# 07 - 315 Sepsis and Septic Shock

### 315 Sepsis and Septic Shock

Gitz Holler et al: Etiology of shock in the emergency department: A 

12-year population-based cohort study. Shock 51:60, 2019.
McGuire WC et al: Management strategies for acute pulmonary 
embolism in the intensive care unit. Chest 166:1532, 2024.
Munroe ES et al: Evolving management practices for early sepsisinduced hypoperfusion: A narrative review. Am J Respir Crit Care 
Med 207:1283, 2023.
Tehrani BN et al: A standardized and comprehensive approach to 
the management of cardiogenic shock. JACC Heart Fail 8:879, 2020.
Vincent JL, De Backer D: Circulatory shock. N Engl J Med 369:1726, 
2013.
PART 8
Critical Care Medicine
Jeffrey R. Strich, Daniel S. Chertow

Sepsis and Septic Shock
Sepsis is an infectious syndrome that results in considerable morbidity, 
mortality, and long-term sequelae among survivors. Sepsis, derived 
from the Greek word sipsi, “to make rotten,” was first described by 
Hippocrates in the 400s b.c. In the 1800s, Sir William Osler opined on 
sepsis by saying, “except on few occasions, the patient appears to die 
from the body’s response to infection rather than from it.” The first 
consensus definition of sepsis, published in 1992, recognized sepsis as 
the body’s systemic response to infection. To operationalize this defini­
tion, systemic inflammatory response syndrome (SIRS) clinical criteria 
were established, which included temperature <36°C or >38°C, heart 
rate >90 beats/min, respiratory rate >20 breaths/min or partial pres­
sure of CO2 <32 mmHg, and leukocyte count <4000/µL or >12,000/µL 
or >10% bands. Suspected infection with two or more SIRS criteria 
was classified as sepsis, while the term severe sepsis required evidence 
of hypoperfusion or end-organ dysfunction including oliguria, acute 
alteration in mental status, or lactic acidosis. Septic shock was defined 
as sepsis-induced hypotension, determined by systolic blood pressure 
<90 mmHg or reduced ≥40 mmHg from baseline, absent other causes, 
despite adequate volume resuscitation. Sepsis-2, the second consen­
sus definition established in 2003, acknowledged clinical complexity 
beyond existing SIRS criteria and expanded the list of clinical and 
laboratory criteria to diagnose sepsis. Sepsis-3, established in 2016 
as the current consensus definition, abandoned SIRS criteria, given 

Percent (%)

Sepsis mortality
Sepsis incidence
FIGURE 315-1  Sepsis incidence and mortality. Sepsis incidence and mortality. Sepsis incidence is expressed as a proportion of sepsis cases among 7,801,624 adult 
hospitalizations across 409 U.S. hospitals from 2009–2014. Mortality is the proportion of sepsis deaths among sepsis cases.

poor specificity for distinguishing sepsis from other noninfectious 
inflammatory processes, and eliminated the term severe sepsis. Sepsis 
was redefined as life-threatening organ dysfunction caused by a dys­
regulated host response to infection, and septic shock was defined as a 
subset of sepsis in which profound circulatory, cellular, and metabolic 
abnormalities increase mortality risk beyond sepsis alone.
EPIDEMIOLOGY
Each year, an estimated 48.9 million sepsis cases occur globally, and 
1.7 million cases occur in the United States. Data from >400 U.S. 
academic, community, and federal hospitals indicate that sepsis 
occurs in ~6% of hospitalized adults, with stable incidence over time 
(Fig. 315-1). Approximately 11 million sepsis deaths occur globally 
each year, accounting for one in five total global deaths, with 85% 
occurring in low- and middle-income countries. An estimated 350,000 
sepsis deaths or discharges to hospice occur annually in the United 
States, with an estimated 15% overall mortality among U.S. hospital­
ized adults with sepsis (Fig. 315-1) and up to 40% mortality in patients 
with septic shock. Data from the U.S. Centers for Medicare and Med­
icaid Services indicate the aggregate cost for inpatient hospital and 
skilled nursing facility sepsis admissions was an estimated $13.4 billion 
dollars in 2018. A retrospective evaluation of sepsis costs in U.S. hospi­
tals during 2010–2016 suggests a cost of $16,324 and $38,298 per sepsis 
and septic shock admission, respectively.
■
■PATHOGENS AND SITES OF INFECTION
Approximately 88% of sepsis cases are community onset, defined as 
being detected within 48 h of hospitalization, whereas an estimated 
12% are hospital onset, detected after 48 h of hospitalization. While 
viruses, fungi, and other pathogens may induce sepsis, the role of 
bacterial infection is best described. An estimated 53% of sepsis cases 
in the United States are bacterial culture positive, with a relatively even 
split between gram-positive and gram-negative organisms.
A retrospective cohort study of 17,430 adult community-onset 
culture-positive sepsis cases from 104 U.S. hospitals during 2009 to 
2015 identified Staphylococcus aureus, Streptococcus spp., and Entero­
coccus spp. as the most prevalent gram-positive organisms isolated, of 
which 13.6% were antibiotic-resistant, including methicillin-resistant 
S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). 
Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa were the 
most frequently isolated gram-negative organisms, of which 13.2% 
were resistant to ceftriaxone, extended-spectrum β-lactams, or car­
bapenems. The most frequently reported anatomic site of primary 
infection was the urinary tract (48.9%), followed by the respiratory 
tract (32.9%), an intraabdominal site (13.6%), and skin or soft tissue 
(10.3%). Bacteria were most frequently isolated from urine (52.1%), 
blood (40.0%), and the respiratory tract (16.7%).
Year

