Special Article

Corticosteroid therapy for patients in septic shock: Some progress

in a difficult decision
Charles L. Sprung, MD; Mayer Brezis, MD; Serge Goodman, MD, PhD; Yoram G. Weiss, MD

Objectives: Reversible adrenal insufficiency has been fre-
quently diagnosed in critically ill patients with sepsis who have
either low basal cortisol levels or low cortisol responses to
adrenocorticotrophic hormone (ACTH) stimulation. It is generally
accepted that a phenomenon called “endotoxin tolerance” con-
tributes to immunosuppression during sepsis. The present study
was to investigate whether endotoxin tolerance occurs in the
adrenal gland, leading to hyporesponsiveness of adrenal gland
during sepsis.
Design: Controlled laboratory experiment.
Setting: University research laboratory.
Subjects: Sprague-Dawley male rats 200 –250 g, and primary
isolated adrenal fasciculata-reticularis cells. Interventions: Rats
received intra-arterial injection of purified lipopolysaccharide
(LPS, 0.5 mg/kg) through indwelling femoral arterial catheters,
and 24 h later the adrenocortical sensitivity to exogenous ACTH
(10 ng/kg) was detected. Primary F/R cells were pretreated with
LPS at 0.1–100 ng/mL or with ACTH at 0.01–10 ng/mL, and then
challenged, in fresh media, with 1 ␮g/mL LPS or 10 ng/mL ACTH.
Measurements and Main Results: Toll-like receptor 4 were
expressed in adrenal gland and primary fasciculata-reticularis cells.
Plasma corticosterone response to ACTH was decreased in rats
receiving preinjection of LPS. LPS pretreatment caused a significant
decrease in corticosterone production in response to subsequent
ACTH and LPS stimulation in primary fasciculata-reticularis cells.
LPS pretreatment inhibited ACTH- and LPS-induced expression of
steroid metabolizing enzymes. LPS significantly decreased toll-like
receptor 4 and ACTH receptor expression.
Conclusions: Pre-exposure to LPS resulted in hyporesponsive-
ness to ACTH stimulation in rats. In vitro, LPS pretreatment
impaired corticosterone production of F/R cells in response to
ACTH and LPS, which was associated with decreased expression
of synthetic enzymes required for corticosterone production. Our
results indicate that endotoxin tolerance of adrenal gland is one
of mechanisms for adrenocortical insufficiency during sepsis.
(Crit Care Med 2011; 39:571–574)
KEY WORDS: corticosteroids; steroids; infections; sepsis; septic
shock; meta-analyses

T he use of corticosteroids for
patients with infections, sep-
sis, or septic shock has been
controversial for decades (1).
Despite the many studies performed on
corticosteroids in septic patients, there
are still many unresolved issues. These
include whether steroids are beneficial
for septic patients without shock, for pa-
tients with septic shock, when given early
or late, the optimal dose, given in a bolus
or continuous infusion, the duration of
therapy, whether to wean and whether
fludrocortisone should be added. In this
commentary, we provide some guidance
for physicians on what appears to be rea-
sonable practice in light of conflicting
From the Department of Anesthesiology and Crit-
ical Care Medicine (CLS, SG, YGW) and the Center for
Clinical Quality and Safety (MB), Hadassah Hebrew
University Medical Center, Jerusalem, Israel.
The authors have not disclosed any potential con-
flicts of interest.
For information regarding this article, E-mail:
charles.sprung@ekmd.huji.ac.il
Copyright © 2011 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/CCM.0b013e31820ab1ec
evidence emerging from recent studies
and meta-analyses.
Overview on Recent Studies
and Meta-Analyses
The use of high doses of steroids as
anti-inflammatory agents was common
until several studies in patients with se-
vere sepsis and septic shock demon-
strated no survival benefit and a potential
for superinfections (2– 6). Subsequently,
low-dose steroids for patients with septic
shock, used for relative adrenal insuffi-
ciency, were shown in several small stud-
ies to reverse shock and improve survival
(7–9). Based primarily on the Annane
study (9), a large randomized, multicen-
tered, controlled trial (RCT), the Surviv-
ing Sepsis Campaign guidelines recom-
mended the use of hydrocortisone for
patients with septic shock requiring va-
sopressors despite fluid replacement (10)
and steroids once again were commonly
used for patients with septic shock. Re-
cently, the Sprung et al Corticus study
(11), in contrast to the previous Annane
study (9), did not demonstrate improved
survival after hydrocortisone therapy in
patients with septic shock. The contradic-
tory findings in these two large multicen-
tered studies created controversy on the
appropriateness of giving steroids to any
septic patient or patient with septic shock
or in contrast only to those patients with
septic shock not responsive to aggressive
conventional therapy. Because several
new studies evaluating the use of steroids
in septic patients have been performed
over the last few years, four recent meta-
analyses (12–15) have been published at-
tempting to shed light on the contro-
versy. The additional studies and meta-
analyses should help elucidate which
septic patients might benefit from corti-
costeroids. Unfortunately, they also show
some conflicting results (Table 1).
