E Sepsis

Sepsis and Septic Shock

73  Tom van der Poll and Willem Joost Wiersinga

SHORT VIEW SUMMARY

Definition • Gram-negative bacteria are identified in 38% history and physical examination combined
• Sepsis is a life-threatening organ dysfunction to 62% of cases, gram-positive bacteria with laboratory, radiology, and microbiology
caused by a dysregulated host response to are identified in 40% to 52%, and fungi are testing is typically required for the
infection. identified in 5% to 19%. Viral infections are diagnosis.
detected in 1% to 7% of cases. • Host response biomarkers can be of diagnostic
Clinical Signs and Symptoms
value, discriminating infectious from
• Pneumonia, peritonitis, urinary tract infections, Pathogenesis
noninfectious conditions or determining the
and soft tissue infections are—in descending • Pattern-recognition receptors are essential for
causative pathogen; of prognostic value,
order—the most important sources of sensing invading bacteria and subsequent
assigning risk profiles and predicting outcome;
sepsis. initiating of the immune response. These
or of theranostic (combining diagnosis and
• Organ failure is the hallmark sign of sepsis receptors recognize both pathogen-associated
therapy) value, aiding in selection and
and most frequently occurs in the respiratory molecular patterns (conserved motifs
monitoring of therapy (see Fig. 73.6).
and cardiovascular systems, followed by renal, expressed by pathogens) and
central nervous system, hematologic, and danger-associated molecular patterns or Therapy
hepatic dysfunction. alarmins (host molecules released during • Implementation of the Surviving Sepsis
inflammatory stress). Campaign guidelines for management of
Epidemiology
• The host response to sepsis is characterized by sepsis has been associated with improved
• The incidence of sepsis has increased at least
both proinflammatory and antiinflammatory outcome.
in part due to the aging population and
reactions and varies among individuals. • Intravenous antibiotics should be started as
aggressive therapies for chronic diseases.
Proinflammatory responses include cytokine soon as possible after recognition of sepsis
• The case-fatality rate of sepsis has decreased,
release and activation of the complement and within 1 hour for septic shock.
at least in high-income countries, likely in part
system, coagulation system, and vascular • The choice of empirical antibiotic treatment
through implementation of the Surviving
endothelium; antiinflammatory responses can depends on the suspected source of infection,
Sepsis Campaign guidelines and improvement
result in immunosuppression at least in part global geography, setting (e.g., community or
of standard intensive care.
due to apoptotic loss of lymphoid cells. hospital), comorbidity, and local microbial
• The risk of acquiring sepsis is influenced by
• The host response to infection and susceptibility patterns.
age, sex, comorbidity burden, and
noninfectious injury is not fundamentally
socioeconomic status. Prognosis
different.
• Patients who survive sepsis often have
Microbiology
Diagnosis long-term complications including cognitive
• A causative microorganism can be identified in
• There is no gold standard for diagnosing and physical impairments, higher readmission
up to two-thirds of patients admitted to an
sepsis. A clinical pattern based on the patient’s rates, and increased mortality.
intensive care unit for sepsis.

Sepsis is a life-threatening condition with organ failure caused by a clinical problem in the future, owing to the aging population, aggressive
dysregulated host response to an infection. Septic shock is sepsis therapies for chronic diseases, and antimicrobial resistance. Moreover,
accompanied by persistent hypotension. The most common infections with more patients surviving sepsis, attention has been directed toward
causing sepsis and septic shock are pneumonia and peritonitis. Any long-term sequelae, which include cognitive and physical impairments
infection that overrides the protective innate immune response initiated and cardiovascular disease.
in response to a potential pathogen can result in sepsis. Sepsis is most
often caused by bacteria, but fungal and viral infections can also instigate DEFINITION
sepsis. A key pathogenic feature of sepsis is that the multifaceted innate Sepsis is a broad term used for an incompletely understood process, and
immune response fails to return to normal homeostasis in the context there is no gold standard for its diagnosis. The term sepsis originates
of an unsuccessful attempt to eradicate the invading pathogen. Concurrent from the ancient Greek word sêpsis (“putrefaction” or “decay of organic
hyperinflammation and immunosuppression ensue, affecting different matter”) and was first used in a medical context in Homer’s Iliad, written
cell types and organs. The case-fatality rate of sepsis has improved in more than 2700 years ago. In the early 1990s sepsis was clinically defined
recent years, probably as a result of better general clinical practices and by a consensus definition generated by a group of key experts.1 The
development and implementation of sepsis treatment guidelines. Sepsis-1 definition was centered around four systemic inflammatory
Nonetheless, sepsis continues to be the most frequent cause of death response syndrome (SIRS) criteria consisting of tachycardia (heart rate
in hospitalized patients, and it is expected to remain an important >90 beats/min); tachypnea (respiratory rate >20 breaths/min); fever or
990
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 991
hypothermia (temperature >38°C or <36°C); and leukocytosis (white to the Sepsis-3 definition, sepsis is a life-threatening organ dysfunction
blood cells >1200/mm3), leukopenia (white blood cells <4000/mm3), or caused by a dysregulated host response to infection.3 In the clinic, organ
bandemia (≥10%) (Table 73.1). Sepsis-1 was defined as (documented dysfunction can be represented by an increase in the Sequential [Sepsis-
or suspected) infection leading to the onset of SIRS as reflected by the related] Organ Failure Assessment (SOFA) score of 2 points or more;

Chapter 73  Sepsis and Septic Shock

presence of two or more SIRS criteria. Severe sepsis was defined as the baseline SOFA score should be presumed zero unless the patient
sepsis complicated by organ dysfunction, which could progress to septic is known to have preexisting organ dysfunction before the onset of
shock, defined as “sepsis-induced hypotension persisting despite adequate infection (Table 73.2). Septic shock is now defined as a subset of sepsis
fluid resuscitation.”1 By incorporating the SIRS criteria in the definition, in which strong circulatory, cellular, and metabolic abnormalities are
the Sepsis-1 definition sought to capture the then-prevailing view that associated with a greater risk of mortality than with sepsis alone; these
sepsis resulted from a systemic inflammatory response to infection. patients can be clinically identified by a vasopressor requirement to
In 2001 a new task force was assembled to readdress the definition of maintain a mean arterial pressure of 65 mm Hg or greater and serum
sepsis.2 Although the limitations of Sepsis-1 were recognized, alternatives lactate level greater than 2 mmol/L (>18 mg/dL) in the absence of
were not offered owing to absence of supporting evidence. The Sepsis-2 hypovolemia.
definition expanded the list of diagnostic criteria, encompassing a set The 2016 Task Force also introduced the quick SOFA, or qSOFA,
of 24 general, inflammatory, hemodynamic, organ dysfunction, or score, composed of three components that are easy to measure at the
tissue perfusion parameters. In the Sepsis-2 definition the criteria for bedside: respiratory rate of 22 breaths/min or greater, altered mentation,
severe sepsis remained similar, whereas septic shock was defined more and systolic blood pressure of 100 mm Hg or less.3 Evidence indicated
explicitly as refractory hypotension (systolic blood pressure <90 mm that in out-of-hospital, emergency department, and general hospital
Hg or mean arterial blood pressure <70 mm Hg) despite adequate fluid ward settings, adult patients with suspected infection and a higher
resuscitation.2 risk for poor outcomes typical of sepsis can be rapidly identified by
The most recent Sepsis-3 definition, published in 2016,3 seeks to the presence of at least two qSOFA criteria. Importantly, qSOFA is
confine important limitations of Sepsis-1 and Sepsis-2, which include a not part of the new definition of sepsis. Moreover, failure to meet
disproportionate emphasis on inflammation, poor specificity and sensitiv- two or more SOFA or qSOFA criteria should not lead to a delay of
ity of the SIRS criteria, and the incorrect concept that sepsis follows
a continuum through severe sepsis to shock. The Sepsis-3 definition,
in contrast to Sepsis-1 and Sepsis-2, partially relies on large data sets, TABLE 73.2  SOFA Score
which were used to obtain quantitative information in support of the
new criteria. The new definition abandoned the use of SIRS criteria ORGAN SYSTEM SCORE
in the diagnosis of sepsis. In addition, in the new definition the pres- Respiration
ence of organ dysfunction is a requirement for a sepsis diagnosis, and  Pao2/Fio2, mm Hg (kPa)
therefore the term severe sepsis was eliminated in Sepsis-3. According   <400 (53.3) 1
  <300 (40) 2
  <200 (26.7) with respiratory support 3
  <100 (13.3) with respiratory support 4
Central nervous system
TABLE 73.1  Sepsis Definitions   GCS score
  13–14 1
TERM DEFINITION   10–12 2
  6–9 3
1991 Consensus Conference1   <6 4
SIRS At least two of the following:
Cardiovascular
• Temperature >38°C or <36°C
  MAP or use vasopressors (µg/kg/min)
• Heart rate >90 beats/min
  MAP <70 mm Hg 1
• Respiratory rate >20 breaths/min or arterial CO2 <32 mm Hg
   Dopamine <5 or dobutamine (any dose)a 2
• White blood cell count >12 × 109/L or <4 × 109/L or >10%
   Dopamine 5.1–15 or epinephrine ≤0.1 or norepinephrine ≤0.1 3
immature forms
   Dopamine >15 or epinephrine >0.1 or norepinephrine >0.1 4
Sepsis Infectiona + SIRS
Liver
Severe sepsis Sepsis + acute organ dysfunction   Bilirubin, mg/dL (µmol/L)
   1.2–1.9 (20–32) 1
Septic shock Sepsis + persistent hypotension after fluid resuscitation    2.0–5.9 (33–101) 2
   6.0–11.9 (102–204) 3
2001 International Sepsis Definitions Conference2   >12.0 (204) 4
No significant changes from 1991 definitions, with the addition that signs and Coagulation
symptoms of sepsis are more varied than captured by 1991 definitions; this   Platelets, × 103/µL
resulted in the presentation of a list of these signs and symptoms for the   <150 1
diagnosis of sepsis   <100 2
  <50 3
2015 Third International Consensus Definitions for Sepsis and
  <20 4
Septic Shock (Sepsis-3)3
Renal
Sepsisb • Life-threatening organ dysfunction caused by dysregulated   Creatinine, mg/dL (µmol/L) or urine output, mL/day
host response to infection    1.2–1.9 (110–170) 1
• Organ dysfunction can be identified as acute change in total    2.0–3.4 (171–299) 2
SOFA score ≥2 points    3.5–4.9 (300–440) or <500 3
Septic shock • Sepsis in which underlying circulatory and cellular/metabolic   >5.0 (440) or <200 4
abnormalities are profound enough to substantially increase Fio2, Fraction of inspired oxygen; GCS, Glasgow Coma Scale (scores range from 3
mortality to 15; higher score indicates better neurologic function); MAP, mean arterial
• Clinically defined as sepsis with persisting hypotension pressure; Pao2, partial pressure of oxygen; SOFA, Sequential [Sepsis-related] Organ
requiring vasopressors to maintain mean arterial pressure Failure Assessment.
≥65 mm Hg and with serum lactate >2 mmol/L The SOFA score can be used to measure the severity of organ dysfunction. The
a
Suspected or proven. aggregate score is calculated by summing the worst scores for each of the organ
b
In the new sepsis definition, the presence of organ dysfunction is central and a systems.
requirement; previously, organ dysfunction identified “severe” sepsis, a term that
a
Catecholamine doses are given as μg/kg/min for at least 1 hour.
was abandoned in the Sepsis-3 definition. From Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure
CO2, Carbon dioxide; SIRS, systemic inflammatory response syndrome; SOFA, Assessment) score to describe organ dysfunction/failure. On behalf of the Working
Sequential [Sepsis-related] Organ Failure Assessment. Group on Sepsis-Related Problems of the European Society of Intensive Care
Medicine. Intensive Care Med. 1996;22:707–710.

