esteroides en sepsis y shock septico

8/7/2019 esteroides en sepsis y shock septico

1/61

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 Library2010, 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.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


2/61

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

21DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

56DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

57WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

58CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

59INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iCorticosteroids for treating severe sepsis and septic shock (Review)



3/61

[Intervention Review]

Corticosteroids for treating severe sepsis and septic shock

Djillali Annane1, Eric Bellissant2, Pierre Edouard Bollaert3, Josef Briegel4, Didier Keh5, Yizhak Kupfer6

1Critical Care Department, Hpital Raymond Poincar, Assistance Publique - Hpitaux de Paris, Garches, France. 2Centre

dInvestigation Clinique INSERM 0203, Hpital Pontchaillou, Rennes, France. 3Intensive Care Unit, Hpital Central, Nancy, France.4Klinik fr Anaesthesiologie, Klinikum der Universitaet, Munich, Germany. 5University Clinic of Anesthesiology and Intensive Care

Medicine CCM/CVK, Charit-Campus VirchowClinic, Charit Universittsmedizin Berlin, Berlin, Germany. 6Division of Pulmonary

and Critical Care Medicine, Maimonides Medical Center, New York, USA

Contact address: Djillali Annane, Critical Care Department, Hpital Raymond Poincar, Assistance Publique - Hpitaux de Paris,

104. Boulevard Raymond Poincar, Garches, Ile de France, 92380, France. [email protected].

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 Reviews2004, Issue 1. Art. No.: CD002243. DOI: 10.1002/14651858.CD002243.pub2.


A B S T R A C T

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 =

1Corticosteroids for treating severe sepsis and septic shock (Review)

mailto:[email protected]:[email protected]


4/61

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.

P L A I N L A N G U A G E S U M M A R Y

A long course (five days or more) of a low dose of corticosteroids may be considered as an adjunct therapy in patients withseptic 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.




5/61

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 shockSettings: in patient

Intervention: long course low dose corticosteroids

Comparison: placebo or standard therapy

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality

(GRADE

Assumed risk Corresponding risk

placebo or standard

therapy

long course low dose

corticosteroids

All-cause mortalityFollow-up: 28 days

Medium risk population RR 0.84(0.72 to 0.97)1

1228(12 studies)

modera

45 per 100 38 per 100

(32 to 44)

Intensive care unit mor-

tality

Medium risk population RR 0.81

(0.63 to 1.04)

1082

(8 studies)

modera

37 per 100 30 per 100

(23 to 38)

Number of patients with

shock reversalFollow-up: 7 days

Medium risk population RR 1.35

(1.16 to 1.57)

965

(6 studies)

modera50 per 100 68 per 100

(58 to 79)

3

Corticosteroidsfor

treatingseveresepsisandsepticshock(Review)

Copyright2010T

heCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
http://www.thecochranelibrary.com/view/0/SummaryFindings.htmlhttp://www.thecochranelibrary.com/view/0/SummaryFindings.html


6/61


7/61

B A C K G R O U N D

Sepsisis present when a site ofinfection is apparentin a patient andthere 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 rangesfrom 50 to100 cases per100,000

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 stimulatescorticosteroid 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

doseof corticosteroids prolongedsurvivalin 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 alteringthe 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 studyin 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

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 showedno significant difference in ab-

solute mortality rate, but therewas 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 trialsaccounting 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 therewas 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 fluidreplacement and vasopressors (Dellinger 2008).

We therefore aim to systematically review the effects of corticos-

teroids in patients with severe sepsis and septic shock.

O B J E C T I V E S

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.




8/61

M E T H O D S

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 ofblood, 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 metabolicacidosis, 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 g/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

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 therandomized controlled trials on sepsis that have beenconducted 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 ratescould be obtainedfrom 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 ofvasopressor 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 studiesWe attempted to identify allrelevant 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 Groups methods and the journals they hand-

search are published in The Cochrane Library in the section on

Cochrane Review Groups.




9/61

In thisupdated version,we searched the CochraneCentral 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, theinstitution, andthe magnitudeand 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 describedand placebo(s) or dummytechnique meantnei-

ther the participant nor the care provider or assessor knew which

treatment was given); single blind (participant or the care provider

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 version10.0 (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


http://www.controlled-trials.com/mrct/activehttp://www.controlled-trials.com/mrct/activehttp://www.controlled-trials.com/mrct/activehttp://www.controlled-trials.com/mrct/activehttp://www.controlled-trials.com/mrct/activehttp://www.controlled-trials.com/mrct/active


10/61

hydrocortisone or equivalent) as an anti-inflammatory approach,

while the most recent trials used low dose corticosteroids for along 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

from a two-tailed test.

