Clinical

Microbiology
Newsletter
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Vol. 32, No. 5 www.cmnewsletter.com March 1, 2010

Code Sepsis: Rapid Methods To Diagnose Sepsis and Detect

Hematopathogens
Part I: The Impact and Attributes of Sepsis*
Donna M. Wolk, MHA, Ph.D., D(ABMM), Albert B. Fiorello, M.D., Department of Emergency Medicine, University of Arizona,
Tucson, Arizona
Abstract
Bloodstream infections are among the top causes of death in the United States, and substantial mortality is attributed to testing
delays in determinating the microbial cause(s) and selection of the appropriate antibiotic. In this review, we summarize the human
and financial impact of sepsis, as well as the predisposing factors, symptoms, and common modes of bacterial pathogenesis. We
also detail important clinical and laboratory criteria for the diagnosis of sepsis and key aspects of the Surviving Sepsis Campaign
Guidelines as they relate to diagnosis, therapy, and resuscitation from the septic event. Clinical laboratories must expand their
understanding of the complexities related to diagnosing and treating sepsis in order to expand their role as productive members
of interdisciplinary health care teams focused on improving survival from sepsis and limiting the financial impact that sepsis
imposes on our health care systems.

Morbidity and Mortality an intermediate-care or coronary-care Sepsis is commonly associated with

Bloodstream infections can lead to
sepsis, a multi-symptom manifestation
of bloodstream infection that causes
rapid fatalities across all demographic
populations. Sepsis is among the top 10
causes of death for patients in the United
States, with over 750,000 episodes each
year in U.S., at times exceeding 50%
mortality. Over 500 U.S. patients die
per day, nearly 183,000 per year (1-7).
The estimated sepsis incidence rate is
approximately 3 in every 1,000 patients;
of these patients, 51% require intensive
care unit (ICU) care, with an additional
17% requiring mechanical ventilation in
*Editor’s Note: Part II of this article will
appear in the March 15, 2010 issue of
CMN, Volume 32, Number 6.
Mailing address: Donna M. Wolk, MHA,
Ph.D., D(ABMM), Assistant Professor,
Department of Pathology, University of
Arizona, 1501 N. Campbell Ave., P.O. Box
245059, Tucson, AZ 85724-5059. Tel.:
520-626-3676. Fax:520-694-7329.
E-mail: dwolk@email.arizona.edu
unit setting (4). prolonged length of stay in the hospital
Cases of sepsis, primarily caused by and the ICU, up to 8 days longer, accord-
bloodstream infections, are increasing ing to MEDPAR Hospital Discharge
dramatically, recently doubling in inci- Databases 2004 through 2005 and crit-
dence (1-3) and expected to increase ical care reviews (4,12). With reports of
by as much as 1.5% to 10% per year 2.26 cases per 100 hospital discharges,
(1,2,8,9). Sepsis is a growing problem costs to care for septic patients impose
for health care systems worldwide, a large economic burden, averaging
affecting 18 million people and equal- $22,100 to $40,890 per case (2,8,9). In
ing the number of fatalities from acute a study of medication costs in the ICU,
myocardial infarction (10). half of the cost of medications and
nutrition was attributed to antibiotics
Economic Burden to Health Care
Sepsis occurs in approximately 2%
of all hospitalizations and 75% of inten-
sive care patients (1), with enormous
concomitant social and economic bur-
dens. In the U.S., the current per capita
incidence is at least 240 patients per
100,000 people and estimated health
care costs that exceed $17 billion dollars
per year (2,8,9). Emergency medicine
departments (EMDs) are a common
interface with septic patients, who
account for approximately 571,000
EMD visits per year (8,9,11).

Clinical Microbiology Newsletter 32:5,2010 © 2010 Elsevier 0196-4399/00 (see frontmatter) 33

