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E Sepsis

75

Sepsis, Severe Sepsis,


and Septic Shock
Robert S. Munford and Anthony F. Suffredini

SHORT VIEW SUMMARY


Definitions

Sepsis is the bodys harmful systemic reaction


to microbial infection.
Severe sepsis is organ dysfunction complicating
infection; if hypotension is present, it can be
reversed with intravenous fluids.
Septic shock is sepsis-associated hypotension
that requires pharmacologic reversal.

Epidemiology

Most commonly affected persons are the very


young and older adults.
Major outcome determinants are age and
comorbidity, especially immunosuppressive
illness.

Microbiology

Virtually any microbe can trigger sepsis.


Most cases today occur in previously
morbid individuals and are caused by
opportunists from the patients own
microbiome.

Diagnosis

Usual signs: tachycardia, tachypnea,


leukocytosis or leukopenia, fever or
hypothermia
Frequent, suggestive: thrombocytopenia,
lactatemia, delirium, respiratory alkalosis,
hyperbilirubinemia

INTRODUCTION AND DEFINITIONS

Sepsis, severe sepsis, and septic shock are the terms most often used
to describe the bodys harmful systemic responses to infection. Lacking
a precise biochemical characterization of the syndromes or a certain
understanding of their causation, experts have defined them by applying clinical and laboratory findings to a likely framework of pathogenesis. For 2 decades, most authors and clinicians used definitions
developed by a consensus committee of experts in 19921 and revised
in 2001.2 The systemic inflammatory response syndrome (SIRS) was
defined by the presence of two or more acute findings (tachycardia,
leukocytosis or leukopenia, fever or hypothermia, tachypnea); if SIRS
was thought to be caused by presumed or proven infection, the patient
was said to have sepsis (from the Greek for putrefaction). In the
most recent version of consensus definitions, published in 2012 by the
Surviving Sepsis Campaign, the SIRS nomenclature was discarded in
favor of much more fluid criteria.3 Sepsis is a systemic, deleterious
host response to infection leading to severe sepsis (acute organ dysfunction secondary to documented or suspected infection) and septic
shock (severe sepsis plus hypotension not reversed with fluid resuscitation). A patient is said to be septic if infection is documented or
suspected and some additional criteria are met (Table 75-1).
The SIRS definitions were derived by experts who assumed that
even the early systemic responses to infection, such as tachycardia,
leukocytosis, and fever, are inflammatory. We characterize SIRS as an
abnormal generalized inflammatory reaction in organs remote from
the initial insult.4 Many authors criticized these definitions, noting
that the criteria for SIRS are both nonspecific and insufficiently predictive. The 2001 definitions2 attempted to provide a more comprehensive
overview of the clinical manifestations of sepsis by considering predisposing factors (i.e., comorbidities), infection characteristics (organism,
virulence, sensitivity to antimicrobial drugs, site of infection), host
responses (clinical and laboratory markers), and types and degree of
organ dysfunction (i.e., laboratory and functional correlates). A large
retrospective analysis published in 2012 found that both the 1992
and 2001 consensus definitions were highly sensitive but that the
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Therapy

Prompt administration of antimicrobial drugs


that can kill the patients offending microbe
(see Table 75-4)
Intravenous fluids and pressor support as
needed
Source control: eliminating the local site of
infection, usually with surgery or removal of
indwelling device
Supportive care

Prevention

Hospital infection control


Vaccination

specificity of the newer definition was only 61%.5 The fact that these
definitions were still commonly used after almost 2 decades reflects
several points: they seemed to describe a clinically-observable continuum,6,7 they were easy to use, and, perhaps most important, a more
precise or clinically helpful set of definitions has not appeared. The
popularity of the definitions and the changes incorporated into the
most recent version reflect an important deficiency: there are still no
reliable biochemical (laboratory-based) criteria for knowing when a
patients systemic responses to infection have become harmful. The
operational definitions for severe sepsis and septic shock have
nonetheless become standard nomenclature and will be used throughout this chapter.

EPIDEMIOLOGY

Estimates of the incidence of severe sepsis and septic shock are


compromised by the absence of both standardized definitions and
population-based prospective cohort studies.8 Most of the available
estimates are based on hospital discharge diagnoses, which do not use
standardized definitions, and the results may differ substantially when
different recovery methods are used.9 A review of data in the National
Hospital Discharge Survey (United States) found that the incidence of
sepsis increased by almost fourfold to 240 cases per 100,000 population
per year during the interval 1979 to 2000.10 The incidence was higher
in men than in women and in nonwhite persons than in white persons.
Over the same period, the in-hospital case-fatality rate for patients
with a sepsis-related diagnosis fell from 28% to 18%. A newer analysis,
from the Nationwide Inpatient Sample (United States), found that the
incidence of severe sepsis increased from 200 cases per 100,000 population 18 years of age or older in 2003 to 300 cases per 100,000 in 2007,
or 711,736 cases in the United States.11 The authors of the report stated
that the increase in the number of hospitalizations for severe sepsis
likely represents changes in documentation and hospital coding practice that could bias efforts to conduct national surveillance.11
Although the median age for patients with a sepsis-related hospital
discharge diagnosis is approximately 60 years, the attack rate is very

914.e1

KEYWORDS

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

adrenal insufficiency; bacteremia; coagulopathy; delirium;


disseminated intravascular coagulation; endotoxemia; endotoxin;
glycolysis; lactate; LPS; mitochondria; septic shock; sepsis; severe
sepsis

915
TABLE 75-1 Definitions
DEFINITION

COMMENT

Infection

Presence of
microorganisms in a
normally sterile site

May be confused with


colonization, which is
the presence of
microorganisms on an
epithelial surface

Bacteremia

Cultivatable bacteria in the


bloodstream

May be transient and


inconsequential;
inconsistent correlation
with severe sepsis

Systemic
inflammatory
response
syndrome
(SIRS)

Old term for the systemic


response to a wide
range of stresses.
Criteria included two or
more of the following:
Temperature >38 C or
<36 C
Heart rate >90 beats/min
Respiratory rate >20
breaths/min or PaCO2
<32mmHg
WBC >12,000 cells/mm3
or <4,000 cells/mm3,
or >10% immature
(band) forms

A potentially misleading
term. The evidence that
the bodys early responses
to infection cause
systemic inflammation
is controversial. See
Pathogenesis in text.

Sepsis

The systemic response to


infection. If associated
with proven or clinically
suspected infection, SIRS
was called sepsis.1

With the exceptions of


leukopenia and
hypothermia, these
changes are among the
bodys normal systemic
responses to infection and
do not necessarily imply a
poor prognosis
In clinical parlance, the term
septic is often used
informally to describe
patients with severe sepsis
or septic shock

Hypotension

A systolic blood pressure


of <90mmHg, MAP
<70mmHg, or a
reduction of >40mmHg
from baseline

To be considered sepsisrelated, hypotension must


have no other cause

Severe sepsis

Sepsis associated with


dysfunction of organ(s)
distant from the site of
infection, hypoperfusion,
or hypotension. The
term sepsis syndrome
had a similar definition.

Abnormalities may include


lactic acidosis, oliguria,
acutely altered mental
status, and acute lung
injury.2 To be considered
severe sepsis, hypotension
must be reversible by
administering fluids.
Organ dysfunction may
be defined according to
Marshall etal,446 the SOFA
score,447 or the Surviving
Sepsis Campaign criteria.3

Septic shock

Sepsis with hypotension


that, despite adequate
fluid resuscitation,
requires pressor therapy.
In addition, there are
perfusion abnormalities
that may include lactic
acidosis, oliguria, altered
mental status, and acute
lung injury.

If septic shock lasts for


>1hr and does not
respond to pressor
administration, the term
refractory septic shock is
often used

MAP, mean arterial pressure; PaCO2, partial pressure of arterial carbon dioxide;
SOFA, sequential organ failure assessment; WBC, white blood cell count.

high among infants (more than 500 cases/100,000 population/year),


with low-birth-weight newborns experiencing particularly high risk.12
Sepsis-related mortality decreases after the first year of life and then
increases gradually with increasing age. Age and comorbidity are major
determinants of outcome: in persons with no known comorbidity, the
case-fatality rate is less than 10% from age 3 to 5 years through the
third decade, after which it slowly increases to reach approximately
60% by the seventh decade.13 In all age groups, mortality is strongly
enhanced by comorbid conditions such as cancer, diabetes, and
immunosuppression.

PATHOGENESIS

Much of what is known about sepsis pathogenesis has been learned


using animal models. None of these models completely mimics human
responses to infection.18,19 The usefulness of mouse models has recently
been challenged by a report that humans and mice have strikingly different systemic (blood leukocyte) responses to endotoxin, trauma, and
burn injury.20 Mouse models have been extraordinarily helpful for dissecting the contributions of individual genes and molecular pathways
to various immune responses, and the responses of individual cell
types (e.g., macrophages) may be quite similar in humans and laboratory mice. Human and murine systemic responses to acute stress, such
as a bolus injection of endotoxin, may be strikingly different in many
respects, but not all.21 Understanding these differences is essential for
translating the results of animal models into clinical research and
practice.

Early Host Responses to Infection


Local Defenses: Walling Off and Killing
Invading Microbes

When a microbe breaches an epithelial barrier and enters the underlying tissue, it quickly encounters tissue-resident macrophages, mast
cells, and dendritic cells. These cells sense the invader and react by
secreting mediators that mobilize the local inflammatory response.
Their sensory ability is conferred by protein receptors that bind to
highly conserved microbial molecules. The Toll-like receptor system
for the lipopolysaccharides (LPS) made by some gram-negative bac
teria is perhaps best understood, but others exist for sensing the presence of bacterial peptidoglycan, DNA, lipopeptides, flagella, viral
double-standard RNA, and other conserved microbial molecules.22,23
In the case of LPS, a plasma protein (LPS-binding protein [LBP])
can transfer LPS from bacterial membranes to another host protein,
CD14, which is expressed on the surfaces of phagocytes. CD14 then
passes the LPS to a signaling complex that has two members: an extracellular protein called myeloid differentiation protein-2 (MD-2), which
binds the lipid A moiety of LPS,24 and the transmembrane receptor
protein, Toll-like receptor 4 (TLR4). LPS binding to MD-2 triggers
dimerization of TLR4; this transmits the LPS recognition signal to
the interior of the cell, where signal transduction and gene tran
scription pathways promote the production and/or secretion of numerous molecules that mediate the inflammatory response (Fig. 75-1).
These mediators include cytokines (in particular, tumor necrosis factor
[TNF], interleukin [IL]-12), chemokines (IL-8, macrophage inflammatory protein [MIP]-1), lipid mediators (prostaglandins, leukotrienes),
and other mediators, and they result in the familiar elements of local

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

TERM

In surveys performed in intensive care units (ICUs) in the United


States and Europe during the 1990s and 2000s, approximately 70% to
80% of the cases of severe sepsis in adults occurred in individuals who
were already hospitalized for another reason.14-16 In 30% to 50% of the
cases in these and other series, a definite microbial etiology was not
found.6,14,16,17 Moreover, the microorganism cultured from blood or an
infected local site was often one that does not usually cause disease in
otherwise healthy people (in most cases, it was from the patients
microbiome and may have been acquired during hospitalization),14,17
and in approximately one fifth of the patients, more than one isolate
was found (polymicrobial infection).
Respiratory infections most often induce severe sepsis, followed by
abdominal and urinary tract infections. Severe sepsis caused by classic
bacterial pathogens, such as Neisseria meningitidis or Streptococcus
pyogenes, is much less frequently encountered today than is sepsis triggered by commensal microbes that infect individuals whose epithelial
barriers or other antimicrobial defenses have been compromised by
injury or illness. Although for many years gram-negative bacteria were
isolated from the majority of culture-positive patients with severe
sepsis, the fraction of cases associated with gram-positive bacteria has
steadily increased, and now Staphylococcus aureus, coagulase-negative
staphylococci, and enterococci account for approximately 30% to 50%
of the cases in most clinical series. Another recent trend is the emergence of fungi (in particular, Candida spp.) as etiologic agents of severe
sepsis; in some recent series, Candida spp. have caused 5% to 20% of
the microbiologically documented cases.15,16

916
LPS

Part II Major Clinical Syndromes

PG, LP
TLR2/1 TLR2/6

Sensors for bacterial wall structures

Muramyl peptides
NOD1 CARD
NOD2

TLR4 MD-2

MyD88

NOD

CARD NOD
TRIF

RICK

AP-1 NF-B

Proinflammatory
mediators

IRF1 IRF3/7

Pro-IL1/18

TLR3

endosome
TLR7, 8, 9

IFN-, -

Caspase-1
CARD

MyD88
Sensors for nucleic acids

CARD PYD ASC


Mature IL-1, IL-18
NALP3

PYD NOD

Danger (stress) sensors

FIGURE 75-1 Mechanisms that sense bacteria and initiate host responses. Several cell-surface Toll-like receptors (TLRs) sense conserved bacterial
cell wall components. For example, most bacterial lipopolysaccharides that have a hexa-acyl, bis-phosphorylated lipid A structure that binds to MD-2,
inducing a conformational change in TLR4. Via its cytosolic TIR domain, TLR4 initiates transmembrane signaling through two pathways: the MyD88dependent path that leads to activation of NF-B and production of tumor necrosis factor (TNF) and the slower MyD88-independent, TRIF-dependent
pathway that increases interferon- (IFN-) synthesis. The TRIF pathway may be activated after TLR4 has been internalized in an endosome and engaged
TRAM (not shown). Peptidoglycan (PG) and bacterial lipoproteins (LP) interact with TLR2, which oligomerizes with TLR6 or TLR1 to form signaling complexes that activate the MyD88-dependent pathway. Other MyD88-dependent sensors are TLR5, which recognizes bacterial flagellin; TLR9, which senses
DNA with unmethylated CpG motifs; and TLR7 and TLR8, which recognize single-stranded RNA. TLRs 7, 8, and 9 are found within endosomes, as is TLR3,
which recognizes double-stranded RNA and signals via TRIF to induce interferon IFN- production but also can elicit TNF via TRAF2. The members of the
TLR family of transmembrane proteins thus sense diverse microbial molecules and use both combinatorial interactions and different, yet overlapping,
downstream pathways to activate the inflammatory response. A second family of intracellular sensory proteins exists for components of peptidoglycan.
Nucleotide oligomerization domains NOD1 and NOD2 recognize diaminopimelic acid (only found in gram-negative peptidoglycan) and muramyl dipeptide
(found in both gram-negative and gram-positive peptidoglycan), respectively, and initiate signaling via RICK to activate NF-B. Proteins that contain a
NOD may have one or more CARDs, linking them structurally to the members of the inflammasome, intracellular stress sensors that activate caspase-1,
the enzyme that cleaves pro-IL-1 and pro-IL-18 to release the mature cytokines. Not shown are cytosolic sensors for RNA and DNA. See Baccala and
co-workers448 for details. AP-1, activator protein-1; ASC, apoptosis-associated speck-like protein containing a CARD; CARD, caspase activation and recruitment domain; IL, interleukin; IRF, interferon regulatory factor; LP, lipoprotein; LPS, lipopolysaccharide; LRR, leucine-rich repeat; MD-2, myeloid differentiation protein-2 (also called lymphocyte antigen 96 [LY96]); MyD88, myeloid differentiation primary response gene 88; NALP3, NACHT-LRR-PYD
domains-containing protein 3; NLRP, nucleotide-binding oligomerization domain leucine-rich repeatcontaining receptors; PG, peptidoglycan; PYD, pyrin
domain; RICK, receptor-interacting serine/threonine kinase; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptors; TRAF2, TNF receptor-associated factor
2; TRAM, Toll-like receptor 4 adaptor molecule; TRIF, TIR domain-containing adaptor-inducing interferon-). (Modified from Ishi KJ, Koyama S, Nakagawa
A, etal. Host innate immune receptors and beyond: making sense of microbial infections. Cell Host Microbe. 2008;3:352-363.)

inflammation: increased capillary permeability and blood flow, infiltration of neutrophils, and pain. In addition, local deposition of fibrin,
initiated by the expression of tissue factor on activated macrophages
and endothelial cells, helps wall off the infected tissue and, along with
vasoconstriction, provides an important impediment to bloodstream
invasion.
Although neutrophils circulate in the bloodstream, they carry out
phagocytosis largely in tissue spaces, where they can attach to extracellular matrix, spread out, get traction, and ingest. They also may die and
expel strands of DNA to form neutrophil extracellular traps (NETs).
Extracellular neutrophil DNA, decorated with antimicrobial proteins,
such as histones, myeloperoxidase, cathepsin G, and neutrophil elastase, has been shown to kill a wide variety of microbes.25 Because
phagocytes may also release reactive oxygen species (ROS; superoxide,
hydrogen peroxide) and the other contents of their lysosomes as they

eat, limiting this activity to local tissues minimizes the release of digestive enzymes and oxidants into the circulating blood. The major inherited mechanisms for killing microbes in the blood are soluble molecules:
the mannose-binding lectin and C-reactive protein (CRP) pathways
for activating complement, the alternative complement pathway, antibacterial proteins (such as bactericidal permeability-increasing protein
[BPI]), and natural immunoglobulin M (IgM) antibodies. Increased
capillary permeability allows these molecules to diffuse into tissues
where there is local inflammation.
In most instances, invading microbes are eliminated by phagocytes,
complement, antimicrobial peptides, NETs, and perhaps natural antibodies, and the invaded tissue returns to normal. These rapidlyactivated, broadly-applicable host defenses are hardwired in the
genome. They have been collectively called innate immune mechanisms to distinguish them from the acquired mechanisms that

917
TABLE 75-2 Innate and Acquired Immunity
Innate Immunity
Senses microbes through proteins that bind highly conserved microbial
molecules (e.g., lipopolysaccharide, peptidoglycan)

Leukocytosis

Mobilizes neutrophils into the circulation

Hardwired, that is, inherited in the genome; shaped by evolution

Tachycardia

Increases cardiac output, blood flow to injured tissue

Responds rapidly to microbial invasion

Fever

Elements: mannose-binding lectin, alternative complement pathway, natural


antibodies (gene rearrangements present at birth), pattern-recognition
proteins (e.g., LBP, MBP), cellular sensors (Toll-like receptors, NODs,
inflammasome proteins), the professional phagocytes, mast cells, natural
killer cells, Th17 cells

Raises core temperature; peripheral vasoconstriction


shunts blood flow to injured tissue. Occurs much
more often when infection is the trigger for systemic
responses.