Meta-analyses are useful to improve
the validity of consistent effects observed
throughout individual studies and to ex-
plore potential reasons for discrepant re-
sults. As shown in Table 1, reversal of
shock by steroids is consistently observed
throughout the recent meta-analyses and
RCTs. Meta-analyses may demonstrate an
effect not shown in individual studies be-
cause they have more statistical power,

Crit Care Med 2011 Vol. 39, No. 3 571

Table 1. Summaries of findings from recent meta-analyses and large RCTs
Source: First Author, Year Marik, 2008 (12)
Type of study Meta-analysis
Total number of patients 965
Reversal of shock by steroids Yes
Heterogeneity No
Reduced mortality by steroids No
Heterogeneity No
RCT, randomized controlled trial; NA, not applicable.
a
Heterogeneity explained by steroids dosage and/or severity of illness (low dose more beneficial in the more severely ill patients).
but as shown in Table 1, conclusions on
the effect of corticosteroids on mortality
are contradictory between meta-analyses
or RCTs of comparable size. In addition,
in the recent meta-analyses of sepsis
studies (12–15), different methods were
used to include or exclude patients, dif-
ferent studies were included in their eval-
uations, and hence unsurprisingly the
authors came up with different conclu-
sions.
Conflicting Evidence Between
Meta-Analyses and RCTs: A
General Problem
Conflicting results between meta-
analyses and large RCTs are not unusual
(16), including studies in the recent crit-
ical care literature. One meta-analysis
suggested that noninvasive ventilation
lowers mortality in patients with cardiac
failure (17), whereas a subsequent large
RCT showed no benefit (18). In head
trauma, although meta-analyses were in-
conclusive, a large RCT concluded that
steroids increase the risk of death (19). In
childhood bacterial meningitis, a Co-
chrane systematic review (20) showed
that steroids reduce severe hearing loss, a
conclusion refuted by a subsequent RCT
(21). Discrepancies may occur even if the
meta-analysis includes studies with con-
tradictory conclusions. For instance,
there have been contradictory studies
on the impact of tight glucose control
with insulin in critically ill patients; a
large RCT showing an increase in mor-
tality in the intervention group (22) was
not confirmed by a meta-analysis that
included this study (23). Conversely, a
Cochrane systematic review recently
demonstrated that ultrasound guidance
during embryo transfer improves the
chances of pregnancies (24) despite in-
clusion of a negative large RCT in the
meta-analysis (25).
Major explanations for discrepancies
between meta-analyses and large RCTs
572
Annane, 2009 (13) Sligl, 2009 (14) Minneci, 2009 (15)
Meta-analysis Meta-analysis Meta-analysis
2384 1876
Yes Yes Yes
Yesa No No
Yes No No
Yesa No Yesa
are publication bias and heterogeneity
(16). Negative studies, unpublished be-
cause of lack of interest by authors and
editors, can completely wipe out an effect
apparent in RCTs and meta-analyses (26).
Publication bias may be present in the
literature on steroids in septic shock be-
cause a funnel plot analysis showed a
disproportionately high number of small
trials with benefit from steroids, suggest-
ing underreporting of negative small tri-
als (15). Heterogeneity between studies
can also be an important determinant of
variability of results that allow definition
of a patient subpopulation or treatment
regimens more likely to be effective. An
analysis of heterogeneity in Table 1 sug-
gested decreased mortality by low-dose
steroids only in the most severely ill
patients.
