A systems approach to the early recognition and rapid

administration of best practice therapy in sepsis and septic shock

Duane Funka,b, Frank Sebatc and Anand Kumara,d
a
Department of Medicine, Section of Critical Care
Medicine, bDepartment of Anesthesia, University of
Manitoba, Winnipeg, Canada, cCritical Care Medicine,
Freemont Rideout Healthcare, Marysville, California,
USA and dDepartment of Medical Microbiology,
Department of Pharmacology/Therapeutics, University
of Manitoba, Winnipeg, Canada
Correspondence to Dr Anand Kumar, MD, Health
Sciences Centre, JJ399, 820 Sherbrook Street,
Winnipeg, MB R3A-1R9, Canada
E-mail: akumar61@yahoo.com
Current Opinion in Critical Care 2009,
15:301–307
Purpose of review
The early recognition and treatment of sepsis is paramount to reducing the mortality of
this disease. However, unlike trauma, stroke or acute myocardial infarction, the initial
signs of sepsis are subtle and easily missed by clinicians. Thus, hospital-based systems
are needed to identify and triage patients who might be septic. This review focuses on
the early diagnosis of sepsis and the implementation of a systems-based approach to
help coordinate the identification and treatment of patients with this disease.
Recent findings
Alterations in traditional hemodynamic parameters, such as blood pressure and heart
rate, are poor predictors of the presence of septic shock. Other more subtle findings
(such as the 10 signs of vitality) are stronger determinants of poor tissue perfusion in a
patient who may be septic. Early detection of a patient who is ‘in trouble’ on the ward by
bedside nurses or physicians and activation of a medical emergency team has been
shown to improve outcome. By coupling the medical emergency team with early goal-
directed therapy, patients with sepsis can be discovered earlier and have therapy
instituted within the so-called ‘golden hour’, first appreciated with trauma care.
Summary
The institution of a rapid response system for the detection and treatment of septic
shock requires a multidisciplinary approach. The infrastructure to create such a system
must be facilitated by administrators and implemented by front-line healthcare providers.
Continuous assessment of the outcome benefit of such a system by a quality assurance
team is the final part of a truly integrated approach to sepsis treatment.

Keywords
medical emergency teams, rapid response teams, sepsis, septic shock, systems-
based medicine

Curr Opin Crit Care 15:301–307

ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295

to society at $16 billion/year with an estimated consump-

Introduction
The successful treatment of acutely ill patients with a
high risk of death is predicated on early recognition and
treatment. The key role of early intervention has been
recognized in the creation of the term ‘the golden hour’ as
it relates to therapy of life-threatening conditions. Early
accelerated treatment has been shown to improve out-
come for a variety of acute, life-threatening illnesses
including acute myocardial infarction (MI), stroke,
trauma/hemorrhagic shock and, most recently, septic
shock. Over the past 20 years, systems have evolved in
order to better recognize patients with these acute ill-
nesses and to accelerate appropriate treatment.
Septic shock has been reported to occur in 750 000 people
annually in the United States with an associated mortality
risk exceeding 30–40% [1]. Estimates place the total cost
1070-5295 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
tion of 0.5–1.0% of the American gross domestic product
(GDP) [2]. A primary difficulty with the management of
patients with septic shock is ensuring early recognition
of this disease state. Because of varying causes of sepsis
and differing patient presentations and comorbidities,
patients are often left undiagnosed or untreated or both
for long periods of time and are often outside of their
‘golden hour’.
There is evidence to show that early application of basic
therapies for sepsis reduces mortality [3,4,5]. The early
interventions that Rivers et al. and Sebat et al. performed
in their respective academic and community emergency
departments were, for the most part, simple to implement
and applicable in numerous settings. This bundled
approach of aggressive, goal-directed resuscitation inclu-
ded several therapeutic interventions. The interventions
DOI:10.1097/MCC.0b013e32832e3825

