C H A P T E R 130 

Sepsis Syndromes
Nathan I. Shapiro | Alan E. Jones

PRINCIPLES indwelling devices such as intravascular catheters, prosthetic

devices, and endotracheal tubes also contribute to the risk of
Background systemic infection and sepsis.

Sepsis syndrome represents the body’s host response to an infec- Pathophysiology

tion. The causative agent and host’s activated inflammatory
cascade overwhelm the body’s defenses and regulatory systems, Sepsis results from the complex interaction of detection molecules,
leading to disruption in homeostasis. Tachycardia, tachypnea, signaling molecules, and numerous inflammatory and coagula-
fever, and immune system activation are common manifestations. tion mediators in response to infection. Although our under-
If the body is unable to overcome this insult, cellular injury, tissue standing of the pathophysiologic process of sepsis has evolved, it
damage, shock, multiorgan failure, or death may ensue. remains incomplete. The initial host response is to mobilize
In 1992, the American College of Chest Physicians and Society inflammatory cells, particularly neutrophils and macrophages, to
of Critical Care Medicine issued a consensus statement to establish the site of infection. These inflammatory cells then release circu-
uniform criteria defining the sepsis syndromes. The goal was to lating molecules, including cytokines, which trigger a cascade of
create a common nomenclature for disease classification and other inflammatory mediators that result in a coordinated host
systematic comparisons across studies of septic patients. The term response. Synthesis of the components of the cascade is increased
systemic inflammatory response syndrome (SIRS) is defined as two at many steps along the pathway. If these mediators are not
or more of the following: tachycardia, tachypnea, hyperthermia appropriately regulated, sepsis will occur. In the setting of ongoing
or hypothermia, high or low white blood cell count, or bandemia. toxin release, a persistent inflammatory response occurs, with
Sepsis is the combination of infection plus SIRS, severe sepsis is ongoing mediator activation, cellular hypoxia, tissue injury, shock,
sepsis plus organ dysfunction, and septic shock is sepsis plus multiorgan failure, and potentially death.
hypotension, defined as a systolic blood pressure below 90  mm Hg,
not responsive to a fluid challenge (Box 130.1). This nomenclature Mediators of Sepsis
is intended to provide clinicians and researchers with a common
classification. Efforts to validate this classification scheme in the Host response and pathogen characteristics are both important in
emergency department (ED) population have demonstrated that the pathogenesis of sepsis. More than 100 discrete markers have
the term sepsis, when characterized by fulfilling the SIRS criteria been identified and attributed to the sepsis cascade, but the true
alone, is overly sensitive and nonspecific and does not convey an culprits have not been clearly identified.2 A pathogen is sensed by
increased mortality risk. SIRS is not specific because it can be pattern recognition receptors, most notably Toll-like receptors,
present in noninfectious inflammatory states and in localized located on the surface of the white blood cell. The resulting host-
infections that are not inclined to lead to sepsis, such as strepto- pathogen interaction activates the inflammatory and coagulation
coccal pharyngitis or viral illnesses. However, organ dysfunction cascades. The subsequent inflammatory signaling occurs through
and shock have been shown to portend worse outcomes. Newer cytokines, chemokines, and other soluble mediators, including
efforts have proposed the PIRO approach, which may help us increased circulating levels of the interleukins IL-1, IL-6, and IL-8
better understand and prognosticate the severity of illness. PIRO and tumor necrosis factor alpha (TNF-α). Activation of the clot-
stands for assessment of predisposing conditions, infection source, ting cascade may result in increased D-dimer levels and decreased
response of the host, and organ dysfunction and has been pro- circulating levels of protein C.
posed to help improve classification.1 In benign conditions, a self-limited response helps clear the
Bacteremia may be present, but positive cultures are not pathogen. If the innate immune response is inadequate, mediators
obligatory in the diagnosis of sepsis. Culture-negative and culture- create a procoagulant state. Coagulation and fibrinolytic compo-
positive septic populations have similar outcomes in patients with nents are proinflammatory, precipitating a worsening cycle of
similar severity of illness. Pneumonia, abdominal abscess with procoagulant and proinflammatory mediators. Propagation of
viscus perforation, and pyelonephritis are common primary this cascade ultimately contributes to end-organ damage and
causes of sepsis. Gram-positive organisms account for 25% to often to disseminated intravascular coagulation (DIC). If it is not
50% of infections, gram-negative organisms for 30% to 60%, and effectively reversed, the process leads to cellular hypoxia, organ
fungi for 2% to 10%. The distribution varies with the study and, dysfunction, shock, and death.
more importantly, with host factors such as the status of the host The primary mediators are cytokines that are primarily proin-
immune system, age of the patient, recent hospitalizations, and flammatory, antiinflammatory, or growth-promoting. The
presence of indwelling vascular catheters. molecular mechanisms whereby they are regulated are not well
The health status of the host is a potentially important risk understood. An initial cytokine, TNF-α, is found in serum
factor in the development and progression of sepsis. Older adults approximately 90 minutes after the administration of endotoxin
and those with multiple comorbidities may be more susceptible to healthy volunteers. IL-6 and IL-8 reach peak levels at approxi-
to developing a systemic infection. Chemotherapy-induced neu- mately 120 minutes. The main proinflammatory cytokines include
tropenia, acquired immunodeficiency syndrome, and steroid IL-1, TNF-α, and IL-8. The primary antiinflammatory cytokines
dependency increase susceptibility to sepsis. Increased use of are IL-10, IL-6, transforming growth factor-β, soluble receptors to
1723
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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%

