Acta Anaesthesiologica Taiwanica 50 (2012) 74e77

Contents lists available at SciVerse ScienceDirect

Acta Anaesthesiologica Taiwanica

journal homepage: www.e-aat.com

Review Article

Possible interventional therapies in severe sepsis or septic shock

Chin-Chen Wu*
Department of Pharmacology, National Defense Medical Center, Neihu, Taipei, Taiwan, ROC

a r t i c l e i n f o a b s t r a c t

Article history: For many years, basic research with relatively straightforward pathophysiologic approaches has driven
Received 14 March 2012 clinical trials using molecules that supposedly interfere positively with inflammatory processes.
Received in revised form However, most of these trials have failed to demonstrate any outcome benefit. Indeed, we need to revisit
17 April 2012
current paradigms and to think about the possibility that outcome may be predetermined in severe
Accepted 20 April 2012
sepsis or septic shock. In addition, an early diagnosis of sepsis prior to the onset of clinical decline is also
of particular interest to health practitioners because this information increases the possibilities for early
Key words:
and specific treatment of this life threatening condition. Indeed, the time to initiate therapy is thought to
sepsis;
mortality;
be crucial and the major determent factor in surviving sepsis. Despite substantial progress in sepsis
therapy therapy, the gap between the discovery of new effective medical molecules and their implementation in
the daily clinical practice of the intensive care unit remains a major hurdle. Fortunately, ongoing research
continues to provide new information on the management of sepsis, in particular, severe sepsis or septic
shock. High quality and effective management tools are necessary to bring evidence-based therapy to the
bedside. On this basis, new therapies could be tested to reduce mortality rates with respect to recently
published studies.
Copyright Ó 2012, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights
reserved.

1. Introduction show a reduction in mortality, thus raising the question whether

Intensive care unit (ICU) mortality rate for severe sepsis and
septic shock is ranging from 25%e70% when complicated by shock
and multiple organ failure.1e4 So far, the treatment of severe sepsis
and septic shock consists of source control, early antimicrobial
therapy, and supportive and adjunctive therapies. Further reduc-
tion in mortality may be achievable through knowledge and use
of the expanding field of adjunctive therapy, e.g., the early
administration of appropriate antibiotic therapy and source control,
early-goal directed management of hypotension and perfusion
abnormalities with fluid resuscitation and vasoactive agents
support, and the use of lung protective ventilator support strate-
gies, as necessary.5
The prominent role of inflammatory molecules and pathways
suggests a possible therapeutic role in the management of severe
sepsis and septic shock. However, numerous trials, irrespective of
unsuccessful ones, which targeted at inhibiting various essential
inflammatory mediators and receptors involved in the sepsis
syndrome, e.g., shock and multiple organ failure, have failed to
* Department of Pharmacology, National Defense Medical Center, Number 161,
Section 6, Minquan East Road, Neihu District, Taipei City 114, Taiwan, ROC.
E-mail address: ccwu@mail.ndmctsgh.edu.tw.
mortality in sepsis actually derives from an uncontrolled proin-
flammatory response. Corticosteroids and activated drotrecogin
alfa are to date the only drugs that have demonstrated mortality
benefits in large randomized controlled trials. This could be due to
their broad based attempts at modulating the inflammatory
response to infection. However, despite decades of experimental
animal and human trials, the role of corticosteroid therapy, even
with the evaluation of hypothalamic-pituitary-adrenal axis in
sepsis remains uncertain and sometimes controversial.5e12 Thus, in
this review, we attempt to focus our attention on adjunctive sepsis
therapies, which are based on animal studies in the literature, with
emphasis on mortality outcome.
2. Recent clinical relevance
2.1. Corticosteroids
A remarkable finding in the recently published Corticosteroid
Therapy of Septic Shock (CORTICUS) trial of hydrocortisone therapy
in septic shock was a large and significant reduction of shock in
those treated with steroids, yet Day 28 mortality rate was similar
compared with those receiving placebo.13 This relatively stable
mortality rate, which persists despite better mechanistic

