127
Sepsis Syndrome
Nathan I. Shapiro and Alan E. Jones
KEY CONCEPTS
• S epsis is a progressive disease due to a dysregulated inflammatory cas-
cade, leading to organ dysfunction and circulatory compromise in severe
cases.
• Older adults, immunocompromised and neutropenic patients, and patients
with multiple comorbidities are at increased risk for the development of
sepsis syndromes.
• A thorough history, physical examination, and laboratory testing should
guide the diagnostic evaluation.
• Early treatment should focus on appropriate identification, improvement
of tissue perfusion (through the administration of fluids and vasopressor
medications), improvement of tissue oxygenation (through administration
of oxygen and positive-­pressure ventilation), administration of antibiotics,
and early identification of infections requiring surgical management.
• Prompt administration of antibiotics is essential and should be based on the
suspected source of infection.
FOUNDATIONS
Background
Sepsis syndrome represents the body’s host response to an infection.
The causative agent and host’s activated inflammatory cascade over-
whelm the body’s defenses and regulatory systems, leading to dis-
ruption in homeostasis. Tachycardia, tachypnea, fever, and immune
system activation are common manifestations. If the body is unable to
overcome this insult, cellular injury, tissue damage, shock, multiorgan
failure, or death may ensue.
In 1992, the American College of Chest Physicians and Society
of Critical Care Medicine issued a consensus statement to establish
uniform criteria defining the sepsis syndromes. The goal was to cre-
ate a common nomenclature for disease classification and system-
atic comparisons across studies of septic patients. The term systemic
inflammatory response syndrome (SIRS) is defined as two or more of
the following: tachycardia, tachypnea, hyperthermia or hypother-
mia, high or low white blood cell count, or bandemia. Sepsis is the
combination of infection plus SIRS, severe sepsis is sepsis plus organ
dysfunction, and septic shock is sepsis plus hypotension, defined as a
systolic blood pressure below 90 mm Hg, not responsive to a fluid chal-
lenge (Box 127.1). This nomenclature is intended to provide clinicians
and researchers with a common classification. Efforts to validate this
classification scheme in the emergency department (ED) population
have demonstrated that the term sepsis, when characterized by fulfill-
ing the SIRS criteria alone, is overly sensitive and nonspecific and does
not convey an increased mortality risk. SIRS is not specific because it
can be present in noninfectious inflammatory states and in localized
infections that are not inclined to lead to sepsis, such as streptococcal
1740
pharyngitis or viral illnesses. However, organ dysfunction and shock
have been shown to portend worse outcomes.
The Third International Consensus Definitions Task Force (SEP-3)
is a group who revisited the sepsis definitions and published a set of
revised definitions.1 The quick SOFA (qSOFA) score emerged as a risk
stratification tool for the Emergency Department (ED).2 The qSOFA
score uses three clinical criteria with each receiving one point if pres-
ent: respiratory rate of 22 breaths or less per minute, altered mental
status, and hypotension defined by a systolic blood pressure (SBP) 100
mm Hg or less. A qSOFA score of two or greater was associated with an
increased risk of mortality. The definitions group proposed using a sus-
pected infection plus a qSOFA of 2 or greater to help identify patients
with potential sepsis in the non-­ICU setting. Subsequent validation
studies have called the accuracy into question; ultimately it appears
that it is a reasonable tool that is less sensitive and more specific than
the original sepsis criteria. However, consensus is lacking as to whether
it should be used to define sepsis.3
Bacteremia may be present, but positive cultures are not obligatory
in the diagnosis of sepsis. Culture-­negative and culture-­positive sep-
tic populations have similar outcomes in patients with similar illness
severity. Pneumonia, abdominal abscess with viscus perforation, and
pyelonephritis are common primary causes of sepsis. Gram-­positive
organisms account for 25% to 50% of infections, gram-­negative organ-
isms for 30% to 60%, and fungi for 2% to 10%. The distribution varies
with the study and, more importantly, with host factors such as the
status of the host immune system, age of the patient, recent hospital-
izations, and presence of indwelling vascular catheters.
The health status of the host is an important risk factor in the devel-
opment and progression of sepsis. Older adults and those with multi-
ple comorbidities may be more susceptible to developing a systemic
infection. Chemotherapy-­induced neutropenia, acquired immunode-
ficiency syndrome, and steroid dependency increase susceptibility to
sepsis. Increased use of indwelling devices such as intravascular cath-
eters, prosthetic devices, and endotracheal tubes also contribute to the
risk of systemic infection and sepsis.
Pathophysiology
Sepsis results from the complex interaction of detection molecules,
signaling molecules, and numerous inflammatory and coagulation
mediators in response to infection. Although our understanding of the
pathophysiologic process of sepsis has evolved, it remains incomplete.
The initial host response is to mobilize inflammatory cells, particularly
neutrophils and macrophages, to the site of infection. These inflam-
matory cells then release circulating molecules, including cytokines,
which trigger a cascade of other inflammatory mediators that result
in a coordinated host response. Synthesis of the components of the
cascade is increased at many steps along the pathway. If these media-
tors are not appropriately regulated, sepsis will occur. In the setting of

