Clinical Review
Early Recognition: The Rate-Limiting Step
to Quality Care for Severe Sepsis Patients in
the Emergency Department
Jason H. Maley, MD, David F. Gaieski, MD, and Mark E. Mikkelsen, MD, MSCE
Abstract
• Objective: To detail strategies to improve sepsis recognition and the quality of care provided to the septic
patient.
• Methods: Review of the literature.
• Results: Severe sepsis affects nearly 3 million individuals each year in the United States, and cost estimates for these hospitalizations exceed $24 billion.
Effective management is predicated on timely recognition. In this review, we detail strategies to improve
early identification of potentially septic patients as well
as the quality of care provided to the septic patient in
the emergency department (ED). The strategies discussed are based upon an understanding of the signs
and symptoms of sepsis and the clinical risk factors
associated with sepsis, which can be used to design
novel strategies to screen patients for sepsis and risk
stratify patients at risk for clinical deterioration.
• Conclusion: ED structures and processes can be
used to increase adherence with sepsis management
guidelines to improve patient outcomes.
S
evere sepsis affects nearly 3 million individuals
each year in the United States and cost estimates
for these hospitalizations exceed $24 billion [1–3].
Sepsis is a life-threatening condition characterized by a
suspected or identified infection accompanied by a vigorous host inflammatory response. In severe sepsis, end-organ dysfunction manifests in myriad forms, including altered mental status, acute kidney injury, liver dysfunction,
pulmonary dysfunction, and hemodynamic compromise
[4,5]. This protean presentation of a deadly condition
makes identification and risk stratification both challenging and essential to improving patient outcomes. The
majority of patients with severe sepsis will receive their
initial care within an emergency department (ED) [6,7].
It is essential that emergency medicine providers have
www.jcomjournal.com
the means to appropriately identify patients presenting
with severe sepsis in a timely manner—thus facilitating life-saving measures such as early intravenous fluid
resuscitation and administration of timely and appropriate antimicrobials.
In this review, we detail strategies to improve sepsis
recognition and the quality of care provided to the septic
patient in the ED. The strategies discussed are based upon
an understanding of the signs and symptoms of sepsis and
the clinical risk factors associated with sepsis, which can
be used to design novel strategies to screen patients for
sepsis and risk stratify patients for clinical deterioration.
Then, we review suggested ED structures and processes
to increase adherence with sepsis-based guidelines to
improve patient outcomes. Successful implementation is
predicated on hospital administrative support towards the
efforts given the time and resources required and strong
and committed leadership across the health care system.
Epidemiology of Severe Sepsis
Estimates of annual cases of severe sepsis vary, ranging
from 1 million to 3 million cases in the United States
[1–3]. In-hospital mortality for this condition ranges
from 14% to 30% [5]. The incidence of severe sepsis in
the United States has been increasing at a rate of 13% annually, with an estimated cost of greater than $24 billion
per year [1,2]. In 2 large cohorts of hospitalized patients,
it was found that sepsis contributed to 1 in every 2 to
3 deaths following inpatient admission [8]. Coincident
with these increased estimates, advances in the early identification and treatment of sepsis have led to decreasing
mortality rates over the past decade [1,9].
From the Department of Medicine, University of Pennsylvania, and the Department of Emergency Medicine, Thomas
Jefferson University Hospital, Philadelphia, PA.
Vol. 22, No. 5 May 2015 JCOM 211
Severe Sepsis
Of importance to the ED clinician, an episode of sepsis has long-term effects on cognitive and physical function, quality-of-life, and survival [10,11]. Post-discharge,
approximately one-quarter of sepsis survivors will be
readmitted within 30 days [12–14]. In as many as half
of these instances, another life-threatening infection is
the cause for readmission, making the past medical history, including a detailed accounting of recent episodes
of sepsis, an important part of the initial ED evaluation
[12]. Furthermore, severe sepsis survivors spend a large
proportion of their time following discharge within a
health care facility, and will frequently present to the
ED with an acute condition from such an environment.
Important factors for predicting readmission after a sepsis hospitalization include patient age, severity of illness,
hospital length of stay, and the need for intensive care
during the initial hospitalization [12–14].
Principles of Effective Sepsis Management
The principles of effective sepsis management begin with
early identification in the pre-hospital setting, at triage,
or when a patient begins to decompensate in the hospital. After the point of initial recognition, core principles
include risk stratification, timely and appropriate antimicrobial administration, initial intravenous fluid boluses
and ongoing resuscitation guided by physical examination and objective resuscitation end-points [4,5]. These
practices have been operationalized in the care bundles of
the Surviving Sepsis Campaign Guidelines [4]. Within 3
hours, the resuscitation bundle includes measuring serum
lactate to risk stratify patients, obtaining blood cultures,
administering broad-spectrum antibiotics, and administering 30 mL/kg crystalloid in patients with hypotension
or hyperlactatemia [4]. The 6-hour bundle expands upon
these initial measures and includes additional management
recommendations based on resuscitation end-points.
As effective management is predicated on timely recognition, an understanding of the impact of delayed recognition is essential to provide optimal care for the severe
sepsis patient in the ED. Decades of research has revealed
that certain markers predict adverse outcomes, including transition to septic shock and death, as do delayed
processes of care. Importantly, while early quantitative
resuscitation was demonstrated to improve outcomes in
a meta-analysis, there was no demonstrable benefit when
resuscitation was initiated late (> 24 hours) in the course
in the ICU (odds ratio of death, 1.16 [95% confidence
interval, 0.60–2.22]) [15].
