Chapter | 44 | William A Lynn

Sepsis

This chapter examines the consequences of the systemic effects of

Table 44.2  Clinical signs and laboratory parameters in the diagnosis of
infection, broadly referred to as sepsis.
sepsis

Infection – documented or suspected, plus some of the

EPIDEMIOLOGY following:
Clinical signs Fever temperature >110.4° F (38.3° C) or
Definition and nomenclature Hypothermia temperature <96.8° (36° C)
Physicians have long recognized that infection can lead to general- Heart rate >90 beats/min
ized circulatory collapse and death. In the 1990s Bone initiated a Hypotension SBP <90 mmHg,
debate on the terminology of sepsis, identifying key clinical criteria MAP <70 mmHg, SBP fall of >40 mmHg
and definitions.1 Bone recognized that similar physiologic changes from baseline
could occur in noninfective inflammatory processes, such as pancre- Prolonged capillary refill time or tissue
atitis, and introduced the term the systemic inflammatory response mottling – indicates poor tissue perfusion
syndrome (SIRS) to define a common set of diagnostic criteria for Tachypnoea: respiratory rate >20 breaths/
infected (sepsis) and noninfected patients.1 The term SIRS has been min or arterial CO2 tension <32 mmHg
criticized for being too imprecise2 but the concept and definition of (4.3 kPa)
sepsis has remained.3 It is important to remember that sepsis is a het- Altered mental state from baseline
erogeneous condition resulting from the interaction of host, pathogen Inflammatory markers WBC >12 000 cells/mm3, <4000 cells/
and environmental factors. Some authors have questioned the validity mm3 or >10% immature forms (bands)
of grouping all such patients together, particularly in research studies Plasma C-reactive protein >2× normal
of new therapeutic agents.4 range
Severe sepsis (Table 44.1) may be defined simply as ‘sepsis plus Procalcitonin >2× normal range
sepsis-induced organ dysfunction or tissue hypoperfusion’.5 The chal-
lenge for clinicians is to recognize the presentation of sepsis/severe Organ dysfunction Metabolic acidosis: elevated base
sepsis (Table 44.2) and intervene early. deficit ≥5, increased blood lactate
Hypoxia: Pao2/Fio2 <300
Oliguria: urine output <0.5 ml/kg for
Incidence and prevalence of sepsis >2 h despite fluid resuscitation
Creatinine rise from baseline >40 μmol/l
Host and environmental factors interact in the development of sepsis
Coagulopathy: INR >1.5 in absence
with varying rates in different patient populations. Furthermore, varia-
of anticoagulation, platelet count
tion in the organization of health care in different medical systems
<100 × 109/l
makes comparisons between countries difficult. Angus and co-work-
Hyperbilirubinemia: bilirubin >4 mg/dl or
ers examined the epidemiology of sepsis in the USA.6 Using existing
70 μmol/l
databases they analyzed discharge records of over 6 million patients
Hyperglycemia or hypoglycemia in
from seven US states during 1995 and extrapolated the results for the
nondiabetic

Table 44.1  Definitions of infection-related syndromes
• Bacteremia: viable bacteria cultured from bloodstream – patient may
or may not have evidence of sepsis/severe sepsis
• Sepsis: infection, documented or suspected, plus systemic
­manifestations (see Table 44.2)
• Severe sepsis: sepsis-induced organ dysfunction or tissue
­hypoperfusion (see Table 44.2)
• Septic shock: sepsis-induced hypotension not responding to fluid
resuscitation
INR; international normalized ratio; MAP, mean arterial pressure; SBP; systolic
blood pressure; WBC, white blood count.
Adapted from Dellinger et al.5
whole US population. Data collected in this way should be viewed
with some caution but the size of this study demands attention. They
estimated an annual incidence for severe sepsis of 3 cases per 1000
(2.26 cases/100 hospital discharges), equivalent to 751 000 cases each
year. Incidence rose from 0.2/1000 in childhood to 26/1000 over the
age of 85. Severe sepsis was estimated to cost around $16 billion per

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 Sepsis Chapter | 44 |

year. In a separate study, Martin et ­al. reported similar figures and also
that the incidence of sepsis in the USA was rising at around 9% per
year, reaching 240/100 000 in 2000.7 A review of 330 million emer-
gency department attendances in the USA showed that 0.69% were for
severe sepsis.8
In Europe Van Gestel et al. performed a point prevalence study in
47 intensive care units (ICU) across the Netherlands, showing that
29.5% of patients fulfilled severe sepsis criteria.9 Extrapolating from
these data indicated that severe sepsis was responsible for 0.61% of
all hospital admissions but 11% of admissions to intensive care in
The Netherlands. Similar data showed a point prevalence for severe
sepsis in ICU admissions of 28.7% in the UK10 and 27% in France.11
In Australia and New Zealand severe sepsis has been estimated in
0.77 per 1000 of the population and is responsible for 11.8/100 ICU
admissions.12
with sepsis often have serious co-morbidity, but even when this is
taken into account the attributable mortality from severe sepsis is still
25%,15 increasing to over 60% if four or more organs are failing.13
Long-term mortality is high after an episode of severe sepsis.16 Some
studies have suggested that while the incidence of severe sepsis con-
tinues to increase, there has been a recent improvement in mortality,
possibly due to the introduction of a more systematic approach to
­recognition and therapy.10,17
Risk factors for sepsis
Broadly speaking, risk factors for sepsis are those factors that weaken/
breach host defenses, increasing the likelihood of bacterial invasion of
otherwise sterile tissue as summarized in Figure 44.1.

PATHOGENESIS AND PATHOLOGY

Morbidity and mortality rates
The mortality of sepsis varies because of variations in infection preva-
lence, case definition, ICU facilities and patient populations. In an
analysis of four large sepsis trials, 14-day mortality averaged 26% and
28-day mortality 42%.1 In the Angus study cited above overall mortal-
ity was 28.6%, equivalent to 215 000 deaths per annum in the USA.6
In this study mortality in childhood was around 10%, rising to 38.4%
in those over age 85.6
Factors associated with early death include the number of organ
systems involved,13 acidosis, and shock.14 Late deaths are associated
with medical co-morbidities, underlying illness and multiple sources
of infection. Pseudomonas aeruginosa, Candida spp. and mixed infec-
tions have a higher attributable mortality than other agents. Patients
Etiologic agents of sepsis
Bacteria are the commonest underlying pathogens in patients with
community and hospital-acquired sepsis. Nonbacterial pathogens
may also induce the pathologic responses leading to sepsis, including
fungi, rickettsiae, protozoa and certain viruses. The epidemiology of
community-acquired sepsis varies considerably between tropical and
nontropical zones. Alterations in host immunity also influence the
nature of the underlying organisms in sepsis.
Historically, Gram-negative bacteria were most commonly asso-
ciated with septic shock but a shift in etiology occurred during the
1990s, with increasing infection due to Gram-positive bacteria and

Potential risk factors leading to sepsis

Genetic polymorphisms
For example in genes regulating
• Cytokine responses
• Coagulation
• Mannose binding proteins

Intrinsic factors
• Age Community factors
• Co-morbidities • Travel
• Immunosuppression • Disease outbreaks
• Vaccination • Contacts
• Nutrition • Specific exposure
• Mucosal integrity

Hospital factors
• Duration of hospitalization
Surgery • Where in hospital
• Wounds
(e.g. intensive care unit)
• 'Dirty' vs clean procedure • Local antimicrobial
• Emergency vs elective
resistance rates
• Prosthetic material • Outbreaks

Procedures
• Urinary catheters
• Intravenous cannulas
• Wound dressings

Fig. 44.1  Potential risk factors leading to sepsis. Complex interaction of factors that may influence both the susceptibility to and clinical outcome of
severe sepsis.

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Section |2| Bloodstream, heart and vessels

f­ ungal pathogens particularly within the ICU.13,18 Vincent et al.

