Society of Critical Care Anesthesiologists

Section Editor: Avery Tung

Low-Dose Hydrocortisone Therapy Attenuates

SepticShock in Adult Patients but Does Not Reduce
28-DayMortality: A Meta-Analysis of Randomized
Controlled Trials
Changsong Wang, MD,* Jiaxiao Sun, MSc,* Juanjuan Zheng, MSc, Lei Guo, MD,*
Hongyan Ma, MD,* Yang Zhang,* Fengmin Zhang, PhD, and Enyou Li, MD*
BACKGROUND: The role of low-dose hydrocortisone in attenuating septic shock and reducing
short-term mortality in adult patients with septic shock is unclear. We conducted a m
eta-analysis
of previous studies to determine whether hydrocortisone could ameliorate the effects of septic
shock at 7 and 28 days and reduce 28-day morality.
METHODS: Randomized controlled trials (RCTs) of corticosteroids versus placebo (or supportive treatment alone) were retrieved from electronic searches (Medline, Embase, and Cochrane
Library databases; LILACS; and Web of Knowledge) and manual searches (up to May 2012).
From a pool of 1949 potentially relevant articles, duplicate independent review identified 10 relevant, RCTs of low-dose hydrocortisone therapy in septic shock. Four pairs of reviewers agreed
on the criteria for trial eligibility. One reviewer entered the data into the computer, and 3 reviewers checked the data. Missing data were obtained from the authors of the relevant trials. The
primary outcome analyzed was an estimate of 28-day mortality.
RESULTS: Eight publications were included in the meta-analysis. Low-dose hydrocortisone therapy did not reduce 28-day mortality (N = 1063; odds ratio (OR) = 0.891, 95% confidence interval (CI), 0.691.15). Low-dose hydrocortisone therapy ameliorated shock at 7 days (6 RCTs,
N=964, OR = 2.078, 95% CI, 1.582.73, P < 0.0001, and I2 = 26.9%) and 28 days (6 RCTs,
N = 947, OR = 1.495, 95% CI, 1.121.99, P = 0.006, and I2 = 0.0%).
CONCLUSIONS: Although low-dose hydrocortisone therapy ameliorates septic shock at 7 and
28 days, it does not reduce 28-day mortality. (Anesth Analg 2014;118:34657)

he incidence of septic shock can be as high as 20% among

hospitalized patients.1 Even after the appropriate treatment is administered, mortality from septic shock
remains approximately 50%.2,3 Since the first publication of the
use of glucocorticoids in severe infection,4 researchers have
explored the use of steroids in septic shock. A half-century
later, the role of glucocorticoids for decreasing mortality from
septic shock remains controversial.5,6 A 1995 meta-analysis
found that a short course of high-dose glucocorticoid therapy

From the *Department of Anesthesiology, The First Affiliated Hospital of Harbin

Medical University; Department of Medical Records, the First Hospital of
Quanzhou, Quanzhou, China; Department of Microbiology, The Heilongjiang
Key Laboratory of Immunity and Infection, Pathogenic Biology, Harbin Medical
University; and Key Laboratory of Bio-Pharmaceutical, Harbin Medical
University, Ministry of Education, Harbin, China.Jiaxiao Sun, MSc, is currently
affiliated with Department of Anesthesiology, the First Hospital of Quanzhou,
Quanzhou, China. Juanjuan Zheng, is currently affiliated with Department of
Medical Records, the First Hospital of Quanzhou, Quanzhou, China.
Accepted for publication October 18, 2013.
Funding: Financial support by grants from the National Natural Science
Foundation of China (No.30972839), China Postdoctoral Science Foundation
(No. 2013M531069), Foundation of Heilongjiang Educational Committee
(No.12531245) and Doctoral Fund of the First Affiliated Hospital of Harbin
Medical University (No.2012B006) are gratefully acknowledged.
Dr. Changsong Wang and Jiaxiao Sun contributed equally to this work.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Enyou Li, MD, Department of Anesthesiology,
The First Affiliated Hospital of Harbin Medical University, No 23 Youzheng
St., Nangang District, Harbin, Heilongjiang 150001, China. Address e-mail to
enyouli@aliyun.com.
Copyright 2014 International Anesthesia Research Society
DOI: 10.1213/ANE.0000000000000050