Patients with hospital-onset sepsis differ from community-onset 
sepsis patients in that they more often have comorbidities and expe­
rience intraabdominal infections and bacteremia with Enterococcus, 
Candida, and Pseudomonas. Patients with hospital-onset sepsis also 
experience higher intensive care unit (ICU) admission rates, longer 
hospital length of stay, and increased mortality.
■
■RISK AND PROGNOSTIC FACTORS
U.S. Centers for Disease Control and Prevention (CDC) data from 
2021 show that sepsis mortality increases with age and is higher among 
men than women in all age groups: 232.7 versus 173.0 (65–74 years), 
477.3 versus 349.8 (75–84 years), and 1037.8 versus 755.5 (≥85 years) 
deaths per 100,000 population, respectively. Preexisting medical condi­
tions including diabetes and obesity; neurologic, respiratory, or cardiac 
conditions; renal or hepatic insufficiency; and cancer or other immu­
nosuppressing conditions increase sepsis mortality risk. Recent hos­
pital admission for any reason has also been associated with threefold 
increased risk of developing sepsis in the following 90 days.
Multiple composite illness severity scoring systems have been 
applied to hospitalized septic patients to predict outcome or guide 
stratification or post-hoc analyses in clinical trials or observational 
studies of sepsis. For example, the Sequential Organ Failure Assess­
ment (SOFA) score quantifies dysfunction in six organ systems includ­
ing neurologic, using the Glasgow Coma Scale score; cardiovascular, 
using mean arterial blood pressure or use of vasoactive agents; respira­
tory, using the ratio of arterial blood partial pressure of oxygen (Pao2) 
to fraction of inspired oxygen (Fio2) or use of mechanical ventilation; 
hepatic, using serum bilirubin levels; renal, using serum creatinine lev­
els; and coagulation, using blood platelet levels. Elevated SOFA scores 
are associated with increased sepsis mortality at the population level 
but cannot accurately predict outcomes of individual patients.
Improved stratification of sepsis patients based on clinical “phe­
notype,” determined by clustering of clinical variables using machine 
learning tools to better predict outcome, has been proposed. In a ret­
rospective analysis of >45,000 patients who met Sepsis-3 criteria, sta­
tistical, machine learning, and simulation tools were applied to clinical 
data obtained within 6 h of emergency room presentation to identify 
α, β, γ, and δ phenotypes, with associated 2%, 5%, 15%, and 32% mor­
tality rates, respectively. Beyond using immediately available clinical 
data to identify sepsis phenotypes, integration of transcriptional and 
proteomic data to define sepsis “endotypes” has also been attempted. 
While these approaches hold promise to guide improved clinical trial 
design and patient care, additional research is needed to contextualize 
and operationalize them across patients and pathogens.
PATHOGENESIS
The host-pathogen interaction during sepsis is heterogeneous, based on 
patient demographic and clinical factors and pathogen type and viru­
lence. Consequently, the pathophysiology and molecular pathogenesis 
of sepsis vary across hosts and pathogens. However, a working frame­
work for sepsis pathogenesis, with commonalities across hosts and 
pathogens, provides a basis for understanding which factors contribute 
to organ injury and dysfunction during severe infections. During local 
infection, a prototypical physiologic response is characterized by patho­
gen recognition followed by balanced inflammatory, anti-inflammatory, 
and repair responses resulting in pathogen clearance with minimal 
disruption to systemic homeostasis. During sepsis, however, pathogen 
components and exuberant cellular and soluble immune responses con­
tribute to systemic illness, resulting in end-organ injury and dysfunc­
tion (Fig. 315-2). Pathogen components and host responses to infection 
may also impair or delay adaptive immunity and tissue repair.
Pathologic responses in sepsis are mediated by myeloid lineage 
cells (i.e., neutrophils, monocytes, macrophages, and dendritic cells), 
lymphoid lineage cells (i.e., natural killer [NK] cells and lymphocytes), 
parenchymal cells (e.g., endothelial and epithelial cells), and soluble 
mediators (e.g., cytokines, chemokines, nitric oxide, histamine, prosta­
glandin, and bradykinin). Activated leukocytes adhere to endothelium, 
migrate into tissue, and perform end-effector functions, including 
reactive oxygen species (ROS) generation, that contribute to tissue 

injury. Activation of endothelial cells, platelets, the clotting cascade, 
and the complement system contribute to a prothrombotic state. When 
platelets and clotting factors are consumed, hemorrhage risk increases. 
Pathophysiologic manifestations of sepsis include systemic vasodila­
tion, capillary leakage with interstitial fluid accumulation, and micro­
vascular thrombosis resulting in impaired oxygen delivery, uptake, 
and utilization. Taken together, these factors drive cellular injury and 
end-organ dysfunction.

■
■TRIGGERS OF HOST IMMUNE RESPONSES
Host immune responses in sepsis are initiated by pathogen compo­
nents termed pathogen-associated molecular patterns (PAMPs) and 
propagated by host factors termed damage-associated molecular pat­
terns (DAMPs). PAMPs and DAMPs interact with innate and adaptive 
immune cells and parenchymal cells early during sepsis, amplifying 
immune responses. PAMPs include bacterial lipopolysaccharide (LPS) 
or other bacterial cell wall or membrane components, pathogen nucleic 
acids, including single- or double-stranded RNA, and other pathogenrelated molecules. DAMPs include proteins, lipids, nucleic acids, 
and other components released from injured cells. Examples include 
histones, high mobility group box 1 proteins, S100 proteins, oxidized 
phospholipids, double-stranded DNA, and adenosine triphosphate. 
PAMPs and DAMPs are recognized by extra- or intracellular receptors, 
termed pattern recognition receptors (PRRs). Multiple PRRs, including 
toll-like receptors (TLR), of which 10 have been described in humans, 
C-type lectin receptors (CLR), receptors for advanced glycation 
end products (RAGE), retinoic acid–inducible gene-I-like receptors 
(RIG-I), and nucleotide-binding oligomerization domain-like (NOD) 
receptors, have been implicated in sepsis signaling. Recognition of 
PAMPs and DAMPs by PRRs on innate immune cells such as neutro­
phils, monocytes, and macrophages activates inflammatory pathways, 
triggers release of proinflammatory cytokines and chemokines, and 
increases surface expression of vascular adhesion molecules.
CHAPTER 315
Sepsis and Septic Shock
■
■MYELOID RESPONSES
Neutrophils, monocytes, and macrophages provide early innate immune 
defenses against invading pathogens but also contribute to sepsis patho­
genesis by promoting inflammation and cellular injury and, in some 
cases, limiting adaptive immunity. Differentiated mature neutrophils 
are the most abundant circulating leukocytes in healthy individuals. 
Upon activation during sepsis, neutrophils upregulate surface adhe­
sion molecule expression (e.g., CD11b) to bind endothelium. Within 
the microvasculature, neutrophils release neutrophil extracellular traps 
(NETs), web-like structures of DNA decorated with antimicrobial pro­
teins such as cathepsin-G, myeloperoxidase, and neutrophil elastase to 
limit dissemination of invading pathogens. NETs interact with activated 
platelets, endothelial cells, and fibrin to form microvascular thrombo­
ses. Activated neutrophils also migrate into tissues to combat microbes 
through phagocytosis, degranulation, ROS generation, NET formation, 
and proinflammatory cytokine and chemokine release. Neutrophil 
granule components degrade extracellular matrix, while ROS oxidize 
proteins and lipids contributing to cellular injury and dysfunction. 
Soluble inflammatory mediators further recruit immune cells to sites of 
infection, exacerbating inflammation and cellular injury. Mediators such 
as interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor, 
and granulocyte colony-stimulating factor trigger release of immature 
neutrophils from the bone marrow, a process termed emergency granu­
lopoiesis that is associated with poor outcomes in septic patients.
Monocytes are innate myeloid cells that circulate in healthy indi­
viduals for up to 7 days following release from the bone marrow. 
Three main monocyte populations are defined by CD14 and CD16 
surface expression, including classical (CD14+, CD16–), intermediate 
(CD14+, CD16+), and nonclassical (CD14lowCD16+) monocytes. Clas­
sical monocytes account for 85% of circulating monocytes in healthy 
individuals but rapidly migrate to infected tissues during sepsis, 
resulting in transient monocytopenia and an increased proportion 
of circulating nonclassical and intermediate monocytes. Nonclassical 
monocytes are more terminally differentiated blood-resident mono­
cytes thought to patrol the endothelium during sepsis. Monocytes

