Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study.

Abstract

The use of low-dose steroid therapy in the management of septic shock has been extensively studied. However, the association between the timing of low-dose steroid therapy and the outcome has not been evaluated. Therefore, we evaluated whether early initiation of low-dose steroid therapy is associated with mortality in patients with septic shock.
We retrospectively analyzed the clinical data of 178 patients who received low-dose corticosteroid therapy for septic shock between January 2008 and December 2009. Time-dependent Cox regression models were used to adjust for potential confounding factors in the association between the time to initiation of low-dose corticosteroid therapy and in-hospital mortality.
The study population consisted of 107 men and 71 women with a median age of 66 (interquartile range, 54 to 71) years. The 28-day mortality was 44% and low-dose corticosteroid therapy was initiated within a median of 8.5 (3.8 to 19.1) hours after onset of septic shock-related hypotension. Median time to initiation of low-dose corticosteroid therapy was significantly shorter in survivors than in non-survivors (6.5 hours versus 10.4 hours; P=0.0135). The mortality rates increased significantly with increasing quintiles of time to initiation of low-dose corticosteroid therapy (P=0.0107 for trend). Other factors associated with 28-day mortality were higher Simplified Acute Physiology Score (SAPS) 3 (P<0.0001) and Sequential Organ Failure Assessment (SOFA) scores (P=0.0007), dose of vasopressor at the time of initiation of low-dose corticosteroid therapy (P<0.0001), need for mechanical ventilation (P=0.0001) and renal replacement therapy (P<0.0001), while the impaired adrenal reserve did not affect 28-day mortality (81% versus 82%; P=0.8679). After adjusting for potential confounding factors, the time to initiation of low-dose corticosteroid therapy was still significantly associated with 28-day mortality (adjusted odds ratio (OR) 1.025, 95% confidence interval (CI) 1.007 to 1.044, P=0.0075). The early therapy group (administered within 6 hours after the onset of septic shock, n=66) had a 37% lower mortality rate than the late therapy group (administered more than 6 hours after the onset of septic shock, n=112) (32% versus 51%, P=0.0132).
Early initiation of low-dose corticosteroid therapy was significantly associated with decreased mortality.

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RESEARCHOpen Access
Early initiation of low-dose corticosteroid therapy
in the management of septic shock: a
retrospective observational study
Hye Yun Park1, Gee Young Suh1, Jae-Uk Song1, Hongseok Yoo1, Ik Joon Jo2, Tae Gun Shin2, So Yeon Lim1,
Sookyoung Woo3and Kyeongman Jeon1*
Abstract
Introduction: The use of low-dose steroid therapy in the management of septic shock has been extensively
studied. However, the association between the timing of low-dose steroid therapy and the outcome has not been
evaluated. Therefore, we evaluated whether early initiation of low-dose steroid therapy is associated with mortality
in patients with septic shock.
Methods: We retrospectively analyzed the clinical data of 178 patients who received low-dose corticosteroid
therapy for septic shock between January 2008 and December 2009. Time-dependent Cox regression models were
used to adjust for potential confounding factors in the association between the time to initiation of low-dose
corticosteroid therapy and in-hospital mortality.
Results: The study population consisted of 107 men and 71 women with a median age of 66 (interquartile range,
54 to 71) years. The 28-day mortality was 44% and low-dose corticosteroid therapy was initiated within a median
of 8.5 (3.8 to 19.1) hours after onset of septic shock-related hypotension. Median time to initiation of low-dose
corticosteroid therapy was significantly shorter in survivors than in non-survivors (6.5 hours versus 10.4 hours; P =
0.0135). The mortality rates increased significantly with increasing quintiles of time to initiation of low-dose
corticosteroid therapy (P = 0.0107 for trend). Other factors associated with 28-day mortality were higher Simplified
Acute Physiology Score (SAPS) 3 (P < 0.0001) and Sequential Organ Failure Assessment (SOFA) scores (P = 0.0007),
dose of vasopressor at the time of initiation of low-dose corticosteroid therapy (P < 0.0001), need for mechanical
ventilation (P = 0.0001) and renal replacement therapy (P < 0.0001), while the impaired adrenal reserve did not
affect 28-day mortality (81% versus 82%; P = 0.8679). After adjusting for potential confounding factors, the time to
initiation of low-dose corticosteroid therapy was still significantly associated with 28-day mortality (adjusted odds
ratio (OR) 1.025, 95% confidence interval (CI) 1.007 to 1.044, P = 0.0075). The early therapy group (administered
within 6 hours after the onset of septic shock, n = 66) had a 37% lower mortality rate than the late therapy group
(administered more than 6 hours after the onset of septic shock, n = 112) (32% versus 51%, P = 0.0132).
