The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock

Article (PDF Available)inIntensive Care Medicine 35(11):1868-1876 · November 2009with82 Reads
DOI: 10.1007/s00134-009-1603-4 · Source: PubMed
Abstract
Rationale: Use of etomidate in the critically ill is controversial due to its links with an inadequate response to corticotropin and potential for excess mortality. In a septic shock population, we tested the hypotheses that etomidate administration induces more non-responders to corticotropin and increases mortality and that hydrocortisone treatment decreases mortality in patients receiving etomidate. Methods: An a-priori sub-study of the CORTICUS multi-centre, randomised, double-blind, placebo-controlled trial of hydrocortisone in septic shock. Use and timing of etomidate administration were collected. Endpoints were corticotropin response and all-cause 28-day mortality in patients receiving etomidate. Measurements and main results: Five hundred patients were recruited, of whom 499 were analysable; 96 (19.2%) were administered etomidate within the 72 h prior to inclusion. The proportion of non-responders to corticotropin was significantly higher in patients who were given etomidate in the 72 h before trial inclusion than in other patients (61.0 vs. 44.6%, P = 0.004). Etomidate therapy was associated with a higher 28-day mortality in univariate analysis (P = 0.02) and after correction for severity of illness (42.7 vs. 30.5%; P = 0.06 and P = 0.03) in our two multi-variant models. Hydrocortisone administration did not change the mortality of patients receiving etomidate (45 vs. 40%). Conclusions: The use of bolus dose etomidate in the 72 h before study inclusion is associated with an increased incidence of inadequate response to corticotropin, but is also likely to be associated with an increase in mortality. We recommend clinicians demonstrate extreme caution in the use of etomidate in critically ill patients with septic shock.
Brian H. Cuthbertson
Charles L. Sprung
Djillali Annane
Sylvie Chevret
Mark Garfield
Serge Goodman
Pierre-Francois Laterre
Jean Louis Vincent
Klaus Freivogel
Konrad Reinhart
Mervyn Singer
Didier Payen
Yoram G. Weiss
The effects of etomidate on adrenal
responsiveness and mortality in patients
with septic shock
Received: 24 January 2009
Accepted: 29 June 2009
Ó Springer-Verlag 2009
On behalf of the Corticus Study Group.
B. H. Cuthbertson (
)
)
Health Services Research Unit,
University of Aberdeen,
3rd Floor, Health Sciences Building,
Foresterhill, Aberdeen AB25 2ZD, UK
e-mail: b.h.cuthbertson@abdn.ac.uk
Tel.: ?44-1224-552730
Fax: ?44-1224-554580
C. L. Sprung S. Goodman Y. G. Weiss
Department of Anesthesiology and Critical
Care Medicine, Hadassah Hebrew
University Medical Center, Jerusalem,
Israel
D. Annane
General Intensive Care Unit, Raymond
Poincare
´
Hospital (AP-HP), University of
Versailles, SQY, Garches, France
S. Chevret
Biostatistics Department, St Louis Hospital,
Paris, France
M. Garfield
Intensive Care Unit, Ipswich Hospital NHS
Trust, Ipswich, UK
P.-F. Laterre
Department of Critical Care Medicine,
St Luc University Hospital, UCL, Brussels,
Belgium
J. L. Vincent
Intensive Care Unit, Erasme University
Hospital, Brussels, Belgium
K. Freivogel
Analytica International GmbH,
Untere Herrenstr, Lo
¨
rrach, Germany
K. Reinhart
Department of Anaesthesiology and
Intensive Care Medicine, Friedrich-Schiller
Universitat, Jena, Germany
M. Singer
Department of Medicine, Wolfson Institute
of Biomedical Research, University College
London, London, UK
D. Payen
Reanimation, Hopital Lariboisiere, Paris,
France
Abstract Rationale: Use of
etomidate in the critically ill is
controversial due to its links with an
inadequate response to corticotropin
and potential for excess mortality. In
a septic shock population, we tested
the hypotheses that etomidate
administration induces more non-
responders to corticotropin and
increases mortality and that hydro-
cortisone treatment decreases
mortality in patients receiving etom-
idate. Methods: An a-priori sub-
study of the CORTICUS multi-centre,
randomised, double-blind, placebo-
controlled trial of hydrocortisone in
septic shock. Use and timing of
etomidate administration were col-
lected. Endpoints were corticotropin
response and all-cause 28-day mor-
tality in patients receiving etomidate.
Measurements and main results:
Five hundred patients were recruited,
of whom 499 were analysable; 96
(19.2%) were administered etomidate
within the 72 h prior to inclusion. The
proportion of non-responders to cor-
ticotropin was significantly higher in
patients who were given etomidate in
the 72 h before trial inclusion than in
other patients (61.0 vs. 44.6%,
P = 0.004). Etomidate therapy was
associated with a higher 28-day
mortality in univariate analysis
(P = 0.02) and after correction for
severity of illness (42.7 vs. 30.5%;
P = 0.06 and P = 0.03) in our two
multi-variant models. Hydrocortisone
administration did not change the
mortality of patients receiving etom-
idate (45 vs. 40%).