20%
TNF, and IL-1 receptor antagonist (IL-1RA). If the resultant 13%
inflammatory response is adequate, the infection is controlled and 10% 6%
cleared. If the response is deficient or excessive, however, a persis- 1%
tent and worsening cascade is produced, ultimately leading to 0%
(once again) shock, organ failure, and potentially death. 0 1 2 3 4 or more
Instability in vascular tone has become increasingly important B Number of organ failures
in understanding the pathophysiologic mechanism of sepsis.
Vasopressin, also known as antidiuretic hormone, is a naturally Fig. 130.1.  Mortality rates by sepsis syndrome (A) and number of organ
occurring hormone that is essential for cardiovascular stability. It dysfunctions (B). SIRS, Systemic inflammatory response syndrome.
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 dysfunction of a single organ, two organs, three organs, and four
followed by a prolonged and severe suppression. This pattern or more organs were 6%, 13%, 26%, and 53%, respectively (see
of secretion is different from other forms of shock, in which Fig. 130.1B).
vasopressin levels remain elevated. Vasopressin has numerous
physiologic effects, including vasoconstriction of the systemic Neurologic Impairment. Patients with sepsis may display
vasculature, osmoregulation, and maintenance of normovolemia. neurologic impairment manifested by altered mental status and
Nitric oxide (NO) is a gas that has an important role in septic lethargy, commonly referred to as septic encephalopathy. The
shock, regulating vascular tone by an indirect effect on smooth incidence has been reported as between 10% and 70%. The
muscle cells. NO also contributes to platelet adhesion, insulin mortality rate in patients with septic encephalopathy is higher
secretion, neurotransmission, tissue injury, and inflammation and than that in septic patients without significant neurologic involve-
cytotoxicity. Its half-life is short (6–10 seconds), and it easily dif- ment. Although the pathophysiologic process has not been clearly
fuses into cells. Although its mechanisms of action are not well defined, contributing factors may include direct bacterial inva-
understood, it seems to be a key mediator of sepsis. Animal data sion, endotoxemia, altered cerebral perfusion or metabolism,
have shown that nitric oxide synthase, the enzyme that produces metabolic derangements, multiorgan system failure, and iatro-
NO, is upregulated in cases of sepsis. Enhanced NO production is genic injury. In addition, impaired renal or hepatic function in the
thought to contribute to the profound vasodilation found in absence of overt organ failure has been shown to correlate with
patients in septic shock. encephalopathy.
In the setting of ongoing inflammatory activation, the media-
tors of sepsis continue to be produced, and the cascade is perpetu- Cardiovascular Dysfunction. Cardiovascular dysfunction
ated. Unless it is appropriately and rapidly controlled, the ultimate is common with sepsis. The cardiovascular dysfunction and
effect is a sequence of events starting with cellular dysfunction and failure arise from direct myocardial depression and distributive
ultimately leading to tissue damage, organ dysfunction, and death. shock. Gram-negative, gram-positive, and killed organisms can
cause myocardial depression. The direct insults of the toxic
Organ System Dysfunction mediators as well as the mobilization of host mediators of sepsis
produce a distributive shock. Early in sepsis, a hyperdynamic
The organ dysfunction that results from sepsis is central to the state develops, characterized by increased cardiac output and
pathogenesis of the disease. The mortality of patients with sepsis decreased systemic vascular resistance. Although the cardiac
increases as the number of failing organs increases (Fig. 130.1A). output is increased, it is at the expense of ventricular dilation and
In one large study, the mortality rate was 1% for sepsis patients decreased ejection fraction (EF). Vigorous fluid resuscitation
with no organ dysfunction, whereas the rates for patients with usually increases preload and, secondarily, EF, thereby improving

