Effect of Treatment With Low Doses of Hydrocortisone and Fludrocortisone on
Mortality in Patients With Septic Shock


Author Information <http://jama.ama-assn.org/issues/v288n7/rfull/#aainfo>
Djillali Annane, MD, PhD; Véronique Sébille, PhD; Claire Charpentier, MD;
Pierre-Edouard Bollaert, MD, PhD; Bruno François, MD; Jean-Michel Korach,
MD; Gilles Capellier, MD, PhD; Yves Cohen, MD, PhD; Elie Azoulay, MD; Gilles
Troché, MD; Philippe Chaumet-Riffaut, MD; Eric Bellissant, MD, PhD
Context  Septic shock may be associated with relative adrenal insufficiency.
Thus, a replacement therapy of low doses of corticosteroids has been
proposed to treat septic shock.
Objective  To assess whether low doses of corticosteroids improve 28-day
survival in patients with septic shock and relative adrenal insufficiency.
Design and Setting  Placebo-controlled, randomized, double-blind,
parallel-group trial performed in 19 intensive care units in France from
October 9, 1995, to February 23, 1999.
Patients  Three hundred adult patients who fulfilled usual criteria for
septic shock were enrolled after undergoing a short corticotropin test.
Intervention  Patients were randomly assigned to receive either
hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone
(50-µg tablet once daily) (n = 151) or matching placebos (n = 149) for 7
days.
Main Outcome Measure  Twenty-eight-day survival distribution in patients
with relative adrenal insufficiency (nonresponders to the corticotropin
test).
Results  One patient from the corticosteroid group was excluded from
analyses because of consent withdrawal. There were 229 nonresponders to the
corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to
the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders,
there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the
corticosteroid group (hazard ratio, 0.67; 95% confidence interval,
0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46
patients (40%) in the placebo group and in 65 patients (57%) in the
corticosteroid group (hazard ratio, 1.91; 95% confidence interval,
1.29-2.84; P = .001). There was no significant difference between groups in
responders. Adverse events rates were similar in the 2 groups.
Conclusion  In our trial, a 7-day treatment with low doses of hydrocortisone
and fludrocortisone significantly reduced the risk of death in patients with
septic shock and relative adrenal insufficiency without increasing adverse
events.
JAMA. 2002;288:862-871
JCE10061
Severe sepsis remains an important cause of death, accounting for 9.3% of
all deaths in the United States in 1995. 1
<http://jama.ama-assn.org/issues/v288n7/rfull/#r1>  If our understanding of
the mechanisms of host response to stress has strongly progressed during the
last 2 decades, 2 <http://jama.ama-assn.org/issues/v288n7/rfull/#r2>  the
various drugs developed for specific targets of the cytokine cascade have
failed to improve patient survival. 3
<http://jama.ama-assn.org/issues/v288n7/rfull/#r3> , 4
<http://jama.ama-assn.org/issues/v288n7/rfull/#r4>
Corticosteroids were the first anti-inflammatory drugs tested in randomized
trials. At high doses during short courses, they did not induce favorable
effects. 5 <http://jama.ama-assn.org/issues/v288n7/rfull/#r5> , 6
<http://jama.ama-assn.org/issues/v288n7/rfull/#r6>  However, the observation
that severe sepsis may be associated with relative adrenal insufficiency 7
<http://jama.ama-assn.org/issues/v288n7/rfull/#r7> , 8
<http://jama.ama-assn.org/issues/v288n7/rfull/#r8>  or systemic
inflammation-induced glucocorticoid receptor resistance 9
<http://jama.ama-assn.org/issues/v288n7/rfull/#r9>  prompted renewed
interest of a replacement therapy with low doses of corticosteroids during
longer periods. 10 <http://jama.ama-assn.org/issues/v288n7/rfull/#r10> , 11
<http://jama.ama-assn.org/issues/v288n7/rfull/#r11>
The interest of this new approach was confirmed by the demonstration that a
single intravenous administration of 50 mg of hydrocortisone strongly
improved norepinephrine and phenylephrine mean arterial pressure
dose-response relationships in patients with septic shock, 12
<http://jama.ama-assn.org/issues/v288n7/rfull/#r12> , 13
<http://jama.ama-assn.org/issues/v288n7/rfull/#r13>  particularly in those
with relative adrenal insufficiency. 12
<http://jama.ama-assn.org/issues/v288n7/rfull/#r12>  Moreover, 2 small
placebo-controlled randomized trials also showed that prolonged treatment (5
days) with low doses of hydrocortisone (about 300 mg daily) significantly
improved the time to vasopressor therapy withdrawal in septic shock. 14
<http://jama.ama-assn.org/issues/v288n7/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v288n7/rfull/#r15>  Thus, we designed this
placebo-controlled study to assess whether a replacement therapy with
hydrocortisone and fludrocortisone (assuming the possibility of a primary
adrenal insufficiency) 16
<http://jama.ama-assn.org/issues/v288n7/rfull/#r16>  could improve 28-day
survival in patients with septic shock, with particular interest in patients
with relative adrenal insufficiency.