BOX 127.1  Definitions of Sepsis
• Bacteremia (fungemia)—presence of viable bacteria (fungi) in the blood, as
evidenced by positive blood cultures
• Systemic inflammatory response syndrome (SIRS)—at least two of the
following conditions: oral temperature > 38°C (100.4°F) or < 35°C (95°F);
respiratory rate > 20 breaths/min or partial pressure of arterial carbon
dioxide (Paco2) < 32 mm Hg; heart rate > 90 beats/min; leukocyte count >
12,000/dL or < 4000/dL; or >10% bands
• Sepsis—systemic inflammatory response syndrome (SIRS) that has a
proven or suspected microbial source
• Septic shock—sepsis with hypotension that is unresponsive to fluid resus-
citation plus organ dysfunction or perfusion abnormalities, as listed for
severe sepsis
• Multiple organ dysfunction syndrome (MODS)—dysfunction of more than
one organ, requiring intervention homeostasis
Adapted from: Bone R, Balk RA, Cerra FB, et al. Definitions for sepsis
and organ failure and guidelines for the use of innovative therapies in
sepsis. The APP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine. Chest.
1992;101:1644-1655.
ongoing toxin release, a persistent inflammatory response occurs, with
ongoing mediator activation, cellular hypoxia, tissue injury, shock,
multiorgan failure, and potentially death.
Mediators of Sepsis
Host response and pathogen characteristics are both important in
the pathogenesis of sepsis. More than 100 discrete markers have
been identified and attributed to the sepsis cascade, but the true
culprits have not been clearly identified.1 A pathogen is sensed by
pattern recognition receptors, most notably Toll-­ like receptors,
located on the surface of the white blood cell. The resulting host-­
pathogen interaction activates the inflammatory and coagulation
cascades. The subsequent inflammatory signaling occurs through
cytokines, chemokines, and other soluble mediators, including
increased circulating levels of the interleukins IL-1, IL-6, and IL-8
and tumor necrosis factor alpha (TNF-­α). Activation of the clotting
cascade may result in increased D-­dimer levels and decreased cir-
culating levels of protein C.
In benign conditions, a self-­limited response helps clear the patho-
gen. If the innate immune response is inadequate, mediators create
a procoagulant state. Coagulation and fibrinolytic components are
proinflammatory, precipitating a worsening cycle of procoagulant and
proinflammatory mediators. Propagation of this cascade ultimately
contributes to end-­organ damage and often to disseminated intravas-
cular coagulation (DIC). If it is not effectively reversed, the process
leads to cellular hypoxia, organ dysfunction, shock, and death.
The primary mediators are cytokines that are primarily proinflam-
matory, antiinflammatory, or growth-­promoting. The molecular mech-
anisms whereby they are regulated are not well understood. An initial
cytokine, TNF-­α, is found in serum approximately 90 minutes after the
administration of endotoxin to healthy volunteers. IL-6 and IL-8 reach
peak levels at approximately 120 minutes. The main proinflammatory
cytokines include IL-1, TNF-­α, and IL-8. The primary antiinflamma-
tory cytokines are IL-10, IL-6, transforming growth factor-­β, soluble
receptors to TNF, and IL-1 receptor antagonist (IL-1RA). If the resul-
tant inflammatory response is adequate, the infection is controlled and
cleared. If the response is deficient or excessive, however, a persistent
and worsening cascade is produced, ultimately leading to (once again)
shock, organ failure, and potentially death.
CHAPTER 127  Sepsis Syndrome 1741
Instability in vascular tone has become increasingly important in
understanding the pathophysiologic mechanism of sepsis. Vasopres-
sin, also known as antidiuretic hormone, is a naturally occurring hor-
mone that is essential for cardiovascular stability. It is produced as a
prohormone in the hypothalamus. The hormone is stored in the pitu-
itary gland and released in response to stressors such as pain, hypoxia,
hypovolemia, and hyperosmolality. In severe sepsis, there is a brief rise
in circulating vasopressin levels followed by a prolonged and severe
suppression. This pattern of secretion is different from other forms of
shock, in which vasopressin levels remain elevated. Vasopressin has
numerous physiologic effects, including vasoconstriction of the sys-
temic vasculature, osmoregulation, and maintenance of normovolemia.
Nitric oxide (NO) is a gas that has an important role in septic shock,
regulating vascular tone by an indirect effect on smooth muscle cells.
NO also contributes to platelet adhesion, insulin secretion, neurotrans-
mission, tissue injury, and inflammation and cytotoxicity. Its half-­life
is short (6–10 seconds), and it easily diffuses into cells. Although its
mechanisms of action are not well understood, it seems to be a key
mediator of sepsis. Animal data have shown that nitric oxide syn-
thase, the enzyme that produces NO, is upregulated in cases of sepsis.
Enhanced NO production is thought to contribute to the profound
vasodilation found in patients in septic shock.
In the setting of ongoing inflammatory activation, the mediators
of sepsis continue to be produced, and the cascade is perpetuated.
Unless it is appropriately and rapidly controlled, the ultimate effect is
a sequence of events starting with cellular dysfunction and ultimately
leading to tissue damage, organ dysfunction, and death.
Organ System Dysfunction
The organ dysfunction that results from sepsis is central to the patho-
genesis of the disease. The mortality of patients with sepsis increases as
the number of failing organs increases (Fig. 127.1A). In one large study,
the mortality rate was 1% for sepsis patients with no organ dysfunc-
tion, whereas the rates for patients with dysfunction of a single organ,
two organs, three organs, and four or more organs were 6%, 13%, 26%,
and 53%, respectively (see Fig. 127.1B).
Neurologic Impairment. Patients with sepsis may display neurologic
impairment manifested by altered mental status and lethargy,
commonly referred to as septic encephalopathy. The incidence has been
reported as between 10% and 70%. The mortality rate in patients with
septic encephalopathy is higher than that in septic patients without
significant neurologic involvement. Although the pathophysiologic
process has not been clearly defined, contributing factors may include
direct bacterial invasion, endotoxemia, altered cerebral perfusion or
metabolism, metabolic derangements, multiorgan system failure, and
iatrogenic injury. In addition, impaired renal or hepatic function in
the absence of overt organ failure has been shown to correlate with
encephalopathy.
Cardiovascular Dysfunction. Cardiovascular dysfunction is
common with sepsis. The cardiovascular dysfunction and failure arise
from direct myocardial depression and distributive shock. Gram-­
negative, gram-­positive, and killed organisms can cause myocardial
depression. The direct insults of the toxic mediators as well as the
mobilization of host mediators of sepsis produce a distributive shock.
Early in sepsis, a hyperdynamic state develops, characterized by
increased cardiac output and decreased systemic vascular resistance.
Although the cardiac output is increased, it is at the expense of
ventricular dilation and decreased ejection fraction (EF). Vigorous
fluid resuscitation usually increases preload and, secondarily, EF,
thereby improving the cardiac index. Much of the cardiovascular
compromise from septic shock is reversible, and normal cardiovascular
function usually returns within 10 days.
1742 PART III  Emergency Medicine by System

pathogenesis of sepsis; some of the mediators of sepsis are produced

30% 27.8%
by the liver.
25% Endocrine Disorders. An absolute or relative adrenal insufficiency
is common in sepsis. Depending on the balance of circulating
28-day mortality

20% cytokines, augmentation or suppression of the hypothalamic-­pituitary

15% axis is possible. IL-1 and IL-6 both activate the hypothalamic-­pituitary-­
adrenal axis. TNF-­α and cortistatin depress pituitary function. Other
9.2%
10% factors that may contribute to adrenal insufficiency in sepsis include
decreased blood flow to the adrenal cortex, decreased pituitary
5% 2.1% 1.3% function, and decreased pituitary secretion of adrenocorticotropic
0% hormone due to severe stress. As a result of these interactions, the
No SIRS/ Severe Septic hypothalamic thermoregulatory mechanism may be reset, and
SIRS sepsis sepsis shock temperature fluctuations may develop.
A Sepsis syndrome Hematologic Abnormalities. Sepsis causes abnormalities in many
parts of the coagulation system. Endotoxin, TNF-­α, and IL-1 are the
60% key mediators. Pathologic activation of the extrinsic (tissue factor–
53% dependent) pathway, protein C, protein S, and fibrinolysis lead to
50% consumption of essential coagulation factors, causing DIC. The
activation of the coagulation cascade produces fibrin deposition and
28-day mortality

