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Although acute infection generally is associated with an increased white
blood cell count, fever, and localizing signs, these symptoms may be
absent in less severe disease. More severe infection, including sepsis,
may be associated with hypotension, disseminated intravascular
coagulation, and end-organ dysfunction.
Other disease states, particularly autoimmune disease and malignancy,
may mimic infectious diseases. Although it should be considered a
diagnosis of exclusion, drug-induced fever should be ruled out,
particularly in patients without other classic signs and symptoms of
Site-specific signs and symptoms and host factors generally predict the
most likely pathogens, and empirical antimicrobial therapy should be
directed against these organisms. Rapid detection tests improve the
efficiency identifying a pathogen; however, they are more costly than
Isolation of an organism may reflect infection; however, colonization and
contamination must be ruled out to avoid unnecessary antimicrobial
exposure. Once a pathogen is identified, susceptibility tests, particularly
disk diffusion or broth dilution, can demonstrate the most active
Once the site of infection is confirmed and the likely pathogens are
identified, drug distribution to the site of infection, dosage, route of
administration, antimicrobial toxicity, side effects, and costs, must be
considered before selection of therapy.
Antimicrobial dosing should reflect site of infection, route of elimination,
and pharmacokinetics and pharmacodynamics.
Antimicrobial failure may be related to pharmacologic factors
(inadequate dosing, insufficient penetration to the site of infection, and
inadequate duration) and host factors (presence of prosthetic material,
undrained focus of infection, and immune status). Adjunct therapies,
including pressors and volume repletion, may improve outcomes in
The proper choice, dose, and duration of antimicrobial therapy are based on several
factors. Before initiating therapy, it is important first to confirm an infectious versus
noninfectious process. Once infection has been documented, the most likely site must
be identified, and signs and symptoms (e.g., erythema associated with cellulitis)
generally direct the clinician to the likely source. Because certain pathogens are
known to be associated with a specific site of infection, empirical therapy often can
be directed against these organisms. Additional laboratory tests, including the Gram
stain, serologic analysis, and antimicrobial susceptibility testing, generally identify
the primary pathogen and active agents. Spectrum of activity, established clinical
efficacy, adverse effect profile, pharmacokinetic disposition, and cost considerations
ultimately guide the choice of therapy. Once an agent has been selected, the dosage
and duration should be based on the size of the patient, site of infection, route of
elimination, and other factors.
ESTABLISHING THE PRESENCE OF AN
yellow–green secretions are suctioned from his endotracheal tube.
mL/hour for the past 2 hours. Erythema is noted around the central venous catheter.
urine cultures are pending. Other laboratory values include the following:
Sodium (Na), 131 mEq/L (normal, 135–147)
Potassium (K), 4.1 mEq/L (normal, 3.5–5)
Chloride (Cl), 110 mEq/L (normal, 95–105)
, 16 mEq/L (normal, 20–29 mEq/L)
Blood urea nitrogen (BUN), 58 mg/dL (normal, 8–18)
Serum creatinine (SCr), 3.8 mg/dL (increased from 0.9 mg/dL at admission; normal, 0.6–1.2)
Glucose, 320 mg/dL (normal, 70–110)
Serum albumin, 2.1 g/dL (normal, 4–6)
Hemoglobin (Hgb), 10.3 g/dL (13.5–17.5 g/dL male patients)
Hematocrit (Hct), 33% (normal, 39%–49% [male patients])
WBC count, 15,600/μL (normal, 4,500–10,000/μL) with bands present
Platelets, 40,000/μL (normal, 130,000–400,000)
Prothrombin time (PT), 18 seconds (normal, 10–12)
Erythrocyte sedimentation rate (ESR), 65 mm/hour (normal, 0–20)
Procalcitonin, 1 mcg/L (normal <0.25mcg/L)
Which of R.G.’s signs and symptoms are consistent with infection?
