Editorial

Physicians Should Administer Low-Dose Corticosteroids Selectively to

Septic Patients until an Ongoing Trial Is Completed

ost physicians prefer administering therapies that

have a physiologic rationale and proven benefit. We
urgently need beneficial therapies for sepsis severe enough
to cause shock, which is responsible for approximately
400 000 intensive care unit admissions and 200 000 deaths
each year in the United States (1). In this issue, a metaanalysis by Minneci and colleagues (2) from the National
Institutes of Health (NIH) concludes that low but not
high doses of corticosteroids reduce mortality from septic
shock and that we should administer these agents to all
patients who have vasopressor-dependent sepsis. How the
investigators reached these conclusions and why I agree
with the first but not the second of them are the subjects of
this editorial.
The adrenal glands release cortisol during various
stresses, of which septic shock is one of the most profound.
Both high and low plasma levels of the endogenously released hormone are associated with increased mortality,
presumably because high levels reflect severe stress and low
levels an inability to respond to stress by releasing cortisol
(3). The beneficial actions of cortisol are due to its antiinflammatory effects (including inhibition of cytokine production and prevention of circulating inflammatory cell
migration into tissues) and cardiovascular effects (including
attenuation of nitric oxide synthase induction and enhancement of the vasoconstrictive response to catecholamines) (4).
Between 1959 and 1986, investigators administered
short courses of high (also called pharmacologic) doses of
corticosteroids (for example, methylprednisolone, 30
mg/kg of body weight, in 4 intravenous doses over 24
hours) to almost 1300 septic patients in 9 clinical trials.
One rationale for these trials was to interrupt the inflammatory cascade hypothesized to perpetuate sepsis (5). Unfortunately, no large randomized trial demonstrated that
corticosteroids improved mortality. Such improvement was
seen only in a single-center study with both prospective
and retrospective enrollment. Furthermore, 2 of the large
trials reported an increase in secondary infections among
patients who received high-dose corticosteroids. In 1995, 2
meta-analyses of these investigations concluded that highdose corticosteroids were ineffective in treating septic
shock and might be harmful (6, 7). Two years later, another meta-analysis conducted by NIH investigators (8)
showed that high doses of both corticosteroid and noncorticosteroid anti-inflammatory agents had no benefit in patients with septic shock. These findings cast doubt on the
then-prevalent rationale for use of these agents.
Although the use of high-dose corticosteroids decreased after these publications, physicians have continued
to administer lower doses of exogenous hormone (typically

70 6 July 2004 Annals of Internal Medicine Volume 141 Number 1

100 mg of intravenous hydrocortisone 3 times daily,

known as a low or replacement dose even though it is
supraphysiologic) to septic patients who have meningococcemia, long-term corticosteroid use, and other known
causes of adrenal insufficiency. Some physicians have done
so without proving that such insufficiency exists. Others
have diagnosed adrenal insufficiency by obtaining a low
baseline cortisol level during stress (a review published in
1996 [9] suggested a level 525 nmol/L, especially if the
level does not increase 30 or 60 minutes after adrenal stimulation with 250 g of intravenous corticotropin).
In recent years, a new rationale for the use of corticosteroids has emerged: Relative adrenal insufficiency may be
a complication of septic shock. Early observational studies
showed that, despite adequate baseline cortisol levels, up to
40% of patients in septic shock had a blunted response to
corticotropin stimulation and many of these patients also
manifested impaired vasopressor sensitivity to catecholamines (10, 11). In 2000, Annane and colleagues (12)
observed that the mortality from septic shock was greatest
in patients whose baseline cortisol levels exceeded 938
mmol/L and did not increase by more than 248 nmol/L
after corticotropin stimulation. These findings suggested
that impaired adrenal reserve occurred in septic shock and
implied that replacement corticosteroids might help to resolve this condition.
After this observational study, Annane and colleagues
(13) administered either placebo or hydrocortisone (50 mg
every 6 hours) and fludrocortisone (50 g by mouth daily)
for 7 days to 300 patients with septic shock who had just
undergone corticotropin stimulation. Their goal was to determine whether corticosteroids affect survival distribution
28 days after randomization in patients whose cortisol levels did not increase by more than 248 mmol/L in response
to corticotropin stimulation. The investigators found that
the median time until death was longer in those nonresponders who received corticosteroids than in those who
received placebo, but it was not longer in responders. The
median time until death was longer overall for patients
who received corticosteroids than for those who received
placebo, largely because nonresponders outnumbered responders in the study, but 28-day crude mortality did not
differ between the 2 groups. The time to withdrawal of
vasopressors was shorter in the nonresponders who received corticosteroids than in nonresponders who received
placebo. The time to withdrawal among responders was
not statistically different, but because the nonresponders
outnumbered responders, vasopressors were withdrawn
more rapidly from patients who received corticosteroids
overall. As a result of these findings, the investigators recommended that all patients with vasopressor-dependent
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Administering Low-Dose Corticosteroids Selectively to Septic Patients