Localized
Damage
Systemic
Damage
Pathogens
A
Triggers of
Immune system
Phagocytosis
Cell
damage
PAMPS
DAMPs
Chemokines
Cytokines
PART 8
Critical Care Medicine
B
PRR
Damaged
endothelial
Monocyte
TF
PRR
TF+VIIa
vWF
C
Xa
X
Neutrophil
Antithrombin
Increased
adhesion
molecules
D
E
Complement cascade
C3
C5
C5a
VE-Cadherin
MAC
ICAMs
VCAM-1
C3a
F
Neutrophil
Lymphocyte
Exhausted
Apoptotic
↓ Proliferation
Monocyte
FIGURE 315-2  Sepsis pathogenesis. (A) Invading pathogens and tissue-resident and recruited leukocyte responses induce localized cell damage. (B) Systemic damage 
is mediated by pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cytokines, and chemokines that activate pattern 
recognition receptors (PRRs) on circulating monocytes and neutrophils. (C) Increasing tissue factor (TF) on endothelium and leukocytes triggers the clotting cascade 
and fibrin generation. Adherent neutrophils release extracellular traps (NETs) and microthrombi form, composed of leukocytes, fibrin, and platelet aggregates, bound 
together by von Willebrand factor (vWF). Antithrombin levels are decreased, promoting clot formation, and plasminogen activator inhibitor-1 (PAI-1) levels are increased, 
impairing clot breakdown. (D) Complement activation generates C3a and C5a, which activate platelets and myeloid cells. The C5b-9 membrane attack complex (MAC) 
promotes endothelial injury. (E) Activated and injured endothelium increase intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule (VCAM)-1 
expression, glycocalyx breakdown, apoptosis, and loss of intercellular vascular endothelial (VE)-cadherin and tight junctions contributing to interstitial edema, decreased 
oxygen diffusion, and leukocyte migration. (F) Activated neutrophils degranulate and release reactive oxygen species (ROS) and NETs, and monocytes differentiate into 
proinflammatory (M1) macrophages, contributing to cellular injury and dysfunction. Activated myeloid cells also suppress lymphocyte function, through exhaustion, 
apoptosis, and decreased proliferation. (G) Arterial vasodilation, partially mediated by excess nitric oxide, contributes to tissue hypoperfusion and ischemia. (H) With or 
without adequate oxygen delivery, cellular mitochondrial and metabolic functions are disrupted during sepsis.

Interstitium
Vasculature
G
Vasodilation
NO
Thrombosis
PAI-1
Activated
platelets
Thrombin
Fibrinogen
Fibrin
NETosis
Glycocalyx
degredation
Edema
O2 diffusion
Leakage due to
leaky endothelial cells
H
Tissue
Cellular
injury
ROS
NETosis
Degranulation
Mitochondrial and
metabolic dysfunction
M1
Proinflammatory
macrophage

that migrate into tissues are exposed to PAMPs, DAMPS, cytokines, 
and other mediators, stimulating them to differentiate into den­
dritic cells or macrophages. Dendritic cells are phenotypically and 
transcriptionally diverse professional antigen-presenting cells with a 
broad PRR and cytokine secretion repertoire. These cells contribute 
to pathogen clearance and inflammation and bridge innate and adap­
tive immune responses through antigen presentation and lymphocyte 
activation. Macrophages that originate from bone marrow–derived 
monocytes are distinct from tissue-resident macrophages, which 
derive from embryonic progenitors. Depending on environmental 
conditions within tissues, bone marrow–derived monocytes polarize 
to become proinflammatory (M1) or anti-inflammatory, reparative 
(M2) macrophages. M1 macrophages contribute to pathogen clearance 
through phagocytosis, extracellular trap formation, ROS generation, 
and inflammatory cytokine release (e.g., IL-1β, IL-6, and tumor necro­
sis factor [TNF]-α). However, these same effector functions contribute 
to tissue injury. Macrophages also process and present antigens on 
surface major histocompatibility complex (MHC) II molecules, which 
are required for development of antigen-specific effector and memory 
B- and T-cell responses. This essential link between myeloid and lym­
phoid cells can be disrupted by diverse pathogen-induced mechanisms 
including downregulation of MHC surface expression or interruption 
of antigen processing or presentation by pathogen proteins and other 
components.
While myeloid cells typically contribute to inflammation in sepsis, 
a subset of pathologically activated myeloid cells in tissues, termed 
myeloid-derived suppressor cells, functionally suppress NK-cell, T-cell, 
and B-cell function, contributing to immunosuppression in sepsis.
■
■LYMPHOID RESPONSES
NK cells are a heterogenous group of innate lymphocytes that migrate to 
sites of infection, contribute to pathogen clearance, and mediate inflam­
matory responses during sepsis. NK cells have activating and inhibi­
tory cell surface receptors that modulate their activity. NK-cell PRRs 
recognize PAMPs including LPS, peptidoglycan, and double-stranded 
RNA. NK-cell cytokine receptors recognize inflammatory cytokines 
including type 1 interferons (IFN) and IL-12. Activated NK cells release 
proinflammatory cytokines including IFN-γ and IL-32, which activate 
myeloid cells in a positive feedback loop. Activated NK cells also directly 
kill infected cells that have downregulated MHC class I surface molecule 
expression, through release of cytotoxic granules including perforin and 
granzyme. In studies of human sepsis, circulating NK cells with increased 
CD69 expression, indicative of activation, and increased plasma concen­
trations of IFN-γ and granzyme A and B support a proinflammatory 
role of NK cells. However, NK cells also release IL-10, known to suppress 
myeloid cell–mediated inflammatory responses, highlighting an antiinflammatory role of NK cells in sepsis as well.
B- and T-cell responses in sepsis are essential for recognizing and 
clearing pathogens. B cells produce antibodies against foreign antigens 
and form antigen-specific memory cells. CD8+ T cells lyse infected 
cells that present foreign antigens in association with MHC surface 
molecules and form memory cells. CD4+ (TH1) cells activate CD8+ 
T cells and support memory T-cell formation, CD4+ (TH2) cells con­
tribute to B-cell class switching, and CD4+ (TH17) cells protect against 
extracellular fungal and bacterial infections. B- and T-cell dysfunction 
in sepsis impairs adaptive immunity and predisposes to subsequent 
infections among survivors. Contributing factors to adaptive immune 
dysfunction in sepsis include death of lymphocytes in the circulation 
and tissue, cellular exhaustion, decreased proliferation, and apoptosisrefractory regulatory T cells, all of which can inhibit inflammatory 
responses. Functional manifestations of T-cell exhaustion include 
impaired cytokine production and diminished cytotoxic activity, while 
diminished antibody production is observed in exhausted B cells.
■
■ENDOTHELIAL ACTIVATION
During homeostasis, endothelial cells line blood vessels and regu­
late vascular tone and the exchange of cells, fluid, and molecules 
between the bloodstream and surrounding tissues. The endothelial 
glycocalyx, a network of proteoglycans, glycoproteins, glycolipids, 