Conclusions: Early initiation of low-dose corticosteroid therapy was significantly associated with decreased mortality.
Introduction
Septic shock is one of the most common causes of
death in patients admitted to the ICU [1,2]. Despite
advances in early and appropriate antibiotic therapy,
initial resuscitation, source control, and organ support,
septic shock remains a major source of short-term and
long-term morbidity and mortality [3]. Although multi-
ple adjunctive therapies for septic shock have been
developed and studied in clinical trials, few of these
methods have demonstrated improvements in survival
[4]. Corticosteroid treatment has been studied exten-
sively as adjunctive therapy in patients with septic shock
for over 40 years. Initial trials investigating a short
course of high-dose corticosteroid as an anti-
* Correspondence: kjeon@skku.edu
1Division of Pulmonary and Critical Care Medicine, Department of Medicine,
Samsung Medical Center, Sungkyunkwan University School of Medicine, 81
Irwon-ro, Gangnam-gu, Seoul, 135-710, Republic of Korea
Full list of author information is available at the end of the article
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© 2012 Park et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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inflammatory regimen found no evidence of a survival
benefit [5,6]. In contrast, more recent trials demon-
strated that a longer course (≥ 5 days) of low-dose corti-
costeroid resulted in shock reversal [7] and improved
mortality rate [8,9]. Based primarily on a large rando-
mized, multicenter, controlled study performed by
Annane et al. [9], the Surviving Sepsis Campaign guide-
lines recommend the use of low-dose corticosteroid in
patients with septic shock requiring vasopressors despite
fluid replacement [3]. Recently, however, the Corticos-
teroid Therapy of Septic Shock (CORTICUS) study by
Sprung et al. [10] did not demonstrate an improvement
in mortality rate after low-dose corticosteroid therapy in
patients with septic shock. The contradictory findings of
these two large multicenter studies generated contro-
versy regarding the appropriateness of corticosteroid
therapy in patients with septic shock.
Although a number of factors may have accounted for
the differences in the results of these two large multicenter
studies, the difference in the time window of enrollment
should be considered [11]. Annane et al. initially enrolled
patients in the study within three hours of the onset of
shock, and this time window from the onset of septic shock
to randomization was increased to eight hours [9]. In con-
trast, in the CORTICUS study, patients were required to
undergo randomization within 24 hours after the onset of
septic shock, and this time window was subsequently
increased to 72 hours [10]. Therefore, it is probable that
the benefit of low-dose corticosteroid therapy may diminish
with a delay in instituting the treatment [12]. However,
there have been no reports regarding the association
between the timing of corticosteroid therapy and mortality
in patients with septic shock. Therefore, we performed a
retrospective analysis of the clinical data from patients who
received low-dose corticosteroid therapy for septic shock to
determine whether early initiation of this therapy is asso-
ciated with decreased mortality in such cases.
Materials and methods
This was a retrospective study performed in a cohort of
patients with septic shock admitted to the medical ICU
of Samsung Medical Center (a 1,960-bed, university-
affiliated, tertiary referral hospital in Seoul, South
Korea), which has 30 beds providing care for approxi-
mately 860 critically ill patients per year. The study was
approved by the institutional review board of Samsung
Medical Center to review and publish information from
the patients’ records. Informed consent was waived
because of the retrospective nature of the study.
