crit care clin 23 (2008) s1–s47

Improving Outcomes for SevereSepsis and Septic Shock: Tools

for Early Identification of At-RiskPatients and TreatmentProtocol 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 ofdeath in the United States based on 2004 data from the National Centerfor Health Statistics (NCHS) [1]. The mortality rate among patients withsevere sepsis has been reported at 20% to 50%, and sepsis incidence isincreasing at an estimated annual rate of 1.5% [2,3]. In addition, the grow-ing numbers of sepsis patients who have organ dysfunction indicate thatsepsis severity is also increasing [3]. A study of National Hospital DischargeSurvey (NHDS) data identified organ failure in 19.1% of sepsis patientsfrom 1979 to 1989 and 30.2% from 1990 to 2000 [3]. Comparing datafrom the 5-year time frame between 1979 and 1984 with the span from1995 to 2000, the number of patients who had dysfunctional organs morethan doubled (2.7% to 7.1%), and the number of patients who had at leastthree 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 currentchallenge facing health care professionals (HCPs) is behavioral change toconsistently implement evidence-based interventions and realize the poten-tial to improve severe sepsis and septic shock outcomes.

Crit Care Clin 23 (2008) S1–S47

Addressing the problem: quality improvement initiatives

The demonstration that interventions can reduce mortality caused bysevere sepsis and septic shock has led several organizations to spearhead

0749-0704/08/$ - see front matter � 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 Societyof Critical Care Medicine (SCCM), the European Society of Intensive CareMedicine (ESICM), and the International Sepsis Forum (ISF) announcedthe Surviving Sepsis Campaign (SSC) [4]. The SSC has generated the follow-ing six-point action plan to reduce global mortality from severe sepsis by25% 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), andguideline translation to clinical protocols with assessment of practice perfor-mance (ongoing) [4,5]. Continuing efforts include publication of updatedguidelines in 2008 and the collaborative development with the Institute forHealthcare Improvement (IHI) of resources to promote guideline implemen-tation [4,6,7]. Resources for guideline implementation include severe sepsiscare bundles, which are selected evidence-based practice recommendationsrelated to sepsis management that result in better outcomes when executedas a group [4]. Adherence to bundle components improves clinical outcomesand 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 ofHealthcare Organizations (JCAHO), and Johns Hopkins Universitytogether launched a 3-year initiative in 2003 to develop national qualitymeasures of severe sepsis care in the ICU [9]. A severe sepsis bundle fromthe VHA has been available for nearly 2 years. The JCAHO bundle hasbeen approved by the National Quality Forum but is not yet available forclinical application [8].

As a global initiative, the SSC depends on the participation of institutionsworldwide [5]. Participants are charged with identifying institution-specificaction 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 aninstitutional improvement initiative and are vital to the success of the SSC[5]. A general overview of the stages of an institutional quality improvementinitiative for sepsis management is presented in Fig. 1.

Recognizing

One Has a

Problem?

Early

Staging of

Illness

Severity

Timely

Interventions

Upon Arrival

Definitive

Care:

ED or ICU?

Realizing

Improved

Outcomes

Quality and

CostsCare Teams

6-Hour

Bundle

Understanding

the

Pathogenesis

Epidemiology

CME and

Peer

Informing

Documentation

and Orders

24-Hour

Bundle

Early

Markers

Evaluating

Current

Sepsis Care

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

S3SEPSIS RECOGNITION AND TREATMENT PROTOCOLS

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 tothe 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 toimprovement by convincing others of the importance of the initiative,recruiting team members, and promoting an atmosphere that encouragesteamwork and values quality care [5].

The generation of consensus definitions to overcome conceptual barriers

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

Box 1. Potential barriers to sepsis management protocols

Paradigmatic obstacles to transforming sepsis from a benignillness to one as serious as acute myocardial infarction,trauma, or stroke

Professional barriersVariation in expertise among HCPsLack of expertise acknowledgmentDifficulty providing education regarding protocol components

and implementation (primarily because of work shiftconsiderations)

Staff resistance to changeLack of familiarity with equipment

Institutional barriersInterdepartmental communicationDepartmental collaborationDepartmental competitionSilo mentality between the emergency department (ED),

ICU, and other floorsLimited staff numbers

Physical plant barriersSpace constraints in the EDLack of ICU bedsLack of equipment

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[14]. Physicians agree, however, that a common definition of sepsis wouldimprove treatment [5,14].

The American College of Chest Physicians/Society of Critical Care Med-icine (ACCP/SCCM) Consensus Conference convened in 1991 to developstandardized definitions for sepsis, sepsis sequelae, and organ failure [15].The ACCP/SCCM definitions published in 1992 were revisited and refinedat a 2001 international sepsis definitions conference sponsored by theSCCM, ESICM, ACCP, American Thoracic Society (ATS), and SurgicalInfection Society (SIS) (Box 2) [16]. The refined SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions have been incorporated into the2008 SSC international guidelines for management of severe sepsis andseptic shock [5–7].

The SCCM/ESICM/ACCP/ATS/SIS consensus committee left the 1991ACCP/SCCM definitions essentially intact, but a more detailed list ofsigns and symptoms for sepsis was developed to improve specificity andfacilitate 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 infectionwith 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 ageTachypneaAltered mental statusSignificant 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 diabetesInflammatory variables

Leukocytosis (white blood cell [WBC] count >12,000/mL)Leukopenia (WBC count <4000/mL)Normal WBC count with >10% immature formsPlasma C-reactive protein >2 SD above normal valuePlasma procalcitonin (PCT) >2 SD above normal value

Severe sepsis is defined as sepsis associated with organdysfunction, hypoperfusion, or hypotension.Organ dysfunction variables

Arterial hypoxemia (partial pressure of arterial oxygen/fractionof inspired oxygen [PaO2/FIO2] <300)

Acute oliguria (urine output <.5 mL/kg/h or 45 mmol/Lfor at least 2 hours)

Creatinine >2.0 mg/dLCoagulation 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 variablesArterial hypotension (systolic blood pressure [SBP]

<90 mm Hg, mean arterial blood pressure [MAP]<65 mm Hg, or SBP decrease >40 mm Hg)


Septic shock is defined as acute circulatory failureunexplained 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), andat least one of the following indications of altered organ dysfunction: alteredmental status, hypoxemia, increased serum lactate level, bounding pulses.