Conclusions: The use of bolus dose
etomidate in the 72 h before study
inclusion is associated with an
increased incidence of inadequate
response to corticotropin, but is also
likely to be associated with an
increase in mortality. We recommend
clinicians demonstrate extreme cau-
tion in the use of etomidate in
critically ill patients with septic
shock.
Keywords Etomidate Relative
adrenal insufficiency Septic shock
Mortality Hydrocortisone
Intensive Care Med
DOI 10.1007/s00134-009-1603-4
ORIGINAL
Introduction
Septic shock is a major cause of morbidity and mortality
worldwide [14]. The administration of moderate doses of
corticosteroids for sepsis in septic shock has been con-
troversial for many years [57]. Recent meta-analyses,
reviews and guidelines have advocated the use of ‘low-
dose’ hydrocortisone in septic shock [813]. It is clear
that an altered response to the ACTH stimulation test is
associated with an increased mortality in patients with
septic shock [1418].
Many critically ill patients require mechanical venti-
lation, and the imidazole anaesthetic agent etomidate is
often used to facilitate endotracheal intubation in these
patients. It has been known for many years that etomidate
inhibits adrenocortical steroid synthesis by reversibly
blocking the action of the enzyme 11-b-hydroxylase [19,
20]. This can last for at least 24 h following a single bolus
of etomidate [2022]. The deleterious effects of etomidate
by infusion were first recognised in the critically ill when
an excess mortality was identified in trauma patients who
received infusions of etomidate for sedation [23, 24]. Its
use is now recognised as an important cause of inadequate
response to corticotropin (IRC) in the critically ill [18,
25]. Some authorities have even recommended that
etomidate administration either be discontinued altogether
or should always be accompanied by steroid replacement
therapy to counter these effects [2629]. The evidence for
a direct effect of a single bolus dose of etomidate on
mortality in these patients is more controversial, with
some studies showing an increased mortality [14, 3032]
and others showing no difference [33, 34]. Many of these
studies were small and underpowered. Despite this evi-
dence many clinicians still use etomidate in the critically
ill because of its remarkably safe cardiovascular profile
[33, 34].
Using data from CORTICUS, a large, prospective
multi-centre study of hydrocortisone treatment in septic
shock, we tested the hypotheses that bolus doses of
etomidate results in an increased proportion of non-
responders to corticotropin and an increase in mortality,
and that hydrocortisone treatment decreases mortality in
patients receiving etomidate.
Methods
Patients
This study is an a-priori sub-study of the CORTICUS
study, which was a multi-centre, randomised, double-
blind, placebo-controlled trial of low-dose hydrocortisone
in septic shock [35]. Following formal approval by the
Ethics Committees of the 52 participating adult intensive
care units (ICUs), adult patients were enrolled from
March 2002 until November 2005. Patients in partici-
pating ICUs were included if they met the inclusion
criteria, including: (1) clinical evidence of infection, (2)
evidence of a systemic response to infection, (3) contin-
ued evidence of shock within the previous 72 h defined by
a systolic blood pressure (SBP) \90 mmHg despite ade-
quate fluid replacement OR need for vasopressors for at
least 1 h, and evidence of hypoperfusion or organ dys-
function attributable to sepsis and (4) informed consent
according to local regulations [35]. Notable exclusion
criteria included underlying disease with a poor progno-
sis, immunosuppression and prior administration of
corticosteroids [35]. The use of etomidate was discour-
aged because of its perceived potential for adrenal
suppressive effects but did not constitute an exclusion
criterion. Patients received hydrocortisone hemisuccinate
or placebo for 11 days in a tapering dose and then stopped
[35]. Evidence-based guidelines for patient management
were encouraged [36].
Data collection
Data collected included general demographics, SAPS II
score [37] and the use and timing of etomidate adminis-
tration over the trial period. Organ system failure was
defined for each of the six major organ systems as a
sequential organ failure assessment (SOFA) score of 3 or 4
points [38]. A short corticotropin test was performed using
blood samples taken immediately before and 60 min after
an intravenous bolus of 0.25 mg tetracosactrin (Novartis,
Nuremberg, Germany, or Alliance, Chippenham, UK).
Non-responders to the corticotropin test were defined by a
cortisol increase of B9 lg/dl (248 nmol l
-1
)[39, 40].
Final analyses were undertaken in a central laboratory
using the ELECSYS Cortisol assay
Ò
(Roche Diagnostics,
Mannheim/Penzberg, Germany). Reversal of shock was
defined as the maintenance of a SBP C90 mmHg without
vasopressor support for C24 h. Patients were followed up
for vital status at a 28-day period after randomisation.
Random quality assurance evaluations were performed in
10% of all data.
Outcomes
A-priori endpoints for this sub-study were corticotropin
response in patients who received etomidate, all-cause
28-day mortality in septic shock patients who received or
did not receive etomidate and whether hydrocortisone
decreased mortality in patients receiving etomidate.
Etomidate administration was defined as any dose
administered within the 72 h prior to trial randomisation
(day 0). Patients receiving etomidate within 72 h of trial
inclusion were prospectively defined as the patients most
likely to develop IRC after etomidate administration [35].
Patients who received etomidate [72 h prior to trial
inclusion were not included in the etomidate group as it
was assumed that the effects of etomidate would not
persist beyond 3 days.