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 302 ICU care processes
included respiratory support to improve oxygen avail-
ability and decrease work of breathing, aggressive infu-
sion of intravenous fluids (along with vasopressors
and inotropes) for the restoration of blood pressure
(BP) and tissue perfusion and transfusion of red blood
cells (RBCs). Similarly, several studies have demon-
strated that earlier initiation of effective antimicrobial
therapy in life-threatening infection is associated with
increased survival [4,6–9]. Kumar et al. [4] have
shown that the speed with which appropriate antimicro-
bial therapy is initiated following documentation of hypo-
tension in septic shock may be the single strongest
predictor of survival.
With the recognition that early therapy of the physiologic
instability of sepsis was the best practice guideline, the
next step was to create systems (much like trauma, stroke
or acute MI teams) in which the rapid recognition and
administration of these life-saving therapies could be
performed outside a critical care environment. Thus,
the concept of a medical emergency team (MET) or
an ICU without walls was created. Several hospitals
adopted the slogan that critical care was ‘a need and
not a place’. The presence of MET or shock teams in
hospitals has also been shown to reduce the need for ICU
admission or mortality or both from acute illness such as
septic shock [5,10–12,13].
The present article will discuss the early recognition of
sepsis, the evidence for an early goal-directed resuscita-
tion of sepsis and some of the controversies surrounding
some of the specific therapies that this encompasses (e.g.,
RBC transfusion) and the use of institutional systems to
facilitate the early recognition and rapid treatment of
sepsis with best practice.
Early recognition of sepsis
The recognition of sepsis, in contrast to other conditions
requiring immediate resuscitative efforts such as trauma,
stroke and MI, can be difficult. Although clinical signs of
the other conditions can be obvious and very specific, the
symptoms and signs of severe infection and sepsis are
much less so. Recognition of severe sepsis (sepsis with
organ failure), by convention, has been tied to its defining
criteria, which include elements of the systemic inflam-
matory response (tachycardia, tachypnea, fever, elevated
white count or increased left shift), a suspected source of
infection and at least one dysfunctional organ. These
criteria require results of a complete blood count (CBC)
and/or chest radiograph, urinanalysis, blood cultures and
computed tomography (CT) of the abdomen, which,
because of their turn around time, may contribute to a
delay in recognition and treatment. This delay can be
avoided by utilizing easily measured bedside parameters
to identify at-risk patients and immediately begin treat-
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1 The 10 signs of vitality
Ten signs of vitality Triggering parameter
Temperature 368C
Pulse <50 or >100/min
Pain New or significant increase
Respiratory rate <6 or >20/min
SaO2 <90% and increased fiO2
Blood pressure SBP < 90 mmHg, MAP < 60 mmHg
Level of consciousness Anxiety/lethargy
Capillary refill >3 s
Urinary output <30 ml/h  5 h (<100 ml/4 h –excluding
renal failure)
ScvO2/base deficit <65% or B deficit  5 or lactic acid > 2.0
The seven signs of vitality in bold are key in deciding if the patient has a
perfusion deficit and is at risk. MAP, mean arterial pressure; SBP,
systolic blood pressure.
ment while waiting for additional information. Hence,
these bedside parameters are referred to as the 10 signs of
vitality (10 SOV) (Table 1). When considered in combi-
nation, the 10 SOV can identify early patients at risk,
many of whom are septic. This early identification of
physiologic instability expedites basic resuscitation that
is cause independent while collecting additional infor-
mation. Operationally, this is accomplished by utilizing a
significant abnormality in any one of the five convention-
al vital signs as a trigger (Table 1). Once a significant vital
sign abnormality is recognized [facilitated by electronic
alerts in the monitoring devices or electronic medical
record (EMR)], a full 10 SOV assessment is performed at
the bedside [14–17]. Nine of the 10 SOV can be assessed
within several minutes; the 10th [base deficit or central
venous oxygen saturation (ScVO2)] requires an arterial or
central blood gas, a 15 min turn around time at many
hospitals. Seven of the 10 SOV are key (bolded) in
deciding if the patient has a perfusion deficit and is at
risk. If two of these seven parameters are present, the
patient is considered at high risk, often with decreased
tissue oxygen delivery. This approach will identify early
sepsis and other at-risk patients all of whom will benefit
from the additional evaluation and treatment.
Early evaluation, triggered by a significant abnormality in
one of the conventional vital signs, will maintain detec-
tion sensitivity, whereas a requirement of at least two of
the seven key SOV will increase identification specificity.
In one study of 500 consecutive patients, utilizing a
similar approach, 50% were subsequently determined
to be septic [13].
Respiratory rate and capillary refill are two vital signs
whose value has been underappreciated [18–29].
Although both lack specificity, a respiratory rate of more
than 20 bpm or a capillary refill of more than 3 s can be
very sensitive in identifying at-risk patients. Because of
their lack of specificity, it is important to evaluate them in
the context of a full bedside assessment. For example, a
patient with capillary refill of more than 3 s or with