40% microvascular thrombi. If these depositions are not corrected, they

30% 26%
20%
13%
10% 6%
1%
0%
0 1 2 3
B Number of organ failures
Fig. 127.1  Mortality rates by sepsis syndrome (A) and number of organ
dysfunctions (B). SIRS, Systemic inflammatory response syndrome.
Pulmonary Involvement. Involvement of the lung is often seen in
the inflammatory response to infection. These effects are apparent,
irrespective of the primary infection that caused sepsis. Early
infiltration with neutrophils, surfactant dysfunction, and edema gives
way to monocyte infiltration and fibrosis. Significant right-­ to-­
left
shunting, arterial hypoxemia, and intractable hypoxemia occur. The
resulting morbidity is high and is a common endpoint to sepsis-­related
deaths.
Sepsis produces a highly catabolic state and places significant
demands on the respiratory system to maintain the acid-­base status.
At the same time, airway resistance may be increased, and muscle
function is impaired. Irrespective of whether pneumonia is the cause
of sepsis, a common pulmonary endpoint is acute respiratory distress
syndrome (ARDS). ARDS is defined clinically and correlates with the
pathologic finding of diffuse alveolar damage (see Chapter 2). Because
of alveolar-­capillary membrane damage, fluid accumulates in the alve-
oli. Rather than being a diffuse disease, ARDS is a heterogeneous pro-
cess that results in interspersed damaged and normal alveoli.
Gastrointestinal Effects. Splanchnic blood flow is dependent on
mean arterial pressure because there is relatively little autoregulation.
Therefore, hemodynamic dysfunction may have a profound effect
on viscus metabolism. A shock state causes significant deleterious
effects on a hollow viscus and its oxygen supply. A prolonged ileus
may accompany hypoperfusion and persist beyond the perfusion
deficit.
Solid organ involvement is also common. Even in the previously
normal host, elevations in aminotransferases and bilirubin levels are
common early in sepsis. The liver has also been implicated in the
can compromise organ perfusion and contribute to organ failure.
Tissue factor expression on monocytes is increased. This results in
fibrin deposition and perhaps contributes to an increased incidence of
multiorgan failure due to microvascular thrombi.
Protein C has been identified as an important modulator of inflam-
mation and coagulation in patients with sepsis. Impairment of the
protein C–dependent anticoagulation pathway is critical to the devel-
opment of the thrombotic complications of sepsis. In healthy people,
4 or more protein C is activated by a combination of thrombin and thrombomod-
ulin. The activation of protein C results in the downregulation of many
portions of the coagulation cascade, including release of tissue factor,
inactivation of factors VIIIa and Va, and stimulation of fibrinolysis. It
is possible that protein C activation in early sepsis is impaired because
of an inflammatory cytokine–mediated downregulation of thrombo-
modulin. As a result, a consumptive coagulopathy ensues. This leads
to increased fibrin deposition and a resulting upregulation of the fibri-
nolytic pathway, as identified by low plasma levels of the fibrinolytic
proteins and increased fibrin split products. This sequence of events
leads to consumption of coagulation factors and DIC. In late sepsis, the
fibrinolytic system is suppressed.
Genetic Factors
There has been increasing evidence that genetics are a risk factor for
the outcome of sepsis. An individual may contain a set of individual
characteristics or polymorphisms that may affect the ways in which
he or she responds to sepsis in general, or perhaps there may be dif-
ferences in response to specific sepsis therapeutics. Identifying and
understanding these differences in an individual’s genetic makeup
is likely to lead to tailored approaches to diagnosis and therapy. The
impact of genetics on future treatment modalities for sepsis remains
unclear, but the prospect of customized genetic therapy for sepsis is a
promising early development.
CLINICAL FEATURES
Symptoms and Signs
The approach to a patient with sepsis relies on identification of the pres-
ence of a systemic infection and localization of the source of the initial
infection. This allows appropriate treatment directed to the source of
infection. Often, the source is not readily apparent, but early identi-
fication of the septic state allows implementation of broad-­spectrum
antibiotics.
 CHAPTER 127  Sepsis Syndrome 1743