Study population
All consecutive patients with septic shock admitted to
the medical ICU between January 2008 and December
2009 were screened for inclusion in this study if they
had received low-dose corticosteroid therapy (≤ 300 mg/
day of hydrocortisone or equivalent) for septic shock.
Patients were excluded if they were less than 18 years
old, had received systemic corticosteroid therapy within
the last 3 months before septic shock, had received
high-dose steroid therapy (> 300 mg/day of hydrocorti-
sone or equivalent), or did not receive low-dose corti-
costeroid therapy for septic shock. Additionally,
immunocompromised patients, such as those with HIV
infection and those who had undergone stem cell or
solid organ transplantations, were excluded from the
study.
Initial resuscitation and hemodynamic management for
septic shock
A specific protocol for early recognition and manage-
ment of patients with severe sepsis or septic shock has
been implemented in our center since 2004 [13]. Addi-
tionally, to improve the compliance with the initial
resuscitation bundle and management for sepsis, we
revised, approved, and promoted our early goal-directed
therapy (EGDT) protocol with an educational program
named ‘Emergency Approach to Sepsis Treatment
(EAST)’ in early 2008. Our EGDT protocol is an adapta-
tion of the protocol reported by Rivers et al. [14]. Fluid
resuscitation and hemodynamic monitoring were
initiated in patients fulfilling the criteria for severe sepsis
or septic shock, with placement of a central venous
catheter via the internal jugular or subclavian vein
approach for central venous pressure (CVP) and central
venous oxygen saturation (ScvO2) monitoring. Broad-
spectrum antibiotics were administered as soon as possi-
ble. Hemodynamic resuscitation was conducted accord-
ing to a predetermined treatment plan. First, isotonic
crystalloid was administered in boluses to target CVP ≥
8 mmHg. Second, systolic blood pressure ≥ 90 mmHg
or mean arterial pressure (MAP) ≥ 65 mmHg, if not
achieved with fluid administration, was targeted by initi-
ating and titrating vasopressors (preferably norepinephr-
ine as a first-line agent) to achieve this desired blood
pressure. Finally, ScvO2≥ 70% was targeted after CVP
and blood pressure goals were met. If ScvO2was lower
than 70% and the hematocrit was lower than 30%,
packed red blood cells were transfused to achieve a
hematocrit of at least 30%. If ScvO2remained lower
than 70% when hematocrit was 30% or higher, dobuta-
mine was initiated at the treating physician’s discretion
and titrated in attempts to reach ScvO2≥ 70%. When
the patient remained hypotensive after at least one hour
of resuscitation with fluids and vasopressor [9], low-
dose corticosteroid therapy was recommended as soon
as possible after sampling for adrenocorticotropic hor-
mone (ACTH) test if possible. However, the time to
initiation of low-dose corticosteroid therapy was decided
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by the treating physician in the emergency department
or ICU. Hydrocortisone was administered intravenously
every 6 hours as a 50-mg bolus for 5 days and then
tapered (50 mg intravenously every 12 hours for 3 days,
followed by 50 mg intravenously daily for 3 days). Flu-
drocortisone was not to be administered in conjunction
with hydrocortisone. If hemodynamic stabilization was
achieved, the vasopressor was tapered based on the deci-
sion of the attending physician, keeping MAP above 65
mmHg and urinary output higher than 0.5 mL/kg/hour.