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 992
treatment of infection or any other intervention deemed necessary by A
physicians.
The Sepsis-3 definition and qSOFA have limitations, and criticism
exists regarding their use in clinical practice. Although large cohorts
Part II  Major Clinical Syndromes

were used to support Sepsis-3 and qSOFA, patient data were almost
exclusively derived from high-income countries (especially the United
States), which leaves uncertainty with regard to extrapolation to resource-
poor settings. In addition, supporting data were generated in adult
patients and cannot be readily extrapolated to pediatric sepsis. The
measurement of serum lactate is required for the diagnosis of septic
shock, which is not feasible in many areas of the world. Finally, the
Sepsis-3 definition does not entail a molecular or pathogenic component
that may stratify patients into more homogeneous subgroups based on
their predominant pathophysiologic abnormality and thereby guide
individualized therapies.
B
CLINICAL SIGNS AND SYMPTOMS
Correctly recognizing a septic patient can be challenging, as clinical
signs and symptoms at presentation can be variable and nonspecific.4,5
The manifestations of sepsis depend on the source of infection, the
causative pathogen, the type and extent of organ dysfunction, drug use
and comorbidity of the patient, and the delay before consulting a physician
or before start of treatment. The most common underlying comorbidities
of patients admitted for sepsis include chronic obstructive pulmonary
disease, neoplasm, human immunodeficiency virus (HIV) infection,
chronic liver disease, chronic renal disease, diabetes, peripheral vascular
disease, and autoimmune disease.6 General variables include fever,
tachycardia, tachypnea, altered mental status, significant edema, or
positive fluid balance (>20 mL/kg over 24 hours).2 Hypothermia is
observed in 9% to 35% of patients with sepsis and is associated with C
adverse outcomes.7,8

Source of Sepsis
Pneumonia is the most common source of sepsis in adults, followed
by abdominal, urinary tract, and skin/soft tissue infections (Fig.
73.1A).6,9,10,11,12 These preferred sites account for 80% to 90% of all adult
sepsis cases, the remainder being caused by bone/joint infections,
ear-nose-throat infections, and others. More than one source is found
in approximately 6% of episodes.9 The primary source of infection often
depends on the comorbidity of the patient and the presence of indwelling
catheters or devices. For instance, the presence of obstructive lung disease
is a significant predictor of hospitalizations caused by respiratory tract
infections but not of hospitalizations due to infections outside the FIG. 73.1  Most common sites of infection, types of organ failure,
respiratory system.13 Likewise, in patients on long-term renal replacement and causative organisms identified in patients with sepsis. (A) Most
therapy, sepsis more often is caused by central venous catheter infections, common sites of infection. Bars show the means plus standard error of
peritonitis, or an ischemic bowel.14 However, in most series, no obvious data from six representative studies.6,9,10,11,12,70 The lung and abdomen are
source of infection can be found in one-sixth of patients.6,9,10,11,12 the most common primary sites. (B) Most common types of organ failure
in sepsis. Bars show means plus standard error of data from four representa-
Organ Failure in Sepsis tive studies.6,10,15,16 The definitions used to diagnose organ dysfunction
varied from study to study. Central nervous system (CNS) dysfunction was
Organ failure is the hallmark sign of sepsis, and respiratory and cardio- uncommon in some series and very common in others. (C) Incidence of
vascular failure most frequently occurs, followed by renal, central nervous sepsis by causative organism. Bars show means plus standard error of
system (CNS), hematologic, and hepatic failure (Fig. 73.1B).5,6,10,15,16 causative organisms isolated in patients with sepsis from four representative
Respiratory failure, shock, and kidney failure are the most common studies.10,16,57,70 A significant number of patients have two or more causative
reasons for admission to the intensive care unit (ICU).10,15 Most patients organisms identified. DIC, Disseminated intravascular coagulation.
have failure of a single organ, whereas approximately 20% have failure
of two organs, and approximately 5% have acute failure of three or
more organs.6,11 There is a direct relationship between the number of noncardiac origin (Fig. 73.2).19 ARDS can be classified as mild (200 mm
organs failing in patients with sepsis and mortality.10 A study from Hg < partial pressure of arterial oxygen [Pao2]/fractional inspired
across Europe showed mortality rates were 26% among patients with oxygen [Fio2] < 300 mm Hg), moderate (100 mm Hg < Pao2/Fio2 ≤
dysfunction of two organs on ICU admission, whereas mortality rates 200 mm Hg), or severe (Pao2/Fio2 ≤ 100 mm Hg).19 The underlying
were 65% among patients with failure of four or more organs.10 Severity pathology is diffuse alveolar epithelial injury, with increased barrier
of organ dysfunction has been assessed with various scoring systems that permeability and exudation of protein-rich fluid into the interstitial
quantify abnormalities according to clinical findings, laboratory data, and airspace compartments.20 Neutrophils and monocytes accumulate
or therapeutic interventions.3 The predominant system in current use in the lungs and may form cellular aggregates in pulmonary vessels.
is the SOFA score (see Table 73.2).17 A higher SOFA score is associated Significant right-to-left shunting occurs. Dead space volume increases
with an increased probability of mortality.18 and compliance decreases, augmenting the work of breathing. Mechanical
ventilation is needed in most severe cases. In the past 2 decades, mortality
Acute Lung Injury among patients with ARDS has decreased from approximately 60% to
Respiratory failure commonly manifests as acute respiratory distress 25%, which can be accounted for in part by the application of a lung-
syndrome (ARDS), defined as hypoxemia and bilateral infiltrates of protective ventilation strategy (with low airway pressure and low tidal

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 993

A C

Chapter 73  Sepsis and Septic Shock

B D

FIG. 73.2  Common complications of sepsis. The most common sepsis complications include brain dysfunction, acute lung injury, acute kidney injury,
ileus, cardiovascular dysfunction (including shock), disseminated intravascular coagulation (with thrombocytopenia), and liver injury. (A) Typical chest x-ray
and (B) computed tomography scan of acute respiratory distress syndrome showing patchy opacification, loculated pneumothoraces, and bilateral chest
drains. (C) Plain abdominal x-ray showing an ileus (note dilated loops of small and large bowel with no cutoff). (D) Purpura as a manifestation of severe
disseminated intravascular coagulation. (A from Khan A, Kantrow S, Taylor DE. Acute respiratory distress syndrome. Hosp Med Clin. 2015;4:500–512; B
from Randhawa R, Bellingan G. Acute lung injury. Anaesth Intensive Care Med. 2007;8:477–480; C from Glancy DG. Intestinal obstruction. Surgery.
2014;32:204–211; D from Piette WW. Purpura. In: Callen JP, Jorizzo JL, Zone JJ, Piette W, Rosenbach MA, Vleugels RA, eds. Dermatological Signs of
Systemic Disease. 5th ed. Philadelphia: Elsevier; 2017:109–116, courtesy Dr. Neil A. Fenske, Tampa, FL.)

volumes) in addition to better supportive care in the ICU.21 However, myocyte cell death was rare, whereas sepsis-induced focal mitochondrial
up to half of patients who recover from ARDS may have significant injury was present in many cells.26
functional impairment related to the healing process, which can produce
restrictive defects, reduced diffusing capacity, and an inability to return Renal Dysfunction
to work.21,22 Acute kidney injury (AKI) is characterized by decreased urinary output
with increasing serum creatinine levels; many patients with sepsis require
Cardiovascular Dysfunction renal replacement therapy.27 Sepsis-associated AKI is associated with
The cardiovascular impact of sepsis has two components: myocardial a high burden of morbidity (e.g., dependency on dialysis at the time
dysfunction and relative hypovolemia resulting from vasodilation.23,24 of hospital discharge) and mortality in patients with critical illness. The
Sepsis-associated myocardial dysfunction includes reduced left and right renal abnormalities range from minimal proteinuria to profound renal
ventricular ejection fractions, increased left and right ventricular end- failure; postmortem studies have found focal acute tubular injury and
diastolic volumes, and an elevated heart rate and cardiac output. The minimal glomerular damage.26 The underlying pathogenic mechanisms
cardiac depression associated with septic shock reflects the effects of include hypovolemia, hypotension, renal vasoconstriction, and toxic
inflammatory mediators on cardiac myocyte and microcirculatory drugs (e.g., aminoglycosides) or contrast agents used for medical
function, is not caused by ischemia, and usually does not require inotropic imaging.27 In most patients, sepsis-induced renal injury is largely revers-
therapy. However, if hypovolemic shock cannot be reversed by administer- ible. Nonetheless, even small acute increases in serum creatinine are
ing intravenous fluids, the use of vasopressors is indicated to restore associated with decreased long-term survival in critically ill patients.28
tissue perfusion pressure. Not surprisingly, survival in patients with septic shock is directly linked
Adrenergic agonists are the first-line vasopressors, norepinephrine to the severity of AKI.29
being the first-choice agent.25 In cases of refractory septic shock, another Novel promising biomarkers in urine and plasma for the early
vasopressor with a different mechanism of action (nonadrenergic) can diagnosis of sepsis-associated AKI include cystatin C, neutrophil
be added. Mechanisms implicated in the development of sepsis-induced gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase 2,
myocardial depression include alterations in calcium homeostasis, and insulinlike growth factor–binding protein 7. At the present time,
mitochondrial dysfunction, apoptosis, circulating cardiosuppressant however, data on these biomarkers are insufficient to support their use
mediators, and nitric oxide. A postmortem study found that cardiac in clinical management of patients with sepsis-associated AKI.30

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 994
Dysfunction of Brain, Peripheral Nerves, A “shock liver” is unusual, but if the duration of septic shock is prolonged,
and Muscles a massive rise in serum transaminases may follow hypoxic necrosis of
Brain dysfunction in sepsis may manifest as coma or delirium. Formally, centrilobular liver cells.
sepsis-associated encephalopathy (SAE) is defined as diffuse cerebral At the end, the function of every organ may be affected. Skin mani-
Part II  Major Clinical Syndromes

dysfunction that accompanies sepsis in the absence of direct CNS festations of sepsis include a cutaneous reaction at a local inoculation
infection, structural abnormalities, or other types of encephalopathy.31 site (pustule, eschar), lesions that appear at sites of hematogenous seeding
Delirium occurs in 30% to 50% of patients with severe sepsis. In general, of the skin or underlying soft tissue (petechiae, pustules, ecthyma
the severity of SAE parallels the severity of other manifestations of gangrenosum, cellulitis), diffuse eruptions caused by bloodborne toxins
sepsis. Because there are no specific markers for SAE, the diagnosis (e.g., toxic shock syndrome toxin), and hemorrhagic or necrotic lesions.
relies on excluding primary CNS infections and other causes of Other common manifestations of sepsis include altered glycemic control,
encephalopathy. Proposed underlying mechanisms include microscopic adrenal dysfunction, and sick euthyroid syndrome.5
brain injury, blood-brain barrier and cerebral microcirculation dysfunc-
tion, altered CNS metabolism, and impaired cholinergic neurotransmis- EPIDEMIOLOGY
sion. Patients who experience severe sepsis may have cognitive and In May 2017 the World Health Organization recognized sepsis as a
functional defects that last for years.32 Critical illness polyneuropathy global health priority by adopting the “Improving the Prevention,
(CIP) and critical illness myopathy (CIM) are other common complica- Diagnosis, and Management of Sepsis” resolution, underscoring the
tions in patients with prolonged ICU stay. Clinical features include recognition of the substantial burden of sepsis at the individual, health
difficulty in weaning from a ventilator, generalized wasting of the limbs, system, and societal level.43,44 Nonetheless, the true burden of sepsis
and diffuse weakness.33 The diagnosis of CIP and CIM relies on clinical, remains unknown. There is substantial variability in the reported
electrophysiologic, and muscle biopsy investigations.33 The septic incidence and mortality of sepsis depending on the case definitions
inflammatory response is thought to play an important role in their and diagnosis codes used to identify patients.45,46
pathogenesis.34 CIP and CIM are associated with prolonged ICU stays
and increased mortality.33,34 Incidence
The current global estimates of 31.5 million episodes of sepsis per year
Coagulopathy and Disseminated comes from a systematic review that extrapolated data from selected high-
Intravascular Coagulation income countries (United States, Germany, Australia, Taiwan, Norway,
Sepsis is frequently complicated by coagulopathy. Abnormalities range Spain, and Sweden).47 For these countries, the aggregate population
from subclinical coagulation disorders to prolongation of clotting times incidence rate of sepsis hospitalization was 270 per 100,000 person-
(most notably prothrombin time and partial thromboplastin time), low years with a large confidence interval.47 Estimates for the incidence
platelet counts, and elevated D-dimer levels. In patients with sepsis the of sepsis in the United States range from 300 to more than 1000 cases
reported prevalence of the most severe form of coagulopathy, dissemi- per 100,000 person-years depending on method of database abstrac-
nated intravascular coagulation (DIC), is 35%.35 Commonly used tion.48 There are no population-level sepsis incidence estimates from
screening assays for DIC include (1) a reduced or downward trend in lower-income countries, which limits the prediction of global cases
the platelet count (usually <100,000/mm3); (2) the presence of fibrin- and deaths.
related markers including fibrin degradation products, D-dimers, or In high-income countries, sepsis represents approximately 6% of
soluble fibrin in plasma; (3) prolongation of PT or APTT (>1.2 times adult hospitalizations and 10% to 37% of ICU admissions.6,10,49 The
the upper limit of normal); and (4) low plasma levels of endogenous overall incidence rate of hospitalization among emergency medical
anticoagulants such as antithrombin and protein C.36 Clinically, severe services encounters is greater for sepsis than for acute myocardial
DIC can be characterized by widespread thrombosis in small and midsize infarction or stroke.50 A retrospective cohort study of 173,690 adult
vessels with simultaneous hemorrhage from various sites (Fig. 73.2). patients with sepsis admitted to hospitals across the United States in
Earlier studies have shown that the development of DIC in patients 2014 showed that 54.7% required ICU care during hospitalization, and
with sepsis can double the risk of death.35 At the present time, no specific 15.8% had septic shock.49 Median ICU length of stay was 5 days (range,
therapy for DIC exists apart from treatment of the underlying disorder.25 2–6 days).49 Median hospital length of stay was 10 days (range, 8–12
Studies on the potential benefit of the use of antithrombin (of which days).49 The cost of treating sepsis in US hospitals was estimated to be
the plasma activity is decreased in patients with sepsis and DIC), soluble $24 billion in 2013, making it the most expensive condition treated in
thrombomodulin, or heparin in patients with sepsis and DIC were US hospitals in that year.44
negative or are still ongoing.37–39 Recombinant activated protein C, which
was originally recommended in the 2004 and 2008 Surviving Sepsis Mortality
Campaign guidelines, was not shown to be effective in adult patients Sepsis is estimated to account for more than 5.3 million deaths around
with septic shock in the PROWESS-SHOCK trial and was subsequently the world each year.47 In the United States, sepsis contributes to one in
withdrawn from the market.25,40 every two to three in-hospital deaths51 and represents the most frequent
cause of death in noncoronary ICUs.46 The case-fatality rate depends
Gastrointestinal Tract and Hepatic Injury on the setting and severity of disease. US data from 2014 show that of
Gastrointestinal tract injuries include disruption of the intact intestinal all patients admitted for sepsis, 15.0% died in the hospital, and 6.2%
epithelium, which may lead to the translocation of inflammatory were discharged to a hospice.49 Data from Australia and New Zealand
mediators; the occurrence of erosions of the gastric and duodenal mucosa show hospital fatality rates for sepsis and septic shock of 14% and 22%,
that predispose to upper gastrointestinal bleeding; and the development respectively.52 The extent and number of organ failures are the strongest
of ileus, which may persist for several days after the resolution of septic denominators of mortality in sepsis.46,49 There are significant differences
shock (Fig. 73.2).41,42 The gut microbiota of patients with sepsis are in reported acute mortality rates around the globe. As an example, a
characterized by lower diversity, lower abundances of key commensal 1-day point prevalence study among 227 ICUs in Brazil identified 794
genera, and in some cases overgrowth by one bacterial genus, a state patients with sepsis, in whom mortality was observed in more than
otherwise known as dysbiosis.42 Preclinical work underscores the role 50%.53 In this setting, low availability of resources and adequacy of
of the microbiota in maintaining gut-barrier function and suggests that treatment were independently associated with mortality.53
impaired communication across the gut-organ axes is associated with
brain, lung, and kidney failure.42 Trends in Time: Incidence and Mortality
Hepatic dysfunction includes cholestatic jaundice characterized by In the past 2 decades, numerous studies have suggested that the incidence
elevations in conjugated and unconjugated bilirubin, often seen in of sepsis is increasing over time, while mortality is decreasing.52,54–57
association with elevated levels of alkaline phosphatase and amino- An observational study from the period 2000–2012 using an ICU
transferase levels. Preexisting liver disease can aggravate these values. registry of more than 100,000 patients with severe sepsis in Australia