346 www.anesthesia-analgesia.org

provided no advantage for the treatment of septic shock and

could have negative effects.7 A 2004 meta-analysis found that
steroids did not affect mortality from septic shock.8 However,
a subgroup analysis of patients treated with low doses of steroids ( 300 mg hydrocortisone or equivalent per day) for >5
days found that sustained low-dose steroid therapy reduced
28-day mortality. In 2009, the same group of researchers
repeated a meta-analysis on the same issue by integrating
recent randomized controlled trials (RCTs).9 The analysis was
restricted only to the response to steroid therapy in an adult
population with severe sepsis and septic shock. The results
demonstrated that long-term, low-dose steroid therapy can
increase short-term survival rates.
These studies involved analyses of various corticosteroid therapies10,11 but did not focus on the effect of a single
steroid therapy. Glucocorticoids differ in receptor binding,
biological half-life, and glucocorticoidmineralocorticoid
hormone actions.12 Glucocorticoids may differ in their efficacy in septic shock. As hydrocortisone is the endogenous
glucocorticoid released by the adrenal gland, it might be the
best choice of replacement therapy in shock.
An initial literature search found that studies of low-dose
corticosteroid therapy for septic shock accounted for most
recent studies. Therefore, we investigated the effects of lowdose hydrocortisone on shock reversal and survival in patients
with septic shock. We performed a conventional meta-analysis
of published trials and a cumulative meta-analysis to evaluate
the effects of each study on the final, generalized results.13
February 2014 Volume 118 Number 2

METHODS

We conducted a systematic review and several m

eta-analyses
of the literature according to the methods recommended in
the PRISMA statement for reporting systematic reviews
and meta-analyses of studies that evaluate health care
interventions.

Groups

Our investigators were divided into 4 groups. CW was primarily responsible for the literature search group (CW and
LG). JS and HM were responsible for the 2 literature review
groups (JS, FZ, HM, and YZ). JZ was responsible for the
data analysis group (JZ and EL). After the 2 separate literature review groups conducted the literature exclusion and
inclusion and the data extraction, the data were verified. If
there was an inconsistency, the data extraction was repeated
until a consensus was reached.

Literature Search

The trials were identified by electronic and manual searches.

The electronic searches were performed by 2 authors
who independently searched the Medline, Embase, and
Cochrane Library databases; the Cochrane Controlled Trials

Register; LILACS (http://www.bireme.br; assessed May

2012); and Web of Knowledge (Conference Proceedings
Citation Index-Science, Conference Proceedings Citation
Index-Social Sciences & Humanities). We did not restrict
our search based on language or year of publication. The
last search update was May 2012. The Medline database
was searched using the PubMed interface. The following search terms (in all fields) were used: sepsis, septic
shock, steroids, corticosteroids, adrenal cortex hormones,
and glucocorticoids. Embase was searched using the following search terms: sepsis, septic shock, steroids, and
corticosteroids. The search terms sepsis and septic shock
were searched in the Cochrane infectious diseases groups
trial register. We searched the Cochrane central register
using the following search terms: sepsis, septic shock, steroids, and corticosteroids. LILACS was searched using the
search terms sepsis, steroids, and corticosteroids, and we
searched the proceedings of the annual meetings by using
the search terms sepsis, septic shock, steroids, and corticosteroids in the Web of Knowledge (Conference Proceedings
Citation
Index-Science, Conference Proceedings Citation
Index-Social Sciences & Humanities) database. We

reviewed the reference lists of published meta-analyses. In

1949 abstracts identified by electronic database search

1239 MEDLINE
410 COCHRANE LIBRARY
56 LILACS
223 EMBASE
21 WEB OF KNOWLEDGE Summary of the meeting

120 abstracts of interest identified and further reviewed

69 MEDLINE
23 COCHRANE LIBRARY
8 LILACS
5 EMBASE
15 WEB OF KNOWLEDGE

MEDLINE: excluded 33 review articles, 2 repetitive articles, and

4 repetitive experiments; 23 were excluded for other
reasons.
COCHRANE LIBRARY: excluded 8 review articles and 13
repetitive articles; 2 were excluded for
other reasons.
LILACS: excluded 7 review articles; 1 was excluded for other
reasons.
EMBASE: excluded 4 review articles; 1 was excluded for other
reasons.
WEB OF KNOWLEDGE: excluded 6 review articles and 2
repetitive experiments; 6 were
excluded for other reasons.
Reference 3, excluded 3.