METHODS



Experimental Design and Study Organization

This placebo-controlled, randomized, double-blind study was performed on 2
parallel groups at 19 intensive care units (ICUs) in France ( Figure 1
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f1.html> ). It was
supported by Groupe d'Etude et de Recherche sur le Médicament (GERMED),
which awarded a grant from publicly funded resources. The protocol was
approved by the Comité Consultatif de Protection des Personnes dans la
Recherche Biomédicale of Saint-Germain en Laye, France, on February 9, 1995.
Inclusions were authorized from September 11, 1995. Two interim analyses
were planned. An independent main end point and safety monitoring board met
after each interim analysis to decide whether the study should be continued
or stopped. Enrollment ended March 15, 1999. At the end of the study, an
independent diagnosis validation committee blindly classified each patient
as being unquestionable, probable, or nonprobable for having had septic
shock.
Patients

All patients 18 years or older and hospitalized in participating ICUs were
prospectively enrolled in the study if they met all the following criteria:
(1) documented site (or at least strong suspicion) of infection, as
evidenced by one or more of the following: presence of polymorphs in a
normally sterile body fluid (except blood), positive culture or Gram stain
of a normally sterile body fluid, clinical focus of infection (eg, fecal
peritonitis), wound with purulent discharge, pneumonia or other clinical
evidence of systemic infection (eg, purpura fulminans); (2) temperature
higher than 38.3°C or lower than 35.6°C; (3) heart rate greater than 90
beats per minute; (4) systolic arterial pressure lower than 90 mm Hg for at
least 1 hour despite adequate fluid replacement and more than 5 µg/kg of
body weight of dopamine or current treatment with epinephrine or
norepinephrine; (5) urinary output of less than 0.5 mL/kg of body weight for
at least 1 hour or ratio of arterial oxygen tension to the fraction of
inspired oxygen (PaO2/FIO2) of less than 280 mm Hg; (6) arterial lactate
levels higher than 2 mmol/L; and (7) need for mechanical ventilation.
Written informed consent had to be obtained from the patients themselves or
their relatives and a short corticotropin test had to be performed before
randomization. Finally, patients had to be randomized within 3 hours of the
onset of shock.
Patients were excluded if they were pregnant or had evidence for acute
myocardial infarction or pulmonary embolism, advanced form of cancer or
acquired immunodeficiency syndrome (AIDS) infection, and contraindication or
formal indication for corticosteroids.
During recruitment, we refined the eligibility criteria by not making the
arterial lactate requirement mandatory (the 6th criterion) but adding it as
an option to the 5th criterion. We also increased the maximum delay from the
onset of septic shock and randomization from 3 to 8 hours (amendment of July
18, 1996); and we excluded patients who received etomidate during the 6
hours preceding randomization because it is a selective inhibitor of the 11
beta-hydroxylase and therefore could interfere with cortisol response to
corticotropin (amendment of June 19, 1997).
Randomization

Randomization was centrally performed, concealed, and stratified by center
in blocks of 4 according to a computer-generated random number table. In
each center, sequentially numbered boxes containing the whole treatment for
each patient were delivered to the investigator by the pharmacist following
the order of the randomization list. All patients, medical and nursing
staffs, and pharmacists remained blinded throughout the study period.
Treatments

Hydrocortisone came in vials containing 100 mg of hydrocortisone
hemisuccinate powder and ampoules containing 2 mL of glucose solution
solvent, which was administered intravenously every 6 hours as a 50-mg bolus
(Roussel-Uclaf, Romainville, France). One tablet containing 50 µg of
9-alpha-fludrocortisone was administered daily through a nasogastric tube
with 10 to 40 mL of water over 30 seconds (Pharmacie Centrale des Hôpitaux,
Paris, France). Placebos were indiscernible from active treatments.
Treatment duration was 7 days.
Data Collection at Inclusion

Clinical Evaluation
The following data were recorded: (1) general characteristics including
estimated prognosis of any underlying disease 17
<http://jama.ama-assn.org/issues/v288n7/rfull/#r17>  and level of activity
limitation 18 <http://jama.ama-assn.org/issues/v288n7/rfull/#r18> ; (2)
severity of illness assessed by vital signs, Simplified Acute Physiology
Score II (SAPS II), 19 <http://jama.ama-assn.org/issues/v288n7/rfull/#r19>
and Logistic Organ Dysfunction (LOD) score 20
<http://jama.ama-assn.org/issues/v288n7/rfull/#r20> ; and (3) interventions
including the volume of fluid infusion and the type and doses of
vasopressors and antibiotics.
Laboratory Variables
Hematological and chemistry data, arterial lactate and blood gas
determinations, and blood cultures and cultures of specimen drawn from the
site of infection were done systematically. The short corticotropin test was
performed using a 250-µg intravenous bolus of tetracosactrin (Synacthène
Ciba, Rueil-Malmaison, France). Blood samples were taken immediately before
the test and 30 and 60 minutes after the test. After centrifugation, plasma
samples were stored at -80°C until assayed. Cortisol was measured blindly
and serially before interim and final statistical analyses using Immunotech
radioimmunoassay. 21 <http://jama.ama-assn.org/issues/v288n7/rfull/#r21>  To
reduce heterogeneity in cortisol determination, all plasma samples were
measured at a central laboratory. Cortisol response was defined as the
difference between the highest of the concentrations taken after the test
and those taken before the test. Relative adrenal insufficiency (ie,
nonresponders) was defined by a response of 9 µg/dL or less. 7
<http://jama.ama-assn.org/issues/v288n7/rfull/#r7> , 8
<http://jama.ama-assn.org/issues/v288n7/rfull/#r8>
Follow-up

