patients (five corticosteroid group and
two placebo group) were not analysed (Oppert 2005). Four of
these patients (two corticosteroid group and two placebo group)
were discharged alive from the ICU and then were definitely lost
to follow up. The three remaining patients (corticosteroid group)
died, two before receiving hydrocortisone and the last at study day
17. In the second study, 12 out of 52 patients were dropped out
of the study, six in the control group and six in the corticosteroid
group (Rinaldi 2006). Nine patients (four in the control group)
were excluded as they developed renal failure. Two of the control
patients died in the ICU at day five and day seven, respectively.
Three of the corticosteroid-treated patients died, at day five, six,
and 28 respectively. Three other patients (two control group) were
excluded as they developed septic shock. They all died at days
three, five, and six, respectively.
Explicit definition of septic shock
Twelve trials provided an explicit definition of severe sepsis or sep-
tic shock (as defined in the method section of this review) (Annane
2002; Annane 2010; Bollaert 1998; Briegel 1999; Chawla 1999;
Cicarelli 2007; Huh 2007; Keh 2003; Oppert 2005; Sprung 1984;
Sprung 2008; Tandan 2005). Nine trials provided a definition of
severe sepsis and on septic shock without referring to the need for
vasopressor agents (Bone 1987; Klastersky 1971; Lucas 1984; Luce
1988; Rinaldi 2006; Schumer 1976; Slusher 1996; VASSCSG
1987; Yildiz 2002). The definition for severe sepsis or septic shock
was not explicitly given in two studies (CSG 1963; Wagner 1955).
Two trials explicitly defined severe sepsis due to community ac-
quired pneumonia (Confalonieri 2005; Mikami 2007). In one
13
trial on early acute respiratory distress syndrome (ARDS), contact
with the primary author confirmed that explicit definitions of se-
vere sepsis and septic shock were used (Meduri 2007).
Effects of interventions
See: Summary of findings for the main comparison Long course
low dose corticosteroids compared to placebo or standard therapy
for severe sepsis and septic shock
We did not pool the data from two trials that included chil-
dren (CSG 1963; Slusher 1996), one crossover trial (Keh 2003),
one trial that compared two durations of hydrocortisone treat-
ment (Huh 2007), and one trial that compared hydrocortisone to
the combination of hydrocortisone plus fludrocortisone (Annane
2010).
28-day all-cause mortality
Data for 28-day mortality were available for 16 trials; among these
two trials had no corticosteroid-free arm. In addition, we used
data on 14-day mortality (n = 3 trials) or hospital mortality (n =
3 trials). Thus, we computed data from 20 trials (17 randomized
and three quasi-randomized trials) that accounted for 2384 par-
ticipants. There were 416/1220 participants in the treated group
that died by day 28 compared to 424/1164 participants in the
placebo group. There was significant heterogeneity in the results
(Chi2 = 34.18, P = 0.02, I2 = 44%). The RR of dying at 28 days
was 0.87 (95% CI 0.74 to 1.01, P = 0.07; random-effects model)
(Analysis 1.1).
We analysed separately the 14 studies for which 28-day mortality
was available and the three studies reporting only 14-day mortal-
ity (Analysis 1.2). There were 291/718 deaths at 28 days in the
corticosteroid-treated group and 293/654 deaths in the control
group (RR 0.88, 95% CI 0.77 to 1.01, P = 0.06; random-effects
model) with moderate heterogeneity in the results (Chi2 = 15.00,
P = 0.31, I2 = 13%). In the studies reporting only 14-day mortality
rates, there were 93/326 deaths in the corticosteroid-treated group
and 77/326 deaths in the control group (RR 1.21, 95% CI 0.94
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to 1.58, P = 0.14; random-effects model), without heterogeneity
in the results (Chi2 = 1.36, P = 0.51, I2 = 0%).
Heterogeneity across trials may have been explained by different
therapeutic regimens and different populations. Subgroup analysis
on the 12 trials that tested a long course (≥ 5 days) of low dose
corticosteroids (≤ 300 mg hydrocortisone or equivalent) showed
less heterogeneity across the trials (Chi2 = 12.89, P = 0.30, I2 =
15%) and a RR of dying at 28 days of 0.84 (95% CI 0.72 to
0.97, P = 0.02) in favour of the corticosteroid group (Analysis
1.3). We also conducted a sensitivity analysis by excluding the trial
on community acquired pneumonia (Confalonieri 2005). This
analysis still showed a RR of 0.87 (95% CI 0.77 to 0.98, P = 0.02)
in favour of the corticosteroid group and almost no heterogeneity
(Chi2 = 10.09, P = 0.43; I² = 1%). Subgroup analyses on the
trials that tested a short course of high dose corticosteroids showed
significant heterogeneity across the trials (Chi2 = 18.63; P = 0.005,
I2 = 68%) and a RR of dying at 28 days of 0.94 (95% CI 0.69 to
1.30; random-effects model) (Analysis 1.3).
Differences in methodological quality across the trials may have
also accounted for the observed heterogeneity in the results. Sub-
group analyses based on the trials with an adequate method for
generation of the allocation sequence showed a RR of dying at
28 days of 0.92 (95% CI 0.99 to 1.07) (Analysis 1.4). Similarly,
subgroup analyses based on studies with adequate allocation con-
cealment showed a RR of dying at 28 days of 0.90 (95% CI 0.76
to 1.06); and subgroup analyses on double-blind trials showed a
RR of dying at 28 days of 0.91 (95% CI 0.79 to 1.05) (Analysis
1.4).
One trial of a large dose of corticosteroids was a statistical outlier
and was excluded from the meta-regression analysis (Schumer
1976). Meta-regression analysis confirmed the positive interaction
between dose and duration of corticosteroid treatment and survival
with: a lower RR of dying with prolonged duration treatment at
a low dose (P = 0.01) (Figure 3), lower daily doses (P = 0.02)
(Figure 4), and lower cumulative doses (P = 0.02) (Figure 5). Meta-
regression showed less interaction of mortality rate in the control
group with corticosteroid effects (P = 0.06).
14
 Figure 3. Figure displays the relative risk of death plotted against the duration of glucocorticoid treatment
at full dose, given in hours. Individual studies are depicted by a bubble, which size indicates the weight of that
particular study in the meta-regression analysis. There were significant association between the relative risk of
death and the time of treatment at full dose (P = 0.015).

Corticosteroids for treating severe sepsis and septic shock (Review) 15

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 4. Figure displays the relative risk of death plotted against the dose of glucocorticoid treatment at
study day 1and expressed in hydrocortisone equivalent. Individual studies are depicted by a bubble, which size
indicates the weight of that particular study in the meta-regression analysis. There were significant association
between the relative risk of death and the time of treatment at full dose (P = 0.022).

Corticosteroids for treating severe sepsis and septic shock (Review) 16

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 5. Figure displays the relative risk of death plotted against the cumulated dose of glucocorticoid
treatment , expressed in hydrocortisone equivalent. Individual studies are depicted by a bubble, which size
indicates the weight of that particular study in the meta-regression analysis. There were significant association
between the relative risk of death and the time of treatment at full dose (P = 0.018).

Subgroup analysis of patients with adrenal insufficiency showed

no heterogeneity in the results. There were 135/288 deaths in the
treated group and 145/275 in the placebo group. The RR of dying
was 0.88 (95% CI 0.76 to 1.02) (Analysis 1.4).
Funnel plot analysis, including all trials, suggested some asymme-
try (Figure 6). Contour enhanced funnel plot analysis including
trials of a long course of low dose corticosteroids also suggested
significant asymmetry (P = 0.01) (Figure 7).

Corticosteroids for treating severe sepsis and septic shock (Review) 17

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 6. Funnel plot of comparison: 1 Steroids versus control, outcome: 1.1 28-day all-cause mortality.

Corticosteroids for treating severe sepsis and septic shock (Review) 18

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 7. Scatter plot of the intervention effect estimates (RR) from the 12 individual studies on prolonged
treatment with low-dose corticosteroids against each study precision (standard error of log[RR]). Lines define
areas according to significance levels, i.e. 1%, 5% and 10%). Because the precision of the intervention effect
estimate is proportional to the study’s size, effect estimates from small studies scatter more widely at the
bottom of the graph, with the spread narrowing among larger studies.

In one trial comparing hydrocortisone alone to hydrocortisone

plus fludrocortisone, the hazard ratio of death was of 0.94 (95%
CI 0.73 to 1.21) (Annane 2010).
Intensive care unit (ICU) mortality
Data were available in eight trials, accounting for 1082 partici-
pants. All these trials investigated a long course of a low dose of
corticosteroids. There were 226/558 participants in the treated
group and 239/524 participants in the placebo group that died
in the ICU. There was some heterogeneity in the results (Chi2 =
12.86, P = 0.08, I2 = 46%). The RR of dying in the ICU was 0.81
(95% CI 0.63 to 1.04; random-effects model) (Analysis 1.6).
Hospital mortality
We could extract data for hospital mortality from 15 trials that
accounted for 1672 participants. There were 344/866 participants
in the treated group compared to 355/806 in the control group
that died in hospital. There was significant heterogeneity in the
results (Chi2 = 27.95, P = 0.01, I2 = 50%). The RR of dying in
hospital was 0.83 (95% CI 0.68 to 1.00; random-effects model)
(Analysis 1.7).
Subgroup analysis on 10 trials that tested a long course (≥ 5 days)
of low dose corticosteroids (≤ 300 mg hydrocortisone or equiva-
lent) showed less heterogeneity in the results and a RR of dying in
hospital of 0.85 (95% CI 0.72 to 1.00; random-effects model) in
favour of the corticosteroids group. Subgroup analyses on the tri-
als that tested a short course of high dose corticosteroids showed a
significant heterogeneity across the trials (Chi2 = 16.81, P = 0.002,
I2 = 76%) and a RR of dying at 28 days of 0.84 (95% CI 0.52 to
1.36, P = 0.47; random-effects model) (Analysis 1.7).
Differences in methodological quality across the trials may also
have accounted for the observed heterogeneity in the results. Sub-