8 included in meta-analysis

Figure 1. Flow diagram of the literature search.

February 2014 Volume 118 Number 2

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Low-Dose Hydrocortisone Therapy in Septic Shock

addition, we manually searched the Index Medicus of RCTs,

meta-analyses, and systematic reviews for studies that were
missed in the initial electronic search.
The search strategy identified 1949 studies. Two literature review groups conducted the literature exclusion; 120
studies were included for potential interest. The studies with
one or more of the following terms mentioned were considered for inclusion: steroid, any class of glucocorticoid, septic
shock, and human study. The selected studies were repeatedly reviewed for exclusion by the literature search groups.
The exclusion and inclusion criteria were independently
applied to each study by the 2 study review groups (Fig.1).

Strategy Design

The literature search and data extraction strategy were discussed and designed by 2 authors. After all the authors had
discussed and reviewed the strategy, the corresponding
author approved the final version of the study strategy design.

Definition of Septic Shock

Septic shock was defined according to the standard established by the 1992 American College of Chest Physicians/
Society of Critical Care Medicine (ACCP/SCCM) Consensus

Conference.14 Shock reversal was defined as a stable state

of systolic blood pressure (> 90 mmHg) for a period of 24
hours or more without vasopressor support or transfusion.9
Low-dose hydrocortisone was defined as a daily dose of
hydrocortisone 300 mg.9

Inclusion and Exclusion Criteria

The literature inclusion and exclusion procedures were performed independently by 2 literature review groups. We first
excluded retrospective analyses, repeated literature reports,
and repeated experiments (the same experiment analyzed
and evaluated in different literature reports); purely physiological studies (e.g., the effects of steroids on neutrophils
in patients with septic shock);15 imaging studies; pediatric
studies; studies with high-dose medications; studies on
medications other than hydrocortisone (the initial design
was to conduct a separate analysis on a single steroid of
other glucocorticoid types; however, the analysis could not
be performed separately due to the lack of relevant studies
on other medications); nonrandomized controlled studies;
and studies without a control group (Table1). If data were
missing, the literature search group contacted the authors
for the relevant data.

Table 1.Excluded Literature

Authors
Cooperative study group4

Publication year
1963

Schumer38
Lucas and Ledgerwood39
Sprung etal.40
Hughes41
Lederer42
Hellman and Alestig43
Bone etal.44
Luce etal.45
Marks etal.46
Oppert etal.47
Briegel etal.48
Annane and Bellissant49
Keh etal.50
Laterre etal.51
Guzman etal.52
Levy etal.35
Tandan etal.53
Rinaldi etal.54
Cicarelli etal.31
Loisa etal.55
Mcgee etal.56

1976
1984
1984
1984
1984
1985
1987
1988
1990
2000
2001
2002
2003
2003
2005
2005
2005
2006
2007
2007
2007

Cicarelli57
Kaufmann etal.15
Kurugundla etal.58
Bchele etal.59
Hayashi60
Hu etal.61
Russell etal.62
Yu etal.34
Valoor etal.63
Beale etal.64
COIITSS study investigators30
Jung etal.65
Schelling etal.66
Huh etal.67

2008
2008
2008
2009
2009
2009
2009
2009
2009
2010
2010
2011
2001
2011

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Exclusion reason
No information is provided on the number of patients who may have had shock in this
study. No clear definition of mortality; low methodological quality; unable to get accurate
information for adults.
Study medications did not match, dexamethasone, methylprednisolone
High-dose
High-dose
Methylprednisolone, no relevant results
Betamethasone, high-dose
High-dose
High-dose
High-dose
Nonrandomized controlled study, physiological study, no relevant results
Nonrandomized controlled study, no control group
Physiological study, no relevant data
Physiological study, no relevant data, study objective did not match analysis
Study method did not match, steroid application overlapped in 2 groups
Study objective did not match, no relevant data
Study objective did not match, no relevant data
Study objective did not match, no relevant data
No hydrocortisone dose and duration
Physiological study, effects of steroid on albumin, no relevant data
Study medication did not match, dexamethasone
No control group
Study method did not match, no control group, comparison of steroid effects with different
dosage.
Study medication did not match, dexamethasone
Physiological study, no relevant data
No relevant data
Nonrandomized controlled study
No relevant data
Study objective did not match, no relevant data
Study objective did not match, comparison of 2 hypertension medication, no control group
Comparison with effects of methylprednisolone, no control group
Pediatric population
Report, nonrandomized controlled study
No control group
Imaging report, not relevant to study results
Physiological study, no relevant results
Comparison between IV administration of steroids at day 3 and day 7, no control group

