The Surviving Sepsis

Campaign 2014: An Update

on the Management and
Performance Improvement
For Adults in Severe Sepsis
Wed, 10/15/14 - 10:47

Authors:
R. Phillip Dellinger, MD
Citation:
Consultant. 2014;54(10):767-771
ABSTRACT: The Surviving Sepsis Campaign includes both guidelines for the
management of severe sepsis and septic shock as well as an international
performance improvement program centered around the sepsis bundles. In
order to logically approach management of severe sepsis, it is important to
understand both the definitions of sepsis as well as the burden placed on
society by sepsis. This article reviews the key targets for improving outcome
in severe sepsis, including early diagnosis, early antibiotics, and early and
appropriate fluid resuscitation targeting adequate tissue perfusion.

Born in 2002, the Surviving Sepsis Campaign (SSC) is a global program

created by professional societies to (a) reduce mortality rates from severe
sepsis through the creation of evidence-based management guidelines and
(b) facilitate knowledge transfer and performance improvement at the
bedside. Although initially seeded by industry grants, professional
organization funding began between 2004 and 2008 and in 2009, the Gordon
and Betty Moore Foundation, an independent philanthropic organization, has
funded the cause. Figure 1 shows a timeline of The Surviving Sepsis
Campaign over the years.
Definitions

In order to understand the management of severe sepsis and associated

performance improvement programs, it is first necessary to understand
current definitions.
Sepsis is defined as a known or suspected infection plus systemic
manifestations of infections (eg, traditional systemic inflammatory response
syndrome criteriatachy-cardia, tachypnea, white blood count changes, and
fever/hypothermia as well as other metabolic perturbations or organ
dysfunctions).
Severe sepsis is defined as sepsis plus infection-induced organ dysfunction
or infection-induced acute tissue hypoperfusion. Organ dysfunctions
associated with sepsis include acute lung injury, acute kidney injury,
coagulopathy, liver dysfunction, and cardiovascular abnormality. Tissue
hypoperfusion abnormalities include hypotension, elevated lactate, oliguria,
and altered mental status.There is some overlap between tissue
hypoperfusion abnormalities and organ dysfunction associated with the
cardiovascular system.
BURDEN OF SEPSIS
Severe sepsis is the leading cause of hospital death. 1,2 An enormous
economic burden is attributed to severe sepsis and the general consensus is
that early identification and early appropriate evidence-based medical care
will impact this burden.
The Guidelines
The first guidelines were published in 2004 3 and sponsored by 14 international
scientific organizations with interest and expertise in education and
management related to severe sepsis. The 2008 guidelines were sponsored
by 16 organizations4 and the 2013 guidelines were sponsored by 30
organizations (Figure 2).5
Since 2008, the SSC has had a strong affiliation with one of the premier
evidence-based medicine groups, Grades of Recommendation Assessment,
Development and Evaluation (The GRADE Group). Figures 3 and 4
demonstrate the categorization of both a quality of evidence assigned to each
SSC recommendation and more importantly, the strength of the
recommendation.

Key Recommendations
Key recommendations from the 2013 guidelines publication include:
Early quantitative resuscitation of the septic patient during the first 6 hours
after recognition
Blood cultures before antibiotic therapy
Administration of broad-spectrum antimicrobials therapy within 1 hour of
recognition of septic shock and severe sepsis without septic shock as the goal
of therapy
Imaging studies performed promptly to confirm a potential source of infection
Infection source control with attention to the balance of risks and benefits of
the chosen method within 12 hours of diagnosis
Initial fluid resuscitation with crystalloid and consideration of the addition of
albumin in patients who continue to require substantial amounts of crystalloid
to maintain adequate mean arterial pressure as well as the avoidance of
hetastarch formulations
Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion
and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of
crystalloids (more rapid administration and greater amounts of fluid may be
needed in some patients)
Fluid challenge technique continued as long as hemodynamic improvement,
as based on either dynamic or static variables
Norepinephrine as the first-choice vasopressor to maintain mean arterial
pressure 65 mm Hg
Epinephrine or vasopressin (0.03 U/min) when an additional agent is needed
to maintain adequate blood pressure
Dopamine is not recommended except in highly selected circumstances
Dobutamine infusion administered or added to vasopressor in the presence
of (a) myocardial dysfunction as suggested by elevated cardiac filling
pressures and low cardiac output, or (b) ongoing signs of hypoperfusion
despite achieving adequate intravascular volume and adequate mean arterial