Definitions
Septic shock was defined as sepsis with acute circulatory
failure characterized by persistent arterial hypotension
(systolic arterial pressure < 90 mmHg in 156 patients
(88%), mean arterial pressure < 60 mmHg in 147 (83%)],
or a reduction in systolic blood pressure > 40 mmHg
from baseline in 21 (12%)) despite adequate volume
resuscitation [15]. Organ dysfunction was defined as
Sequential Organ Failure Assessment (SOFA) score ≥ 2
for each organ system [15,16]. Critical-illness-related
corticosteroid insufficiency (CIRCI) was diagnosed by a
delta serum cortisol level of < 9 μg/dL after ACTH (250
μg) administration (relative adrenal insufficiency) or ran-
dom total serum cortisol < 10 μg/dL [12]. Appropriate
antibiotic therapy was considered if the initially pre-
scribed antibiotics were active against the identified
pathogens, based on in vitro susceptibility testing. The
time to initiation of antibiotic therapy relative to the
onset of septic shock was defined as the time from the
initial onset of septic shock-related hypotension to the
initiation of antibiotics [17]. Time to initiation of low-
dose corticosteroid therapy was defined as the time
from the initial onset of septic shock-related hypoten-
sion to the initiation of corticosteroid. Reversal of shock
was defined as the maintenance of a systolic blood pres-
sure of at least 90 mmHg without vasopressor support
for at least 24 hours [8,10].
Data collection
The following data recorded at the time of initiation of
low-dose corticosteroid therapy were collected from the
electronic medical records: general characteristics of the
patients including demographic data, infection source,
laboratory measurements including initial lactate,
amount of fluid administered before initiation of vaso-
pressor, doses of vasopressor (norepinephrine or equiva-
lent), and organ dysfunction. The severity of illness was
assessed by Simplified Acute Physiology Score 3 (SAPS
3) [18] and SOFA scores [19]. SAPS 3 was calculated as
the worst value for that variable during the first one
hour of ICU admission, and SOFA scores were calcu-
lated from the data on admission. On ICU admission,
the following conditions were evaluated: the need for
mechanical ventilation and renal replacement therapy,
appropriateness of empirical antibiotic therapy, and pre-
sence of bacteremia.
The primary outcome was 28-day mortality. To
address the primary research question of whether mor-
tality and time to initiation of low-dose steroid therapy
are associated, we considered age, gender, time to initia-
tion of antibiotic therapy and severity of illness as
potential confounders [17,20]. The secondary outcomes
were reversal of shock, ICU mortality, in-hospital mor-
tality and the duration of ICU and hospital stay.
Statistical analysis
Data are presented as medians and interquartile range
(IQR) for continuous variables and as numbers (percen-
tages) for categorical variables. Data were compared
using the Mann-Whitney U-test for continuous variables
and the c2or Fisher’s exact test for categorical variables.
To assess whether there was an association between 28-
day mortality and the time to initiation of low-dose cor-
ticosteroid therapy, the Mantel-Haenszel test was used
to examine trends across the quintiles of time.
A logistic regression model was used to adjust for
potential confounding factors in the association between
the time to initiation of low-dose corticosteroid therapy
and 28-day mortality. Three models were constructed:
model 1 was adjusted for age and gender, model 2 was
additionally adjusted for time to initiation of antibiotic
therapy and severity of illness, and model 3 additionally
included factors with P < 0.25 in univariate analysis as
confounding factors [21]. Data are presented as odds
ratios (OR) with 95% confidence intervals (CI).
The baseline characteristics and outcome measures of
interest were then compared between the patients
receiving low-dose corticosteroid therapy within versus
after six hours from the initial onset of septic shock-
related hypotension. Kaplan-Meier estimation was used
to determine the 90-day survival curves for these two
times to initiation of low-dose corticosteroid therapy,
which were then compared using the log-rank test for
survival data. Statistical analyses were performed using
SAS version 9.1 (SAS Institute, Cary, NC), and two-
sided P < 0.05 was considered significant.
Results
Over the study period, a total of 300 patients with septic
shock were admitted to the medical ICU. Of these, 112
patients were excluded according to the exclusion cri-
teria: systemic corticosteroid therapy within the last 3
months before septic shock (n = 63), high-dose steroid
therapy (n = 40), and immunocompromised status (n =
9). Moreover, ten patients who were transferred from
other hospitals after initiation of vasopressors were also
excluded. Finally, 178 patients who received low-dose
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steroid therapy for septic shock were included in this
study.