respiratory rate more than 20, who is otherwise stable, is
not likely to be at risk or septic compared with a similar
patient who also has an abnormality of one of the other
key seven SOV. Once the patient is identified at risk,
rapid administration of basic resuscitation is begun avoid-
ing delay while differential diagnoses are considered.
The systematic early warning or rapid response
system (RRS) for early identification of at-risk patients
coupled with aggressive basic, but sometimes overlooked
(AOVIPPS, see ‘The early treatment of sepsis and goals
of resuscitation’) resuscitation, is key to improving out-
comes in sepsis. This is particularly true when com-
prehensive educational programs empower frontline
providers to rapidly evaluate at-risk patients and to inde-
pendently initiate basic treatment while institutional
resources are mobilized. One study utilizing this
approach looked at all patients who presented to the
emergency department (ED) or were on hospital wards
and met an early warning shock criteria; one half of those
patients subsequently were determined to be septic. This
generalized approach to shock identification and resusci-
tation, regardless of the cause, was able to decrease the
mortality of septic shock from 50 to 10% over a 5-year
period [13]. This approach is being promoted by RRS
throughout the world facilitated by the Society of Critical
Care Medicine RRS courses and manual [30].
The early treatment of sepsis and goals of
resuscitation
Sepsis causes progressive derangements in normal physi-
ology resulting in inadequate delivery of oxygen to
tissues, lactic acidosis and organ dysfunction. If left
untreated, irreversible shock, multisystem organ failure
and death ensue. The concept of irreversible shock [31]
recognizes that delayed resuscitation and correction of
hemodynamic instability, while providing physiologic
improvement to isolated oxygen transport parameters,
can still occur too late to prevent organ injury leading to
inevitable deterioration and death. Thus, early restor-
ation of end organ oxygen delivery and early elimination
of the infectious source is paramount.
During septic shock, excessive production or decreased
elimination or both of nitric oxide results in profound
vasodilatation and relative hypovolemia. This results in
hypotension and inadequate cardiac output [32]. Com-
pounding this situation is microvascular clotting [33] due
to activation of the inflammatory and coagulation cas-
cades [34] along with activation of neutrophils at the
endothelial surface. In aggregate, these processes result
in migration of intravascular fluids into the interstitium,
gross tissue edema, and often acute lung injury [35]. The
latter increases VO2resp (the oxygen cost of breathing)
that normally accounts for approximately 5% of total body
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Best practice therapy in sepsis and septic shock Funk et al. 303
oxygen consumption, but in sepsis, can account for 40%
of oxygen demand [36]. This increased work of breathing
requires that blood flow be diverted from other vital
organs at a time when total body oxygen consumption
may be increased because of tachycardia or fever. One of
the most important goals in early sepsis management is to
reduce VO2resp. Support of the respiratory system with
noninvasive ventilation or early intubation is often over-
looked and can be key to reducing mortality [3,37].
Early support of ventilation in septic and other forms of
shock was first emphasized in the 1969 mnemonic VIP
[38]. This mnemonic stands for Ventilatory support, Infuse
volume aggressively and Pressors support of BP. It was
later expanded by the same authors to VIPPS shock resus-
citation adding Pharmacologic and Specific invasive inter-
ventions to resuscitation and most recently to AOVIPPS
to emphasize Airway and Oxygenation issues [30].
Mnemonic AOVIPPS stands for
(1) Airway;
(2) Oxygen;
(3) Ventilation support;
(4) Infuse volume aggressively;
(5) Pressors support of BP;
(6) Pharmacologic interventions, that is, antibiotics, acti-
vated protein C (APC) etc.;
(7) Specific, invasive therapies.
Along with early support of ventilation/oxygenation, most
authorities consider goal-directed rapid administration of
fluids paramount. In the Rivers et al. study [3], early and
aggressive fluid loading appeared to be the key interven-
tion that led to the decrease in mortality. Several other
studies have similarly suggested that early aggressive
fluid resuscitation is associated with improved outcome
in sepsis [3,39,40]. Maintenance of adequate tissue per-
fusion with early support of the respiratory system,
aggressive volume resuscitation, and vasopressors or ino-
tropes, if needed, is part of basic shock resuscitation and
should begin immediately regardless of the cause [41,42].
For effective treatment of sepsis and, particularly, septic
shock, early elimination of the pathogenic bioburden that
drives the septic process and resuscitation are equally
important. Administration of appropriate antibiotics
along with source control should be done in parallel with
the resuscitative therapy. Ibrahim et al. [43] looked at the
result of inadequate antimicrobial therapy on outcome in
patients with bacteremia. In this study, an inadequate
antimicrobial agent was defined as one that did not have
activity against that class of microorganism (e.g., anti-
biotics for fungal infection) or one to which the organism
was resistant. They found that when patients were given
inadequate therapy, their mortality was increased by