glycosaminoglycans, and bound plasma proteins, lines luminal endo­
thelium and maintains homeostatic functions. During sepsis, PAMPs 
and DAMPs activate endothelial cells, altering their structure and 
function. Glycocalyx breakdown disrupts blood flow and mediates 
proadhesive, procoagulant, and proinflammatory endothelial proper­
ties. Activated endothelial cells increase surface adhesion molecule 
expression, including intercellular adhesion molecules (ICAMs) and 
vascular cell adhesion molecule (VCAM)-1, that coordinates leukocyte 
adhesion, rolling, and diapedesis. Activated endothelium promotes 
clotting through increased tissue factor (TF) expression and platelet 
adhesion and impairs fibrinolysis through increased plasminogen 
activator inhibitor (PAI)-1 release, among other factors. Activated 
endothelial cells also produce proinflammatory cytokines, including 
IL-1β, IL-6, and IFN-α, contributing to local and systemic inflam­
mation. Beyond glycocalyx breakdown, barrier function is impaired 
through endothelial cell apoptosis and loss of intercellular adher­
ence (e.g., vascular endothelial [VE]-cadherin) and tight junctions. 
Loss of endothelial barrier function contributes to interstitial fluid 
accumulation, increased interstitial pressure, and tissue hypoperfusion. 
Alterations in endothelial cell nitric oxide (NO) metabolism in sepsis 
contribute to systemic vasodilation and cellular injury.

CHAPTER 315
Sepsis and Septic Shock
■
■COAGULOPATHY
The coagulation system, composed of plasma proteins, platelets, and 
the endothelium, maintains vascular integrity. During sepsis, PAMPs 
and DAMPs interact with these components, innate immune cells, and 
the complement system to promote thrombus formation and impair 
clot breakdown. Increased TF expression on activated leukocytes and 
endothelium triggers the extrinsic clotting cascade, thereby driving 
thrombin-mediated conversion of fibrinogen to fibrin. Endothelial 
injury exposes von Willebrand factor (vWF) on subendothelial sur­
faces, which binds platelets via glycoprotein Ib receptors, and platelets 
bind fibrinogen via glycoprotein IIb/IIIa receptors. Activated platelets 
and endothelium release additional vWF from intracellular stores (i.e., 
Weibel-Palade bodies in endothelial cells), forming multimers that 
aggregate platelets at the endothelial surface. Activated monocytes and 
neutrophils bind to these platelet aggregates, and neutrophils release 
NETs, contributing to a meshwork of fibrin-rich microthrombi. The 
complement system, which is composed of >50 soluble or membrane 
bound proteins, also contributes to microthrombi formation. During 
sepsis all three complement pathways (classical, alternative, and lectin) 
become activated. Release of C3a and C5a anaphylatoxins further acti­
vates platelets and myeloid cells, and assembly of the membrane attack 
complex (MAC), composed of C5b-9, promotes endothelial injury. 
Counterregulatory anticoagulant molecules, including antithrombin, 
tissue factor pathway inhibitor, and activated protein C, are impaired 
in sepsis, and increased activity of antifibrinolytic molecules, including 
PAI and thrombin-activatable fibrinolysis inhibitor, limit clot break­
down. When clotting factors and platelets are consumed, spontaneous 
and provoked hemorrhage can occur.
■
■CELLULAR INJURY AND DYSFUNCTION
A hallmark of sepsis is multiorgan cellular injury and dysfunction. 
Arterial hypotension due to systemic vasodilation, myocardial depres­
sion, and hypovolemia; increased interstitial edema due to vascular 
leakage resulting in increased oxygen diffusion distance; and micro­
circulatory dysfunction in part due to endothelial activation, injury, 
and microvascular thrombosis all contribute to inadequate oxygen 
delivery and cellular injury and dysfunction during sepsis. Cell death 
or dysfunction can also result from direct interactions with PAMPs, 
DAMPs, activated leukocytes, and their associated mediators including 
cytokines, chemokines, toxic granules, ROS, and reactive nitrogen spe­
cies (RNS), including peroxynitrite, nitrogen dioxide, and dinitrogen 
trioxide. ROS and RNS contribute to protein and lipid oxidation and 
DNA damage of proximate cells. Even in the setting of adequate oxygen 
delivery, cellular mitochondrial and metabolic functions are disrupted 
during sepsis, including ATP generation through glycolysis and oxida­
tive phosphorylation, ion (i.e., Na+, K+, and Ca2+) homeostasis, and 
regulation of cell death pathways.

CLINICAL MANIFESTATIONS 

AND MANAGEMENT
Sepsis may present with nonspecific signs and symptoms including 
fever, tachycardia, lethargy, and myalgias with or without localizing 
end-organ findings such as cough, pyuria, or abdominal pain or evi­
dence of end-organ dysfunction such as oliguria or altered mental 
status. There is no gold standard diagnostic test for sepsis, so epidemio­
logic, demographic, clinical, laboratory, radiologic, and microbiologic 
parameters must be considered in diagnosing sepsis. In addition to a 
focused history and physical examination to elicit signs, symptoms, 
and physical manifestations of sepsis, an initial laboratory evaluation 
should include complete blood count with differential, basic metabolic 
panel, liver function test, serum lactate, coagulation panel, urinalysis, 
and point-of-care pathogen testing when available. Microbiologic 
testing with culture of blood and other potentially infected sites (e.g., 
urine, sputum, wound), ideally prior to antimicrobial administra­
tion, should be performed to identify a specific infection and guide 
antimicrobial therapy. Focused imaging examination by x-ray, com­
puted tomography, or ultrasound of potentially infected sites (e.g., 
lung, abdomen) to support a diagnosis of sepsis and guide efforts to 
control the source of infection should also be pursued. Sepsis mim­
ics include but are not limited to noninfectious inflammatory febrile 
syndromes such as connective tissue diseases and vasculitides; heart 
failure and other noninfectious causes of pneumonitis or lung injury; 
noninfectious abdominal syndromes including mesenteric ischemia 
and inflammatory bowel disease; and hypotension due to noninfec­
tious causes including hypovolemia, autonomic dysfunction, and 
adrenal insufficiency. In a recent study of septic patients admitted to 
the ICU, 25% were retrospectively deemed to have sepsis mimics. The 
most common mimics were cardiovascular (e.g., heart failure, cardiac 
arrest) and respiratory (e.g., noninfectious chronic obstructive pul­
monary disease). In patients with suspected sepsis or septic shock in 
whom infection is not confirmed, continuous reevaluation for alternative 
diagnoses is imperative.