6. We assessed the validity of the subgroup analysis (dose andduration) 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).

R E S U L T S

Description of studies

See: Characteristics of includedstudies; Characteristicsof excluded

studies; Characteristics of ongoing studies.

Our search results are detailed in Figure 1 .




11/61

Figure 1. Search flow diagram




12/61

The search strategy yielded 35 randomized controlled trials thatevaluated 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 thembelow (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 ofthese trials was tocom-

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 includedonly 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 trialswere multicentre trials (that is more than twocentres) (

Annane 2002; Annane 2010; Bone 1987; CSG1963; Confalonieri

2005; Sprung 2008; VASSCSG 1987).

Age of participants

Onestudy enrolled both childrenand adults (CSG1963). 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 g/dl after a corticotropin bolus (Huh

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).

Inone 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, fluidresuscitation, 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




13/61

1984). Three trials reported only 14-day mortality rates (Bone

1987; Lucas 1984; VASSCSG 1987). Five trials reported onlyhospital 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

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 studiesThe detailed methodological quality of individual trials are re-

ported in the risk of bias tables, Figure 2, and in Appendix 6.




14/61

Figure 2. Methodological quality summary: review authors judgements about each methodological quality

item for each included study.




15/61

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) andin one trial on unsealed envelopes

(Schumer 1976). In one trial, in one of the two participatingcentres 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; Keh2003; Lucas 1984; Meduri 2007; Oppert2005; 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).

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 inthe methodsection ofthisreview) (Annane

2002; Annane 2010; Bollaert 1998; Briegel 1999; Chawla 1999;

Cicarelli 2007; Huh 2007; Keh2003; Oppert2005; 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; Klastersky1971; 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 (CSG1963; Wagner 1955).

Two trials explicitly defined severe sepsis due to community ac-

quired pneumonia (Confalonieri 2005; Mikami 2007). In one




16/61

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: Summaryof 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 thestudies reportingonly 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

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 differentpopulations.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; I = 1%). Subgroup analyses on the

trials that tested a short course of high dose corticosteroids showedsignificant 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 doseand durationof corticosteroid treatmentand 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), andlower 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).




17/61

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 thatparticular 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).




18/61

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 sizeindicates 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).




19/61

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 sizeindicates 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 suggestedsignificant asymmetry (P = 0.01) (Figure 7).




20/61

Figure 6. Funnel plot of comparison: 1 Steroids versus control, outcome: 1.1 28-day all-cause mortality.




21/61

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 defineareas according to significance levels, i.e. 1%, 5% and 10%). Because the precision of the intervention effect

estimate is proportional to the studys 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 (Chi 2 =

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-




22/61

group analyses based on trials with an adequate method for gen-

erating the allocation sequence showed a RR of dying in hospitalof 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 1268participants. Therewere 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 (Analysis1.8).

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 28We 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% CI1.02 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

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 inthe 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 (Chi = 4.09, P =

0.39; I = 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 lengthof stay in the ICU was -3.11 (-5.79 to -0.43, P = 0.02) with some

heterogeneity across the studies (Chi = 9.72, P = 0.21, I = 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 (Chi = 2.78, P = 0.90; I =

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; Yildiz2002) 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 thathad 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).




23/61

Hyperglycaemia

The number of participants who presented with hyperglycaemiawas 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.

D I S C U S S I O NIn 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(thatis, 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 improvedstandard of care during thedecade

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

therapy alone or a placebo. One trial had a crossover design (Keh

2003) and we could obtain none of the foreseen outcomes forthis 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 investigatorsof twoof thesestud-

ies (Chawla 1999; Tandan 2005) provided sufficient unpublisheddata 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 andunpublished datawere available

for 13 trials (Annane 2002; Bollaert 1998; Briegel 1999; Chawla

1999;Cicarelli2007; Confalonieri 2005; Keh2003; 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-

ityfrom severesepsis or septicshock. However, forthese 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 yieldeda 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




24/61

( 5 days) of low dose ( 300 mg) hydrocortisone or equivalent.

