Pathophysiology and treatment of septic shock.
The New England Journal of Medicine (2003)
Available from www.ncbi.nlm.nih.gov
or
Abstract
The mortality from septic shock continues to range between 40% to 60% despite advances in cardiovascular support and antibiotic therapy. Impairment of host defenses predisposes to the development of both severe infection and septic shock. The activation of a myriad of cellular and plasma mediators by microbial toxins produces the systemic and metabolic manifestations of sepsis. The clinical presentation includes characteristic clinical, hemodynamic, and laboratory abnormalities. Multiple organ systems are involved during septic shock, with outcome dependent on the circulatory response and the development of sequential organ failures. Initial resuscitation is directed at restoring tissue perfusion with fluids and vasoactive drugs, guided by assessment of the patient's hemodynamic status. Identification of the site of infection and choice of appropriate antibiotics are critical to the success of therapy. Newer therapeutic modalities include immunologic interventions that attenuate mediator activity and modulate the immune response. Pharmacologic therapies are also being developed that are aimed at blocking the actions of specific mediators.
Author-supplied keywords
Available from www.ncbi.nlm.nih.gov
Page 1
Pathophysiology and treatment of septic shock.
review article
The
new england journal
of
medicine
n engl j med
348;2
www.nejm.org january
9, 2003
138
medical progress
The Pathophysiology and Treatment of Sepsis
Richard S. Hotchkiss, M.D., and Irene E. Karl, Ph.D.
From the Departments of Anesthesiology
(R.S.H.), Medicine (R.S.H., I.E.K.), and
Surgery (R.S.H.), Washington University
School of Medicine, St. Louis. Address re-
print requests to Dr. Hotchkiss at the De-
partment of Anesthesiology, Washington
University School of Medicine, Campus
Box 8054, St. Louis, MO 63110, or at
hotch@morpheus.wustl.edu.
epsis is the leading cause of death in critically ill patients in
the United States. Sepsis develops in
750,000 people annually, and more than 210,000 of them die.
1,2
After numerous
unsuccessful trials of antiinflammatory agents in patients with sepsis, investigators
doubted that mortality could be decreased. Advances in unraveling the pathophysiolo-
gy and genetic basis for the host response to sepsis have changed the prevailing under-
standing of the syndrome, and several therapies have demonstrated surprising effica-
cy. In this article, we examine evolving concepts of sepsis and discuss new and
potential therapies.
The prevailing theory has been that sepsis represents an uncontrolled inflammatory
response.
3-5
Lewis Thomas popularized this notion when he wrote that “the micro-
organisms that seem to have it in for us...turn out...to be rather more like
bystanders....It is our response to their presence that makes the disease. Our arse-
nals for fighting off bacteria are so powerful...that we are more in danger from
them than the invaders.”
6
A consensus conference defined sepsis as “the systemic in-
flammatory response syndrome that occurs during infection.”
3
Numerous trials were
conducted of agents that block the inflammatory cascade — corticosteroids,
7
antien-
dotoxin antibodies,
8
tumor necrosis factor (TNF) antagonists,
9,10
interleukin-1–recep-
tor antagonists,
11
and other agents.
12
The failure of antiinflammatory agents led inves-
tigators to question whether death in patients with sepsis results from uncontrolled
inflammation.
4,13-15
Clinical trials of treatments for sepsis are difficult because of the
heterogeneity of patients and the high rates of culture-negative sepsis. Interpretation is
complicated, because the analysis of outcomes generates post hoc stratifications that
have not been prospectively defined.
The theory that death from sepsis was attributable to an overstimulated immune
system was based on studies in animals that do not seem to reflect the clinical picture
in humans.
16-18
These studies used large doses of endotoxin or bacteria; consequently,
levels of circulating cytokines such as tumor necrosis factor
a
(TNF-
a
) were exponen-
tially higher in animals than they are in patients with sepsis.
17
In these studies, the an-
imals died from “cytokine storm,” and compounds and macromolecules that block
these mediators improved survival.
16-18
In certain forms of sepsis — for example, meningococcemia — circulating TNF-
a
levels are high and correlate with mortality.
19,20
Of 55 children with severe infectious
purpura (32 of them with
Neisseria meningitidis
infection), 91 percent had elevated levels
of circulating TNF-
a
.
19
Nevertheless, studies have shown that the frequency of an ex-
aggerated systemic inflammatory response is lower than it was originally thought to
be.