PART 8
Critical Care Medicine
■
■RECOGNIZING SEPSIS
Early recognition and treatment of bacterial septic shock with appro­
priate antibiotics has been associated with reduced mortality. There­
fore, the 2023 CDC Hospital Sepsis Program Core Elements guidance 
document and the 2021 Surviving Sepsis Campaign guidelines recom­
mend hospitals have dedicated sepsis improvement programs that 
include standard operating procedures for sepsis screening and early 
treatment. To operationalize updated Sepsis-3 definitions, consensus 
criteria for sepsis include an increase of ≥2 in SOFA score from base­
line in patients with suspected or confirmed infection, and criteria for 
septic shock include septic patients requiring vasopressor therapy to 
maintain a mean arterial pressure >65 mmHg and lactate >2 mmol/L 
despite fluid resuscitation. To more rapidly screen patients for sepsis, 
the quick (q)SOFA score has been proposed, which includes respira­
tory rate ≥22 breaths/min, Glasgow Come Scale score <15, and systolic 
blood pressure ≤100 mmHg. A qSOFA score ≥2 is associated with poor 
outcome and is more specific, although less sensitive, than SIRS criteria 
for identifying patients with end-organ dysfunction due to infection. 
Multiple other sepsis screening tools have been proposed including 
the National Early Warning Score, the Modified Early Warning Score, 
and the artificial intelligence–based Targeted Real-Time Early Warning 
System. Given that each screening tool has advantages and limitations, 
none is preferentially endorsed for sepsis screening by the 2021 Surviv­
ing Sepsis Campaign guidelines.
■
■INITIAL SEPSIS MANAGEMENT
Initial treatment of patients with sepsis or septic shock includes timely 
blood pressure and end-organ support, antimicrobial therapy, and 
identification and elimination of the source of infection. The 2021 
Surviving Sepsis Campaign treatment guidelines provide the most 
up-to-date and evidenced-based approach for initial and subsequent 
treatment of patients with sepsis and septic shock. Initial manage­
ment recommendations include obtaining intravenous access with 
peripheral or central venous catheters, administering appropriate and 

timely antibiotics, treating life-threating hypotension with intravenous 
crystalloid and vasopressor therapy, and managing respiratory insuf­
ficiency or failure with supplemental oxygen, airway support, and 
mechanical ventilation, when indicated. Following initial stabilization 
in patients who are critically ill or in shock, admission to the ICU 
within 6 h should be targeted.
Of these interventions, early appropriate antibiotic administration 
in patients with bacterial septic shock has been most clearly associ­
ated with improved survival. In patients with bacterial septic shock, 
there is an estimated 7–8% increase in mortality for every 1-h delay 
in appropriate antibiotic administration following shock recognition. 
Consequently, in patients with suspected or confirmed septic shock, 
immediate empiric antimicrobial therapy within 1 h of shock recogni­
tion is recommended. The association between time to antibiotics and 
mortality in patients with suspected or confirmed sepsis without shock 
has not been established. In patients in whom a diagnosis of sepsis is 
less certain and shock is absent, further time-limited clinical evaluation 
is recommended prior to empiric antibiotic administration. If an alter­
native diagnosis is not identified within 3 h of clinical presentation, 
empiric antibiotic administration is recommended.
Selection of initial empiric antibiotics should consider site of infec­
tion and potential etiologic organisms; community versus health care 
exposure; known prior infections, antibiotic usage, and local antimi­
crobial resistance profiles; and the patient’s immune status, comor­
bidities, and illness severity. Recommendations for initial empiric 
antibiotic use based on site of infection and other pertinent factors are 
summarized in Table 315-1. In patients with undifferentiated sepsis, in 
whom the primary site of infection is unclear, use of broad-spectrum 
antibiotics with a high likelihood of in vitro susceptibility to all organ­
isms likely causing infection is recommended. In patients in whom 
Pseudomonas is not considered a likely pathogen, then a third-generation 
cephalosporin such as ceftriaxone or cefotaxime is recommended 
for gram-negative bacteria coverage. If Pseudomonas is likely, then 
cefepime, piperacillin-tazobactam, or a carbapenem such as imipenem 
or meropenem is recommended for gram-negative bacteria coverage. 
In patients at risk for highly resistant gram-negative infections (e.g., 
patients with prior known highly resistant infections or colonization), 
use of two empiric gram-negative antibiotics is recommended. Finally, 
in patients with undifferentiated sepsis with risk factors for MRSA (e.g., 
frequent health care exposure or hospital-onset sepsis), vancomycin or 
linezolid administration is recommended.
Optimization of antibiotic delivery, such as administering β-lactam 
antibiotics prior to vancomycin, prolonged infusion of β-lactam anti­
biotics after the initial infusion, and optimization of pharmacokinetics/
pharmacodynamics, should be considered in consultation with trained 
pharmacy and infectious diseases experts. Routine empiric antifungal 
therapy use in patients with undifferentiated sepsis is not recom­
mended. However, in patients at increased risk of fungal infection (e.g., 
recent abdominal surgery, parenteral nutrition, liver failure, diabetes, 
colonization of multiple anatomic sites with Candida spp.), empiric 
echinocandin administration is recommended. While the Surviving 
Sepsis Campaign does not provide recommendations on antiviral use, 
remdesivir or neuraminidase inhibitor (e.g., oseltamivir) administra­
tion in septic patients with severe acute respiratory syndrome corona­
virus-2 (SARS-CoV-2) and influenza infection, respectively, should be 
considered.
In addition to providing appropriate and timely antibiotics, identify­
ing sources of infection amendable to control is imperative. Examples 
include, but are not limited to, intraabdominal abscess, bowel perfora­
tion, pyelonephritis, cholangitis, and necrotizing skin and soft tissue 
infections that are amendable to surgical or procedural source control. 
Source control should occur as rapidly as possible. Furthermore, 
removal of indwelling catheters should occur if the catheter appears 
infected (e.g., erythema or purulence at the catheter insertion site), if 
endovascular infection (e.g., endocarditis) is suspected or documented, 
and in critically ill patients without a clear alternate source of infection. 
Finally, antibiotic stewardship to limit development of resistant organ­
isms and other antibiotic-associated complications (e.g., Clostridioides 
difficile infection, hypersensitivity/allergic reaction, and acute kidney