(13). A common precursor to sepsis,
bacteremia, acquired in the ICU, is
associated with increased mortality, a
longer ICU stay, and a 25% increase in
costs of hospital care ($85,137 versus
$67,879) (14).
Predisposing Underlying
Diseases Increase Risks
Contributing factors are varied and
include the following.
Critical care and surgery
Sepsis can be a fatal outcome for post-
surgical patients in a variety of settings,
including transplantation, wound sur-
gery, splenectomy, intra-abdominal
surgery, and cancer surgery (15-20).
Cancer
An estimated 5% of cancer patients
acquire severe sepsis. Hospitalized
patients with cancer are more than 5
times more likely to die (37.8%) than
cancer patients without sepsis. Patients
with hematologic cancers are 15 times
more likely than the average person to
suffer from severe sepsis (21). The use
of cytotoxic agents is largely responsi-
ble for immune suppression in these
patients, which predisposes them to
sepsis. In addition, malignant neo-
plasms can provide entry for bacteria
into the bloodstream.
Age
People over 65 years old account
for only 1/8 of the U.S. population but
account for two-thirds of all sepsis cases.
Age over 40 is a risk factor for sepsis
(22,23), with the poorest outcomes in
patients over age 85, who have a mor-
tality rate over 38.4% (4). At the other
end of the age spectrum, children share
elevated mortality rates (12).
Other
In addition, rheumatic or congenital
heart disease; septic abortion; pelvic
infection; intravenous drug abuse; other
infections, such as severe CAP (com-
34 0196-4399/00 (see frontmatter)
munity-acquired pneumonia), abdomi-
nal infection, and urinary tract infection
(with risk in descending order); alcohol-
ism; meningitis; cellulitis; and chronic
diseases (including diabetes, heart fail-
ure, chronic renal failure, and chronic
obstructive pulmonary disease), surgery,
or cirrhosis are all risk factors for sep-
sis. Immunocompromised status due to
HIV/AIDS increases risks, as do other
immunosuppressive states. Indeed, due
to hospital-associated drug-resistant
infections, the simple act of hospital-
ization increases the risk for blood-
stream infections and sepsis.
Pathogenesis and the
Inflammatory Response
to Sepsis
Bloodstream infections can lead to
sepsis in the following manner. At onset,
a bacterial cell triggers the host immune
response. For gram-negative hemato-
pathogens, the bacterial cell wall endo-
toxin, a lipopolysacharride from the cell
wall, initiates the human inflammatory
response. For gram-positive hemato-
pathogens, it is the lipoteichoic acid,
peptidoglycan, and extracellular prod-
ucts (toxins) that trigger the response.
An inflammatory response follows,
functioning to mount protective host
responses, vascular, cellular, and chem-
ical. These responses are designed to
stop injury with edema, which dilutes
toxins, and phagocytosis, which removes
bacteria and cell debris.
The pathogenesis of sepsis involves
pro-inflammatory mediators, anti-inflam-
matory mediators, and vasoinflammatory
mediators. There are several inflamma-
tory responses of importance, which are
linked to human cells that respond to
bacterial invasion: (i) phagocytes (mon-
coytes/macrophages, neutrophils, eosino-
phils, and, to a lesser extent, mast cells;
(ii) mast cells, which are induced by lipo-
polysacharride and complement (C3a
and C5a) to release immune mediators;
© 2010 Elsevier
and (iii) natural killer cells, which cause
lysis of target cells and production of
cytokines like gamma interferon and
tumor necrosis factor alpha in a process
called cell-mediated cytotoxicity. Other
physiological changes include reduced
protein C activity, micro-plugging of
vessels, cellular necrosis (ischemic
injury), fibrinolysis inhibition, apopto-
sis, leukocyte-mediated tissue injury,
endothelial disfunction, and cytopathic
hypoxia.
While some patients may die from
infection due to their inability to mount
an effective immune response, in
essence, sepsis results from a human
immune response to bacteria (or other
pathogens), which goes awry and gets
out of control (Fig. 1). Patient survival