Corticosteroids for treating severe sepsis and septic shock (Review) 19

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
group analyses based on trials with an adequate method for gen-
erating the allocation sequence showed a RR of dying in hospital
of 0.90 (95% CI 0.77 to 1.06), with less heterogeneity across the
studies (Analysis 1.7). Similarly, subgroup analyses based on stud-
ies with adequate allocation concealment showed a RR of dying
in hospital of 0.89 (95% CI 0.76 to 1.05), and subgroup analyses
on blinded trials showed a RR of dying in hospital of 0.89 (95%
CI 0.75 to 1.05) (Analysis 1.7).
In one trial comparing hydrocortisone alone to hydrocortisone
plus fludrocortisone, the RR of death was 0.94 (95% CI 0.77 to
1.14) (Annane 2010).
Shock reversal at day seven
We could extract data from eight trials that accounted for 1268
participants. There were 418/658 participants in the treated group
and 315/610 in the placebo group that had shock reversed at day
seven. There was significant heterogeneity in the results (Chi2 =
21.48, P = 0.003, I2 = 67%). The RR of having shock reversed
at day seven was 1.29 (95% CI 1.06 to 1.58, P = 0.01; random-
effects model) in favour of the corticosteroids group (Analysis 1.8).
Heterogeneity in the results could be explained by differences in
treatment strategies used in the various trials. Two trials evalu-
ated one or two boluses of high dose corticosteroids (Bone 1987;
Sprung 1984) while the six remaining trials all studied a replace-
ment therapy with low dose (200 to 300 mg) hydrocortisone for
more than five days. When analysing the six trials with a simi-
lar therapeutic strategy, there was less heterogeneity in the results.
Then, there were 308/485 in the treated group and 226/480 pa-
tients in the placebo group that had shock reversed at day seven.
The RR of having shock reversed was 1.35 (95% CI 1.16 to 1.57,
P = 0.0001) in favour of the corticosteroids group (Analysis 1.8).
In one crossover trial, hydrocortisone was given for three days at
a dose of 240 mg per day (Keh 2003). Although this trial could
not provide information on shock reversal at day seven, it showed
that at day three fewer hydrocortisone patients required nore-
pinephrine treatment than placebo-treated patients (6/20 versus
14/20, P = 0.025).
Shock reversal at day 28
We could extract data from six trials accounting for 952 partici-
pants. There were 322/481 participants in the treated group that
had shock reversed at day 28 and 276/471 in the placebo group.
There was little heterogeneity in the results. The RR of having
shock reversed was 1.12 (95% CI 1.02 to 1.23, P = 0.02) in favour
of the corticosteroids group (Analysis 1.8).
Number of organ dysfunction-free days
This outcome was not reported in the various trials. In one study
(Briegel 1999) the corticosteroids treatment was associated with
a non-significant (P = 0.18) trend to earlier resolution of organ
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
dysfunction. Five additional studies reported the changes of an
organ dysfunction score (sepsis-related organ failure assessment,
SOFA) within the first week from randomization (Annane 2002;
Cicarelli 2007; Oppert 2005; Rinaldi 2006; Sprung 2008). The
weighted mean difference in the SOFA score at day seven was -1.47
(95% CI -2.01 to -0.92, P < 0.00001) in favour of corticosteroids.
There was no heterogeneity across the studies (Chi² = 4.09, P =
0.39; I² = 2%) (Analysis 1.8).
Length of stay in the intensive care unit (ICU)
In eight trials (n = 1083) (Annane 2002; Bollaert 1998; Briegel
1999; Chawla 1999; Confalonieri 2005; Meduri 2007; Rinaldi
2006; Sprung 2008), the weighted mean difference for the length
of stay in the ICU was -3.11 (-5.79 to -0.43, P = 0.02) with some
heterogeneity across the studies (Chi² = 9.72, P = 0.21, I² = 28%).
We could extract data from these trials on 622 intensive care unit
survivors. The mean difference for the length of stay in the ICU
was -4.49 days (95% CI -7.04 to -1.94, P = 0.0006). There was
no heterogeneity across the studies (Chi² = 2.78, P = 0.90; I² =
0%) (Analysis 1.10).
Length of hospital stay
In seven trials (n = 1031) (Annane 2002; Bollaert 1998; Chawla
1999; Confalonieri 2005; Meduri 2007; Sprung 2008; Yildiz
2002) we could extract data for all patients and for 552 hospital
survivors. There was no evidence for a difference between the two
groups (WMD -2.54, 95% CI -7.93 to 2.47) (Analysis 1.11).
Adverse events
Gastroduodenal bleeding
We could extract data from 13 trials. There were 65/827 partici-
pants in the treated group and 56/767 in the placebo group that
had an episode of gastroduodenal bleeding. There was no hetero-
geneity in the results. The RR of having gastroduodenal bleeding
was 1.12 (95% CI 0.81 to 1.53) (Analysis 1.12).
Superinfection
We could extract data from 14 trials. There were 184/983 partici-
pants in the treated group and 170/934 participants in the placebo
group that had an episode of nosocomial infection. There was no
heterogeneity in the results. The RR of having superinfection was
1.01 (95% CI 0.82 to 1.25) (Analysis 1.12).
20
Hyperglycaemia
The number of participants who presented with hyperglycaemia
was reported for nine trials. There was no heterogeneity in the
results. The RR of having hyperglycaemia was 1.16 (95% CI 1.07
to 1.25) (Analysis 1.12).
One trial comparing tight glucose control to standard care did not
find any benefit in normalizing blood glucose levels in corticos-
teroid-treated septic shock patients (Annane 2010).
Hypernatraemia
The number of participants who presented with hypernatraemia
was reported for three trials. There was no heterogeneity in the
results. The RR of having hypernatraemia was 1.61 (95% CI 1.26
to 2.06) (Analysis 1.12).
Neuromuscular weakness
The number of participants who presented with neuromuscular
weakness was reported for three trials. The RR of having neu-
romuscular weakness was 0.63 (95% CI 0.12 to 3.35) (Analysis
1.12).
The main results are summarized in the ’Summary of findings’
table 1.
DISCUSSION
In this review, we performed a comprehensive search of the liter-
ature with no restriction on language so we can assume that there
was a very limited risk of missing important trials. The asymmet-
rical funnel plot for the primary outcome of this review suggests
some publication bias. However, potential sources of an asym-
metrical funnel plot include selection biases, poor methodological
quality of smaller studies, true heterogeneity, artefacts, or chance
(Egger 1997). Visual inspection of the funnel plot suggests a small-
study effect (that is, among small studies the positive ones are more
likely to be published). Nevertheless, our thorough search strategy
and the need to enrol studies in public clinical trial registries may
have decreased the risk of missing any randomized control trial. As
discussed in the review, all studies on low dose corticosteroids had
acceptable methodological quality. True heterogeneity seems to be
a more plausible explanation of the observed asymmetrical funnel
plot. Indeed, the effect of low dose corticosteroids on mortality
may be proportional to the basal risk of death, and CORTICUS
included patients at lower risk of death (Sprung 2008). In ad-
dition, smaller intervention effects in the CORTICUS trial may
have resulted from an improved standard of care during the decade
that separated most of the smaller trials and CORTICUS. Finally,
the asymmetrical funnel plot may have been due to chance.
According to the primary objective of this systematic review, we
only included the trials that compared corticosteroids to standard
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
therapy alone or a placebo. One trial had a crossover design (Keh
2003) and we could obtain none of the foreseen outcomes for
this review. This trial concluded that prolonged treatment with
a low dose of hydrocortisone improved haemodynamic and im-
mune outcomes. Another trial compared three days versus seven
days of hydrocortisone therapy and suggested better outcomes in
patients treated for seven days (Huh 2007). Two other trials have
included children (CSG 1963; Slusher 1996). We considered that
pooling the results of the remaining 20 trials in a meta-analysis
was acceptable.
At the time this review was written, three of the 24 trials were
published only as an abstract (Chawla 1999; Huh 2007; Tandan
2005). Nevertheless, the primary investigators of two of these stud-
ies (Chawla 1999; Tandan 2005) provided sufficient unpublished
data to compute the primary outcome and several secondary out-
comes for this review, allowing us to include these trials in the
meta-analysis. Both published and unpublished data were available
for 13 trials (Annane 2002; Bollaert 1998; Briegel 1999; Chawla
1999;Cicarelli 2007; Confalonieri 2005; Keh 2003; Meduri 2007;
Oppert 2005; Rinaldi 2006; Sprung 1984; Sprung 2008; Yildiz
2002) and the primary author of each trial validated the data ex-
traction form. For one study, contact with the primary investigator
did not result in additional data (Luce 1988).
We chose to convert the outcome measures that correspond to
censored data into dichotomous variables, that is, the proportion
of participants with a particular event after one week and four
weeks, or at ICU or hospital discharge.
Overall, this review showed no evidence of an effect of corticos-
teroids on 28-day mortality, ICU mortality, or on hospital mortal-
ity from severe sepsis or septic shock. However, for these outcomes
the nominal P values were close to 0.05 and there was strong het-
erogeneity in the results. Sensitivity analyses based on trials with
adequate generation of allocation sequence, trials with adequate
allocation concealment, or double-blind trials also failed to show
any benefit from corticosteroids.
Interestingly, when sorting the trials by year, almost all trials con-
ducted before 1992 yielded a relative risk of dying at 28 days that
was above one, and almost all trials conducted after 1992 yielded
a relative risk below one. The date coincided with harmonization
of the definition of severe sepsis and septic shock (ACCP/SCCM
1992) and with a new understanding of the role of the adrenal
glands in survival following septic shock (Rothwell 1991). Before
1992 there was no standard definition of sepsis and no gradation
of patients into sepsis, severe sepsis, and septic shock. This is why
trials conducted before 1992 were more likely to include patients
with very different risks of death. Most trials designed after 1992
focused on septic shock (the group of patients with the highest
risk of death) using the same definition, which requires the need
for vasopressor agents to maintain blood pressure and organ per-
fusion. These trials also used the same strategy with a long course
21
(≥ 5 days) of low dose (≤ 300 mg) hydrocortisone or equivalent.
Sensitivity analyses on the trials of a long course (≥ 5 days) of low
dose corticosteroids (≤ 300 mg of hydrocortisone or equivalent)
showed that, in patients with septic shock, this treatment signifi-
cantly reduced 28-day all-cause mortality.
Although this subgroup analysis is a between-study and not
within-study hypothesis, we thought its validity was acceptable
according to recently proposed criteria (Guyatt 2008b). First, the
hypothesis for an interaction between dose and duration and cor-
ticosteroid effects on mortality was defined a priori. Second, we
conducted only three subgroup analyses (based on methodological
quality of studies, dose and duration, and baseline risk of death).
Third, treatment effect was large, about a 6.6% absolute differ-
ence in mortality, and rather consistent between 28-day and hos-
pital mortality (RRs of 0.84 and 0.85, respectively). Meta-regres-
sion analysis further confirmed the interaction of the dose and
duration with corticosteroids effects on mortality. Fourth, there
is strong external evidence supporting these results. Experimental
and human studies have shown that a dose of 300 mg or less of
hydrocortisone or equivalent can reverse the systemic inflamma-
tory response, endothelial activation, and coagulation disorders
secondary to an infection (Annane 2005); thus arguing against the
use of higher doses. Moreover, at these low doses corticosteroids
have been shown to improve rather than to suppress innate im-
munity in patients with septic shock (Kaufman 2008). It is now
established that severe sepsis results in a sustained pro-inflamma-
tory state, arguing against a short course of treatment (Kellum
2007). Similarly, one randomized controlled trial has compared a
short course of treatment (three days) with a longer course (seven
days) (Huh 2007). This study suggested both reduction in shock