The septic patient may manifest signs of systemic infection through The musculoskeletal history includes the presence of any localizing
tachycardia, tachypnea, hyperthermia or hypothermia and, if severe, symptoms to a particular joint. Redness, swelling, and warmth over a
hypotension. Very early in the patient’s presentation, vital sign changes joint, especially if there is a decreased range of motion in that joint, may
such as tachycardia and tachypnea may be first indicators of sepsis. If be signs of septic arthritis and may mandate arthrocentesis. The skin
the patient is in shock, a rapid assessment that excludes other causes, should be examined for evidence of cellulitis, abscess, wound infection,
such as hypovolemic or cardiogenic shock, is essential to the proper or traumatic injury. Deep injuries, foreign bodies, and fasciitis may be
initial treatment. A septic patient will often have flushed skin with difficult to identify clinically. The emergency clinician should look for
warm, well-­perfused extremities secondary to the early vasodilation crepitus, bullae, or skin edema extending beyond areas of erythema
and hyperdynamic state. Alternatively, the severely hypoperfused that may indicate the presence of an aggressive, gas-­forming organism
patient with advanced shock may appear cyanotic. A complete detailed (see Chapter 126). Back pain and fever may be signs of an epidural
clinical examination will help the emergency clinician determine the abscess. Local lymphadenopathy, swelling, and streaking should also
cause of the shock state (see Chapter 3). These are classic signs; how- be noted as signs of an advancing infection. Petechiae and purpura
ever, these findings may not be manifested in a septic patient, and signs may represent a Neisseria meningitidis infection or DIC. Generalized
and symptoms may be subtle or absent. erythroderma and rash may represent an exotoxin from pathogens
Both underlying comorbidities and the cause of sepsis should be con- such as Staphylococcus aureus and Streptococcus pyogenes.
sidered. Risk factors such as immunocompromised states (e.g., acquired A history of fevers or chills in the setting of injection drug use, arti-
immunodeficiency syndrome, malignant disease, diabetes, splenectomy, ficial heart valve, or mitral valve prolapse should increase the suspicion
concurrent chemotherapy), older age, debilitation, high-­risk environ- for endocarditis. The emergency clinician should suspect endocarditis
ments for iatrogenic infections (e.g., acute care hospitalizations, long-­ in the presence of a murmur or other stigmata of endocarditis (e.g.,
term care facilities), and multiple comorbidities should be considered. splinter hemorrhages, Roth’s spots, Janeway’s lesions) (see Chapter 69).
The respiratory system is the most common source of infection in Emergency clinicians must identify the severity of illness in patients
the septic patient (see Chapter 62). A history of a productive cough, with infection and initiate early resuscitation for those with the poten-
fevers, chills, upper respiratory symptoms, sore throat, or ear pain tial of becoming critically ill. Although a patient may meet SIRS crite-
should be sought. Physical examination should also include a detailed ria, this alone has little predictive value in determining the severity of
evaluation for focal infection, such as exudative tonsillitis, sinus ten- illness and mortality. There are many scoring systems that have been
derness, tympanic membrane injection, and crackles or dullness on developed to risk-­stratify illness severity. Most scoring systems are
lung auscultation. Also, pharyngeal thrush should be noted as a poten- not clinically relevant and not routinely used. The Mortality in Emer-
tial marker of an immunocompromised state. gency Department Sepsis (MEDS) score is one proposed method to
The gastrointestinal system is the second or third (depending on risk stratify ED patients with sepsis. The MEDS prediction rule assigns
the study) most common source of sepsis. A history of abdominal point values to specific clinical characteristics (Table 127.1). The total
pain, including its description, location, timing, and modifying factors, score can be used to assess risk of death. Thus, the greater the number
should be sought. Further history, including the presence of nausea, of risk factors, the more likely a patient is to die during hospitaliza-
vomiting, and diarrhea and time of the last bowel movement should tion. Although typically not calculated for all patients, the elements of
be noted. A careful physical examination, looking for signs of perito- the score may be identified and considered as a red flag when risk-­
neal irritation, abdominal tenderness, and hyperactive or hypoactive stratifying a patient.
bowel sounds, is critical in identifying the source of abdominal sepsis.
Particular attention should be paid to physical findings suggestive of
common sources of infection or disease—Murphy sign indicating cho-
lecystitis, pain at McBurney point indicating appendicitis, left lower TABLE 127.1  Mortality in Emergency
quadrant pain suggesting diverticulitis, or rectal examination revealing Department Sepsis (MEDS) Prediction Rule
a rectal abscess or prostatitis. Odds Ratio Meds Score
The neurologic system should be evaluated for signs of meningitis, Risk Factor for Death (Points)
encephalitis, or epidural abscess, including nuchal rigidity, fevers, and
change in consciousness (see Chapter 95). Lethargy or altered menta- Terminal illness (death within 30 days) 6.1 6
tion may indicate primary neurologic disease or may be the result of Tachypnea or hypoxia 2.7 3
decreased brain perfusion. Septic shock 2.7 3
The genitourinary (GU) history includes queries about the presence Platelet count < 150,000/mm3 2.5 3
of flank pain, dysuria, polyuria, discharge, Foley catheter placement, Bands > 5% 2.3 3
and genitourinary instrumentation. However, one must also remember Age > 65 yr 2.2 3
that GU infection is a common source of infection in older patients
Pneumonia 1.9 2
and is a common offender in patients with nonspecific symptoms.
Obstructed nephrolithiasis with associated urinary tract infection is a Nursing home resident 1.9 2
potentially lethal source of infection that can advance rapidly without Altered mental status 1.6 2
decompression by nephrostomy.
Total Meds Score (% of
Rarely, sexually transmitted infections may be the cause of sepsis.
Risk of Death Sepsis Deaths)
The genital examination could reveal ulcers, discharge, penile or vul-
var lesions, or the woody induration of Fournier gangrene. Cervical Very low 0–4 (1.1%)
motion tenderness indicates pelvic inflammatory disease, and adnexal Low 5–7 (4.4%)
tenderness in a toxic-­appearing woman may represent a tubo-­ovarian Moderate 8–12 (9.3%)
abscess. Tampons are rarely a cause of toxic shock syndrome, but when High 13–15 (16.1%)
no other source of septic shock is found, a retained tampon should be
Very high >15 (39%)
considered.
1744 PART III  Emergency Medicine by System