Data from Refs. [5], [16].

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predisposing factors, comorbidities, infection characteristics, physiologicvariables, organ dysfunction indicators, and biomarkers [16,17].

Derivation of evidence-based guidelines to overcome barriersto optimal patient care

Development of evidence-based guidelines for sepsis management com-prised the second phase of the SSC initiative [5]. Updated SSC guidelineswere published in 2008 and incorporated data published from 1991 to2007 [6,7]. Although the SSC receives unrestricted educational grantsfrom 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 the2004 guidelines or during the 2006–2007 revision process, and no committeemembers received honoraria for participating in the 2004 or 2006–2007guidelines processes [6]. A policy of full disclosure of committee members’potential conflicts also was adopted [6]. The revised guidelines are sponsoredby 14 international critical care organizations [6].

For the 2008 revision, the guidelines committee adopted the Grades ofRecommendation, Assessment, Development, and Evaluation (GRADE)system for determining quality of evidence [6]. The GRADE system is basedon sequential determination of evidence quality and recommendationstrength according to predetermined criteria [6]. A letter grade, A (high)to D (low), is assigned to designate evidence quality, and managementrecommendations are graded as strong (1) or weak (2) [6]. The recommen-dation strength is felt to be more important than the letter grade in thecontext of adopting a recommendation for clinical practice [6].

The guidelines consider various topics relevant to managing severe sepsisand septic shock. Topics directly relevant to the management of severesepsis 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)/acuterespiratory 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 guidelinesfor specifics regarding recommendations [6,7].

As previously mentioned, the SSC and IHI have developed care bundlesto facilitate the rapid, consistent, and systematic implementation of SSCguideline recommendations. The severe sepsis bundles include selected keySSC 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 carebundle components [6]. In particular, noteworthy changes were maderegarding 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 notrespond 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 tobenefit from hydrocortisone treatment [6]. The CORTICUS study revealedno differences in 28-day mortality between groups receiving placebo and hy-drocortisone, regardless of corticotropin responsiveness [18]. Patients in thehydrocortisone group underwent shock reversal more quickly than those inthe placebo group (3.3 days [95% CI, 2.9 to 3.9 days] and 5.8 days [95% CI,

Box 3. Severe sepsis bundles

Sepsis resuscitation bundle: Tasks to be completed within6 hours of presentation1. 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-EDICU 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 arterialpressure (MAP) ‚65 mm Hg.

5. In the event of persistent hypotension despite fluidresuscitation (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 within24 hours of presentation1. 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 theSurviving Sepsis Campaign. Des Plaines, Brussels, and Land O Lakes: Societyof Critical Care Medicine, European Society of Intensive Care, and InternationalSepsis Forum; 2005; with permission.

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5.2 to 6.9 days], respectively), but the proportion of patients experiencingshock 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, andbecause steroid treatment is associated with adverse effects such as increasedinfection risk and myopathy, the SSC guidelines committee downgraded the


recommendation for corticosteroid use from strong to weak in adultpatients who have septic shock [6].

Recommendations regarding the use of rhAPC also were revised basedon availability of new data [6,19,20]. Use of rhAPC in the indicated popu-lation (ie, patients who have sepsis-induced organ dysfunction and highrisk of death [eg, Acute Physiology and Chronic Health Evaluation,APACHE II score greater than or equal to 25]) is suggested, and a strongrecommendation was added indicating that adult patients who have severesepsis and low risk of death should not receive rhAPC [6]. The evidencefor 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 ofDRotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS).PROWESS first demonstrated a 6% absolute risk reduction in mortalitywhen all groups were considered [21]. A subsequent subgroup analysis re-vealed a greater reduction in mortality risk (13%) for patients identifiedto be at high risk for death based on an APACHE II score greater than24 [22]. The results of the ADDRESS trial supported the lack of value ofrhAPC 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, samplingbias, selection error, and inadequate statistical power. Concerns regardingthe use of subgroup analyses and the trial outcome discrepancies led toa weak recommendation for the indicated use of rhAPC [6]. The data, how-ever, consistently indicate a lack of rhAPC benefit in patients who have lowrisk of death. Based on these considerations, a strong recommendation wasmade 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 treatmentof severe sepsis and septic shock improve outcomes. Early initiation ofhemodynamic resuscitation with specified treatment endpoints, also referredto as early goal-directed therapy (EGDT), consistently has improvedmortality rates in numerous clinical trials [11]. The components of EGDTare 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 shockallowed patient enrollment for up to 72 hours after ICU admission andproduced negative results. These null findings led experts to propose inves-tigating earlier intervention.

Participants in the study by Rivers and colleagues [23] were assigned toreceive goal-directed or standard resuscitation therapy. Patients in the

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.)

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goal-directed therapy group were resuscitated according to the EGDTprotocol 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 were30.5%, 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 pointwas significantly lower (P%.03) in the EGDT protocol group comparedwith the standard therapy group [23]. In addition, APACHE II scores, Sim-plified Acute Physiology (SAPS) II values, multiple organ dysfunctionscores (MODS), and some coagulation indicators (prothrombin time, con-centration of fibrin-split products, d-dimer concentration) were significantlybetter in the EGDT group 7 to 72 hours after protocol entry [23]. A recentanalysis of the literature by Otero and colleagues [11] affirmed that the


findings of Rivers and colleagues [23] are reproducible, generalizable, andhave external validity.

The importance of timely treatment can be extended to other sepsisinterventions also. In a study by Sebat and colleagues [10], sepsis protocolimplementation shortened time-to-treatment intervals for several sepsisinterventions (intensivist arrival, ICU/operating room admission, fluid ad-ministration, pulmonary artery catheterization) and significantly decreasedmortality 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 hoursin 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]. Patientrisk assessment based on epidemiologic considerations, screening toolresults, and scoring systems can be helpful in determining whether a patienthas severe sepsis or septic shock and what intervention is appropriate[16,17,26]. Once severe sepsis or septic shock has been recognized, tasks inthe SSC and IHI sepsis resuscitation bundle should be performed as quicklyas 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 theSCCM, 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 inflammatoryresponse 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 patientswho are more likely to develop sepsis. An analysis of NHDS data from1995 to 2000 indicated that the average patient with sepsis is elderly (60.8plus 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

MalnutritionHypothermiaCentral venous catheter useEndotracheal intubation/mechanical ventilationAspirationChronic illness

DiabetesRenal failureHepatic failure

ImmunodeficiencyAIDSAlcoholismChemotherapy

Surgery or invasive procedures

From Picard KM, O’Donoghue SC, Young-Kershaw DA, et al. Development andimplementation 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 sepsisdevelopment is more likely for blacks and other nonwhite patients thanfor white patients [3].