It should be remembered that these
observations in meta-analyses, retrospec-
tive by nature, are exploratory research
mainly allowing generation of hypotheses
to be confirmed or refuted by prospective
studies. Instability of evidence will often
be resolved by larger trials. Uncertainty
about the role of steroids in several com-
mon conditions (head trauma [19], men-
ingitis [21], and sepsis) suggests that in-
stability of evidence may be the result of
the lack of funding for larger trials, espe-
cially because corticosteroids are now ge-
neric. New medications, with massive
funding for megatrials by the pharmaceu-
tical companies, appear to achieve faster
homogeneity of information. Older drugs
may paradoxically leave us with less clear
evidence in some important areas where
public funding is not sufficient.
Recommendations for Practice
Meanwhile, what is a physician to do?
The meta-analyses recommend the use of
steroids for patients with vasopressor-
dependent or refractory septic shock (12–
15). There is also consensus that patients
Annane, 2002 (9) Sprung, 2008 (11)
Large RCT Large RCT
2468 300 499
Yes Yes
NA NA
Yes No
NA NA
who previously received steroids for var-
ious medical disorders and develop septic
shock should receive steroid supplemen-
tation as a result of their history (10).
Whether to use steroids in any patient
with severe sepsis or septic shock appears
to be more controversial.
The meta-analyses of Annnane et al
(13) and Minneci et al (15) analyzed pa-
tients with both sepsis and septic shock.
Although many of the mechanisms in-
volved in the disease process may be sim-
ilar, the severity of disease, morbidity,
mortality, and response to therapy may
be very different for patients with sepsis
and those with septic shock (4, 9, 27–29).
Interestingly, these two meta-analyses
used different publications for their anal-
yses and for some issues had different
conclusions (13, 15). Minneci et al (15)
assessed five studies (30 –34), which An-
nane et al did not (13) and Annane et al
(13) evaluated one study (35) Minneci et
al did not (15). Although both analyses
found differences in mortality between
high- and low-dose steroid treatment and
reversal of shock in steroid-treated pa-
tients, overall mortality was not different
between patients treated with corticoste-
roids (both high and low doses) when
compared with control patients (13, 15).
The lower mortality found in the steroid-
treated patients with low-dose steroids
(12–15) included a disproportionately
high number of published small studies
demonstrating beneficial steroid effects
with a potential publication bias (15).
Septic shock studies arranged in chrono-
logical order found a steroid survival ben-
efit in the smaller, earlier studies, which
was not found in later, larger studies (14).
Minneci et al (15) found diversity and
significance for steroid effect based on
patient severity of disease but Annane et
al (13) did not find diversity and only a
trend for steroid effect based on severity
of disease. In patients with less severe
disease, steroids appeared harmful,
Crit Care Med 2011 Vol. 39, No. 3
whereas in patients with severe disease,
steroids appeared more beneficial (13,
15). Interestingly, there was no relation-
ship between the severity of disease and
the steroid effect on shock reversal (15).
Marik et al (12) and Sligl et al (14) in
their meta-analyses evaluated only pa-
tients treated with low doses of cortico-
steroids who were in septic shock and did
not include patients who were only septic
without shock. They also did not include
the same studies (12, 14). Because these
meta-analyses based their evaluation only
on patients with septic shock, we believe
these meta-analyses are more relevant for
answering our question of which patient
with septic shock should or should not
receive steroids.
These latter two meta-analyses found
that corticosteroids provided no benefit
in decreasing mortality (12, 14), a benefit
in reversing septic shock (12, 14), and
overall no difference in adverse events of
superinfections (14). These findings are
similar to those found in the Corticus
study and bring up the same question
(11). If steroids do indeed improve shock
reversal, why is this not translated into
an improved survival that should occur if
more patients reverse their shock (11)?
The answer should not be one of inade-
quate power because the Annane et al
study (9) with far less patients than in the
meta-analyses did find a difference with
improved survival in patients with septic
shock treated with steroids. There might
be some partly identified steroid effect
that, although improving shock reversal,
does not lead to improved survival.
Although the Corticus study was per-
formed by several of us, the study has
limitations. It had a lower than expected
death rate in the control group and this
combined with the early stopping of the
study with 500 rather the planned 800
patients meant that the study had a
power of ⬍35% to detect a 20% reduc-
tion in the relative risk of death (36).
Despite this fact, the 95% confidence in-
tervals for the difference in mortality for
the two treatment groups in the entire
Corticus patient population were ⫺5.8 –
10.6%. Therefore, the maximal benefit
could be a 5.8% decrease in mortality
even if 800 patients were enrolled. The
reason why a superior result with corti-
costeroid therapy can be excluded despite
the smaller sample size is the observed
higher mortality in the hydrocortisone
group compared with placebo.