 304 ICU care processes
almost two-fold. Further, Kumar et al. [4] have shown
that the speed with which appropriate antimicrobials are
initiated after onset of hypotension in patients with septic
shock is one of the critical determinants in their survival
[44]. Survival dropped approximately 7.5% per hour delay
over the first 6 h. Early drainage of abscesses or debride-
ment of infected necrotic tissue is also vital in the treat-
ment of sepsis [44,45].
When resuscitating a patient, the clinician has to decide
when perfusion defects have been reversed. Wo et al. [46]
have shown that resuscitation goals such as BP alone are
unreliable markers of adequate blood flow to organs.
Utilizing multiple resuscitation goals in combination
has reduced mortality [3,5,13]. The most easily
measured and often useful goals of resuscitation are
mental status, work and rate of breathing, urine output,
cap refill or extremity temperature, BP and heart rate.
However, these goals may or may not show the whole
picture. Rivers et al. added ScVO2 more than 70% as a
resuscitation goal and by doing so decreased septic shock
mortality from approximately 40 to 30%. Frequently
utilized resuscitation goals that are useful when evaluated
together are listed below:
(1) improved or normalized mental status;
(2) SaO2 > 90%;
(3) decreased work of breathing;
(4) mean arterial pressure (MAP) > 60–65%;
(5) capillary refill < 6 s;
(6) urinary output > 0.5 ml/h;
(7) ScvO2 > 60%, lactic acid < 2.0 mmol/l.
One of the more controversial aspects of sepsis manage-
ment is the role of blood transfusion to improve mixed
venous oxygen saturation. In the Rivers study, red cell
transfusions were initiated if the mixed venous oxygen
tension was less than 70% after respiratory, fluid and
vasopressor support and if the hematocrit was less than
30%. This seems to contradict other studies that showed
no difference in mortality when red cells were given to
critically ill patients [47] or, in fact, made them worse
[48,49] because of infection and lung injury. As red cell
transfusion was part of a ‘bundle’ of interventions, it is
hard to discern what role individual parts had in the
reduction of mortality. However, it is also notable that
this intervention was performed early during the acute
phase of illness whereas other studies examining RBC
transfusion were performed later.
It cannot be overemphasized that there is almost no
therapy that is more beneficial when administered later
in the course of critical illness, whether one is talking
about intubation, fluids, antibiotics or surgical interven-
tion. In addition to effective antimicrobials and appro-
priate resuscitative efforts, drotrecogin-alpha is another
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
example of a therapy whose benefits are maximal when
administered early in the course of disease yet whose
administration is often delayed [50,51].
Institutional systems can improve earlier
recognition and treatment of sepsis
Early recognition and rapid application of best practice in
sepsis as in other critical illnesses is often delayed or
inadequate [5,40,52–54]. Insufficient knowledge of
frontline providers or lack of their empowerment to
initiate basic resuscitative therapy independently or to
mobilize additional institutional resources substantially
compounds this problem. Resistance to change by health-
care providers or inability to break down barriers to
improve process or both further contributes to delays
in the adoption of best practice [5,33,40,55]. Developing
institution-wide systems that address these issues will
and has improved outcomes [3,10,11,13,40,56–64].
The key to improving sepsis outcomes is implementation
of a prehospital and hospital-wide system that recognizes
at-risk or septic patients early and rapidly administers
effective therapy. This is best accomplished by identifying
physicians, nurses, administrators and quality-assurance
personnel that can be champions of a sepsis RRS (Fig. 1)
[30,65]. This system should emphasize education, as well
as policies and procedures that empower frontline provi-
ders to recognize sepsis early, and independently institute
basic resuscitation as additional resources are mobilized.
Creation of an RRS for sepsis requires not only various
champions to drive it, but also needs an effective structure
for its development, education of staff, implementation
and continuous process improvement.
Providing substantial education and training to the
bedside nurses and respiratory therapists increases
the chance of early identification and resuscitation (by
protocol) of septic patients while activating the sepsis or
rapid response team early enough to make a difference.
Early recognition of sepsis, which is 90% of the battle, is
labor intensive because, in contrast to other conditions,
such as massive hemorrhage, stroke and MI, the mani-
festations of sepsis can be relatively nonspecific. As a
consequence, an institutional capacity for early recog-
nition requires intense education and training of nearly
all healthcare providers. However, once this is accom-
plished, assuring rapid administration of best practice
therapy is easier as it requires educating a much smaller
number of response team members. Attention to both the
afferent and efferent arms of the RRS is critical and has
been demonstrated to decrease time to recognition and
treatment and improve outcomes [13].
The RRS administrative, afferent, efferent and quality
assurance arms are essential components for success
 Best practice therapy in sepsis and septic shock Funk et al. 305

