Crit Care Clin 23 (2008) S1-S47

Crit Care Clin 23 (2008) S1–S47
Improving Outcomes for Severe

Sepsis and Septic Shock: Tools
for Early Identification of At-Risk
Patients and Treatment
Protocol Implementation
Emanuel P. Rivers, MD, MPH,
Tom Ahrens, DNS, RN, CCNS, FAAN
The scope of the problem: why is quality improvement necessary?

Sepsis is a significant problem. Septicemia is the 10th leading cause of
death in the United States based on 2004 data from the National Center
for Health Statistics (NCHS) [1]. The mortality rate among patients with
severe sepsis has been reported at 20% to 50%, and sepsis incidence is
increasing at an estimated annual rate of 1.5% [2,3]. In addition, the grow-
ing numbers of sepsis patients who have organ dysfunction indicate that
sepsis severity is also increasing [3]. A study of National Hospital Discharge
Survey (NHDS) data identified organ failure in 19.1% of sepsis patients
from 1979 to 1989 and 30.2% from 1990 to 2000 [3]. Comparing data
from the 5-year time frame between 1979 and 1984 with the span from
1995 to 2000, the number of patients who had dysfunctional organs more
than doubled (2.7% to 7.1%), and the number of patients who had at least
three dysfunctional organs more than tripled (0.5% to 1.9%) [3].
Although the statistics are sobering, there is mounting proof that evi-
dence-based interventions decrease sepsis-related mortality. The current
challenge facing health care professionals (HCPs) is behavioral change to
consistently implement evidence-based interventions and realize the poten-
tial to improve severe sepsis and septic shock outcomes.
Addressing the problem: quality improvement initiatives

The demonstration that interventions can reduce mortality caused by
severe sepsis and septic shock has led several organizations to spearhead
0749-0704/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2008.04.002 criticalcare.theclinics.com
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quality improvement initiatives for sepsis management. In 2002, the Society

of Critical Care Medicine (SCCM), the European Society of Intensive Care
Medicine (ESICM), and the International Sepsis Forum (ISF) announced
the Surviving Sepsis Campaign (SSC) [4]. The SSC has generated the follow-
ing six-point action plan to reduce global mortality from severe sepsis by
25% by 2009 [5]:
Build awareness of sepsis.
Improve early and accurate diagnosis.
Increase the use of appropriate treatments and interventions.
Educate HCPs about sepsis diagnosis, treatment, and management.
Improve access to post-ICU care for sepsis patients.
Develop global standards of care.
The SSC has been implemented in three phases: campaign introduction
(2002), practice guideline development and publication (2003 to 2004), and
guideline translation to clinical protocols with assessment of practice perfor-
mance (ongoing) [4,5]. Continuing efforts include publication of updated
guidelines in 2008 and the collaborative development with the Institute for
Healthcare Improvement (IHI) of resources to promote guideline implemen-
tation [4,6,7]. Resources for guideline implementation include severe sepsis
care bundles, which are selected evidence-based practice recommendations
related to sepsis management that result in better outcomes when executed
as a group [4]. Adherence to bundle components improves clinical outcomes
and also can serve as an indicator of health care quality [8].
In parallel with the SSC initiative, the Voluntary Hospitals of America
(VHA) Health Foundation, the Joint Commission on the Accreditation of
Healthcare Organizations (JCAHO), and Johns Hopkins University
together launched a 3-year initiative in 2003 to develop national quality
measures of severe sepsis care in the ICU [9]. A severe sepsis bundle from
the VHA has been available for nearly 2 years. The JCAHO bundle has
been approved by the National Quality Forum but is not yet available for
clinical application [8].
As a global initiative, the SSC depends on the participation of institutions
worldwide [5]. Participants are charged with identifying institution-specific
action plan items, such as [5]:
Assessing the epidemiology and current management of sepsis
Implementing coordinated, system-wide efforts
Developing institution-specific protocols based on SSC sepsis manage-
ment recommendations
Assessing the performance of sepsis management and outcomes
Protocol development and performance assessment are key aspects of an
institutional improvement initiative and are vital to the success of the SSC
[5]. A general overview of the stages of an institutional quality improvement
initiative for sepsis management is presented in Fig. 1.
SEPSIS RECOGNITION AND TREATMENT PROTOCOLS S3
Understanding
6-Hour Quality and
Epidemiology the Care Teams
Bundle Costs
Pathogenesis
Early
Recognizing Timely Definitive Realizing
Staging of
One Has a Interventions Care: Improved
Illness
Problem? Upon Arrival ED or ICU? Outcomes
Severity
Evaluating CME and

Early 24-Hour Documentation
Current Peer
Markers Bundle and Orders
Sepsis Care Informing
Fig. 1. Overview of a sepsis quality improvement initiative.
Acting on the problem: overcoming barriers to quality improvement

The role of leaders in overcoming systematic barriers
There are many potential systematic barriers to implementing sepsis man-
agement protocols (Box 1) [5,10–12]. As part of the improvement process,
the SSC recommends identifying a leader or group of leaders dedicated to
the sepsis care quality improvement effort and with the knowledge,
resources, and authority to remove barriers such as equipment limitations,
staff shortages, and resistance from institutional administration and staff
[5]. A passionate champion for change also can help overcome barriers to
improvement by convincing others of the importance of the initiative,
recruiting team members, and promoting an atmosphere that encourages
teamwork and values quality care [5].
The generation of consensus definitions to overcome conceptual barriers

Historically, the interchangeable use of different sepsis definitions has
caused confusion, and fragmented perceptions of sepsis continue to be prob-
lematic [13,14]. A recent survey of physicians who care for patients with
sepsis revealed that most of those interviewed (67%) were concerned about
the lack of a common definition for sepsis [14]. Survey findings confirmed
the lack of consensus regarding sepsis definitions. At most, 17% of the
respondents agreed with any given definition of sepsis, and six different def-
initions were mentioned by at least 10% of respondents [14]. Disparity
regarding signs and symptoms of sepsis was also evident, with 71% of
respondents citing fever as a prerequisite for sepsis and less than 30% men-
tioning tachycardia, leukocytosis/leukopenia, hypothermia, or tachypnea
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Box 1. Potential barriers to sepsis management protocols

Paradigmatic obstacles to transforming sepsis from a benign
illness to one as serious as acute myocardial infarction,
trauma, or stroke
Professional barriers
Variation in expertise among HCPs
Lack of expertise acknowledgment
Difficulty providing education regarding protocol components
and implementation (primarily because of work shift
considerations)
Staff resistance to change
Lack of familiarity with equipment
Institutional barriers
Interdepartmental communication
Departmental collaboration
Departmental competition
Silo mentality between the emergency department (ED),
ICU, and other floors
Limited staff numbers
Physical plant barriers
Space constraints in the ED
Lack of ICU beds
Lack of equipment
[14]. Physicians agree, however, that a common definition of sepsis would

improve treatment [5,14].
The American College of Chest Physicians/Society of Critical Care Med-
icine (ACCP/SCCM) Consensus Conference convened in 1991 to develop
standardized definitions for sepsis, sepsis sequelae, and organ failure [15].
The ACCP/SCCM definitions published in 1992 were revisited and refined
at a 2001 international sepsis definitions conference sponsored by the
SCCM, ESICM, ACCP, American Thoracic Society (ATS), and Surgical
Infection Society (SIS) (Box 2) [16]. The refined SCCM/ESICM/ACCP/
ATS/SIS international sepsis definitions have been incorporated into the
2008 SSC international guidelines for management of severe sepsis and
septic shock [5–7].
The SCCM/ESICM/ACCP/ATS/SIS consensus committee left the 1991
ACCP/SCCM definitions essentially intact, but a more detailed list of
signs and symptoms for sepsis was developed to improve specificity and
facilitate bedside diagnosis [16]. Recommendations for further improve-
ments toward better definition of sepsis stages included incorporation of
Box 2. Sepsis definitions

Sepsis is defined as documented or suspected infection
with one or more of the followinga:
General variables
Fever (core temperature >38.3 C)
Hypothermia (core temperature <36 C)
Heart rate >90 beats/min or >2 standard deviations (SD) above
normal range for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (>20 mL/kg over
24 hours)
Hyperglycemia (plasma glucose >120 mg/dL or 7.7 mmol/L)
in the absence of diabetes
Inflammatory variables
Leukocytosis (white blood cell [WBC] count >12,000/mL)
Leukopenia (WBC count <4000/mL)
Normal WBC count with >10% immature forms
Plasma C-reactive protein >2 SD above normal value
Plasma procalcitonin (PCT) >2 SD above normal value
Severe sepsis is defined as sepsis associated with organ
dysfunction, hypoperfusion, or hypotension.
Organ dysfunction variables
Arterial hypoxemia (partial pressure of arterial oxygen/fraction
of inspired oxygen [PaO2/FIO2] <300)
Acute oliguria (urine output <.5 mL/kg/h or 45 mmol/L
for at least 2 hours)
Creatinine >2.0 mg/dL
Coagulation abnormalities (international normalized ratio
[INR] >1.5 or activated partial thromboplastin time
[aPTT] >60 seconds)
Thrombocytopenia (platelet count <100,000/mL)
Hyperbilirubinemia (plasma total bilirubin >2.0 mg/dL
or 35 mmol/L)
Tissue perfusion variables
Hyperlactatemia (>2 mmol/L)
Decreased capillary refill or mottling
Hemodynamic variables
Arterial hypotension (systolic blood pressure [SBP]
<90 mm Hg, mean arterial blood pressure [MAP]
<65 mm Hg, or SBP decrease >40 mm Hg)
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Septic shock is defined as acute circulatory failure

unexplained by other causes.
Acute circulatory failure is indicated by persistent arterial
hypotension despite adequate volume resuscitation.
a
Diagnostic criteria for sepsis in the pediatric population are signs and symp-
toms of inflammation plus infection with hyper- or hypothermia (rectal tempera-
ture >38.5 or <35 C), tachycardia (may be absent in hypothermic patients), and
at least one of the following indications of altered organ dysfunction: altered
mental status, hypoxemia, increased serum lactate level, bounding pulses.
Data from Refs. [5], [16].
predisposing factors, comorbidities, infection characteristics, physiologic

variables, organ dysfunction indicators, and biomarkers [16,17].
Derivation of evidence-based guidelines to overcome barriers