Crit Care Med 2011 Vol. 39, No. 3
Expected Impact From
Corticosteroids in Septic Shock
What should the end point for adjunct
drug therapy such as hydrocortisone be?
Because steroids work by enhancing va-
somotor tone through their interaction
with adrenergic receptors (37) and are
acting similar to vasopressors, then re-
versing shock might be an acceptable end
point. Unfortunately, the actions of cor-
ticosteroids are not just like those of a
vasopressor such as norepinephrine,
which is commonly used for septic shock.
Steroids are also anti-inflammatory
agents with potent adverse effects (1)
sometimes observed in these trials (such
as hypernatremia [8] and infections [11])
but often not (9, 14). Interestingly, even
the two meta-analyses by Lefering and
Cronin (5, 6) of high-dose steroids in
septic patients and patients with septic
shock did not find a significantly higher
incidence of secondary infections in ste-
roid-treated patients. Instability of evi-
dence may relate here also to limited
power of current studies; a sample size of
⬎6000 treated patients (with a similar
number of control subjects) might be re-
quired to show a significant 10% increase
in rate of infection. In future trials, it
might be worth considering evaluation of
shorter regimens of steroids to minimize
potential adverse effects.
Catecholamines are also not without
adverse events (38). In addition to the
risk of hypoperfusion and ischemia (38),
catecholamines have also been shown to
interfere with the immune system (39).
This includes bacterial growth stimula-
tion (40), increased factors related to bac-
terial virulence (40), and compromising
host resistance to bacteria by affecting
the activity and survival of immune cells
(41). The adverse effects of cat-
echolamines, however, do not approach
the more common and severe adverse of
steroids, even in low doses.
Some of these adverse effects may not
have been identified in clinical trials. For
instance, critically ill patients with sepsis
have an increased risk for developing cy-
tomegalovirus infections (42) and pa-
tients receiving steroids also have an in-
creased incidence of cytomegalovirus
infections (43). Critically ill patients who
develop infections with cytomegalovirus
have higher mortality rates, longer time
on ventilators, and longer lengths of stay
in the intensive care unit, which could
explain a lack of survival in patients re-
versing their shock (42, 43). If there is no
improved survival benefit by using corti-
costeroids and the shock reversal may not
be a true reversal but merely a “dis-
guised” vasopressor effect of steroids,
than there is no advantage for using ste-
roids instead of standard vasopressor
agents, which have far less immune de-
pressant side effects. Therefore, a few ad-
ditional days of norepinephrine therapy
are probably a better therapeutic choice
than steroids.
CONCLUSION
Without a strong signal for a decrease
in mortality with steroid therapy, physi-
cians should not be using steroids for all
patients in septic shock. Corticosteroids
should only be used in patients meeting
the severe septic shock criteria in the
Annane et al study of a systolic blood
pressure ⬍90 mm Hg for ⬎1 hr in which
steroids were found to improve survival
(9) or perhaps the Surviving Sepsis Cam-
paign’s recent updated recommendations
“septic shock patients … identified to be
poorly responsive to fluid resuscitation
and vasopressor therapy (44).” We believe
only the former Annane et al patients
meeting the criteria of severe unrespon-
sive septic shock should be treated with
steroids but understand why some physi-
cians might use the Surviving Sepsis
Campaign recommendations. However,
even this practice can be called into ques-
tion. If physicians base their clinical prac-
tice on the meta-analyses and use ste-
roids to reverse shock in patients with
septic shock with more severe, unrespon-
sive shock or greater disease severity, one
wonders if steroids should be used in this
population because there was no relation-
ship between steroid’s reversing shock
and the severity of disease (15). Patients
with severe sepsis not in shock or pa-
tients with septic shock stabilized with
fluid and vasopressor therapy should not
receive steroid therapy. Physicians
should always follow the dictum “pri-
mum non nocere.” The ability to resolve
the controversy will require stronger ev-
idence after appropriate funding for
much larger trials.
ACKNOWLEDGMENTS
Supported by The Walter F. and Alice
Gorham Foundation, Inc.
