Hora de Oro en Sepsis Grave y Shock Séptico

Transcription

Sociedad Argentina de Terapia Intensiva
Personería Jurídica Nº 2481
Hora de Oro en
Sepsis Grave y Shock Séptico
El diagnóstico y tratamiento de la Sepsis es una verdadera emergencia
médica. La Sepsis mata más gente que el SIDA y que los cánceres de mama y
próstata juntos. Cada hora mueren alrededor de 1.000 personas de Sepsis
alrededor del mundo. Si se diagnostica en la primera hora luego de su
presentación, la Sepsis tiene 80 % de supervivencia. Si se diagnostica después
de la sexta hora el paciente tiene sólo 30 % de posibilidades de sobrevivir. Es
por esto, que es de suma importancia que los síntomas precoces de Sepsis
sean reconocidos por ambos, el público y los agentes de salud. Esto permite
comenzar el tratamiento dentro de la primera hora – la HORA de ORO-. Si esto
fuera así, el riesgo de muerte de Sepsis disminuye a la mitad.
El concepto “hora de oro” surge del enfoque terapéutico inicial de los
pacientes con politraumatismos y traumatismo de cráneo. Dicho enfoque
intenta transmitir que las maniobras diagnósticas y terapéuticas de los primeros
momentos de la atención del paciente politraumatizado resultan en una clara
disminución de la morbilidad y mortalidad cuando se implementan siguiendo las
recomendaciones de un protocolo estricto.
Este tipo de protocolo, que se conforma sobre la base de la evidencia
científica publicada y por la experiencia de expertos en el tema, contempla no
sólo, qué estrategias de diagnóstico y que tratamientos emplear, sino, y
especialmente, cómo es la implementación de estas estrategias en el tiempo
(“Timing” de la literatura en inglés). La trascendencia de la precocidad con la
que se realizan los tratamientos iniciales han conducido a llamar a estos
primeros momentos “Horas de Oro”, lenguaje ampliamente difundido y
fácilmente entendido por la mayoría de los agentes de salud.
Este concepto, que ha sido trascendental en los resultados del tratamiento
de los politraumatizados, se ha extendido a otras patologías agudas que
también se caracterizan por provocar una evolución complicada de la
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enfermedad aguda durante la internación, en muchos casos severa
incapacidad y en otros la muerte, precoz y/o tardía.
En el Infarto Agudo de Miocardio el cuidado de los pacientes en unidades
especiales (Unidades Coronarias) en la década del 70, la sistematización y la
rapidez de la detección y del tratamiento de las complicaciones iniciales y la
implementación en los últimos años de los “Trombolíticos” o la Angioplastia en
las horas iniciales (Horas de oro) con el objetivo de recanalizar la arteria
coronaria obstruida, han disminuido las complicaciones agudas, las secuelas y
la mortalidad a cifras impensadas en el pasado.
Recientemente se ha comprobado que el uso de las drogas trombolíticas,
ya mencionadas en el tratamiento del Infarto de Miocardio, ha mejorado la
evolución de los accidentes cerebrales provocados por embolia o trombosis de
las arterias que perfunden el sistema nervioso central. Según los datos de los
que se dispone actualmente, dicho tratamiento es eficaz sólo cuando se
implementa en las primeras 3 á 4,5 horas de iniciado el cuadro del accidente
vascular cerebral (Horas de Oro).
Estos dos últimos ejemplos que, sin ninguna duda han sido trascendentales
en mejorar las secuelas y la sobrevida de patologías graves y muy comunes,
tienen el inconveniente que deben ser aplicadas en centros con una
complejidad importante en lo que se refiere a equipamiento y recursos
humanos entrenados, hecho que dificulta la aplicación de estos protocolos en
muchos casos, sobre todo en centros asistenciales alejados de las grandes
ciudades.
Recientemente, un grupo de expertos, actuando en representación de las
sociedades científicas más importantes relacionadas con el tema que nos
ocupa, decide implementar una estrategia que permita disminuir el 25 % la
mortalidad de los pacientes con Sepsis Severa y/o Shock Séptico. Dicha
estrategia, delineada en el año 2002 en la llamada “Declaración de Barcelona”,
por ser esa la ciudad de realización de la reunión de consenso mencionada,
implicaba la implementación de un conjunto de medidas diagnósticas y
terapéuticas con el concepto de “Horas de Oro”. La diferencia fundamental con
las estrategias que deben emplearse en el tratamiento del Infarto de Miocardio
y el Accidente Vascular Cerebral, es que para el tratamiento de la Sepsis
Severa y el Shock Séptico se necesita solamente ordenar en forma diferente
los tratamientos comunes que ya se empleaban. Esto permite que esta
estrategia terapéutica, que contempla el concepto de las Horas de Oro en el
tratamiento de la Sepsis Severa y el Shock Séptico, pueda implementarse en
instituciones de baja complejidad con personal que no necesita un alto nivel de
capacitación. La Sepsis Severa y el Shock Séptico son formas de extrema
gravedad de una infección convencional. Las infecciones pulmonares, las
infecciones de piel y partes blandas, infecciones en la infancia y en la mujer
embarazada pueden presentarse con un cuadro muy grave que, según sus
características clínicas se puede clasificar como Sepsis Severa o Shock
Séptico. La mortalidad de estos cuadros oscila entre 40 y 50 %, una mortalidad
de las más altas en la medicina crítica. Es por eso que este esfuerzo de las
instituciones científicas para disminuir la mortalidad de esta patología se ha
difundido en todo el mundo en forma de “Campaña para Sobrevivir a la Sepsis”
(Surviving Sepsis Campaign). (1)
La Campaña fue patrocinada por las siguientes Sociedades
Internacionales:
American Association of Critical-Care Nurses
American College of Chest Physicians
American College of Emergency Physicians
Canadian Critical Care Society
European Society of Clinical Microbiology and Infectious Diseases
European Society of Intensive Care Medicine
European Respiratory Society
International Sepsis Forum
Japanese Association for Acute Medicine
Japanese Society of Intensive Care Medicine
Society of Critical Care Medicine
Society of Hospital Medicine
Surgical Infection Society
World Federation of Societies of Intensive and Critical Care
Como consejo fundamental, la campaña establece que el estado de
“ALERTA” es el elemento número uno para la cura de la Sepsis. Aumentar el
reconocimiento precoz de la enfermedad y aumentar el número de pacientes
tratados en la “hora de oro” constituyen la medida más importante para salvar
vidas.
Todos los miembros del equipo de salud deberían ser capaces de
reconocer el cuadro de Sepsis Grave o el de Shock Séptico, de comenzar
inmediatamente el tratamiento antibiótico y la expansión de volumen antes de
llegar al hospital. El tratamiento precoz de los pacientes con Sepsis es tan
importante como el del Infarto Agudo de Miocardio el del Stroke Isquémico.
La implementación de la Campaña en diferentes hospitales del mundo y en
nuestro país ha logrado disminuir la mortalidad significativamente. La Sociedad
Española de Medicina Intensiva ha publicado un estudio sobre los resultados
de una campaña de educación en los conceptos de la Campaña
comprobándose en forma concluyente la mejoría en la sobrevida de los
pacientes Sépticos (2). El eje de la campaña es el ordenamiento y la premura
en tratar al paciente en las primeras 6 horas de la llegada de su llegada a la
Institución (Horas de Oro), sin ningún elemento adicional a los que ya se están
utilizando en cualquier institución.
Con el riesgo de ser repetitivo, vale la pena destacar nuevamente que una
de los elementos más importante de esta Campaña es que para aplicar el
concepto de “Hora de Oro” en Sepsis se necesita “SÓLO” un ordenamiento
asistencial con ningún agregado en complejidad o recurso humano
especializado.
La Campaña Internacional ha finalizado su etapa inicial con la
incorporación de más de 15.000 pacientes en todo el mundo y ha comprobado
fehacientemente la disminución de la mortalidad de la Sepsis Grave y el Shock
Séptico cuando se implementan sus recomendaciones.(3)
Las características de la Campaña y el hecho que desde la Sociedad
Argentina de Terapia Intensiva ya se ha incorporado a algunos hospitales del
país, nos obliga a intensificar esfuerzos para que el protocolo terapéutico de la
Campaña se utilice en el tratamiento inicial de todos los pacientes con Sepsis
Severa o Shock Séptico. Esto redundaría en una disminución importante de la
mortalidad en diferentes estratos de la población, incluyendo especialmente a
la infancia y embarazadas.
DIAGNÓSTICO:
INFECCIÓN + HIPOTENSIÓN ARTERIAL
TRATAMIENTO INICIAL INMEDIATO:
1) COLOCAR VÍA CENTRAL (SI ES POSIBLE).
MIENTRAS SE IMPLEMENTA COMENZAR
EXPANSIÓN DE VOLUMEN CON SOLUCIÓN SALINA
O RINGER LACTATO POR UNA VÍA VENOSA
SIMPLE.
2) EXPANDIR HASTA NORMALIZAR LA TA (>90 DE
SISTÓLICA) O HASTA LLEGAR A 15 CM DE H2O DE
PRESIÓN VENOSA CENTRAL
3) SI NO SE NORMALIZA LA TA CON UNA EXPANSIÓN
INICIAL DE APROXIMADAMENTE 20 ML/KG
COMENZAR CON UNA INFUSIÓN DE DOPAMINA O
NORADRENALINA (PUEDE USARSE UNA INFUSIÓN
DE ADRENALINA A LAS MISMAS DOSIS QUE LA
NORADRENALINA EN AUSENCIA DE LAS
ANTERIORES)
4) SIMULTÁNEAMENTE DEBEN TOMARSE LOS
CULTIVOS QUE LA INFECCIÓN DEL PACIENTE
AMERITE: 2 HEMOCULTIVOS (SIEMPRE),
UROCULTIVO, LÍQUIDO CEFALORRAQUÍDEO,
PUNCIONES DE ZONAS SOPECHOSAS, ETC.
5) COMENZAR CON ANTIBIÓTICOS
EMPÍRICOS INTRAVENOSOS ANTES DE LA
HORA DEL INICIO DE LA HIPOTENSIÓN
ARTERIAL (AUMENTA APROXIMADAMENTE 8 %
LA MORTALIDAD POR CADA HORA DE RETRASO
EN LA ADMINISTRACIÓN DE LOS ATB).
6) DERIVAR EL PACIENTE A UNA UNIDAD DE TERAPIA
INTENSIVA LO ANTES POSIBLE
BIBLIOGRAFÍA
1. Surviving Sepsis Campaign: International guidelines for management of
severe sepsis and septic shock: 2008. Intensive Care Medicine and Critical
Care Medicine. R. Phillip Dellinger et al.
2. Improvement in Process of Care and Outcome After a Multicenter Severe
Sepsis Educational Program in Spain. JAMA. 2008. Ricard Ferrer; Antonio
Artigas; Mitchell M. Levy et al.
3. The Surviving Sepsis Campaign: Results of an international guideline
based performance improvement program targeting severe sepsis. Critical
Care Medicine 2010. Mitchell M. Levy, et al. on behalf of the Surviving Sepsis Campaign
NOTA: Se acompañan copias de los artículos mencionados
Intensive Care Med
DOI 10.1007/s00134-007-0934-2
SPE C I A L A R T I C L E
R. Phillip Dellinger
Mitchell M. Levy
Jean M. Carlet
Julian Bion
Margaret M. Parker
Roman Jaeschke
Konrad Reinhart
Derek C. Angus
Christian Brun-Buisson
Richard Beale
Thierry Calandra
Jean-Francois Dhainaut
Herwig Gerlach
Maurene Harvey
John J. Marini
John Marshall
Marco Ranieri
Graham Ramsay
Jonathan Sevransky
B. Taylor Thompson
Sean Townsend
Jeffrey S. Vender
Janice L. Zimmerman
Jean-Louis Vincent
Surviving Sepsis Campaign:
International guidelines for management
of severe sepsis and septic shock: 2008
Received: 3 August 2007
Accepted: 25 October 2007
Medicine**. Participation and endorsement
by the German Sepsis Society and the Latin
American Sepsis Institute.
© Society of Critical Care Medicine 2007
The article will also be published in Critical
Care Medicine.
* Sponsor of 2004 guidelines; ** Sponsor
of 2008 guidelines but did not participate
formally in revision process; *** Members
of the 2007 SSC Guidelines Committee are
listed in Appendix I.; **** Please see Appendix J for author disclosure information.
for the International Surviving Sepsis
Campaign Guidelines Committee***, ****
Sponsoring Organizations: American Association of Critical-Care Nurses*, American
College of Chest Physicians*, American
College of Emergency Physicians*, Canadian Critical Care Society, European Society of Clinical Microbiology and Infectious
Diseases*, European Society of Intensive
Care Medicine*, European Respiratory
Society*, International Sepsis Forum*,
Japanese Association for Acute Medicine,
Japanese Society of Intensive Care Medicine, Society of Critical Care Medicine*,
Society of Hospital Medicine**, Surgical
Infection Society*, World Federation of
Societies of Intensive and Critical Care
R. P. Dellinger (u)
Cooper University Hospital,
One Cooper Plaza, 393 Dorrance,
Camden 08103, NJ, USA
e-mail: [email protected]
M. M. Levy · S. Townsend
Rhode Island Hospital,
Providence RI, USA
J. M. Carlet
Hospital Saint-Joseph,
Paris, France
J. Bion
Birmingham University,
Birmingham, UK
M. M. Parker
SUNY at Stony Brook,
Stony Brook NY, USA
D. C. Angus
University of Pittsburgh,
Pittsburgh PA, USA
C. Brun-Buisson
Hopital Henri Mondor,
Créteil, France
R. Beale
Guy’s and St Thomas’ Hospital Trust,
London, UK
T. Calandra
Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
J.-F. Dhainaut
French Agency for Evaluation of Research
and Higher Education,
Paris, France
H. Gerlach
Vivantes-Klinikum Neukoelln,
Berlin, Germany
R. Jaeschke
McMaster University,
Hamilton, Ontario, Canada
M. Harvey
Consultants in Critical Care, Inc.,
Glenbrook NV, USA
K. Reinhart
Friedrich-Schiller-University of Jena,
Jena, Germany
J. J. Marini
University of Minnesota,
St. Paul MN, USA
J. Marshall
St. Michael’s Hospital,
Toronto, Ontario, Canada
M. Ranieri
Università di Torino,
Torino, Italy
G. Ramsay
West Hertfordshire Health Trust,
Hemel Hempstead, UK
J. Sevransky
The Johns Hopkins University School
of Medicine,
Baltimore MD, USA
B. T. Thompson
Massachusetts General Hospital,
Boston MA, USA
J. S. Vender
Evanston Northwestern Healthcare,
Evanston IL, USA
J. L. Zimmerman
The Methodist Hospital,
Houston TX, USA
J.-L. Vincent
Erasme University Hospital,
Brussels, Belgium
Abstract Objective: To provide
an update to the original Surviving
Sepsis Campaign clinical management guidelines, “Surviving Sepsis
Campaign guidelines for management
of severe sepsis and septic shock,”
published in 2004. Design: Modified
Delphi method with a consensus
conference of 55 international experts, several subsequent meetings
of subgroups and key individuals,
teleconferences, and electronic-based
discussion among subgroups and
among the entire committee. This
process was conducted independently
of any industry funding. Methods:
We used the GRADE system to
guide assessment of quality of evidence from high (A) to very low (D)
and to determine the strength of
recommendations. A strong recommendation [1] indicates that an
intervention’s desirable effects clearly
outweigh its undesirable effects (risk,
burden, cost), or clearly do not. Weak
recommendations [2] indicate that
the tradeoff between desirable and
undesirable effects is less clear. The
grade of strong or weak is considered
of greater clinical importance than
a difference in letter level of quality
of evidence. In areas without complete
agreement, a formal process of resolution was developed and applied.
Recommendations are grouped into
those directly targeting severe sepsis,
recommendations targeting general
care of the critically ill patient that
are considered high priority in severe
sepsis, and pediatric considerations.
Results: Key recommendations,
listed by category, include: early
goal-directed resuscitation of the
septic patient during the first 6 hrs
after recognition (1C); blood cultures
prior to antibiotic therapy (1C); imaging studies performed promptly to
confirm potential source of infection
(1C); administration of broadspectrum antibiotic therapy within
1 hr of diagnosis of septic shock (1B)
and severe sepsis without septic shock
(1D); reassessment of antibiotic therapy with microbiology and clinical
data to narrow coverage, when appropriate (1C); a usual 7–10 days of
antibiotic therapy guided by clinical
response (1D); source control with
attention to the balance of risks and
benefits of the chosen method (1C);
administration of either crystalloid or
colloid fluid resuscitation (1B); fluid
challenge to restore mean circulating
filling pressure (1C); reduction in rate
of fluid administration with rising
filing pressures and no improvement
in tissue perfusion (1D); vasopressor
preference for norepinephrine or
dopamine to maintain an initial target
of mean arterial pressure ≥ 65 mm Hg
(1C); dobutamine inotropic therapy
when cardiac output remains low
despite fluid resuscitation and combined inotropic/vasopressor therapy
(1C); stress-dose steroid therapy
given only in septic shock after blood
pressure is identified to be poorly
responsive to fluid and vasopressor
therapy (2C); recombinant activated
protein C in patients with severe
sepsis and clinical assessment of high
risk for death (2B except 2C for postoperative patients). In the absence of
tissue hypoperfusion, coronary artery
disease, or acute hemorrhage, target
a hemoglobin of 7–9 g/dL (1B); a low
tidal volume (1B) and limitation of
inspiratory plateau pressure strategy
(1C) for acute lung injury (ALI)/
acute respiratory distress syndrome
(ARDS); application of at least
a minimal amount of positive endexpiratory pressure in acute lung
injury (1C); head of bed elevation
in mechanically ventilated patients
unless contraindicated (1B); avoiding routine use of pulmonary artery
catheters in ALI/ARDS (1A); to decrease days of mechanical ventilation
and ICU length of stay, a conservative fluid strategy for patients with
established ALI/ARDS who are not
in shock (1C); protocols for weaning
and sedation/analgesia (1B); using
either intermittent bolus sedation or
continuous infusion sedation with
daily interruptions or lightening (1B);
avoidance of neuromuscular blockers,
if at all possible (1B); institution
of glycemic control (1B) targeting
a blood glucose < 150 mg/dL after
initial stabilization ( 2C ); equivalency
of continuous veno-veno hemofiltration or intermittent hemodialysis
(2B); prophylaxis for deep vein
thrombosis (1A); use of stress ulcer
prophylaxis to prevent upper GI
bleeding using H2 blockers (1A) or
proton pump inhibitors (1B); and
consideration of limitation of support
where appropriate (1D). Recommendations specific to pediatric severe
sepsis include: greater use of physical
examination therapeutic end points
(2C); dopamine as the first drug of
choice for hypotension (2C); steroids
only in children with suspected or
proven adrenal insufficiency (2C);
a recommendation against the use of
recombinant activated protein C in
children (1B). Conclusion: There
was strong agreement among a large
cohort of international experts regarding many level 1 recommendations
for the best current care of patients
with severe sepsis. Evidenced-based
recommendations regarding the acute
management of sepsis and septic
shock are the first step toward improved outcomes for this important
group of critically ill patients.
Keywords Sepsis · Severe sepsis ·
Septic shock · Sepsis syndrome ·
Infection · GRADE · Guidelines ·
Evidence-based medicine · Surviving
Sepsis Campaign · Sepsis bundles
Introduction
Severe sepsis (acute organ dysfunction secondary to infection) and septic shock (severe sepsis plus hypotension
not reversed with fluid resuscitation) are major healthcare
problems, affecting millions of individuals around the
world each year, killing one in four (and often more),
and increasing in incidence [1–5]. Similar to polytrauma,
acute myocardial infarction, or stroke, the speed and
appropriateness of therapy administered in the initial
hours after severe sepsis develops are likely to influence
outcome. In 2004, an international group of experts in the
diagnosis and management of infection and sepsis, representing 11 organizations, published the first internationally
accepted guidelines that the bedside clinician could use to
improve outcomes in severe sepsis and septic shock [6, 7].
These guidelines represented Phase II of the Surviving
Sepsis Campaign (SSC), an international effort to increase
awareness and improve outcomes in severe sepsis. Joined
by additional organizations, the group met again in 2006
and 2007 to update the guidelines document using a new
evidence-based methodology system for assessing quality
of evidence and strength of recommendations [8–11].
These recommendations are intended to provide guidance for the clinician caring for a patient with severe sepsis
or septic shock. Recommendations from these guidelines
cannot replace the clinician’s decision-making capability
Table 1 Determination
of the Quality of Evidence
when he or she is provided with a patient’s unique set of
clinical variables. Most of these recommendations are appropriate for the severe sepsis patient in both the intensive
care unit (ICU) and non-ICU settings. In fact the committee believes that, currently, the greatest outcome improvement can be made through education and process change
for those caring for severe sepsis patients in the non-ICU
setting and across the spectrum of acute care. It should also
be noted that resource limitations in some institutions and
countries may prevent physicians from accomplishing particular recommendations.
Methods
Sepsis is defined as infection plus systemic manifestations
of infection (Table 1) [12]. Severe sepsis is defined as
sepsis plus sepsis-induced organ dysfunction or tissue
hypoperfusion. The threshold for this dysfunction has
varied somewhat from one severe sepsis research study to
another. An example of typical thresholds identification
of severe sepsis is shown in Table 2 [13]. Sepsis induced
hypotension is defined as a systolic blood pressure(SBP)
of < 90 mm Hg or mean arterial pressure < 70 mm Hg or
a SBP decrease > 40 mm Hg or < 2 SD below normal
for age in the absence of other causes of hypotension.
Septic shock is defined as sepsis induced hypotension
• Underlying methodology
A
RCT
B
Downgraded RCT or upgraded observational studies
C
Well-done observational studies
D
Case series or expert opinion
• Factors that may decrease the strength of evidence
1.
Poor quality of planning and implementation of available RCTs suggesting high likelihood of bias
2.
Inconsistency of results (including problems with subgroup analyses)
3.
Indirectness of evidence (differing population, intervention, control, outcomes, comparison)
4.
Imprecision of results
5.
High likelihood of reporting bias
• Main factors that may increase the strength of evidence
1.
Large magnitude of effect (direct evidence, relative risk (RR) > 2 with no plausible confounders)
2.
Very large magnitude of effect with RR > 5 and no threats to validity (by two levels)
3.
Dose response gradient
RCT, randomized controlled trial; RR, relative risk
Table 2 Factors Determining Strong vs. Weak Recommendation
What should be considered
Recommended Process
Quality of evidence
Relative importance of the outcomes
Baseline risks of outcomes
Magnitude of relative risk including
benefits, harms, and burden
Absolute magnitude of the effect
The lower the quality of evidence the less likely a strong recommendation
If values and preferences vary widely, a strong recommendation becomes less likely
The higher the risk, the greater the magnitude of benefit
Larger relative risk reductions or larger increases in relative risk of harm make a strong
recommendation more or less likely respectively
The larger the absolute benefits and harms, the greater or
lesser likelihood respectively of a strong recommendation
The greater the precision the more likely is a strong recommendation
The higher the cost of treatment, the less likely a strong recommendation
Precision of the estimates of the effects
Costs
persisting despite adequate fluid resuscitation. Sepsis
induced tissue hypoperfusion is defined as either septic
shock, an elevated lactate or oliguria.
The current clinical practice guidelines build on
the first and second editions from 2001 (see below)
and 2004 [6, 7, 14]. The 2001 publication incorporated
a MEDLINE search for clinical trials in the preceding
10 years, supplemented by a manual search of other relevant journals [14]. The 2004 publication incorporated the
evidence available through the end of 2003. The current
publication is based on an updated search into 2007 (see
methods and rules below).
The 2001 guidelines were coordinated by the International Sepsis Forum (ISF); the 2004 guidelines were
funded by unrestricted educational grants from industry
and administered through the Society of Critical Care
Medicine (SCCM), the European Society of Intensive
Care Medicine (ESICM), and ISF. Two of the SSC
administering organizations receive unrestricted industry
funding to support SSC activities (ESICM and SCCM), but
none of this funding was used to support the 2006–2007
committee meetings.
It is important to distinguish between the process of
guidelines revision and the Surviving Sepsis Campaign.
The Surviving Sepsis Campaign (SSC) is partially funded
by unrestricted educational industry grants, including
those from Edwards LifeSciences, Eli Lilly and Company, and Philips Medical Systems. SSC also received
funding from the Coalition for Critical Care Excellence
of the Society of Critical Care Medicine. The great
majority of industry funding has come from Eli Lilly and
Company.
Current industry funding for the Surviving Sepsis Campaign is directed to the performance improvement initiative. No industry funding was used in the guidelines revision process.
For both the 2004 and the 2006/2007 efforts there were
no members of the committee from industry, no industry
input into guidelines development, and no industry presence at any of the meetings. Industry awareness or comment on the recommendations was not allowed. No member of the guideline committee received any honoraria for
any role in the 2004 or 2006/2007 guidelines process. The
committee considered the issue of recusement of individual committee members during deliberation and decision
making in areas where committee members had either financial or academic competing interests; however, consensus as to threshold for exclusion could not be reached. Alternatively, the committee agreed to ensure full disclosure
and transparency of all committee members’ potential conflicts at time of publication (see disclosures at the end of
this document).
The guidelines process included a modified Delphi
method, a consensus conference, several subsequent meetings of subgroups and key individuals, teleconferences
and electronically based discussions among subgroups
and members of the entire committee and two follow-up
nominal group meetings in 2007.
Subgroups were formed, each charged with updating
recommendations in specific areas, including corticosteroids, blood products, activated protein C, renal
replacement therapy, antibiotics, source control, and
glucose control, etc. Each subgroup was responsible for
updating the evidence (into 2007, with major additional
elements of information incorporated into the evolving
manuscript throughout 2006 and 2007). A separate search
was performed for each clearly defined question. The
committee chair worked with subgroup heads to identify
pertinent search terms that always included, at a minimum,
sepsis, severe sepsis, septic shock and sepsis syndrome
crossed against the general topic area of the subgroup as
well as pertinent key words of the specific question posed.
All questions of the previous guidelines publications were
searched, as were pertinent new questions generated by
general topic related search or recent trials. Quality of
evidence was judged by pre-defined Grades of Recommendation, Assessment, Development and Evaluation
(GRADE) criteria (see below). Significant education
of committee members on the GRADE approach was
performed via email prior to the first committee meeting
and at the first meeting. Rules were distributed concerning
assessing the body of evidence and GRADE experts were
available for questions throughout the process. Subgroups
agreed electronically on draft proposals that were presented to committee meetings for general discussion. In
January 2006, the entire group met during the 35th SCCM
Critical Care Congress in San Francisco, California, USA.
The results of that discussion were incorporated into the
next version of recommendations and again discussed
using electronic mail. Recommendations were finalized
during nominal group meetings (composed of a subset of
the committee members) at the 2007 SCCM (Orlando)
and 2007 International Symposium on Intensive Care and
Emergency Medicine (Brussels) meetings with recirculation of deliberations and decisions to the entire group
for comment or approval. At the discretion of the chair
and following adequate discussion, competing proposals
for wording of recommendations or assigning strength of
evidence were resolved by formal voting. On occasions,
voting was performed to give the committee a sense of
distribution of opinions to facilitate additional discussion.
The manuscript was edited for style and form by the
writing committee with final approval by section leads for
their respective group assignment and then by the entire
committee.
The development of guidelines and grading of recommendations for the 2004 guideline development process
were based on a system proposed by Sackett in 1989,
during one of the first American College of Chest Physicians (ACCP) conferences on the use of antithrombotic
therapies [15]. The revised guidelines recommendations
are based on the Grades of Recommendation, Assessment,
Development and Evaluation (GRADE) system – a structured system for rating quality of evidence and grading
strength of recommendation in clinical practice [8–11].
The SSC Steering Committee and individual authors
collaborated with GRADE representatives to apply the
GRADE system to the SSC guidelines revision process.
The members of GRADE group were directly involved,
either in person or via e-mail, in all discussions and
deliberations amongst the guidelines committee members
as to grading decisions. Subsequently, the SSC authors
used written material prepared by the GRADE group
and conferred with GRADE group members who were
available at the first committee meeting and subsequent
nominal group meetings. GRADE representatives were
also used as a resource throughout subgroup deliberation.