to optimal patient care
Development of evidence-based guidelines for sepsis management com-
prised the second phase of the SSC initiative [5]. Updated SSC guidelines
were published in 2008 and incorporated data published from 1991 to
2007 [6,7]. Although the SSC receives unrestricted educational grants
from industry for activities such as the performance improvement initiative,
no industry funding was used in the guideline revision process [6]. Further-
more, there was no industry presence or input during the development of the
2004 guidelines or during the 2006–2007 revision process, and no committee
members received honoraria for participating in the 2004 or 2006–2007
guidelines processes [6]. A policy of full disclosure of committee members’
potential conflicts also was adopted [6]. The revised guidelines are sponsored
by 14 international critical care organizations [6].
For the 2008 revision, the guidelines committee adopted the Grades of
Recommendation, Assessment, Development, and Evaluation (GRADE)
system for determining quality of evidence [6]. The GRADE system is based
on sequential determination of evidence quality and recommendation
strength according to predetermined criteria [6]. A letter grade, A (high)
to D (low), is assigned to designate evidence quality, and management
recommendations are graded as strong (1) or weak (2) [6]. The recommen-
dation strength is felt to be more important than the letter grade in the
context of adopting a recommendation for clinical practice [6].
The guidelines consider various topics relevant to managing severe sepsis
and septic shock. Topics directly relevant to the management of severe
sepsis and septic shock include [6]:
Initial resuscitation
Infection diagnosis
Antibiotic therapy
Infection source control
Fluid therapy
Vasopressors
Inotropic therapy
Corticosteroids
Recombinant human activated protein C (rhAPC)
Blood product administration
Supportive therapy topics include [6]:
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/acute
respiratory distress syndrome (ARDS)
Sedation, analgesia, and neuromuscular blockade in sepsis
Glucose control
Renal replacement
Bicarbonate therapy
Deep vein thrombosis prophylaxis
Stress ulcer prophylaxis
Selective digestive tract decontamination
Consideration for limitation of support
The SSC guidelines also include a section devoted to special consider-

ations regarding the management of severe sepsis and septic shock in pedi-
atric patients [6]. Readers are encouraged to refer to the revised guidelines
for specifics regarding recommendations [6,7].
As previously mentioned, the SSC and IHI have developed care bundles
to facilitate the rapid, consistent, and systematic implementation of SSC
guideline recommendations. The severe sepsis bundles include selected key
SSC guideline recommendations to be implemented within 6 hours (resusci-
tation bundle) and 24 hours (management bundle) of severe sepsis diagnosis
[4]. Components of the sepsis care bundles are outlined in Box 3 [5].
Several SSC practice recommendation updates are relevant to sepsis care
bundle components [6]. In particular, noteworthy changes were made
regarding corticosteroid and rhAPC recommendations.
Results from the Corticosteroid Therapy of Septic Shock (CORTICUS)
study prompted the SSC guidelines committee to downgrade the recommen-
dation for corticosteroid use in adult patients with septic shock who do not
respond well to fluid resuscitation and vasopressor therapy [6,18]. In addi-
tion, the revised guidelines suggest that clinicians should not use adrenocor-
ticotropic hormone (ACTH) stimulation tests to identify patients likely to
benefit from hydrocortisone treatment [6]. The CORTICUS study revealed
no differences in 28-day mortality between groups receiving placebo and hy-
drocortisone, regardless of corticotropin responsiveness [18]. Patients in the
hydrocortisone group underwent shock reversal more quickly than those in
the placebo group (3.3 days [95% CI, 2.9 to 3.9 days] and 5.8 days [95% CI,
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Box 3. Severe sepsis bundles

Sepsis resuscitation bundle: Tasks to be completed within
6 hours of presentation
1. Measure serum lactate.
2. Obtain blood cultures before antibiotic administration.
3. Administer broad-spectrum antibiotics within 3 hours from
time of presentation 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 crystalloid (or
colloid equivalent).
b. Apply vasopressors for hypotension not responding to
initial fluid resuscitation to maintain mean arterial
pressure (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 (CVP) ‚8 mm Hg.
b. Achieve central venous oxygen saturation (ScvO2) ‚70%
(or SvO2 ‚65%).
Sepsis management bundle: Tasks to be completed within

24 hours of presentation
1. Administer low-dose steroids for septic shock in accordance
with standardized ICU policy.
2. Standardized ICU protocol.
3. Maintain glucose control greater than or equal to the lower
limit of normal, but <150 mg/dL (8.3 mmol/L).
4. Maintain inspiratory plateau pressures <30 cm H2O for
mechanically ventilated patients.
From Townsend S, Dellinger RP, Levy MM, et al, editors. Implementing the
Surviving Sepsis Campaign. Des Plaines, Brussels, and Land O Lakes: Society
of Critical Care Medicine, European Society of Intensive Care, and International
Sepsis Forum; 2005; with permission.
5.2 to 6.9 days], respectively), but the proportion of patients experiencing

shock reversal was not significantly different between the groups (79.7%
and 74.2%, respectively; P ¼ .18) [18]. Furthermore, the incidence of super-
infections increased in the hydrocortisone group [18]. Because hydrocorti-
sone treatment does not clearly improve mortality in septic shock, and
because steroid treatment is associated with adverse effects such as increased
infection risk and myopathy, the SSC guidelines committee downgraded the
recommendation for corticosteroid use from strong to weak in adult

patients who have septic shock [6].
Recommendations regarding the use of rhAPC also were revised based
on availability of new data [6,19,20]. Use of rhAPC in the indicated popu-
lation (ie, patients who have sepsis-induced organ dysfunction and high
risk of death [eg, Acute Physiology and Chronic Health Evaluation,
APACHE II score greater than or equal to 25]) is suggested, and a strong
recommendation was added indicating that adult patients who have severe
sepsis and low risk of death should not receive rhAPC [6]. The evidence
for these recommendations comes primarily from two randomized con-
trolled trials of rhAPC, Recombinant Human Activated PRotein C World-
wide Evaluation in Severe Sepsis (PROWESS) and ADministration of
DRotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS).
PROWESS first demonstrated a 6% absolute risk reduction in mortality
when all groups were considered [21]. A subsequent subgroup analysis re-
vealed a greater reduction in mortality risk (13%) for patients identified
to be at high risk for death based on an APACHE II score greater than
24 [22]. The results of the ADDRESS trial supported the lack of value of
rhAPC treatment in patients who have low risk of death [6]. Subgroup anal-
yses can be misleading because of the absence of an intent to treat, sampling
bias, selection error, and inadequate statistical power. Concerns regarding
the use of subgroup analyses and the trial outcome discrepancies led to
a weak recommendation for the indicated use of rhAPC [6]. The data, how-
ever, consistently indicate a lack of rhAPC benefit in patients who have low
risk of death. Based on these considerations, a strong recommendation was
made that patients who have low risk of death should not receive rhAPC [6].
Early severity assessment and timely intervention: optimizing management

of severe sepsis and septic shock
Importance of early identification and treatment
Several lines of evidence indicate that early identification and treatment
of severe sepsis and septic shock improve outcomes. Early initiation of
hemodynamic resuscitation with specified treatment endpoints, also referred
to as early goal-directed therapy (EGDT), consistently has improved
mortality rates in numerous clinical trials [11]. The components of EGDT
are diagrammed in Fig. 2 [23].
Prior to a seminal study by Rivers and colleagues [23], trials of hemody-
namic resuscitation as an intervention for patients who had septic shock
allowed patient enrollment for up to 72 hours after ICU admission and
produced negative results. These null findings led experts to propose inves-
tigating earlier intervention.
Participants in the study by Rivers and colleagues [23] were assigned to
receive goal-directed or standard resuscitation therapy. Patients in the
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Fig. 2. Components of EGDT. Abbreviations: EGDT, early goal-directed therapy; CVP, cen-
tral venous pressure; MAP, mean arterial pressure; ScvO2, central venous oxygen saturation.
(From Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001;345:1368–77; with permission.)
goal-directed therapy group were resuscitated according to the EGDT

protocol for at least 6 hours immediately following arrival in the ED [23].
In-hospital, 28-day, and 60-day mortality rates for the EGDT group were
30.5%, 33.3%, and 44.3%, respectively, compared with 46.5%, 49.2%,
and 56.9% in the standard therapy group [23]. Mortality at each time point
was significantly lower (P%.03) in the EGDT protocol group compared
with the standard therapy group [23]. In addition, APACHE II scores, Sim-
plified Acute Physiology (SAPS) II values, multiple organ dysfunction
scores (MODS), and some coagulation indicators (prothrombin time, con-
centration of fibrin-split products, d-dimer concentration) were significantly
better in the EGDT group 7 to 72 hours after protocol entry [23]. A recent
analysis of the literature by Otero and colleagues [11] affirmed that the
findings of Rivers and colleagues [23] are reproducible, generalizable, and

have external validity.
The importance of timely treatment can be extended to other sepsis
interventions also. In a study by Sebat and colleagues [10], sepsis protocol
implementation shortened time-to-treatment intervals for several sepsis
interventions (intensivist arrival, ICU/operating room admission, fluid ad-
ministration, pulmonary artery catheterization) and significantly decreased
mortality in the protocol group (28.2%) compared with the control group
(40.7%). Fig. 3 presents results of a study by Kumar and colleagues [24]
that revealed increased mortality associated with delayed initiation of anti-
microbial therapy. Similarly, Morrell and colleagues [25] observed a signifi-
cant increase in mortality risk associated with delays greater than 12 hours
in administration of antifungal therapy (adjusted odds ratio, 2.09; 95% CI,
1.53 to 2.84).
Because rapid and appropriate treatment is likely to improve outcomes,
early recognition of severe sepsis and septic shock is important [6]. Patient
risk assessment based on epidemiologic considerations, screening tool
results, and scoring systems can be helpful in determining whether a patient
has severe sepsis or septic shock and what intervention is appropriate
[16,17,26]. Once severe sepsis or septic shock has been recognized, tasks in
the SSC and IHI sepsis resuscitation bundle should be performed as quickly
as possible within 6 hours, and components of the sepsis management bun-
dle should be completed as quickly as possible within 24 hours [27,28].
Current tools and practices for early recognition of severe sepsis