Several comorbid conditions are also associated with poorer outcomesfor patients with sepsis. Cancer, cirrhosis, congestive heart failure, andHIV infection have been associated with increased risk of sepsis progressionand/or death [17,29]. The risk of death is twice as great for sepsis patientswith cancer as for those without and is comparable to the risk observedin sepsis patients who have HIV infection [29]. Awareness of risk factorscan 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 ofblood 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 thathas been in place for at least 48 hours. Cultures of other fluids that mayidentify a source of infection (eg, urine, cerebrospinal fluid, wound fluids,respiratory secretions) also should be collected [6]. Source identificationand control also are emphasized in the SSC guidelines [6]. Clinicians areurged to identify an anatomic site of infection within 6 hours of patient pre-sentation [6]. Imaging studies to confirm potential infection sources shouldbe 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 recordsfrom 1995 revealed the prevalence rates for common sites of infectionamong 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, Albertiand colleagues [17] identified increased risk of progression associated withpneumonia, peritonitis, bacteremia, and catheter-related infections. Inpatients who have cancer, the source of infection often is related to thepatient’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 inflammatoryresponse. An international study of data from Europe, Canada, and Israelconfirmed increased risk of progression from sepsis to severe sepsis or septic

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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 andoutcome, it is important that clinicians collect adequate and appropriatevital sign information. Because the diagnostic criteria for sepsis include pa-rameters such as SBP, MAP, and CVP, hemodynamic monitoring also canaid clinicians in identifying patients who are developing severe sepsis (seeBox 2) [16].

Checklists and questions incorporated into screening tools can assistclinicians in considering relevant physiologic indicators. Protocols mayincorporate frequent monitoring (ie, hourly) of vital signs including bodytemperature, respiratory rate, blood pressure (BP) including MAP, heartrate, urine output, oxygen saturation, ScvO2, CVP, and neurologic checks[12]. Frequent monitoring is especially valuable in identifying trends, whichcan provide a more complete clinical picture than individual measurements[30–32].

It is also important to include queries regarding lactate levels in protocolsand screening tools. Elevated lactate levels are a marker for tissue hypoxia inseptic shock and are associated with increased mortality rate in patients whohave sepsis [12,30,33,34]. Repeated lactate measurements provide a betterindication of tissue oxygenation than single measurements [30]. In addition,lactate clearance of at least 10% during the first 6 hours following EDadmission 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 ofthis resource, epidemiologic data indicate that the percentage of sepsispatients who have organ dysfunction is increasing [3]. As new support tech-nologies have become available to sustain critically ill patients, progressiveorgan failure, rather than underlying illness, has emerged as a major threatto survival [15]. It is important to recognize that [15]:
� Organ dysfunction occurs on a progressive continuum.� Recognition of early organ abnormalities can facilitate treatment atearlier stages of MODS.


� Measures of organ dysfunction over time provide a better indication ofdisease course than individual measurements.� Organ dysfunction can be affected by many factors, including those thatare host- and intervention-related.

Mortality doubles as the number of dysfunctional organs increases fromone to two, and it increases three- to fourfold as the number of dysfunctionalorgans increases from one to 4 or more [2,35,36]. Because early recognition ofsevere sepsis facilitates timely intervention, it increases opportunities tomain-tain tissue perfusion and oxygenation and limit additional organ dysfunction[35].Unfortunately, clinicians do not always recognize that dysfunction in oneorgan, along with indications of sepsis, qualifies the patient as having severesepsis [35]. Concurrent signs of infection and SIRS should motivate cliniciansto seek signs of organ dysfunction and hypoperfusion, even in the absence ofhypotension [37]. Because indications of organ dysfunction can be attribut-able to several causes other than sepsis (eg, surgical procedures, acutemyocar-dial infarction, drug therapies, or underlying disease states), clinicians shouldwork to identify or eliminate other easily identifiable causes [16].

A list of some signs of organ dysfunction and hypoperfusion is providedin 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 theSSC severe sepsis screening tool [38]. Awareness of organ systems that areoften dysfunctional in severe sepsis also may guide clinicians to recognizesigns of organ dysfunction. Organ dysfunction in sepsis is observed mostcommonly in the respiratory, cardiovascular, renal, hematologic, centralnervous, and hepatic systems [2,3,39].

Scoring systems. Scoring systems provide an aggregate quantitative indica-tor of several patient characteristics, including organ dysfunction and vitalsigns, to assess condition severity, prognosis, or progression [40]. Descrip-tions of commonly used scoring systems are included in Table 1. Web-basedtools to calculate patient scores are available for many of these scoringsystems [40,41]. Physiologic scoring systems have been applied to severalpurposes, including therapeutic decision support, outcomes and evaluationresearch, quality care analysis, and benchmarking [26]. In clinical decisionprocesses, scoring systems have been used to determine illness severity andpredict mortality risk [37]. In the case of one therapeutic intervention(rhAPC), a scoring system output (APACHE II score) has been identifiedas an indication to initiate therapy [42].