Statistical analysis
Twenty-eight-day all-cause mortality was analysed by the
Fisher’s exact test for differences between treatment
groups. The Fisher exact test was used when comparing
responsiveness versus non-responsiveness in patients
receiving etomidate or not. Multivariate analyses of the
28-day mortality were carried out using logistic regres-
sion models. Cumulative incidence of shock reversal was
estimated by nonparametric methods, accounting death
prior to reversal as a competing risk for the outcome.
Curves were compared across groups using the Gray test.
Two-sided P-values of 5% were considered statistically
significant. Statistical analyses were performed using SAS
9.1 (SAS Inc., Cary, NC) and R 2.6.1 (http://www.
R-project.org) software packages.
Role of the funding source
The EU Commission and other sponsors had no role in the
design and conduct of the study; collection, management,
analysis and interpretation of the data; or in the prepara-
tion, review or approval of the manuscript.
Results
Relevant baseline demographics of the 499 patients and in
the 96 patients who received etomidate within 72 h of trial
inclusion are shown in Table 1. Data on reasons for etomi-
date use were not collected. Etomidate was used in 96
(19.2%) patients in the 72 h before trial inclusion and a
further 33 (7%) of patients in the week before, or month
after, trial inclusion (total receiving etomidate at any time
129 (26%). The number of non-responders to corticotropin
was significantly higher in patients who were given etomi-
date than in other patients [58 of 95 (61.0%), vs. 175 of 392
(44.6%), P = 0.004]. For patients who received etomidate
within 72 h of trial inclusion, the median time between
etomidate dosage and inclusion was 14.5 h [interquartile
range (IQR) 4.25–28.4]. In seven patients receiving etomi-
date 3–7 days prior to randomisation, 3 (42.9%) were
nonresponders versus 4 (57.1%) responders to corticotropin.
In a univariate analysis an increased mortality was
observed in those who received etomidate (OR = 1.70,
95% CI: 1.07–2.68; P = 0.02) (Tables 1, 2; Fig. 1), with
similar causes of death in both groups (P = 0.26)
(Table 1). We developed two logistic regression models
adjusting for the treatment group (steroid/placebo),
response to corticotropin (responder/non-responder),
baseline cortisol value (as continuous variable) and SAPS
II score in the first and these co-variants plus SOFA score
in the second. In the first model we demonstrated a non-
significant increase in mortality (OR = 1.60, 95%CI:
0.98–2.62; P = 0.06), and in the second model this
become statistically significant (OR = 1.75, 95%CI:
1.06–2.90; P = 0.03) (Table 3). Hydrocortisone admin-
istration did not change the mortality of patients receiving
etomidate (45 vs. 40%) (Tables 2, 3). In the hydrocorti-
sone group and the placebo group, the cumulative
incidence of shock reversal was not effected by the
administration of etomidate (P = 0.42 and P = 0.41,
respectively; Fig. 1). In the placebo group, mean time to
reversal of shock was 6.2 days (95% CI 4.4–8.2) in those
receiving etomidate and 5.7 days (95% CI 4.6–6.8) in
those who did not (P = 0.41 by the Gray test); in the
hydrocortisone group, mean time to reversal of shock was
3.0 days (95% CI: 2.5–3.5) in those receiving etomidate
and 3.8 days (95% CI: 3.1–4.4) in those who did not
(P = 0.42 by the Gray test)(Fig. 1).
There was no effect of etomidate on SOFA scores.
SOFA scores for patients treated with etomidate com-
pared to patients who did not receive etomidate were 10
[8–13] and 11 [9–13] (P = 0.14) at baseline (Table 1)
and at day 7 were 6 [3–10] and 6 [3–9], (p = 0.65),
respectively. The change in SOFA score from baseline to
day 7 for patients treated with etomidate compared to
patients who did not receive etomidate were -4[-6;-2]
and -4[-7;-1] (P = 0.36), respectively.
Discussion
This study confirms that a bolus dose of etomidate is
associated with an increased incidence of IRC and is also
associated with increased mortality in at least one of our
models. Hydrocortisone treatment had no effect on out-
come in patients who received etomidate.
Use of etomidate
This study documents that etomidate is still widely used
in intensive care practice across Europe. Even though the
use of etomidate was discouraged in this study, it was still
given to more than one quarter of the patients enrolled
and 19.2% within 72 h of trial inclusion. Etomidate is still
used primarily for its low cardiovascular complication
rate during induction of anaesthesia [34, 41]. Despite this
potential benefit, there are no studies demonstrating
improved outcome over other agents [34, 42]. The use of
etomidate for induction of anaesthesia was similar in this
study to the Annane study (26 vs. 24%) [35, 39], but
lower than in other studies [30].
Etomidate and inadequate response to corticotropin
The potential for etomidate to induce an IRC has been
known for many years [23]. A single bolus dose of
etomidate can inhibit steroid metabolism for at least 24–
48 h in critically ill patients [15, 22, 25, 43]. Patients
given etomidate were at least 12 times more likely to
develop an IRC than those not receiving the drug [14, 15,
22, 25]. An association between etomidate and the like-
lihood of an IRC was found in this study.