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 995
and New Zealand provided compelling evidence for gradually declining risk is caused by a relative protection against the acquisition of an
mortality rates from 35% in 2000 to 18.4% in 2012.52 Each year absolute infection or the development of organ failure. Potential explanations
mortality decreased 1.3% throughout the study period. In the absence for this sex difference include gender dissimilarities in behavior, social
of comorbidities and older age, the case-fatality rate of severe sepsis or factors, chronic comorbidities, and the effect of sex hormones.

Chapter 73  Sepsis and Septic Shock

septic shock was less than 5% in 2012.52 This key investigation, which Sepsis occurs more frequently in blacks than in whites.61 Moreover,
used strict diagnostic criteria during the entire observation period, reported sepsis-related ICU case-fatality rates are also higher in blacks
confirmed the declining mortality rates derived from large retrospective than in whites.61 These racial differences in sepsis are explained by both
analyses.46 a higher infection rate and a higher risk of acute organ dysfunction in
In contrast, one more recent study from the United States that used blacks relative to whites.62 A study in the United States showed that
clinical data from electronic health record systems of greater than 170,000 mortality rates adjusted for patient characteristics were higher for patients
sepsis cases from 2009 to 2014 could not demonstrate any change in in all minority groups compared with white patients.63 In this cohort,
the incidence of sepsis or mortality.49 The shorter observation period racial disparities in sepsis mortality could be explained by differences
in this study together with differences in coding and registration practices in hospital characteristics for white, black, and Hispanic patients but
can partly explain the variation in the reported incidence and mortality not for Asian/Pacific Islanders.63 The fact that racial differences are not
of sepsis compared with previous studies.5,46,49,52 entirely explained by differences in socioeconomic factors or access to
The steady decrease of sepsis-related mortality over time most likely care suggest that genetic variation plays a role.
reflects the overall improvement in ICU practice in the last 20 to 30 Environmental factors and socioeconomic status also influence the
years. This is supported by the finding from the above-mentioned incidence of sepsis. For example, poor socioeconomic status enhances
Australian and New Zealand ICU registry study that the observed annual the risk for bloodstream infection.64 Data from the United States illustrate
reduction in mortality did not differ between patients with severe sepsis that communities with higher poverty rates as determined by ZIP codes
and other diagnoses.52 Key factors that contribute to the overall rise in have a higher incidence of sepsis.61 In addition, infections causing sepsis
the worldwide incidence of sepsis include the aging of the population, show seasonal variation, with pneumonia occurring more frequently
the emergence of antimicrobial resistance, the growing use of immu- in the winter and genitourinary tract infections occurring more often
nosuppressive drugs and therapies, and the increased number of patients in summer.46,65 The outcome of sepsis also shows seasonal differences,
who are at risk for developing sepsis. with higher case-fatality rates in winter despite comparable disease
severity.65
Risk Factors Chronic comorbidities are present in most patients with sepsis.66
Any infection can trigger sepsis in a susceptible host. People at the Certain diseases increase the risk for sepsis including chronic obstructive
highest risk of developing sepsis include infants and elderly adults pulmonary disease, chronic renal or liver disease, diabetes, cancer, and
as well as patients with chronic or serious illnesses such as diabetes HIV infection. Patients with cancer have a threefold to fourfold increased
and cancer and patients with an impaired immune system.46 The risk to be hospitalized for sepsis compared with the overall population.67
most important risk factors for the development of sepsis are listed This risk can even be 10 times higher in patients with certain hematologic
in Table 73.3. malignancies. The risk of death in patients with cancer compared with
Demographic risk factors for sepsis include age, male sex, and black patients without cancer who acquire sepsis is approximately 50%
race. Patients 65 years of age and older account for nearly 65% of sepsis higher.67,68 Similarly, the use of immunosuppressive therapies increases
cases.58 In addition, advancing age is a major risk factor for poor outcome, the likelihood of infection and thereby sepsis. Even so, there is evidence
which is explained in part by the presence of comorbidities and immu- that chronic comorbidities have an impact on both infection risk and
nosenescence, which refers to the gradual age-related deterioration of sepsis outcome. For example, patients with diabetes have an increased
the immune system.58,59 Most studies report a lower risk for women to risk of developing infections and sepsis.69 Most common among diabetic
develop sepsis,6,52,57,60 although it is uncertain whether this decreased patients with sepsis are urinary tract and skin/soft tissue infections
compared with nondiabetic patients.66 The influence of diabetes on
sepsis outcome is less clear, however. Some studies have shown an
association with increased mortality, others found no effect, and still
TABLE 73.3  Risk Factors for Sepsis others found improved survival.69
Demographic Factors MICROBIOLOGY
Older age (>65 years old) Virtually any microbe can trigger sepsis. Most cases today occur in
Male sex patients with previous morbidities and are caused by opportunists from
Black race the patient’s own microbiome.4 It is important to determine the exact
Nutrition
Vaccination status cause of sepsis, investigate microbial resistance both in a given patient
Genetic polymorphisms and in the population, and have insights into how these microorganisms
express their pathogenicity by means of their virulence.
Environmental Factors
Poor socioeconomic status Main Causative Agents
Seasonal variation and contacts A causative microorganism can be identified in up to two-thirds of
Disease outbreaks
Travel patients admitted to an ICU for sepsis.5,10,70 Blood cultures are positive
in approximately one-third of patients.5 An epidemiologic study of sepsis
Comorbidities showed that during the period 1979–2000, the incidence of sepsis caused
Diabetes by gram-positive microorganisms steadily increased and overtook
Chronic obstructive pulmonary disease gram-negative microorganisms as the predominant causative microorgan-
Cancer
Chronic renal disease
isms.57 However, a large survey done in 2007 that aimed to investigate
Chronic liver disease the patterns of infection in ICUs and included more than 14,000 patients
Human immunodeficiency virus from 75 countries showed that gram-negative bacteria accounted for
Use of immunosuppressive agents 62% of positive isolates in the ICU, gram-positive bacteria accounted
Hospital Factors for 47%, and fungi accounted for 19% (Table 73.4).70 An aggregate of
recent representative studies on the main groups of causative agents in
Duration of hospitalization
Antibiotic resistance
patients with sepsis is shown in Fig. 73.1C. Viral infections account for
Catheters (e.g., urine catheters, intravenous lines) 1% to 7% of cases.10,57,70 In a significant number of patients, two or more
Complications of surgery (wound infection, emergency vs. elective surgery) microorganisms are identified. The most common isolated gram-positive

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 996
bacterial pathogens are Staphylococcus aureus, Streptococcus pneumoniae, that can lead to sepsis. First, they must adhere to and traverse the
and Enterococcus spp.; the most common gram-negative pathogens are mucosal barrier, after which they must multiply and overcome antimi-
Escherichia coli, Klebsiella spp., Pseudomonas spp., and Acinetobacter crobial host defense systems.75 To do so, these pathogens have a formidable
spp.10,57,70 In patients with multiple comorbidities or sepsis acquired in armory of virulence factors.
Part II  Major Clinical Syndromes

the ICU, an increase in the incidence of antimicrobial-resistant staphy- Bacteria can coordinate their gene expression according to the density
lococci, Acinetobacter spp., Pseudomonas spp., and Candida spp. is of their local population in a process known as quorum sensing.76,77
seen.10,70 Through these signaling networks, individual bacteria communicate
Significant differences in these patterns are seen around the globe. with each other by releasing and sensing small signal molecules. Acti-
Compared with Western Europe and North America, the prevalence vation of quorum sensing can help a bacterial population to remain
of gram-negative infections in Eastern Europe, Central and South inactive and not express virulence factors to avoid detection by the
America, and Asia is significantly higher, mainly caused by higher host or—at the other side of the spectrum—increase the expression
numbers of Klebsiella spp., Pseudomonas spp., and Acinetobacter spp. of virulence factors and launch a coordinated overpowering attack on
(see Table 73.4).70 Regional differences can show an even more diverse the host.77 Quorum sensing activation can also lead to the production
picture. For example, in northeast Thailand, melioidosis is among the and maintenance of biofilms (slimy layers of bacteria that can protect
most common causes of community-acquired sepsis, as illustrated by themselves against the immune system and antibiotics), the production
the finding that its causative agent, Burkholderia pseudomallei, is the and release of proteins needed for tissue invasion, and the activation
cause of 20% of community-acquired bloodstream infections.71 A of toxins.
meta-analysis that included greater than 15,000 patients admitted to Pathogens can also injure the host by the expression of toxins that
hospitals across Africa for a bloodstream infection showed that Salmonella damage natural barriers such as the mucosa to enable further bacterial
enterica was found in 29% of isolates, making it the most prevalent spread. Toxic shock syndrome is caused by the production of so-called
nonmalaria bloodstream infection.72 Most of these isolates were non- superantigens during an invasive streptococcal infection or a localized
typhoidal Salmonella spp.72 staphylococcal infection. The bacterial production of these exotoxins
The increase of fungal infections over the last 2 decades could not cause nonspecific activation of T cells, resulting in the massive release
be prevented by the introduction of new antifungals.57,73 This is worrisome, of proinflammatory cytokines.78 S. aureus secretes 24 different superan-
as fungal sepsis is associated with a high mortality. Candida spp. are tigens, and group A streptococcal strains are capable of producing 11
the most prominent of all the fungi that can cause sepsis. Reported superantigens.78 These bacterial toxins can be injected into the cytosol
ICU mortality is more than 1.5 times higher in patients with Candida of host cells by specialized nanosyringes called type III secretion
bloodstream infections compared with bacterial bloodstream infections.74 systems.
Important risk factors for candidemia include immunosuppressed or Lastly, microorganisms that cause sepsis express multiple pathogen-
neutropenic state, prior intense antibiotic therapy, indwelling vascular associated molecular patterns (PAMPs) that are able to inflict damage
catheters, prolonged ICU stay, and colonization in multiple sites. to host tissues through the generation of an excessive and damaging
host inflammatory response.73 Examples of bacterial PAMPs are lipo-
Virulence Factors of Bacteria polysaccharide (LPS), peptidoglycan, lipopeptides (constituents of many
Causing Sepsis pathogens), lipoteichoic acid (a cell wall component of gram-positive
Invading microorganisms employ multiple mechanisms to escape bacteria), flagellin (factor in the mobility of bacteria), and bacterial
antimicrobial defenses and overwhelm the host in the cascade of events DNA. Systemic release of these PAMPs can activate innate immune cell

TABLE 73.4  Distribution in Percentages of Identified Organisms in Culture-Positive Infected Patients

Included in the EPIC II Study According to Geographic Region
WESTERN EASTERN CENTRAL/SOUTH NORTH
ORGANISM EUROPE EUROPE AMERICA AMERICA OCEANIA AFRICA ASIA
Gram-Positive
Staphylococcus aureus 20% 22% 19% 27% 28% 30% 16%
Staphylococcus epidermidis 11% 12% 9% 12% 8% 15% 9%
Streptococcus pneumoniae 5% 5% 3% 4% 3% 6% 2%
Enterococcus spp. 13% 15% 4% 10% 9% 0% 6%
Other 7% 4% 4% 11% 9% 7% 4%

Gram-Negative
Escherichia coli 17% 15% 14% 14% 13% 11% 17%
Enterobacter 7% 8% 9% 8% 3% 7% 5%
Klebsiella spp. 10% 21% 16% 9% 12% 19% 21%
Pseudomonas spp. 17% 29% 26% 13% 15% 15% 30%
Acinetobacter spp. 6% 17% 14% 4% 4% 15% 19%
Other 18% 15% 17% 11% 21% 20% 15%
Anaerobes 5% 3% 1% 8% 3% 2% 3%

Fungi
Candida 19% 19% 13% 19% 13% 11% 16%
Aspergillus 2% 1% 1% 3% 2% 0% 1%
Parasites accounted for 1% or fewer of all isolates in all regions. Percentages do not necessarily equal 100 because patients may have had more than one type of infection
or microorganism.
Data from Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302:2323–2329.

