C H A P T E R 130 
Sepsis Syndromes
PRINCIPLES
Background
Sepsis syndrome represents the body’s host response to an infec-
tion. The causative agent and host’s activated inflammatory
cascade overwhelm the body’s defenses and regulatory systems,
leading to disruption 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
create a common nomenclature for disease classification and
systematic 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 hypothermia, 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 challenge (Box 130.1). 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 fulfilling 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 strepto-
coccal pharyngitis or viral illnesses. However, organ dysfunction
and shock have been shown to portend worse outcomes. Newer
efforts have proposed the PIRO approach, which may help us
better understand and prognosticate the severity of illness. PIRO
stands for assessment of predisposing conditions, infection source,
response of the host, and organ dysfunction and has been pro-
posed to help improve classification.1
Bacteremia may be present, but positive cultures are not
obligatory in the diagnosis of sepsis. Culture-negative and culture-
positive septic populations have similar outcomes in patients with
similar severity of illness. 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 organisms 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 hospitalizations, and
presence of indwelling vascular catheters.
The health status of the host is a potentially important risk
factor in the development and progression of sepsis. Older adults
and those with multiple comorbidities may be more susceptible
to developing a systemic infection. Chemotherapy-induced neu-
tropenia, acquired immunodeficiency syndrome, and steroid
dependency increase susceptibility to sepsis. Increased use of
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Nathan I. Shapiro | Alan E. Jones
indwelling devices such as intravascular catheters, 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 coagula-
tion mediators in response to infection. Although our under-
standing 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 inflammatory cells then release circu-
lating 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 mediators are not
appropriately regulated, sepsis will occur. In the setting of 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.2 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 clot-
ting cascade may result in increased D-dimer levels and decreased
circulating levels of protein C.
In benign conditions, a self-limited response helps clear the
pathogen. If the innate immune response is inadequate, mediators
create a procoagulant state. Coagulation and fibrinolytic compo-
nents 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 intravascular 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 proin-
flammatory, antiinflammatory, or growth-promoting. The
molecular mechanisms 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 approxi-
mately 120 minutes. The main proinflammatory cytokines include
IL-1, TNF-α, and IL-8. The primary antiinflammatory cytokines
are IL-10, IL-6, transforming growth factor-β, soluble receptors to
1723
1724 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases

BOX 130.1  30% 27.8%

Definitions of Sepsis 25%

28-day mortality
20%
• Bacteremia (fungemia)—presence of viable bacteria (fungi) in the
blood, as evidenced by positive blood cultures 15%
• Systemic inflammatory response syndrome (SIRS)—at least two of 9.2%
the following conditions: oral temperature > 38° C (100.4° F) or < 10%
35° C (95° F); respiratory rate > 20 breaths/min or partial pressure
5%
of arterial carbon dioxide (PaCO2) < 32 mm Hg; heart rate > 90 2.1% 1.3%
beats/min; leukocyte count > 12,000/dL or < 4000/dL; or >10% 0%
bands
No SIRS/ Severe Septic
• Sepsis—systemic inflammatory response syndrome (SIRS) that has SIRS sepsis sepsis shock
a proven or suspected microbial source
• Septic shock—sepsis with hypotension that is unresponsive to fluid A Sepsis syndrome
resuscitation plus organ dysfunction or perfusion abnormalities, as
listed for severe sepsis 60%
• Multiple organ dysfunction syndrome (MODS)—dysfunction of 53%
more than one organ, requiring intervention homeostasis 50%
Adapted from Bone R, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure

28-day mortality
and guidelines for the use of innovative therapies in sepsis. The APP/SCCM Consensus 40%
Conference Committee. American College of Chest Physicians/Society of Critical Care
Medicine. Chest 101:1644–1655, 1992. 30% 26%

TNF, and IL-1 receptor antagonist (IL-1RA). If the resultant
inflammatory response is adequate, the infection is controlled and
cleared. If the response is deficient or excessive, however, a persis-
tent and worsening cascade is produced, ultimately leading to
(once again) shock, organ failure, and potentially death.
Instability in vascular tone has become increasingly important
in understanding the pathophysiologic mechanism of sepsis.
Vasopressin, also known as antidiuretic hormone, is a naturally
occurring hormone that is essential for cardiovascular stability. It
is produced as a prohormone in the hypothalamus. The hormone
is stored in the pituitary gland and released in response to stress-
ors 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 systemic
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, neurotransmission, tissue injury, and inflammation and
cytotoxicity. Its half-life is short (6–10 seconds), and it easily dif-
fuses 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 synthase, 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 media-
tors of sepsis continue to be produced, and the cascade is perpetu-
ated. 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
pathogenesis of the disease. The mortality of patients with sepsis
increases as the number of failing organs increases (Fig. 130.1A).
In one large study, the mortality rate was 1% for sepsis patients
with no organ dysfunction, whereas the rates for patients with
20%
13%
10% 6%
1%
0%
0 1 2 3 4 or more
B Number of organ failures
Fig. 130.1.  Mortality rates by sepsis syndrome (A) and number of organ
dysfunctions (B). SIRS, Systemic inflammatory response syndrome.
dysfunction of a single organ, two organs, three organs, and four
or more organs were 6%, 13%, 26%, and 53%, respectively (see
Fig. 130.1B).
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 involve-
ment. Although the pathophysiologic process has not been clearly
defined, contributing factors may include direct bacterial inva-
sion, endotoxemia, altered cerebral perfusion or metabolism,
metabolic derangements, multiorgan system failure, and iatro-
genic 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