Acute-Phase Responses (Categorized According to Possible


Roles in Defense)

Acquired Immunity

Anti-infective

Increases synthesis of complement factors, microbe


pattern-recognition molecules (mannose-binding
lectin, LBP, CRP, CD14, others)
Sequesters iron (lactoferrin, hepcidin) and zinc
(metallothionein)

Anti-inflammatory

Releases anti-inflammatory neuroendocrine hormones


(cortisol, ACTH, epinephrine, -MSH)
Increases synthesis of proteins that help prevent
inflammation within the systemic compartment
Cytokine antagonists (IL-1Ra, sTNF-Rs)
Anti-inflammatory mediators (e.g., IL-4, IL-6, IL-6R,
IL-10, IL-13, TGF-)
Protease inhibitors (e.g., 1-antiprotease)
Antioxidants (haptoglobin)
Reprograms circulating leukocytes (epinephrine, cortisol,
PGE2, ? other factors)

Procoagulant

Walls off infection, prevents systemic spread


Increases synthesis or release of fibrinogen, PAI-1, C4b
Decreases synthesis of protein C, antithrombin III

Metabolic

Preserves euglycemia, mobilizes fatty acids, amino acids


Epinephrine, cortisol, glucagon, cytokines

Thermoregulatory

Inhibits microbial growth


Fever

Recognizes microbial epitopes using T- and B-cell receptors cellular and


humoral immunity
Requires gene rearrangements during the life of the individual
Develops slowly after microbial invasion
Protects the body from subsequent exposure to same and some related
(cross-reactive) microbes
Is the basis for vaccine-induced immunity
Elements: antibodies, cytotoxic and helper T cells
LBP, LPS-binding protein; MBP, mannose-binding protein; NODs, nucleotide
oligomerization domains.

develop more slowly and use gene rearrangements to achieve exquisite


specificity in the recognition of foreign molecules (Table 75-2).26
Shaped by evolution, the innate system normally provides effective
protection from the hosts commensal flora and from those pathogens
that can be sensed via innate immune receptors. The innate defenses
are significantly less effective toward those pathogens that escape
recognition by the host. For example, Yersinia pestis adapts to grow
at mammalian body temperature by modifying its lipid A so that it
can no longer be sensed by MD-2TLR4. Engineering Y. pestis to
make it produce LPS that activates host cells via TLR4 rendered the
bacteria nonpathogenic in mice.27 Avoiding host recognition by producing a nonrecognizable lipid A is probably a key feature of the pathogenesis of plague, a disease in which bacteria grow to high density in
blood. The same phenomenon has been shown for other gram-negative
bacteria, including another designated biothreat agent, Francisella
tularensis.28
Remarkably, many innate immune mechanisms may become nonessential for host defense as adaptive immune defenses mature with
age.29,30 In contrast, activation of inflammation by innate immune
mechanisms plays a major role in the pathogenesis of sepsis throughout life. In addition to the TLR-initiated pathways for mobilizing host
defenses, which can be activated by both microbial and endogenous
molecules (e.g., high-mobility group box-1 protein [HMGB-1], highmobility group nucleosome-binding1 protein [HMGNB-1]),31 and
certain glycosphingolipids32), there are networks that sense microbial
and/or endogenous ligands via nucleotide oligomerization domain
(NOD) proteins (see Fig. 75-1). NOD1 and NOD2 are cytosolic sensors
for bacterial peptidoglycan fragments, whereas the constituents of the
intracellular inflammasome respond to certain endogenous ligands
(uric acid and adenosine triphosphate [ATP], for example) and regulate the release of IL-1 and IL-18 from cells by activating the cleavage
enzyme caspase-1. The roles played by the NOD proteins and inflammasome activation in the pathogenesis of severe sepsis are uncertain.
Most patients with inherited deficiencies or mutations in these proteins
have experienced local tissue inflammation without shock; monocytes
from patients with severe sepsis had low levels of caspase-1,33 and, in
another study, monocytes from patients with early sepsis had diminished messenger RNA (mRNA) levels for several inflammasome proteins, in keeping with the deactivation state noted for many other
monocyte genes (see later). On the other hand, one study noted a high
frequency of pyrin mutations in Turkish patients with severe sepsis,34
high monocyte pyrin mRNA levels were associated with death in pediatric patients,35 and mice deficient in caspase-1 were protected from
endotoxic shock.36 High levels of IL-18 were found in the plasma of
patients with acute respiratory distress syndrome (ARDS) and were
associated with ICU morbidity and mortality.37 Other studies found

ACTH, adrenocorticotropic hormone; CRP, C-reactive protein; IL, interleukin; LBP,


lipopolysaccharide-binding protein; MSH, melanocyte-stimulating hormone; PAI-1,
plasminogen activator inhibitor-1; PGE2, prostaglandin E2; sTNF-R, soluble tumor
necrosis factor receptor; TGF, transforming growth factor.

that caspase-1 also controls the production of HMGB-1, a proinflammatory alarmin, in mice.38

Early Systemic Responses: Keeping Infection


and Inflammation Localized

Much evidence supports the notion that the bodys systemic responses
to injury, infection, and other stresses generally suppress inflammation
within the bloodstream.39 Systemic responses enhance local defenses
by providing antimicrobial molecules (Table 75-3) and effector leukocytes (neutrophils, natural killer [NK] cells, monocytes), and they
prevent systemic damage by minimizing leukocyte-endothelial adhesion in uninvolved tissues and neutralizing chemical mediators (e.g.,
oxidants and proteases) that enter the blood from inflamed sites.
The early systemic responses are controlled principally by the brain
and prominently involve the liver. Their regulation has much in
common with that of the bodys systemic flight or fight reaction to
noninfectious stresses. They are important here because they are activated in response to stress and local infection and thus, in most
instances, they form the physiologic stage on which sepsis progresses
to severe sepsis and shock.

Central Nervous System Regulation of Systemic Responses

The central nervous system (CNS) receives news about microbial invasion via at least two routes. First, afferent impulses along nociceptive
and vagal nerves rapidly transmit signals from infected or inflamed
local tissues to the hypothalamus and brainstem, where they can activate the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic
nervous system, and the hypothalamic thermoregulatory center. Tolllike receptors have been identified in dorsal root,40 nociceptive,41
enteric,42 and trigeminal43 neurons and shown to respond to LPS in
mice.41 Second, bloodborne mediators (IL-1, TNF, IL-6, interferons
[IFNs], prostaglandin E2) can cross the blood-brain barrier and/or be
transported passively through the fenestrated capillaries in the cir
cumventricular organs to reach the hypothalamus.44 Remarkably, the

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

TABLE 75-3 Normal Systemic Responses to


Infection and Injury: Presumed Contributions to
Host Defense

Part II Major Clinical Syndromes

918
output of three major CNS efferent pathways (the HPA, the sympathetic nervous system, and the parasympathetic nervous system)
inhibits inflammation within the circulating blood (see later and Table
75-3), and the thermoregulatory center may enhance antimicrobial
activity by elevating body temperature.45

The Liver: Essential Roles in Systemic Responses


to Infection

The liver is anatomically situated to remove microorganisms that cross


the gut mucosa and enter the portal circulation; whether or not translocating microbes or their products enter the blood without first traveling through the lymphatic system is uncertain.46 The liver is nonetheless
the major filter for endotoxin and for nonopsonized particulate matter,
including many microbes, whereas the spleen is the major trap for
opsonized microorganisms. Impairment of the hepatic filter (e.g., by
cirrhosis) predisposes to bacteremic infections with Vibrio vulnificus
and certain other gut bacteria, and individuals with hyposplenism may
experience overwhelming bloodstream infections, usually with encapsulated bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae type b or Neisseria meningitidis). Whereas hepatic macrophages
(Kupffer cells) and sinusoidal endothelial cells can extract bacterial LPS
from blood and inactivate it,47 they also release mediators that induce
hepatocytes to produce many of the bodys acute-phase and metabolic
responses to injury and infection. IL-6, which is released by many types
of cells in response to injury or other stimuli, is the major trigger for
most elements of the acute-phase response; IL-1 may also be an
important stimulus.48 Whereas a minor population of circulating
monocytes (CD14+CD16+DR++) seems to account for most of the TNF
produced by blood cells,49 most of the TNF that circulates in the blood
after an intravenous (IV) injection of endotoxin is produced within the
splanchnic bed, largely in the liver.50
The liver may also play a role in the sensory system that informs the
CNS that microbes have invaded. In rodents, the ability of low intravenous doses of endotoxin or IL-1 to induce fever and activate the HPA
axis can be blocked by cutting or poisoning the hepatic branches of the
vagus nerve.51 Activation of vagal afferents by pyrogens is thought to
involve prostaglandin E2.51 Conversely, stimulation of vagus nerve
efferents suppresses endotoxin-induced TNF production in rats via a
cholinergic anti-inflammatory pathway that involves inhibition of
macrophage cytokine synthesis by acetylcholine.52 This inhibitory
action is most potent in the spleen,53 which lacks cholinergic innervation; in an unexpected twist, it was reported recently that adrenergic
stimulation induces T and B lymphocytes to synthesize and release
acetylcholine in the spleen and other tissues.54 Because much of the
TNF produced in response to intravenous challenge with endotoxin
arises from the splanchnic bed,50 which is richly innervated with cholinergic neurons and hosts choline acetyltransferaseexpressing T cells
in Peyers patches,55 acetylcholine may be very important for regulating
systemic responses to microbial agonists within the bloodstream.
The liver is thus a key player in the systemic response to infection
as a blood filter that collects and kills bloodborne microbes and inactivates bacterial endotoxins, as a listening station that senses low
concentrations of circulating cytokines and transmits this information
to the CNS, as a factory for the production of many (acute-phase) elements of the systemic response, and as a major site of infectionassociated metabolic adaptations.56

Acute Phase Responses

It is convenient to think of the acute systemic responses to injury,


infection, and other stresses in five categories (see Table 75-2): antiinfective, anti-inflammatory, procoagulant, metabolic, and thermoregulatory. The scavenging and wound-healing responses will not be
discussed here.

Anti-infective Responses

Acute leukocytosis, which largely reflects the demargination of neutrophils, is brought about by epinephrine, cortisol, and possibly IL-10 and
other mediators. Mobilization of marrow neutrophils by granulocyte
colony-stimulating factor (G-CSF) and other cytokines also plays an
important role. Circulating neutrophils adhere to inflammationactivated endothelium at sites of infection and move by diapedesis into

the infected tissue. Enhanced surface expression of CD11b/CD18 on


neutrophils57 may promote their adhesion to intercellular adhesion
molecule-1 (ICAM-1) on the surfaces of activated endothelial cells. In
addition to mobilizing neutrophils into the circulation and delivering
them to sites of infection, the acute-phase response also involves
increased production of several proteins that bind conserved microbial
molecules and assist in recognizing and/or killing microbes (LBP,
mannose-binding lectin, CRP, CD14, BPI, and complement components [C3, C4b]). Lactoferrin release from neutrophils and the production of hepcidin by the liver promote sequestration of iron in the
reticuloendothelial system,58 whereas zinc is retained within cells by
binding to metallothionein.

Anti-inflammatory Responses

The mechanisms that induce neutrophils to demarginate also seem to


inhibit their ability to adhere to noninflamed vascular endothelium,
thereby preventing unnecessary accumulation of neutrophils in
uninfected tissues. Other responses that may prevent inflammation
within the systemic compartment include increases in the blood
levels of cytokine antagonists (IL-1Ra, soluble TNF receptors), other
anti-inflammatory mediators (epinephrine, cortisol, -melanocytestimulating hormone [-MSH], adrenocorticotropic hormone
[ACTH], IL-4, IL-6, IL-10, IL-13, transforming growth factor- [TGF], CRP), protease inhibitors, and antioxidants.
Another phenomenon that may dampen local or systemic inflammation occurs after animals have reacted to certain microbial molecules. Known as innate immune tolerance or reprogramming, it
may follow exposure to either bacterial or viral molecules.59,60 In
general, a second exposure to the same or another microbial agonist
fails to elicit the usual proinflammatory response (production of TNF,
IL-1, IL-12), whereas the production of some anti-inflammatory molecules (IL-10, IL-1Ra) is maintained. This adaptation, which generally
lasts a few days after the primary infection or exposure, is thought to
prevent untoward inflammation. Produced by complex cellular processes that include chromatin remodeling (gene silencing),61-64 tolerance may contribute to postinfection immune suppression. At least in
the case of LPS, inactivation of the inciting ligand by a host enzyme,
acyloxyacyl hydrolase, may be necessary to allow restoration of normal
host defenses.65,66 A novel way to reverse tolerance in the late stages of
sepsis was recently reported in a murine model of peritonitis: adoptive
transfer of CD34+ hematopoietic stem-progenitor cells enhanced bacterial clearance and improved long-term survival,67 presumably by
providing nontolerant immune cells.
In an important experiment, van der Poll and co-workers68 showed
how systemic responses may be modulated by the sympathetic nervous
system during periods of stress. They infused a bolus of endotoxin into
volunteers and then measured blood levels of TNF and IL-10 over
several hours. Another group of volunteers received an infusion of
epinephrine for 3 hours before the endotoxin bolus. Epinephrine dramatically shifted the response from proinflammatory (TNF IL-10)
to anti-inflammatory (IL-10 TNF). Epinephrine-induced reprogramming of cellular responses to endotoxin can also be demonstrated
in whole blood ex vivo; similar reprogramming can be caused by histamine, prostaglandin E2, and other agonists that raise intracellular
cyclic adenosine monophosphate (cAMP). Infusing hydrocortisone
also has dramatic (though somewhat less predictable) effects on the
cytokine response to an endotoxin bolus.69 A similar reprogramming
of circulating blood cells seems to occur in vivo in response to relatively minor stresses.70
There is strong evidence that the bodys inflammatory responses to
infection and other stresses are compartmentalized. In patients with
pancreatitis, for example, Dugernier and co-workers71 found that the
concentrations of proinflammatory and anti-inflammatory cytokines
decreased from the peritoneal fluid to the lymph to the blood; net antiinflammatory activity was measured in virtually all lymph and blood
samples, whereas net proinflammatory activity was detected only in
ascites. Similarly, in patients with acute appendicitis, TNF and IFN-
were found in peritoneal fluid but not in plasma, whereas high concentrations of IL-10 and IL-4 were found in plasma, which inhibited the
ability of LPS to stimulate monocytes ex vivo.72 Studies performed in
rabbits suggested that, with low bacterial inocula, the proinflammatory

919
73

Metabolic Responses

Several mechanisms maintain euglycemia in the face of stress. Epinephrine, glucagon, cortisol, and possibly other hormones stimulate
glycogenolysis and gluconeogenesis in the liver; the major precursors
for hepatic gluconeogenesis are lactate, which is derived from glucose
via glycolysis in immune cells and muscle, and alanine, which is largely
produced by transamination of pyruvate in muscle and other tissues.
Insulin resistance reduces glucose uptake by muscle and contributes to
muscle catabolism.77 The counterregulatory hormones also induce
lipolysis (so blood levels of free fatty acids and glycerol increase) and
muscle proteolysis. Lipolysis, which occurs principally in adipocytes,
involves the actions of adipose triglyceride lipase and hormonesensitive lipase; lipoprotein lipase is inhibited, accounting in part for
the increase in circulating triglycerides that often occurs. Muscle proteolysis releases amino acids (alanine, glutamine, and others) that are
used for hepatic gluconeogenesis and for producing acute-phase
proteins.
A long-accepted rationale for increased glucose production is the
requirement to maintain blood glucose levels at concentrations that

can supply the brain and immune cells until levels of ketone bodies
(produced by the liver from fatty acids) and lactate, which can be used
for food by the CNS, rise later in the course of starvation or critical
illness.78 Treatment of critically ill patients with intravenous glucose
solutions and parenteral and/or enteral feeding largely satisfies the
bodys need to maintain euglycemia and may induce hyperglycemia in
many individuals.
It is important to note that the systemic responses that help restrict
inflammation to infected sites and optimize metabolism are carried
out by many of the same molecules, most prominently, catecholamines
and glucocorticoids. The effects of cortisol on metabolismpromoting
gluconeogenesis, glycogenolysis, insulin resistance, and lipolysisare
dose related in a monogenic fashion. In contrast, cortisols effects on
various aspects of inflammation may be permissive at normal concentrations (allowing acute-phase protein synthesis, for example) and
either suppressive (inhibiting cytokine and acute-phase protein production) or stimulatory (increasing IL-10 production) at high con
centrations within the physiologic concentration range.79 It is also
important that the regulated mechanisms that diminish the impact of
glucocorticoids (e.g., receptor downregulation, the actions of macrophage migration-inhibitory factor [MIF], others) affect both immune
and nonimmune cells. In a similar way, the tachyphylaxis or desensitization that reduces responses to catecholamines affects both vascular
smooth muscle and inflammatory cells.68,80,81 Mechanisms that may
have evolved to prevent stress-induced hypertension and dampen systemic anti-inflammation may also contribute to the pathogenesis of
severe sepsis and septic shock.

Procoagulant Responses

Inflammation and coagulation are closely linked.82,83 Inflammationinduced procoagulant responses contribute to abscess formation and
delayed hypersensitivity reactions in humans.
In individuals who have sustained physical trauma, activation of
coagulation and inhibition of fibrinolysis occur roughly in proportion
to the severity of injury.84 Briefly, inflammation-induced expression of
tissue factor on the surfaces of monocytes and endothelial cells is
thought to initiate the production of thrombin via factors VIIa and Xa,
whereas increased production of plasminogen activator inhibitor-1
(PAI-1) inhibits fibrinolysis (Fig. 75-2).85

Inflammatory
mediators
(IL-6 + )

Tissue
factor
+VIIa

Plasminogen
Plasminogen
activators

Xa
(+ V)

IXa
(+ VIII)

PAI-1

Thrombin
Fibrinogen

Fibrin

Thrombin

Low levels of
AT-III, TFPI,
proteins C and S
Anticoagulation

Fibrin formation

Plasmin

Fibrin

Fibrin
D-dimers

Fibrinolysis

Inadequate fibrin removal

Thrombosis of small
and midsize vessels
FIGURE 75-2 Inflammation-activated coagulation. Inflammation-associated coagulation begins when cytokines, Toll-like receptor agonists, or other
stimuli induce tissue factor expression on the surfaces of monocytes and vascular endothelial cells. Increased concentrations of plasminogen activator
inhibitor-1 (PAI-1) prevent the formation of plasmin, thus decreasing fibrinolysis. Tissue factor pathway inhibitor (TFPI) modulates thrombin activation by
blocking the activity of the tissue factor/factor VIIa/factor Xa complex. Hepatic synthesis of protein C and antithrombin III (AT-III) decreases during the
acute-phase response, whereas an increase in the plasma concentration of complement factor C4b binds more of the available protein S, reducing its
ability to inhibit clotting. Factors may also be consumed during clot formation. Despite these procoagulant and antifibrinolytic changes, clinically apparent
intravascular thrombosis is unusual. IL-6, interleukin-6. (Modified from Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med.
1999;341:586-592. Copyright 1999 Massachusetts Medical Society.)