The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment
of the balance between benefits versus risks, burden, and
cost and, based on the above, development and grading of
a management recommendations [9–11]. Keeping the rating of quality of evidence and strength of recommendation
explicitly separate constitutes a crucial and defining feature of the GRADE approach. This system classifies quality of evidence as high (Grade A), moderate (Grade B), low
(Grade C), or very low (Grade D). Randomized trials begin as high quality evidence, but may be downgraded due
to limitations in implementation, inconsistency or imprecision of the results, indirectness of the evidence, and possible reporting bias (see Table 1). Examples of indirectness
of the evidence include: population studied, interventions
used, outcomes measured, and how these relate to the question of interest. Observational (non-randomized) studies
begin as low-quality evidence, but the quality level may
be upgraded on the basis of large magnitude of effect. An
example of this is the quality of evidence for early administration of antibiotics.
The GRADE system classifies recommendations as
strong (Grade 1) or weak (Grade 2). The grade of strong
or weak is considered of greater clinical importance than
a difference in letter level of quality of evidence. The committee assessed whether the desirable effects of adherence
will outweigh the undesirable effects, and the strength
of a recommendation reflects the group’s degree of confidence in that assessment. A strong recommendation in
favor of an intervention reflects that the desirable effects
of adherence to a recommendation (beneficial health outcomes, less burden on staff and patients, and cost savings)
will clearly outweigh the undesirable effects (harms, more
burden and greater costs). A weak recommendation in
favor of an intervention indicates that the desirable effects
of adherence to a recommendation probably will outweigh
the undesirable effects, but the panel is not confident about
these tradeoffs – either because some of the evidence is
low-quality (and thus there remains uncertainty regarding
the benefits and risks) or the benefits and downsides are
closely balanced. While the degree of confidence is a continuum and there is a lack of a precise threshold between
a strong and a weak recommendation, the presence of
important concerns about one or more of the above factors
makes a weak recommendation more likely. A “strong”
recommendation is worded as “we recommend” and
a weak recommendation as “we suggest.”
The implications of calling a recommendation “strong”
are that most well-informed patients would accept that
intervention, and that most clinicians should use it in
most situations. There may be circumstances in which
a “strong” recommendation cannot or should not be
followed for an individual patient because of that patient’s
preferences or clinical characteristics which make the
recommendation less applicable. It should be noted that
being a “strong” recommendation does not automatically
imply standard of care. For example, the strong recommendation for administering antibiotics within one hour
of the diagnosis of severe sepsis, although desirable,
is not currently standard of care as verified by current
practice (personal communication, Mitchell Levy from
first 8,000 patients entered internationally into the SSC
performance improvement data base). The implication of
a “weak” recommendation is that although a majority of
well-informed patients would accept it (but a substantial
proportion would not), clinicians should consider its use
according to particular circumstance.
Differences of opinion among committee members
about interpretation of evidence, wording of proposals,
or strength of recommendations were resolved using
a specifically developed set of rules. We will describe this
process in detail in a separate publication. In summary,
the main approach for converting diverse opinions into
a recommendation was: 1. to give a recommendation
a direction (for or against the given action). a majority
of votes were to be in favor of that direction, with no
more than 20% preferring the opposite direction (there
was a neutral vote allowed as well); 2. to call a given
recommendation “strong” rather than “weak” at least 70%
“strong” votes were required; 3. if fewer than 70% of votes
indicated “strong” preference, the recommendation was
assigned a “weak” category of strength. We used a combination of modified Delphi Process and Nominal (Expert)
Group techniques to ensure both depth and breadth of
review. The entire review group (together with their
parent organizations as required) participated in the larger,
iterative, modified Delphi process. The smaller working
group meetings which took place in person functioned as
the Nominal Groups. If a clear consensus could not be
obtained by polling within the Nominal Group meetings,
the larger group was specifically asked to use the polling
process. This was only required for corticosteroids and
glycemic control. The larger group had the opportunity to
review all outputs. In this way the entire review combined
intense focused discussion (Nominal Group) with broader
review and monitoring using the Delphi process.
Note: Refer to Tables 3, 4, and 5 for condensed adult
recommentations.
I. Management of Severe Sepsis
A. Initial Resuscitation
1. We recommend the protocolized resuscitation of
a patient with sepsis-induced shock, defined as tissue
hypoperfusion (hypotension persisting after initial
fluid challenge or blood lactate concentration equal
to or greater than 4 mmol/L). This protocol should be
initiated as soon as hypoperfusion is recognized and
should not be delayed pending ICU admission. During
the first 6 hrs of resuscitation, the goals of initial
resuscitation of sepsis-induced hypoperfusion should
include all of the following as one part of a treatment
protocol:
Central venous pressure (CVP): 8–12 mm Hg
Mean arterial pressure (MAP) ≥ 65 mm Hg
Urine output ≥ 0.5 mL.kg–1 .hr –1
Central venous (superior vena cava) or mixed
venous oxygen saturation ≥ 70% or ≥ 65%, respectively (Grade 1C)
Rationale. Early goal-directed resuscitation has been
shown to improve survival for emergency department
patients presenting with septic shock in a randomized,
controlled, single-center study [16]. Resuscitation directed toward the previously mentioned goals for the
initial 6-hr period of the resuscitation was able to reduce
28-day mortality rate. The consensus panel judged use
Table 3 Initial Resuscitation and Infection Issues
Initial resuscitation (first 6 hours)
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ◦ indicates a weak recommendation or “we suggest”
• Begin resuscitation immediately in patients with hypotension or elevated serum lactate > 4mmol/l; do not delay pending ICU
admission. (1C)
• Resuscitation goals: (1C)
– Central venous pressure (CVP) 8–12 mm Hg*
– Mean arterial pressure ≥ 65 mm Hg
– Urine output ≥ 0.5 mL.kg-1.hr-1
– Central venous (superior vena cava) oxygen saturation ≥ 70%, or mixed venous ≥ 65%
◦ If venous O2 saturation target not achieved: (2C)
– consider further fluid
– transfuse packed red blood cells if required to hematocrit of ≥ 30% and/or
– dobutamine infusion max 20 µg.kg−1 .min−1
∗ A higher target CVP of 12–15 mmHg is recommended in the presence of mechanical ventilation or pre-existing decreased
ventricular compliance.
Diagnosis
• Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration. (1C)
– Obtain two or more blood cultures (BCs)
– One or more BCs should be percutaneous
– One BC from each vascular access device in place > 48 h
– Culture other sites as clinically indicated
• Perform imaging studies promptly in order to confirm and sample any source of infection; if safe to do so. (1C)
Antibiotic therapy
• Begin intravenous antibiotics as early as possible, and always within the first hour of recognizing severe sepsis (1D)
and septic shock (1B) .
• Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with good penetration
into presumed source.(1B)
• Reassess antimicrobial regimen daily to optimise efficacy, prevent resistance, avoid toxicity & minimise costs. (1C)
◦ Consider combination therapy in Pseudomonas infections. (2D)
◦ Consider combination empiric therapy in neutropenic patients. (2D)
◦ Combination therapy no more than 3–5 days and deescalation following susceptibilities. (2D)
• Duration of therapy typically limited to 7–10 days; longer if response slow, undrainable foci of infection,
or immunologic deficiencies. (1D)
• Stop antimicrobial therapy if cause is found to be non-infectious. (1D)
Source identification and control
• A specific anatomic site of infection should be established as rapidly as possible (1C) and within first 6 hrs of presentation (1D) .
• Formally evaluate patient for a focus of infection amenable to source control measures (eg: abscess drainage, tissue debridement). (1C)
• Implement source control measures as soon as possible following successful initial resuscitation. (1C)
Exception: infected pancreatic necrosis, where surgical intervention best delayed. (2B)
• Choose source control measure with maximum efficacy and minimal physiologic upset. (1D)
• Remove intravascular access devices if potentially infected. (1C)
Table 4 Hemodynamic Support and Adjunctive Therapy
Fluid therapy
• Fluid-resuscitate using crystalloids or colloids. (1B)
• Target a CVP of ≥ 8 mm Hg (≥ 12 mm Hg if mechanically ventilated). (1C)
• Use a fluid challenge technique while associated with a haemodynamic improvement. (1D)
• Give fluid challenges of 1000 ml of crystalloids or 300–500 ml of colloids over 30 min. More rapid and larger volumes may be required
in sepsis-induced tissue hypoperfusion. (1D)
• Rate of fluid administration should be reduced if cardiac filling pressures increase without concurrent hemodynamic improvement. (1D)
Vasopressors
• Maintain MAP ≥ 65 mm Hg. (1C)
• Norepinephrine or dopamine centrally administered are the initial vasopressors of choice. (1C)
◦ Epinephrine, phenylephrine or vasopressin should not be administered as the initial vasopressor in septic shock. (2C)
– Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation of an effect
equivalent to norepinephrine alone.
◦ Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly responsive to norepinephrine
or dopamine. (2B)
• Do not use low-dose dopamine for renal protection. (1 A)
• In patients requiring vasopressors, insert an arterial catheter as soon as practical. (1D)
Inotropic therapy
• Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac filling pressures and low cardiac output. (1C)
• Do not increase cardiac index to predetermined supranormal levels. (1B)
Steroids
◦ Consider intravenous hydrocortisone for adult septic shock when hypotension remains poorly responsive to adequate
fluid resuscitation and vasopressors. (2C)
◦ ACTH stimulation test is not recommended to identify the subset of adults with septic shock who should receive hydrocortisone. (2B)
◦ Hydrocortisone is preferred to dexamethasone. (2B)
◦ Fludrocortisone (50 µg orally once a day) may be included if an alternative to hydrocortisone is being used which lacks significant
mineralocorticoid activity. Fludrocortisone is optional if hydrocortisone is used. (2C)
◦ Steroid therapy may be weaned once vasopressors are no longer required. (2D)
• Hydrocortisone dose should be ≤ 300 mg/day. (1 A)
• Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s endocrine or corticosteroid history warrants it. (1D)
Recombinant human activated protein C (rhAPC)
◦ Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death
(typically APACHE II ≥ 25 or multiple organ failure) if there are no contraindications. (2B,2Cfor post-operative patients)
• Adult patients with severe sepsis and low risk of death (e. g.: APACHE II<20 or one organ failure) should not receive rhAPC. (1 A)
of central venous and mixed venous oxygen saturation
targets to be equivalent. Either intermittent or continuous
measurements of oxygen saturation were judged to be
acceptable. Although blood lactate concentration may
lack precision as a measure of tissue metabolic status,
elevated levels in sepsis support aggressive resuscitation.
In mechanically ventilated patients or patients with
known pre-existing decreased ventricular compliance,
a higher target CVP of 12–15 mm Hg is recommended
to account for the impediment to filling [17]. Similar consideration may be warranted in circumstances
of increased abdominal pressure or diastolic dysfunction [18]. Elevated central venous pressures may also be
seen with pre-existing clinically significant pulmonary
artery hypertension. Although the cause of tachycardia
in septic patients may be multifactorial, a decrease in
elevated pulse rate with fluid resuscitation is often a useful marker of improving intravascular filling. Recently
published observational studies have demonstrated an
association between good clinical outcome in septic
shock and MAP ≥ 65 mm Hg as well as central venous oxygen saturation (ScvO2 , measured in superior
vena cava, either intermittently or continuously) of
≥ 70% [19]. Many recent studies support the value of
early protocolized resuscitation in severe sepsis and
sepsis-induced tissue hypoperfusion [20–25]. Studies
of patients with shock indicate that SvO2 runs 5–7%
lower than central venous oxygen saturation (ScvO2 ) [26]
and that an early goal directed resuscitation protocol
can be established in a non-research general practice
venue [27].
There are recognized limitations to ventricular filling
pressure estimates as surrogates for fluid resuscitation [28, 29]. However, measurement of CVP is currently
the most readily obtainable target for fluid resuscitation.
There may be advantages to targeting fluid resuscitation
to flow and perhaps to volumetric indices (and even
to microcirculation changes) [30–33]. Technologies
currently exist that allow measurement of flow at the
bedside [34, 35]. Future goals should be making these
technologies more accessible during the critical early
resuscitation period and research to validate utility.
These technologies are already available for early ICU
resuscitation.
Table 5 Other Supportive Therapy of Severe Sepsis
Blood product administration
• Give red blood cells when hemoglobin decreases to < 7.0 g/dl (< 70 g/L) to target a hemoglobin of 7.0–9.0 g/dl in adults. (1B)
– A higher hemoglobin level may be required in special circumstances (e. g.: myocardial ischaemia, severe hypoxemia, acute
haemorrhage, cyanotic heart disease or lactic acidosis)
• Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons. (1B)
• Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures. (2D)
◦ Do not use antithrombin therapy. (1B)
• Administer platelets when: (2D)
– counts are < 5000/mm3 (5 × 109 /L) regardless of bleeding.
– counts are 5000 to 30,000/mm3 (5–30 × 109 /L) and there is significant bleeding risk.
– Higher platelet counts (≥ 50,000/mm3 (50 × 109 /L)) are required for surgery or invasive procedures.
Mechanical ventilation of sepsis-induced acute lung injury (ALI)/ARDS
• Target a tidal volume of 6 ml/kg (predicted) body weight in patients with ALI/ARDS. (1B)
• Target an initial upper limit plateau pressure ≤ 30 cm H2 O. Consider chest wall compliance when assessing plateau pressure. (1C)
• Allow PaCO2 to increase above normal, if needed to minimize plateau pressures and tidal volumes. (1C)
• Positive end expiratory pressure (PEEP) should be set to avoid extensive lung collapse at end expiration. (1C)
◦ Consider using the prone position for ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure,
provided they are not put at risk from positional changes. (2C)
• Maintain mechanically ventilated patients in a semi-recumbent position (head of the bed raised to 45 ◦ ) unless contraindicated (1B) ,
between 30◦ –45◦ (2C) .
◦ Non invasive ventilation may be considered in the minority of ALI/ARDS patients with mild-moderate hypoxemic respiratory failure.
The patients need to be hemodynamically stable, comfortable, easily arousable, able to protect/clear their airway and expected
to recover rapidly. (2B)
• Use a weaning protocol and a spontaneous breathing trial (SBT) regularly to evaluate the potential for discontinuing
mechanical ventilation. (1 A)
– SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2 O or a T-piece.
– Before the SBT, patients should:
– be arousable
– be haemodynamically stable without vasopressors
– have no new potentially serious conditions
– have low ventilatory and end-expiratory pressure requirement
– require FiO2 levels that can be safely delivered with a face mask or nasal cannula
• Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ARDS. (1 A)
• Use a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion. (1C)
Sedation, analgesia, and neuromuscular blockade in sepsis
• Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients. (1B)
• Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily
interruption/lightening to produce awakening. Re-titrate if necessary. (1B)
• Avoid neuromuscular blockers (NMBs) where possible. Monitor depth of block with train of four when using continuous infusions. (1B)
Glucose control
• Use IV insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU. (1B)
• Aim to keep blood glucose < 150 mg/dl (8.3 mmol/L) using a validated protocol for insulin dose adjustment. (2C)
• Provide a glucose calorie source and monitor blood glucose values every 1–2 hrs (4 hrs when stable) in patients receiving
intravenous insulin. (1C)
• Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood
or plasma glucose values. (1B)
Renal replacement
◦ Intermittent hemodialysis and continuous veno-venous haemofiltration (CVVH) are considered equivalent. (2B)
◦ CVVH offers easier management in hemodynamically unstable patients. (2D)
Bicarbonate therapy
• Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating
hypoperfusion-induced lactic acidemia with pH ≥ 7.15. (1B)
Deep vein thrombosis (DVT) prophylaxis
• Use either low-dose unfractionated heparin (UFH) or low-molecular weight heparin (LMWH), unless contraindicated. (1 A)
• Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when
heparin is contraindicated. (1 A)
◦ Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for DVT. (2C)
◦ In patients at very high risk LMWH should be used rather than UFH. (2C)
Stress ulcer prophylaxis
• Provide stress ulcer prophylaxis using H2 blocker (1 A) or proton pump inhibitor (1B) . Benefits of prevention of upper GI bleed must
be weighed against the potential for development of ventilator-associated pneumonia.
Consideration for limitation of support
• Discuss advance care planning with patients and families. Describe likely outcomes and set realistic expectations. (1D)
2. We suggest that during the first 6 hrs of resuscitation of
severe sepsis or septic shock, if SCV O2 or SvO2 of 70%
or 65% respectively is not achieved with fluid resuscitation to the CVP target, then transfusion of packed red
blood cells to achieve a hematocrit of ≥ 30% and/or
administration of a dobutamine infusion (up to a maximum of 20 µg.kg–1 .min–1 ) be utilized to achieve this
goal (Grade 2C).
Rationale. The protocol used in the study cited previously
targeted an increase in SCV O2 to ≥ 70% [16]. This was
achieved by sequential institution of initial fluid resuscitation, then packed red blood cells, and then dobutamine.
This protocol was associated with an improvement
in survival. Based on bedside clinical assessment and
personal preference, a clinician may deem either blood
transfusion (if Hct is less than 30%) or dobutamine the
best initial choice to increase oxygen delivery and thereby
elevate SCV O2 . When fluid resuscitation is believed to
be already adequate. The design of the afore mentioned
trial did not allow assessment of the relative contribution
of these two components (i. e. increasing O2 content or
increasing cardiac output) of the protocol on achievement
of improved outcome.
B. Diagnosis
to be identified. Two or more blood cultures are recommended [36]. In patients with indwelling catheters (for
> 48 h) at least one blood culture should be drawn through
each lumen of each vascular access device. Obtaining
blood cultures peripherally and through a vascular access
device is an important strategy. If the same organism
is recovered from both cultures, the likelihood that the
organism is causing the severe sepsis is enhanced. In
addition, if the culture drawn through the vascular access device is positive much earlier than the peripheral
blood culture (i. e., > 2 hrs earlier), the data support the
concept that the vascular access device is the source of
the infection [37]. Quantitative cultures of catheter and
peripheral blood are also useful for determining whether
the catheter is the source of infection. Volume of blood
drawn with the culture tube should be at least 10 mL [38].
Quantitative (or semi-quantitative) cultures of respiratory
tract secretions are recommended for the diagnosis of
ventilator-associated pneumonia [39]. Gram stain can
be useful, in particular for respiratory tract specimens,
to help decide the micro-organisms to be targeted. The
potential role of biomarkers for diagnosis of infection in
patients presenting with severe sepsis remains at present
undefined. The procalcitonin level, although often useful,
is problematic in patients with an acute inflammatory
pattern from other causes (e. g. post-operative, shock) [40]
In the near future, rapid diagnostic methods (polymerase
chain reaction, micro-arrays) might prove extremely
helpful for a quicker identification of pathogens and major
antimicrobial resistance determinants [41].
1. We recommend obtaining appropriate cultures before
antimicrobial therapy is initiated if such cultures do not
cause significant delay in antibiotic administration. To
optimize identification of causative organisms, we rec- 2. We recommend that imaging studies be performed
ommend at least two blood cultures be obtained prior to
promptly in attempts to confirm a potential source of
antibiotics with at least one drawn percutaneously and
infection. Sampling of potential sources of infection
one drawn through each vascular access device, unless
should occur as they are identified; however, some
the device was recently (< 48 h) inserted. Cultures of
patients may be too unstable to warrant certain inother sites (preferably quantitative where appropriate)
vasive procedures or transport outside of the ICU.
such as urine, cerebrospinal fluid, wounds, respiratory
Bedside studies, such as ultrasound, are useful in these
secretions, or other body fluids that may be the source
circumstances (Grade 1C).
of infection should also be obtained before antibiotic
therapy if not associated with significant delay in anti- Rationale. Diagnostic studies may identify a source of
biotic administration (Grade 1C).
infection that requires removal of a foreign body or drainage to maximize the likelihood of a satisfactory response
Rationale. Although sampling should not delay timely to therapy. However, even in the most organized and
administration of antibiotics in patients with severe sepsis well-staffed healthcare facilities, transport of patients
(example: lumbar puncture in suspected meningitis), can be dangerous, as can placing patients in outside-unit
obtaining appropriate cultures prior to their administration imaging devices that are difficult to access and monitor.
is essential to confirm infection and the responsible Balancing risk and benefit is therefore mandatory in those
pathogen(s), and to allow de-escalation of antibiotic settings.
therapy after receipt of the susceptibility profile. Samples
can be kept in the refrigerator or frozen if processing C. Antibiotic Therapy
cannot be performed immediately. Immediate transport to
a microbiological lab is necessary. Because rapid steriliza- 1. We recommend that intravenous antibiotic therapy
tion of blood cultures can occur within a few hours after
be started as early as possible and within the first
the first antibiotic dose, obtaining those cultures before
hour of recognition of septic shock (1B) and severe
starting therapy is essential if the causative organism is
sepsis without septic shock (1D). Appropriate cultures
should be obtained before initiating antibiotic therapy, the initial selection of antimicrobial therapy should be
but should not prevent prompt administration of broad enough to cover all likely pathogens. There is
antimicrobial therapy (Grade 1D).
ample evidence that failure to initiate appropriate therapy
(i. e. therapy with activity against the pathogen that is
Rationale. Establishing vascular access and initiating subsequently identified as the causative agent) correlates
aggressive fluid resuscitation is the first priority when with increased morbidity and mortality [45–48].
managing patients with severe sepsis or septic shock.
Patients with severe sepsis or septic shock warrant
However, prompt infusion of antimicrobial agents should broad-spectrum therapy until the causative organism
also be a priority and may require additional vascular and its antibiotic susceptibilities are defined. Restriction
access ports [42, 43]. In the presence of septic shock of antibiotics as a strategy to reduce the development
each hour delay in achieving administration of effective of antimicrobial resistance or to reduce cost is not an
antibiotics is associated with a measurable increase in appropriate initial strategy in this patient population.
mortality [42]. If antimicrobial agents cannot be mixed
All patients should receive a full loading dose of each
and delivered promptly from the pharmacy, establishing antimicrobial. However, patients with sepsis or septic
a supply of premixed antibiotics for such urgent situations shock often have abnormal renal or hepatic function
is an appropriate strategy for ensuring prompt adminis- and may have abnormal volumes of distribution due to
tration. In choosing the antimicrobial regimen, clinicians aggressive fluid resuscitation. Drug serum concentration
should be aware that some antimicrobial agents have the monitoring can be useful in an ICU setting for those drugs
advantage of bolus administration, while others require that can be measured promptly. An experienced physician
a lengthy infusion. Thus, if vascular access is limited and or clinical pharmacist should be consulted to ensure that
many different agents must be infused, bolus drugs may serum concentrations are attained that maximize efficacy
offer an advantage.
and minimize toxicity [49–52].
2a. We recommend that initial empirical anti-infective 2b. We recommend that the antimicrobial regimen be retherapy include one or more drugs that have activity
assessed daily to optimize activity, to prevent the deagainst all likely pathogens (bacterial and/or fungal)
velopment of resistance, to reduce toxicity, and to reand that penetrate in adequate concentrations into the
duce costs (Grade 1C).
presumed source of sepsis (Grade 1B).
Rationale. Although restriction of antibiotics as a strategy
Rationale. The choice of empirical antibiotics depends to reduce the development of antimicrobial resistance
on complex issues related to the patient’s history includ- or to reduce cost is not an appropriate initial strategy
ing drug intolerances, underlying disease, the clinical in this patient population, once the causative pathogen
syndrome, and susceptibility patterns of pathogens in has been identified, it may become apparent that none
the community, in the hospital, and that previously have of the empiric drugs offers optimal therapy; i. e., there
been documented to colonize or infect the patient. There may be another drug proven to produce superior clinis an especially wide range of potential pathogens for ical outcome which should therefore replace empiric
agents.
neutropenic patients.
Narrowing the spectrum of antibiotic coverage and reRecently used antibiotics should generally be avoided.
Clinicians should be cognizant of the virulence and ducing the duration of antibiotic therapy will reduce the
growing prevalence of oxacillin (methicillin) resistant likelihood that the patient will develop superinfection with
Staphylococcus aureus (ORSA or MRSA) in some com- pathogenic or resistant organisms such as Candida species,
munities and healthcare associated settings (especially in Clostridium difficile, or vancomycin-resistant Enterococthe United States) when they choose empiric therapy. If cus faecium. However, the desire to minimize superinfecthe prevalence is significant, and in consideration of the tions and other complications should not take precedence
virulence of this organism, empiric therapy adequate for over the need to give the patient an adequate course of therthis pathogen would be warranted. Clinicians should also apy to cure the infection that caused the severe sepsis or
consider whether Candidemia is a likely pathogen when septic shock.
choosing initial therapy. When deemed warranted, the
selection of empiric antifungal therapy (e. g., fluconazole, 2c. We suggest combination therapy for patients with
known or suspected Pseudomonas infections as
amphotericin B, or echinocandin) will be tailored to the
a cause of severe sepsis (Grade 2D).
local pattern of the most prevalent Candida species, and
any prior administration of azoles drugs [44]. Risk factors 2d. We suggest combination empiric therapy for neutropenic patients with severe sepsis (Grade 2D).
for candidemia should also be considered when choosing
2e. When used empirically in patients with severe sepsis,
initial therapy.
we suggest that combination therapy should not be adBecause patients with severe sepsis or septic shock
ministered for more than 3 to 5 days. De-escalation
have little margin for error in the choice of therapy,
to the most appropriate single therapy should be performed as soon as the susceptibility profile is known.
(Grade 2D).
Rationale. Although no study or meta-analysis has convincingly demonstrated that combination therapy produces
a superior clinical outcome for individual pathogens in
a particular patient group, combination therapies do
produce in vitro synergy against pathogens in some
models (although such synergy is difficult to define and
predict). In some clinical scenarios, such as the two above,
combination therapies are biologically plausible and are
likely clinically useful even if evidence has not demonstrated improved clinical outcome [53–56]. Combination
therapy for suspected known Pseudomonas pending
sensitivities increases the likelihood that at least one drug
is effective against that strain and positively affects outcome [57].
3. We recommend that the duration of therapy typically
be 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable
foci of infection, or who have immunologic deficiencies including neutropenia (Grade 1D).
4. If the presenting clinical syndrome is determined to be
due to a noninfectious cause, we recommend antimicrobial therapy be stopped promptly to minimize the
likelihood that the patient will become infected with
an antibiotic resistant pathogen or will develop a drug
related adverse effect (Grade 1D).
Rationale. Clinicians should be cognizant that blood cultures will be negative in more than 50% of cases of severe sepsis or septic shock, yet many of these cases are
very likely caused by bacteria or fungi. Thus, the decisions
to continue, narrow, or stop antimicrobial therapy must be
made on the basis of clinician judgment and clinical information.
D. Source Control
1a. We recommend that a specific anatomic diagnosis
of infection requiring consideration for emergent
source control- for example necrotizing fasciitis,
diffuse peritonitis, cholangitis, intestinal infarction
– be sought and diagnosed or excluded as rapidly
as possible (Grade 1C) and within the first 6 hours
following presentation (Grade 1D).
1b. We further recommend that all patients presenting
with severe sepsis be evaluated for the presence
of a focus of infection amenable to source control
measures, specifically the drainage of an abscess
or local focus of infection, the debridement of infected necrotic tissue, the removal of a potentially
infected device, or the definitive control of a source
of ongoing microbial contamination (Grade 1C) (see
Appendix A for examples of potential sites needing
source control).
2. We suggest that when infected peripancreatic necrosis
is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and non-viable tissues has occurred
(Grade 2B).
3. We recommend that when source control is required,
the effective intervention associated with the least
physiologic insult be employed e. g., percutaneous
rather than surgical drainage of an abscess (Grade
1D).
4. We recommend that when intravascular access
devices are a possible source of severe sepsis or septic
shock, they be promptly removed after establishing
other vascular access (Grade 1C).
Rationale. The principles of source control in the management of sepsis include a rapid diagnosis of the
specific site of infection, and identification of a focus of
infection amenable to source control measures (specifically the drainage of an abscess, the debridement of
infected necrotic tissue, the removal of a potentially
infected device, and the definitive control of a source
of ongoing microbial contamination) [58]. Foci of infection readily amenable to source control measures
include an intra-abdominal abscess or gastrointestinal
perforation, cholangitis or pyelonephritis, intestinal ischemia or necrotizing soft tissue infection, and other
deep space infection such as an empyema or septic
arthritis. Such infectious foci should be controlled as
soon as possible following successful initial resuscitation [59], accomplishing the source control objective
with the least physiologic upset possible (e. g., percutaneous rather than surgical drainage of an abscess [60],
endoscopic rather than surgical drainage of biliary
tree), and removing intravascular access devices that
are potentially the source of severe sepsis or septic
shock promptly after establishing other vascular access [61, 62]. A randomized, controlled trial comparing
early vs. delayed surgical intervention for peripancreatic necrosis showed better outcomes with a delayed
approach [63]. However, areas of uncertainty, such as
definitive documentation of infection and appropriate
length of delay exist. The selection of optimal source
control methods must weigh benefits and risks of the
specific intervention as well as risks of transfer [64].