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the cardiac index, even late in shock. Much of the cardiovascular
compromise from septic shock is reversible, and normal cardio-
vascular function usually returns within 10 days.
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 give way to monocyte infiltration and fibrosis. Significant
right-to-left shunting, arterial hypoxemia, and intractable hypox-
emia 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. At the same time, airway
resistance is increased, and muscle function is impaired. Irrespec-
tive of whether pneumonia is the cause of sepsis, the common
pulmonary endpoint is acute respiratory distress syndrome
(ARDS). ARDS is defined clinically and correlates with the patho-
logic finding of diffuse alveolar damage. The development of
ARDS occurs hours to days after radiographic abnormalities
develop. Because of alveolar-capillary membrane damage, fluid
accumulates in the alveoli. Rather than being a diffuse disease,
ARDS is a heterogeneous process that results in interspersed
damaged and normal alveoli.
Gastrointestinal Effects. A shock state causes significant
deleterious effects on a hollow viscus and its oxygen supply. A
prolonged ileus accompanies hypoperfusion and persists beyond
the perfusion deficit. 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.
Solid organ involvement is also common. Even in the previ-
ously normal host, elevations in aminotransferases and bilirubin
levels are common early in sepsis. The liver has also been impli-
cated in the pathogenesis of sepsis; some of the mediators of sepsis
are produced by the liver.
Endocrine Disorders.  An absolute or relative adrenal insuf-
ficiency is common in sepsis. Depending on the balance of
circulating cytokines, augmentation or suppression of the
hypothalamic-pituitary axis is possible. IL-1 and IL-6 both activate
the hypothalamic-pituitary-adrenal axis. TNF-α and corticostatin
depress pituitary function. Other factors that may contribute to
adrenal insufficiency in sepsis include decreased blood flow to the
adrenal cortex, decreased pituitary function, and decreased pitu-
itary secretion of adrenocorticotropic hormone due to severe
stress. As a result of these interactions, the hypothalamic thermo-
regulatory mechanism may be reset, and temperature fluctuations
may develop.
Hematologic Abnormalities. Sepsis causes abnormalities
in many parts of the coagulation system. Endotoxin, TNF-α, and
IL-1 are the key mediators. Pathologic activation of the extrinsic
(tissue factor–dependent) pathway, protein C, protein S, and
fibrinolysis lead to consumption of essential coagulation factors,
causing DIC. The activation of the coagulation cascade produces
fibrin deposition and microvascular thrombi. If these depositions
are not corrected, they can compromise organ perfusion and
contribute to organ failure. Tissue factor expression on monocytes
is increased. This results in fibrin deposition and perhaps contrib-
utes to an increased incidence of multiorgan failure due to
microvascular thrombi.
Protein C has been identified as an important modulator of
inflammation and coagulation in patients with sepsis. Impair-
ment of the protein C–dependent anticoagulation pathway is
critical to the development of the thrombotic complications of
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CH APTER 130  Sepsis Syndromes 1725
sepsis. In healthy peoples, protein C is activated by a combination
of thrombin and thrombomodulin. 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 fibrinolytic 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.3 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 differences 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 modali-
ties 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 presence 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 appar-
ent, but early identification of the septic state allows implementa-
tion of broad-spectrum antibiotics.
The septic patient may manifest signs of systemic infection
through tachycardia, tachypnea, hyperthermia or hypothermia
and, if severe, hypotension. A septic patient will often have flushed
skin with warm, well-perfused extremities secondary to the early
vasodilation and hyperdynamic state. Alternatively, the severely
hypoperfused patient with an advanced shock state may appear
cyanotic. Very early in the patient’s presentation, vital sign changes
such as tachycardia and tachypnea may be first indicators of sepsis.
If the patient is in shock, a rapid assessment that excludes other
causes, such as hypovolemic or cardiogenic shock, is essential to
the proper initial treatment. A complete detailed clinical examina-
tion will help the emergency clinician determine the cause of the
shock state (see Chapter 6). These are classic signs; however, these
findings may not be manifested in a septic patient, and signs and
symptoms may be subtle or absent.
Both underlying comorbidities and the cause of sepsis should
be considered. Risk factors such as immunocompromised states
(eg, acquired immunodeficiency syndrome, malignant disease,
diabetes, splenectomy, concurrent chemotherapy), older age,
debilitation, high-risk environments for iatrogenic infections (eg,
acute care hospitalizations, long-term care facilities), and multiple
comorbidities should be considered.
The respiratory system is the most common source of infection
in the septic patient. A history of a productive cough, fevers, chills,
upper respiratory symptoms, and throat and ear pain should be
sought. Physical examination should also include a detailed evalu-
ation for focal infection, such as exudative tonsillitis, sinus tender-
ness, tympanic membrane injection, and crackles or dullness on
lung auscultation. Also, pharyngeal thrush should be noticed as a
potential marker of an immunocompromised state.
1726 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases

The gastrointestinal system is the second or third (depending TABLE 130.1 

on the study) most common source of sepsis. A history of
abdominal pain, including its description, location, timing, and Mortality in Emergency Department Sepsis (MEDS)
modifying factors, should be sought. Further history, including Prediction Rule
time of the last bowel movement and presence of nausea, vomit-
ing, and diarrhea, should be noted. A careful physical examination, ODDS RATIO MEDS SCORE
looking for signs of peritoneal irritation, abdominal tenderness, RISK FACTOR FOR DEATH (points)
and hyperactive or hypoactive bowel sounds, is critical in identify-
Terminal illness (death within 30 days) 6.1 6
ing the source of abdominal sepsis. Particular attention should be
paid to physical findings suggestive of common sources of infec- Tachypnea or hypoxia 2.7 3
tion or disease—Murphy’s sign indicating cholecystitis, pain at Septic shock 2.7 3
McBurney’s point indicating appendicitis, left lower quadrant
pain suggesting diverticulitis, or rectal examination revealing a Platelet count < 150,000/mm3 2.5 3
rectal abscess or prostatitis. Bands > 5% 2.3 3
The neurologic system is examined by looking for signs of
Age > 65 yr 2.2 3
meningitis, encephalitis, or epidural abscess, including nuchal
rigidity, fevers, and change in consciousness. Lethargy or altered Pneumonia 1.9 2
mentation may indicate primary neurologic disease or may be the Nursing home resident 1.9 2
result of decreased brain perfusion.
The genitourinary (GU) history includes queries about the Altered mental status 1.6 2
presence of flank pain, dysuria, polyuria, discharge, Foley catheter TOTAL MEDS SCORE (% OF
placement, and genitourinary instrumentation. However, one RISK OF DEATH SEPSIS DEATHS)
must also remember that GU infection is a common source of
infection in older patients and is a common offender in patients Very low 0–4 (1.1%)
with nonspecific symptoms. A sexual history should assess for the Low 5–7 (4.4%)
risk of sexually transmitted diseases. The genital examination Moderate 8–12 (9.3%)
could reveal ulcers, discharge, penile or vulvar lesions, or the
woody induration of Fournier’s gangrene. A rectal examination High 13–15 (16.1%)
could reveal a tender, boggy prostate, consistent with prostatitis. Very high >15 (39%)
A red and friable cervix, cervical discharge, or cervical motion
tenderness is consistent with a sexually transmitted disease.
Adnexal tenderness in a toxic-appearing woman may represent a
tubo-ovarian abscess. Also, a pelvic examination in women should values to specific clinical characteristics (Table 130.1). The total
also include an inspection to ensure that there is no retained score can be used to assess risk of death. Thus, the greater the
tampon that may serve as a source for toxic shock syndrome. number of risk factors, the more likely a patient is to die during
The musculoskeletal history includes the presence of any local- hospitalization. Although typically not calculated for all patients,
izing symptoms to a particular joint. Redness, swelling, and the elements of the score may be identified and considered as a
warmth over a joint, especially if there is a decreased range of red flag when risk-stratifying a patient.
motion in that joint, may be signs of septic arthritis and may
mandate arthrocentesis. The skin should be examined for evidence DIAGNOSTIC CONSIDERATIONS
of cellulitis, abscess, wound infection, or traumatic injury. Deep
injuries, foreign bodies, and fasciitis may be difficult to identify Differential Diagnoses
clinically. The emergency clinician should look for crepitus, bullae,
or skin edema extending beyond areas of erythema that may The sepsis syndromes represent a spectrum of disease and clinical
indicate the presence of an aggressive, gas-forming organism. presentations. Often, noninfectious sources can cause a syndrome
Back pain and fever may be signs of an epidural abscess. Local that mimics that of sepsis5; thus, one must keep in mind a broad
lymphadenopathy, swelling, and streaking should also be noted as differential diagnosis when approaching these patients (Box
signs of an advancing infection. Petechiae and purpura may rep- 130.2). A detailed history and physical examination are the first
resent a Neisseria meningitidis infection or DIC. Generalized steps in narrowing the differential diagnosis to identify the true
erythroderma and rash may represent an exotoxin from pathogens source.
such as Staphylococcus aureus and Streptococcus pyogenes.
A history of fevers or chills in the setting of injection drug Diagnostic Testing
abuse, artificial heart valve, or mitral valve prolapse should
increase the suspicion for endocarditis. The emergency clinician Diagnostic studies are used to identify the type and location of
should suspect endocarditis in the presence of a murmur or other the infecting organisms and define the extent and severity of the
stigmata of endocarditis (eg, splinter hemorrhages, Roth’s spots, infection to assist in focusing therapy. As a result, the diagnostic
Janeway’s lesions). approach should be tailored to the particular patient.
Emergency clinicians must identify the severity of illness in
patients with infection and initiate early resuscitation for those Laboratory Testing
with the potential of becoming critically ill. Although a patient
may meet SIRS criteria, this alone has little predictive value in Hematology.  The white blood cell count can be an indicator
determining the severity of illness and mortality. There are many of inflammation and activation of the inflammatory cascade.
scoring systems that have been developed to risk-stratify illness Leukocytosis is associated with infection and is incorporated in
severity. Most scoring systems are not clinically relevant and are the consensus definition of sepsis; however, it is often insensitive
not routinely used. The Mortality in Emergency Department and nonspecific, limiting its value in the ED. The febrile neutro-
Sepsis (MEDS) score is one proposed method to risk stratify ED penic patient has been shown to be at increased risk for severe
patients with sepsis.4 The MEDS prediction rule assigns point infection. Thus, a neutrophil count of less than 500 cells/mm3