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

cytokine responses to infection are compartmentalized to the lung or


peritoneum,74 depending upon the site of inoculation.
Another view was suggested by a report that the initial response to
major trauma is a genomic storm in which mRNA abundance for
both proinflammatory and anti-inflammatory molecules is upregulated simultaneously in peripheral blood leukocytes.75 The findings
which actually suggested that the bodys acute responses to trauma are
well organized and relatively consistent from person to person, whether
or not patients subsequently succumbwere cited as evidence to refute
the old notion4 that the initially proinflammatory systemic response to
injury is followed by a compensatory anti-inflammatory response.
Because others have found that circulating leukocytes do not produce
most of the cytokines found in the blood (see earlier), interpreting the
significance of events occurring within peripheral blood leukocytes is
difficult; perhaps they could be used as evidence for immune dissonance, another old concept,76 but the reported changes were far from
being chaotic, dissonant, or stormlike. Studies of blood leukocytes may
provide a misleading view of the bodys overall responses to infection
and other stresses.

Part II Major Clinical Syndromes

920
Protein C is a natural anticoagulant that is converted to its activated
form (aPC) when thrombin binds thrombomodulin, an endothelial
cell surface protein. Activated protein C then dissociates from its own
receptor, endothelial protein C receptor (EPCR), before binding soluble
protein S to produce a complex that inactivates factors Va and VIIIa,
thereby blocking the activation of thrombin.86 During acute-phase
responses, depletion of protein C and antithrombin III parallels the fall
in serum albumin concentration, suggesting that these anticoagulants
are negative acute-phase reactants.87 Protein C may also be degraded
by elastase. The available molecules of protein S decrease as it binds to
its circulating partner, C4b, a positive acute-phase reactant. Paradoxically, generation of low amounts of thrombin may inhibit clotting by
activating protein C.

Thermoregulatory Responses

The adaptations to stress just described often occur in the absence of


fever; in fact, there is evidence that fever and the other elements of the
acute-phase response are independently regulated.88 Because TNF,
IL-6, and other putative pyrogens can be found in the blood in the
absence of fever, and because the evidence that endogenous pyrogens
circulate in human blood is surprisingly limited,44,89 it is possible that
infection-related thermogenesis is induced when local inflammation
activates neural afferent signals to the thermoregulatory center, either
via nociceptive neurons40,41,90 or the vagus.51 The physiologic responses
that increase body temperature include shivering (rhythmic contractions of skeletal muscles) and redirection of blood flow from the skin
and extremities to internal organs by means of vasoconstriction.
An increase in body temperature may favor host survival in several
ways.45 It may help inhibit bacterial growth and increase the bactericidal activities of neutrophils and macrophages,91 for example, and the
redistribution of blood flow that occurs during thermogenesis may
increase blood delivery to infected tissues.

Summary

There is considerable overlap between the bodys acute systemic


responses to infection, injury, and many other stresses. Indeed, many
of the same responses occur after strenuous exercise and during periods
of psychological stress. As shown best in studies performed in patients
who have sustained trauma, the intensity of the response generally
increases with increasing stimulus severity,92 and there is individual
variability in the expression of its different elements. The evidence that
the bodys early systemic responses to stress can be immunosuppressive, increasing risk for acquiring viral as well as bacterial infections,
is intriguing but still largely circumstantial. This phenomenon may
account, in part, for the increased susceptibility to nosocomial bacterial
infection and recrudescence of viral infections (e.g., cytomegalovirus,
herpes simplex; see later) experienced by patients who have sustained
major trauma or are experiencing critical illness.
In most patients in whom severe sepsis occurs today, many of the
acute-phase responses discussed here would probably have been activated by injury or illness before the infectious challenge. Local inflammation would provide a further stimulus to these responses, broadening
and intensifying their expression. If uncontrolled infection then
induces severe sepsis and septic shock, it does so when antiinflammatory influences may dominate in the peripheral blood; as will
be discussed later, a net anti-inflammatory advantage seems to be
maintained during severe sepsis, and immunosuppression becomes
even more prominent.

Harmful Responses to Infection:


Severe Sepsis and Septic Shock
Severe Sepsis

If severe sepsis is organ hypofunction or dysfunction occurring as a


result of infection, what is organ hypofunction or dysfunction, and
how does it develop? Hypofunction implies an inadequate level of
activity, whereas dysfunction suggests that organ performance is in
some way abnormal. Are harmful changes in organ activity level or
function precipitated by specific pathologic event(s) or triggers, or do
they develop when normally adaptive stress responses are pushed
beyond their ability to be protective? Two general ideas have dominated thinking about pathogenesis. The older and more widely held

view is that cytokines and other molecules, produced either locally or


systemically, circulate via the blood and induce injury to the vascular
endothelium and/or microcirculation in different organs. A newer
view invokes an extension of the bodys normal neuroendocrine
responses to stress, in essence, an exhaustion of ATP in critical organs
when the inflammatory stimulus is too strong or too prolonged. In
both concepts, microvascular derangement and mitochondrial dysfunction are thought to play central roles.

Cytokines and Other Mediators

The discovery of the major proinflammatory cytokines (TNF and


IL-1) was quickly followed by evidence that these proteins, individually or in combination, can induce severe sepsis and septic shock in
experimental animals. Moreover, higher-than-normal levels of these
cytokines were found in the blood of many septic patients, and, in
some studies, these levels correlated with risk of dying. During the
1990s, however, investigators found that the blood of severely septic
patients contains not only these and other proinflammatory mediators
(e.g., IL-12, platelet-activating factor [PAF]) but also a broad array of
anti-inflammatory molecules (e.g., IL-4, IL-10, IL-1Ra, soluble TNF
receptors). Remarkably, attempts to define the dominant molecules
in the plasma of septic patients concluded that the anti-inflammatory
cytokines, in particular, IL-10 and IL-4, were most active.93-95 In other
studies, peripheral blood monocytes from patients with severe sepsis
responded to LPS and other agonists ex vivo by producing lower-thannormal amounts of TNF, IL-12, and IFN-, yet normal or high amounts
of IL-1Ra and IL-10.96-99
It has been especially challenging to understand the role of IL-6.100
Although early studies suggested that this abundant cytokine is pro
inflammatory, there is also evidence suggesting that it is an SOS
signal that can be produced by most cells in response to injury. Indeed,
epinephrine induces IL-6 production in vivo, whereas IL-6 infusion
enhances blood levels of IL-1Ra, IL-10, and cortisol.101 Experiments in
genetically manipulated mice suggest that IL-6 is the most important
activator of the HPA axis in response to stress,102 and IL-6deficient
mice have exaggerated inflammatory responses to bacterial infections.103,104 Studies in volunteers and in chimpanzees suggest that IL-6
is the major procoagulant cytokine.82 More than any other cytokine,
IL-6 seems to direct the bodys systemic acute-phase responses.100,105
Two proinflammatory mediators may become important late in the
course of the response to severe infection. MIF is a product of T lymphocytes and macrophages that is induced by, and opposes the actions
of, glucocorticoids.106 Although MIF normally circulates at a low, basal
level, its plasma concentration increases during infection and stress,
and very high levels have been found in the plasma of patients with
severe sepsis.107,108 The role played by MIF in endotoxin-induced sepsis
has been disputed, however.107,109 A second late proinflammatory
molecule is a transcription factor, HMGB-1, that appears in the blood
several hours after infection begins and contributes to death in a mouse
endotoxin challenge model.110 Because recombinant HMGB-1 has little
proinflammatory activity itself, its ability to bind to various bacterial
products may be important for its activities in vivo111; it is considered
an alarmin and may be critical for LPS-induced responses in mice, for
example.112 However, there has been poor correlation between HMGB-1
blood levels and clinical severity or outcome.113,114
For many years, it seemed that TNF and other proinflammatory
mediators are produced at a local site of infection, diffuse into the
blood stream, initiate systemic inflammation, and are then opposed by
a counterregulatory anti-inflammatory response. An imbalance in
these opposing forces (immune dissonance76) was thought to cause
severe sepsis. This view found support in the results of numerous
studies that measured the cytokine responses of healthy subjects to a
bolus injection of endotoxin,115 as well as in observations made in
patients with fulminant meningococcemia. It is difficult to envision the
same sequence of events in patients who, as a consequence of trauma
or illness, are already experiencing acute-phase systemic responses at
the time that infection begins. In such patients, systemic antiinflammatory mechanisms may dominate throughout the clinical
course. Indeed, an early anti-inflammatory systemic response, as
reflected in a high ratio of IL-10 to TNF in plasma at the time of
hospital admission, has been associated with a poor outcome.116,117

921

Other Candidate Triggers

Several kinds of molecules have been proposed to trigger severe sepsis


by circulating in the bloodstream and either eliciting inflammation or
disrupting the vascular endothelium. They include proinflammatory
cytokines, as discussed earlier; microparticles derived from platelets,
vascular endothelial cells, and other cell types118; mitochondrial
DNA119,120; S100A8 and S100A9, the most abundant cytoplasmic
proteins of neutrophils and monocytes; HMGB-1112; and formyl peptides120,121 derived from mitochondria. Higher-than-normal concentrations of each of these molecules have been found in the blood of
patients with severe sepsis, and each can induce organ dysfunction
when injected into experimental animals. With some exceptions,122 the
ability of these molecules to induce severe sepsis has been studied
almost exclusively in animal models, usually performed in mice, using
artificial challenges such as bolus injections of endotoxin or hyperacute
peritonitis. Their role in human disease remains uncertain.

Complement Activation

The ability of normal human serum to kill bacteria is largely conferred


by the complement system, which can be activated by antigen-antibody
complexes or CRP (classical pathway), certain bacterial surface sugars
(mannose-binding lectin pathway), or (lipo)polysaccharides (alternative pathway). There is evidence that each of these pathways can be
activated in the serum of patients with sepsis,123-125 and at least two
complement proteins may contribute to the septic response. Activation
of both the complement and the contact systems is regulated by
C1-esterase inhibitor, an acute-phase protein that undergoes proteolytic inactivation in patients with severe sepsis125; administration of the
inhibitor had only modest effects on the outcome of severe sepsis in a
nonhuman primate model,126 yet it had impressive efficacy in models
of septic peritonitis in mice.127 Factor C5a is a potent chemoattractant
that also can induce vasodilation, increase vascular permeability, and
augment the release of granule enzymes from phagocytes.128 The blood
neutrophils of humans with early sepsis may lose responsiveness to
C5a. Studies in septic rodents suggest that antibody-mediated neutralization of C5a or its receptor may prevent death.19

Coagulopathy

Activation of the coagulation cascade and inhibition of anticoagulation


and fibrinolysis are commonly observed during sepsis.129 In most
patients, these changes may simply be extensions of the normal acutephase response to infection (see earlier), but in others, they may be
triggered by vascular endothelial injury or dysfunction either at a
local site of infection or more diffusely. The endothelium is pivotal
in promoting coagulation via its expression of tissue factor and von
Willebrand factor and its association with activated platelets. Key anticoagulant molecules (antithrombin, protein C, tissue factor pathway
inhibitor) also interact with the endothelial surface and can be compromised during activation of coagulation by inflammatory mediators.82 In addition, cell fragments or microparticles derived from
activated or apoptotic cells may express tissue factor and contribute to
the procoagulant state.118,129,130
The extent to which coagulopathy contributes to organ dysfunction
in septic humans is controversial.82,83 The occurrence of disseminated
intravascular coagulation (DIC) is a strong predictor of death in
patients with severe sepsis or septic shock.131 Although there is an
experimental basis for suspecting that microthrombi (comprising
platelet or fibrin aggregates as well as fibrin thrombi) form in a generalized fashion when patients develop DIC, numerous autopsy studies
have not found a convincing link between fibrin deposition and organ
failure.132-136 When thrombosis was found, it was usually associated
with an indwelling catheter or device, and hemorrhage was usually
more life-threatening than was thrombosis.133 Although some studies

noted microthrombi in up to 20% of cases of shock, the thrombi were


often discontinuous and may have undergone perimortem fibrinolysis.
It is conceivable that fibrin deposition and microthrombi compromise
blood flow without producing overt ischemia; downstream cells might
then survive in a state of hibernation (see later). Of importance, a
recent study of histopathologic changes in the heart and kidney did
not reveal significant cell necrosis, apoptosis, microthrombus deposition, or ischemic changes.136 Perhaps the strongest evidence against a
prominent role for coagulopathy in sepsis-induced organ dysfunction
is the fact that three different anticoagulant drugs (tissue factor pathway
inhibitor, antithrombin III, activated protein C) did not reproducibly
improve organ function or increase survival in patients with severe
sepsis.137,138
The best-documented and most dramatic exception is fulminant
meningococcemia. Autopsy studies have found meningococci within
the lumina of dermal vessels, as well as in endothelial cells, and thrombi
have been noted in small vessels of many tissues, most notably the
skin and adrenal glands. Arterial thrombosis, especially of midsized
to small-sized vessels, also occurs with other etiologies of purpura
fulminans and can precipitate digital ischemia and extremity loss,
especially when combined with intense vasoconstriction.139 Impressive
evidence for early activation of the vascular endothelium was also
obtained in a study of volunteers infected with Rickettsia rickettsii,
which also infects endothelial cells.140 In contrast, in patients with viral
hemorrhagic fevers (e.g., Ebola virus), DIC typically occurs late in the
course and the clotting factor abnormalities, triggered in part by
expression of tissue factor on infected monocytes, may be surprisingly
modest; mucosal hemorrhage may be largely a consequence of platelet
dysfunction,141 and there is little evidence that DIC contributes to
organ injury.

Activation or Injury of the Vascular Endothelium

The vascular endothelium is involved in three processes that play major


roles in sepsis pathophysiology: vascular tone, vascular permeability,
and coagulation.129 The evidence that endothelial activation and/or
injury contributes to the observed abnormalities in blood pressure,
fluid extravasation, and coagulation is almost entirely derived from
studies in endotoxin-challenged animals or from in vitro investigations.142,143 In humans, there is ample clinical evidence that capillary
permeability increases in the dysfunctional organs of patients with
severe sepsis; it is most obvious in patients with acute lung injury (see
later). Similarly, a role for endothelial activation in the initiation or
propagation of intravascular coagulopathy seems likely, although
direct evidence for this in humans is limited almost entirely to patients
with fulminant meningococcemia.86 Mutunga and co-workers144 found
that patients with severe sepsis and septic shock had higher concentrations of von Willebrand factorpositive (endothelial) cells in their
plasma than did healthy human control subjects, suggesting that endothelial damage occurs in human sepsis. Although the source of these
circulating endothelial cells was not determined, others have found
both high circulating levels of immunoreactive von Willebrand factor
and decreased von Willebrand factor staining in dermal vessels of
septic patients, suggesting a generalized endothelial response to
inflammation.145 One important endothelial activator is vascular endothelial growth factor (VEGF); in mice, sepsis-induced mortality could
be prevented by treatment with soluble VEGF receptor (FLT).146 There
is also much interest in angiopoietin-2, which circulates in high levels
in patients with severe sepsis and can disrupt the endothelial barrier.147
In one study of muscle biopsies from patients with severe sepsis,
endothelial activation was suggested by increased expression of
ICAM-1 and by an increased proportion of capillaries expressing
P-selectin and E-selectin.148 On the other hand, others have found that
the skin microcirculation of patients with septic shock has normal
endothelium-dependent responses to vasodilators149 and that circulating levels of soluble adhesion molecules do not correlate well with
endothelial activation in skin biopsies.150 There is considerable heterogeneity in the structure and function of endothelial cells in different
tissue beds,151 so it is quite possible that the changes noted in the tissues
that are most accessible to examination (skin, skeletal muscle, tongue)
are not representative of those in the organs that are affected most
significantly during severe sepsis (lungs, kidneys, liver, brain).

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

To date, no theory proposed adequately accounts for the transition


to severe sepsis or septic shock, however. Prospective studies that
combine clinical observation with serial measurements of mediator
biosynthesis, cellular responsiveness, and tissue metabolism in patients
at risk (e.g., previously healthy young individuals who sustain major
trauma) might provide the information needed to produce an accurate
account.