anesthesia & analgesia

Table 2.General Information of Included Studies

No. of
research
centers
2

Publication
type
Article

Design
Double-blind

Article

Double-blind

44

Report

Double-blind

Annane etal.,22

299

19

Article

Double-blind

Oppert etal.,28

41

Article

Double-blind

Mussack etal.,23
(2005)

24

Article

Double-blind

499

13

Article

Double-blind

75

Article

Double-blind

Article
Bollaert etal.,27

No. of
samples
41

Briegel etal.,26

40

Chawla etal.,21

Sprung etal.,24

Arabi etal.,25

Subsequently, the 2 study review groups performed the

initial verification. A disagreement occurred only in 1 study,
which was eventually excluded after a discussion among all
of the authors.
The process yielded 8 published studies, one of which
was only published as a meeting abstract. Two groups of
researchers independently conducted a second round of
data extraction from the literature. Key data were 28-day
mortality and shock reversal at 7 and 28 days. If the relevant

February 2014 Volume 118 Number 2

Intervention
In the patient group, 100 mg
hydrocortisone was IV administered
3 times daily for a total of 5 d with a
matching placebo of physiologic saline
for the control group.
In the patient group, 100 mg hydrocortisone
was IV administered as a loading dose;
then, hydrocortisone was continuously
administered at 0.18 mg/kg/h. If
shock reversal was present, the dose
was reduced to 0.08 mg/kg/h for
6d. Physiologic saline was used as a
matching placebo for the control group.
In the patient group, 100 mg hydrocortisone
was IV administered every 8 h for a total
of 3 d; the dosage was then tapered
over time for 4 d. Physiologic saline
was used as a matching placebo for the
control group.
In the patient group, 50 mg hydrocortisone
was IV administered every 6 h, and 50
g fludrocortisone was taken orally once
daily for a total of 7 d. Physiologic saline
was used as a matching placebo for the
control group.
In the patient group, 100 mg
hydrocortisone as a loading dose
was administered IV; hydrocortisone
was then continuously administered
at 0.18mg/kg/h. If shock reversal
was present, the dose was reduced to
0.06mg/kg/h and subsequently slowly
tapered. Physiologic saline was used as
a matching placebo for the control group.
In the patient group, 100 mg hydrocortisone
as a loading dose was IV injected;
hydrocortisone was then continuously
administered at 0.18 mg/kg/h for a total
of 6 d. Physiologic saline was used as a
matching placebo for the control group.
In the patient group, 50 mg hydrocortisone
was IV ly administered every 6 h for a
total of 5 d. Afterwards, hydrocortisone
50 mg was IV administered every 12 h
from day 6 to day 8, and 50 mg every
24 h from day 9 to day 11. Physiologic
saline was used as a matching placebo
for the control group.
In the patient group, 50 mg hydrocortisone
was IV administered every 6 h until
hemodynamic stability was achieved
and was than tapered over time for
8d. Physiologic saline was used as a
matching placebo for the control group.

Outcome
Mortality (28 d),
shock reversal
(7 d and 28 d)

Mortality (28 d),

shock reversal
(7 d and 28 d)

Mortality (28 d),

shock reversal
(7 d and 28 d)

Mortality (28 d),

shock reversal
(7 d and 28 d)

Mortality (28 d),

shock reversal
(7 d)

Mortality (28 d),

shock reversal
(28 d)

Mortality (28 d),

shock reversal
(7 d and 28 d)

Mortality (28 d)

data were missing or ambiguous, we contacted the authors

for clarification.

Quality Assessment

Quality assessments were performed separately by the 2

literature review groups. Studies that received inconsistent
scores were scored again by all of the authors. The quality
of the study was assessed using a modified Jadad scale16
in which the generation of random sequences, blinding

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Low-Dose Hydrocortisone Therapy in Septic Shock

method, reasons for withdrawal, and dropout at the time of

follow-up were evaluated. A 7-point scale was used, with
1 to 3 indicating a low-quality study and 4 to 7 indicating
a high-quality study. No studies were excluded from the
analysis because of the quality assessment.