is dependent on whether or not physi-
cians can balance the patient immune
response to microbial pathogens and
bring patients’ systems back to homeo-
stasis.
Pathophysiology: Sepsis
Symptoms Form a Disease
Gradient
Due to the widespread inflammatory
response (22), disease symptoms are
widely variable and include fever, chills,
hypotension, neutrophilic leukocytosis
or neutropenia, hypothermia (especially
in the elderly), diaphoresis, apprehen-
sion, change in mental status, tachyp-
nea, tachycardia, hyperventilation and
respiratory alkalosis, reduced vascular
tone, and ultimately organ dysfunction.
Hematologic findings are also extremely
important, as the septic patient can pre-
sent with thrombocytopenia, toxic gran-
ulations of neutrophils, or disseminated
intravascular coagulation. Renal and
gastrointestinal (GI) signs include acute
tubular necrosis, oliguria, anuria, upper
GI bleeding, cholestatic jaundice,
increased transaminase levels, and
hypoglycemia.
Clinical Microbiology Newsletter 32:5,2010
 There are consensus definitions that
define the serial stages of sepsis (23), a
progression of disease detailed below.
1. Bacteremia, the presence of viable
bacteria in blood
2. Systemic inflammatory response
syndrome (SIRS), a systemic inflam-
matory response to insults (e.g., infec-
tion, burns, or trauma) that requires
two or more of the following:
a. Temperature of >38°C or <36°C
b. Heart rate of >90 beats per min
c. Respiratory rate of >20 or PaCO2
< 32 mm Hg.
d. White blood cell count >12 × 109/L
or <4 × 109/L or 10% immature
forms (bands)
Figure 1. Inflammation responses that occur in response to bacterial bloodstream infection.
3. Sepsis, the SIRS secondary to infec-
tion, suspected or proven by culture
4. Severe sepsis, which is sepsis plus
signs of hypoperfusion, hypotension,
or organ dysfunction
5. Septic shock, which is refractory
arterial hypotension or hypoperfu-
sion despite adequate intravascular
fluid resuscitation. Hypoperfusion
may be manifested as lactic acidosis,
oliguria, or mental status changes.
Figure 2 illustrates the substantial
overlap of the disease gradient that arises
with bacteremia or another microbial
infection and ends with septic shock.
Non-specific causes of inflammation
can cause SIRS and must be considered
in assessment of patients who present
with inflammatory symptoms.
Rapid Antibiotic Therapy
Saves Lives
In cases of sepsis, rapid intervention
with appropriate antimicrobial therapy Figure 2. There is substantial overlap between infection, inflammatory response, and sepsis.
can be critical to patient survival There are also non-infectious causes of inflammation, which must be eliminated before
(24,25). For aerobes, anaerobes, and treatment for microbial sepsis. (Not to scale.)
fungi, appropriate antibiotic therapy
increases survival by approximately
25 to 45%. Eliminating delays in Diagnostic Approach to pathogens, bloodstream infections,
appropriate antibiotic administration the Septic Patient and sepsis.
increases survival by ~7 to 10% per Unfortunately, despite the enormous
hour (26). Optimized antibiotic care
Requirements for an
human and financial impact of sepsis, Interdisciplinary Team
requires intravenous broad-spectrum this diagnosis remains largely a clinical
antibiotics with daily re-evaluation to As with all complex diseases, the
one (28), due to the lack of rapid, sen-
optimize efficacy, prevent resistance, diagnostic approach to sepsis is multi-
sitive, and specific laboratory tests to
avoid toxicity, and minimize costs, faceted. Laboratory collaboration with
detect the causative pathogens. In order
EMDs and critical care services is
with the ultimate goal of discontinuing to provide a more accurate diagnosis,
essential. Laboratories can participate
broad-spectrum therapy within 3 to 5 there is a significant need to improve
with the entire health care team by set-
days and continuing antibiotics targeted the speed and diagnostic breadth of lab-
ting goals to provide rapid laboratory
to the causative pathogen (27). oratory detection methods for hemato-