Source control interventions may cause further complications such as bleeding, fistulas, or inadvertent organ
injury. Surgical intervention should be considered when
lesser interventional approaches are inadequate, or when
diagnostic uncertainty persists despite radiological evaluation. Specific clinical situations require consideration
of available choices, patient’s preferences, and clinician’s
expertise.
E. Fluid Therapy
F. Vasopressors
1. We recommend fluid resuscitation with either nat- 1. We recommend mean arterial pressure (MAP) be
ural/artificial colloids or crystalloids. There is no
maintained ≥ 65 mm Hg (Grade 1C).
evidence-based support for one type of fluid over
another (Grade 1B).
Rationale. Vasopressor therapy is required to sustain life
and maintain perfusion in the face of life-threatening
Rationale. The SAFE study indicated albumin adminis- hypotension, even when hypovolemia has not yet been
tration was safe and equally effective as crystalloid [65]. resolved. Below a certain mean arterial pressure, autoregThere was an insignificant decrease in mortality rates with ulation in various vascular beds can be lost, and perfusion
the use of colloid in a subset analysis of septic patients can become linearly dependent on pressure. Thus, some
(p = 0.09). Previous meta-analyses of small studies of ICU patients may require vasopressor therapy to achieve
patients had demonstrated no difference between crystal- a minimal perfusion pressure and maintain adequate
loid and colloid fluid resuscitation [66–68]. Although ad- flow [71, 72]. The titration of norepinephrine to as low
ministration of hydroxyethyl starch may increase the risk as MAP 65 mm Hg has been shown to preserve tissue
of acute renal failure in patients with sepsis variable find- perfusion [72]. In addition, pre-existing comorbidities
ings preclude definitive recommendations [69, 70]. As the should be considered as to most appropriate MAP target.
volume of distribution is much larger for crystalloids than For example, a MAP of 65 mm Hg might be too low in
for colloids, resuscitation with crystalloids requires more a patient with severe uncontrolled hypertension, and in
fluid to achieve the same end points and results in more a young previously normotensive, a lower MAP might
edema. Crystalloids are less expensive.
be adequate. Supplementing end points such as blood
pressure with assessment of regional and global perfusion,
2. We recommend fluid resuscitation initially target such as blood lactate concentrations and urine output, is
a CVP of at least 8 mm Hg (12 mm Hg in mechani- important. Adequate fluid resuscitation is a fundamental
cally ventilated patients). Further fluid therapy is often aspect of the hemodynamic management of patients with
required (Grade 1C).
septic shock, and should ideally be achieved before vaso3a. We recommend that a fluid challenge technique be pressors and inotropes are used, but using vasopressors
applied, wherein fluid administration is continued early as an emergency measure in patients with severe
as long as the hemodynamic improvement (e. g., shock is frequently necessary. When that occurs great
arterial pressure, heart rate, urine output) continues effort should be directed to weaning vasopressors with
(Grade 1D).
continuing fluid resuscitation.
3b. We recommend fluid challenge in patients with
suspected hypovolemia be started with at least 2. We recommend either norepinephrine or dopamine as
the first choice vasopressor agent to correct hypoten1000 mL of crystalloids or 300–500 mL of colloids
sion in septic shock (administered through a central
over 30 min. More rapid administration and greater
catheter as soon as one is available) (Grade 1C).
amounts of fluid may be needed in patients with sepsis
induced tissue hypoperfusion (see initial resuscitation 3a. We suggest that epinephrine, phenylephrine, or
vasopressin should not be administered as the initial
recommendations) (Grade 1D).
vasopressor in septic shock (Grade 2C). Vasopressin
3c. We recommend the rate of fluid administration be
.03 units/min may be subsequently added to norereduced substantially when cardiac filling pressures
pinephrine with anticipation of an effect equivalent to
(CVP or pulmonary artery balloon-occluded presnorepinephrine alone.
sure) increase without concurrent hemodynamic
3b. We suggest that epinephrine be the first chosen alterimprovement (Grade 1D).
native agent in septic shock that is poorly responsive
to norepinephrine or dopamine (Grade 2B).
Rationale. Fluid challenge must be clearly separated from
simple fluid administration; it is a technique in which large
amounts of fluids are administered over a limited period Rationale. There is no high-quality primary evidence to
of time under close monitoring to evaluate the patient’s re- recommend one catecholamine over another. Much literasponse and avoid the development of pulmonary edema. ture exists that contrasts the physiologic effects of choice
The degree of intravascular volume deficit in patients with of vasopressor and combined inotrope/vasopressors in
severe sepsis varies. With venodilation and ongoing capil- septic shock [73–85]. Human and animal studies suggest
lary leak, most patients require continuing aggressive fluid some advantages of norepinephrine and dopamine over
resuscitation during the first 24 hours of management. In- epinephrine (the latter with the potential for tachycardia as
put is typically much greater than output, and input/output well as disadvantageous effects on splanchnic circulation
ratio is of no utility to judge fluid resuscitation needs dur- and hyperlactemia) and phenylephrine (decrease in stroke
volume). There is, however, no clinical evidence that
ing this time period.
epinephrine results in worse outcomes, and it should be
the first chosen alternative to dopamine or norepinephrine.
Phenylephrine is the adrenergic agent least likely to
produce tachycardia, but as a pure vasopressor would be
expected to decrease stroke volume. Dopamine increases
mean arterial pressure and cardiac output, primarily
due to an increase in stroke volume and heart rate.
Norepinephrine increases mean arterial pressure due to
its vasoconstrictive effects, with little change in heart
rate and less increase in stroke volume compared with
dopamine. Either may be used as a first-line agent to correct hypotension in sepsis. Norepinephrine is more potent
than dopamine and may be more effective at reversing
hypotension in patients with septic shock. Dopamine
may be particularly useful in patients with compromised
systolic function but causes more tachycardia and may
be more arrhythmogenic [86]. It may also influence the
endocrine response via the hypothalamic-pituitary axis
and have immunosuppressive effects.
Vasopressin levels in septic shock have been reported
to be lower than anticipated for a shock state [87]. Low
doses of vasopressin may be effective in raising blood
pressure in patients refractory to other vasopressors, and
may have other potential physiologic benefits [88–93].
Terlipressin has similar effects but is long lasting [94].
Studies show that vasopressin concentrations are elevated
in early septic shock, but with continued shock, concentration decreases to normal range in the majority of
patients between 24 and 48 hrs [95]. This has been called
“relative vasopressin deficiency” because in the presence
of hypotension, vasopressin would be expected to be
elevated. The significance of this finding is unknown.
The recent VASST trial, a randomized, controlled trial
comparing norepinephrine alone to norepinephrine plus
vasopressin at .03 units per minute showed no difference
in outcome in the intent to treat population. An a priori
defined subgroup analysis showed that the survival of
patients receiving less than 15 µg/min norepinephrine at
the time of randomization was better with vasopressin. It
should be noted however that the pre-trial rationale for
this stratification was based on exploring potential benefit
in the 15 µg or greater norepinephrine requirement population. Higher doses of vasopressin have been associated
with cardiac, digital, and splanchnic ischemia and should
be reserved for situations where alternative vasopressors
have failed [96]. Cardiac output measurement to allow
maintenance of a normal or elevated flow is desirable
when these pure vasopressors are instituted.
of normal renal function), or secondary outcomes (survival
to either ICU or hospital discharge, ICU stay, hospital
stay, arrhythmias) [97, 98]. Thus the available data do not
support administration of low doses of dopamine solely to
maintain renal function.
6. We recommend that all patients requiring vasopressors
have an arterial line placed as soon as practical if resources are available (Grade 1D).
Rationale. In shock states, estimation of blood pressure
using a cuff is commonly inaccurate; use of an arterial cannula provides a more appropriate and reproducible measurement of arterial pressure. These catheters also allow
continuous analysis so that decisions regarding therapy can
be based on immediate and reproducible blood pressure information.
G. Inotropic Therapy
1. We recommend a dobutamine infusion be administered in the presence of myocardial dysfunction as
suggested by elevated cardiac filling pressures and low
cardiac output (Grade 1C).
2. We recommend against the use of a strategy to
increase cardiac index to predetermined supranormal
levels (Grade 1B).
Rationale. Dobutamine is the first-choice inotrope for
patients with measured or suspected low cardiac output in
the presence of adequate left ventricular filling pressure (or
clinical assessment of adequate fluid resuscitation) and adequate mean arterial pressure. Septic patients who remain
hypotensive after fluid resuscitation may have low, normal,
or increased cardiac outputs. Therefore, treatment with
a combined inotrope/vasopressor such as norepinephrine
or dopamine is recommended if cardiac output is not measured. When the capability exists for monitoring cardiac
output in addition to blood pressure, a vasopressor such as
norepinephrine may be used separately to target specific
levels of mean arterial pressure and cardiac output. Two
large prospective clinical trials that included critically ill
ICU patients who had severe sepsis failed to demonstrate
benefit from increasing oxygen delivery to supranormal
targets by use of dobutamine [99, 100]. These studies
did not target specifically patients with severe sepsis and
did not target the first 6 hours of resuscitation. The first
6 hours of resuscitation of sepsis induced hypoperfusion
need to be treated separately from the later stages of severe
5. We recommend that low dose dopamine not be used
sepsis (see initial resuscitation recommendations).
for renal protection (Grade 1A).
Rationale. A large randomized trial and meta-analysis H. Corticosteroids
comparing low-dose dopamine to placebo found no difference in either primary outcomes (peak serum creatinine, 1. We suggest intravenous hydrocortisone be given only
to adult septic shock patients after blood pressure is
need for renal replacement, urine output, time to recovery
identified to be poorly responsive to fluid resuscitation The relationship between free and total cortisol varies
and vasopressor therapy (Grade 2C).
with serum protein concentration. When compared to
a reference method (mass spectrometry), cortisol imRationale. One french multi-center, randomized, con- munoassays may over- or underestimate the actual cortisol
trolled trial (RCT) of patients in vasopressor-unresponsive level, affecting the assignment of patients to responders
septic shock (hypotension despite fluid resuscitation or nonresponders [105]. Although the clinical significance
and vasopressors) showed a significant shock reversal is not clear, it is now recognized that etomidate, when
and reduction of mortality rate in patients with relative used for induction for intubation, will suppress the HPA
adrenal insufficiency (defined as post-adrenocorticotropic axis [106].
hormone (ACTH) cortisol increase 9 µg/dL or less) [101].
Two additional smaller RCTs also showed significant 3. We suggest that patients with septic shock should not
effects on shock reversal with steroid therapy [102, 103].
receive dexamethasone if hydrocortisone is available
However, a recent large, European multicenter trial (COR(Grade 2B).
TICUS), which has been presented in abstract form but
not yet published, failed to show a mortality benefit with Rationale. Although often proposed for use until an ACTH
steroid therapy of septic shock [104]. CORTICUS did stimulation test can be administered, we no longer sugshow a faster resolution of septic shock in patients who gest an ACTH test in this clinical situation (see #3 above).
received steroids. The use of the ACTH test (responders Furthermore, dexamethasone can lead to immediate and
and nonresponders) did not predict the faster resolution prolonged suppression of the HPA axis after administraof shock. Importantly, unlike the French trial, which tion [107].
only enrolled shock patients with blood pressure unresponsive to vasopressor therapy, the CORTICUS study 4. We suggest the daily addition of oral fludrocortisone
included patients with septic shock, regardless of how
(50 µg) if hydrocortisone is not available and the
the blood pressure responded to vasopressors. Although
steroid that is substituted has no significant mineracorticosteroids do appear to promote shock reversal, the
locorticoid activity. Fludrocortisone is considered
lack of a clear improvement in mortality-coupled with
optional if hydrocortisone is used (Grade 2C).
known side effects of steroids such as increased risk of
infection and myopathy-generally tempered enthusiasm Rationale. One study added 50 µg of fludrocortisone
for their broad use. Thus, there was broad agreement orally [101]. Since hydrocortisone has intrinsic minerthat the recommendation should be downgraded from the alcorticoid activity, there is controversy as to whether
previous guidelines (Appendix B). There was considerable fludrocortisone should be added.
discussion and consideration by the committee on the
option of encouraging use in those patients whose blood 5. We suggest clinicians wean the patient from steroid
therapy when vasopressors are no longer required
pressure was unresponsive to fluids and vasopressors,
(Grade 2D).
while strongly discouraging use in subjects whose shock
responded well to fluids and pressors. However, this more
complex set of recommendations was rejected in favor of Rationale. There has been no comparative study between
a fixed duration and clinically guided regimen, or between
the above single recommendation (see Appendix B).
tapering and abrupt cessation of steroids. Three RCTs used
2. We suggest the ACTH stimulation test not be used a fixed duration protocol for treatment [101, 103, 104],
to identify the subset of adults with septic shock who and in two RCTs, therapy was decreased after shock resolution [102, 108]. In four RCTs steroids were tapered over
should receive hydrocortisone (Grade 2B).
several days [102–104, 108], and in two RCTs [101, 109]
Rationale. Although one study suggested those who did steroids were withdrawn abruptly. One cross-over study
not respond to ACTH with a brisk surge in cortisol (failure showed hemodynamic and immunologic rebound effects
to achieve or > 9 µg/dL increase in cortisol 30–60 mins after abrupt cessation of corticosteroids [110]. It remains
post-ACTH administration) were more likely to benefit uncertain whether outcome is affected by tapering of
from steroids than those who did respond, the overall steroids or not.
trial population appeared to benefit regardless of ACTH
result, and the observation of a potential interaction 6. We recommend doses of corticosteroids comparable
to > 300 mg hydrocortisone daily not be used in severe
between steroid use and ACTH test was not statistically
sepsis or septic shock for the purpose of treating septic
significant [101]. Furthermore, there was no evidence of
shock (Grade 1A).
this distinction between responders and nonresponders in
a recent multicenter trial [104]. Commonly used cortisol
immunoassays measure total cortisol (protein-bound and Rationale. Two randomized prospective clinical trials and
free) while free cortisol is the pertinent measurement. a meta-analyses concluded that for therapy of severe sepsis
or septic shock, high-dose corticosteroid therapy is inef- APACHE II ≥ 25) and more than one organ failure in
fective or harmful [111–113]. Reasons to maintain higher Europe.
doses of corticosteroid for medical conditions other than
The ADDRESS trial involved 2,613 patients judged to
septic shock may exist.
have a low risk of death at the time of enrollment. 28 day
mortality from all causes was 17% on placebo vs. 18.5%
7. We recommend corticosteroids not be administered on APC, relative risk (RR) 1.08, 95% CI 0.92–1.28 [116].
for the treatment of sepsis in the absence of shock. Again, debate focused on subgroup analyses; analyses reThere is, however, no contraindication to continuing stricted to small subgroups of patients with APACHE II
maintenance steroid therapy or to using stress does score over 25, or more than one organ failures which failed
steroids if the patient’s endocrine or corticosteroid to show benefit; however these patient groups also had
administration history warrants (Grade 1D).
a lower mortality than in PROWESS.
Relative risk reduction of death was numerically lower
Rationale. No studies exist that specifically target severe in the subgroup of patients with recent surgery (n = 502) in
sepsis in the absence of shock that offer support for use the PROWESS trial (30.7% placebo vs. 27.8% APC) [119]
of stress doses of steroids in this patient population. when compared to the overall study population (30.8%
Steroids may be indicated in the presence of a prior placebo vs. 24.7% APC) [115]. In the ADDRESS trial,
history of steroid therapy or adrenal dysfunction. A re- patients with recent surgery and single organ dysfunccent preliminary study of stress dose level steroids in tion who received APC had significantly higher 28 day
community- acquired pneumonia is encouraging but needs mortality rates (20.7% vs. 14.1%, p = 0.03, n = 635) [116].
confirmation [114].
Serious adverse events did not differ in the
studies [115–117] with the exception of serious bleeding,
which occurred more often in the patients treated with
I. Recombinant Human Activated Protein C (rhAPC)
APC: 2% vs. 3.5% (PROWESS; p = 0.06) [115]; 2.2% vs.
1. We suggest that adult patients with sepsis induced 3.9% (ADDRESS; p < 0.01) [116]; 6.5% (ENHANCE,
organ dysfunction associated with a clinical assess- open label) [117]. The pediatric trial and implications are
ment of high risk of death, most of whom will have discussed in the pediatric consideration section of this
APACHE II ≥ 25 or multiple organ failure, receive manuscript (see Appendix C for absolute contraindications
rhAPC if there are no contraindications (Grade 2B to use of rhAPC and prescribing information for relative
except for patients within 30 days of surgery where it contraindications).
Intracranial hemorrhage (ICH) occurred in the
is Grade 2C). Relative contraindications should also
PROWESS trial in 0.1% (placebo) and 0.2% (APC)
be considered in decision making.
2. We recommend that adult patients with severe sep- (n. s.) [106], in the ADDRESS trial 0.4% (placebo) vs.
sis and low risk of death, most of whom will have 0.5% (APC) (n. s.) [116]; in ENHANCE 1.5% [108].
APACHE II < 20 or one organ failure, do not receive Registry studies of rhAPC report higher bleeding rates
than randomized controlled trials, suggesting that the risk
rhAPC (Grade 1A).
of bleeding in actual practice may be greater than reported
Rationale. The evidence concerning use of rhAPC in in PROWESS and ADDRESS [120, 121].
The two RCTs in adult patients were methodologically
adults is primarily based on two randomized controlled
trials (RCTs): PROWESS (1,690 adult patients, stopped strong, precise, and provide direct evidence regarding
early for efficacy) [115] and ADDRESS (stopped early for death rates. The conclusions are limited, however, by
futility) [116]. Additional safety information comes from inconsistency that is not adequately resolved by subgroup
an open-label observational study ENHANCE [117]. The analyses (thus the designation of moderate quality eviENHANCE trial also suggested early administration of dence). Results, however, consistently fail to show benefit
for the subgroup of patients at lower risk of death, and
rhAPC was associated with better outcomes.
PROWESS involved 1,690 patients and documented consistently show increases in serious bleeding. The RCT
6.1% in absolute total mortality reduction with a relative in pediatric severe sepsis failed to show benefit and has
risk reduction (RRR) of 19.4%, 95% CI 6.6–30.5%, no important limitations. Thus, for low risk and pediatric
number needed to treat (NNT):16 [115]. Controversy patients, we rate the evidence as high quality.
For adult use there is probable mortality reduction in
associated with the results focused on a number of subgroup analyses. Subgroup analyses have the potential to patients with clinical assessment of high risk of death, most
mislead due to the absence of an intent to treat, sampling of whom will have APACHE II ≥ 25 or multiple organ failbias, and selection error [118]. The analyses suggested ure. There is likely no benefit in patients with low risk of
increasing absolute and relative risk reduction with greater death, most of whom will have APACHE II < 20 or single
risk of death using both higher APACHE II scores and organ dysfunction. The effects in patients with more than
greater number of organ failures [119]. This led to drug one organ failure but APACHE II < 25 are unclear and in
approval for patients with high risk of death (such as that circumstance one may use clinical assessment of the
Rationale. Although clinical studies have not assessed the
impact of transfusion of fresh frozen plasma on outcomes
in critically ill patients, professional organizations have
recommended fresh frozen plasma for coagulopathy when
there is a documented deficiency of coagulation factors
(increased prothrombin time, international normalized
ratio, or partial thromboplastin time) and the presence
of active bleeding or before surgical or invasive procedures [129–131]. In addition, transfusion of fresh frozen
plasma in nonbleeding patients with mild abnormalities of
prothrombin time usually fails to correct the prothrombin
time [132]. There are no studies to suggest that correction
J. Blood Product Administration
of more severe coagulation abnormalities benefits patients
1. Once tissue hypoperfusion has resolved and in who are not bleeding.
the absence of extenuating circumstances, such as
myocardial ischemia, severe hypoxemia, acute hem- 4. We recommend against antithrombin administration
orrhage, cyanotic heart disease, or lactic acidosis
for the treatment of severe sepsis and septic shock
(see recommendations for initial resuscitation), we
(Grade 1B).
recommend that red blood cell transfusion occur
when hemoglobin decreases to < 7.0 g/dL (< 70 g/L) Rationale. A phase III clinical trial of high-dose anto target a hemoglobin of 7.0–9.0 g/dL (70–90 g/L) in tithrombin did not demonstrate any beneficial effect on
adults (Grade 1B).
28-day all-cause mortality in adults with severe sepsis
and septic shock. High-dose antithrombin was associated
Rationale. Although the optimum hemoglobin for patients with an increased risk of bleeding when administered with
with severe sepsis has not been specifically investigated, heparin [133]. Although a post hoc subgroup analysis of
the Transfusion Requirements in Critical Care trial patients with severe sepsis and high risk of death showed
suggested that a hemoglobin of 7–9 g/dL (70–90 g/L) better survival in patients receiving antithrombin, anwhen compared to 10–12 g/dL (100–200 g/L) was not tithrombin cannot be recommended at this time until
associated with increased mortality rate in adults [123]. further clinical trials are performed [134].
Red blood cell transfusion in septic patients increases
oxygen delivery but does not usually increase oxygen 5. In patients with severe sepsis, we suggest that platelets
consumption [124–126]. This transfusion threshold of
should be administered when counts are < 5000/mm3
7 g/dL (70 g/L) contrasts with the early goal-directed
(5 × 109 /L) regardless of apparent bleeding. Platelet
resuscitation protocol that uses a target hematocrit of 30%
transfusion may be considered when counts are
in patients with low SCV O2 (measured in superior vena
5,000–30,000/mm3 (5–30 × 109 /L) and there is
cava) during the first 6 hrs of resuscitation of septic shock.
a significant risk of bleeding. Higher platelet counts
(≥ 50,000/mm3 (50 × 109 /L)) are typically required
2. We recommend that erythropoietin not be used as
for
surgery or invasive procedures (Grade 2D).
a specific treatment of anemia associated with severe
sepsis, but may be used when septic patients have other
accepted reasons for administration of erythropoietin Rationale. Guidelines for transfusion of platelets are desuch as renal failure-induced compromise of red blood rived from consensus opinion and experience in patients
undergoing chemotherapy. Recommendations take into accell production (Grade 1B).
count the etiology of thrombocytopenia, platelet dysfuncRationale. No specific information regarding erythro- tion, risk of bleeding, and presence of concomitant disorpoietin use in septic patients is available, but clinical ders [129, 131].
trials in critically ill patients show some decrease in red
cell transfusion requirement with no effect on clinical II. Supportive Therapy of Severe Sepsis
outcome [127, 128]. The effect of erythropoietin in severe
sepsis and septic shock would not be expected to be A. Mechanical Ventilation of Sepsis-Induced Acute Lung
more beneficial than in other critical conditions. Patients Injury (ALI)/Acute Respiratory Distress Syndrome
with severe sepsis and septic shock may have coexisting (ARDS).
conditions that do warrant use of erythropoietin.
risk of death and number of organ failures to support decision. There is a certain increased risk of bleeding with
administration of rhAPC which may be higher in surgical
patients and in the context of invasive procedures. Decision on utilization depends upon assessing likelihood of
mortality reduction versus increases in bleeding and cost
(see appendix D for nominal committee vote on recommendation for rhAPC). A European Regulatory mandated
randomized controlled trial of rhAPC vs. placebo in patients with septic shock is now ongoing [122].
3. We suggest that fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of
bleeding or planned invasive procedures (Grade 2D).
1. We recommend that clinicians target a tidal volume
of 6 ml/kg (predicted) body weight in patients with
ALI/ARDS (Grade 1B).
2. We recommend that plateau pressures be measured
in patients with ALI/ARDS and that the initial upper
limit goal for plateau pressures in a passively inflated
patient be ≤ 30 cm H2 O. Chest wall compliance should
be considered in the assessment of plateau pressure
(Grade 1C).
Rationale. Over the past 10 yrs, several multi-center
randomized trials have been performed to evaluate the
effects of limiting inspiratory pressure through moderation of tidal volume [135–139]. These studies showed
differing results that may have been caused by differences between airway pressures in the treatment and
control groups [135, 140]. The largest trial of a volumeand pressure-limited strategy showed a 9% decrease
of all-cause mortality in patients with ALI or ARDS
ventilated with tidal volumes of 6 mL/kg of predicted
body weight (PBW), as opposed to 12 mL/kg, and aiming
for a plateau pressure ≤ 30 cm H2 O [135]. The use of lung
protective strategies for patients with ALI is supported
by clinical trials and has been widely accepted, but the
precise choice of tidal volume for an individual patient
with ALI may require adjustment for such factors as the
plateau pressure achieved, the level of PEEP chosen,
the compliance of the thoracoabdominal compartment
and the vigor of the patient’s breathing effort. Some
clinicians believe it may be safe to ventilate with tidal
volumes higher than 6 ml/kg PBW as long as the plateau
pressure can be maintained ≤ 30 cm H2 O [141, 142]. The
validity of this ceiling value will depend on breathing
effort, as those who are actively inspiring generate higher
trans-alveolar pressures for a given plateau pressure than
those who are passively inflated. Conversely, patients
with very stiff chest walls may require plateau pressures
higher than 30 cm H2 O to meet vital clinical objectives.
One retrospective study suggested that tidal volumes
should be lowered even with plateau pressures that are
≤ 30 cm H2 O [143]. An additional observational study
suggested that knowledge of the plateau pressures was
associated with lower plateau pressures; however in this
trial, plateau pressure was not independently associated
with mortality rates across a wide range of plateau
pressures that bracketed 30 cm H2 O [144]. The largest
clinical trial employing a lung protective strategy coupled
limited pressure with limited tidal volumes to demonstrate
a mortality benefit [135].
High tidal volumes that are coupled with high plateau
pressures should be avoided in ALI/ARDS. Clinicians
should use as a starting point the objective of reducing
tidal volumes over 1–2 hrs from its initial value toward
the goal of a “low” tidal volume (≈ 6 mL per kilogram of
predicted body weight) achieved in conjunction with an
end-inspiratory plateau pressure ≤ 30 cm H2 O. If plateau
pressure remains > 30 after reduction of tidal volume to
6 ml/kg/PBW, tidal volume should be reduced further to
as low as 4 ml/kg/PBW (see Appendix E for ARDSnet
ventilator management and formula to calculate predicted
body weight).
No single mode of ventilation (pressure control, volume control, airway pressure release ventilation, high frequency ventilation, etc.) has been consistently shown advantageous when compared with any other that respects
the same principles of lung protection.
3. We recommend that hypercapnia (allowing PaCO2
to increase above its pre-morbid baseline, so-called
permissive hypercapnia) be allowed in patients with
ALI/ARDS if needed to minimize plateau pressures
and tidal volumes (Grade 1C).
Rationale. An acutely elevated PaCO2 may have physiologic consequences that include vasodilation as well
as an increased heart rate, blood pressure, and cardiac
output. Allowing modest hypercapnia in conjunction
with limiting tidal volume and minute ventilation has
been demonstrated to be safe in small, nonrandomized
series [145, 146]. Patients treated in larger trials that have
the goal of limiting tidal volumes and airway pressures
have demonstrated improved outcomes, but permissive
hypercapnia was not a primary treatment goal in these
studies [135]. The use of hypercapnia is limited in patients
with preexisting metabolic acidosis and is contraindicated
in patients with increased intracranial pressure. Sodium
bicarbonate or tromethamine (THAM® ) infusion may
be considered in selected patients to facilitate use of
permissive hypercarbia [147, 148].
4. We recommend that positive end-expiratory pressure
(PEEP) be set so as to avoid extensive lung collapse at
end-expiration (Grade 1C).
Rationale. Raising PEEP in ALI/ARDS keeps lung
units open to participate in gas exchange. This will
increase PaO2 when PEEP is applied through either an
endotracheal tube or a face mask [149–151]. In animal experiments, avoidance of end-expiratory alveolar
collapse helps minimize ventilator induced lung injury
(VILI) when relatively high plateau pressures are in use.
One large multi-center trial of the protocol-driven use of
higher PEEP in conjunction with low tidal volumes did
not show benefit or harm when compared to lower PEEP
levels [152]. Neither the control nor experimental group
in that study, however, was clearly exposed to hazardous
plateau pressures. A recent multi-center Spanish trial compared a high PEEP, low-moderate tidal volume approach
to one that used conventional tidal volumes and the least
PEEP achieving adequate oxygenation. A marked survival
advantage favored the former approach in high acuity
patients with ARDS [153]. Two options are recommended
for PEEP titration. One option is to titrate PEEP (and tidal
volume) according to bedside measurements of thoracopulmonary compliance with the objective of obtaining
terally in the supine position developing VAP [162]. However, the bed position was only monitored once a day, and
patients who did not achieve the desired bed elevation were
not included in the analysis [162]. A recent study did not
show a difference in in incidence of VAP between patients
maintained in supine and semirecumbent positions [163].