­surveyed over 3000 ICU patients across Europe in the SOAP study. Host immune responses in sepsis
A  microbiologic cause was only identified in 60% of patients with
severe sepsis which is comparable to other studies and indicates the
need for better diagnostic tests. Gram-positive bacteria were responsi- Invading micro-organism
ble for 40%, Gram-negative bacteria 38% and fungi (mainly Candida
spp.) in 17% of cases. Twenty percent of patients were bacteremic, Toxins Toxins eg: TSST1
with pulmonary, abdominal, skin and urinary tract the most common
local sites of infection.13 PAMPs PAMPs PAMPs
The epidemiology of severe bacterial sepsis continually changes in
response to the emergence of new bacterial strains and alterations in
Cell death Innate immune Specific immune
host or environmental factors. Recent years have seen the emergence
Apoptosis system responses
of community-acquired methicillin-resistant Staphylococcus aureus DAMPs
(MRSA)19 and more virulent strains of Clostridium difficile20 as caus-
ative agents of severe sepsis in the USA with subsequent spread to
other parts of the world.

Bacterial products involved in sepsis Proinflammatory mediators Anti-inflammatory mediators

Bacteria produce a variety of exotoxins and endogenous cell wall prod-
ucts that induce proinflammatory responses in vitro that may culmi-
nate in sepsis in vivo. Such products are released by bacteria during
local or systemic infection and, in turn, may have local or distant
proinflammatory effects.21 The innate immune system is our first line
of defense against invading micro-organisms and immune activation
through this route is central to the pathogenesis of sepsis.
Innate immune recognition of microbial products
In recent years the concept of pathogen recognition systems trigger-
ing an initial, and very rapid, innate immune response to pathogens
has emerged.21 Pathogen-associated molecular patterns (PAMPs) are
the microbial products that trigger these receptor recognition systems
that are found in almost all higher eukaryotes.22 The same receptor
systems may be triggered by other harmful stimuli known as damage-
associated molecular patterns (DAMPs). The relevance of this to severe
sepsis is that innate immunity is, in most cases, the first defense mech-
anism against invading organisms and this activation system plays a
pivotal role in setting in motion the inflammatory and anti-inflamma-
tory processes that determine whether the infection resolves, dissemi-
nates or leads to sepsis (Fig. 44.2).
Identification of the Toll-like receptor (TLR) family and the rec-
ognition of the central role of TLR in the innate response to infec-
tion is one of the most important discoveries in understanding the
molecular basis for severe sepsis.23 Toll receptors were first identified
as important in the recognition of fungi in Drosophila and have been
recognized in widely diverse organisms including plants, animals and
insects. To date, 10 functional Toll receptors have been identified in
humans; they are involved in the recognition and response to PAMPs
and DAMPs (Table 44.3).24 Further elucidation of the Toll receptor
pathway and signaling in sepsis may lead to a greater understanding
of the molecular basis for severe sepsis in different infections and lead
to new therapeutic targets.25 Endotoxin (lipopolysaccharide) is one of
the most potent PAMPs and cellular activation by endotoxin is examined
in more detail below.
Gram-negative bacterial endotoxin
Endotoxin (lipopolysaccharide, LPS) is found only in ­Gram-­negative
bacteria, where it forms part of the outer leaflet of the bacterial
cell wall (Fig. 44.3). It consists of a polysaccharide domain cova-
lently bound to a unique di-glucosamine-based phospholipid, lipid
A (Fig. 44.3), which is the key toxic moiety of LPS. Lipid A and
LPS induce a wide range of both proinflammatory and counter-
­regulatory responses in vitro and in vivo. In human volunteers,
administration of small amounts of endotoxin induce fever and
release of cytokines including tumor necrosis factor (TNF), interleu-
kin (IL)-1 and IL-6.26
Control Failure Dominant Immunosuppressive
infection to control inflammatory response
response
Resolution Dissemination Sepsis Secondary
Organ failure infections
Death Late organ
failure
Death
Fig. 44.2  Host immune responses in sepsis. Invading pathogens may
activate the immune system by release of soluble toxins or by interaction
of structural components (pathogen-associated molecular patterns,
PAMPs) with the Toll-like receptor pathway. Immune activation releases
a variety of inflammatory mediators that may have local or distant
actions. Cell death and tissue damage may result from the direct effect
of bacterial toxins or as a result of the inflammatory cascade initiated by
the infection. Some host products released following cell damage are
damage-associated molecular patterns (DAMPs) and may lead to further
immune activation. Anti-inflammatory mediators are also released as
part of a feedback loop to limit inflammatory damage. If the balance
between proinflammatory and anti-inflammatory mechanisms is correct
then localization and resolution of infection will occur. If there is a
hyperinflammatory response then there is a risk of sepsis, organ damage
and death. If an anti-inflammatory pathway predominates then there is an
increased risk of secondary infection leading to further episodes of sepsis
and death.
The cellular interaction of LPS is complex, involving both serum
LPS-binding proteins and cell-bound and soluble LPS receptors27 (Fig.
44.4).
Secreted toxins – exotoxins
Exotoxins are released by bacteria and other pathogens, and can
cause substantial damage through direct toxic effects or by provoking
inflammatory responses (Table 44.4). Type 1 toxins, such as superanti-
gens, do not directly enter cells but bind to surface receptors, triggering
­specific responses. Type 2 toxins cause direct cell damage and there are
many examples of these that are linked to bacterial pathogenesis (e.g.
DNAse or protease enzymes). A good example discussed earlier is the
emergence of a highly virulent strain of community-acquired MRSA
associated with skin and soft tissue infections, necrotizing pneumonia
and severe sepsis.19 Pathogenicity is linked to the Panton–Valentine
leukocidin (PVL) gene. PVL is directly toxic to neutrophils and the
purified toxin can cause necrotizing pneumonia and sepsis in experi-
mental models.

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Table 44.3  Toll-like receptor binding ligands relevant to sepsis

Source Stimulus Released by Receptor

Bacteria Lipopolysaccharide, endotoxin, LPS Gram-negative bacteria TLR4
Peptidoglycan Gram-positive bacteria TLR2
Lipoteichoic acid Almost all bacteria TLR2
Triacyl lipopeptides Almost all bacteria TLR1, TLR2
Porins Neisseria spp. TLR2
Flagellin Flagellated bacteria TLR5
CpG DNA All bacteria TLR 9
Fungi Zymosan Saccharomyces TLR2, TLR6
Phospholipomannan Candida albicans TLR2
Mannan Candida albicans TLR4
O-linked mannosyl residues Candida albicans TLR4
Glucans Candida albicans TLR2
Parasites Glycosylphosphatidylinositol Plasmodium falciparum TLR2
Human cells Heat shock proteins Tissue damage TLR4
Fibronectin Tissue damage TLR4
Hyaluronic acid Tissue damage TLR4
Biglycans Tissue damage TLR4
HMGB1 Tissue damage TLR2, TLR4

HMGB1, high-mobility group box 1 protein; TLR; Toll-like receptor.