1875-4597/$ e see front matter Copyright Ó 2012, Taiwan Society of Anesthesiologists. Published by Elsevier Taiwan LLC. All rights reserved.
doi:10.1016/j.aat.2012.05.003
Therapy for severe sepsis/septic shock
understanding, more rapid, targeted, and aggressive resuscitation14
as well as more rigorous supportive therapies, suggests that rela-
tively constant pathways still lead to death in some patients. It
seems that the mechanisms underlying organ failure and death still
remain difficult to assess and to counteract. For instance, inflam-
matory processes interacting with a metabolic failure continue to
be key issues.15,16
2.2. Hydroxyethyl starch
A recent study on hydroxyethyl starch (HES) 130/0.4 that ful-
filled the inclusion criteria, was carried out in the form of
a randomized clinical trial (RCT) in adults requiring acute volume
therapy and admission to ICU or emergency unit for comparing HES
with non-HES fluid.17 Despite its lack of evidence in severely ill
patients, HES 130/0.4 has been given to more than 24 million
patients worldwide according to a certain manufacturer.18 In one-
third of 73 Scandinavian ICUs that participated in a survey pub-
lished in 2008, colloids were used as first-line fluid for resuscitation
and HES 130/0.4 was the preferred colloid in the majority of ICUs.18
However, previous two large randomized studies reveal that the
use of 10% HES 200/0.5 and 6% HES 200/0.6e0.66 is associated with
acute renal failure in severe sepsis patients as compared with
Ringer’s lactate or gelatin.19,20 In view of these data, the safest
options of colloidal fluid resuscitation in sepsis for early hemody-
namic stabilization appear to consider the modification of fluid
gelatin and albumin used in combination with crystalloids or
crystalloids on own expense.
2.3. Vasopressin
In addition, a recent large-scale multicenter study performed in
patients with septic shock, called the Vasopressin and Septic Shock
Trial (VASST), indicated that a combination therapy consisting of
low-dose arginine vasopressin (AVP,  1.8 U/hour) and norepi-
nephrine (NE) infusion is equally safe and efficacious as treatment
with NE alone.21 At the same mean arterial pressure, AVP infusion
offered a significant reduction in NE requirement. A prior subgroup
analysis manifests that in patients with less severe sepsis
(requirement of <15 mg/minute NE at randomization), the overall
mortality on Days 28 and 90 is similar. The treatment with AVP plus
NE markedly decreases 90-day mortality compared with NE infu-
sion alone (35.8% vs. 46.1%). It seems that AVP treatment in the
early stage of sepsis is potentially superior to whatever treatment in
the last resort. However, an effective dose of AVP for patients with
grave severity of shock remains a vitally important issue in these
patients because of the staggeringly high mortality rate. More
recently, Torgersen and colleauges22 have reported that in patients
with severe septic shock administration of a higher dose of AVP
(0.067 U/minute) than used in the VASST trial could result in a more
effective restoration of cardiovascular function. Although the
number of patients randomized into Torgersen’s study is sufficient
to provide useful hemodynamic information, it is not adequate
enough to test for differences in survival outcome.23 Thus,
randomized controlled trials that are adequately powered to test
for survival differences in severely ill patients are still warrantable.
2.4. Glycemic control
The importance of glycemic control also surges as an interest of
a European sepsis trial in which cardiac surgery patients were
randomized to receive intensive insulin therapy versus ordinary
glucose management.24 Although the study demonstrates that
increased benefit in the intensive insulin group,24 concerns
regarding glucose loading which overtakes standard practice in
75
glucose administration in the control group somewhat tempers
these findings.25 In fact, in the trial by the same group in medical
ICU patients, no significant difference in mortality with the use of
intensive or conventional insulin therapy has been shown26;
intensive insulin therapy decreased the rate of death among
patients who remained in the ICU for 3 days or more but increased
the rate of death among patients whose stay lasted fewer than 3
days.26,27 The mechanisms by which intensive insulin therapy
benefits surgical patients are not known, but they could include the
induction of euglycemia, the benefaction form increased insulin
levels, or both.28 However, the appropriate target glucose range and
insulin dose in patients with sepsis were unknown, because these
trials were not conducted in specifically studied patients with
sepsis. Actually, among the mixed medical and surgical subjects in
these RCTs, 950 could be identified as having sepsis at the time of