Statistical Analyses

The outcomes of interest were 28-day mortality and

the shock reversal at 7 and 28 days. The adverse events
superinfection, gastrointestinal (GI) bleeding, and hyperglycemia were also evaluated. Statistical analysis was performed using Stata (version 11.1, StataCorp LP, College
Station, TX). Because the mortality rate was calculated in
most RCTs at different time points, we used the hazard
ratio as the parameter for calculating the mortality rate.17
Intratrial variability among the RCTs may have introduced bias in the hazard ratio calculation. Considering
that the hazard ratio is very similar to the odds ratio (OR),
we calculated the OR value and 95% confidence intervals
(CIs) as the approximate parameters for evaluating the
effects of hydrocortisone therapy on mortality and shock
reversal.18,19
The statistical variable I2 was used to compare heterogeneity among studies (25% indicated low heterogeneity,
50% indicated moderate heterogeneity, and 75% indicated
high heterogeneity; I2 > 50% indicated significant heterogeneity).20 The fixed-effects model was applied if there was
significant heterogeneity. The DerSimonianLaird test was
applied for the pooled OR value. The fixed-effects model
was applied if there was low significant heterogeneity. The
MantelHaenszel test was applied for the pooled OR value.
The Z-test was applied for the significance test for pooled
OR values.
To find the source of heterogeneity and ensure the stability of results, we performed a sensitivity analysis for
28-day mortality and 7-day shock reversal. We performed

subgroup analyses for sample size (< 100 or > 100) and quality score (6 or 7) for 28-day mortality. To explain the relationship between the log value of the 28-day mortality and the
patients average age and gender, we performed a secondary analysis by meta-regression method. The variables time
and sample size were used in a cumulative meta-analysis to
investigate the dynamic changes among 3 indictors: 28-day
mortality, 7 day shock reversal, and 28-day shock reversal.
To assess publication bias and test for small sample size
bias, we used Eggers test in continuous data analyses.
However, the response variable of this study was a binary
variable. Therefore, Harbord test was performed for quantitative assessment, and Beggs funnel plot was used to qualitatively demonstrate the bias.

RESULTS

Eight publications (Table 2) were incorporated in the

meta-analysis, which included 1 meeting abstract.21 All 8
studies were included in the analysis of 28-day mortality.
Among these studies, the raw data were provided in 6 studies.2025 The raw data for the remaining 2 studies21,26 were
acquired by writing to the authors. Six studies21,22,24,2628 were
included for shock reversal analysis on day 7. Among these
studies, the raw data were originally provided in 4 studies.22,24,27,28 The raw data for the remaining 2 studies21,26 were
acquired by writing to the authors. Six studies2124,26,27 were
included in the analysis of shock reversal on day 28. Among
these studies, the raw data were provided in 4 studies.2224,27
The raw data for the remaining 2 studies21,26 were acquired
by writing to the authors.

28-Day Mortality

Eight RCTs with a total of 1063 participants were included

in the analysis (535 subjects in the patient group and 528 in
the control group). The 28-day mortality values were 227
(42.43%) and 237 (44.89%) in the patient and control groups,

Figure 2. Effects of low-dose hydrocortisone therapy on mortality at 28 days in patients with septic shock.

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anesthesia & analgesia

Table 3.Outcome Effect Estimates

Outcome
Mortality
Total
Sample size <100
Sample size >100
Quality assessment score = 6
Quality assessment score = 7
Shock reversal (7 days)
Total
Sample size <100
Sample size >100
Quality assessment score = 6
Quality assessment score = 7
Shock reversal (28 d)
Meta-regression (log odds mortality)
Sex
Age

OR (95% CI)

POR

I2 (P)

8
6
2
3
4

0.891 (0.6911.148)
0.665 (0.3921.129)
0.972 (0.7281.299)
1.052 (0.7421.493)
0.786 (0.5341.159)

0.371
0.131
0.850
0.775
0.224

29.2% (0.195)
25.2% (0.245)
40.0% (0.197)
0.0% (0.490)
45.7% (0.137)

0.225
0.543

0.051
0.970

6
4
2
2
3
6

2.078 (1.5822.729)
2.848 (1.4595.559)
1.949 (1.4452.628)
1.896 (1.3162.731)
3.118 (1.2357.873)
1.495 (1.1241.988)