21-24
Debets et al. reported that only 11 of 43 patients with sepsis had detectable cir-
culating TNF (limit of detection, 5 to 10 pg per milliliter).
21
In another study of 87 pa-
s
a disorder due to uncontrolled inflammation?
The
new england journal
of
medicine
n engl j med
348;2
www.nejm.org january
9, 2003
138
medical progress
The Pathophysiology and Treatment of Sepsis
Richard S. Hotchkiss, M.D., and Irene E. Karl, Ph.D.
From the Departments of Anesthesiology
(R.S.H.), Medicine (R.S.H., I.E.K.), and
Surgery (R.S.H.), Washington University
School of Medicine, St. Louis. Address re-
print requests to Dr. Hotchkiss at the De-
partment of Anesthesiology, Washington
University School of Medicine, Campus
Box 8054, St. Louis, MO 63110, or at
hotch@morpheus.wustl.edu.
epsis is the leading cause of death in critically ill patients in
the United States. Sepsis develops in
750,000 people annually, and more than 210,000 of them die.
1,2
After numerous
unsuccessful trials of antiinflammatory agents in patients with sepsis, investigators
doubted that mortality could be decreased. Advances in unraveling the pathophysiolo-
gy and genetic basis for the host response to sepsis have changed the prevailing under-
standing of the syndrome, and several therapies have demonstrated surprising effica-
cy. In this article, we examine evolving concepts of sepsis and discuss new and
potential therapies.
The prevailing theory has been that sepsis represents an uncontrolled inflammatory
response.
3-5
Lewis Thomas popularized this notion when he wrote that “the micro-
organisms that seem to have it in for us...turn out...to be rather more like
bystanders....It is our response to their presence that makes the disease. Our arse-
nals for fighting off bacteria are so powerful...that we are more in danger from
them than the invaders.”
6
A consensus conference defined sepsis as “the systemic in-
flammatory response syndrome that occurs during infection.”
3
Numerous trials were
conducted of agents that block the inflammatory cascade — corticosteroids,
7
antien-
dotoxin antibodies,
8
tumor necrosis factor (TNF) antagonists,
9,10
interleukin-1–recep-
tor antagonists,
11
and other agents.
12
The failure of antiinflammatory agents led inves-
tigators to question whether death in patients with sepsis results from uncontrolled
inflammation.
4,13-15
Clinical trials of treatments for sepsis are difficult because of the
heterogeneity of patients and the high rates of culture-negative sepsis. Interpretation is
complicated, because the analysis of outcomes generates post hoc stratifications that
have not been prospectively defined.
The theory that death from sepsis was attributable to an overstimulated immune
system was based on studies in animals that do not seem to reflect the clinical picture
in humans.
16-18
These studies used large doses of endotoxin or bacteria; consequently,
levels of circulating cytokines such as tumor necrosis factor
a
(TNF-
a
) were exponen-
tially higher in animals than they are in patients with sepsis.
17
In these studies, the an-
imals died from “cytokine storm,” and compounds and macromolecules that block
these mediators improved survival.
16-18
In certain forms of sepsis — for example, meningococcemia — circulating TNF-
a
levels are high and correlate with mortality.
19,20
Of 55 children with severe infectious
purpura (32 of them with
Neisseria meningitidis
infection), 91 percent had elevated levels
of circulating TNF-
a
.
19
Nevertheless, studies have shown that the frequency of an ex-
aggerated systemic inflammatory response is lower than it was originally thought to
be.
21-24
Debets et al. reported that only 11 of 43 patients with sepsis had detectable cir-
culating TNF (limit of detection, 5 to 10 pg per milliliter).
21
In another study of 87 pa-
s
a disorder due to uncontrolled inflammation?
Page 2
n engl j med
348;2
www.nejm.org january
9, 2003
medical progress
139
tients with sepsis, fewer than 10 percent had meas-
urable TNF-
a
or interleukin-1
b
.
22,23
Although cytokines are considered to be cul-
prits, they also have beneficial effects in sepsis.
Studies in an animal model of peritonitis demon-
strated that blocking TNF-
a
worsens surviv-
al.
25,26
Combination immunotherapy against
TNF-
a
and interleukin-1 receptors was fatal in a
neutropenic model of sepsis.
27
In clinical trials, a
TNF antagonist increased mortality.