admission to the ICU.26 Though how intensive insulin therapy
affects patients with sepsis remains unclear, it is doubtless that
glycemic control offers an intuitive sense.
2.5. Genetic aspect
Obviously, critical care physicians have all been frustrated by the
common scenario in which two patients of similar age and having
similar comorbidities are treated in an identical manner, yet only
one of whom survives, while the other progresses to multiple organ
system failure and succumbs. The answer to why one does survive
and the other patient does not may be that they are different in
genetic make-up. In other words, our genes may affect the way we
respond to infection. While no clear “sepsis gene” has yet been
identified, genetic factors undoubtedly play an important role in
the pathophysiology of sepsis.29 A recent study demonstrates that
a class-defining 100-gene signature depicted for each individual
patient using mosaics generated by the Gene Expression Dynamics
Inspector.30 Composite mosaics are generated representing the
average expression patterns for each of the previously published,
genome-wide, expression-based sub-classes (subclasses A, B, and
C) having clinically relevant phenotypic differences. This study
shows that respective sensitivities, specificities, positive predictive
values, and negative predictive values of the sub-classification
strategy are 84% across the three subclasses. The authors
conclude that this study provides initial evidence (proof of concept)
for a clinically feasible and robust stratification strategy for pedi-
atric septic shock based on a 100-gene signature and gene
expression mosaics. However, there is a major barrier that needed
to be solved. That is the application of genomic data in the field of
critical care medicine has been the translation, interpretation, and
acceptance of these complex data by clinicians. Hopefully, further
research in this area will lead to a more individualized approach to
the management of critically ill patients with sepsis and septic
shock, taking into account both the genetic makeup of the host, as
well as the characteristics of the immune response.
3. Individual animal study
3.1. Apoptosis
While it is generally accepted that sepsis is an inflammatory
state resulting from the systemic response to infection, “apoptosis”
is implicated to be an important mechanism of the death of
lymphocytes, gastrointestinal and lung epithelial cells, and vascular
endothelial cells associated with the development of multiple
organ failure in sepsis. The pivotal role of cell apoptosis is now
highlighted by multiple studies demonstrating that prevention of
cell apoptosis can improve survival in clinically relevant animal
models of sepsis. Apoptosis is regulated by the caspase family of
76
cysteine proteases and is triggered in response to proapoptotic
stimuli and that result in disassembly of the cell. As inhibition of
caspase family members represents a novel approach to disease
treatment, some pharmaceutical companies have developed
compounds that inhibit activation of caspase. Hotchkiss and
coworkers31 have reported that treatment with the broad-
spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluo-
romethylketone (z-VAD-fmk) decreases lymphocyte apoptosis,
decreases blood bacterial counts, and improves survival in mice
with cecal ligation and puncture (CLP)-induced sepsis. In a related
study, Kawasaki and others32 have noted that z-VAD-fmk decreases
apoptosis on pulmonary endothelial cells and epithelial cells and
elevates the survival rate in a lipopolysaccharide (LPS)-induced
acute lung injury mouse model. However, Méthot and coauthors33
have warned us that the ability of low potency caspase inhibitors
such as z-VAD-fmk to improve survival in CLP-induced sepsis is not
always a result of inhibition of active caspase-3, although a caspase-
3especific reversal inhibitor, if any, would represent a potential
therapeutic approach in sepsis.
3.2. Nuclear factor-kappa B pathway
It is clear that the nuclear factor-kappa B (NF-kB) pathway is
linked to the dysregulated inflammation that is characteristic of
sepsis. Thus, the NF-kB pathway would then appear to be a logical
therapeutic target for the treatment of critically ill patients with
sepsis.34 Several recent studies have led to questions surrounding
this kind of therapeutic strategy.35 For example, given its critical role
in the innate and adaptive immune responses to infection, inhibi-
tion of NF-kB may worsen pathogen clearance and increase the risk
of mortality from overwhelming infection. Alternatively, NF-kB
plays an important antiapoptotic role (see below)dinhibition may
then have unintended and untoward effects on cell survival and
function. Finally, other studies suggest that NF-kB has a critical anti-
inflammatory function in preventing an overwhelming host