Adapted from van der Poll & Opal.21

A third type of bacterial exotoxin is formed of A and B subunits; the
A subunit mediates cell entry and the B component is cytotoxic. A good
example of the relevance to severe sepsis has come with the emergence
of a hypervirulent strain of C. difficile known as NAP1/027.20 Virulence
of C. difficile NAP1/027 is linked to mutation of a toxin suppressor
gene leading to increased production of both A and B toxins. Patients
with infection due to NAP1/027 have more symptomatic disease and
higher rates of toxic megacolon, severe sepsis and death.
Superantigenic toxins
Superantigenic bacterial toxins can cause profound hypoten-
sion, inflammation and organ failure.28 Strains of Staph. aureus and
Streptococcus pyogenes that are able to express these toxins are implicated
in the pathogenesis of staphylococcal and streptococcal toxic shock.
The principle behind immune activation by superantigens is outlined
in Figure 44.5. Essentially, the bacterial toxin is capable of bypassing
the normal highly antigen-specific mechanisms of T-lymphocyte acti-
vation by directly linking major histocompatibility complex (MHC)
II on antigen-presenting cells to the Vβ subunit of the T-lymphocyte
receptor. This triggers cell activation and massive cytokine release
which, in turn, can lead to severe sepsis and organ failure.29 Whether
an individual infected with a superantigen-producing organism devel-
ops toxic shock is complex depending on the quantity of toxin pro-
duced, the presence or absence of pre-existing neutralizing antitoxin
antibodies and on the composition of an individual’s MHC molecules
and T-lymphocyte repertoire of Vβ subunits.30 An epidemic of men-
struation-associated staphylococcal toxic shock syndrome occurred in
the 1970s linked to use of a particular type of superabsorbent tam-
pon that enhanced proliferation and increased toxin production by
­staphylococci in the vagina.31
Host genetic factors in susceptibility
to sepsis
One of the most intriguing aspects of severe sepsis is why one indi-
vidual will respond to a particular infection with devastating conse-
quences of septic shock whilst another resolves a similar infection.
A full discussion is beyond the scope of this chapter but it is clear that
genetic variation explains aspects of the human response to infection.
Animal models and some human studies have linked polymorphisms
in key bacterial response genes, including cytokine, mannose-binding
protein, CD14 and Toll-receptor genes, to outcome in severe sepsis.30,32
Human leukocyte antigen (HLA) type II polymorphisms have been
linked to responses to superantigens.33 Further understanding of the
genetic basis for response to infection may lead to targeted therapies
for patients with sepsis.
Host responses in severe sepsis
Some of the central pathways leading to tissue damage in severe sep-
sis are shown in Figure 44.5 and key mediators are listed in Table
44.5. Selected pathogenetic mechanisms are discussed in more detail
below.
Inflammatory and anti-inflammatory cytokines
Historically much attention was given to the search for the ‘key medi-
ator’ of sepsis and the focus has at various times settled on comple-
ment, arachidonic metabolites, kinins, lipid mediators and cytokines.
Rather than being due to one mediator, severe sepsis is the result of
a complex interaction of inflammatory and anti-inflammatory pro-
cesses as depicted in Figure 44.5.
Throughout the 1990s attention focused on the cytokines TNF, IL-1
and interferon gamma (IFN-γ). The evidence that proinflammatory
cytokines, such as TNF and IL-1, play a causative role in sepsis stems
from several lines of research. First, IL-1 and TNF can induce septic
shock in animals and inhibitors of these cytokines can prevent the
onset of sepsis in these models.34 Secondly, mice deficient in the genes
encoding receptors for TNF are resistant to septic shock induced by
endotoxin. Finally, these cytokines are elevated in human sepsis, and
high levels of cytokines correlate with a poor outcome in some but not
all studies. TNF is released early in response to LPS challenge,26 and the
cooperative effects of TNF, IL-1 and IFN-γ in producing inflammatory
responses made these three cytokines prime targets for experimental
intervention in sepsis.

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The Gram-negative bacterial cell wall

O-specific chain Core Lipid A

P EtN KDO P P EtN

D D GlcNAc Gal Hep P KDO GlcN

C B A C B A Glc Gal Glc Hep Hep KDO GlcN

n P P AraN

Lipopoly-
saccharide
Outer membrane

Peptidoglycan Periplasmic
layer space

Phospholipid Inner membrane

bilayer

Membrane
proteins

Fig. 44.3  The Gram-negative bacterial cell wall. In the cell wall of a Gram-negative bacterium such as Escherichia coli, the inner membrane is composed
of phospholipids and membrane proteins and is separated from the outer membrane by the periplasmic space and peptidoglycan. Lipopolysaccharide
(expanded box) is found only in the outermost leaflet of the outer membrane with the lipid A moiety in the membrane and the polysaccharide (O) side
chain directed outwards. Lipid A is highly conserved across Gram-negative bacteria and consists of a phosphorylated diglucosamine backbone decorated
with six or seven acyl side chains. Dephosphorylation or deacylation of lipid A abrogates its toxicity. Lipid A is covalently linked to an inner core of
sugar residues that is relatively well conserved across species and antibodies directed against the core may protect against challenge with heterologous
Gram-negative bacilli. The core is followed by an outer polysaccharide chain, of repeating sugar residues, that varies between different bacterial strains
(O antigen). Antibodies directed against the O antigen will only protect against challenge with that individual bacterial strain. Gal, d-galactose; Glc,
d-glucose; GlcNAc, N-acetyl-d-glucosamine; Hep, l-glycero-d-manno-heptose; KDO, 3-deoxy-d-manno-octuylosonic acid.

High-mobility group box 1 protein (HMGB1) has attracted atten-
tion as a late mediator of inflammatory responses in sepsis.35 HMGB1
does not appear until more than 8 hours after the onset of sepsis. It is
a nuclear protein found in all human cells and is released from mac-
rophages and natural killer cells following infectious challenge. Many
cell types following cell injury also release it. HMGB1 is released fol-
lowing apoptosis and anti-HMGB1 monoclonal antibodies improve
outcome in animal models of sepsis.36
Macrophage migration inhibitory factor (MIF) is released by a vari-
ety of cells during sepsis and also in response to glucocorticoids. MIF
appears to be important in sepsis pathogenesis as it enhances release
of other proinflammatory cytokines, including TNF, and upregulates
macrophage expression of TLR4 which increases responsiveness to
LPS.37 Furthermore, MIF prolongs macrophage life by delaying apop-
tosis. These actions will tend to sustain a proinflammatory profile,
potentially worsening tissue damage, and blockade of MIF protects
animals from lethal sepsis.
In addition to the large number of proinflammatory mediators
induced during severe sepsis, there are many counter-regulatory mediators
(see Table 44.5). Counter-regulatory mediators have specific actions and
may neutralize or detoxify bacterial products, block the synthesis or release
of cytokines, neutralize circulating inflammatory mediators or downregu-
late cell responses to inflammatory stimuli. Thus, it is the balance between
these opposing mechanisms that will determine whether inflammation is
successful in eliminating infection and then ‘shutting down’, or progress-
ing so that healthy tissues become victims of ‘friendly fire’ (see Fig. 44.5).
In individual patients with severe sepsis it may be this balance between
the proinflammatory and anti-inflammatory processes that determines
whether infection resolves, disseminates or leads to severe sepsis.
Coagulopathy
Widespread activation of coagulation pathways is common in sep-
sis and disseminated intravascular coagulation (DIC) may occur as
a result. Bacterial products and inflammatory mediators can acti-
vate coagulation, anticoagulation and fibrinolytic pathways with a
net procoagulant profile. Activated monocytes and endothelial cells
increase secretion of tissue factor, which initiates the coagulopathy

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CD14 and toll receptor pathway of cellular activation by T-lymphocyte activation by superantigens
bacterial lipopolysaccharide

Bacteria
LPS
MD2
LBP LPS LPS Range of nonsusceptible
LBP TLR-4 Superantigenic
Vβ-restricted T lymphocytes
CD14 exotoxin
LBP
MYD88