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 CH APTER 130  Sepsis Syndromes 1727

BOX 130.2  diabetic ketoacidosis, but other causes need to be ruled out. An
elevated serum creatinine concentration or decreased glomerular
Differential Diagnosis of Sepsis and Septic Shock filtration rate signals renal dysfunction or failure, which, if due
primarily to sepsis, indicates organ failure and a worse prognosis.
Calcium, magnesium, and phosphorus levels should be checked.
SEPSIS
Dehydration An elevated lactate level is associated with inadequate perfu-
Acute respiratory distress syndrome sion, shock, and poorer prognosis. One study has shown a pro-
Anemia gression in mortality rate with increasing venous lactate level—a
Ischemia lactate level of 0 to 2.5 mg/dL was associated with a 5% mortality
Hypoxia rate, a lactate level of 2.5 to 4.0 mg/dL, 9% mortality, and a lactate
Congestive heart failure level greater than 4 mg/dL, 28% mortality. An arterial blood gas
Vasculitis assessment may be helpful in identifying and classifying acid-base
Toxicologic disturbances. Metabolic acidosis suggests inadequate tissue perfu-
Poisonings sion. Liver function tests can be used to identify liver failure or
Overdose dysfunction. An elevated bilirubin level may suggest the gallblad-
Drug-induced der as a cause of sepsis. An elevated lipase level may represent
Neuroleptic malignant syndrome pancreatitis as the cause of SIRS.
Pancreatitis
Hypothalamic injury Microbiology.  Proper blood, sputum, urine, cerebrospinal
Disseminated intravascular coagulation fluid, and other tissue culture samples are important in guiding
Anaphylaxis therapy. Although the results of culture are not helpful in the
Metabolic initial management, culture samples should be obtained before or
Hyperthyroidism soon after the administration of antibiotics in the patient with
Diabetic ketoacidosis
sepsis syndrome. The initiation of antibiotic therapy should not
Adrenal dysfunction
be delayed significantly while waiting for culture samples to be
Environmental
Burn obtained. Studies have suggested that the yield of initial blood
Heat exhaustion or stroke cultures is low (5%–10%), but this is probably an artifact of the
Trauma lack of reliable discriminatory guidelines for obtaining blood
Blood loss culture samples in the ED. Among patients with clinical sepsis,
Cardiac contusion only 30% to 40% of patients will have positive cultures. The
results of initial microbiologic tests, including Gram staining
SEPTIC SHOCK whenever possible, will help guide subsequent antibiotic treat-
Hypovolemic shock ment. Initial empirical therapy should be broad spectrum to allow
Acute blood loss early treatment of all likely organisms.
Severe dehydration
Cardiogenic shock
Pulmonary embolus
Special Procedures
Myocardial infarction We believe that a central venous pressure (CVP) line is helpful in
Pericardial tamponade guiding fluid resuscitation in sepsis patients. Although CVP
Tension pneumothorax measurements do not correlate well with volume responsiveness,
Vasogenic shock a low CVP usually indicates the need for continued fluid repletion.
Anaphylaxis The use of arterial lines and Swan-Ganz catheters can be helpful
Paralysis in managing sepsis, but they are rarely available in the ED setting.
When available, 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. Swan-
should prompt consideration for admission, isolation, and Ganz catheters are rarely used in sepsis management in the ED,
empirical intravenous (IV) antibiotics in most chemotherapy although the physiologic measurements may be useful in identify-
patients. A bandemia (≥5%–10% bands on a peripheral smear) ing the cause of shock and guiding fluid and inotropic therapy.
represents the release of immature cells from the bone marrow Low systemic vascular resistance and high cardiac output are
and may be a sign of infection and inflammation. Like the white usually associated with sepsis, although this may vary with the
blood cell count, it is an imperfect indicator of infection. The stage of shock and individual patient. The science and technology
absence of leukocytosis or bandemia does not preclude the pos- of noninvasive or minimally invasive cardiac output monitoring
sibility of severe sepsis nor does their presence confirm it. The has been evolving and, where available, may help guide fluid
hemoglobin and hematocrit levels should be determined to ensure administration by evaluating cardiac output alone or in conjunc-
adequate oxygen delivery in shock. Platelets are an acute-phase tion with a fluid challenge or passive leg raise approach.
reactant and may be elevated in the presence of infection. Con-
versely, a low platelet count may be seen in patients with sepsis Radiology
and septic shock. Thrombocytopenia, elevated prothrombin time,
elevated activated partial thromboplastin time, decreased fibrino- Imaging studies are generally used to identify the source of infec-
gen, and increased fibrin split products are associated with DIC tion. A chest radiograph should be considered in patients with
and severe sepsis syndrome. suspected sepsis syndrome, looking not only for a focal infiltrate
representing pneumonia but also for the fluffy bilateral infiltrates
Blood Chemistry. Electrolyte abnormalities should be indicative of ARDS. The pathophysiologic changes of ARDS are
identified and corrected. A low bicarbonate level suggests acidosis often delayed as much as 24 hours after radiographic identifica-
and inadequate perfusion. An elevated anion gap acidosis in the tion. An upright chest radiograph should be considered for sus-
setting of sepsis syndrome commonly represents lactic acidosis or pected bowel perforation to detect free air under the diaphragm.