<0.0001
0.002
<0.0001
0.001
0.016
0.006

26.9% (0.233)
47.6% (0.126)
0.0% (0.721)
46.8% (0.170)
53.1% (0.118)
0.0% (0.604)

0.553
0.328

0.287
0.019

7
7

0.842 (0.3252.184)
1.033 (0.9281.150)

0.662
0.471

Pharbord

Figure 3. Forest plot of estimates of sensitivity for 28-day mortality.

respectively. The analysis results were OR = 0.891, 95% CI,

0.691.15, P = 0.371, and I2 = 29.2%. There were no significant
differences in the 28-day mortality analysis (Fig.2; Table3).

Sensitivity Analysis of 28-Day Mortality

A sensitivity analysis was performed for the included 8

studies to investigate the source of heterogeneity (Fig. 3).
The result for 28-day mortality remained stable after the
exclusion of any 1 study. No significant differences were
found in the 28-day mortality rates (Table3).

Subgroup Analysis of 28-Day Mortality

We performed subgroup analyses of the 8 studies to investigate the effects of sample size (categorized to >100 and
<100) and quality score (divided into a 6-score group and a
7-score group) on heterogeneity (Table3). Two studies with

February 2014 Volume 118 Number 2

sample sizes of >100 were included in this subgroup with

OR = 0.972, 95% CI, 0.731.30, P = 0.850, and I2 = 40.0%. Six
studies were included in the subgroup with sample sizes
of <100, with OR = 0.665, 95% CI, 0.391.13, P = 0.131, and
I2= 25.2%. The subgroup with quality assessment scores of
6 included 3 studies, with OR = 1.052, 95% CI, 0.741.49,
P = 0.775, and I2 = 0.0%. Four studies were included in the
subgroup with quality assessment scores of 7, with OR =
0.786, 95% CI, 0.531.16, P = 0.224, and I2 = 45.7%. One study
was only published as a meeting abstract and therefore
could not be included for quality analysis.
The results of the subgroup analysis showed no significant differences in the 28-day mortality rates among
subgroups. Heterogeneity decreased in some subgroups
(such as the subgroup with sample sizes of <100 and the
subgroup with quality assessment scores of 6), whereas

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Low-Dose Hydrocortisone Therapy in Septic Shock

Figure 4. Effects of low-dose hydrocortisone therapy on 7 and 28-day shock reversal in patients with septic shock.

For exploratory purposes, a secondary analysis was performed by meta-regression method between the log value
of the 28-day mortality and the patients average age and
gender (Table3). Among the 8 studies, 7 studies provided
gender information and 7 studies provided age information
(P = 0.471). Therefore, gender and age were not associated
with the heterogeneity of 28-day mortality.

The 28-day shock reversal analysis included 6 RCTs with

a total of 947 participants (478 subjects in the hydrocortisone group and 469 in the placebo group). The number of
patients with 28-day shock reversal was 328 (68.62%) in the
patient group and 283 (60.34%) in the control group. The
increase in shock reversal at 28 days with hydrocortisone
was statistically significant: OR = 1.495, 95% CI, 1.121.99, P
= 0.006, and I2 = 0.0% (Fig.4; Table3).
A sensitivity analysis was performed to investigate the
source of heterogeneity of 7-day shock reversal (Fig.5). The
results remained stable after the exclusion of any 1 study.
Because no heterogeneity (I2 = 0.0%) was observed in the
28-day shock reversals, a sensitivity analysis was not performed for this variable.

Shock Reversal

Publication Bias Analysis

heterogeneity increased in the subgroup with sample sizes

of >100 and the subgroup with quality assessment scores
of 7, compared with overall heterogeneity. These results
suggest that sample size and quality assessment were not
sources of heterogeneity.

Secondary Analysis of 28-Day Mortality

The 7-day shock reversal analysis included 6 RCTs with a

total of 964 participants (484 subjects in the patient group
and 480 in the control group). The number of patients with
7-day shock reversal was 307 (63.43%) in the patient group
and 228 (47.50%) in the control group. The increase in shock
reversal at 7 days with hydrocortisone was statistically
significant: OR = 2.078, 95% CI, 1.582.73, P < 0.0001, and
I2= 26.9% (Fig.4, Table3). The source of heterogeneity was
not found by a subgroup analysis of sample size or quality
assessment score (Table3).