The following data were recorded daily during the 28-day period following
randomization: vital signs, results from standard laboratory tests and
cultures of specimen drawn from any new site of infection, and
interventions. In addition, the patient's status at discharge from ICU and
hospital and 1 year after randomization was recorded.
End Points

The main end point was the 28-day survival distribution from randomization
in nonresponders to the short corticotropin test. Secondary end points were
28-day survival distributions from randomization in responders to the short
corticotropin test and in all patients; 28-day, ICU, hospital, and 1-year
mortality rates; and time to vasopressor therapy withdrawal during the 28
days from randomization in the 2 subsets of patients and in all patients.
Adverse events were carefully monitored and classified as being possibly
related to corticosteroids (superinfection, gastrointestinal bleeding, psych
iatric disorders), possibly related to vasopressors (life-threatening
arrhythmia, myocardial infarction, limb or cerebral ischemia), related to
ICU invasive procedures, and not related to 1 of the 3 previous categories.
Sample Size and Statistical Analysis

A total of 270 patients was the calculated sample size needed to detect, in
a 1-sided test performed with a 0.05 type I error, a difference between the
2 groups of nonresponders on the 28-day mortality rate of 20% with a 90%
probability, assuming a mortality rate of 95% in the nonresponder placebo
subgroup 7 <http://jama.ama-assn.org/issues/v288n7/rfull/#r7> , 22
<http://jama.ama-assn.org/issues/v288n7/rfull/#r22>  and a frequency of
nonresponders of 40% in the population of patients with septic shock. 7
<http://jama.ama-assn.org/issues/v288n7/rfull/#r7>  A 1-sided formulation
was chosen to compute the sample size because the trial was designed to test
whether low doses of corticosteroids were more effective than placebo, and
we had no interest in formally demonstrating the opposite alternative
hypothesis (a deleterious effect of corticosteroids). 22
<http://jama.ama-assn.org/issues/v288n7/rfull/#r22> , 23
<http://jama.ama-assn.org/issues/v288n7/rfull/#r23>
The 2 interim analyses were planned using an O'Brien and Fleming stopping
boundary. 24 <http://jama.ama-assn.org/issues/v288n7/rfull/#r24>  With this
procedure, the differences between the 2 groups were considered significant
if the critical z values were higher than 3.471, 2.454, and 2.004 at the
first, second, and final analyses, respectively (corresponding to nominal
2-sided P values <.0005, <.0141 and <.0451, respectively).
The statistical analysis, prospectively defined, was performed according to
the intent-to-treat principle (in all analyses, patients were grouped
according to their original randomized treatment) with SAS statistical
software (SAS Institute, Cary, NC). For continuous variables, the mean (SDs)
are reported whereas, for categorical variables, the number of patients in
each category and the corresponding percentages are given.
Analyses were similarly performed in nonresponders, in responders, and in
all patients. Pretreatment characteristics were compared between groups
using the t test (for continuous variables) or chi2 or Fisher exact tests
when appropriate (for categorical variables). Cumulative event curves
(28-day survival and time-to-vasopressor therapy withdrawal end points) were
estimated with the Kaplan-Meier procedure and median times to event were
reported. The effects of treatments on these end points were estimated from
adjusted Cox proportional hazards regression models 25
<http://jama.ama-assn.org/issues/v288n7/rfull/#r25>  using baseline
cortisol, cortisol response, McCabe classification, LOD score, arterial
lactate levels, and PaO2/FIO2 results for the adjustment. 8
<http://jama.ama-assn.org/issues/v288n7/rfull/#r8>  Corresponding hazard
ratios (HRs) along with their 95% confidence intervals (CIs) were reported.
Proportionality among the event rates in the Cox models was assessed by the
plot of the log (-log [survival function]) vs time. When the proportionality
assumption was not upheld, Cox models were not used and only the
Kaplan-Meier curves were reported along with log-rank tests. For 28-day
survival, patients who were still alive at 28 days were treated as censored.
For this end point, the number needed to treat at 28 days was estimated. 26
<http://jama.ama-assn.org/issues/v288n7/rfull/#r26>  For
time-to-vasopressor-therapy withdrawal, among patients who had more than 1
outcome event during the 28 days from randomization, time to the first event
was used in the analyses. For this end point, the patients who died before
vasopressor therapy could be withdrawn and those for whom vasopressor
therapy could not be withdrawn during the 28 days from randomization were
treated as censored. The effects of treatments on the frequency of fatal
events (28-day, ICU, hospital and 1-year mortality rates) were estimated
from logistic regression analysis using the same variables for the
adjustment as the Cox models. Corresponding adjusted odds ratios (ORs) along
with their 95% CIs were reported. We also computed the 28-day, ICU,
hospital, and 1-year relative risks (RRs) of death along with their 95% CIs.
The frequency of adverse events was compared between groups using the chi2
or Fisher exact tests when appropriate. All reported P values are 2-sided.