Critically ill patients treated with etomidate have been
found to have a greater incidence of an IRC [14, 15, 22],
and the prognostic importance of adrenal insufficiency in
septic shock has been well described [16]. Mohammed
et al. [14] retrospectively studied 152 patients with septic
shock who had undergone an ACTH stimulation test.
Twenty-five percent of the patients received etomidate at
some time before the stimulation test, and the incidence
of an IRC in these patients was significantly higher than
in those who had not received etomidate (76 vs. 51%
P \ 0.01), although numbers were limited.
Etomidate and concurrent steroid therapy
Routine testing of adrenal function has been advocated to
guide steroid therapy, and indeed some authorities have
recommended replacement steroid therapy concurrent to
etomidate dosage to counter its known adrenal suppres-
sive effects [8, 9, 16, 39, 42]. It is somewhat surprising
that experts would recommend treating the dangerous side
effects of one drug by the administration of another with
well known and dangerous side effects of its own [42]. An
association between etomidate and an IRC was found in
this study. Despite this increased incidence of an IRC,
there was no evidence for any benefit from hydrocortisone
treatment at the dosage used in the study. The lack of
effect could be explained by the temporal separation
between etomidate and steroid therapy, a wider immu-
nosuppressive action of etomidate not just affecting
adrenal 11-b-hydroxylase or the ACTH test evaluating
adrenal gland stimulation but not necessarily adrenal
Table 1 Baseline demographics, ACTH response and mortality
Baseline demographics Etomidate in 72 h
(n = 96)
No etomidate in 72 h
(n = 403)
All patients
(n = 499)
Age (years) 68 [61–74] 64 [52–74] 65 [53–74]
Male gender 64 (66.7) 268 (66.5) 332 (66.5)
SAPS II 49 [37–66] 47 [37–58] 48 [37–60]
SOFA score (baseline) 10 [8–13] 11 [9–13] 10 [9–13]
SOFA cardiovascular component (baseline) 4 [4–4] 4 [4–4] 4 [4–4]
Race—Caucasian 92 (95.8) 372 (92.3) 464 (93.0)
Reason for admission
Medical 29 (30.2) 145/400 (36.2) 174/496 (35.1)
Elective surgical 12 (12.5) 40/400 (10) 52/496 (10.5)
Emergency surgery 55 (57.3) 215/400 (53.7) 270/496 (54.4)
Cortisol (lg/dl); n = 487
Before administration 20.3 [12.6–32.6] 25.9 [16.7–37.1] 25.1 [16.1–36.1]
After 60 min 30.2 [20.8–37.9] 37.3 [26.5–49.8] 35.5 [25.0-47.7]
Difference 7.2 [1.9–11.3] 9.8 [3.8–16.3] 9.2 [3.3–15.6]
ACTH responders* 37 (38.9) 217 (55.4) 254 (52.2)
Day 28 mortality** 41 (42.7) 123 (30.5) 164 (32.9)
Due to refractory shock 9 (22.0) 42 (34.2) 51 (31.1)
Due to multi-system organ failure 24 (58.5) 55 (44.7) 79 (48.2)
Due to other cause 8 (19.5) 26 (21.1) 34 (20.7)
The table is divided according to whether the patients had received
etomidate in the 72 h before trial inclusion, those who did not
receive etomidate and all study patients. Data are presented as
number (%) or median and [IQR]
*P = 0.004 by the chi-square test; **P = 0.02 by the chi-square
test
Table 2 Univariate analysis of factors relating to 28 day mortality
Etomidate 28-day mortality (%) Odds ratio (95%CI) P-value
All patients
No 123/400 (30.5%) 1.00 0.02
Yes 41/96 (42.7%) 1.70 (1.07–2.68)
Hydrocortisone
No 63/200 (31.5%) 1.00 0.07
Yes 23/51 (45.1%) 1.79 (0.95–3.34)
Placebo
No 60/203 (29.6%) 1.00 0.18
Yes 18/45 (40.0%) 1.59 (0.81–3.10)
Data presented with regard to etomidate administration in all
patients, patients who received hydrocortisone and those who
received placebo
0 5 10 15 20 25
0.18.06.04.02.00.0
Hydrocortisone group
Days
htaed fo ecnedicni evitalumuC
No etomidate
etomidate
0 5 10 15 20 25
0.18.06.04.02.00.0
Placebo group
Days
htaed fo ecnedicni evitalumuC
No etomidate
etomidate
0 5 10 15 20 25
0.18.06.04.
0
2.00.
0
Hydrocortisone group
Days
lasrever k
cohs f
o
e
c
n
edic
ni
evital
umuC
No etomidate
etomidate
0 5 10 15 20 25
0.18.06.04.0
2
.00.0
Placebo group
Days
lasre
v
er k
c
oh
s
f
o ec
n
edicni
evitalu
m
uC
No etomidate
etomidate
Fig. 1 Cumulative incidence of
death (top) and shock reversal
(bottom) within the first 28 days
following randomisation.