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 997
signaling, coagulation, and complement activation and eventually can of microorganisms and return to normal homeostasis. In sepsis the
contribute to the induction of septic shock. pathogen has succeeded in evading protective immunity, while continuing
to stimulate host cells, resulting in an unbalanced and harmful immune
Antimicrobial Resistance Trends in the response and a failure to return to homeostasis. Knowledge of the course

Chapter 73  Sepsis and Septic Shock

Setting of Sepsis of immune dysregulation during infection is almost exclusively derived
The widespread emergence of antibiotic resistance genes among bacteria, from animal studies, which are limited by lack of sufficient relevance
viruses, fungi, and even protozoa has led to enormous challenges in for sepsis in humans. Most investigations on the host response in patients
the treatment of sepsis. Not only will empirical antibiotic treatment be during sepsis have been done on admission to the hospital, thereby not
less efficient, the same holds true for the chosen definitive antibiotic affording information about the time course and character of the immune
treatment. Equally worrisome is the finding that antibiotic-resistant response before clinical recognition of severe disease and the diagnosis
bacteria can increase the total burden of sepsis.79 For example, a Dutch of sepsis.
study that analyzed trends in nosocomial bloodstream infections from Patients with sepsis show signs of both hyperinflammation and
1998 to 2007 found an increase in nosocomial bloodstream infections immunosuppression, two seemingly opposite reactions that involve
due to antibiotic-resistant bacteria that occurred in addition to—instead partially different cell types and organ systems (Fig. 73.3). Likely, this
of in replacement of—infections caused by antibiotic-susceptible disturbed immune response is not only the result of persistent stimulation
bacteria.79 As a result, the total disease burden increases.79 by pathogens and their virulence factors but also the release of damage-
This clinical implication of the increasing antimicrobial resistance associated molecular patterns (DAMPs), or alarmins, which are molecules
rates is best illustrated by the results from a recent surveillance study derived from host cells released into the extracellular environment on
conducted in Malawi between 1998 and 2016 in which 29,183 pathogens injury. DAMPs can trigger many of the PRRs that also sense PAMPs,
derived from 194,539 blood cultures were analyzed.80 In this 18-year giving rise to a vicious cycle with sustained immune activation and
time period, extended-spectrum β-lactamase resistance increased from dysfunction.89 Patients who fail to recover after early therapeutic measures
1% to 30% in E. coli and from 12% to 90% in Klebsiella spp. Resistance and continue to require intensive care often develop a chronic critical
to ciprofloxacin rose from 3% to 31% in E. coli and from 2% to 70% in illness that has been named “persistent inflammation, immunosuppres-
Klebsiella spp.80 By contrast, more than 92% of common gram-positive sion, and catabolism syndrome.”90 The notion that the course of sepsis
pathogens remained susceptible to either penicillin or chloramphenicol. as seen by clinicians in the hospital nowadays is more chronic than
Methicillin-resistant Staphylococcus aureus (MRSA) represented 18% acute is important for understanding the pathophysiologic mechanisms
of S. aureus isolates (an increase from 8%). A similar study from India at play. In patients with sepsis with a prolonged clinical course, the
analyzed 18,695 bacterial pathogens from 35,268 blood cultures derived disturbances in the host response involve different leukocyte subsets
from a large private laboratory network in the period 2008–2014.81 and parenchymal cells, encompassing key functions at both intercellular
Carbapenem resistance increased in both E. coli (8%–12%) and Klebsiella and intracellular levels, such as barrier function of epithelium and
pneumoniae (42%–57%). Carbapenem resistance was 70% for Acineto- endothelium and cellular metabolism and mitochondrial dysfunction.
bacter spp. and 49% for Pseudomonas aeruginosa.81 MRSA rates were respectively. In the next section, we describe the most important features
relatively stable at 44%. These results highlight the growing challenge of the septic host response.
of bloodstream infections that are effectively impossible to treat in
resource-limited settings. Hyperinflammation
Regional differences in the prevalence of antibiotic resistance are Instigation of Inflammation
significant. In the Netherlands, for example, the proportion of extended- PRRs are germline-encoded sensors that are especially expressed by
spectrum cephalosporin-resistant E. coli and K. pneumoniae isolates in innate immune cells such as macrophages, monocytes, neutrophils,
blood samples collected from 2008 to 2012 increased from 4% to 7% dendritic cells, and epithelial cells. PRRs are grouped according to their
and from 6% to 10%, respectively.82 MRSA prevalence in blood culture localization, ligand specificity, and function. Prominent PRR families
isolates remains low (<1%).82 include Toll-like receptors (TLRs), C-type lectin receptors, retinoic acid–
Increasing resistance has been associated with higher mortality rates. inducible gene-like receptors, and nucleotide-binding oligomerization
In ICU patients, MRSA infection was reported to be independently domain-like receptors. Nucleotide-binding oligomerization domain-like
associated with an almost 50% higher likelihood of hospital death receptors include inflammasomes, which are cytosolic multimolecular
compared with methicillin-resistant S. aureus infection.83 A retrospective complexes that sense intracellular microbial danger signals and metabolic
cohort study from the United States also reported increased hospital perturbations. Inflammasome activation results in activation of caspase-1
stays and increased mortality when the initial antibiotic therapy was and the release of proinflammatory cytokines interleukin-1β (IL-1β)
inappropriate in patients with gram-negative sepsis.84 However, other and IL-18 as well as cell death. Recognition of pathogens by PRRs is
studies were unable to demonstrate a link between antibiotic resistance an important defense mechanism against invading pathogens, inducing
and outcome. As an example, a study from Western Europe did not inflammatory gene transcription and initiation of innate immunity. In
find an association between inadequate treatment and mortality of S. sepsis the inflammatory response is disproportional due to concurrent
aureus bacteremia.85 Moreover, a retrospective analysis of the EPIC II recognition of multiple PAMPs and DAMPs resulting in activation of
study demonstrated that being hospitalized in an ICU in a region with multiple PRRs and subsequent triggering of downstream signaling
high levels of antimicrobial resistance (Greece, Israel, Italy, Malta, cascades. Activation of nuclear factor kappa B is key for induction of
Portugal, Spain, and Turkey) was not associated with a worse outcome the inflammatory response, resulting in the transcription of multiple
compared with countries with low resistance levels (Denmark, Finland, early activation genes including those encoding cytokines. Cytokines are
the Netherlands, Norway, and Sweden).86 small proteins (5–20 kDa) that regulate immune responses locally and
systemically. Proinflammatory cytokines implicated in sepsis pathogenesis
PATHOGENESIS include tumor necrosis factor (TNF), IL-1β, IL-12, and IL-18. These
Sepsis is the result of a dysregulated host response that at the very start cytokines are released in the circulation in animals challenged with high
of the infection was initiated to eliminate invading pathogens.87 The doses of bacteria or their products, and in these models their inhibition
innate immune system consists of a variety of cell types that are able or elimination protects against organ damage and mortality.91
to “sense” pathogens by virtue of their capacity to recognize PAMPs Examples of DAMPs involved in proinflammatory responses during
through a range of pattern-recognition receptors (PRRs).88 Cells involved sepsis include high mobility group box 1 (HMGB1) and S100A8/9
in the early response to pathogens include not only leukocytes but also (calprotectin). HMGB1 is a nuclear protein that is released passively
parenchymal cells such as epithelial and endothelial cells and especially during cell injury or secreted actively on inflammatory stimuli.92
populate parts of the body from which they constantly can sample their Depending on specific posttranslational redox modifications, HMGB1
surroundings. In most cases the first encounter between pathogens and can act as a cytokine via receptors such as Toll-like receptor 4 or as a
host innate immune cells results in a balanced reaction that entails chemotactic factor. HMGB1 levels are elevated during sepsis, and
inflammatory, antiinflammatory, and repair responses, with elimination postponed treatment (24 hours after the challenge) of mice with

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Part II  Major Clinical Syndromes
998

A B
FIG. 73.3  Host response to infection and during sepsis. (A) During a protective immune response, innate immune cells recognize invading pathogens
by sensing pathogen-associated molecular patterns (PAMPs) through a collection of cell surface and intracellular pattern recognition receptors including
Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs) (which include inflammasomes), retinoic acid–inducible gene-like
receptors (RLRs), and C-type lectin receptors (CLRs). A balanced response entails a variety of proinflammatory reactions such as release of cytokines, influx
of phagocytes, and local activation of the complement and coagulation systems, followed by a return to homeostasis by a set of compensatory mechanisms
aimed at tempering the initial inflammation and tissue repair. (B) If the pathogen succeeds in multiplying, the immune response becomes unbalanced
and harmful to the host. The host response during sepsis is characterized by concurrent hyperinflammation (top) and immunosuppression (bottom). See
text for description of hyperinflammatory and immunosuppressive responses in sepsis. DAMPs, Damage-associated molecular patterns.

antibodies to HMGB1 diminished lethality of experimental abdominal The complement system is triggered on exposure to PAMPs and DAMPs,
sepsis.92 S100A8/9 is a heterodimeric protein especially expressed in mediated by an interaction with complement components C1q, mannose-
neutrophils.91 S100A8/9 can stimulate systemic inflammation through binding lectin, and ficolins.95 Although according to traditional concepts
activation of Toll-like receptor 4. Patients with sepsis display elevated the complement system can be initiated by three distinct pathways
circulating levels of S100A8/9, and mice deficient for this protein are (classical, lectin, and alternative), it should be noted that many intracel-
protected from endotoxin shock and E. coli–induced abdominal sepsis. lular proteases (e.g., elastase, neutral proteases) and extracellular proteases
This harmful hyperinflammatory response, initiated by proinflam- (e.g., thrombin, several activated clotting factors) can also generate C3a
matory cytokines and referred to as the “cytokine storm,” has long been and C5a, exemplifying the complex nature of inflammation. On comple-
held responsible for injury and death associated with sepsis, resulting ment activation, small activation fragments known as anaphylatoxins
in a large number of clinical trials with antibodies or inhibitors of TNF are generated, particularly C3a and C5a, which exert strong proinflam-
and IL-1β or other antiinflammatory strategies.93,94 At the present time, matory effects on leukocytes, endothelial cells, and platelets.95 The main
it is appreciated that systemic challenge models in animals have limited activities of complement activation in protective immunity are opsoniza-
relevance for human sepsis, although early mortality in sepsis, generally tion of pathogens by cleavage products of C3 (C3b and iC3b) and C4
due to cardiovascular collapse and multiple organ dysfunction, likely (C4b), attraction and activation of leukocytes by C3a and C5a, direct
is mainly driven by hyperinflammation. Besides cytokines, several other elimination of pathogens through phagocytosis via complement receptors
mediator systems have received attention with regard to their potential or cell lysis mediated by the so-called membrane attack complex (C5b
involvement in sepsis pathogenesis, most notably the complement system, through C9), and regulation of adaptive immune responses by stimulation
the coagulation system, and the vascular endothelium. of B cells and T cells. Uncontrolled activation of complement can cause
collateral damage to surrounding tissues and multiple organ failure at
Activation of the Complement System the systemic level. Inhibition of C5a improved the outcome in several
The complement system comprises a group of small proteins mostly animal sepsis models including E. coli sepsis in baboons and polymi-
synthesized by the liver that typically circulate as inactive precursors. crobial abdominal sepsis in rats.96 The C3 convertase inhibitor compstatin

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 999
not only suppressed complement activation during E. coli sepsis in injury of vessels exposes tissue factor to blood coagulation factors,
baboons but also attenuated other inflammatory responses, coagulation inducing clotting. Cells in close contact with blood such as endothelial
activation, and multiple organ failure.97 cells and macrophages normally do not express large quantities of tissue
factor but can be triggered to do so by PAMPs and proinflammatory

Chapter 73  Sepsis and Septic Shock

Activation of Coagulation and cytokines. Tissue factor also can be present in microparticles derived
Vascular Endothelium from leukocytes, endothelial cells, vascular smooth muscle cells, and
Hemostasis, the termination of bleeding, is a continuous process that platelets. The interaction between coagulation and inflammation is
under physiologic conditions favors an anticoagulant state. In the early augmented by virtue of the capacity of tissue factor and clotting factors
stages of host-pathogen interaction, activation of coagulation elicits VIIa, Xa, thrombin, and fibrin to induce proinflammatory signaling.
immune defense mechanisms including the release of antimicrobial The G protein–coupled PAR family plays a major role herein. Inhibition
peptides, recruitment and activation of phagocytizing cells, and induction of the tissue factor–factor VIIa pathway in humans and nonhuman
of innate immune responses through activation of protease-activated primates strongly attenuated coagulation activation after infusion of
receptors (PARs).98 Accordingly, inhibitors of elements of the coagulation endotoxin or bacteria, whereas in a model of otherwise lethal sepsis in
system were shown to impair microbial clearance and increase mortality baboons, tissue factor inhibition in addition prevented multiple organ
during a variety of experimental infections.98 The term immunothrombosis failure and mortality.100
has recently been proposed to reflect the codependency of the coagulation In addition to the tissue factor–mediated extrinsic route, coagulation
and innate immune systems.99 can be activated via the so-called intrinsic pathway mediated by the
Sepsis is associated with a strong activation of coagulation, which, contact system.101 The contact system is initiated by factor XII, which
together with an impairment of endogenous anticoagulant mechanisms, can activate coagulation via factor XI and thrombin and stimulate
results in a net procoagulant state and a tendency toward microvascular inflammation via the kallikrein-kinin system. Inhibition of factor XII
thrombosis (Fig. 73.4).100 The most severe manifestation of coagulopathy limits thrombosis in experimental settings without causing hemorrhage.
in sepsis is DIC, which clinically can be associated with both micro- This has raised interest in factor XII as a therapeutic target, although
vascular thrombosis and hemorrhage, owing to widespread fibrin clinical evaluation in sepsis has not been reported.
depositions and consumption of clotting factors and platelets, respectively. The tendency toward thrombosis during sepsis is increased by
Tissue factor drives coagulation activation after infection via the so-called concomitantly compromised activity of three main anticoagulant
extrinsic pathway, which involves activation of factor VII and subsequent pathways: antithrombin, tissue factor pathway inhibitor (TFPI), and
formation of factor Xa, thrombin, and fibrin. Perivascular cells such as protein C system.100 The anticoagulant properties of antithrombin
fibroblasts, pericytes, and epithelial cells express tissue factor constitu- (the main inhibitor of thrombin and factor Xa) and TFPI (the main
tively, thereby safeguarding hemostasis and vessel integrity. In sepsis, inhibitor of the tissue factor–factor VIIa complex) are supported