132

922

Part II Major Clinical Syndromes

Mitochondrial and Microcirculatory Dysfunction

Infection-associated abnormalities in organ function are often reversible. Moreover, there is often little or no detectable evidence for cell
death in the microscopic appearance of tissues of patients or experimental animals who die from severe sepsis.134,152,153 Pathologists have
found apoptosis of cells in the spleen and intestine,152 myopathic
changes in skeletal muscle,148 and changes in blood vessel morphology
(in meningococcal disease, for example86), but significant necrosis does
not seem to occur in the major organs,136,152 arguing against a prominent
general role for thrombosis or necrotic cell death in the early pathogenesis of organ dysfunction. On the other hand, much evidence points
to the importance of microcirculatory dysfunction and abnormal
oxygen use, and the long course of recovery and frequent occurrence
of long-term sequelae (see later) suggest that biochemical derangements may persist much longer than has been generally suspected.
In septic patients, the readily measurable indices of macrocirculatory function (mean arterial pressure, cardiac output, mixed venous
oxygen saturation) often do not parallel the severity of organ dysfunction.154 It is now widely believed that a critical cause of abnormal organ
function in severe sepsis resides in the microcirculatory units (arteriole, capillary bed, venule) within tissues. Evidence for this hypothesis
has been obtained using orthogonal polarization spectral (OPS)
imaging of the most accessible muscle, the tongue. When they were
compared with control subjects, patients with severe sepsis had significantly lower vessel density, and the proportion of perfused small
vessels was also below normal155,156; in other studies, restoration of the
sublingual microcirculation was associated with survival.157 Shunting
of blood around weak microcirculatory units could account for the
maintenance of relatively normal mixed venous oxygen saturation
despite apparent tissue dysoxia.158 Mechanisms often invoked to
account for changes in the microcirculation include reduced deformability of erythrocytes and activated neutrophils, neutrophil aggregation, and microthrombosis.159 There is little evidence that any of these
phenomena alters microcirculatory function in humans, however, and
the aforementioned changes noted by spectral imaging were reversible
by the application of acetylcholine155 or nitroprusside,156 indicating that
they were not anatomically fixed. Maldistribution of blood flow at the
level of the microcirculation thus may contribute to low oxygen use by
affected tissues; paradoxically, tissue oxygen levels are often elevated,
suggesting a defect in oxygen use at the cellular level.
When they are activated by exposure to microbial molecules, myocytes160 and most leukocytes (alternatively activated macrophages and
regulatory CD4 T cells are exceptions) rely upon glycolysis rather than
oxidative phosphorylation to provide ATP and maintain membrane
potentials.161 This phenomenon is an example of aerobic glycolysis or
the Warburg effect, noted initially in tumor cells: the use of glycolysis
to produce ATP despite the availability of oxygen.162,163 As the stimulus
increases or persists for long periods, ATP concentrations eventually
fall, impairing cell function in part by allowing mitochondrial membrane potential collapse.164 This normal response to cell activation is
conceptually similar to the state of cytopathic hypoxia, proposed by
Fink165 to denote diminished production of ATP despite normal (or
even supranormal) po2 values in the vicinity of mitochondria within
cells. Many phenomena might contribute, including diminished entry
of pyruvate into the tricarboxylic acid cycle161 and uncoupling of oxidation from phosphorylation because of collapse of the proton gradient
across the mitochondrial membrane.164 Nitric oxide (NO) and ROS
are thought to play major roles in triggering mitochondrial loss and
hypofunction.166 The ability of peroxynitrite and NO to activate poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) may also
be important because PARP rapidly polymerizes cellular ADP and thus
robs cells of ATP.167 It is likely that many influences intersect to alter
mitochondrial function, including both cell-intrinsic mechanisms (e.g.,
mitochondrial loss via autophagy [mitophagy]168) and cell-extrinsic
stimuli, such as thyroid hormone, cortisol, and hyperglycemia.169
Mitochondrial dysfunction in muscle170 and peripheral blood
monocytes171 has correlated with sepsis severity in clinical studies,
whereas mitochondrial preservation of tissue ATP concentrations170
and early activation of mitochondrial biogenesis172 have been associated with survival. Noting that cell necrosis has been an uncommon
finding in patients who died from severe sepsis,133,136,152 Singer and

co-workers166 proposed that multiorgan failure is an attempt by the


body to ensure cell survival in the face of sustained critical illness, with
affected cells entering a dormant state analogous to hibernation... . A
cautionary note has been raised by Jeger and co-workers,173 whose
review of the literature concluded that the current data from mostly
young and otherwise healthy animals does not support the view that
mitochondrial dysfunction is the general denominator for multiple
organ failure in severe sepsis and septic shock. Whether this is true
if underlying comorbidities are present, especially in older patients,
should be addressed in further studies. As they point out, an accurate
noninvasive method to measure mitochondrial function in vivo would
be a major advance.

Immunosuppression

Sick individuals often lose their ability to exhibit cutaneous delayed


hypersensitivity to recall antigens, becoming anergic174; this change is
temporally associated with decreased surface expression of class II
(human leukocyte antigen [HLA]-DR) and co-stimulatory175 molecules on circulating monocytes. When compared with monocytes from
normal controls, peripheral blood monocytes from septic patients
produce less TNF when stimulated ex vivo with LPS but maintain or
increase their production of IL-1Ra and/or IL-10.93,95,97 There is evidence that IL-10 both inhibits TNF production97 and promotes intracellular sequestration of HLA-DR.176 These changes normalize as
patients recover.96
Neutrophils obtained from severely septic patients show reduced
IL-1177 and IL-8178 production when stimulated with LPS or streptococci; similar behavior can be induced in normal neutrophils by treatment with IL-10.178 These phenomena resemble, at least in part,179 the
state of tolerance discussed earlier (Acute Phase Responses/ Antiinflammatory Responses). In a study of blood leukocytes obtained
from trauma victims, early changes in gene expression gradually
resolved over time, with no hint of a second hit of inflammation
when patients developed complications in the ICU,75 perhaps reflecting
such tolerance. Prolonged tolerance also occurred in mice that were
exposed to gram-negative bacteria and lacked the host lipase that inactivates LPS,65,66 raising the possibility that immunologic recovery from
other infectious agents may also require inactivating the microbial
stimuli that induce the hosts inflammatory responses.
Hotchkiss and co-workers180,181 have noted extensive apoptosis of
CD4 and CD8 lymphocytes, dendritic cells, and B cells in the spleens
of patients with severe sepsis who died. Intestinal epithelial cells may
also undergo apoptosis.152 These changes were not noted in critically
ill but nonseptic patients, suggesting that they do not contribute to the
immunosuppressive state that follows injury and other stresses.152
Studies of inflammation-associated apoptosis in experimental animals
suggest that glucocorticoids are more important inducers of apoptosis
than are TNF or the Fas ligand.182 Hyperactivation of splenic sympathetic input may also play a role. How loss of these cells contributes to
the pathogenesis of severe sepsis is uncertain, however. Remarkably, in
the murine model of septic peritonitis, death could be prevented by
administering a caspase-3 inhibitor or overexpressing Bcl-2, an antiapoptotic protein, in lymphocytes183 or other cells.184 Unlike lymphocytes, the life span of neutrophils is prolonged by proinflammatory
mediators, such as TNF and G-CSF, and shortened by IL-10, which
promotes neutrophil apoptosis.185

Septic Shock

Septic shock may have two distinguishable phases. Vasoconstrictive


(cold) shock, characterized by low cardiac output and high peripheral
resistance, occurs in patients who are hypovolemic; factors that contribute to decreased effective intravascular volume include redistribution of blood flow, venous pooling, increased capillary permeability,
increased insensible losses, and poor fluid intake. During this phase,
the blood pressure is supported by peripheral vasoconstriction. Restoration of effective intravascular volume by the administration of fluids
is usually followed by vasodilation. Vasodilation is not often seen with
acute hemorrhagic shock or cardiogenic shock, and it does not usually
occur in patients with shock caused by viral hemorrhagic fevers or
hantavirus infections, which cause myocardial dysfunction and profound increases in capillary permeability.186,187 The clinical hallmarks

Infection Susceptibility and Outcome:


Genetic Influences

A major obstacle to understanding the pathogenesis of severe sepsis is


the striking heterogeneity of the patient population that experiences
the syndrome. Patients may differ in age, sex, ethnic group, underlying
disease, inciting microbe, medications, and numerous other variables.
Genetic epidemiology studies suggest that genetic variation contributes to both susceptibility and outcome in infectious diseases.198 Many
polymorphisms or haplotypes have been associated with meningococcal disease and/or pneumococcal disease.199,200
Several groups have described single nucleotide polymorphism
(SNP)-outcome associations in small groups of critically ill patients
with sepsis caused by diverse pathogens. However, a systematic review
of the quality of 147 genetic association studies found that most of the
reported SNP-sepsis associations were not reproducible.201 Further,
studies using meta-analysis of polymorphisms of different inflammatory molecules (i.e., PAI-1, TLR4, TNF, lymphotoxin- [LT-]) and
their relationship to the development of sepsis or survival has revealed

50
40
30
20

Other

IV catheter

Soft tissues

Urinary tract

Abdomen

Lung

10

FIGURE 75-3 Presumed sites of infection in patients with culturepositive severe sepsis. Bars show the means of data from four
studies.17,315,449,450 Brackets show the minimum and maximum values
reported. Note that the lung and abdomen are the most common primary
sites. IV, intravenous.

either limited or no associations.202-205 A genome-wide association


study (GWAS) evaluated treatment responses in severe sepsis and noted
that the prognostic models were dominated by clinical variables.206 It is
difficult to take into account all of the many gene interactions and clinical factors that influence the outcome of serious infections.

Microbial Triggers for Severe Sepsis

The most commonly identified sites of primary infection in patients


with severe sepsis are the lungs and the abdomen (Fig. 75-3). No
obvious source of infection can be found in approximately one third to
one half of the cases in most series.6,137,207 Culture-negative and culturepositive cases have had similar morbidity and mortality rates.6,208
In keeping with the discovery that conserved gram-positive
(lipoproteins, lipoteichoic acid) and gram-negative (LPS) bacterial
molecules are recognized by distinct receptors on leukocytes, with
overlapping yet distinctive downstream signaling pathways (see Fig.
75-1), patients with severe sepsis caused by gram-positive and gramnegative bacteria may have somewhat different cytokine responses. In
one study, IL-1, IL-6, and IL-18 concentrations were higher in the
plasma of patients with sepsis caused by gram-positive bacteria209;
others have found higher levels of TNF or IL-6 in the plasma of patients
with severe sepsis caused by gram-negative bacteria.210,211 Microarray
analysis of mRNA from macrophages and whole blood stimulated ex
vivo has also identified numerous differences in gene expression in
response to gram-positive compared with gram-negative stimuli in
most,209,212-214 but not all,215 studies. In septic children, a microarrayderived mRNA pattern in blood leukocytes discriminated successfully
between influenza, gram-positive, and gram-negative etiologies.216
Although the clinical features of severe sepsis caused by different
microbes are very similar, it is possible that these new molecular signatures will provide insights into pathogenesis and be useful both for
diagnosis and for directing therapy.

Bacteremia

How local infection leads to multiorgan dysfunction and hypotension


is uncertain. One long-favored hypothesis is that uncontrolled local
infection eventuates in bacteremia or toxinemia; circulating bacteria or
their products then stimulate inflammatory reactions within the vasculature and distant organs that lead to organ dysfunction and hypotension. Given the long history of this idea, it is surprising that strong
evidence for it is actually limited to a few special situations. The most
prominent example is fulminant meningococcemia, when N. meningitidis bacteria grow in the blood and induce DIC, severe sepsis, and
shock. Other examples are the neutropenic or splenectomized individuals who develop overwhelming bacteremia217 and patients with
Yersinia pestis,218 Burkholderia pseudomallei,219 nontyphoidal Salmonella,220 Bacillus anthracis, or Capnocytophaga canimorsus bacteremia.
These examples are special because the responsible bacteria are
usually human pathogens, able to cause disease in immunocompetent,

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

of vasodilation are decreased systemic vascular resistance and high


cardiac output. The following factors may contribute to inflammationinduced vasodilation:
Tachyphylaxis to catecholamines, which diminishes the sensitivity
of vascular smooth muscle to catecholamines administered as
pressors80
The underproduction or peripheral resistance of glucocorticoids,
which upregulate adrenergic receptors80
The underproduction or ineffectiveness of aldosterone188,189
The production of adrenomedullin, which has vasodilatory actions,
increases renal blood flow, and inhibits aldosterone secretion190
The release of NO from sites of inflammation191 and/or distant vascular endothelium
The absence of the normal baroreflex response that increases circulating vasopressin levels (and depletion of neurohypophyseal vasopressin stores)192
The release of platelet activating factor
The activation of potassium (K)ATP channels in arteriolar smooth
muscle cells by hypoxia and lactate193
The generation of bradykinin, a vasodilator that also increases capillary permeability194
Remarkably, inflammation-induced vasodilation can occur when
there are very high blood levels of several vasoconstrictor hormones
(norepinephrine, epinephrine, endothelin-1, and angiotensin II). The
best clue to its pathogenesis may be the ability of treatment with hydrocortisone or vasopressin to improve the pressor effect of catecholamines in many patients (see Therapy).
The basic mechanisms that compromise essential cell function from
hypoperfusion are alterations in cell membrane permeability and mitochondrial energy production. Hypoxic cells switch to anaerobic glycolysis and accumulate lactate, hydrogen ion, and inorganic phosphates.
Cellular ATP stores decrease because of diminished synthesis, continued consumption, and the actions of ATPases.195 Energy-dependent
sodium and calcium pumps in the plasma membrane are affected,
resulting in the loss of cellular potassium and the accumulation of
sodium, calcium, and water.196 This is apparent histologically as generalized cell swelling. In addition, protein synthesis is impeded, ribosomes detach from the endoplasmic reticulum, and mitochondrial and
lysosomal membranes are damaged. Protein misfolding further contributes to cell injury and death.196 High conductance, nonselective
permeability channels develop in the mitochondrial inner membrane
(the mitochondrial permeability transition); the loss of membrane
potential impedes oxidative phosphorylation and allows leakage of
cytochrome C into the cytoplasm, compromising electron transport
and serving as a major signal to initiate apoptosis.197 Increases in intracellular calcium may initiate cell injury and an imbalance between
free-radical generation and radical-scavenging systems may enhance
oxidative stress. Reactive oxygen species (i.e., superoxide anion, hydrogen peroxide, and hydroxyl ions) can accelerate cell injury via lipid
peroxidation, damaging plasma and organelle membranes. Further,
oxidative modification of proteins enhances their degradation by the
proteosome and may result in the loss of vital protein components.

Site of infection (% of cases)

923

Part II Major Clinical Syndromes

924
previously healthy individuals. In contrast, the great majority of the
cases of severe sepsis occur in previously ill persons and are associated
with bacterial or fungal microorganisms that are acquired from the
patients own microbiota.221 These commensal microbesenteric
gram-negative bacilli, coagulase-negative staphylococci, enterococci,
Candida species, and othersinfrequently cause disease in humans
who have normal immune defenses. Individuals who develop serious
disease caused by a commensal bacterium generally have a significant
immune defect, most often, epithelial barrier disruption (e.g., catheters, bites, cuts), obstruction of a drainage conduit, or immunosuppression.221 Accordingly, it has been difficult to identify virulence factors
in these bacteria that promote bloodstream invasion per se.222-224 Even
geography and ethnicity may be important; for example, Yu and
co-workers225 found that 94% of Klebsiella pneumoniae blood isolates
from immunocompetent patients who developed community-acquired
pneumonia in Taiwan and South Africa had a mucoid phenotype,
whereas this association did not occur in patients with hospitalacquired K. pneumoniae or in patients from five other countries.
The evidence that circulating commensal gram-negative bacteria
stimulate inflammation within the blood stream is limited to a few
observations. Blood cultures were positive more commonly in patients
who have severe sepsis than in those with sepsis,6 for example, and the
fraction of patients who have a positive blood culture is even greater
among those with septic shock.6,14 In patients with severe sepsis and
documented infection, moreover, bacteremia has been associated with
early mortality.17 Bloodstream infection with certain microorganisms,
such as Candida albicans,226 methicillin-resistant S. aureus (MRSA),227
and vancomycin-resistant Enterococcus faecium,228 has also been associated with significant attributable mortality (an often-used but imperfect surrogate outcome for severe sepsis/septic shock), and one study
found that catheter-associated bacteremia was more often accompanied by hypotension when the infecting agent was a gram-negative
aerobe.229
Other lines of evidence suggest that circulating commensal bacteria
may not directly trigger severe sepsis or septic shock.208 First, bacteremia is usually low grade and transient, provided that reseeding of the
bloodstream does not occur. The bodys innate immune mechanisms
for clearing commensal bacteria and fungi from the bloodstream are
evidently very effective. Second, with some exceptions (such as S.
aureus bacteremia, meningococcemia, plague218 and septicemic melioidosis219), the risk for developing severe sepsis has not correlated
directly with the density of cultivatable bacteria in the blood. Third,
bacteremia has no distinctive clinical featuresat the bedside, bacteremic patients with severe sepsis are indistinguishable from those whose
cultures are negative230,231; a diagnostic algorithm that identified 88% of
patients with bacteremia as a complication of community-acquired
pneumonia was only 53% specific.232 Finally, the case-fatality rates for
culture-positive and culture-negative patients with severe sepsis and
septic shock have been very similar,6,17,233 suggesting that bacteremia
may contribute little to outcome. In keeping with this idea, little or no
excess mortality could be attributed to bacteremia associated with
indwelling vascular catheters,234-236 antibiotic-resistant nosocomial
bacteria,237 transfusion-related Serratia,238 nosocomial Enterobacter,239
or with bacteremia that occurred in a tertiary hospital population.240
A second hypothesis might account for the occurrence of severe
sepsis in patients who have primary extravascular infections with commensal organisms (see discussion and references within Munford208).
It holds that inflammatory mediators produced in the infected tissue
activate the CNS by stimulating local nerves; when they enter the
bloodstream, these mediators also may stimulate cells in the vasculature or in distant organs. In such patients, circulating bacteria would
be a marker for uncontrolled local infection, not the direct trigger for
severe sepsis.
The conclusion reached by Felty and Keefer241 in their 1924 review
of patients with Escherichia coli bacteremia seems valid for many
patients today: We are inclined toward the view not only that the
symptoms of the generalized infection are difficult to differentiate from
those of the local process, but also that the prognosis depends largely
on the character of the primary focus. In short, the essential feature is
the extent, severity and amenability to treatment, of the local process
rather than the sepsis itself.