Groups are divided according to
previous administration of
etomidate in the 72 h before
trial inclusion within the two
randomised groups
Table 3 Results of multiple regression analyses showing independent predictors of mortality
Model 1 Model 2
OR (95%CI) P-value OR (95%CI) P-value
All patients (n = 487)
SAPS II 1.03 (1.02–1.04) \0.0001 1.02 (1.01–1.04) 0.0009
Etomidate 1.60 (0.98–2.62) 0.06 1.75 (1.06–2.90) 0.03
Hydrocortisone group 1.05 (0.70–1.56) 0.81 1.04 (0.69–1.56) 0.84
ACTH non-responder 1.37 (0.91–2.05) 0.13 1.32 (0.87–1.98) 0.19
Baseline cortisol 1.01 (1.00–1.02) 0.045 1.01 (1.00–1.02) 0.04
SOFA n/a n/a 1.10 (1.03–1.19) 0.005
Hydrocortisone group (n = 243)
SAPS II 1.03 (1.01–1.04) 0.005 1.02 (1.00–1.22) 0.05
Etomidate 1.51 (0.77–3.00) 0.23 1.54 (0.77–3.08) 0.22
ACTH non-responder 1.42 (0.81–2.49) 0.22 1.37 (0.78–2.42) 0.28
Baseline cortisol 1.01 (0.99–1.02) 0.18 1.01 (0.99–1.02) 0.22
SOFA n/a n/a 1.10 (1.00–1.22) 0.04
Placebo group (n = 244)
SAPS II 1.04 (1.02–1.06) \0.0001 1.03 (1.01–1.05) 0.006
Etomidate 1.83 (0.88–3.82) 0.10 2.15 (1.01–4.61) 0.048
ACTH non-responder 1.32 (0.74–2.38) 0.35 1.25 (0.69–2.27) 0.46
Baseline cortisol 1.01 (1.0–1.03) 0.14 1.01 (0.99–1.03) 0.11
SOFA n/a n/a 1.11 (1.00–1.24) 0.05
Data presented for risk of mortality in all patients and according to
the randomisation group. Logistic regression model 1 adjusts for
the treatment group (steroid/placebo), response to corticotropin
(responder/non-responder), baseline cortisol value (as continuous
variable) and SAPS II score. Model 2 adjusts for these co-variants
plus baseline SOFA score
function. This study provides no supportive evidence for
the routine use of steroid therapy to treat the adrenal
suppressive side effects of etomidate with or without prior
corticotropin testing in patients with septic shock. How-
ever, it cannot exclude potential benefits from steroid
therapy if given immediately after an etomidate bolus,
and this area warrants further study. Etomidate also
inhibits the synthesis of aldosterone, and the absence of
aldosterone replacement may have accounted for the
observed lack of steroid benefit.
Etomidate and mortality
This study suggested that etomidate administration was
associated with an increased mortality in one of our
logistic regression analyses. An obvious hypothesis is that
the increased mortality was due to the adrenal suppressive
effects of etomidate. It is noted that the Kaplan-Meier
curves for mortality do not separate until approximately
10 days after study inclusion. It could be argued that the
toxic side-effects of a drug should have a more rapid
effect on mortality. Such rapid effects are indeed seen in
adrenal responses after etomidate administration. How-
ever, this later temporal relationship for death could still
be due to the toxic side effects of etomidate, especially if
the early adrenal suppressive effect caused by etomidate
is the main factor that later leads to the excess mortality.
Another possible explanation could be that etomidate was
used more commonly in patients with higher severity of
illness due to its improved cardiovascular stability. The
patients who received etomidate had increased severity of
illness (according to SAPS II but not SOFA scores)
compared to those who did not receive the drug, but, after
correcting for severity of illness, etomidate was still
associated with an increased mortality (P = 0.03) in one
of our models. The analysis of SOFA scores shows no
differences in baseline or day 7 SOFA scores or in the
change in SOFA score between baseline and day 7
between groups. Further, there was no difference in
baseline cardiovascular SOFA scores between groups, so
the presence of organ failure is unable to further explain
these effects. Perhaps the combination of higher baseline
severity of illness and the adrenal effects of etomidate
combined to lead to a higher mortality but the mortality
effect was delayed. We do not have enough data to
explain these observations in the current study or to make
a clear hypothesis as to the cause of this observation.
In a retrospective study of 477 septic patients from 20
European ICUs who had undergone an ACTH stimulation
test on the day of sepsis onset [30], Lipiner-Friedman
et al. showed that 237 (50%) of patients had received
etomidate in the 24 h prior to inclusion. Patients receiving
etomidate were at increased risk of death on univariate
analysis, but the differences were no longer statistically
significant on multivariate analysis [30]. There are three
other studies that showed no mortality differences in
patients who received etomidate or not [14, 31, 34]. In the
study by Mohammed et al. [14] there was no difference in
mortality between those who received etomidate and
those who did not (63 vs. 55% P = 0.45). Riche
´
et al.
[31] studied 118 septic shock patients who underwent a
laparotomy or drainage for intra-abdominal infection; the
58% who had received etomidate in the 24 h preceding
cortisol measurements had a similar mortality as the other
patients. Ray et al. [34] reviewed 159 septic shock
patients over a 40-month period and found that 46.5% had
received etomidate within 24 h of their ICU admission.
