Chapter 42 - Sepsis, Septic Shock, and Multiple Organ Failure

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Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure
Russell J. McCulloh; Steven M. Opal
KEY POINTS
KEY POINTS
1. Sepsis is increasing in incidence worldwide. This is the result of a number of factors including: the aging of the population with a large increase
in patients more than 65 years; progressive increase in antibiotic resistance; increased reliance on implanted devices, organ transplantation and
other invasive surgical procedures; and increasing prevalence of patients with long-term immunosuppressive diseases and medications who are
at risk for severe infection and sepsis.
2. Sepsis is a syndrome consisting of a constellation of signs, symptoms, hemodynamic, and laboratory findings caused by an excessive and/or
dysfunctional host immune response to severe infection. There is currently no single diagnostic test sufficient to make a definitive diagnosis of
sepsis.
3. The key to optimal care of the septic patient is early recognition and early initiation of appropriate treatment. This places the responsibility for
early recognition on the health care team in managing acutely ill patients. The lack of a rapid diagnostic test and the often subtle initial
presentation of sepsis make the early detection of sepsis a real challenge.
4. Septic shock is a medical emergency and should be treated as such. The major therapeutic approach is aggressive fluid resuscitation, early and
appropriate antibiotic therapy, early determination of the source of the causative infection site and source control if possible (drain abscess,
remove necrotic tissue or infected catheters or other devices, etc).
5. The prevention and expert management of organ dysfunction as a result of sepsis is critical for survival and prevention of long-term disability.
Expert supportive care by critical care specialists will improve outcomes.
INTRODUCTION
Sepsis and the multiorgan failure that often accompanies the systemic inflammatory response syndrome (SIRS) is a leading cause of mortality in the
intensive care unit. Over 750,000 patients develop sepsis annually in the United States accounting for about 10% of all intensive care unit (ICU)
admissions. Of these patients, 5% to 15% will be diagnosed with septic shock. The hospital mortality for septic shock remains approximately 35% to
54%, despite concerted efforts to improve the treatment options and outcome.
Although modest improvements in the prognosis have been made over the past 2 decades and promising new therapies continue to be investigated,
innovations in the management of septic shock are still required. This chapter will describe the molecular pathophysiology of sepsis, current
diagnostic and therapeutic strategies, and the management of septic shock.
SEPSIS DEFINITIONS
New definitions for sepsis were published by the Third International Sepsis Task Force in 2016. According to these updated definitions, sepsis is
defined as a life-threatening condition caused by a dysregulated host response to infection accompanied by acute organ dysfunction. Septic shock is a
subset of sepsis in which underlying cellular metabolism abnormalities are sufficiently profound to significantly increase mortality. Septic shock is
clinically recognized as arterial hypotension, refractory to simple fluid resuscitation, with evidence of hyperlactatemia. Multiple other clinical entities
related to sepsis, including SIRS and multiple organ dysfunction syndrome (MODS) are defined in Table 42–1. These definitions account for the finding
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that sepsis can result from various infectious agents and microbial mediators and is not necessarily associated with bloodstream infection.Page
Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal 1 / 15of
The goal
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the updated definitions is to increase consistency for epidemiologic studies and clinical trials and to help improve earlier recognition and timely
management of patients with sepsis or at risk for developing sepsis.
SEPSIS DEFINITIONS
University of Phayao
New definitions for sepsis were published by the Third International Sepsis Task Force in 2016. According to these updated definitions, sepsis is
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defined as a life-threatening condition caused by a dysregulated host response to infection accompanied by acute organ dysfunction. Septic shock is a
subset of sepsis in which underlying cellular metabolism abnormalities are sufficiently profound to significantly increase mortality. Septic shock is
clinically recognized as arterial hypotension, refractory to simple fluid resuscitation, with evidence of hyperlactatemia. Multiple other clinical entities
related to sepsis, including SIRS and multiple organ dysfunction syndrome (MODS) are defined in Table 42–1. These definitions account for the finding
that sepsis can result from various infectious agents and microbial mediators and is not necessarily associated with bloodstream infection. The goal of
the updated definitions is to increase consistency for epidemiologic studies and clinical trials and to help improve earlier recognition and timely
management of patients with sepsis or at risk for developing sepsis.
Table 42–1
Common definitions and terms used in sepsis.
Term Definition Comments
ARDS* (acute Acute onset (< 7 days) respiratory symptoms; bilateral infiltrates A severity score divides patients into 3 groups depending on
respiratory on chest radiograph not explained by other pleural or lung PaO2/FiO2 ratio and predict outcome: 200 to ≤ 300 mm Hg (mild 27
distress disease; infiltrates not due to cardiac failure or fluid overload ± 3% mortality); 100 to ≤ 200 mm Hg (moderate 32 ± 3% mortality)
syndrome) (must exclude hydrostatic edema if suspected) or ≤ 100 mm Hg (severe 45 ± 2% mortality)
Bacteremia Detection of viable bacteria in the bloodstream Transient bacteremia without clinical symptoms can occur;
bacteremia may or may not be present in sepsis
SIRS Temperature > 38.5°C (101.3°F) or Two or more criteria needed; may be caused by infectious and
(systemic < 36°C (96.8°F) noninfectious etiologies; clinical features attributable to systemic
inflammatory Tachypnea (> 20 breath/min) release of inflammatory mediators into the circulation
response Tachycardia (> 90 beat/min)
syndrome) WBC count > 12,000 cells/mm3 or > 10% immature forms or < 4000
cells/mm3
Sepsis Life-threatening acute organ dysfunction caused by a May be caused by viral, bacterial, fungal, or parasitic pathogens;
dysregulated host response to infection. Organ dysfunction: acute bloodstream infection need not be present
change in SOFA score ≥ 2 points from infection
Septic shock Sepsis with hypotension requiring vasopressors to maintain MAP Hospital mortality in septic shock exceeds 40%
≥ 65 mm Hg and having a serum lactate level > 2 mmol/dL despite
adequate volume resuscitation
The 2012 Berlin definition (JAMA 307; 2526, 2012) now supersedes the former 1994 European-American Consensus Committee on ARDS definition. PaO2, arterial
oxygen tension; F1O2, fraction of inspired oxygen; WBC, white blood count.
Current sepsis definitions are based upon the fact that the dysregulated immune response itself, not the infectious agent, underlies the
pathophysiology of the septic process. The nature of the causative microorganism also clearly contributes to the ultimate fate of the patient.
Pathogens differ in their susceptibility to host defenses, their potential for developing antimicrobial resistance, and their ability to generate toxins—all
of which affect pathogenicity. Failing to account for these differences in microbial virulence limits the utility of current sepsis definitions.
Many patients who present with sepsis have multiple predisposing factors, a variety of preexisting illnesses, and have major underlying organ
dysfunction from comorbid diseases. The degree to which sepsis contributes to further disordered organ function is be difficult to accurately
determine. Similarly, the degree to which sepsis contributes to the mortality in patients with other serious underlying diseases (attributable risk of
mortality) can be difficult to quantify. Further refinements in sepsis terminology may be possible when rapid diagnostic techniques become available
to assess the immune status of septic patients. Functional genomics and proteomics may assist in characterizing septic patients in the future.
EPIDEMIOLOGY
Between 1979 and 2000, the incidence of sepsis in the United States increased by 8.7% annually, from 82.7 to 240.4 per 100,000 population.Page
Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal These2 / 15
trends are observed worldwide and will likely continue because sepsis incidence increases with the aging of the population. Innovations in organ
transplantation, implanted prosthetic devices, and long-term vascular access devices continue to expand this vulnerable patient population at risk for
sepsis. The gradual aging of the population in many developed and developing countries and the increasing prevalence of antibiotic-resistant
dysfunction from comorbid diseases. The degree to which sepsis contributes to further disordered organ function is be difficult to accurately
determine. Similarly, the degree to which sepsis contributes to the mortality in patients with other serious underlying diseases (attributable risk of
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mortality) can be difficult to quantify. Further refinements in sepsis terminology may be possible when rapid diagnostic techniques become available
to assess the immune status of septic patients. Functional genomics and proteomics may assist in characterizing septic patients in the future.
EPIDEMIOLOGY
Between 1979 and 2000, the incidence of sepsis in the United States increased by 8.7% annually, from 82.7 to 240.4 per 100,000 population. These
trends are observed worldwide and will likely continue because sepsis incidence increases with the aging of the population. Innovations in organ
transplantation, implanted prosthetic devices, and long-term vascular access devices continue to expand this vulnerable patient population at risk for
sepsis. The gradual aging of the population in many developed and developing countries and the increasing prevalence of antibiotic-resistant
microbial pathogens also contribute to the rising incidence of septic shock.
PATHOGENESIS: MICROBIAL FACTORS