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1728 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases
The presence of pneumomediastinum is suggestive of esophageal
perforation and current 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 diagnostic. 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 diverticulitis, appendicitis, necrotizing
pancreatitis, microperforation of the stomach or bowel, or forma-
tion of an intra-abdominal abscess, may be best diagnosed by a
CT scan. A head CT scan can identify septic emboli from endo-
carditis 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 sus-
pected 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 mortal-
ity from sepsis. The primary goal is timely administration of
appropriate antimicrobial therapy—or interventional source
control as required—and maintenance of adequate tissue oxygen-
ation 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, and vaso-
pressor support, remains the foundation on which new efforts
may be applied.
From a historical perspective, Rivers and associates have pro-
vided 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.6 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 resuscitation algorithm to
guide the resuscitation. The theory behind the protocol was to
normalize preload and pressure and prevent tissue hypoxia by
matching oxygen delivery with consumption. Use of this protocol,
which facilitated earlier and more aggressive fluid resuscitation
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 interven-
tions in combination were likely responsible for the better out-
comes in the intervention group.
The principles of EGDT, as well as efforts such as the Surviving
Sepsis Campaign, helped underscore the importance of early
identification and timely resuscitation. However, until 2014, the
evidence in support of the formal EGDT protocol was only in the
form of the original single- center trial and subsequent observa-
tional efforts. More recently, the ProCESS, ProMISE, and ARISE
studies have all been large multicenter trials that sought to validate
the value of EGDT.7-9 Each of the trials showed no mortality
benefit to EGDT as compared to usual resuscitation measures;
thus, although EGDT is one strategy to consider, it is not a
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superior approach from an evidence-based perspective. It is,
however, important to underscore that the usual care groups in
these newer trials were all identified early, received antibiotics, and
received generous amounts of fluids (on average, ≈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
they 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 is achieved by mechanical ventilation,
sedation, and paralysis. Although there are no clear intubation
guidelines, hypercapnia, persistent hypoxemia, airway compro-
mise, and profound acidosis are valid indicators for intubation.
In addition to airway protection, intubation and mechanical
ventilatory support provide positive-pressure ventilation. The
pattern of injury in ARDS is such that normal lung parenchyma
is adjacent to affected tissue. Therefore, increased airway pressures
are required to maintain normal oxygen delivery. Current recom-
mendations are to maintain transalveolar pressures (measured as
plateau pressures) below 35 cm H2O because increased pressures
are associated with ventilator-induced lung injury. Maintenance
of a relatively low transalveolar pressure with increasing end-
expiratory pressure is an effective way to increase arterial oxygen
delivery. The ARDSNet trial established the benefit of low tidal
volumes (6 mL/kg) in mechanically ventilated patients with acute
lung injury to prevent iatrogenic lung damage.
Cardiovascular Support
Fluid Resuscitation
Patients with sepsis often require IV fluid to maintain adequate
perfusion. The primary reasons for this intravascular hypovolemia
are venodilation and diffuse capillary leak. Initial therapy for
adults with septic shock should generally be up to 2 L of isotonic
crystalloid. As much as 6 to 10 L of crystalloid may be required
in the first 24 hours. Fluid replacement should be titrated to clini-
cal parameters such as heart rate, blood pressure, change in mental
status, capillary refill, cool skin, and adequate urine output
(0.5–1 mL/kg/hr). Normal saline (0.9%) and lactated Ringer’s
solution are equally effective and neither worsens lactic acidosis.
Colloids are as effective as crystalloids, but they are more expen-
sive and less readily available. Although one should be increasingly
vigilant in watching for fluid overload in patients who are predis-
posed, such as older adults, those with congestive heart failure
(CHF) and a known impaired EF, or those with renal impairment,
these patients are not precluded from volume resuscitation, as
described above. Efforts to identify ways to measure regional
perfusion more directly, such as direct measurement of splanchnic
blood flow, have been proposed. Even in the absence of global
hypoxia and impaired tissue perfusion, there is evidence that
regional hypoperfusion and ischemia exist.
Vasoactive Drug Therapy
If appropriate fluid resuscitation has failed, vasopressor support
may be required (Table 130.2). Only in cases of profound hypo-
tension should vasopressors be started before adequate fluid
resuscitation has been initiated. Use of mean arterial pressure
alone as an indicator of overall efficacy of therapeutic intervention
is not always helpful. A mean arterial pressure of 65 mm Hg has
been recommended in otherwise healthy, normovolemic adult