212 JCOM May 2015 Vol. 22, No. 5
Strategies to Improve Recognition
Pre-Hospital Environment
As many as 40% of severe sepsis cases admitted to the
hospital from the ED will present to the ED via emergency medical services (EMS) transport, and this rate
appears to be increasing over time [16]. Thus, efforts
to improve identification and risk-stratification of potential cases of severe sepsis should begin in the prehospital environment. These EMS encounters frequently exceed 45 minutes [16], pre-hospital interventions
appear to be uncommon [16,17], and establishment of
intravenous access paired with fluid resuscitation in the
pre-hospital environment may improve survival [18].
Further, when EMS providers recognize sepsis, ED care
processes (eg, time to antibiotics, protocol-directed resuscitation) are improved, with shorter time to antibiotics
and initiation of early goal-directed therapy (EGDT)
[19] and a trend towards achieving goal mean arterial
pressure earlier [17]. In sum, while further investigation
is required to facilitate this transition, efforts to improve
sepsis outcomes should also include the interface between
the pre-hospital environment and the ED (Figure).
From EMS to ED Triage
Borrowing the principle “time equals tissue” from a
variety of time sensitive conditions (eg, myocardial infarction management [“time equals muscle”] and stroke
care [“time equals brain”]), clinicians and researchers
have realized that expedited recognition of severe sepsis
patients begins at the time of initial contact with the
health care system. For severe sepsis patients, clinicians
need to think “time equals organ function.” Given the
frequency with which sepsis patients arrive to the ED via
EMS, effective communication between EMS and ED
providers could be leveraged to prepare the ED team
to provide timely care for the sepsis patient via a “sepsis
alert.” While confirmation of its applicability to sepsis
care is required in the absence of a regionalized network
of sepsis centers, the rationale is based on the experience
of the effectiveness of trauma and stroke alert systems
[20–22]. For patients not recognized as potentially being
infected by EMS providers during transport, repeat
vital signs during ED triage can be screened to identify
patients exhibiting signs of the systemic inflammatory
response syndrome (SIRS) [4,23]. The same principles
of effective communication apply for patients being
sent from medical clinics to the ED for evaluation and
treatment of potential severe sepsis. For patients arrivwww.jcomjournal.com
Clinical Review
Afferent arm to improve sepsis recognition
Pre-hospital environment
Emergency department
Hospital ward
vs.
intensive care unit
Efferent arm to improve guideline adherence and patient outcomes
Figure. Design to improve sepsis recognition and guideline adherence to improve patient-centered outcomes.
ing independent of EMS, focused triage and initial vital
signs are the starting point for identifying severe sepsis
at the most proximal phase of entry into the health care
system.
Vital Signs and SIRS Criteria in the ED
The vast majority of patients who are hypotensive in
triage are expedited to a treatment room and early resuscitation is begun. However, these patients represent a
minority of severe sepsis patients seen in triage; therefore,
all available data need to be analyzed to capture the highest percentage of severe sepsis patients. Acknowledging
that SIRS criteria are not specific for sepsis [24], will
miss as many as 1 out of 8 patients initially [25], and may
not predict mortality [26], their presence is nonetheless
characteristic of sepsis. As such, identifying the presence
of SIRS at triage, or during the ED stay via serial vital
signs, facilitates sepsis recognition, as do strategies that
leverage routine vital signs to calculate predictors of instability including the shock index (heart rate/systolic blood
pressure), where a shock index ≥ 0.7 has been associated
with illness severity [27]. An increased respiratory rate
www.jcomjournal.com
has been demonstrated to identify risk for transfer from a
floor bed to the ICU within 24 hours of ED admission
[28]. Further, clinical manifestations of sepsis, including end-organ dysfunction, are protean, and patients
frequently present with nonspecific, constitutional symptoms (eg, weakness, malaise, fever, chills, nausea) that
could reflect one of many diseases (Table 1).
The Afferent Arm: Multimodal Screening Strategies
While institutional practice improvement initiatives to facilitate sepsis recognition and care should incorporate educational strategies, led by champions with expertise in sepsis,
the complex presentation of sepsis requires multimodal
approaches [29]. These multimodal approaches, beginning
at the time of ED triage, should be designed to harness
information technology to screen patients to improve severe
sepsis recognition (the afferent arm) and to utilize structures and processes of care efficiently and effectively (the
efferent arm) to guide severe sepsis management according
to sepsis-care bundles espoused by guidelines (Figure) [4].