Endotoxemia

It is also widely held that bacterial endotoxin, when it enters the


bloodstream, triggers systemic inflammation. Fulminant meningo
coccemia has provided the most striking evidence for this idea; the
high levels of circulating endotoxin found in patients with this syndrome have correlated directly with plasma TNF levels and the risk
of dying.242-244 Infusing endotoxin directly into the bloodstream of
healthy volunteers readily confirms the ability of this substance to
induce dramatic changes in circulating mediator concentrations and
to cause symptoms.245,246
Fulminant meningococcemia is a very distinctive syndrome,
however, in which a pathogenic bacterium invades a healthy individual
and grows within the vasculature before the victim can mount an effective defense. In most instances, there is no local (i.e., nasopharyngeal)
inflammation to impede bacterial invasion or induce systemic
responses. Moreover, meningococci can grow to very high density in
the blood244 and shed membrane blebs that contain endotoxin and
other molecules; these particles may serve as surfaces for activating
complement and coagulation within the bloodstream. Meningococcemia may thus be a poor model for the typical case of endotoxemia,
in which a commensal such as E. coli or Klebsiella invades an alreadysick patient, triggers inflammation in a local tissue, and transiently
invades the bloodstream to achieve low-level bacteremia. The endotoxin infusion model resembles meningococcemia in important ways
(healthy subjects, acute exposure to endotoxin, no local infection/
inflammation), and it may thus be a better model for meningococcemia than for other forms of endotoxemia.
For 4 decades, the Limulus amebocyte lysate (LAL) assay has been
used to measure endotoxin in plasma. This method and a newer
antibody-based assay247 measure both active endotoxin and inactive
endotoxin that may circulate in plasma. It is thus uncertain that the
plasma endotoxin detected by using these assays is truly able to induce
inflammation in vivo. Moreover, there is now evidence that much of
the endotoxin produced in tissues may be inactivated by acyloxyacyl
hydrolase before it reaches the blood,248 and several other endotoxinneutralizing mechanisms have increased activity in the plasma of sick
humans.249-251,252 The factors that promote the binding of endotoxin to
lipoproteins, which sequester the lipid A moiety and prevent cell activation, are more effective.251 For example, and blood levels of BPI, a
neutrophil-derived, endotoxin-neutralizing protein, increase.253 The
low amounts of endotoxin that circulate in septic patients may thus be
unable to stimulate cells within the systemic compartment. In addition,
even relatively mild stress induces changes in circulating monocytes
that reprogram them to produce less TNF when they are stimulated
by endotoxin.70 Finally, the high concentrations of LBP that are found
in plasma during the systemic response to infection may inhibit the
ability of LPS to activate monocytes, possibly by preventing LPS transfer from CD14 to MD-2TLR4.254,255
It is thus not surprising that the correlation between endotoxemia,
gram-negative bacteremia, and severe sepsis has been inconsistent
and often weak.256-258 This does not mean that endotoxin contributes
little or nothing to the pathogenesis of severe sepsis, however. In
most patients who develop severe sepsis caused by a gram-negative
bacterium that produces hexaacyl LPS (and thus can be sensed by
MD-2TLR4),259 the major site for the stimulatory action of endo
toxin may be in an infected extravascular tissue, not the circulating
blood. It is also possible that endotoxin is more active in the blood of
acutely infected, previously healthy patients, in whom the enhanced
endotoxin-inactivating mechanisms cited previously have yet to be
induced and in whom circulating endotoxin has been associated with
poor outcome.243,256

Other Bacterial Toxins

Staphylococcal and streptococcal toxic shock syndrome toxins (TSST1, streptococcal pyrogenic exotoxins, streptococcal mitogenic exotoxin
Z260) are superantigens that can activate large numbers of circulating
T cells to release cytokines. They do so by cross linking major com
patibility complex (MHC) class II molecules on antigen-presenting
cells with T-cell receptor V domains, thus triggering the T cell to
release proinflammatory cytokines.261-263 Although there is strong
circumstantial evidence that these toxins play a central role in

925
versus intravascular infection, infection with commensal versus pathogen, or others? Answers to these questions may become possible when
a quantitative description of the underlying biochemical mechanisms
of severe sepsis and septic shock is achieved.

Summary

RECOVERY MECHANISMS

The evidence reviewed here suggests that severe sepsis is a hetero


geneous disorder of tissue metabolism in which an altered micro
circulation plays a major role. Because tissue metabolism and the
microcirculation are normally regulated via peripheral nerves and circulating hormones, it seems likely that neuroendocrine derangements
are closely tied to organ dysfunction and septic shock. The most proximal cause(s) remain unknown, however, and how the phenomena
discussed here (e.g., complement activation, coagulopathy, mediator
action or desensitization thereto, endothelial injury, microcirculatory
dysfunction) interact to produce the syndromes is uncertain. On the
other hand, it is possible to draw tentative conclusions regarding the
interactions between certain microbial triggers and the human host.
Three scenarios illustrate the spectrum:
1. Opportunistic commensal bacteria typically invade across disrupted epithelia, often into hosts in whom immunosuppressive
acute-phase responses are already occurring because of illness,
injury, or infection. A vigorous local inflammatory response, usually
initiated by host sensing of conserved microbial molecules,265 is
unable to kill the bacteria because of mechanical failure (obstructed
drainage pathway), immunosuppression (neutropenia, endogenous immunosuppression), or other factors (including bacterial
virulence determinants). These bacteria invade the bloodstream
when local defenses are unable to kill or contain them; bacteremia,
when it occurs, is often transient and may be less important than
locally-produced mediators as a trigger for severe sepsis and septic
shock.208 Outcome is strongly related to the patients underlying
physiologic fitness. In the acute management of these patients, a
diligent search for the primary focus of infection is essential.
2. At the other end of the spectrum are pathogenic microbes that can
survive and multiply in previously healthy humans. They can invade
without eliciting clinically significant inflammation other than, in
some cases, pneumonia, lymphadenopathy, or a lesion at a cutaneous entry site. If their growth is not controlled by innate immune
defenses, the microbes may enter the bloodstream, infect vascular
endothelial cells and/or blood cells, and release toxins or other
molecules that stimulate inflammation or induce damage within the
blood and tissues. The circulating microbes may provoke both
shock and profound coagulopathy that not uncommonly results in
hemorrhage and/or arterial thrombosis. Examples include S. pneumoniae, N. meningitidis, R. rickettsii, Y. pestis, Salmonella Typhi,
B. anthracis and probably V. vulnificus and C. canimorsus. With
many of these, the absence of an early proinflammatory (local) host
defense is an important key to pathogenesis.27,265 Certain viruses
may also be in this category; there is evidence that symptomatic
infection with filoviruses (e.g., Ebola), for example, which invade
without provoking local inflammation and infect monocytemacrophages in many tissues, may be prevented by an early proinflammatory systemic response.266 Recent research has associated
inherited defects in innate and/or acquired immune function with
susceptibility to some of these pathogens.267
3. Other stimuli, such as gram-positive bacterial superantigens, may
be produced by extravascular bacteria and diffuse into the blood or
be released into it by circulating bacteria. They activate T lymphocytes in the blood and tissues to release cytokines; in poorly understood ways, these cytokines induce organ dysfunction and cause
shock.262,263
Although each of these microbe-host interactions leads to the syndromes known now as severe sepsis and septic shock, they are sufficiently different from one another that they force the question: Is the
apparent continuum from sepsis to septic shock truly a single process,
a final common path that can be induced by many different initiating
events, or do different microbe-host interactions produce severe sepsis
and septic shock in different ways? If the latter, which are the most
important determinants: susceptibility genes, underlying disease, age,
physiologic state at the time infection occurs, primary extravascular

Recovery follows successful host defense so regularly that its mechanisms have attracted little investigation, yet the time required for
recovery is by no means predictable after host defenses have failed (see
Prognosis). Renewed interest in understanding recovery has followed the discovery of novel arachidonic acid derivatives (lipoxins,
resolvins) that help resolve inflammation in tissues. Anti-inflammation
(preventing inflammation-induced damage) and resolution (clearing
the battlefield and promoting return of homeostasis) are overlapping
yet distinct processes with somewhat different regulatory mechanisms.268 Tissue resolution mechanisms include neutrophil apoptosis,
macrophage emigration, efferocytosis of dead cells, and the production
of lipoxins, resolvins (and other lipids), proteases, and gaseous signals
that promote restoration of homeostasis in tissues.269 Little is known
about how these processes are regulated during recovery from infection, either in local tissues or in the blood and uninfected organs.
What happens when a sick patient turns the corner and begins to
improve? What turns off the bodys anti-inflammatory (immunocompromising) responses? Do hypofunctioning organs only recover when
the inflammation-inducing stimulus has been removed? If killing the
inciting microbes is necessary, is it sufficient, or must potent microbial
signal molecules, such as LPS, also be inactivated?65,66 Does severe
sepsis induce epigenetic or other changes that alter host physiology
long term64,270? What is the nervous systems role in recovery? Are late
deaths and disability caused by damage incurred during the acute
crisis,271 failure of some key recovery mechanism(s), or other processes? These are among the questions that await future students of the
bodys harmful responses to infection. Answering them may uncover
new ways to improve outcome.

CLINICAL MANIFESTATIONS

Patients with severe sepsis and septic shock experience derangements


in both of the bodys major communication networks, the nervous
system, and the blood. The function of every organ may be affected.

Nervous and Neuroendocrine Systems


Cerebral Function

Individuals who experience relatively mild infectious illnesses may


exhibit subtle abnormalities in cognitive performance. It is therefore
not surprising that confusion and other alterations in higher cerebral
function are often early manifestations of severe sepsis, particularly in
older adult patients, or that the severity of these changes has correlated
with patients overall severity of illness.272
Sepsis-associated encephalopathy (SAE) is defined as diffuse cerebral dysfunction that accompanies sepsis in the absence of direct CNS
infection, structural abnormalities, or other types of encephalopathy.273 Delirium is the most common clinical manifestation, occurring
in 30% to 50% of patients with severe sepsis. In general, the severity of
SAE parallels the severity of other manifestations of sepsis. Because
there are no specific markers for SAE, the diagnosis relies upon excluding primary CNS infections and other causes of encephalopathy. Proposed underlying mechanisms include microscopic brain injury,
blood-brain barrier and cerebral microcirculation dysfunction, altered
CNS metabolism, and impaired cholinergic neurotransmission. One
study found white matter lesions, suggesting increased blood-brain
barrier permeability, in five of nine septic patients evaluated using
magnetic resonance imaging274; a more recent survey concluded that
prolonged delirium may be associated with smaller brain volumes and
long-term cognitive impairment.275 Another analysis found that
patients who experience severe sepsis may have cognitive and functional defects that last for years.276

Hypothalamic-Pituitary-Adrenal Axis

The normally pulsatile pattern of pituitary hormone release (growth


hormone, ACTH, prolactin) is often blunted in critically ill patients, as
is the normal circadian variability in levels of cortisol, leptin, IL-6, and

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

producing the gram-positive bacterial toxic shock syndromes, proof of


causation has not been attained. There is also evidence that bacterial
cell wall lipoproteins, which can signal cells via TLR2, may circulate in
the blood of septic animals and provoke inflammation.264

Part II Major Clinical Syndromes

926
other hormones. As patients develop septic shock, high plasma concentrations of vasopressin are followed by relatively low levels, possibly
reflecting both loss of baroreflex feedback regulation and vasopressin
depletion from the posterior pituitary.192,277,278 The diagnosis and significance of inappropriately low plasma vasopressin levels have been
controversial.272

Adrenal Insufficiency

Activation of the hypothalamic pituitary adrenal axis is essential for


survival from severe stresses. Adrenalectomized animals are unable
to survive septic or traumatic shock without corticosteroid replacement. Rarely, infectious agents cause primary adrenal insufficiency by
directly inducing adrenal hemorrhage or necrosis. The most frequently
implicated microbes are N. meningitidis, Mycobacterium tuberculosis,
cytomegalovirus (CMV), and Histoplasma capsulatum. CMV-related
adrenalitis has been common in patients with end-stage human immunodeficiency virus (HIV) infection, but its significance has been uncertain. Among the other factors that may contribute to hypoadrenalism
in septic patients are hypoperfusion, cytokine-induced dysfunction of
the adrenals, drug-induced steroid hypermetabolism (rifampin, phenytoin) or inhibition of steroidogenesis (ketoconazole, etomidate),
and desensitization to glucocorticoid responsiveness at the cellular
level.279,280 Adrenal suppression by prior therapy with glucocorticoid or
megestrol should also be considered. Secondary adrenal insufficiency,
caused by pituitary infection or apoplexy, is quite rare. Adrenal responsiveness to ACTH infusion typically returns to normal in patients who
recover from septic shock.281
Traditionally, adrenal insufficiency has been diagnosed if the
plasma cortisol level was less than 10g/dL in the setting of significant
stress or if the level did not increase more than 9g/dL in response to
ACTH stimulation (250g synthetic ACTH [1-24] [cosyntropin]).282-284
Unfortunately, these criteria do not adequately measure the reversible
dysfunction of the HPA axis that occurs in critically ill septic patients.
A clinical entity, critical illnessrelated corticosteroid insufficiency
(CIRCI), has been proposed to describe this state, which reflects inadequate cellular corticosteroid activity resulting from adrenal insufficiency, tissue corticosteroid resistance, or both.285 CIRCI is associated
with exaggerated and prolonged inflammatory responses to infection.
Whereas the aldosterone response to exogenous ACTH seems to be
maintained in most patients with severe sepsis,284 a state of hyperreninemic hypoaldosteronism has been described in critically ill individuals,
most of whom have been hypotensive.188,189
The textbook manifestations of adrenal insufficiency (hyponatremia with hyperkalemia, hypothermia, eosinophilia, hyperpigmentation, nausea, vomiting) are not often attributed to adrenal dysfunction
in septic patients. Hypotension and hypoglycemia may be the most
commonly recognized manifestations.

Autonomic Dysfunction

Heart rate variability286 is influenced by the balance of vagal and sympathetic inputs to the sinoatrial node. Autonomic reflexes can modulate these inputs, as can the central (vasomotor and respiratory centers)
and peripheral (arterial pressure and respiratory movement) oscillators. Studies have found that abnormalities in heart rate characteristics,
measured using spectral analysis, precede (in neonates287,288) or coincide with (in adults289) the onset of septic shock, and that they may
predict in-hospital mortality in some settings.290 Although the precise
basis for these changes is uncertain, in general they seem to reflect a
decrease in sympathetic input to the cardiac pacemaker. They may
reflect an uncoupling of the biologic oscillations in heart rate, blood
pressure, respiration, temperature, and other functions that are normally connected through neural networks.291,292

Peripheral Nerves, Muscles

Critical illness polyneuropathy and myopathy may occur in patients


who have been ill for a week or more.293 The clinical features include
difficulty in weaning from a ventilator, generalized wasting of the
limbs, and diffuse weakness (tetraparesis). The diagnosis is usually
made when electromyographic examination294 reveals denervation
potentials compatible with axonal polyneuropathy, predominantly of
distal motor fibers. A muscle biopsy may show edema, atrophy, and

necrosis; a mononuclear cell infiltrate may be present.295 Glucocorticoids and neuromuscular blocking agents may contribute to the pathogenesis and further complicate the clinical picture.296

Blood Compartment
Blood Cells

The composition of the circulating blood has usually been viewed


through a limited window, the peripheral vein. A neutrophilic leukocytosis is the normal response to bacterial or fungal infection. It is
produced by mobilizing neutrophils from the marginal pool as well as
the marrow (see acute-phase and anti-infective responses under
Pathogenesis). Failure to mount a neutrophilic leukocytosis has been
associated with a poor outcome.
At the onset of sepsis, peripheral blood lymphopenia occurs,
reflecting diminished numbers of T, B, and NK cells.297-299 The apparent
effects of sepsis on different T-lymphocyte subsets has varied among
studies, resulting in part from differences in the timing of blood sampling, patient selection, and presentation of the data as either absolute
cell numbers (usually decreased) or relative percentages of the total
lymphocyte population (often unchanged). At least in part, the reduction in circulating CD4+ cells may be due to apoptosis.298,300 In contrast,
the numbers of circulating B-lymphocytes may increase301 despite
apoptotic cell death. Cytokine production by circulating T cells often
has had a helper T-cell 2 (Th2) predominance.302 T-regulatory lym
phocyte (CD4+CD25+Foxp3+) numbers have been unchanged or
increased.303,304 The percentage of T-helper lymphocytes producing
IL-17 increases, and the fraction that produces IFN- decreases at
the onset of sepsis; this pattern may reverse after 1 week.304 NK-cell
(CD3+, CD56+) absolute numbers fall and their IFN- production is
reduced.299
Monocyte numbers do not change substantially, but their cellular
function is altered. Decreased cytokine responses and cell-surface
expression of HLA-DR are common and have been used as biomarkers
of immunosuppression in severely ill patients.305 Increased expression
of CD163 and CD206, markers of alternative activation phenotypes,
occurs within the first week of severe sepsis.304
Thrombocytopenia is a frequent finding in patients with severe
sepsis.83,207 Although thrombocytopenia often accompanies DIC, it
may be the only routinely measured clotting parameter that is abnormal; on the other hand, many patients with low-grade DIC do not have
thrombocytopenia. The basis for isolated thrombocytopenia in septic
patients is probably multifactorial, with peripheral nonimmune
destruction,306 hemophagocytic histiocytosis,307 and marrow suppression playing variable roles.

Plasma Lipids

Striking changes occur in the circulating lipids and lipoproteins.308


High-density lipoprotein (HDL) and low-density lipoprotein (LDL)
levels decrease, whereas triglyceride, free fatty acid, and very lowdensity lipoprotein (VLDL) levels increase. The decrease in serum
cholesterol is almost entirely accounted for by lower concentrations of
cholesterol esters in circulating HDL and LDL.251

Glucose

Hypoglycemia is a relatively uncommon manifestation of sepsis.


Although many of the reported cases have occurred in patients with
hepatic or renal disease or malnutrition, hypoglycemia has also been
observed in patients with no definable cause other than sepsis.309 The
pathogenesis of hypoglycemia is not well understood, but adrenal
insufficiency should be considered in such patients. Moderate or severe
hypoglycemia was associated with an increased risk of death from
distributive shock in patients who received either intensive or conventional glucose control.310 The bodys acute metabolic responses to infection maintain the blood sugar concentration through gluconeogenesis,
glycogenolysis, and insulin resistance (see acute-phase and metabolic
responses under Pathogenesis); hyperglycemia may result, especially
in diabetics or when glucose-containing fluids are administered.