DIAGNOSTIC CONSIDERATIONS Laboratory Testing

Hematology. The white blood cell count can be an indicator of
Differential Diagnoses inflammation and activation of the inflammatory cascade. Leukocytosis
The sepsis syndromes represent a spectrum of disease and clinical pre- is associated with infection and is incorporated in the consensus
sentations. Often, noninfectious sources can cause a syndrome that definition of sepsis; however, it is often insensitive and nonspecific,
mimics that of sepsis; thus, one must keep in mind a broad differen- limiting its value in the ED. The febrile neutropenic patient has been
tial diagnosis when approaching these patients (Box 127.2). A detailed shown to be at increased risk for severe infection. Thus, a neutrophil
history and physical examination are the first steps in narrowing the count of less than 500 cells/mm3 should prompt consideration for
differential diagnosis to identify the true source. admission, isolation, and empirical intravenous (IV) antibiotics in
most chemotherapy patients. A bandemia (≥5%–10% bands on a
Diagnostic Testing peripheral smear) represents the release of immature cells from the
Diagnostic studies are used to identify the type and location of the bone marrow and may be a sign of infection and inflammation. Like
infecting organisms and define the extent and severity of the infec- the white blood cell count, it is an imperfect indicator of infection. The
tion to assist in focusing therapy. As a result, the diagnostic approach absence of leukocytosis or bandemia does not preclude the possibility
should be tailored to the particular patient. of severe sepsis nor does their presence confirm it. The hemoglobin
level should be determined to ensure adequate oxygen delivery in
shock. Platelets are an acute-­phase reactant and may be elevated in
the presence of infection. Conversely, a low platelet count may be seen
in patients with sepsis and septic shock. Thrombocytopenia, elevated
BOX 127.2  Differential Diagnosis of Sepsis prothrombin time, elevated activated partial thromboplastin time,
and Septic Shock decreased fibrinogen, and increased fibrin split products are associated
with DIC and severe sepsis syndrome.
Sepsis
Blood Chemistry. Electrolyte abnormalities should be identified and
Dehydration
corrected. A low bicarbonate level suggests acidosis and inadequate
Acute respiratory distress syndrome
perfusion. An elevated anion gap acidosis in the setting of sepsis
Anemia
syndrome commonly represents lactic acidosis or diabetic ketoacidosis,
Ischemia
but other causes need to be ruled out. An elevated serum creatinine
Hypoxia
concentration or decreased glomerular filtration rate signals renal
Congestive heart failure
dysfunction or failure, which, if due primarily to sepsis, indicates organ
Vasculitis
failure and a worse prognosis. Calcium, magnesium, and phosphorus
Toxicologic
levels should be checked.
Poisonings
An elevated lactate level is associated with inadequate perfusion,
Overdose
shock, and poorer prognosis. In one study, the mortality rate correlated
Drug-­induced
with the venous lactate level—a lactate level of 0 to 2.5 mg/dL was asso-
Neuroleptic malignant syndrome
ciated with a 5% mortality rate, a lactate level of 2.5 to 4.0 mg/dL, 9%
Pancreatitis
mortality, and a lactate level greater than 4 mg/dL, 28% mortality. A
Hypothalamic injury
blood gas assessment is helpful in identifying and classifying acid-­base
Disseminated intravascular coagulation
disturbances, with metabolic acidosis suggesting inadequate tissue
Anaphylaxis
perfusion. Liver function tests can be used to identify liver failure or
Metabolic
dysfunction. An elevated bilirubin level may suggest the gallbladder as
Hyperthyroidism
a cause of sepsis. An elevated lipase level may represent pancreatitis as
Diabetic ketoacidosis
the cause of SIRS. Procalcitonin and C-­reactive protein are biomarkers
Adrenal dysfunction
sometimes used in the diagnosis and prognosis of sepsis. The litera-
Environmental
ture primarily supports procalcitonin in serial measurements and for
Burn
antibiotic stewardship, but the role for procalcitonin in the ED has not
Heat exhaustion or stroke
been clearly delineated.
Trauma
Urinalysis. Urinalysis is another essential laboratory test, especially
Blood loss
in older patients with higher risk of urinary tract infection who may
Cardiac contusion
not manifest localizing symptoms of infection. Urinalysis is likewise
important to rule out infection in patients with renal colic or ureteral
Septic Shock
obstruction.
Hypovolemic shock
Microbiology. Proper blood, urine, sputum, cerebrospinal fluid,
Acute blood loss
and other tissue culture samples are important in guiding therapy.
Severe dehydration
Although the results of culture are not helpful in the initial management,
Cardiogenic shock
culture samples ideally should be obtained before the administration of
Pulmonary embolus
antibiotics in the patient with sepsis. The initiation of antibiotic therapy
Myocardial infarction
should not be delayed significantly while waiting for culture samples
Pericardial tamponade
to be obtained. Studies have suggested that the yield of initial blood
Tension pneumothorax
cultures is low (5%–10%), but this is probably an artifact of the lack of
Vasogenic shock
reliable discriminatory guidelines for obtaining blood culture samples
Anaphylaxis
in the ED. Among patients with clinical sepsis, only 30% to 40% of
Paralysis
patients will have positive cultures. The results of initial microbiologic