duration and mortality, in favour of the seven-day strategy.
However, we judged the quality of evidence as moderate rather
than high because one of the two largest trials on a long course
of low-dose corticosteroids did not find a survival benefit (Sprung
2008). In addition, there are still several differences between the
various trials conducted after 1992 that should be pointed out.
First, two trials included both severe sepsis and vasopressor-depen-
dent septic shock patients (Slusher 1996; Yildiz 2002), one trial
focused on severe sepsis due to community acquired pneumonia
(Confalonieri 2005), two trials included only septic shock with
documented adrenal insufficiency (Huh 2007; Tandan 2005), and
one trial included only patients with severe sepsis who were free
of vasopressor therapy (Rinaldi 2006). Second, there was no stan-
dardization of concomitant therapy. For example, in some trials
patients may have received anti-thrombin III supplementation or
intravenous polyclonal immunoglobulins (Briegel 1999 Sprung
2008) while these treatments were not given in the other trials. The
duration of shock also may have varied from one trial to another.
Some trials included only early septic shock (Annane 2002; Huh
2007; Tandan 2005) while other trials included late septic shock
(Bollaert 1998; Chawla 1999; Cicarelli 2007) or both early and
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
late septic shock (Briegel 1999; Keh 2003; Sprung 2008). Finally,
one trial used both hydrocortisone and fludrocortisone and found
a survival benefit (Annane 2002). One trial of 509 septic shock
patients found a non-significant 3% absolute reduction in in-hos-
pital mortality when fludrocortisone was added to hydrocortisone
(Annane 2010).
The beneficial effects observed on mortality with a long course of
low dose corticosteroids may be related to the favourable effect
of the treatment on the duration of shock. Indeed, this review
showed that treatment with a long course of low dose corticos-
teroids resulted in a substantial reduction in shock duration with
fewer patients remaining on vasopressor therapy by day seven and
day 28. Treatment with a long course of low dose corticosteroids
may also attenuate the severity of inflammation (Confalonieri
2005; Keh 2003; Mikami 2007a; Oppert 2005; Rinaldi 2006) and
the intensity and duration of organ system failure (Briegel 1999;
Confalonieri 2005; Keh 2003; Oppert 2005; Sprung 2008), as
shown in this review by a marked decrease in the SOFA score at
seven day. In addition, subsequent to the favourable effect on car-
diovascular and other organ function, the corticosteroid therapy
resulted in a substantial shortening of intensive care unit length
of stay. Finally, this review also showed no evidence of effect of
corticosteroids on the rates of gastroduodenal bleeding or super-
infection, or on the proportion of patients with acquired neuro-
muscular weakness. Corticosteroids were associated with an in-
creased risk for developing hyperglycaemia and hypernatraemia.
One randomized controlled trial suggested that continuous in-
fusion of hydrocortisone resulted in fewer episodes of hypergly-
caemia than bolus administration (Loisa 2007). One trial on 509
corticosteroid-treated septic shock patients did not find any ben-
efit in normalizing blood glucose levels (Annane 2010).
The current review cannot provide recommendations to select sep-
tic shock patients who may be the best candidates for a long course
of low dose corticosteroids. The analysis of seven trials, including
patients with adrenal insufficiency, suggested a non-significant re-
duction in the risk of death. However, studies did not use the same
definition for adrenal insufficiency. Further studies are needed to
determine the best diagnostic tool for adrenal insufficiency in se-
vere sepsis or septic shock patients (Cooper 2003).
AUTHORS’ CONCLUSIONS
Implications for practice
Overall, corticosteroids did not impact on 28-day all-cause mor-
tality in severe sepsis and septic shock. Meta-analysis of a subgroup
of 12 trials investigating prolonged courses of low dose corticos-
teroids showed a favourable impact on all-cause mortality. The
dose used in these studies was 200 to 300 mg of hydrocortisone
(or equivalent), by bolus intravenous injection or continuous in-
fusion, for roughly a week. Although the evidence is not partic-
ularly robust, we suggest that treatment should be given at full
22
dose for at least 100 hours only in adults with vasopressor-depen-
dent septic shock. There is insufficient evidence from this review
to support either an abrupt or gradual interruption of treatment.
The evidence accumulated from eight trials uniformly does not
support the use of a short course of high dose corticosteroids in
severe sepsis or septic shock.
Implications for research
The criteria for adrenal insufficiency in septic shock remain to be
defined.
Ongoing trials should clarify:
1. the role of a long course of low dose corticosteroids for
treating septic shock in children;
2. the role of a long course of low dose corticosteroids for
treating severe sepsis, particularly for patients with community
acquired pneumonia;
3. the additional role of mineralocorticoid replacement;
4. the potential interaction of corticosteroids and activated
protein C in patients with septic shock.
REFERENCES
References to studies included in this review
Annane 2002 {published and unpublished data}
Annane D, Sebille V, Charpentier C, Bollaert PE, François B,
Korach JM, et al.Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with
septic shock. JAMA 2002;288(7):862–71. [PUBMED: 12186604]
Annane 2010 {published and unpublished data}
COIITSS Study Investigators, Annane D, Cariou A, Maxime V,
Azoulay E, D’honneur G, Timsit JF, et al.Corticosteroid treatment
and intensive insulin therapy for septic shock in adults: a
randomized controlled trial. JAMA 2010;303:341–8.
Bollaert 1998 {published and unpublished data}
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G,
Larcan A. Reversal of late septic shock with supraphysiologic doses
of hydrocortisone. Critical Care Medicine 1998;26(4):645–50.
[PUBMED: 9559600]
Bone 1987 {published data only}
Bone RG, Fisher CJ, Clemmer TP, Slotman GJ, Metz CA, Balk RA.
A controlled clinical trial of high-dose methylprednisolone in the
treatment of severe sepsis and septic shock. New England Journal of
Medicine 1987;317(11):653–8.
Briegel 1999 {published and unpublished data}
Briegel J, Forst H, Haller M, Schelling G, Kilger E, Kuprat G, et
al.Stress doses of hydrocortisone reverse hyperdynamic septic shock:
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The role of a long course of low dose corticosteroids for treating
septic shock needs to be evaluated in developing countries to ex-
tend generalizability.
The optimal timing to start treatment, the optimal dose of hy-
drocortisone (or equivalent), and the duration and modality of
withdrawal of treatment require further trials.
ACKNOWLEDGEMENTS
We would like to thank Dr R DeGaudio, Dr GU Meduri, Dr M
Oppert, Dr C Sprung, and Dr S Tandan for providing us with
unpublished data.
This review was initially developed within the Infectious Diseases
Group, supported by a grant from the Department for Interna-
tional Development, UK. The review was transferred to the Anaes-
thesia Group in May 2005.
We would like to thank Prof Harald Herkner (content edi-
tor), Marialena Trivella (statistical editor), Peter Minneci, Charles
Natanson, Gordon Guyatt, Matthias Briel (peer reviewers) and
Karen Hovhannisyan (Cochrane Anaesthesia Review Group Trials
search co-ordinator) for their help and editorial advice during the
preparation of this updated review.
a prospective, randomized, double-blind, single-center study.
Critical Care Medicine 1999;27(4):723–32. [PUBMED:
10321661]
Chawla 1999 {published and unpublished data}
Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory
septic shock. Critical Care Medicine 1999;27(1):A33.
Cicarelli 2007 {published data only}
Cicarelli DD, Vieira JE, Benseñor FE. Early dexamethasone
treatment for septic shock patients: a prospective randomized
clinical trial. Sao Paulo Medical Journal 2007;125:237–41.
[PUBMED: 17992396 ]
Confalonieri 2005 {published data only}
Confalonieri M, Urbino R, Potena A, Piatella M, Parigi P, Giacomo
P, et al.Hydrocortisone infusion for severe community acquired
pneumonia: a preliminary randomized study. American Journal of
Respiratory and Critical Care Medicine 2005;171:242–8.
CSG 1963 {published data only}
Cooperative Study Group. The effectiveness of hydrocortisone in
the management of severe infections. JAMA 1963;183:462–5.
Huh 2007 {published data only}
Huh JW, Lim CM, Koh Y, Hong SB. Effect of low doses of
hydrocortisone in patient with septic shock and relative adrenal
insufficiency: 3 days versus 7 days treatment. Critical Care
Medicine 2007;34 Suppl:A101.
23
Keh 2003 {published and unpublished data}
Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, Bercker
S, et al.Immunologic and hemodynamic effects of “low-dose”
hydrocortisone in septic shock: a double-blind, randomized,
placebo-controlled, crossover study. American Journal of Respiratory
and Critical Care Medicine 2003;167(4):512–20. [PUBMED:
12426230 ]
Klastersky 1971 {published data only}
Klastersky J, Cappel R, Debusscher L. Effectiveness of
betamethasone in management of severe infections. A double-blind
study. New England Journal of Medicine 1971;284(22):1248–50.
[PUBMED: 4929896]
Lucas 1984 {published data only}
Lucas C, Ledgerwood A. The cardiopulmonary response to massive
doses of steroids in patients with septic shock. Archives of Surgery
1984;119(5):537–41. [PUBMED: 6712466 ]
Luce 1988 {published and unpublished data}
Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray
JF. Ineffectiveness of high-dose methylprednisolone in preventing
parenchymal lung injury and improving mortality in patients with
septic shock. American Review of Respiratory Diseases 1988;138(1):
62–8. [PUBMED: 3202402 ]
Meduri 2007 {published and unpublished data}
Meduri GU, Golden E, Freire AX, Taylor E, Zaman M, Carson SJ,
et al.Methylprednislone infusion in early ARDS: result of a
randomised controlled trial. Chest 2007;131(4):954–63.
[PUBMED: 17426195]
Oppert 2005 {published and unpublished data}
Oppert M, Schindler R, Husung C, Offerman K, Graef KJ,
Boenisch O, et al.Low-dose hydrocortisone improves shock reversal
and reduces cytokine levels in early hyperdynamic septic shock.
Critical Care Medicine 2005;33:2457–64. [PUBMED: 16276166 ]
Rinaldi 2006 {published data only}
Rinaldi S, Adembri C, Grechi S, DE Gaudio R. Low-dose
hydrocortisone during severe sepsis: effects on microalbumineria.
Critical Care Medicine 2006;34:2334–9. [PUBMED: 16850006]
Schumer 1976 {published data only}
Schumer W. Steroids in the treatment of clinical septic shock.
Annals of Surgery 1976;184(3):333–41. [PUBMED: 786190 ]
Slusher 1996 {published data only}
Slusher T, Gbadero D, Howard C, Lewinson L, Giroir B, Toro L, et
al.Randomized, placebo-controlled, double blinded trial of
dexamethasone in African children with sepsis. Pediatric Infectious
Diseases Journal 1996;15(7):579–83. [PUBMED: 8823850]
Sprung 1984 {published and unpublished data}
Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long
WM, et al.The effects of high-dose corticosteroids in patients with
septic shock. A prospective, controlled study. New England Journal
of Medicine 1984;311(18):1137–43. [PUBMED: 6384785 ]
Sprung 2008 {published and unpublished data}
∗
Sprung C, Annane D, Keh D, Moreno R, Singer M, Freivogel K,
et al.The CORTICUS randomized, double-blind, placebo-
controlled study of hydrocortisone therapy in patients with septic
shock. New England Journal of Medicine 2008;358:111–24.
[PUBMED: 18184957]
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tandan 2005 {unpublished data only}
Tandan SM, Guleria R, Gupta N. Low dose steroids and
adrenocortical insufficiency in septic shock: a double-blind
randomised controlled trial from India. Proceedings of the
American Thoracic Society Meeting. 2005:A24.
VASSCSG 1987 {published data only}
The Veterans Administration Systemic Sepsis Cooperative Study
Group. Effect of high-dose glucocorticoid therapy on mortality in
patients with clinical signs of systemic sepsis. New England Journal
of Medicine 1987;317(11):659–65. [PUBMED: 2888017]
Wagner 1955 {published data only}
Wagner HN, Bennett IL, Lasagna L, Cluff LE, Rosenthal MB,
Mirick GS. The effect of hydrocortisone upon the course of
pneumococcal pneumonia treated with penicillin. Bulletin of Johns
Hopkins Hospital 1955;98:197–215. [PUBMED: 13304518]
Yildiz 2002 {published data only}
Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A.