TABLE 130.2  than norepinephrine in the treatment of hypotension in septic
Dosing of Vasoactive Therapy
DRUG DOSAGE
Dobutamine 5–15 µg/kg/min
Dopamine 2–20 µg/kg/min
Epinephrine 5–20 µg/min
Norepinephrine 5–20 µg/min
Phenylephrine 2–20 µg/min
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.
The 2012 Surviving Sepsis Campaign guidelines have provided
consensus recommendations for treatment of septic shock.10 Fluid
resuscitation remains the fundamental treatment option and
should be the initial treatment. Norepinephrine should be used as
the initial vasopressor, with the addition of epinephrine or vaso-
pressin to norepinephrine as a reasonable adjunct. Vasopressin
alone has been shown to be ineffective compared with norepi-
nephrine in the initial treatment of refractory septic shock.
Dobutamine should be used as the primary inotropic agent if
myocardial dysfunction is evident. After an initial stabilization
period, vasopressors should be titrated down, as tolerated;
however, the duration of this stabilization period is variable and
may be hours to days.
Norepinephrine.  Norepinephrine is a mixed α- and
β-agonist with minimal β2 activity and primarily functions to
increase cardiac output and systemic vascular resistance. In a large
study examining patients with shock from multiple causes, nor-
epinephrine was shown to have fewer adverse events (particularly
arrhythmias) compared with dopamine, which had a higher
mortality rate in patients with cardiogenic shock.11 In another
meta-analysis, norepinephrine was shown to be superior to
dopamine in both in-hospital and 28-day mortality.12
Compared with dopamine in septic patients, norepinephrine
increases glomerular filtration and urine output equally well. It is
an important component of the therapy for septic shock as a sole
vasopressor or in conjunction with other vasopressors. Recom-
mended doses are 8 to 12 µg/min.
Dopamine.  Dopamine is also often used for septic shock
unresponsive to adequate volume expansion. Dopamine is the
immediate precursor of norepinephrine and epinephrine. It is
primarily an α-, β1-, and dopaminergic agonist. Although low
doses alone are not effective, they may be effective in combination
with other agents. So-called renal dose dopamine has not been
shown to reduce mortality or decrease dialysis dependence and
should not be used. Dosages higher than 20 µg/kg/min may
produce significant vasoconstriction. Persistent tachycardia,
decreased partial pressure of arterial oxygen, and increased pul-
monary artery occlusion pressure are common side effects of
dopamine use.
Phenylephrine.  Phenylephrine is a selective α1-agonist,
increasing systemic vascular resistance without significant changes
in cardiac output. It can produce a reflexive bradycardia or sup-
pression 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
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CH APTER 130  Sepsis Syndromes 1729
patients; however, there was no difference in other measured
hemodynamic parameters, including oxygen delivery. Phenyleph-
rine does not impair cardiac and renal function and may be a good
choice when significant tachyarrhythmia limits the use of other
agents.
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. Adverse effects may include
peripheral vasospasm and a critical reduction in extremity perfu-
sion, leading to gangrene.
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. This
is the foundation for the use of vasopressin as an adjunct therapy
for patients with severe sepsis. Vasopressin should not be used as
the sole initial therapy for refractory septic shock. In a well-
designed randomized trial, investigators demonstrated no change
in mortality for patients with severe sepsis when vasopressin was
added to catecholamine vasopressors.
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 hypoper-
fusion in spite of adequate volume expansion and the use of other
vasopressor agents. In patients undergoing formal, early, goal-
directed therapy, when preload, perfusion pressure, and oxygen-
carrying capacity have been normalized and a low Scvo2 persists,
dobutamine is used to increase cardiac output and oxygen deliv-
ery. 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 treat-
ment for patients with presumed lactic acidosis. Current consensus
is that it should be reserved for severe acidemia (pH < 7.0–7.2)
because there may be a paradoxical decrease in intracellular pH
as a result of diffusion 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 130.3). Surgically correctable
conditions, such as intra-abdominal abscesses, perforated viscus,
retained products of conception, or retained foreign body (eg, a
tampon), should be treated concurrently. Antibiotics should be
administered as soon as possible in patients with serious infec-
tions. Although some observational studies and national bench-
marks have called for the administration of antibiotics within a
predefined time period of 3 hours from ED presentation, a com-
prehensive meta-analysis failed to support an association between
1730 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases

TABLE 130.3 

Suggested Initial Antibiotic Managementa

INFECTION
Sepsis, unknown source
Pneumonia
Abdominal infection
Cellulitis
Intravenous catheter
infection (remove
catheter)
Cerebrospinal infection
Injection drug abuse
a
Pending microbiologic identification of organism and sensitivity.
MODIFYING FACTORS ANTIBIOTIC
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
HIV infection Ticarcillin-clavulanate plus tobramycin
Immunocompetent Second- or third-generation cephalosporin plus second-generation
macrolide or fluoroquinolone
Legionella suspected Azithromycin, fluoroquinolone, or high-dose erythromycin
Immunocompetent Ampicillin plus aminoglycoside plus metronidazole
Multidrug-resistant organism suspected Ticarcillin-clavulanate or 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, or ticarcillin-clavulanate, or 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 Nafcillin plus aminoglycoside
MRSA suspected Vancomycin plus aminoglycoside

antibiotics administered after 3 hours and mortality.13 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 avail-
able, therapy should be modified. There is no consensus about the
need for double or triple antibiotic coverage for particular organ-
isms, although it is common practice to double-cover virulent
organisms, such as Pseudomonas aeruginosa, as well as areas com-
monly infected with multiple organisms, such as the peritoneum.
With increasing rates of methicillin-resistant organisms, combi-
nations 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
inflammatory response, corticosteroids are a logical treatment
modality as antiinflammatory 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, but increase the rate of
secondary infection, contributing to a null effect overall. At this
time, we believe that the role of steroid therapy in sepsis remains
controversial and recommend their use in patients on chronic
steroid therapy when there is refractory cardiovascular insuffi-
ciency, despite maximal supportive therapy and replacement
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 condi-
tion. For 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 (eg, young patients with pharyngitis) may be
appropriate for discharge.

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 CH APTER 130  Sepsis Syndromes 1731

KEY CONCEPTS
• Sepsis is a progression of disease due to a dysregulated
inflammatory cascade, leading to organ dysfunction and circulatory
compromise in severe cases.
• Sepsis is subtle and often difficult to detect, so the emergency
clinician should maintain a high index of suspicion when assessing
patients in the ED.
• Older adults, immunocompromised and neutropenic patients, and
patients with multiple comorbidities are at increased risk for the
development of sepsis syndromes.
• A thorough history and physical examination should guide the
diagnostic evaluation.
• Early treatment should focus on appropriate identification,
improvement of tissue perfusion (through 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.

The references for this chapter can be found online by accessing the accompanying Expert Consult website.