The 2001 International Sepsis Definitions Conference, sponsored by the
SCCM, ESICM, ACCP, ATS, and SIS, identified categories of
Fig. 3. Delayed initiation of antimicrobial therapy increases mortality. Bars represent 95% CI.
(From Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in human septic shock.
Crit Care Med 2006;34(6):1589–96; with permission.)
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characteristics important in determining the baseline risk of adverse out-

come and potential to respond to therapy among patients who have sepsis
[16]. These categories include [16]:
Predispositiondpremorbid illness, cultural or religious beliefs, age, sex
Infectiondcharacteristics of infecting pathogens, source control options
Responsedpatient response to infection (eg, systemic inflammatory
response syndrome [SIRS], signs of septic shock)
Organ dysfunctiondas described by number of failing organs or com-
posite score
Current and emerging tools and practices for measuring patient predispo-
sition, infection, response, and organ dysfunction (PIRO) are discussed.
Predisposition
A list of risk factors for the development of sepsis is included in Box 4
[12]. Epidemiologic data have provided some insight regarding patients
who are more likely to develop sepsis. An analysis of NHDS data from
1995 to 2000 indicated that the average patient with sepsis is elderly (60.8
plus or minus 13.7 years old) [3]. NHDS data from 1979 to 2000 revealed
Box 4. Risk factors for the development of sepsis

Age
<1 year
>65 years
Malnutrition
Hypothermia
Central venous catheter use
Endotracheal intubation/mechanical ventilation
Aspiration
Chronic illness
Diabetes
Renal failure
Hepatic failure
Immunodeficiency
AIDS
Alcoholism
Chemotherapy
Surgery or invasive procedures
From Picard KM, O’Donoghue SC, Young-Kershaw DA, et al. Development and
implementation of a multidisciplinary sepsis protocol. Crit Care Nurse 2006;
26(3):43–54; with permission.
that men are more likely than women to develop sepsis and that sepsis
development is more likely for blacks and other nonwhite patients than
for white patients [3].
Several comorbid conditions are also associated with poorer outcomes
for patients with sepsis. Cancer, cirrhosis, congestive heart failure, and
HIV infection have been associated with increased risk of sepsis progression
and/or death [17,29]. The risk of death is twice as great for sepsis patients
with cancer as for those without and is comparable to the risk observed
in sepsis patients who have HIV infection [29]. Awareness of risk factors
can aid clinicians in identifying patients at higher risk for progressing to se-
vere sepsis.
Infection identification and source control

According to recommendations in the SSC guidelines, cultures to identify
causative organisms should be drawn before starting antimicrobial therapy,
as long as sampling does not delay antibiotic administration significantly [6].
Sampling before antibiotic therapy is important, because sterilization of
blood cultures can occur within a few hours of the first dose [6]. Identifica-
tion of causative organisms facilitates adjustment of antibiotic therapy [6].
At least two blood cultures should be drawn, and at least one should be per-
cutaneous. One sample also should be taken from each vascular device that
has been in place for at least 48 hours. Cultures of other fluids that may
identify a source of infection (eg, urine, cerebrospinal fluid, wound fluids,
respiratory secretions) also should be collected [6]. Source identification
and control also are emphasized in the SSC guidelines [6]. Clinicians are
urged to identify an anatomic site of infection within 6 hours of patient pre-
sentation [6]. Imaging studies to confirm potential infection sources should
be performed promptly as allowed by the patient’s condition. In addition,
sources of infection should be sampled as they are identified [6].
An epidemiologic study of United States hospital discharge records
from 1995 revealed the prevalence rates for common sites of infection
among patients who had severe sepsis: respiratory (44.0%), bacteremia
(17.3%), genitourinary (9.1%), abdominal (8.6%), and wound/soft tissue
(6.6%) [2]. In their analysis of risk factors for sepsis progression, Alberti
and colleagues [17] identified increased risk of progression associated with
pneumonia, peritonitis, bacteremia, and catheter-related infections. In
patients who have cancer, the source of infection often is related to the
patient’s tumor type [29].
Response
Physiologic indicators of sepsis, severe sepsis, and septic shock (see
Box 2) reflect a patient’s reaction to infection and a systemic inflammatory
response. An international study of data from Europe, Canada, and Israel
confirmed increased risk of progression from sepsis to severe sepsis or septic
S14 RIVERS & AHRENS
shock in patients who had the following physiologic characteristics at pre-

sentation [17]:
Temperature greater than 38.2 C
Heart rate greater than 120 beats/min
SBP less than 110 mm Hg
Platelet count less than 150 109/L
Leukocyte count less than 4 109/L
Sodium greater than 145 mmol/L
Bilirubin greater than 30 mmol/L
Urea greater than 15 mmol/L
Given the correlation between presenting physiologic characteristics and
outcome, it is important that clinicians collect adequate and appropriate
vital sign information. Because the diagnostic criteria for sepsis include pa-
rameters such as SBP, MAP, and CVP, hemodynamic monitoring also can
aid clinicians in identifying patients who are developing severe sepsis (see
Box 2) [16].
Checklists and questions incorporated into screening tools can assist
clinicians in considering relevant physiologic indicators. Protocols may
incorporate frequent monitoring (ie, hourly) of vital signs including body
temperature, respiratory rate, blood pressure (BP) including MAP, heart
rate, urine output, oxygen saturation, ScvO2, CVP, and neurologic checks
[12]. Frequent monitoring is especially valuable in identifying trends, which
can provide a more complete clinical picture than individual measurements
[30–32].
It is also important to include queries regarding lactate levels in protocols
and screening tools. Elevated lactate levels are a marker for tissue hypoxia in
septic shock and are associated with increased mortality rate in patients who
have sepsis [12,30,33,34]. Repeated lactate measurements provide a better
indication of tissue oxygenation than single measurements [30]. In addition,
lactate clearance of at least 10% during the first 6 hours following ED
admission is associated with increased survival likelihood [32].
Organ dysfunction
Signs. Severe sepsis is defined as sepsis accompanied by organ dysfunction,
hypoperfusion, or hypotension (see Box 2) [15]. As noted at the beginning of
this resource, epidemiologic data indicate that the percentage of sepsis
patients who have organ dysfunction is increasing [3]. As new support tech-
nologies have become available to sustain critically ill patients, progressive
organ failure, rather than underlying illness, has emerged as a major threat
to survival [15]. It is important to recognize that [15]:
Organ dysfunction occurs on a progressive continuum.
Recognition of early organ abnormalities can facilitate treatment at
earlier stages of MODS.
Measures of organ dysfunction over time provide a better indication of

disease course than individual measurements.
Organ dysfunction can be affected by many factors, including those that
are host- and intervention-related.
Mortality doubles as the number of dysfunctional organs increases from
one to two, and it increases three- to fourfold as the number of dysfunctional
organs increases from one to 4 or more [2,35,36]. Because early recognition of
severe sepsis facilitates timely intervention, it increases opportunities to main-
tain tissue perfusion and oxygenation and limit additional organ dysfunction
[35]. Unfortunately, clinicians do not always recognize that dysfunction in one
organ, along with indications of sepsis, qualifies the patient as having severe
sepsis [35]. Concurrent signs of infection and SIRS should motivate clinicians
to seek signs of organ dysfunction and hypoperfusion, even in the absence of
hypotension [37]. Because indications of organ dysfunction can be attribut-
able to several causes other than sepsis (eg, surgical procedures, acute myocar-
dial infarction, drug therapies, or underlying disease states), clinicians should
work to identify or eliminate other easily identifiable causes [16].
A list of some signs of organ dysfunction and hypoperfusion is provided
in Box 5 [16,35,37]. It may be useful for severe sepsis screening tools to in-
clude queries regarding signs of organ dysfunction similar to those in the
SSC severe sepsis screening tool [38]. Awareness of organ systems that are
often dysfunctional in severe sepsis also may guide clinicians to recognize
signs of organ dysfunction. Organ dysfunction in sepsis is observed most
commonly in the respiratory, cardiovascular, renal, hematologic, central
nervous, and hepatic systems [2,3,39].
Scoring systems. Scoring systems provide an aggregate quantitative indica-

tor of several patient characteristics, including organ dysfunction and vital
signs, to assess condition severity, prognosis, or progression [40]. Descrip-
tions of commonly used scoring systems are included in Table 1. Web-based
tools to calculate patient scores are available for many of these scoring
systems [40,41]. Physiologic scoring systems have been applied to several
purposes, including therapeutic decision support, outcomes and evaluation
research, quality care analysis, and benchmarking [26]. In clinical decision
processes, scoring systems have been used to determine illness severity and
predict mortality risk [37]. In the case of one therapeutic intervention
(rhAPC), a scoring system output (APACHE II score) has been identified
as an indication to initiate therapy [42].
The use of scoring systems in the ED has been limited but is becoming
increasingly important as more critically ill patients are housed for extended
periods in the ED [26]. One study to assess the impact of ED intervention on
outcomes demonstrated that the highest scores (APACHE II, SAPS II,
MODS) and predicted mortality occurred during the ED stay, emphasizing
the importance of developing scores for use in the ED setting [26]. Scoring
S16 RIVERS & AHRENS
Box 5. Indicators of organ dysfunction and hypoperfusion

Respiratory
Tachypnea
Acute respiratory distress syndrome [ARDS]
Arterial hypoxemia (PaO2/FiO2 •300)
Decreased arterial oxygen partial pressure (PaO2 <70 mm Hg)
Decreased arterial oxygen saturation (arterial oxygen saturation
[SaO2] <90%)
Cardiovascular
Tachycardia
Hypotension
Altered central venous pressure (CVP)
Altered pulmonary artery occlusive pressure (PAOP)
Abnormal cardiac index
Renal
Oliguria
Anuria
Increased creatinine
Hepatic/gastrointestinal (GI)
Hyperbilirubinemia
Increased enzymes
Decreased albumin
Increased prothrombin time (PT)
Ileus
Central nervous system

Altered mental status
Altered consciousness
Psychosis
Hematologic
Thrombocytopenia
Coagulation abnormalities
Hypoperfusion
Increased serum lactate levels
Decreased capillary refill
Skin mottling
Data from Refs. [16], [30], [35], [37].