IRAK
Vβ
TRAF6
T
MAP3K
Gene Vα
activation APC MHC II

NFκB IκB Susceptible Vβ-restricted

T lymphocyte
NFκB
Conventional antigen
Antigen processing
and presentation
Fig. 44.4  CD14 and toll receptor pathway of cellular activation by
bacterial lipopolysaccharide. Schematic representation of events at the
inflammatory cell surface. Lipopolysaccharide (LPS), either free or as part Vβ
of lipoprotein complexes, is bound by LPS-binding protein (LBP) in the T
fluid phase. The LPS–LBP complex binds to the cell surface receptor CD14
on neutrophils and macrophages. CD14 lacks an intracellular domain Vα
and acts as a co-receptor presenting LPS to toll-like receptor 4 (TLR-4), APC MHC II
leading in turn to activation of intracellular signaling and gene activation.
IκB, inhibitor of kappa B; IRAK, interleukin 1 receptor-associated Antigen-specific T lymphocyte
kinase; MAP3K, mitogen-activated protein 3-kinase; MYD88, myeloid response
differentiation factor 88; NFκB, nuclear factor kappa B; TRAF6, tumor
necrosis factor receptor-associated factor 6. Fig. 44.5  T lymphocyte activation by superantigens. In the conventional
response to bacterial antigens (bottom) the antigen is processed and
presented by the antigen-presenting cell (APC) in association with MHC II.
Table 44.4  Examples of bacterial exotoxins in sepsis Only T lymphocytes with the correct antigen recognition site can then
be activated (i.e. this is a highly antigen-specific process). Superantigens
Category Source Examples (top) are able to bypass this process by bridging between MHC II and the
Vβ subunit of the T-lymphocyte receptor. Thus the entire population of T
Pore-forming Staphylococcus α-Hemolysin lymphocytes expressing that particular Vβ subunit can be activated; this
exotoxins aureus Panton–Valentine leukocidin can be up to 20% of the total T-lymphocyte population.
(PVL)
Streptococcus Streptolysin-O
pyogenes
Escherichia coli E. coli hemolysin
Aeromonas spp. Aerolysin
damage. There is a high risk of bleeding due to thrombocytopenia and
exhaustion of clotting factors and activated protein C. This is seen in
Superantigens Staph. aureus Toxic shock syndrome toxin its most extreme in purpura fulminans in meningococcal bacteremia.
1, enterotoxins A–F Modulation of coagulation has been a therapeutic target in severe sep-
Strep. pyogenes SPEA, SPEC, SMEZ sis and recombinant human activated protein C is licensed for use in
severe sepsis with a high risk of mortality.
Enzymes Staph. aureus Coagulase, DNAse,
proteases
Strep. pyogenes IL-1b convertase, proteases Nitric oxide
Clostridium Phospholipase C Nitric oxide (NO) may be involved in the pathophysiology of sepsis
perfringens through a number of mechanisms.39 First, NO is a free radical and has
the ability to kill phagocytosed organisms. Second, NO is a potent
IL-1, interleukin-1; SPE, streptococcal pyrogenic exotoxin.
vasodilator and a basal level of NO is required for the maintenance
of normal arteriolar tone. Synthesis of NO is increased by a num-
ber of bacterial products, including LPS and cytokines. In particular,
seen in sepsis.38 Involvement of platelets and von Willebrand’s factor TNF, IL-1 and IFN-γ appear to increase NO synthesis synergistically.
may also stimulate coagulation. Sepsis is characterized by widespread peripheral vasodilatation and
Anticoagulant pathways involve antithrombin II, activated protein loss of the normal regulation of tissue blood flow. There is consid-
C and tissue-factor pathway inhibitor (TFPI) which are important in erable experimental evidence in animals to suggest that the vaso­
counteracting the procoagulant effect of inflammation.38 Plasminogen dilatation in sepsis is mediated by increased NO levels. In humans,
activator inhibitor type 1 (PAI-1) is important in controlling fibrinoly- elevated urinary nitrite levels are found in sepsis, implying increased
sis. Occlusion of small blood vessels during DIC leads to further tissue NO synthesis.

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Table 44.5  Examples of important soluble mediators in sepsis Immunosuppression as a result of sepsis
Sepsis is a dynamic condition and the dominant pathologic processes
Target Proinflammatory Inhibitory or counter can change rapidly. After the initial inflammatory episode of sepsis
mediators regulatory mediators patients may enter a phase of relative immunosuppression.41 This can
Monocyte/ TNF, IL-1, IL-8, IL-6, IL-1 Ra, sTNFr, TGF-β be followed by recovery but additional infectious or noninfectious
macrophage IL-12, IFN-γ, tissue insults may trigger further inflammatory responses, relapse of severe
factor, prostanoids, sepsis and worsening of tissue damage (see Fig. 44.5).
kinins, leukotrienes, The mechanism underlying immunosuppression is multifactorial.
PAF, NO, MIF, HMGB1 The responses of immune cells may be blunted for a period of time
with neutrophils, monocytes and lymphocytes releasing fewer inflam-
Neutrophils Integrin expression, BPI, CAP 57, defensins, matory mediators for a given stimulus.42 In part this is due to down-
superoxide production, acyloxyacylhydrolase regulation of cellular receptors, anti-inflammatory cytokines such as
kinins IL-10 and transforming growth factor beta. In addition, evidence has
Lymphocytes IFN-γ, IFN-β, IL-2 IL-4, IL-10, sIL-2r accumulated that sepsis can trigger apoptosis and cell death of a vari-
ety of cell types including lymphoid cells.43 The contribution of sepsis-
Endothelia Selectins, VCAM, Tissue factor pathway related immunosuppression to mortality is not fully understood and
ICAM, NO, tissue inhibitor experimental approaches to boost immunity after the initial phase of
factor sepsis are under evaluation.
Platelets Serotonin, prostanoids PDGF
Coagulation Tissue factor, TFPI, AT-III, PAI Pathophysiologic events leading to organ
pathway coagulation cascade failure in sepsis
leading to thrombin
generation How do the complicated and often confusing inflammatory responses
outlined above lead to tissue damage and eventually multiorgan fail-
Plasma Complement activation, Lipoprotein complexes,
ure? At the cellular level, the end result of the inflammatory process is
components bradykinin LBP, CRP
apoptosis and cell death. In part this is mediated by local hypoxia but
AT-III, antithrombin III; BPI, bacterial/permeability-increasing protein; CRP,
apoptosis may also be induced by some proinflammatory mediators. In
C-reactive protein; HMGB1, high-mobility group box 1 protein; ICAM, the whole organism the key to organ damage lies in the breakdown of
intercellular adhesion molecule; IFN, interferon; IL, interleukin; LBP, normal vascular homeostasis, oxygen delivery and oxygen utilization by
lipopolysaccharide-binding protein; MIF, macrophage migration inhibitory factor; tissues. This leads to hypoxia and lactic acidosis which further impair
NO, nitric oxide; PAF, platelet-activating factor; PAI, plasminogen activator organ function (Fig. 44.6). All organs may be affected but clinically the
inhibitor; PDGF, platelet-derived growth factor; sIL-2r, soluble IL-2 receptor; sTNFr, most important are depressed myocardial function, alterations in the
soluble tumor necrosis factor receptor; TFPI, tissue factor pathway inhibitor; TGF-β peripheral vasculature and failure of oxygen exchange in the lung.
transforming growth factor beta; TNF, tumor necrosis factor; VCAM, vascular cell
adhesion molecule.
Cardiac function
One of the features of severe sepsis is peripheral vasodilatation, which
Complement should lead to an increase in cardiac output to compensate. The rise in
cardiac output is often less than that predicted and it is recognized that
Activation of complement leads to a proteolytic cascade resulting in most patients who have severe sepsis have impaired myocardial func-
the liberation of molecules that can act as opsonins and chemoattrac- tion. Cumulative evidence suggests that the impairment of myocardial
tants, and can also mediate bacterial lysis. Lipopolysaccharide and contractility seen in sepsis is a consequence of circulating cytokines.
other bacterial products activate complement by the alternative path- Tumor necrosis factor directly reduces myocyte contractility and induc-
way. Massive local activation of complement during sepsis will fuel tion of myocardial NO synthesis by cytokines also impairs myocardial
the inflammatory response by recruiting neutrophils, and through function. IL-6 has also been shown to impair myocardial function.
the activation of kinins and histamine will contribute to increased
endothelial permeability and capillary leakage. C5a is increased dur-
ing severe sepsis and C5a receptors are upregulated.40 C5a recruits neu-
trophils and other inflammatory cells to sites of inflammation. C5a Organ failure in severe sepsis
also activates neutrophils by increasing the release of neutrophil gran-
ule proteins and prolongs neutrophil lifespan by inhibiting apoptosis.
Blockade of C5a improves outcome in models of severe sepsis. Mitochondrial dysfunction
Microcirculation Uncoupling of oxidative
Neutrophil–endothelial cell interactions Shunting Macrocirculation phosphorylation
Endothelial dysfunction Hypotension Poly ADP ribopolymerase
An early response to the local production of inflammatory mediators Capillary leak Hypoxemia Depletion of ATP/NAD
is the upregulation of adhesion molecules on endothelial cells and
the release of chemokines that recruit neutrophils and other inflam-
matory cells to the site of infection. Exposure of neutrophils to LPS Hypoxic hypoxia Cellular hypoxia
and some cytokines enhances the ability of neutrophils to release Failure of supply Failure of utilization
inflammatory molecules and primes neutrophils for the generation of Organ failure
oxygen radicals and proteolytic enzymes. These mechanisms enable
neutrophils to survive longer in an inflammatory environment and
to kill more bacteria, but excessive activation of endothelial adhesion Fig. 44.6  Organ failure in severe sepsis. Organ dysfunction and finally
may result in the migration of primed activated neutrophils into sites organ failure is the result of cellular hypoxia and acidosis. Hypoxia and
distant from infection. The ensuing tissue damage stimulates a vicious acidosis result both from a failure of oxygen delivery due to disturbances
cycle of re-recruitment of inflammatory cells that may ultimately lead in circulation and limitation of the cellular ability to utilize oxygen as a
to organ damage and failure. result of mitochondrial dysfunction.

