Corticosteroid therapy in septic shock

Authors
David A Kaufman, MD
Jordi Mancebo, MD
Section Editor
Polly E Parsons, MD
Deputy Editor
Geraldine Finlay, MD
Contributor disclosures

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Aug 2016. | This topic last updated: Mar 17, 2016.

INTRODUCTION Interest in the role of glucocorticoids in the pathophysiology of critical illness

has existed since the early part of the 20th century, when investigators observed that the adrenal
glands are crucial to survival under conditions of physiologic stress [1,2]. The subsequent
development of cortisone for clinical use was followed by clinical studies exploring the potential
therapeutic role of corticosteroids in the treatment of severe infections [3-7].

The following issues are discussed in this topic review:

Effects of critical illness on the hypothalamic-pituitary-adrenal axis. (See 'Effects of critical

illness' below.)
Methods of evaluating adrenal reserve (random cortisol levels, synthetic adrenocorticotropic
hormone [ACTH] stimulation tests, free cortisol levels) and the impact of each on prognosis.
(See 'Assessing adrenal reserve' below.)
The concept of relative adrenal insufficiency. (See 'Relative adrenal insufficiency' below.)
Clinical evidence from trials evaluating the effect of corticosteroid therapy in patients with
septic shock, plus practical aspects of corticosteroid administration. (See 'Corticosteroid
therapy' below.)
Recommendations regarding the role of corticosteroid therapy in patients with septic shock.
(See 'Summary and recommendations' below.)

Other aspects of the management of severe sepsis and septic shock are reviewed separately.
(See "Evaluation and management of suspected sepsis and septic shock in adults".)

EFFECTS OF CRITICAL ILLNESS The hypothalamus continuously integrates stimuli and

secretes corticotropin releasing hormone (CRH) whenever homeostasis is threatened. CRH
stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary, which
induces cortisol secretion from the adrenal glands. Cortisol is the effector molecule of the
hypothalamic-pituitary-adrenal (HPA) axis.

Activation of the HPA axis Normal serum cortisol levels range between 5 and 24 mcg/dL, with
significant variability depending upon the time of day [8]. The HPA axis is activated and diurnal
variation is lost during physiological stress (eg, major surgery, hypotension, severe infection) [9,10].
Serum cortisol increases as a result, reaching levels as high as 40 to 50 mcg/dL (figure 1) [9,11-15].

In addition to activation of the HPA axis by physiological stress, cortisol metabolism and function
may be considerably altered by other aspects of critical illness:
 Reduced cortisol breakdown, related to suppressed expression and activity of cortisol-
metabolizing enzymes, may contribute to hypercortisolemia and corticotropin suppression [15].
Renal dysfunction may prolong the half-life of circulating cortisol.
Plasma concentrations of both cortisol binding globulin (CBG) and albumin, which bind >90
percent of circulating cortisol under normal circumstances, are frequently diminished. This
results in an increase in the free cortisol, which is believed to be the physiologically active form
of the hormone [11,16,17].
Inflammatory cytokines may increase glucocorticoid receptor affinity, disable glucocorticoid
inactivation, and/or increase the peripheral conversion of precursors to cortisol [11,18,19].

Impairment of the HPA axis There are circumstances in which cortisol availability cannot be
increased sufficiently to meet demand. As an example, drugs like ketoconazole, phenytoin,
and etomidate may impair cortisol synthesis [11,20,21]. An observational study of 62 patients found
that the use of etomidate for intubation was associated with increased likelihood of having a poor
response (9 mcg/dL) to ACTH stimulation 24 hours later (odds ratio 12, 95% CI 3-50) [22].

The clinical importance of this observation is uncertain. While some evidence suggests that a single
dose of etomidate is associated with worse outcomes in patients with septic shock [23], a
randomized trial that compared etomidate with ketamine for rapid sequence induction found that
etomidate was NOT associated with worse clinical outcomes despite an increased incidence of
adrenocortical hyporesponsiveness to synthetic adrenocorticotropic hormone (ACTH) [24]. The
clinical implications of these findings are uncertain because both studies measured plasma cortisol
using an immunoassay, which correlates poorly with the reference standard (liquid chromatography
with mass spectroscopy) [25].

Head injury, central nervous system depressants, pituitary infarction, adrenal hemorrhage,
infections, malignancy, and previous corticosteroid therapy can also impair the HPA axis [11].
Sometimes an etiology cannot be identified.

ASSESSING ADRENAL RESERVE Assessing adrenal insufficiency or relative adrenal

insufficiency in critically ill patients is challenging. Laboratory assays of plasma cortisol
concentration and response to adrenocorticotropic hormone (ACTH) stimulation are likely unreliable
in critically ill patients. Studies describing the performance (diagnostic and prognostic) of these tests
in critically ill patients are discussed below.

Random serum cortisol Total serum cortisol levels vary widely in patients with septic shock
[14,26-31]. This observation led multiple investigators to try to determine whether serum cortisol is
predictive of mortality in patients with septic shock. Numerous studies found increased mortality
associated with both low serum cortisol levels and high serum cortisol levels [32-37]. Other studies
were unable to find a relationship between cortisol levels and mortality [27,29,38].