Operational processes to screen for sepsis in the ED
will need to account for ED organizational flow (eg,
Vol. 22, No. 5 May 2015 JCOM 213
Severe Sepsis
Table 1. Epidemiologic Risk Factors, Signs, Symptoms, and Organ Dysfunction Associated With Severe Sepsis
Variable
Prevalence
Reference
Clinical risk factors Age
2,4–5, 23,43
Diabetes mellitus
2,4–5, 23,43
Alcohol abuse
2,4–5, 23,43
Malignancy
2,4–5, 23,43
Transplant
2,4–5, 23,43
Immunosuppression
2,4–5, 23,43
Recent hospitalization
12–14
Recent sepsis hospitalization
12–14
Vital signs
Temperature*
23
Tachycardia*
23
Shock index (heart rate/systolic blood pressure)
27
Tachypnea*
23
Inflammatory variables
White blood cell count*
23
Bandemia
23
Hyperglycemia
23
Organ dysfunction in the emergency department†
Serum lactate (≥ 2 mmol/L)
76%
43
Systolic blood pressure < 90 mm Hg‡
42%
43
Acute kidney injury, creatinine > 0.5 above baseline
Mean arterial pressure < 60 mm Hg‡
33%
43
30%
43
Altered mental status
27%
43
Acute kidney injury, creatinine > 2.0 mg/dL
Shock (refractory hypotension)‡
27%
43
24%
43
Acute thrombocytopenia‡
Coagulation dysfunction‡
15%
43
11%
43
Arterial hypoxemia‡
Hyperbilirubinemia‡
11%
43
8%
43
Acute kidney injury, oliguria
6%
43
Not available
23
Ileus
*Traditional SIRS criteria defined as temperature > 38.3 or < 36.0, heart rate > 90/minute, tachypnea > 20/minute or PaCO2 < 32 mm Hg,
white blood cell count > 12,000 or < 4000.
†In descending order of prevalence, based on published data.
‡Hypotension defined as systolic blood pressure < 90 mm Hg, mean arterial pressure < 70 mm Hg, or a systolic blood pressure decrease
> 40 mm Hg from baseline; arterial hypoxemia defined as a partial pressure of arterial oxygen to fraction of inspired oxygen of less than
300; hyperbilirubinemia defined as total bilirubin > 4 mg/dL; acute kidney injury as oliguria (< 0.5 mL/kg/hour for 2 or more hours despite
fluid resuscitation) or creatinine increase > 0.5 mg/dL; coagulation dysfunction as international normalized ratio (INR) > 1.5 or activated
partial thromboplastin time > 60s; platelet count < 100.
average time from registration to triage, average time
from triage to being seen by a physician, average length
of stay in the ED, number of hospital beds) and handoff practices (eg, care transition from ED team to floor
214 JCOM May 2015 Vol. 22, No. 5
or ICU team, or within ED at shift change). For ED
organizations with shorter ED lengths of stay (eg, < 2
hours), screening practices at ED triage will serve as the
focal point to identify cases of sepsis. Boarding, defined
www.jcomjournal.com
Clinical Review
as caring for a patient in the ED pending transfer, is
common, increasing as a result of ED closures [30,31],
and associated with prolonged hospital length of stay
and increased in-hospital mortality when ICU transfer
is delayed [32]. Sepsis patients in particular appear to
be a vulnerable group of patients. While many explanations exist to account for the relationship between
delayed transfer and adverse outcomes, timely recognition and management of the septic patient could be
compromised with prolonged boarding. To combat this
potential effect, continual assessment during the entire
ED stay may unmask an initially unclear presentation of
sepsis.
One strategy to identify sepsis in ED organizations
with prolonged ED lengths of stay is through the use of
a track-and-trigger system, or early warning system. Traditionally, track-and-trigger systems were implemented
on the hospital wards, as means to identify physiological deterioration in a timely manner to prevent clinical
deterioration [33]. More recently, early warning systems
have been used to identify patients with sepsis on the
hospital wards and within EDs, as these systems rely on
physiological parameters such as SIRS that are cardinal
features of sepsis [34]. However, given the potential for
alert fatigue, designing a system that operates with high
accuracy is imperative.
Efforts are underway to redefine sepsis, using a simplified approach and readily available physiological variables,
with the main goal of targeting those most at-risk of an
adverse outcome during the hospitalization. Simultaneously, an understanding of the overt and more occult
manifestations are essential to incorporate into the clinical decision-making and pattern recognition required to
identify sepsis in a timely and accurate manner. In Table 2,
the signs and symptoms that may serve as flags for
severe sepsis are presented.
Mature early warning systems, designed to leverage
the electronic medical record (EMR) by capturing vital
signs, laboratory measures, (eg, elevated serum creatinine
compared to a recent hospitalization) and symptoms
(eg, altered mental status), are well-positioned to herald
clinical deterioration (eg, cardiac arrest) with improved
accuracy [35] and to be applied to sepsis specifically
[34]. While sophisticated analytical strategies, such as
machine learning, are being used to improve the test
characteristics of these early warning systems, iterative,
prospective chart review is an essential and complementary performance improvement step to refine the process.
www.jcomjournal.com
Further, chart review affords the opportunity to ensure
compliance with sepsis care bundles.
Knowledge of the risk factors associated with development of sepsis is critical for the front-line emergency
physician and nurse. Additionally, as many of these risk
factors are associated with adverse outcomes, including unplanned ICU transfer and in-hospital mortality,
which occur in as many as one out of 8 patients admitted directly to the ward, they have utility for early riskstratification and triaging purposes in the ED. Advanced
age and pre-existing comorbid conditions, particularly an
oncologic diagnosis and/or chronic organ dysfunction,
are major risk factors for sepsis and worse outcomes result
in those who develop sepsis [2]. Further, illness severity,
including an elevated serum lactate level, is associated
with adverse outcomes. These factors can be incorporated into triage decisions and/or close monitoring for
patients admitted to the general ward [36]. Conversely,
because patients admitted to the ICU setting and subsequently stepped down through their hospitalization
may experience better outcomes compared to patients
admitted to the general ward who then require step-up
to an ICU setting (37,38), attention to triage practices is
critical.