The use of scoring systems in the ED has been limited but is becomingincreasingly important as more critically ill patients are housed for extendedperiods in the ED [26]. One study to assess the impact of ED intervention onoutcomes demonstrated that the highest scores (APACHE II, SAPS II,MODS) and predicted mortality occurred during the ED stay, emphasizingthe importance of developing scores for use in the ED setting [26]. Scoring

Box 5. Indicators of organ dysfunction and hypoperfusion

RespiratoryTachypneaAcute 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%)

CardiovascularTachycardiaHypotensionAltered central venous pressure (CVP)Altered pulmonary artery occlusive pressure (PAOP)Abnormal cardiac index

RenalOliguriaAnuriaIncreased creatinine

Hepatic/gastrointestinal (GI)HyperbilirubinemiaIncreased enzymesDecreased albuminIncreased prothrombin time (PT)Ileus

Central nervous systemAltered mental statusAltered consciousnessPsychosis

HematologicThrombocytopeniaCoagulation abnormalities

HypoperfusionIncreased serum lactate levelsDecreased capillary refillSkin mottling

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

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Table 1

Common scoring systems for patients with severe sepsis or septic shock

Scoring System Description

ICU scoring systems

Acute Physiology and Chronic

Health Evaluation (APACHE) II

Online calculators:

http://www.icumedicus.com/icu_scores/apache.php

http://www.sfar.org/scores2/apache22.html

Developed as mortality prediction tool

Consists of variables including

temperature, MAP, heart rate,

respiratory rate, oxygenation, arterial pH,

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

Online calculators:

http://www.icumedicus.com/icu_scores/saps.php

http://www.sfar.org/scores2/saps2.html

Introduced in 1994

Includes variables similar to APACHE

Sequential Organ Failure Assessment (SOFA)

Online calculators:

http://www.icumedicus.com/icu_scores/sofa.php

http://www.sfar.org/scores2/sofa2.html

Developed to describe severity

of organ dysfunction

Includes questions regarding

cardiovascular, neurologic, renal, liver,

respiratory, and coagulation function

Multiple Organ Dysfunction Score (MODS)

Online calculators:

http://www.icumedicus.com/icu_scores/mods.php

http://www.sfar.org/scores2/mods2.html

Developed to describe severity

of organ dysfunction

Includes questions regarding

cardiovascular, neurologic, renal, liver,

respiratory, and coagulation function

ED scoring systems

Mortality in Emergency Department

Sepsis Score (MEDS)

Identifies ED patients at risk for infection

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 andinitiation of evidence-based protocols for critically ill patients [26]. Imple-mentation of sepsis protocols before ICU transfer is expected to improveoutcomes for severe sepsis patients greatly [6].

http://www.icumedicus.com/icu_scores/apache.php

http://www.sfar.org/scores2/apache22.html


http://www.sfar.org/scores2/saps2.html

http://www.icumedicus.com/icu_scores/sofa.php

http://www.sfar.org/scores2/sofa2.html



http://www.sfar.org/scores2/mods2.html

S18 RIVERS & AHRENS

New scoring systems should be developed to accommodate the spectrumof severity from the ED to the ICU, or current systems should be recali-brated to this end [26]. ED-specific scoring systems should consider easeof use and bedside availability, shorter time frame of data collection, andcomparability with existing scores [26]. The MEDS score is one that hasbeen developed specifically for ED use [26,43]. It is designed to identifyED patients at risk for infection and categorize them based on mortalityrisk [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 greaterthan 5%, age over 65 years, lower respiratory infection, nursing homeresident, and altered mental status [43]. The MEDS score may prove tobe 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 perfusionis critical, because global tissue hypoxia is a key step toward multiple organfailure [23]. Fluid resuscitation recommendations have been updated in the2008 SSC guidelines but remain based on the demonstrated effectiveness ofEGDT in managing septic shock [6,44]. Readers are encouraged to consultthe 2008 SSC guidelines for more comprehensive information regardinginitial 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 necessarilyreflect blood flow and oxygenation [30]. Even when resuscitation goals forCVP and MAP have been achieved, additional measurements of venousoxygenation 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 necessaryto determine whether the ultimate goal of resuscitation, an adequate oxygensupply 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 theuse of available technologies [48]. Newer, less-invasive techniques, such asexternal and esophageal Doppler and thoracic bioimpedance, increasinglyare employed by clinicians [30,48]. Acceptance in particular clinical settingslikely will depend on ease and speed of use, expense, and accuracy [30]. Forexample, Doppler techniques are minimally invasive, inexpensive, rapid, andaccurate, 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 patientphysical limitations [49]. Given the ultimate goal of adequate tissue oxygen-ation, blood flow measurements should be coupled with measurements oftissue oxygenation [30].

Measurements that are in common use to assess tissue oxygenation areSvO2, ScvO2, and lactate [30]. All three are global, indirect measures of tis-sue oxygenation that require venous access [30,47]. Decreased SvO2 andScvO2 values reflect increased oxygen extraction by tissues experiencingoxygen deficit in early sepsis [30]. Increased lactate levels signal increasedanaerobic metabolism in the face of insufficient oxygen to meet tissue needs[30]. For all three indices (SvO2, ScvO2, and lactate), trends provide a morecomplete 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

Technique

Arterial/venous

access required?

Cost !$25

per patient?

Suitable for

all patients?

External Doppler No Yes Yes

Esophageal Doppler No No No, the patient

must be sedated.

Thoracic

bioimpedance

No Yes No, the patient must have

normal anatomy and

access to the neck.

Exhaled CO2

Fick method

No No No, the patient must be

on a ventilator.

Pulse contour Yes No No, the patient must have

at least an arterial line

in place.

Pulmonary

artery catheter

Yes No No, the patient must have

a central line in place.

From Ahrens T. Hemodynamics in sepsis. AACN Adv Crit Care 2006;17(4):435–45; with

permission.

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

Central venous O2 saturation CVC (right atrium)–fiber optic cable ScvO2 Global Invasive

Lactate Laboratory – enzymatic testing Lactate Global Invasive

Emerging techniques

Gastrointestinal tonometry

and sublingual capnography

Measurement of pCO2 in an air-filled

or saline-filled balloon or sublingual probe

prCO2/pCO2 gap, pHi,

sublingual pCO2

Regional Minimally invasive

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].

S20

RIV

ERS&

AHRENS


assessments [30]. The outcome impact of PACs as a hemodynamic optimi-zation tool has been controversial. Studies, including meta-analyses, haverevealed mixed outcomes (eg, decreased morbidity, improved outcome fol-lowing surgery, no benefit in the ICU, increased mortality) associatedwith PAC use [47].