Table 1
Common scoring systems for patients with severe sepsis or septic shock
Scoring System Description
ICU scoring systems
Acute Physiology and Chronic Developed as mortality prediction tool
Health Evaluation (APACHE) II Consists of variables including
Online calculators: temperature, MAP, heart rate,
http://www.icumedicus.com/icu_scores/apache.php respiratory rate, oxygenation, arterial pH,
http://www.sfar.org/scores2/apache22.html serum sodium, serum potassium, serum
creatinine, hematocrit, white blood
count, GCS, age, chronic health
APACHE IV is recommended except
for sepsis patients, in whom
APACHE II is more appropriate
APACHE II score R25 indicates
rhAPC administration is appropriate
Simplified Acute Physiology Score (SAPS) II Introduced in 1994
Online calculators: Includes variables similar to APACHE
http://www.icumedicus.com/icu_scores/saps.php
http://www.sfar.org/scores2/saps2.html
Sequential Organ Failure Assessment (SOFA) Developed to describe severity
Online calculators: of organ dysfunction
http://www.icumedicus.com/icu_scores/sofa.php Includes questions regarding
http://www.sfar.org/scores2/sofa2.html cardiovascular, neurologic, renal, liver,
respiratory, and coagulation function
Multiple Organ Dysfunction Score (MODS) Developed to describe severity
Online calculators: of organ dysfunction
http://www.icumedicus.com/icu_scores/mods.php Includes questions regarding
http://www.sfar.org/scores2/mods2.html cardiovascular, neurologic, renal, liver,
respiratory, and coagulation function
ED scoring systems
Mortality in Emergency Department Identifies ED patients at risk for infection
Sepsis Score (MEDS) One of first systems to examine course
of sepsis beginning in the ED
Rapid Acute Physiology Score (RAPS) Abbreviated APACHE II system
Predicts mortality before, during,
and after critical care transport
Rapid Emergency Medicine Score (REMS) RAPS plus age and peripheral oxygen
saturation data
Predictive value better that RAPS,
similar to APACHE II
Abbreviations: ED, emergency department; GCS, Glasgow Coma Score; MAP, mean
arterial pressure; rhAPC, recombinant human activated protein C. (Data from Refs. [26],
[36], [42], [105–107].)
systems can be a valuable tool to aid ED clinicians in early diagnosis and

initiation of evidence-based protocols for critically ill patients [26]. Imple-
mentation of sepsis protocols before ICU transfer is expected to improve
outcomes for severe sepsis patients greatly [6].
S18 RIVERS & AHRENS
New scoring systems should be developed to accommodate the spectrum

of severity from the ED to the ICU, or current systems should be recali-
brated to this end [26]. ED-specific scoring systems should consider ease
of use and bedside availability, shorter time frame of data collection, and
comparability with existing scores [26]. The MEDS score is one that has
been developed specifically for ED use [26,43]. It is designed to identify
ED patients at risk for infection and categorize them based on mortality
risk [26]. In developing the MEDS score, independent predictors of mortal-
ity for ED patients were determined. These include terminal illness, tachyp-
nea or hypoxia, septic shock, platelets less than 150,000/mm3, bands greater
than 5%, age over 65 years, lower respiratory infection, nursing home
resident, and altered mental status [43]. The MEDS score may prove to
be useful in identifying patients who will benefit from aggressive interven-
tion [43].
Current tools and practices for early therapeutic intervention

The highest priority tasks that should be performed within 6 hours of a se-
vere sepsis diagnosis focus on [27]:
Hemodynamic stabilization/resuscitation
Restoring tissue oxygenation
Infection identification
Infection control (antibiotic therapy/source control)
Monitoring hemodynamics, perfusion, and tissue oxygenation

Once severe sepsis or septic shock has been identified, the highest man-
agement priorities are establishing vascular access and initiating fluid resus-
citation to improve tissue perfusion [6,30]. Maintenance of tissue perfusion
is critical, because global tissue hypoxia is a key step toward multiple organ
failure [23]. Fluid resuscitation recommendations have been updated in the
2008 SSC guidelines but remain based on the demonstrated effectiveness of
EGDT in managing septic shock [6,44]. Readers are encouraged to consult
the 2008 SSC guidelines for more comprehensive information regarding
initial resuscitation recommendations [6].
Hemodynamic monitoring is essential to resuscitation efforts based on at-
taining specified targets for BP and oxygen saturation (see Fig. 2) [6,23,45].
BP measurements, CVP in particular, are readily available targets for direct-
ing fluid resuscitation [6]. BP measurements, however, do not necessarily
reflect blood flow and oxygenation [30]. Even when resuscitation goals for
CVP and MAP have been achieved, additional measurements of venous
oxygenation and lactate may reveal inadequate oxygenation and tissue per-
fusion and indicate that additional resuscitation efforts are required [46].
Therefore, measurements of tissue perfusion and oxygenation are necessary
to determine whether the ultimate goal of resuscitation, an adequate oxygen
supply to tissues, has been attained [30].
Several methods are available to assess blood flow and tissue oxygena-
tion. They are summarized in Tables 2 and 3 [27,47]. Blood flow measure-
ments often have been neglected because of difficulties associated with the
use of available technologies [48]. Newer, less-invasive techniques, such as
external and esophageal Doppler and thoracic bioimpedance, increasingly
are employed by clinicians [30,48]. Acceptance in particular clinical settings
likely will depend on ease and speed of use, expense, and accuracy [30]. For
example, Doppler techniques are minimally invasive, inexpensive, rapid, and
accurate, but their use requires highly experienced operators in the ED
[30,49]. Thoracic bioimpedance is a technology that is less operator-depen-
dent and may be appropriate in an ED setting, but it is subject to patient
physical limitations [49]. Given the ultimate goal of adequate tissue oxygen-
ation, blood flow measurements should be coupled with measurements of
tissue oxygenation [30].
Measurements that are in common use to assess tissue oxygenation are
SvO2, ScvO2, and lactate [30]. All three are global, indirect measures of tis-
sue oxygenation that require venous access [30,47]. Decreased SvO2 and
ScvO2 values reflect increased oxygen extraction by tissues experiencing
oxygen deficit in early sepsis [30]. Increased lactate levels signal increased
anaerobic metabolism in the face of insufficient oxygen to meet tissue needs
[30]. For all three indices (SvO2, ScvO2, and lactate), trends provide a more
complete picture of tissue oxygenation status than single measurements [30].
SvO2 and ScvO2 are measured by means of pulmonary artery catheters
(PACs) and right-atrial central venous catheters (CVCs), respectively, pro-
viding indications of global oxygenation rather than local tissue-level
Table 2
Techniques for measuring blood flow
Arterial/venous Cost !$25 Suitable for
Technique access required? per patient? all patients?
External Doppler No Yes Yes
Esophageal Doppler No No No, the patient
must be sedated.
Thoracic No Yes No, the patient must have
bioimpedance normal anatomy and
access to the neck.
Exhaled CO2 No No No, the patient must be
Fick method on a ventilator.
Pulse contour Yes No No, the patient must have
at least an arterial line
in place.
Pulmonary Yes No No, the patient must have
artery catheter a central line in place.
From Ahrens T. Hemodynamics in sepsis. AACN Adv Crit Care 2006;17(4):435–45; with
permission.
S20
Table 3
Techniques for measuring tissue oxygenation
Measure Method Variables Global/regional Invasive/noninvasive
Established techniques
Systemic oxygenation PAC VO2/DO2/ERO2 Global Invasive
Mixed venous O2 saturation PAC–blood gas analyses SvO2 Global Invasive
RIVERS & AHRENS

Central venous O2 saturation CVC (right atrium)–fiber optic cable ScvO2 Global Invasive
Lactate Laboratory – enzymatic testing Lactate Global Invasive
Emerging techniques
Gastrointestinal tonometry Measurement of pCO2 in an air-filled prCO2/pCO2 gap, pHi, Regional Minimally invasive
and sublingual capnography or saline-filled balloon or sublingual probe sublingual pCO2
Near-infrared spectroscopy Near-infrared absorbance analysis Hb/O2Hb, cytochrome aa3 Regional Noninvasive
Tissue oxygen tension Polarographic probes pO2 Regional Minimally invasive
Abbreviations: CVC, central venous catheter; DO2, oxygen delivery; ERO2, oxygen extraction ratio; Hb/O2Hb, deoxygenated/oxygenated hemoglobin;
PAC, pulmonary artery catheter; pCO2 gap, arterial-to-intramucosal partial pressure of carbon dioxide difference; pHi, gastric intramucosal pH; pO2, partial
pressure of oxygen; prCO2, regional gastric carbon dioxide tension; ScvO2, central venous oxygen saturation; SvO2, mixed venous oxygen saturation; VO2,
oxygen consumption.
Data from Refs. [40], [37].
assessments [30]. The outcome impact of PACs as a hemodynamic optimi-

zation tool has been controversial. Studies, including meta-analyses, have
revealed mixed outcomes (eg, decreased morbidity, improved outcome fol-
lowing surgery, no benefit in the ICU, increased mortality) associated
with PAC use [47].
A study comparing PAC- and CVC-directed therapy in patients who had
established ALI revealed no differences in outcomes such as mortality, ICU-
free days, and number of ventilator-free days [50]. Patients in the PAC
group, however, had approximately twice as many catheter-related compli-
cations, such as placement difficulty, catheter malfunction, and arrhythmia,
as the CVC group [50]. In addition, the time from randomization to first
protocol instruction was significantly greater in the PAC group than the
CVC group [50]. This finding was attributed to the longer time required
for PAC insertion [50]. At this time, the SSC guidelines for managing severe
sepsis and septic shock indicate that SvO2 and ScvO2 are equivalent for
monitoring resuscitation [6]. The use of PACs for routine monitoring of
patients with ALI/ARDS is not recommended, however.
Antimicrobial therapy
The importance of timely antimicrobial treatment has been mentioned
(see Fig. 3) [24,25]. Delaying empiric antibiotic treatment to await culture
results has negative consequences [6,25]. Clinicians should be aware that
blood cultures will be negative in more than 50% of severe sepsis/septic
shock cases [6]. Furthermore, restricting use of antibiotics to limit develop-
ment of resistance or reduce cost is not appropriate in this patient popula-
tion. Broad-spectrum therapy is warranted until information (causative
agent, antibiotic susceptibilities) is available for therapeutic adjustment [6].
Selection of an appropriate antimicrobial agent, often in the absence of
microbiologic confirmation, requires consideration of patient-related char-
acteristics such as drug intolerances, recently used antibiotics, previous
infections, underlying disease, and clinical syndrome [6]. Awareness of the
prevalence of infections caused by specific organisms can provide clinicians
with insight into appropriate empiric antimicrobial therapy. Pathogen resis-
tance patterns in the hospital and community, along with hospital protocols
to limit antibiotic resistance, also should be considered [6]. The SSC guide-
lines recommend that clinicians consider the setting-specific prevalence of
oxacillin (methicillin)-resistant Staphylococcus aureus (ORSA or MRSA)
and the possibility of candidemia when selecting an initial antibiotic therapy
[6]. Clinicians also should be cognizant of general microbial trends. Based
on epidemiologic data from 1979 to 2000, gram-positive bacteria have
become the most common cause of infection in patients who have sepsis
(52%), followed by gram-negative bacteria (38%), polymicrobial infections
(5%), and fungal infections (5%) [3]. Gram-positive bacteria replaced gram-
negative as the most common causative organism in 1988, and sepsis caused
by fungal infections increased 207% from 1979 to 2000 [3]. Furthermore,
S22 RIVERS & AHRENS
an analysis of international epidemiologic data identified gram-positive

and -negative bacterial infections as risk factors for sepsis progression [17].
Emerging tools and practices