Causative microorganisms
The microbiology of sepsis continues to evolve due to changes in microbial epidemiology, pathogen virulence, and pathogens' susceptibility to
antimicrobials. The predominant microbial pathogens responsible for sepsis in the 1960s and 1970s were enteric gram-negative bacilli and
Pseudomonas aeruginosa, but switched to predominantly gram-positive bacterial pathogens in the mid-1980s through 2010, due mostly to the rapid
development of antibiotic resistance in gram-positive pathogens and their strong association with vascular-catheter-associated infections. Gram-
negative bacterial pathogens are now returning as the dominant cause of sepsis, due largely to progressive antibiotic resistance and the lack of new
antibacterial agents effective against gram-negative bacterial pathogens. Opportunistic fungal pathogens are also increasing in frequency as a cause of
sepsis.
Bacterial endotoxin and other pathogen-associated molecular pattern molecules
Bacterial endotoxin, or lipopolysaccharide (LPS), is an intrinsic component of the outer membrane of gram-negative bacteria and is essential for the
viability of enteric bacteria. Endotoxin functions as an alarm molecule alerting the host to invasion by gram-negative bacteria. Endotoxin in the
circulation provokes a vigorous systemic inflammatory response. Humans are especially susceptible to the profound immunostimulant properties of
endotoxin; even minute doses may be lethal. Other highly conserved pathogen-associated molecular pattern molecules such as bacterial lipoteichoic
acid, lipopeptides and even sequences of bacterial and viral DNA can be detected by the immune system and activate innate immune responses.
The Toll-like receptor (TLR) family is the most important cellular, pathogen-associated pattern recognition receptor system in humans. The TLRs are
transmembrane receptors for detecting endotoxin and many other microbial mediators, such as peptidoglycan, lipopeptides, bacterial flagellin,
lipoteichoic acid, microbial-derived nucleic acids, and viral and fungal cell components. Nucleoside oligomerization domain proteins recognize
specific components of bacterial peptidoglycan and other microbial elements with the cytosol and activate the acute phase response with the release
of the proinflammatory cytokine interleukin-1 beta.
Other pattern-recognition molecules include alternative complement components, mannose-binding lectin, and CD14. The innate immune system is a
nonspecific, rapid response system, making this system a critical survival mechanism in the initial stages of infection. However, widespread activation
of the innate immune system and its cellular components (neutrophils, monocytes, macrophages, and natural killer [NK] cells) can cause collateral
damage to host tissues and contributes to the induction of multiorgan injury and septic shock.
In human blood and body fluids, LPS signaling is mediated by interactions with the acute-phase plasma protein LPS-binding protein (LBP). LBP binds
to polymeric LPS aggregates and transfers LPS monomers to CD14. After docking to membrane-bound CD14, LPS is delivered to the extracellular
adaptor protein MD2. The LPS-MD2 complex is then presented to the extracellular domain of TLR4. This subsequently triggers a signal to the
intracellular space that activates LPS-responsive genes. CD14 also binds to bacterial peptidoglycan and lipopeptides and delivers these ligands to
TLR2.
TLR4 binding to LPS leads to sequential activation of specific tyrosine and threonine/serine kinases and phosphorylation, ubiquitylation, and
degradation of inhibitory κB (I-κB) along with other transcriptional activators. IκB degradation releases nuclear factor κB (NF-κB) from the cytoplasm.
NF-κB then translocates into the nucleus and increases transcription of genes encoding clotting elements, complement, other acute phase proteins,
cytokines, chemokines, and nitric oxide synthase. The outpouring of inflammatory cytokines and other inflammatory mediators after LPS exposure
contributes to SIRS and is central to the pathogenesis of septic shock induced by gram-negative bacteria.
Bacterial superantigens
Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal Page 3 / 15
Bacterial superantigens comprise a diverse group of protein-based exotoxins from streptococci, staphylococci, and other pathogens that all share the
capacity to bind to specific sites on major histocompatibility class II molecules on antigen presenting cells and activate large numbers of CD4+ T cells,
bypassing the usual mechanism of antigen processing and presentation. Superantigens bind to and cross-link to a limited number of Vβ regions of the
degradation of inhibitory κB (I-κB) along with other transcriptional activators. IκB degradation releases nuclear factor κB (NF-κB) from the cytoplasm.
NF-κB then translocates into the nucleus and increases transcription of genes encoding clotting elements, complement, other acute phase proteins,
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cytokines, chemokines, and nitric oxide synthase. The outpouring of inflammatory cytokines and other inflammatory mediators after LPS exposure
contributes to SIRS and is central to the pathogenesis of septic shock induced by gram-negative bacteria.
Bacterial superantigens
Bacterial superantigens comprise a diverse group of protein-based exotoxins from streptococci, staphylococci, and other pathogens that all share the
capacity to bind to specific sites on major histocompatibility class II molecules on antigen presenting cells and activate large numbers of CD4+ T cells,
bypassing the usual mechanism of antigen processing and presentation. Superantigens bind to and cross-link to a limited number of Vβ regions of the
T cell receptor on CD4+ T cells, along with the costimulatory molecule CD28. This bridging complex brings CD4+ T cells and macrophages into close
proximity, which activates both the monocyte-macrophage and T cell populations.
Superantigens can stimulate up to 10% to 20% of the entire circulating lymphocyte population, compared to only about one in 105 circulating
lymphocytes stimulated by typical bacterial antigens. This stimulation results in excessive activation of lymphocytes and macrophages, which leads to
uncontrolled inflammatory cytokine synthesis and release. Superantigen-induced immune activation may terminate in septic shock (eg, streptococcal
toxic shock syndrome) if the process is left unchecked. Infections associated with release of both bacterial superantigens and endotoxin may be
particularly injurious to the host; the toxicity of bacterial endotoxin is greatly enhanced by superantigens that prime the immune system to react to
endotoxin in an overly sensitized manner.
Other microbial mediators
During periods of prolonged systemic hypotension such as septic shock, redistribution of blood flow to the tissues results in splanchnic
vasoconstriction. The ischemia and subsequent reperfusion of the gastrointestinal tract disrupts the intestinal mucosal barrier to bacterial products
and damaged tissue releases host-derived alarmins that further activate inflammatory signaling. Translocation of microbial components such as
bacterial endotoxin occurs from the GI tract to the circulation during periods of severe stress and hypoperfusion of the GI mucosa. Bacterial endotoxin
and perhaps other gut-derived microbial mediators might play a pathogenic role in the ongoing inflammatory process after systemic hypotension
produced by infectious or noninfectious insults. This finding has initiated interest in attempts to strengthen the GI mucosal barrier function through
immunonutrition, epithelial growth factors, and selective decontamination of the GI tract in critical illness, which remain active areas of research.
PATHOGENESIS: HOST-DERIVED MEDIATORS