A study comparing PAC- and CVC-directed therapy in patients who hadestablished ALI revealed no differences in outcomes such as mortality, ICU-free days, and number of ventilator-free days [50]. Patients in the PACgroup, 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 firstprotocol instruction was significantly greater in the PAC group than theCVC group [50]. This finding was attributed to the longer time requiredfor PAC insertion [50]. At this time, the SSC guidelines for managing severesepsis and septic shock indicate that SvO2 and ScvO2 are equivalent formonitoring resuscitation [6]. The use of PACs for routine monitoring ofpatients 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 cultureresults has negative consequences [6,25]. Clinicians should be aware thatblood cultures will be negative in more than 50% of severe sepsis/septicshock 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 (causativeagent, antibiotic susceptibilities) is available for therapeutic adjustment [6].

Selection of an appropriate antimicrobial agent, often in the absence ofmicrobiologic confirmation, requires consideration of patient-related char-acteristics such as drug intolerances, recently used antibiotics, previousinfections, underlying disease, and clinical syndrome [6]. Awareness of theprevalence of infections caused by specific organisms can provide clinicianswith insight into appropriate empiric antimicrobial therapy. Pathogen resis-tance patterns in the hospital and community, along with hospital protocolsto limit antibiotic resistance, also should be considered [6]. The SSC guide-lines recommend that clinicians consider the setting-specific prevalence ofoxacillin (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. Basedon epidemiologic data from 1979 to 2000, gram-positive bacteria havebecome 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 causedby fungal infections increased 207% from 1979 to 2000 [3]. Furthermore,

S22 RIVERS & AHRENS

an analysis of international epidemiologic data identified gram-positiveand -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 measurementof tissue oxygen levels, and in diagnosis of infection. These advances shouldallow 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 withinitial 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 findingwas because of the large variability in levels between patients.

Contrary to the observation of Kinasewitz, other studies have identifieda relationship between protein C levels and sepsis or therapeutic outcome[52,53]. At this time, a predictive correlation between protein C levels andsepsis outcome has been demonstrated [54,55]. Procalcitonin (PCT) alsohas been identified as a biomarker for progression to severe sepsis and septicshock. As with protein C, data have not demonstrated consistently that PCTis a sensitive and specific indicator of sepsis. Results of recent meta-analysesindicate that PCT may be a poor, moderate, or good diagnostic marker forsepsis [56–58]. Many recent studies, however, have documented the benefitsof PCT measurements for sepsis evaluation in critically ill patients and inguiding 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/SISInternational 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 needto assess the specific roles of biomarkers in different aspects of sepsis (eg,coagulopathy and adrenal dysfunction) [16]. The current SSC guidelinesdo not include information regarding the use of biomarkers, aside froma 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 polymorphismspredisposing individuals topooror goodoutcomes fol-lowing severe sepsis or septic shock. The author cited a list of studies exploringthe association between gene polymorphisms and sepsis outcome or suscepti-bility. Overall, the studies yielded contradictory results, negative results, or re-sults that havenot been confirmed in experiments demonstrating causality [67].Genes considered in these studies included TNF-a, TNF-b, IL-10, IL-8, andCXCR2 [67]. In addition, a recent article by Jessen and colleagues [68] revealedno association between commonly described single nucleotide polymorphismsof 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 systemfor staging sepsis stratifiespatients according topredisposing conditions, natureand extent of infection, nature and magnitude of host response, and degree oforgan 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 toolbased on the relative risk contributions of the components, and chara-cterized the tool’s performance in a set of 1531 patients. The risk factorsincluded in the model are [17]:

Bilirubin greater than 30 mmol/LHeart rate greater than 120 beats/minSodium greater than 145 mmol/LPlatelets less than 150 � 109/LSBP less than 110 mm HgTemperature greater than 38.2�CMechanical ventilationPneumoniaPeritonitisGram-positive cocciAerobic gram-negative bacilliPrimary bacteremia

This scoring system is unique in its consideration of progression risk as anendpoint.

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, becausesplanchnic 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 tissueoxygen tension measurement by means of electrodes is the ability to measuremany different tissue sites [47]. Visualization of sublingual microcirculatoryperfusion using orthogonal polarization spectral imaging is also an emerg-ing technique [69]. In an observational study to compare microcirculatoryperfusion indices in severe sepsis/septic shock survivors and nonsurvivors,measurements taken early in sepsis using this minimally invasive techniquerevealed that microcirculatory indices were more markedly impaired in non-survivors than survivors [69]. This was a preliminary study, however, andfurther 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 ofpeptide nucleic acid fluorescent in situ hybridization (PNA-FISH), real-time polymerase chain reaction (PCR), and pyrosequencing in the detectionof suspected causative agents [70]. Pyrosequencing is an emerging techniqueparticularly suitable for detecting antimicrobial resistance and bacterialstrain identification [70]. In proof-of-concept studies, multidrug-resistant(MDR) isolates of Mycobacterium tuberculosis could be characterized ina matter of hours [70]. PNA-FISH is the simplest of the three technologies,and results are available in several hours [70]. Fluorescently labeled PNAprobes are available to detect S aureus, Enterococcus faecalis, Candida albi-cans, Escherichia coli, and Pseudomonas aeruginosa [70]. Application ofPNA-FISH to direct vancomycin therapy in a non-ICU setting resulted ina decrease in the median length of stay and cost savings of about $4000per patient [70]. An FDA-cleared, commercially available real-time PCRproduct is available for rapid detection of methicillin-resistant S aureusfrom nasal swab samples [70]. A commercial product that is not FDAcleared is also available; results from this assay are available in less than3 hours [70]. Availability of rapid assays for detecting and characterizingmicrobes is increasing and should help clinicians in earlier diagnosis in casesof sepsis.

Definitive care: guideline implementation resources

The previous sections provided an overview of tools and techniques thatcan facilitate earlier recognition and treatment of severe sepsis and septicshock. Evidence-based management guidelines provide recommendationsregarding the most effective application of tools and techniques. Guideline


recommendations, however, cannot direct outcome improvement if they arenot 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 resourcesto the implementation and monitoring process. Advice and resources fordirecting clinical change through protocol development, implementation,and quality improvement monitoring are available. An overview ofresources 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 severesepsis: 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 teamsremove barriers and provide resources, and stakeholder teams need to beinformed of change progress [5]. The types of teams that are formed atthe institution depend on the desired goals. In an example provided in theSSC handbook, an ED trying to decrease the time to sepsis and severe sepsisdiagnosis may rely on a strong working team. Members of an interdepart-mental, multidisciplinary working team assembled for this purpose mightinclude an ED physician, triage nurse, staff nurse, laboratory technician,laboratory supervisor, and admissions clerk [5].