There was a difference in mortality between patients who
received etomidate and those receiving other induction
agents (69 vs. 55%), but the differences did not achieve
statistical significance. In the study of Annane et al. [6, 9,
39], 68 of the 72 patients (94%) who received etomidate
for the induction of anesthesia did not respond to a cor-
ticotropin test and had a higher mortality. In the placebo
arm, non-responders had a mortality rate of 77% in the
etomidate-treated patients and 67% in those who did not
receive etomidate (Prof. D. Annane, personal communi-
cation). The present results should lead to extreme caution
in the use of etomidate in patients with septic shock
because of an likely excess mortality. It is unclear whe-
ther these results apply to the use of etomidate in other
stages of sepsis or in other critical illnesses, but it would
seem appropriate to advise marked caution in the use of
this drug in such patients.
Etomidate and reversal of shock
An effect of hydrocortisone therapy on time to reversal of
shock was seen in the CORTICUS study, although the
total number in whom shock was reversed did not differ
between groups [35]. However, etomidate did not affect
the time to reversal of shock in survivors or the number of
survivors who ultimately achieved reversal of shock. It
could be hypothesised that etomidate would slow time to
reversal of shock or reduce the number of patients who
reversed shock due to effects on adrenal hormone levels
affecting adrenoceptor function [35]. This suggests an
effect of steroids on adrenoceptor function or further
mechanisms mediated through a direct interaction with
mechanisms producing vascular hyporeactivity or other
anti-inflammatory actions [35]. However, regardless of
effects on adrenal function, etomidate does not affect the
speed of resolution, or number of patients who resolve,
their septic shock.
Strengths and limitations
Strengths of this study include the fact that it was a
European-wide, investigator-initiated study including 52
ICUs from nine countries. It is the largest study of its kind
that reports on the impact of etomidate use in septic
shock. A central laboratory was used for measuring cor-
tisol, and quality assurance evaluations revealed few
problems. Limitations of the study include the limited
power as only 500 patients were enrolled and the fact that
this study was a sub-study and was not designed or
powered to test the outcomes prospectively. We do not
know the patient’s severity of illness at the time etomidate
was used so cannot say to what degree their severity of
illness on trial entry and subsequent outcome was directly
influenced by etomidate use. The multivariate approach is
limited by the variables included in the analysis, so that
other unmeasured variables could have contributed to the
final results. Some of these variables are not truly base-
line-independent variables as they were measured after
etomidate dosage and may have been affected by etomi-
date (i.e. baseline cortisol and corticotropin test results).
Conclusions
Etomidate treatment is associated with an increased
incidence of non-responsiveness to corticotropin in septic
shock patients. Patients who received etomidate did have
a higher severity of illness, but after correction for
severity of illness there is still an increased mortality
associated with etomidate administration in one of our
models. Importantly, hydrocortisone administration had
no effect on outcome in these patients, and therefore the
use of hydrocortisone to treat etomidate adrenal insuffi-
ciency should be reevaluated. These data raise serious
concerns about the use of etomidate in cases of septic
shock. We recommend that clinicians demonstrate
extreme caution in the use of etomidate in critically ill
patients with septic shock because of its association with
an IRC and risk of increased mortality.
Acknowledgments This study was supported by the European
Commission contract QLK2-CT-2000-00589, the European Society
of Intensive Care Medicine, the International Sepsis Forum, the
Gorham Foundation and Roche Diagnostics GmbH, Mannheim/
Penzberg, Germany, who provided Elecsys
Ò
Cortisol immuno-
assay. The EU Commission and other sponsors had no role in the
design and conduct of the study, in the collection, management,
analysis and interpretation of the data or in the preparation, review
or approval of the manuscript. This research study is endorsed and
supported by the ECCRN of the ESICM. The activities of the
CORTICUS research group endorsed by the ECCRN of the ESICM
do not represent official statements and positions of the ESICM.
Conflicts of interest statement B.H.C. has received a consulting
fee, grant support and lecture fees from Eli Lilly. C.S. reports
having served as a member of a data-monitoring and safety com-
mittee for Artisan Pharma, Inc., Chiron/Novartis Corporation and
Hutchinson Technology incorporated. C.S. reports having served as
a consultant for AstraZeneka, Eisai Corporation, Eli Lilly and
GlaxoSmithKline. C.S. reports having received grant support from
the European Commission, Takeda and Eisai Corporation. C.S.
reports having been paid lecture fees by Eli Lilly. D.A. has no
conflicts of interest. S.C. has no conflicts of interest. M.G. has no
conflicts of interest. S.G. has no conflicts of interest. P.-F.L. has
received consulting fees from Eli Lilly. J.L.V. has no conflicts of
interest. K.F. has no conflicts of interest. M.S. has received con-
sulting fees from Eli Lilly and Ferring. D.P. has received consulting
fees from Edwards Life Sciences, Eli Lilly and Hutchinson Tech-
nology and grant support from Eli Lilly and Hutchinson
Technology. Y.G.W. has no conflicts of interest. There are no other
potential conflicts of interest relevant for this article.
Appendix
Steering Committee: C. Sprung (Chairman); D. Annane;
J. Briegel; D. Keh; R. Moreno; D. Pittet; M. Singer; Y.
Weiss.