These complementary strategies, which serve as the
afferent arm of the system, summon health care providers
to the bedside of a vulnerable patient. However, clinical
effectiveness in the management of severe sepsis requires a
robust, sophisticated, and mature efferent arm capable of
delivering expert care to the now recognized septic patient.
Principles of Effective Management PostRecognition
Risk Stratification
An elevated serum lactate level was initially described in
pathological states in the mid 19th century by Johann
Joseph Scherer [39] and has long been associated with
increased mortality in hospitalized patients [40]. Lactate
is a useful biomarker for risk stratification in a variety of
patients arriving to the ED, particularly those who have
been identified at high risk for sepsis. Jansen and colleagues examined the measurement of pre-hospital serum
lactate at the time of paramedic on-scene assessment in a
group of acutely ill patients [41]. Patients with point-ofcare lactate levels of 3.5 mmol/L or greater were found
to have an in-hospital mortality of 41% versus 12% for
those with lactate levels less than 3.5 mmol/L. Within
the population with an elevated lactate, patients with a
Vol. 22, No. 5 May 2015 JCOM 215
Severe Sepsis
systolic blood pressure greater than 100 mgHg experienced a mortality of nearly 30%, while it was greater
than 50% in hypotensive patients with an elevated lactate, highlighting the value of both hemodynamic and
serum lactate measures. Upon arrival to the ED, lactate
measurements have a strong correlation with mortality.
In one retrospective cohort, lactate level was linearly associated with mortality in a broad array of patients older
than age 65 years [42]. An initial serum lactate level in
the ED in the intermediate (2.0 – 3.9 mmol/L) or high
range (≥ 4 mmol/L) has been associated with increased
odds of death 2 to 5 times higher independent of organ
dysfunction in severe sepsis specifically [43].
As the association between serum lactate levels and
death is independent of organ dysfunction, serum lactate
is a simple and reliable tool to both enhance detection
and risk-stratify patients presenting to the ED with severe
sepsis. Given the frequency with which hyperlactatemia
is present in patients with suspected infection [43],
operationalizing serum lactate measures with the initial
phlebotomy draw is an important step to risk-stratify
patients. This step can be coupled later with intravenous
fluid resuscitation for those with marked elevations
(≥ 4 mmol/L), in accord with guideline recommendations [4]. Screening of initial lactate values can be further
expedited by utilizing fingerstick point-of-care lactate
devices [44]. Last, while serial lactate measures can
be incorporated into triage decisions, there is no clear
threshold that warrants ICU admission. Rather, persistent elevations in serum lactate can be used to identify
patients who require close observation regardless of their
admission location.
Several scoring systems have been developed to augment sepsis risk stratification within the ED. The most
prominent of these are the Predisposition Insult Response
and Organ failure (PIRO), Sequential Organ Failure
Assessment (SOFA), and Mortality in the Emergency
Department Sepsis (MEDS) scores, and the National
early warning score (NEWS) [45-48]. The MEDS score
incorporates host factors including age and co-morbid illness, as well as physiologic and laboratory tests which can
be obtained rapidly in an ED setting. Multiple prospective and retrospective examinations of the MEDS scoring
systems have demonstrated that it performs optimally in
ED patients with sepsis but not those with severe sepsis,
in terms of predicting 30-day mortality [46,47]. The
PIRO score more extensively incorporates predisposing
co-morbidities, physiologic and laboratory parameters, and
216 JCOM May 2015 Vol. 22, No. 5
has been modified to consider presumed source of infection, leading to a stronger predictive ability for mortality
in more severely ill patients. In patients presenting to the
ED with severe sepsis and septic shock, a prospective observational study found the PIRO to be the best predictor
of mortality, compared to SOFA and MEDS scores [45].
In a recent study by Corfield et al, sepsis patients with a
higher NEWS, according to initial ED vital signs (temperature, pulse, respiratory rate, systolic blood pressure,
oxyhemoglobin saturation) and consciousness level, were
significantly more likely to be admitted to an ICU within
48 hours or to experience in-hospital mortality [48].
Timely and Appropriate Antibiotics
In a landmark study published by Kumar and colleagues
in 2006, the relationship between timing of antibiotics
and mortality was established [49]. In 2731 adult septic
shock patients, mortality increased 7.6% for every hour
delay in effective antimicrobial administration. A striking
finding, given that the study population was limited to
patients cared for in the ICU, was the fact that only 50% of
patients received appropriate antibiotics within 6 hours of
onset of shock and nearly one-quarter of patients did not
receive antibiotics until the 15th hour. As a direct result,
in-hospital mortality was observed to be 58% in this study.
Over the ensuing decade, a series of studies have
demonstrated a narrowing of the quality gap in this
regard, and the result has coincided with a significant
improvement in survival. In 2010, Gaieski and colleagues demonstrated a significant improvement in the
prompt administration of antibiotic delivery in patients
presenting to an ED with severe sepsis, with the median
time from shock onset (sustained hypotension or lactate
≥ 4 mmol/L) to antibiotics down to 42 minutes [50].
Importantly, consistent with the Kumar study, time to
appropriate antibiotics, rather than simply initial antibiotics, remained associated with in-hospital mortality
independent of initiating early goal-directed therapy. In
2011, Puskarich and colleagues revealed that time to
antibiotics continued to improve and, as a result, the
investigators did not identify a relationship between
time from triage to antibiotics and in-hospital mortality
[51]. However, when antibiotics were delayed until after
shock recognition, consistent with the study by Kumar
and colleagues, survival decreased. Until recently, this
important observation was challenging to operationalize
clinically as little was known about how to facilitate riskstratification of those at risk to develop shock. However,
www.jcomjournal.com
Clinical Review
Capp and colleagues recently found that deterioration
to septic shock 48 hours after ED presentation occurs
in approximately one out of eight patients and identified
gender (female), transient hypotension, and/or hyperlactatemia upon presentation as risk factors associated with
such a deterioration [52].