Inclusion of representatives from different departments is important forseveral reasons. More than 50% of ICU patients with nontraumatic shockmay 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 transferto the ICU [11,26]. Those becoming septic outside the ICU have pooreroutcomes, 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, theSSC guidelines committee has stated the opinion that the potential foroutcome 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 patientswill be addressed [5]. Multidisciplinary teams have been important in improv-ing patient and process outcomes in other areas of critical care. The AmericanHeart AssociationGetWith theGuidelines (GWTG) program encourages re-cruitment of multidisciplinary practice improvement teams, and implementa-tion of GWTG-Stroke has reducedmortality and improved practice guidelineadherence [73–76]. Similarly, the American College of Cardiology GuidelinesApplied in Practice (GAP) initiative also has generated positive results [77].For example, the Acute Myocardial Infarction GAP Project in Michigan

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/individualchartmeasurementtool.pdf

� Evaluation for Severe Sepsis Screening Tool (paper)dhttp://www.survivingsepsis.org/files/Tools/evaluationforseveresepsisscreeningtool.pdf

� Monthly Measurement Worksheet (paper)dhttp://www.survivingsepsis.org/files/Tools/monthlymeasurementworksheet.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 measurementworksheet, individual chart measurement tool (paper anddatabase)dhttp://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/

S26 RIVERS & AHRENS

http://www.survivingsepsis.org/


http://www.survivingsepsis.org/manual_database

http://www.survivingsepsis.org/manual_database

http://www.survivingsepsis.org/implement/bundles


http://www.survivingsepsis.org/files/Tools/individualchartmeasurementtool.pdf



http://www.survivingsepsis.org/files/Tools/evaluationforseveresepsisscreeningtool.pdf



http://www.survivingsepsis.org/files/Tools/monthlymeasurementworksheet.pdf



http://www.survivingsepsis.org/gettingstarted

http://www.survivingsepsis.org/node/155

http://www.survivingsepsis.org/node/155

http://www.survivingsepsis.org/campaign/join


http://www.ihi.org/ihi

http://www.ihi.org/ihi

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/


http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/HowtoImprove/

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/HowtoImprove/

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Measures/


http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/ImprovementStories/

http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/ImprovementStories/

http://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 flowsheet)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 mortalityrates decreased from 38.3% before GAP to 33.2% after implementation(P!.02) [78]. Reported successes of multidisciplinary sepsis managementteams 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]. Outcomeimprovements following the implementation of protocols developed fromevidence-based guidelines (SSC guidelines or comparable) already havebeen 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 byRivers 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 similaracross all studies [10,81–91]. Following implementation of sepsis protocols,the relative risk reduction exceeded 0.25 (25%), and absolute risk reductionexceeded 9% in all studies (see Fig. 4). The mean relative and absolute riskreduction 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 and16%, respectively [10,23,81–89,91,92].

http://sepsis.bidmc.harvard.edu/Content/start_frameset.htm


http://sepsis.bidmc.harvard.edu/Content/Guides/BIDMC_MUST_Protocol_Guide_082504.pdf

http://sepsis.bidmc.harvard.edu/Content/Guides/BIDMC_MUST_Protocol_Guide_082504.pdf

http://sepsis.bidmc.harvard.edu/Content/Guides/BIDMC_MUST_flow_sheet_0204.pdf

http://sepsis.bidmc.harvard.edu/Content/Guides/BIDMC_MUST_flow_sheet_0204.pdf



http://lomalindahealth.org/common/legacy/llumc/emergency/patientcare/documents/patientcare-sepsis.pdf



0.34

0.53

0.34

0.49

0.31

0.58

0.38

0.26

0.68

0.47

0.8

0.29

0.33

0.00 0.20 0.40 0.60 0.80 1.00

Rivers, 2001

Gao, 2005

Sebat, 2005

Kortgen, 2006

Shapiro, 2006

Trzeciak, 2006

Micek, 2006

Lin, 2006

Qu, 2006

Nguyen, 2007

Sebat, 2007

El Solh, 2007

Jones, 2007

Relative Risk Reduction

Fig. 4. Sepsis protocol implementation reduces mortality risk. (Data from Refs. [10,23,81–92].)

S28 RIVERS & AHRENS

Among the studies included in Fig. 4, several assessed protocols that weredeveloped based on the SSC care bundles. The reported outcome improve-ments were similar to those reported for all of the protocol implementationstudies. Nguyen and colleagues [88] observed hospital mortality rates of21% for patients who received all treatments specified in the bundles and40% for those who did not (P%.01). Gao and colleagues [83] also identifiedincreased hospital mortality in patients who did not receive all sepsis bundletreatments. The SSC recommends that the sepsis care bundles form the basisfor 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% ofthe 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 nationalcost of treating sepsis in the United States increased more (183%) thanfor 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 sincethe SSC sepsis management guidelines were introduceddreveals many pub-lications regarding the economic impact of sepsis and of individual aspectsof 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 approximately23%, primarily because of shortened hospital stay [94].

Research demonstrating the full economic benefits of implementing allcomponents 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] revealeddecreased per-patient costs after protocol implementation ($21,985 beforecompared with $16,103 after implementation; P ¼ .009) and a significant5-day decrease in the median length of stay (P ¼ .023). The decreased patientcosts were attributed to decreased ICU and ward bed day charges [95].

Variability in sepsis management approaches and inherent difficulties inperforming cost-effectiveness analyses in critical care (eg, short-term end-points, patient complexity) have made it difficult to assess the economicbenefits of sepsis interventions [96,97]. Part of the problem has been thelack of a defined standard of care for treating patients with severe sepsis[96]. With the development of widely accepted, evidence-based treatmentguidelines, 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 remindingHCPs to complete all tasks required for optimal care [5].