Free cortisol In critically ill patients, loss of cortisol binding globulin (CBG) results in decreased
protein-bound cortisol and increased free cortisol. Therefore, for any given amount of serum total
cortisol, there is a shift from inactive protein-bound cortisol to physiologically active free cortisol.
This suggests that standard assays for plasma cortisol (which measure total plasma cortisol)
underestimate hypothalamic-pituitary-adrenal (HPA) axis activity. It has been proposed that free
cortisol more accurately reflects HPA axis activation [39].
This was illustrated by a study comparing total serum cortisol and free serum cortisol levels in 33
healthy volunteers to those in 60 critically ill patients (18 had sepsis) [39]. The critically ill patients
had total serum cortisol concentrations that were two to three times higher and free cortisol levels
that were 7 to 10 times higher than healthy volunteers. Although the total serum cortisol appeared
lower in critically ill patients with hypoalbuminemia (albumin 2.5 g/dL)than in critically ill patients
with preserved albumin concentrations, the free cortisol levels were similar.

The study has two major limitations. First, the critically ill patients did not include any patients with
septic shock [40]. Second, the degree of hemodynamic instability at the time of plasma cortisol
sampling was not reported. Thus, it is impossible to correlate the cortisol level with severity of
illness or physiologic status [41]. The applicability of the study to routine clinical practice is uncertain
because the free cortisol assay is not available at most clinical centers [42].

In another investigation, 74 patients had their total and free cortisol levels measured before and
after the administration of 250 mcg of cosyntropin [43]:

Pre-stimulation free cortisol levels were higher in patients with septic shock
(186 nmol/L) than sepsis (29 nmol/L) or healthy controls (13 nmol/L).
Pre-stimulation free cortisol levels reflected the severity of illness more closely than total
cortisol levels.
The calculated free cortisol level (based on direct measurements of total cortisol and the
CBG concentration) correlated well with the direct measurement of free cortisol.

Further complicating our understanding of HPA physiology in critical illness, one study suggested
that plasma levels of cortisol have only moderate correlation with tissue availability of the hormone
[44]. In a small study (n = 35) of critically ill patients with sepsis, total and free plasma cortisol levels
were compared to tissue levels of cortisol, measured using microdialysis catheters inserted into the
subcutaneous adipose tissue of the thigh. Plasma cortisol level correlated only moderately with
tissue levels. These observations suggest that during critical illness, blood levels of cortisol poorly
reflect the amount of hormone available to target tissues.

Whether the free cortisol level provides useful prognostic information in critically ill patients has not
been formally investigated.

ACTH stimulation tests The ACTH stimulation test requires that a baseline serum cortisol be
drawn, synthetic ACTH (cosyntropin) administered intravenously and serum cortisol levels are
drawn 30 and 60 minutes later. The response to 250 mcg (high-dose ACTH stimulation test), and 1
mcg (low-dose ACTH stimulation test) of synthetic ACTH has been evaluated in patients with septic
shock. ACTH stimulation testing for non-critically-ill patients is discussed separately.
(See "Evaluation of the response to ACTH in adrenal insufficiency", section on 'ACTH stimulation
tests'.)

High-dose ACTH test Studies using a high-dose ACTH stimulation test have yielded variable
results in septic shock [27,30,38,45,46]. A prospective cohort study performed high-dose ACTH
stimulation tests on 189 patients with septic shock [46]. The results correlated with 28-day mortality:
a baseline serum cortisol level >34 mcg/dL and a maximum increase in cortisol of 9 mcg/dL were
identified as risk factors for death. Three prognostic groups were proposed:
 Good prognosis (26 percent mortality): Baseline plasma cortisol 34 mcg/dL and a cortisol
increase >9 mcg/dL in response to cosyntropin.
Poor prognosis (82 percent mortality): Baseline plasma cortisol >34 mcg/dL and a cortisol
increase 9 mcg/dL in response to cosyntropin.
Intermediate prognosis (67 percent mortality): Baseline plasma cortisol >34 mcg/dL and a
cortisol increase >9 mcg/dL in response to cosyntropin, or baseline plasma cortisol
34 mcg/dL and a cortisol increase 9 mcg/dL in response to cosyntropin.

The results from this study are supported by a larger retrospective cohort study, in which 477
patients with severe sepsis or septic shock underwent high-dose ACTH testing [47]. Nonsurvivors
had a higher baseline cortisol level (30 versus 24 mcg/dL) and a smaller cortisol increase (6 versus
11 mcg/dL) than survivors. Patients with either a baseline cortisol level <15 mcg/dL or a cortisol
increase 9 mcg/dL had a higher mortality, longer duration of shock, or shorter survival time.

Low-dose ACTH test Some investigators believe that 250 mcg of cosyntropin is
supraphysiologic and stimulates adrenal secretion of cortisol even when adrenal dysfunction exists,
noting that even patients with impaired adrenal reserve can mount an apparently normal adrenal
response to such a high dose of cosyntropin. Use of low-dose (1 mcg) cosyntropin has been
proposed as an alternative [48]. (See "Evaluation of the response to ACTH in adrenal insufficiency",
section on 'Low-dose ACTH stimulation test'.)