FIG. 73.4  Activation of the coagulation and complement systems during sepsis. Sepsis results in a procoagulant state via at least three mechanisms:
tissue factor–mediated thrombin generation (black font), dysfunctional endogenous anticoagulant mechanisms (green font), and impaired fibrin removal
due to suppression of the fibrinolytic system by plasminogen activator inhibitor 1 (PAI-1) (red font). Besides in cell-associated form, tissue factor can reside
in microparticles. The anticoagulant properties of antithrombin and tissue factor pathway inhibitor (TFPI) are supported by the glycocalyx, a glycoprotein-
polysaccharide layer covering the endothelium, the continuity of which is disturbed in sepsis. Activated protein C (APC) is generated from protein C at
the surface of resting endothelial cells, a process mediated by binding of thrombin to thrombomodulin (TM) and amplified by the endothelial protein C
receptor (EPCR). Multiple interactions exist between the coagulation and complement systems, and coagulation proteases can activate the complement
system and vice versa. Vascular inflammation and coagulation are augmented by the release of neutrophil extracellular traps (NETs) by neutrophils. tPA,
Tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator.

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 1000
by the glycocalyx, a glycoprotein-polysaccharide layer covering the receptor-activating ligand. Four PARs (PAR1 through PAR4) have been
endothelium. Sepsis is associated with a disruption of the continuity of identified, which can either disrupt or protect endothelial barrier function,
the endothelial glycocalyx, which impairs the function of antithrombin depending on which intracellular signaling pathway is activated. Each
and TFPI and increases vascular permeability. Activated protein C PAR can be activated by several proteases. Thrombin is the best-
Part II  Major Clinical Syndromes

(APC) is generated from protein C at the surface of endothelial cells characterized PAR activator, capable of cleaving PAR1, PAR3, and PAR4;
by a process that is accelerated by the endothelial protein C recep- these receptors can also be activated by plasmin, trypsin, or cathepsin
tor (EPCR) and inhibits coagulation by inactivating the coagulation G. PAR1 signaling on endothelial cells is controlled by the activating
cofactors Va and VIIIa. Many investigations have supported the protease and heterodimerization with PAR2 or PAR3. Activation of
anticoagulant potency of the protein C system in vivo, showing that endothelial cell PAR1 by thrombin can contribute to endothelial dysfunc-
weakening its function converts nonlethal bacteremia into lethal tion by inducing cytoskeletal derangements, inducing endothelial cell
sepsis with DIC.102 APC also has antiinflammatory, antiapoptotic, contraction and rounding and thereby destabilizing cell-to-cell contacts
and vasculoprotective properties,102 and the anticoagulant effects of and increasing vascular permeability. Notably, thrombin linked to PAR1
APC are not essential for protection against lethality in experimental at relatively low doses can protect barrier function by transactivating
sepsis as demonstrated in studies using nonanticoagulant APC mutants PAR2 into a PAR1-PAR2 heterodimer.110 PAR1 can also be activated
with selective cytoprotective properties.103 Considering the impaired by APC, which results in antiinflammatory, antiapoptotic, and vascu-
activity of antithrombin, TFPI, and the protein C system, there is a clear loprotective signals in endothelial cells when APC remains attached to
rationale to supplement these anticoagulant pathways in sepsis. However, EPCR, and several studies have shown that the APC-EPCR-PAR1 pathway
clinical trials in patients with sepsis in whom antithrombin, recombinant plays an important cytoprotective role in sepsis and endotoxemia.102
TFPI, or recombinant APC was infused did not show a consistent APC potently inhibits thrombin-induced vascular hyperpermeability
benefit.37,40,104,105 by a mechanism dependent on transactivation of the sphingosine 1
phosphate (S1P) receptor 1 (S1P1), whereas thrombin induces vascular
Interaction Between Complement and hyperpermeability dependent on another S1P receptor, S1P3.111 Activation
Coagulation Systems of endothelial cell S1P1 preserves vascular integrity through cytoskeletal
Evidence has accumulated that coagulation proteases can activate the reorganization, adherens junction, and tight junction assembly. Another
complement system and vice versa (see Fig. 73.4).106 Components of mechanism implicated in maintaining vascular integrity is angiopoietin
the coagulation and fibrinolytic systems can activate C3 and C5. Specifi- 1–induced activation of the endothelial Tie2 receptor.107 Angiopoietin
cally, clotting factors IXa, Xa, and XIa as well as thrombin and the 2 is a functional antagonist of angiopoietin 1 that can disrupt endothelial
central fibrinolytic protease plasmin can convert C3 and C5 into C3a barrier function. Matrix metalloproteinase (MMP) 1 and MMP13 can
and C5a, respectively. Proteases of the coagulation cascade can also activate PAR1 on cells through noncanonical sites.109 MMP1 has been
activate the complement system upstream of C3 and C5; for example, detected at high levels in the circulation of patients with sepsis. Cleavage
C1 can be activated by factor XIIa, resulting in instigation of the classical of PAR1 by MMP1 results in barrier disruption, and MMP1-induced
complement pathway. Ficolin and mannose-binding lectin can interact PAR1 signaling is associated with poor outcomes in experimental models
with fibrinogen/fibrin, which can modulate the activation of C3 and of septic shock.112
C4 and complement deposition on the surface of microorganisms.
Chondroitin sulfate expressed at the surface of platelets can contribute Neutrophil Extracellular Traps
to binding of C1q and regulators of the complement system C1 inhibitor, Vascular inflammation and coagulation are amplified by so-called
C4b-binding protein, and factor H. In a reciprocal way, complement neutrophil extracellular traps (NETs) released by neutrophils.113 NETs
products can activate the coagulation system.106 C5a and the membrane are composed of histones, DNA, and neutrophil-derived proteases
attack complex can stimulate expression of tissue factor in endothelial and can contribute to protective immunity by capturing and killing
cells. Complement products can also cause structural changes in the microorganisms. However, NETs have also been implicated in responses
endothelium that can modify the clotting tendency of blood. For example, that are detrimental to the host, including collateral tissue damage and
C5a can facilitate the release of the endothelial surface proteoglycan thrombosis. NETs can facilitate coagulation and thrombus formation
heparan sulfate, which can result in a procoagulant shift due to a reduced by serving as a scaffold for platelets and proteins such as fibrinogen,
function of antithrombin. fibronectin, and von Willebrand factor and by activating the intrinsic
pathway of the coagulation system, thereby stabilizing blood clots.
Endothelial Dysfunction Accordingly, disassembling NETs reduced thrombosis in animal
In health the vascular endothelium affords a semipermeable barrier models. Bystander injury and thrombus formation caused by NETs
that regulates the movement of fluids, solutes, gases, macromolecules, are at least in part mediated by their histone components, which
and blood cells. Normal barrier function of the endothelium is preserved can exert cytotoxic effects, induce thrombin generation, and activate
by the cell cytoskeleton, the glycocalyx, intercellular adhesion molecules, platelets.
and other supportive proteins.107 Connections between cells that comprise
the vascular lining are upheld by adherens junctions such as vascular Platelets
endothelial–cadherin and tight junctions (zona occludens), predominantly Platelets are small circulating anucleate cells that are of vital importance
consisting of occludins and claudins.108 On infection, leukocytes and in hemostasis. More recently it has become clear that platelets also play
platelets adhere to the vascular endothelium and migrate to locations an important role in inflammation and immunity (Fig. 73.5).114,115 Sepsis
of proliferating microorganisms. In sepsis, exaggerated inflammation is associated with activation of platelets through a variety of mecha-
enhances these processes, which can result in barrier incompetency. In nisms.114 Thrombin, generated as a consequence of coagulation activation,
fact, sepsis is almost invariably associated with a disruption of the is an important platelet activator via PAR1, PAR3, and PAR4. In addition,
integrity of the endothelial barrier, which can expose underlying collagen von Willebrand factor can activate platelets by binding platelet glyco-
fibers and tissue factor to circulating blood, eliciting activation of platelets protein Ibα. During normal hemostasis, von Willebrand factor stabilizes
and the coagulation system. Moreover, sepsis is associated with break- the adhesion of platelets at sites of vascular injury, a process regulated
down of the glycocalyx, further damaging barrier function and in addition by ADAMTS13 (a disintegrin and metalloproteinase with thrombos-
impeding anticoagulant mechanisms.107 pondin type 1 motif 13), which cleaves large von Willebrand factor
The mechanisms underlying vascular leak have been the subject of multimers. Sepsis is accompanied by a relative deficiency of ADAMTS13,
many investigations. Activation of PARs has been implicated in alterations resulting in increased concentrations of ultra-large von Willebrand factor
in vascular barrier function.109 PARs can be activated by various serine multimers, which facilitate platelet adhesion to injured endothelium.
proteases, a process that involves the cleavage of the N-terminal part Additional platelet activation during sepsis can be induced by suben-
of the receptor, which exposes a new previously cryptic sequence. The dothelial collagen (via platelet glycoprotein VI), complement products
exposed sequence remains tethered to the receptor, acting as a (via the C1q receptor), bacteria, and DAMPs (e.g., histones).114 On

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 1001

Chapter 73  Sepsis and Septic Shock

FIG. 73.5  Role of platelets in sepsis. Activated platelets release several regulatory proteins including cytokines, chemokines, coagulation mediators,
and antimicrobial peptides. Platelets play an important role in hemostasis and maintenance of the endothelial barrier, and platelets bound to endothelium
support adhesion of neutrophils following selectin-mediated tethering and rolling, thereby guiding neutrophils to transmigrate. Platelets can amplify
inflammation by interacting with leukocytes and by facilitating the formation of neutrophil extracellular traps. Platelets play an additional role in
immunothrombosis, in which platelets and products of the coagulation pathway regulate the effector function of innate immune cells and recruit additional
cells. NET, Neutrophil extracellular trap. (Illustration by Sacha de Stoppelaar.)

activation, platelets release molecules such as thromboxane A2 and for a two-staged host response to sepsis proposed in the late 1990s,119
adenosine diphosphate, which further augment platelet activation. Platelet does not seem to exist. Rather, as discussed earlier, patients with sepsis
activation triggers platelet-platelet aggregation, platelet-leukocyte complex who continue to require intensive care experience a condition referred
formation, and the release of granular content, which includes coagulation to as persistent inflammation, immunosuppression, and catabolism
factors, chemokines, adhesive proteins, mitogenic factors, and regulators syndrome.87,90 Although the inflammatory response during early sepsis
of angiogenesis. likely is mainly driven by PAMPs and DAMPs, the etiology of persistent
Low platelet counts are independently associated with mortality in inflammation is relatively unknown. Sustained release of DAMPs probably
patients with sepsis,116 and thrombocytopenic mice demonstrated an plays a role.
impaired host defense during pneumonia-derived sepsis.117 Platelets Clinically the consequences of sustained immunosuppression
likely play a protective role in the initial stages of an infection by virtue may be the occurrence of secondary infections often caused by
of their capacity to release bactericidal products, to activate leukocytes, weakly virulent organisms such as Stenotrophomonas, Acinetobacter,
and to induce the formation of NETs. However, during sepsis, excessive Enterococcus, and Candida and by reactivation of latent viruses such as
platelet activation contributes to the development of complications such cytomegalovirus and herpes simplex virus.120 We discuss the main features
as DIC, acute lung injury, and AKI. Platelets have been implicated in of immunosuppression and their underlying mechanisms in sepsis
the pathogenesis of organ failure in sepsis by contributing to leukocyte further on.
recruitment and hyperinflammation, by driving the development of
vasoocclusive thrombi in the microvasculature, and by direct cell toxic Suppression of Innate Immune Cell Functions
effects of platelets and platelet-derived microparticles.114 Several anti- Several cell types involved in innate immunity show strong phenotypic
platelet agents improved survival in sepsis models, and prior use of the and functional changes in patients with sepsis.87,120 Although neutrophils
platelet inhibitor acetylsalicylic acid was associated with reduced mortality clearly contribute to sepsis-induced inflammation, at least in part through
of sepsis in a recent meta-analysis.118 The potential therapeutic effect the release of NETs, they also demonstrate dysfunctional features that
of platelet inhibitors in human sepsis has not been investigated in impair their antimicrobial capacities. Key findings in sepsis are delayed
randomized trials. apoptosis of neutrophils, defects in neutrophil chemotaxis and recruit-
ment to sites of infection, and an impaired capacity of neutrophils to
Antiinflammatory Mechanisms and produce essential effector molecules such as reactive oxygen species
Immunosuppression and cytokines. In addition, antigen-presenting cells such as monocytes,
A balanced immune response to an infection entails early induction of macrophages, and dendritic cells display a reduced expression of HLA-DR
antiinflammatory reactions meant to limit excessive and potential harmful and a diminished capacity to release proinflammatory cytokines on
activity of inflammation as well as resolution of inflammation and stimulation. Although this latter phenomenon has been referred to as
instigation of tissue repair. In sepsis, sustained antiinflammatory reactions “immunoparalysis” or “endotoxin tolerance,” these terms are not correct,
can result in immunosuppression involving different cell types and as these cells seem reprogrammed rather than generally suppressed.
caused by a variety of pathologic mechanisms. Patients admitted to the Indeed, certain functions remain intact or even are enhanced, such as
ICU with sepsis show signs of concurrent hyperinflammation and the release of antiinflammatory mediators (e.g., IL-10). Alterations in
immunosuppression; a clear separation in time between SIRS and so- the function of antigen-presenting cells during sepsis are at least in part
called compensatory antiinflammatory response syndrome, a concept caused by epigenetic changes. Regulation of gene transcription occurs