Safety and Efficacy Monitoring Committee: J. Cohen
(Chairman); C. Dore; T. Evans; N. Soni, F. Sorenson
(Imor/Analytica).
Study Coordinating Center: C. Sprung (Physician
Coordinator); J. Benbenishty (Nurse Coordinator); A.
Avidan, E. Ludmir; J. Kabiri; K. Furmanov; B. Hain; O.
Kalugin; I. Zack.
Clinical Evaluation Committee: Y. Weiss (Chairman);
D. Annane; J. Briegel; S. Goodman; D. Keh; R. Moreno;
M. Singer; C. Sprung.
Berlin Coordinating Center: D. Keh (Chairman); A.
Gossinger.
French Coordinating Center: D. Annane (Chairman);
N. Zinsou, D. Friedman.
Corticus Investigators: Austria: LKH Feldkirch,
Feldkirch (P. Fae); Krankenhaus Barmherzige Schwest-
ern, Linz (J. Reisinger); Universitaetsklinik fuer Innere
Medizin II, Wien (G. Heinz); Belgium: Hopital
St. Joseph, Arlon (M. Simon); Department of Critical
Care Medicine, St Luc University Hospital, UCL, Brus-
sels (P.-F. Laterre, X. Wittebole, MN France); University
Hospital Erasme, Brussels (J.L. Vincent, D. DeBacker);
CHU Charleroi, Charleroi (P. Biston). France: Hopital de
Caen, Caen (C. Daubin); Hopital Raymond Poincare,
Garches (D. Annane, D. Lipiner, V. Maxime); Hopital
Huriez, Lille (B. Vallet); Hopital Caremeau, Nimes
(J.Y. Lefrant); Hopital Saint-Antoine, Paris (G. Offens-
tadt); Hopital Lariboisiere, Paris (D. Payen, A.C.
Lukaszewicz). Germany: Zentralklinikum Augsburg,
Augsburg (H. Forst, G. Neeser, Y. Barth); Charite Uni-
versitaetsmedizin Berlin, Campus Virchow-Klinikum
(D. Keh, J.Langrehr, M.Oppert, C.Spies), Campus Mitte
(C. Spies, S.Rosseau), Campus Benjamin Franklin
(J. Weimann); Evangelisches Waldkrankenhaus Spandau,
Berlin (M. Reyle Hahn); St. Joseph—Krankenhaus, Ber-
lin (M. Schmutzler); Vivantes Klinikum Spandau, Berlin
(K.J. Slama), Vivantes Klinikum Neukoelln, Berlin
(H.Gerlach), Vivantes Klinikum im Friedrichshain,Berlin
(S. Veit); Klinikum Ernst von Bergmann, Potsdam
(D. Pappert); Inst. For Anaesthesia and Operative Inten-
sive Care Medicine, Darmstadt (M. Welte, L. Von Beck);
University Hospital Carl Gustav Carus, Dresden
(C. Marx); Krankenhaus Hennigsdorf, Hennigsdorf
(A. Lange); Friedrich-Schiller Universitaet, Jena (K.
Reinhart, F. Bloos, F. Brunkhorst); Klinikum Kempten-
Oberallgaeu, Kempten (M. Haller); Klinikum of Land-
shut, Landshut (U. Helms,); Klinikum Mannheim,
Mannheim (A. Kalenka, F. Fiedler); Klinik fuer
Anaesthesiologie, Klinikum der Universitaet, Ludwig-
Maximilians-Universitaet, Munich (J. Briegel); Depart-
ment of Surgery, Klinikum der Universitaet—
Grosshadern, Munich (W. Hartl); Staedtisches Kranken-
haus Muenchen—Harlaching, Munich (M. Klimmer,
T. Helmer); Universitaet Erlangen-Namberg, Nuernberg
(M. Baumgaertel); Klinikum Ernst von Bergman, Pots-
dam (D. Pappert). Israel: Haemek Hospital, Afula
(A. Lev); Hadassah Medical Organization, Jerusalem
(Y. Weiss, C. Sprung, J. Benbenishty, O. Shatz); Belinson
Medical Centre, Petach Tikva (P. Singer); Ichilov Hos-
pital, Tel Aviv (A. Nimrod). Italy: Policlinico di Tor
Vergata, Rome (S. Natoli); Centro di Rianimazione,
Ospedale S. Eugenio, Rome (F. Turani). The Netherlands:
Erasmus University Medical Center, Rotterdam (B. Van
der Hoven). Portugal: Hospital de St. Antonio do Capu-
chos, Lisbon (R. Moreno, R. Matos). UK: Aberdeen
Royal Infirmary, Aberdeen (B.H. Cuthbertson, S. Rough-
ton); The Ipswich Hospital NHS, Ipswich (M. Garfield);
The General Infirmary at Leeds, Leeds (A. Mallick);
University College London Hospitals NHS Foundation
Trust, London (M. Singer, M McKendry); Southampton
General Hospital, Southampton (T. Woodcock).