Two investigations have compared a low-dose (1 mcg) ACTH stimulation test to a high-dose (250
mcg) ACTH stimulation test [49,50].

The first study was a prospective cohort study of 59 patients with septic shock who were
sequentially administered 1 mcg and 250 mcg of cosyntropin intravenously [49]. All of the patients
then received hydrocortisone 100 mg intravenously every eight hours. Patients were designated as
steroid responsive if they were able to maintain a mean arterial blood pressure >65 mmHg
without norepinephrine infusion within 24 hours after starting hydrocortisone:

Adrenal insufficiency (defined as post-cosyntropin serum cortisol of <18 mcg/dL) was

detected in more patients by low-dose ACTH testing than high-dose ACTH testing (22 versus
8 percent).
54 percent of steroid responders had a diagnostic low-dose ACTH stimulation test, while 22
percent had a diagnostic high-dose ACTH stimulation test. This suggests that adrenal
insufficiency detected by low-dose ACTH stimulation was superior to that detected by high-
dose ACTH stimulation in predicting hemodynamic responsiveness to corticosteroids.
Retrospective evaluation demonstrated that a random serum cortisol level <25 mcg/dL was
the most accurate diagnostic threshold, predicting steroid responsiveness in 96 percent of the
subjects.

The second study was similar, administering low-dose (1 mcg) and high-dose (250 mcg)
cosyntropin consecutively to 46 patients with septic shock [50]. Serum cortisol levels were
measured at baseline and after each stimulation test. A positive response to ACTH stimulation was
defined as a serum cortisol increase >9 mcg/dL. Patients who responded to low-dose and high-
dose ACTH were more likely to survive than those who did not respond to either dose. In addition, a
response only to high-dose ACTH stimulation was associated with lower survival than a response to
both low-dose and high-dose ACTH stimulation, suggesting that low-dose ACTH stimulation
identified a subgroup of patients with inadequate adrenal reserve that would have been missed by
high-dose ACTH stimulation alone.

Limitations ACTH stimulation tests may be unreliable in critically ill patients for several reasons:

Some critically ill individuals have spontaneous increases in their serum cortisol of
9 mcg/dL WITHOUT cosyntropin stimulation [51]. Thus, this threshold may not be clinically
helpful.
ACTH stimulation tests may give inconsistent results in the same individuals if performed on
more than one occasion [27,52].
Most clinical laboratories use immunoassays to measure the total cortisol because the
reference standard, liquid chromatography-tandem mass spectrometry (LC-MS/MS), is a time-
and labor-intensive assay that is not available in most centers [53]. However, immunoassays
appear to correlate poorly with LC-MS/MS during septic shock. This was illustrated by a study
of 425 ACTH stimulation tests (850 cortisol samples) that found that approximately 27 percent
of the samples were incorrectly classified by immunoassays [54].
Altered metabolism of cortisol appears to be partly responsible for hypercortisolemia
observed in critically-ill patients [15]. Although the diagnostic implications for this are not clear,
it is reasonable to suggest that the usual interpretation of ACTH-stimulation testing in this
context, cannot be assured.
Etomidate, which suppresses the HPA axis [24,55], if used for intubating patients with septic
shock, could potentially interfere with the results of ACTH stimulation.

Conclusions Laboratory assays of plasma cortisol concentration and response to ACTH are
likely unreliable in critically ill patients. More studies are needed before the value of ACTH testing in
critically ill patients can be fully understood. The role of ACTH stimulation in the selection of patients
that may respond to corticosteroids as a therapy for septic shock is discussed separately.
(See 'Corticosteroid therapy' below.)

RELATIVE ADRENAL INSUFFICIENCY While cortisol is necessary to survive critical illness, the
optimum level is unclear [1,2].

Absolute adrenal insufficiency is rare among critically ill patients, with an incidence estimated to be
3 percent [56]. However, the following observations argue that suboptimal cortisol production may
be common and associated with worse outcomes:

A maximum increase of serum cortisol 9 mcg/dL following intravenous synthetic

adrenocorticotropic hormone (ACTH) stimulation is associated with increased mortality from
septic shock [46,50].
Baseline and post-ACTH serum cortisol <23.7 mcg/dL predict responsiveness to exogenous
steroids in septic shock, where responsiveness is defined by the ability to maintain a mean
arterial blood pressure >65 mmHg without norepinephrine infusion within 24 hours after
startinghydrocortisone [49].

Suboptimal cortisol production during septic shock has been termed "functional" or "relative"
adrenal insufficiency [11]. This condition has also been called "critical illness-related corticosteroid
insufficiency (CIRCI)" [57]. There is no consensus about the diagnostic criteria or indications for
treatment of this entity. In addition, there exists considerable disagreement over what cortisol level
is "normal" or "appropriate" in septic shock, what constitutes an adequate response to ACTH, and
what dose of synthetic ACTH should be used for stimulation testing.