pressure
Avoiding use of intravenous hydrocortisone in adult septic shock patients if
adequate fluid resuscitation and vasopressor therapy are able to restore
hemodynamic stability
Addressing goals of care, including treatment plans and end of life planning,
as early as feasible, but within 72 hours of intensive care unit admission
Initial Treatment and Stabilization
Early diagnosis, early antibiotic administration, and adequate fluid
resuscitation are key in decreasing sepsis morbidity and mortality. Sepsisinduced tissue hypoperfusion is defined as either a requirement for
vasopressors after adequate fluid challenge or a lactate of 4 mg/dL. A myriad
of physiological changes drive potential sepsis-induced tissue hypoperfusion
in the patient with severe sepsis (Figure 5). This includes increased venous
capacitance, decreased arteriolar resistance, decreased ventricular
contractility, and capillary leak. Initial fluid therapy is considered paramount in
the successful resuscitation of sepsis-induced tissue hypoperfusion.
Crystalloids are recommended as the initial fluid of choice. Considerable
discussion now exists about the choice of crystalloids between an unbalanced
crystalloid (ie, normal saline) and balanced crystalloids (eg, lactated Ringers
for Ringers acetate). More research is needed in this area but there is some
concern as to the decreased pH and hyperchloremia associated with
unbalanced crystalloids. This may be associated with untoward renal effects.

Although randomized trials have failed to demonstrate benefit of albumin

versus saline, meta-analysis data supports potential benefit of adding
albumin to fluid resuscitation regimens in severe sepsis and septic shock
when the patient requires substantial amounts of crystalloid. 6,7 Recent data
would suggest that there is no advantage of albumin resuscitation targeting
normalization of serum albumin over the first week of therapy of severe
sepsis.8 Hydroxyethyl starches are not recommended for fluid resuscitation for
severe sepsis and septic shock due to concern for producing acute kidney
injury.9-11
Following initial fluid bolus, a patient with sepsis-induced hypotension or
tissue hypoperfusion may require vasopressors to maintain blood pressure.
Since following adequate intravascular volume repletion, the etiology of
persistent hypotension must be related to some combination of decreased
inotropy and arterial vasodilation; a combined inotrope vasopressor is
recommended. The first choice for vasopressor therapy is norepinephrine. 12,13
A mean arterial pressure (MAP) target of 65 mm Hg is recommended. 14,15 If a
MAP target of 65 mm Hg cannot be obtained with norepinephrine, then the 2
alternatives are: the addition of epinephrine to norepinephrine (with the
potential for combination therapy or substitution of epinephrine) or low-dose

vasopressin (up to .03 U/per minute).

High dose vasopressin >.04 U/per minute is not recommended.
Phenylephrine is also not recommended in the treatment of septic shock
except (a) when norepinephrine is associated with serious arrhythmias, (b)
cardiac output is known to be high and blood pressure target is difficult to
maintain with combined inotrope vasopressors, or (c) as salvage therapy
when other drugs are unsuccessful. Dopamine is also not recommended for
vasopressor therapy except when the patient has a combination of both
bradycardia and hypotension.
Quantitative Resuscitation
When a patient is characterized as having sepsis-induced tissue
hypoperfusion, protocolized care is recommended with attention drawn to
achieving specific variables (ie, protocol targets). This would include basic
targets such as MAP of 65 mm Hg and urine output of 0.5 ml/kg. Note:
Evidence dating back to the early to mid 2000s support MAP target of 60 mm
Hg to 65 mm Hg and more recently, comparisons of the use of norepinephrine
in septic shock to targets of either 65 mm Hg to 75 mm Hg or 75 mm Hg to 85
mm Hg demonstrate no difference in outcome between the low target and
high target group.14,16 However, there were increased serious arrhythmias
associated with the high target group.
The current recommended bolus strategy for quantitative resuscitation is a
minimum of an initial 30 mL/kg of crystalloids (a portion of this may be
albumin equivalent) and more rapid administration and greater amounts of
fluid may be needed in some patients (grade 1B).
In 2004, the guidelines recommended traditional early goal-directed therapy
targets of a central venous pressure (CVP) of 8 mm Hg to 12 mm Hg and
ScvO2 target of 70%. However, there has been a significant transition of
SSC thought process over the years with a turn toward a more generalized
quantitative resuscitation approach.17 The Campaign has recognized and
expressed the known limitations of CVP as a target to predict fluid
responsiveness and has encouraged alternative methods as additional
variables to integrate into decision-making when these are available. These
include tracking delta systolic or delta pulse pressure variation with
mechanical ventilator induced increases in intrathoracic pressure or stroke
volume, tracking changes in these variables with incremental fluid boluses.
Tracking flow can be done with a variety of methods to include FloTrac
(Edward Lifesciences Corporation), Picco (Phillips Medical), or LiDCO (Lidco
LLC), as well as the traditional pulmonary artery catheter. Likewise, the use of