9
The role of
TNF-
a
in combating infection has recently been
underscored by the finding that sepsis and other
infectious complications developed in patients with
rheumatoid arthritis who were treated with TNF
antagonists.
28
The debate about the merits of inhibiting cyto-
kines in patients with sepsis has been rekindled by
a recent trial that indicated that a subgroup of pa-
tients with sepsis who had therapy directed against
TNF-
a
had improved survival.
29
Also, a meta-analy-
sis of clinical trials of antiinflammatory agents in
patients with sepsis showed that although high
doses of antiinflammatory agents were generally
harmful in such patients, a subgroup of patients
(approximately 10 percent) benefited.
13
Advances in our understanding of cell-signal-
ing pathways that mediate the response to microbes
have demonstrated that the concept of blocking
endotoxin in order to prevent septic complications
may be simplistic. Cells of the innate immune sys-
tem recognize microorganisms and initiate respons-
es through pattern-recognition receptors called toll-
like receptors (TLRs).
30-32
Insight into the role of
TLRs in combating infection has been provided by
studies in C3H/HeJ mice,
30
which are resistant to
endotoxin because of a mutation in the toll-like re-
ceptor 4 gene (
TLR4
). Despite their resistance to
endotoxin, these mice have increased mortality with
authentic sepsis.
33,34
TLR4
mutations have been
identified in humans and may make persons more
susceptible to infection.
35
Therefore, although en-
dotoxin has deleterious effects, total blockade of en-
dotoxin may be detrimental. Reasons for the failure
of monoclonal antiendotoxin antibodies to improve
outcomes in trials involving patients with sepsis
are complex.
36
Patients with sepsis have features consistent with
immunosuppression, including a loss of delayed
hypersensitivity, an inability to clear infection, and
a predisposition to nosocomial infections.
37-39
One
reason for the failure of antiinflammatory strate-
gies in patients with sepsis may be a change in the
syndrome over time. Initially, sepsis may be charac-
terized by increases in inflammatory mediators; but
as sepsis persists, there is a shift toward an antiin-
flammatory immunosuppressive state.
38,39
There
is evidence of immunosuppression in sepsis from
studies showing that lipopolysaccharide-stimulat-
ed whole blood from patients with sepsis releases
markedly smaller quantities of the inflammatory cy-
tokines TNF-
a
and interleukin-1
b
than does that of
control patients.
40
The adverse sequelae of sepsis-
induced immunosuppression were reversed with
the administration of interferon-
g
in patients with
sepsis.
41
This immune stimulant restored macro-
phage TNF-
a
production and improved survival.
41
a shift to antiinflammatory cytokines
Activated CD4 T cells are programmed to secrete
cytokines with either of two distinct and antago-
nistic profiles.
42,43
They secrete either cytokines
with inflammatory (type 1 helper T-cell [Th1]) prop-
erties, including TNF-
a
, interferon-
g
, and interleu-
kin-2, or cytokines with antiinflammatory (type 2
helper T-cell [Th2]) properties — for example, in-
terleukin-4 and interleukin-10 (Fig. 1). The factors
that determine whether CD4 T cells have Th1 or Th2
responses are unknown but may be influenced by
the type of pathogen, the size of the bacterial inocu-
lum, and the site of infection.
42
Mononuclear cells
from patients with burns or trauma have reduced
levels of Th1 cytokines but increased levels of the
Th2 cytokines interleukin-4 and interleukin-10,
and reversal of the Th2 response improves survival
among patients with sepsis.
38,44
Other studies have
demonstrated that the level of interleukin-10 is in-
creased in patients with sepsis and that this level
predicts mortality.
43,45
anergy
Anergy is a state of nonresponsiveness to antigen.
T cells are anergic when they fail to proliferate or
secrete cytokines in response to their specific an-
tigens. Heidecke et al. examined T-cell function in
patients with peritonitis and found that they had de-
creased Th1 function without increased Th2 cyto-
kine production, which is consistent with anergy.
46
Defective T-cell proliferation and cytokine secretion
failure of the immune system?
mechanisms of immune
suppression in sepsis
348;2
www.nejm.org january
9, 2003
medical progress
139
tients with sepsis, fewer than 10 percent had meas-
urable TNF-
a
or interleukin-1
b
.
22,23
Although cytokines are considered to be cul-
prits, they also have beneficial effects in sepsis.