The question of how much cortisol is enough for a critically ill patient is confounded by the
possibility that glucocorticoid resistance exists at the target-tissue level. Few data support the notion
that genetic or acquired glucocorticoid receptor abnormalities affect critically ill patients. Assays of
the cellular activity of cortisol, cortisol-glucocorticoid-receptor binding, and glucocorticoid-receptor
transcription activity are limited to experimental investigations and their clinical relevance is
unknown [58]. The mechanisms of glucocorticoid resistance are discussed separately.
(See "Mechanisms and clinical implications of glucocorticoid resistance in asthma", section on
'Mechanisms of glucocorticoid resistance'.)

Using an overnight metyrapone stimulation test as the reference standard, a prospective cohort
study found that patients with septic shock who had a baseline total cortisol level <10 mcg/dL or a
change in total cortisol <9 mcg/dL after high-dose ACTH stimulation, were likely to have adrenal
insufficiency [59]. Conversely, patients with septic shock who had a baseline total cortisol level
44 mcg/dL or a change in total cortisol 16.8 mcg/dL, were unlikely to have adrenal insufficiency.
The generalizability of these results has been questioned because the frequency of absolute
adrenal insufficiency in this study was nearly four times that previously reported [60]. In addition, the
values were not used to guide therapeutic decision making and, therefore, their impact on clinical
outcome is unknown.

We believe that it is uncertain whether "relative adrenal insufficiency" or a synonymous condition is

a true diagnostic entity, since a clear definition is lacking and the cortisol assays that are available
at most clinical laboratories are unreliable in the critically ill patient.

CORTICOSTEROID THERAPY Interest in the possible therapeutic role of corticosteroids in

severe infections has existed for at least 50 years [4-7,61,62]. The major theoretical purpose of
corticosteroids in sepsis is to restore balance to the altered hypothalamic-pituitary-adrenal (HPA)
axis with the goal of improved outcomes such as mortality.

Clinical evidence In the 1980s, three randomized, double-blind, placebo-controlled studies of

high-dose corticosteroids (eg, 30 mg/kg ofmethylprednisolone) showed no mortality benefit (at 14
days) in critically ill patients [63-65]. In the 1990s, three small trials (approximately 40 patients each)
showed that compared to placebo, low-dose hydrocortisone (eg, 200 to 400 mg per day) in patients
with septic shock resulted in faster shock reversal (pressor withdrawal) [66-68]. These trials
prompted the following larger randomized trials.

French trial In a multicenter, double-blind trial conducted in France, 300 patients were randomly
assigned to receive placebo or hydrocortisone (50 mg intravenously every six hours)
plus fludrocortisone (50 mcg enterally once a day) for pressor-dependent shock [69]. Treatment
began within eight hours of the onset of septic shock and continued for seven days. Based upon a
high-dose (250 mcg) adrenocorticotropic hormone (ACTH) stimulation test, the patients were
classified as having adequate adrenal reserve (maximum increase in serum cortisol of
>9 mcg/dL) or inadequate adrenal reserve (maximum cortisol increase of 9 mcg/dL):

Among all patients, hydrocortisone administration decreased 28-day mortality (55 versus 61
percent)
 Among patients defined as having inadequate adrenal reserve, hydrocortisone administration
decreased 28-day mortality (53 versus 63 percent), ICU mortality (58 versus 70 percent), and
hospital mortality (61 versus 72 percent), as well as faster shock reversal by 28 days (57
versus 40 percent)
Among patients defined as having adequate adrenal reserve, there was no difference in
mortality or vasopressor withdrawal

The trial was criticized for its high placebo-group mortality and the statistical methods used to
describe outcomes [70-72], and results were in conflict with those published in a second large
randomized trial (CORTICUS) [73].

CORTICUS The Corticosteroid Therapy of Septic Shock (CORTICUS) trial was a multicenter,
randomized, double-blind, placebo-controlled trial of 499 patients with septic shock (regardless of
pressor dependency) treated with hydrocortisone (50 mg) or placebo intravenously every six hours
for five days, followed by a tapering regimen [73]. Based upon a high-dose (250 mcg) ACTH
stimulation test, the patients were classified as having inadequate adrenal reserve (maximum
cortisol increase of 9 mcg/dL) or adequate adrenal reserve (maximum increase in serum cortisol of
>9 mcg/dL).

Hydrocortisone administration did not improve 28-day mortality (35 versus 32 percent in the placebo
group). This was also true in the two pre-defined subgroups: patients with inadequate adrenal
reserve and patients with adequate adrenal reserve. The hydrocortisone group had faster reversal
of shock among all patients (3.3 versus 5.8 days in the placebo group) and increased incidence of
new infection that did not reach statistical significance (odds ratio 1.27, 95% CI 0.96-1.68). The trial
was criticized for the lower than expected placebo-group mortality (32 percent versus the
anticipated 50 percent).

Comparison of French trial and CORTICUS These randomized trials have important
differences that may, at least in part, explain their conflicting results.