In this study, patients in the semirecumbent position did
not consistently achieve the desired head of the bed elevation, and the head of bed elevation in the supine group approached that of the semirecumbent group by day 7 [163].
When necessary, patients may be laid flat for procedures,
hemodynamic measurements, and during episodes of hy5. We suggest prone positioning in ARDS patients requir- potension. Patients should not be fed enterally with the
ing potentially injurious levels of FI O2 or plateau pres- head of the bed at 0°.
sure who are not at high risk for adverse consequences
of positional changes in those facilities who have expe- 7. We suggest that noninvasive mask ventilation (NIV)
only be considered in that minority of ALI/ARDS parience with such practices (Grade 2C).
tients with mild-moderate hypoxemic respiratory failure (responsive to relatively low levels of pressure supRationale. Several smaller studies and one larger study
port and PEEP) with stable hemodynamics who can be
have shown that a majority of patients with ALI/ARDS
made comfortable and easily arousable, who are able
respond to the prone position with improved oxygenato protect the airway, spontaneously clear the airway of
tion [156–159]. One large multi-center trial of prone
secretions, and are anticipated to recover rapidly from
positioning for approximately 7 hrs/day did not show imthe precipitating insult. A low threshold for airway inprovement in mortality rates in patients with ALI/ARDS;
tubation should be maintained (Grade 2B).
however, a post hoc analysis suggested improvement
in those patients with the most severe hypoxemia by
PaO2 /FI O2 ratio, in those exposed to high tidal volumes, Rationale. Obviating the need for airway intubation conand those who improved CO2 exchange as a result of fers multiple advantages: better communication, lower inproning [159]. A second large trial of prone positioning, cidence of infection, reduced requirements for sedation.
conducted for an average of approximately 8 hours per Two RCTs demonstrate improved outcome with the use
day for 4 days in adults with hypoxemic respiratory of NIV when it can be employed successfully [164, 165].
failure of low-moderate acuity, confirmed improvement Unfortunately, only a small percentage of patients with life
in oxygenation but also failed to show a survival advan- threatening hypoxemia can be managed in this way.
tage [160]. However, a randomized study that extended the
length of time for proning each day to a mean of 17 hours 8. We recommend that a weaning protocol be in place,
for a mean of 10 days supported benefit of proning,
and mechanically ventilated patients with severe sepwith randomization to supine position an independent
sis undergo spontaneous breathing trials on a regular
risk factor for mortality by multivariate analysis [161].
basis to evaluate the ability to discontinue mechaniProne positioning may be associated with potentially
cal ventilation when they satisfy the following criteria:
life-threatening complications, including accidental disa) arousable; b) hemodynamically stable (without valodgment of the endotracheal tube and central venous
sopressor agents); c) no new potentially serious concatheters, but these complications can usually be avoided
ditions; d) low ventilatory and end-expiratory pressure
with proper precautions.
requirements; and e) FI O2 requirements that could be
safely delivered with a face mask or nasal cannula. If
the spontaneous breathing trial is successful, consider6. A) Unless contraindicated, we recommend mechaniation should be given for extubation (see Appendix E).
cally ventilated patients be maintained with the head
Spontaneous breathing trial options include a low level
of the bed elevated to limit aspiration risk and to preof pressure support, continuous positive airway presvent the development of ventilator-associated pneumosure (≈ 5 cm H2 O) or a T-piece (Grade 1A).
nia (Grade 1B).
B) We suggest that the head of bed is elevated approxRationale. Recent studies demonstrate that daily spontimately 30–45 degrees (Grade 2C).
aneous breathing trials in appropriately selected patients
Rationale. The semirecumbent position has been demon- reduce the duration of mechanical ventilation [166–169].
strated to decrease the incidence of ventilator-associated Successful completion of spontaneous breathing trials
pneumonia (VAP) [164]. Enteral feeding increased the risk leads to a high likelihood of successful discontinuation of
of developing VAP; 50% of the patients who were fed en- mechanical ventilation.
the best compliance, reflecting a favorable balance of lung
recruitment and overdistention [154]. The second option
is to titrate PEEP based on severity of oxygenation deficit
and guided by the FI O2 required to maintain adequate
oxygenation [135] (see Appendix D.). Whichever the
indicator-compliance or oxygenation-recruiting maneuvers are reasonable to employ in the process of PEEP
selection. Blood pressure and oxygenation should be
monitored and recruitment discontinued if deterioration
in these parameters is observed. A PEEP > 5 cm H2 O is
usually required to avoid lung collapse [155].
9. We recommend against the routine use of the pul- Rationale. A growing body of evidence indicates that the
monary artery catheter for patients with ALI/ARDS use of protocols for sedation of critically ill ventilated
(Grade 1A).
patients can reduce the duration of mechanical ventilation and ICU and hospital length of stay [186–188].
Rationale. While insertion of a pulmonary artery catheter A randomized, controlled clinical trial found that protocol
may provide useful information on a patient’s volume use resulted in reduced duration of mechanical ventilastatus and cardiac function, potential benefits of such infor- tion, reduced lengths of stay, and reduced tracheostomy
mation may be confounded by differences in interpretation rates [186].
of results [170–172], lack of correlation of pulmonary
A report describing the implementation of protocols,
artery occlusion pressures with clinical response [173], including sedation and analgesia, using a short-cycle
and absence of a proven strategy to use catheter results improvement methodology in the management of critito improve patient outcomes [174]. Two multi-center cally ill patients demonstrated a decrease in the cost per
randomized trials: one in patients with shock or acute patient day and a decrease of ICU length of stay [187].
lung injury [175], and one in patients with acute lung Furthermore, a prospective before-and-after study on
injury [176] failed to show benefit with the routine use the implementation of a sedation protocol demonstrated
of pulmonary artery catheters in patients with acute lung enhanced quality of sedation with reduced drug costs. Alinjury. In addition, other studies in different types of criti- though this protocol also may have contributed to a longer
cally ill patients have failed to show definitive benefit with duration of mechanical ventilation, ICU discharge was
routine use of the pulmonary artery catheter [177–179]. not delayed [188]. Despite the lack of evidence regarding
Well-selected patients remain appropriate candidates for the use of subjective methods of evaluation of sedation in
pulmonary artery catheter insertion when the answers to septic patients, the use of a sedation goal has been shown
important management decisions depend on information to decrease the duration of mechanical ventilation in critionly obtainable from direct measurements made within cally ill patients [186]. Several subjective sedation scales
the pulmonary artery.
have been described in the medical literature. Currently,
however, there is not a clearly superior sedation evaluation
10. To decrease days of mechanical ventilation and ICU methodology against which these sedation scales can be
length of stay we recommend a conservative fluid evaluated [189]. The benefits of sedation protocols appear
strategy for patients with established acute lung injury to outweigh the risks.
who do not have evidence of tissue hypoperfusion
(Grade 1C).
2. We recommend intermittent bolus sedation or
continuous infusion sedation to predetermined end
Rationale. Mechanisms for the development of pulmonary
points (e. g., sedation scales) with daily interrupedema in patients with acute lung injury include increased
tion/lightening of continuous infusion sedation with
capillary permeability, increased hydrostatic pressure and
awakening and retitration if necessary for sedation addecreased oncotic pressure [180, 181]. Small prospective
ministration to septic mechanically ventilated patients
studies in patients with critical illness and acute lung injury
(Grade 1B).
have suggested that less weight gain is associated with improved oxygenation [182] and fewer days of mechanical Rationale. Although not specifically studied in patients
ventilation [183, 184]. Use of a fluid conservative strat- with sepsis, the administration of intermittent sedation,
egy directed at minimizing fluid infusion and weight gain daily interruption, and retitration or systemic titration to
in patients with acute lung injury based on either a cen- a predefined end point have been demonstrated to decrease
tral venous catheter or a pulmonary artery catheter along the duration of mechanical ventilation [186, 189, 190]. Pawith clinical parameters to guide treatment strategies led tients receiving neuromuscular blocking agents (NMBAs)
to fewer days of mechanical ventilation and reduced length must be individually assessed regarding discontinuation
of ICU stay without altering the incidence of renal failure of sedative drugs because neuromuscular blocking drugs
or mortality rates [185]. Of note, this strategy was only must also be discontinued in that situation. The use of
used in patients with established acute lung injury, some of intermittent vs. continuous methods for the delivery of
whom had shock present. Active attempts to reduce fluid sedation in critically ill patients has been examined. An
volume were conducted only during periods free of shock. observational study of mechanically-ventilated patients
showed that patients receiving continuous sedation had
B. Sedation, Analgesia, and Neuromuscular Blockade
significantly longer durations of mechanical ventilation
in Sepsis
and ICU and hospital length of stay [191].
Similarly, a prospective, controlled study in 128
1. We recommend sedation protocols with a sedation mechanically-ventilated adults receiving continuous intragoal when sedation of critically ill mechanically venous sedation demonstrated that a daily interruption in
ventilated patients with sepsis is required (Grade 1B). the “continuous” sedative infusion until the patient was
awake decreased the duration of mechanical ventilation
and ICU length of stay [192]. Although the patients did
receive continuous sedative infusions in this study, the
daily interruption and awakening allowed for titration
of sedation, in effect, making the dosing intermittent.
Systematic (protocolized) titration to a predefined end
point has also been shown to alter outcome [186]. Additionally, a randomized prospective blinded observational
study demonstrated that although myocardial ischemia is
common in critically ill ventilated patients, daily sedative
interruption is not associated with an increased occurrence
of myocardial ischemia [193]. Thus, the benefits of daily
interruption of sedation appear to outweigh the risks.
These benefits include potentially shorter duration of
mechanical ventilation and ICU stay, better assessment of
neurologic function, and reduced costs.
is a clear indication for neuromuscular blockade that
can not be safely achieved with appropriate sedation and
analgesia” [195].
Only one prospective, randomized clinical trial has
evaluated peripheral nerve stimulation vs. standard clinical
assessment in ICU patients. Rudis et al. [202] randomized
77 critically ill patients requiring neuromuscular blockade
in the ICU to receive dosing of vecuronium based on
train-of-four stimulation or clinical assessment (control).
The peripheral nerve stimulation group received less drug
and recovered neuromuscular function and spontaneous
ventilation faster than the control group. Nonrandomized
observational studies have suggested that peripheral nerve
monitoring reduces or has no effect on clinical recovery
from NMBAs in the ICU setting [203, 204].
Benefits to neuromuscular monitoring, including faster
recovery of neuromuscular function and, shorter intubation
3. We recommend that NMBAs be avoided if possible in times, appear to exist. A potential for cost savings (reduced
the septic patient due to the risk of prolonged neuro- total dose of NMBAs and shorter intubation times) also
muscular blockade following discontinuation. If NM- may exist, although this has not been studied formally.
BAs must be maintained, either intermittent bolus as
required or continuous infusion with monitoring the
depth of blockade with train-of-four monitoring should C. Glucose Control
be used (Grade 1B).
1. We recommend that, following initial stabilization, paRationale. Although NMBAs are often administered
tients with severe sepsis and hyperglycemia who are
to critically ill patients, their role in the ICU setting is
admitted to the ICU receive IV insulin therapy to renot well defined. No evidence exists that maintaining
duce blood glucose levels (Grade 1B).
neuromuscular blockade in this patient population reduces 2. We suggest use of a validated protocol for insulin
mortality or major morbidity. In addition, no studies have
dose adjustments and targeting glucose levels to the
been published that specifically address the use of NMBAs
< 150 mg/dl range (Grade 2C).
in septic patients.
3. We recommend that all patients receiving intravenous
The most common indication for NMBA use in
insulin receive a glucose calorie source and that blood
the ICU is to facilitate mechanical ventilation [194].
glucose values be monitored every 1–2 hours until gluWhen appropriately utilized, NMBAs may improve
cose values and insulin infusion rates are stable and
chest wall compliance, prevent respiratory dyssynthen every 4 hours thereafter (Grade 1C).
chrony, and reduce peak airway pressures [195]. Mus- 4. We recommend that low glucose levels obtained with
cle paralysis may also reduce oxygen consumption
point-of-care testing of capillary blood be interpreted
with caution, as such measurements may overestimate
by decreasing the work of breathing and respiratory
arterial blood or plasma glucose values (Grade 1B).
muscle blood flow [196]. However, a randomized,
placebo-controlled clinical trial in patients with severe sepsis demonstrated that oxygen delivery, oxy- Rationale. The consensus on glucose control in severe
gen consumption, and gastric intramucosal pH were sepsis was achieved at the first committee meeting and
not improved during profound neuromuscular block- subsequently approved by the entire committee (see
Appendix G for committee vote). One large randomized
ade [197].
An association between NMBA use and myopathies single center trial in a predominantly cardiac surgical
and neuropathies has been suggested by case studies ICU demonstrated a reduction in ICU mortality with
and prospective observational studies in the critical intensive IV insulin (Leuven Protocol) targeting blood
care population [195, 198–201]. The mechanisms by glucose to 80–110 mg/dl (for all patients relative 43%,
which NMBA’s produced or contribute to myopathies and absolute 3.4% mortality reduction, and for those with
and neuropathies in critically ill patients are presently > 5 day ICU length of stays (LOS) a 48% relative and
unknown. There appears to be an added association with 9.6% absolute mortality reduction) [205]. A reduction in
the concurrent use o NMBA’s and steroids. Although organ dysfunction and ICU LOS (from a median of 15
no specific studies exist specific to the septic patient to12 days) was also observed in the subset with ICU LOS
population, it seems clinically prudent based on existent > 5 days. A second randomized trial of intensive insulin
knowledge that NMBA’s not be administered unless there therapy using the Leuven Protocol enrolled medical ICU
patients with an anticipated ICU LOS of > 3 days in
three MICUs [206]. Overall, mortality was not reduced
but ICU and hospital LOS were reduced associated with
earlier weaning from mechanical ventilation and less
acute kidney injury. In patients with a medical ICU LOS
> 3 days, hospital mortality was reduced with intensive
insulin therapy (43% versus 52.5%; p = 0.009). However,
investigators were unsuccessful in predicting ICU LOS
and 433 patients (36%) had an ICU LOS of < 3 days.
Furthermore, use of the Leuven Protocol in the medical
ICU resulted in a nearly three-fold higher rate of hypoglycemia than in the original experience (18% versus
6.2% of patients) [205, 206].
One large before-and-after observational trial showed
a 29% relative and 6.1% absolute reduction in mortality
and a 10.8% reduction in median ICU LOS [207]. In a subgroup of 53 patients with septic shock there was an absolute mortality reduction of 27% and a relative reduction of
45% (p = 0.02). Two additional observational studies report an association of mean glucose levels with reductions
in mortality, polyneuropathy, acute renal failure, nosocomial bacteremia, and number of transfusions, and suggest
a glucose threshold for improved mortality lies somewhere
between 145 and 180 mg/dl [208, 209]. However, a large
observational study (n = 7,049) suggested that both a lower
mean glucose and less variation of blood glucose may be
important [210]. A meta-analysis of 35 trials on insulin
therapy in critically ill patients, including 12 randomized
trials, demonstrated a 15% reduction in short term mortality (RR 0.85, 95% confidence interval 0.75–0.97) but
did not include any studies of insulin therapy in medical
ICUs [211].
Two additional multicenter RCTs of intensive insulin
therapy, one focusing on patients with severe sepsis
(VISEP) and the second on medical and surgical ICU
patients, failed to demonstrate improvement in mortality,
but are not yet published [212, 213]. Both stopped earlier
than planned because of high rates of hypoglycemia and
adverse events in the intensive insulin groups. A large
RCT that is planned to compare targeting 80–110 mg/dl
(4.5–6.0 mmol/L) versus 140–180 mg/dl (8–10 mmol/L)
and recruit more than 6,000 patients (Normoglycemia in
Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation, or NICE-SUGAR) is ongoing [214].
Several factors may affect the accuracy and reproducibility of point-of-care testing of blood capillary blood
glucose, including the type and model of the device used,
user expertise, and patient factors including hematocrit
(false elevation with anemia), PaO2 , and drugs [215]. One
report showed overestimation of arterial plasma glucose
values by capillary point-of-care testing sufficient to result
in different protocol-specified insulin dose titration. The
disagreement between protocol-recommended insulin
doses was largest when glucose values were low [216].
A recent review of 12 published insulin infusion protocols
for critically ill patients showed wide variability in insulin
dose recommendations and variable glucose control during simulation [217]. This lack of consensus about optimal
dosing of IV insulin may reflect variability in patient
factors (severity of illness, surgical vs. medical settings,
etc) or practice patterns (e. g., approaches to feeding,
IV dextrose) in the environments in which these protocols
were developed and tested. Alternatively, some protocols
may be more effective than other protocols. This conclusion is supported by the wide variability in hypoglycemia
rates reported with protocols [205–207, 212, 213]. Thus,
the use of a validated and safe intensive insulin protocol
is important not only for clinical care but also for the
conduct of clinical trials to avoid hypoglycemia, adverse
events, and premature termination of these trials before
the efficacy signal, if any, can be determined.
The finding of reduced morbidity and mortality within
the longer ICU length of stay subsets along with acceptable cost weighed heavily on our recommendation to attempt glucose control after initial stabilization of the patient with hyperglycemia and severe sepsis. However, the
mortality benefit and safety of intensive insulin therapy
(goal to normalize blood glucose) has been questioned by
2 recent trials and we recommend maintaining glucose levels < 150 mg/dl until recent and ongoing trials are published or completed. Further study of protocols that have
been validated to be safe and effective for controlling blood
glucose concentrations and blood glucose variation in the
severe sepsis population are needed.
D. Renal Replacement
1. We suggest that continuous renal replacement therapies and intermittent hemodialysis are equivalent
in patients with severe sepsis and acute renal failure
(Grade 2B).
2. We suggest the use of continuous therapies to facilitate management of fluid balance in hemodynamically
unstable septic patients (Grade 2D).
Rationale. Although numerous nonrandomized studies
have reported a nonsignificant trend toward improved
survival using continuous methods [218–225], 2 metaanalyses [226, 227] report the absence of significant difference in hospital mortality between patients who receive
continuous and intermittent renal replacement therapies.
This absence of apparent benefit of one modality over the
other persists even when the analysis is restricted to only
randomized studies [227]. To date, 5 prospective randomized studies have been published [228–232]. Four of them
found no significant difference in mortality [229–232].
One study found significantly higher mortality in the
continuous treatment group [228], but imbalanced randomization had led to a higher baseline severity of illness
in this group. When a multivariable model was used to
adjust for severity of illness, no difference in mortality was
apparent between the groups [228]. It is important to note
that most studies comparing modes of renal replacement
in the critically ill have included a small number of patients and some major weaknesses (randomization failure,
modifications of therapeutic protocol during the study
period, combination of different types of continuous renal
replacement therapies, small number of heterogenous
groups of patients enrolled). The most recent and largest
randomized study [232] enrolled 360 patients and found
no significant difference in survival between the 2 groups.
Moreover, there is no current evidence to support the use
of continuous therapies in sepsis independent of renal
replacement needs.
Concerning the hemodynamic tolerance of each
method, no current evidence exists to support a better
tolerance with continuous treatments. Only 2 prospective
studies [230, 233] have reported a better hemodynamic
tolerance with continuous treatment, with no improvement
in regional perfusion [233] and no survival benefit [230].
Four other prospective studies did not find any significant
difference in mean arterial pressure or drop in systolic
pressure between the 2 methods [229, 231, 232, 234].
Concerning fluid balance management, 2 studies report
a significant improvement in goal achievement with continuous methods [228, 230]. In summary, current evidence
is insufficient to draw strong conclusions regarding the
mode of replacement therapy for acute renal failure in
septic patients.
Four randomized, controlled trials have addressed
whether the dose of continuous renal replacement affects
outcomes in patients with acute renal failure [235–238].
Three found improved mortality in patients receiving
higher doses of renal replacement [235, 237, 238], while
one [236] did not. None of these trials was conducted
specifically in patients with sepsis. Although the weight
of current evidence suggests that higher doses of renal
replacement may be associated with improved outcomes,
these results may not be easily generalizable. The results
of 2 very large multicenter randomized trials comparing
the dose of renal replacement (ATN in the United States
and RENAL in Australia and New Zealand) will be
available in 2008 and will greatly inform practice.
E. Bicarbonate Therapy
1. We recommend against the use of sodium bicarbonate
therapy for the purpose of improving hemodynamics
or reducing vasopressor requirements in patients with
hypoperfusion-induced lactic acidemia with pH ≥ 7.15
(Grade 1B).
Rationale. No evidence supports the use of bicarbonate
therapy in the treatment of hypoperfusion-induced lactic acidemia associated with sepsis. Two randomized,
blinded, crossover studies that compared equimolar saline
and bicarbonate in patients with lactic acidosis failed to
reveal any difference in hemodynamic variables or vasopressor requirements. [239, 240] The number of patients
with pH < 7.15 in these studies was small. Bicarbonate
administration has been associated with sodium and fluid
overload, an increase in lactate and pCO2 , and a decrease
in serum ionized calcium; but the relevance of these
parameters to outcome is uncertain. The effect of bicarbonate administration on hemodynamics and vasopressor
requirements at lower pH as well as the effect on clinical
outcomes at any pH is unknown. No studies have examined
the effect of bicarbonate administration on outcomes.
F. Deep Vein Thrombosis Prophylaxis
1. We recommend that severe sepsis patients receive
deep vein thrombosis (DVT) prophylaxis with either
(a) low-dose unfractionated heparin (UFH) administered b.i.d. or t.i.d. or (b) daily low-molecular weight
heparin (LMWH) unless there are contraindications
(i. e., thrombocytopenia, severe coagulopathy, active
bleeding, recent intracerebral hemorrhage) (Grade 1A).
2. We recommend that septic patients who have a contraindication for heparin use receive mechanical prophylactic device such as graduated compression stockings (GCS) or intermittent compression devices (ICD)
unless contraindicated (Grade 1A).
3. We suggest that in very high-risk patients such as those
who have severe sepsis and history of DVT, trauma,
or orthopedic surgery, a combination of pharmacologic
and mechanical therapy be used unless contraindicated
or not practical (Grade 2C).
4. We suggest that in patients at very high risk, LMWH
be used rather than UFH as LMWH is proven superior
in other high-risk patients (Grade 2C).
Rationale. ICU patients are at risk for DVT [241]. Significant evidence exists for benefit of DVT prophylaxis in ICU
patients in general. No reasons suggest that severe sepsis
patients would be different from the general patient population.
Nine randomized placebo controlled clinical trials of
DVT prophylaxis in general populations of acutely ill patients exist [242–250]. All 9 trials showed reduction in
DVT or PE. The prevalence of infection/sepsis was 17%
in all studies in which this was ascertainable, with a 52%
prevalence of infection/sepsis patients in the study that included ICU patients only. Benefit of DVT prophylaxis is
also supported by meta-analyses [251, 252]. With that in
mind, DVT prophylaxis would appear to have a high grade
for quality of evidence (A). As the risk of administration
to the patient is small, the gravity of the potential result of
not administering is great, and the cost is low, the grading
of the strength of the recommendation is strong. The evidence supports equivalency of LMWH and UFH in gen-
eral medical populations. A recent meta-analysis comparing b.i.d. and t.i.d. UFH demonstrated that t.i.d. UFH produced better efficacy and b.i.d. less bleeding [253]. Practitioners should use underlying risk for VTE and bleeding to
individualize choice of b.i.d. versus t.i.d.
The cost of LMWH is greater and the frequency of injection is less. UFH is preferred over LMWH in patients
with moderate to severe renal dysfunction.
Mechanical methods (ICD and GCS) are recommended when anticoagulation is contraindicated or as
an adjunct to anticoagulation in the very high-risk patients [254–256]. In very high-risk patients, LMWH is
preferred over UFH [257–259]. Patients receiving heparin
should be monitored for development of heparin-induced
thrombocytopenia (HIT).
G. Stress Ulcer Prophylaxis (SUP)
We recommend that stress ulcer prophylaxis using H2
blocker (Grade 1A) or proton pump inhibitor PPI (Grade
1B) be given to patients with severe sepsis to prevent upper
GI bleed. Benefit of prevention of upper GI bleed must be
weighed against potential effect of an increased stomach
pH on development of ventilator-associated pneumonia.
Rationale. Although no study has been performed
specifically in patients with severe sepsis, trials confirming
the benefit of stress ulcer prophylaxis reducing upper GI
bleeds in general ICU populations would suggest that
20–25% of patients enrolled in these types of trials have
sepsis [260–263]. This benefit should be applicable to patients with severe sepsis and septic shock. In addition, the
conditions shown to benefit from stress ulcer prophylaxis
(coagulopathy, mechanical ventilation, hypotension) are
frequently present in patients with severe sepsis and septic
shock [264, 265].
Although there are individual trials that have not
shown benefit from SUP, numerous trials and a metaanalysis show reduction in clinically significant upper
GI bleeding, which we consider significant even in the
absence of proven mortality benefit [266–269]. The benefit
of prevention of upper GI bleed must be weighed against
the potential effect of increased stomach pH on greater
incidence of ventilator-associated pneumonia [270]. Those
severe sepsis patients with the greatest risk of upper GI
bleeding are likely to benefit most from stress ulcer prophylaxis. The rationale for the preference for suppression
of acid production over sulcrafate was based on the study
of 1200 patients by Cook et al comparing H2 blockers
and sucralfate and a meta-analysis [271, 272]. 2 studies
support equivalency between H2 blockers and PPIs. One
was in very ill ICU patients. The second study is larger and
demonstrates non-inferiority of omeprazole suspension
for clinically significant stress ulcer bleeding [273, 274].
No data relating to utility of enteral feeding in stress
ulcer prophylaxis exist. Patients should be periodically
evaluated for continued need for prophylaxis.
H. Selective Digestive Tract Decontamination (SDD)
The guidelines group was evenly split on the issue of SDD,
with equal numbers weakly in favor and against recommending the use of SDD (see appendix H). The committee
therefore chose not to make a recommendation for the use
of SDD specifically in severe sepsis at this time. The final
consensus on use of SDD in severe sepsis was achieved at
the last nominal committee meeting and subsequently approved by the entire committee (see Appendix H for committee vote).
Rationale. The cumulative conclusion from the literature demonstrates that prophylactic use of SDD (enteral
non-absorbable antimicrobials and short-course intravenous antibiotics) reduces infections, mainly pneumonia,
and mortality in the general population of critically
ill and trauma patients [275–286] without promoting
emergence of resistant Gram negative bacteria. Post hoc
subgroup analyses [287, 288] of two prospective blinded
studies [289, 290] suggest that SDD reduces nosocomial
(secondary) infections in ICU patients admitted with
primary infections [268] and may reduce mortality [288].
No studies of SDD specifically focused on patients with
severe sepsis or septic shock. The use of SDD in severe
sepsis patients would be targeted toward preventing
secondary infection. As the main effect of SDD is in preventing ventilator-associated pneumonia (VAP), studies
comparing SDD with non-antimicrobial interventions
such as ventilator bundles for reducing VAP are needed.
Further investigation is required to determine the comparative efficacy of these two interventions, separately or
in combination. Although studies incorporating enteral
vancomycin in the regimen appear to be safe [291, 292,
293] concerns persist about the potential for emergence of
resistant Gram positive infections.
I. Consideration for Limitation of Support
We recommend that advance care planning, including the
communication of likely outcomes and realistic goals of
treatment, be discussed with patients and families (Grade
1D).
Rationale. Decisions for less aggressive support
or withdrawal of support may be in the patient’s best
interest. [294–296] Too frequently, inadequate physician/family communication characterizes end-of-life care
in the ICU. The level of life support given to ICU patients
may not be consistent with their wishes. Early and frequent
caregiver discussions with patients who face death in the
ICU and with their loved ones may facilitate appropriate
application and withdrawal of life-sustaining therapies.
A recent RCT demonstrated reduction of anxiety and
depression in family members when end-of-life meetings
were carefully planned, conducted, included advance
care planning, and provided relevant information about
diagnosis, prognosis, and treatment [297].
III. Pediatric Considerations in Severe Sepsis
While sepsis in children is a major cause of mortality, the
overall mortality from severe sepsis in children is much
lower that that in adults, estimated at about 10% [298].
The definitions for severe sepsis and septic shock in
children are similar but not identical to the definitions in
adults [299]. In addition to age-appropriate differences
in vital signs, the definition of systemic inflammatory
response syndrome requires the presence of either temperature or leukocyte abnormalities. The presence of
severe sepsis requires sepsis plus cardiovascular dysfunction or ARDS or 2 or more other organ dysfunctions [299].