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We analyzed publication bias for the studies included in

the analyses of 28-day mortality and 7-day/28-day shock
reversal. Because the dependent variable was a binary
variable, we conducted the Harbord test for quantitative
assessment of 3 indicators to determine the possibility of
publication bias. Beggs funnel plot was performed for
qualitative analysis. The P value was 0.225 for 28-day mortality, 0.553 for 7-day shock reversal, and 0.019 for 28-day
shock reversal. Beggs funnel plot for 28-day mortality is
shown in Figure6.

anesthesia & analgesia

Figure 5. Forest plot of estimates of sensitivity for 7-day mortality.

the 95% CI decreased from (1.0113.40) to (1.121.99) as a

function of publication date. However, the OR value and
95% CI were still significantly >1 (Fig.7).
The 3 indicators did not show any trend with increases
in sample size.

Complications

Figure 6. Funnel graph for the assessment of potential publication

bias for 28-day mortality.

Cumulative Analysis

Using the variables publication year and sample size, a

cumulative meta-analysis was performed for 28-day mortality and 7-day/28-day shock reversal. The cumulative
analysis of 28-day mortality showed that the OR value
gradually increased from 0.27 to 0.89 and that the 95% CI
increased from (0.070.99) to (0.691.15) as a function of
publication date. The tendency of the OR value to approach
1 was significant (Fig.7).
The cumulative analysis of 7-day shock reversal showed
that the OR value gradually decreased from 8.04 to 2.08 and
the 95% CI decreased from (1.9433.30) to (1.582.73) as a
function of publication date. However, the OR value and
95% CI were still significantly >1 (Fig.7).
The cumulative analysis of 28-day shock reversal showed
that the OR value gradually decreased from 3.67 to 1.49 and

February 2014 Volume 118 Number 2

Meta-analysis of superinfection showed an OR = 1.103,

95% CI, 0.831.18, P = 0.507, and I2 = 3.1%. The results were
not significant, indicating that low-dose hydrocortisone
therapy did not increase the likelihood of superinfection in
patients with septic shock. No significant trend was found
in the cumulative analysis (Table4).
Meta-analysis of GI bleeding showed an OR = 1.601,
95% CI, 0.992.60, P = 0.057, and I2 = 26.9%. Although
the result did not reach statistical significance, the OR
(1.6) and the nearly significant results (P = 0.057) do not
comfortably exclude an increase in GI bleeding. The
cumu
lative analysis showed that the negative result
became more stabilized in studies reported in recent
years (Table4).
Meta-analysis of hyperglycemia showed an OR = 2.143,
95% CI, 1.413.26, P < 0.0001, and I2 = 0.0%. The results
were significant, indicating that low-dose hydrocortisone
increases the incidence of hyperglycemia in patients with
septic shock. Because only 3 studies were included, a cumulative analysis was not performed (Table4).

DISCUSSION

This meta-analysis demonstrated that low-dose hydrocortisone therapy attenuated septic shock in adult
patients at 7 and 28 days but did not reduce 28-day

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Low-Dose Hydrocortisone Therapy in Septic Shock

Figure 7. Cumulative analysis of 28-day mortality and 7/28-day shock reversal.

Table 4.Complications Analysis

Outcome
Superinfection
GI bleed
Hyperglycemia

N
6
6
3

OR (95% CI)
1.103(0.8251.475)
1.601(0.9872.598)
2.143(1.4103.257)

POR
0.507
0.057
<0.0001

I2 (P)
3.1%(0.397)
26.9%(0.233)
0.0%(0.489)

Pharbord
0.389
0.590
0.705

GI = gastrointestinal.

mortality. Hydrocortisone increased the blood glucose levels in patients with septic shock and was associated with
increased GI bleeding, although this last finding did not

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reach statistical significance. The available evidence does

not support the use of low-dose hydrocortisone as a routine
treatment for adult patients with septic shock.