ultrasound to judge inferior vena cava size and respiratory variation as well as
echocardiography to look at left ventricular chamber size and function may
also be useful. Finally, recent data suggest that lactate clearance may offer
benefit as part of a quantitative resuscitation protocol. 18,19
Although aggressive fluid resuscitation and associated stabilization of
hemodynamics in a patient with septic shock are considered essential for
increasing survival and decreasing morbidity from initial cardiovascular
instability, this early aggressive fluid resuscitation may be problematic during
the later course of the septic patient. With capillary leak that is present with
sepsis-induced tissue hypoperfusion, considerable fluid will accumulate
outside of the intravascular space and may be associated with lung, brain,
and other organ edema. Most patients autodiurese as they recover from
sepsis. There is now considerable discussion but no evidence-based
medicine that mobilization of this fluid from third spaces might be facilitated
with diuretics once cardiovascular stability is returned with more rapid
recovery. However, this is currently speculation.
Steroids
In 2004, the Campaign recommended steroids for the treatment of septic
shock. Over the next 2 revisions of the guidelines, the Campaign has since
transitioned away for this stance on steroid benefit and is currently
recommending against the use of intravenous corticosteroids in adults with
septic shock if adequate fluid resuscitation and vasopressor therapy restore
hemodynamic stability. When significant hemodynamic stability remains
following fluids and vasopressors, corticosteroids are recommend at an IV
dose of 200 mg hydrocortisone every 24 hours.
Performance Improvement Program
Although considered an important body of knowledge for physician education
and a reference source for optimal treatment, guidelines do not have high
impact on bedside healthcare practitioner performance. Simply put, guidelines
are not enough. In order to change bedside behavior, protocols and
performance improvement programs with audit and feedback are needed.
Early screening and hospital-based performance improvement programs are
now recommended by the Campaign.
Guidelines are converted to sepsis bundles, which are measureable goals
ascertained by review of medical records. These quality indicators are to be
achieved in this specific disease state over specific time periods. The current
sepsis bundles are outlined in Figures 6 and 7. The first set of bundles was

created in 2005, followed by an international performance improvement

campaign associated with free software and educational materials for
voluntary hospital participation.
Data from 10,000 patients were transmitted into a database housed at the
Society of Critical Care Medicine. The results of this sepsis performance
improvement program were published in 2010 and showed an association
between increasing compliance with the sepsis bundles and decrease in
mortality.20 Unpublished data from 30,000 patients continues to show this
finding in an even more pronounced fashion. When the database is examined,
it is noticed that patients admitted directly to the intensive care unit (ICU) from
the emergency department have a much better prognosis than those patients
admitted to the ICU from the hospital wards. This is somewhat surprising but
may relate to less vigilant monitoring on the hospital floors.
A recently launched performance improvement program, sponsored by a
collaboration between the Society of Critical Care Medicine and the Society of
Hospital Medicine (also funded by the Henry and Betty Moore Foundation), is
looking at the impact of early recognition and management of severe sepsis
on a specifically designated hospital floor performance improvement initiative.

ProCESS Trial
In 2014, the Protocolized Care for Early Septic Shock (ProCESS) trial was
published as the first of 3 trials (in progress or completed) that compare
alternative resuscitation methodology to the traditional early goal-directed
therapy target variables.21 The ProCESS trial compared the currently
recommended early goal-directed therapy variables for quantitative
resuscitation to a special ProCESS trial protocol that did not include central
monitoring.
Surprisingly, there was no difference between any of these approachesa
fact that has been regarded by some as an indictment against the need for
quantitative resuscitation. This trial was conducted primarily in large academic
centers, well versed with severe sepsis and severe sepsis resuscitation, and
most likely all patients received some type of quantitative resuscitation in the
mind of the treating team.