A. Antibiotics
1. We recommend antibiotics be administered within one
hour of the identification of severe sepsis, after appropriate cultures have been obtained (Grade 1D).
fluid resuscitation with crystalloids or colloids is of
fundamental importance to survival of septic shock in
children [303–308]. Three randomized, controlled trials
compare the use of colloid to crystalloid resuscitation in
children with dengue shock [303, 307, 308]. No difference
in mortality between colloid or crystalloid resuscitation
was shown.
Children normally have a lower blood pressure than
adults, and fall in blood pressure can be prevented by
vasoconstriction and increasing heart rate. Therefore,
blood pressure by itself is not a reliable end point for
assessing the adequacy of resuscitation. However, once
hypotension occurs, cardiovascular collapse may soon
follow. Hepatomegaly occurs in children who are fluid
overloaded and can be a helpful sign of adequacy of fluid
resuscitation. Large fluid deficits typically exist and initial
volume resuscitation usually requires 40–60 mL/kg but
can be much higher [304–308]. However, the rate of fluid
administration should be reduced substantially when there
are (clinical) signs of adequate cardiac filling without
hemodynamic improvement.
Early antibiotic therapy is as critical for children with severe sepsis as it is for adults.
D. Vasopressors/Inotropes (should be used in volume
loaded patients with fluid refractory shock)
B. Mechanical Ventilation
No graded recommendations.
Due to low functional residual capacity, young infants
and neonates with severe sepsis may require early intubation [300]. Drugs used for intubation have important side
effects in these patients, for example, concerns have been
raised about the safety of using etomidate in children with
meningococcal sepsis because of adrenal suppression effect [301]. The principles of lung-protective strategies are
applied to children as they are to adults.
1. We suggest dopamine as the first choice of support
for the pediatric patient with hypotension refractory to
fluid resuscitation (Grade 2C).
In the initial resuscitation phase, vasopressor therapy may
be required to sustain perfusion pressure, even when hypovolemia has not yet been resolved. Children with severe
sepsis can present with low cardiac output and high systemic vascular resistance, high cardiac output and low systemic vascular resistance, or low cardiac output and low
systemic vascular resistance shock. At various stages of
sepsis or the treatment thereof, a child may move from
one hemodynamic state to another. Vasopressor or inotrope
C. Fluid Resuscitation
therapy should be used according to the clinical state of the
child.
1. We suggest initial resuscitation begin with inDopamine-refractory shock may reverse with
fusion of crystalloids with boluses of 20 mL/kg epinephrine or norepinephrine infusion [309].
over 5–10 minutes, titrated to clinical monitors
of cardiac output, including heart rate, urine out- 2. We suggest that patients with low cardiac output
put, capillary refill, and level of consciousness
and elevated systemic vascular resistance states (cool
(Grade 2C).
extremities, prolonged capillary refill, decreased urine
output but normal blood pressure following fluid
resuscitation) be given dobutamine (Grade 2C).
Intravenous access for fluid resuscitation and inotrope/vasopressor infusion is more difficult to attain
in children than in adults. The American Heart Associ- The choice of vasoactive agent is determined by the clination along with the American Academy of Pediatrics ical examination. For the child with a persistent low carhas developed pediatric advanced life support guidelines diac output state with high systemic vascular resistance
for emergency establishment of intravascular support despite fluid resuscitation and inotropic support, vasodilaencouraging early intraosseous access [302]. On the basis tor therapy may reverse shock [310]. When pediatric paof a number of studies, it is accepted that aggressive tients remain in a normotensive low cardiac output and
high vascular resistance state despite epinephrine and vasodilator therapy, the use of a phosphodiesterase inhibitor
may be considered [311–313]. In the case of extremely
low systemic vascular resistance despite the use of norepinephrine, vasopressin use has been described in a number of case-reports. Thus far there is no clear evidence for
the use of vasopressin in pediatric sepsis [314, 315].
E. Therapeutic End Points
1. We suggest that the therapeutic end points of resuscitation of septic shock be normalization of
the heart rate, capillary refill of < 2 secs, normal pulses with no differential between peripheral
and central pulses, warm extremities, urine output
> 1mL.kg –1 .hr–1 , and normal mental status [290]
(Grade 2C).
Capillary refill may be less reliable in a cold environment.
Other end points that have been widely used in adults and
may logically apply to children include decreased lactate
and improved base deficit, ScvO2 ≥ 70% or SvO2 ≥ 65%,
CVP of 8–12 mm Hg or other methods to analyze cardiac
filling. Optimizing preload optimizes cardiac index. When
using measurements to assist in identifying acceptable cardiac output in children with systemic arterial hypoxemia
such as cyanotic congenital heart disease or severe pulmonary disease, arterial-venous oxygen content difference
is a better marker than mixed venous hemoglobin saturation with oxygen. As noted previously, blood pressure by
itself is not a reliable end point for resuscitation. If a thermodilution catheter is used, therapeutic end points are cardiac index > 3.3 and < 6.0 L.min–1 .m–2 with normal coronary perfusion pressure (mean arterial pressure – central
venous pressure) for age. [290] Using clinical endpoints
such as reversal of hypotension and restoration of capillary refill for initial resuscitation at the community hospital level before transfer to a tertiary center was associated
with significantly improved survival rates in children with
septic shock [305]. Development of a transport system including publicizing to local hospitals and transport with
mobile intensive care services significantly decreased the
case fatality rate from meningococcal disease in the United
Kingdom [316].
Patients at risk for adrenal insufficiency include children
with severe septic shock and purpura [318, 319], children
who have previously received steroid therapies for chronic
illness, and children with pituitary or adrenal abnormalities. Children who have clear risk factors for adrenal insufficiency should be treated with stress dose steroids (hydrocortisone 50 mg/m2 /24hr).
Adrenal insufficiency in pediatric severe sepsis is
associated with a poor prognosis [320]. No strict definitions exist, but absolute adrenal insufficiency in the
case of catecholamine-resistant septic shock is assumed
at a random total cortisol concentration < 18 µg/dL
(496 nmol/L). A post 30- or 60-min ACTH stimulation
test increase in cortisol of ≤ 9 µg/dL (248 mmol/L) has
been used to define relative adrenal insufficiency. The
treatment of relative adrenal insufficiency in children
with septic shock is controversial. A retrospective study
from a large administrative database recently reported
that the use of any corticosteroids in children with severe
sepsis was associated with increased mortality (OR 1.9
95% CI 1.7–2.2) [321]. While steroids may have been
given preferentially to more severely ill children, the
use of steroids was an independent predictor of mortality in multivariable analysis [321]. Given the lack
of data in children and potential risk, steroids should
not be used in those children who do not meet minimal
criteria for adrenal insufficiency. A randomized, controlled trial in children with septic shock is very much
needed.
H. Protein C and Activated Protein C
1. We recommend against the use rhAPC in children
(Grade 1B).
Protein C concentrations in children reach adult values
at the age of 3 yrs. This might indicate that the importance of protein C supplementation either as protein
C concentrate or as rhAPC is even greater in young
children than in adults [322]. There has been one dose
finding, randomized, placebo-controlled study performed
using protein C concentrate. This study was not powered to show an effect on mortality rate, but did show
a positive effect on sepsis-induced coagulation disturF. Approach to Pediatric Septic Shock
bances [323]. An RCT of rhAPC in pediatric severe
sepsis patients was stopped by recommendation of the
Figure 1 shows a flow diagram summarizing an approach Data Monitoring Committee for futility after enrolto pediatric septic shock [317].
lment of 399 patients. 28-day all cause mortality: 18%
placebo group vs. 17% APC group. Major amputaG. Steroids
tions occurred in 3% of the placebo group vs. 2% in
the APC group [324]. Due to the increased risk of
1. We suggest that hydrocortisone therapy be reserved for bleeding (7% vs. 6% in the pediatric trial) and lack of
use in children with catecholamine resistance and sus- proof of efficacy, rhAPC is not recommended for use in
children.
pected or proven adrenal insufficiency (Grade 2C).
Fig. 1 Approach to Pediatric
Shock
I. DVT Prophylaxis
commonly used in children, and central venous catheterassociated DVTs occur in approximately 25% of children
1. We suggest the use of DVT prophylaxis in post- with a femoral central venous catheter. Heparin-bonded
pubertal children with severe sepsis (Grade 2C).
catheters may decrease the risk of catheter-associated
DVT and should be considered for use in children with
severe sepsis. [325, 326] No data on the efficacy of unfracMost DVTs in young children are associated with tionated or low-molecular weight heparin prophylaxis to
central venous catheters. Femoral venous catheters are prevent catheter-related DVT in children in the ICU exist.
Appropriate sedation and analgesia are the standard of care
for children who are mechanically ventilated. Although
there are no data supporting any particular drugs or regiNo graded recommendations.
Studies have shown that the rate of clinically important mens, it should be noted that propofol should not be used
gastrointestinal bleeding in children occurs at rates sim- for long term sedation in children because of the reported
ilar to adults [327, 328]. As in adults, coagulopathy and association with fatal metabolic acidosis [332, 333].
mechanical ventilation are risk factors for clinically important gastrointestinal bleeding. Stress ulcer prophylaxis
strategy is commonly used in mechanically-ventilated chil- N. Blood Products
dren, usually with H2 blockers. Its effect is not known.
K. Renal Replacement Therapy
The optimal hemoglobin for a critically ill child with
severe sepsis is not known. A recent multicenter trial
reported similar outcomes in stable critically ill children
Continuous veno-venous hemofiltration (CVVH) managed with a transfusion threshold of 7 gm/dl commay be clinically useful in children with anuria/severe pared to those managed with a transfusion threshold of
oliguria and fluid overload, but no large RCTs have 9.5 g/dL [334]. Whether a lower transfusion trigger is safe
been performed comparing CVVH with intermittent dia- or appropriate in the initial resuscitation of septic shock
lysis. A retrospective study of 113 critically ill children has not been determined.
reported that children with less fluid overload before
CVVH had better survival, especially in those children O. Intravenous Immunoglobulin
with dysfunction of 3 or more organs [329]. CVVH or
other renal replacement therapy should be instituted in 1. We suggest that immunoglobulin may be considered in
children with anuria/severe oliguria before significant
children with severe sepsis (Grade 2C).
fluid overload occurs.
Administration of polyclonal intravenous immunoglobulin
L. Glycemic Control
has been reported to reduce mortality rate and is a promising adjuvant in the treatment of sepsis and septic shock in
neonates. A recent randomized controlled study of polyIn general, infants are at risk for developing hypo- clonal immunoglobulin in pediatric sepsis syndrome paglycemia when they depend on intravenous fluids. This tients (n = 100), showed a significant reduction in mortalmeans that a glucose intake of 4–6 mg.kg–1 .min–1 or ity, LOS, and less progress to complications, especially
maintenance fluid intake with glucose 10%/NaCl contain- DIC [335].
ing solution is advised. Associations have been reported
between hyperglycemia and an increased risk of death P. Extracorporeal membrane oxygenation (ECMO)
and longer length of stay [330]. A recent retrospective
PICU study reported associations of hyperglycemia, 1. We suggest that use of ECMO be limited to refractory
pediatric septic shock and/or respiratory failure that
hypoglycemia, and glucose variability with length of
cannot be supported by conventional therapies (Grade
stay and mortality rates. [331] No studies in pediatric
2C).
patients (without diabetes mellitus) analyzing the effect
of strict glycemic control using insulin exist. In adults,
the recommendation is to maintain a serum glucose ECMO has been used in septic shock in children, but its
below 150 mg/dL. Insulin therapy to avoid long periods impact is not clear. Survival from refractory shock or resof hyperglycemia seems sensible in children as well, piratory failure associated with sepsis is 80% in neonates
but the optimal goal glucose is not known. However, and 50% in children. In one study analyzing 12 patients
continuous insulin therapy should only be done with with meningococcal sepsis in ECMO, eight of the 12 pafrequent glucose monitoring in view of the risks for hypo- tients survived, with six leading functionally normal lives
at a median of 1 yr (range, 4 months to 4 yrs) of follow-up.
glycemia.
Children with sepsis on ECMO do not perform worse than
children without sepsis at long-term follow-up [336, 337].
M. Sedation/Analgesia
Although the pediatric considerations section of this
manuscript offers important information to the practicing
pediatric clinician for the management of critically ill chil1. We recommend sedation protocols with a sedation dren with sepsis, the reader is referred to the references at
goal when sedation of critically ill mechanically the end of the document for more in-depth descriptions of
ventilated patients with sepsis is required (Grade 1D). appropriate management of pediatric septic patients.
J. Stress Ulcer Prophylaxis
Summary and Future Directions
The reader is reminded that although this document
is static, the optimum treatment of severe sepsis and
septic shock is a dynamic and evolving process. New
interventions will be proven and established interventions,
as stated in the current recommendations, may need
modification. This publication represents an ongoing
process. The Surviving Sepsis Campaign and the consensus committee members are committed to updating
the guidelines on a regular basis as new interventions are
tested and published in the literature.
Although evidence-based recommendations have been
frequently published in the medical literature, documentation of impact on patient outcome is limited [338].
There is, however, growing evidence that protocol implementation associated with education and performance
feedback does change clinician behavior and may improve
outcomes in and reduce costs in severe sepsis [20, 24, 25].
Phase III of the Surviving Sepsis Campaign targets the
implementation of a core set of the previous recommendations in hospital environments where change in
behavior and clinical impact are being measured. The
sepsis bundles were developed in collaboration with the
Institute of Healthcare Improvement [339]. Concurrent or
retrospective chart review will identify and track changes
in practice and clinical outcome. Software and software
support is available at no cost in 7 languages, allowing
bedside data entry and allows creation of regular reports
for performance feedback. The Campaign also offers
significant program support and educational materials at
no cost to the user (www.survivingsepsis.org ).
Engendering evidence-based change in clinical
practice through multi-faceted strategies while auditing
practice and providing feedback to healthcare practitioners is the key to improving outcomes in severe sepsis.
Nowhere is this more evident than in the worldwide
enthusiasm for Phase III of the Campaign, a performance
improvement program using SSC guideline-based sepsis
bundles. Using the guidelines as the basis, the bundles
have established a global best practice for the management
of critically ill patients with severe sepsis. As of November
2007, over 12,000 patients have been entered into the SSC
central database, representing the efforts of 239 hospitals
in 17 countries. Change in practice and potential effect on
survival are being measured.
Acknowledgment of Support As mentioned above in the methods
section, the Surviving Sepsis Campaign (SSC) is partially funded
by unrestricted educational industry grants, including those from
Edwards LifeSciences, Eli Lilly and Company, and Philips Medical
Systems. SSC also received funding from the Coalition for Critical
Care Excellence of the Society of Critical Care Medicine. The great
majority of industry funding has come from Eli Lilly and Company.
Current industry funding for the Surviving Sepsis Campaign
is directed to the performance improvement initiative. No industry
funding was used for committee meetings. No honoraria were
provided to committee members. The revision process was funded
primarily by the Society of Critical Care Medicine, with the
sponsoring professional organizations providing travel expenses for
their designated delegate to the guidelines revision meeting where
needed.
Other Acknowledgements Toni Piper and Rae McMorrow for their
assistance in bringing the manuscript together. Gordon Guyatt and
Henry Masur, M.D. for their guidance on grading of evidence and
antibiotic recommendations respectively.
Nine of the 11 organizations that sponsored the first guidelines
are sponsors of the revision. Four additional national organizations
(Canadian Critical Care Society, Japanese Association for Acute
Medicine, Japanese Society of Intensive Care Medicine, and
Society of Hospital Medicine), the World Federation of Societies of
Intensive and Critical Care Medicine and two sepsis organizations
(German Sepsis Society and the Latin American Sepsis Institute)
have also come on board as sponsors. Two organizations that
sponsored the first guidelines (American Thoracic Society and
Australian and New Zealand Intensive Care Society) elected not to
sponsor the revision.
A. Source Control
Source Control
Technique
Examples
Drainage
• Intra-abdominal abscess
• Thoracic empyema
• Septic arthritis
• Pyelonephritis, cholangitis
• Infected pancreatic necrosis
• Intestinal infarction
• Mediastinitis
• Infected vascular catheter
• Urinary catheter
• Infected intrauterine contraceptive device
• Sigmoid resection for diverticulitis
• Cholecystectomy for gangrenous cholecystitis
• Amputation for clostridial myonecrosis
Debridement
Device
removal
Definitive
control
B. Steroids
Considerable difference of opinion existed among committee members as to the best option for the style of the
steroid in septic shock recommendations. Some committee
members argued for two recommendations and pointed to
the two distinct patient populations of (1) the French Trial
(enrollment early in septic shock and blood pressure unresponsive to vasopressors) and (2) the CORTICUS trial
(enrollment allowed up to 72 hrs and did not target patients with blood pressure unresponsive to vasopressin),
leading to two distinct results. Furthermore, a single recommendation suggested to some that this approach might
lead to excessive use of steroids and increased incidence of
super-infections, citing the sepsis and septic shock adverse
events in the steroid treated patients in the CORTICUS
trial. Those that argued for one recommendation pointed to
problems with two different recommendations that would
require the bedside clinician to choose a time point for
classification of one or the other as well as a distinct blood
pressure cut-off with the potential for the blood pressure
to vary over time. In addition there is inadequate data to
provide standardization of how much fluids and vasopressors should be in place to call the blood pressure unresponsive or poorly responsive. They also pointed to the fact that
the increased super-infection/sepsis/septic shock adverse
events in CORTICUS are contrary to the results of other
stress dose steroid trials such as early ARDS (lower incidence of infections) (341), late ARDS (decreased development of septic shock) (342), and community-acquired
pneumonia (decreased development of septic shock) (114).
Based on GRADE adjudication guidelines, a secret ballot
vote was conducted to resolve the issue.
One recommendation option
1. We suggest intravenous hydrocortisone be given
only to adult septic shock patients with blood pressure
poorly responsive to fluid resuscitation and vasopressor
therapy (Grade 2C).
The committee vote that determined the current recommendation was:
Favor two recommendation option – 19
Favor one recommendation option – 31
Abstain – 1
C. Contraindications to use of recombinant human
activated protein C (rhAPC)
rhAPC increases the risk of bleeding. rhAPC is contraindicated in patients with the following clinical situations in
which bleeding could be associated with a high risk of
death or significant morbidity.
• Active internal bleeding
• Recent (within 3 months) hemorrhagic stroke
• Recent (within 2 months) intracranial or intraspinal
surgery, or severe head trauma
• Trauma with an increased risk of life-threatening
bleeding
• Presence of an epidural catheter
• Intracranial neoplasm or mass lesion or evidence of
cerebral herniation
• Known hypersensitivity to rhAPC or any component of
the product
See labeling instructions for relative contraindications. The
committee recommends that platelet count be maintained
at ≥ 30,000 or greater during infusion of rhAPC.
Two recommendation option
Physicians’ Desk Reference. 61st Edition. Montvale,
NJ,
Thompson PDR, 2007, p 1829
1. We suggest intravenous hydrocortisone be given
to adult septic shock patients if blood pressure is
inadequate with appropriate fluid resuscitation and
D. Recombinant Activated Protein C Nominal Group
vasopressor therapy (Grade 2B).
2. We suggest intravenous hydrocortisone not be given Vote
to adult septic shock patients if blood pressure is adequate with appropriate fluid resuscitation and vasopres- Strong
Weak
Neutral
Weak for
Strong for
sor therapy (Grade 2B).
for use
for use
not using
not using
The two options put to vote were:
6
15
1
0
0
E. ARDSNET Ventilator Management (96)
• Assist control mode – volume ventilation
• Reduce tidal volume to 6 mL/kg lean body weight
• Keep inspiratory plateau pressure (Pplat) ≤ 30 cm H2 O
– Reduce TV as low as 4 mL/kg predicted body weight to limit Pplat
• Maintain SaO2 /SpO2 88–95%
• Anticipated PEEP settings at various FIO2 requirements
FiO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9
PEEP 5
5
8
8
10
10
10
12
14
14
14
16
* Predicted Body Weight Calculation
• Male – 50 + 2.3 (height (inches) – 60) or 50 + 0.91 (height (cm) – 152.4)
• Female – 45.5 + 2.3 (height (inches) – 60) or 45.5 + 0.91 (height (cm) – 152.4)
0.9
18
1.0
20–24
TV, tidal volume; SaO2 , arterial oxygen saturation; SpO2 , pulse oximetry oxyhemoglobin saturation;
PEEP, positive end-expiratory pressure
F. Use of spontaneous breathing trial in weaning
ARDS patients
Original illness resolving; no new illness
Off vasopressors and continuous sedatives
Cough during suctioning
PaO2 /FI O2 > 200
PEEP ≤ 5 cm H2 O
Minute ventilation < 15 L min
Frequency/tidal volume (F/TV) ratio ≤ 105 during
two-minute spontaneous breathing trial
↓
Spontaneous Breathing Trial * (30 to 120 minutes)
Respiratory rate > 35
Oxygen saturation < 90
Pulse > 140/min or change ≥ 20%
SBP > 180 mm Hg or < 90 mm Hg
Agitation, diaphoresis, or anxiety F/TV ratio >105
Note: Achieving any of these criteria for a sustained
period at any time during the trial represents a weaning
failure and the need to return to maintenance MV.
G. Glycemic control committee vote
Glycemic Control – 90%
Total votes = 51
Agree – 34
Too conservative, but accept – 4
Too liberal, but accept – 8
Disapprove, too conservative – 0
Disapprove, too liberal – 5
Disapprove, other – 0
H. Selective Digestive Decontamination Nominal
Group Vote
Antibiotics
Strong
for use
Syst and oral –
Syst alone
–
Weak
for use
Neutral
Weak for
not using
Strong for
not using
9
2
4
7
8
5
1
3
Syst, systemic
I. 2008 SSC Guidelines Committee
PEEP, positive end-expiratory pressure; F/TV,
frequency/tidal volume; SBP, systolic blood pressure;
MV, mechanical ventilation; * Options include T-Piece,
continuous positive airway pressure 5 cm H2 O or low
level (5–10 cm H2 O typically based on ET tube size)
pressure support ventilation (167–170)
R. Phillip Dellinger (Chair), Tom Ahrens a , Naoki
Aikawa b , Derek Angus, Djillali Annane, Richard Beale,
Gordon R. Bernard, Julian Bion c , Christian BrunBuisson, Thierry Calandra, Joseph Carcillo, Jean Carlet c ,
Terry Clemmer, Jonathan Cohen, Edwin A. Deitch d ,
Jean-Francois Dhainaut, Mitchell Fink, Satoshi Gando b ,
Herwig Gerlach c , Gordon Guyatt e , Maurene Harvey, Jan
Hazelzet, Hiroyuki Hirasawa f , Steven M. Hollenberg,
Michael Howell, Roman Jaeschke e , Robert Kacmarek,
Didier Keh, Mitchell M. Levy g , Jeffrey Lipman, John J.
Marini, John Marshall, Claude Martin c , Henry Masur,
Steven Opal, Tiffany M Osborn h , Giuseppe Pagliarello i ,
Margaret Parker, Joseph Parrillo, Graham Ramsay c ,
Adrienne Randolph, Marco Ranieri c , Robert C. Read j ,
Konrad Reinhart k , Andrew Rhodes c , Emmanuel Rivers h ,
Gordon Rubenfeld, Jonathan Sevransky, Eliezer Silva l ,
Charles L. Sprung c , B. Taylor Thompson, Sean R.
Townsend, Jeffery Vender m , Jean-Louis Vincent n , Tobias
Welte o , Janice Zimmerman
a – American Association of Critical-Care Nurses
b – Japanese Association for Acute Medicine
c – European Society of Intensive Care Medicine
d – Surgical Infection Society
e – Grades of Recommendation, Assessment, Development and Evaluation (GRADE) Group
f – Japanese Society of Intensive Care Medicine
g – Society of Critical Care Medicine
h – American College of Emergency Physicians
i – Canadian Critical Care Society
j – European Society of Clinical Microbiology and Infectious Diseases
k – German Sepsis Society
l – Latin American Sepsis Institute
m – American College of Chest Physicians
n – International Sepsis Forum
o – European Respiratory Society
J. Author Disclosure Information 2006–2007
Dr. Dellinger has consulted for AstraZeneca, Talecris,
and B Braun. He has received honoraria from Eli Lilly
(2), Brahms (2), INO Therapeutics (1), Pulsion (1), and
bioMerieux (1). He has also received grant support from
AstraZeneca and Artisan.
Dr. Levy has received honoraria from Eli Lilly and
Edwards Lifesciences. He has also received grant support
from Phillips Medical Systems, Edwards Lifesciences,
Phillips Medical Systems, Novartis, Biosite, and Eisai.
Dr. Carlet has consulted for Forrest, Wyeth, Chiron,
bioMerieux, and GlaxoSmithKline. He has also received
honoraria from Eli Lilly, Becton Dickinson, Jansen, Cook,
AstraZeneca, Hutchinson, Bayer, Gilead, MSD, and Targanta.
Dr. Bion has not disclosed any potential conflicts of interest.
Dr. Parker has consulted for Johnson & Johnson.
Dr. Jaeschke has received honoraria from AstraZeneca,
Boehringer, Eli Lilly, GlaxoSmithKline, and MSD.
Dr. Reinhart has consulted for Eli Lilly and Edwards
Lifesciences. He has also received honoraria from B Braun
and royalties from Edwards Lifesciences.
Dr. Angus has consulted for or received speaking
fees from AstraZeneca, Brahms Diagnostica, Eisai, Eli
Lilly, GlaxoSmithKline, OrthoBiotech, Takeda, and
Wyeth-Ayerst. He has also received grant support from
GlaxoSmithKline, OrthoBiotech, and Amgen.
Dr. Brun-Buisson has not disclosed any potential conflicts of interest.
Dr. Beale has received honoraria from Eisai and speaking fees (paid to university) from Lilly UK, Philips, Lidco,
and Chiron.
Dr. Calandra has consulted for Baxter, received honoraria from Roche Diagnostics, and grant support from Baxter and Roche Diagnostics. He also served on the advisory
board for Biosite.
Dr. Dhainaut has consulted for Eli Lilly and Novartis.
He has also received honoraria from Eli Lilly.
Dr. Gerlach has not disclosed any potential conflicts of
interest.
Ms. Harvey has not disclosed any potential conflicts of
interest.
Dr. Marini has consulted for KCI and received honoraria from Maquet.
Dr. Marshall has consulted for Becton-Dickinson,
Takeda, Pfizer, Spectral Diagnostics, Eisai, and LeoPharma. He has also received honoraria from Spectral
Diagnostics.
Dr. Ranieri has served on the advisory board for
Maquet and received support for a sponsored trial from
Eli Lilly. He has also received grant support from Tyco,
Draeger, and Hamilton.
Dr. Ramsay has consulted for Edwards Lifesciences
and Respironics.
Dr. Sevransky has not disclosed any potential conflicts
of interest.
Dr. Thompson has consulted for Eli Lilly, Abbott, and
AstraZeneca. He has also received grant support from the
NIH for a study on computerized glucose control.
Dr. Townsend has not disclosed any potential conflicts
of interest.
Dr. Vender has consulted and received honoraria from
Eli Lilly.
Dr. Zimmerman has not disclosed any potential conflicts of interest.
Dr. Vincent has consulted for AstraZeneca, Biosite,
bioMerieux, Edwards Lifesciences, Eli Lilly Eisai,
Ferring, GlaxoSmithKline, Intercell, Merck, Novartis,
NovoNordisk, Organon, Pfizer, Phillips Medical Systems,
Roche Diagnostics, Spectral Diagnostics, Takeda, and
WyethLederle. He has also received honoraria from Eli
Lilly, Edwards Lifesciences, Eisai, GlaxoSmithKline,
Novartis, NovoNordisk, and Pfizer.
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3.
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Improvement in Process of Care and Outcome After a
Multicenter Severe Sepsis Educational Program in Spain
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Ricard Ferrer; Antonio Artigas; Mitchell M. Levy; et al.
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CARING FOR THE
CRITICALLY ILL PATIENT
Improvement in Process of Care
and Outcome After a Multicenter
Severe Sepsis Educational Program in Spain
Ricard Ferrer, MD
Antonio Artigas, MD, PhD
Mitchell M. Levy, MD, FCCM
Jesús Blanco, MD, PhD
Gumersindo González-Dı́az, MD, PhD
José Garnacho-Montero, MD, PhD
Jordi Ibáñez, MD, PhD
Eduardo Palencia, MD, PhD
Manuel Quintana, MD
Marı́a Victoria de la
Torre-Prados, MD, PhD
for the Edusepsis Study Group
S
EPSIS IS ONE OF THE MOST PREVA-
lent diseases and one of the
main causes of death among
hospitalized patients.1 Severe
sepsis accounts for 1 in 5 admissions
to intensive care units (ICUs) and is a
leading cause of death in noncardiac
ICUs.2,3 In Spain, the incidence of severe sepsis is 104 cases per 100 000
adult residents per year with a hospital mortality of 20.7%, and the incidence of septic shock is 31 cases per
100 000 adult residents per year with
a mortality of 45.7%.4 In the United
States, the incidence of severe sepsis
is higher (300 cases per 100 000 population) as is the mortality rate (28.6%),
which represents 215 000 deaths
annually.1
Early appropriate antibiotic therapy,5-7
early goal-directed therapy (EGDT),8
corticosteroids,9 recombinant human
activated protein C or drotrecogin
alfa (activated),10 and lung protective
For editorial comment see p 2322.