The baseline characteristics of the patients at the time
of initiation of low-dose corticosteroid therapy are pre-
sented in Table 1. There were 107 male and 71 female
patients, and the median age was 66 (IQR, 54 to 71)
years. The median SAPS 3 and SOFA scores on ICU
admission were 81 (72 to 90) and 11 (9 to 13), respec-
tively. Pneumonia was the most common cause of septic
shock (n = 80, 45%), followed by gastrointestinal tract
infection (n = 47, 26%) and urinary tract infection (n =
19, 11%). Microbiologically proven infection was
observed in 58% of the cohort, and 37% had proven
bloodstream infection. Seventy-nine percent of these
patients received appropriate antibiotic treatment.
Mechanical ventilation was needed in 124 (70%) patients,
and renal replacement therapy was needed in 58 (33%)
patients on ICU admission. Median dose of vasopressor
(norepinephrine or equivalent) at the time of initiation of
low-dose corticosteroid therapy was 0.48 μg/kg/minute.
ACTH stimulation tests were performed in 96 (54%)
patients, and CIRCI was diagnosed in 78 patients. The
number of patients with relative adrenal insufficiency
defined by a delta serum cortisol level of < 9 μg/dL after
ACTH administration was 71 (91% of patients with
CIRCI). The median time to initiation of low-dose corti-
costeroid therapy was 8.5 (3.8 to 19.1) hours.
Reversal of shock was achieved in 67% after a median
time of 35 (18 to 65) hours of low-dose corticosteroid
therapy. Twenty eight-day mortality was 44%. ICU mor-
tality was 43%, and median length of ICU stay was 6 (3
to 11) days. In-hospital mortality was 58%, and median
length of hospital stay was 16 (7 to 31) days. Ninety-day
mortality was 50%. Twenty eight-day mortality rates
according to the time to initiation of low-dose corticos-
teroid therapy in quintiles are presented in Figure 1.
The mortality rates increased significantly with increas-
ing quintiles of time to initiation of low-dose corticos-
teroid therapy (P = 0.0107, test for trend).
Univariate comparisons of baseline characteristics at the
time of initiation of low-dose corticosteroid therapy
between survivors and non-survivors are presented in
Table 2. There were no significant differences in age, sex,
sites of infection, bacteremia, time to initiation of antibio-
tic therapy, or appropriate antibiotic treatment between
groups. However, mortality was associated with severity of
illness and organ failure requiring mechanical support.
Median SAPS 3 and SOFA scores were significantly higher
in non-survivors than in survivors (P < 0.0001 and P =
0.0007, respectively). Median dose of vasopressor at the
time of initiation of low-dose corticosteroid therapy was
higher in non-survivors compared with survivors (P <
0.0001). The need for mechanical ventilation and renal
replacement therapy were also greater in non-survivors
compared with survivors (P = 0.0001 and P < 0.0001,
respectively). The median time to initiation of low-dose
corticosteroid therapy was significantly shorter in survi-
vors (6.5 hours, IQR 3.6 to 13.9 hours) than in non-survi-
vors (10.4 hours, IQR 5.5 to 23.5 hours) (P = 0.0135).
Although there was no difference in prevalence of CIRCI
(81% in survivors versus 82% in non-survivors, P =
0.8679), the proportion of patients who underwent a
reversal of shock within 48 hours after initiation of low-
dose corticosteroid therapy was higher in survivors (74%
versus 22%, respectively, P < 0.0001).
The results of multivariate analyses with the logistic
regression model are presented in Table 3. Time to
initiation of low-dose corticosteroid therapy was asso-
ciated with crude 28-day mortality (OR 1.015, 95% CI
1.001 to 1.030, P = 0.0483). After adjusting for a priori
variables of age and gender (model 1), and time to initia-
tion of antibiotic therapy and severity of illness (model
2), the association remained significant. The final logistic
regression model (model 3) included the a priori para-
meters of age, gender, time to initiation of antibiotic ther-
apy, and severity of illness assessed by SAPS 3 as well as
other variables with P-values less than 0.25 on univariate
analysis (Table 2). After adjusting for potential confound-
ing factors, the time to initiation of low-dose corticoster-
oid therapy was still significantly associated with 28-day
mortality (adjusted OR 1.025, 95% CI 1.007 to 1.044, P =
0.0075). Other factors independently associated with in-
hospital mortality were higher SAPS 3 (adjusted OR
1.063, 95% CI 1.029 to 1.098, P = 0.0003), higher dose of
vasopressor (norepinephrine or equivalent) (adjusted OR
1.921, 95% CI 1.014 to 3.639, P = 0.0453) and need for
renal replacement therapy (adjusted OR 3.623, 95% CI
1.635 to 8.026, P = 0.0015).