The quality of care delivered to these patients is reflected by the fact that all
groups in ProCESS received greater than 2 L average fluid prior to
randomization and 75% received antibiotics prior to randomization. In
addition, a majority of patients in both the ProCESS and usual care arms had
CVP catheters although the trial was not powered to compare patients without
CVP catheters with the early goal-directed therapy group.
The 18% mortality in septic shock in the ProCESS trial does not reflect
mortality in typical hospitals in which performance improvement programs,
including protocolized care, are still recommended. The ProCESS trial,
however, does support the fact that CVP and ScvO2 measurement may not
be necessary if the treating physician is knowledgeable of the
pathophysiology of severe sepsis and keenly aware of early antibiotic and
fluid resuscitation needs.
Two additional trialsthe Australian Resuscitation In Sepsis Evaluation
(ARISE) trial and Protocolized Management in Sepsis (ProMISe) trial are
forthcoming. These trials will likely give more important information that will
allow an SSC reassessment of current protocolized care and targets used for
resuscitation of severe sepsis and septic shock
The Surviving Sepsis Campaign has been a remarkable journey into
international consensus on the management of severe sepsis as well as the
linked sepsis performance improvement program. Guideline
recommendations and performance improvement quality indicators continue
to evolve as new evidence emerges. The performance improvement program
continues to expand its scope both geographically and across different
hospital areas.
References:
1.Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. 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(5):1244-1250.
2.Hall MJ, Williams SJ, DeFrances CJ, Golosinskiy A. Inpatient care for
septicemia or sepsis: a challenge for patients and hospitals. NCHS Data
Brief. 2011;62:1-8.
3.Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign
guidelines for management of severe sepsis and septic shock. Crit Care Med.
2004;32:858-873.

4.Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign:
International guidelines for management of severe sepsis and septic shock:
2008. Crit Care Med. 2008;36:296-327 [pub corrections appears in
2008;36:1394-1396].
5.Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign:
international guidelines for management of severe sepsis and septic shock:
2012. Crit Care Med. 2013;41:580-637.
6.Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for
fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:22472256.
7.Delaney AP, Dan A, McCaffrey J, Finfer S. The role of albumin as a
resuscitation fluid for patients with sepsis: A systematic review and metaanalysis. Crit Care Med. 2011; 39(2):386-391.
8.Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with
severe sepsis or septic shock. N Engl J Med. 2014;370(15):1412-1421.
9.Perner A, Haase N, Guttormsen AB, et al; 6S Trial Group; Scandinavian
Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringers
acetate in severe sepsis. N Engl J Med. 2012;367(2):124-134.
10.Myburgh JA, Finfer S, Bellomo R, et al; CHEST Investigators; Australian
and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl
starch or saline for fluid resuscitation in intensive care. N Engl J Med.
2012;367(2):1901-1911.
11.Brunkhorst FM, Engel C, Bloos F, et al; German Competence Network
Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in
severe sepsis. N Engl J Med. 2008;358(2):125-139.
12.De Backer D, Biston P, Devriendt J, et al; SOAP II Investigator.
Comparison of dopamine and norepinephrine in the treatment of shock. N
Engl J Med. 2010;362:779-789.
13.De Backer D, Aldecoa C, Njimi H, et al. Dopamine versus norepinephrine
in the treatment of septic shock: A meta-analysis*. Crit Care Med.
2012;40(3):725-730.
14.LeDoux D, Astiz ME, Carpati CM, Rackow EC. Effects of perfusion
pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28(8):2729-

2732.
15.Varpula M, Tallgren M, Saukkonen K, et al. Hemodynamic variables related
to outcome in septic shock. Intensive Care Med. 2005;31(8):1066-1071.
16.Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target
in patients with septic shock. N Engl J Med. 2014;370:1583-1593.
17.Rivers E, Nguyen B, Havstad S, et al; Early Goal-Directed Therapy
Collaborative Group. Early goal-directed therapy in the treatment of severe
sepsis and septic shock. N Engl J Med. 2001;345(19):1368-1377.
18.Jones AE, Shapiro NI, Trzeciak S, et al; Emergency Medicine Shock
Research Network (EMShockNet) Investigators. Lactate clearance vs central
venous oxygen saturation as goals of early sepsis therapy: A randomized
clinical trial. JAMA. 2010;303(8):739-746.
19.Jansen TC, van Bommel J, Schoonderbeek FJ, et al; LACTATE study
group. Early lactate-guided therapy in intensive care unit patients: A
multicenter, open-label, randomized controlled trial. Am J Respir Crit Care
Med. 2010;182(6):752-761.
20.Levy MM, Dellinger RP, Townsend SR, et al; Surviving Sepsis Campaign.
The Surviving Sepsis Campaign: Results of an international guideline-based
performance improvement program targeting severe sepsis. Crit Care Med.
2010;38(2):367-374.
21.ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, et al. A
randomized trial of protocol-based care for early septic shock. N Engl J Med.
2014;370(18):1683-1693.