RESULTS



Study Description

From October 9, 1995, to February 23, 1999, 1326 patients were screened and
300 patients (placebo, 149; corticosteroids, 151) were included in the study
( Figure 1
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f1.html> ). Interim
analyses were performed on April 3, 1997, and April 20, 1998, after the
evaluation of 114 and 220 patients, respectively. After each analysis, the
independent main end point and safety monitoring board advised the study
chairpersons to continue the study. We included the patient in the placebo
group who died before study drugs could be administered in our
intent-to-treat analysis. One patient in the corticosteroid group was
excluded from the final analysis because of consent withdrawal. Among the
299 remaining patients, there were 229 nonresponders (placebo, 115;
corticosteroids, 114) and 70 responders (placebo, 34; corticosteroids, 36).
Characteristics of Study Patients at Inclusion

At baseline, the 2 groups were balanced with respect to general
characteristics ( Table 1
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t1.html> ) and
severity of illness ( Table 2
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t2.html> ).
Cortisol response to corticotropin was higher in the corticosteroid group
than in the placebo group in the all-patients analysis, but the distribution
of patients according to our 3-level prognostic classification 8
<http://jama.ama-assn.org/issues/v288n7/rfull/#r8>  was similar in the 2
groups. The type and site of infection and the type of organism involved
were also similar in the 2 groups ( Table 3
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t3.html> ).
Finally, a blinded evaluation determined that appropriate antibiotic
therapy, based on the site of infection and available cultures, was promptly
(<24 hours from diagnosis of severe sepsis) started and continued for at
least 7 days in most cases (ie, 95% in the placebo group, 91% in the
corticosteroid group).
Mortality Distribution

Nonresponders
At day 28, there were 73 deaths (63%) in the placebo group and 60 deaths
(53%) in the corticosteroid group. The median time to death was 12 days in
the placebo group and 24 days in the corticosteroid group. The HR estimated
using a Cox model was 0.67 (95% CI, 0.47-0.95; P = .02; Figure 2
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f2.html> A). The
number of patients needed to treat to save 1 additional life at day 28 is 7
(95% CI, 4-49).
Responders
At day 28, there were 18 deaths (53%) in the placebo group and 22 deaths
(61%) in the corticosteroid group. The median time to death was 14 days in
the placebo group and 16.5 days in the corticosteroid group. The
proportionality assumption was not supported for the Cox model and
comparison of survival distributions was performed using a log-rank test (P
= .81) ( Figure 2
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f2.html> B).
All Patients
At day 28, there were 91 deaths (61%) in the placebo group and 82 deaths
(55%) in the corticosteroid group. The median time to death was 13 days in
the placebo group and 19.5 days in the corticosteroid group. The HR
estimated using a Cox model was 0.71 (95% CI, 0.53-0.97; P = .03) ( Figure 2
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f2.html> C). The
number of patients needed to treat to save 1 additional life at day 28 is 8
(95% CI, 5-81).
Mortality Rates

Nonresponders
As mentioned above, at day 28, there were 73 deaths (63%) in the placebo
group and 60 deaths (53%) in the corticosteroid group (RR, 0.83; 95% CI,
0.66-1.04; adjusted OR, 0.54; 95% CI, 0.31-0.97; P = .04). There were 81
deaths (70%) in the placebo group and 66 deaths (58%) in the corticosteroid
group at the end of ICU stay (RR, 0.82; 95% CI, 0.68-1.00; adjusted OR,
0.50; 95% CI, 0.28-0.89; P = .02). A similar significant difference was
observed at the end of hospital stay. There were 88 deaths (77%) in the
placebo group and 77 deaths (68%) in the corticosteroid group after 1 year
of follow-up (RR, 0.88; 95% CI, 0.75-1.04; adjusted OR, 0.57; 95% CI,
0.31-1.04; P = .07) ( Table 4
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t4.html> ).
Responders
There was no significant effect of corticosteroids on 28-day, ICU, hospital,
and 1-year mortality rates in responders ( Table 4
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t4.html> ).
All Patients
There was no significant effect of corticosteroids on 28-day, ICU, hospital,
and 1-year mortality rates in all patients. For example, the ICU mortality
is represented by RR, 0.89 (95% CI, 0.75-1.05), adjusted OR, 0.61 (95% CI,
0.37-1.02), P = .06 and year of follow-up is represented by RR, 0.91 (95%
CI, 0.78-1.04), adjusted OR, 0.62 (95% CI, 0.36-1.05), P = .08 ( Table 4
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t4.html> ).
Time-to-Vasopressor-Therapy Withdrawal

Nonresponders
The median time to vasopressor therapy withdrawal was 10 days in the placebo
group and 7 days in the corticosteroid group. The HR estimated using a Cox
model was 1.91 (95% CI, 1.29-2.84; P = .001) ( Figure 3
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f3.html> A). At day
28, vasopressor therapy had been withdrawn in 46 patients (40%) in the
placebo group and in 65 patients (57%) in the corticosteroid group.
Responders
The median time-to-vasopressor-therapy withdrawal was 7 days in the placebo
group and 9 days in the corticosteroid group. The proportionality assumption
was not supported for the Cox model and comparison of
time-to-vasopressor-therapy withdrawal distributions was performed using a
log-rank test (P = .49, Figure 3
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f3.html> B). At day
28, vasopressor therapy had been withdrawn in 18 patients (53%) in the
placebo group and in 18 patients (50%) in the corticosteroid group.
All Patients
The median time to vasopressor therapy withdrawal was 9 days in the placebo
group and 7 days in the corticosteroid group. The HR estimated using a Cox
model was 1.54 (95% CI, 1.10-2.16; P = .01; Figure 3
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_f3.html> C). At day
28, vasopressor therapy had been withdrawn in 64 patients (43%) in the
placebo group and in 83 patients (55%) in the corticosteroid group.
Adverse Events

There were no significant differences between the 2 groups in the rates of
adverse events possibly related to corticosteroids or vasopressors, or
related to ICU invasive procedures ( Table 5
<http://jama.ama-assn.org/issues/v288n7/fig_tab/jce10061_t5.html> ).