Additionally, patients were categorized as early ther-
apy group (low-dose corticosteroid administered within
6 hours from the initial onset of septic shock-related
hypotension, n = 66) and late therapy group (low-dose
corticosteroid administered after 6 hours from the initial
onset of septic shock-related hypotension, n = 112).
Both groups had similar characteristics, such as age, sex,
severity of illness, sites of infection, bacteremia, time to
initiation of antibiotic therapy, appropriate antibiotic
treatment, laboratory data, and organ failure, except for
need of mechanical ventilation (P = 0.0071) (Table 4).
Although the proportion of patients who showed rever-
sal of shock rate was similar in both groups (P =
0.0683), ICU mortality rate was better in the early-ther-
apy group (32%) than in the late-therapy group (49%) (P
= 0.0243). Finally, the early therapy group had a 37%
lower 28-day mortality rate than the late therapy group
(32% versus 51%, P = 0.0132) and a similar difference in
mortality rate was observed up to 90 days (Table 4 and
Figure 2). After adjusting for potential confounding
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factors, initiation of low-dose corticosteroid therapy
more than 6 hours after the onset of septic shock was
independently associated with increased 28-day mortal-
ity (adjusted OR 2.142, 95% CI 1.047 to 4.382, P =
0.0369) (Table 5).
Discussion
This is the first study to evaluate the association
between early initiation of low-dose corticosteroid ther-
apy and decreased mortality in patients with septic
shock. The results of our retrospective cohort study
Table 1 Baseline characteristics of 178 patients with septic shock receiving low-dose corticosteroid therapy
Characteristics Number (%) or median (interquartile range)
Age, years
Sex, male
Severity of illness
SAPS 3
SOFA
Site of infection
Lung
Gastrointestinal tract
Urinary tract
Catheter related
Skin and soft tissue
Others
Acquisition of infection
Community
Hospital
Locale before ICU admission
Emergency department
General ward
Positive culture
At any site
Gram-positive only
Gram-negative only
Fungus only
Mixed
Of blood
Gram-positive only
Gram-negative only
Fungus only
Mixed
Time to initiation of antibiotic therapy, hour
Appropriate antibioticsa
Organ failureb
Respiratory
Coagulation
Liver
Renal
Amount of fluid administered before vasopressor, L
Vasopressor (norepinephrine or equivalent) dose, μg/kg/min
Need for mechanical ventilation
Need for renal replacement therapy
CIRCIc
Relative adrenal insufficiencyc
Time to initiation of low-dose corticosteroid therapy, hour
66 (54-71)
107 (60)
81 (72-90)
11 (9-13)
80 (45)
47 (26)
19 (11)
5 (3)
6 (3)
21 (12)
129 (72)
49 (28)
119 (67)
59 (33)
104 (58)
33/104 (32)
55/104 (53)
4/104 (4)
12/104 (12)
67 (37)
24/67 (36)
36/67 (54)
2/67 (3)
5/67 (7)
0 (-5.4 - 1.4)
82/104 (79)
138 (78)
109 (61)
64 (36)
67 (38)
1.6 (1.0-2.2)
0.48 (0.29 - 0.80)
124 (70)
58 (33)
78/96 (81)
71/96 (74)
8.5 (3.8-19.1)
CIRCI, critical-illness-related corticosteroid insufficiency; SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment.aAppropriate
antibiotics were based on the site of infection and available cultures.;bOrgan failure was defined as SOFA score of 2 or more per system;cResults of
adrenocorticotropic hormone test were available for 96 (54%) patients.
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