The French trial enrolled patients within eight hours after the onset of shock and included
patients with a greater severity of illness that were vasopressor-dependent [69]. The mean
Simplified Acute Physiology Score II (SAPS II) was 55.5 and septic shock was defined as a
systolic blood pressure <90 mmHg for more than one hour despite adequate fluid resuscitation
and vasopressor administration.
The CORTICUS trial enrolled patients within 72 hours of the onset of shock and included
patients with a lower severity of illness [73]. The mean SAPS II was 49 and septic shock was
defined as a systolic blood pressure <90 mmHg despite adequate fluid resuscitation, or the
need for vasopressor administration for more than one hour.

Meta-analyses Meta-analyses have attempted to resolve conflicting data and suggest that
corticosteroid therapy may be more likely to benefit patients with severe septic shock that are
pressor-dependent [74-79]. This was supported by two meta-analyses that looked at the effects of
long courses of low-dose steroids (300 mg per day of hydrocortisone or an equivalent for 5 days)
in patients with septic shock:

Two meta-analyses of 12 trials showed that, compared to placebo or supportive care,

corticosteroid treatment decreased mortality (38 versus 44 percent) with relative risk ranging
from 0.64 to 0.84, 95% CI 0.72-0.97 [74,75]. Subsequent meta-regression analysis found that
 severely ill patients were more likely to benefit from corticosteroid therapy [76,77] and one
analysis suggested that it may be harmful in less severely ill patients [77]. Both meta-analyses
found possible publication bias and one had a moderate amount of heterogeneity, limiting our
confidence in the estimate of the effect.
One additional meta-analysis, identified six randomized placebo-controlled trials, of 1187
patients, considered high-quality and low risk of bias, that showed no difference in mortality
with corticosteroid therapy (RR, 1.0; 95% CI 0.84 1.18) [78].
All meta-analyses confirmed improved shock reversal with low-dose corticosteroid use [74-
79].

Surviving sepsis campaign The Surviving Sepsis Campaign provides a large observational
database of 17,847 patients who required vasopressor therapy despite fluid resuscitation and met
eligibility criteria for low-dose systemic corticosteroids (hydrocortisone 50 mg intravenously every
six hours or 100 mg every eight hours) [80]. A total of 8992 patients (50 percent) received low-dose
corticosteroids, and the hospital mortality was higher in those receiving corticosteroids than those
without (41 versus 35 percent, respectively) with an adjusted odds ratio of 1.18 (95% CI 1.09-
1.213). No significant difference in mortality was noted in those who received corticosteroids before
8 hours or between 8 and 24 hours. Despite the large size of this study, the observational nature
potentially limits the conclusions.

Conclusions Several conclusions can be based upon the available evidence for corticosteroid
use in patients with septic shock:

In patients without shock, or patients with less severe septic shock (defined as those in
whom fluid resuscitation and pressor therapy have restored hemodynamic stability),
corticosteroid therapy does not appear to be beneficial.
Some studies suggest that corticosteroid therapy is most likely to be beneficial in patients
who have severe septic shock (defined as a systolic blood pressure <90 mmHg for more than
one hour despite adequate fluid resuscitation and vasopressor administration). Until data from
ongoing clinical trials confirm that benefit we typically administer hydrocortisone to this
population of refractory septic shock.
The ACTH stimulation test has failed to consistently identify patients with septic shock who
benefit from corticosteroid use. This, together with the unreliability of available plasma cortisol
assays, suggests that ACTH stimulation testing is not clinically useful in distinguishing
responders from not responders.

Administration Hydrocortisone is a pharmacologic form of cortisol. Compared to

hydrocortisone, other pharmacologic corticosteroids bind cortisol-binding globulin (CBG) poorly,
resulting in more free, physiologically active, corticosteroid and greater potency at any given dose.
The different preparations vary widely in anti-inflammatory and mineralocorticoid potency.

Dose Most studies evaluating the effect of corticosteroids in septic shock used hydrocortisone in
divided doses, although administration protocols and treatment durations varied. Although one small
prospective study showed less variability in blood glucose levels with continuous hydrocortisone
infusions, the clinical benefit, from a mortality and shock reversal standpoint, remains unknown [81].
We typically administer 200 to 300 mg per day of hydrocortisone intravenously in divided doses (50
mg every six hours or 100 mg every eight hours).
Type Hydrocortisone is the most commonly used corticosteroid in large randomized trials.
Although one of the large randomized trials addedfludrocortisone at a dose of 50 mcg per day for
seven days, we do not typically add fludrocortisone because we believe that hydrocortisone alone
has sufficient mineralocorticoid effect and absorption of the enterally administered drug is
questionable in situations of compromised splanchnic perfusion [69]. Our decision to forego
fludrocortisone is supported by a trial (the Corticosteroids and Intensive Insulin Therapy for Septic
Shock [COIITSS] trial) that randomly assigned 509 patients with septic shock to receive either
hydrocortisone plus fludrocortisone or hydrocortisone alone [82]. There was no difference in any of
the clinical outcomes.

Duration There is no consensus regarding the optimal duration of treatment with, or withdrawal
of, corticosteroids. No large study has compared fixed-duration regimens to clinically-guided
regimens, or tapering to abrupt cessation. However, in one small clinical study, abrupt cessation
was associated with rebound of hemodynamic abnormalities and increased inflammatory markers
[83]. We typically administer five to seven days of therapy and a tapered approach to withdrawal
that is guided by the clinical response (eg, taper quickly following pressor withdrawal, or taper more
slowly for a coexistent indication such as COPD exacerbation).