REFERENCES
1. Schein RMH, Sprung CL: The use of cortico-
steroids in the sepsis syndrome. In: Critical
573
 Care—State of the Art. Fullerton, CA, The
Society of Critical Care Medicine, 1986, pp
131–149
2. Sprung CL, Caralis PV, Marcial EH, et al: The
effects of high-dose corticosteroids in pa-
tients with septic shock. A prospective, con-
trolled study. N Engl J Med 1984; 311:
1137–1143
3. Bone RC, Fisher CJ Jr, Clemmer TP, et al: A
controlled clinical trial of high-dose methyl-
prednisolone in the treatment of severe sep-
sis and septic shock. N Engl J Med 1987;
317:653– 658
4. The Veterans Administration Systemic Sepsis
Cooperative Study Group: Effect of high-dose
glucocorticoid therapy on mortality in pa-
tients with clinical signs of systemic sepsis.
N Engl J Med 1987; 317:659 – 665
5. Lefering R, Neugebauer EAM: Steroid con-
troversy in sepsis and septic shock: A meta-
analysis. Crit Care Med 1995; 23:1294 –1303
6. Cronin L, Cook DJ, Carlet J, et al: Cortico-
steroid treatment for sepsis: A critical ap-
praisal and meta-analysis of the literature.
Crit Care Med 1995; 24:1430 –1439
7. Bollaert PE, Charpentier C, Levy S, et al:
Reversal of late septic shock with supraphysi-
ologic doses of hydrocortisone. Crit Care
Med 1988; 26:645– 650
8. Briegel J, Frost H, Haller M, et al: Stress
doses of hydrocortisone reverse hyperdy-
namic septic shock: A prospective, random-
ized, double-blind, single center study. Crit
Care Med 1999; 27:723–732
9. Annane D, Sebille V, Charpentier C, et al:
Effect of treatment with low doses of hydro-
cortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:
862– 870
10. Dellinger P, Carlet JM, Masur H, et al: Sur-
viving Sepsis Campaign guidelines for the
management of severe sepsis and septic
shock. Crit Care Med 2004; 32:858 – 873
11. Sprung CL, Annane D, Keh D, et al; for the
Corticus Study Group: The CORTICUS ran-
domized, double-blind, placebo-controlled
study of hydrocortisone therapy in patients
with septic shock. N Engl J Med 2008; 358:
111–124
12. Marik PE, Pastores SM, Annane D, et al:
Clinical practice guidelines for the diagnosis
and management of corticosteroid insuffi-
ciency in critical illness: Recommendations
of an international task force. Crit Care Med
2008; 36:1937–1949
13. Annane D, Bellissant E, Bollaert PE, et al:
Corticosteroids in the treatment of severe
sepsis and septic shock in adults—A system-
atic review. JAMA 2009; 301:2362–2375
14. Sligl WI, Milner DA, Sundar S, et al: Safety
and efficacy of corticosteroids for the treat-
ment of septic shock: A systematic review
and meta-analysis. Clin Infect Dis 2009; 49:
93–101
574
15. Minneci PC, Deans KJ, Eichacker PQ, et al:
The effects of steroids during sepsis depend
on dose and severity of illness: An updated
meta-analysis. Clin Microbiol Infect 2009;
15:308 –318
16. LeLorier J, Gregoire G, Benhaddad A, et al:
Discrepancies between meta-analyses and
subsequent large randomized, controlled tri-
als. N Engl J Med 1997; 337:536 –542
17. Masip J, Roque M, Sanchez B, et al: Nonin-
vasive ventilation in acute cardiogenic pul-
monary edema: Systematic review and meta-
analysis. JAMA 2005; 294:3124
18. Gray A, Goodacre S, Newby DE, et al: Non-
invasive ventilation in acute cardiogenic pul-
monary edema. N Engl J Med 2008; 359:
142–151
19. Edwards P, Arango M, Balica L, et al: Final
results of MRC CRASH, a randomised placebo-
controlled trial of intravenous corticosteroid
in adults with head injury—Outcomes at 6
months. Lancet 2005; 365:1957–1959
20. van de Beek D, de Gans J, McIntyre P, et al:
Corticosteroids for acute bacterial meningi-
tis. In: Cochrane Database of Systematic Re-
views. Chichester, UK, John Wiley & Sons,
Ltd, 2007
21. Peltola H, Roine I, Fernandez J, et al: Hear-
ing impairment in childhood bacterial men-
ingitis is little relieved by dexamethasone or