Physiologic-dose steroid therapy in sepsis. Critical Care 2002;6(3):
251–9. [PUBMED: 12133187]
References to studies excluded from this review
Cicarelli 2006 {published data only}
Cicarelli DD, Bensenor FEM, Vieira JE. Effects of single dose of
dexamethasone on patients with systemic inflammatory response.
Sao Paulo Medical Journal 2006;124:90–5. [PUBMED: 16878192
]
Hahn 1951 {published data only}
Hahn EO, Houser HB, Rammelkamp CH, Denny FW,
Wannamaker LW. Effect of cortisone on acute streptococcal
infections and post-streptococcal complications. Journal of Clinical
Investigation 1951;30:274–81.
Hughes 1984 {published data only}
Hughes GS Jr. Naloxone and methylprednisolone sodium succinate
enhance sympathomedullary discharge in patients with septic
shock. Life Sciences 1984;35(23):2319–26. [PUBMED: 6390057]
Kaufman 2008 {published and unpublished data}
Kaufmann I, Briegel J, Schliephake F, Hoelzl A, Chouker A,
Hummel T, et al.Stress doses of hydrocortisone in septic shock:
beneficial effects on opsonization-dependent neutrophil functions.
Intensive Care medicine 2008;34:344–9. [PUBMED: 17906853 ]
McKee 1983 {published data only}
McKee JI, Finlay WE. Cortisol replacement in severely stressed
patients. Lancet 1983;1(8322):484. [PUBMED: 6131207 ]
Meduri 1998b {published and unpublished data}
Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA,
Kelso T, et al.Effect of prolonged methylprednisolone therapy in
unresolving acute respiratory distress syndrome: a randomized
controlled trial. JAMA 1998;280(2):159–65. [PUBMED:
9669790]
Mikami 2007 {published data only}
Mikami K, Suzuki M, Kitagawa H, Kawakami M, Hirota N,
Yamaguchi H, et al.Efficacy of corticosteroids in the treatment of
community-acquired pneumonia requiring hospitalization. Lung
2007;185:249–55. [PUBMED: 17710485]
24
Rogers 1970 {published data only}
Rogers J. Large doses of steroids in septicaemic shock. British
Journal of Urology 1970;42(6):742. [PUBMED: 4923652]
Thompson 1976 {published data only}
Thompson WL, Gurley HT, Lutz BA, Jackson DL, Kvols LK,
Morris IA. Inefficacy of glucocorticoids in shock (double-blind
study). Clinical Research 1976;24:258A.
Weigelt 1985 {published data only}
Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early
steroid therapy for respiratory failure. Archives of Surgery 1985;120
(5):536–40. [PUBMED: 3885915 ]
References to ongoing studies
IRSCTN99675218 2006 {published data only (unpublished sought
but not used)}
Effect of treatment with low-dose hydrocortisone on cirrhotic
patients presenting with septic shock to the intensive care unit.
Ongoing study 01/04/2004.
NCT00127985 2005 {published data only}
6-methylprednisolone for multiple organ dysfunction syndrome.
Ongoing study 01/08/2005.
NCT00149123 2005 {published data only}
Low dose hydrocortisone in acutely burned patients. Ongoing
study 01/04/2005.
NCT00368381 2008 {unpublished data only}
Hydrocortisone versus hydrocortisone plus fludrocortisone for the
treatment of adrenal insufficiency in severe sepsis. Ongoing study
September 2006.
NCT00471640 2008 {published data only}
Dexamethasone infusion in community acquired pneumonia.
Ongoing study 01/05/2008.
NCT00562835 2008 {published data only}
Steroids in patients with early ARDS. Ongoing study February
2008.
NCT00625209 2008 {unpublished data only}
Activated Protein C and Corticosteroids for Human Septic Shock
(APROCCHS). Ongoing study April 2008.
NCT00670254 2008 {published data only}
Hydrocortisone for prevention of septic shock. Ongoing study 01/
06/2008.
NCT00732277 2008 {published data only}
Evaluation of corticosteroid therapy in childhood severe sepsis: a
randomized pilot study. Ongoing study 01/04/2008.
Additional references
ACCP/SCCM 1992
ACCP/SCCM consensus conference panel. American College of
Chest Physicians/Society of Critical Care Medicine Consensus
Conference: definitions for sepsis and organ failure and guidelines
for the use of innovative therapies in sepsis. Critical Care Medicine
1992;20(6):864–74. [PUBMED: 1597042 ]
Annane 2000
Annane D, Sébille V, Troché G, Raphael JC, Gajdos P, Bellissant E.
A 3-level prognostic classification in septic shock based on cortisol
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
levels and cortisol response to corticotropin. JAMA 2000;283(8):
1038–45. [PUBMED: 10697064]
Annane 2003
Annane D, Aegerter P, Jars-Guincestre MC, Guidet B, CUB-Rea
Network. Current epidemiology of septic shock: the CUB-Réa
Network. American Journal of Respiratory and Critical Care
Medicine 2003;168(2):165–72. [PUBMED: 12851245]
Annane 2005
Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet 2005;
365:63–78. [PUBMED: 15639681]
Annane 2009b
Annane D. Improving clinical trials in the critically ill: unique
challenge: sepsis. Critical Care Medicine 2009;37 Suppl:117–28.
[PUBMED: 19104211]
Barnes 1995
Barnes PJ, Greening AP, Crompton GK. Glucocorticoid resistance
in asthma. American Journal of Respiratory and Critical Care
Medicine 1995;152 Suppl(6 Pt 2):125–40. [PUBMED: 7489120]
Bone 1991
Bone RC. Sepsis, the sepsis syndrome, multi-organ failure: a plea
for comparable definitions. Annals of Internal Medicine 1991;114
(4):332–3. [PUBMED: 1987879]
Briegel 1994
Briegel J, Kellermann W, Forst H, Haller M, Bittl M, Hoffmann
GE, et al.Low-dose hydrocortisone infusion attenuates the systemic
inflammatory response syndrome. The Phospholipase A2 Study
Group. Clinical Investigation 1994;72:782–7. [PUBMED:
7865982]
Chrousos 1995
Chrousos GP. The hypothalamic-pituitary-adrenal axis and
immune-mediated inflammation. New England Journal of Medicine
1995;322(20):1351–62. [PUBMED: 7715646]
Cooper 2003
Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill
patients. New England Journal of Medicine 2003;348(8):727–34.
[PUBMED: 12594318 ]
Cronin 1995
Cronin L, Cook DJ, Carlet J, Heyland DK, King D, Lansang
MAD, et al.Corticosteroid treatment for sepsis: a critical appraisal
and meta-analysis of the literature. Critical Care Medicine 1995;23
(8):1430–9. [PUBMED: 7634816 ]
de Kruif 2007
de Kruif MD, Lemaire LC, Giebelen IA, van Zoelen MA, Pater JM,
van den Pangaart PS, et al.Prednisolone dose-dependently
influences inflammation and coagulation during human
endotoxemia. Journal of Immunology 2007;178:1845–51.
[PUBMED: 17237435]
Dellinger 2008
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke
R, et al.Surviving Sepsis Campaign: international guidelines for
management of severe sepsis and septic shock: 2008. Critical Care
Medicine 2008;36:296–327. [PUBMED: 20035219 ]
Devereaux 2001
Devereaux PJ, Manns BJ, Ghali WA, Quan H, Lacchetti C,
Montori VM, et al.Physician interpretations and textbook
25
 definitions of blinding terminology in randomized controlled trials.
JAMA 2001;285:2000–3. [PUBMED: 11308438 ]
Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-
analysis detected by a simple, graphical test. BMJ 1997;315:
629–34. [PUBMED: 9310563]
Fabian 1982
Fabian TC, Patterson R. Steroid therapy in septic shock. Survival
studies in a laboratory model. American Surgeon 1982;48(12):
614–7. [PUBMED: 6760756]
Finfer 2004
Finfer S, Bellomo R, Lipman J, French C, Dobb G, Myburgh J.
Adult population incidence of severe sepsis in Australian and New
Zealand intensive care units. Intensive Care Medicine 2004;30:589-
96. [PUBMED: 14963646]
Guyatt 2008a
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-
Coello P, et al.GRADE Working Group. GRADE: an emerging
consensus on rating quality of evidence and strength of
recommendations. BMJ 2008;336:924–6. [PUBMED: 18436948
] Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of
Guyatt 2008b
Guyatt GH, Wyer P, Ioannidis J. When to believe a subgroup
analysis. In: Guyatt G, Rennie R, Meade M, Cook D editor(s).
User’s Guides to the Medical Literature: A Manual for Evidence-Based
Clinical Practice. New York: McGraw-Hill, 2008.
Heller 2003
Heller AR, Heller SC, Borkenstein A, Stehr SN, Koch T.
Modulation of host defense by hydrocortisone in stress doses during
endotoxemia. Intensive Care Medicine 2003;29:1456–63.
[PUBMED: 12879235 []
Higgins 2005
Higgins JPT, Green S, editors. Cochrane Handbook for Systematic
Reviews of Interventions 4.2.5 [updated May 2005]. In: The
Cochrane Library. Issue 3, 2005. Chichester, UK: John Wiley &
Sons, Ltd.
Hotta 1986
Hotta M, Baird A. Differential effects of transforming growth
factor type beta on the growth and function of adrenocortical cells
in vitro. Proceedings of the National Academy of Sciences of the United
States of America 1986;83(20):7795–9. [PUBMED: 3020557]
Huang 1987
Huang ZH, Gao H, Xu RB. Study on glucocorticoid receptors
during intestinal ischemia shock and septic shock. Circulatory Shock
1987;23(1):27–36. [PUBMED: 3690811]
Jaattela 1991
Jaattela M, Ilvesmaki V, Voutilainen R, Stenman UH, Saksela E.
Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-
induced cortisol production and steroidogenic P450 enzyme gene
expression in cultured human fetal adrenal cells. Endocrinology
1991;128(1):623–9. [PUBMED: 1702707]
Juni 2001
Juni P, Altman DG, Egger M. Systematic reviews in healthcare:
Assessing the quality of controlled clinical trials. BMJ 2001;323
(7303):42–6.
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kellum 2007
Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky
MR, et al.Understanding the inflammatory cytokine response in
pneumonia and sepsis: results of the Genetic and Inflammatory
Markers of Sepsis (GenIMS) Study. Archives of Internal Medicine
2007;168:1468–9. [PUBMED: 17698689]
Lefering 1995
Lefering R, Neugebauer EAM. Steroid controversy in sepsis and
septic shock: a meta-analysis. Critical Care Medicine 1995;23(7):
1294–303. [PUBMED: 7600840 ]
Lipiner 2007
Lipiner D, Sprung CL, Laterre PF, Weiss Y, Goodman SV, Vogeser
M, et al.Adrenal function in sepsis: The restrospective corticus
cohort study. Critical Care Medicine 2007;35:1012–8.
Loisa 2007
Loisa P, Parviainen I, Tenhunen J, Hovilehto S, Ruokonen E. Effect
of mode of hydrocortisone administration on glycemic control in
patients with septic shock: A prospective randomized trial. Critical
Care 2007;11:R21. [PUBMED: 17306016 ]
Martin 2003
sepsis in the United States from 1979 through 2000. New England
Journal of Medicine 2003;348:1546–54. [PUBMED: 12700374 ]
Meduri 1998a
Meduri GU, Chrousos GP. Duration of glucocorticoid treatment
and outcome in sepsis: is the right drug used the wrong way?. Chest
1998;114(2):355–60. [PUBMED: 9726712]
Molijn 1995
Molijn GJ, Koper JW, van Uffelen CJ, de Jong FH, Brinkmann
AO, Bruining HA, et al.Temperature-induced down-regulation of
the glucocorticoid receptor in peripheral blood mononuclear
leucocyte in patients with sepsis or septic shock. Clinical
Endocrinology 1995;43(2):197–203. [PUBMED: 7554315 ]
Padkin 2003
Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K.
Epidemiology of severe sepsis occurring in the first 24 hrs in
intensive care units in England, Wales, and Northern Ireland.
Critical Care Medicine 2003;31:2332-8. [PUBMED: 14501964 ]
Parrillo 1993
Parrillo JE. Pathogenic mechanisms of septic shock. New England
Journal of Medicine 1993;328(20):1471–7.
Peters 2008
Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Contour-
enhanced meta-analysis funnel plots help distinguish publication
bias from other causes of asymmetry. Journal of Clinical
Epidemiology 2008;61:991–6.
RevMan 5
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan) Version 5.0. Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2008.
Rothwell 1991
Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to
corticotropin and survival in septic shock. Lancet 1991;337(8741):
582–3.
26
The EPISPESIS group 2004
The EPISPESIS group. EPISEPSIS: a reappraisal of the
epidemiology and outcome of severe sepsis in French intensive care
units. Intensive Care Medicine 2004;30:580–8. [PUBMED:
14997295]
Tsao 2004
Tsao CM, Ho ST, Chen A, Wang JJ, Li CY, Tsai SK, et al.Low-dose
dexamethasone ameliorates circulatory failure and renal dysfunction
in conscious rats with endotoxemia. Shock 2004;21::484–91.
Vachharajani 2006
Vachharajani V, Vital S, Russell J, Scott LK, Granger DN.
Corticosteroids for treating severe sepsis and septic shock (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Glucocorticoids inhibit the cerebral microvascular dysfunction
associated with sepsis in obese mice. Microcirculation 2006;13:
477–87. [PUBMED: 16864414 ]
References to other published versions of this review
Annane 2009
Annane D, Bellissant E, Bollaert PE, Briegel J, Confalonieri M, De
Gaudio R, et al.Corticosteroids in the treatment of severe sepsis and
septic shock in adults: a systematic review. JAMA 2009;301:
2362–75. [PUBMED: 19509383 ]
∗
Indicates the major publication for the study
27
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Annane 2002