As an essential element of sepsis care bundles, a focus
on timely use of antibiotics in patients with suspected infection, has the potential to increase the use of antibiotics
in the ED in patients determined subsequently to not be
infected. To combat this acknowledged downstream effect, reconsideration of the utility of empiric antibiotics
48 to 72 hours after admission is required. This step can
be accomplished through the use of a sepsis care pathway
and/or a formal antibiotic stewardship program.
Quantitative Resuscitation
Rivers and colleagues, in a landmark 2001 trial, examined the effectiveness of a protocolized resuscitation
strategy in the most proximal phase of severe sepsis
and septic shock [53]. A distinguishing characteristic
between the usual care arm and the intervention in this
ED-based study, in addition to whether mixed central
venous oxygen saturation was measured as a resuscitation
end-point, was the inclusion of an ED provider at the
bedside to attend to clinical management. The intervention, aimed at achieving physiologic targets, resulted in
significantly more fluid resuscitation (3.5 L vs. 5.0 L
within the first 6 hours) and a significant decrease in inhospital mortality compared to the usual care arm (46.5
vs. 30.5%). The study revolutionized the culture and
practice of sepsis care, in part by shining a light on the
importance of timely resuscitation at the most proximal
point of contact between the patient and the healthcare
system. It also highlighted the importance of integrating
serum lactate measurement into the early screening and
risk stratification processes for sepsis care delivery.
The 2014 randomized trial of Protocol-Based Care
for Early Septic Shock (ProCESS) revisited this concept,
comparing the Rivers 2001 protocol to both a current
guideline-based non-invasive algorithmic protocol and
what had become usual ED care in the interim [54]. The
ProCESS trial, which operationalized a team of bedside
providers to direct care for each of the 3 distinct arms,
found no significant difference between the arms in
terms of 90-day and 1-year mortality, but mortality was
approximately 10% less in all arms compared with the
intervention arm of the Rivers trial. Further, subjects in
www.jcomjournal.com
each of the 3 arms received in excess of 2 L intravenous
fluid resuscitation pre-randomization and 4.4–5.5 L
when resuscitation spanned from pre-randomization to
6 hours post-randomization. The conclusion drawn is
that the commonalities between the arms—early fluid
resuscitation, early antibiotics, and the option to use
physiologic measures as markers of the adequacy of treatment, all guided by bedside ED providers—are the most
important factors for surviving sepsis. And the result is
that practitioners have refined these tools over a decade,
leading to steady improvements in survival.
Consistent with the ProCESS trial, a recent Australia
and New Zealand trial confirmed no significant difference in 90-day mortality between protocolized EGDT
and current usual care for septic shock within an ED
[55]. Consistent with ProCESS and ProMISe [56],
subjects enrolled in ARISE received in excess of 2.5 L in
resuscitation pre-randomization, which when paired with
fluid resuscitation in the 0-6 hour post-randomization
period (1.96 L in the EGDT arm and 1.71 in the usualcare arm) resulted in resuscitation in the 4.5 to 5L range
during the initial resuscitation. The ARISE trial was
unique in that appropriate antibiotic administration was
a requirement prior to randomization, ensuring that this
important driver of mortality reduction was standardized
between the two arms of the trial. In summary, while the
ideal fluid resuscitation amount is unknown, requires a
personalized approach, and further investigation is required to effectively incorporate non-invasive measures
to guide fluid responsiveness, early and aggressive resuscitation paired with early antibiotic administration are
essential aspects of effective sepsis management.
The Efferent Arm: Structure and Processes
to Improve Outcomes
The efferent arm of the system, beyond risk stratification, requires the implementation of optimal staffing and
processes to care for the septic patient. While options
will vary, preparation is a requisite, as are strategies that
efficiently lead the clinician at the bedside to the use of
evidence-based medicine (Table 2).
Personnel and Staffing
Quality care for the septic patient requires immediate
availability of a multidisciplinary care team, including
physicians and nurses with critical care experience who
can be rapidly deployed to the bedside. The location of
care provision may include on-going care in the initial
Vol. 22, No. 5 May 2015 JCOM 217
Severe Sepsis
Table 2. Strategies to Improve Sepsis Recognition and Quality of Care
Strategy
References
Implement a quality improvement program focused on sepsis care delivery
Coordinate efforts between pre-hospital, ED, and hospital providers
4,61–62
16–19,32
Automate alert using EMR to improve sepsis recognition
33–35,46–48
Automate serum lactate measurements into triage process to risk stratify patients presenting with sepsis
40–44
Design and implement a standardized sepsis protocol, including sepsis care bundles
4,61,62
Design and implement sepsis-specific clinical decision support processes
61–63
Design new or identify existing resuscitation rooms for rapid initial management of patients with potential
severe infections
57
Streamline the process from antibiotic order to antibiotic delivery, including the use of an antibiogram for
antibiotic selection
49–51,64
Measure adherence to guideline recommendations (eg, blood cultures obtained, time to antibiotics)
Review performance at set intervals as part of an audit-and-feedback component of the program
61,62
29,61,62
EMR = electronic medical record.