484
 Sepsis Chapter | 44 |

Peripheral vasculature History and symptomatology

The hallmark of severe sepsis is widespread peripheral vasodilatation
and, in refractory septic shock, it may resist all attempts at pharma-
cologic intervention. As mentioned earlier, this is largely the conse-
quence of increased NO production in response to cytokines. The
most serious consequence of the vasodilatation is the loss of homeo-
static regulation of tissue blood flow. Thus, much of the circulating
blood volume is shunted through capillary beds, bypassing deep tis-
sues and reducing the opportunity for oxygen extraction. This in turn
exacerbates tissue hypoxia and helps to drive the metabolic acidosis
that is one of the prominent features of severe sepsis. Further local
impairment of perfusion may occur as the result of aggregation of
platelets and activation of coagulation in the microcirculation.
Symptoms that suggest the onset of sepsis are often nonspecific and
include sweats, chills or rigors, breathlessness, nausea and vomiting
or diarrhea, and headache. Confusion may be found in 10–30% of
patients, especially the elderly, and sepsis-related encephalopathy is
associated with a poorer clinical outcome. There may be specific local-
izing symptoms or signs to suggest the underlying pathology, such as
cough, dysuria or meningism, but in many cases there are no clues.
Other important information to elicit includes recent travel, contact
with animals, local infectious disease outbreaks, recent surgical proce-
dures, indwelling prosthetic devices, hospitalization, prior antibiotics,
underlying pathology and immunosuppressive illness or medication
(see Fig. 44.1).

Renal failure Physical signs on examination

Renal impairment is common in severe sepsis and is related to impair-
With progression to severe sepsis and shock there is increasing evi-
ment of the renal microvasculature reducing renal perfusion and glomer-
dence of organ dysfunction; the key physical signs and physiologic
ular filtration followed by the development of acute tubular necrosis.44
changes indicating this are encapsulated in Table 44.2 and Figure 44.7.
Remember that sepsis is a dynamic evolving clinical picture and fre-
Respiratory failure quent re-evaluation of the patient is essential.
The characteristic patient is febrile, tachypneic, tachycardic with
The lung is one of the most vulnerable organs in sepsis, and TNF, plate-
warm peripheries and a bounding arterial pulse, hypotensive, disori-
let-activating factor (PAF), C5a, IL-8 and thromboxane appear to play
ented and oliguric. With impending circulatory collapse the patient
prominent roles in the development of the adult respiratory distress
syndrome (ARDS). The passage of neutrophils across the endothe-
lium and subsequent degranulation in the lung interstitium leads to
impairment of endothelial integrity and the accumulation of fluid
Systemic manifeststions of Gram-negative bacterial sepsis
and inflammatory cells in the alveolar spaces. Impaired gas exchange
inevitably produces hypoxia, which further worsens the situation. The
combination of hypoxia and increased pulmonary thromboxane syn-
thesis increases pulmonary vascular resistance, in contrast to the fall DATE Day 1 Day 2 Day 3
in systemic vascular resistance. Thus the end result of the pulmonary
events in sepsis is the development of interstitial edema and pulmo- 105.8 300
nary hypertension, the hallmarks of ARDS.45
104.0 280

102.2 260
PREVENTION
Temperature (°F)

100.4 240

The morbidity, mortality and hospital costs associated with severe 98.6 220
­sepsis demand that strenuous efforts must be made to reduce the
96.8 200

Blood pressure (mmHg)

­incidence of this serious disease. These can be divided as follows:
• vaccination strategies for at-risk populations; 180 95.0 180
• assiduous infection control for high-risk patients;
160 93.2 160
• use of prophylactic antibiotic therapies; and
• prompt recognition and treatment of infection and severe sepsis. 140 91.4 140
Vaccination strategies are discussed elsewhere under sections on
120 89.6 120
­specific pathogens but it is worth noting the success of meningococ-
Pulse per min

cal type C conjugate vaccine in reducing the incidence of fulminant 100 87.8 100
meningococcal disease. Interestingly, a recent study from the USA
detected a reduction in invasive pneumococcal disease in adults after 80 86.0 80
their children had been immunized with the pneumococcal conju-
60 60
gate vaccine.46 Unfortunately the majority of cases of severe sepsis are
caused by organisms for which no vaccine is available. 40 40

20 20
CLINICAL FEATURES 0 0

A rigorous history, physical examination and directed investigations
are essential to arrive at the correct diagnosis of any infectious dis-
ease. However, severe sepsis and shock is a medical emergency and
therefore full assessment may have to be delayed until resuscitation
and empiric antimicrobial therapy have been commenced. The aims
of clinical evaluation are to establish the diagnosis of sepsis, estimate
disease severity and prognosis, and elucidate the underlying cause. The
exact presentation will depend on the site of infection, the nature of
the infecting organism, the host response and coexistent illness.
Fig. 44.7  Systemic manifestations of Gram-negative bacterial sepsis.
Observation chart of a 49-year-old woman admitted to hospital with a
suspected drug fever. For the first 24 hours she was observed without
antimicrobial chemotherapy and demonstrated a persistent fever and
tachycardia (sepsis). At this point she suddenly became confused,
hypotensive and oliguric, indicating the development of severe sepsis. The
underlying cause was an Escherichia coli bacteremia from an unsuspected
urinary tract infection. She responded to fluid replacement and antibiotics
and made a full recovery.

485
Section |2| Bloodstream, heart and vessels

may develop peripheral vasoconstriction with cool peripheries and
a prolonged capillary refill time. The observation chart of a patient
with severe sepsis is shown in Figure 44.7 and the clinical course of a
patient with streptococcal toxic shock in Figure 44.8. Some patients,
particularly the elderly or immunocompromised, have a more subtle
presentation necessitating a high index of suspicion to recognize early
disease. Most patients are febrile but severe sepsis may present with
hypothermia. A detailed physical examination is vital and it is impor-
tant to examine the skin, all wounds and to perform full ear, nose and
throat, rectal and vaginal examinations and fundoscopy as these sites
are often overlooked. In the hospitalized patient pay particular atten-
tion to indwelling intravenous/intra-arterial lines, insist on exposing
and examining all wounds, and carefully review the pressure areas as
these are frequently neglected sites.
Occasionally, the physical examination will directly establish the
diagnosis; helpful signs include the purpuric rash or peripheral gan-
grene of meningococcemia (Fig. 44.9), peripheral emboli in endo-
carditis, the erythematous rash or desquamation in staphylococcal
or streptococcal toxic shock (Fig. 44.10), ecthyma gangrenosum in
patients who have neutropenia and P. aeruginosa bacteremia, or the

Toxic shock syndrome

Blanching rash
Group A Streptococcus Group D Streptococcus
(pus and blood) (high vaginal swab and urine)

Antibiotic 1

Antibiotic 2

Antibiotic 3

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
ITU Ward Day

Adrenaline
(epinephrine)
Dobutamine
Dopexamine
Inotropic support

Shock
DIC
ARDS

Fig. 44.8  Toxic shock syndrome. A 30-year-old woman presented with a short history of fever, breathlessness, diarrhea and abdominal pain. She was
pyrexial and hypotensive with a blanching macular rash noted on day 2. Blood cultures grew a group A β-hemolytic streptococcus. Laparotomy revealed
800 ml of peritoneal pus with no intestinal perforation consistent with spontaneous bacterial peritonitis. She required ventilatory support plus inotropes
to maintain blood pressure for 6 days and developed evidence of disseminated intravascular coagulation (DIC) and adult respiratory distress syndrome
(ARDS). She made a gradual recovery complicated by an enterococcal urinary tract infection, finally leaving hospital 27 days after presentation. The group
A streptococcal isolate from her blood was subsequently shown to release streptococcal mitogenic exotoxin Z (SMEZ), a potent superantigen. Courtesy of
Dr P Gothard and Dr S Sriskanden, Hammersmith Hospital, London.

a b

Fig. 44.9  Cutaneous changes in meningococcal infection. (a) Petechial hemorrhages are the hallmark of meningococcal infection and may be found on
the periphery or, as in this case, the conjunctivae. (b) In severe disease the purpura may become confluent (purpura fulminans) and lead to severe digital
gangrene. Courtesy of J Cohen, Brighton.