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 CH APTER 130  Sepsis Syndromes 1725

the cardiac index, even late in shock. Much of the cardiovascular sepsis. In healthy peoples, protein C is activated by a combination
compromise from septic shock is reversible, and normal cardio- of thrombin and thrombomodulin. The activation of protein C
vascular function usually returns within 10 days. results in the downregulation of many portions of the coagulation
cascade, including release of tissue factor, inactivation of factors
Pulmonary Involvement.  Involvement of the lung is often VIIIa and Va, and stimulation of fibrinolysis. It is possible that
seen in the inflammatory response to infection. These effects are protein C activation in early sepsis is impaired because of an
apparent, irrespective of the primary infection that caused sepsis. inflammatory cytokine–mediated downregulation of thrombo-
Early infiltration with neutrophils, surfactant dysfunction, and modulin. As a result, a consumptive coagulopathy ensues. This
edema give way to monocyte infiltration and fibrosis. Significant leads to increased fibrin deposition and a resulting upregulation
right-to-left shunting, arterial hypoxemia, and intractable hypox- of the fibrinolytic pathway, as identified by low plasma levels of
emia occur. The resulting morbidity is high and is a common the fibrinolytic proteins and increased fibrin split products. This
endpoint to sepsis-related deaths. sequence of events leads to consumption of coagulation factors
Sepsis produces a highly catabolic state and places significant and DIC. In late sepsis, the fibrinolytic system is suppressed.
demands on the respiratory system. At the same time, airway
resistance is increased, and muscle function is impaired. Irrespec- Genetic Factors
tive of whether pneumonia is the cause of sepsis, the common
pulmonary endpoint is acute respiratory distress syndrome There has been increasing evidence that genetics are a risk factor
(ARDS). ARDS is defined clinically and correlates with the patho- for the outcome of sepsis.3 An individual may contain a set of
logic finding of diffuse alveolar damage. The development of individual characteristics or polymorphisms that may affect the
ARDS occurs hours to days after radiographic abnormalities ways in which he or she responds to sepsis in general, or perhaps
develop. Because of alveolar-capillary membrane damage, fluid there may be differences in response to specific sepsis therapeutics.
accumulates in the alveoli. Rather than being a diffuse disease, Identifying and understanding these differences in an individual’s
ARDS is a heterogeneous process that results in interspersed genetic makeup is likely to lead to tailored approaches to diagnosis
damaged and normal alveoli. and therapy. The impact of genetics on future treatment modali-
ties for sepsis remains unclear, but the prospect of customized
Gastrointestinal Effects. A shock state causes significant genetic therapy for sepsis is a promising early development.
deleterious effects on a hollow viscus and its oxygen supply. A
prolonged ileus accompanies hypoperfusion and persists beyond CLINICAL FEATURES
the perfusion deficit. Splanchnic blood flow is dependent on mean
arterial pressure because there is relatively little autoregulation. Symptoms and Signs
Therefore, hemodynamic dysfunction may have a profound effect
on viscus metabolism. The approach to a patient with sepsis relies on identification of
Solid organ involvement is also common. Even in the previ- the presence of a systemic infection and localization of the source
ously normal host, elevations in aminotransferases and bilirubin of the initial infection. This allows appropriate treatment directed
levels are common early in sepsis. The liver has also been impli- to the source of infection. Often, the source is not readily appar-