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 1002
through organization of gene loci on chromatin into transcriptionally may impair T-cell function at the local tissue level.128 Inhibition of
active or silent states.121 Histones “wrap” DNA in a chromatin structure, the PD-1–PD-L1 pathway improved survival in experimental sepsis,
and specific histone modifications can wind or unwind chromatin to pointing at an unfavorable causal role for T-cell exhaustion and identify-
make it inaccessible (heterochromatin) or accessible (euchromatin) for ing the PD-1–PD-L1 axis as a potential therapeutic target in sepsis.129
Part II  Major Clinical Syndromes

transcription, respectively. Histone acetylation of lysines typically Another mechanism that may contribute to reduced T-cell function is
promotes transcription, whereas methylation can support either active an increase in the fraction of regulatory T cells (Tregs) and expansion
euchromatin or silent heterochromatin formation, depending on the of myeloid-derived suppressor cells, which are immature myeloid cells
lysine that is methylated.121 Immune cell function can also be regulated that can impede immune responses, particularly T-cell functions. Tregs
at the posttranscriptional level by noncoding RNAs including micro- can also inhibit monocyte and neutrophil functions, and blocking of
RNAs that can reduce protein expression through targeted degradation Tregs improved immune function and increased microbial killing in
of specific messenger RNAs. experimental sepsis.120
The term trained immunity has been introduced to reflect the fact
that the function of innate immune cells can be influenced by previous DIAGNOSIS
encounters with pathogens or their products.122 Previous exposure to There is no gold standard for diagnosing sepsis. A clinical pattern based
microbial products can render macrophages less responsive to a second on the patient’s history and physical examination combined with labora-
stimulation (endotoxin tolerance) but can also prime them for stronger tory, radiology, and microbiology testing is typically required for the
second responses. Both phenotypes are mediated by specific alterations diagnosis. Once the diagnosis of sepsis is made, it is critical to determine
in cellular metabolism and epigenetic reprogramming. Manipulation the cause of the underlying infection and the extent of organ dysfunction.
of trained immunity may reverse some of the effects of immunosup- We present a set of tools consisting of some basic laboratory, microbiology,
pression in sepsis, as suggested by a more recent study reporting that and imaging examinations that are important to help establish the
induction of trained immunity by β-glucan can restore the epigenetic, diagnosis, detect any level of organ failure, and identify the causative
transcriptional, and functional program of monocytes during endotoxin- agent. In addition, host response biomarkers can be of diagnostic value
induced tolerance.123 Alterations in cellular metabolism have been linked (to discriminate infection from noninfectious conditions or to determine
to reprogramming of antigen-presenting cells in sepsis.124 A shift from the causative pathogen), of prognostic value (assigning risk profiles and
oxidative phosphorylation to glycolysis (the so-called Warburg effect) predicting outcome), and of potential theranostic value (aid in selection
leads to succinate accumulation, which stabilizes hypoxia-inducible and monitoring of therapy).130
factor 1α to increase IL-1β transcription. Whereas LPS induces a classic
Warburg effect, whole microorganisms can trigger an increase in both Hematologic and Biochemical Evaluation
glycolysis and oxidative phosphorylation in monocytes.125 Likewise, the All patients suspected to have sepsis should have blood drawn for a
defects of monocyte metabolism in patients with sepsis with immunosup- complete blood count, metabolic panel, renal and liver function, and
pression not only involve glycolysis but also entail a broad inhibition coagulation parameters. Inflammatory variables classically used as helpful
of metabolic processes including glycolysis, fatty acid oxidation, and criteria for the diagnosis of sepsis include leukocytosis (white blood
oxidative phosphorylation.126 Hence, although a disbalance in cellular cell count, >12,000/mm3), leukopenia (white blood cell count, <4000/
metabolism is involved in immunosuppression in sepsis, the mechanisms mm3), normal white blood cell count with >10% immature forms, an
seem more complex than a simple shift between oxidative phosphoryla- elevated plasma C-reactive protein (>2 SD above the upper limit of the
tion and glycolysis. normal range), and elevated plasma procalcitonin (>2 SD above the
Inhibition of inflammation can occur through the so-called neuro- upper limit of the normal range).5
inflammatory reflex, which involves peripheral sensory input transmitted High procalcitonin levels are associated with bacterial infection and
through the afferent vagus nerve to the brainstem, with subsequent sepsis.130 However, the usefulness of procalcitonin in diagnosing sepsis
stimulation of the efferent vagus nerve and activation of the splenic is limited; a meta-analysis reported a sensitivity of 0.77 and specificity
nerve in the celiac plexus. This results in norepinephrine release in the of 0.79 of procalcitonin to differentiate between sepsis and noninfectious
spleen and acetylcholine secretion by a subset of CD4+ T cells.127 critical illness,131 which is not good enough for the decision to start or
Acetylcholine limits proinflammatory cytokine release by macrophages. withhold antibiotics in patients admitted to the ICU with suspected
In experimental endotoxemia, vagotomy increases proinflammatory sepsis. Procalcitonin may, however, help to guide the decision on when
cytokine release and lethality, whereas stimulation of the efferent vagus to stop antibiotic treatment in critically ill patients with infections.
nerve attenuates systemic inflammation.127 Whether the neuroinflam- Procalcitonin guidance to reduce the duration of antibiotic treatment
matory reflex contributes to immunosuppression in sepsis remains to has been shown to be feasible and safe in patients with an established
be established. diagnosis of sepsis.132,133
First signs of AKI are an increase in creatinine (>0.5 mg/dL or
Suppression of Adaptive Immune 44.2 µmol/L) with or without acute oliguria (urine output <0.5 mL/
Cell Functions kg/h for at least 2 hours despite adequate fluid resuscitation).5 Marked
Sepsis is associated with a profound reduction in the number of CD4+ and hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 µmol/L)
CD8+ T cells, B cells, and dendritic cells caused by apoptosis (programmed can indicate liver dysfunction. Renal and liver tests should be monitored
cell death).120,128 Postmortem studies of patients who died of sepsis in during the course of sepsis.
addition demonstrated signs of T-cell exhaustion; T cells obtained from Thrombocytopenia (platelet count <100,000 µL−1) is seen in up to
the spleen shortly after death produced lower amounts of interferon-γ 50% of patients with sepsis.116 Low platelet counts can suggest DIC,
(IFN-γ) and TNF than splenic T cells harvested from patients who had which is also characterized by coagulation abnormalities (international
died of a noninfectious cause.128 Inhibition of lymphocyte apoptosis normalized ratio >1.5 or activated partial thromboplastin time >60
improved the outcome of sepsis in several experimental models, sug- seconds), low fibrinogen levels, and elevated markers of fibrinolysis
gesting a causal role for the loss of lymphocytes in sepsis lethality. (fibrin degradation products or D-dimer levels).36 Coagulation disorders
Checkpoint molecules may be an appealing target for therapeutic in sepsis are discussed in more detail in “Pathogenesis.”
intervention in patients with immunosuppression. Checkpoint molecules Lactate levels can be elevated (>1 mmol/L or >9 mg/dL, or twice
are normally expressed at low levels on various cell types and can be these values in septic shock) and signal poor tissue perfusion. High
upregulated in a variety of circumstances. Examples important for levels are associated with poor outcome.134 Arterial blood gas analysis
sepsis include programmed cell death 1 (PD-1) and its ligand (PD-L1), often shows a metabolic acidosis with compensatory respiratory alkalosis;
which are found mainly on surfaces of T cells and antigen-presenting acidosis and hypoxia are markers of severe disease. Other laboratory
cells, respectively. An interaction between PD-1 and PD-L1 results features often seen in sepsis include hyperglycemia (plasma glucose
in broad immunosuppressive effects. CD4+ T cells of patients with >140 mg/dL or 7.7 mmol/L) in the absence of diabetes and low albumin
sepsis displayed enhanced expression of PD-1, whereas macrophages levels due to capillary leakage, altered hepatic metabolism, or poor
and endothelial cells displayed enhanced expression of PD-L1, which nutrition.

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 1003
Pathogen Detection can aid in distinction between sepsis and noninfectious critical illness
Routine microbiologic cultures (blood, urine, sputum, wound, cere- or between causative organisms; such biomarkers could be helpful in
brospinal fluid, joint fluid) should be obtained before starting antimi- antibiotic stewardship and reduction of inadequate use of antibiotics.
crobial therapy in patients with suspected sepsis or septic shock.25 Two Prognostic biomarkers can help to predict adverse outcomes, including

Chapter 73  Sepsis and Septic Shock

sets of blood cultures (aerobic and anaerobic) should always be included. specific complications. In recent years, efforts have been made to use
In patients with an intravascular catheter (in place >48 hours), at least biomarker profiles to stratify patients with sepsis in different subgroups
one blood culture set should be obtained from the catheter (along with or endotypes based on particular pathophysiologic features; this approach
simultaneous peripheral blood cultures) to assist in the diagnosis of a likely is key for personalized medicine with implementation of individual-
potential catheter-related bloodstream infection.25 ized treatment based on the patient’s unique characteristics.87 The term
The culprit pathogen can be identified only in approximately 60% theranostics has been introduced to indicate biomarker-guided selection
to 65% of patients with sepsis.5 Often the reason for this will be the of patients for a specific therapy followed by biomarker-guided assessment
start of antibiotic treatment before cultures were obtained. In addition, of treatment response.
culture-based pathogen identification is relatively slow, and sensitivity Despite the fact that numerous host response biomarkers have been
can be low. To overcome these problems, rapid culture-independent evaluated in sepsis, none are routinely used in sepsis management,143 and
diagnostic methods including matrix-associated laser desorption ioniza- the Surviving Sepsis Campaign guidelines list procalcitonin only as poten-
tion time-of-flight (MALDI-TOF) mass spectrometry (MS), polymerase tially useful in guiding antibiotic treatment in critically ill patients.25 Other
chain reaction (PCR), and microarrays have been introduced.135 These well-studied protein sepsis biomarkers include C-reactive protein, LPS
methods can be very helpful for quicker and more accurate identification binding protein, IL-6, soluble triggering receptor expressed on myeloid
of microorganisms. MALDI-TOF MS has received much attention, cells 1, and soluble urokinase-type plasminogen activator receptor, all
permitting fast and correct identification of bacteria and fungi based with a lower sensitivity and specificity relative to procalcitonin.130 To date,
on the generation of unique mass spectral protein fingerprint signatures. the most robust biomarkers of sepsis-induced immunosuppression have
A recent investigation has suggested that use of MALDI-TOF MS may been measured by flow cytometry.144 Of these, decreased expression of
reduce the time to appropriate antibiotic therapy, the length of ICU monocyte HLA-DR is considered a good surrogate marker of monocyte
stay, and the mortality of patients with bacteremia.136 Early detection anergy. Reduced monocyte HLA-DR expression is an independent
of antimicrobial resistance is essential to reduce the risk of inappropriate predictor of mortality in patients with sepsis and has been used as
therapy. MALDI-TOF MS coupled with a PCR-based rapid diagnosis an inclusion criterion for immunostimulatory trials. Overexpression
of MRSA diminished unnecessary coverage of MRSA.137 A study in six of PD-1 on lymphocytes and overexpression of its ligand PD-L1 on
European countries in critically ill patients with bloodstream infections monocytes have also been used as markers of immunosuppression and
or pneumonia showed the enhanced sensitivity to identify a pathogen risk prediction.144
when using the combination of PCR and electrospray ionization MS In more recent years the search for sepsis biomarkers has moved
compared with standard culture techniques.138 Using PCR/electrospray from individual proteins to sets of (potential) markers using systems-
ionization MS also demonstrated the ability to rule out infection with based approaches.87,130 The “omics” field includes genomics, epigenetics,
a negative predictive value of 97% at 6 hours from sample acquisition.138 transcriptomics, proteomics, and metabolomics. Increasingly, “omics”-
Several studies have evaluated the use of rapid point-of-care testing for based methodologies are used to study host-pathogen interactions and
respiratory viruses showing its benefit in better pathogen detection and biomarkers in sepsis.87,145 Especially transcriptomics has been used for
improved use of antimicrobials.139,140 As these techniques are emerging, the discovery of biomarkers that can discriminate between sepsis and
their clinical value and cost-effectiveness have to be assessed as well as noninfectious causes of critical illness,146–148 and one such test has been
their potential to determine antimicrobial resistance for which isolation registered in the United States with this indication.146 Host gene expression
and direct testing of viable pathogens remain key. Nevertheless, these signatures may also help in identifying causative pathogens in patients
molecular assays are expected to eventually replace present-day con- with infections; for example, in adults presenting to the emergency
ventional microbiologic techniques for the detection of infections causing department with suspected community-acquired acute respiratory tract
sepsis. infections, different RNA signatures were revealed in patients with
Regarding invasive fungal infections, blood cultures are positive in a diseases of bacterial, viral, or noninfectious origin.149 Blood leukocyte
minority of cases and often late in the course of infection. Non–culture- gene expression profiles that can assist in the discrimination between
based laboratory techniques may contribute to early diagnosis. The use bacterial and viral infection have also been reported in other clinical
of galactomannan and β-D-glucan to assist in the assessment of invasive
Aspergillus (and a broad range of fungal pathogens) has become well
accepted in patients with high-risk hematologic conditions.141 Regard-
ing invasive candidiasis, the value of antigen-based tests that target
the Candida-specific cell wall component mannan or the nonspecific
fungal element β-D-glucan is still poorly defined in an ICU popula-
tion.142 The same applies for the use of Candida-specific PCR in blood
and serum.