486

a b
Fig. 44.10  Cutaneous changes in toxic shock. (a) Localized infection at the edge of a patch of eczema in a patient presenting with staphylococcal toxic
shock syndrome. (b) Desquamation of the palm following an episode of staphylococcal toxic shock. Courtesy of Dr M Jacobs.
retinal lesions of Candida endophthalmitis. Focal physical signs may
help to identify the site of infection, for example renal angle tender-
ness, pulmonary consolidation, new cardiac murmur or finding an
intra-abdominal mass.
If the patient is hypotensive, other causes of shock such as car-
diac dysfunction (including myocardial infarction and cardiac tam-
ponade), hypovolemia and redistributive shock from pancreatitis and
physical injuries need to be considered. Remember that hypotension
in sepsis is often multifactorial and sepsis may complicate or coexist
with other causes of shock.
DIAGNOSIS
Laboratory investigations
These can be broadly divided into those that help to confirm that the
patient has sepsis and detect and follow complications such as organ
failure, and those that establish the underlying cause.
Hematologic and biochemical evaluation
in sepsis
Full blood count and blood film
Look for a neutrophil leukocytosis or leukopenia. The blood film
may suggest bacterial infection with toxic granulation of neutrophils
(increased band forms) even when the white cell count is normal.
Leukopenia is a poor prognostic sign. Low platelet count suggests
DIC and evidence of microangiopathic hemolysis may be visible. In
patients who have traveled to an endemic area perform blood films
for malaria parasites.
Coagulation screen
Look for evidence of DIC – prolonged prothrombin or activated
­partial thromboplastin time, low fibrinogen and elevated markers of
fibrinolysis (fibrin degradation products or d-dimer levels).
Electrolytes and renal function
Monitor renal function closely; elevated potassium may indicate
­rhabdomyolysis, which may complicate severe sepsis.
Sepsis Chapter | 44 |
Liver tests
Minor abnormalities are common in patients with sepsis and do not
necessarily signify hepatic infection. Elevated bilirubin, alkaline phos-
phatase or transaminases of two to three times the normal level may
be seen in up to 30–50% of patients. These are generally transient
and not of prognostic importance. More markedly abnormal liver
tests suggest underlying hepatic or biliary tract infection. Progressively
deteriorating liver biochemistry in patients who have sepsis suggests
hepatocellular damage or acalculous cholecystitis, which may compli-
cate severe sepsis.
Plasma albumin
An acute fall in albumin, to as low as 1.5–2.0 g/dl over 24 hours,
may occur as a result of widespread endothelial damage and capillary
leakage of protein. In patients with chronic underlying illness or pro-
longed infection, the albumin may fall due to poor nutrition and a
switch in hepatic metabolism towards acute-phase proteins.
Blood glucose
Hypoglycemia or hyperglycemia may occur in severe sepsis. In patients
who are diabetic close monitoring and normalization of blood ­glucose
are essential.
Arterial blood gases
Typically the patient has a metabolic acidosis with compensatory
respiratory alkalosis. The degree of acidosis is a marker of the severity
of illness. The onset of hypoxia indicates severe disease and a high risk
of ARDS. Measurement of venous and arterial oxygen content allows
calculation of oxygen delivery and consumption.
Plasma lactate
This is often increased three- to fivefold in severe sepsis (normal 1.0–
2.5 mmol/l) and relates to the degree of tissue hypoxia. Lactate estima-
tions are helpful in diagnosing severe sepsis, predicting mortality and
monitoring the response to therapy.5,47
Other biochemical investigations
Amylase, creatinine phosphokinase, calcium and magnesium levels
may be disturbed in patients with severe sepsis.
487
Section |2| Bloodstream, heart and vessels

C-reactive protein
C-reactive protein (CRP) is an acute-phase reactant that rises within
a few hours of bacterial infection. High levels are detectable in most
patients who have severe sepsis although the level of CRP does not
reliably distinguish infective from noninfective causes of shock or
between sepsis and severe sepsis.48 Patients with fulminant sepsis may
have a normal CRP at presentation.

Procalcitonin
Procalcitonin has been suggested as a more sensitive and specific
marker of bacterial infection than CRP and is preferred in some cen-
ters. Procalcitonin levels may be able to discriminate between sepsis
and severe sepsis but this has not entered routine clinical practice.48,49

Endotoxin or cytokine levels

In some but not all studies plasma levels of endotoxin and cytokines
such as TNF and IL-6 have correlated with outcome of Gram-negative
sepsis. Variation in reported data along with technical difficulties in
performing these assays in real time makes routine testing impractical Fig. 44.11  Acute tubular necrosis. The tubules are dilated with flattened
in most settings. epithelial cells, and contain debris; the glomerulus is not greatly affected.
Hematoxylin and eosin. With permission from Williams JD et al., Clinical
Atlas of the Kidney. London: Mosby; 1991.
Microbiologic investigations in sepsis
Establishing an accurate microbiologic diagnosis of the cause of ­sepsis
is a crucial part of patient management. Microbiologic diagnosis is
needed to confirm the diagnosis and to direct antimicrobial ther-
apy, particularly with reports of increased antimicrobial resistance
in patients with severe sepsis. Despite modern laboratory techniques
microbiologic confirmation can only be achieved in around 60% of
cases and there is a clear need for improved diagnostic methods.50
Ideally, all relevant cultures should be taken before initiating antibiotic
therapy, but treatment is urgent and should not be unduly delayed.
Blood cultures are the most important microbiologic investiga-
tion. Two or three separate blood cultures (total 20–30 ml of blood)
should be inoculated into one of the standard commercial blood
­culture media.5 Culturing an inadequate volume of blood is the most
common reason for not detecting bacteremia.51 The bottles should
be incubated aerobically and anaerobically at 98°F (37°C), prefera-
bly agitated, for 7 days. The development of automated blood cul-
ture analysis allows for more rapid identification of positive cultures.
Where there is a high risk of underlying fungal infection then specific
fungal media may be helpful.
Sputum and urine microscopy and culture should be performed in
all cases. All wounds should be swabbed and sterile body sites such
as cerebrospinal fluid (CSF), joint or pleural fluid sampled as indi-
cated. In cases in which toxic shock syndrome is suspected, wound,
nose, throat and vaginal swabs should be taken. If staphylococci or
­streptococci are isolated in cases of toxic shock then the appropri- Fig. 44.12  Acute hemorrhagic necrosis of the adrenal glands
ate reference laboratories can assay the isolate for toxin production. (Waterhouse–Friderichsen syndrome). Both adrenal glands of a child with
Cultures should be repeated as directed by previous results and the meningococcal septicemia show hemorrhagic necrosis leading to acute
condition of the patient. adrenal failure. With permission from Stevens A, Lowe J. Pathology.
London: Mosby; 1995.

Histopathologic changes in sepsis

Organ pathology in sepsis is due to the combined effects of hypoxia,
impairment in tissue perfusion and severe acidosis. In the lung the
changes are those of ARDS, with early findings of interstitial and alve-
olar edema, fibrosis developing at a later stage. The kidneys may show
acute tubular necrosis that is generally reversible (Fig. 44.11). Hepatic
changes are of an ischemic zonal necrosis and some cases may develop
an acalculous cholecystitis. In the brain there may be areas of focal
ischemia or hemorrhage. In severe cases of septic shock associated
with Neisseria meningitidis or Capnocytophaga canimorsus there may be
peripheral gangrene due to severe impairment of perfusion (see Fig.
44.9 and also Fig. 12.6) and hemorrhage into the adrenal glands (Fig.
44.12). The gut is also affected by ischemia and may show mucosal
ulcerations and areas of infarction.
Radiologic investigations
Chest radiography is necessary in all cases and may show signs of
ARDS. Other studies may also be indicated. Radiologic investigations
can be of great help in identifying occult sites of infection (Fig. 44.13)
and close liaison with the diagnostic radiology department is vital.
Ultrasound and CT are particularly useful when trying to detect deep
abscesses; in selected cases nuclear medicine techniques may pin-
point the site of infection. Access to an interventional radiologist who
can perform percutaneous sampling/drainage of sites of infection is
invaluable.

