Professional Documents
Culture Documents
75
Epidemiology
Microbiology
Diagnosis
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
914
Therapy
Prevention
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
914.e1
KEYWORDS
915
TABLE 75-1 Definitions
DEFINITION
COMMENT
Infection
Presence of
microorganisms in a
normally sterile site
Bacteremia
Systemic
inflammatory
response
syndrome
(SIRS)
A potentially misleading
term. The evidence that
the bodys early responses
to infection cause
systemic inflammation
is controversial. See
Pathogenesis in text.
Sepsis
Hypotension
Severe sepsis
Septic shock
MAP, mean arterial pressure; PaCO2, partial pressure of arterial carbon dioxide;
SOFA, sequential organ failure assessment; WBC, white blood cell count.
PATHOGENESIS
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
TERM
916
LPS
PG, LP
TLR2/1 TLR2/6
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
PYD NOD
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
Tachycardia
Fever
Acquired Immunity
Anti-infective
Anti-inflammatory
Procoagulant
Metabolic
Thermoregulatory
that caspase-1 also controls the production of HMGB-1, a proinflammatory alarmin, in mice.38
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.
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
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
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
Anti-inflammatory Responses
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
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.)
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
Summary
921
Complement Activation
Coagulopathy
132
922
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
Immunosuppression
Septic Shock
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.
Bacteremia
923
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
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
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
Hypothalamic-Pituitary-Adrenal Axis
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
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
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
Plasma Lipids
Glucose
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
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.
50
Shock
DIC
CNS
Hepatic
Renal
25
Pulmonary
Clotting Factors
75
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
927
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.
Hepatic Dysfunction
Septic Shock
Immune Dysfunction
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.
929
DIAGNOSIS
Differential Diagnosis
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.
Diagnostic Imaging
THERAPY
930
comprehensive supportive care, and measures aimed at reversing predisposing causes are the cornerstones of successful management.
Antimicrobial Drugs
TABLE 75-4 Empirical Antibiotic Options for Patients with Severe Sepsis or Septic Shock
SUSPECTED SOURCE
Skin/Soft Tissue
Lung
Abdomen
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)
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
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
931
932
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
Anticoagulants
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
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PROGNOSIS
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
occurred in septic patients given granulocyte-macrophage colonystimulating factor (GM-CSF).419 A meta-analysis of the clinical trials
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429
934
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