New tools and techniques are emerging that may assist clinicians in as-
sessing patient risk of sepsis progression, in minimally invasive measurement
of tissue oxygen levels, and in diagnosis of infection. These advances should
allow clinicians to provide appropriate interventions more quickly.
Biomarkers
Studies have been performed to identify biomarkers for use in the early
identification of patients at risk of developing severe sepsis and septic shock.
Kinasewitz and colleagues [51] identified 13 biomarkers that correlated with
initial sepsis severity: d-dimer, interleukin (IL)-6, protein C, antithrombin
(AT), activated partial thromboplastin time (APTT), prothrombin time
(PT), protein S, plasminogen activator inhibitor (PAI), thrombin-activat-
able fibrinolysis inhibitor (TAFI), soluble thrombomodulin (sTM), IL-10,
IL-8, and tumor necrosis factor (TNF)-a. None of these factors, however,
were predictive of outcome. The authors speculated that this null finding
was because of the large variability in levels between patients.
Contrary to the observation of Kinasewitz, other studies have identified
a relationship between protein C levels and sepsis or therapeutic outcome
[52,53]. At this time, a predictive correlation between protein C levels and
sepsis outcome has been demonstrated [54,55]. Procalcitonin (PCT) also
has been identified as a biomarker for progression to severe sepsis and septic
shock. As with protein C, data have not demonstrated consistently that PCT
is a sensitive and specific indicator of sepsis. Results of recent meta-analyses
indicate that PCT may be a poor, moderate, or good diagnostic marker for
sepsis [56–58]. Many recent studies, however, have documented the benefits
of PCT measurements for sepsis evaluation in critically ill patients and in
guiding antimicrobial therapy [59–65]. US Food and Drug Administration
(FDA)-approved PCT assays are commercially available [66].
Despite identification of correlations between some biomarkers and sep-
sis outcome, commentary from the 2001 SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definitions Conference suggests that further investiga-
tion is required before biomarkers can be used for staging sepsis [16]. Epide-
miologic studies of biomarkers were deemed to be essential, as was the need
to assess the specific roles of biomarkers in different aspects of sepsis (eg,
coagulopathy and adrenal dysfunction) [16]. The current SSC guidelines
do not include information regarding the use of biomarkers, aside from
a comment indicating that they are not useful for diagnosing infection [6].
Currently, information suggests that biomarkers may be useful in identify-
ing patients at risk for developing severe sepsis or septic shock, but guide-
lines for clinical application are not available.
Genetic predisposition
A recent editorial illuminated the current status of research to identify
genetic polymorphisms predisposing individuals to poor or good outcomes fol-
lowing severe sepsis or septic shock. The author cited a list of studies exploring
the association between gene polymorphisms and sepsis outcome or suscepti-
bility. Overall, the studies yielded contradictory results, negative results, or re-
sults that have not been confirmed in experiments demonstrating causality [67].
Genes considered in these studies included TNF-a, TNF-b, IL-10, IL-8, and
CXCR2 [67]. In addition, a recent article by Jessen and colleagues [68] revealed
no association between commonly described single nucleotide polymorphisms
of TNF-a, IL-1b, plasminogen activator-1, urokinase plasminogen activator,
CD14, and toll-like receptor 4. These publications indicate that the develop-
ment of genetic screens to determine sepsis predisposition is at an early stage.
Scoring systems
Alternative scoring systems have been proposed to better predict the risk of
sepsis progression and potential response to therapy [16,17]. The PIRO system
for staging sepsis stratifies patients according to predisposing conditions, nature
and extent of infection, nature and magnitude of host response, and degree of
organ dysfunction [16]. The system remains in the early stages of development.
In contrast, Alberti and colleagues [17] have performed multivariate anal-
ysis of sepsis progression risk factors, developed a weighted grading tool
based on the relative risk contributions of the components, and chara-
cterized the tool’s performance in a set of 1531 patients. The risk factors
included in the model are [17]:
Bilirubin greater than 30 mmol/L
Heart rate greater than 120 beats/min
Sodium greater than 145 mmol/L
Platelets less than 150 109/L
SBP less than 110 mm Hg
Temperature greater than 38.2 C
Mechanical ventilation
Pneumonia
Peritonitis
Gram-positive cocci
Aerobic gram-negative bacilli
Primary bacteremia
This scoring system is unique in its consideration of progression risk as an
endpoint.
Noninvasive measurement of tissue oxygenation

Newer, less invasive techniques are becoming more readily available for
direct measurement of tissue oxygenation. Among these are GI tonometry,
near-infrared spectroscopy, and tissue oxygen tension by means of
S24 RIVERS & AHRENS
implantable electrodes [47]. Gastric tonometry and sublingual capnography,

the more recent application of this technique, are advantageous, because
splanchnic hypoperfusion seems to be affected earlier than systemic hemo-
dynamic and metabolic parameters [47]. Ease of use and noninvasive mea-
surement make near-infrared spectroscopy attractive. A strength of tissue
oxygen tension measurement by means of electrodes is the ability to measure
many different tissue sites [47]. Visualization of sublingual microcirculatory
perfusion using orthogonal polarization spectral imaging is also an emerg-
ing technique [69]. In an observational study to compare microcirculatory
perfusion indices in severe sepsis/septic shock survivors and nonsurvivors,
measurements taken early in sepsis using this minimally invasive technique
revealed that microcirculatory indices were more markedly impaired in non-
survivors than survivors [69]. This was a preliminary study, however, and
further studies are needed [69].
Infection identification and control

Molecular technologies for rapid identification of infectious agents are
becoming more accessible for clinical use. Tenover reviewed application of
peptide nucleic acid fluorescent in situ hybridization (PNA-FISH), real-
time polymerase chain reaction (PCR), and pyrosequencing in the detection
of suspected causative agents [70]. Pyrosequencing is an emerging technique
particularly suitable for detecting antimicrobial resistance and bacterial
strain identification [70]. In proof-of-concept studies, multidrug-resistant
(MDR) isolates of Mycobacterium tuberculosis could be characterized in
a matter of hours [70]. PNA-FISH is the simplest of the three technologies,
and results are available in several hours [70]. Fluorescently labeled PNA
probes are available to detect S aureus, Enterococcus faecalis, Candida albi-
cans, Escherichia coli, and Pseudomonas aeruginosa [70]. Application of
PNA-FISH to direct vancomycin therapy in a non-ICU setting resulted in
a decrease in the median length of stay and cost savings of about $4000
per patient [70]. An FDA-cleared, commercially available real-time PCR
product is available for rapid detection of methicillin-resistant S aureus
from nasal swab samples [70]. A commercial product that is not FDA
cleared is also available; results from this assay are available in less than
3 hours [70]. Availability of rapid assays for detecting and characterizing
microbes is increasing and should help clinicians in earlier diagnosis in cases
of sepsis.
Definitive care: guideline implementation resources

The previous sections provided an overview of tools and techniques that
can facilitate earlier recognition and treatment of severe sepsis and septic
shock. Evidence-based management guidelines provide recommendations
regarding the most effective application of tools and techniques. Guideline
recommendations, however, cannot direct outcome improvement if they are

not consistently translated into clinical practice.
The key to success in introducing evidence-based practices lies in the will-
ingness of the hospital and clinicians to devote time, energy, and resources
to the implementation and monitoring process. Advice and resources for
directing clinical change through protocol development, implementation,
and quality improvement monitoring are available. An overview of
resources is provided, and a list is provided in Box 6.
Forming ‘‘change teams’’

The SSC has identified three types of teams that may be needed to imple-
ment cultural change directed at improving the management of severe
sepsis: working, leadership, and stakeholder teams [5]. Working teams man-
age daily activities related to change (eg, daily planning, documentation,
communication, education, monitoring, and evaluation); leadership teams
remove barriers and provide resources, and stakeholder teams need to be
informed of change progress [5]. The types of teams that are formed at
the institution depend on the desired goals. In an example provided in the
SSC handbook, an ED trying to decrease the time to sepsis and severe sepsis
diagnosis may rely on a strong working team. Members of an interdepart-
mental, multidisciplinary working team assembled for this purpose might
include an ED physician, triage nurse, staff nurse, laboratory technician,
laboratory supervisor, and admissions clerk [5].
Inclusion of representatives from different departments is important for
several reasons. More than 50% of ICU patients with nontraumatic shock
may be transferred from the ED or other floors in a given hospital setting
[10]. Patients may be delayed in the ED or on other floors awaiting transfer
to the ICU [11,26]. Those becoming septic outside the ICU have poorer
outcomes, but initiating sepsis protocols in non-ICU areas can reduce mor-
tality [71,72]. Sepsis recognition and management can begin earlier if provi-
sions are made to provide such intervention in these settings. In fact, the
SSC guidelines committee has stated the opinion that the potential for
outcome improvements in non-ICU settings is substantial [6].
Formation of multidisciplinary teams ensures the participation of individ-
uals responsible for different aspects of care for critically ill patients and pro-
vides better assurance that all tasks associated with the care of these patients
will be addressed [5]. Multidisciplinary teams have been important in improv-
ing patient and process outcomes in other areas of critical care. The American
Heart Association Get With the Guidelines (GWTG) program encourages re-
cruitment of multidisciplinary practice improvement teams, and implementa-
tion of GWTG-Stroke has reduced mortality and improved practice guideline
adherence [73–76]. Similarly, the American College of Cardiology Guidelines
Applied in Practice (GAP) initiative also has generated positive results [77].
For example, the Acute Myocardial Infarction GAP Project in Michigan
S26 RIVERS & AHRENS
Box 6. Resources for protocol development and implementation