R.G. has numerous signs and symptoms consistent with an infectious process. His
WBC count (15,600/μL) is increased, and a “shift to the left” (presence of bands,
i.e., immature neutrophils) is observed on the differential. An increased WBC count
is commonly observed with infection, particularly with bacterial pathogens. The
WBC differential in patients with a bacterial infection often demonstrates a shift to
the left owing to the bone marrow response to infection. Although infection is usually
associated with an increased WBC, overwhelming sepsis can also be associated
with a markedly decreased WBC count. In less acute infection (e.g., uncomplicated
urinary tract infection, localized abscess), the WBC count may remain within the
normal range because less bone marrow response would be anticipated.
R.G.’s temperature is 40°C by axillary measurement. Fever is a common
manifestation of infection, with oral temperatures generally greater than 38°C. Oral
and axillary temperatures tend to be approximately 0.4°C lower compared with
rectal measurement. As a result, R.G.’s temperature would be expected to be 40.4°C
if his temperature had been taken rectally. In general, rectal measurement of
temperature is a more reliable determination of fever. Some patients with
overwhelming infection, however, may present with hypothermia with temperatures
less than 36°C. Furthermore, patients with localized infections (e.g., uncomplicated
urinary tract infection, chronic abscesses) may be afebrile.
The bilateral lower lobe infiltrates on R.G.’s chest radiograph, the presence of
copious amounts of yellow–green secretions from his endotracheal tube, and the
erythema surrounding his central venous catheter is also compatible with one or more
infectious processes. Furthermore, R.G. has signs and symptoms consistent with
ESTABLISHING THE SEVERITY OF AN
CASE 62-1, QUESTION 2: What signs and symptoms manifested by R.G. are consistent with a serious
The term sepsis, while a poorly defined syndrome, generally suggests a more
systemic infection with the presence of pathogenic microorganisms and/or their
toxins in the blood. A uniform system for defining the spectrum of disorders
associated with sepsis has been established, but it remains difficult to precisely
The pathogenesis of sepsis is complex (Fig. 62-1) and only partially understood.
Gram-negative aerobes produce endotoxin that results in a cascade of endogenous
mediator release, including tumor necrosis factor (TNF), interleukin 1 (IL-1) and
interleukin 6 (IL-6), platelet-activating factor (PAF), and various other substances
from mononuclear phagocytes and other cells. Although this initial stimulus
commonly is associated with gram-negative endotoxin, other substances, including
gram-positive exotoxin and fungal cell wall constituents, may also be associated with
cytokine release. After release of TNF, IL-1, and PAF, arachidonic acid is
metabolized to form leukotrienes, thromboxane A2
, and prostaglandins, particularly
prostaglandin E2 and prostaglandin I2
. IL-1 and IL-6 activate the T cells to produce
releases two hemodynamically active substances: endothelium-derived relaxing
factor (EDRF) and endothelin-l. Activation of the complement cascade (fragments
C3a and C5a) follows, with additional vascular abnormalities and neutrophil
activation. Other potentially important agents in this cascade include adhesion
molecules, kinins, thrombin, myocardial depressant substance, endorphins, and heat
shock protein. The net result of this cascade involves several hemodynamic, renal,
acid–base, and other disorders. Uncontrolled inflammation and coagulation have a
particularly important role in this sepsis cascade.
Critically ill patients often have central intravenous (IV) lines in place for measuring
cardiac output and systemic vascular resistance (SVR). In other words, these lines
are placed in the pulmonary artery and allow for more precise measurement of
critical hemodynamics. A normal SVR of 800 to 1,200 dyne·s·cm–5 may fall to 500 to
in septic shock as a result of extensive vasodilation. In response to
vasodilation the heart rate increases leading to increased cardiac output from a
normal 4 to 6 L/minute to up to 11 to 12 L/minute in septic patients; stroke volume
remains unchanged or decreased. In addition to reflex tachycardia causing a rise in
heart rate, stress-induced catecholamine release (norepinephrine, epinephrine) also
contributes. The initial increase in cardiac output generally is insufficient to
overcome the vasodilatory state, and hypotension ensues. In overwhelming septic
shock, myocardial depression may result, resulting in a decreased cardiac output.