Lactate

Increased blood lactate concentrations and an increased lactate-topyruvate ratio are often seen in patients with severe sepsis, even in the

The prevalence of DIC increases as the inflammatory response intensifies,6 reaching approximately 30% to 50% in patients with severe sepsis.
The patients underlying condition (e.g., infection, solid cancers, hematologic malignancies, obstetric diseases, trauma, liver disease) can
influence diagnostic laboratory tests. In addition, all of these conditions can be complicated by the development of sepsis, making the
diagnosis and treatment of DIC dependent on the clinical context
rather than on any one specific laboratory parameter.316
Commonly used screening assays for DIC include (1) a reduced or
downward trend in the platelet count (usually < 100,000/mm3); (2) the
presence of fibrin-related markers, including fibrin degradation products, D-dimers, or soluble fibrin in plasma; (3) prolongation of the
prothrombin time or the activated partial thromboplastin time (>1.2
times the upper limit of normal); and (4) low plasma levels of endogenous anticoagulants, such as antithrombin III and protein C.85,317
Reduced levels of ADAMTS13 activity and/or elevation of soluble
thrombomodulin, plasminogen activator inhibitor, von Willebrand
factor, and von Willebrand factor propeptide may be seen, although
none of these tests offers a secure diagnosis of DIC or predicts its
outcome.318 Serial measurements of these tests may improve the diagnostic certainty of suspected DIC.316 The use of low levels of antithrombin and protein C for the diagnosis of DIC was challenged by Asakura
and co-workers,87 who found no differences in the plasma activity of
antithrombin and protein C between septic and control patients after
stratification for plasma albumin levels.
The most common adverse consequence of DIC is hemorrhage,
which is most often apparent as oozing from wounds or as gastrointestinal (GI) bleeding. Thrombosis of large and small vessels may also
occur, usually in relationship to local tissue infection or indwelling
catheters.133,319 In general, thrombosis-induced tissue injury is most
apparent when there is cutaneous necrosis and especially when blood
flow to a distal structure (finger, toe, hand, foot, tip of the nose) is
interrupted. There is evidence that vasoconstriction contributes to the
pathogenesis of arterial thrombosis, and most attempts to restore blood
flow have involved interfering with the sympathetic nerve supply to
the affected extremity.320 In one instructive case, a young boy with
purpura fulminans developed gangrene of three extremities; in the
spared limb, vasoconstriction was impaired because of a brachial
plexus injury acquired at birth.139

Dysfunction of Other Organs

Patients entered into studies of severe sepsis must have evidence for
one or more dysfunctional organ systems. As is shown in Figure 75-4,
hypotension is the most commonly noted abnormality; the frequency
with which other organ systems are affected ranges from 5% to 50%.
There is considerable patient-to-patient variability in the manifestations of severe sepsis.

Acute Lung Injury

Hyperventilation, with respiratory alkalosis, can be one of the earliest


manifestations of sepsis. Similarly, pulmonary dysfunction typically
occurs early in the course of severe sepsis.321 The clinical diagnosis of
ARDS is based upon four elements: (1) the occurrence of lung injury
within 1 week of a known clinical insult, (2) chest imaging that shows
bilateral opacities, (3) the absence of cardiac failure or fluid overload,

50

Shock

DIC

CNS

Hepatic

Renal

25

Pulmonary

Clotting Factors

75

FIGURE 75-4 Organ dysfunction at entry into studies of


severe sepsis. Bars show means of data from six representative
studies.14,315,449,451-453 Brackets show the minimal and maximal values
reported. The definitions used to diagnose organ dysfunction varied somewhat from study to study. Renal dysfunction was uncommon in some
series and very common in others. CNS, central nervous system; DIC, disseminated intravascular coagulation.

and (4) hypoxemia. The descriptive term acute lung injury has been
supplanted by new definitions (the Berlin Definition): ARDS is classified as mild (200mmHg < partial pressure of arterial oxygen (Pao2)/
fractional inspired oxygen (Fio2) < 300mmHg), moderate (100mmHg
< Pao2/Fio2 200mmHg), or severe (Pao2/Fio2 100mmHg).322 The
underlying pathology is diffuse alveolar epithelial injury, with increased
barrier permeability and exudation of protein-rich fluid into the interstitial and airspace compartments.321 Elevated plasma angiopoietin-2
levels have been found to presage onset of ARDS in high-risk patients,323
supporting an important role for endothelial injury in pathogenesis.
Neutrophils and monocytes accumulate in the lungs and may form
cellular aggregates in pulmonary vessels. Significant right-to-left
shunting occurs. Dead space volume increases and compliance
decreases, augmenting the work of breathing and often necessitating
mechanical ventilation. Indeed, a common indication for mechanical
ventilation is respiratory muscle fatigue; in patients who are obtunded
or have impaired gag reflexes, intubation may also be used to prevent
aspiration of oropharyngeal or gastric contents.
Patients who recover from ARDS may have significant functional
impairment related to the healing process, which can produce restrictive defects and diminish diffusing capacity.

Renal Dysfunction

Severe sepsis is often accompanied by azotemia and oliguria. The renal


abnormalities range from minimal proteinuria to profound renal
failure; postmortem studies have found focal acute tubular injury and
minimal glomerular damage.136 The pathogenetic mechanisms include
hypovolemia, hypotension, renal vasoconstriction, and toxic drugs (in
particular, aminoglycosides).324 In most cases, sepsis-induced renal
injury is largely reversible. On the other hand, sepsis can also occur in
patients who have acute kidney injury of other etiologies and then
acquire nosocomial infection. Predictors of sepsis after acute kidney
injury included oliguria, higher fluid accumulation, higher severity of
illness score, nonsurgical procedures after acute kidney injury, and
dialysis.325 Sepsis that follows acute kidney injury is associated with
high mortality and a high rate of dependency on dialysis at the time
of hospital discharge.

Gastrointestinal Tract Injury

Peripheral vasodilation redistributes the cardiac output so that visceral


organs are underperfused; the morbidity and mortality of septic shock
have correlated with the degree of tissue (e.g., gastric) hypoperfusion.
Several mechanisms have been proposed for gut failure that results in
sepsis and multiple organ hypofunction: disruption of an intact intestinal epithelium, reperfusion injury, and translocation into the bloodstream via mesenteric lymphatics of bacteria, bacterial products, and
inflammatory mediators.326 One study of critically ill patients in an ICU

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

absence of shock. Contrary to long-standing dogma, the accumulation


of lactate and pyruvate in the blood is not simply a consequence of
limited tissue oxygenation (hypoxia).311 Rather, there is evidence that
it results from the marked increases in aerobic glycolysis that occurs
in muscle, phagocytes, and other cells (see earlier), triggered by
cytokine-induced glucose uptake and/or catecholamine-stimulated
increases in Na+-K+ pump activity.312-314 Increases in blood lactate may
also result from decreased lactate clearance by the liver, mitochondrial
dysfunction, and (respiratory) alkalosis, which decreases lactate uptake
by cells. Correction of hypotension with vasopressors does not always
correct lactic acidosis, possibly because tissue perfusion remains compromised by vasoconstriction or abnormal microcirculatory vasoregulation. Intravenous ibuprofen significantly lowered blood lactate levels
in one clinical trial without improving outcome.315

Percent of cases (at study entry)

927

Part II Major Clinical Syndromes

928
found that increased GI permeability preceded the onset of multiple
organ hypofunction.327
In addition, aspiration of the microbial and chemical contents of
the upper GI tract into the tracheobronchial tree may initiate nosocomial pneumonia. Small erosions of the gastric and duodenal mucosa
predispose to upper GI bleeding. Ileus, a common feature of septic
shock, may persist for a day or two after shock resolves.

Desquamation of the skin of the distal extremities does not usually


occur until the second week of illness.
Ischemic changes (dusky or pallid color, coldness, loss of pulses)
usually occur in the hands and feet, where they may follow thrombosis
of small-sized to midsized arteries. Inflammation-induced coagulopathy and vasoconstriction both contribute to their pathogenesis, as
noted earlier.

Hepatic Dysfunction

Septic Shock

The principal sepsis-associated abnormality is cholestatic jaundice,


characterized by elevations in conjugated and unconjugated bilirubin
(<10mg/dL). These changes occur in patients with and without preexisting liver disease and may precede recognition of infection.328 In
patients with severe sepsis, elevated alkaline phosphatase, bilirubin,
and amino transferase levels are common, but frank hepatic failure
(shock liver) is unusual. If the duration of septic shock is prolonged,
however, a massive rise in serum transaminases may follow hypoxic
necrosis of centrilobular liver cells.329 Hypoxic hepatitis has a poor
prognosis.

Immune Dysfunction

Reactivation of latent herpes simplex and CMV infections occurs in


approximately 35% of critically ill patients,330-333 and CMV viremia has
been described in a similar fraction of patients with severe sepsis.334
The extent to which CMV contributes to immunosuppression in these
patients is not known, yet patients with CMV antigenemia have had
higher rates of nosocomial infection, prolonged hospitalization, and
mortality.332,335 Although clinical experience suggests that patients with
severe sepsis are at increased risk for secondary infections,336 a quantitative documentation of this risk has not been published. In one
autopsy study of patients who died in an ICU, 80% had an undiagnosed
infectious focus.337

Cutaneous Manifestations

A wide range of skin lesions may occur in patients with severe sepsis.
They include the cutaneous reaction at a local inoculation site (pustule,
eschar), lesions that appear at sites of hematogenous seeding of the skin
or underlying soft tissue (petechiae, pustules, ecthyma gangrenosum,
cellulitis), diffuse eruptions caused by bloodborne toxins (e.g., TSST),
and hemorrhagic or necrotic lesions. Recognition of certain characteristic lesions can greatly assist etiologic diagnosis.
Musher338 distinguished three patterns of tissue involvement by
gram-negative enteric bacilli.
1. Cellulitis and thrombophlebitis are associated with intense local
inflammation. Bacteria implicated in case reports include Campylobacter fetus, Vibrio species, and Aeromonas hydrophila.
2. When the inflammatory response is impaired, usually by neutro
penia, ecthyma gangrenosum or bullous lesions may occur (see
later); Pseudomonas aeruginosa is the most commonly isolated
microorganism.
3. In symmetrical peripheral gangrene associated with DIC, fibrin
thrombi are seen in small vessels, but neither inflammatory cells nor
bacteria are found.
Palpable petechiae or purpura suggests leukocytoclastic vasculitis,
which may be caused by N. meningitidis, R. rickettsii, S. pneumoniae,
H. influenzae, and occasionally S. aureus.339 Pustules often contain
S. aureus or C. albicans. Cellulitis is most often caused by S. pyogenes
but may, in unusual settings, result from bacteremia caused by clostridial species or one of the gram-negative bacilli mentioned earlier.
The term ecthyma gangrenosum (necrotic blister) is used for
lesions that begin as papules surrounded by erythema and edema and
evolve into hemorrhagic, necrotic ulcers. They typically appear between
the umbilicus and the knees. Although often considered pathognomonic for P. aeruginosa bacteremia, ecthyma gangrenosum has also
been observed in patients whose blood cultures grew Klebsiella, Serratia, A. hydrophila, or E. coli. Pathologic examination reveals direct
invasion of venules by bacteria and local thrombosis. Almost all
patients with ecthyma gangrenosum are neutropenic at the time the
lesions develop.
Diffuse erythema (erythroderma) is a characteristic finding in
toxic shock syndrome caused by either S. aureus or S. pyogenes.

In prospective studies of the natural history of critical illness,6,340


patients have progressed from sepsis to severe sepsis to septic shock,
suggesting that these syndromes are part of a continuum. In the study
by Rangel-Frausto and co-workers, 71% of the patients who developed
septic shock had been previously classified as having severe sepsis,
sepsis, or SIRS.6
The cardiovascular impact of sepsis has two components: myocardial dysfunction and relative hypovolemia resulting from vasodilation.
A pattern of sepsis-associated myocardial dysfunction was recognized
during the 1980s. It includes reduced left and right ventricular ejection
fractions, increased left and right ventricular end-diastolic volumes,
and an elevated heart rate and cardiac output.341 This pattern typically
follows fluid resuscitation, occurs 24 to 48 hours after the onset of
severe sepsis, and is reversible in patients who survive 5 to 10 days after
its onset. The cardiac depression associated with septic shock reflects
the effects of inflammatory mediators on cardiac myocyte and microcirculatory function, is not caused by ischemia, and does not usually
require inotropic therapy. However, a small fraction of patients with
septic shock may develop profound myocardial depression in conjunction with vasodilatory shock and require inotropic support (i.e., dobutamine) in addition to vasopressor therapy.
Mechanisms implicated in the development of sepsis-induced myocardial depression include alterations in calcium homeostasis, mitochondrial dysfunction, apoptosis, circulating cardiosuppressant
mediators, nitric oxide, and peroxynitrite. Some authors have posited
that sepsis-induced cardiodepression is a form of cardiac hibernation.342 A postmortem study found that cardiac myocyte cell death was
rare, whereas sepsis-induced focal mitochondrial injury was present in
many cells.136 Connexin-43, a gap junction protein that forms electrical
synapses between myocytes, was altered in a way that suggested cardiomyocyte injury. These findings were said to be in keeping with the
reversible nature of the myocardial injury induced by sepsis.136,343
Hypovolemic shock can usually be reversed by administering
intravenous fluids. In the normovolemic patients with vasodilatory
(warm, hyperdynamic) shock, studied prospectively by Abraham and
co-workers,344,345 the first noticeable change was a fall in oxygen consumption, which was followed by compensatory increases in cardiac
output and oxygen delivery; peripheral vascular resistance decreased
progressively over the 24-hour period before the onset of overt hypotension. The lowest blood pressure was recorded when the cardiac
output failed to compensate for low vascular resistance.

Severe Sepsis and Septic Shock: Is


There a Tipping Point?

When they compared whole-blood gene expression profiles in patients


with sterile SIRS and early sepsis (infection-induced SIRS), Johnson
and co-workers346 found that upregulation of mitogen-activated
protein kinase-14 (MAPK-14) (p38) occurred up to 48 hours before
the diagnosis of clinical sepsis. Other mRNAs that increased in abundance in early sepsis were those for members of the IL-1 receptor and
IL-22 receptor families. A subsequent study by the same group found
that many TLR-related effector molecules were upregulated (less than
twofold) in peripheral blood cells 24 hours before the diagnosis of
clinical sepsis347; MAPK-14 was again among the harbinger molecules.
Using mass spectrometry to identify plasma proteins, the authors also
reported that 134 unique plasma proteins were overrepresented in
sepsis patients compared with ICU patients who had only SIRS; most
were coagulation or complement proteins.348
Another potential marker for the transition to severe sepsis is a
decrease in the natural variability in heart rate, respiratory rate, or
temperature. There may also be loss of the normal circadian variability
in plasma cortisol, glucose, iron, and cytokine levels. Heart rate

929

DIAGNOSIS

No bedside or laboratory test provides a definitive diagnosis. There is


also considerable inter-individual and time-dependent variability in
the expression of the bodys responses to infection, so a diagnostically
useful profile of laboratory tests is not possible. On the other hand,
certain findings are sufficiently suggestive that they should prompt
further evaluation. In addition to the signs that comprised SIRS (tachycardia, tachypnea, leukocytosis or leukopenia, and fever or hypothermia; see Table 75-1), findings such as altered mental status, unexplained
hyperbilirubinemia, lactatemia, metabolic acidosis or respiratory alkalosis, and thrombocytopenia can be useful clues. The appearance of
new lesions on the skin or mucosae may also be suggestive.
One normal response to infection is a neutrophilic leukocytosis in
the peripheral blood. Infections that are typically associated with
peripheral blood leukopenia include typhoid fever, brucellosis, Rocky
Mountain spotted fever, Colorado tick fever, and ehrlichiosis; in individuals with severe sepsis induced by bacteria, leukopenia is more
common among children than adults.306 Fever is also a normal response
to infection, and an increase in body temperature above a certain level
(usually 38.0 or 38.3 C) is often the trigger for initiating a diagnostic
evaluation. Some septic patients may be euthermic or hypothermic,
however. These include older adults, patients with open wounds or
large burns, and patients taking anti-inflammatory or antipyretic
drugs. In patients with comorbid conditions or immunosuppression,
the clinical manifestations of sepsis may also be atypical: for example,
the fever response may be blunted (concomitant glucocorticoid use,
continuous renal replacement therapy), the white blood cell count may
be normal (depressed bone marrow reserves resulting from chemotherapy or stem cell transplantation), and the heart rate may be normal
(-blockers, sick sinus syndrome).

Differential Diagnosis

Numerous noninfectious conditions can mimic sepsis by presenting


with hypotension and/or organ failure. They include burns, trauma,
adrenal insufficiency, pancreatitis, pulmonary embolism, dissecting or
ruptured aortic aneurysm, myocardial infarction, occult hemorrhage,
cardiac tamponade, and drug overdose. Fever and hypotension can
also be caused by a number of noninfectious processes, including
adrenal insufficiency, thyroid storm, pancreatitis, drug hypersensitivity
reactions, malignant hyperthermia, serotonin syndrome, and heatstroke. Vasodilatory shock can be a manifestation of anaphylaxis. A
sepsis-like syndrome may follow cardiopulmonary bypass; there is circumstantial evidence that the trigger is either pump trauma to circulating leukocytes or bacterial endotoxin absorbed from the gut. Indeed,
sepsis and septic shock may complicate any of the disease states
described above. One should always consider occult sepsis in the differential diagnosis of fever, acutely altered mental status, thrombocytopenia, or hypotension.350

Cultures

Cultures are essential for identifying the likely microbial invaders and
ascertaining antimicrobial susceptibility patterns. For optimal sensitivity and specificity, blood cultures (split between aerobic and anaerobic
bottles) should be drawn from two or three different venipuncture
sites.351 The volume of blood drawn (adults 20 to 30mL/venipuncture,
children no more than 1% of total blood volume) is the most important
variable in detecting bacteremia.352
Bacteremia may be categorized as transient, intermittent, or continuous (reviewed by Mancini and co-workers353). Transient bacteremia lasts minutes to hours and may occur with manipulation of either
anatomic sites colonized by normal flora (i.e., colonoscopy) or local
infected sites. Intermittent bacteremia is associated with closed-space
infections (e.g., abscesses) or focal infections (e.g., pneumonia). Persistent low-grade bacteremia is associated with an intravascular focus,
such as endocarditis or vascular graft infection.

In patients with indwelling vascular catheters, the rate of microbial


growth in a culture of blood drawn through the catheter may be compared with that of blood drawn from a peripheral vein; a difference in
the time to positivity of 2 or more hours suggests catheter infection.354 Careful preparation of the skin is essential to avoid false positive cultures from skin contaminants. Chlorhexidine (2%) has a short
(15 to 30 seconds) drying time compared with 10% povidone-iodine
or 1% to 2% tincture of iodine (approximately 2 minutes)355; in one
recent trial, cleansing with 2% chlorhexidine in 70% alcohol was superior to 10% aqueous povidone-iodine for preventing culture contamination.356 Using these agents properly can reduce costs and preserve
resources.352
Cultures and microscopic examination of urine, sputum (including
tracheal aspirate if done within a few hours of intubation), likely
infected fluids, purulent wound drainage, and skin lesions should also
be obtained. Gram-stained material obtained from biopsies or needle
aspirates of petechial lesions can provide a rapid diagnosis in patients
with meningococcemia.357
New molecular and other nonculture-based methods have the
potential to speed diagnosis of serious infections. These include nucleic
acidbased diagnostics applied to cultures from clinical samples or
used directly on blood or serum.353 Detection of microbial nucleic
acids does not necessarily indicate that a viable organism was present
or that transient bacteremia was related to a true infection.353

Diagnostic Imaging

Axial tomography is an important complement to routine chest and


abdominal radiography to assess for unrecognized sources of infection
in the sinuses, lungs, liver, and abdomen. Ultrasonography and cholescintigraphy (hepatobiliary iminodiacetic acid [HIDA] scanning)
may be useful for evaluating gallbladder function.