cated in the pathogenesis of sepsis; some of the mediators of sepsis ent, but early identification of the septic state allows implementa-
are produced by the liver. tion of broad-spectrum antibiotics.
The septic patient may manifest signs of systemic infection
Endocrine Disorders.  An absolute or relative adrenal insuf- through tachycardia, tachypnea, hyperthermia or hypothermia
ficiency is common in sepsis. Depending on the balance of and, if severe, hypotension. A septic patient will often have flushed
circulating cytokines, augmentation or suppression of the skin with warm, well-perfused extremities secondary to the early
hypothalamic-pituitary axis is possible. IL-1 and IL-6 both activate vasodilation and hyperdynamic state. Alternatively, the severely
the hypothalamic-pituitary-adrenal axis. TNF-α and corticostatin hypoperfused patient with an advanced shock state may appear
depress pituitary function. Other factors that may contribute to cyanotic. Very early in the patient’s presentation, vital sign changes
adrenal insufficiency in sepsis include decreased blood flow to the such as tachycardia and tachypnea may be first indicators of sepsis.
adrenal cortex, decreased pituitary function, and decreased pitu- If the patient is in shock, a rapid assessment that excludes other
itary secretion of adrenocorticotropic hormone due to severe causes, such as hypovolemic or cardiogenic shock, is essential to
stress. As a result of these interactions, the hypothalamic thermo- the proper initial treatment. A complete detailed clinical examina-
regulatory mechanism may be reset, and temperature fluctuations tion will help the emergency clinician determine the cause of the
may develop. shock state (see Chapter 6). These are classic signs; however, these
findings may not be manifested in a septic patient, and signs and
Hematologic Abnormalities. Sepsis causes abnormalities symptoms may be subtle or absent.
in many parts of the coagulation system. Endotoxin, TNF-α, and Both underlying comorbidities and the cause of sepsis should
IL-1 are the key mediators. Pathologic activation of the extrinsic be considered. Risk factors such as immunocompromised states
(tissue factor–dependent) pathway, protein C, protein S, and (eg, acquired immunodeficiency syndrome, malignant disease,
fibrinolysis lead to consumption of essential coagulation factors, diabetes, splenectomy, concurrent chemotherapy), older age,
causing DIC. The activation of the coagulation cascade produces debilitation, high-risk environments for iatrogenic infections (eg,
fibrin deposition and microvascular thrombi. If these depositions acute care hospitalizations, long-term care facilities), and multiple
are not corrected, they can compromise organ perfusion and comorbidities should be considered.
contribute to organ failure. Tissue factor expression on monocytes The respiratory system is the most common source of infection
is increased. This results in fibrin deposition and perhaps contrib- in the septic patient. A history of a productive cough, fevers, chills,
utes to an increased incidence of multiorgan failure due to upper respiratory symptoms, and throat and ear pain should be
microvascular thrombi. sought. Physical examination should also include a detailed evalu-
Protein C has been identified as an important modulator of ation for focal infection, such as exudative tonsillitis, sinus tender-
inflammation and coagulation in patients with sepsis. Impair- ness, tympanic membrane injection, and crackles or dullness on
ment of the protein C–dependent anticoagulation pathway is lung auscultation. Also, pharyngeal thrush should be noticed as a
critical to the development of the thrombotic complications of potential marker of an immunocompromised state.