SUMMARY AND RECOMMENDATIONS

Summary

Laboratory assays of plasma cortisol concentration and response to adrenocorticotropic

hormone (ACTH) stimulation are likely unreliable in critically ill patients. (See 'Assessing
adrenal reserve' above.)
Suboptimal cortisol production during septic shock has been termed "functional" adrenal
insufficiency, "relative" adrenal insufficiency, or "critical illness-related corticosteroid
insufficiency (CIRCI)." Broadly accepted consensus about diagnostic criteria for this entity is
lacking. (See 'Relative adrenal insufficiency' above.)
In patients without shock, or patients with less severe septic shock (defined as those in
whom fluid resuscitation and pressor therapy have restored hemodynamic stability),
corticosteroid therapy does not appear to be beneficial.
Some studies suggest that corticosteroid therapy is most likely to be beneficial in patients
who have severe septic shock (defined as a systolic blood pressure <90 mmHg for more than
one hour despite adequate fluid resuscitation and vasopressor administration). Whether or not
there are subgroups of septic shock patients that could benefit from corticosteroid therapy is
still unknown. (See 'Clinical evidence' above.)
The ACTH stimulation test has failed to consistently identify patients with septic shock that
benefit from corticosteroid use. This, together with the unreliability of available plasma cortisol
assays suggest that ACTH stimulation testing is not clinically useful in distinguishing
responders from not responders. (See 'Clinical evidence' above.)

Recommendations

We suggest that intravenous corticosteroid therapy (200 to 300 mg per day) be administered
to adult patients with severe septic shock (defined as a systolic blood pressure <90 mmHg for
more than one hour despite both adequate fluid resuscitation and vasopressor administration)
(Grade 2C).
 We suggest NOT administering corticosteroid therapy to patients without shock, or patients
with less severe septic shock (defined as those in whom fluid resuscitation and pressor
therapy have restored hemodynamic stability) (Grade 2B).
Response to ACTH testing should not be used to select patients for corticosteroid therapy.
(See 'Clinical evidence' above.)
We typically administer hydrocortisone for five to seven days and taper the dose as guided
by the clinical response. Close observation of those patients whose steroid therapy is stopped
without being tapered is warranted. We do not add fludrocortisone to our regimen.
(See 'Administration'above.)
Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Scott WJ. THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE : II. THE
TOXIC EFFECT OF KILLED BACTERIA IN ADRENALECTOMIZED RATS. J Exp Med 1924;
39:457.

2. Seyle, H. A syndrome produced by diverse nocuous agents. Nature 1936; 138:32.

3. HENCH PS, SLOCUMB CH, POLLEY HF, KENDAL EC. Effect of cortisone and pituitary
adrenocorticotropic hormone (ACTH) on rheumatic diseases. J Am Med Assoc 1950; 144:1327.

4. SPINK WW. ACTH and adrenocorticosteroids as therapeutic adjuncts in infectious

diseases. N Engl J Med 1957; 257:1031.

5. WAGNER HN Jr, BENNETT IL Jr, LASAGNA L, et al. The effect of hydrocortisone upon the
course of pneumococcal pneumonia treated with penicillin. Bull Johns Hopkins Hosp 1956; 98:197.

6. KASS EH. Adrenocorticosteroids and the management of infectious diseases. AMA Arch
Intern Med 1958; 102:1.

7. Bennett, IL Jr, Finland, M, Hamburger, M. The effectiveness of hydrocortisone in the

management of severe infections. JAMA 1963; 183:462.

8. Stewart PM. The Adrenal Cortex. In: Williams Textbook of Endocrinology, Polonsky KS (Ed),
Saunders, Philadelphia 2002. p.491.

9. Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in severe illness. N Engl J
Med 1997; 337:1285.

10. Shenker Y, Skatrud JB. Adrenal insufficiency in critically ill patients. Am J Respir Crit Care
Med 2001; 163:1520.

11. Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med
2003; 348:727.

12. Newsome HH, Rose JC. The response of human adrenocorticotrophic hormone and growth
hormone to surgical stress. J Clin Endocrinol Metab 1971; 33:481.

13. HUME DM, BELL CC, BARTTER F. Direct measurement of adrenal secretion during
operative trauma and convalescence. Surgery 1962; 52:174.
14. Vadas P, Pruzanski W. Plasma cortisol levels in patients with septic shock. Crit Care Med
1991; 19:300.

15. Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical
illness. N Engl J Med 2013; 368:1477.

16. Beishuizen A, Thijs LG, Vermes I. Patterns of corticosteroid-binding globulin and the free
cortisol index during septic shock and multitrauma. Intensive Care Med 2001; 27:1584.

17. Hammond GL, Smith CL, Paterson NA, Sibbald WJ. A role for corticosteroid-binding
globulin in delivery of cortisol to activated neutrophils. J Clin Endocrinol Metab 1990; 71:34.