tests, including Gram staining whenever possible, will help guide
subsequent antibiotic treatment. Initial empirical therapy should be
broad spectrum to allow early treatment of all likely organisms.
Special Procedures
Historically, a central venous pressure (CVP) line was thought helpful
in guiding fluid resuscitation in sepsis patients. We do not recommend
the routine use of CVP to determine fluid responsiveness. When avail-
able, arterial lines can be useful for close monitoring of hypotensive
patients, especially when one or more vasopressors are being titrated
to maintain an adequate blood pressure. However, they are not rou-
tinely placed in the ED. The technology of noninvasive or minimally
invasive cardiac output monitoring is evolving and, where available,
may help guide fluid administration by evaluating cardiac output alone
or in conjunction with a fluid challenge or passive leg raise approach.
Cardiac ultrasound, while unproven, is also commonly used to assess
volume status and cardiac function.
Radiology
Imaging studies are generally used to identify the source of infection.
A chest radiograph should be considered in patients with suspected
sepsis syndrome, looking not only for a focal infiltrate representing
pneumonia but also for the bilateral infiltrates indicative of ARDS. An
upright chest radiograph should be considered for suspected bowel
perforation to detect free air under the diaphragm. The presence of
pneumomediastinum is suggestive of esophageal perforation and cur-
rent or impending mediastinitis.
Soft tissue plain radiographs of infected areas can be obtained,
looking for air in the soft tissues associated with necrotizing or gas-­
forming infection, although plain x-­rays are not sensitive for tissue
infection. Periosteal thickening or bone erosion may be seen on plain
radiographs of patients with osteomyelitis; a bone scan may be diag-
nostic. Computed tomography (CT) of superficial infections may be
more helpful to quantify the extent of infection further and identify
abscesses that are not readily evident on physical examination. A CT
scan of the abdomen and pelvis may identify abdominal or pelvic
pathologic lesions, provided there is no clear clinical indication for
immediate operative intervention. Suspected disease, such as divertic-
ulitis, appendicitis, necrotizing pancreatitis, microperforation of the
stomach or bowel, or formation of an intra-­abdominal abscess, may
be best diagnosed by a CT scan. A head CT scan can identify septic
emboli from endocarditis or increased intracranial pressure from a
mass and should be considered before a lumbar puncture is performed.
An abdominal ultrasound examination may be indicated for suspected
cholecystitis, and a pelvic ultrasound examination may be indicated
for tubo-­ovarian abscess or endometritis. If endocarditis is suspected,
a transesophageal cardiac ultrasound study may be performed for the
detection of any valvular vegetations. Magnetic resonance imaging
(MRI) can be useful to identify soft tissue infection, such as necrotizing
fasciitis or epidural abscess.
MANAGEMENT
Early detection and appropriate treatment can reduce the mortality
from sepsis. The primary goal is timely administration of appropriate
antimicrobial therapy—or interventional source control as required—
and maintenance of adequate tissue oxygenation and perfusion through
titrated resuscitation. With early detection and early resuscitation there
is increasing evidence that the natural history of sepsis can be altered.
Initial resuscitation, including appropriate airway management, IV
access, oxygen, early and appropriate antibiotics, fluid resuscitation,
CHAPTER 127  Sepsis Syndrome 1745
and vasopressor support, remains the foundation on which new efforts
may be applied.
From a historical perspective, Rivers and associates2a provided
compelling evidence supporting the importance of this concept when
they published a protocol of standardized timely and titrated care being
used to guide resuscitation in the ED. This randomized, double-­blind,
placebo-­controlled study showed a 16% mortality reduction in patients
with severe sepsis and septic shock. The protocol, termed early goal-­
directed therapy (EGDT), measures targeted goals and uses a resus-
citation algorithm to guide the resuscitation. The theory behind the
protocol was to normalize preload and blood pressure and prevent
tissue hypoxia by matching oxygen delivery with consumption. Use of
this protocol, which facilitated earlier and more aggressive fluid resus-
citation through the use of increased fluids, increased blood products,
increased use of dobutamine, and greater degree of normalization of
tissue hypoxia, reduced mortality at their center. The interventions
in combination were likely responsible for the better outcomes in the
intervention group.
The principles of EGDT, as well as efforts such as the Surviving Sep-
sis Campaign, helped underscore the importance of early identification
and timely resuscitation.3 However, until 2014, the evidence in support
of the formal EGDT protocol was only in the form of the original sin-
gle-­center trial and subsequent observational efforts. Subsequently, the
ProCESS, ProMISE, and ARISE studies were large multicenter trials
that sought to validate the value of EGDT.4,5 Each of the trials showed
no mortality benefit to EGDT as compared to usual resuscitation mea-
sures; thus, although EGDT is one strategy to consider, it is not a supe-
rior approach. It is important to underscore, however, that the usual
care groups in these newer trials were all identified early, received anti-
biotics, and received generous amounts of fluids (on average, approx-
imately 40–60 mL/kg in the first 6 hours across the trials), supporting
the principle that early identification of sepsis, early antibiotics, and
carefully titrated resuscitation should remain a core tenant.
Respiratory Support
Altered mental status is common in patients in septic shock, and
patients may require rapid airway protection. Because patients with
impending respiratory failure use a disproportionately large amount
of energy for the muscles of respiration, improved oxygen delivery to
other organs may be achieved by mechanical ventilation, sedation, and
paralysis. Although there are no clear intubation guidelines, hypercap-
nia, persistent hypoxemia, airway compromise, and profound acidosis
are valid indicators for intubation.
In addition to airway protection, intubation and mechanical venti-
latory support provide positive-­pressure ventilation. Pulmonary com-
pliance is often low in ARDS, resulting in increased airway pressures
to maintain oxygen delivery. The ARDSNet trial established the benefit
of low tidal volumes (6 mL/kg) and plateau pressures of 30 cm H2O or
below in mechanically ventilated patients to prevent iatrogenic lung
damage (see Chapter 2). Maintenance of a relatively low plateau pres-
sure with higher positive end-­expiratory pressure is an effective way to
increase arterial oxygen delivery.
Cardiovascular Support
Fluid Resuscitation
Patients with sepsis are often administered IV fluid to maintain ade-
quate perfusion. The primary reasons for this intravascular hypovo-
lemia are venodilation and diffuse capillary leak. Initial therapy for
adults with septic shock should generally be up to 30 mL/kg of isotonic
crystalloid. Additional fluid replacement should be titrated to clinical
parameters such as heart rate, blood pressure, change in mental status,
1746 PART III  Emergency Medicine by System
capillary refill, cool skin, and adequate urine output (0.5–1 mL/kg/hr).
Colloids are as effective as crystalloids, but they are more expensive
and less readily available. Balanced salt solutions (e.g., lactated Ringers)
have been shown to have beneficial effects over normal saline, due pri-
marily to adverse renal effects associated with normal saline. Evidence
suggests that balanced solutions are likely as good or better than nor-
mal saline; thus, we recommend the use of balanced solutions for sepsis
resuscitation.
Although one should be increasingly vigilant in watching for fluid
overload in patients who are predisposed, such as older adults, those
with congestive heart failure (CHF), or those with renal impairment,
these patients are not precluded from volume resuscitation as described
previously. Efforts to identify ways to measure regional perfusion more
directly, such as direct measurement of splanchnic blood flow, have
been proposed, but are not commonly used in clinical practice. Even
in the absence of global hypoxia and impaired tissue perfusion, there is
evidence that regional hypoperfusion and ischemia exist.
Vasoactive Drug Therapy
Use of mean arterial pressure alone as an indicator of overall efficacy of
therapeutic intervention is not always sufficient. A mean arterial pres-
sure of 65 mm Hg has been recommended in otherwise healthy, nor-
movolemic adult patients but must be correlated with other indicators
of adequate perfusion, such as mental status and urine output. Patients
with previously uncontrolled hypertension may require a mean arterial
pressure of 75 mm Hg or even higher. If appropriate fluid resuscitation
has failed to maintain end-­organ perfusion, vasopressor support may
be required (Table 127.2).
The 2016 Surviving Sepsis Campaign guidelines provided consen-
sus recommendations for treatment of septic shock.6 Norepinephrine
should be used as the initial vasopressor, with the addition of epineph-
rine or vasopressin to norepinephrine as adjuncts. Vasopressin has
not been shown to improve outcomes when added to norepinephrine
in refractory septic shock, but there is no evidence of harm. As such,
the optimum role for vasopressin is unclear. Once the mean arterial
pressure is adequately supported, dobutamine should be used as the
primary inotropic agent if myocardial dysfunction is evident. Patients
requiring vasopressors and inotropes require frequent reassessment
and medication titration, as needs can change greatly during the first
few hours of resuscitation.
Norepinephrine. Norepinephrine is predominantly α-­agonist with
some β1-­agonism with minimal β2 activity and primarily functions
to increase systemic vascular resistance and cardiac output. In a large
study examining patients with varied causes of shock, norepinephrine
was associated with fewer adverse events (particularly arrhythmias)
compared with dopamine. Dopamine was also associated with a
higher mortality rate in patients with cardiogenic shock. In another
meta-­analysis, norepinephrine was shown to be superior to dopamine
in both in-­hospital and 28-­day mortality. Compared with dopamine
in septic patients, norepinephrine increases glomerular filtration and
TABLE 127.2  Dosing of Vasoactive Therapy
Drug Dosage
Dobutamine 2–15 μg/kg/min
Epinephrine 5–20 μg/min
Norepinephrine 3–30 μg/min
Phenylephrine 2–300 μg/min
Vasopressin 0.01–0.04 units/min
urine output equally well. We recommend norepinephrine as the first-­
line vasopressor for septic shock, either as a sole vasopressor or in
conjunction with other agents. Norepinephrine can be started at 3 to 5
μg/min and titrated to achieve the goal mean arterial pressure.
Dopamine. Dopamine is the immediate precursor of norepinephrine
and epinephrine. It is primarily an α-­, β1-­, and dopaminergic agonist.
Dopamine was previously thought to improve renal outcomes, but it has
not been shown to reduce mortality or decrease dialysis dependence,
and should not be used for these indications. Persistent tachycardia,
decreased partial pressure of arterial oxygen, and increased pulmonary
artery occlusion pressure are common side effects of dopamine use. We
do not recommend the routine use of dopamine if other vasopressors
are available.
Vasopressin. Vasopressin is a naturally occurring peptide that
is synthesized as a large prohormone in the hypothalamus. In states
of septic shock, there is an early surge of vasopressin followed by a
profound drop in circulating vasopressin levels. In a well-­designed
randomized trial, investigators demonstrated no change in mortality
for patients with severe sepsis when vasopressin was added to
catecholamine vasopressors. Vasopressin should not be used as the sole
initial therapy for refractory septic shock. However, vasopressin does
not increase pulmonary vascular resistance, making it a useful adjunct
in patients with pulmonary hypertension, obstructive shock secondary
to PE, or right ventricular dysfunction.
Epinephrine. Epinephrine is a potent mixed α-­ and β-­agonist.
Epinephrine infusion is also associated with increased oxygen
consumption, increased systemic lactate concentrations, and
decreased splanchnic blood flow. The rise in the lactate level is short
term, and there is no evidence regarding its long-­term effects. As a
result of all the possible adverse effects of epinephrine, it is currently
recommended only for those patients who are unresponsive to
other vasopressors. Epinephrine can be a good adjunct for patients
with combined septic and cardiogenic shock, given its vasopressor
and inotropic activity.
Phenylephrine. Phenylephrine is a selective α1-­agonist, increasing
systemic vascular resistance without significant changes in cardiac
output. It can produce reflexive bradycardia or suppression in cardiac
output. A single small study has shown that phenylephrine is effective
in restoring perfusion in patients with septic shock refractory to
dopamine or dobutamine. Another small study has demonstrated that
phenylephrine is less effective than norepinephrine in the treatment
of hypotension in septic patients; however, there was no difference in
other measured hemodynamic parameters, including oxygen delivery.
Phenylephrine does not impair cardiac and renal function and may be
a good choice when significant tachyarrhythmia limits the use of other
agents.
Dobutamine. Dobutamine is a mixed α-­ and β-­agonist. In dosage
ranges from 2 to 28 μg/kg/min, the cardiac index is increased at the
expense of heart rate. In addition, decreased splanchnic blood flow
is common. Dobutamine should be used in patients with depressed
cardiac index and persistent hypoperfusion in spite of adequate volume
expansion and the use of other vasopressor agents. Dobutamine
decreases systemic vascular resistance, and therefore should not be
used as the sole agent in a hypotensive patient. One study has suggested
that survival in sepsis is associated with the patient’s increase in stroke
volume in response to dobutamine.
Bicarbonate
Bicarbonate supplementation was previously the standard treatment
for patients with presumed lactic acidosis. Current consensus is that
it should be reserved for severe acidemia (pH < 7.0–7.2) because there
 CHAPTER 127  Sepsis Syndrome 1747