Methods Randomized controlled trial with 2 parallel groups.

19 centres.

Participants Adults (n = 300) with vasopressor- and ventilator-dependent septic shock.

Stratification according to cortisol response to 250µg Synacthene into non-responders
(delta cortisol of 9µg/dl or less) and responders (>9µg/dl).

Interventions (1) Hydrocortisone (50 mg intravenous bolus every 6 hours for 7 days plus fludrocorti-
sone 50 µg taken orally every 24 hours for 7 days). (2) Respective placebos.
Treatments have to be initiated within 8 hours from shock onset.

Outcomes PRIMARY
(1) 28-day mortality in non responders.
SECONDARY
(2) 28-day mortality in responders and in all patients.
(3) Intensive care unit mortality rate.
(4) Hospital mortality rate.
(5) 1 year mortality rate.
(6) Shock reversal.
(7) Organ system failure free days.
(8) Safety.

Notes Study location: France.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes Randomization was centralised

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes lost to follow up: none

All outcomes

Free of selective reporting? Yes access to study protocol excluding report-

ing bias

Corticosteroids for treating severe sepsis and septic shock (Review) 28

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Annane 2002 (Continued)

Free of other bias? Yes full access to data excluding selection bias

Annane 2010

Methods Randomized controlled trial with 2 x 2 factorial design

11 centres.

Participants Adults (n = 509) with vasopressor-dependent septic shock.

Interventions (1) Hydrocortisone (50 mg intravenous bolus every 6 hours for 7 days) plus fludrocorti-
sone (50 µg taken orally every 24 hours for 7 days) and intravenous insulin to maintain
blood glucose between 80 and 110 mg/dL.
(2) Hydrocortisone (50 mg intravenous bolus every 6 hours for 7 days ) and intravenous
insulin to maintain blood glucose between 80 and 110 mg/dL.
(3) Hydrocortisone (50 mg intravenous bolus every 6 hours for 7 days) plus fludrocor-
tisone (50 µg taken orally every 24 hours for 7 days) and conventional control of blood
glucose levels.
(4) Hydrocortisone (50 mg intravenous bolus every 6 hours for 7 days) and conventional
control of blood glucose levels.
Treatments have to be initiated within 24h from shock onset.

Outcomes PRIMARY
(1) Hospital mortality in non-responders.
SECONDARY
(2) Mortality rates at 28-day mortality, 90-day, 180-day and at ICU discharge
(3) Vasopressor-free days
(4) Organ failure-free days
(5) ICU and hospital length of stay
(6) Safety.

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated

Allocation concealment? Yes Randomization was centralised through a

secured website

Blinding? No Patients: yes

All outcomes Care givers: no
Data collectors: yes
Outcome assessors: no
Data analysts: yes

Corticosteroids for treating severe sepsis and septic shock (Review) 29

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Annane 2010 (Continued)

Incomplete outcome data addressed? Yes No loss to follow up

All outcomes

Free of selective reporting? Yes Access to study protocol excluding report-

ing bias

Free of other bias? Yes Full access to data excluding selection bias

Bollaert 1998

Methods Randomized controlled trial with 2 parallel groups.

2 centres.

Participants Adults (n = 41) with vasopressor- and ventilator-dependent septic shock.

Stratification according to cortisol response to 250µg Synacthene into non-responders
(delta cortisol of 6µg/dl or less) and responders (>6µg/dl).

Interventions (1) Hydrocortisone (100 mg intravenous bolus every 8 hours for 5 days then tapered
over 6 d).
(2) Placebo.
Treatments have to be initiated after 48 hours or more from shock onset.

Outcomes PRIMARY
(1) Shock reversal.
SECONDARY
(2) 28-day mortality.
(3) Improvement in haemodynamics.
(4) Safety.

Notes Study location: France.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes The randomization list was kept confiden-

tial by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Corticosteroids for treating severe sepsis and septic shock (Review) 30

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bollaert 1998 (Continued)

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Yes Access to study protocol excluding report-

ing bias

Free of other bias? Yes Full access to data excluding selection bias

Bone 1987

Methods Randomized controlled trial with 2 parallel groups.

19 centres.

Participants Adults (n = 382) with severe sepsis (n = 234) or septic shock (n = 148).

Interventions (1) Methylprednisolone (30 mg/kg 20 min intravenous infusion, every 6 hours for 24
hours).
(2) Placebo.
Treatments have to be initiated 2 hours from time entry criteria were met.

Outcomes PRIMARY
(1) 14-day development of shock for severe sepsis.
(2) Shock reversal for septic shock.
(3) 14-day death and safety.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes Randomization was centralized

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol to exclude re-

porting bias

Corticosteroids for treating severe sepsis and septic shock (Review) 31

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bone 1987 (Continued)

Free of other bias? Yes No access to full data including screening

log to exclude selection bias

Briegel 1999

Methods Randomized controlled trial with 2 parallel groups.

1 centre.

Participants Adults (n = 40) with vasopressor- and ventilator-dependent septic shock.

Interventions (1) Hydrocortisone (100 mg 30 min intravenous infusion followed by 0.18 mg/kg/h
continuous infusion until shock reversal and then tapered off ).
(2) Placebo.
Treatments have to be initiated within 72 hours from shock onset.

Outcomes PRIMARY
(1) Shock reversal.
SECONDARY
(2) 28-day mortality.
(3) Improvement in haemodynamics.
(4) Organ system failure.
(5) Safety.

Notes Study location: Germany.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes Adequate

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Yes Access to study protocol excluding report-

ing bias

Free of other bias? Yes Access to full data including screening log

Corticosteroids for treating severe sepsis and septic shock (Review) 32

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Chawla 1999

Methods Randomized controlled trial with 2 parallel groups.

1 centre.

Participants Adults (n = 44) with vasopressor-dependent septic shock.

Interventions (1) Hydrocortisone (100 mg intravenous bolus every 8 hours for 3 days then tapered
over 4 days).
(2) Placebo.
Treatments have to be initiated after 72 hours or more from shock onset.

Outcomes PRIMARY
(1) Shock reversal.
SECONDARY
(2) 28-day mortality.
(3) Improvement in haemodynamics.
(4) Safety.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes The randomization list was kept confiden-

tial by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes lost to follow up: none

All outcomes

Free of selective reporting? Yes access to study protocol excluding report-

ing bias

Free of other bias? Yes access to full data including screening log

Corticosteroids for treating severe sepsis and septic shock (Review) 33

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cicarelli 2007

Methods Randomized controlled trial with 2 parallel groups.

Participants Adults (n = 29) with vasopressor-dependent septic shock.

Interventions (1) dexamethasone (0.2 mg/kg intravenous, three doses at intervals of 36 hours).

Outcomes (1) duration of vasopressor support (SOFA score for cardiovascular system of two or
more),
(2) duration of mechanical ventilation,
(3) 28-day mortality.

Notes Study location: Brasil.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes The randomization list was kept confiden-

tial by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care-givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Unclear Lost to follow up: none; 3 patients were
All outcomes withdrawn after next of kin refused to con-
sent

Free of selective reporting? Unclear No access to study protocol to rule out re-
porting bias

Free of other bias? Unclear No access to data to rule out selection bias

Confalonieri 2005

Methods Randomized controlled trial with 2 parallel groups.

6 centres.

Participants 46 patients with severe community acquired pneumonia.

Interventions (1) Hydrocortisone (200 mg intravenous loading bolus followed by a continuous infusion
at a rate of 10 mg/hour for 7 days then tapered over 4 days).
(2) Placebo.