Context Concern exists that current guidelines for care of patients with severe sepsis
and septic shock are followed variably, possibly due to a lack of adequate education.
Objective To determine whether a national educational program based on the Surviving Sepsis Campaign guidelines affected processes of care and hospital mortality
for severe sepsis.
Design, Setting, and Patients Before and after design in 59 medical-surgical intensive care units (ICUs) located throughout Spain. All ICU patients were screened daily
and enrolled if they fulfilled severe sepsis or septic shock criteria. A total of 854 patients
were enrolled in the preintervention period (November-December 2005), 1465 patients
during the postintervention period (March-June 2006), and 247 patients during the longterm follow-up period 1 year later (November-December 2006) in a subset of 23 ICUs.
Intervention The educational program consisted of training physicians and nursing staff
from the emergency department, wards, and ICU in the definition, recognition, and treatment of severe sepsis and septic shock as outlined in the guidelines. Treatment was organized in 2 bundles: a resuscitation bundle (6 tasks to begin immediately and be accomplished
within 6 hours) and a management bundle (4 tasks to be completed within 24 hours).
Main Outcome Measures Hospital mortality, differences in adherence to the bundles’
process-of-care variables, ICU mortality, 28-day mortality, hospital length of stay, and
ICU length of stay.
Results Patients included before and after the intervention were similar in terms of age,
sex, and Acute Physiology and Chronic Health Evaluation II score. At baseline, only 3 processof-care measurements (blood cultures before antibiotics, early administration of broadspectrum antibiotics, and mechanical ventilation with adequate inspiratory plateau pressure) we had compliance rates higher than 50%. Patients in the postintervention cohort
had a lower risk of hospital mortality (44.0% vs 39.7%; P=.04). The compliance with
process-of-care variables also improved after the intervention in the sepsis resuscitation
bundle (5.3% [95% confidence interval [CI], 4%-7%] vs 10.0% [95% CI, 8%-12%];
P⬍.001) and in the sepsis management bundle (10.9% [95% CI, 9%-13%] vs 15.7%
[95% CI, 14%-18%]; P=.001). Hospital length of stay and ICU length of stay did not
change after the intervention. During long-term follow-up, compliance with the sepsis
resuscitation bundle returned to baseline but compliance with the sepsis management
bundle and mortality remained stable with respect to the postintervention period.
Conclusions A national educational effort to promote bundles of care for severe
sepsis and septic shock was associated with improved guideline compliance and lower
hospital mortality. However, compliance rates were still low, and the improvement in
the resuscitation bundle lapsed by 1 year.
www.jama.com
JAMA. 2008;299(19):2294-2303
strategies11 have all been associated with
survival benefits. These and other therapeutic advances led to the development of the Surviving Sepsis Campaign (SSC) guidelines12 as part of a plan
2294 JAMA, May 21, 2008—Vol 299, No. 19 (Reprinted)
Author Affiliations and the Edusepsis Study Group are
listed at the end of this article.
Corresponding Author: Ricard Ferrer, MD, Centre de
Crı́tics, Hospital de Sabadell, Sabadell, Barcelona 08208
Spain ([email protected]).
Caring for the Critically Ill Patient Section Editor:
Derek C. Angus, MD, MPH, Contributing Editor, JAMA.
©2008 American Medical Association. All rights reserved.
OUTCOME AFTER A SEVERE SEPSIS EDUCATIONAL PROGRAM
to reduce severe sepsis mortality by 25%
by 2009. For improving sepsis care, the
SSC and the Institute for Healthcare
Improvement recommend implementing a 6-hour resuscitation bundle including lactate determination, early cultures and antibiotics, and EGDT, as
well as a first 24-hour management
bundle including optimization of glycemic control, respiratory inspiratory
plateau pressure, and determination of
the need for corticosteroids or drotrecogin alfa (activated).
Although some of the recommendations are controversial, several singlecenter studies13-17 suggested qualityimprovement efforts based on the SSC
guidelines were associated with better
outcome.
The aim of the present study was to
determine whether a national educational program based on the SSC guidelines could improve compliance with
recommended processes of care in severe sepsis in Spanish ICUs. We hypothesized that better adherence to
guidelines would result in improved patient outcomes.
METHODS
Study Design
A before and after study design was used.
The before period (preintervention) consisted of all consecutive patients with severe sepsis who were admitted to the participating ICUs 2 months before the
educational program began (NovemberDecember 2005). The intervention was
introduced over a 2-month period (January-February 2006), during which no
patient data were collected. The postintervention period consisted of all consecutive patients with severe sepsis admitted to the participating ICUs during
a 4-month period (March-June 2006). In
addition, to determine the longevity of
the effects of the educational program,
a third observation period, composed of
all consecutive patients admitted to a subset of the participating ICUs during a
2-month period (May-June 2007) 1 year
later was included.
Intervention
Ethics Committee Approval
Each participating centers’ research and
ethical review boards approved the
study and patients remained anonymous. The need for informed consent
was waived in view of the observational and anonymous nature of the
study.
Study Sites
The steering committee of the Edusepsis study defined the project’s purpose, timeline, interventions, and design. Through the Spanish Society of
Intensive Care, all Spanish ICUs for
adults (280 units) were invited to participate. No fees were provided for participation. The study was launched in
July 2005. The ICUs were not asked to
provide reasons for not participating.
Seventy-seven medical-surgical Spanish ICUs homogeneously distributed
around the country were included in
the study. All ICUs were closed units
with a critical care specialist on hand
24 hours per day, 365 days per year.
The general coordinating center was
located at the Critical Care Center of the
Hospital of Sabadell, Barcelona. Each
ICU belonged to a geographical area coordinated by an area coordinator and at
least 1 physician was designated principal investigator in each center.
partial thromboplastin time greater than
60 seconds; (4) thrombocytopenia,
platelet count of less than 100 ⫻ 103/
µL; (5) hyperbilirubinemia, total plasma
bilirubin level of greater than 2.0 mg/dL
(to convert to µmol/L, multiply by
17.104); (6) hypoperfusion, lactate level
greater than 18 mg/dL (to convert to
mmol/L, multipy by 0.111); or (7) hypotension, systolic blood pressure of
less than 90 mm Hg, mean arterial pressure of less than 65 mm Hg, or a reduction in systolic blood pressure of
greater than 40 mm Hg from baseline
measurements. Septic shock was defined as acute circulatory failure (systolic blood pressure ⬍90 mm Hg, mean
arterial pressure ⬍65 mm Hg, or a reduction in systolic blood pressure ⬎40
mm Hg from baseline) despite adequate volume resuscitation.
Patients
All ICU admissions from the emergency department or medical and surgical wards and all ICU patients were
actively screened daily for the presence of severe sepsis or septic shock
using a screening tool, which included definitions of sepsis and organ
dysfunction. When the onset of severe
sepsis could not be determined, patients were not included in the study.
Severe sepsis was defined as sepsis
associated with acute organ dysfunction: (1) respiratory dysfunction, bilateral pulmonary infiltrates with a ratio of PaO2 to FIO2 of less than 300
mm Hg; (2) renal dysfunction, urine
output of less than 0.5 mL/kg per hour
for at least 2 hours or creatinine level
of greater than 2.0 mg/dL (to convert
to µmol/L, multiply by 88.4); (3) coagulation abnormalities, international
normalized ratio greater than 1.5 or a
To standardize the educational program, the general coordinating center
organized meetings with the area coordinators and the principal investigator of the participating centers before
and after each study period. Before the
implementation of the educational program, the importance of the study was
explained to the hospital manager at
each participating center to ensure full
institutional support. The general coordinating center provided specific material for this meeting with information regarding the epidemiology,
morbidity, mortality, and costs of severe sepsis.
The principal investigator acted as local champion, charged with creation of
a local multidisciplinary team with representatives of all pertinent stakeholders, including physicians and nurses
from the ICU and infectious diseases,
emergency, and internal medicine departments. The local multidisciplinary team reviewed the preintervention performance data and shared ideas
about the process improvement goals
and strategies.
Between January and February 2006,
the local multidisciplinary team at each
hospital implemented a homogeneous
predefined multifaceted educational pro-
(Reprinted) JAMA, May 21, 2008—Vol 299, No. 19
2295
gram based on the SSC guidelines.12 The
educational program consisted of training physicians and nursing staff in the
definitions of severe sepsis and septic
shock, their early recognition, and the
treatments included in the guidelines.
The educational program was implemented in the emergency department,
medical and surgical wards, and the ICU.
Each center was provided with specific
training and educational material including: (1) a PowerPoint (Microsoft,
Redmond, Washington) presentation
regarding sepsis definitions, early recognition and treatment including
decision-making algorithms; (2) a
Spanish translation of the SSC guidelines in poster and pocket format; (3)
posters focused on the early recognition of sepsis with definitions of systemic inflammatory response syndrome and sepsis, and information about
its morbidity and mortality; and (4) feedback from the general coordinating center with the baseline period data of each
center compared with global baseline
period data (audit and feedback). Posters were displayed in prominent places
in the emergency departments, medical and surgical wards, and ICUs. Pocket
versions were distributed to all participants in the educational program sessions. All teaching material also was
available from the SEMICYUC’s (Sociedad Española de Medicina Intensiva,
Critica y Unidades Coronarias) Web site
(http://www.semicyuc.org).
The general coordinating center
maintained continuous contact with
the principal investigator of each
center through a mailing list (edu-sepsis
@semicyuc.org). Moreover, after the
educational program, a survey was distributed to all principal investigators to
check that all participating centers had
completed the educational program,
to know the number and duration of
lectures, and to know the subjective
evaluation of the principal investigator
of the main end points of the educational program, which were institutional support, creation of a multidisciplinary team, improvement in
knowledge, and improvement in hospital processes.
Process-of-Care
and Outcome Measurements
The clinical and demographic characteristics of all patients, including age,
sex, Acute Physiology and Chronic
Health Evaluation II (APACHE II)
score, diagnosis at admission, origin of
infection, and organ dysfunction at sepsis presentation were recorded. The onset of sepsis (time zero) was determined according to the patient’s
location within the hospital when sepsis was diagnosed. In patients diagnosed with sepsis in the emergency department, time zero was defined as the
time of triage. For patients admitted to
the ICU from the medical and surgical
wards or other non–emergency department units, time zero was determined
by searching the clinical documentation for the time of diagnosis of severe
sepsis. This might include, for example, a physician’s note or timed and
dated orders, a timed and dated note of
a nurse’s discussion of severe sepsis with
a physician, or timed records initiating referral to the ICU for severe sepsis. If no time and date could be found
by searching the chart, the default time
of presentation was the time of admission to the ICU. Lastly, for patients who
developed severe sepsis after admission to the ICU, the time of presentation was again determined on the basis of the clinical documentation.
The primary outcome measure was
hospital mortality. Secondary outcome measures included other outcome measurements (ICU mortality,
28-day mortality, hospital length of stay,
and ICU length of stay) and processof-care variables. Process-of-care variables included 10 tasks grouped in the
sepsis resuscitation bundle (comprising 6 tasks that should begin immediately and be accomplished within the
first 6 hours of presentation) and the
sepsis management bundle (consisting of 4 management tasks that should
begin immediately and be completed
within 24 hours of presentation). Time
(0 to 12 hours) also was recorded from
sepsis presentation to the process-ofcare variables of serum lactate measurement, blood culture extraction, the
administration of broad spectrum antibiotics, achievement of central venous pressure of 8 mm Hg or greater,
and central venous oxygen saturation
of 70% or greater.
Data Collection
and Quality Control
Data were collected prospectively daily
using preprinted case report forms. Detailed instructions explaining the aim
of the study, instructions for the data
collection, and definitions for various
items were made available to all investigators before data collection started.
Completed data forms were mailed to
the coordinating center and registered
in the database by a research nurse with
experience in sepsis trials. Errors or
blank fields generated queries that were
returned to each center for correction.
For quality assurance purposes, data
were checked for completeness, accuracy, and uniformity. Also, a random
sample of 10% of patients was reevaluated. Inter-rater reliability for the variables was assessed in this sample. ␬ coefficients were calculated as appropriate.
A reliability of 96.5% of all variables per
case report form was observed.
Statistical Analysis
The study was designed with a power
of 80% and a type I error of 5% to detect a 15% relative reduction in septic
shock mortality, which was estimated
at 45%,4 and for logistic reasons the preintervention to postintervention ratio
was 1:2. Therefore, a total of 1875 patients were needed. To reach this number, we calculated that we needed 2
months for the baseline period and 4
months for the postinterventional period with the participation of at least 55
ICUs. Descriptive statistics included frequencies and percentages for categorical variables and means, standard deviations, confidence intervals (CIs),
medians, and interquartile ranges for
continuous variables. To compare continuous variables during the 2 study periods, the t test or the Mann-Whitney
test was used when appropriate. To analyze categorical variables during the 2
study periods, ␹2 analysis was used.
Multivariate logistic regression was
performed, with hospital mortality as
the dependent variable and the educational program, APACHE II score, age,
patient location at sepsis diagnosis, and
the presence of shock as independent
variables. Because the 2 periods of the
study took place in different seasons
and pneumonia may have a different
seasonal incidence, a sensitivity analysis was conducted by fitting the previous multivariate logistic regression
model but including pneumonia as another independent variable into the
model. Kaplan-Meier curves representing the 28-day mortality stratified according to group assignment were compared using a log-rank test. Because the
missing data rate in the study was low
(the variable with the highest missing
rate was an APACHE II score with a rate
of 1.5%), no imputation of missing data
was performed. Although statistical
tests were 2-tailed and significance was
set at a level of .05 for process-of-care
variables, corrections for multiple comparisons also were pursued using the
Bonferroni method (for the 10 variables, an adjusted significance level cutoff of .005 was used). All analyses were
conducted using SPSS version 15.0
(SPSS, Chicago, Illinois).
RESULTS
Eighteen of the 77 participating ICUs
were excluded because they failed to
complete the postintervention period.
One hundred fifty-one patients treated
in these units were excluded. Data from
59 ICUs with a total of 965 critical care
beds were included in the final analysis. All ICUs were medical-surgical and
most (68%) were located in teaching hospitals with residents in training. The excluded units also were mainly medicalsurgical units, with residents in training
(66%) and had a total of 250 critical care
beds. Patients from the excluded ICUs
(n=151) were not different from the preintervention cohort in terms of age,
APACHE II score, sex, diagnosis at admission, patient location at sepsis diagnosis, main sources of sepsis, or mortality (44.0% [95% CI, 41%-47%] vs 45.0%
[95% CI, 37%-53%]; P=.82). Eight pa-
tients were excluded because time 0
could not be determined (5 in the preintervention cohort and 3 in the postintervention cohort).
Educational Program
Educational lectures and dissemination sessions for attending physicians
and nurses from the emergency department, medical and surgical wards, and
ICU were conducted at all sites. The
mean time dedicated to lectures was
10.6 hours at each center, mostly focused in the ICU (3.5 hours) and the
emergency department (2.5 hours). The
principal investigators considered that
they received the institutional support of their centers in 68% of cases, but
only succeeded in the creation of a mul-
tidisciplinary team in 47.2% of cases.
The principal investigators considered that the staff’s knowledge improved in 96.2% of centers, while they
considered that hospital processes improved in 86.8% of centers.
Patient Characteristics
A total of 2319 patients fulfilled severe sepsis or septic shock criteria during the preintervention and postintervention periods. The mean (SD) age
was 62.2 (16.3) years and the mean
(SD) APACHE II score was 21.2 (7.7);
60.8% (n = 1411) were male, 79.4%
(n=1842) had septic shock, and hospital mortality was 41.2% (n=956). An
additional 254 patients were included
in the long-term follow-up period.
Table 1. Demographic and Clinical Characteristics of Patients
Characteristic
APACHE II
Age, y
Male sex
Diagnosis on admission
Medical
Surgical, urgent
Surgical, nonurgent
Trauma
Other
Patient location at sepsis diagnosis
Emergency department
Medical-surgical ward
ICU
Origin of infection
Pneumonia
Acute abdominal infection
Urinary tract infection
Meningitis
Soft-tissue infection
Catheter-related bacteriemia
Other infections
Multiple infection sites
Organ dysfunction criteria at sepsis
presentation
Hemodynamic
Respiratory
Renal
Hyperbilirubinemia
Thrombocytopenia
Coagulation
Hyperlactatemia
Preintervention
Cohort (n = 854)
Mean (SD) [95% CI]
21.0 (7.5) [20.5-21.5]
62.4 (16.4) [61.3-63.5]
Postintervention
Cohort (n = 1465)
P
Value
21.3 (7.8) [20.9-21.7]
62.1 (16.3) [61.3-63.0]
.39
.74
No. (%) [95% CI]
529 (61.9) [59-65]
882 (60.2) [58.0-63.0]
.41
539 (63.1) [60-66]
243 (28.5) [25-31]
47 (5.5) [4-7]
18 (2.1) [1-3]
7 (0.8) [0-1]
902 (61.7) [59-64]
419 (28.6) [26-31]
86 (5.9) [5-7]
37 (2.5) [2-3]
19 (1.3) [1-2]
.65
351 (41.1) [38-44]
385 (45.1) [42-48]
118 (13.8) [12-16]
613 (41.8) [39-44]
641 (43.8) [41-46]
211 (14.4) [13-16]
.81
329 (38.5) [35-42]
248 (29.0) [26-32]
82 (9.6) [8-12]
17 (2.0) [1-3]
37 (4.3) [3-6]
19 (2.2) [1-3]
108 (12.6) [10-15]
14 (1.6) [1-2]
503 (34.3) [32-37]
424 (28.9) [27-31]
165 (11.3) [10-13]
56 (3.8) [3-5]
49 (3.3) [2-4]
35 (2.4) [2-3]
170 (11.6) [10-13]
63 (4.3) [3-5]
.002
712 (83.4) [81-86]
573 (67.1) [64-70]
615 (72.0) [69-75]
164 (19.2) [17-22]
213 (24.5) [22-28]
301 (35.2) [32-38]
287 (33.6) [30-37]
1191 (81.3) [79-83]
923 (63.0) [61-65]
1076 (73.4) [71-76]
247 (16.9) [15-19]
361 (24.6) [22-27]
503 (34.3) [32-37]
513 (35.0) [33-37]
.21
.05
.45
.15
.87
.66
.49
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; ICU, intensive care unit.
2297
The preintervention cohort included 854 patients and the postintervention cohort included 1465 pa-
tients. The characteristics of patients
in the preintervention cohort and the
postintervention cohort were similar
Table 2. Performance of Process-of-Care Measurements
Preintervention
Cohort (n = 854)
No. (%) [95% CI]
Type of Measure
Sepsis resuscitation bundle
(first 6 h after presentation)
Measure lactate
Blood cultures before
antibiotics
Broad-spectrum
antibiotics
Fluids and vasopressors
Central venous pressure
ⱖ8 mm Hg
Central venous oxygen
saturation ⱖ70%
All resuscitation measures
Sepsis management bundle
(first 24 h after presentation)
Consideration of low-dose
steroids for septic shock
according to ICU policy
Consideration of drotrecogin
alfa (activated) according
to ICU policy
Glucose control
Plateau-pressure control
All management measures
Administration of medication
Low-dose steroids
Drotrecogin alfa (activated)
Postintervention
Cohort (n = 1465)
P
Value
334 (39.0) [36-42]
465 (54.4) [51-58]
736 (50.1) [48-53]
914 (62.4) [60-65]
⬍.001
⬍.001
568 (66.5) [63-70]
1009 (68.9) [67-71]
.24
329 (40.9) [37-44]
167 (21.4) [19-24]
630 (46.7) [44-49]
344 (26.7) [24-29]
.008
.007
49 (6.3) [5-8]
147 (11.4) [10-13]
⬍.001
45 (5.3) [4-7]
147 (10.0) [8-12]
⬍.001
320 (45.4) [42-49]
662 (54.7) [51-57]
⬍.001
378 (44.3) [41-48]
760 (51.9) [49-54]
⬍.001
381 (44.6) [41-48]
424 (85.7) [83-89]
93 (10.9) [9-13]
726 (49.6) [47-52]
712 (82.7) [80-85]
230 (15.7) [14-18]
.02
.15
.001
311 (36.4) [33-40]
51 (6.0) [4-8]
611 (41.7) [39-44]
74 (5.1) [4-6]
⬍.001
.20
Mean (SD) [95% CI]
Time from presentation, min
Serum lactate measured
Blood culture obtained
Antibiotics administered
Central venous pressure
ⱖ8 mm Hg achieved
Central venous oxygen
saturation ⱖ70% achieved
152.5 (146.5) [137.4-167.5]
136.5 (165.5) [120.0-153.0]
156.0 (167.0) [139.9-172.0]
238.4 (188.6) [219.4-257.3]
140.4 (137.4) [130.8-150.1]
116.4 (146.3) [106.2-126.6]
129.4 (136.8) [120.2-138.6]
241.6 (193.4) [226.7-256.5]
245.0 (212.0) [203.9-286.3] 258.9 (200.5) [235.4-282.5]
.18
.03
.003
.79
.55
Abbreviations: CI, confidence interval; ICU, intensive care unit.
Table 3. Performance of Outcome Measurements
Preintervention
Cohort (n = 854)
Mortality, No. (%) [95% CI]
Hospital
28-d
ICU
Hospital stay, d a
Mean (SD) [95% CI]
Median (IQR)
ICU stay, d a
Mean (SD) [95% CI]
Median (IQR)
Postintervention
Cohort (n = 1465)
P
Value
376 (44.0) [41-47]
311 (36.4) [33-40]
315 (36.9) [34-40]
580 (39.7) [37-42]
456 (31.1) [29-33]
474 (32.4) [30-35]
.04
.009
.03
28.7 (23.4) [26.6-30.8]
20.9 (13.5-35.7)
30.7 (25.7) [29.0-32.4]
22.8 (13.3-41.4)
.16
.25
13.4 (16.0) [11.9-14.0]
7.6 (4.5-15.0)
13.6 (16.3) [12.5-14.7]
7.7 (4.0-15.9)
.87
.83
Abbreviations: CI, confidence interval; ICU, intensive care unit; IQR, interquartile range.
a Deaths are excluded.
(TABLE 1), with no statistically significant differences in age, sex, or APACHE
II score. Diagnosis on admission was
mainly medically or surgically urgent
in both cohorts. Patient location at sepsis diagnosis was predominantly in the
emergency department and the medical-surgical wards with no significant
differences between the 2 periods. The
main sources of sepsis were pneumonia and acute abdominal infections in
both periods. Pneumonia was more frequent in the preintervention cohort. In
the postintervention cohort, patients
with urinary tract infection, meningitis, and multiple infection sites were
slightly more frequent. There were no
differences in organ dysfunction criteria at sepsis presentation, except for respiratory dysfunction, which was more
frequent in the preintervention cohort. Hemodynamic dysfunction was
present in more than 80% of cases in
both periods.
Performance of Process-of-Care
Indicators
At baseline (TABLE 2), compliance with
the SSC recommendations was only
5.3% (95% CI, 4%-7%) for the sepsis
resuscitation bundle and 10.9% (95%
CI, 9%-13%) for the sepsis management bundle. Regarding the sepsis resuscitation bundle, the only 2 processof-care measurements that showed
compliance higher than 50% were
blood cultures before antibiotics (54.4%
[95% CI, 51%-58%]) and early administration of broad spectrum antibiotics (66.5% [95% CI, 63%-70%]). The
measures related to EGDT, which required the insertion of a central venous catheter, were implemented in
only 40.9% (95% CI, 37%-44%) of cases
for fluids and vasopressors, 21.4% (95%
CI, 19%-24%) for optimization of central venous pressure, and 6.3% (95% CI,
5%-8%) for optimization of central venous oxygen saturation. Regarding the
sepsis management bundle, the ventilatory support was adequate in 85.7%
(95% CI, 83%-89%) of mechanically
ventilated patients; however, glucose
control was adequate in only 44.6%
(95% CI, 41%-48%) of cases. The pos-
Figure. Probability of Survival in Patients With Severe Sepsis in the Preintervention and
Postintervention Cohorts According to the Length of Survival
1.0
Probability of Survival
sible use of low-dose steroids was contemplated, although not necessarily carried out, in only 45.4% (95% CI, 42%49%) of septic shock patients, while in
the rest of patients it was not even considered. Regarding drotrecogin alfa (activated), the possible use was contemplated, although not necessarily carried
out, in only 44.3% (95% CI, 41%48%) of patients.
Process-of-care measurements
improved after the educational program (Table 2). All elements of the sepsis resuscitation bundle improved significantly after the educational program,
except early administration of broadspectrum antibiotics (66.5% [95% CI,
63%-70%] to 68.9% [95% CI, 67%71%]; P=.24). Likewise, all elements of
the sepsis management bundle improved
significantly after the educational program, except control of plateau pressure (85.7% [95% CI, 83%-89%] to
82.7% [95% CI, 80%-85%]; P=.15). The
percentage of patients in whom care complied with all resuscitation and all management measures improved significantly after the educational program.
Following correction for multiple comparisons, lactate measurement, blood cultures before antibiotics, central venous
oxygen saturation of 70% or greater, and
steroids and drotrecogin alfa according
to ICU policy maintained their initial significant differences. Fluids plus vasopressors (central venous pressure ⱖ8
mm Hg) and glucose control lost their
significance. While the recommendation to consider steroids in septic shock
and drotrecogin alfa (activated) was better implemented after the intervention
(steroids, 45.4% [95% CI, 42%-49%] vs
54.7% [95% CI, 51%-57%]; P⬍.001 and
drotrecogin alfa, 44.3% [95% CI, 41%48%] vs 51.9% [95% CI, 49%-54%];
P ⬍ .001), the percentage of cases in
which low-dose steroids were administered increased from 36.4% (95% CI,
33%-40%) to 41.7% (95% CI, 39%44%) (P⬍.001) after the educational program, but the percentage of cases in
which drotrecogin alfa (activated) was
actually administered remained stable.
The time from sepsis presentation to
process-of-care variables is reported in
0.8
Postintervention cohort
0.6
Preintervention cohort
0.4
0.2
0
Log-rank P = .01
7
14
21
28
569
1050
543
1009
Time, d
No. at risk
Preintervention 854
Postintervention 1465
675
1201
Table 2. After the educational program, the mean time to the obtainment
of blood cultures and to the administration of broad-spectrum antibiotics was
reduced by 20 and 26 minutes, respectively. The educational program did not
shorten the time elapsed before lactate
determination (central venous pressure ⱖ8 mm Hg achievement or central venous oxygen saturation of ⱖ70%
achievement).
Outcome Indicators
The outcome data are shown in
TABLE 3. Patients in the postintervention cohort had a statistically significant lower risk of hospital mortality
(44.0% [95% CI, 41%-47%] vs 39.7%
[95% CI, 37%-42%]; P = .04) and 28day mortality (36.4% [95% CI, 33%40%] vs 31.1% [95% CI, 29%-33%];
P = .009) compared with the preintervention cohort. A Kaplan-Meier plot of
the probability of remaining alive is
shown in the FIGURE. The ICU mortality also was significantly lower in the
postintervention cohort. No differences were observed in hospital or ICU
stay in the surviving populations before and after the educational program.
Multivariate logistic regression
(TABLE 4) to adjust for possible confounders (APACHE II score, age, patient location at sepsis diagnosis, and the
presence of shock) showed that the postintervention cohort was independently
613
1105
Table 4. Multivariate Analysis of Factors
Associated With Mortality
Odd Ratio
Factor
(95% CI)
Interventional cohort 0.81 (0.67-0.98)
1.014
Age a
(1.008-1.020)
1.10 (1.08-1.11)
APACHE II b
Sepsis presentation
and diagnosis c
Medical1.63 (1.34-1.99)
surgical
ward
ICU
2.39 (1.81-3.15)
Shock
1.28 (1.01-1.62)
P
Value
.03
⬍.001
⬍.001
⬍.001
⬍.001
.04
Abbreviations: APACHE II, Acute Physiology and Chronic
Health Evaluation II; CI, confidence interval; ICU, intensive care unit.
a Per year.
b Per each point increase.
c Compared with the emergency department.
associated with lower hospital mortality (odds ratio, 0.81 [95% CI, 0.670.98]; P=.03). The sensitivity analysis
that included pneumonia into the regression showed highly consistent results with the results presented in Table 4
(odds ratio for the postintervention cohort 0.83 [95% CI, 0.68-1.00); P=.04).