Cytokine networks
Inflammatory cytokines play a pivotal role in sepsis pathogenesis. The major proinflammatory cytokines, TNF-α and IL-1β, induce their hemodynamic
and metabolic effects in concert with an expanding group of host-derived inflammatory mediators that work in a coordinated fashion to produce the
systemic inflammatory response (see Table 42–2). The cytokine system functions as a network of communication signals between neutrophils,
monocytes, macrophages, and endothelial cells. Autocrine and paracrine activation results in synergistic potentiation of the inflammatory response
once it is activated by a systemic microbial challenge. Much of the inflammatory response is localized and compartmentalized in the primary region of
initial inflammation. If left unchecked, the inflammatory response enters the systemic circulation, resulting in a generalized reaction culminating in
diffuse endothelial injury, coagulation activation, and septic shock. The endocrine-like effect of systemic cytokine and chemokine release drives the
inflammatory process and causes coagulation activation throughout the body.
Table 42–2
Host-derived inflammatory mediators in septic shock.
Proinflammatory Mediators Anti-Inflammatory Mediators
Tumor necrosis factor-α Interleukin-1 receptor antagonist

Interferon gamma Soluble tumor necrosis factor receptor
Lymphotoxin-α Soluble interleukin-1 receptor
Interleukin-2 Type II interleukin-1 receptor
Interleukin-8 Transforming growth factor-β
Interleukin-12 Interleukin-4
sCD14, MD2 Interleukin-11
Complement components (C5a and C3a) Interleukin-13
Mannose binding lectin Prostaglandin E2α
Leukotriene B4 Granulocyte colony-stimulating factor
once it is activated by a systemic microbial challenge. Much of the inflammatory response is localized and compartmentalized in the primary region of
initial inflammation. If left unchecked, the inflammatory response enters the systemic circulation, resulting in a generalized reaction culminating in
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diffuse endothelial injury, coagulation activation, and septic shock. The endocrine-like effect of systemic cytokine and chemokine release drives the
inflammatory process and causes coagulation activation throughout the body.
Table 42–2
Host-derived inflammatory mediators in septic shock.
Proinflammatory Mediators Anti-Inflammatory Mediators
Tumor necrosis factor-α Interleukin-1 receptor antagonist

Interferon gamma Soluble tumor necrosis factor receptor
Lymphotoxin-α Soluble interleukin-1 receptor
Interleukin-2 Type II interleukin-1 receptor
Interleukin-8 Transforming growth factor-β
sCD14, MD2 Interleukin-11
Complement components (C5a and C3a) Interleukin-13
Mannose binding lectin Prostaglandin E2α
Leukotriene B4 Granulocyte colony-stimulating factor
Platelet-activating factor Antioxidants

Bradykinin Anticoagulants (antithrombin, activated protein C, tissue factor pathway inhibitor)
Nitric oxide Interferon alfa
Reactive oxygen species Interferon beta
Granulocyte macrophage colony-stimulating factor Glucocorticoids
Chemokines Epinephrine
Macrophage inhibitory factor Cholinergic agonists
High mobility group box I Resolvins, protectins
Histamine, thrombin, other clotting factors Lipoxygenase pathway
TREM-1 (triggering receptor expressed on myeloid cells)
The inflammatory cytokines and chemokines found in excess quantities in the bloodstream in patients with septic shock are matched by a group of
anti-inflammatory mediators (see Table 42–2). The proinflammatory mediators tend to predominate locally and in the first 12 to 24 hours of sepsis,
whereas the endogenous anti-inflammatory components often prevail systemically in the later phases. Monocyte-macrophage–generated cytokines
and chemokines primarily promote sepsis early on; the lymphocyte-derived cytokines and interferons become important in the regulation of later
phases of sepsis and may ultimately determine the outcome in septic shock.
CD4+ T helper cells
Activated, yet uncommitted, T cells (TH0 cells) have four major pathways of functional differentiation (TH1, TH2, TH17, or Treg cells). TH0 cells exposed
to IL-12 in the presence of IL-2 are driven toward a TH1-type functional development. These cells produce IFN-γ, TNF-α, and IL-2 and promote an
inflammatory, cell-mediated immune response. TH0 cells exposed to IL-4 will preferentially develop into a TH2-type phenotype; TH2 cells secrete IL-4,
IL-10, and IL-13, which promote humoral immune responses and attenuate T helper cells, and myeloid cell activity. Sepsis is often accompanied by a
TH2-type response after an initial septic insult, likely due in part to the expression of adrenocorticotropic hormone, corticosteroids, and
catecholamines that promote a TH2 response. CD4 cells are selectively depleted by apoptosis in sepsis further limiting cell-mediated immunity and T
helper cell capacity.
A phase of relative immune refractoriness occurs in septic patients that place them at increased risk for secondary bacterial or fungal infection. Part of
the pathophysiology of sepsis-induced immunosuppression is mediated by Th17 cells and regulatory T cells. Th17 cells are stimulated by dendritic
cell-derived interleukin-23 to produce IL-17, chemokines, and antibacterial and antifungal peptides. Th17 cells are depleted in sepsis and might
explain the propensity of septic patients to develop late, opportunistic bacterial and fungal infections. Regulatory T cells expand during sepsis and
produce anti-inflammatory cytokines such as IL-10 and transforming growth factor beta contributing to T cell exhaustion. This pathophysiologic state
is associated with endotoxin tolerance, anti-inflammatory cytokine synthesis, and deactivation of monocytes, macrophages, and neutrophils.
The coagulation system
Activation of the coagulation cascade and generation of a consumptive coagulopathy and diffuse microthrombi are well-recognized events in sepsis.
A phase of relative immune refractoriness occurs in septic patients that place them at increased risk for secondary bacterial or fungal infection. Part of
the pathophysiology of sepsis-induced immunosuppression is mediated by Th17 cells and regulatory T cells. Th17 cells are stimulated by dendritic
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cell-derived interleukin-23 to produce IL-17, chemokines, and antibacterial and antifungal peptides. Th17 cells are depleted in sepsis and might
explain the propensity of septic patients to develop late, opportunistic bacterial and fungal infections. Regulatory T cells expand during sepsis and
produce anti-inflammatory cytokines such as IL-10 and transforming growth factor beta contributing to T cell exhaustion. This pathophysiologic state
is associated with endotoxin tolerance, anti-inflammatory cytokine synthesis, and deactivation of monocytes, macrophages, and neutrophils.