Diagnostic Imaging
Imaging studies should be performed promptly to confirm a potential
source of infection.25 In addition to chest radiography for the evaluation
of pneumonia, standard computed tomography can be helpful to assess
infection in the sinuses, lungs, liver, and abdomen. Ultrasonography
may be useful for evaluating gallbladder and kidney dysfunction.

Host Response Biomarkers

Biomarkers are molecules, genes, or other factors that can assist in the
identification of physiologic or pathologic processes.130 The ideal bio-
marker provides specific and sensitive information about a process or FIG. 73.6  Sepsis biomarkers. Biomarkers can be used to differentiate
sepsis from noninfectious critical illness or to determine causative pathogens,
disease state and can be measured rapidly by a point-of-care test with thereby contributing to antibiotic stewardship. Furthermore, biomarkers
low production costs. To be clinically useful, a biomarker needs to assist can assist in stratifying patients based on risk profiles, predicting outcome,
the physician in therapeutic decision making. Biomarkers that have or identifying pathophysiologic pathways that can be the target for personal-
been evaluated in patients with sepsis can be arbitrarily divided into ized therapy. Theranostics entails biomarker tests that select and monitor
diagnostic and prognostic markers (Fig. 73.6). Diagnostic biomarkers specific therapies.

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 1004
settings including in the ICU.150 In addition, transcriptomic signatures TABLE 73.5  Key Recommendations of the
have been used to stratify patients with sepsis into endotypes with Surviving Sepsis Campaign: International
pathophysiologic and prognostic significance.151,152 These signatures Guidelines for Management of Sepsis and
could be the key to targeted therapy and theranostics in the future.
Part II  Major Clinical Syndromes

Septic Shock: 2016

RNA biomarkers can be incorporated in PCR-based bedside tests
with limited or no hands-on time, which—if proven valuable—make • Sepsis and septic shock are medical emergencies, and treatment and
them attractive for implementation in clinical practice. Proteomics, resuscitation should begin immediately.
• Routine microbiologic cultures are obtained before starting antimicrobial
metabolomics, and lipidomics represent other new areas of biomarker therapy in patients with suspected sepsis. These always include at least two
research.153 sets of blood cultures (aerobic and anaerobic).
• Patients with hypoperfusion should receive at least 30 mL/kg of IV
THERAPY crystalloid within 3 hours and should be reassessed frequently.
• For patients who require vasopressors, initial target mean arterial pressure
Sepsis is a medical emergency. Early clinical suspicion, rigorous diagnostic should be 65 mm Hg.
measures, aggressive initiation of appropriate antimicrobial therapy, • Norepinephrine is the first choice for patients who need vasopressors.
comprehensive supportive care, and measures aimed at reversing Vasopressin or epinephrine can be added. For patients who remain unstable,
predisposing causes are the cornerstones of successful management. dobutamine is recommended.
• IV hydrocortisone (200 mg/day) is suggested for patients who are
hemodynamically unstable despite fluids and vasopressors.
Surviving Sepsis Campaign Guidelines • Blood transfusion should be reserved for patients with hemoglobin
The Surviving Sepsis Campaign consists of a group of international concentration <7.0 g/dL except in special circumstances such as hemorrhage
critical care and infectious disease experts that aims to improve the and myocardial ischemia. Platelets should be given if the platelet count is
<10,000/mm3 or <20,000/mm3 with bleeding.
outcome of sepsis and septic shock. The third revision of the Surviving • Mechanical ventilation with a target tidal volume of 6 mL/kg predicted body
Sepsis Campaign guidelines was published in 2017.25 Of note, this last weight is recommended compared with 12 mL/kg in adult patients with
revision was conducted before publication of the Sepsis-3 definitions3 sepsis-induced ARDS. An upper limit goal for plateau pressures of 30 cm
and does not incorporate them. Adherence to the Surviving Sepsis H2O over higher plateau pressures is recommended in patients with
sepsis-induced severe ARDS. The use of higher PEEP over lower PEEP is
Campaign guidelines has been associated with reduced hospital mortality recommended in patients with sepsis-induced moderate-to-severe ARDS.
rates.154,155,156 Table 73.5 summarizes key recommendations for the initial • A protocolized approach to blood glucose management in ICU patients with
management of sepsis, which are aimed to provide rapid cardiorespiratory sepsis is recommended, initiating insulin dosing when two consecutive
resuscitation and diminish the immediate danger of the underlying blood glucose levels are >180 mg/dL. This approach should target an upper
blood glucose level ≤180 mg/dL.
infection. • Either continuous or intermittent renal replacement therapy can be used in
Cardiorespiratory resuscitation involves intravenous fluids, vasopres- patients with sepsis and acute kidney injury.
sors, and mechanical ventilation where needed. Compared with the • Sodium bicarbonate should not be used for most patients with pH ≥7.15.
2012 version of the guidelines,157 the current version deemphasizes • Pharmacologic prophylaxis against venous thromboembolism with
unfractionated heparin or LMWH should be given in the absence of
protocolization of care and invasive monitoring, instead suggesting that contraindications for these agents.
patients be reevaluated frequently. An earlier landmark study from 2001 • Stress ulcer prophylaxis should be given to patients with sepsis or septic
showed that early goal-directed therapy (EGDT), a well-defined interven- shock who have risk factors for gastrointestinal bleeding.
tion to guide hemodynamic resuscitation according to targets for central • Administration of early parenteral nutrition alone or parenteral nutrition in
combination with enteral feedings is not recommended in critically ill
venous pressure, mean arterial blood pressure, urinary output, and patients who can be fed enterally. The administration of parenteral nutrition
central venous oxygen saturation, decreased mortality of patients with is not recommended over the first 7 days in critically ill patients with sepsis
severe sepsis and septic shock.158 However, follow-up multicenter, or septic shock for whom early enteral feeding is not feasible.
randomized controlled trials from the United States (ProCESS),159 • Goals of care and prognosis should be set and discussed with patients and
families as early as feasible.
Australia (ARISE),160 and the United Kingdom (ProMISe)161 could not
demonstrate a survival benefit of EGDT compared with usual resuscita- See Table 73.6 for specific recommendations on antimicrobial therapy and source
control.
tion in patients with septic shock. Also, measurements of central venous ARDS, Acute respiratory distress syndrome; ICU, intensive care unit; IV, intravenous;
pressure and central venous oxygen saturation were not beneficial in LMWH, low-molecular-weight heparin; PEEP, positive end-expiratory pressure.
patients with lactate values greater than 4 mmol/L.159,160,161 Finally, a Data from Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign:
patient-level meta-analysis of the ProCESS, ARISE, and ProMISe trials International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit
Care Med. 2017;45:486–552.
not only confirmed that EGDT did not result in better outcomes than
usual care but also showed that this strategy was associated with higher
hospitalization costs.162
The initial management of infection involves identifying the most
likely source of infection, obtaining cultures (whenever possible before of antibiotics will negatively impact outcome in all patients with sepsis.165
start of antibiotic therapy), administration of empirical antimicrobial A recent study from the Netherlands could not demonstrate an effect
therapy, and source control (ubi pus, ibi evacua [“where there is pus, on survival in patients with sepsis if prehospital antibiotics were already
there evacuate it”]) where appropriate. The importance of source control administered in the ambulance.166 In addition, one may fear that using
cannot be overstated.163 Common occult sources are found in the lungs, a fixed time period may lead to antibiotic overuse.165 In patients who
urinary tract, or abdomen (e.g., diverticulitis, cholecystitis). Signs of are not critically ill there is often more time to generate additional
septic arthritis, endocarditis, and osteomyelitis should be looked for. diagnostic information and—in some cases—prevent the administration
Intravascular access devices that are a possible source of sepsis should of broad-spectrum antibiotics to patients who do not have infections
be promptly removed after other vascular access has been established. but present with a sepsis-like syndrome. Taken together, the benefits
The same holds true for urinary catheters. The Surviving Sepsis Campaign of treating patients with infections need to be balanced against the
recommendations on antimicrobial therapy and source control are listed harms of treating patients who at first appear as if they may have infec-
in Table 73.6.25 It should be noted that the formulation of these recom- tions but in fact do not.164 Other guidelines have proposed that a 3-hour
mendations has stirred an ongoing debate.164 target for the initiation of empirical antibiotic therapy for sepsis is
reasonable.164 One should keep in mind that the recognition of sepsis
Empirical Antibiotic Therapy can be difficult; broad-spectrum antibiotics given to patients with
The Surviving Sepsis Campaign guidelines recommend that intravenous syndromes that look like infections who do not actually have infections
antibiotics should be started as soon as possible after recognition and should be stopped as soon as possible.
within 1 hour for both sepsis and septic shock.25 If the patient is infected Inadequate empirical antibiotic therapy in patients with sepsis is
and is severely ill or has shock, there is little margin for error. However, associated with increased mortality,167 indicating that antibiotics covering
in patients with less severe disease, this recommendation has been all probable pathogens should be given as early as possible. The choice
criticized, as uncertainty exists if a 1-hour delay in the administration of empirical antibiotic treatment depends on the suspected source of

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 1005

TABLE 73.6  Surviving Sepsis Campaign Recommendations on Antimicrobial Therapy and Source Control
RECOMMENDATION GRADE

Chapter 73  Sepsis and Septic Shock

Antimicrobial Therapy
1 Intravenous antimicrobials should be initiated as soon as possible after recognition and within 1 hour for both Strong recommendation, moderate quality of
sepsis and septic shock. evidence
2 Empirical broad-spectrum therapy is recommended with one or more antimicrobials for patients presenting with Strong recommendation, moderate quality of
sepsis or septic shock to cover all likely pathogens (including bacterial and potentially fungal or viral coverage). evidence
3 Antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established or Best practice statement
adequate clinical improvement is noted.
4 Sustained systemic antimicrobial prophylaxis is not recommended in patients with severe inflammatory states of Best practice statement
noninfectious origin (e.g., severe pancreatitis, burn injury).
5 Dosing strategies of antimicrobials should be optimized based on accepted pharmacokinetic/pharmacodynamic Best practice statement
principles and specific drug properties in patients with sepsis or septic shock.
6 It is suggested to use empirical combination therapy (using at least two antibiotics of different antimicrobial Weak recommendation, low quality of
classes) aimed at the most likely bacterial pathogens for initial management of septic shock. evidence
7 It is suggested that combination therapy is not routinely used for ongoing treatment of most other serious Weak recommendation, low quality of
infections including bacteremia and sepsis without shock.a evidence
8 The use of combination therapy for routine treatment of neutropenic sepsis/bacteremia is not recommended.a Strong recommendation, moderate quality of
evidence
9 If combination therapy is used for septic shock, it is recommended to deescalate with discontinuation of Best practice statement
combination therapy within the first few days in response to clinical improvement or evidence of infection
resolution. This applies to both targeted (for culture-positive infections) and empirical (for culture-negative
infections) combination therapy.a
10 Antimicrobial treatment duration of 7–10 days is adequate for most serious infections associated with sepsis Weak recommendation, low quality of
and septic shock. evidence
11 Longer courses are appropriate in patients who have a slow clinical response, undrainable foci of infection, Weak recommendation, low quality of
bacteremia with Staphylococcus aureus, some fungal and viral infections, or immunologic deficiencies evidence
including neutropenia.
12 Shorter courses are appropriate in some patients, particularly patients with rapid clinical resolution following Weak recommendation, low quality of
effective source control of intraabdominal or urinary sepsis and patients with anatomically uncomplicated evidence
pyelonephritis.
13 Daily assessment for deescalation of antimicrobial therapy in patients with sepsis and septic shock is Best practice statement
recommended.
14 Measurement of procalcitonin levels can be used to support shortening the duration of antimicrobial therapy in Weak recommendation, low quality of
sepsis patients. evidence
15 Procalcitonin levels can be used to support discontinuation of empirical antibiotics in patients who initially Weak recommendation, low quality of
appeared to have sepsis but subsequently have limited clinical evidence of infection. evidence

Source Control
1 A specific anatomic diagnosis of infection requiring emergent source control should be identified or excluded as Best practice statement
rapidly as possible in any patient with sepsis. Required source control interventions should be implemented as
soon as medically and logistically possible.
2 Prompt removal of intravascular access devices that are a possible source of sepsis or septic shock is Best practice statement
recommended after other vascular access has been established.
a
Combination therapy is defined in these guidelines as the use of multiple antibiotics with the specific intent of covering the known or suspected pathogen or pathogens
with more than one antibiotic (e.g., piperacillin/tazobactam and an aminoglycoside or fluoroquinolone for gram-negative pathogens) to accelerate pathogen clearance
rather than to broaden antimicrobial coverage. Other proposed applications of combination therapy include inhibition of bacterial toxin production (e.g., clindamycin with
β-lactams for streptococcal toxic shock) or potential immunomodulatory effects (macrolides with a β-lactam for pneumococcal pneumonia). These statements do not
preclude the use of multidrug therapy to broaden antimicrobial activity. Consult local guidelines.
Recommendations according to Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.25 Uncertainty about the effect of
some of these recommendations on clinical outcome has resulted in widespread variation in clinical practice. See text for a summary of the criticism of some aspects of
these guidelines.164
Data from Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med.
2017;45:486–552.