COMMENT



We found that a 7-day replacement therapy with hydrocortisone (50 mg
intravenous bolus every 6 hours) and fludrocortisone (50 µg tablet once
daily) significantly reduced 28-day mortality and duration of vasopressor
administration in all patients with septic shock, in particular those with
relative adrenal insufficiency. In addition, among the latter,
corticosteroid therapy significantly reduced mortality during both ICU and
hospital stays, and tended to reduce 1-year mortality. Our results indicate
that, in this population, 1 additional life could be saved at day 28 for
every 7 patients treated with corticosteroids. Replacement therapy had no
significant effect on the same variables in patients who had septic shock
without relative adrenal insufficiency. If the power to detect differences
in responders was lower than that in nonresponders due to the lower
proportion of responders, it should be observed that no tendency toward
efficacy (or deleterious effect) was observed in responders for any of the
above mentioned variables. These results confirm the hypothesis on which the
study was planned that patients with septic shock with relative adrenal
insufficiency could benefit from replacement therapy.
Our results are consistent with a study of healthy volunteers challenged
with endotoxin 27 <http://jama.ama-assn.org/issues/v288n7/rfull/#r27>  and
with 2 studies of patients with septic shock, 12
<http://jama.ama-assn.org/issues/v288n7/rfull/#r12> , 13
<http://jama.ama-assn.org/issues/v288n7/rfull/#r13>  that showed that low
doses of hydrocortisone can restore vascular responsiveness to
catecholamines. Our results are also consistent with those of 2 small trials
showing that replacement therapy with hydrocortisone reduces the
time-to-vasopressor-therapy withdrawal in septic shock. 14
<http://jama.ama-assn.org/issues/v288n7/rfull/#r14> , 15
<http://jama.ama-assn.org/issues/v288n7/rfull/#r15>  Finally, our study
establishes that a short corticotropin test performed at early onset of
septic shock is useful for identifying patients that could most benefit from
replacement therapy with corticosteroids. However, it has to be stressed
that the time required to obtain the results largely depends on the method
used to measure cortisol (eg, enzymatic method, radioimmunoassay) and
therefore that treatment should be started as soon as the test has been
completed.
The sample size was calculated to detect a difference of 20% between the 2
groups of nonresponders on the 28-day mortality rate using a 1-sided
formulation. Such a formulation was chosen because the preliminary reports
that were available at the planning phase of the study 22
<http://jama.ama-assn.org/issues/v288n7/rfull/#r22> , 23
<http://jama.ama-assn.org/issues/v288n7/rfull/#r23>  had shown that for
several days patients tolerated well 200 to 300 mg of hydrocortisone daily,
and we had no interest in formally demonstrating a hypothetical deleterious
effect of corticosteroids. However, as recommended by the 9th International
Conference on Harmonization, at the time of analysis, all tests were
performed using a 2-sided formulation and all reported P values were
2-sided. The sample size was also computed based on the assumptions of a
mortality rate of 95% in the nonresponder placebo subgroup and a frequency
of nonresponders of 40% in the population of patients with septic shock. In
fact, the mortality rate in the nonresponder placebo subgroup (63%) was much
lower than expected compared with the reports that were available at the
planning phase of the study 7
<http://jama.ama-assn.org/issues/v288n7/rfull/#r7> , 22
<http://jama.ama-assn.org/issues/v288n7/rfull/#r22>  and with the hypothesis
that patients with adrenal insufficiency would very likely die without
hormone replacement. Conversely, the proportion of nonresponders (77%) was
much higher than expected and the resulting increase in the sample size of
nonresponders (from 108 to 229) may have favored the detection of a lower
difference (10%) than expected between the 2 groups.
Several differences between the design of this positive study and previous
negative studies 28-33 <http://jama.ama-assn.org/issues/v288n7/rfull/#r28>
deserve comment. First, our trial was focused on a very specific population
who were presumed to benefit from corticosteroids because of relative
adrenal insufficiency. Second, low doses of a combination of the natural
hormone hydrocortisone and fludrocortisone were used (as recommended to
treat adrenal insufficiency) 16
<http://jama.ama-assn.org/issues/v288n7/rfull/#r16>  rather than high doses
of a synthetic glucocorticoid compound. The addition of fludrocortisone to
hydrocortisone was justified because primary adrenal insufficiency could not
be ruled out 16 <http://jama.ama-assn.org/issues/v288n7/rfull/#r16>  since
it has been shown that 40% to 65% of critically ill patients have
high-plasma renin activity and low-plasma aldosterone concentrations. 34
<http://jama.ama-assn.org/issues/v288n7/rfull/#r34> , 35
<http://jama.ama-assn.org/issues/v288n7/rfull/#r35>  Moreover, in situations
that require high amounts of active glucocorticoid, the reduction of
fludrocortisone to cortisol can serve as a second source of cortisol in
addition to that of adrenal glands. 36
<http://jama.ama-assn.org/issues/v288n7/rfull/#r36>  Third, patients were
treated for a longer time (ie, 7 days) than those treated in previous
trials. Indeed, recent work in healthy volunteers challenged with endotoxin
37 <http://jama.ama-assn.org/issues/v288n7/rfull/#r37>  and in patients with
septic shock 23 <http://jama.ama-assn.org/issues/v288n7/rfull/#r23> , 38
<http://jama.ama-assn.org/issues/v288n7/rfull/#r38>  have shown that short
courses of corticosteroid treatment may be followed by a rebound of the
systemic inflammatory response.
In conclusion, in catecholamine-dependent septic shock patients,
particularly those with relative adrenal insufficiency, a 7-day treatment
with the combination of hydrocortisone and fludrocortisone is safe and
associated with a significant reduction in short-term and long-term
mortality. In practice, we suggest that all patients with
catecholamine-dependent septic shock should be given the combination of
hydrocortisone and fludrocortisone as soon as a short corticotropin
stimulation test is performed. When the results of the test are available,
treatment may be withdrawn in responders and continued up to 7 days in
nonresponders. Further studies are required to better determine the optimal
dose and duration of corticosteroids to be given in this setting. The
interest of a replacement therapy with corticosteroids in patients with
septic shock without relative adrenal insufficiency deserves additional
investigation.



