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CHAPTER 64: Sepsis, Severe Sepsis, and Septic Shock 567

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systematically evaluating the patient from head to toe to find symptoms INTERLEUKIN-6
and signs of infection and organ dysfunction. Starting from the head, the Tumor necrosis alpha (TNF-α) induces IL-6, which has a longer half-life
patient’s neurological status should be assessed. Is the patient alert and than other inflammatory cytokines and thus can be measured reliably
oriented or confused and agitated? Is the patient hypoactive or hyperac- in the serum after the host mounts an immune response. IL-6 has been
tive, either of which may be signs of encephalopathy? In patients with identified as an important mediator in septic shock and has shown a
preexisting cerebrovascular disease or dementia, sepsis may worsen correlation with disease severity. A retrospective study of the pla-
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baseline neurological function. Does the patient have nuchal rigid- cebo arm of the Recombinant Human Activated Protein C Worldwide
ity secondary to meningitis? Orbital and oral examinations are also Evaluation in Severe Sepsis (PROWESS) trial found that IL-6 levels cor-
important. Patients may have subtle signs of oral candidiasis often seen related with AKI. However, IL-6 lacks specificity because it is elevated
45
in immunocompromised patients. Auscultation of the lungs may reveal in various noninfectious inflammatory conditions as in trauma, surgery,
rhonchi or crackles (suggesting pneumonia) or dullness to percussion and critical illness. Previous studies have revealed that the accuracy of
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(suggesting pleural effusion). The abdominal examination may reveal IL-6 likely depends on the timing and frequency of measurements, with
ascites, tenderness, or other physical findings indicative of abdominal levels >1000 ng/mL being highly predictive of sepsis-related death.
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infections. Cholecystitis and acute cholangitis may cause pain in the IL-6 levels are not routinely available from a clinical laboratory.
right upper quadrant, while pancreatitis may present similarly in
the epigastrium. Diverticulitis, appendicitis, and peritonitis can present ■ C-REACTIVE PROTEIN
with diffuse abdominal pain. Also, the skin should not be forgotten for
signs of erythema, rash, or skin breakdown, which could be entry points C-reactive protein is an acute phase protein with both pro- and
for infectious pathogens. Cellulitis in diabetic patients can cause sepsis anti-inflammatory properties that is produced mostly by hepa-
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and may indicate a polymicrobial infection. Necrotizing fasciitis can tocytes and alveolar macrophages. CRP, through the expression of
cause rapidly progressive sepsis and organ dysfunction starting with sub- anti- inflammatory cytokine transforming growth factor β (TGF- β),
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tle skin findings, advancing to crepitus and myonecrosis within hours. augments opsonization and phagocytosis of apoptotic cells. Clinically,
■ LABORATORY STUDIES AND RADIOLOGIC IMAGING CRP levels are often used to monitor antibiotic treatment response to
various chronic infections, such as osteomyelitis. Similar to IL-6, CRP
Every attempt should be made to locate and identify the infec- is elevated in various noninfectious states and although inexpensive and
tious pathogen. This usually involves blood, urine, and respiratory widely accessible, it is not sufficiently specific for clinical use in patients
cultures. Additional directed samples from suspected sources such with sepsis. In addition, studies have found that CRP levels are elevated
as cerebrospinal fluid in suspected meningitis, pleural fluid from sus- in sepsis but they do not correlate well with Sequential Organ Failure
70,71
pected empyema, bronchial alveolar lavage or bronchial brushings from Assessment scores (see the section Severity Index Scores).
respiratory bronchi, and ascitic fluid in suspected peritonitis may be ■
warranted (see the section Source Control). SOLUBLE TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS
Other diagnostic studies include a complete white blood cell count Soluble triggering receptor expressed on myeloid cells (sTREM-1),
with differential, a complete metabolic profile evaluating electrolytes, part of the immunoglobulin superfamily, is stimulated in response
kidney, and liver function as well as a coagulation profile (platelets, to infection. Previous studies have investigated the use of sTREM-1
prothrombin time, and partial thromboplastin time). If the coagulation as a diagnostic biomarker for febrile neutropenic patients and found
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profile is abnormal, further evaluation with specific parameters to evalu- sTREM-1 sensitivity and specificity were 88% and 48%, respectively.