The coagulation system
Activation of the coagulation cascade and generation of a consumptive coagulopathy and diffuse microthrombi are well-recognized events in sepsis.
The tissue factor pathway (also known as the extrinsic pathway) is the predominant mechanism by which the coagulation system is activated. The
contact factors in the intrinsic pathway are also activated, which helps perpetuate clotting and secondarily initiates vasodilation through bradykinin
generation. Activation of intravascular coagulation results in microthrombi and contributes to microcirculatory dysfunction and the multiorgan failure
that occur in septic patients. Depletion of coagulation factors and activation of plasmin, antithrombin III, and protein C may subsequently lead to a
hemorrhagic diathesis. Depletion of these endogenous anticoagulants may secondarily lead to a procoagulant state and portend a poor prognosis.
Neutrophil–endothelial cell interactions
The recruitment of neutrophils to an area of localized infection is an essential component of the host inflammatory response. Localization and
eradication of invading microbial pathogens at the site of initial infection is the principal objective of the immune response to microbial pathogens.
This physiologic process becomes deleterious if diffuse neutrophil–endothelial cell interactions occur throughout the circulation in response to
systemic inflammation.
Complex mechanisms govern the migration of neutrophils from the intravascular space into the interstitium, where invasive microorganisms may
reside. Activated neutrophils degranulate, exposing endothelial surfaces and surrounding structures to reactive oxygen intermediates, nitric oxide,
and a variety of proteases. This process contributes not only to microbial clearance but also to diffuse endothelial injury in the setting of systemic
inflammation.
Nitric oxide
Nitric oxide is a highly reactive free radical that plays an essential role in the pathophysiology of septic shock. Its half-life of 1 to 3 seconds limits its
activity to local tissues, where it is first generated by nitric oxide synthase. Full expression of inducible nitric oxide synthase requires TNF-α, IL-1, LPS,
and probably other regulatory elements.
Nitric oxide is the major endothelial-derived relaxing factor that initiates the vasodilation and systemic hypotension observed in septic shock. Nitric
oxide activates guanylate cyclase, which increases cyclic guanosine monophosphate levels inside vascular smooth muscle cells. This results in systemic
vasodilation and decreased vascular resistance. Excessive and prolonged release of nitric oxide results in generalized vasodilatation and systemic
hypotension.
Nitric oxide also helps increase intracellular killing of microbial pathogens and regulation of platelet and neutrophil adherence in septic patients. It is a
highly diffusible gas that does not require specific receptors to cross cell membranes. In the presence of superoxide anion, nitric oxide leads to the
formation of peroxynitrite and highly cytotoxic molecules, such as hydroxyl radicals and nitrosyl chloride, which then initiate lipid peroxidation and
cause irreversible cellular damage. Nitric oxide inhibits a variety of key enzymes in the tricarboxylic acid pathway, the glycolytic pathway, DNA repair
systems, electron transport pathways, and energy-exchange pathways. Because of its potent reactivity, nitric oxide alters the function of many metallo-
enzymes, carrier proteins, and structural elements.
Late host-derived mediators
Macrophage migration inhibitory factor is a late mediator that activates immune cells, upregulates TLR4 expression, and contributes to lethal septic
shock. This corticosteroid-regulated mediator promotes inflammation and has become a target for therapeutic agents in sepsis. The nuclear protein
high-mobility group box–1 protein is released into the extracellular space with cell injury and necrosis and also participates in late-onset inflammatory
phase of septic shock.
Pathogenesis: organ dysfunction
The diffuse endothelial injury accompanying septic shock results in organ dysfunction distant from the original site of the septic insult. The signal that
results in diffuse endovascular injury is thought to be relayed by plasma factors (eg, inflammatory cytokines, complement, kinins, and other host-
derived inflammatory mediators) or cellular signals from immune effector cells.
Inadequate tissue blood supply and repeated episodes of ischemia-reperfusion produces MODS. The failure of the microcirculation to support tissue
maintenance may result from capillary bed hypoperfusion, blood flow redistribution within vascular beds, functional arteriovenous shunting, blood
flow obstruction from microthrombi, platelet or white blood cell aggregates, or abnormal red blood cell deformability. Nitric oxide, reactive oxygen
phase of septic shock.
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Pathogenesis: organ dysfunction
The diffuse endothelial injury accompanying septic shock results in organ dysfunction distant from the original site of the septic insult. The signal that
results in diffuse endovascular injury is thought to be relayed by plasma factors (eg, inflammatory cytokines, complement, kinins, and other host-
derived inflammatory mediators) or cellular signals from immune effector cells.
Inadequate tissue blood supply and repeated episodes of ischemia-reperfusion produces MODS. The failure of the microcirculation to support tissue
maintenance may result from capillary bed hypoperfusion, blood flow redistribution within vascular beds, functional arteriovenous shunting, blood
flow obstruction from microthrombi, platelet or white blood cell aggregates, or abnormal red blood cell deformability. Nitric oxide, reactive oxygen
intermediates, inflammatory cytokines, and apoptosis inducers may directly damage endothelial surfaces. Endothelial swelling shifts intravascular
fluid into extravascular and intracellular spaces, mechanically obstructing capillary lumens and further limiting microvascular blood flow.
Myocardial performance and pulmonary function also diminish over the course of septic shock and may contribute to the development of MODS.
Myocardial contractility decreases in response to various myocardial depressant factors. TNF-α is a prominent cause of myocardial dysfunction; IL-1,
IL-6, nitric oxide, and other host-derived inflammatory mediators may be contributing factors. Acute lung injury occurs in septic shock as a result of
damage to pulmonary vascular circulation and excess permeability of alveolar capillary membranes. A supply-dependent dysoxia, along with altered
capacity for oxidative phosphorylation (cytopathic hypoxia), likely contributes to tissue injury and multiorgan failure in sepsis.
DIAGNOSTIC APPROACH TO SEPSIS