TABLE 315-1  Site-Specific Empiric Antibiotic Recommendations
SITE OF INFECTION
INITIAL EMPIRIC THERAPY
OTHER CONSIDERATIONS
Pulmonary
CAP
Multidrug therapy with a β-lactam 
(ampicillin + sulbactam, ceftriaxone, 
or ceftaroline) and a macrolide 
(azithromycin or clarithromycin)
Monotherapy with a respiratory 
fluoroquinolone (levofloxacin or 
moxifloxacin)
Risk factors for MRSA and/or Pseudomonas aeruginosa: add vancomycin or linezolid for MRSA 
coverage; replace standard CAP therapy with antipseudomonal coverage such as piperacillintazobactam, cefepime, meropenem, or imipenem.
Recommendation based on “local validation” of risk factors for community-onset MRSA or 
P. aeruginosa or prior isolation of these organisms in the previous year, particularly from 
respiratory specimens.
HAP/VAP
Multidrug therapy with vancomycin or 
linezolid and piperacillin-tazobactam, 
cefepime, ceftazidime, imipenem, 
meropenem, or aztreonam
Two antipseudomonal antibiotics from different classes (addition of fluoroquinolones, 
aminoglycosides, or polymyxins) if prior intravenous antibiotic use within 90 days for HAP/VAP 
and septic shock at time of VAP, ARDS preceding VAP, 5 or more days of hospitalization prior to 
VAP, or acute renal replacement therapy prior to VAP.
If prior colonization with carbapenem-resistant Enterobacterales or KPC-producing organism, 
ceftazidime-avibactam and meropenem-vaborbactam should be considered, but further efficacy 
data are needed.
Empiric regimens should be informed by local distribution of pathogens and their antimicrobial 
susceptibilities.
Central Nervous System
Health care–associated 
ventriculitis and meningitis
Vancomycin and cefepime, 
ceftazidime, or meropenem
β-Lactam choice based on local in vitro susceptibility patterns. If carbapenem-resistant 
Acinetobacter is suspected, addition of meropenem and colistin or polymyxin B.
Meningitis
Vancomycin and ceftriaxone
Age >50, alcohol abuse, or immunocompromised: add ampicillin.
Penetrating head trauma, CSF shunt, or postneurosurgery, vancomycin and cefepime, 
ceftazidime, or meropenem.
Clinical presentation suggestive of Rickettsia or Ehrlichia, add doxycycline.
Skin and Soft Tissue
Necrotizing fasciitis 
including Fournier 
gangrene
Multidrug therapy with vancomycin or 
linezolid and piperacillin-tazobactam, 
a carbapenem, or ceftriaxone and 
metronidazole
Prompt surgical consultation is recommended for patients with aggressive infections associated 
with signs of systemic toxicity or suspicion of necrotizing fasciitis or gas gangrene.
Nonpurulent cellulitis/
erysipelas (severe)
Vancomycin and 
piperacillin-tazobactam
Emergent surgical inspection to rule out necrotizing process.
Purulent furuncle/
carbuncle/abscess (severe)
Vancomycin, daptomycin, linezolid, 
telavancin, or ceftaroline
Incision and drainage as indicated.
Intraabdominal
Community-onset 
extrabiliary (mild)
Cefoxitin, ertapenem, moxifloxacin, or 
tigecycline
Health care setting with high prevalence of ESBL-producing Enterobacterales or >20% of 
Pseudomonas resistant to ceftazidime, consider carbapenem or piperacillin-tazobactam.
Community-onset 
extrabiliary (severe)
Imipenem-cilastatin, meropenem, 
doripenem, or piperacillin-tazobactam
Health care associated: imipenem-cilastatin, meropenem, or piperacillin-tazobactam, 
levofloxacin, or cefepime each along with metronidazole, vancomycin added to each regimen.
Community-onset
biliary (mild to moderate)
Cefazolin, cefuroxime, or ceftriaxone
Empiric therapy should be driven by local microbiologic data and source control performed as 
indicated.
Community-onset biliary 
(severe) or cholangitis
Imipenem-cilastatin, meropenem, or 
piperacillin-tazobactam, levofloxacin, 
or cefepime each in combination with 
metronidazole
Genitourinary
Acute pyelonephritis (IDSA 
archived)
Ceftriaxone, trimethoprimsulfamethoxazole, or ciprofloxacin
Requiring hospitalization: intravenous fluoroquinolone, aminoglycoside, extended-spectrum 
cephalosporin, extended-spectrum penicillin, or carbapenem with choice of agents based on 
local resistance data.
Do not use fluoroquinolone if >10% resistance prevalence or trimethoprim-sulfamethoxazole in 
areas of high resistance.
Abbreviations: ARDS acute respiratory distress syndrome; CAP, community acquired pneumonia; CSF, cerebrospinal fluid; HAP, hospital-acquired pneumonia; IDSA, 
Infectious Diseases Society of America; KPC, Klebsiella pneumoniae carbapenemase; ESBL, extended spectrum beta-lactamase; MRSA, methicillin-resistant 
Staphylococcus aureus; VAP, ventilator-associated pneumonia.
injury) requires regular reassessment of the patient’s clinical course and 
available microbiologic data to guide narrowing the spectrum of anti­
biotic therapy and using shorter rather than longer courses of therapy.
■
■NEUROLOGIC COMPLICATIONS
Encephalopathy, manifested by altered consciousness, cognition, or 
attention, ranging from mild delirium to coma, that is not attributable 
to an alternative etiology, is the most common neurologic complica­
tion of sepsis (Table 315–2). Sepsis-associated encephalopathy occurs 
in over half of septic patients and is associated with increased mortal­
ity and long-term functional and neuropsychiatric sequalae among 

CHAPTER 315
Sepsis and Septic Shock
survivors. Septic patients may also experience hyper- or hypoactive 
delirium, seizure, stoke, central nervous system infection, or coma, 
not directly attributable to sepsis. Thus, further diagnostic evalua­
tion is needed in septic patients with clinical findings indicative of 
seizures (i.e., electroencephalogram), stroke (i.e., brain imaging), or 
meningoencephalitis (i.e., lumbar puncture) to identify and treat these 
complications. Underlying factors contributing to sepsis-associated 
encephalopathy include decreased cerebral perfusion, microcirculatory 
and blood-brain barrier disruption, and exposure of brain parenchyma 
to circulating inflammatory mediators and oxidative stress resulting in 
neuronal injury, dysfunction, and death. Neuronal and glial apoptosis

TABLE 315-2  Organ-Specific Clinical Findings and Management
EPIDEMIOLOGY
CLINICAL FINDINGS
DIAGNOSIS
TREATMENT
Neurologic
54% of septic patients develop 
encephalopathy
Altered consciousness, 
cognition, or attention; 
seizure, stroke, or 
meningism
Cardiovascular
25% of septic patients 
develop shock and half have 
myocardial dysfunction
Tachycardia, hypotension, 
skin mottling, prolonged 
capillary refill, oliguria, 
altered mental status
Respiratory
7% of septic patients develop 
ARDS
Tachypnea, hypoxia, 
increased work of breathing
PART 8
Critical Care Medicine
Genitourinary
67% of septic patients have 
acute kidney injury
Oligura or anuria
Elevated serum creatinine 
and blood urea nitrogen, 
acidemia, hyperkalemia
Gastrointestinal
50% of septic shock patients 
have liver dysfunction
Right upper quadrant pain, 
asterixis, jaundice
Hematologic
35% of septic shock 
patients have disseminated 
intravascular coagulation
Clinical or subclinical 
thrombosis or hemorrhage
Abbreviations: ARDS, acute respiratory distress syndrome; CT, computed tomography; EEG, electroencephalogram; INR, international normalized ratio; LVEF, left ventricular 
ejection fraction; MRI, magnetic resonance imaging; PT, prothrombin time.
are correlative findings at autopsy among fatal cases. The management 
of sepsis-associated encephalopathy includes early recognition, treat­
ment of the underlying infection, supportive care including correction 
of metabolic or electrolyte abnormalities, and limiting exposure to 
pharmacologic agents that are neurotoxic (e.g., cefepime) or have cen­
tral nervous system effects including opiates and benzodiazepines that 
might exacerbate the condition or predispose to long-term disability or 
neurocognitive dysfunction.
■
■CARDIOVASCULAR DYSFUNCTION
Cardiovascular comprise, manifested as hypotension or shock, occurs 
in ~25% of septic patients. Hypotension results from peripheral 
arteriolar vasodilation and decreased cardiac venous return due to 
venous vasodilation and intra- to extravascular fluid shifts. Clinical 
signs of diminished tissue perfusion include skin mottling, prolonged 
capillary refill time, oliguria, and altered mental status. During early 
compensated shock, heart rate and cardiac output increase. As septic 
shock progresses, loss of vascular smooth muscle contractility, despite 
endogenous neurohormonal stimuli and exogenous catecholamine 
administration, results in progressive or refractory shock.
Up to half of patients with septic shock also have myocardial dys­
function, which is associated with increased mortality. Sepsis-induced 
cardiomyopathy manifests as decreased left ventricular ejection frac­
tion, increased end-diastolic volume index, and right ventricular 
impairment. Contributing factors to sepsis-induced cardiomyopathy 
include global ischemia, hypoxia, and impaired myocardial metabo­
lism; endothelial damage, increased adhesion molecule expression, 
and coronary microcirculatory dysfunction; and direct cardiomyocyte 
suppression, mitochondrial dysfunction, or cardiomyocyte death from 
exposure to inflammatory mediators including cytokines (e.g., IL-1β, 
IL-6, and TNF-α), complement proteins, and NO.