Cytokine and Biomarker Levels

Although there have been many attempts to identify a cytokine profile


that would distinguish infected patients from those with systemic
responses to other stimuli, none has been very successful. A review
of 178 biomarkers used for diagnostic and prognostic purposes
noted that all lack sufficient sensitivity and specificity to be used in
routine clinical practice.358 Studies of biomarkers in severe sepsis have
often been limited by the absence of immunosuppressed patients
or patients with nonrespiratory tract infections. Variability in physician adherence to treatment algorithms may also compromise their
validity.

Adrenal Insufficiency in Patients with


Septic Shock

The clinical and laboratory diagnoses of sepsis-associated relative


adrenal insufficiency are inexact and controversial (see adrenal insufficiency under Clinical Manifestations). Unresolved issues include
the need to measure free cortisol, the diagnostic significance of
cortisol-binding proteins, the utility of salivary cortisol levels, and the
quantitation of tissue glucocorticoid resistance.359 The most useful
clinical definition of relative adrenal insufficiency may be based simply
upon the response to hydrocortisone administration (see Other Therapies). The presence of pressor-dependent hypotension that responds
to the administration of 50 to 100mg hydrocortisone every 6 hours
would strongly support the diagnosis.360 Many experts now recommend obtaining a baseline serum cortisol level before initiating hydrocortisone therapy. A value less than 15g/dL in a patient with septic
shock should encourage careful evaluation for adrenal insufficiency
after recovery from the septic episode. The diagnostic value of the
ACTH stimulation test is less clear285; of importance, the reversal of
vasopressor-dependent shock by low dose steroids is not predicted by
the response to the ACTH stimulation test.361

THERAPY

Sepsis, severe sepsis, and septic shock are medical emergencies.


Despite intensive effort, including more than three dozen clinical
trials, optimal therapy has changed little since the 1960s.362 As summarized by Young,363 Early clinical suspicion, rigorous diagnostic
measures, aggressive initiation of appropriate antimicrobial therapy,

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

variability (HRV) has been studied most intensively; although a


decrease in HRV may herald the onset of systemic organ hypofunction,
particularly in neonates, many therapeutic interventions may influence
HRV in sick patients. Using a composite measure of variability has
been proposed.349

930

Part II Major Clinical Syndromes

comprehensive supportive care, and measures aimed at reversing predisposing causes are the cornerstones of successful management.

Antimicrobial Drugs

Numerous analyses have concluded that early treatment of bacteremic


patients with an appropriate antimicrobial drug improves survival.364-366,367,368 In most of these studies, a drug was considered appropriate if it was able to inhibit the patients microbial isolate(s) in vitro
and was administered within 24 to 48 hours of the onset of bacteremia
or severe sepsis. One study found that appropriate antimicrobial
therapy, as defined by the recommendations of an authoritative antibiotic guidebook, was equally beneficial to patients with septic shock
who did and did not have positive culture results.233 Among patients
with septic shock who received appropriate antimicrobial therapy,
ICU-acquired infection and severity of illness (Acute Physiology and
Chronic Health Evaluation [APACHE] II) were the most significant
determinants of outcome.369 In another case series, inappropriate
antimicrobial treatment was most common (45%) in patients with
nosocomial infections that developed after treatment for a communityacquired infection.364
There is also strong evidence now that survival is more likely
if septic patients receive appropriate antimicrobial drugs as soon
as possible after the diagnosis is suspected. In keeping with the
important role for rapid antibiotic administration promoted by Greisman370 almost 30 years ago, a retrospective review by Kumar and
co-workers371 found a strong relationship between the delay in effective
antimicrobial initiation and in-hospital mortality of septic shock. Each
hour of delay in antimicrobial administration was associated with an
average decrease in survival of 8%. The time to initiation of effective
antimicrobial therapy was the single strongest predictor of outcome.
Others found that antimicrobial administration within 4 hours of
arrival at the hospital was associated with decreased mortality in older
patients with community-acquired pneumonia,372 and antifungal

therapy administered within 24 hours of the onset of shock reduced


mortality from candidemia by almost 50% when combined with adequate source control.373
Patients with severe sepsis should thus receive a broad-spectrum,
intravenous regimen that is effective for both gram-negative and grampositive bacteria, and they should receive it as quickly as possible. The
choice of drugs should be modified according to the patients own
microbiologic culture data and the resistance patterns prevalent in the
patients community or hospital. Under some circumstances, such as
when a patient is neutropenic or develops severe sepsis after having
received a broad-spectrum regimen for another infection, empirical
therapy for Candida species may be warranted (Candida species now
account for 10% or more of the cases of severe sepsis in such patients).
Anti-Candida therapy should also be considered in patients with
severe sepsis who have indwelling catheters. Specific recommendations
are provided in Table 75-4.
With the possible exception of neutropenic patients or those
with P. aeruginosa disease, there is little evidence to support the use
of combination therapy using an aminoglycoside instead of monotherapy with a broad-spectrum drug such as a carbapenem.374 Many
experts consider an extended-spectrum penicillin, combined with a
-lactamase inhibitor, to be effective empirical therapy for most
patients in locales where multiresistant gram-negative bacteria are not
prevalent. This recommendation was questioned recently by a metaanalysis that found that combination antimicrobial therapy improved
survival in patients with septic shock but may be harmful in those with
less severe sepsis.375 Like so many other therapeutic interventions in
septic patients,376 antibiotic benefit seems greatest in the sickest
individuals.
In much of the world, S. aureus isolates are so frequently methicillinresistant that, if S. aureus is a potential causative organism, a drug
active against MRSA is recommended for empirical therapy in pref
erence to oxacillin or nafcillin. Fortunately, S. aureus resistance to

TABLE 75-4 Empirical Antibiotic Options for Patients with Severe Sepsis or Septic Shock
SUSPECTED SOURCE
Skin/Soft Tissue

Lung

Abdomen

Major CommunityAcquired Pathogens

Streptococcus pneumoniae
Haemophilus influenzae
Legionella
Chlamydia pneumoniae

Escherichia coli
Bacteroides fragilis

Streptococcus pyogenes
Staphylococcus aureus
Polymicrobial

Urinary Tract
E. coli
Klebsiella species
Enterobacter species
Proteus spp.
Enterococci

Source Uncertain

Empirical Antibiotic
Therapy

Moxifloxacin or
levofloxacin or
azithromycin plus
cefotaxime or
ceftazidime or cefepime
or piperacillintazobactam

Imipenem or meropenem
or doripenem or
piperacillin-tazobactam
aminoglycoside
If biliary source:
piperacillin-tazobactam,
ampicillin-sulbactam,
or ceftriaxone with
metronidazole

Vancomycin or
daptomycin plus
either imipenem or
meropenem or
piperacillintazobactam;
clindamycin (see text)

Ciprofloxacin or
levofloxacin (if
gram-positive cocci,
use ampicillin or
vancomycin
gentamicin)

Vancomycin plus either


doripenem or ertapenem
or imipenem or
meropenem

Major Commensal
or Nosocomial
Microorganisms

Aerobic gram-negative
bacilli

Aerobic gram-negative
rods
Anaerobes
Candida spp.

Staphylococcus aureus
(? MRSA)
Aerobic gram-negative
rods

Aerobic gram-negative
rods
Enterococci

Consider MDRO if in area


of high prevalence
Consider echinocandin if
neutropenic or indwelling
intravascular catheter

Empirical Antibiotic
Therapy

Imipenem or meropenem
or doripenem or
cefepime (if
Acinetobacter baumanii
or carbapenem-resistant
Klebsiella in ICU, add
colistin)

Imipenem or meropenem
aminoglycoside
(consider echinocandin)

Vancomycin or
daptomycin plus
imipenem-cilastatin
or meropenem or
cefepime,
clindamycin

Vancomycin plus
imipenem or
meropenem or
cefepime

Cefepime plus vancomycin


caspofungin

Dosages for intravenous administration (normal renal function):


*Imipenem-cilastatin, 0.5-1.0g q6-8h
Ciprofloxacin, 400mg q8-12h
*Meropenem, 1-2g q8h
Moxifloxacin, 400mg qd
*Doripenem, 0.5g q8h
Ceftriaxone, 2.0g q24h
Piperacillin-tazobactam, 3.375g q4h or 4.5g q6h
Caspofungin, 70mg, followed by 50mg q24h
Vancomycin, load 25-30mg/kg, then 15-20 q8-12h
Colistin: loading dose = 5mg/kg body weight. For maintenance dosing,
Cefepime, 1-2g q8h
see University of California, Los Angeles Dosing Protocol:
Levofloxacin, 750mg q24h
www.infectiousdiseases-ucla-affiliated.org/Intranet/FILES/ColistinDosing.pdf
*Carbapenems are less susceptible to extended-spectrum -lactamases; base choice on local resistance pattern.
ICU, intensive care unit; MDRO, multidrug-resistant organisms; MRSA, methicillin-resistant Staphylococcus aureus.
For MDRO, resistance usually includes carbapenems.

931

Antimicrobial Chemotherapy for


Specific Etiologies of Severe Sepsis

Although empirical broad-spectrum regimens will provide agents that


are active against most pathogens, some situations may warrant different or additional coverage. For example, tick exposure might warrant
treatment with doxycycline (Rocky Mountain spotted fever) or
atovaquone-azithromycin for babesiosis (with clindamycin if critically
ill) in different exposure environments. Travel to the tropics might
suggest the need for antimalarial therapy. In patients with suspected
or proven streptococcal myositis/fasciitis or toxic shock syndrome,
clindamycin should be given in addition to penicillin G to reduce toxin
production. If staphylococcal toxic shock syndrome is considered,
clindamycin should be given with either oxacillin (if methicillinsusceptible S. aureus [MSSA]), vancomycin, or linezolid. In patients
who may have eaten raw oysters and acquired V. vulnificus bacteremia,
intravenous doxycycline should be used along with ceftazidime or a
fluoroquinolone. Severe sepsis that follows a dog bite may be due to C.
canimorsus, which is usually susceptible to cephalosporins, carbapenems, -lactam-lactamase inhibitor combinations, and quinolones
but resistant to trimethoprim-sulfamethoxazole and aminoglycosides.
Cefotaxime or ceftriaxone is preferred for asplenic patients, who may
have overwhelming bacteremia with S. pneumoniae, N. meningitidis,
H. influenzae type b, or C. canimorsus.

Surgical Drainage (Source Control)

Recovery from severe sepsis or septic shock is unlikely, even with


appropriate antimicrobial therapy and diligent ICU care, if the patient
has an undrained abscess or obstructed viscus.380 An excellent discussion of surgical and nonsurgical source control measures was published by Marshall and others.381 In patients with community-acquired
infections, the most common occult sources are in the lungs and the
urinary tract. Intra-abdominal infections (e.g., diverticulitis, cholecystitis, pylephlebitis), septic arthritis, endocarditis, and osteomyelitis
should also be sought. Nosocomial infections often arise at sites of
epithelial barrier disruption and thus frequently involve intravascular
catheters, endotracheal tubes (pneumonia and paranasal sinusitis),
urinary catheters, and operative wounds or other sites of traumatic
injury.
In general, when a patient develops severe sepsis, all intravascular
and bladder catheters should be removed, with reinsertion at new
sites as needed. It is not often necessary to do surgical exploration
of an infected thrombus because medical management usually
suffices.350

Intravenous Fluids and Vasopressors

Fluid resuscitation is the mainstay of hemodynamic support in patients


with septic shock. Whereas antibiotics or fluids alone did not improve
outcome in animal models of septic shock, these interventions were
found to act synergistically to improve survival.382 Crystalloid is generally used for resuscitation instead of colloid.383 The Saline versus
Albumin Fluid Evaluation (SAFE) trial384 compared fluid resuscitation
with 4% albumin versus saline in a heterogeneous population of ICU
patients who required fluids for intravascular volume depletion. Survival was similar in the two arms at 28 days, and the two fluids were
considered comparable in patients with severe sepsis. Although a
meta-analysis found that albumin was associated with lower mortality
when compared with other fluids,385 a recent trial found that patients
who received crystalloid plus albumin to maintain a serum albumin
concentration of 30 g/L were no more likely to survive than were
patients who received only crystalloid.385a The use of hydroxyethyl
starch preparations for resuscitation caused an increase in mortality
and acute kidney injury in critically ill patients386 and in patients with
septic shock.387 It should be not be used.
The goals of fluid resuscitation in severe sepsis and septic shock are
to ensure adequate tissue perfusion by restoring effective intravascular
volume (depleted by vasodilation and increases in vascular permeability) and to optimize cardiac output by enhancing venous return and
cardiac filling. A reasonable goal in general is maintenance of mean
arterial pressure (MAP) greater than 65mmHg, although in some
patients with long-standing hypertension, a higher MAP may be
required. In most patients, 15 to 30mL/kg or up to 4 to 6L of crystalloid may be required in the early phases of resuscitation. Too little fluid
may cause tissue hypoperfusion and worsen organ function, whereas
excessive fluid administration may impair organ function resulting
from tissue edema. When no further benefit is apparent from additional fluid administration (i.e., restoration of mean arterial blood
pressure), vasopressor administration is essential to maintain adequate
tissue perfusion. However, considerable controversy exists regarding
which hemodynamic parameters should guide resuscitation in septic
patients.388-390 Three international multicenter trials are currently
addressing critical end points in resuscitation.391 Protocol-based resuscitation using an oximetric central venous catheter to monitor central
venous pressures and oxygen saturation did not improve survival of
patients with septic shock diagnosed in the emergency room. Using
this catheter to guide the administration of fluids, vasopressors, dobutamine, or packed red cell transfusions to achieve specific hemodynamic targets was no better than usual care composed of early
antibiotics, fluid resuscitation, and, if needed for venous access, a
central venous catheter.391a
For many years, dopamine was considered the drug of choice for
restoring normotension in patients with septic shock. When used at
low doses (<5g/kg/min), its preferential interaction with dopaminergic receptors was thought to produce renal and splanchnic vasodilation. This notion has been challenged by recent studies and analyses.
In particular, a randomized, controlled clinical trial found that lowdose dopamine infusion did not improve survival or prevent renal
failure in critically ill patients at risk for renal dysfunction,392 and a
similar conclusion was reached by a retrospective analysis of patients
with septic shock in a large clinical trial.393 Many experts now favor
using norepinephrine over dopamine for septic shock.394 A trial of
norepinephrine plus dobutamine (added if needed) compared with
epinephrine found no difference in 28-day all-cause mortality.395
Vasopressin levels initially rise as patients develop shock, then they
fall with more prolonged hypotension. Continuous infusion of arginine vasopressin (AVP) may help restore normotension in patients
with catecholamine-resistant vasodilatory shock. The doses of vasopressin that increase blood pressure in septic patients are lower than
those required in normal individuals. Landry and Oliver193 speculated
that the increase in vasopressor potency may be caused by unoccupied
vascular receptors for vasopressin, the coexistence of autonomic failure
(which potentiates vasopressin action), or vasopressins ability to
enhance the vasoconstrictor effect of norepinephrine, which is present
in markedly elevated concentrations in patients with septic shock.
Vasopressin also directly inactivates KATP channels in vascular smooth
muscle and inhibits the inducible form of NO synthase. Vasopressin is

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

vancomycin or daptomycin continues to be rare in most communities.