Figure 1 Rapid response system structure

Rapid response system structure

Administration/design team
Oversees all functions

Governance/administrative structure:
• Provide resources to facilitate system development
• Implement and sustain the service
• Education and ongoing training of staff
• Interpret response team effectiveness data to manage resources
• Application of process improvement strategies to improve system and to reduce
future occurrences

Afferent Efferent
Event detection and Crisis response, RRT/MET
response triggering • Resources arrive quickly: first response
<5 min. for RN; 15 min. for MD
• Selection/diagnostic/triggering • Personnel (possess a defined set of
criteria, Ten signs of vitality competencies)
• Human and technologic monitoring • Equipment
• Method for assessing urgent needs
with alarm limits
Crisis intervention: VIPPS algorit
• Mechanism for triggering response • Crisis resolved, opportunity for education of
floor staff
• Crisis continues, transfer to ICU
• Specialized teams:
• Sepsis
• Cardiac arrest
• Trauma
• Stroke
• AMI

Quality assurance
Data collection and analysis for process improvement

• Event rate/1000 admissions:

• # Code blues, # Respiratory, # Cardiac arrest, LOS, mortality
• # Unplanned floor admissions to ICU, LOS, mortality
• Analysis of events to improve process and reduce future events

• Feedback of events and outcomes for process improvement and to foster

adoption by:
• Clinicians and providers • Patient/family
• System designers • Administration

Reproduced with permission from [30].

[30,65]. They provide for system design, education of
bedside clinicians and team responders, implementation,
team response including treatment, data collection/
analysis and process improvement. The sepsis RRS func-
tions should include
(1) Administrative arm: coordinates development, edu-
cation and implementation of the RRS. This includes
development of hospital policy and procedure that
defines brisk best practice resuscitation to be
initiated by bedside providers, continued by the
response team followed by rapid triage to the most
appropriate location (i.e. remain at current location,
diagnostic suite, operating room or ICU). The admin-
istrative arm is also responsible for process change
based on data and recommendations from the quality
assurance arm.
(2) Afferent arm (bedside clinicians): should receive
a formalized and comprehensive educational
program that facilitates early recognition of at-
risk and septic patients along with tools and sys-
tems that increase recognition such as lanyard
cards or electronic alerts as vital signs are mea-
sured or charted and mock sepsis drills are con-
ducted.
(3) Afferent arm that through cognitive recognition or
conventional vital sign EMR alerts assess further at-
risk patients utilizing 10 SOV or three of the classic
sepsis criteria. Once preestablished criteria are recog-
nized by bedside personnel, or are met by prepro-
grammed logic within the EMR, alerts activate the
efferent arm (response team).
(4) Efferent arm or rapid response sepsis team should
include critical care nursing, respiratory therapy,

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 306 ICU care processes
pharmacy, sepsis lab panel radiograph and nursing
supervisor for triage assistance.
(5) Quality assurance arm is responsible for collecting
and analyzing demographics (incidence, location),
outcome data [length of stay (LOS), vent days] and
surrogates for outcomes [i.e. time to mobilization of
the rapid response team (RRT), antibiotics, 2 l of
fluids, drotrecogin-alpha, source control].
Summary
For decades, healthcare workers faced the challenge of
how to adequately treat sepsis and septic shock. Several
recent studies have conclusively shown that the early
recognition and treatment of sepsis reduce mortality. The
challenge that hospitals must now face is how best to
implement systems to facilitate this goal. This is accom-
plished by involving all members of the healthcare team,
including physicians, nurses, respiratory therapists and
pharmacists. The role of administrators is in identifying
champions of the concept of an RRS and then facilitating
the development of the necessary infrastructure to edu-
cate and train staff on the recognition and treatment of
sepsis. The need for continuous data collection and
analysis by members of a quality assurance team will
ensure that best practices are followed and that there is
ongoing focus on process improvement. Only with this
team approach will healthcare providers be able to reduce
the mortality of this deadly disease.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
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