Author/Article Information


Author Affiliations: Service de Réanimation Médicale, Hôpital Raymond
Poincaré, Université de Paris V, Faculté de Médecine Paris-Ouest, Garches
(Dr Annane); Service de Pharmacologie, Unité de Pharmacologie Clinique,
Hôpital de Pontchaillou, Université de Rennes I, Rennes (Drs Sébille and
Bellissant); Service de Réanimation Chirurgicale (Dr Charpentier) and de
Réanimation Médicale (Dr Bollaert), Hôpital Central, Nancy; the Service de
Réanimation Polyvalente, Hôpital Dupuytren, Limoges (Dr François); Service
de Réanimation Polyvalente, Centre Hospitalier, Chalons en Champagne (Dr
Korach); Service de Réanimation Médicale, Hôpital Jean Minjoz, Besançon (Dr
Capellier); Service de Réanimation Médico-Chirurgicale, Hôpital Avicenne,
Bobigny (Dr Cohen); Service de Réanimation Médicale (Dr Azoulay) and
Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris
(Dr Chaumet-Riffaut), Hôpital Saint-Louis, Paris; and the Service de
Réanimation Chirurgicale, Hôpital Antoine Béclère, Clamart (Dr Troché),
France. Dr Sébille is now at the Loboratoire de Biostatistiques at the
Faculté de Pharmacie at the Université de Nantes, France.