The SSC, in partnership with the IHI, has developed two sepsis bundlesto facilitate the development of protocols consistent with evidence-basedrecommendations [5,98,99]. Information on these bundles and theirimplementation 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 throughits Web site (http://www.survivingsepsis.org/) to guide clinicians in develop-ing and implementing sepsis management protocols. Implementing theSurviving Sepsis Campaign is a manual that compiles the SSC guidelinesand care bundles, information on creating a team for clinical practicechange, practical steps to protocol development, performance assessmenttool instructions, and professional insights on overcoming barriers (http://ssc.sccm.org/files/Implementing%20the%20Surviving%20Sepsis%20Campaign.pdf) [5]. Several supplementary educational tools and clinical referenceitems to support protocol implementation are also available, includ-ing slides, posters, pocket guides, and care bundle badge cards




http://ssc.sccm.org/files/Implementing%20the%20Surviving%20Sepsis%20Campaign.pdf



S30 RIVERS & AHRENS

(http://www.survivingsepsis.org/gettingstarted). The severe sepsis screeningtool is also available online (http://www.survivingsepsis.org/files/Tools/evaluationforseveresepsisscreeningtool.pdf). The SSC severe sepsis screeningtool and care bundle badge cards are provided in Figs. 5 and 6 as examplesand 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

forHealthcare Improvement; with permission.Available at: http://www.survivingsepsis.org/files/

Tools/evaluationforseveresepsisscreeningtool.pdf.)

http://www.survivingsepsis.org/gettingstarted





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 facilitatinginformation exchange between institutions and providing a venue for shar-ing personal experiences regarding severe sepsis quality improvementefforts. A newsletter (Campaign Update) and update sessions at partnersociety congresses provide information regarding SSC progress, includingsuccesses 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 theone 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 bundlesinto one protocol, and another may choose to develop separate protocolsfor each step.

Resources are available from other groups that have developed andimplemented protocols. Parallel quality initiatives have been pursued bymany groups [9]. For example, the 6-hour Strategies to Timely Obviatethe 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 bya multidisciplinary team at Beth Israel Deaconess Medical Center in Boston[9,12,45,81,88]. These institutions have published their protocol resources onthe Internet (see Box 6), providing a useful information pool. Groups alsohave published aspects of their protocols in the medical literature[10,12,45]. Examples of generalized protocols applicable to implementingthe 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 meansto accelerate positive clinical change in sepsis management [100–102]. TheModel for Improvement is based on an iterative process of selectingchanges, testing the changes, studying the outcome, and adjusting accord-ingly. Measuring and reporting changes are inherently important to thisprocess. The SSC and IHI have collaborated to develop tools for measuringand reporting improvement in sepsis management with the goal of decreas-ing mortality caused by sepsis. The tools include quality indicators, a chartreview database, a monthly measurement worksheet, an interim glucocorti-coid administration policy, and tools for severe sepsis screening, individualchart measurement, median plateau pressure calculation, and medianglucose calculation. These tools are available at the IHI Web site (http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Tools/). Organizations workingto 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 incorporatedinto the database indicate outcome changes (eg, reduced mortality fromsevere sepsis and septic shock) and process changes (eg, timely completionof sepsis bundle elements) [104]. The chart review database is particularlyuseful, because it can be used to easily generate graphs and flowcharts todocument and report progress [103]. In addition, this database providesan option for sending data to the SSC [103]. The SSC encourages datasharing 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].

Fig. 8. Example: early goal-directed therapy tracking form.

S34 RIVERS & AHRENS

Summary

Because sepsis-related mortality is unacceptably high, the SSC has seta quality improvement goal to reduce mortality caused by severe sepsisand septic shock by 25% by 2009. Clearer definitions of sepsis, severe sep-sis, and septic shock will help in achieving this goal, as will recentlyupdated evidence-based management guidelines for severe sepsis and septicshock. To be effective, these definitions and guidelines need to be appliedto the early identification and aggressive treatment of patients who havesevere sepsis or septic shock. Early goal-directed therapy to achieve hemo-dynamic stabilization has been demonstrated to decrease mortality inpatients who have septic shock. Currently, clinicians must rely on cluesto sepsis progression in the patient’s medical history, vital signs, hemody-namic monitoring, lactate levels, and indications of organ dysfunctiondallin the context of infectiondto identify patients who have severe sepsis.Of these, hemodynamic monitoring, lactate levels, and indications of organdysfunction 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 identifyingpatients who have severe sepsis. Once a patient who has severe sepsishas been identified, timely implementation of guideline recommendationsshould follow. Resources and tools are available through the SSC andIHI 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 sepsisand septic shock

A 63-year-old male arrives in the ED with a foot wound of prolongedduration. His wife encouraged him to visit the ED when she noticed thatthe wound ‘‘looked and smelled infected.’’ She commented to the triagenurse 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 historyof peripheral neuropathy. Temperature and respiratory rate are elevated; BPand heart rate are in normal ranges.

Vital Signs at Presentation (ED)

Temperature 38.4�CHeart 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 ampicillinplus sulbactam) is initiated within 45 minutes of presentation.

Vital Signs at Follow-up (ED; 2 hours post-presentation)




Pulse oximetry 99%

Two hours after presentation (approximately 1 hour after antibiotic ad-ministration), the patient’s temperature has increased; respiratory rate is stillelevated, and BP has decreased slightly. An ICU consultation is requested.

Vital Signs at ICU Consult (ED; 4 hours post-presentation)




The intensivist arrives 2 hours after the request for consultation (4 hoursafter presentation). The patient’s temperature and respiratory rate have in-creased. His heart rate also has increased, although it is still within normallimits. 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 isadmitted to the ICU, but transfer takes 3 hours because of bed and resourcelimitations.

Vital Signs on Transfer to ICU (ICU; 7 hours post-presentation)




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’slactate 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 withprotective lung strategies in place. Persistently elevated serum lactate levelsindicate that tissue perfusion remains impaired. Norepinephrine was initi-ated at 5 mg/min and has been increased to 10 mg/min, in addition to fluidresuscitation. Vasopressin is added at 0.04 U, and the patient is given 1dose of 50 mg of hydrocortisone.

Because the patient’s temperature has remained elevated, and sepsis hasprogressed to septic shock, reassessment of antibiotic therapy is appropriate.Cultures were not collected before antibiotic therapy, so information frommicrobiologic results is not available to inform the choice of a second agent.Therefore, an empiric approach, possibly informed by culture of the woundat this time, will be used.