TABLE 127.3  Suggested Initial Antibiotic Managementa

Infection Modifying Factors Antibiotic
Sepsis, unknown source Immunocompetent Antipseudomonal cephalosporin plus aminoglycoside or fluoroquinolone,
or antipseudomonal penicillin plus aminoglycoside or fluoroquinolone,
or carbapenem plus aminoglycoside or fluoroquinolone
Anaerobic infection Add metronidazole or clindamycin to above regimen.
Methicillin-­resistant Staphylococcus aureus (MRSA) Add vancomycin to above regimen.
Neutropenia Antipseudomonal penicillin plus aminoglycoside or fluoroquinolone, or
carbapenem plus aminoglycoside or fluoroquinolone
Splenectomy Cefotaxime or ceftriaxone

Pneumonia Immunocompetent Second-­or third-­generation cephalosporin plus second-­generation

Abdominal infection
Cellulitis
Intravenous catheter infection
(remove catheter)
Cerebrospinal infection
Injection drug abuse
aPending microbiologic identification of organism and sensitivity.
macrolide or fluoroquinolone
Legionella suspected Azithromycin, fluoroquinolone, or high-­dose erythromycin
Immunocompetent Ampicillin plus aminoglycoside plus metronidazole
Multidrug-­resistant organism suspected Carbapenem, or piperacillin-­tazobactam plus aminoglycoside
Urinary tract source Fluoroquinolone, or third-­generation cephalosporin, or ampicillin plus
aminoglycoside
Nonnecrotizing fasciitis Cefazolin or nafcillin
MRSA possible Vancomycin
Necrotizing fasciitis (surgical drainage) Ampicillin-­sulbactam, piperacillin plus aminoglycoside plus clindamycin,
or carbapenem
Outpatient-­acquired Third-­generation cephalosporin
MRSA suspected Add vancomycin.
Fungal infection Amphotericin B
Immunocompetent Ceftriaxone plus vancomycin
Older adult or immunocompromised patient Add ampicillin.
MRSA not suspected Cefazolin or nafcillin plus aminoglycoside
MRSA suspected Vancomycin plus aminoglycoside

may be a paradoxical decrease in intracellular pH as a result of diffu-
sion of soluble carbon dioxide across the cell membrane. Alternatively,
hyperventilation has been suggested to help increase systemic pH.
Antibiotics
Early antibiotic therapy should target the nidus of infection if known.
If the patient’s condition permits, appropriate culture specimens
should be obtained before the administration of broad-­ spectrum
antibiotics (Table 127.3). Surgically correctable conditions, such as
intra-­
abdominal abscesses, perforated viscus, retained products of
conception, or retained foreign body (e.g., a tampon), should be
treated concurrently. Antibiotics should be administered as soon as
possible in patients with serious infections. Although some observa-
tional studies and national benchmarks have called for the administra-
tion of antibiotics within a predefined time period of 3 hours from ED
presentation, a comprehensive meta-­analysis failed to support an asso-
ciation between antibiotics administered after 3 hours and mortality.7
Thus, early antibiotics are important, but their exact timing remains
undefined.
In the absence of an obvious source of infection, the use of broad-­
spectrum antibiotics is recommended. The specific agent depends on
many variables, including institutional preference and local resistance
patterns. As results from cultures become available, therapy should be
modified. There is no consensus about the need for double or triple
antibiotic coverage for particular organisms, although it is common
practice to double-­cover virulent organisms, such as Pseudomonas
aeruginosa, as well as areas commonly infected with multiple organ-
isms, such as the peritoneum. With increasing rates of methicillin-­
resistant organisms, combinations that include nonpenicillin choices
may be warranted.
Steroid Therapy
It has been nearly 40 years since the first treatment attempts to block
inflammation in sepsis. Because sepsis involves a systemic inflamma-
tory response, corticosteroids are a logical treatment modality as anti-
inflammatory agents. Physicians have been working for decades to
prove or disprove their value. Steroids appear to be more effective in
reducing the amount of time patients spend in a hypotensive state, and
moderate-­quality evidence suggests a mortality benefit, especially in the
most critically ill patients.8-10 However, the optimum timing, dose, drug,
and method of administration (continuous or bolus dosing) remains
unknown. At this time, we believe that the role of steroid therapy in sep-
sis remains controversial and recommend their use when there is refrac-
tory cardiovascular insufficiency, despite fluid and vasopressor therapy.
DISPOSITION
Once ED management is complete, patients who are deemed at
increased risk should be admitted to the hospital into a setting that
is deemed appropriate for the severity of the patient’s condition. For
1748 PART III  Emergency Medicine by System
example, in patients who remain hypotensive, are on vasopressors, or
who are unstable and require more frequent monitoring, the intensive
care unit may be appropriate. Other patients who are more stable but
still require monitoring and perhaps IV therapy may be admitted to a
hospital ward. Finally, in certain cases, patients initially meeting sepsis
criteria but who are not severely ill (e.g., young patients with pharyngi-
tis) may be appropriate for discharge.
The references for this chapter can be found online at ExpertConsult.
com.
  