Corresponding Author and Reprints: Djillali Annane, MD, PhD, Service de
Réanimation Médicale, Hôpital Raymond Poincaré, 104 Blvd Raymond Poincaré,
92380 Garches, France (e-mail: [log in to unmask]
<mailto:[log in to unmask]> ).
Author Contributions: Study concept and design: Annane, Chaumet-Riffaut,
Bellissant.
Acquisition of data: Annane, Charpentier, Bollaert, François, Korach,
Capellier, Cohen, Azoulay, Troché.
Analysis and interpretation of data: Annane, Sébille, Bollaert, Bellissant
Drafting of the manuscript: Annane, Sébille, Bellissant.
Critical revision of the manuscript for important intellectual content:
Annane, Sébille, Charpentier, Bollaert, François, Korach, Capellier, Cohen,
Azoulay, Troché, Bellissant.
Statistical expertise: Annane, Sébille, Bellissant.
Obtained funding: Annane, Bollaert, François, Troché, Chaumet-Riffaut,
Bellissant.
Administrative, technical, or material support: Annane, Chaumet-Riffaut.
Study supervision: Annane, Bellissant.
Funding/Support: This work was supported by grant GER-inf-05R2 from GERMED,
Assistance Publique Hôpitaux de Paris, Paris, France.
Previous Presentations: Portions of this study were presented at the Society
Critical Care Medicine Annual Meeting, San Francisco, Calif, February 10-14,
2001. The abstract of our presentation was published in Crit Care Med.
2000;28(suppl 12):A46.
Study Organization: Study Chairpersons: Djillali Annane (principal
investigator), Eric Bellissant (methodologist).
Statistician: Véronique Sébille.
Monitor: Caroline Fisch, Délégation à la Recherche Clinique, Hôpital
Saint-Louis, Paris.
Research nurse: Béatrice Barbier, Délégation à la Recherche Clinique,
Hôpital Saint-Louis, Paris.
Data management: Habiba Mesbah, Service de Pharmacologie, Unité de
Pharmacologie Clinique, Hôpital de Pontchaillou, Rennes.
Quality Assurance: Marie-Françoise Mordelet, Service de Pharmacologie, Unité
de Pharmacologie Clinique, Hôpital de Pontchaillou, Rennes.
Pharmacists: Annick Tibi and Blandine Lehmann, Pharmacie Centrale des
Hôpitaux, Paris.
Independent main end point and safety monitoring board: Claude Carbon
(chair, Paris), Marie-Claude Jars-Guincestre (Garches), Pierre de Truchis
(Paris).
Independent diagnosis validation committee: Jean Carlet (Paris), Didier
Dreyfuss (Colombes), Philippe Veyssier (Compiègne).
Study Investigators: Bernard Clair, Jean-Claude Raphaël, and Philippe
Gajdos, Service de Réanimation Médicale, Hôpital Raymond Poincaré, Garches;
Marie-Claire Laxenaire, Service de Réanimation Chirurgicale, Hôpital
Central, Nancy; Bruno Lévy, Service de Réanimation Médicale, Hôpital
Central, Nancy; Hervé Gastinne, Service de Réanimation Polyvalente, Hôpital
Dupuytren, Limoges; Evelyne Belle, Service de Réanimation Médicale, Hôpital
Jean Minjoz, Besançon; Jean-Philippe Fosse, Service de Réanimation
Médico-Chirurgicale, Hôpital Avicenne, Bobigny; Benoit Schlemmer, Service de
Réanimation Médicale, Hôpital Saint-Louis, Paris; Mercé Jourdain and Claude
Chopin, Service de Réanimation Polyvalente, Hôpital Roger Salengro, Lille;
Bruno Lafon and Philippe Loirat, Service de Réanimation Polyvalente, Centre
Médico-Chirurgical Foch, Suresnes; Jean-Luc Diehl and Jacques Labrousse,
Service de Réanimation Médicale, Hôpital Boucicaut, Paris; Bernard de Jonghe
and Hervé Outin, Service de Réanimation Médicale, Centre Hospitalier
Intercommunal, Poissy; Antoine Parrot and Charles Marie Mayaud, Unité de
Réanimation Pneumologique, Hôpital Tenon, Paris; Michel Wolff and Bernard
Regnier, Service de Réanimation des Maladies Infectieuses, Hôpital Bichat,
Paris; Dominique Perrotin, Service de Réanimation Médicale Polyvalente,
Hôpital Bretonneau, Tours.
Advisory Board: David Bihari, MD; Christian Brun-Buisson, MD; Timothy Evans,
MD; John Heffner, MD; Norman Paradis, MD; Adrienne Randolph, MD.


Caring for the Critically Ill Patient Section Editor: Deborah J. Cook, MD,
Consulting Editor, JAMA.