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    • "Fig. 3. Mean arterial pressure before induction agent and up to 72 hours postinduction agent administration. transient period of etomidate-associated adrenal insufficiency [8] [9] [10] [11]. A retrospective cohort study including patients with severe sepsis and septic shock investigated the association between adrenal dysfunction and mortality and found that etomidate was associated with an increased mortality risk (OR, 1.53; 95% CI, 1.1-2.3), "
    [Show abstract] [Hide abstract] ABSTRACT: Purpose The safety of single bolus etomidate to facilitate intubation in septic patients is controversial due to its potential to suppress adrenal steroidogenesis. The purpose of this study was to evaluate the effects of etomidate on the development of shock when used as an induction agent to facilitate intubation in septic patients. Methods A multi-center, retrospective, propensity-matched cohort study comparing patients with sepsis or severe sepsis who either received etomidate or did not receive etomidate for intubation was conducted. The primary outcome was the difference in the need for vasopressor support within 72 hours following intubation. Secondary outcomes included the use of multiple vasopressors, intensive care unit (ICU) length of stay (LOS), and in-hospital mortality. Results A total of 411 patients were analyzed. Eighty-three patients were matched by propensity score. There was no difference in the matched cohort in regards to vasopressor use within 72 hours of intubation (OR 0.95; 95% CI 0.52 – 1.76; p = 0.88). Furthermore, there were no significant differences observed with regards to secondary outcomes, including in-hospital mortality (p = 0.76). Conclusions The use of etomidate for intubation in septic patients did not increase vasopressor requirements within 72 hours following intubation.
    Full-text · Article · Aug 2014
    • "Ever since, intensive care, emergency, and anesthesia communities have been discussing the use of even a single dose of etomidate controversially. Various studies and meta-analyses found either an increased78910 or an equal11121314151617 risk of mortality and risk variables after administration of etomidate in critically ill patients with sepsis. In trauma patients, an increased susceptibility to pneumonia is attributed to etomidate [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction It is well known that etomidate may cause adrenal insufficiency. However, the clinical relevance of adrenal suppression after a single dose of etomidate remains vague. The aim of this study was to investigate the association between the administration of a single dose of etomidate or an alternative induction regime ahead of major cardiac surgery and clinical outcome parameters associated with adrenal suppression and onset of sepsis. Methods The anesthesia and intensive care unit (ICU) records from patients undergoing cardiac surgery over five consecutive years (2008 to 2012) were retrospectively analyzed. The focus of the analysis was on clinical parameters like mortality, ventilation hours, renal failure, and sepsis-linked serum parameters. Multivariate analysis and Cox regression were applied to derive the results. Results In total, 3,054 patient records were analyzed. A group of 1,775 (58%) patients received a single dose of etomidate; 1,279 (42%) patients did not receive etomidate at any time. There was no difference in distribution of age, American Society of Anesthesiologists physical score, duration of surgery, and Acute Physiology and Chronic Health Evaluation II score. Postoperative data showed no significant differences between the two groups in regard to mortality (6.8% versus 6.4%), mean of mechanical ventilation hours (21.2 versus 19.7), days in the ICU (2.6 versus 2.5), hospital days (18.7 versus 17.4), sepsis-associated parameters, Sequential Organ Failure Assessment score, and incidence of renal failure. Administration of etomidate showed no significant influence (P = 0.6) on hospital mortality in the multivariate Cox analysis. Conclusions This study found no evidence for differences in key clinical outcome parameters based on anesthesia induction with or without administration of a single dose of etomidate. In consequence, etomidate might remain an acceptable option for single-dose anesthesia induction.
    Full-text · Article · Jul 2014
    • "Etomidate is also a short-acting drug, which is commonly used for induction and maintenance of anesthesia.[13] The most important side-effects of Etomidate are nausea and vomiting that may lead to aspiration in patients.[141516] "
    [Show abstract] [Hide abstract] ABSTRACT: Etomidate and Propofol are common anesthetic agents. Previous studies say that Etomidate can be used in patients with limited hemodynamic reserve and Propofol can lead to more hemodynamic instabilities. This study was performed to explore the cardiovascular response during the induction of anesthesia with Etomidate or for comparison, Propofol in elective orthopedic surgeries. This study was a double-blinded randomized clinical trial study including patients 18-45 years of age that were admitted for elective orthopedic surgeries in 2012. 25consenting, ASA I (American Society of Anaesthesiologists), patients were evaluated randomly in two groups, and their cardiovascular responses including: systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and O2 saturation (O2 sat) were measured before the laryngoscopy, during the anesthesia induction with Etomidate (0.3 mg/kg) in group A and propfol (2-2.5 mg/kg) in group B and at 1, 3, 5,10 min after the induction. There were no statistical differences between both groups regarding gender, age, body mass index, and laryngoscopic grade of patients (P > 0.05). Changes of SBP in the group B was significantly higher (P = 0.019). Furthermore, changes of the DBP was significantly higher in the group B (P = 0.001). The changes of MAP was higher in group B (P = 0.008). Hypotension happened in 26.1% of group B and 8% of group A (P = 0.09). There were no significant differences among groups A and B in terms of HR (P = 0.47) and O2 sat (P = 0.21), tachycardia (P = 0.6), bradycardia (P = 0.66) and hypertension (P = 0.95). Since, patients receiving Etomidate have more stable hemodynamic condition, if there would be no contraindications, it could be preferred over Propofol for general anesthesia.
    Full-text · Article · Oct 2013
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