In the context of continued hypoperfusion and multiple organ dysfunc-tion (respiratory, cardiovascular), an APACHE II score will be determinedto assess the appropriateness of rhAPC therapy for this patient. AnAPACHE II score of at least 25, indicating high risk of death, wouldmake 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 triageclinician 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 mentalstatus) as signs that the patient likely had severe sepsis at presentation in


the ED. These findings would trigger immediate actions that could affect thecourse of this case positively, including lactate measurement, appropriatecultures, initial fluid bolus, and EGDT. In addition, a surgical consultationshould have been requested to determine appropriate source control mea-sures. In this case, amputation of the foot may have been appropriate. Sebatand colleagues [10] demonstrated that protocol implementation can decreasethe time to reach treatment goals. Times were decreased significantly pre-versus postprotocol for intensivist arrival (2:00 versus 0:50), ICU/operatingroom 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 mortalitycaused 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 protocolsfor managing severe sepsis and septic shock have been implemented.

Setting with a hospital-wide protocol for managing severe sepsisand septic shock

The components of the sepsis management protocol for this hospitalinclude:

� A screening tool to promote the early recognition of patients who havesevere 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, andgeneral wards� Provision for dedicated sepsis beds in the ICU

Using the screening tool, the ED clinician notes presence of an infectedwound; 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 severesepsis. In the hour following presentation, the following tasks are completedin the ED:

� Staff designated for management of severe sepsis and septic shock arealerted and arrive in the ED.� Blood and wound cultures are collected before initiation of antibiotictherapy.� CVC with ScvO2 monitoring capability is placed.� Serum lactate level is determined.� IV antibiotic appropriate for diabetic foot wound (ampicillin plussulbactam) 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 followingpresentation:

� 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 areavailable, there is no delay in transfer.

In this scenario, adherence to protocol recommendations decreased timeto ICU admission and fluid resuscitation administration from 7 hours to3 hours. Placement of the CVC and initiation of fluid resuscitation in theED have decreased the time to fluid therapy from 7 hours to 1 hour, animportant 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 andhypercholesterolemia. Initially, the patient was doing well and was friendlyand talkative with the postoperative staff. Approximately 48 hours after sur-gery, her mental status changed, and she began to alternate between agitatedand listless states. Vital signs at that time indicate decreased BP and elevatedheart rate, respiratory rate, and temperature.

Vital Signs (Surgical Ward; 48 hours post-op)

Temperature 38.6�CRespiratory rate 24 breaths/min

Heart rate 92 beats/min

CVP 3 mm Hg

MAP 62 mm Hg

Urinary output 0.6 mL/kg�hrScvO2 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 inflammatoryresponse (ie, fever, elevated respiratory and heart rates, elevated serum lac-tate) and organ dysfunction (ie, respiratory, cardiovascular, central nervoussystem) indicate severe sepsis, and the hospital-wide sepsis protocol is initi-ated. Sepsis response team members are alerted, cultures are collected formicrobiology, and a diagnostic work-up, including abdominal CT scan forsource control, is initiated. The patient is provided with supplemental oxygenby means of a non-rebreather mask, and fluid therapy with 1000 mL


crystalloid every 30 minutes is initiated. As fluid boluses are administered, thepatient’s response (eg, ScvO2, CVP, urinary output, and MAP) is monitoredto determine the necessity of further hemodynamic optimization.

Vital Signs (Surgical Ward; 3 hours after resuscitation initiated)



CVP 6 mm Hg

MAP 60 mm Hg





After 3 hours, the patient’s MAP and ScvO2 remain depressed, and herrespiratory rate and lactate levels remain elevated. After resuscitation toachieve 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 inthe 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)



CVP 14 mm Hg

MAP 60 mm Hg





The patient’s condition has not improved substantially with aggressiveresuscitation (ie, continued fluid resuscitation, vasopressor treatment, ste-roid therapy, and mechanical ventilation). In addition, her urinary outputhas decreased, suggesting renal failure in addition to other organ dysfunc-tion. The patient also has evidence of myocardial depression, and inotropictherapy has been instituted to increase the ScvO2. Her recalculatedAPACHE 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 afterICU admission, multiple organ dysfunction and an APACHE II score ofat least 25 indicate a high risk of death. An appropriate action in continuingaggressive treatment and after addressing the surgical issues for this patientwould be rhAPC administration.

Case study 3

Female college student presents to emergency department with suspectedurinary tract infection and fatigue

A 20-year-old female college student presents in the ED with severe painon urination and marked sluggishness since the previous day. She thinks shehas 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 wakingup and concentrating on anything, but that may be because she has beenstaying up late to study for examinations. She takes a daily vitamin. Tylenol,aspirin, and over-the-counter antihistamines and decongestants are used asneeded.

Vital Signs at Presentation (ED)




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) within30 minutes. The patient’s lactate level is 4.2 mmol/L. The ED clinicianorders appropriate empirical antibiotics and EGDT. An appropriate antibi-otic is administered. The patient’s vital signs are essentially unchanged frompresentation, however. A CT scan of the abdomen is ordered.

Members of the sepsis team arrive 1 hour after presentation and confirma diagnosis of severe sepsis, probably secondary to the UTI. The patient istransferred to the ICU, and the transfer is completed within 1 hour (3 hoursafter presentation).

Vital Signs on Transfer to ICU (ICU; 3 hours post-presentation)




MAP 63 mm Hg

CVP 7 mm Hg

ScvO2 55%




The patient’s temperature, heart rate, and BP remain the same, but herMAP, CVP, and ScvO2 are low. Fluid therapy is initiated.

Vital Signs (ICU; 4 hours post-presentation, 1 hour post–fluid therapy)




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, andinotropic therapy is started.

Vital Signs (ICU; 6 hours post-presentation, 3 hours post–fluid therapy)

Temperature 37�CHeart rate 79 beats/min



MAP 67 mm Hg

CVP 10 mm Hg

ScvO2 72%



Resuscitation goals are met. Aggressive fluid resuscitation and inotropictherapy are discontinued, and the patient is removed from the sepsismanagement protocol. Patient is transferred to a medical–surgical floorfor 24 hours of observation. Microbiology results confirm that the patientwas 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, thepatient 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 signssuggesting severe sepsis (ie, infection, fever, potential organ dysfunction[elevated heart rate, recent onset of severe fatigue]) and performed a serumlactate screen. This confirmed the suspicion that the patient should beentered into the severe sepsis protocol. Following EGDT initiation, thepatient’s condition improved quickly.

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