488

Fig. 44.13  Radiologic detection of occult foci of infection in severe sepsis.
Plain abdominal X-ray in a diabetic with an Escherichia coli urinary tract
infection and pyelonephritis who had developed hypotension and oliguria.
X-ray reveals gas around the kidney due to a perinephric abscess requiring
urgent drainage.
MANAGEMENT
Mortality from sepsis and multiorgan failure remains high but by early
recognition and prompt therapeutic intervention patients can be pre-
vented from progressing down this path. There is no complete con-
sensus on how best to manage severe sepsis and few randomized trial
data dealing with optimal treatment. An approach to therapy is encap-
sulated in the Surviving Sepsis Campaign guidelines first produced in
2004 and updated in 2008.5,52 These guidelines have not met with uni-
versal approval, mainly because severe sepsis is not a homogeneous
condition and a generalized approach to treatment can be criticized.
However, they do provide a logical and structured approach to the
septic patient.
The key principles in the management of severe sepsis are:
• treat infection with prompt and effective antimicrobial therapy
and, where indicated, source control;
• maintain tissue perfusion/oxygenation and preserve organ
function; and
• prevent complications during/following the episode of severe
sepsis.
Antibiotic chemotherapy
Incorrect empiric antibiotic choice is strongly associated with a higher
mortality in severe sepsis.18,53 Furthermore, delay in administration of
antibiotics worsens survival. Kumar et al. reviewed 2154 patients with
Sepsis Chapter | 44 |
Table 44.6  Principles of antibiotic administration and selection of
antimicrobial agents in severe sepsis
Antibiotic administration
Intravenous high dose therapy within 1 h of the recognition of severe
sepsis
Broad-spectrum choice to include one or more drugs active against the
likely infecting pathogen
Chosen antibiotic should penetrate the likely site of infection
Review antibiotic choice every 24 h in the light of clinical response and
microbiology results
Consider combination therapy for known or suspected Pseudomonas
infection or in neutropenic sepsis
Selection of antimicrobial agent
Clinical syndrome/likely microbiology
Site of infection
Risk of resistance based on local and national data
Host factors including immunocompromised state
Co-morbidities including organ function and drug allergy
Risk of Clostridium difficile and other hospital-acquired infections
based on local epidemiology
septic shock and found that only 50% had received antibiotics within
1 hour of the onset of shock.14 In this study the mortality rate was
20.1% if antibiotics were administered within the first hour after the
onset of hypotension and rose by 7.6% per hour of delay, becoming
statistically significant if antibiotics were delayed more than 2 hours.
It is not possible to provide specific antimicrobial guidelines for
severe sepsis as there are many local variables that must be taken into
consideration such as local resistance patterns and risks of C. difficile.
An overview of the principles underpinning antibiotic choice in severe
sepsis is provided in Table 44.6. There are few outcome data on dura-
tion of antibiotic therapy in severe sepsis and a course of 7–10 days is
frequently recommended, although shorter courses may be given to
selected patients and helps to reduce resistance.
Antibiotic-induced endotoxin release
In experimental models, and some limited situations in humans,
release of endotoxin from bacteria has been shown to increase the
inflammatory response.54 Thus, a school of thought has developed
that antibiotics should be chosen on the basis of their potential to
cause endotoxin release.55 However, beyond a handful of small studies
there are few clinical data to support a major role for this hypothesis
in severe sepsis. Antibiotics should be selected on the basis of efficacy
for the specific clinical picture, rather than on the risk of endotoxin
release.
Source control – detection and removal
of infected material
It is essential to drain/remove all possible infective foci as these are
often the cause for treatment failure (see Fig. 44.13). Thus, abscesses
should be drained, dead tissue resected and infected foreign material,
such as an infected central venous catheter, removed. Guidance sug-
gests that source control should occur as early as possible after initial
resuscitation and is ideally performed within 6 hours of the onset of
severe sepsis.5 One exception to early intervention is severe necrotic
pancreatitis where current practice is to defer percutaneous drainage
due to the high complication rate and secondary infective risk.56 The
critically ill patient on intensive care may have repeated episodes of
sepsis; locating the underlying focus often requires considerable deter-
mination, repeated radiologic investigation and sometimes persistent
discussions with surgical colleagues.
489
Section |2| Bloodstream, heart and vessels
Supportive therapy
The goal of supportive therapy is to try to maintain tissue oxygen
delivery, a concept advanced by Shoemaker and others throughout
the 1970s.57 The potential benefit of early aggressive supportive ther-
apy is shown in a study by Rivers et al.58 in which 263 patients with
severe sepsis were randomized to receive standard therapy or ‘goal-
directed’ therapy where cardiac preload, afterload and contractility
were actively managed to try to balance oxygen delivery with demand
prior to admission to the ICU. In-hospital mortality was reduced from
46.5% in the standard group to 30.5% in the goal-directed group
(p <0.009). Goal-directed therapy appears to improve outcome during
initial resuscitation when patients first develop severe sepsis and the
applicability of this approach to all comers with sepsis has been ques-
tioned. However, the Rivers study establishes the importance of paying
attention to prompt and effective resuscitation in severe sepsis.
Ideally, patients who have sepsis should be closely monitored in
an intensive therapy or high-dependency unit. Indeed a review of
41 patients who had septic shock revealed increased mortality when
patients were managed outside of the intensive therapy unit, 70% ver-
sus 39%, even though the patients had less severe illness.59 Minimal
requirements for safe management include facilities for measurement
of blood pressure, cardiac monitoring, central venous pressure record-
ing, arterial blood gas analysis, oxygen and facilities for assisted/
mechanical ventilation or dialysis when required. Invasive monitoring
is useful in excluding other causes of shock and in directing therapy.
However, invasive monitoring is not a substitute for repeated exami-
nation and clinical assessment of the patient. Many factors such as
cardiovascular disease, hypovolemia or inotropic drugs can confound
such data; results must be interpreted in the context of the clinical
­situation. Normal values and the typical ranges for hemodynamic
parameters in severe sepsis are given in Table 44.7.
Severe sepsis is a heterogeneous condition and it is not possible
to be didactic about the management of individual patients. Patients
should be monitored closely during resuscitation and interventions
tailored to physiologic measurements of organ function/perfusion.
Improvement in acidosis and reduction in serum lactate is a reli-
able guide to improved tissue perfusion and oxygenation. A stepwise
approach to initial resuscitation is provided by the Surviving Sepsis
Campaign guidelines:5
• Begin resuscitation immediately in patients with hypotension
or serum lactate >4.0 mmol/l.
Table 44.7  Hemodynamic changes in severe sepsis
Parameter Normal range Changes in severe
sepsis
Heart rate (HR) 72–88 beats/min Sinus tachycardia
Mean arterial 70–105 mmHg Hypotension <60 mmHg
pressure (MAP)
Cardiac output 4–8 l/min Increased but not
(CO) enough to compensate
for low SVR
Systemic vascular 800–1500 Reduced (<600 if no
resistance (SVR) dyne/s/cm2 pressor agents)
Oxygen delivery 520–720 ml/min/m2 Decreased
(Do2)
Oxygen 100–180 ml/min/m2 Typically increased
consumption (Vo2)
CO = SV × HR; SVR = (MAP – CVP)/CO × 79.92
Do2 = Cl × arterial oxygen × 10; Vo2 = Cl × (arterial – venous oxygen) × 10
CI, cardiac index (CO/m2 surface area); CVP, central venous pressure; SV, stroke
volume.
490
• Do not delay pending ICU admission.
• Resuscitation goals:
– CVP 8–12 mmHg
– Mean arterial pressure >65 mmHg
– Urine output >0.5 ml/kg/h
– Central venous oxygen saturation >70%.
Intravenous fluid therapy
Fluid resuscitation is critical and should precede any pharmacologic
agents. Crystalloid or colloids can be used as there are no clear data
supporting one over the other.5 Concerns over the safety of human
albumin have been decreased by the SAFE study which showed
equal efficacy and safety when albumin was used in comparison to
saline in ICU patients.60 One recent study has found an unexplained
increase in adverse events in patients who were resuscitated with
pentastarch compared to Ringer’s lactate.61 This finding requires fur-
ther investigation before a definitive recommendation can be made
about colloid solutions based on starch derivatives. In hypotensive
or hypovolemic adults, an initial fluid challenge of 1000 ml crystal-
loid or 300–500 ml colloid should be administered over 30 minutes.
Fluid filling should be continued as long as patients have evidence of
hypovolemia and impaired organ perfusion. Patients must be mon-
itored closely as cardiac filling pressures increase to avoid cardiac
failure.
Vasopressors
Pharmacologic intervention is indicated if evidence of hypoperfusion
– persistent hypotension or acidosis – persists despite fluid filling.
Initial treatment is with noradrenaline (norepinephrine) or dop-
amine. There is no evidence that one agent is superior to the other. In
refractory cases vasopressin or terlipressin may also be considered but
large trial data on these agents are lacking.62 The dose of pressor agents
is titrated to maintain an arterial pressure of 65 mmHg or greater with
improved organ perfusion. Patients receiving pressor agents require
continuous arterial pressure monitoring and close attention to periph-
eral perfusion as ischemia of the extremities may complicate their
use. There is no role for ‘renal dose’ dopamine in the management of
severe sepsis.
Inotropes
Substantial experimental and clinical data indicate that myocar-
dial function is impaired in severe sepsis. Inotropes increase cardiac
contractility and can increase cardiac output and tissue perfusion
in severe sepsis. Adrenaline (epinephrine) or dobutamine can
­fulfill this role and there is no evidence that either agent is supe-
rior. Inotropes are indicated where there is evidence of a persistent
low cardiac output despite fluid resuscitation and treatment with
­pressor agents. Inotropes should not be given to patients who are
still hypovolemic. Some researchers have used inotropes to try to
achieve supranormal oxygen delivery in severe sepsis but there is
no ­evidence that this strategy improves clinical outcome and it is
­potentially deleterious.63
Insulin therapy in severe sepsis
Assiduous control of the blood glucose level is essential in diabetic
patients with severe sepsis. Several studies had previously indicated a
benefit from tight glycemic control with intensive insulin therapy in
nondiabetic patients with critical illness, including those with severe
sepsis.64 However, a large multicenter randomized study reported in
2008 has shown no overall benefit from insulin therapy in sepsis and
a significant increase in hypoglycemic events.61 Therefore, at this time,
insulin should only be used in septic patients with hyperglycemia
until more data are available.