Clinical features
In his classic treatise on human nature (The Prince, circa 1505), Machiavelli states, “Hectic fever [meaning sepsis] at its inception is difficult to recognize
but easy to treat; left untended, it becomes easy to recognize but difficult to treat.” This statement is as true today as it was 500 years ago. Fully
developed septic shock is a readily apparent clinical syndrome that is seldom confused with other pathologic states. However, the early phases of
septic shock may be quite subtle even in carefully monitored patients. Although fever is characteristic, hypothermia may occur and connotes a poor
prognosis. Unexplained tachycardia and tachypnea are often part of the systemic inflammatory response seen in sepsis. It is important to note that
many noninfectious diseases may masquerade as sepsis such as acute pancreatitis, pulmonary emboli, myocardial infarction, blood transfusion
reactions, and organ transplant rejection. A summary of the major hemodynamic findings of sepsis is provided in Table 42–3.
Table 42–3
Common hemodynamic findings in sepsis.
Typical
Parameter Comments
Findings
Heart rate ≥ 100 Major compensatory mechanism for low systemic vascular resistance
beat/min
Mean arterial blood pressure < 65 mm Hg Hallmark of septic shock if it remains low after adequate fluid resuscitation
Cardiac index (cardiac output/m2 > 4 L/min/m2 Cardiac index usually elevated in early septic shock; may be depressed in late septic shock
[surface area])
Pulmonary arterial occlusion 8-16 mm Hg Assure that hypovolemia is not the cause of hypotension; perform fluid resuscitation until PAOP
pressure (PAOP) returns to normal
Central venous pressure (CVP) 6-12 mm Hg Reliable resuscitation goal indicating adequate blood volume for ventricular filling pressure
Systemic vascular resistance (SVR) < 800 SVR often low in early septic shock; may become elevated in later phases of septic shock
dyne/s/cm-5
Oxygen delivery (DO2) < 550 Try to provide sufficient DO2 to maintain adequate mixed venous O2 saturation
Cardiac index (CI) × arterial O2 mL/min/m2
content (A)
Mixed venous O2 saturation (SvO2) < 70% Low mixed venous O2 saturation or central venous O2 saturation (from superior vena cava)
or < 65% indicates poor oxygen delivery to tissues

septic shock may be quite subtle even in carefully monitored patients. Although fever is characteristic, hypothermia may occur and connotes a poor
prognosis. Unexplained tachycardia and tachypnea are often part of the systemic inflammatory response seen in sepsis. It is important to note that
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many noninfectious diseases may masquerade as sepsis such as acute pancreatitis, pulmonary emboli, myocardial infarction, blood transfusion
reactions, and organ transplant rejection. A summary of the major hemodynamic findings of sepsis is provided in Table 42–3.
Table 42–3
Common hemodynamic findings in sepsis.
Typical
Parameter Comments
Findings
Heart rate ≥ 100 Major compensatory mechanism for low systemic vascular resistance
beat/min
Mean arterial blood pressure < 65 mm Hg Hallmark of septic shock if it remains low after adequate fluid resuscitation
Cardiac index (cardiac output/m2 > 4 L/min/m2 Cardiac index usually elevated in early septic shock; may be depressed in late septic shock
[surface area])
Pulmonary arterial occlusion 8-16 mm Hg Assure that hypovolemia is not the cause of hypotension; perform fluid resuscitation until PAOP
pressure (PAOP) returns to normal
Central venous pressure (CVP) 6-12 mm Hg Reliable resuscitation goal indicating adequate blood volume for ventricular filling pressure
Systemic vascular resistance (SVR) < 800 SVR often low in early septic shock; may become elevated in later phases of septic shock
dyne/s/cm-5
Oxygen delivery (DO2) < 550 Try to provide sufficient DO2 to maintain adequate mixed venous O2 saturation
Cardiac index (CI) × arterial O2 mL/min/m2
content (A)
Mixed venous O2 saturation (SvO2) < 70% Low mixed venous O2 saturation or central venous O2 saturation (from superior vena cava)
or < 65% indicates poor oxygen delivery to tissues