ED room assignment or transfer to a dedicated area for
the care of the critically ill patient within the ED.
To provide optimal care in the era of overcrowding
and delayed transfer to an ICU, a movement towards
ED intensive care units (ED-ICUs) has emerged [57].
The models of practice range from a model based upon
ED intensivists, with expertise in critical care medicine,
providing care within the traditional structure of an ED,
to a model wherein a portion of the ED is assigned for
the care of the critically ill for extended periods of time
beyond the initial resuscitation. As these models mature
from resuscitation bays capable of scaling up based on
need to dedicated ED-ICUs, investments in shared Unit
leadership (physician and nursing), staffing (physician,
critical care nursing, respiratory therapy, critical care
pharmacist) and processes of care (eg, multidisciplinary
rounds) in line with established ICUs will be necessary.
While attractive conceptually, large-scale implementation of this movement is unlikely to occur outside of
tertiary care academic medical centers. In the many EDs
across the US without ED intensivists, and confronted
with limited clinician resources, flexible physician and
nursing staffing models will be necessary to ensure that
care provisions are in accord with established guidelines.
Potential solutions to provide the resources to meet the
needs of these high-intensity patients include critical
care consultation and a strategy traditionally applied to
the ICU, telemedicine [58]. Last, given the relationship
between hospital volume and mortality in severe sepsis
[59,60], timely transfer to a high-volume center for spe218 JCOM May 2015 Vol. 22, No. 5
cific cases may be appropriate, although the optimal timing, case selection, and impact of transfer on outcomes
warrant further examination.
Clinical Decision Support Strategies
To complement the identification and risk-stratification
available by screening and scoring systems, clinical decision support systems are novel tools to improve outcomes
in the era of electronic medical records (EMR). Specific
to sepsis care delivery, performance improvement initiatives including audit-and-feedback practice can increase
severe sepsis guideline adherence, and even modest
improvements in adherence appear to lead to sustained
improvements that contributed to a 25% relative risk reduction in the observed mortality rate [61,62]. Clinical
decision support tools can be used to link early recognition to optimal care processes, such as the Surviving
Sepsis Campaign resuscitation and management bundles.
The use of prompts as strategies to ensure that bundles of
care are ordered and carried out is an important aspect to
operationalize during the design phase [63].
Significant preparation is required to effectively carry
out the clinical decision support design strategy. For
example, to ensure timely antibiotic dispensing, a number of process steps will be required, including prompt
notification to a central pharmacist or preferably, an ED
pharmacist with access to a local pharmacy pre-stocked
with commonly used antibiotics [64]. In addition, the
use of an institution-specific antibiogram within the
physician computer-order entry sepsis order set, that
www.jcomjournal.com
Clinical Review
includes site-specific recommendations (eg, pulmonary,
gastrointestinal source) and susceptibility patterns, is an
essential aspect of optimal sepsis processes of care. Last,
the antibiogram will need to be frequently updated to
include season-specific (eg, oseltamivir administration
for high-risk cases during influenza season) recommendations to ensure that providers are prompted with the
most up-to-date clinical information.
Audit and Feedback and Continuous Performance
Improvement
The multimodal approach required to translate knowledge
(eg, guidelines) into sepsis care implemented at the bedside is an iterative process. An ED armed with a robust
track-and-trigger system and an effective efferent arm,
including sophisticated clinical decision support strategies,
will require frequent auditing in the plan-do-study-act
model of quality improvement to yield clinical effectiveness
[61,62,65]. Auditing, paired with feedback to frontline
providers, is essential to refine and improve the complex
process required to provide expert care to the septic patient [29,65]. Sustained success in optimizing sepsis care
delivery is the goal, yet significant work is required to determine the best strategies to achieve this endpoint.
Conclusion
Severe sepsis affects millions of individuals each year in
the United States. Delays in recognition result in increased morbidity and mortality, at a tremendous cost
to the patient and society. By designing strategies to
identify sepsis in a timely, efficient, and effective manner,
and by implementing ED structures and processes to increase adherence with sepsis-based guidelines, improved
patient-centered outcomes can be realized.
Corresponding author: Mark E. Mikkelsen, MD, MSCE,
Gates 05.042, 3400 Spruce St., Philadelphia, PA 19104,
[email protected].
Financial disclosures: None.
Author contributions: conception and design, JHM, MEM;
analysis and interpretation of data, DFG; drafting of article,
JHM, DFG, MEM; critical revision of the article, JHM, MEM.
References
1. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United
States. Crit Care Med 2013;41:1167–74.
2. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiol-
www.jcomjournal.com
ogy of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med
2001;29:1303–10.
3. Lagu T, Rothberg MB, Shieh MS, et al. Hospitalizations,
costs, and outcomes of severe sepsis in the United States 2003
to 2007. Crit Care Med 2012;40:754–61.
4. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of
severe sepsis and septic shock, 2012. Intensive Care Med
2013;39:165–228.
5. Angus DC, van der Poll T. Severe sepsis and septic shock. N
Engl J Med 2013;369:840–51.
6. Wang HE, Shapiro NI, Angus DC, Yealy DM. National
estimates of severe sepsis in United States emergency departments. Crit Care Med 2007;35:1928–36.
7. Dombrovskiy VY, Martin AA, Sunderram J, et al. Rapid increase in hospitalization and mortality rates for severe sepsis in
the United States: a trend analysis from 1993 to 2003. Crit
Care Med 2007;35:1244–50.
8. Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in
patients with sepsis from 2 independent cohorts. JAMA
2014;312:90–2.
9. Kaukonen KM, Bailey M, Suzuki S, et al. Mortality related to severe sepsis and septic shock among critically ill
patients in Australia and New Zealand, 2000-2012. JAMA
2014;311:1308–16.
10. Yende S, Angus DC. Long-term outcomes from sepsis. Curr
Infect Dis Rep 2007;9:382–6.
11. Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability among survivors of
severe sepsis. JAMA 2010; 304:1787–94.
12. Ortego A, Gaieski DF, Fuchs BD, et al. Hospital-based acute care
use in survivors of septic shock. Crit Care Med 2015;43:729–37.
13. Prescott HC, Langa KM, Liu V, et al. Increased 1-year healthcare use in survivors of severe sepsis. Am J Respir Crit Care
Med 2014;190:62–9.
14. Liu V, Lei X, Prescott HC, et al. Hospital readmission and
healthcare utilization following sepsis in community settings.
J Hosp Med 2014;9:502–7.
15. Jones AE, Brown MD, Trzeciak S, et al. The effect of a quantitative resuscitation strategy on mortality in patients with
sepsis: a meta-analysis. Crit Care Med 2008;36:2734–9.
16. Seymour CW, Rea TD, Kahn JM, et al. Severe sepsis in prehospital emergency care: analysis of incidence, care, and outcome. Am J Respir Crit Care Med 2012;186:1264–71.
17. Seymour CW, Cooke CR, Mikkelsen ME, et al. Out-ofhospital fluid in severe sepsis: effect on early resuscitation in
the emergency department. Prehosp Emerg Care 2010;14:
145–52.
18. Seymour CW, Cooke CR, Heckbert SR, et al. Prehospital
intravenous access and fluid resuscitation in severe sepsis: an
observational cohort study. Crit Care 2014;18:533
19. Studnek JR, Artho MR, Garner CL, Jones AE. The impact of
emergency medical services on the ED care of severe sepsis.
Am J Emerg Med 2012;30:51–6.
20. Guss DA, Meyer FT, Neuman TS, et al. The impact of a
regionalized trauma system on trauma care in San Diego
Vol. 22, No. 5 May 2015 JCOM 219
Severe Sepsis
County. Ann Emerg Med 1989;18:1141–5.
21. Liberman M, Mulder DS, Jurkovich GJ, Sampalis JS. The
association between trauma system and trauma center components and outcome in a mature regionalized trauma system.
Surgery 2005;137:647–58.
22. Hachinski V, Donnan GA, Gorelick PB, et al. Stroke: working
toward a prioritized world agenda. Stroke 2010;41:1084–99.
23. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/
ESICM/ACCP/ATS/SIS International Sepsis Definitions
Conference. Crit Care Med 2003;31:1250–6.
24. Sibbald W, Doig G, Inman K. Sepsis, SIRS, and infection.
Intensive Care Med 1995;21:299–301.
25. Kaukonen KM, Bailey M, Pilcher D, et al. Systemic inflammatory response syndrome criteria in defining severe sepsis. N
Engl J Med 2015; online March 17, 2015.
26. Shapiro NI, Howell MD, Bates D, et al. The association of
sepsis syndrome and organ dysfunction with mortality in
emergency department patients with suspected infection. Ann
Emerg Med 2006;48:583–90.
27. Berger T, Green J, Horeczko T, et al. Shock index and early
recognition of sepsis in the emergency department: pilot
study. West J Emerg Med 2013;14:168–74.
28. Farley H, Zubrow MT, Gies J, et al. Emergency department tachypnea predicts transfer to a higher level of care
in the first 24 hours after ED admission. Acad Emerg Med
2010;17:718–22.
29. Sinuff T, Muscadere J, Adhikari NK, et al. Knowledge translation interventions for critically ill patients: a systematic review.
Crit Care Med 2013;41:2627–40.
30. Hoot NR, Aronsky D. Systematic review of emergency department crowding: causes, effects, and solutions. Ann Emerg
Med 2008;52:126–36.
31. Hsia RY, Kellermann AL, Shen YC. Factors associated with
closures of emergency departments in the United States.
JAMA 2011;305:1978–85.
32. Chalfin DB, Trzeciak S, Likourezos A, et al. Impact of delayed
transfer of critically ill patients from the emergency department
to the intensive care unit. Crit Care Med 2007;35:1477–83.
33. Subbe CP, Kruger M, Rutherford P, et al. Validation of a
modified early warning score in medical admissions. Q J Med
2001;94:521–6.
34. Umscheid CA, Betesh J, VanZandbergen C, et al. Development, implementation, and impact of an automated
early warning and response system for sepsis. J Hosp Med
2015;10:26–31.
35. Churpek MM, Yuen TC, Winslow C, et al. Multicenter development and validation of a risk stratification tool for ward
patients. Am J Respir Crit Care Med 2014;190:649–55.
36. Whittaker SA, Fuchs BD, Gaieski DF, et al. Epidemiology
and outcomes in patients with severe sepsis admitted to the
hospital wards. J Crit Care 2015;30:78–84.
37. Delgado MK, Liu V, Pines JM, et al. Risk factors for unplanned transfer to intensive care within 24 hours of admission
from the emergency department in an integrated healthcare
system. J Hosp Med 2013;8:13–9.