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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 superior approach from an evidence-based perspective. It is,
perforation and current or impending mediastinitis. however, important to underscore that the usual care groups in
Soft tissue plain radiographs of infected areas can be obtained, these newer trials were all identified early, received antibiotics, and
looking for air in the soft tissues associated with necrotizing or received generous amounts of fluids (on average, ≈40–60 mL/kg
gas-forming infection, although plain x-rays are not sensitive for in the first 6 hours across the trials), supporting the principle that
tissue infection. Periosteal thickening or bone erosion may be seen early identification of sepsis, early antibiotics, and carefully
on plain radiographs of patients with osteomyelitis; a bone scan titrated resuscitation should remain a core tenant.
may be diagnostic. Computed tomography (CT) of superficial
infections may be more helpful to quantify the extent of infection Respiratory Support
further and identify abscesses that are not readily evident on
physical examination. A CT scan of the abdomen and pelvis may Altered mental status is common in patients in septic shock, and
identify abdominal or pelvic pathologic lesions, provided there is they may require rapid airway protection. Because patients with
no clear clinical indication for immediate operative intervention. impending respiratory failure use a disproportionately large
Suspected disease, such as diverticulitis, appendicitis, necrotizing amount of energy for the muscles of respiration, improved oxygen
pancreatitis, microperforation of the stomach or bowel, or forma- delivery to other organs is achieved by mechanical ventilation,
tion of an intra-abdominal abscess, may be best diagnosed by a sedation, and paralysis. Although there are no clear intubation
CT scan. A head CT scan can identify septic emboli from endo- guidelines, hypercapnia, persistent hypoxemia, airway compro-
carditis or increased intracranial pressure from a mass and should mise, and profound acidosis are valid indicators for intubation.
be considered before a lumbar puncture is performed. An In addition to airway protection, intubation and mechanical
abdominal ultrasound examination may be indicated for sus- ventilatory support provide positive-pressure ventilation. The
pected cholecystitis, and a pelvic ultrasound examination may be pattern of injury in ARDS is such that normal lung parenchyma
indicated for tubo-ovarian abscess or endometritis. If endocarditis is adjacent to affected tissue. Therefore, increased airway pressures
is suspected, a transesophageal cardiac ultrasound study may be are required to maintain normal oxygen delivery. Current recom-
performed for the detection of any valvular vegetations. Magnetic mendations are to maintain transalveolar pressures (measured as
resonance imaging (MRI) can be useful to identify soft tissue plateau pressures) below 35 cm H2O because increased pressures
infection, such as necrotizing fasciitis or epidural abscess. are associated with ventilator-induced lung injury. Maintenance
of a relatively low transalveolar pressure with increasing end-
MANAGEMENT expiratory pressure is an effective way to increase arterial oxygen
delivery. The ARDSNet trial established the benefit of low tidal
Early detection and appropriate treatment can reduce the mortal- volumes (6 mL/kg) in mechanically ventilated patients with acute
ity from sepsis. The primary goal is timely administration of lung injury to prevent iatrogenic lung damage.
appropriate antimicrobial therapy—or interventional source
control as required—and maintenance of adequate tissue oxygen- Cardiovascular Support
ation and perfusion through titrated resuscitation. With early
detection and early resuscitation there is increasing evidence that Fluid Resuscitation
the natural history of sepsis can be altered. Initial resuscitation,
including appropriate airway management, IV access, oxygen, Patients with sepsis often require IV fluid to maintain adequate
early and appropriate antibiotics, fluid resuscitation, and vaso- perfusion. The primary reasons for this intravascular hypovolemia
pressor support, remains the foundation on which new efforts are venodilation and diffuse capillary leak. Initial therapy for
may be applied. adults with septic shock should generally be up to 2 L of isotonic
From a historical perspective, Rivers and associates have pro- crystalloid. As much as 6 to 10 L of crystalloid may be required
vided compelling evidence supporting the importance of this in the first 24 hours. Fluid replacement should be titrated to clini-
concept when they published a protocol of standardized timely cal parameters such as heart rate, blood pressure, change in mental
and titrated care being used to guide resuscitation in the ED.6 This status, capillary refill, cool skin, and adequate urine output
randomized, double-blind, placebo-controlled study showed a (0.5–1 mL/kg/hr). Normal saline (0.9%) and lactated Ringer’s
16% mortality reduction in patients with severe sepsis and septic solution are equally effective and neither worsens lactic acidosis.
shock. The protocol, termed early goal-directed therapy (EGDT), Colloids are as effective as crystalloids, but they are more expen-
measures targeted goals and uses a resuscitation algorithm to sive and less readily available. Although one should be increasingly
guide the resuscitation. The theory behind the protocol was to vigilant in watching for fluid overload in patients who are predis-
normalize preload and pressure and prevent tissue hypoxia by posed, such as older adults, those with congestive heart failure
matching oxygen delivery with consumption. Use of this protocol, (CHF) and a known impaired EF, or those with renal impairment,
which facilitated earlier and more aggressive fluid resuscitation these patients are not precluded from volume resuscitation, as
through the use of increased fluids, increased blood products, described above. Efforts to identify ways to measure regional
increased use of dobutamine, and greater degree of normalization perfusion more directly, such as direct measurement of splanchnic
of tissue hypoxia, reduced mortality at their center. The interven- blood flow, have been proposed. Even in the absence of global
tions in combination were likely responsible for the better out- hypoxia and impaired tissue perfusion, there is evidence that
comes in the intervention group. regional hypoperfusion and ischemia exist.
The principles of EGDT, as well as efforts such as the Surviving
Sepsis Campaign, helped underscore the importance of early Vasoactive Drug Therapy
identification and timely resuscitation. However, until 2014, the
evidence in support of the formal EGDT protocol was only in the If appropriate fluid resuscitation has failed, vasopressor support
form of the original single- center trial and subsequent observa- may be required (Table 130.2). Only in cases of profound hypo-
tional efforts. More recently, the ProCESS, ProMISE, and ARISE tension should vasopressors be started before adequate fluid
studies have all been large multicenter trials that sought to validate resuscitation has been initiated. Use of mean arterial pressure
the value of EGDT.7-9 Each of the trials showed no mortality alone as an indicator of overall efficacy of therapeutic intervention
benefit to EGDT as compared to usual resuscitation measures; is not always helpful. A mean arterial pressure of 65 mm Hg has
thus, although EGDT is one strategy to consider, it is not a been recommended in otherwise healthy, normovolemic adult