infection, global geography, location where the infection was acquired Empirical antifungal therapy should be limited to patients at high
(e.g., community, nursing home, or hospital), medical history, and local risk for invasive candidiasis. A randomized trial from France showed
microbial susceptibility patterns. As a result empirical antibiotic guidelines that among nonneutropenic critically ill patients with ICU-acquired
for sepsis are different in different parts of the world. It should be sepsis, Candida spp. colonization at multiple sites, and multiple organ
emphasized that local guidelines should be referred to first. For example, failure, empirical treatment with micafungin did not increase fungal
multidrug empirical antibiotic therapy is appropriate for patients with infection–free survival at day 28 compared with placebo.168 Novel
risk factors for multidrug-resistant organisms but are often not required biomarkers or clinical risk algorithms are needed to identify patients
for patients with less severe disease who present to a hospital with low who would benefit from empirical antifungal therapies.
levels of antibiotic resistance.164 Once culture results become available,
deescalation of initial broad-spectrum antibiotic therapy is safe and Immunomodulation
may reduce the appearance of resistant microorganisms, possible drug Based on the assumption that sepsis mortality is driven by excessive
toxicity, and costs. inflammation, many trials have been performed with a variety of

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 1006
antiinflammatory agents. None of these trials showed benefit, strongly agents have been studied in patients with diseases other than sepsis,
suggesting that inhibition of specific components of the inflammatory including angiopoietin-1/Tie-2 modulators, S1P1 agonists, fibrinopeptide
response does not improve survival in all-comers with sepsis selected Bβ15–42, and a PAR1 pepducin.107
based on severity of disease.93,94 Following the more recent observations
Part II  Major Clinical Syndromes

of sustained immunosuppression in patients with sepsis, several investiga- Therapeutics That Seek to Stimulate the
tors now suggest use of immunostimulants in the treatment of sepsis, Immune System
arguing that this would restore normal immune functions and thereby Several interventions that may stimulate the immune system in sepsis have
reduce the incidence of secondary infections and late sepsis mortality.120,169 been evaluated in small clinical trials.120,169 Immunostimulating cytokines
However, a recent investigation estimated that overall sepsis mortality have been studied most extensively in this regard. IFN-γ primarily targets
in the ICU is only 10% attributable to secondary infections.170 Although antigen-presenting cells and can enhance the capacity of phagocytosis
this finding in Dutch ICUs needs to be confirmed in different settings, and killing of phagocytes. IFN-γ administration to patients with sepsis
including settings with higher incidences of antimicrobial resistance, partially reversed two hallmark features of immunosuppression—reduced
it does raise doubt about the potential benefit of immunostimulation HLA-DR expression on monocytes and the diminished capacity of blood
in unselected sepsis populations. The key to success of any type of leukocytes to produce proinflammatory cytokines on stimulation.183,184
immunomodulation, either antiinflammatory or immunostimulatory, IL-7 targets T cells and may reverse immunosuppression in sepsis by
is to identify the patients who may benefit from a particular intervention. stimulation of T-cell proliferation, inhibition of lymphocyte apoptosis,
Considering the complexity of the host response during sepsis and the and augmentation of the expression of adhesion molecules resulting in
diversity of pathophysiologic mechanisms at play, it is unlikely that the improved cell trafficking.185 Addition of IL-7 to T cells from patients
present “one-target” and “one-size-fits-all” strategy will ever be successful. with sepsis was associated with enhanced proliferation and IFN-γ
In addition, clinical researchers who support inhibiting inflammation production, mediated at least in part through alterations in cellular
and clinical researchers who propose stimulating the immune system metabolism initiated by mechanistic target of rapamycin activation,186,187
in sepsis may well both be right. Subgroups of patients with sepsis may suggesting that IL-7 may impact T-cell dysfunction in human sepsis.
benefit from combined treatments that seek to constrain certain inflam- Recombinant IL-7 had a good safety profile in patients with HIV infec-
matory responses, while stimulating others. Ideally, each therapeutic tion and patients with cancer and increased CD4+ and CD8+ T-cell
should be connected with a specific biomarker that provides insight counts188 and is currently being tested in small trials in patients with
into the expression of the target, a strategy referred to as theranostics sepsis. Granulocyte-macrophage colony-stimulating factor (GM-CSF)
as noted earlier. In the following paragraphs we discuss therapeutics enhances the production of neutrophils, monocytes, and macrophages.
that have been tested in patients with sepsis, roughly divided into GM-CSF administration to patients with sepsis restored several features
antiinflammatory and immunostimulating agents. of immunosuppression in the patients, enhancing monocyte HLA-DR
expression and the capacity of blood leukocytes to release TNF-α on
Therapeutics That Seek to Inhibit stimulation,189,190 which in children with sepsis was associated with a
Hyperinflammation diminished incidence of secondary infections.190 A larger trial assessing
The Surviving Sepsis Campaign guidelines suggest the use of hydro- the ability of GM-CSF to avert secondary infections in patients with sepsis
cortisone (200 mg/day intravenously) for patients who are hemodynami- with reduced monocyte HLA-DR expression is ongoing. Granulocyte
cally unstable despite fluids and vasopressors.25 This recommendation colony-stimulating factor, which enhances the production of granulocytes,
is graded as weak with low quality of evidence. Indeed, several systematic did not impact sepsis mortality in several trials.191 So-called checkpoint
reviews that have examined the use of low-dose hydrocortisone in septic inhibitors have been suggested as sepsis treatment as a method to restore
shock have shown contradictory results.171–,173,174 The most recent random- T-cell functions.120 In this respect antibodies against PD1 and PD-L1
ized controlled trial on this subject, a trial from Australia comprising have received the most attention. These antibodies have been widely
3800 patients with septic shock undergoing mechanical ventilation, used in patients with cancer,192 and an anti-PD-L1 antibody is now
could not demonstrate a 90-day survival benefit of a continuous infusion being studied in patients with sepsis. Thymosin alpha 1 is a thymic
of hydrocortisone at a dose of 200 mg/day given for 7 days compared peptide that increased HLA-DR expression on blood monocytes and
with placebo.175 In addition, low-dose hydrocortisone in patients with tended to reduce mortality in patients with sepsis.193
septic shock can cause hyperglycemia and hypernatremia as side effects.175
Other antiinflammatory agents tested in clinical sepsis trials over Mesenchymal Stem Cells
the past decades include corticosteroids, TNF antibodies, soluble TNF Administration of allogeneic mesenchymal stem (or stromal) cells (MSCs)
receptors, IL-1 receptor antagonist, nitric oxide inhibitors, and platelet- represents a potential immunomodulatory therapy in sepsis that cannot
activating factor inhibitors; none of these improved mortality.93,94 be readily classified as antiinflammatory or immunostimulatory. MSCs
Moreover, clinical trials that determined the efficacy of antithrombin, improved survival in animal models of sepsis by mechanisms that
APC, and TFPI (anticoagulants that also exert antiinflammatory effects) comprise antimicrobial, antiapoptotic, immunomodulatory, and barrier-
showed no consistent benefit in patients with sepsis.37,40,104,105 Several preserving properties.194 Administration of MSCs to humans appears
techniques have been developed seeking to remove bacterial and host to be safe, and their effect is currently being studied in patients with
inflammatory products from the circulation of patients. Strategies to sepsis or ARDS or both.
remove LPS from blood include polymyxin B hemoperfusion, of which
the effect on the outcome of patients with sepsis was not consistent.176–178 PROGNOSIS
CytoSorb is an extracorporeal cytokine adsorber that was evaluated in Patients who survive sepsis often have long-term complications after
a small randomized trial in 100 patients with sepsis.179 Hemadsorption admission, a higher readmission rate for sepsis, and an increased
did not lower plasma IL-6 concentrations, and 60-day-mortality was mortality. The magnitude of this problem increases as the number of
higher in the treatment group, although the difference was not significant patients who survive sepsis treatment increases. Impaired quality of
after adjustment for baseline imbalances.179 AB103 is a peptide that life in the physical and mental domains can persist for months to years
impedes the interaction between bacterial superantigens and the T-cell after a sepsis episode.195 Sepsis survivors have an increased risk for
receptor CD28.180 Besides reducing mortality in mouse models of physical disability, cognitive impairment, renal failure, and cardiovascular
superantigen-induced shock, AB103 also improved outcome of experi- events. In the year after sepsis, cardiovascular events were reported to
mental polymicrobial sepsis,180,181 suggesting that this peptide may have occur in 30% of patients, which was higher compared with matched
activity beyond T cells. AB103 is currently being evaluated in patients control populations.195 As a result, health care use will increase nearly
with necrotizing soft tissue infections.182 Other antiinflammatory threefold compared with levels before sepsis.
therapeutics studied in clinical sepsis trials are a humanized anti-C5a One study from the United States comprising almost 3500 patients
monoclonal antibody (CaCP29; phase II) and soluble recombinant with severe sepsis found that 43% of survivors were rehospitalized within
human thrombomodulin (ART-123; phase III). An attractive therapeutic 90 days.196 The most common readmission diagnoses included heart
strategy in sepsis is to restore endothelium barrier function. Several failure, pneumonia, chronic obstructive pulmonary disease exacerbation,

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 1007
and urinary tract infections. Readmissions for a primary diagnosis of from Taiwan that included more than 15,000 ICU patients who survived
infection (sepsis, pneumonia, urinary tract infection, and skin/soft tissue sepsis and received rehabilitation within 3 months after discharge showed
infection) occurred in 12% of severe sepsis survivors compared with that referral to rehabilitation within 90 days of hospital discharge was
8% of patients with matched acute medical conditions.196 Of the patients associated with lower risk of 10-year mortality compared with propensity-

Chapter 73  Sepsis and Septic Shock

readmitted with sepsis within 90 days, about two-thirds have an infection matched control subjects.199
at the same site as their initial admission.197
Sepsis increases the risk of death for up to 5 years after the initial FUTURE PERSPECTIVES
sepsis episode even after accounting for comorbidities.195 Not surprisingly, Despite the recent decline in case-fatality rates, sepsis will remain a
survival after sepsis is strongly modified by age; for instance, reported major health burden worldwide due to its increasing incidence and the
1-year survival was 94% for patients <45 years old and 54% for patients emergence of antibiotic resistance. Better recognition of the sepsis
≥85 years old in a retrospective study from California.198 syndrome, faster administration of antibiotics and cardiopulmonary
Taken together, these poor long-term outcomes in terms of physical resuscitation, and a general increase in the standard of ICU care most
and cognitive impairment add to the total burden of sepsis-related likely all have contributed to the better early survival of patients with
death and disability.195 Recently, more emphasis has been placed on sepsis.
recovery from sepsis. Suggestions made to enhance sepsis recovery Nonetheless, many questions remain. Main research topics include
include early referral for treatment of new physical, mental, and cognitive faster detection of causative microorganisms, development of novel
problems and thorough evaluation of treatable conditions that commonly treatment strategies that save lung and kidney function, and development
result in hospitalization such as infection, heart failure, renal failure, of more individualized treatment approaches. The development of new
and aspiration. Rehabilitation with physical and occupational therapy biomarkers will be essential for any personalized medicine approach
may benefit a subset of patients after sepsis.195 An observational study in sepsis. Fig. 73.7 gives an overview of current and future advances in

FIG. 73.7  Current and future advances in sepsis therapy development. Therapeutic targets for sepsis have traditionally been identified by studies
in animals challenged with high-dose endotoxin (or other bacterial components) or viable bacteria or subjected to infection of the lungs, abdomen, or
other body sites. Although such animal sepsis models may be useful in finding potential therapeutic targets, they do not adequately resemble the lengthy
course of sepsis in patients and usually do not include common variables in human sepsis such as old age, comorbidities, and supportive therapies.
Possible therapeutic targets derived from animal models should be verified in patients by detailed measurements over time, which is also important to
develop host response biomarkers that afford insight into the expression of the targeted pathway. Such biomarkers could be implemented in inclusion
of patients and treatment monitoring, an approach that has been termed theranostics. Thus far clinical sepsis trials used 28-day all-cause mortality as
their primary end point. However, many patients with sepsis are still hospitalized at day 28. Adaptive trial designs and end points that take into account
late physical and cognitive sequelae could alter the focus for drug development, moving away from efforts to modify the early host response and instead
aiming to support faster and more complete recovery.

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 1008
sepsis therapy development. Prevention of sepsis is an emerging research with a blood sample. The results—combined with the clinical signs and
area. A better understanding of the long-term health sequelae of sepsis symptoms and laboratory, imaging, and other phenotype data—could
will be instrumental to develop therapies that truly enhance sepsis be analyzed with smart computer tools that use continuing learn-
recovery. ing algorithms to design individualized treatment options, which
Part II  Major Clinical Syndromes

In the future, for any patient presenting with a sepsis-like illness, will help the attending physician, patients, and family members to
rapid bedside genetic sequencing of known causative pathogens and initiate and monitor the optimal treatment to improve the outcome
simultaneous analysis of the host immune response could be performed of sepsis.200

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