Sensitivity analyses on the trials of a long course ( 5 days) of lowdose 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 threesubgroup 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 (Kellum2007). 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 givenin theothertrials. 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

late septic shock (Briegel 1999; Keh 2003; Sprung 2008). Finally,

one trial used both hydrocortisone and fludrocortisone and founda 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 (Confalonieri2005; Keh2003; 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 providerecommendations to selectsep-

ticshock patients who maybe the best candidates fora 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).

A U T H O R S C O N C L U S I O N SImplications for practice

Overall, corticosteroids did not impact on 28-day all-cause mor-

talityin severesepsis andseptic 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




25/61

dose for at least 100 hours only in adults with vasopressor-depen-

dent septic shock. There is insufficient evidence from this reviewto 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.

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.

A C K N O W L E D G E M E N T S

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-

tionalDevelopment, UK. Thereview wastransferred tothe 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.

R E F E R E N C E S

References to studies included in this review

Annane 2002 {published and unpublished data}

Annane D, Sebille V, Charpentier C, Bollaert PE, Franois 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):86271. [PUBMED: 12186604]

Annane 2010 {published and unpublished data}

COIITSS Study Investigators, Annane D, Cariou A, Maxime V,

Azoulay E, Dhonneur G, Timsit JF, et al.Corticosteroid treatment

and intensive insulin therapy for septic shock in adults: a

randomized controlled trial. JAMA 2010;303:3418.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 Medicine1998;26(4):64550.

[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

Medicine1987;317(11):6538.

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:

a prospective, randomized, double-blind, single-center study.

Critical Care Medicine1999;27(4):72332. [PUBMED:

10321661]

Chawla 1999 {published and unpublished data}

Chawla K, Kupfer Y, Tessler S. Hydrocortisone reverses refractory

septic shock. Critical Care Medicine1999;27(1):A33.

Cicarelli 2007 {published data only}

Cicarelli DD, Vieira JE, Benseor FE. Early dexamethasone

treatment for septic shock patients: a prospective randomized

clinical trial. Sao Paulo Medical Journal2007;125:23741.

[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 Medicine2005;171:2428.

CSG 1963 {published data only}

Cooperative Study Group. The effectiveness of hydrocortisone in

the management of severe infections. JAMA 1963;183:4625.

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

Medicine2007;34 Suppl:A101.




26/61

Keh 2003 {published and unpublished data}

Keh D, Boehnke T, Weber-Cartens S, Schulz C, Ahlers O, BerckerS, 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 Medicine2003;167(4):51220. [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 Medicine1971;284(22):124850.

[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):53741. [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 Diseases1988;138(1):

628. [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. Chest2007;131(4):95463.

[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 Medicine2005;33:245764. [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 Medicine2006;34:23349. [PUBMED: 16850006]

Schumer 1976 {published data only}

Schumer W. Steroids in the treatment of clinical septic shock.

Annals of Surgery1976;184(3):33341. [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 ofdexamethasone in African children with sepsis. Pediatric Infectious

Diseases Journal1996;15(7):57983. [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 Medicine1984;311(18):113743. [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 Medicine2008;358:11124.

[PUBMED: 18184957]

Tandan 2005 {unpublished data only}

Tandan SM, Guleria R, Gupta N. Low dose steroids andadrenocortical 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 Medicine1987;317(11):65965. [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 Hospital1955;98:197215. [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 Care2002;6(3):

2519. [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 Journal2006;124:905. [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;30:27481.

Hughes 1984 {published data only}

Hughes GS Jr. Naloxone and methylprednisolone sodium succinate

enhance sympathomedullary discharge in patients with septic

shock. Life Sciences1984;35(23):231926. [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 medicine2008;34:3449. [PUBMED: 17906853 ]

McKee 1983 {published data only}McKee JI, Finlay WE. Cortisol replacement in severely stressed

patients. Lancet1983;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):15965. [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;185:24955. [PUBMED: 17710485]




27/61

Rogers 1970 {published data only}

Rogers J. Large doses of steroids in septicaemic shock. BritishJournal of Urology1970;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 Surgery1985;120

(5):53640. [PUBMED: 3885915 ]

References to ongoing studies

IRSCTN996752

esteroides en sepsis y shock septico

Documents

Transcript of esteroides en sepsis y shock septico