inflammatory response to infectious challenge.36e39 Obviously,
further studies, both in the preclinical and clinical settings will be
necessary to further validate this therapeutic approach.
3.3. Levosimendan
It is well recognized that sepsis accounts for the majority of ICU
mortality, predominantly via the development of multiple organ
failure (MOF). Myocardial dysfunction, which often affects both
ventricles, is a well-recognized manifestation of septic organ
dysfunction. The role of “levosimendan” in sepsis and septic shock
has recently been thoroughly reviewed by Pinto and colleagues.40
The theoretical benefits of levosimendan in treatment of septic
shock, such as calcium-sensitizing action, opening of KATP channels
(resulting in improved tissue oxygenation and organ protection)
along with the anti-inflammatory action of levosimendan, have
been supported by vast experimental data.41e45 Morelli and
others46,47 have previously conducted two prospective, random-
ized clinical studies assessing levosimendan in patients with sepsis
and reported improved cardiac performance and global oxygen
transport in addition to decreased pulmonary dysfunction.
3.4. Immunomodulators
Despite advancements in our understanding of innate and
adaptive immunity, applying this knowledge to the treatment of
sepsis has proven difficult. Many factors modulate innate and
adaptive immune responses and link the two branches of immunity
during infection. Recently, type 1 interferons (IFNs) are shown to
act downstream of Toll-like receptor signaling48 to induce a specific
C.-C. Wu
gene activation signature, including induction of chemokines such
as CXCL10. Type 1 IFNs also serve as a link between the innate and
adaptive immune systems,49 participating in autoimmunity50 and
viral51 and bacterial infection.52,53 During endotoxicosis or highly
lethal bacterial infections where systemic inflammation predomi-
nates, mice deficient in IFN-a/breceptor (IFNAR) display decreased
systemic inflammation and improved outcome. However, human
sepsis mortality often occurs during a prolonged period of immu-
nosuppression and not from exaggerated inflammation. Kelly-
Scumpia and others54 used a low lethality cecal ligation and
puncture (CLP) model of sepsis to determine the role of type I IFNs
in host defense during sepsis. Despite increased endotoxin resis-
tance, they found IFNARe/eand chimeric mice which lacked IFNAR
in hematopoietic cells display increased mortality to CLP. This was
not associated with an altered early systemic inflammatory
response, except for decreased CXCL10 production. IFNARe/emice
display persistently elevated peritoneal bacterial counts
compared with wild-type mice, reduced peritoneal neutrophil
recruitment, and recruitment of neutrophils with poor phagocytic
function despite normal to enhanced adaptive immune function
during sepsis. Importantly, CXCL10 treatment in IFNARe/emice
improves survival and decreases peritoneal bacterial loads, and
CXCL10 increases mouse and human neutrophil phagocytosis.
Using a low lethality sepsis model, they identify a critical role of
type I IFNedependent CXCL10 in host defense during polymicrobial
sepsis by increasing neutrophil recruitment and function. Other
pleiotropic molecules such as complement C5a receptors and High
Mobility Group Box 1 can also show immunomodulatory effects on
host defense and inflammation depending on the severity of the
septic insult.55 These studies highlight the plasticity of immuno-
modulatory signaling cascades and their ability to participate in
either detrimental systemic inflammatory cascades or protective
host defense responses depending on the bacterial burden.
4. Conclusion
The “one size fits all” approach that has been utilized in the
clinical design of these studies will not work in the future. We need
to address the role of host factors, such as age, gender, presence of
comorbidities, and genetic predisposition in determining the
individual response to therapy. When designing clinical trials,
critically ill patients should be stratified according to severity of
illness in order to maximize the signal-to-noise ratio of new ther-
apeutic agents. Ideally, those patients who would generally survive
with standard therapy alone should not be included in such studies.
In addition, we need to recognize that immunomodulation as
a therapeutic strategy encompasses both augmentation of the
immune response in critically ill patients with the immunopar-
alysis phenotype, as well as suppression of the immune response in
those patients with a predominantly proinflammatory phenotype.
It is likely that one particular therapeutic agent directed against any
one mediator is not likely to be successful. Given the inherent
complexity and redundancy of the host inflammatory response,
future management strategies will likely encompass the use of