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REFERENCES
1. Howell MD, Talmor D, Schuetz P, et al: Proof of principle: the predisposition, infec-
tion, response, organ failure sepsis staging system. Crit Care Med 39:322–327, 2011.
2. Pierrakos C, Vincent JL: Sepsis biomarkers: a review. Crit Care 14:R15, 2010.
3. Sheu CC, Gong MN, Zhai R, et al: Clinical characteristics and outcomes of sepsis-
related vs non-sepsis-related ARDS. Chest 138:559–567, 2010.
4. Shapiro NI, Wolfe RE, Moore RB, et al: Mortality in Emergency Department Sepsis
(MEDS) score: a prospectively derived and validated clinical prediction rule. Crit
Care Med 31:670–675, 2003.
5. Heffner AC, Horton JM, Marchick MR, et al: Etiology of illness in patients with severe
sepsis admitted to the hospital from the emergency department. Clin Infect Dis
50:814–820, 2010.
6. 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 345:1368–1377, 2001.
7. Investigators A, Group ACT, Peake SL, et al: Goal-directed resuscitation for patients
with early septic shock. N Engl J Med 371:1496–1506, 2014.
CHAPTER 130: QUESTIONS & ANSWERS
130.1. 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. 21-year-old woman with abdominal pain,
temperature 38.3° C (100.9° F)
C. 53-year-old man with respirations, 30 breaths/min,
white blood cell (WBC) count, 16,000 cells/mm3
D. 74-year-old woman with chest pain, heart rate 130
beats/min
E. 81-year-old man with WBC count, 2700 cells/mm3,
heart rate, 73 beats/min
Answer: C. SIRS is defined as two or more of the following—
tachycardia, 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 dys-
function. Septic shock involves systolic blood pressure below
90 mm Hg.
130.2. Sepsis is characterized by which of the following?
A. Depression of arachidonic acid metabolites
B. Depression of tumor necrosis factor levels
C. Increased endogenous anticoagulant levels
D. Prolonged suppression of nitric oxide levels
E. Prolonged suppression of vasopressin levels
Answer: E. Clinical sepsis is induced by sustained levels of proin-
flammatory and procoagulant mediators. Cytokines (interleukin-1,
interleukin-6, and tumor necrosis factor alpha) and prostaglan-
dins are primary mediators. Nitric oxide synthase is upregulated,
resulting in sustained elevations of the serum nitric oxide level,
with subsequent vasodilations. Sustained suppression of vasopres-
sin adds to this sometimes refractory vasodilated state.
130.3. 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.
E. Ventricular dilation is unusual.
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 myocar-
dial effects are typically reversible.
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CH APTER 130  Sepsis Syndromes 1731.e1
8. Pro CI, Yealy DM, Kellum JA, et al: A randomized trial of protocol-based care for
early septic shock. N Engl J Med 370:1683–1693, 2014.
9. Mouncey PR, Osborn TM, Power GS, et al: Trial of early, goal-directed resuscitation
for septic shock. N Engl J Med 372:1301–1311, 2015.
10. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock, 2012. Intensive Care
Med 39:165–228, 2013.
11. De Backer D, Biston P, Devriendt J, et al: Comparison of dopamine and norepineph-
rine in the treatment of shock. N Engl J Med 362:779–789, 2010.
12. Vasu TS, Cavallazzi R, Hirani A, et al: Norepinephrine or dopamine for septic shock:
systematic review of randomized clinical trials. J Intensive Care Med 27:172–178,
2012.
13. 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 43:1907–1915, 2015.
130.4. 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
E. Skin > respiratory
Answer: C. Epidemiology studies show that pneumonia is the
most common cause of sepsis, followed by an intra-abdominal
source. However, a careful investigation to identify the source of
infection should occur.
130.5. 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
E. <2000 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.
130.6. 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%
E. Varies according to patient comorbidities
Answer: B. While blood cultures are perhaps a gold standard for
identification and isolation of bacteria, they may negative, even
when the etiology of illness is clearly infectious. Empiric antibiotic
treatment in the ED remains a standard approach.
130.7. A 65-year-old man presents with blood pressure of
88/40 mm Hg, heart rate of 105 beats/min, respiratory
rate of 24 breaths/min, O2 saturation of 92%, and
temperature of 38.5° C (101.3° F). Fluid resuscitation,
oxygen, and empirical antibiotics are begun. Blood
pressure after 2 L of saline is 98/50 mm Hg. A central
venous catheter is placed, with a central venous pressure
of 11 mm Hg. A venous blood gas sample drawn from
this catheter shows hematocrit of 24%, Po2 of 34 mm
Hg, Pco2 of 46 mm Hg, pH of 7.29, and O2 saturation of
1731.e2 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases

63%. O2 saturation by pulse oximeter is now 96%. What meets criteria for septic shock. Intermittent central venous (eg,
is the most appropriate next step according to the early mixed) blood gas analysis is likely to be adequate. Therapeutic
goal-directed therapy protocol? targets are a central venous pressure of 8 to 12 mm Hg in the
A. Dopamine, 10 µg/kg/min nonintubated patient and a mixed venous O2 saturation of 70%
B. Endotracheal intubation (review of the oxyhemoglobin desaturation curve reminds us that
C. Packed red blood cell transfusion 75% is normal). After volume resuscitation, this patient still had
D. Phenylephrine, 50 µg/min a low mixed venous saturation, indicating inadequate peripheral
E. Saline 0.9%, 2 L more oxygen delivery and increased extraction by the tissues. With O2
saturation nearly normal (96%), the only way to increase oxygen
Answer: C. For the optimal management of sepsis, central venous
delivery is by red blood cell transfusion to increase the plasma
pressure monitoring (ideally with oximetric capabilities) and
hemoglobin concentration.
mixed venous blood gas monitoring are indicated. This patient

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