EEG, brain imaging (MRI or 
CT), lumbar puncture
Early recognition and supportive care; treat 
underlying cause; correct metabolic and electrolyte 
abnormalities; limit neurotoxic agents and sedatives
Invasive blood pressure 
monitoring, dynamic 
assessment of volume status, 
echocardiogram
Intravenous fluid resuscitation with balanced 
crystalloid, ~30 mL/kg; vasopressors for persistent 
hypotension, norepinephrine (first agent), 
vasopressin (second agent), epinephrine (third 
agent); hydrocortisone 200 mg/d if ongoing 
vasopressor requirement; consider adding 
dobutamine to norepinephrine or switch to 
epinephrine in septic shock patients with decreased 
LVEF; consider use of pulmonary artery catheter in 
patients with mixed septic and cardiogenic shock
Chest x-ray or ultrasound 
with noncardiogenic bilateral 
infiltrates and Pao2/Fio2
<300 mmHg or Spo2/Fio2 ≤315
Maintain Spo2 90–96%; use high-flow nasal canula 
in patients with adequate neurologic status; target 
plateau pressure <30 cmH2O and tidal volume of 
6–8 mL; consider rescue therapies in patients with 
refractory hypoxia
Treat underlying infection, maintain renal perfusion, 
avoid nephrotoxic agents; start renal replacement 
therapy for progressive acidemia, hyperkalemia, 
uremia, or volume overload; infuse sodium 
bicarbonate if renal failure and pH ≤7.2.
Elevated bilirubin, alkaline 
phosphatase, and 
transaminases; right upper 
quadrant ultrasound
Treat underlying infection, avoid hypotension and 
hepatoxic agents; stress ulcer prophylaxis for highrisk patients; enteral feeding if shock controlled 
within 48 h; parenteral feeding if nutrition goal not 
met within 7 days; insulin if blood glucose ≥180 g/dL
Thrombocytopenia, increased 
fibrin split products, 
decreased fibrinogen, 
prolonged PT/INR
Administer cryoprecipitate for fibrinogen <150 mg/dL, 
platelets for platelet count ≤50 × 109/L and evidence 
of bleeding, and fresh frozen plasma for prolongated 
PT/INR and evidence of bleeding; transfuse packed 
red blood cells for hemoglobin <7.0 g/dL
Intravenously administered fluids and vasopressors are used to 
restore and maintain blood pressure and tissue perfusion in the 
setting of septic shock. An indwelling arterial catheter should be 
placed as soon as feasible to continuously monitor blood pressure 
invasively. Crystalloid solutions are preferred over colloid for ini­
tial volume resuscitation, although colloid such as albumin can be 
considered in patients who have already received large volumes of 
crystalloid. Balanced crystalloid solution, such as lactated Ringer’s, 
may be preferrable to 0.9% normal saline, which is more likely to 
induce hyperchloremic metabolic acidosis associated with renal 
vasoconstriction and kidney injury. Use of pentastarch or hydroxy­
ethyl starch is associated with severe kidney injury and death and 
should be avoided.
Crystalloid should be administered as a bolus over 5–10 min at 
a volume of ~30 mL/kg. However, 30 mL/kg may not be appropri­
ate for all patients, including those with end-stage renal disease and 
systolic heart failure. Protocolized fluid resuscitation targets including 
central venous pressure (CVP) of 8–12 mmHg, central venous oxygen 
saturation >70%, and urine output ≥0.5 mL/kg per h have not been 
associated with improved mortality and so are not recommended to 
guide total fluid replacement. Instead, dynamic assessment of volume 
responsiveness using capillary refill time, passive leg raise maneuver, 
and point-of-care ultrasound, with iterative reevaluation, should guide 
total volume administered and is preferred over static measurements of 
volume responsiveness such as CVP. Notably, a 2017–2018 clinical trial 
conducted in 28 ICUs in five countries found that resuscitation guided 
by capillary refill time compared with lactate level–targeted resuscita­
tion did not reduce all-cause 28-day mortality, an important finding for 
sepsis care in resource-limited settings.
In patients who have received adequate fluid resuscitation yet remain 
hypotensive, a continuous norepinephrine drip should be initiated as