Surviving Sepsis Campaign (SSC)dhttp://www.
survivingsepsis.org/
Implementing the Surviving Sepsis Campaign (manual) and
Chart Review Database (software)dhttp://www.
survivingsepsis.org/manual_database
Severe Sepsis Bundlesdhttp://www.survivingsepsis.org/
implement/bundles
Individual Chart Measurement Tool (paper)dhttp://www.
survivingsepsis.org/files/Tools/individualchart
measurementtool.pdf
Evaluation for Severe Sepsis Screening Tool (paper)dhttp://
www.survivingsepsis.org/files/Tools/evaluationfor
severesepsisscreeningtool.pdf
Monthly Measurement Worksheet (paper)dhttp://www.
survivingsepsis.org/files/Tools/monthlymeasurement
worksheet.pdf
SSC Guideline reference aids (poster, care bundle badge cards,
pocket guide)dhttp://www.survivingsepsis.org/gettingstarted
SSC Campaign Updates (newsletter)dhttp://www.
survivingsepsis.org/node/155
Educational opportunities (symposia, conferences)dhttp://
www.survivingsepsis.org/campaign/join
Institute for Health care Improvement (IHI)dhttp://www.ihi.
org/ihi
Severe Sepsis Bundles and Sepsis Commentarydhttp://www.
ihi.org/IHI/Topics/CriticalCare/Sepsis/
How to Improve/Model for Improvementdhttp://www.ihi.org/
IHI/Topics/CriticalCare/Sepsis/HowtoImprove/
Measuresdhttp://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/
Measures/
Changesdhttp://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/
Changes/
Improvement Storiesdhttp://www.ihi.org/IHI/Topics/
CriticalCare/Sepsis/ImprovementStories/
Tools–definitions, care bundles, measures, quality indicators,
screening tool, chart review database, monthly measurement
worksheet, individual chart measurement tool (paper and
database)dhttp://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/
Tools/
Beth Israel Deaconess Medical Center Sepsis Guidedhttp://

sepsis.bidmc.harvard.edu/Content/start_frameset.htm
Multiple Urgent Sepsis Therapies (MUST) Protocol
Handbookdhttp://sepsis.bidmc.harvard.edu/Content/
Guides/BIDMC_MUST_Protocol_Guide_082504.pdf
Nurses’ Intake and Tracking Form (resuscitation flow
sheet)dhttp://sepsis.bidmc.harvard.edu/Content/Guides/
BIDMC_MUST_flow_sheet_0204.pdf
Publication listdhttp://sepsis.bidmc.harvard.edu/Content/
start_frameset.htm
Loma Linda University Medical Center
Strategies to Timely Obviate the Progression of Sepsis
(STOP Sepsis) Bundle Toolkitdhttp://lomalindahealth.org/
common/legacy/llumc/emergency/patientcare/documents/
patientcare-sepsis.pdf
used a multidisciplinary approach and reported significant decreases in mor-

tality and improvement in guideline adherence [78–80]. One-year mortality
rates decreased from 38.3% before GAP to 33.2% after implementation
(P!.02) [78]. Reported successes of multidisciplinary sepsis management
teams validate their value in improving sepsis outcomes also [10,12,81].
The case for developing and implementing protocols

Protocols provide a set of rules and an organized plan to promote adher-
ence to evidence-based recommendations in clinical settings [5,45]. Outcome
improvements following the implementation of protocols developed from
evidence-based guidelines (SSC guidelines or comparable) already have
been demonstrated.
Evidence for improved survival

Fig. 4 illustrates the improvement in mortality rates observed with proto-
col implementation. The data presented in Fig. 4 were derived from 11 peer-
reviewed reports of study results that were published after the study by
Rivers and colleagues. A total of 1569 patients were included in the 11 stud-
ies, and the mean age, sex, APACHE II scores, and mortality were similar
across all studies [10,81–91]. Following implementation of sepsis protocols,
the relative risk reduction exceeded 0.25 (25%), and absolute risk reduction
exceeded 9% in all studies (see Fig. 4). The mean relative and absolute risk
reduction were 0.46 plus or minus 0.26 and 20.3 plus or minus 12.7%, re-
spectively. These findings are superior to those of Rivers and colleagues,
who reported relative and absolute mortality risk reductions of 0.34 and
16%, respectively [10,23,81–89,91,92].
S28 RIVERS & AHRENS
Jones, 2007 0.33

El Solh, 2007 0.29
Sebat, 2007 0.8
Nguyen, 2007 0.47
Qu, 2006 0.68
Lin, 2006 0.26
Micek, 2006 0.38
Trzeciak, 2006 0.58
Shapiro, 2006 0.31
Kortgen, 2006 0.49
Sebat, 2005 0.34
Gao, 2005 0.53
Rivers, 2001 0.34
0.00 0.20 0.40 0.60 0.80 1.00

Relative Risk Reduction
Fig. 4. Sepsis protocol implementation reduces mortality risk. (Data from Refs. [10,23,81–92].)
Among the studies included in Fig. 4, several assessed protocols that were
developed based on the SSC care bundles. The reported outcome improve-
ments were similar to those reported for all of the protocol implementation
studies. Nguyen and colleagues [88] observed hospital mortality rates of
21% for patients who received all treatments specified in the bundles and
40% for those who did not (P%.01). Gao and colleagues [83] also identified
increased hospital mortality in patients who did not receive all sepsis bundle
treatments. The SSC recommends that the sepsis care bundles form the basis
for institution-specific sepsis protocols [5]. These studies reinforce this rec-
ommendation and demonstrate the care bundles’ value in clinical settings.
Economic benefits of protocol implementation

Sepsis is one of the top 10 most expensive diseases managed by hospitals.
It accounted for over $24.8 billion in United States hospital costsd2.8% of
the national hospital billdin 2005 [93]. Of the United States charges, ap-
proximately $19.5 billion were charged to Medicare and Medicaid [93].
Data from the Agency for Healthcare Research and Quality (AHRQ)
Healthcare Cost and Use Project (HCUP) also indicate that the national
cost of treating sepsis in the United States increased more (183%) than
for other conditions from 1997 to 2005 [93].
A Medline search using the medical subject heading (MESH) sepsis/eco-
nomics for articles published between 2003 and 2008dthe time frame since
the SSC sepsis management guidelines were introduceddreveals many pub-
lications regarding the economic impact of sepsis and of individual aspects
of sepsis care, such as catheterization, rhAPC administration, and EGDT.
A notable, recent economic analysis demonstrated that implementation of
EGDT alone resulted in a decrease in net hospital costs of approximately

23%, primarily because of shortened hospital stay [94].
Research demonstrating the full economic benefits of implementing all
components of the SSC sepsis care bundles is limited, however. Only one pub-
lication specifically addressed the impact of severe sepsis protocol implemen-
tation on economic outcomes. A study by Shorr and colleagues [95] revealed
decreased per-patient costs after protocol implementation ($21,985 before
compared with $16,103 after implementation; P ¼ .009) and a significant
5-day decrease in the median length of stay (P ¼ .023). The decreased patient
costs were attributed to decreased ICU and ward bed day charges [95].
Variability in sepsis management approaches and inherent difficulties in
performing cost-effectiveness analyses in critical care (eg, short-term end-
points, patient complexity) have made it difficult to assess the economic
benefits of sepsis interventions [96,97]. Part of the problem has been the
lack of a defined standard of care for treating patients with severe sepsis
[96]. With the development of widely accepted, evidence-based treatment
guidelines, studies regarding the economic impact of current and new inter-
ventions should become more feasible, reliable, and important.
Resources for protocol development and examples of operationalization

Resources developed by quality improvement organizations
Protocols facilitate the assessment of intervention effectiveness by
standardizing interventions so that they are applied consistently and repro-
ducibly. Protocols are, therefore, a tool to promote the health care improve-
ment process. Protocols also improve health care outcomes by reminding
HCPs to complete all tasks required for optimal care [5].
The SSC, in partnership with the IHI, has developed two sepsis bundles
to facilitate the development of protocols consistent with evidence-based
recommendations [5,98,99]. Information on these bundles and their
implementation is available at the SSC and IHI Web sites:
http://www.survivingsepsis.org/implement/bundles
http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/
The SSC has also provided a collection of additional resources through
its Web site (http://www.survivingsepsis.org/) to guide clinicians in develop-
ing and implementing sepsis management protocols. Implementing the
Surviving Sepsis Campaign is a manual that compiles the SSC guidelines
and care bundles, information on creating a team for clinical practice
change, practical steps to protocol development, performance assessment
tool instructions, and professional insights on overcoming barriers (http://
ssc.sccm.org/files/Implementing%20the%20Surviving%20Sepsis%20Camp
aign.pdf) [5]. Several supplementary educational tools and clinical reference
items to support protocol implementation are also available, includ-
ing slides, posters, pocket guides, and care bundle badge cards
S30 RIVERS & AHRENS
(http://www.survivingsepsis.org/gettingstarted). The severe sepsis screening

tool is also available online (http://www.survivingsepsis.org/files/Tools/
evaluationforseveresepsisscreeningtool.pdf). The SSC severe sepsis screening
tool and care bundle badge cards are provided in Figs. 5 and 6 as examples
and for the readers’ convenience.
Fig. 5. Example: Surviving Sepsis Campaign and Institute for Healthcare Improvement evalua-
tion for severe sepsis screening tool. (Courtesy of the Surviving Sepsis Campaign and the Institute
for Healthcare Improvement; with permission. Available at: http://www.survivingsepsis.org/files/
Tools/evaluationforseveresepsisscreeningtool.pdf.)
Fig. 6. Example: Surviving Sepsis Campaign sepsis care bundle badge cards. (Courtesy of the
Surviving Sepsis Campaign; with permission.)
The SSC and IHI also provide means to overcome barriers by facilitating
information exchange between institutions and providing a venue for shar-
ing personal experiences regarding severe sepsis quality improvement
efforts. A newsletter (Campaign Update) and update sessions at partner
society congresses provide information regarding SSC progress, including
successes and approaches of participating institutions. Information regard-
ing educational opportunities such as symposia and other presentations is
S32 RIVERS & AHRENS
also available at the SSC Web site (http://www.survivingsepsis.org/

campaign/join).
Resources developed through institutional efforts

It also may be valuable for change teams to consider protocols developed
by other groups. Protocols can take on several forms. For example, check-
lists may be accepted readily in one institution, while flowcharts, such as the
one for EGDT depicted in Fig. 2, may work better in another. In addition,
one team may choose to collect several aspects of the sepsis care bundles
into one protocol, and another may choose to develop separate protocols
for each step.
Resources are available from other groups that have developed and
implemented protocols. Parallel quality initiatives have been pursued by
many groups [9]. For example, the 6-hour Strategies to Timely Obviate
the Progression of Sepsis (STOP Sepsis) bundle, based on the SSC guide-
lines, was developed at Loma Linda University in California, and the Mul-
tiple Urgent Sepsis Therapies (MUST) protocol was implemented by
a multidisciplinary team at Beth Israel Deaconess Medical Center in Boston
[9,12,45,81,88]. These institutions have published their protocol resources on
the Internet (see Box 6), providing a useful information pool. Groups also
have published aspects of their protocols in the medical literature
[10,12,45]. Examples of generalized protocols applicable to implementing
the SSC sepsis resuscitation bundle also are provided in this article
(Figs. 7 and 8).
Improved outcomes: monitoring quality improvement