REFERENCES
1. van Engelen, Tjitske SR, et al. Biomarkers in sepsis. Crit Care Clin.
2018;34(1):139–152. https://doi.org/10.1016/j.ccc.2017.08.010.
PubMed.
2. Singer M, et al. The Third International consensus definitions for sepsis
and septic shock (sepsis-3). J Am Med Assoc. 2016;315(8):801–810.
https://doi.org/10.1001/jama.2016.0287. PubMed.
2a. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy
in the treatment of severe sepsis and septic shock. N Engl J Med.
2001;345(19):1368–77.
3. Mouncey PR, Osborn TM, Power GS, et al. Trial of early, goal-directed
resuscitation for septic shock. N Engl J Med. 2015;372:1301–1311.
4. Seymour CW, et al. Assessment of Clinical Criteria for Sepsis: for the
Third International consensus definitions for sepsis and septic shock
(sepsis-3). J Am Med Assoc. 2016;315(8):762–774. https://doi.org/10.1001/
jama.2016.0288. PubMed.
5. Henning DJ, et al. An emergency department validation of the SEP-3
sepsis and septic shock definitions and comparison with 1992 consensus
   C H A P T E R 1 2 7 : Q U E S T I O N S A N D A N S W E R S
1. Which of the following patients meets the criteria for systemic
inflammatory response syndrome (SIRS)?
a. 6-­year-­old boy with pneumonia, temperature 39.0°C (102.2°F)
b. 53-­year-­old man with respirations 30 breaths/min, white blood
cell (WBC) count 16,000 cells/mm3
c. 74-­year-­old woman with chest pain, heart rate 130 beats/min
d. 81-­year-­old man with WBC count, 2700 cells/mm3, heart rate,
73 beats/min
Answer: B. SIRS is defined as two or more of the following—tachy-
cardia, tachypnea, temperature higher than 38°C (100.4°F) or lower
than 35°C (95°F), high or low WBC count, or bandemia. Sepsis is SIRS
with infection. Severe sepsis includes organ dysfunction. Septic shock
involves systolic blood pressure below 90 mm Hg.
2. Sepsis is characterized by which of the following?
a. Depression of tumor necrosis factor levels
b. Increased endogenous anticoagulant levels
c. Prolonged suppression of nitric oxide levels
d. Increased inflammatory cytokine levels
Answer: D. Clinical sepsis is induced by sustained levels of proinflam-
matory and procoagulant mediators. Cytokines (interleukin-1, inter-
leukin-6, and tumor necrosis factor-­α) and prostaglandins are primary
mediators. Nitric oxide synthase is upregulated, resulting in sustained
elevations of the serum nitric oxide level, with subsequent vasodila-
tions. Sustained suppression of vasopressin adds to this sometimes
refractory vasodilated state.
3. Which of the following statements regarding septic shock is true?
a. Cardiac output is always decreased.
b. Much of the cardiac decompensation is reversible.
c. Systemic vascular resistance is high.
d. The ejection fraction is always increased.
Answer: B. Sepsis affects myocardial function and peripheral vascular
tone. The systemic vascular resistance is usually markedly depressed.
Cardiac output is generally increased because of a compensatory
tachycardia that can at least partially overcome the ventricular dilation
and depressed ejection fraction. The myocardial effects are typically
reversible.
definitions. Annal Emer Med. 2017;70(4):544–552.e5. https://doi.
org/10.1016/j.annemergmed.2017.01.008. PubMed.
6. Rhodes A, et al. Surviving sepsis campaign: international guidelines
for management of sepsis and septic shock: 2016. Inten Care Med.
2017;43(3):304–377. https://doi.org/10.1007/s00134-017-4683-6. PubMed.
7. Sterling SA, Miller WR, Pryor J, et al. The impact of timing of antibiotics
on outcomes in severe sepsis and septic shock: a systematic review and
meta-analysis. Crit Care Med. 2015;43:1907–1915.
8. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for
treating sepsis in children and adults. Cochrane Database Syst Rev.
2019;12(12):CD002243. https://doi.org/10.1002/14651858. Published 2019
Dec 6. CD002243.pub4.
9. Fang F, Zhang Y, Tang J, et al. Association of corticosteroid treatment
with outcomes in adult patients with sepsis: a systematic review and meta-
analysis. JAMA Intern Med. 2019;179(2):213–223. https://doi.org/10.1001/
jamainternmed.2018.5849.
10. Lamontagne F, Rochwerg B, Lytvyn L, et al. Corticosteroid therapy for
sepsis: a clinical practice guideline. BMJ. 2018;362:k3284. https://doi.
org/10.1136/bmj.k3284. Published 2018 Aug 10.
4. What are the two most common sources of infection in cases of
sepsis?
a. Genitourinary > respiratory
b. Musculoskeletal > genitourinary
c. Respiratory > gastrointestinal
d. Respiratory > genitourinary
Answer: C. Epidemiology studies show that pneumonia is the most
common cause of sepsis, followed by an intra-­abdominal source. How-
ever, a careful investigation to identify the source of infection should
occur.
5. In most chemotherapy patients, which neutrophil count should
prompt admission, isolation, and empirical antibiotics?
a. <250 cells/mm3
b. <500 cells/mm3
c. <750 cells/mm3
d. <1000 cells/mm3
Answer: B. Patients with an ANC <500 cells/mm3 are at increased risk
of infection; thus, a conservative approach should be taken in these
patients.
6. Among patients with clinical septic shock, which percentage will
have positive blood cultures?
a. 0%–30%
b. 30%–60%
c. 60%–90%
d. 90%–100%
Answer: B. Although blood cultures are perhaps a gold standard for
identification and isolation of bacteria, they may be negative even
when the etiology of illness is clearly infectious. Empirical antibiotic
treatment in the ED remains a standard approach.
1748.e1