septic shock receive corticosteroids initially but that only

those who do not respond to corticotropin should continue to receive these agents for 7 days.
The observational and experimental studies by Annane
and colleagues (12, 13) have been highly influential. The
most recent major review of adrenal insufficiency recommends that 2 groups of patients with septic shock receive
low doses of glucocorticoids (but not necessarily of mineralocorticoids). The first group has regular adrenal insufficiency (baseline cortisol levels 414 mmol/L). The second group has relative adrenal insufficiency (baseline
levels between 414 and 938 mmol/L and failure to increase
by 248 mmol/L after corticotropin stimulation). The authors of this review also recommend that all patients with
suspected adrenal insufficiency undergo corticotropin stimulation and state that patients without absolute or relative
adrenal insufficiency need not continue to receive low-dose
corticosteroid therapy (14).
These recommendations and those of Annane and colleagues (13) differ from those of Minneci and colleagues
(2). These NIH investigators reiterate their previous metaanalysis of the 9 trials conducted before 1997 and conclude
that high doses of corticosteroids are not beneficial in patients with septic shock. I agree with this conclusion. They
also provide a meta-analysis of 5 randomized, doubleblind, placebo-controlled trials published after 1997 in
which corticosteroids were given in low doses over several
days. The trial conducted by Annane and colleagues (13)
was by far the largest of these recent trials; the other 4 trials
enrolled approximately 40 patients each, and only 4 trials
analyzed mortality and shock reversal. Other than the trial
of Annane and colleagues (13), no trial was large enough to
demonstrate a statistically significant outcome difference in
patients given low-dose corticosteroids. Furthermore, in
the trial of Annane and colleagues (13), corticosteroids
only increased the median time until death and decreased
the time until shock reversal but did not reduce crude
mortality. Nevertheless, Minneci and colleagues (2) interpreted this trial as demonstrating benefit and, after combining it with the other trials, concluded that low-dose
corticosteroids were beneficial overall.
Only 3 of the 5 trials stratified patients as responders
and nonresponders to corticotropin stimulation. One trial
used the same definition of unresponsiveness that Annane
and colleagues (13) did; the third study used a smaller
increase in cortisol. Only 2 trials, including that of Annane
and colleagues (13), reported mortality and shock reversal
separately for responders and nonresponders. When comparing time until death and vasopressor withdrawal,
Annane and colleages (13) found that these outcomes were
different in nonresponders but not in responders. However, Minneci and colleagues (2) found no statistically significant differences comparing crude rates of mortality or
vasopressor withdrawal. Because of these latter findings,
Minneci and colleagues (2) conclude that response to corticotropin stimulation does not predict benefit from cortiwww.annals.org