Central venous O2 saturation
(ScvO2)
Oxygen consumption (VO2) > 180 Typically increased in early septic shock
(CI) × (A-VO2) × 10 L/min/m2
Laboratory indicators of sepsis and septic shock
The updated international guidelines use the Sequential [Sepsis-Related] Organ Failure Assessment Score to define sepsis (SOFA, see Table 42–4).
Laboratory criteria included in the SOFA focus on the presence of coagulopathy, hepatic dysfunction, and/or renal dysfunction. Other nonspecific
laboratory criteria, such as peripheral white blood cell count can aid in the general diagnosis of infection but are no longer used to define sepsis or
septic shock.
Table 42–4
Common laboratory findings in sepsis.
Laboratory
Typical Findings Comments
Study
White blood Leukocytosis or leukopenia

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Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal
cell count cause transient neutropenia; toxic granulation Page 8 / 15
Platelet Thrombocytopenia (< 150,000/mm3) Look for evidence of fragmentation hemolysis; thrombocytopenia
count may be accompanied by DIC
The updated international guidelines use the Sequential [Sepsis-Related] Organ Failure Assessment Score to define sepsis (SOFA, see Table 42–4).
Laboratory criteria included in the SOFA focus on the presence of coagulopathy, hepatic dysfunction, and/or renal dysfunction. Other nonspecific
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laboratory criteria, such as peripheral white blood cell count can aid in the general diagnosis of infection but are no longer used to define sepsis or
septic shock.
Table 42–4
Common laboratory findings in sepsis.
Laboratory
Typical Findings Comments
Study
White blood Leukocytosis or leukopenia Stress response, increased margination of neutrophils in sepsis can
cell count cause transient neutropenia; toxic granulation
Platelet Thrombocytopenia (< 150,000/mm3) Look for evidence of fragmentation hemolysis; thrombocytopenia
count may be accompanied by DIC
Total Lymphopenia (< 1200/mm3) All lymphocyte types decreased from trafficking out to extravascular
lymphocyte sites and excess apoptosis except Treg cells
count
Eosinophil Eosinopenia (< 40/mm3) Can suggest infection-related acute inflammatory processes
count
Coagulation Elevated prothrombin time (INR), aPTT, low fibrinogen levels, Coagulopathy very common, but overt DIC is not common (< 15% of
studies elevated D-dimer; evidence of fibrinolysis patients)
Liver Elevated alkaline phosphatase, bilirubin, and transaminases; These are generally a late finding in sepsis
enzymes low albumin
Blood Bacteremia or fungemia Positive blood cultures not required for the diagnosis of sepsis
cultures
Plasma > 2.2 mmol/L caused by hypermetabolism, anaerobic Poor prognostic feature if not improved rapidly by fluid resuscitation;
lactate metabolism, inhibition of pyruvate dehydrogenase diagnostic criterion for septic shock
C-reactive Elevated as an acute phase reactant from hepatic synthesis Acute-phase reactant, sensitive, but not specific for sepsis
protein
Glucose Hyperglycemia or hypoglycemia Acute stress response, inhibition of gluconeogenesis can lead to
hypoglycemia
Arterial Respiratory alkalosis (early); metabolic acidosis (late) Reduced arterial O2 content and mixed venous O2 saturation
blood gases
DIC, disseminated intravascular coagulation; Treg cells, regulatory T cells; INR, international normalized ratio; aPTT, activated partial thromboplastin time.
White blood cell count and differential
Either leukocytosis or leukopenia may occur in sepsis. An absolute lymphocyte count less than 1200 cells/mm3 and a ANC:ALC ratio more than 10 have
been found to be better predictors of bacteremia than the total white blood cell count or absolute neutrophil count. Interesting, eosinopenia (< 40%) is
as useful as C reactive protein in distinguishing SIRS as an immunologically regulated response to infection and SIRS from sepsis.
Coagulation parameters
Systemic inflammation induced during sepsis can activate the coagulation cascade. In a clinical trial of recombinant human activated Protein C in
patients with severe sepsis more than 95% of patients had coagulation abnormalities at the time of study entry. Thrombocytosis may occur early as an
acute phase response, while thrombocytopenia may occur as a late ominous sign. Additional coagulation findings in severe sepsis are prolongation of
the prothrombin time and an increase in fibrin split products or D-dimer. Greater aberrations in coagulation markers are noted in patients with severe
Either leukocytosis or leukopenia may occur in sepsis. An absolute lymphocyte count less than 1200 cells/mm3 and a ANC:ALC ratio more than 10 have
been found to be better predictors of bacteremia than the total white blood cell count or absolute neutrophil count. Interesting, eosinopenia (< 40%) is
as useful as C reactive protein in distinguishing SIRS as an immunologically regulated response to infection and SIRS from sepsis. Access Provided by:
Coagulation parameters
Systemic inflammation induced during sepsis can activate the coagulation cascade. In a clinical trial of recombinant human activated Protein C in
patients with severe sepsis more than 95% of patients had coagulation abnormalities at the time of study entry. Thrombocytosis may occur early as an
acute phase response, while thrombocytopenia may occur as a late ominous sign. Additional coagulation findings in severe sepsis are prolongation of
the prothrombin time and an increase in fibrin split products or D-dimer. Greater aberrations in coagulation markers are noted in patients with severe
sepsis with bloodstream infections compared with those without bloodstream infections. Two endogenous anticoagulants, Protein C and
Antithrombin become depleted early on in the development of sepsis far in advance of the development of organ dysfunction.
Chemistries
Unexplained lactic acidemia as a sign of global tissue hypoperfusion occurs in sepsis; a level of more than 2 mmol/dL (18 mg/dL) is a poor prognostic
factor and may indicate septic shock as noted earlier. Failure to clear lactate after early fluid resuscitation (> 30 mL/kg intravenous crystalloid) at a rate
of at least 10% per hour is a very poor prognostic sign. Chemistry panels can also be used to detect the presence of sepsis-induced organ dysfunction.
Acute kidney injury can be recognized by a rise in the serum creatinine of 0.3 mg/dL or more in 48 hours or a serum creatinine that rise more than 1.5
times baseline levels within the previous 7 days. A total plasma bilirubin more than 4 mg/dL is indicative of sepsis-induced hepatic dysfunction.
Acute phase reactants/biomarkers
Biomarkers that are readily available to most clinicians are the ESR (erythrocyte sedimentation rate) and C-reactive protein (CRP). The use of the ESR
has largely been supplanted by the CRP in the evaluation of acute infectious diseases like sepsis. CRP is helpful when normal but is not specific for
infection when elevated. CRP can be elevated for days following surgery and will also be elevated in rheumatologic and neoplastic illnesses. Very high
CRP levels (> 85 mg/L) is useful in distinguishing infection from non-infectious causes of acute systemic inflammation.
A newer biomarker for the diagnosis of sepsis is serum procalcitonin (PCT). In heath, PCT is precursor peptide in calcitonin synthesis by C cells in the
thyroid; in septic patients, PCT is generated in prodigious amounts by numerous extra-thyroidal tissues. Elevated levels of PCT are seen 4 to 6 hours
after a systemic challenge with endotoxin or other septic stimuli. PCT levels drop quickly following trauma and surgery and are not elevated by
malignancies or rheumatologic diseases. PCT is an FDA approved test to aid in the risk assessment of patients with sepsis. A recent meta-analysis of
studies examining confirms the value of PCT to distinguish sepsis for noninfectious causes of systemic inflammation. Levels of PCT more than 2 ng/mL
is the best cutoff value in the early diagnosis of bacterial sepsis.
An additional biomarker approved by the FDA for assessing the risk of sepsis in in the ICU is the endotoxin activity assay (EAA). Endotoxin is a known
mediator in the pathogenesis of sepsis and septic shock. The EAA relies upon priming of the endogenous neutrophil population by circulating
endotoxin. This chemiluminescent assay compares the respiratory burst by endotoxin in the test sample to the maximum burst when the sample is
spiked with excess LPS. In one study, elevated endotoxin levels were found in 58% of patients admitted to a mixed surgical-medical ICU, irrespective of
the reason for admission. Elevated EAA in patients admitted to the ICU portends a greater chance of septic shock and excess mortality.
Use of the sofa to assess sepsis severity
Hallmark strong predictor of sepsis mortality is the development of organ dysfunction. The SOFA score assesses the degree of organ dysfunction
across several domains and has been integrated into the 2016 guidelines for diagnosing sepsis (Tables 42–1 and 42–5). A SOFA score of 2 or more
reflects an overall mortality risk of roughly 10% in the setting of suspected infection. Additionally, use of the bedside qSOFA (Quick SOFA) criteria has
been validated as a reliable bedside tool for identifying adult patients with suspected infection who are likely to have poor outcomes. Presence of any 2
of the following criteria represents a positive qSOFA: (1) respiratory rate of 22/min or more; (2) altered mentation (defined as any Glasgow Coma Scale
score < 15); and/or (3) systolic blood pressure of 100 mm Hg or less. The qSOFA is best applied as an early warning sign of infection-induced organ
dysfunction for use on the medical or surgical floor, whereas the standard SOFA score has greater predictive power in the critical care setting. It is
essential that clinicians recognize these early signs and symptoms because successful management of sepsis depends on early recognition and
appropriate intervention. The mortality rate in sepsis increases with an increasing number of organ dysfunctions.
Table 42–5
The Sequential [Sepsis-Related] Organ Failure Assessment (SOFA) Score.1
Score
0 1 2 3 4
Respiration ≥ 400 < 400 < 300 (40) < 200 (26.7) with respiratory support < 100 (13.3) with respiratory support
score < 15); and/or (3) systolic blood pressure of 100 mm Hg or less. The qSOFA is best applied as an early warning sign of infection-induced organ
dysfunction for use on the medical or surgical floor, whereas the standard SOFA score has greater predictive power in the critical care setting. It is
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essential that clinicians recognize these early signs and symptoms because successful management of sepsis depends on early recognition and
appropriate intervention. The mortality rate in sepsis increases with an increasing number of organ dysfunctions.
Table 42–5
The Sequential [Sepsis-Related] Organ Failure Assessment (SOFA) Score.1
Score
0 1 2 3 4
Respiration ≥ 400 < 400 < 300 (40) < 200 (26.7) with respiratory support < 100 (13.3) with respiratory support
PaO2/FiO2, mm Hg (53.3) (53.3)
(kPa)
Coagulation ≥ 150 < 150 < 100 < 50 < 20