Corticosteroids for treating severe sepsis and septic shock (Review) 34

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Confalonieri 2005 (Continued)

Outcomes PRIMARY
(1) Improvement in PaO2:FiO2 and in multiple organ dysfunction syndrome score by
study day 8.
SECONDARY
(2) Duration of mechanical ventilation.
(3) Length of stay.
(4) Survival to hospital discharge and to 60 days.
(5) Safety.

Notes Study location:

Italy.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes Randomization was centralized

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: 2 at 60 days after ran-
All outcomes domization, all in the placebo group

Free of selective reporting? No Study was stopped prematurely for appar-

ent benefit; there were no a priori defined
sample size but the authors used the trian-
gular test as a stopping rule, analysing the
primary outcome after each 20 patients

Free of other bias? Yes Access to full data including screening log

CSG 1963

Methods Randomized controlled trial with 2 parallel groups.

5 centres.

Participants Adults (n = 194) and children (n = 135) with vasopressor-dependent septic shock.

Interventions (1) Hydrocortisone (intravenous infusion of 300 mg for 24 hours then 250 mg for 24
hours, followed by 200 mg orally on day 3, then tapered off in steps of 50 mg per day,
i.e. total duration of treatment 6 days).

Corticosteroids for treating severe sepsis and septic shock (Review) 35

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CSG 1963 (Continued)

(2) Placebo.

Outcomes PRIMARY
(1) Hospital mortality.
SECONDARY
(2) Safety.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not given

Allocation concealment? Unclear Not given

Blinding? Unclear Patients: yes

All outcomes Care givers: yes
Data collectors:unclear
Outcome assessors: unclear
Data analysts: unclear

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol to exclude re-

porting bias

Free of other bias? Unclear No access to data to exclude selection bias

Huh 2007

Methods Randomized controlled trial with 2 parallel groups.

Participants 82 patients with septic shock and adrenal insufficiency.

Interventions Hydrocortisone was administered intravenously every 6 hours as a 50mg bolus for 3 days
versus 7 days.

Outcomes PRIMARY
(1) 28-day mortality.
SECONDARY
(2) Shock reversal.
(3) Duration of mechanical ventilation.
(4) Length of stay.
(5) Safety.

Corticosteroids for treating severe sepsis and septic shock (Review) 36

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Huh 2007 (Continued)

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not given

Allocation concealment? Unclear Not given

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Unclear Lost to follow up: none

All outcomes

Free of selective reporting? Unclear Only abstract from scientific meeting pro-
ceeding

Free of other bias? Unclear Only abstract from scientific meeting pro-
ceeding

Keh 2003

Methods Randomized controlled trial with crossover design.

Participants Adults (n = 40) with vasopressor dependent septic shock.

Interventions (1) Hydrocortisone (100 mg 30 min intravenous infusion followed by 10 mg/h contin-
uous infusion for 3 days.
(2) Placebo.
All participants received hydrocortisone for 3 days preceded or followed by placebo for
3 days.

Outcomes PRIMARY
(1) Immune response.
SECONDARY
(2) Improvement in haemodynamics and organ system failure.
(3) Safety.

Notes Study location: Germany.

Risk of bias

Corticosteroids for treating severe sepsis and septic shock (Review) 37

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Keh 2003 (Continued)

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes The randomization list was kept confiden-

tial by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Yes Access to study protocol

Free of other bias? Yes Full access to data including screening log

Klastersky 1971

Methods Randomized controlled trial with parallel groups.

1 centre.

Participants Adults (n = 85) with disseminated cancer and life-threatening infection.

Interventions (1) Betamethasone (1 mg/kg per day in 2 intravenous doses for 3 consecutive days).
(2) Placebo.

Outcomes (1) 30-day mortality.

(2) Rate of adverse events.

Notes Study location: Belgium.

Treatment kits chosen by random number.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not given

Allocation concealment? Unclear Not given

Corticosteroids for treating severe sepsis and septic shock (Review) 38

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Klastersky 1971 (Continued)

Blinding? Unclear Patients: yes

All outcomes Care givers: yes
Data collectors: unclear
Outcome assessors: unclear
Data analysts: unclear

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Lucas 1984

Methods Randomized controlled trial.

1 centre.

Participants Adults (n = 48) with septic shock.

Interventions (1) Dexamethasone (2 mg/kg as a single intravenous bolus followed a maintenance

infusion of 2 mg/kg/24 h for 2 days).
(2) Standard treatment.

Outcomes PRIMARY
(1) 14-day mortality (unclear).
SECONDARY
(2) Improvement in haemodynamics.
(3) Improvement in pulmonary function.
(4) Safety.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? No Hospital number

Allocation concealment? No Hospital number

Blinding? No Patients: no
All outcomes Care givers: no
Data collectors: no
Outcome assessors: no
Data analysts: no

Corticosteroids for treating severe sepsis and septic shock (Review) 39

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Lucas 1984 (Continued)

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? No No access to study protocol

Free of other bias? No No access to data to exclude selection bias

Luce 1988

Methods Randomized controlled trial.

1 centre.

Participants Adults (n = 75) with septic shock.

Interventions (1) Methylprednisolone (30 mg/kg 15 min intravenous infusion, every 6 hours for 24
hours).
(2) Placebo.

Outcomes PRIMARY
(1) Prevention of acute respiratory distress syndrome.
SECONDARY
(2) Hospital mortality.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization scheme

Allocation concealment? Yes The randomization list was kept confidential

by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? No 12 out of 87 randomized patients were not

All outcomes analysed and their follow up not given

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No access to data to exclude selection bias

Corticosteroids for treating severe sepsis and septic shock (Review) 40

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Meduri 2007

Methods Randomized controlled trial (2:1 scheme), 5 centres.

Participants Adults (n=91) with early ARDS (72 hours or less from diagnosis of ARDS). 61 (67%)
had severe sepsis or septic shock, and the primary author provided separate data for these
patients.
Stratification according to cortisol response to 250µg Synacthene into non responders
(delta cortisol of 9µg/dl or less) and responders (>9µg/dl).

Interventions (1) Methylprednisolone loading dose of 1 mg/kg followed by a continuous infusion of

1 mg/kg/day from day 1 to day 14, then 0.5 mg/kg/day from day 15 to day 21, then
0.25 mg/kg/day from day 22 to day 25, then 0.125mg/kg/day from day 26 to day 28. If
the patient was extubated before day 14, he/she was advanced to day 15 of drug therapy.
Treatment was given intravenously until enteral intake was restored, then it was given as
a single oral dose.
(2) Placebo.

Outcomes Primary outcome

(1) improvement in Lung Injury Score (LIS) at day 7. This improvement was defined as
a reduction in the score of 1 point or more and a day 7 score of 2 or less (if randomization
LIS score <3) or of 2.5 or less (if randomization LIS score <3).
Secondary outcome
(2) Mechanical ventilation free days.
(3) Multiple organ dysfunction (MOD) score at study day 7.
(4) Survival.
(5) C reactive protein levels at study day 7.
(6) Safety.

Notes If the patient failed to improve on a Lung Injury Score between day 7 and day 9, he/she
received open labelled methylprednisolone at 2mg/kg/day for unresolving ARDS

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated

Allocation concealment? Yes Randomization was centralized

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Full access to data excluding any attrition
All outcomes bias

Free of selective reporting? No The study was stopped prematurely for ef-
ficacy

Corticosteroids for treating severe sepsis and septic shock (Review) 41

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Meduri 2007 (Continued)

Free of other bias? Yes Full access to data including screening log

Oppert 2005

Methods Randomized controlled trial with 2 parallel groups.

1 centre

Participants Adults (n = 40) with vasopressor dependent septic shock.

Interventions (1) Hydrocortisone (50 mg of intravenous bolus followed by 0.18 mg per Kg of body
weight per hour continuous infusion up to cessation of vasopressor for 1 hour or more,
and was reduced to a dose of 0.02 mg per Kg of body weight per hour for 24 hours and
then it was reduced by 0.02 mg/kg of body weight per hour every day.
(2) Placebo.

Outcomes PRIMARY
(1) Time to cessation of vasopressor support.
SECONDARY
(2) Cytokine response
(3) 28-day survival
(4) Sequential Organ Failure Assesment (SOFA) score.

Notes Study location: Germany.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes The randomization list was kept confiden-

tial by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed?
All outcomes
Yes 7 out of 48 randomized patients were not
analysed, 5 in the corticosteroid group and
2 in the placebo group. Four of these 7 pa-
tients were lost to follow up and 3 died (all
in the steroid group)

Corticosteroids for treating severe sepsis and septic shock (Review) 42

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Oppert 2005 (Continued)

Free of selective reporting? Yes Access to study protocol excluding report-

ing bias

Free of other bias? Unclear Full access to data including screening log

Rinaldi 2006

Methods Randomized controlled trial with 2 parallel groups.

1 centre

Participants Adults (n=40) with severe sepsis and not receiving a vasopressor support.

Interventions (1) Hydrocortisone (300 mg per day as a continuous infusion for 6 days and then tapered
off ).
(2) Standard therapy.

Outcomes PRIMARY
(1) not explicitly stated.
SECONDARY
(2) Markers of inflammation: microalbuminuria to creatinine ratio, serum levels of C
reactive protein and procalcitonin
(3) Duration of mechanical ventilation
(4) Sequential Organ Failure Assesment (SOFA) score.
(5) Length of stay
(6) Hospital mortality.

Notes Study location:

Italy.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated list

Allocation concealment? Yes Sealed envelopes

Blinding? No Patients: no
All outcomes Care givers: no
Data collectors: no
Outcome assessors: no
Data analysts: no

Incomplete outcome data addressed? Yes 12 out of 52 patients dropped out of the
All outcomes study, 6 in the control group and 6 in the
corticosteroid group; contact with primary
author permitted to complete follow up for

Corticosteroids for treating severe sepsis and septic shock (Review) 43

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rinaldi 2006 (Continued)

all of the 12 patients

Free of selective reporting? Yes Access to study protocol excluding any re-
porting bias

Free of other bias? Yes Full access to data including screening log

Schumer 1976

Methods Randomized controlled trial with 3 parallel groups.

1 centre.

Participants Adults (n = 172) with septic shock with positive blood cultures.

Interventions (1) Dexamethasone (3 mg/kg as a single intravenous bolus).

(2) Methylprednisolone (30 mg/kg as a single intravenous bolus).
(3) Placebo.
Treatments might have been repeated once after 4 h and have to be initiated at the time
of diagnosis.

Outcomes PRIMARY
(1) Hospital mortality.
SECONDARY
(2) Complications rates.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? No Randomized card system

Allocation concealment? No Unsealed envelopes

Blinding? Unclear Patients: yes

All outcomes Care givers: unclear
Data collectors: unclear
Outcome assessors: unclear
Data analysts: unclear

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Corticosteroids for treating severe sepsis and septic shock (Review) 44

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Slusher 1996

Methods Randomized controlled trial.

2 centres.

Participants African children (n = 72; 1 to 16 years) with severe sepsis or septic shock.