multiple, synergistic agents acting upon different steps in the
mediator cascade.
References
1. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR.
Epidemiology of severe sepsis in the United States: analysis of incidence,
outcome, and associated costs of care. Crit Care Med 2001;29:1303e10.
2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the
United States from 1979 through 2000. N Engl J Med 2003;348:1546e54.
3. Russell JA. Management of sepsis. N Engl J Med 2006;355:699e713.
Therapy for severe sepsis/septic shock
4. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospital-
ization and mortality rates for severe sepsis in the United States: a trend
analysis from 1993 to 2003. Crit Care Med 2007;35:1244e50.
5. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving
Sepsis Campaign: International guidelines for management of severe sepsis
and septic shock: 2008. Crit Care Med 2008;36:296e327.
6. Marik PE. Critical illness-related corticosteroid insufficiency. Chest
2009;135:181e93.
7. Moran JL, Graham PL, Rockliff S, Bersten AD. Updating the evidence for the role
of corticosteroids in severe sepsis and septic shock: a Bayesian meta-analytic
perspective. Crit Care 2010;14. R134.
8. Annane D. Corticosteroids for sepsis: registry versus Cochrane systematic
review. Crit Care 2010;14:185.
9. Lipiner-Friedman D, Sprung CL, Laterre PF, Weiss Y, Goodman SV, Vogeser M,
et al. Adrenal function in sepsis: the retrospective Corticus cohort study. Crit
Care Med 2007;35:1012e8.
10. Morel J, Venet C, Donati Y, Charier D, Liotier J, Frere-Meunier D, et al. Adrenal
axis function does not appear to be associated with hemodynamic improve-
ment in septic shock patients systematically receiving glucocorticoid therapy.
Intens Care Med 2006;32:1184e90.
11. Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P. Diagnosis of
adrenal insufficiency in severe sepsis and septic shock. Am J Respir Crit Care
Med 2006;174:1319e26.
12. Dellinger RP. Steroid therapy of septic shock: the decision is in the eye of the
beholder. Crit Care Med 2008;36:1987e9.
13. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydro-
cortisone therapy for patients with septic shock. N Engl J Med 2008;358:
111e24.
14. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-
directed therapy in the treatment of severe sepsis and septic shock. N Engl J
Med 2001;345:1368e77.
15. Calvano SE, Xiao W, Richards DR, Felciano RM, Baker HV, Cho RJ, et al.
A network-based analysis of systemic inflammation in humans. Nature
2005;437:1032e7.
16. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive,
endocrinemediated, metabolic response to overwhelming systemic inflam-
mation. Lancet 2004;364:545e8.
17. Zarychanski R, Turgeon AF, Fergusson DA, Cook DJ, Hebert P, Bagshaw SM, et al.
Renal outcomes and mortality following hydroxyethyl starch resuscitation of
critically ill patients: systematic review and meta-analysis of randomized trials.
Open Med 2009;3:E196e209.
18. FLUIDS study investigators for the Scandinavian Critical Care Trials Group.
Preferences for colloid use in Scandinavian intensive care units. Acta Anaes-
thesiol Scand 2008;52:750e8.
19. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, et al.
Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis:
a multicentre randomized study. Lancet 2001;357:911e6.
20. Sakr Y, Payen D, Reinhart K, Sipmann FS, Zavala E, Bewley J, et al. Effects of
hydroxylethyl starch administration on renal function in critically ill patients.
Br J Anaesth 2007;98:216e24.
21. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, et al. Vaso-
pressin versus norepinephrine infusion in patients with septic shock. N Engl J
Med 2008;358:877e87.
22. Torgersen C, Dunser MW, Wenzel V, Jochberger S, Mayr V, Schmittinger CA,
et al. Comparing two different arginine vasopressin doses in advanced vaso-
dilatory shock: a randomized, controlled, open-label trial. Intens Care Med
2010;36:57e65.
23. Maybauer MO, Walley KR. Best vasopressor for advanced vasodilatory shock:
should vasopressin be part of the mix? Intens Care Med 2010;36:1484e7.
24. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al.
Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359e67.
25. Wilmer A, van den Berghe G. Management of sepsis. N Engl J Med
2007;356:178.
26. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ,
Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med
2006;354:449e61.
27. Russell JA. Management of sepsis. New Engl J Med 2006;355:1699e713.
28. Raghavan M, Marik PE. Management of sepsis during the early “golden hours”.
J Emer Med 2006;31:185e99.
29. Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat
Rev Genet 2001;2:967e77.
30. Wong HR, Wheeler DS, Tegtmeyer K, Poynter SE, Kaplan JM, Chima RS, et al.
Toward a clinically feasible gene expression-based subclassification strategy