platelets, ×103/μL
Liver bilirubin, < 1.2 (20) 1.2-1.9 2.0-5.9 (33-101) 6.0-11.9 (102-204) > 12.0 (204)
mg/dL (μmol/L) (20-32)
Cardiovascular MAP ≥ 70 MAP < 70 Dopamine < 5 or Dopamine 5.1-15 or epinephrine ≤ 0.1 Dopamine > 15 or epinephrine > 0.1
mm Hg mm Hg dobutamine (any dose)2 or norepinephrine ≤ 0.12 or norepinephrine > 0.12
Central nervous 15 13-14 10-12 6-9 <6

system
Glasgow Coma Scale
Score
Renal creatinine, <1.2 1.2-1.9 2.0-3.4 (171-299) 3.5-4.9 (300-440) > 5.0 (440)
mg/dL (μmol/L) (110) (110-
or 170)
Urine output, mL/d < 500 < 200
1Reproduced with permission from Vincent JL, Moreno R, Takala J, et. al. Working Group on Sepsis-Related Problems of the European Society of Intensive Care
Medicine. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med. 1996 Jul;22(7):707-710.
2Catecholamine doses are given as mcg/kg/min for 1 hour or more.
SEPTIC SHOCK
Septic shock occurs in up to 15% of patients with sepsis, and is defined as a hypotension requiring vasopressors to maintain a MAP of 65 or more and a
serum lactate level of more than 2 mmol/L (18 mg/dL). The most common hemodynamic findings in early septic shock are a high cardiac output and a
low systemic vascular resistance state. Myocardial performance is markedly diminished in septic shock. Without adequate intervention, circulating
blood volume is continually lost into the interstitial space and intracellular locations, perpetuating systolic hypotension. Deterioration of myocardial
performance, accompanied by diffuse vasoconstriction, marks the late refractory state of septic shock.
Acute respiratory distress syndrome
The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in septic shock. Increased capillary permeability in
these patients results in pulmonary edema, which manifests clinically as dyspnea and cough; standard radiographs will typically show bilateral,
symmetrical alveolar opacities in all four quadrants. The initial diagnostic criteria for ARDS include the absence of clinical evidence of left atrial
hypertension, the requirement for intubation and positive pressure ventilation, and a PaO2/FiO2 ratio of 200 or less. The new Berlin definition
Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal Pageof 11ARDS
/ 15
simplifies the diagnostic criteria for ARDS and classifies the patients into three diagnostic and prognostic categories depending upon the severity of
gas exchange based on the PaO2/FIO2 ratio (see Table 42–1). A detailed analysis of the Berlin definition of ARDS from a large patient database found
Acute respiratory distress syndrome
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The acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in septic shock. Increased capillary permeability in
these patients results in pulmonary edema, which manifests clinically as dyspnea and cough; standard radiographs will typically show bilateral,
symmetrical alveolar opacities in all four quadrants. The initial diagnostic criteria for ARDS include the absence of clinical evidence of left atrial
hypertension, the requirement for intubation and positive pressure ventilation, and a PaO2/FiO2 ratio of 200 or less. The new Berlin definition of ARDS
simplifies the diagnostic criteria for ARDS and classifies the patients into three diagnostic and prognostic categories depending upon the severity of
gas exchange based on the PaO2/FIO2 ratio (see Table 42–1). A detailed analysis of the Berlin definition of ARDS from a large patient database found
that a PaO2/FiO2 ratio of between 200 and 300 mm Hg or less (classified as mild ARDS) was associated with a mortality rate 27±3% mortality. Moderately
severe ARDS with a PaO2/FiO2 ratio of 100 to 200 mm Hg or less was associated with a mortality rate of 32±3%. Severe ARDS manifest by a PaO2/FiO2
ratio 100 mm Hg or less is accompanied by a mortality rate of 45±2%.
Management of septic shock
The management of a patient with septic shock begins with prompt recognition of the condition and the rapid administration of appropriate antibiotic
therapy as well as source control of infection. Attention is simultaneously given to failing organs with institution of measures including fluid
resuscitation, vasopressors, blood transfusions, and inotropic agents as needed to maximize oxygen delivery. Patients with ARDS are managed with
low tidal volume ventilator strategies to minimize damage induced by overstretching the alveoli. Consideration is also given to the use of low dose
corticosteroids in in cases of refractory septic shock. Reasonable glycemic control is utilized in effort to minimize septic complications. Guidelines for
the initial management of sepsis are provided in the Surviving Sepsis Campaign guidelines.
Microbiologic workup
A rapid systematic search for infection should include a thorough physical exam, review of pertinent radiographic studies, and microbiologic studies.
The three most common sites of infection are the lung followed by infection in the abdomen and genitourinary tract. In approximately 30% of cases a
causative organism and focus of infection is never found. Based upon history and physical exam imaging and culturing of normally sterile body sites
should be done to define infection. In community-acquired pneumonia obtaining high-quality sputum samples for making an etiologic diagnosis is
quite difficult. A rapid immunoassay that detects the C-polysaccharide from the cell wall of Streptococcus pneumoniae from the urine is clinically
useful for the diagnosis of pneumococcal pneumonia. A similar urine immunoassay is available for Legionella spp. pneumonia. Two sets of blood
cultures should be collected as soon as possible and preferably before starting antibiotics. If a central venous catheter is present, one blood culture
should be drawn from the catheter and one from a peripheral venipuncture. A blood culture drawn from a central line that becomes positive 2 or more
hours before a peripheral venipuncture drawn at the same time supports a diagnosis of a catheter-related bloodstream infection. In patients at high
risk for candidemia, a beta-d-glucan assay should be obtained. This assay is often positive for 2 or more days before the blood culture grows Candida
spp.
Appropriate antibiotic therapy
Numerous studies in patients with sepsis have demonstrated a survival advantage in patients who have received appropriate versus inappropriate
antibiotic therapy. Furthermore, animal and human studies demonstrate a decrease in survival for each hour delay in the administration of antibiotic
therapy from the onset of septic shock. Optimal antimicrobial therapy in sepsis depends on the site of infection, local susceptibility patterns, prior
antimicrobial exposure, presence or absence of pregnancy, hepatic and renal function, and history of drug allergy. Suggested empiric antibiotic
regimens for the different sites of infection are presented in Table 42–6. A propensity matched analysis comparing monotherapy to combination
therapy for sepsis favored combination therapy for both gram-positive and gram-negative infections in severely ill patients at increased risk of death
(estimated mortality rate > 25%). Empiric treatment for methicillin-resistant Staphylococcus aureus (MRSA) depends upon the clinical context
especially given the increasing incidence of infections due community-acquired, methicillin-resistant Staphylococcus aureus (CA-MRSA). Empiric
antifungal therapy in patients with sepsis is not routinely recommended, but should be reserved for cases where patients have well-described risk
factors for fungemia including a history of receiving multiple antibiotics for multiple days, the presence of a central venous catheter for TPN or
hemodialysis, elevated beta-d-glucan levels or Candida spp. previously isolated from multiple anatomic sites. Initial antimicrobial therapy should be
reconsidered at 72 hours and “deescalated” based upon the final culture and susceptibility data.
Table 42–6
Suggested initial empiric antibiotic choices for sepsis.
Source of
Antimicrobial Choice
Infection
Community- Third-generation cephalosporin with a macrolide or respiratory fluoroquinolone. Use cefepime or piperacillin-tazobactam in place of third-
acquired generation cephalosporin if risk factors for Pseudomonas infection or MDR pathogens
antifungal therapy in patients with sepsis is not routinely recommended, but should be reserved for cases where patients have well-described risk
factors for fungemia including a history of receiving multiple antibiotics for multiple days, the presence of a central venous catheter for TPN or
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hemodialysis, elevated beta-d-glucan levels or Candida spp. previously isolated from multiple anatomic sites. Initial antimicrobial therapy should be
reconsidered at 72 hours and “deescalated” based upon the final culture and susceptibility data.
Table 42–6
Suggested initial empiric antibiotic choices for sepsis.
Source of
Antimicrobial Choice
Infection
Community- Third-generation cephalosporin with a macrolide or respiratory fluoroquinolone. Use cefepime or piperacillin-tazobactam in place of third-
acquired generation cephalosporin if risk factors for Pseudomonas infection or MDR pathogens
pneumonia
Hospital- Third- or fourth-generation cephalosporin or an extended-spectrum penicillin ± an aminoglycoside or a fluoroquinolone (or: carbapenems,
acquired β-lactam—β-lactamase inhibitor); add vancomycin or linezolid if MRSA suspected
pneumonia
Urinary tract Extended-spectrum β-lactam agent ± aminoglycoside or fluoroquinolone). Use cefepime or a carbapenem if history of, or at risk for MDR
infection organism
Intra- A carbapenem or piperacillin-tazobactam as monotherapy or a third or fourth-generation cephalosporin or fluoroquinolone in

abdominal combination with metronidazole
infection
Neutropenic Monotherapy with an antipseudomonal beta-lactam agent, such as cefepime, a carbapenem (meropenem), or piperacillin-tazobactam is
sepsis recommended (add vancomycin when there is evidence of gram-positive infection or linezolid if MRSA or VRE suspected); add a triazole
(voriconazole or fluconazole) or β-glucan inhibitor (eg, caspofungin or micafungin) if systemic fungal infection suspected
Necrotizing Vancomycin and piperacillin-tazobactam ± clindamycin