Interventions (1) Dexamethasone (0.20 mg/kg every 8 h for 2 days).

(2) Placebo.
Treatments have to be initiated 5 to 10 min before the first dose of antibiotic.

Outcomes PRIMARY
(1) Hospital mortality (unclear).
SECONDARY
(2) Haemodynamic stability at 48 h.
(3) Complications.

Notes Study location: USA, Kenya, and Nigeria.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not given

Allocation concealment? Unclear Unclear; not reported

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Sprung 1984

Methods Randomized controlled trial with 3 parallel groups.

2 centres.

Participants Adults (n = 59) with vasopressor-dependent septic shock.

Interventions (1) Dexamethasone (6 mg/kg as a single intravenous 10 to 15 min infusion).

(2) Methylprednisolone (30 mg/kg as a single intravenous 10 to 15 min infusion).
(3) No treatment.

Corticosteroids for treating severe sepsis and septic shock (Review) 45

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sprung 1984 (Continued)

(4) Placebo.
Treatments might have been repeated once after 4 h if shock have persisted and have to
be initiated at the time of diagnosis.

Outcomes PRIMARY
(1) Hospital mortality.
(2) Shock reversal.
SECONDARY
(3) Complications of septic shock.
(4) Treatments’ safety.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? No In one centre it is not clear how the ran-

domization list was kept confidential

Blinding? No Patients: yes in one centre, no in the other

All outcomes Care givers: yes in one centre, no in the
other
Data collectors: yes in one centre, no in the
other
Outcome assessors: yes in one centre, no in
the other
Data analysts: unclear
The university of Miami research commit-
tee did not allow the study to be performed
in a double blind manner nor that patients
received a placebo

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Corticosteroids for treating severe sepsis and septic shock (Review) 46

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sprung 2008

Methods Randomized controlled trial with 2 parallel groups.

Participants Adults (n = 499) with septic shock.

Interventions (1) Hydrocortisone (50 mg every 6 hours for 5 days then 50 mg every 12 hours for 3
days and then 50 mg once a day for 3 days.
(2) Placebo.

Outcomes PRIMARY
(1) 28-day mortality in non-responders.
SECONDARY
(2) 28-day mortality in responders and in all patients.
(3) Intensive care unit mortality rate.
(4) Hospital mortality rate.
(5) 1 year mortality rate.
(6) Shock reversal.
(7) Organ system failure free days.
(8) Safety.

Notes Study location: Europe and Israel.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization

scheme

Allocation concealment? Yes Randomization was centralized

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none; 1 patients with-
All outcomes drew his consent

Free of selective reporting? Yes Access to study protocol to confirm the ab-
sence of reporting bias

Free of other bias? No Only 500 patients were included while the
expected size was 800 patients

Corticosteroids for treating severe sepsis and septic shock (Review) 47

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tandan 2005

Methods Randomized controlled trial with 2 parallel groups.

Participants Adults (n=28) with septic shock and adrenal insufficiency.

Interventions (1) Hydrocortisone (stated low dose but actual dose and duration not reported).
(2) Placebo.

Outcomes PRIMARY
(1) 28-day mortality or survival to hospital discharge.
SECONDARY
(2) Shock reversal.
(3) Improvement in APACHE II score
(4) Safety.

Notes Study location: India.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated

Allocation concealment? Yes The randomization list was kept confiden-

tial by the local pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Unclear Lost to follow up: unknown

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

VASSCSG 1987

Methods Randomized controlled trial.

10 centres.

Participants Adults (n = 223) with severe sepsis or septic shock (n = 100).

Interventions (1) Methylprednisolone (30 mg/kg as a single intravenous 10 to 15 min infusion, followed
by a constant infusion of 5 mg/kg/h for 9 h).
(2) Placebo.

Corticosteroids for treating severe sepsis and septic shock (Review) 48

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
VASSCSG 1987 (Continued)

Treatments had to be initiated within 2 h.

Outcomes PRIMARY
(1) 14-day mortality.
SECONDARY
(2) Complications.

Notes Study location: USA.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization scheme

Allocation concealment? Yes Randomization was centralized

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Wagner 1955

Methods Quasi-randomized controlled trial with 2 parallel groups.

2 centres.

Participants Adults (n = 113) with pneumococcal pneumonia; shock was present only in 3 patients.

Interventions (1) Hydrocortisone (orally 80 mg on admission followed by 60 mg 3 times on day 1,

then 40 mg 4 times on day 2, 20 mg 4 times on day 3, 10 mg 4 times on day 4, and 10
mg twice on day 5).
(2) Standard therapy (first 85 patients).
(3) Placebo (last 28 patients).

Outcomes (1) Fever.

(2) Pleuritic pains.
(3) Patient’s well being.

Notes Study location: USA.

Corticosteroids for treating severe sepsis and septic shock (Review) 49

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Wagner 1955 (Continued)

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? No Hospital number

Allocation concealment? No Hospital number

Blinding? No Patients: no, except for the last 28 patients

All outcomes Care givers: no, except for the last 28 pa-
tients
Data collectors: no
Outcome assessors:
Data analysts: no
A placebo was used only for the 28 last pa-
tients, out of 113

Incomplete outcome data addressed? Unclear Lost to follow up: unknown

All outcomes

Free of selective reporting? Unclear No access to study protocol

Free of other bias? Unclear No data to exclude selection bias

Yildiz 2002

Methods Randomized controlled trial.

1 centre.

Participants Adults (n = 40) with sepsis (n = 14), severe sepsis (n = 17), and septic shock (n = 9).

Interventions (1) Prednisolone (2 intravenous bolus, 5 mg at 06:00 and 2.5 mg at 18:00 for 10 days).
(2) Placebo.

Outcomes PRIMARY
(1) 28-day mortality.
SECONDARY
(2) Complications.

Notes Study location: Turkey.

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated randomization scheme

Corticosteroids for treating severe sepsis and septic shock (Review) 50

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Yildiz 2002 (Continued)

Allocation concealment? Yes The randomization list was kept confidential

by the pharmacist

Blinding? Yes Patients: yes

All outcomes Care givers: yes
Data collectors: yes
Outcome assessors: yes
Data analysts: yes

Incomplete outcome data addressed? Yes Lost to follow up: none

All outcomes

Free of selective reporting? Unclear No access to protocol

Free of other bias? Unclear No data to exclude selection bias

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Cicarelli 2006 Mixed population of critically ill patients, and separate data from septic shock not available.

Hahn 1951 Patients with acute streptococcal infections but not septic shock.
This trial has investigated the effect of hydrocortisone on fever, anti-streptolysin titers, and onset of rheumatic
fever. No data are reported for the analysis of the various outcomes considered in this systematic review.

Hughes 1984 Only acute effects (within 1 h) of methylprednisolone and/or naloxone on haemodynamic data were available,
and no data for any of the outcomes considered in this systematic review were reported.

Kaufman 2008 In this study, patients were randomly assigned to receive hydrocortisone or its placebo for 24 hours only. Then,
treatment with open-labelled hydrocortisone was given at physicians discretion. The study was aimed at exploring
hydrocortisone effects on immune cells function.

McKee 1983 Mixed population of critically ill patients, and separate data from septic shock not available.

Meduri 1998b This trial included patients with late acute respiratory distress syndrome phase and not patients with septic shock.

Mikami 2007 This study has included patients with community acquired pneumonia and has explicitly excluded patients with
sepsis, or those needing admission to the intensive care unit, or those requiring mechanical ventilation

Rogers 1970 Study published only as an abstract, no contact with authors was possible, incomplete information for primary
and secondary outcomes.

Thompson 1976 Study published only as an abstract, no contact with authors was possible, incomplete information for primary
and secondary outcomes.

Corticosteroids for treating severe sepsis and septic shock (Review) 51

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

Weigelt 1985 Mixed population of critically ill patients.

Separate data from septic shock not available.

Characteristics of ongoing studies [ordered by study ID]

IRSCTN99675218 2006

Trial name or title Effect of treatment with low-dose hydrocortisone on cirrhotic patients presenting with septic shock to the
intensive care unit

Methods Randomized, double blind, placebo-controlled study on 2 parallel groups

Participants Septic shock in adults cirrhotic patients

Interventions Hydrocortisone versus placebo

Outcomes Primary outcome: 28-day all cause mortality

Starting date 01/04/2004

Contact information Yaseen Arabi, yaseenarabi@yahoo.com

Notes

NCT00127985 2005

Trial name or title 6-methylprednisolone for multiple organ dysfunction syndrome

Methods Randomized, double blind, placebo-controlled study on 2 parallel group

Participants Adults with persistent multiple organ dysfunction

Interventions Intravenous administration of 6-methylprednisolone or a placebo for 32 days

Loading dose of 160mg followed by iv bolus q6 of 40 mg from day 1 to 14, 20mg from day 15 to 21, 10 mg
from day 22 to 28, 5mg on days 29 and 30 and 2.5mg on days 31 and 32.

Outcomes Primary outcome: 28-day all cause mortality

Starting date 01/08/2005

Contact information Miguel Sanchez, miguelsanchez.areachip@wanadoo.es

Notes

Corticosteroids for treating severe sepsis and septic shock (Review) 52

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
NCT00149123 2005

Trial name or title Low dose hydrocortisone in acutely burned patients

Methods Randomized, double blind, placebo-controlled study on 2 parallel group

Participants Adults with burns of more than 30% of body surface and vasopressor-dependent

Interventions Hydrocortisone 200 mg per day

Outcomes Primary outcome: number of patients vasopressor-free at day 4 from shock onset

Starting date 01/04/2005

Contact information Sylvie Tissot, sylvie.tissot@chu-lyon.fr

Notes

NCT00368381 2008

Trial name or title Hydrocortisone versus hydrocortisone plus fludrocortisone for the treatment of adrenal insufficiency in severe
sepsis

Methods Treatment, randomized, single blind, placebo control, parallel assignment, efficacy study

Participants Adults with severe sepsis and positive corticotropin test (basal cortisol of 34µg/dl or less and delta cortisol of
9µg/dl or less

Interventions Hydrocortisone versus hydrocortisone plus fludrocortisone

Outcomes 28-day mortality

Starting date September 2006

Contact information Contact: John A Bethea, Pharm.D.

304-388-6260
audis.bethea@camc.org

Contact: Carol A Morreale, Pharm.D.