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 CH APTER 130  Sepsis Syndromes 1729

TABLE 130.2  than norepinephrine in the treatment of hypotension in septic

patients; however, there was no difference in other measured
Dosing of Vasoactive Therapy hemodynamic parameters, including oxygen delivery. Phenyleph-
rine does not impair cardiac and renal function and may be a good
DRUG DOSAGE choice when significant tachyarrhythmia limits the use of other
Dobutamine 5–15 µg/kg/min agents.
Dopamine 2–20 µg/kg/min Epinephrine.  Epinephrine is a potent mixed α- and
Epinephrine 5–20 µg/min β-agonist. Epinephrine infusion is also associated with increased
oxygen consumption, increased systemic lactate concentrations,
Norepinephrine 5–20 µg/min
and decreased splanchnic blood flow. The rise in the lactate level
Phenylephrine 2–20 µg/min 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
patients but must be correlated with other indicators of adequate unresponsive to other vasopressors. Adverse effects may include
perfusion, such as mental status and urine output. Patients with peripheral vasospasm and a critical reduction in extremity perfu-
previously uncontrolled hypertension may require a mean arterial sion, leading to gangrene.
pressure of 75 mm Hg or even higher.
The 2012 Surviving Sepsis Campaign guidelines have provided Vasopressin.  Vasopressin is a naturally occurring peptide
consensus recommendations for treatment of septic shock.10 Fluid that is synthesized as a large prohormone in the hypothalamus.
resuscitation remains the fundamental treatment option and In states of septic shock, there is an early surge of vasopressin
should be the initial treatment. Norepinephrine should be used as followed by a profound drop in circulating vasopressin levels. This
the initial vasopressor, with the addition of epinephrine or vaso- is the foundation for the use of vasopressin as an adjunct therapy
pressin to norepinephrine as a reasonable adjunct. Vasopressin for patients with severe sepsis. Vasopressin should not be used as
alone has been shown to be ineffective compared with norepi- the sole initial therapy for refractory septic shock. In a well-
nephrine in the initial treatment of refractory septic shock. designed randomized trial, investigators demonstrated no change
Dobutamine should be used as the primary inotropic agent if in mortality for patients with severe sepsis when vasopressin was
myocardial dysfunction is evident. After an initial stabilization added to catecholamine vasopressors.
period, vasopressors should be titrated down, as tolerated;
however, the duration of this stabilization period is variable and Dobutamine.  Dobutamine is a mixed α- and β-agonist. In
may be hours to days. dosage ranges from 2 to 28 µg/kg/min, the cardiac index is
increased at the expense of heart rate. In addition, decreased
Norepinephrine.  Norepinephrine is a mixed α- and splanchnic blood flow is common. Dobutamine should be used
β-agonist with minimal β2 activity and primarily functions to in patients with depressed cardiac index and persistent hypoper-
increase cardiac output and systemic vascular resistance. In a large fusion in spite of adequate volume expansion and the use of other
study examining patients with shock from multiple causes, nor- vasopressor agents. In patients undergoing formal, early, goal-
epinephrine was shown to have fewer adverse events (particularly directed therapy, when preload, perfusion pressure, and oxygen-
arrhythmias) compared with dopamine, which had a higher carrying capacity have been normalized and a low Scvo2 persists,
mortality rate in patients with cardiogenic shock.11 In another dobutamine is used to increase cardiac output and oxygen deliv-
meta-analysis, norepinephrine was shown to be superior to ery. One study has suggested that survival in sepsis is associated
dopamine in both in-hospital and 28-day mortality.12 with the patient’s increase in stroke volume in response to
Compared with dopamine in septic patients, norepinephrine dobutamine.
increases glomerular filtration and urine output equally well. It is
an important component of the therapy for septic shock as a sole Bicarbonate
vasopressor or in conjunction with other vasopressors. Recom-
mended doses are 8 to 12 µg/min. Bicarbonate supplementation was previously the standard treat-
ment for patients with presumed lactic acidosis. Current consensus
Dopamine.  Dopamine is also often used for septic shock is that it should be reserved for severe acidemia (pH < 7.0–7.2)
unresponsive to adequate volume expansion. Dopamine is the because there may be a paradoxical decrease in intracellular pH
immediate precursor of norepinephrine and epinephrine. It is as a result of diffusion of soluble carbon dioxide across the cell
primarily an α-, β1-, and dopaminergic agonist. Although low membrane. Alternatively, hyperventilation has been suggested to
doses alone are not effective, they may be effective in combination help increase systemic pH.
with other agents. So-called renal dose dopamine has not been
shown to reduce mortality or decrease dialysis dependence and Antibiotics
should not be used. Dosages higher than 20 µg/kg/min may
produce significant vasoconstriction. Persistent tachycardia, Early antibiotic therapy should target the nidus of infection if
decreased partial pressure of arterial oxygen, and increased pul- known. If the patient’s condition permits, appropriate culture
monary artery occlusion pressure are common side effects of specimens should be obtained before the administration of
dopamine use. broad-spectrum antibiotics (Table 130.3). Surgically correctable
conditions, such as intra-abdominal abscesses, perforated viscus,
Phenylephrine.  Phenylephrine is a selective α1-agonist, retained products of conception, or retained foreign body (eg, a
increasing systemic vascular resistance without significant changes tampon), should be treated concurrently. Antibiotics should be
in cardiac output. It can produce a reflexive bradycardia or sup- administered as soon as possible in patients with serious infec-
pression in cardiac output. A single small study has shown that tions. Although some observational studies and national bench-
phenylephrine is effective in restoring perfusion in patients with marks have called for the administration of antibiotics within a
septic shock refractory to dopamine or dobutamine. Another predefined time period of 3 hours from ED presentation, a com-
small study has demonstrated that phenylephrine is less effective prehensive meta-analysis failed to support an association between

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1730 PART III  Medicine and Surgery  |  SECTION Twelve  Infectious Diseases