18. Cooper MS, Bujalska I, Rabbitt E, et al. Modulation of 11beta-hydroxysteroid

dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from
glucocorticoid inactivation to activation. J Bone Miner Res 2001; 16:1037.

19. Franchimont D, Martens H, Hagelstein MT, et al. Tumor necrosis factor alpha decreases,
and interleukin-10 increases, the sensitivity of human monocytes to dexamethasone: potential
regulation of the glucocorticoid receptor. J Clin Endocrinol Metab 1999; 84:2834.

20. WERK EE Jr, MACGEE J, SHOLITON LJ. EFFECT OF DIPHENYLHYDANTOIN ON

CORTISOL METABOLISM IN MAN. J Clin Invest 1964; 43:1824.

21. Ledingham IM, Watt I. Influence of sedation on mortality in critically ill multiple trauma
patients. Lancet 1983; 1:1270.

22. Malerba G, Romano-Girard F, Cravoisy A, et al. Risk factors of relative adrenocortical

deficiency in intensive care patients needing mechanical ventilation. Intensive Care Med 2005;
31:388.

23. Cuthbertson BH, Sprung CL, Annane D, et al. The effects of etomidate on adrenal
responsiveness and mortality in patients with septic shock. Intensive Care Med 2009; 35:1868.

24. Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence
intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet 2009; 374:293.

25. Kaufman D. Etomidate versus ketamine for sedation in acutely ill patients. Lancet 2009;
374:1240.

26. MELBY JC, SPINK WW. Comparative studies on adrenal cortical function and cortisol
metabolism in healthy adults and in patients with shock due to infection. J Clin Invest 1958;
37:1791.

27. Bouachour G, Roy PM, Guiraud MP. The repetitive short corticotropin stimulation test in
patients with septic shock. Ann Intern Med 1995; 123:962.

28. Sibbald WJ, Short A, Cohen MP, Wilson RF. Variations in adrenocortical responsiveness
during severe bacterial infections. Unrecognized adrenocortical insufficiency in severe bacterial
infections. Ann Surg 1977; 186:29.

29. Schein RM, Sprung CL, Marcial E, et al. Plasma cortisol levels in patients with septic shock.
Crit Care Med 1990; 18:259.
30. Moran JL, Chapman MJ, O'Fathartaigh MS, et al. Hypocortisolaemia and adrenocortical
responsiveness at onset of septic shock. Intensive Care Med 1994; 20:489.

31. Briegel J, Schelling G, Haller M, et al. A comparison of the adrenocortical response during
septic shock and after complete recovery. Intensive Care Med 1996; 22:894.

32. McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1983;
1:484.

33. Jurney TH, Cockrell JL Jr, Lindberg JS, et al. Spectrum of serum cortisol response to ACTH
in ICU patients. Correlation with degree of illness and mortality. Chest 1987; 92:292.

34. Span LF, Hermus AR, Bartelink AK, et al. Adrenocortical function: an indicator of severity of
disease and survival in chronic critically ill patients. Intensive Care Med 1992; 18:93.

35. Jarek MJ, Legare EJ, McDermott MT, et al. Endocrine profiles for outcome prediction from
the intensive care unit. Crit Care Med 1993; 21:543.

36. Drucker D, Shandling M. Variable adrenocortical function in acute medical illness. Crit Care
Med 1985; 13:477.

37. Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine
parameters. Crit Care Med 1995; 23:78.

38. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in
septic shock. Lancet 1991; 337:582.

39. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill
patients. N Engl J Med 2004; 350:1629.

40. Polderman KH, van Zanten A, Girbes AR. Free cortisol and critically ill patients. N Engl J
Med 2004; 351:395.

41. Dubey A, Boujoukos AJ. Measurements of serum free cortisol in critically ill patients. Crit
Care 2005; 9:E2.

42. Khan T, Kupfer Y, Tessler S. Free cortisol and critically ill patients. N Engl J Med 2004;
351:395.

43. Ho JT, Al-Musalhi H, Chapman MJ, et al. Septic shock and sepsis: a comparison of total
and free plasma cortisol levels. J Clin Endocrinol Metab 2006; 91:105.

44. Vassiliadi DA, Ilias I, Tzanela M, et al. Interstitial cortisol obtained by microdialysis in
mechanically ventilated septic patients: correlations with total and free serum cortisol. J Crit Care
2013; 28:158.

45. Bouachour G, Tirot P, Gouello JP, et al. Adrenocortical function during septic shock.
Intensive Care Med 1995; 21:57.

46. Annane D, Sbille V, Troch G, et al. A 3-level prognostic classification in septic shock
based on cortisol levels and cortisol response to corticotropin. JAMA 2000; 283:1038.
47. Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: the
retrospective Corticus cohort study. Crit Care Med 2007; 35:1012.

48. Marik P, Zaloga G. Prognostic value of cortisol response in septic shock. JAMA 2000;
284:308.

49. Marik PE, Zaloga GP. Adrenal insufficiency during septic shock. Crit Care Med 2003;
31:141.

50. Siraux V, De Backer D, Yalavatti G, et al. Relative adrenal insufficiency in patients with
septic shock: comparison of low-dose and conventional corticotropin tests. Crit Care Med 2005;
33:2479.