Clinical Microbiology Newsletter 32:5,2010 © 2010 Elsevier 0196-4399/00 (see frontmatter) 35

testing to maximize the effectiveness
of early goal-directed therapy, improve
targeted antibiotic therapy, shorten
antibiotic treatment duration, avoid
development of antibiotic resistance
and side effects, decrease mortality
and morbidity, decrease length of stay,
and decrease overall hospital costs.
The clinical microbiology laboratory
must help drive antibiotic intervention
in partnership with pharmacists and
physicians.
Upon presentation of a patient with
symptoms of infection, physicians will
seek the primary site of infection and
attempt to direct therapy to that primary
site. A full history is important to define
the potential source and risks. For
instance, important factors include the
source of infection, community or hos-
pital acquired; prior or current medica-
tions; recent manipulations or surgery;
underlying or chronic diseases; and
travel history.
In addition, there are several stan-
dardized classification systems for ICU
patients, created to assess the severity
of illness (29); one common scoring
system is the APACHE II (Acute Phys-
iology and Chronic Health Evaluation)
score. After admission of a patient to an
ICU, an integer score from 0 to 71 is
computed based on several measure-
ments, including assessment of tem-
perature, arterial blood gas pH, mean
arterial pressure (MAP), serum sodium,
serum creatinine, heart rate, hematocrit,
respiratory rate, white blood cell counts,
oxygenation parameters, and the Glas-
gow Coma Score. Higher scores imply
more severe disease and a higher risk
of death.
Combining a variety of clinical
assessments with various laboratory
tests from clinical microbiology, hema-
tology, chemistry, point-of-care testing,
and blood gas laboratories is an impor-
tant aspect of the optimum care and
treatment of septic patients.
Other Evidence-Based Sepsis
Guidelines
The Surviving Sepsis Campaign is
a worldwide consortium of health care
providers committed to improving the
outcomes for patients with sepsis (23,30).
All components of the Surviving Sepsis
Campaign guidelines are focused on
reducing mortality by using standard-
ized criteria for patient assessment and
36 0196-4399/00 (see frontmatter)
treatment (23). The guidelines, aspects
of which are also referred to as “early
goal-directed therapy” (EGDT), often
rely on laboratory data for optimal use.
EGDT is a combination of prompt rec-
ognition of the symptoms of severe
sesis and septic shock, early antibiotic
administration, and aggressive, proto-
col-driven resuscitation interventions
and subsequent continuous monitoring
of patients.
River’s landmark paper (25) on
EGDT demonstrated a 16% absolute
reduction in mortality in patients treated
using EGDT compared to standard ther-
apy. A more recent review of the litera-
ture regarding EGDT continues to show
significant improvement in mortality
when EGDT is implemented (30). Used
appropriately, EGDT has been shown
to effect a reduction in mortality from
46.5% to 30.5% (31). However, despite
its success, implementing EGDT is both
costly and resource intensive. Physicians
must place invasive lines and monitor
resuscitation of patients closely. Nurses
must perform frequent blood draws,
manage multiple medications (includ-
ing pressors), and tailor prescribed ther-
apy based upon a number of parameters
– some of which may be measured con-
tinuously, and some of which require
periodic blood draws. In light of the
resource and cost intensity of EGDT,
there is concern that overly sensitive
and insufficiently specific criteria for
identifying patients with true bacterial
sepsis may cause overuse of this inter-
vention. Overly sensitive criteria may
also lead to over-administration of anti-
biotics, increasing bacterial resistance
and putting patients at risk of experi-
encing side effects, from allergic
reaction to organ toxicity.
To focus EGDT on the most appro-
priate patients, EMD and ICU services
may use a “sepsis team,” experts whose
focus is implementation and follow-up
with practices called “sepsis bundles,”
as detailed below.
Sepsis resuscitation bundle
(Often triggered in EMD or ICU in
what is sometimes referred to as a
“code sepsis” response)
1. Serum lactate measured
2. Blood cultures obtained prior to
antibiotic administration
3. From the time of presentation, broad-
spectrum antibiotics administered
© 2010 Elsevier
within 3 hours for ED admissions and
1 hour for non-ED ICU admissions
4. In the event of hypotension and/or
lactate > 4 mmol/L (36 mg/dl):
a. Deliver an initial minimum of 20
ml/kg of body weight of crystal-
loid (or colloid equivalent).
b. Apply vasopressors for hypoten-
sion not responding to initial fluid
resuscitation to maintain MAP
>65 mm Hg.
5. In the event of persistent hypotension
despite fluid resuscitation (septic
shock) and/or lactate >4 mmol/L
(36 mg/dl):
a. Achieve central venous pressure
> 8 mm Hg.
b. Achieve central venous oxygen
saturation >70%.
Sepsis management bundle
(Follow-up to the resuscitation bundle)
1. Steroid replacement: low-dose ster-
oids administered for septic shock
that is poorly responsive to adequate
fluid resuscitation and vasopressors
in accordance with a standardized
ICU policy
2. Drotrecogin alpha (recombinant
activated protein C) administered
in accordance with a standardized
ICU policy
3. Glycemic control: glucose main-
tenance approximating 150 mg/dl
(8.3 mmol/L) (nutritional support
and insulin control are often included
in this focus). (Note: aspects of this
intervention are still controversial.)
4. Inspiratory plateau pressures main-
tained at < 30 cm H2O for mechani-
cally ventilated patients
Summary
Bloodstream infections and sepsis
are among the top causes of mortality
in the U.S., killing nearly 600 people
per day. Many septic patients are treated
in EMDs or critical care units (CCUs),
settings in which rapid administration
of targeted antibiotic therapy drastically
reduces mortality. Unfortunately, routine
blood cultures are too slow to support
rapid therapeutic interventions. As a
result, empiric, broad-spectrum treat-
ment is common, a costly approach that
may fail to effectively target the correct
microbe, may inadvertently harm patients
via antimicrobial toxicity, and may con-
tribute to the evolution of drug-resistant
microbes. To meet these diagnostic
Clinical Microbiology Newsletter 32:5,2010
challenges, laboratories must understand
the complexity of diagnosing and treat-
ing septic patients in order to focus on
creating algorithms that help direct tar-
geted antibiotic therapy and synergize
with existing EMD and CCU clinical
practices put forth in the Surviving
Sepsis Campaign guidelines.
Editor’s Note: Part II of this article
will appear in the March 15, 2010 issue
of CMN (Volume 32, Number 6).
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0196-4399/00 (see frontmatter) 37