Editorial

costeroid administration. They also found that no recent

trial reported an increase in secondary infections from corticosteroids. As a result, they recommend that low-dose
corticosteroids be administered to all patients with vasopressor-dependent septic shock until the results of larger
studies are available.
Physicians should follow this recommendation if they
are convinced that low-dose corticosteroids have been
proven to benefit and not harm septic patients. Furthermore, physicians need not perform corticotropin stimulation if they believe that corticosteroids are truly effective
regardless of responsiveness or nonresponsiveness to this
test. Yet I remain concerned that the meta-analysis is based
on a small number of low-dose corticosteroid trials, most
of which enrolled few patients, and not all of which performed the same analyses. The large trial of Annane and
colleagues (13) accounts for three quarters of the patients
in the meta-analysis, and these investigators concluded that
low-dose corticosteroids benefited primarily patients who
did not respond to corticotropin stimulation, a conclusion
different from that of Minneci and colleagues (2). Because
only 1 other trial determined corticotropin responsiveness
by using the same criteria as Annane and colleagues (13),
we cannot determine whether only a subgroup of septic
patients is helped by corticosteroids. More important, we
cannot be certain whether a subgroup is harmed.
Earlier this year, Annane and colleagues (15) also published a meta-analysis of the dose-dependent effects of corticosteroids in septic shock. These investigators also concluded that, when combined, the trials conducted since
1997 demonstrate that low-dose corticosteroids are beneficial. However, because too few recent trials of low doses of
corticosteroids had subgroup analyses comparing the therapeutic responses in septic patients with and without adrenal insufficiency, the investigators refrained from recommending which patients with septic shock should receive
corticosteroids. Nevertheless, Dr. Annane personally speculates that patients without adrenal insufficiency may not
benefit from corticosteroids, that the agents may even be
harmful in this group of patients, and that further studies
are needed to define which septic patients should receive
corticosteroids (Annane D. Personal communication). So,
this contentious matter is unresolved at present.
Fortunately, an ongoing clinical experiment may soon
resolve the controversy. Sprung and colleagues are conducting an 800-patient trial, called CORTICUS, to test
the hypothesis that hydrocortisone (50 mg intravenously 4
times daily for 5 days, then tapered over 6 days) will reduce
28-day mortality by 10% in patients with septic shock
whose cortisol levels do not increase by more than 248
mmol/L in response to corticotropin stimulation (16). The
trial will also analyze the effects of low-dose corticosteroids
on responders to corticotropin. Analyzing large numbers of
patients in both groups is necessary to determine which
septic patients are benefited or harmed by low-dose corticosteroids, that is, whether the agents are of proven benefit,
6 July 2004 Annals of Internal Medicine Volume 141 Number 1 71

Editorial

Administering Low-Dose Corticosteroids Selectively to Septic Patients

References

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1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky

MR. Epidemiology of severe sepsis in the United States: analysis of incidence,

2004 American College of Physicians

and whether these outcomes can be predicted by corticotropin responsiveness and thus have a physiologic rationale.
Until CORTICUS is completed, I recommend that physicians who are not enrolling patients in the trial give lowdose corticosteroids to all patients in septic shock but continue to give the agents only in patients with proven
adrenal insufficiency.
Although CORTICUS is designed to determine
whether hydrocortisone reduces mortality in septic patients
with relative adrenal insufficiency, the trial should be large
enough to evaluate the effects of this agent in all patients
regardless of their response to corticotropin stimulation. In
addition, the investigators plan to compare total and free
cortisol levels at baseline and after stimulation in their patients. This comparison is important because a recent study
by Hamrahian and colleagues (17) suggests that cortisol
secretion is markedly increased during critical illness, but
this increase may not be discernible if only total cortisol
levels are measured, as has been the case in previous investigations. Thus, in addition to its clinical findings, CORTICUS should provide new information about adrenal
gland function in septic shock and help us develop a new
diagnostic strategy for adrenal insufficiency.
John M. Luce, MD
University of California, San Francisco
San Francisco General Hospital
San Francisco, CA 94110
Potential Financial Conflicts of Interest: None disclosed.
Current Author Address: John M. Luce, MD, Division of Pulmonary

and Critical Care Medicine, San Francisco General Hospital, 1001 Potrero Avenue, Room 5 K1, San Francisco, CA 94110; e-mail,
john.luce@sfdph.org.
Ann Intern Med. 2004;141:70-72.

72 6 July 2004 Annals of Internal Medicine Volume 141 Number 1

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