Effect of Treatment With Low Doses of Hydrocortisone and
Fludrocortisone on Mortality in Patients With Septic Shock
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withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65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
Severe sepsis remains an important cause of
death, accounting for 9.3% of all deaths in the United States in 1995.1 If our understanding
of the mechanisms of host response to stress has strongly progressed during the
last 2 decades,2 the various
drugs developed for specific targets of the cytokine cascade have failed to
improve patient survival.3, 4
Corticosteroids were the first anti-inflammatory
drugs tested in randomized trials. At high doses during short courses, they did
not induce favorable effects.5, 6 However, the
observation that severe sepsis may be associated with relative adrenal
insufficiency7, 8 or systemic
inflammation-induced glucocorticoid receptor resistance9 prompted renewed
interest of a replacement therapy with low doses of corticosteroids during
longer periods.10, 11
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, 13 particularly in those
with relative adrenal insufficiency.12 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, 15 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 could improve 28-day
survival in patients with septic shock, with particular interest in patients
with relative adrenal insufficiency.
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).
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 -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--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 disease17 and level of activity
limitation18; (2) severity
of illness assessed by vital signs, Simplified Acute Physiology Score II (SAPS
II),19 and Logistic
Organ Dysfunction (LOD) score20; 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 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, 8
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, psychiatric 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
subgroup7, 22 and a frequency of
nonresponders of 40% in the population of patients with septic shock.7 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, 23
The 2 interim analyses were planned using an
O'Brien and Fleming stopping boundary.24 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 2 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 models25 using baseline
cortisol, cortisol response, McCabe classification, LOD score, arterial lactate
levels, and PaO2/FIO2 results for the adjustment.8 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 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 2 or Fisher exact tests when appropriate. All reported P values are 2-sided.
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).
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)
and severity of illness (Table 2).
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 classification8 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).
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 2A).
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 2B).
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 2C).
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).
Responders
There was no significant effect of corticosteroids on 28-day, ICU, hospital,
and 1-year mortality rates in responders (Table 4).
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).
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 3A).
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 3B).
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 3C).
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).
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 endotoxin27 and with 2 studies of
patients with septic shock,12, 13 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, 15 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 study22, 23 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 study7, 22 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 studies28-33 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 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 out16 since it has
been shown that 40% to 65% of critically ill patients have high-plasma renin
activity and low-plasma aldosterone concentrations.34, 35 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 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 endotoxin37 and in patients with
septic shock23, 38 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]).
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.
1.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.