Effectiveness of the Intervention
According to Process of Care
at Baseline
The ICUs were classified in 3 categories
by percentiles depending on the process of care at baseline, measured by the
number of tasks included in the bundles
completed (TABLE 5). Baseline care of pa-
2299
Table 5. Impact of the Educational Program on Process-of-Care Measurement and Outcome
Depending on Hospital Categorization According to Baseline Compliance With the Guidelines
Type of Measure
Category 1 hospitals (n = 20)
No. of tasks completed,
mean (SD) [95% CI]
Resuscitation bundle completed,
No. (%) [95% CI]
Management bundle completed,
No. (%) [95% CI]
Hospital mortality, No. (%) [95% CI]
APACHE II, mean (SD) [95% CI]
mean (SD) [95% CI]
No. (%) [95% CI]
No. (%) [95% CI]
mean (SD) [95% CI]
No. (%) [95% CI]
No. (%) [95% CI]
Preintervention
Cohort
Postintervention
Cohort
P
Value
3.25 (1.56) [3.0-3.4]
4.42 (1.97) [4.2-4.6]
⬍.001
1 (0.5) [0-1]
13 (6.4) [3-10]
16 (4.7) [2-7]
.006
36 (10.6) [7-14]
.10
98 (48.0) [41-55]
20.6 (7.4) [19.6-21.6]
134 (39.3) [34-44]
20.0 (7.3) [19.2-20.8]
.05
.37
4.65 (1.72) [4.46-4.85]
5.22 (1.98) [5.06-5.38]
⬍.001
11 (3.6) [2-6]
47 (7.8) [6-10]
.02
24 (7.9) [5-11]
67 (11.2) [9-14]
.13
135 (44.7) [39-50]
20.7 (7.3) [19.8-21.6]
245 (40.9) [37-45]
21.8 (8.1) [20.9-22.0]
.28
.07
5.90 (1.92) [5.70-6.11]
6.45 (2.00) [6.27-6.62]
⬍.001
33 (9.5) [6-13]
56 (16.1) [12-20]
143 (41.1) [36-46]
21.5 (7.3) [20.7-22.3]
84 (16) [13-19]
.006
127 (24.2) [21-28]
.004
201 (38.3) [34-42]
21.6 (7.7) [21.0-22.0]
.41
.87
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval.
tients treated in category 1 ICUs (20
ICUs) complied with less than 4 tasks;
baseline care in category 2 ICUs (19
ICUs) complied with 4 to 5 tasks; and
baseline care in category 3 ICUs (20
ICUs) complied with more than 5 tasks.
The educational program improved the
process of care in all 3 categories of ICUs
(relative improvement of tasks completed of 36.0% in category 1, 12.2% in
category 2, and 9.3% in category 3) but
only reduced mortality in category 1
ICUs (48.0% [95% CI, 41%-55%] vs
39.3% [95% CI, 34%-44%]; P=.046).
Long-term Follow-up
One year after the postintervention period, 23 centers participated in a
2-month follow-up study to measure
the long-term effects of the educational program (n = 247 patients). No
differences in the epidemiological characteristics of patients were observed
(TABLE 6). The percentage of patients
in whom care complied with all resuscitation measures returned to baseline
in the long-term follow-up period (preintervention, 6.3% [95% CI, 4%-9%];
postintervention, 12.9% [95% CI, 10%16%]; long-term follow-up, 7.3% [95%
CI, 4%-11%]; P = .003). The percentage of patients in whom care complied with all management measures
was stable with respect to the postintervention period (preintervention, 9.4%
[95% CI, 6%-13%]; postintervention,
19.6% [95% CI, 16%-23%]; long-term
follow-up, 26.7% [95% CI, 21%32%]; P ⬍ .001), and mortality remained stable with respect to the postintervention period (preintervention,
42.5% [95% CI, 37%-48%]; postintervention, 38.7% [95% CI, 34%-43%];
long-term follow-up, 38.5% [95% CI,
32%-45%]; P =.50).
COMMENT
Implementing an educational program
based on the SSC guidelines and bundles
improved the process-of-care variables
and reduced mortality in patients with
severe sepsis and septic shock. Given the
incidence of septic shock of 31 cases per
100 000 adult residents per year and the
total adult population of 36 million in
Spain, 490 lives may have been saved by
this effort in 1 year if the educational program had been extended to all Spanish
hospitals. The strengths of this study are
its preintervention and postintervention design, the large cohort of patients,
and the participation of 59 centers in
Spain (21% of all ICUs in the country).
The mortality, age, comorbidities, and
source of sepsis in our study population is comparable with those found in
several epidemiological studies on
sepsis.4,18
At baseline, the adherence to SSC recommendations was poor; however, this
is not surprising because it has been reported by other investigators in Spain.19
Gao et al17 found better compliance
rates in 2 teaching hospitals in England, whereas Nguyen et al16 found
better baseline compliance with antibiotic use but results similar to ours for
EGDT and steroids. In the study by
Micek et al,14 baseline compliance was
slightly better for antibiotics but worse
for the rest of the medical care processes recommended by the guidelines.
All process-of-care measurements improved after the educational program, except antibiotic use and plateau pressure
control. These were the 2 measures
implemented best in the preintervention cohort; therefore, it is likely that they
did not improve because there was less
room for improvement. On the other
hand, the time to antibiotic treatment was
significantly shorter after the educational program, and this could be considered an improvement in the overall
use of antibiotics.
This is the first study to prospectively evaluate the impact of an educational program on guideline compliance and mortality in patients with
severe sepsis. This strategy has been
tested before in community-acquired
pneumonia with similar results.20,21
However, other investigators could not
reproduce these results.22 Recently, also
in community-acquired pneumonia,
Barlow et al23 showed that a multifaceted educational strategy was able to re-
duce door-to-antibiotic time, a processof-care variable associated with better
outcome.
At long-term follow-up, some of the
improvements achieved by the educational program had returned to baseline, especially process-of-care measures in the acute phase of treatment.
However, it is well-known that qualityimprovement initiatives should be sustained,24 especially in areas like the
emergency department in which physician turnover is higher than in other
areas of the hospital. Applying the
“plan-do-study-act” cycles is probably
the best approach to sustain the effect
of the educational program.
Previous studies found that better
compliance with the SSC guidelines was
associated with better outcome, but
most of these were single-center trials,
involving small numbers of patients and
did not prospectively test the ability to
change clinical practice with a multifacteted educational initiative.13-17 Shapiro et al 25 were unable to demonstrate mortality benefits, but they
showed that it is feasible to change the
quality of care in severe sepsis using
protocols based on the SSC guidelines. Our data showed that there is a
possible relationship between baseline compliance with the guidelines and
the effect of the educational program,
suggesting that educational efforts are
most effective when applied in ICUs
with low baseline compliance with the
guidelines.
The decreased mortality observed in
our study and other studies13-17 might
derive from better identification of
patients with severe sepsis or from improved compliance with quality indicators, including earlier administration of antibiotics, or both. Kumar et
al6 showed that a 1-hour decrease in the
time to antibiotic administration could
improve survival. The design of this
study did not enable these hypotheses
to be tested separately. It is unlikely that
the improvement in mortality in the
postintervention cohort was due to differences between the 2 cohorts, although it could be postulated that the
decrease in mortality was due to a
slightly higher frequency of urinary
tract infection in the postintervention
cohort, which is associated to lower
mortality,5 or due to seasonal effect with
lower incidence of pneumonia in the
postintervention cohort. The sensitivity analysis showed that the effect of the
educational program on mortality was
independent of the cause of sepsis.
Several areas for improvement have
been identified through this process, including the rate of compliance with the
EGDT-related variables remained below 50% in the postinterventional pe-
Table 6. Long-term Follow-up
Type of Measure
Sepsis resuscitation bundle (first 6 h after presentation)
Measure lactate
Blood cultures before antibiotics
Broad-spectrum antibiotics
Central venous pressure ⱖ8 mm Hg
Central venous oxygen saturation ⱖ70%
All resuscitation measures
Sepsis management bundle (first 24 h after presentation)
Consideration of therapy according ICU policy
Low-dose steroids for septic shock
Glucose control
Plateau-pressure control
Preintervention
Cohort (n = 318)
No. (%) [95% CI]
Postintervention
Cohort (n = 504)
Long-term
Cohort (n = 247)
P
Value
136 (42.8) [37-48]
170 (53.5) [48-59]
208 (65.4) [60-71]
134 (44.7) [37-48]
73 (25.2) [18-28]
29 (10.0) [6-12]
20 (6.3) [4-9]
308 (61.1) [57-65]
305 (60.5) [56-65]
358 (71.0) [67-75]
267 (53.0) [49-57]
151 (30.0) [26-34]
69 (13.7) [11-17]
65 (12.9) [10-16]
172 (69.6) [64-75]
146 (59.1) [53-65]
140 (56.7) [51-63]
161 (65.2) [59-71]
97 (39.3) [33-45]
36 (14.6) [10-19]
18 (7.3) [4-11]
⬍.001
.13
⬍.001
⬍.001
⬍.001
.05
.003
116 (44.3) [38-50]
122 (38.4) [33-44]
142 (44.7) [39-50]
166 (87.8) [83-92]
30 (9.4) [6-13]
244 (59.1) [54-64]
247 (49.0) [45-53]
257 (51.0) [47-55]
276 (89.6) [86-93]
99 (19.6) [16-23]
147 (69.7) [63-76]
146 (59.1) [53-65]
139 (56.3) [50-62]
146 (94.8) [91-98]
66 (26.7) [21-32]
⬍.001
⬍.001
.02
.08
⬍.001
Hospital mortality
Administration of medication
Low-dose steroids
135 (42.5) [37-48]
195 (38.7) [34-43]
95 (38.5) [32-45]
.50
113 (35.5) [30-41]
25 (7.9) [5-11]
129 (26.6) [22-29]
32 (6.3) [4-8]
124 (50.2) [44-56]
27 (10.9) [7-15]
.02
.09
APACHE II
Mean (SD) [95% CI]
20.5 (7.0) [19.8-21.3]
20.8 (7.4) [20.2-21.6]
20.5 (7.0) [19.9-21.9]
.81
125.5 (127.4) [112-139]
116.4 (144.1) [99-133]
117.1 (133.6) [101-133]
212.9 (185.1) [181-242]
237.7 (199.6) [201-274]
126.7 (127.3) [108-145]
117.0 (169.1) [90-144]
148.4 (144.8) [125-171]
211.4 (167.3) [184-239]
243.9 (210.5) [234-332]
Time from presentation, min
Serum lactate measured
Blood culture obtained
Antibiotics administered
Central venous pressure ⱖ8 mm Hg achieved
Central venous oxygen saturation ⱖ70% achieved
150.5 (134.7) [129-173]
150.4 (177.5) [121-180]
162.7 (169.7) [135-191]
211.2 (184.6) [181-242]
202.3 (198.8) [146-259]
.13
.10
.01
⬎.99
.09
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; CI, confidence interval; ICU, intensive care unit.
2301
riod. Additionally, the use of low-dose
steroids and drotrecogin alfa (activated) according to a standardized ICU
policy improved after the educational
program, but remained low. While clinicians considered drotrecogin alfa (activated) more frequently after the educational program, they did not administer
the drug more frequently. Further improvement in these areas might help to
increase survival even more.
Rubenfeld 26 categorized the possible reasons for the gap between evidence (guidelines) and practice into 3
major groups: knowledge barriers, attitude barriers, and behavioral barriers. A recent survey conducted in emergency departments of the 25 most
densely populated areas in the United
States concluded that the barriers to
implementing time-sensitive resuscitation to patients with severe sepsis are
shortage of nursing staff, problems in
obtaining central venous pressure
monitoring, and challenges in identifying patients with severe sepsis.27 The
educational program was focused on
overcoming knowledge barriers and
probably had some impact on attitude
and behavioral barriers.
Our study has limitations. First, the
design makes it difficult to establish a
causal connection between the intervention and the improvement in process-of-care variables and outcome. The
use of a control group20 or the use of
groups with progressive intensity of the
education21 would have allowed us to
rule out a possible effect of a secular
trend on the improvement in sepsis
treatment. However, this was not feasible because all the participating units
wanted to do the full intervention and
ethical constraints proscribed failing to
promote the standard of care in some
units. On the other hand, the short period between the 2 study periods lends
weight to the supposition of a true and
strong association between the intervention and the outcome. Second, the
duration of the educational program
was only 2 months, and a longer educational period might have enabled
greater improvements in compliance
with the quality indicators and sur-
vival. Third, the use of other educational strategies like academic detailing has been useful in other studies28
and should be considered in future
quality-improvement projects. Fourth,
because the majority of patients had
septic shock, we cannot know whether
the effects of the educational program
would have been the same on patients
with severe sepsis who had not developed septic shock. Fifth, because our
study was limited to patients admitted
to the ICU, we do not know the effects
of the educational program on patients with severe sepsis cared for in
other areas of the hospital.
CONCLUSIONS
The baseline compliance with the SSC
guidelines in Spain in 2005 was low. A
national educational effort to promote
bundles of care for severe sepsis and
septic shock was associated with improved guideline compliance and lower
hospital mortality. However, compliance rates were still low, and the improvement in the resuscitation bundle
lapsed by 1 year.
Author Affiliations: Centro de Crı́ticos, Hospital de Sabadell, CIBER Enfermedades Respiratorias, Instituto Universitario Parc Tauli, Universidad Autónoma de Barcelona, Barcelona, Spain (Drs Ferrer and Artigas); Medical
Intensive Care Unit, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island
(Dr Levy); Servicio de Medicina Intensiva, Hospital Universitario Rio Hortega, Valladolid, Spain (Dr Blanco);
Servicio de Medicina Intensiva, Hospital General Universitario Morales Meseguer, Murcia, Spain (Dr González-Dı́az); Servicio de Medicina Intensiva, Hospital Universitario Virgen del Rocio, Sevilla, Spain (Dr GarnachoMontero); Servicio de Medicina Intensiva, Hospital
Universitario de Son Dureta, Palma de Mallorca, Spain
(Dr Ibáñez); Servicio de Medicina Intensiva, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Dr
Palencia); Servicio de Medicina Intensiva, Hospital Nuestra Señora del Prado, Talavera de la Reina, Toledo, Spain
(Dr Quintana); and Servicio de Medicina Intensiva, Hospital Clı́nico Universitario Virgen de la Victoria, Málaga,
Spain (Dr de la Torre-Prados).
Author Contributions: Dr Ferrer had full access to all of
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Ferrer, Artigas, Levy, Blanco,
Garnacho-Montero, Ibáñez, Palencia, Quintana, de la
Torre-Prados.
Acquisition of data: Ferrer, Blanco, González-Dı́az,
Garnacho-Montero, Ibáñez, Palencia, Quintana, de la
Torre-Prados.
Analysis and interpretation of data: Ferrer, Artigas,
Levy, González-Dı́az, Palencia.
Drafting of the manuscript: Ferrer, Levy, Artigas.
Critical revision of the manuscript for important intellectual content: Ferrer, Artigas, Levy, Blanco,
González-Dı́az, Garnacho-Montero, Ibáñez, Palencia,
Quintana, de la Torre-Prados.
Statistical analysis: Ferrer.
Obtained funding: Artigas.
Administrative, technical, or material support: Artigas,
Levy, Blanco, González-Dı́az, Palencia, de la Torre-Prados.
S t u d y s u p e r v i s i o n : B l a n c o , G o n z á l e z - D ı́ a z ,
Garnacho-Montero, Ibáñez, Palencia.
Financial Disclosures: Dr Ferrer reported serving as a
speaker in scientific meetings organized and financed
by Eli Lilly & Co. Dr Artigas reported serving as a speaker
in scientific meetings and in the advisory committee
organized and financed by Eli Lilly & Co. Dr Levy reported serving as a speaker in scientific meetings financed by Eli Lilly & Co and Edwards Lifesciences and
reported receiving research support from Eli Lilly & Co,
Phillips Medical Systems, Novartis, and Biosite. No other
authors reported financial disclosures.
Funding/Support: The Spanish Society of Intensive
Medicine and Coronary Units provided logistic support for mailings, the Web site, and meetings of the
steering committee. The Surviving Sepsis Campaign
provided all the printed material for the educational
program and the database.
Role of the Sponsor: The Spanish Society of Intensive Medicine and Coronary Units and the Surviving
Sepsis Campaign had no involvement in the design
and conduct of the study; in the collection, management, analysis, or interpretation of the data; or in the
preparation, review, or approval of the manuscript.
Steering Committee: Antonio Artigas, Jesús Blanco,
Gumersindo Gonzalez-Dı́az, Ricard Ferrer, José Garnacho-Montero, Jordi Ibáñez, Mitchell M. Levy, Eduardo Palencia, Manuel Quintana, and Marı́a Victoria
de la Torre.
General Coordination: Antonio Artigas and Ricard Ferrer.
Surviving Sepsis Campaign Coordination: Mitchell M.
Levy.
Area Coordinators: Jesús Blanco, Gumersindo Gonzalez-Dı́az, Ricard Ferrer, José Garnacho-Montero, Jordi
Ibáñez, Eduardo Palencia, Manuel Quintana, and Marı́a
Victoria de la Torre.
Data Monitoring: Gemma Gomà, research nurse, Centro de Crı́ticos, Hospital de Sabadell, Spain.
Statistical Support: David Suarez, MSc, and Jordi Real,
MSc, Unidad de Epidemiologia, Fundación Parc Tauli,
Universidad Autónoma de Barcelona, Spain.
Administrative Support: Inmaculada Martin, administrative technician, Centro de Crı́ticos, Hospital de Sabadell, Spain.
Edusepsis Study Group: Ana Navas, Ricard Ferrer, Antonio Artigas (Hospital de Sabadell, Consorci Hospitalari Parc Tauli); Marı́a Álvarez (Hospital de Terrassa); Josep Maria Sirvent, Sara Herranz Ulldemolins
(Hospital Universitari Josep Trueta de Girona); Pedro
Galdós, Goiatz Balziscueta (Hospital General de
Móstoles); Pilar Marco, Izaskun Azkarate (Hospital de
Donostia); Rafael Sierra (Hospital Universitario Puerta del Mar); José Javier Izua (Hospital Virgen del
Camino); José Castaño (Hospital Universitario Virgen de las Nieves); Alfonso Ambrós, Julian Ortega
(Hospital General de Ciudad Real); Virgilio Corcoles
(Complejo Hospitalario Universitario de Albacete); Luis
Tamayo (Hospital Rı́o Carrión); Demetrio Carriedo, Milagros Llorente (Hospital de León); Paz Merino, Elena
Bustamante (Hospital Can Misses); Eduardo Palencia, Pablo Garcı́a Olivares, Patricia Santa Teresa
Zamarro (Hospital Gregorio Marañon Madrid); Carlos Pérez (Hospital Santiago Apóstol); Ana Renedo
(Hospital Morales Messeguer); Silvestre NicolásFranco (Hospital Rafael Méndez); Marı́a Salomé
Sánchez (Hospital Vega Baja); Francisco Javier Gil (Hospital Santa Maria del Rosell); Marı́a Jesús Gómez (Hospital General Universitario Reina Sofı́a de Murcia); Enrique Piacentini (Hospital Mútua de Terrassa); Ana Loza
(Hospital Universitario de Valme); Jordi Ibáñez (Hospital Son Dureta); Silvia Rodrı́guez (Hospital de Manresa); Jose Ángel Berezo, Jesús Blanco (Hospital Rı́o
Hortega Valladolid); Angeles Gabán, Marı́a Jesús López
Cambra, Alec Tallet (Hospital General de Segovia);
Miguel Martı́nez, Jose Antonio Fernández, Fernando
Callejo, Marı́a Jesús López Pueyo (Hospital General
Yagüe); Francisco Gandı́a (Hospital Clı́nico Universitario de Valladolid); José Fernández (Hospital Santa
Bárbara); Juan Carlos Ballesteros (Hospital Universitario de Salamanca); Marı́a Teresa Antuña, Santiago
Herrero (Hospital de Cabueñes); Manuel Valledor, Jose
Gutierrez (Hospital San Agustı́n); Carmen Pérez (Hospital Universitario Insular Gran Canaria); Oscar Rodrı́guez (Hospital Clı́nico Universitario de Valencia); Rafael Dominguez (Hospital Alto Guadalquivir); Josefa
Peinado (Empresa Pública Hospital de Poniente); Marı́a
Victoria de la Torre, Cristina Salazar (Hospital Virgen
Victoria de Málaga); Marı́a de la Cruz Martı́n, Joaquin Ramon (Centro Médico Delfos); Fernando Iglesias Llaca, Lorena Forcelledo Espina, Francisco Ta-
boada Costa, José Antonio Gonzalo Guerra (Hospital
Universitario Central de Asturias); Francisco José Guerrero, Felipe Cañada, Milagros Balaguer, Isabel Mertı́n,
Carmen López, Daniel Sánchez (Hospital Torrecardenas); Josep Costa, Milagros Calizaya (Hospital de Barcelona SCIAS); Angel Arenaza, Ana Morillo, Daniel Del
Toro, Tomás Guzman (Hospital Virgen de la Macarena);
Antonio Blesa, Fernando Martı́nez, Alejandro Moneo
(Hospital San Carlos); Jesús Broch (Hospital de Sagunt); Jose Antonio Camacho (Hospital San Agustı́n
de Linares); Francisco J. Garcia (Hospital de Montilla); Xosé Luis Pérez (Hospital Universitario de Bellvitge); Nieves Garcia (Hospital Universitario La Princesa); Juan Carlos Ruiz, Jesús Caballero, Esther Francisco, Tania Requena, Adolfo Ruiz, José Luis Bóveda
(Hospital Universitari Vall Hebrón); José Miguel Soto,
Constantino Tormo (Hospital Universitario Dr Peset);
Rafael Blancas (Hospital La Mancha-Centro); Manuel
Quintana, Miguel Ángel Taberna (Hospital Nuestra Sra
del Prado); Jose Maria Añon, Juan B. Aranjo (Hospital Virgen de la Luz); Manuel Rodrı́guez (Hospital Juan
Ramon Jiménez); José Maria Garcia (Hospital La Serrania de Ronda); Isabel Rodrı́guez (Hospital General
de Baza); Jesús Huertos (Hospital Universitario Puerto
Real); Carlos Ortiz (Hospital Virgen del Rocio); Eugenia Yuste (Hospital Universitario San Cecilio); Juan Francisco Machado (Hospital Santa Ana-Motril); Dolores
Ocaña (Hospital La Inmaculada); Ramón Vegas (Hospital Valle de los Pedroches); and Luis Vallejo (Hospital SAS La Linea).
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clinical practice in the intensive care unit: the central
role of respiratory care. Respir Care. 2004;49(7):
837-843.
27. Carlbom DJ, Rubenfeld GD. Barriers to implementing protocol-based sepsis resuscitation in the
emergency department: results of a national survey.
Crit Care Med. 2007;35(11):2525-2532.
28. Mol PG, Wieringa JE, Nannanpanday PV, et al.
Improving compliance with hospital antibiotic guidelines: a time-series intervention analysis. J Antimicrob Chemother. 2005;55(4):550-557.
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2001;29(7):1303-1310.
2. Brun-Buisson C, Doyon F, Carlet J, et al; French ICU
Group for Severe Sepsis. Incidence, risk factors, and
outcome of severe sepsis and septic shock in adults:
a multicenter prospective study in intensive care units.
JAMA. 1995;274(12):968-974.
3. Guidet B, Aegerter P, Gauzit R, Meshaka P, Dreyfuss
D. Incidence and impact of organ dysfunctions associated with sepsis. Chest. 2005;127(3):942951.
4. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Sepsis incidence and outcome: contrasting the intensive
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5. Garnacho-Montero J, Garcia-Garmendia JL,
Barrero-Almodovar A, Jimenez-Jimenez FJ, PerezParedes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients
admitted to the intensive care unit with sepsis. Crit
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6. Kumar A, Roberts D, Wood KE, et al. Duration of
hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in
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1589-1596.
7. MacArthur RD, Miller M, Albertson T, et al.
Adequacy of early empiric antibiotic treatment and
survival in severe sepsis: experience from the
MONARCS trial. Clin Infect Dis. 2004;38(2):284288.
8. Rivers E, Nguyen B, Havstad S, et al. Early goaldirected therapy in the treatment of severe sepsis and
septic shock. N Engl J Med. 2001;345(19):13681377.
9. Annane D, Sebille V, Charpentier C, et al. Effect
of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic
shock. JAMA. 2002;288(7):862-871.
2303
Special Article
The Surviving Sepsis Campaign: Results of an international guidelinebased performance improvement program targeting severe sepsis
Mitchell M. Levy, MD; R. Phillip Dellinger, MD; Sean R. Townsend, MD; Walter T. Linde-Zwirble;
John C. Marshall, MD; Julian Bion, MD; Christa Schorr, RN, MSN; Antonio Artigas, MD; Graham Ramsay, MD;
Richard Beale, MD; Margaret M. Parker, MD; Herwig Gerlach, MD, PhD; Konrad Reinhart, MD; Eliezer Silva, MD;
Maurene Harvey, RN, MPH; Susan Regan, PhD; Derek C. Angus, MD, MPH; on behalf of the Surviving Sepsis
Campaign
Objective: The Surviving Sepsis Campaign (SSC or “the Campaign”) developed guidelines for management of severe sepsis
and septic shock. A performance improvement initiative targeted
changing clinical behavior (process improvement) via bundles
based on key SSC guideline recommendations.
Design and Setting: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the intensive
care unit, emergency department, and wards of individual hospitals
and regional hospital networks was implemented voluntarily in the
United States, Europe, and South America. Elements of the guidelines
were “bundled” into two sets of targets to be completed within 6 hrs
and within 24 hrs. An analysis was conducted on data submitted
from January 2005 through March 2008.
Subjects: A total of 15,022 subjects.
Measurements and Main Results: Data from 15,022 subjects at
165 sites were analyzed to determine the compliance with bundle
targets and association with hospital mortality. Compliance with the
entire resuscitation bundle increased linearly from 10.9% in the first
S
site quarter to 31.3% by the end of 2 yrs (p < .0001). Compliance
with the entire management bundle started at 18.4% in the first
quarter and increased to 36.1% by the end of 2 yrs (p ⴝ .008).
Compliance with all bundle elements increased significantly, except
for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37% to 30.8% over 2 yrs
(p ⴝ .001). The adjusted odds ratio for mortality improved the longer
a site was in the Campaign, resulting in an adjusted absolute drop of
0.8% per quarter and 5.4% over 2 yrs (95% confidence interval, 2.5–8.4).
Conclusions: The Campaign was associated with sustained,
continuous quality improvement in sepsis care. Although not
necessarily cause and effect, a reduction in reported hospital
mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts. (Crit Care Med 2010; 38:000 – 000)
KEY WORDS: severe sepsis; septic shock; knowledge transfer;
performance measures; Surviving Sepsis Campaign; performance
improvement; sepsis bundles; quality improvement
evere sepsis accounts for 20%
of all admissions to intensive
care units (ICUs) and is the
leading cause of death in noncardiac ICUs, yet comprehensive clinical
practice guidelines had not existed (1, 2).
In 2002, hopeful that outcomes of sep-
sis might be improved by standardizing
care and informed by data from an increasing number of clinical trials (3–
10), the European Society of Intensive
Care Medicine, the International Sepsis
Forum, and the Society of Critical Care
Medicine launched the Surviving Sepsis
Campaign (SSC or “the Campaign”)
(11). Evidence-based guidelines were
developed through a formal and transparent process (12–14). The initial
guidelines were published in 2004 (endorsed by 11 professional societies); an
updated version was published in 2008
From the Division of Pulmonary, Sleep and Critical
Care Medicine Care Medicine (MML), Brown University
School of Medicine, Rhode Island Hospital, Providence, RI;
Department of Medicine (RPD, CS), University of Medicine
and Dentistry of New Jersey, Cooper University Hospital,
Camden, NJ; The Institute for Healthcare Improvement
(SRT), Cambridge, MA; Division of Pulmonary, Sleep,
Allergy, and Critical Care Medicine (SRT), University of
Massachusetts Medical School, Worcester, MA; ZD Associates LLC (WTL-Z), Perkasie, PA; Department of Surgery (JCM), Li Ka Shing Knowledge Institute, St. Michael’s
Hospital, University of Toronto, Toronto, ON, Canada;
University Department of Anaesthesia & Intensive Care
Medicine (JB), Queen Elizabeth Hospital, Edgbaston, Birmingham, UK; Critical Care Centre (AA), Sabadell Hospital,
CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Barcelona, Spain; Mid Essex Hospital
Services NHS Trust (GR), London, UK; Guy’s and St.