anesthesia & analgesia

Our results are similar to those of Sligl etal.,29 who demonstrated that corticosteroid therapy does not reduce mortality rates but does appear to consistently reduce the time to
shock reversal. The role of hydrocortisone therapy, in addition to fludrocortisone, was also evaluated in the COIITSS
Trial.30 The authors failed to demonstrate a survival benefit
associated with fludrocortisone treatment, but there may be
a higher risk for increased infection.
Our results differ from the results of Annane et al.9 in
2009 because of different inclusion criteria. We limited our
analysis to hydrocortisone therapy. Therefore, we excluded
the 3 studies that Annane etal.9 included, Cicarelli etal.,31
Yildiz etal.,32 and Meduri etal.,33 because these investigators studied prednisolone, dexamethasone, and methylprednisolone, respectively. In addition, we included a 2010
report by Arabi etal.25
Yu et al.34 compared the effects of hydrocortisone and
methylprednisolone on septic shock. They found that the
survival rates for patients who received hydrocortisone
were higher than for patients who received methylprednisolone, although the difference was not significant. These
results suggest that different types of glucocorticoids may
have different effects on septic shock treatment.
The study by Levy etal.35 was not included in our analysis because it was a retrospective cohort study; the steroid
type, dose, and duration were also unspecified. The study
by Raurich etal.36 was also excluded in our analysis because
it was a case-control study. The study by Annane et al.22
was excluded because it evaluated hydrocortisone and
fludrocortisone.
Cumulative meta-analysis showed that the OR value
of 7-day shock reversal gradually decreased from 8.04 to
2.08, whereas the 95% CI decreased from (1.9433.30) to
(1.582.73) as a function of publication year. However, the
OR values and 95% CI were both significantly higher than 1,
indicating that although the positive results of 7-day shock
reversal gradually weakened over the years, the results were
still significantly positive and became stable in recent years.
The cumulative analysis of 28-day shock reversal showed
that the OR value decreased gradually from 3.67 to 1.49 and
that the 95% CI decreased from (1.0113.40) to (1.121.99)
as a function of publication year. However, the OR values
and 95% CI were both significantly higher than 1, indicating
that although the positive results of 28-day shock reversal
gradually weakened over the years, the results were still
significantly positive and became stable in recent years.
It is not clear why mortality at 28 days did not decrease,
since the data demonstrate that shock was ameliorated at
7 and 28 days in septic patients. This lack of an effect on
28-day mortality rate might be attributed to adverse events
such as superinfection, GI bleeding, and hyperglycemia.
In this study, we found that low-dose hydrocortisone
increased blood glucose levels in patients, had a trend
toward increased GI bleeding that was not statistically
significant, and did not increase the risk of superinfection.
Because of the small sample size and few adverse events
in these studies, additional studies with increased sample
sizes are warranted to explain the lack of improvement in
mortality.
Our study demonstrates that although low-dose hydrocortisone therapy can improve shock reversal in patients
February 2014 Volume 118 Number 2

with sepsis, the therapy has no significant impact on

28-day mortality rate. The new International Guidelines
for Management of Severe Sepsis and Septic Shock suggest
that it is not advisable to use IV hydrocortisone as a treatment for adult septic shock patients if adequate fluid resuscitation and vasopressor therapy can restore hemodynamic
stability. If hemodynamic stability cannot be maintained,
the guidelines suggest IV hydrocortisone alone at a dose of
200 mg per day.37 Our results are consistent with these new
guidelines. The available evidence does not support the
argument that low-dose hydrocortisone should be used as
a routine treatment in adult patients with septic shock. E
DISCLOSURES

Name: Changsong Wang, MD.

Contribution: This author helped design and conduct the
study, analyze the data, and write the manuscript.
Attestation: Changsong Wang has seen the original study data,
reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Jiaxiao Sun, MSc.
Contribution: This author helped conduct the study, analyze
the data, and write the manuscript.
Attestation: Jiaxiao Sun has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Juanjuan Zheng, MSc.
Contribution: This author helped analyze the data.
Attestation: Juanjuan Zheng has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Lei Guo, MD.
Contribution: This author helped conduct the study and write
the manuscript.
Attestation: Lei Guo has seen the original study data, reviewed
the analysis of the data, and approved the final manuscript.
Name: Hongyan Ma, MD.
Contribution: This author helped conduct the study.
Attestation: Hongyan Ma has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Yang Zhang.
Contribution: This author helped conduct the study and write
the manuscript.
Attestation: Yang Zhang has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Fengmin Zhang, PhD.
Contribution: This author helped design the study, analyze the
data, and write the manuscript.
Attestation: Fengmin Zhang has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Enyou Li, MD.
Contribution: This author helped design and conduct the
study and write the manuscript.
Attestation: Enyou Li has seen the original study data, reviewed
the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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