Blood products in severe sepsis
There is some controversy around red cell transfusions in patients with
severe sepsis. Early goal-directed therapy suggests transfusion of red
cells to maintain a hematocrit >30% in patients with a superior vena
cava oxygen saturation of <70% after fluid resuscitation. In contrast,
the Transfusion Requirements in Critical Care trial suggests that there
is no benefit in transfusing above a threshold hemoglobin of 7 g/dl in
patients in ICU.65
Thrombocytopenia is common in severe sepsis. Platelet trans-
fusion should be considered if the absolute platelet count is less
than 5 × 109/l in the absence of bleeding or less than 30 × 109/l in
the presence of bleeding. Replacement of coagulation factors with
fresh frozen plasma or cryoprecipitate may be required to combat
bleeding. Plasma also contains potentially proinflammatory com-
ponents such as complement and replacing these may increase
inflammation.
Other supportive treatments
Patients with severe sepsis should receive thromboprophylaxis
unless there is a specific contraindication. Stress ulcer prophylaxis is
indicated with an H2 blocker or a proton pump inhibitor. Nutrition
should be maintained, preferably by the enteral route. In renal
impairment or severe acidosis early consideration should be given
to hemofiltration. In the intubated and ventilated patient a reduced
risk of ARDS and improved clinical outcome can be achieved using a
volume and pressure limited strategy and, where necessary, permis-
sive hypercapnia.5
IMMUNOMODULATION AND ADJUNCTIVE
THERAPIES IN SEVERE SEPSIS
The concept that organ damage in sepsis is the result of the host
inflammatory response has led to an enormous research effort to
understand and intervene in this process. Many therapeutic strategies
have been investigated in the laboratory setting and within large ran-
domized clinical trials. This has highlighted the difficulties inherent
in performing interventional studies in sepsis and initial results have
often been conflicting and disappointing with the notable failure of
antiendotoxin and anticytokine treatments. In the past decade a num-
ber of adjunctive treatments – namely low-dose corticosteroids, intra-
venous immunoglobulins and recombinant human activated protein
C – have entered clinical practice for selected groups of patients with
severe sepsis and these are discussed in more detail below.
Corticosteroids
There has been considerable controversy surrounding the use of
­corticosteroids in severe sepsis. In animal models pretreatment with
corticosteroids protected against endotoxemia, and initial promising
reports in humans led to the widespread use of high-dose cortico­
steroids in sepsis. Subsequently, two large multicenter trials failed to
show benefit and meta-analyses of suitable trials confirmed that the
use of high-dose corticosteroids in sepsis is not of benefit and may
potentially be deleterious by increasing rates of secondary infection.66
However, impairment of the hypothalamic–pituitary–adrenal axis is
seen in some patients with sepsis and is associated with a poor out-
come. This led to a re-evaluation of the role of lower dose corticoster-
oid replacement therapy.
In 2002 Annane et al. reported a significant increase in survival
of patients with severe sepsis, who had catecholamine-refractory
shock and a poor response to synacthen, indicating adrenal failure,
when treated with a combination of hydrocortisone and fludrocor-
tisone.67 As a result of this, corticosteroid replacement has been rec-
ommended for patients with severe sepsis and a poor response to
Sepsis Chapter | 44 |
fluids and vasopressors.5 Hydrocortisone is usually given at a dose of
200–400 mg/day in divided doses with or without fludrocortisone
50 μg/day.
In 2008 a large multicenter study, CORTICUS, was reported
which failed to confirm the mortality benefit seen in earlier stud-
ies.68 However, in this study, shock resolution was significantly faster
in patients receiving hydrocortisone therapy, supporting a rationale
for steroid replacement therapy in severe sepsis. Further work will be
required to define the precise role of corticosteroid therapy for patients
with severe sepsis.
Intravenous immunoglobulin therapy
Intravenous immunoglobulin therapy (IVIG) administration has been
examined in bacterial sepsis with variable data.69 At present it is not
possible, on the basis of the available evidence, to recommend IVIG
for unselected patients with severe sepsis. In severe sepsis associated
with toxin-producing bacteria, for example staphylococcal or strepto-
coccal toxic shock syndrome, there is a stronger rationale for the use of
high-dose IVIG. Toxic shock is seen in persons with low levels of anti-
toxin antibodies and pooled IVIG contains neutralizing antibodies
against a variety of superantigenic toxins. Experimental data and anec-
dotal reports would support the use of IVIG in this setting but there
are as yet no substantial clinical trials. More recently IVIG has been
suggested for use in patients with severe infections due to Staph. aureus
strains producing the Panton–Valentine leukocidin toxin70 and for
severe C. difficile infection.71
Recombinant human activated protein C
Modulators of coagulation are protective in animal models of severe
sepsis and have entered human trials. Of these, recombinant human
activated protein C (rhAPC) is most promising. In a phase III mul-
ticenter trial of rhAPC versus placebo (PROWESS) in 1690 patients
with severe sepsis, 28-day mortality was reduced from 30.8 to 24.7%
(p <0.005), a relative reduction in risk of death of 19.4%.72 There was
a small but significant increase in serious bleeding in the active ther-
apy group. On the basis of these results rhAPC (drotrecogin alpha)
was granted a product license for the treatment of severe sepsis and
organ failure in adults in 2002. rhAPC has been recommended in
adult patients with sepsis-induced organ dysfunction and a high risk
of death (i.e. APACHE II score >25) and who have no contraindica-
tions that would increase the risk of bleeding.
PROWESS was followed by the ADDRESS trial which looked at
the use of rhAPC in patients with sepsis at a lower risk of death.73 In
this study, involving 2613 patients, no mortality benefit from rhAPC
could be detected over placebo but there was a significant increase
in 28-day mortality rate if they received rhAPC rather than placebo.
Furthermore, in subgroup analysis of patients enrolled into ADDRESS
but at high risk of death (similar criteria to the PROWESS study) no
benefit from rhAPC could be detected.
So where does this leave rhAPC in the treatment of severe sepsis? On
the basis of a well-randomized and performed clinical trial rhAPC has
a product license and has entered treatment guidelines in many coun-
tries. On the available evidence it is reasonable to continue to prescribe
rhAPC for patients with severe sepsis who fulfill the original PROWESS
entry criteria and who do not have a high risk of bleeding complica-
tions. rhAPC should not be given to patients with single organ failure
or a low risk of death due to the risk of bleeding. Further randomized
trials of rhAPC are planned which may answer these questions.
REFERENCES
References for this chapter can be found online
at http://www.expertconsult.com
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