TABLE 130.3 

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
HIV infection Ticarcillin-clavulanate plus tobramycin
Pneumonia Immunocompetent Second- or third-generation cephalosporin plus second-generation
macrolide or fluoroquinolone
Legionella suspected Azithromycin, fluoroquinolone, or high-dose erythromycin
Abdominal infection 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
Cellulitis 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
Intravenous catheter Outpatient-acquired Third-generation cephalosporin
infection (remove MRSA suspected Add vancomycin.
catheter) Fungal infection Amphotericin B
Cerebrospinal infection Immunocompetent Ceftriaxone plus vancomycin
Older adult or immunocompromised patient Add ampicillin.
Injection drug abuse MRSA not suspected Nafcillin plus aminoglycoside
MRSA suspected Vancomycin plus aminoglycoside
a
Pending microbiologic identification of organism and sensitivity.

antibiotics administered after 3 hours and mortality.13 Thus, appear to be more effective in reducing the amount of time
early antibiotics are important, but their exact timing remains patients spend in a hypotensive state, but increase the rate of
undefined. secondary infection, contributing to a null effect overall. At this
In the absence of an obvious source of infection, the use of time, we believe that the role of steroid therapy in sepsis remains
broad-spectrum antibiotics is recommended. The specific agent controversial and recommend their use in patients on chronic
depends on many variables, including institutional preference and steroid therapy when there is refractory cardiovascular insuffi-
local resistance patterns. As results from cultures become avail- ciency, despite maximal supportive therapy and replacement
able, therapy should be modified. There is no consensus about the therapy.
need for double or triple antibiotic coverage for particular organ-
isms, although it is common practice to double-cover virulent DISPOSITION
organisms, such as Pseudomonas aeruginosa, as well as areas com-
monly infected with multiple organisms, such as the peritoneum. Once ED management is complete, patients who are deemed at
With increasing rates of methicillin-resistant organisms, combi- increased risk should be admitted to the hospital into a setting
nations that include nonpenicillin choices may be warranted. that is deemed appropriate for the severity of the patient’s condi-
tion. For example, in patients who remain hypotensive, are on
Steroid Therapy vasopressors, or who are unstable and require more frequent
monitoring, the intensive care unit may be appropriate. Other
It has been nearly 40 years since the first treatment attempts to patients who are more stable but still require monitoring and
block inflammation in sepsis. Because sepsis involves a systemic perhaps IV therapy may be admitted to a hospital ward. Finally,
inflammatory response, corticosteroids are a logical treatment in certain cases, patients initially meeting sepsis criteria but who
modality as antiinflammatory agents. Physicians have been are not severely ill (eg, young patients with pharyngitis) may be
working for decades to prove or disprove their value. Steroids 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 • Early treatment should focus on appropriate identification,
inflammatory cascade, leading to organ dysfunction and circulatory improvement of tissue perfusion (through administration of fluids
compromise in severe cases. and vasopressor medications), improvement of tissue oxygenation
• Sepsis is subtle and often difficult to detect, so the emergency (through administration of oxygen and positive-pressure ventilation),
clinician should maintain a high index of suspicion when assessing administration of antibiotics, and early identification of infections
patients in the ED. requiring surgical management.
• Older adults, immunocompromised and neutropenic patients, and • Prompt administration of antibiotics is essential and should be based
patients with multiple comorbidities are at increased risk for the on the suspected source of infection.
development of sepsis syndromes.
• A thorough history and physical examination should guide the
diagnostic evaluation.

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

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 CH APTER 130  Sepsis Syndromes 1731.e1

REFERENCES
1. Howell MD, Talmor D, Schuetz P, et al: Proof of principle: the predisposition, infec- 8. Pro CI, Yealy DM, Kellum JA, et al: A randomized trial of protocol-based care for
tion, response, organ failure sepsis staging system. Crit Care Med 39:322–327, 2011. early septic shock. N Engl J Med 370:1683–1693, 2014.
2. Pierrakos C, Vincent JL: Sepsis biomarkers: a review. Crit Care 14:R15, 2010. 9. Mouncey PR, Osborn TM, Power GS, et al: Trial of early, goal-directed resuscitation
3. Sheu CC, Gong MN, Zhai R, et al: Clinical characteristics and outcomes of sepsis- for septic shock. N Engl J Med 372:1301–1311, 2015.
related vs non-sepsis-related ARDS. Chest 138:559–567, 2010. 10. Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: international
4. Shapiro NI, Wolfe RE, Moore RB, et al: Mortality in Emergency Department Sepsis guidelines for management of severe sepsis and septic shock, 2012. Intensive Care
(MEDS) score: a prospectively derived and validated clinical prediction rule. Crit Med 39:165–228, 2013.
Care Med 31:670–675, 2003. 11. De Backer D, Biston P, Devriendt J, et al: Comparison of dopamine and norepineph-
5. Heffner AC, Horton JM, Marchick MR, et al: Etiology of illness in patients with severe rine in the treatment of shock. N Engl J Med 362:779–789, 2010.
sepsis admitted to the hospital from the emergency department. Clin Infect Dis 12. Vasu TS, Cavallazzi R, Hirani A, et al: Norepinephrine or dopamine for septic shock:
50:814–820, 2010. systematic review of randomized clinical trials. J Intensive Care Med 27:172–178,
6. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of 2012.
severe sepsis and septic shock. N Engl J Med 345:1368–1377, 2001. 13. Sterling SA, Miller WR, Pryor J, et al: The impact of timing of antibiotics on outcomes
7. Investigators A, Group ACT, Peake SL, et al: Goal-directed resuscitation for patients in severe sepsis and septic shock: a systematic review and meta-analysis. Crit Care
with early septic shock. N Engl J Med 371:1496–1506, 2014. Med 43:1907–1915, 2015.