ate for disseminated intravascular coagulation (fibrinogen, fibrin split When comparing serum sTREM-1 and cytokine levels between septic
products, and D-dimer) should be ordered. For patients with respiratory and nonseptic patients with ARDS, sTREM-1 could not differentiate
dysfunction, arterial blood gases are appropriate to evaluate for pending between groups, although higher initial levels of sTREM-1 and increas-
respiratory failure, and for patients with severe sepsis, a lactate and a ing levels over 5 days predicted higher mortality. Other studies in
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central venous or mixed venous blood gas is also appropriate (see the adults and neonates have failed to demonstrate superiority of sTREM-1
section Fluid Therapy). Septic patients commonly have multiple abnor- over CRP, PCT, or other markers for the diagnosis of sepsis, although
malities on laboratory examination. they are generally prognostically significant. 74,75
As previously discussed, the pathogenesis of sepsis can affect every ■
organ. After a thorough history and physical examination, diagnostic PROCALCITONIN
imaging should be ordered targeting abnormalities noted on physical Procalcitonin, a propeptide of calcitonin, is involved in the host inflam-
examination. Chest imaging is frequently useful, and is necessary matory response. In animal models of sepsis, blocking PCT improved
in patients with suspected respiratory or pleural infection. A simple organ dysfunction. Multiple studies have been done looking at PCT
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flat plate radiograph of the abdomen can help in diagnosing ileus or as a specific diagnostic and prognostic biomarker for sepsis. Riedel et al
perforation, although computed tomography has superior diagnos- studied the usefulness of PCT in the emergency room as a marker
tic capability for the myriad of diseases that occur in the abdomen for blood stream infections. Serum samples of PCT were taken the
(eg, pancreatitis, colitis, biliary diseases, or abscess). Ultrasonography same time blood cultures were obtained in 295 patients. Sensitivity
is increasingly useful in the evaluation of many sources of infection, and specificity for the PCT assay were 75% and 79%, respectively. The
including the chest, abdomen, genitourinary system, soft tissue, and positive predictive value was 17% and the negative predictive value 98%
cardiac structures. compared with blood cultures, suggesting that PCT is a potential useful
■ PROGNOSIS: BIOMARKERS OF SEPSIS marker to evaluate for sepsis. PCT is studied in various other contexts
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as a marker of severity or a prognosticator for mortality such as postop-
Various biomarkers have been evaluated for diagnosis, risk stratifica- erative sepsis, burn-related sepsis, and trauma-induced sepsis. 77-80 These
tion, and prognosis in sepsis. In the most recent sepsis consensus con- studies concluded that incorporating PCT into sepsis management
ference, the diagnostic approach to sepsis remained unchanged largely for diagnosis and prognosis was beneficial. Karlsson et al found that
because no biomarker has sufficient diagnostic accuracy to reliably although median PCT levels were not different between survivors and
diagnose or exclude sepsis. 66,67 However, a few biomarkers are worth nonsurvivors, survivors had a greater than 50% decrease in their admis-
discussing for either conceptual illustration or because of purported sion PCT levels compared to nonsurvivors, suggesting that the percent
clinical value: interleukin-6 (IL-6), C-reactive protein (CRP), soluble decrease of PCT levels was more important than the absolute level of
triggering receptor expressed on myeloid cells (sTREM)-1, and procal- PCT. Comparing PCT to CRP, IL-6, and lactate, PCT is consistent in
81
citonin (PCT). 66 detecting sepsis with a strong negative predictive value. 70,82 The US Food

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