If a vancomycin-resistant enterococcus (VRE) is the likely trigger for
severe sepsis, linezolid should be included. Daptomycin is another
alternative drug for MRSA, but its efficacy in patients with severe sepsis
has not been tested, and it should not be used for the treatment of
pneumonia because its activity is inhibited by pulmonary surfactant.
Linezolids toxicities (i.e., thrombocytopenia, anemia, rare serotonin
syndrome) limit its attractiveness as a substitute for vancomycin.
Although there are few data on the use of once-daily dosing of
aminoglycosides in critically ill patients, the available evidence suggests that this administration method is safe.377 The volume of dis
tribution of both tobramycin and gentamicin is higher in critically
ill patients with septic shock than in those without shock. A oncedaily dosage of 7mg/kg produced maximal peak concentration (Cmax)
to minimal inhibitory concentration (MIC) ratios in most patients.
This should be avoided if possible in patients with unstable renal function, anuria, or an increased volume of distribution (i.e., ascites,
anasarca) because of the difficulty in predicting peak and trough
drug levels. Therapeutic drug monitoring is warranted, and more than
one drug level may be needed to determine the appropriate dosing
interval.
The available data also generally support using continuous infusions of -lactam drugs to maximize the time that blood concentrations remain above a target bacteriums MIC, yet adequately sized and
controlled clinical trials have not been reported to date.378 The most
recent study found that continuous infusion only benefited the sickest
patients.379

932

Part II Major Clinical Syndromes

often used as a catecholamine-sparing agent in pressor-dependent


shock, but a mortality benefit has not been seen.391

OTHER THERAPIES
Glucocorticoids

Many patients with septic shock exhibit a rightward shift in the doseresponse relationship between blood pressure and catecholamines.
Annane and co-workers80 found that this occurs most often in patients
with impaired adrenal function and that, in such patients, administering hydrocortisone could return the dose-response curve to normal.
Several factors probably contribute to reduced sensitivity to catecholamines, including downregulation of adrenergic receptors and NOinduced vasopressor resistance. Hydrocortisone increases adrenergic
receptor expression. There is thus a plausible theoretical and experimental basis for using glucocorticoids to treat patients with septic
shock.
Investigators noted several decades ago that very high doses of
corticosteroids were beneficial in animal models of septic shock.
Accordingly, high doses of corticosteroids were widely given as adjunctive therapy for human sepsis and septic shock. Unfortunately, randomized clinical trials of high doses of corticosteroids for sepsis (the
median dose was equivalent to 23,975mg hydrocortisone given over
24 hours) showed that this high-dose approach was harmful,361 and
clinicians abandoned it.
Although the ACTH stimulation test may be useful to identify
patients with shock and overt primary or secondary adrenal insufficiency, it has not been adequate to identify the patients with septic
shock and CIRCI who will respond to physiologic doses of steroids.285,361 As such, some experts now recommend that the decision to
treat with low doses of glucocorticoids should be based on clinical
criteria and not on the results of adrenal function testing.285 In patients
with septic shock who have not responded to fluid and vasopressor
resuscitation, hydrocortisone treatment should be initiated (50mg IV
every 6 hours or with a loading dose of 100mg, followed by a continuous infusion of 10mg/hr), continued for 7 days, and then slowly
tapered over 5 to 6 days. Confirmation of this approach awaits further
large clinical trials and new methods to assess the integrity of the HPA
axis and tissue responsiveness to corticosteroids. Whether there is
added benefit to the addition of a mineralocorticoid, fludrocortisone
(50g PO daily), remains uncertain,359,396 but recent trials have been
negative.397

Anti-inflammatory Drugs

During the 1990s, clinical trials were performed to test the ability of
numerous immunomodulatory drugs to improve survival in patients
with severe sepsis.391,398,399 They included large doses of glucocorticoids,
antiendotoxin agents, antibodies to TNF and TNF-immunoglobulin
fusion proteins that trap TNF, IL-1 receptor antagonist and antagonists
to PAF, bradykinin, phospholipase A2, NO synthase, cyclooxygenase,
bradykinin, and others. Although many of these agents appeared promising in preliminary trials, none reproducibly improved 28-day allcause survival, and some (e.g., a NO synthase inhibitor) caused harm.
Explanations offered for the failure of this approach have included
using the wrong drugs, doses, or duration of therapy; administration
of the drug too late in the clinical course; heterogeneity in the clinical
population treated; and ineffectiveness of single interventions. One
group of experts recommended limiting clinical trials in septic patients
to individuals with specific infectious diseases or sites of infection.400
A meta-regression analysis of 23 clinical trials concluded that the
efficacy of anti-inflammatory drugs in patients with severe sepsis
depends on the risk of dying.376 Although many of the agents studied
work through different biologic mechanisms, their efficacy was consistently greater in patients with a high risk of dying, whereas they were
ineffective or harmful in those with low mortality risk. Studies in
experimental animal models showed similar trends.376 Some of the
same drugs have been very effective in the treatment of rheumatoid
arthritis and other rheumatologic diseases, yet they have also predisposed patients to reactivation of tuberculosis and other infections. By
analogy with this experience, perhaps interfering with the proinflammatory response impairs antimicrobial defenses in patients with less
severe sepsis (in whom systemic anti-inflammation may already be

dominant), whereas some benefit can be derived from blocking even


a single proinflammatory mediator in patients at the more severe end
of the spectrum. To date, modifying inflammation with novel agents
has not been shown to be beneficial.391

Antagonists to Gram-Negative Bacterial


Endotoxin and Related Molecules

Clinical trials have evaluated antiendotoxin polyclonal antiserum (six


studies) and monoclonal antibodies against common epitopes of endotoxin (five studies) for their ability to improve outcome from severe
sepsis induced by gram-negative bacteria. None succeeded as either
prophylaxis or therapy.401 Similarly, a monoclonal antibody against
enterobacterial common antigen, a surface antigen closely linked to
endotoxin, did not benefit septic patients.402 The recombinant form of
a naturally occurring endotoxin-neutralizing molecule, recombinant
BPI (rBPI), may have reduced the need for amputation in children with
fulminant meningococcemia, but it did not improve survival.403 A
potent lipid A analogue that competes with LPS for binding MD-2
(Eritoran24) failed to improve outcome in severe sepsis, as did a cyclohexene antagonist of TLR4 signaling (TAK-242).391,404 A trial of a phospholipid emulsion that neutralizes endotoxin was stopped early
because of toxicity,405 whereas a preliminary trial of hemoperfusion
through a matrix containing polymyxin B was stopped prematurely
after it achieved its primary end points.391 Its usefulness must be demonstrated in larger trials.

Anticoagulants

Three recombinant anticoagulant drugs have been tested for their


ability to increase the survival of patients with severe sepsis or septic
shock. None was consistently successful in improving outcomes. Tissue
factor pathway inhibitor (TFPI) and antithrombin III did not improve
outcomes in severe sepsis.137,406 Activated protein C (aPC, drotrecoginalfa [activated]) reduced mortality from 31% (placebo control) to 25%
(treatment group) (P < .005)207 and was licensed for the treatment of
severe sepsis. The basis for the apparent impact of aPC on sepsis survival was questioned by some,407 and concerns were raised about a
significant increase in the incidence of severe bleeding, including intracranial hemorrhage. The efficacy of aPC was not confirmed in trials
performed in children408 and in adults with low risk of dying (APACHE
II score 25)409; each of these trials was stopped when an interim
analysis revealed that the drug would not reduce mortality. Because of
concerns in Europe regarding the drugs efficacy and toxicity, a confirmatory trial was done in patients with septic shock. aPC failed to
reduce mortality at 28 or 90 days, compared with placebo,410 and it was
withdrawn from the market in 2011. A second confirmatory trial also
found no benefit in patients with septic shock.411 The protein C molecule has recently been modified so that it is not an anticoagulant yet
retains anti-inflammatory potency.412 It is conceivable that such
mutated versions will be useful anti-inflammatory drugs and have less
risk of hemorrhage than does aPC.
It is noteworthy that, in each of the three large trials of anticoagulant drugs, administration of heparin in a nonrandomized fashion to
patients in the placebo group was associated with a reduction in mortality. The basis for these results is not clear; because most ICU patients
receive low-dose heparin as prophylaxis for deep venous thrombosis,
unless there is a contraindication to its use, it is possible that the
observed outcome difference simply reflects selection bias. More
recently, a large retrospective review found significantly lower 28-day
mortality in patients who received unfractionated heparin intravenously during the first 48 hours of septic shock.413 Prospective controlled trials of this inexpensive, widely-available agent are needed.

Boosting Host Defenses

During the 1990s, several studies addressed the ability of recombinant


IFN- to prevent severe sepsis in patients who had recently undergone
major surgery or sustained major trauma. Unfortunately, prophylactic
administration of IFN- did not significantly reduce the incidence of
nosocomial infection and severe sepsis,414,415 even though an impact of
the drug on monocyte function was observed.416
Attempts to enhance myeloid cell function in septic patients by
giving growth factors have also not met with success. G-CSF did not

933

Summary

Three elements are the cornerstones of therapy for septic shock: the
rapid administration of antibiotics that are broad in spectrum and
target both the species and antibiotic sensitivity of the likely patho
gen(s), prompt removal or drainage of the source of the infection,
and the use of fluids and vasopressors to reverse hypotension and
tissue hypoperfusion.391 Progress during the last decade has made
it possible to consider a trial of low-dose hydrocortisone in patients
with pressor-dependent septic shock. Although improvements in clinical trial design have reduced the impact of patient heterogeneity by
using more restrictive entry criteria and enrolling larger numbers of
patients, the nonreproducibility of clinical trial results remains a major
problem.400 Using all-cause 28-day mortality as the arbitrary primary
end point ignores the long-term consequences of severe infections
and intensive care (see Prognosis). Clinical trials of combination
therapy, using drugs with different mechanisms of action, have not
been attempted.427

Nutrition and Other Supportive


Measures

Much evidence now supports the use of enteral, instead of intravenous,


nutrition in critically ill patients. Prophylaxis for GI bleeding, deep
venous thrombosis, and decubitus ulcers should be routine. Decubitus
ulcers may be prevented by avoiding prolonged skin exposure to stool
and urine, by frequent repositioning, and by adequate nutrition.
Patients with low bleeding risk should receive low doses of heparin,
whereas intermittent compression devices should be applied to the
lower extremities of those at risk for bleeding. H2-receptor antagonists
are superior to sucralfate or antacids for preventing GI bleeding428;
proton-pump inhibitors would be expected to be similarly effective.
Sedation should be interrupted at least daily in patients who are

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receiving mechanical ventilation. A recent study investigated the


benefits of fever control by using external cooling in sedated patients
with septic shock. The short-term benefits included less vasopressor
requirement and more rapid shock reversal.430 A nonsignificant trend
toward more nosocomial infections was noted at 2 weeks, however.

Preventing Secondary Infections

Because patients with severe sepsis are immunosuppressed and subjected to invasive procedures, they may be at risk for secondary infections. Measures that decrease acquisition of hospital-associated
microorganisms include hand washing431 and the use of barrier precautions when examining patients colonized with resistant bacteria.
Updated guidelines for preventing intravascular catheter infections
were published in 2011 (see Chapter 302).432
The risk for nosocomial pneumonia is greatest in patients who
receive mechanical ventilation for longer than 1 week. Randomized
trials have shown that the semirecumbent body position reduces the
risk for nosocomial pneumonia, especially in patients who receive
enteral nutrition.433 Maintaining an adequate intracuff pressure and
effective aspiration of subglottic secretions may also be important.434
Avoiding nasal gastrointestinal tubes decreases the risk for developing
sinusitis. A closed urinary drainage system is essential. Trials are
needed to evaluate prophylaxis to prevent CMV reactivation in critically ill patients.

PROGNOSIS

Whereas previously healthy young humans almost always (>90%)


survive severe sepsis if their disease-causing microbes can be killed
and supportive care is provided,435,436 severe sepsis and septic shock
have case-fatality rates of approximately 30% and 50%, respectively, in
older patients with comorbidities. As initially noted by McCabe and
Jackson,435 outcome is significantly (and most profoundly) influenced
by the patients underlying disease.240,436 Bacteremia with certain
microbes (e.g., S. aureus) may also be independently related to mortality in multivariate analyses.437 Of the many studied biologic markers,
low monocyte HLA-DR expression, plasma IL-6 levels, and a high
IL-10/TNF ratio116,438,439 may correlate best with risk of dying; circulating levels of numerous other parameters (free DNA, thrombomodulin,
CRP, procalcitonin, soluble phospholipase A2, others) have also been
associated with increased mortality in human severe sepsis. Autonomic dysfunction detected by measuring heart rate variability may
predict mortality for as long as 60 days.440,441 Prognostic scores based
on bedside evaluations, such as the APACHE II, Simplified Acute
Physiology Score (SAPS II), and the sequential organ failure assessments (SOFA), are easier to use in the typical ICU setting, although
their mortality predictions can differ substantially.442,443 Moreover, as
noted by Annane and co-workers,444 organ failure scores may have
difficulty quantitating the contribution that preexisting organ dysfunction (comorbidity) adds to risk. One group found that battery of endocrine tests (thyroxine, thyrotropin, cortisol) was a better discriminator
of outcome than the APACHE II score.445
Although most clinical trials of sepsis therapies have used 28-day
all-cause mortality as the outcome variable, Perl and co-workers436
found that the median day of death was 30.5 days after the onset of
sepsis. Another study concluded that patients who survive an episode
of severe sepsis have significantly decreased life expectancy over the
ensuing 5 years.271 Experiencing severe sepsis may also diminish an
individuals subsequent quality of life271,436 and cognitive function276 for
several years.

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Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

improve outcome when it was used as adjunctive therapy in nonneutropenic patients with sepsis caused by community-acquired pneumonia or hospital-acquired pneumonia.417,418 A similar lack of benefit
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429

Part II Major Clinical Syndromes

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934.e1

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80. Annane D, Bellisant E, Sebille V, et al. Impaired pressor
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83. van der Poll T, Levi M. Crosstalk between inflammation
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84. Gando S, Kameue T, Nanzaki S, et al. Participation of tissue
factor and thrombin in posttraumatic systemic inflammatory syndrome. Crit Care Med. 1997;25:1820-1826.

Chapter 75 Sepsis, Severe Sepsis, and Septic Shock

1. American College of Chest Physicians/Society of Critical


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the diagnostic accuracy of the 1991 American College of
Chest Physicians/Society of Critical Care Medicine and
the 2001 Society of Critical Care Medicine/European
Society of Intensive Care Medicine/American College of
Chest Physicians/American Thoracic Society/Surgical
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11. Lagu T, Rothberg MB, Shieh MS, et al. Hospitalizations,
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of systemic inflammatory response syndrome and sepsis on
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factors, and outcome of severe sepsis and septic shock in
adults. A multicenter prospective study in intensive care
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18. Zanotti-Cavazzoni SL, Goldfarb RD. Animal models of
sepsis. Crit Care Clin. 2009;25:703-719.
19. Ward PA, Bosmann M. A historical perspective on sepsis.
Am J Pathol. 2012;181:2-7.
20. Seok J, Warren HS, Cuenca AG, et al. Genomic responses
in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110:3507-3512.
21. Copeland S, Warren HS, Lowry SF, et al; Inflammation and
the Host Response to Injury Investigators. Acute inflammatory response to endotoxin in mice and humans. Clin
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22. Ishii KJ, Koyama S, Nakagawa A, et al. Host innate immune
receptors and beyond: making sense of microbial infections. Cell Host Microbe. 2008;3:352-363.
23. Baccala R, Gonzalez-Quintial R, Lawson BR, et al. Sensors
of the innate immune system: their mode of action. Nat
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24. Kim HM, Park BS, Kim JI, et al. Crystal structure of the
TLR4-MD-2 complex with bound endotoxin antagonist
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25. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps:
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2012;198:773-783.
26. Medzhitov R, Janeway CA Jr. Decoding the patterns of self
and nonself by the innate immune system. Science. 2002;
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27. Montminy SW, Khan N, McGrath S, et al. Virulence factors
of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol. 2006;7:1066-1073.
28. Hajjar AM, Harvey MD, Shaffer SA, et al. Lack of in vitro
and in vivo recognition of Francisella tularensis subspecies

lipopolysaccharide by Toll-like receptors. Infect Immun.


2006;74:6730-6738.
29. von Bernuth H, Picard C, Jin Z, et al. Pyogenic bacterial
infections in humans with MyD88 deficiency. Science.
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30. Ku CL, von Bernuth H, Picard C, et al. Selective predisposition to bacterial infections in IRAK-4-deficient children:
IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med. 2007;204:2407-2422.
31. Yang D, Postnikov YV, Li Y, et al. High-mobility group
nucleosome-binding protein 1 acts as an alarmin and is
critical for lipopolysaccharide-induced immune responses.
J Exp Med. 2012.
32. Kondo Y, Ikeda K, Tokuda N, et al. TLR4-MD-2 complex
is negatively regulated by an endogenous ligand, globotetraosylceramide. Proc Natl Acad Sci U S A. 2013;110:
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33. Giamarellos-Bourboulis EJ, van de Veerdonk FL, Mouktaroudi M, et al. Inhibition of caspase-1 activation in
Gram-negative sepsis and experimental endotoxemia. Crit
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34. Koc B, Oktenli C, Bulucu F, et al. The rate of pyrin mutations in critically ill patients with systemic inflammatory
response syndrome and sepsis: a pilot study. J Rheumatol.
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35. Hall MW, Gavrilin MA, Knatz NL, et al. Monocyte mRNA
phenotype and adverse outcomes from pediatric multiple
organ dysfunction syndrome. Pediatr Res. 2007;62:
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36. Li P, Allen H, Banerjee S, et al. Mice deficient in IL-1bconverting enzyme are defective in production of mature
IL-1b and resistant to endotoxic shock. Cell. 1995;80:
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37. Dolinay T, Kim YS, Howrylak J, et al. Inflammasomeregulated cytokines are critical mediators of acute lung
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38. Lamkanfi M, Sarkar A, Vande Walle L, et al. Inflammasomedependent release of the alarmin HMGB1 in endotoxemia.
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39. Munford RS, Pugin J. Normal responses to injury prevent
systemic inflammation and can be immunosuppressive.
Am J Respir Crit Care Med. 2001;163:316-321.
40. Liu T, Gao Y-J, Ji R-R. Emerging role of Toll-like receptors
in the control of pain and itch. Neurosci Bull. 2012;28:
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41. Acosta C, Davies A. Bacterial lipopolysaccharide regulates
nociceptin expression in sensory neurons. J Neurosci Res.
2008;86:1077-1086.
42. Barajon I, Serrao G, Arnaboldi F, et al. Toll-like receptors
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and dorsal root ganglia. J Histochem Cytochem. 2009;57:
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43. Wadachi R, Hargreaves KM. Trigeminal nociceptors
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44. Netea MG, Kullberg B-J, Van der Meer JWM. Circulating
cytokines as mediators of fever. Clin Infect Dis. 2000;31:
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45. Cavaillon JM. Good and bad fever. Crit Care. 2012;16:119.
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major torso trauma. J Trauma. 1991;31:629-636.
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48. Leon LR, Kozak W, Peschon J, et al. Altered acute phase
responses to inflammation in IL-1 and TNF receptor
knockout mice. Ann N Y Acad Sci. 1997;813:244-254.
49. Belge KU, Dayyani F, Horelt A, et al. The proinflammatory
CD14+CD16+DR++ monocytes are a major source of
TNF. J Immunol. 2002;168:3536-3542.
50. Fong Y, Marano MA, Moldawer LL, et al. The acute
splanchnic and peripheral tissue metabolic response to
endotoxin in humans. J Clin Invest. 1990;85:1896-1904.
51. Romanovsky AA, Ivanov AI, Szkely M. Neural route of
pyrogen signaling to the brain. Clin Infect Dis. 2000;31:
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52. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve
stimulation attenuates the systemic inflammatory response
to endotoxin. Nature. 2000;405:458-462.
53. Huston JM, Ochani M, Rosas-Ballina M, et al. Splenectomy
inactivates the cholinergic antiinflammatory pathway
during lethal endotoxemia and polymicrobial sepsis. J Exp
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54. Reardon C, Duncan GS, Brustle A, et al. Lymphocytederived ACh regulates local innate but not adaptive immunity. Proc Natl Acad Sci U S A. 2013;110:1410-1415.
55. Pena G, Cai B, Ramos L, et al. Cholinergic regulatory lymphocytes re-establish neuromodulation of innate immune
responses in sepsis. J Immunol. 2011;187:718-725.
56. Munford RS, Pugin J. The crucial role of systemic responses
in the innate (non-adaptive) host defense. J Endotoxin Res.
2001;7:327-332.

Part II Major Clinical Syndromes

934.e2
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100. Tilg H, Dinarello CA, Mier JW. IL-6 and APPs: antiinflammatory and immunosuppressive mediators.
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