REFERENCES



1. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr1>
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR.
Epidemiology of severe sepsis in the United States: analysis of incidence,
outcome, and associated costs of care.
Crit Care Med.
2001;29:1303-1310.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11445675>
2. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr2>
Chrousos GP.
The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.
N Engl J Med.
1995;332:1351-1362.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7715646>
3. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr3>
Zeni F, Freeman B, Natanson C.
Anti-inflammatory therapies to treat sepsis and septic shock: a
reassessment.
Crit Care Med.
1997;25:1095-1100.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9233726>
4. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr4>
Wheeler AP, Bernard GR.
Treating patients with severe sepsis.
N Engl J Med.
1999;340:207-214.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9895401>
5. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr5>
Lefering R, Neugebauer EA.
Steroid controversy in sepsis and septic shock: a meta-analysis.
Crit Care Med.
1995;23:1294-1303.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7600840>
6. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr6>
Cronin L, Cook DJ, Carlet J, et al.
Corticosteroid treatment for sepsis : a critical appraisal and meta-analysis
of the literature.
Crit Care Med.
1995;23:1430-1439.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7634816>
7. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr7>
Rothwell PM, Udwadia ZF, Lawler PG.
Cortisol response to corticotropin and survival in septic shock.
Lancet.
1991;337:582-583.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
1671944>
8. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr8>
Annane D, Sébille V, Troché G, Raphaël JC, Gajdos P, Bellissant E.
A 3-level prognostic classification in septic shock based on cortisol levels
and cortisol response to corticotropin.
JAMA.
2000;283:1038-1045.
ABSTRACT <http://jama.ama-assn.org/issues/v283n8/abs/jce90008.html>   |
FULL TEXT <http://jama.ama-assn.org/issues/v283n8/rfull/jce90008.html>   |
PDF <http://jama.ama-assn.org/issues/v283n8/rpdf/jce90008.pdf>   |   MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10697064>
9. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr9>
Molijn GJ, Spek JJ, van Uffelen JC, et al.
Differential adaptation of glucocorticoid sensitivity of peripheral blood
mononuclear leukocytes in patients with sepsis or septic shock.
J Clin Endocrinol Metab.
1995;80:1799-1803.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7775626>
10. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr10>
Lamberts SW, Bruining HA, de Jong FH.
Corticosteroid therapy in severe illness.
N Engl J Med.
1997;337:1285-1292.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9345079>
11. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr11>
Meduri GU.
An historical review of glucocorticoid treatment in sepsis. Disease
pathophysiology and the design of treatment investigation.
Sepsis.
1999;3:21-38.
12. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr12>
Annane D, Bellissant E, Sébille V, et al.
Impaired pressor sensitivity to noradrenaline in septic shock patients with
and without impaired adrenal function reserve.
Br J Clin Pharmacol.
1998;46:589-597.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9862249>
13. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr13>
Bellissant E, Annane D.
Effect of hydrocortisone on phenylephrinemean arterial pressure
dose-response relationship in septic shock.
Clin Pharmacol Ther.
2000;68:293-303.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11014411>
14. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr14>
Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A.
Reversal of late septic shock with supraphysiologic doses of hydrocortisone.
Crit Care Med.
1998;26:645-650.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9559600>
15. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr15>
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;27:723-732.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10321661>
16. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr16>
Oelkers W.
Adrenal insufficiency.
N Engl J Med.
1996;335:1206-1212.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8815944>
17. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr17>
McCabe WR, Jackson GG.
Gram-negative bacteremia, I: etiology and ecology.
Arch Intern Med.
1962;110:847-855.
18. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr18>
Knaus WA, Zimmerman JE, Wagner DP, Draper EA, Lawrence DE.
APACHE–acute physiology and chronic health evaluation: a physiologically
based classification system.
Crit Care Med.
1981;9:591-597.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7261642>
19. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr19>
Le Gall JR, Lemeshow S, Saulnier F.
A new Simplified Acute Physiology Score (SAPS II) based on a European/North
American multicenter study.
JAMA.
1993;270:2957-2963.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8254858>
20. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr20>
Le Gall JR, Klar J, Lemeshow S, et al.
The Logistic Organ Dysfunction system: a new way to assess organ dysfunction
in the intensive care unit.
JAMA.
1996;276:802-810.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8769590>
21. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr21>
Sapin R, Schlienger JL, Gasser F, Pradignac A, Grucker D.
Improved specificity of a new direct assay for urinary cortisol: application
in corticoid treated patients.
Clin Chem Lab Med.
1998;36:855-858.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
9877091>
22. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr22>
McKee JI, Finlay WE.
Cortisol replacement in severely stressed patients.
Lancet.
1983;1:484.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
6131207>
23. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr23>
Briegel J, Kellermann W, Forst H, et al, The Phospholipase A2 Study Group.
Low-dose hydrocortisone infusion attenuates the systemic inflammatory
response syndrome.
Clin Investig.
1994;72:782-787.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
7865982>
24. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr24>
O'Brien PC, Fleming TR.
A multiple testing procedure for clinical trials.
Biometrics.
1979;35:549-556.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
497341>
25. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr25>
Cox DR.
Regression models and life-tables (with discussion).
J R Stat Soc [B].
1972;34:187-220.
26. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr26>
Altman DG, Andersen PK.
Calculating the number needed to treat for trials where the outcome is time
to an event.
BMJ.
1999;319:1492-1495.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
10582940>
27. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr27>
Bhagat K, Collier J, Vallance P.
Local venous responses to endotoxin in humans.
Circulation.
1996;94:490-497.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8759094>
28. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr28>
Klastersky J, Cappel R, Debusscher L.
Effectiveness of betamethasone in management of severe infections: a
double-blind study.
N Engl J Med.
1971;284:1248-1250.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
4929896>
29. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr29>
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;311:1137-1143.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
6384785>
30. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr30>
Lucas CE, Ledgerwood AM.
The cardiopulmonary response to massive doses of steroids in patients with
septic shock.
Arch Surg.
1984;119:537-541.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
6712466>
31. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr31>
Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA.
A controlled clinical trial of high-dose methylprednisolone in the treatment
of severe sepsis and septic shock.
N Engl J Med.
1987;317:653-658.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
3306374>
32. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr32>
The 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;317:659-665.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
2888017>
33. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr33>
Luce JM, Montgomery AB, Marks JD, Turner J, Metz CA, Murray JF.
Ineffectiveness of high-dose methylprednisolone in preventing parenchymal
lung injury and improving mortality in patients with septic shock.
Am Rev Respir Dis.
1988;138:62-68.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
3202402>
34. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr34>
Zipser RD, Davenport MW, Martin KL, et al.
Hyperreninemic hypoaldosteronism in the critically ill: a new entity.
J Clin Endocrinol Metab.
1981;53:867-873.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
6270176>
35. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr35>
Findling JW, Waters VO, Raff H.
The dissociation of renin and aldosterone during critical illness.
J Clin Endocrinol Metab.
1987;64:592-595.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
3029157>
36. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr36>
Quinkler M, Oelkers W, Diederich S.
Clinical implications of glucocorticoid metabolism by 11beta-hydroxysteroid
dehydrogenases in target tissues.
Eur J Endocrinol.
2001;144:87-97.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11182744>
37. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr37>
Barber AE, Coyle SM, Marano MA, et al.
Glucocorticoid therapy alters hormonal and cytokine responses to endotoxin
in man.
J Immunol.
1993;150:1999-2006.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
8436830>
38. <http://jama.ama-assn.org/issues/v288n7/rfull/#rr38>
Keh D, Weber-Carstens S, Böhnke T, et al.
Effects of stress-dose hydrocortisone therapy in septic shock, I: influence
on hemodynamic stability and plasma nitrite/nitrate levels: Preliminary
results of a double blind, randomised, placebo-controlled cross-over study.
Crit Care.
1999;3:51.
MEDLINE
<http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=
11056724>


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.