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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.

Case 62-1 (Questions 1, 2)

Figure 62-1

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

infection.

Case 62-1 (Question 3)

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

traditional methodology.

Case 62-1 (Questions 4, 5,

Tables 62-1, 62-2)

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

antimicrobial agents.

Case 62-1 (Questions 6, 7,

Tables 62-3 through 62-7)

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.

Case 62-1 (Questions 8–10,

Table 62-8)

Antimicrobial dosing should reflect site of infection, route of elimination,

and pharmacokinetics and pharmacodynamics.

Case 62-1 (Questions 11–13,

Table 62-9)

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

critically ill patients.

Case 62-1 (Questions 14–17)

APPROACHING THE PROBLEM

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.

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p. 1320

ESTABLISHING THE PRESENCE OF AN

INFECTION

CASE 62-1

QUESTION 1: R.G., a 63-year-old, 70-kg man in the intensive care unit, underwent emergency resection of

his large bowel. He has been mechanically ventilated throughout his postoperative course. On day 20 of his

hospital stay, R.G. suddenly becomes confused; his blood pressure (BP) drops to 70/30 mm Hg, with a heart

rate of 130 beats/minute. His extremities are cold to the touch, and he presents with circumoral pallor. His

temperature increases to 40°C (axillary), and his respiratory rate is 24 breaths/minute. Copious amounts of

yellow–green secretions are suctioned from his endotracheal tube.

Physical examination reveals sinus tachycardia with no rubs or murmurs. Rhonchi with decreased breath

sounds are observed on auscultation. The abdomen is distended, and R.G. complains of new abdominal pain. No

bowel sounds can be heard, and the stool is guaiac positive. Urine output from the Foley catheter has been 10

mL/hour for the past 2 hours. Erythema is noted around the central venous catheter.

A chest radiograph demonstrates bilateral lower lobe infiltrates, and urinalysis reveals >50 white blood

cells/high-power field (WBC/HPF), few casts, and a specific gravity of 1.015. Blood, endotracheal aspirate, and

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)

CO2

, 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

sepsis.

ESTABLISHING THE SEVERITY OF AN

INFECTION

CASE 62-1, QUESTION 2: What signs and symptoms manifested by R.G. are consistent with a serious

systemic infection?

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

define.

1

The pathogenesis of sepsis is complex (Fig. 62-1) and only partially understood.

2

,

3

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

interferon, IL-2, IL-4, and granulocyte-macrophage colony-stimulating factor (GMCSF). Increased endothelial permeability ensues. Subsequently, the endothelium

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.

3

Hemodynamic Changes

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

600 dyne·s·cm–5

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

release.

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p. 1321

Figure 62-1 The sepsis cascade. ARDS, acute respiratory distress syndrome; ARF, acute renal failure; DIC,

disseminated intravascular coagulation; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1,

interleukin-1; IL-2, interleukin-2; IL-6, interleukin-6; PAF, platelet-activating factor; TNF, tumor necrosis factor.

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,

mesentery, and extremities.

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

perfusion abnormalities. Decreased blood flow to the kidney as well as mediatorinduced microvascular failure can cause acute-tubular necrosis. R.G.’s uremia

(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

he is in septic shock.

Cellular Changes

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

protein. Procalcitonin is a more specific indicator for infection than ESR or Creactive protein and has been used as a tool to discontinue antibiotics in patients with

noninfectious inflammation.

4 At present, R.G.’s procalcitonin is 1.0 mcg/L, which is

consistent with infection-associated inflammati

Respiratory Changes

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

, 16

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.

5

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

/FIO2

) of less than

100, low

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