glycerol. Pediatrics 2010; 125:e1– e8
22. The NICE-SUGAR Study Investigators: In-
tensive versus conventional glucose control
in critically ill patients. N Engl J Med 2009;
360:1283–1297
23. Griesdale DEG, de Souza RJ, van Dam RM, et
al: Intensive insulin therapy and mortality
among critically ill patients: A meta-analysis
including NICE-SUGAR study data. CMAJ
2009; 180:821– 827
24. Brown J, Buckingham K, Abou-Setta Ahmed
M, et al: Ultrasound versus ‘clinical touch’ for
catheter guidance during embryo transfer in
women. In: Cochrane Database of Systematic
Reviews. Chichester, UK, John Wiley & Sons,
Ltd, 2010
25. Drakeley AJ, Jorgensen A, Sklavounos J, et al:
A randomized controlled clinical trial of 2295
ultrasound-guided embryo transfers. Hum
Reprod 2008; 23:1101–1106
26. Zoungas S, Ninomiya T, Huxley R, et al:
Systematic review: Sodium bicarbonate
treatment regimens for the prevention of
contrast-induced nephropathy. Ann Intern
Med 2009; 151:631– 638
27. Rangel-Frausto MS, Pittet D, Costigan M, et
al: The natural history of the systemic in-
flammatory response syndrome (SIRS). A
prospective study. JAMA 1995; 273:117–123
28. Sands KE, Bates DW, Lanken PN, et al: Epi-
demiology of sepsis syndrome in 8 academic
medical centers. Academic Medical Center
Consortium Sepsis Project Working Group.
JAMA 1997; 278:234 –240
29. Russell JA: Management of sepsis. N Engl
J Med 2006; 355:1699 –1713
30. Bennett IL, Finland M, Hamburger M, et al:
The effectiveness of hydrocortisone in the
management of severe infection. JAMA 1963;
183:462– 465
31. Klastersky J, Cappel R, Debusscher L: Effec-
tiveness of betamethasone in management of
severe infections. A double-blind study.
N Engl J Med 1971; 284:1248 –1250
32. Thompson WL, Gurley HT, Lutz BA, et al:
Inefficacy of glucocorticoids in shock (dou-
ble-blind study). Clin Res 1976; 24:258A
33. Lucas CE, Ledgerwood AM: The cardiopul-
monary response to massive doses of steroids
in patients with septic shock. Arch Surg
1984; 119:537–541
34. Mussack T, Briegel J, Schelling G, et al: Ef-
fect of stress doses of hydrocortisone on
S-100B vs interleukin-8 and polymorphonu-
clear elastase levels in human septic shock.
Clin Chem Lab Med 2005; 43:259 –268
35. Meduri GU, Golden E, Freire AX, et al: Meth-
ylprednisolone infusion in early severe
ARDS: Results of a randomized controlled
trial. Chest 2007; 131:954 –963
36. Finfer S: Corticosteroids in septic shock.
N Engl J Med 2008; 358:188 –190
37. Saito T, Takanashi M, Gallagher E, et al: Cor-
ticosteroid effect on early beta-adrenergic
down-regulation during circulatory shock: He-
modynamic study and beta-adrenergic receptor
assay. Intensive Care Med 1995; 21:204 –210
38. Zaritsky AL: Catecholamines, inotropic med-
ications and vasopressor agents. In: The
Pharmacologic Approach to the Critically Ill
Patient. Chernow B (Ed). Baltimore, MD,
Williams & Wilkins, 1994, pp 387– 404
39. Singer M: Catecholamines treatment for
shock—Equally good or bad? Lancet 2007;
370:636 – 637
40. Lyte M, Freestone PP, Neal CP, et al: Stimu-
lation of Staphylococcus epidermidis growth
and biofilm formation by catecholamine ino-
tropes. Lancet 2003; 361:130 –135
41. Oberbeck R: Catecholamines: physiological
immunomodulators during health and ill-
ness. Curr Med Chem 2006; 13:1979 –1989
42. Heininger A, Jahn J, Engel C, et al: Human
cytomegalovirus infections in nonimmuno-
suppressed critically ill patients. Crit Care
Med 2001; 29:541–547
43. Jaber S, Chanques G, Borry J, et al: Cytomeg-
alovirus infection in critically ill patients.
Chest 2005; 127:233–241
44. Dellinger RP, Levy MM, Carlet JM, et al; for
the International Surviving Sepsis Campaign
Guidelines Committee: Surviving Sepsis
Campaign: International guidelines for man-
agement of severe sepsis and septic shock.
Crit Care Med 2008; 36:296 –327
Crit Care Med 2011 Vol. 39, No. 3