The SSC and IHI have adopted the Model for Improvement as a means
to accelerate positive clinical change in sepsis management [100–102]. The
Model for Improvement is based on an iterative process of selecting
changes, testing the changes, studying the outcome, and adjusting accord-
ingly. Measuring and reporting changes are inherently important to this
process. The SSC and IHI have collaborated to develop tools for measuring
and reporting improvement in sepsis management with the goal of decreas-
ing mortality caused by sepsis. The tools include quality indicators, a chart
review database, a monthly measurement worksheet, an interim glucocorti-
coid administration policy, and tools for severe sepsis screening, individual
chart measurement, median plateau pressure calculation, and median
glucose calculation. These tools are available at the IHI Web site (http://
www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/). Organizations working
to improve sepsis management can use these tools to track progress [5].
The severe sepsis screening tool, individual chart measurement tool,
monthly measurement worksheet, and chart review database facilitate stan-
dardized collection of change data for subsequent analysis of changes
Fig. 7. Example: severe sepsis protocol for admission and antibiotic therapy.
following sepsis protocol implementation [103]. Measures incorporated

into the database indicate outcome changes (eg, reduced mortality from
severe sepsis and septic shock) and process changes (eg, timely completion
of sepsis bundle elements) [104]. The chart review database is particularly
useful, because it can be used to easily generate graphs and flowcharts to
document and report progress [103]. In addition, this database provides
an option for sending data to the SSC [103]. The SSC encourages data
sharing to facilitate learning across institutions participating in the cam-
paign and to improve care and outcomes for patients who have severe sep-
sis and septic shock [4].
S34 RIVERS & AHRENS
Fig. 8. Example: early goal-directed therapy tracking form.
Summary
Because sepsis-related mortality is unacceptably high, the SSC has set
a quality improvement goal to reduce mortality caused by severe sepsis
and septic shock by 25% by 2009. Clearer definitions of sepsis, severe sep-
sis, and septic shock will help in achieving this goal, as will recently
updated evidence-based management guidelines for severe sepsis and septic
shock. To be effective, these definitions and guidelines need to be applied
to the early identification and aggressive treatment of patients who have
severe sepsis or septic shock. Early goal-directed therapy to achieve hemo-
dynamic stabilization has been demonstrated to decrease mortality in
patients who have septic shock. Currently, clinicians must rely on clues
to sepsis progression in the patient’s medical history, vital signs, hemody-
namic monitoring, lactate levels, and indications of organ dysfunctiondall
in the context of infectiondto identify patients who have severe sepsis.
Of these, hemodynamic monitoring, lactate levels, and indications of organ
dysfunction may be most useful in indicating the patient’s stage of sepsis.
In the future, less-invasive measures of hemodynamics and blood flow,
molecular techniques for identifying infectious agents, refined scoring sys-
tems, biomarkers, and genetic screening may aid clinicians in identifying
patients who have severe sepsis. Once a patient who has severe sepsis
has been identified, timely implementation of guideline recommendations
should follow. Resources and tools are available through the SSC and
IHI to facilitate the efficient translation of the SSC guideline recommenda-
tions into clinical practice.
Illustrative case studies

Case study 1
Setting with no hospital-wide protocol for managing severe sepsis
and septic shock
A 63-year-old male arrives in the ED with a foot wound of prolonged
duration. His wife encouraged him to visit the ED when she noticed that
the wound ‘‘looked and smelled infected.’’ She commented to the triage
nurse that he felt feverish, and that he was ‘‘sluggish.’’ The patient is receiv-
ing insulin therapy to control type 2 diabetes and has a complicating history
of peripheral neuropathy. Temperature and respiratory rate are elevated; BP
and heart rate are in normal ranges.
Vital Signs at Presentation (ED)

Temperature 38.4 C
Heart rate 72 beats/min
Respiratory rate 24 breaths/min
Blood pressure 132/78 mm Hg
Pulse oximetry 85%
Supplemental oxygen is provided by means of a nasal cannula at 4 L/min,

and broad-spectrum antibiotic therapy (intravenous [IV] bolus of ampicillin
plus sulbactam) is initiated within 45 minutes of presentation.
Vital Signs at Follow-up (ED; 2 hours post-presentation)

Temperature 39.0 C
Pulse oximetry 99%
Two hours after presentation (approximately 1 hour after antibiotic ad-

ministration), the patient’s temperature has increased; respiratory rate is still
elevated, and BP has decreased slightly. An ICU consultation is requested.
Vital Signs at ICU Consult (ED; 4 hours post-presentation)

Temperature 39.2 C
The intensivist arrives 2 hours after the request for consultation (4 hours
after presentation). The patient’s temperature and respiratory rate have in-
creased. His heart rate also has increased, although it is still within normal
limits. BP is also in normal range but has decreased from presentation.
S36 RIVERS & AHRENS
The intensivist confirms that the patient is severely septic. The patient is
admitted to the ICU, but transfer takes 3 hours because of bed and resource
limitations.
Vital Signs on Transfer to ICU (ICU; 7 hours post-presentation)

Temperature 39.2 C
At ICU presentation (7 hours after presentation), the patient’s tempera-

ture, heart rate, and respiratory rate have increased. BP continues to de-
crease, and the pulse pressure is widening. A CVC is placed. The patient’s
lactate level is measured at 4.8 mmol/L; the following parameters are noted,
and fluid resuscitation is initiated.
Central venous pressure 2 mm Hg

Hemoglobin 13.1 mg/dL
ScvO2 48%
Abbreviation: ScvO2, central venous oxygen saturation.
After 24 hours in the ICU, the patient is on mechanical ventilation with

protective lung strategies in place. Persistently elevated serum lactate levels
indicate that tissue perfusion remains impaired. Norepinephrine was initi-
ated at 5 mg/min and has been increased to 10 mg/min, in addition to fluid
resuscitation. Vasopressin is added at 0.04 U, and the patient is given 1
dose of 50 mg of hydrocortisone.
Because the patient’s temperature has remained elevated, and sepsis has
progressed to septic shock, reassessment of antibiotic therapy is appropriate.
Cultures were not collected before antibiotic therapy, so information from
microbiologic results is not available to inform the choice of a second agent.
Therefore, an empiric approach, possibly informed by culture of the wound
at this time, will be used.
In the context of continued hypoperfusion and multiple organ dysfunc-
tion (respiratory, cardiovascular), an APACHE II score will be determined
to assess the appropriateness of rhAPC therapy for this patient. An
APACHE II score of at least 25, indicating high risk of death, would
make this patient a candidate for rhAPC therapy.
Discussion
In a setting with a protocol for the management of severe sepsis and
septic shock, including education regarding early recognition, the triage
clinician in the ED ideally would have recognized that the presence of an in-
fected wound, systemic inflammatory response (ie, elevated respiratory rate,
fever), and organ dysfunction (ie, sluggishness indicating altered mental
status) as signs that the patient likely had severe sepsis at presentation in
the ED. These findings would trigger immediate actions that could affect the
course of this case positively, including lactate measurement, appropriate
cultures, initial fluid bolus, and EGDT. In addition, a surgical consultation
should have been requested to determine appropriate source control mea-
sures. In this case, amputation of the foot may have been appropriate. Sebat
and colleagues [10] demonstrated that protocol implementation can decrease
the time to reach treatment goals. Times were decreased significantly pre-
versus postprotocol for intensivist arrival (2:00 versus 0:50), ICU/operating
room admission (2:47 versus 1:30), fluid administration (3:52 versus 1:45),
and PAC placement (3:50 versus 2:10). A significant decrease in mortality
caused by septic shock also was achieved following protocol adoption;
mortality rates were 40.7% before and 28.2% after protocol implementation
(P ¼ .035) [10].
Given improvements similar to those described by Sebat and colleagues,
the course of the case might evolve as follows in a setting where protocols
for managing severe sepsis and septic shock have been implemented.
Setting with a hospital-wide protocol for managing severe sepsis

and septic shock
The components of the sepsis management protocol for this hospital
include:
A screening tool to promote the early recognition of patients who have

severe sepsis or septic shock
Guidelines for sepsis staff responsiveness to standing orders for the ini-
tiation of protocol tasks, based on SSC guidelines, in the ED, ICU, and
general wards
Provision for dedicated sepsis beds in the ICU
Using the screening tool, the ED clinician notes presence of an infected

wound; elevated respiratory rate and fever, indicative of a systemic inflam-
matory response; and sluggishness/lethargy, suggesting organ dysfunction.
These observations lead to the determination that the patient has severe
sepsis. In the hour following presentation, the following tasks are completed
in the ED:
Staff designated for management of severe sepsis and septic shock are
alerted and arrive in the ED.
Blood and wound cultures are collected before initiation of antibiotic
therapy.
CVC with ScvO2 monitoring capability is placed.
Serum lactate level is determined.
IV antibiotic appropriate for diabetic foot wound (ampicillin plus
sulbactam) is initiated.
IV fluid resuscitation is started and guided by CVP monitoring.
S38 RIVERS & AHRENS
The following tasks are completed in the next 2 hours following

presentation:
Serum lactate levels greater than 4 mmol/L indicate tissue hypoperfu-
sion. Fluid therapy is initiated in the ED.
The patient is admitted to the ICU. Because designated sepsis beds are
available, there is no delay in transfer.
In this scenario, adherence to protocol recommendations decreased time

to ICU admission and fluid resuscitation administration from 7 hours to
3 hours. Placement of the CVC and initiation of fluid resuscitation in the
ED have decreased the time to fluid therapy from 7 hours to 1 hour, an
important achievement for aggressive EGDT.
Case study 2
Elderly postoperative patient
A 70-year-old woman is hospitalized, recovering following bowel resec-
tion for colon cancer. She also receives medication for hypertension and
hypercholesterolemia. Initially, the patient was doing well and was friendly
and talkative with the postoperative staff. Approximately 48 hours after sur-
gery, her mental status changed, and she began to alternate between agitated
and listless states. Vital signs at that time indicate decreased BP and elevated
heart rate, respiratory rate, and temperature.
Vital Signs (Surgical Ward; 48 hours post-op)