for septic shock: proof of concept. Crit Care Med 2010;38:1955e61.
77
31. Hotchkiss RS, Tinsley KW, Swanson PE, Chang KC, Cobb JP, Buchman TG, et al.
Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc
Natl Acad Sci U S A 1999;96:14541e6.
32. Kawasaki M, Kuwano K, Hagimoto N, Matsuba T, Kunitake R, Tanaka T, et al.
Protection from lethal apoptosis in lipopolysaccharide-induced acute lung
injury in mice by a caspase inhibitor. Am J Pathol 2000;157:597e603.
33. Méthot N, Huang JQ, Coulombe N, Vaillancourt JP, Rasper D, Tam J, et al.
Differential efficacy of caspase inhibitors on apoptosis markers during sepsis in
rats and implication for fractional inhibition requirements for therapeutics.
J Exp Med 2004;199:199e207.
34. Zingarelli B, Sheehan M, Wong HR. Nuclear factor-kappaB as a therapeutic
target in critical care medicine. Crit Care Med 2003;31:S105e11.
35. Uwe S. Anti-inflammatory interventions and NF-kappaB signaling: potential
applications and risks. Biochem Pharmacol 2008;75:1567e79.
36. Alvira CM, Abate A, Yang G, Dennery PA, Rabinovitch M. Nuclear factor-kappaB
activation in neonatal mouse lung protects against lipopolysaccharide-induced
inflammation. Am J Respir Crit Care Med 2007;175:805e15.
37. Gadjeva M, Tomczak MF, Zhang M, Wang YY, Dull K, Rogers AB, et al. A role for
NF-kappaB subunits p50 and p65 in the inhibition of lipopolysaccharide-
induced shock. J Immunol 2004;173:5786e93.
38. Li X, Cui X, Li Y, Fitz Y, Hsu L, Eichacker PQ. Parthenolide has limited effects on
nuclear factorkappaB increases and worsens survival in lipopolysacchardie-
challenged C57BL/6J mice. Cytokine 2006;33:299e308.
39. Su J, Li X, Cui X, Yi L, Fitz Y, Hsu L, et al. Ethyl pyruvate decreased early nuclear
factor-kappB levels but worsened survival in lipopolysaccharide-challenged
mice. Crit Care Med 2008;36:1059e67.
40. Pinto BB, Rehberg S, Ertmer C, Westphal M. Role of levosimendan in sepsis and
septic shock. Curr Opin Anaesthesiol 2008;21:168e77.
41. du Toit EF, Genis A, Opie LH, Pollesello P, Lochner A. A role for the RISK
pathway and K(ATP) channels in pre and postconditioning induced by levo-
simendan in the isolated guinea pig heart. Br J Pharmacol 2008;154:41e50.
42. Oldner A, Konrad D, Weitzberg E, Rudehill A, Rossi P, Wanecek M. Effects of
levosimendan, a novel inotropic calcium-sensitizing drug, in experimental
septic shock. Crit Care Med 2001;29:2185e93.
43. Barraud D, Faivre V, Damy T, Welschbillig S, Gayat E, Heymes C, et al. Levosi-
mendan restores both systolic and diastolic cardiac performance in
lipopolysaccharide-treated rabbits: comparison with dobutamine and milri-
none. Crit Care Med 2007;35:1376e82.
44. Fries M, Ince C, Rossaint R, Bleilevens C, Bickenbach J, Rex S, et al. Levosi-
mendan but not norepinephrine improves microvascular oxygenation during
experimental septic shock. Crit Care Med 2008;36:1886e91.
45. Kersten JR, Montgomery MW, Pagel PS, Warltier DC. Levosimendan, a new
positive inotropic drug, decreases myocardial infarct size via activation of
K(ATP) channels. Anesth Analg 2000;90:5e11.
46. Morelli A, De Castro S, Teboul JL, Singer M, Rocco M, Conti G, et al. Effects of
levosimendan on systemic and regional hemodynamics in septic myocardial
depression. Intens Care Med 2005;31:638e44.
47. Morelli A, Teboul JL, Maggiore SM, Vieillard-Baron A, Rocco M, Conti G, et al.
Effects of levosimendan on right ventricular afterload in patients with acute
respiratory distress syndrome: a pilot study. Crit Care Med 2006;34:
2287e93.
48. Uematsu S, Akira S. Toll-like receptors and type I interferons. J Biol Chem
2007;282:15319e23.
49. Hoebe K, Beutler B. LPS, dsRNA and the interferon bridge to adaptive immune
responses: Trif, Tram, and other TIR adaptor proteins. J Endotoxin Res
2004;10:130e6.
50. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell
differentiation by IFN-alpha in systemic lupus erythematosus. Science
2001;294:1540e3.
51. Muller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, et al.
Functional role of type I and type II interferons in antiviral defense. Science
1994;264:1918e21.
52. O’Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, et al.
Type I interferon production enhances susceptibility to Listeria monocytogenes
infection. J Exp Med 2004;200:437e45.
53. Mancuso G, Midiri A, Biondo C, Beninati C, Zummo S, Galbo R, et al. Type I IFN
signaling is crucial for host resistance against different species of pathogenic
bacteria. J Immunol 2007;178:3126e33.
54. Kelly-Scumpia KM, Scumpia PO, Delano MJ, Weinstein JS, Cuenca AG, Wynn JL,
et al. Type I interferon signaling in hematopoietic cells is required for survival
in mouse polymicrobial sepsis by regulating CXCL10. J Exp Med
2010;2010(207):319e26.
55. Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, et al.
Functional roles for C5a receptors in sepsis. Nat Med 2008;14:551e7.