Studies in an animal model of peritonitis demon-
strated that blocking TNF-
a
worsens surviv-
al.
25,26
Combination immunotherapy against
TNF-
a
and interleukin-1 receptors was fatal in a
neutropenic model of sepsis.
27
In clinical trials, a
TNF antagonist increased mortality.
9
The role of
TNF-
a
in combating infection has recently been
underscored by the finding that sepsis and other
infectious complications developed in patients with
rheumatoid arthritis who were treated with TNF
antagonists.
28
The debate about the merits of inhibiting cyto-
kines in patients with sepsis has been rekindled by
a recent trial that indicated that a subgroup of pa-
tients with sepsis who had therapy directed against
TNF-
a
had improved survival.
29
Also, a meta-analy-
sis of clinical trials of antiinflammatory agents in
patients with sepsis showed that although high
doses of antiinflammatory agents were generally
harmful in such patients, a subgroup of patients
(approximately 10 percent) benefited.
13
Advances in our understanding of cell-signal-
ing pathways that mediate the response to microbes
have demonstrated that the concept of blocking
endotoxin in order to prevent septic complications
may be simplistic. Cells of the innate immune sys-
tem recognize microorganisms and initiate respons-
es through pattern-recognition receptors called toll-
like receptors (TLRs).
30-32
Insight into the role of
TLRs in combating infection has been provided by
studies in C3H/HeJ mice,
30
which are resistant to
endotoxin because of a mutation in the toll-like re-
ceptor 4 gene (
TLR4
). Despite their resistance to
endotoxin, these mice have increased mortality with
authentic sepsis.
33,34
TLR4
mutations have been
identified in humans and may make persons more
susceptible to infection.
35
Therefore, although en-
dotoxin has deleterious effects, total blockade of en-
dotoxin may be detrimental. Reasons for the failure
of monoclonal antiendotoxin antibodies to improve
outcomes in trials involving patients with sepsis
are complex.
36
Patients with sepsis have features consistent with
immunosuppression, including a loss of delayed
hypersensitivity, an inability to clear infection, and
a predisposition to nosocomial infections.
37-39
One
reason for the failure of antiinflammatory strate-
gies in patients with sepsis may be a change in the
syndrome over time. Initially, sepsis may be charac-
terized by increases in inflammatory mediators; but
as sepsis persists, there is a shift toward an antiin-
flammatory immunosuppressive state.
38,39
There
is evidence of immunosuppression in sepsis from
studies showing that lipopolysaccharide-stimulat-
ed whole blood from patients with sepsis releases
markedly smaller quantities of the inflammatory cy-
tokines TNF-
a
and interleukin-1
b
than does that of
control patients.
40
The adverse sequelae of sepsis-
induced immunosuppression were reversed with
the administration of interferon-
g
in patients with
sepsis.
41
This immune stimulant restored macro-
phage TNF-
a
production and improved survival.
41
a shift to antiinflammatory cytokines
Activated CD4 T cells are programmed to secrete
cytokines with either of two distinct and antago-
nistic profiles.
42,43
They secrete either cytokines
with inflammatory (type 1 helper T-cell [Th1]) prop-
erties, including TNF-
a
, interferon-
g
, and interleu-
kin-2, or cytokines with antiinflammatory (type 2
helper T-cell [Th2]) properties — for example, in-
terleukin-4 and interleukin-10 (Fig. 1). The factors
that determine whether CD4 T cells have Th1 or Th2
responses are unknown but may be influenced by
the type of pathogen, the size of the bacterial inocu-
lum, and the site of infection.
42
Mononuclear cells
from patients with burns or trauma have reduced
levels of Th1 cytokines but increased levels of the
Th2 cytokines interleukin-4 and interleukin-10,
and reversal of the Th2 response improves survival
among patients with sepsis.
38,44
Other studies have
demonstrated that the level of interleukin-10 is in-
creased in patients with sepsis and that this level
predicts mortality.
43,45
anergy
Anergy is a state of nonresponsiveness to antigen.
T cells are anergic when they fail to proliferate or
secrete cytokines in response to their specific an-
tigens. Heidecke et al. examined T-cell function in
patients with peritonitis and found that they had de-
creased Th1 function without increased Th2 cyto-
kine production, which is consistent with anergy.
46
Defective T-cell proliferation and cytokine secretion
failure of the immune system?
mechanisms of immune
suppression in sepsis
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