Temperature 38.6 C
CVP 3 mm Hg
MAP 62 mm Hg
Urinary output 0.6 mL/kghr
ScvO2 62%
Neurologic status Alternately agitated and listless
Serum lactate 3.5 mmol/L
Abbreviations: CVP, central venous pressure; MAP, mean arterial pressure; ScvO2, central
venous oxygen saturation.
Surgical site infection is suspected. Signs of systemic inflammatory

response (ie, fever, elevated respiratory and heart rates, elevated serum lac-
tate) and organ dysfunction (ie, respiratory, cardiovascular, central nervous
system) indicate severe sepsis, and the hospital-wide sepsis protocol is initi-
ated. Sepsis response team members are alerted, cultures are collected for
microbiology, and a diagnostic work-up, including abdominal CT scan for
source control, is initiated. The patient is provided with supplemental oxygen
by means of a non-rebreather mask, and fluid therapy with 1000 mL
crystalloid every 30 minutes is initiated. As fluid boluses are administered, the

patient’s response (eg, ScvO2, CVP, urinary output, and MAP) is monitored
to determine the necessity of further hemodynamic optimization.
Vital Signs (Surgical Ward; 3 hours after resuscitation initiated)

Temperature 38.8 C
CVP 6 mm Hg
MAP 60 mm Hg
ScvO2 60%
After 3 hours, the patient’s MAP and ScvO2 remain depressed, and her
respiratory rate and lactate levels remain elevated. After resuscitation to
achieve CVP of 8 to 12 mm Hg, the patient receives 5 mg/min norepineph-
rine in addition to fluid therapy, is transferred to a dedicated sepsis bed in
the ICU, and is placed on mechanical ventilation for ALI. At this point,
the patient’s APACHE II score is determined to be 23.
Vital Signs (Surgical Ward; 24 hours after ICU transfer)

Temperature 39.0 C
CVP 14 mm Hg
MAP 60 mm Hg
ScvO2 57%
The patient’s condition has not improved substantially with aggressive

resuscitation (ie, continued fluid resuscitation, vasopressor treatment, ste-
roid therapy, and mechanical ventilation). In addition, her urinary output
has decreased, suggesting renal failure in addition to other organ dysfunc-
tion. The patient also has evidence of myocardial depression, and inotropic
therapy has been instituted to increase the ScvO2. Her recalculated
APACHE II score is 28.
S40 RIVERS & AHRENS
Discussion
The patient’s condition continued to deteriorate even with good adher-
ence to a protocol for the management of septic shock. At 24 hours after
ICU admission, multiple organ dysfunction and an APACHE II score of
at least 25 indicate a high risk of death. An appropriate action in continuing
aggressive treatment and after addressing the surgical issues for this patient
would be rhAPC administration.
Case study 3
Female college student presents to emergency department with suspected
urinary tract infection and fatigue
A 20-year-old female college student presents in the ED with severe pain
on urination and marked sluggishness since the previous day. She thinks she
has a urinary tract infection (UTI) that started developing a few days earlier.
She says she feels much more tired than usual and is having trouble waking
up and concentrating on anything, but that may be because she has been
staying up late to study for examinations. She takes a daily vitamin. Tylenol,
aspirin, and over-the-counter antihistamines and decongestants are used as
needed.
Vital Signs at Presentation (ED)

Temperature 38.6 C
The patient fulfills several criteria for sepsis: suspected infection, fever,
elevated heart rate, change in mental status (ie, lethargy). Based on this as-
sessment, the ED clinician feels that activation of a sepsis alert is warranted.
Consistent with the sepsis management protocol, he obtains cultures for se-
rum lactate and microbiology.
All cultures are obtained and sent for testing (if appropriate) within
30 minutes. The patient’s lactate level is 4.2 mmol/L. The ED clinician
orders appropriate empirical antibiotics and EGDT. An appropriate antibi-
otic is administered. The patient’s vital signs are essentially unchanged from
presentation, however. A CT scan of the abdomen is ordered.
Members of the sepsis team arrive 1 hour after presentation and confirm
a diagnosis of severe sepsis, probably secondary to the UTI. The patient is
transferred to the ICU, and the transfer is completed within 1 hour (3 hours
after presentation).
Vital Signs on Transfer to ICU (ICU; 3 hours post-presentation)

Temperature 38.6 C
MAP 63 mm Hg
CVP 7 mm Hg
ScvO2 55%
The patient’s temperature, heart rate, and BP remain the same, but her
MAP, CVP, and ScvO2 are low. Fluid therapy is initiated.
Vital Signs (ICU; 4 hours post-presentation, 1 hour post–fluid therapy)

Temperature 37.5 C
MAP 66 mm Hg
CVP 9 mm Hg
ScvO2 59%
One hour after fluid therapy initiation, MAP and CVP are at target resus-
citation levels, but the patient’s heart rate remains elevated, and her ScvO2
has not reached target level (70%). Fluid resuscitation is continued, and
inotropic therapy is started.
Vital Signs (ICU; 6 hours post-presentation, 3 hours post–fluid therapy)

Temperature 37 C
MAP 67 mm Hg
CVP 10 mm Hg
ScvO2 72%
Resuscitation goals are met. Aggressive fluid resuscitation and inotropic

therapy are discontinued, and the patient is removed from the sepsis
management protocol. Patient is transferred to a medical–surgical floor
for 24 hours of observation. Microbiology results confirm that the patient
was treated with an appropriate antibiotic. The CT of the abdomen rules
S42 RIVERS & AHRENS
out a surgical cause of the UTI such as a stone. Following observation, the
patient is discharged with an antibiotic prescription.
Discussion
Despite the patient’s insistence that she had a UTI and was just tired be-
cause of schoolwork, the attending ED clinician did not overlook the signs
suggesting severe sepsis (ie, infection, fever, potential organ dysfunction
[elevated heart rate, recent onset of severe fatigue]) and performed a serum
lactate screen. This confirmed the suspicion that the patient should be
entered into the severe sepsis protocol. Following EGDT initiation, the
patient’s condition improved quickly.
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Improving Outcomes for Severe

The scope of the problem: why is quality improvement necessary?

Addressing the problem: quality improvement initiatives

quality improvement initiatives for sepsis management. In 2002, the Society

Evaluating CME and

Fig. 1. Overview of a sepsis quality improvement initiative.

Acting on the problem: overcoming barriers to quality improvement

The generation of consensus deﬁnitions to overcome conceptual barriers

Box 1. Potential barriers to sepsis management protocols

[14]. Physicians agree, however, that a common deﬁnition of sepsis would

Box 2. Sepsis definitions

Septic shock is deﬁned as acute circulatory failure

predisposing factors, comorbidities, infection characteristics, physiologic

Derivation of evidence-based guidelines to overcome barriers

The SSC guidelines also include a section devoted to special consider-

Box 3. Severe sepsis bundles

Sepsis management bundle: Tasks to be completed within

5.2 to 6.9 days], respectively), but the proportion of patients experiencing

recommendation for corticosteroid use from strong to weak in adult

Early severity assessment and timely intervention: optimizing management

goal-directed therapy group were resuscitated according to the EGDT

ﬁndings of Rivers and colleagues [23] are reproducible, generalizable, and

Current tools and practices for early recognition of severe sepsis

characteristics important in determining the baseline risk of adverse out-

Box 4. Risk factors for the development of sepsis

Infection identiﬁcation and source control

shock in patients who had the following physiologic characteristics at pre-

Measures of organ dysfunction over time provide a better indication of

Scoring systems. Scoring systems provide an aggregate quantitative indica-

Box 5. Indicators of organ dysfunction and hypoperfusion

Central nervous system

Data from Refs. [16], [30], [35], [37].

systems can be a valuable tool to aid ED clinicians in early diagnosis and

New scoring systems should be developed to accommodate the spectrum

Current tools and practices for early therapeutic intervention

Monitoring hemodynamics, perfusion, and tissue oxygenation

RIVERS & AHRENS

assessments [30]. The outcome impact of PACs as a hemodynamic optimi-

an analysis of international epidemiologic data identiﬁed gram-positive

Emerging tools and practices

Noninvasive measurement of tissue oxygenation

implantable electrodes [47]. Gastric tonometry and sublingual capnography,

Infection identiﬁcation and control

Deﬁnitive care: guideline implementation resources

recommendations, however, cannot direct outcome improvement if they are

Forming ‘‘change teams’’

Box 6. Resources for protocol development and implementation

Beth Israel Deaconess Medical Center Sepsis Guidedhttp://

used a multidisciplinary approach and reported signiﬁcant decreases in mor-

The case for developing and implementing protocols

Evidence for improved survival

Jones, 2007 0.33

0.00 0.20 0.40 0.60 0.80 1.00

Economic beneﬁts of protocol implementation

EGDT alone resulted in a decrease in net hospital costs of approximately

Resources for protocol development and examples of operationalization

(http://www.survivingsepsis.org/gettingstarted). The severe sepsis screening

also available at the SSC Web site (http://www.survivingsepsis.org/

Resources developed through institutional eﬀorts

Improved outcomes: monitoring quality improvement

following sepsis protocol implementation [103]. Measures incorporated