304-388-3767
carol.morreale@camc.org

Notes

Corticosteroids for treating severe sepsis and septic shock (Review) 53

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
NCT00471640 2008

Trial name or title Dexamethasone infusion in community acquired pneumonia

Methods Randomized, double blind, placebo-controlled, on 2 parallel group, safety/efficacy study

Participants Adults with community-acquired pneumonia and who do not need ICU treatment

Interventions Ddexamethasone or placebo

Outcomes Primary outcome: length of hospital stay

Starting date 01/05/2008

Contact information S. Meijvis, s.meijvis@antonius.net

Notes

NCT00562835 2008

Trial name or title Steroids in patients with early ARDS

Methods Randomized, double blind, placebo-controlled, on 2 parallel group, safety/efficacy study

Participants Adults with ARDS of less than 72h

Interventions Low dose methylprednisolone versus placebo

Outcomes Primary outcome: 28-day all cause mortality

Starting date February 2008

Contact information Massimo Antonelli, m.antonelli@rm.unicatt.it

Notes

NCT00625209 2008

Trial name or title Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHS)

Methods Randomized, double blind, placebo-controlled trial - 2x2 factorial design

Participants Adults with septic shock

Interventions 1- placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C

2- Hydrocortisone plus fludrocortisone and a placebo of activated protein C
3- placebo of hydrocortisone, placebo of fludrocortisone and activated protein C
4- hydrocortisone plus fludrocortisone plus activated protein C

Corticosteroids for treating severe sepsis and septic shock (Review) 54

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
NCT00625209 2008 (Continued)

Outcomes 90-day mortality

Starting date April 2008

Contact information Djillali Annane, Telephone: 331 47 10 77 87; djillali.annane@rpc.aphp.f

Notes

NCT00670254 2008

Trial name or title Hydrocortisone for prevention of septic shock

Methods Randomized, double blind, placebo-controlled, on 2 parallel group, efficacy study

Participants Severe sepsis

Interventions Hydrocortisone versus placebo

Outcomes Primary outcome: proportion of patients with septic shock at day 14

Starting date 01/06/2008

Contact information Didier Keh, didier.keh@charite.de

Notes

NCT00732277 2008

Trial name or title Evaluation of corticosteroid therapy in childhood severe sepsis: a randomized pilot study

Methods Randomized, open label, uncontrolled, on 2 parallel group, study

Participants Children with sepsis

Interventions Hydrocortisone

Outcomes Primary outcome: 28-day all cause mortality

Starting date 01/04/2008

Contact information Saul N Faust, s.faust@soton.ac.uk

Notes

Corticosteroids for treating severe sepsis and septic shock (Review) 55

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Steroids versus control

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 28-day all-cause mortality 20 2384 Risk Ratio (M-H, Random, 95% CI) 0.87 [0.74, 1.01]
1.1 Randomized controlled 17 2138 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.71, 1.00]
trials
1.2 Quasi randomized 3 246 Risk Ratio (M-H, Random, 95% CI) 1.05 [0.69, 1.58]
controlled trials
2 all-cause mortality by subgroup 17 2024 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.81, 1.05]
based on mortality date
2.1 Studies reporting 28-day 14 1372 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.77, 1.01]
mortality
2.2 Studies reporting only 14- 3 652 Risk Ratio (M-H, Random, 95% CI) 1.21 [0.94, 1.58]
day mortality
3 28-day all-cause mortality by 19 Risk Ratio (M-H, Random, 95% CI) Subtotals only
subgroups based on treatment
dose/duration
3.1 Long course of low dose 12 1228 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.72, 0.97]
corticosteroids
3.2 Short course of high dose 7 1043 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.69, 1.30]
corticosteroids
4 28-day all-cause mortality 17 Risk Ratio (M-H, Random, 95% CI) Subtotals only
by subgroups based on
methodological quality
4.1 Adequate generation of 15 1938 Risk Ratio (M-H, Random, 95% CI) 0.92 [0.79, 1.07]
allocation sequence
4.2 Adequate allocation 14 1879 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.76, 1.06]
concealment
4.3 Blinded trials 15 1940 Risk Ratio (M-H, Random, 95% CI) 0.91 [0.79, 1.05]
5 28-day mortality in patients with 7 563 Risk Ratio (M-H, Random, 95% CI) 0.88 [0.76, 1.02]
adrenal insufficiency
6 Intensive care unit mortality 8 1082 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.63, 1.04]
7 Hospital mortality 16 Risk Ratio (M-H, Random, 95% CI) Subtotals only
7.1 All trials 15 1672 Risk Ratio (M-H, Random, 95% CI) 0.83 [0.68, 1.00]
7.2 Long course of low dose 10 1148 Risk Ratio (M-H, Random, 95% CI) 0.85 [0.72, 1.00]
corticosteroids
7.3 Short course of high dose 5 439 Risk Ratio (M-H, Random, 95% CI) 0.84 [0.52, 1.36]
corticosteroids
7.4 Adequate generation of 11 1254 Risk Ratio (M-H, Random, 95% CI) 0.90 [0.77, 1.06]
allocation sequence
7.5 Adequate allocation 11 1280 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.76, 1.05]
concealment
7.6 Blinded trials 10 1228 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.75, 1.05]
8 Number of patients with shock 9 Risk Ratio (M-H, Random, 95% CI) Subtotals only
reversal
Corticosteroids for treating severe sepsis and septic shock (Review) 56
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 8.1 Shock reversal at day 7 8 1268 Risk Ratio (M-H, Random, 95% CI) 1.29 [1.06, 1.58]
8.2 Shock reversal at day 7 6 965 Risk Ratio (M-H, Random, 95% CI) 1.35 [1.16, 1.57]
in trials on long course of low
dose corticosteroids
8.3 Shock reversal at day 28 6 952 Risk Ratio (M-H, Random, 95% CI) 1.12 [1.02, 1.23]
9 SOFA score at day-7 5 916 Mean Difference (IV, Random, 95% CI) -1.47 [-2.01, -0.92]
10 Length of ICU stay 8 1705 Mean Difference (IV, Random, 95% CI) -3.62 [-5.24, 0.00]
10.1 For all patients 8 1083 Mean Difference (IV, Random, 95% CI) -3.11 [-5.79, -0.43]
10.2 For ICU survivors 8 622 Mean Difference (IV, Random, 95% CI) -4.49 [-7.04, -1.94]
11 Length of hospital stay 7 1563 Mean Difference (IV, Random, 95% CI) -2.51 [-5.25, 0.23]
11.1 For all patients 7 1031 Mean Difference (IV, Random, 95% CI) -2.06 [-5.56, 1.44]
11.2 For hospital survivors 7 532 Mean Difference (IV, Random, 95% CI) -3.32 [-8.14, 1.50]
12 Number of patients with 15 Risk Ratio (M-H, Random, 95% CI) Subtotals only
adverse events
12.1 Gastroduodenal bleeding 13 1594 Risk Ratio (M-H, Random, 95% CI) 1.12 [0.81, 1.53]
12.2 Superinfections 14 1917 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.82, 1.25]
12.3 Hyperglycaemia 9 1434 Risk Ratio (M-H, Random, 95% CI) 1.16 [1.07, 1.25]
12.4 Hypernatremia 3 805 Risk Ratio (M-H, Random, 95% CI) 1.61 [1.26, 2.06]
12.5 Neuromuscular weakness 3 811 Risk Ratio (M-H, Random, 95% CI) 0.63 [0.12, 3.35]

WHAT’S NEW
Last assessed as up-to-date: 31 October 2010.

Date Event Description

1 November 2010 New search has been performed • We reran the searches from August 2003 to October 2009.
• We found 21 new trials. Of those 21 trials we included nine
randomized controlled trials in this update (Annane 2010; Cicarelli 2007;
Confalonieri 2005; Huh 2007; Meduri 2007; Oppert 2005; Rinaldi 2006;
Sprung 2008; Tandan 2005); three were excluded (Cicarelli 2006;
Kaufman 2008; Mikami 2007) and nine are ongoing (IRSCTN99675218
2006; NCT00127985 2005; NCT00149123 2005; NCT00368381 2008;
NCT00471640 2008; NCT00562835 2008; NCT00625209
2008;NCT00670254 2008; NCT00732277 2008).
• Two (Oppert 2002; Sprung 2002) of the three previous ongoing
studies (Oppert 2002; Sprung 2002; Tayer 2002) have now been published
and are included in this update as (Oppert 2005; Sprung 2008). The third
trial has never been completed and no data are available.
• In total, this updated review now includes 25 included studies, 10
excluded studies and 9 ongoing studies.
• The additional included studies did not change the conclusions of this
review.
• We included risk of bias and summary of findings tables in this
updated version.
• Search strategies changed from Silver Platter to Ovid.
• We changed the statistical analysis by using the random-effects model
rather than the fixed-effect model, and we included meta-regression analysis
to explore the influence of dose and duration of corticosteroids on the risk

Corticosteroids for treating severe sepsis and septic shock (Review) 57

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

of death.

HISTORY
Protocol first published: Issue 3, 2000
Review first published: Issue 1, 2004

Date Event Description

25 March 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Conceiving the review: Djillali Annane (DA), Eric Bellissant (EB), Pierre Edouard Bollaert (PEB), Josef Briegel (JB), Didier Keh (DK),
Yizhak Kupfer (YK)
Co-ordinating the review: DA
Undertaking manual searches: DA, PEB, JB, DK
Screening search results: DA, PEB, JB, DK, YK
Organizing retrieval of papers: DA, PEB, JB, DK, YK
Screening retrieved papers against inclusion criteria: DA, PEB, JB, DK, YK
Appraising quality of papers: DA, PEB, JB, DK, YK
Abstracting data from papers: DA,
Writing to authors of papers for additional information: DA,
Providing additional data about papers: DA, PEB, JB, DK, YK
Obtaining and screening data on unpublished studies: DA, PEB, JB, DK, YK
Data management for the review: DA, EB
Entering data into Review Manager (RevMan 5): DA
RevMan statistical data: DA, EB
Other statistical analysis not using RevMan:not applicable
Double entry of data: (data entered by person one:DA; data entered by person two: Laurenne Authelet)
Interpretation of data: DA, EB, PEB, JB, DK, YK
Statistical inferences: EB
Writing the review: DA, EB, PEB, JB, DK, YK
Securing funding for the review: DA
Performing previous work that was the foundation of the present study: DA, EB, PEB, JB, DK, YK
Corticosteroids for treating severe sepsis and septic shock (Review) 58
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Guarantor for the review (one author): DA
Person responsible for reading and checking review before submission: DA

DECLARATIONS OF INTEREST
The following review authors have been involved in randomized controlled trials of low dose of hydrocortisone, which are included
in this updated review: Djillali Annane in Annane 2002 and Sprung 2008; Eric Bellissant in Annane 2002; Pierre Edouard Bollaert
in Bollaert 1998 and Annane 2002; Josef Briegel in Briegel 1999 and Sprung 2008; Didier Keh in Keh 2003 and Sprung 2008; and
Yizhak Kupfer in Chawla 1999.
Djillali Annane is involved with one ongoing study: NCT00625209 2008.
Didier Keh is involved with one ongoing study: NCT00670254 2008.

SOURCES OF SUPPORT

Internal sources
• Hopital Raymond Poincaré, Garches, France.

External sources
• Department for International Development, UK.

NOTES
This review was initially developed within the Infectious Diseases Group, it was transferred to the Anaesthesia Group in May 2005.

INDEX TERMS

Medical Subject Headings (MeSH)

Adrenal Cortex Hormones [∗ therapeutic use]; Randomized Controlled Trials as Topic; Sepsis [∗ drug therapy; mortality]; Shock, Septic
[drug therapy; mortality]

MeSH check words

Humans

Corticosteroids for treating severe sepsis and septic shock (Review) 59

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.