Cortisol Replacement
With the recognition that severe sepsis represents a
state of overwhelming inflammation, corticosteroids
were among the first therapies tested in randomized trials
of patients with sepsis. At large doses and with short
courses, the studies showed a negative effect.40,41 Annane
and associates proposed a different hypothesis in 2002.42
Prompted by studies showing significantly improved
time to withdrawal of vasopressor therapy in patients
with sepsis who received small doses of hydrocortisone
over a longer period (>5 days),43,44 they administered lowdose
steroids for 7 days. Their results showed that among
patients who did not appropriately respond to the corticotropin
test, 63% in the placebo group versus 53% in the
corticosteroid group died (P = 0.02). Vasopressor therapy
was withdrawn in 40% of patients in the placebo group,
as opposed to 57% in the corticosteroid group (P = 0.001).
Despite this initial positive data, the administration of
steroids to patients with sepsis remained controversial. A
large randomized trial recapitulating the study of Annane
and coworkers has been completed and documents the
lack of efficacy of even low-dose steroids and the association
of increased infections with steroid administration.
The Corticosteroid Therapy of Septic Shock (CORTICUS)
study was carried out to assess whether low-dose corticosteroids
improve survival in patients with septic shock
and sepsis.45 A total of 499 patients were enrolled over
a period of 3 years from 52 European ICUs. Patients
received a tapering steroid regimen over an 11-day period
but no mineralocorticoids. The results refuted Annane’s
initial study. The 28-day mortality rate in patients receiving
low-dose steroids was not significantly improved from
that in the placebo group (34% versus 31%, P = 0.57). In
summary, although low-dose steroids with mineralocorticoids
initially appeared to be beneficial, the results have
not been reproducible in a large multicentered randomized
study. Large doses of corticosteroids should not be
used in patients with severe sepsis.
One issue raised by these investigations was the role of
etomidate in causing adrenal suppression. Patients who
received etomidate to facilitate endotracheal intubation
had worse outcomes, thus leading to suggestions that
etomidate not be used. Chan and associates conducted
a meta-analysis with five studies assessing mortality and
seven studies assessing adrenal insufficiency associated
with etomidate use in patients with severe sepsis and septic
shock.46 They found an increased pooled relative risk for
mortality of 1.20 (95% CI 1.02 to 1.42) and an increased
pooled relative risk (RR) for adrenal insufficiency of 1.33
(95% CI 1.22 to 1.46). Although the data are not conclusive,
the literature suggests that perhaps etomidate should
not be the first choice for use in patients with sepsis.