51. Venkatesh B, Mortimer RH, Couchman B, Hall J. Evaluation of random plasma cortisol and
the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: a
prospective study. Anaesth Intensive Care 2005; 33:201.

52. Loisa P, Uusaro A, Ruokonen E. A single adrenocorticotropic hormone stimulation test does
not reveal adrenal insufficiency in septic shock. Anesth Analg 2005; 101:1792.

53. Bornstein SR. Predisposing factors for adrenal insufficiency. N Engl J Med 2009; 360:2328.

54. Briegel J, Sprung CL, Annane D, et al. Multicenter comparison of cortisol as measured by
different methods in samples of patients with septic shock. Intensive Care Med 2009; 35:2151.

55. Allolio B, Drr H, Stuttmann R, et al. Effect of a single bolus of etomidate upon eight major
corticosteroid hormones and plasma ACTH. Clin Endocrinol (Oxf) 1985; 22:281.

56. Burry LD, Wax RS. Role of corticosteroids in septic shock. Ann Pharmacother 2004;
38:464.

57. Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and
management of corticosteroid insufficiency in critically ill adult patients: consensus statements from
an international task force by the American College of Critical Care Medicine. Crit Care Med 2008;
36:1937.

58. Peeters RP, Hagendorf A, Vanhorebeek I, et al. Tissue mRNA expression of the
glucocorticoid receptor and its splice variants in fatal critical illness. Clin Endocrinol (Oxf) 2009;
71:145.

59. Annane D, Maxime V, Ibrahim F, et al. Diagnosis of adrenal insufficiency in severe sepsis
and septic shock. Am J Respir Crit Care Med 2006; 174:1319.

60. Meyer NJ, Hall JB. Relative adrenal insufficiency in the ICU: can we at least make the
diagnosis? Am J Respir Crit Care Med 2006; 174:1282.

61. Schumer W. Steroids in the treatment of clinical septic shock. Ann Surg 1976; 184:333.

62. Shine KI, Kuhn M, Young LS, Tillisch JH. Aspects of the management of shock. Ann Intern
Med 1980; 93:723.

63. Sprung CL, Caralis PV, Marcial EH, et al. The effects of high-dose corticosteroids in
patients with septic shock. A prospective, controlled study. N Engl J Med 1984; 311:1137.
64. Bone RC, Fisher CJ Jr, Clemmer TP, et al. A controlled clinical trial of high-dose
methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987;
317:653.

65. Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose
glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med
1987; 317:659.

66. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with
supraphysiologic doses of hydrocortisone. Crit Care Med 1998; 26:645.

67. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyperdynamic
septic shock: a prospective, randomized, double-blind, single-center study. Crit Care Med 1999;
27:723.

68. Yildiz O, Doganay M, Aygen B, et al. Physiological-dose steroid therapy in sepsis

[ISRCTN36253388]. Crit Care 2002; 6:251.

69. Annane D, Sbille V, Charpentier C, et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862.

70. Beigel J, Eichacker P. Hydrocortisone and fludrocortisone improved 28-day survival in

septic shock and adrenal insufficiency. ACP J Club 2003; 138:44.

71. Rubenfeld, GD. When survival is not the same as mortality. Critical Care Alert 2003; 10:113.

72. Eisen LA. Epoetin alfa in critically ill patients. N Engl J Med 2007; 357:2516; author reply
2516.

73. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock.
N Engl J Med 2008; 358:111.

74. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis
and septic shock in adults: a systematic review. JAMA 2009; 301:2362.

75. Minneci PC, Deans KJ, Eichacker PQ, Natanson C. The effects of steroids during sepsis
depend on dose and severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009;
15:308.

76. Minneci PC, Deans KJ, Natanson C. Corticosteroid therapy for severe sepsis and septic
shock. JAMA 2009; 302:1643; author reply 1644.

77. Minneci PC, Deans KJ, Natanson C. Corticosteroid therapy for severe sepsis and septic
shock. JAMA 2009; 302:1643; author reply 1644.

78. Sligl WI, Milner DA Jr, Sundar S, et al. Safety and efficacy of corticosteroids for the
treatment of septic shock: A systematic review and meta-analysis. Clin Infect Dis 2009; 49:93.

79. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis. Cochrane
Database Syst Rev 2015; :CD002243.

80. Casserly B, Gerlach H, Phillips GS, et al. Low-dose steroids in adult septic shock: results of
the Surviving Sepsis Campaign. Intensive Care Med 2012; 38:1946.
81. Weber-Carstens S, Deja M, Bercker S, et al. Impact of bolus application of low-dose
hydrocortisone on glycemic control in septic shock patients. Intensive Care Med 2007; 33:730.

82. COIITSS Study Investigators, Annane D, Cariou A, et al. Corticosteroid treatment and
intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA 2010;
303:341.

83. Keh D, Boehnke T, Weber-Cartens S, et al. Immunologic and hemodynamic effects of "low-
dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover
study. Am J Respir Crit Care Med 2003; 167:512.

Topic 1654 Version 21.0