38. Valentini I, Pacilli AM, Carbonara P, et al. Influence of the
admission pattern on the outcome of patients admitted to a
220 JCOM May 2015 Vol. 22, No. 5
respiratory intensive care unit: does a step-down admission
differ from a step-up one? Respir Care 2013;58:2053–60.
39. Kompanje EJO, Jansen TC, van der Hoven B, Bakker J. The
first demonstration of lactic acid in human blood in shock by
Johann Joseph Scherer (1814-1869) in January 1843. Intensive Care Med 2007;33:1967–71.
40. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med
2014;371:2309–19.
41. Jansen TC, van Bommel J, Mulder PG, et al. The prognostic
value of blood lactate levels relative to that of vital signs in the
pre-hospital setting: a pilot study. Crit Care 2008;12:R160.
42. del Portal DA, Shofer F, Mikkelsen ME, et al. Emergency
department lactate is associated with mortality in older adults
admitted with and without infections. Acad Emerg Med
2010;17:260–8.
43. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate
is associated with mortality in severe sepsis independent of
organ failure and shock. Crit Care Med 2009;37:1670–7.
44. Gaieski DF, Drumheller BC, Goyal M, et al. Accuracy of
handheld point-of-care fingertip lactate measurement in
the emergency department. West J Emerg Med 2013;14:
58–62.
45. Macdonald SP, Arendts G, Fatovich DM, Brown SG. Comparison of PIRO, SOFA, and MEDS scores for predicting
mortality in emergency department patients with severe sepsis
and septic shock. Acad Emerg Med 2014;21:1257–63.
46. Carpenter CR, Keim SM, Upadhye S, Nguyen HB, Group
BEiEMI. Risk stratification of the potentially septic patient
in the emergency department: the Mortality in the Emergency Department Sepsis (MEDS) score. J Emerg Med
2009;37:319–27.
47. Sankoff JD, Goyal M, Gaieski DF, et al. Validation of the
Mortality in Emergency Department Sepsis (MEDS) score in
patients with the systemic inflammatory response syndrome
(SIRS). Crit Care Med 2008;36:421–6.
48. Corfield AR, Lees F, Zealley I, et al. Utility of a single early
warning score in patients with sepsis in the emergency department. Emerg Med J 2014;31:482–7.
49. 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;34:1589–96.
50. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to
antibiotics on survival in patients with severe sepsis or septic
shock in whom early goal-directed therapy was initiated in the
emergency department. Crit Care Med 2010;38:1045–53.
51. Puskarich MA, Trzeciak S, Shapiro NI, et al. Association between timing of antibiotic administration and mortality from
septic shock in patients treated with a quantitative resuscitation protocol. Crit Care Med 2011;39:2066–71.
52. Capp R, Horton CL, Takhar SS, et al. Predictors of patients
who present to the emergency department with sepsis and
progress to septic shock between 4 and 48 hours of emergency
department arrival. Crit Care Med 2015 Jan 30.
53. 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.
www.jcomjournal.com
Clinical Review
54. The ProCESS Investigators. A ranodmized trial of protocol-based care for early septic shock. N Engl J Med
2014;370:1683–93.
55. The ARISE Investigators and the ANZICS Clinical Trials
Group. Goal-directed resuscitation for patients with early
septic shock. N Engl J Med 2014;371:1496–506.
56. Mouncey PR, Osborn TM, Power GS, et al. Trial of early,
goal-directed resuscitation for septic shock. N Engl J Med
2015; online March 17, 2015.
57. Weingart SD, Sherwin RL, Emlet LL, et al. ED intensivists and
ED intensive care units. Amer J Emerg Med 2013;31:617–20.
58. Lilly CM, Cody S, Zhao H, et al. Hospital mortality, length
of stay, and preventable complications among critically ill patients before and after tele-ICU reengineering of critical care
processes. JAMA 2011;305:2175–85.
59. Walkey AJ, Wiener RS. Hospital case volume and outcomes
among patients hospitalized with severe sepsis. Am J Respir
Crit Care Med 2014;189:548–55.
60. Gaieski DF, Edwards JM, Kallan MJ, et al. The relationship
61.
62.
63.
64.
65.
between hospital volume and mortality in severe sepsis. Am J
Respir Crit Care Med 2014;190:665–74.
Levy MM, Dellinger RP, Townsend SR, et al. The surviving
sepsis campaign: results of an international guideline-based
performance improvement program targeting severe sepsis.
Intensive Care Med 2010;36:222–31.
Levy MM, Rhodes A, Phillips GS, et al. Surviving sepsis campaign: association between performance metrics and outcomes
in a 7.5-year study. Crit Care Med 2015;43:3–12.
Weiss CH, Moazed F, McEvoy CA, et al. Prompting physicians to address a daily checklist and process of care and clinical outcomes: a single-site study. Am J Respir Crit Care Med
2011;184:680–6.
Weant KA, Baker SN. Emergency medicine pharmacists and
sepsis management. J Pharm Pract 2013;26:401–5.
Marwick CA, Guthrie B, Pringle JE, et al. A multifaceted intervention to improve sepsis management in general hospital
wards with evaluation using segmented regression of interrupted time series. BMJ Qual Saf 2014;23:e2.
Copyright 2015 by Turner White Communications Inc., Wayne, PA. All rights reserved.
www.jcomjournal.com
Vol. 22, No. 5 May 2015 JCOM 221