skin/soft
tissue
infection
MDR, multiple antibiotic drug resistant; MRSA, methicillin-resistant Staphylococcus aureus; VRE, vancomycin-resistant enterococcus.
Optimizing tissue oxygenation
In the early phase of sepsis, an imbalance develops between tissue oxygen delivery and oxygen demand. This can be diagnosed by laboratory testing of
lactic acid levels. Rivers and colleagues performed a randomized, clinical trial to see if a protocolized algorithm of early goal directed therapy (EGDT) to
meet a resuscitation goal of a central venous oxygen saturation of 70% decreased mortality in septic shock. In this study, patients with septic shock and
lactic acidemia were randomized to either a standard therapy arm or EGDT arm. Patients in the EGDT group received crystalloid fluid boluses every 30
minutes in attempt to achieve a CVP of 8 to 12 mm Hg. If the mean arterial pressure remained less than 65 mm Hg vasopressors were then added. If
following these maneuvers, the central venous O2 saturation remained less than 70%, red cell transfusions were given to achieve a hematocrit of more
than 30%. If these targets were still not met, dobutamine was then added. The in-hospital mortality was significantly lower in the EGDT group than the
standard treatment group (30.5% vs 46.5%, P = 0009). This treatment strategy is now widely utilized and is generally followed in the recent 2013 sepsis
guidelines. However, three subsequent, large, randomized trials have failed to confirm a clear survival advantage to EGDT versus usual care in the
emergency resuscitation of patients in septic shock.
Fluid resuscitation
Debate continues regarding the appropriateness of colloid versus crystalloid fluids. The lack of clear evidence of benefit of colloid agents (eg, albumin,
dextran, and plasma expanders) and their high cost have generally resulted in the use of saline solutions for volume expansion.
Vasopressor therapy
Failure to improve patient hemodynamics with fluids alone often necessitates the use of vasopressor agents to reestablish adequate tissue perfusion.
Dopamine, epinephrine, norepinephrine, phenylephrine, and vasopressin have been used to reverse hypotension in the setting of septic shock. The
emergency resuscitation of patients in septic shock.
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Fluid resuscitation
Debate continues regarding the appropriateness of colloid versus crystalloid fluids. The lack of clear evidence of benefit of colloid agents (eg, albumin,
dextran, and plasma expanders) and their high cost have generally resulted in the use of saline solutions for volume expansion.
Vasopressor therapy
Failure to improve patient hemodynamics with fluids alone often necessitates the use of vasopressor agents to reestablish adequate tissue perfusion.
Dopamine, epinephrine, norepinephrine, phenylephrine, and vasopressin have been used to reverse hypotension in the setting of septic shock. The
use of any of these agents in septic shock carries with it certain risks and should be reserved for patients with significant hemodynamic instability that
is unresponsive to fluid therapy. The clinical target of vasopressors to maintain organ perfusion is a mean arterial pressure of more than 65 mm Hg.
Results of both individual studies and a meta-analysis have revealed that the use of dopamine is associated with a higher mortality and a higher
incidence of arrhythmias than norepinephrine. As such, norepinephrine is now considered the agent of first choice for septic shock. Dobutamine
remains the inotropic agent of first choice in septic shock in patients with low cardiac output despite adequate fluid resuscitation.
Low-dose corticosteroid therapy for septic shock
The value of corticosteroids in the treatment of sepsis have been the subject of a debate for greater than fifty years. Studies have also suggested that a
state of relative adrenal insufficiency and glucocorticoid resistance occurs during sepsis and is associated with a poor outcome. A study by Annane
observed relative adrenal insufficiency, defined as an increase in serum cortisol less than 9 mg/dL 60 minutes after receiving 250 mg of synthetic ACTH
in patients with septic shock. In a clinical study in patients with vasopressor-dependent refractory septic shock to receive either 50 mg of
hydrocortisone every 6 hours and 50 mg/day of fludrocortisone improved survival over placebo treatment. A large follow-up study failed to confirm the
benefit of low-dose corticosteroids, with the possible exception of patients with refractory septic shock. The current recommendation is to consider
corticosteroids (≤ 200 mg of hydrocortisone/day) in the subpopulation with refractory septic shock. Treatment should be given for at least 5 days
followed by a taper to prevent rebound hypotension.
Blood transfusions
The threshold for blood transfusions in improving the oxygen-carrying capacity of blood is a matter of ongoing research. A large Canadian study, the
TRICC trial (Transfusion requirements in Critical Care) showed that maintaining a hemoglobin (Hgb) level of 7 to 9 gm/dL and setting a transfusion
threshold as low as 7 gm/dL in volume-resuscitated patients is not associated with a worse outcome than maintaining an Hgb of more than 10 gm/dL.
The hemoglobin level may need to be maintained at a higher level include severe coronary artery disease and severe hypoxemia.
Glycemic control
Reasonable glycemic control in sepsis is now considered glucose control (targeted around 150 mg/dL) is now recommended in patients with sepsis-
induced glucose intolerance. Large swings on blood glucose levels are to be avoided and hypoglycemia can be particularly hazardous.
Infection control
Patients with severe sepsis are at risk for the development of new infections and superinfections. In patients on mechanical ventilation, elevating the
head of the bed by 30 to 45 degrees limits the risk of aspiration and ventilator-associated pneumonia. Carts containing all the materials necessary for
sterile insertion of central venous catheters should be used and maintained in all ICUs. Universal MRSA decolonization of ICU patients with nasal
mupirocin and chlorhexidine baths has been shown to decrease the incidence of bloodstream infections.
Experimental therapies for septic shock
Despite the failure of many agents in the past, studies of additional experimental treatments continue. Late-stage therapies are targeting sepsis-
induced DIC and patients with elevated endotoxin activity. Multiple failures using a variety of anti-inflammatory compounds have led to a renewed
appreciation of the immunoparalysis of sepsis. The future therapy of sepsis will likely resemble cancer chemotherapy with personalized combinations
of agents being used to target each patient's unique situation and needs.
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
REFERENCES
1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic
Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure, Russell J. McCulloh; Steven M. Opal Pageshock,
14 / 15
2012. Intensive Care Med . 2013;39:165–228. [PubMed: 23361625]
2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med . 2003;348:1546–
of agents being used to target each patient's unique situation and needs.
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter. Access Provided by:
REFERENCES
1. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock,
2012. Intensive Care Med . 2013;39:165–228. [PubMed: 23361625]
2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med . 2003;348:1546–
1554. [PubMed: 12700374]
3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of
incidence, outcome, and associated costs of care. Crit Care Med . 2001;29:1303–1310. [PubMed: 11445675]
4. Suffredini AF, Munford RS. Novel therapies for septic shock over the past 4 decades. JAMA . 2011;306:194–199. [PubMed: 21750297]
5. Singer M, Deutschman CS, Seymour CW, et al. The Third International Concensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA .
2016;315(8):801–810. [PubMed: 26903338]
6. Cohen J. The immunopathogenesis of sepsis. Nature . 2002;420:885–891. [PubMed: 12490963]
7. Opal SM, Calandra T. Antibiotic usage and resistance: gaining or losing ground on infections in critically ill patients? JAMA . 2009;302:2367–2368.
[PubMed: 19952325]
8. Pridmore AC, Wyllie DH, Abdillahi F, et al. A lipopolysaccharide-deficient mutant of Neisseria meningitidis elicits attenuated cytokine release by
human macrophages and signals via toll-like receptor (TLR) 2 but not via TLR4/MD2. J Infect Dis . 2001;183:89–96. [PubMed: 11076707]
9. Akira S, Takeda K. Toll-like receptor signalling. Nature Rev Immunol . 2004;4:499–511.
10. Hotchkiss RS, Opal S. Immunotherapy for sepsis—a new approach against an ancient foe. N Engl J Med . 2010;363:87–89. [PubMed: 20592301]
11. Vincent JL, Moreno R, Takala J, et al. Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. The SOFA
(Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. Intensive Care Med . 1996;22(7):707–710. [PubMed: 8844239]

Chapter 42 - Sepsis, Septic Shock, and Multiple Organ Failure

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Chapter 42: Sepsis, Septic Shock, and Multiple Organ Failure

Russell J. McCulloh; Steven M. Opal

Term Definition Comments

PATHOGENESIS: MICROBIAL FACTORS

Bacterial endotoxin and other pathogen-associated molecular pattern molecules

Other microbial mediators

PATHOGENESIS: HOST-DERIVED MEDIATORS

Proinflammatory Mediators Anti-Inflammatory Mediators

Tumor necrosis factor-α Interleukin-1 receptor antagonist

Proinflammatory Mediators Anti-Inflammatory Mediators

Tumor necrosis factor-α Interleukin-1 receptor antagonist

Platelet-activating factor Antioxidants

Granulocyte macrophage colony-stimulating factor Glucocorticoids

Histamine, thrombin, other clotting factors Lipoxygenase pathway

TREM-1 (triggering receptor expressed on myeloid cells)

CD4+ T helper cells

The coagulation system

Neutrophil–endothelial cell interactions

Late host-derived mediators

Pathogenesis: organ dysfunction

DIAGNOSTIC APPROACH TO SEPSIS

or < 65% indicates poor oxygen delivery to tissues

or < 65% indicates poor oxygen delivery to tissues

(CI) × (A-VO2) × 10 L/min/m2

Laboratory indicators of sepsis and septic shock

White blood Leukocytosis or leukopenia

White blood cell count and differential

Acute phase reactants/biomarkers

Use of the sofa to assess sepsis severity

The Sequential [Sepsis-Related] Organ Failure Assessment (SOFA) Score.1

The Sequential [Sepsis-Related] Organ Failure Assessment (SOFA) Score.1

Coagulation ≥ 150 < 150 < 100 < 50 < 20

Central nervous 15 13-14 10-12 6-9 <6

Urine output, mL/d < 500 < 200

2Catecholamine doses are given as mcg/kg/min for 1 hour or more.

Acute respiratory distress syndrome

Management of septic shock

Appropriate antibiotic therapy

Intra- A carbapenem or piperacillin-tazobactam as monotherapy or a third or fourth-generation cephalosporin or fluoroquinolone in

Necrotizing Vancomycin and piperacillin-tazobactam ± clindamycin

Optimizing tissue oxygenation

Low-dose corticosteroid therapy for septic shock

Experimental therapies for septic shock

6. Cohen J. The immunopathogenesis of sepsis. Nature . 2002;420:885–891. [PubMed: 12490963]

9. Akira S, Takeda K. Toll-like receptor signalling. Nature Rev Immunol . 2004;4:499–511.

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