the first-line vasopressor to maintain a mean arterial pressure target 
of ≥65 mmHg. Vasopressin should be added as a second agent, and 
epinephrine as a third agent, if needed, to achieve the blood pressure 
target. A contemporary randomized clinical trial tested the efficacy of 
early restrictive (i.e., prioritizing vasopressors and lower intravenous 
fluid volumes) versus liberal (i.e., prioritizing higher volumes of intra­
venous fluids before vasopressors use) fluid management in the first 
4 h of presentation in patients with septic shock. Across 1563 patients 
at 60 U.S. medical centers, there was no difference in 90-day mortality. 
In septic patients with evidence of myocardial dysfunction (e.g., low 
cardiac output, elevated filling pressures) and evidence of persistent 
hypoperfusion following adequate volume resuscitation, consideration 
should be given to adding dobutamine to norepinephrine or using 
epinephrine alone to increase inotropy. While routine use of pulmo­
nary artery catheters to guide fluid management in sepsis has not been 
associated with improved outcomes, use may be considered in patients 
with mixed septic and cardiogenic shock.
In patients with septic shock and ongoing requirement for vasopres­
sor therapy, it is recommended to start intravenous corticosteroids with 
hydrocortisone at a dose of 200 mg/d often provided as 50 mg every 6 h.
■
■ACUTE LUNG INJURY
Lung injury, manifesting as acute hypoxic respiratory insufficiency or 
failure, and termed acute respiratory distress syndrome (ARDS), com­
plicates ~7% of sepsis cases. ARDS is a syndrome that is classified by 
noncardiogenic diffuse pulmonary infiltrates and hypoxemia, in which 
infiltrates can be determined by x-ray or ultrasound imaging, and 
hypoxemia can be determined by Pao2/Fio2 <300 mmHg or percent 
oxygen saturation (Spo2)/Fio2 ≤315. The pathogenesis of ARDS over­
laps with that of sepsis, in which activated myeloid cells and soluble 
inflammatory mediators disrupt pneumocytes’ and endothelial cells’ 
structure and function, resulting in leakage of plasma components and 
further recruitment of immune cells into lung alveolar and interstitial 
spaces. The histopathologic correlate of ARDS is diffuse alveolar dam­
age, which progresses through early exudative, then proliferative, and 
finally fibrotic stages.
Initial management of acute lung injury in sepsis requires admin­
istration of oxygen to meet cellular metabolic demand while limiting 
cellular injury from oxidative stress, with a reasonable Spo2 target 
being 90–96%. In patients with adequate neurologic status, and absent 
other specific contraindications, high-flow nasal canula is preferred 
over noninvasive ventilation to improve hypoxia in patients without 
hypercapnia. For patients with ARDS who require invasive mechani­
cal ventilation, targeting a plateau pressure of <30 cmH2O and a tidal 
volume of 6–8 mL/kg, based on ideal body weight, has been associated 
with reduced mortality and is recommended. In patients with refrac­
tory hypoxia despite low tidal volume ventilation, rescue measures 
including prone positioning, neuromuscular blockade, and venove­
nous extracorporeal membrane oxygenation should be considered.
■
■ACUTE KIDNEY INJURY
Acute kidney injury (AKI) occurs in up to two-thirds of patients 
with sepsis or septic shock and is associated with increased mortal­
ity and risk of chronic kidney disease and disability among survivors. 
Sepsis-associated AKI presents with oliguria or anuria and elevated 
serum creatinine and blood urea nitrogen and accounts for all AKI 
cases occurring within 7 days of sepsis onset. Sepsis-associated AKI 
may be attributed to sepsis, associated complications (e.g., abdominal 
compartment syndrome), and clinical management including admin­
istration of nephrotoxic substances such as antibiotics and intravenous 
contrast dye. Factors that contribute to pathogenesis of AKI due to 
sepsis alone, termed sepsis-induced AKI, include renal hypoperfu­
sion, microvascular injury and dysfunction, inflammatory cellular and 
soluble mediators, and altered renal tubular metabolic and mitochon­
drial function. Many serum and urine biomarkers have been evaluated 
to improve early recognition and treatment of sepsis-associated AKI. 
However, to date, none have been shown to improve outcomes.
Management of sepsis-associated AKI includes treating underlying 
infection, maintaining renal perfusion with fluid resuscitation and 

vasopressors to achieve blood pressure goals, avoiding nephrotoxic 
agents when possible, and identifying and treating reversible causes. 
Initiating early renal replacement therapy (RRT), including intermit­
tent hemodialysis or continuous renal replacement therapy (CRRT), 
during sepsis-associated AKI is not associated with improved out­
comes, and so RRT should be started for standard definitive indica­
tions including progressive acidemia, hyperkalemia, uremia, or volume 
overload. CRRT is better tolerated than intermittent hemodialysis in 
patients with septic shock, allowing for less dynamic intravascular vol­
ume shifts and so is preferred in these patients when available. Sodium 
bicarbonate infusion should be considered only in patients with AKI 
and severe metabolic acidemia (pH ≤7.2) to maintain vasopressor 
effectiveness and mitigate fatal ventricular arrythmia risk.

■
■GASTROINTESTINAL COMPLICATIONS
Approximately 50% of patients with septic shock develop liver dysfunc­
tion, which is associated with increased mortality. Clinical findings 
may include right upper quadrant pain, jaundice, and asterixis depend­
ing on severity. Common laboratory findings include elevated serum 
bilirubin and alkaline phosphatase levels and elevated transaminases if 
marked hypotension occurs. Sepsis-induced cholestasis is attributed to 
impaired bile formation and decreased flow in a nonobstructive pat­
tern. The liver plays an essential role in microbial clearance, in which 
the Kupffer cells phagocytose bacteria, release proinflammatory cyto­
kines and chemokines, and bind platelets. Neutrophils are recruited 
to liver sinusoids, release NETs to trap pathogens, and contribute to 
a proinflammatory and prothrombotic environment. In autopsy stud­
ies of fatal sepsis, hepatitis and steatosis are detected in most patients, 
while portal inflammation, centrilobular necrosis, hepatocellular apop­
tosis, and cholangitis may also be detected. Management of liver injury 
and dysfunction during sepsis includes treating the underlying infec­
tion and avoiding hypotension and hepatoxic medications. In septic 
patients with elevated serum bilirubin, abdominal ultrasound should 
be performed to evaluate for biliary obstruction, cholecystitis, and 
cholangitis.
CHAPTER 315
Sepsis and Septic Shock
Sepsis has also been associated with alteration of the intestinal 
mucosa including increased epithelial permeability, changes in gut 
microbiota, and translocation of enteric microbes into circulation. In 
patients with sepsis and septic shock and risk factors for gastrointes­
tinal bleeding (e.g., mechanical ventilation, coagulopathy, preexisting 
liver disease, high organ failure score, and need for RRT), stress ulcer 
prophylaxis is recommended. Decreased splanchnic perfusion and 
increased interstitial edema contribute to impaired intestinal absorp­
tion, which in combination with the catabolism of sepsis contributes 
to nutritional deficiencies. The route and timing of supplemental 
nutrition administration in patients with sepsis and septic shock are 
debated. Current recommendations are to initiate enteral nutrition 
early, within 48 h of diagnosis, in patients in whom shock is controlled 
with fluids and vasopressors and absent contraindications like bowel 
ischemia. The rationale for early enteral feeding is to maintain enteric 
epithelial integrity while limiting negative nitrogen and caloric balance. 
Supplemental use of parenteral nutrition is suggested if nutritional 
goals are unmet within 7 days by enteric feeding and supplemental 
glucose infusion. Insulin therapy is recommended for patients with 
blood glucose levels >180 mg/dL.
■
■HEMATOLOGIC COMPLICATIONS
Coagulation abnormalities in sepsis are common, ranging from isolated 
thrombocytopenia to disseminated intravascular coagulation (DIC), 
and can manifest with clinical or subclinical thrombosis and hemor­
rhage. Up to 35% of septic shock patients meet DIC criteria, including 
thrombocytopenia, increased fibrin split products, decreased fibrino­
gen, and prolonged prothrombin time (PT)/international normalized 
ratio (INR), which is associated with increased mortality. Given that 
DIC is a late manifestation of coagulation abnormalities in sepsis, a 
scoring system for earlier detection of sepsis-induced coagulopathy 
(SIC) has been proposed. SIC scoring, which considers platelet counts, 
PT, and SOFA score, is more sensitive than DIC criteria for recognizing 
coagulation abnormalities in sepsis. However, the clinical utility of SIC