The combination of decreased cardiac output and decreased SVR results in
hypotension often unresponsive to pressors and IV fluids. R.G. has hemodynamic
evidence of septic shock. He is hypotensive (BP, 70/30 mm Hg) and tachycardic
(130 beats/minute), presumably in response to vasodilation and catecholamine
Although vasodilation commonly occurs in sepsis, this dilation is unequal and
chaotic. Some vascular beds constrict and others dilate, resulting in maldistribution
of blood flow. In sepsis, blood generally is shunted away from the kidneys,
When sepsis has progressed to septic shock, blood flow to most major organs is
decreased. Normal urine output of approximately 0.5 to 1.0 mL/kg/hour (30–70
mL/hour for a 70-kg patient) can decrease to less than 20 mL/hour in sepsis. The
urine output for R.G. has decreased to 10 mL/hour, consistent with sepsis-induced
(BUN, 58 mg/dL) and increased serum creatinine concentration (3.8 mg/dL) are
consistent with decreased renal perfusion secondary to sepsis. Decreased blood flow
to the liver may result in “shock liver,” in which liver function tests, including
alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase, become elevated. The liver function tests for R.G. are not available;
however, his serum albumin concentration is low (2.1 g/dL) and his PT of 18
seconds is prolonged. Decreased blood flow to the musculature classically is
characterized by cool extremities, and decreased blood flow to the brain can result in
decreased mentation. R.G. is confused, his extremities are cold, and the area around
his mouth appears pale. All these signs and symptoms provide strong evidence that
The sepsis syndrome is associated with significant abnormalities in cellular
metabolism. Glucose intolerance commonly is observed in sepsis, and patients with
previously normal blood glucose levels may experience sudden increases in blood
sugar. In some cases, a rise in glucose is one of the first signs of an infectious
process. R.G.’s increased blood glucose concentration (320 mg/dL) is, therefore,
consistent with infection. Other sensitive indicators of sepsis-associated
inflammation include the ESR, C-reactive protein, and procalcitonin, nonspecific
tests that are commonly elevated in various inflammatory states, including infection.
The ESR, C-reactive protein, or procalcitonin can be used to follow the progression
of infection; currently, R.G.’s ESR is elevated at 65 mm/hour. With appropriate
management of infection, the ESR would be expected to decrease; inadequate
treatment would be associated with persistent elevation of the ESR and C-reactive
4 At present, R.G.’s procalcitonin is 1.0 mcg/L, which is
consistent with infection-associated inflammati
Production of organic acids, such as lactate, increased glycolysis, decreased
fractional extraction of oxygen, and abnormal delivery-dependent oxygen
consumption are observed in sepsis.
3 This process leads to metabolic acidosis, with
accompanying decreased serum bicarbonate levels. The lungs normally respond to
metabolic acidosis in a compensatory manner with an increased respiratory rate
(tachypnea), resulting in an increased elimination of arterial carbon dioxide. R.G.’s
acid–base status is consistent with sepsis- associated metabolic acidosis (CO2
mEq/L) and compensatory respiratory alkalosis (respiratory rate, 24 breaths/minute).
A late complication of the above-mentioned sepsis cascade is acute respiratory
distress syndrome (ARDS). ARDS initially was described as noncardiogenic
pulmonary edema with severe hypoxemia caused by right-to-left intrapulmonary
shunting resulting from atelectasis and edema-filled alveoli. The primary
pathophysiology of ARDS is a breakdown in the natural integrity of the alveolar
capillary network in the lung.
In the early phase of ARDS, patients have severe
alveolar edema with large numbers of inflammatory cells, primarily neutrophils. The
chronic phase of ARDS (10–14 days after development of the syndrome) is
associated with significant lung destruction. Emphysema, pulmonary vascular
obliteration, and fibrosis commonly are observed. Severe ARDS is associated with
ratios of arterial oxygen level to fraction of inspired oxygen (Pao2
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