Thomas’ NHS Foundation Trust (RB), St. Thomas’ Hospital, London, UK; Department of Medicine (MMP), Stony
Brook University, NY; Vivantes-Klinikum Neukoelln (HG),
Berlin, Germany; Clinic for Anesthesiology and Intensive
Care (KR), Jena, Germany; Hospital Israelita Albert Einstein (ES), Sao Paolo, Brazil; Department of Medicine (SR),
Harvard Medical School and General Medicine Division,
Massachusetts General Hospital, Boston, MA; Consultants
in Critical Care, Inc. (MH), Glenbrook, NV; CRISMA Laboratory (DCA), Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
This study was funded, in part, by Eli Lilly and
Company, Edwards Lifesciences, Philips Medical Systems, Society of Critical Care Medicine, and European
Society of Intensive Care Medicine.
Supplemental Digital Content is available for this
article. Direct URL citations appear in the printed text and
are provided in the HTML and PDF versions of this article
on the journal’s web site (www.ccmjournal.com).
Disclosure Dr. Levy has received grants from Eli Lilly
& Co and Philips Medical Systems. Dr. Marshall has
consultancies with Eisai, Eli Lilly, Specter Diagnostics,
Bayer, Artisan, and Leo Pharma. Dr. Artigas has received
grants from Eli Lilly. Dr. Beale has disclosed payment
from multiple sources that were paid to his department
and institution (details on file with the editorial office). Drs.
Reinart and Silva have consultancies with Eli Lilly. Dr.
Angus has participation in DSMB, Prowess-Shock, and Eli
Lilly. The remaining authors have nothing to disclose.
This article is being simultaneously published in
Critical Care Medicine and Intensive Care Medicine.
For information regarding this article, E-mail:
[email protected]
Copyright © 2010 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
Crit Care Med 2010 Vol. 38, No. 2
DOI: 10.1097/CCM.0b013e3181cb0cdc
1
Figure 1. Resuscitation and management bundles as provided for Campaign participants’ use. ED, emergency department; ICU, intensive care unit.
Reproduced with permission from the Surviving Sepsis Campaign and the Institute for Healthcare Improvement.
(involving 18 organizations comprising
professional societies and organized
networks of hospitals).
The development and publication of
guidelines often do not lead to changes in
clinical behavior, and guidelines are
rarely, if ever, integrated into bedside
practice in a timely fashion (15–20). The
most effective means for achieving
knowledge transfer remains an unanswered question across all medical disciplines (21, 22). Recognizing that implementing guidelines presents a significant
challenge, the Campaign set out to develop and evaluate a multifaceted model
to change bedside practice to be consistent with the recently published management guidelines for patients with severe
sepsis and septic shock. A central part of
that program was an international registry into which providers could recruit
and enter patients and monitor their institution’s performance. This analysis of
the registry data describes the global initiative, its implementation, and reports
its impact on process improvement and
patient outcomes.
METHODS
The SSC performance improvement initiative was launched in multiple sites internationally to measure changes in the rates
at which the sites achieved the targets of the
guideline bundles and to assess the impact
of compliance with the program on hospital
mortality. The Campaign activities included:
the development of sepsis bundles; creation
of educational materials; recruitment of
sites and local physician and nurse champions through national and international
meetings; organization of regional launch
meetings where the initiative was introduced and educational materials presented;
and the distribution of a secure database
application that allowed for data collection
2
and transfer, and offered a simple means for
providing practice audit and feedback to local clinicians.
Guideline and Bundle
Development
After the development of the evidencebased guidelines, the SSC steering committee
partnered with the Institute for Healthcare
Improvement to develop a quality improvement program to extend the Campaign guidelines to the bedside management of severely
septic and septic shock patients (23, 24). In
partnership with the Institute for Healthcare
Improvement, key elements of the guidelines
were identified and organized into “bundles”
of care (25, 26). A two-phase approach was
established, which included generation of two
sets of performance measures: the first set to
be accomplished within 6 hrs of presentation
with severe sepsis (the “resuscitation bundle”); and a second set to be accomplished
within 24 hrs (the “management bundle”)
(Fig. 1) (27, 28).
Sites and Patient Selection
Any hospital wishing to join the Campaign
was eligible. Participation was voluntary. Participant sites were recruited at professional
critical care congresses and meetings,
through the SSC and Institute for Healthcare
Improvement Web sites, and by interest generated from publication of the SSC guidelines.
Campaign symposia were regularly held at international congresses and other venues between 2004 and 2008 to increase awareness
and participation. Local champions and Campaign faculty were identified and trained to
develop regional and national networks.
Sites were encouraged to set up screening
procedures to identify patients with severe
sepsis based on previously established criteria
(29). Sites were provided a sample screening
tool in the Campaign manual and on the Web
site (30). Participating sites were asked to
screen for patients in the emergency department, the clinical wards, and the ICU. Methods of screening were ultimately established
locally, and no effort to supervise the quality
or completeness of screening was attempted.
To be enrolled, a subject had to have a
suspected site of infection, ⱖ2 systemic inflammatory response syndrome criteria (29),
and ⱖ1 organ dysfunction criteria (see Supplemental Fig. 1, Supplemental Digital Content 1, http://links.lww.com/CCM/A81). Clinical and demographic characteristics and time
of presentation with severe sepsis criteria were
collected for analysis of time-based measures.
Time of presentation was determined through
chart review and defined in instructions to site
data collectors in the Campaign Web site and
educational materials. For patients enrolled
from the emergency department, the time of
presentation was defined as the time of triage.
For patients admitted to the ICU from the
medical and surgical wards and for patients in
the ICU at the time of diagnosis, the time of
presentation was determined by chart review
for the diagnosis of severe sepsis.
Educational Materials and
Resources
Educational materials available on the SSC
Web site included directions for implementing
the bundles and supporting data for each bundle element. A comprehensive manual, Implementing the Surviving Sepsis Campaign, was
published in 2005 and included the data collection tool in CD format (30). The manual
was also distributed at meetings. It included
protocols for participation and links to download the database. It also reviewed issues related to ensuring consistency and quality in
data collection. The manual contents were
placed on the Institute for Healthcare Improvement and SSC Web sites. Cards and posters of the two sepsis bundles (Fig. 1) were
printed and widely distributed.
During the course of the study period, initiation meetings were held for participating
hospital groups and regional SSC launches, at
which educational materials were distributed,
methods for data collection described, institutional change concepts introduced, and examples of implementation discussed. Ultimately,
hospital-level efforts and local protocol development were the purview of individual improvement teams at each institution or network. An e-mail list serve with voluntary
membership was established to allow teams to
collaborate across sites by asking questions of
their colleagues and to direct communication
from the SSC to sites. List members were
encouraged to share tools, protocols, and experiences. Although no formal evaluation was
in place to assess the quality of data entered,
concern regarding this topic was the second
most frequently discussed area among participants (following concern regarding roadblocks to achieving physician engagement).
Two of the authors (C.S. and S.R.T.) served as
primary references for all questions regarding
data collection and entry throughout the
Campaign, and provided training for each site
when requested. A bimonthly electronic newsletter was published to share successes, strategies, and events.
Bundle Targets and Clinical
Outcomes
The primary outcome measure was change
in compliance with bundle targets over time.
We defined compliance as evidence that all
bundle elements were achieved within the indicated time frame (i.e., 6 hrs for the resuscitation bundle; 24 hrs for the management
bundle). As such, failure to comply might occur either because of the failure of the physician to attempt to meet the target, or the
failure to reach the target despite the clinician’s attempt. Secondary outcome measures
included hospital mortality, hospital length of
stay, and ICU length of stay. Ten performance
measures were established, based on the individual elements of the resuscitation bundle
and the management bundle.
Data Collection
Data were entered into the SSC database
locally at individual hospitals into preestablished, unmodifiable fields documenting performance data and the time of specific actions and
findings. Data on the local database contained
private health information that enabled individual sites to audit and review local practice and
compliance as well as provide feedback to clinicians involved in the initiative. Data stripped of
private health information were submitted every
30 days to the secure master SSC server at the
Society of Critical Care Medicine (Mount Prospect, IL) via file transfer protocol or as commadelimited text files attached to e-mail submitted
to the Campaign’s server.
Institutional Review Board
Approval
The global SSC improvement initiative was
reviewed and approved by the Cooper University Hospital Institutional Review Board (Camden, NJ) as meeting criteria for exempt status.
Individual hospitals were encouraged to refer
to these documents and submit to their local
Institutional Review Boards per local policy
for documentation of exempt status or waiver
of consent. The U.S. Department of Health and
Human Services’ Office for Human Research
Protections clarified that quality improvement
activities, such as SSC, often qualify for Institutional Review Board exemption and do not
require individual informed consent (31).
Analysis Set Construction
The analysis set was constructed from the
subjects entered into the SSC database from
its launch in January 2005 through March
2008. The a priori data analysis plan limited
inclusion to sites with at least 20 subjects and
at least 3 months of subject enrollment. Analysis presented here was limited to the first 2
yrs of subjects at each site (Table 1).
Sites were characterized by: hospital size
(⬍250, 250 –500, ⬎500 beds); teaching status;
ICU type (medical, medical/surgical, other);
and geographic region (Europe, North America, South America). Subjects were characterized by baseline severe sepsis information: location of enrollment (emergency department,
ICU, ward); site of infection (pulmonary, urinary tract, abdominal, central nervous system,
skin, bone, wound, catheter, cardiac, device,
other); acute organ dysfunction (cardiovascular, pulmonary, renal, hepatic, hematologic).
Subject age and gender were not collected in
deference to country-specific privacy laws.
Data were organized by quarter through 2
yrs, with the first 3 months that a site entered
subjects into the database defined as the first
quarter, regardless of when those months occurred from January 2005 through March
2008. Results are presented by site quarter,
comparing the initial quarter with the final
quarter for all sites and by comparing the
initial quarter with all subsequent quarters.
Table 1. Inclusion in database by quarter
Quarter
Patients
Sites
1
2
3
4
5
6
7
8
2791
2709
2945
1945
1435
935
940
509
165
160
153
123
76
54
57
34
Because differences in bundle achievement
and outcomes could be confounded by changes
in the characteristics of subjects entered into the
database, risk-adjustment logistic regression
models were constructed to control for baseline
subject characteristics. All baseline characteristics present in the database were included in the
risk-adjustment models, including location of
enrollment, acute organ dysfunctions, and site
of infection. Site of infection was reduced to
pulmonary or nonpulmonary to decrease the
number of covariate patterns in the data and
increase the utility of the model residuals to
assess model fit. Because the collection of some
bundle elements was conditioned on subject
characteristics, different models were constructed for each subpopulation. The model assessing the base set of elements applicable to all
subjects (lactate measurement, blood culture before antibiotic administration, broad-spectrum
antibiotic administration, and glucose control)
included the baseline subject characteristics as
well as these elements. The model assessing the
administration of drotrecogin alfa in subjects
with multiple organ failures also included the
baseline subject characteristics and the base set
of bundle elements. The model assessing plateau
pressure control in mechanically ventilated subjects also included the baseline subject characteristics and the base set of bundle elements. The
model assessing the administration of drotrecogin alfa, low-dose steroids, central venous pressure ⬎8 mm Hg, and ScvO2 ⬎70% in subjects in
shock, despite fluids, also included the baseline
subject characteristics and the base set of bundle
elements.
To demonstrate that a decrease in hospital
mortality over time was not associated with entering less severely ill patients in the database at
individual sites, a logistic regression model was
constructed. It contained all subjects entered
over the maximum of 2 yrs of data collection and
the baseline subject characteristics for the quarter of participation for up to eight quarters. Because sites could enter the Campaign at any
time, the possibility that decreased hospital mortality over time was associated with a global
decrease in mortality for the same severity of
illness was investigated by constructing a logistic regression model for hospital mortality, using the first quarter of data collection from each
site, including the baseline subject characteristics and the calendar quarter (1 for the first
quarter of 2005 through 13 for the first quarter
of 2008).
Statistical Analysis
We compared raw rates, including hospital
mortality and bundle compliance, using Fisher’s
exact test. We expressed the effects of predictor
variables on hospital mortality, using odds ratios
(ORs), including 95% confidence intervals (CIs)
for risk-adjusted results. We assessed logistic regression model fit, using the Hosmer-Lemeshow
3
C statistic, the chi-square dispersion, the proportion of log-likelihood accounted for by the
model, and an examination of model residuals.
We constructed the databases in Access and FoxPro (Microsoft Corp, Redmond, WA) and conducted analyses in DataDesk (Data Description,
Ithaca, NY) and SAS (SAS Institute, Cary, NC).
RESULTS
Between January 2005 and March 2008,
15,775 subjects at 252 qualifying sites were
entered into the SSC database (see Supplemental Table 1, Supplemental Digital Content 2, http://links.lww.com/CCM/A82). Ex-
Table 2. Cohort characteristics
Site Characteristics
Hospital size
⬍250 beds
250–500 beds
⬎500 beds
Teaching status
Teaching
Nonteaching
ICU type
Medical
Medical/surgical
Other
Region
Europe
North America
South America
Patient Characteristics
All
Source
ED
ICU
Ward
Site of Infection
Pneumonia
UTI
Abdominal
Meningitis
Skin
Bone
Wound
Catheter
Endocarditis
Device
Other Infection
Baseline acute organ dysfunctions
Cardiovasculara
Pulmonaryb
Renalb
Hepaticb
Hematologicb
Number of acute organ dysfunctions
1
2
3
4
5
Cardiovascular
No cardiovascular dysfunction
Cardiovascular dysfunction no hypotension
Shock
Lactate ⬎4 only
Vasopressors only
Lactate ⬎4 and vasopressors
Total shock
Subjects, %
n ⫽ 15,022
Sites, %
n ⫽ 165
9.9
42.3
47.8
19.3
39.8
40.9
69.2
30.8
69.3
30.7
23.3
71.3
5.4
17.0
78.4
4.6
31.1
58.9
10.0
41.0
47.0
12.0
Subjects, %
100
Hospital Mortality, %
34.8
52.4
12.8
34.8
27.6
41.3
46.8
44.4
20.8
21.1
1.6
5.9
1.2
3.8
4.1
1.1
1.1
12.7
38.2
25.1
40.8
23.0
28.6
31.9
32.2
33.9
41.0
42.5
33.1
85.6
30.8
39.5
10.2
25.7
35.4
41.5
40.5
45.1
45.0
41.8
32.2
17.8
6.4
1.8
27.4
34.4
43.7
52.5
63.6
13.5
15.0
31.0
21.2
5.4
49.5
16.6
71.5
29.9
36.7
46.1
38.4
ICU, intensive care unit; ED, emergency department; UTI, urinary tract infection.
Includes hypotension regardless of response to fluids and elevated lactate; bper severe sepsis screening
tool (see Supplemental Fig. 1, Supplemental Digital Content 1, http://links.lww.com/CCM/A81).
a
4
cluding hospitals that contributed fewer
than 20 subjects, the final sample consisted
of 15,022 patients at 165 hospitals (median,
57; range, 20 – 471 subjects per hospital).
Data from up to eight quarters were analyzed from each site. Hospitals contributed
data for a mean duration of 15.6 months
(median, 14 months). Table 2 includes site
and patient characteristics.
Change in Achievement of
Bundle Targets Over Time
Compliance rates for achieving all
bundle targets over time— both the overall bundles and the individual elements
within both bundles—increased over
time, although both basal achievement
rates and the magnitude of improvement
varied considerably across targets (Table
3). Compliance with the initial 6-hr bundle targets increased linearly from 10.9%
of subjects in the first site quarter to
31.3% by the end of 2 yrs in the campaign, achieving statistical significance
by the second quarter (10.9% vs. 14.9%,
p ⬍ .0001) (Fig. 2). The ability to achieve
the entire 24-hr management bundle targets started higher, at 18.4% in the first
quarter, and increased to 25.5% by the
end of 2 yrs, but did not achieve statistical significance until the fourth quarter
(18.4% vs. 21.5%, p ⫽ .008).
Changes in Hospital Mortality
Unadjusted hospital mortality decreased
from 37.0% in the first quarter in the Campaign to 30.8% by 2 yrs (p ⫽ .001). On
average, unadjusted mortality decreased by
0.91% (95% CI, 0.42–1.40) for each quarter
in the Campaign. The results of the multivariable model examining the effect of time
in the Campaign on hospital mortality are
summarized in Table 4. The model fit well
(Hosmer and Lemeshow C statistic of 18.1
with 18 df, p ⫽ .34, accounted for 36.6% of
variation in the data, with a chi-square dispersion of 1.04). In both the unadjusted
and adjusted models, the chance of death
decreased the longer a site was in the Campaign, resulting in an adjusted absolute
drop of 0.8% per quarter and 5.4% over the
first 2 yrs (95% CI, 2.5– 8.4). In contrast,
the model examining the first quarter of
data from all sites did not find a secular
trend, associated with calendar time, to be
significantly associated with mortality (p ⫽
.23). The model fit well (Hosmer and Lemeshow C statistic of 16.6 with 18 df, p ⫽ .55,
accounted for 18.4% of variation in the
data, with a chi-square dispersion of 1.05).
Table 3. Change in achievement of bundle targets
Initial care bundle (first 6 hrs of
presentation)
Measure lactate
Blood cultures before
antibiotics
Broad-spectrum antibiotics
CVP ⬎8 mm Hg
ScvO2 ⬎70%
All resuscitative measures
Management bundle (first 24
hrs after presentation)
Steroid policy
Administration of drotrecogin
alfa policy
Glucose control
Plateau pressure control
Initial Quarter
Achieved, %
Final Quarter
Achieved, %a
p Value Compared
With Initial
Remaining Quarters
Achieved, %
p Value Compared
With Initial
61.0
64.5
78.7
78.3
ⱕ.0001
ⱕ.0001
72.5
76.3
ⱕ.0001
ⱕ.0001
60.4
59.8
26.3
13.3
10.9
67.9
77.0
38.0
24.3
21.5
.0002
ⱕ.0001
ⱕ.0001
ⱕ.0001
ⱕ.0001
67.0
71.1
33.9
21.7
21.1
ⱕ.0001
ⱕ.0001
ⱕ.0001
ⱕ.0001
ⱕ.0001
58.5
47.4
73.9
53.5
ⱕ.0001
.003
66.8
49.9
ⱕ.0001
.02
51.4
80.8
18.4
56.8
83.8
25.5
.0009
.24
ⱕ.0001
55.4
82.6
23.3
ⱕ.0001
.09
ⱕ.0001
CVP, central venous pressure; ScvO2, central venous oxygen saturation.
a
Represents the last quarter of data submission from each institution during the 2-yr data analysis period, regardless of total number of quarter of each
institution participation.
Relationship Between Bundle
Targets and Hospital Mortality
After adjustment for baseline characteristics, administration of broad-spectrum antibiotics (OR, 0.86; 95%, CI 0.79 –
0.93; p ⬍ .0001), obtaining blood
cultures before their initiation (OR, 0.76;
95% CI, 0.70 – 0.83; p ⬍ .0001), and
maintaining blood glucose control (OR,
0.67; 95% CI, 0.62– 0.71; p ⬍ .0001) were
all associated with lower hospital mortality. Measuring lactate was not associated
with improved outcome (OR, 0.97; 95%
CI, 0.90 –1.05; p ⫽ .48) (Table 5). The
administration of drotrecogin alfa in the
first 24 hrs was associated with improved
survival in those with shock (OR, 0.81;
95% CI, 0.68 – 0.96; p ⫽ .02). For those
who required mechanical ventilation,
achieving plateau pressure control was
associated with improved outcome (OR,
0.70; 95% CI, 0.62– 0.78; p ⬍ .0001). In
those with septic shock, there was no
association between mortality and the
use of low-dose steroids, the ability to
achieve a central venous pressure
ⱖ8 mm Hg, or demonstration of
ScvO2 ⱖ70%.
DISCUSSION
Figure 2. Compliance and mortality change over time. a, Change in the percentage of patients
compliant with all elements of the resuscitation bundle (dotted line) and the management bundle
(solid line) over 2 yrs of data collection (*p ⬍ .01 compared with first quarter). Note that both Y axes
are truncated at 40% to emphasize relative change over time as opposed to absolute change. b, Change
in hospital mortality over time (*p ⬍ .01 compared with first quarter).
The SSC—a performance improvement effort by hospitals across Europe,
South America, and the United States—
recruited the largest prospective series of
severe sepsis patients yet studied. The
5
effort took place in 30 countries, was voluntary (no sites or clinicians were paid
for data collection or for becoming part of
the Campaign), and was multidisciplinary, reflecting the ethos of the founding professional societies. By instituting a
practice improvement program grounded
in evidence-based guidelines, SSC increased compliance with the change bundles that was associated with better patient outcomes. These results are
consistent with other published studies
that established the impact of performance “bundles” on outcomes (32–35).
SSC was a performance improvement
process, and not a dedicated scientific
evaluation of the impact of the guidelines
on clinical outcome. Efficacy was inferred
by observation of change over time,
rather than through the more rigorous
approach of a randomized, controlled
trial. Thus, conclusions regarding the
clinical impact of bundle elements, or
even of the process itself, must be interpreted with caution. The observation that
early detection of infection and institution of antibiotic therapy led to improved
survival is consistent with both empirical
data (36) and generally held professional
opinion. On the other hand, the observation that achievement of glucose control
is associated with better outcome is not
necessarily supported by recent randomized, controlled trial data (37).
Certain limitations must be considered in interpreting these findings. Participation in the process was entirely voluntary. The hospitals themselves are not
necessarily representative of hospitals
that did not participate, and the generalizability of our findings is, therefore,
speculative. Furthermore, we do not
know whether the patients were a comprehensive or representative sample of all
potentially eligible subjects at each site.
Sites with varying lengths of participa-
Table 4. Multivariable mortality prediction modela
Variable
Admission source
Ward compared to ED
ICU compared to ED
Pneumonia as source of sepsis
compared to other infections
Organ dysfunction at presentation
Cardiovascular
Respiratory
Hematologic
Hepatic
Renal
Site duration in Campaign
Per quarter
OR
95% CI
p
1.87
2.25
1.37
1.73, 2.02
2.02, 2.51
1.27, 1.48
ⱕ.0001
1.39
1.23
1.61
1.28
1.40
1.26, 1.55
1.14, 1.34
1.48, 1.75
1.14, 1.75
1.30, 1.51
ⱕ.0001
ⱕ.0001
ⱕ.0001
ⱕ.0001
ⱕ.0001
0.97
0.96, 0.99
.0006
ⱕ.0001
OR, odds ratio; CI, confidence interval; ED, emergency department; ICU, intensive care unit.
Model fit statistics: C ⫽ 18.1 with 18 df, p ⫽ .34, log-likelihood R2 ⫽ 36.6%, ␹2 dispersion ⫽ 1.04.
a
tion are included in the analysis. Although the rate of enrollment over time
was relatively constant for each site, the
possibility that the types of patients selected changed over time cannot be excluded. We believe the data are encouraging and supportive of the Campaign’s
creating beneficial effects both on patient
care and patient outcome. Because the
bundles combine physiologic end points
and processes of care, measures of compliance may not be precise. However, the
improvement in measures over time
probably reflects improving compliance,
assuming the case-mix was reasonably
stable. The independent association of
these bundle targets with outcome does
not necessarily imply a causal relationship between the bundle care recommendation and outcomes. Failure to achieve a
target may be indicative of greater severity, so compliance with the attempt alone
may produce the false impression that
compliance is associated with reduced
mortality. Therefore, attention to adjustment for severity of patient illness at time
of enrollment should be attempted.
Similarly, failure to achieve blood glucose control, despite attempting to do so,
is not the same as failure to make the
attempt. Attempting to discriminate failure to achieve a target vs. patient responsiveness adds a layer of complexity and
subjectivity to the scoring process that
would be difficult to validate. Nevertheless, because patient responsiveness is
unlikely to change over time, the scoring
should reflect each hospital’s improvement attempts. By combining a number
of elements in the care bundles, the Campaign sought to maximize outcome improvement. At the same time, such an
Table 5. Risk-Adjusted impact of bundle targets on hospital mortalitya
Unadjusted
Risk-Adjusted
Bundle Target
Population
n
OR
p
OR
95% CI
p
Measure lactate
Obtain blood cultures before antibiotics
Commence broad-spectrum antibiotics
Achieve tight glucose control
Administer drotrecogin alfa
Administer drotrecogin alfa
Administer low-dose steroids
Demonstrate CVP ⱖ8 mm Hg
Demonstrate ScvO2 ⱖ70%
Achieve low plateau pressure control
Alla
Alla
Alla
Alla
Multiorgan failureb
Shock despite fluidsc
Mechanical ventilationd
15,022
15,022
15,022
15,022
8733
7854
7854
7854
7854
7860
0.86
0.70
0.78
0.65
0.90
0.91
1.06
1.08
0.94
0.67
⬍.0001
⬍.0001
⬍.0001
⬍.0001
.26
.30
.18
.10
.24
⬍.0001
0.97
0.76
0.86
0.67
0.84
0.81
1.06
1.00
0.98
0.70
0.90, 1.05
0.70, 0.83
0.79, 0.93
0.62, 0.71
0.69, 1.02
0.68, 0.96
0.96, 1.17
0.89, 1.12
0.86, 1.10
0.62, 0.78
.48
⬍.0001
⬍.0001
⬍.0001
.07
.02
.24
.98
.69
⬍.0001
OR, odds ratio; CI, confidence interval; CVP, central venous pressure; ScvO2, central venous oxygen saturation.
Model fit statistics: C ⫽ 22.2 with 18 df, p ⫽ .22, log-likelihood R2 ⫽ 28.1%, ␹2 dispersion ⫽ 1.05; bmodel fit statistics: C ⫽ 28.7 with 18 df, p ⫽ .053,
log-likelihood R2 ⫽ 20.5%, ␹2 dispersion ⫽ 1.08; cmodel fit statistics: C ⫽ 24.3 with 18 df, p ⫽ .15, log-likelihood R2 ⫽ 11.4%, ␹2 dispersion ⫽ 1.00; dmodel
fit statistics: C ⫽ 6.61 with 18 df, p ⫽ .99, log-likelihood R2 ⫽ 27.0%, ␹2 dispersion ⫽ 1.06.
a
6
approach compromises measuring the effect of individual elements.
The fact that performance improvement
studies are susceptible to general trends in
the change in mortality and clinical practice patterns over time is another potential
limitation of the study, but the variable
start times for each site established that
such effects were unlikely to explain the
improvement in mortality. The baseline
mortality rate for sites entering at variable
times throughout the 2-yr study period did
not change. Formal severity scores were
not obtained for patients entered into the
database due to limited personnel resources in the absence of external site funding and confidentiality concerns. Therefore, decreasing mortality seen over the
2-yr initiative might be explained by the
enrollment of less severely ill patients over
time, in spite of the static baseline center
mortality. To control for entry of less severely ill patients in the database over time
as the reason for decreasing mortality, severity was assessed based on variables
linked to patient mortality that were available in the database (Table 4). When mortality was adjusted accordingly, while the
magnitude of the effect was slightly reduced, it remained statistically significant.
In conclusion, the results of this study
demonstrate that the use of a multifaceted performance improvement initiative
was successful in changing sepsis treatment behavior as demonstrated by a significant increase in compliance with
sepsis performance measures. This compliance was associated with a significant
reduction in hospital mortality in patients with severe sepsis and septic shock
over the duration of the 2-yr study, but
the study design does not allow us to say,
with certainty, whether this was due to
some or all bundle elements, increased
awareness of severe sepsis, or other unrelated factors. Many unanswered questions remain that could provide direction
for future research, including the mortality trend in hospitals that have not implemented the bundles, and confirmation
of which components of the bundles reduce mortality. These results are consistent with an earlier report from Spain
(38), and extend the findings of that study
by suggesting that the improvement in
achievement of bundle targets and association with improved outcome is sustained over time and is demonstrated
across a wide number of countries and
settings. Professional societies frequently
generate evidence-based clinical practice
guidelines, but efforts to disseminate
such guidelines have rarely been of a
scale comparable to this Campaign. The
results of this study should encourage
similar efforts to implement guidelines as
a means to improve outcomes.
11.
12.
ACKNOWLEDGMENTS
We gratefully acknowledge the dedication and efforts of Deb McBride during
the Campaign and in the development
of this manuscript. We also acknowledge
the individuals leading the effort at participating sites who made all of this happen as volunteers who believed in the
Campaign and what we were trying to
accomplish as their sole motivation.
13.
14.
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Hora de Oro en Sepsis Grave y Shock Séptico

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