CHAPTER 130: QUESTIONS & ANSWERS

130.1. Which of the following patients meets the criteria for 130.4. What are the two most common sources of infection in
systemic inflammatory response syndrome (SIRS)? cases of sepsis?
A. 6-year-old boy with pneumonia, temperature 39.0° C A. Genitourinary > respiratory
(102.2° F) B. Musculoskeletal > genitourinary
B. 21-year-old woman with abdominal pain, C. Respiratory > gastrointestinal
temperature 38.3° C (100.9° F) D. Respiratory > genitourinary
C. 53-year-old man with respirations, 30 breaths/min, E. Skin > respiratory
white blood cell (WBC) count, 16,000 cells/mm3
Answer: C. Epidemiology studies show that pneumonia is the
D. 74-year-old woman with chest pain, heart rate 130
most common cause of sepsis, followed by an intra-abdominal
beats/min
source. However, a careful investigation to identify the source of
E. 81-year-old man with WBC count, 2700 cells/mm3,
infection should occur.
heart rate, 73 beats/min
Answer: C. SIRS is defined as two or more of the following— 130.5. In most chemotherapy patients, which neutrophil count
tachycardia, tachypnea, temperature higher than 38° C (100.4° F) should prompt admission, isolation, and empirical
or lower than 35° C (95° F), high or low WBC count, or bandemia. antibiotics?
Sepsis is SIRS with infection. Severe sepsis includes organ dys- A. <250 cells/mm3
function. Septic shock involves systolic blood pressure below B. <500 cells/mm3
90 mm Hg. C. <750 cells/mm3
D. <1000 cells/mm3
130.2. Sepsis is characterized by which of the following? E. <2000 cells/mm3
A. Depression of arachidonic acid metabolites
Answer: B. Patients with an ANC <500 cells/mm3 are at increased
B. Depression of tumor necrosis factor levels
risk of infection; thus, a conservative approach should be taken in
C. Increased endogenous anticoagulant levels
these patients.
D. Prolonged suppression of nitric oxide levels
E. Prolonged suppression of vasopressin levels
130.6. Among patients with clinical septic shock, which
Answer: E. Clinical sepsis is induced by sustained levels of proin- percentage will have positive blood cultures?
flammatory and procoagulant mediators. Cytokines (interleukin-1, A. 0%–30%
interleukin-6, and tumor necrosis factor alpha) and prostaglan- B. 30%–60%
dins are primary mediators. Nitric oxide synthase is upregulated, C. 60%–90%
resulting in sustained elevations of the serum nitric oxide level, D. 90%–100%
with subsequent vasodilations. Sustained suppression of vasopres- E. Varies according to patient comorbidities
sin adds to this sometimes refractory vasodilated state.
Answer: B. While blood cultures are perhaps a gold standard for
identification and isolation of bacteria, they may negative, even
130.3. Which of the following statements regarding septic shock
when the etiology of illness is clearly infectious. Empiric antibiotic
is true?
treatment in the ED remains a standard approach.
A. Cardiac output is always decreased.
B. Much of the cardiac decompensation is reversible.
130.7. A 65-year-old man presents with blood pressure of
C. Systemic vascular resistance is high.
88/40 mm Hg, heart rate of 105 beats/min, respiratory
D. The ejection fraction is always increased.
rate of 24 breaths/min, O2 saturation of 92%, and
E. Ventricular dilation is unusual.
temperature of 38.5° C (101.3° F). Fluid resuscitation,
Answer: B. Sepsis affects myocardial function and peripheral oxygen, and empirical antibiotics are begun. Blood
vascular tone. The systemic vascular resistance is usually markedly pressure after 2 L of saline is 98/50 mm Hg. A central
depressed. Cardiac output is generally increased because of a venous catheter is placed, with a central venous pressure
compensatory tachycardia that can at least partially overcome the of 11 mm Hg. A venous blood gas sample drawn from
ventricular dilation and depressed ejection fraction. The myocar- this catheter shows hematocrit of 24%, Po2 of 34 mm
dial effects are typically reversible. Hg, Pco2 of 46 mm Hg, pH of 7.29, and O2 saturation of

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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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