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Special Article

Surviving Sepsis Campaign: International guidelines for


management of severe sepsis and septic shock: 2008*
R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Jean M. Carlet, MD; Julian Bion, MD; Margaret M. Parker, MD; Roman Jaeschke, MD;
Konrad Reinhart, MD; Derek C. Angus, MD, MPH; Christian Brun-Buisson, MD; Richard Beale, MD; Thierry Calandra, MD, PhD;
Jean-Francois Dhainaut, MD; Herwig Gerlach, MD; Maurene Harvey, RN; John J. Marini, MD; John Marshall, MD; Marco Ranieri, MD;
Graham Ramsay, MD; Jonathan Sevransky, MD; B. Taylor Thompson, MD; Sean Townsend, MD; Jeffrey S. Vender, MD;
Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; for the International Surviving Sepsis Campaign Guidelines Committee

Objective: To provide an update to the original Surviving Sepsis Campaign sor therapy (1C); stress-dose steroid therapy given only in septic shock after blood
clinical management guidelines, “Surviving Sepsis Campaign Guidelines for Man- pressure is identified to be poorly responsive to fluid and vasopressor therapy
agement of Severe Sepsis and Septic Shock,” published in 2004. (2C); recombinant activated protein C in patients with severe sepsis and clinical
Design: Modified Delphi method with a consensus conference of 55 interna- assessment of high risk for death (2B except 2C for postoperative patients). In the
tional experts, several subsequent meetings of subgroups and key individuals, absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage,
teleconferences, and electronic-based discussion among subgroups and among target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of
the entire committee. This process was conducted independently of any industry inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respi-
funding. ratory distress syndrome (ARDS); application of at least a minimal amount of
Methods: We used the Grades of Recommendation, Assessment, Development positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in
and Evaluation (GRADE) system to guide assessment of quality of evidence from mechanically ventilated patients unless contraindicated (1B); avoiding routine use
high (A) to very low (D) and to determine the strength of recommendations. A of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical
strong recommendation (1) indicates that an intervention’s desirable effects ventilation and ICU length of stay, a conservative fluid strategy for patients with
clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak established ALI/ARDS who are not in shock (1C); protocols for weaning and
recommendations (2) indicate that the tradeoff between desirable and undesirable sedation/analgesia (1B); using either intermittent bolus sedation or continuous
effects is less clear. The grade of strong or weak is considered of greater clinical infusion sedation with daily interruptions or lightening (1B); avoidance of neuro-
importance than a difference in letter level of quality of evidence. In areas without muscular blockers, if at all possible (1B); institution of glycemic control (1B),
complete agreement, a formal process of resolution was developed and applied. targeting a blood glucose <150 mg/dL after initial stabilization (2C); equivalency
Recommendations are grouped into those directly targeting severe sepsis, rec- of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophy-
ommendations targeting general care of the critically ill patient that are consid- laxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent
ered high priority in severe sepsis, and pediatric considerations. upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors
Results: Key recommendations, listed by category, include early goal-directed (1B); and consideration of limitation of support where appropriate (1D). Recom-
resuscitation of the septic patient during the first 6 hrs after recognition (1C); mendations specific to pediatric severe sepsis include greater use of physical
blood cultures before antibiotic therapy (1C); imaging studies performed promptly examination therapeutic end points (2C); dopamine as the first drug of choice for
to confirm potential source of infection (1C); administration of broad-spectrum hypotension (2C); steroids only in children with suspected or proven adrenal
antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis insufficiency (2C); and a recommendation against the use of recombinant acti-
without septic shock (1D); reassessment of antibiotic therapy with microbiology vated protein C in children (1B).
and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days Conclusions: There was strong agreement among a large cohort of interna-
of antibiotic therapy guided by clinical response (1D); source control with atten- tional experts regarding many level 1 recommendations for the best current care
tion to the balance of risks and benefits of the chosen method (1C); administration of patients with severe sepsis. Evidenced-based recommendations regarding the
of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore acute management of sepsis and septic shock are the first step toward improved
mean circulating filling pressure (1C); reduction in rate of fluid administration with outcomes for this important group of critically ill patients.
rising filing pressures and no improvement in tissue perfusion (1D); vasopressor KEY WORDS: sepsis; severe sepsis; septic shock; sepsis syndrome; infection;
preference for norepinephrine or dopamine to maintain an initial target of mean Grades of Recommendation, Assessment, Development and Evaluation criteria;
arterial pressure >65 mm Hg (1C); dobutamine inotropic therapy when cardiac GRADE; guidelines; evidence-based medicine; Surviving Sepsis Campaign; sepsis
output remains low despite fluid resuscitation and combined inotropic/vasopres- bundles

*The correct citation for this article is as follows. (JFD); Vivantes-Klinikum Neukoelin, Berlin, Germany (HG); tional Sepsis Forum,* Japanese Association for Acute
Dellinger RP, Levy MM, Carlet, JM, et al: Surviving Consultants in Critical Care, Inc, Glenbrook, NV (MH); Univer- Medicine, Japanese Society of Intensive Care Medicine;
Sepsis Campaign: International guidelines for manage- sity of Minnesota, St. Paul, MN (JJM); St. Michael’s Hospital, Society of Critical Care Medicine,* Society of Hospital
Toronto, Ontario, Canada (JM); Università di Torino, Torino, Medicine,** Surgical Infection Society,* World Federation
ment of severe sepsis and septic shock: 2008 [pub- of Critical Care Nurses,** World Federation of Societies of
lished correction appears in Crit Care Med 2008; 36: Italy (MR); West Hertfordshire Health Trust, Hemel Hemp- Intensive and Critical Care Medicine.** Participation and
1394 –1396]. Crit Care Med 2008; 36:296 –327. stead, UK (GR); The Johns Hopkins University School of endorsement by the German Sepsis Society and the Latin
From Cooper University Hospital, Camden, NJ (RPD); Medicine, Baltimore, MD (JS); Massachusetts General Hos- American Sepsis Institute. *Sponsor of 2004 guidelines.
Rhode Island Hospital, Providence, RI (MML); Hospital Saint- pital, Boston, MA (BTT); Rhode Island Hospital, Providence, RI **Sponsors of 2008 guidelines who did not participate
Joseph, Paris, France (JMC); Birmingham University, Bir- (ST); Evanston Northwestern Healthcare, Evanston, IL (JSV); formally in revision process. Members of the 2008 SSC
The Methodist Hospital, Houston, TX (JLZ); Erasme University Guidelines Committee are listed in Appendix I. Appendix J
mingham, UK (JB); SUNY at Stony Brook, Stony Brook, NY provides author disclosure information.
(MMP); McMaster University, Hamilton, Ontario, Canada (RJ); Hospital, Brussels, Belgium (JLV).
Also published in Intensive Care Medicine (January
Friedrich-Schiller-University of Jena, Jena, Germany (KR); Sponsoring organizations: American Association of 2008).
University of Pittsburgh, Pittsburgh, PA (DCA); Hopital Henri Critical-Care Nurses,* American College of Chest Physi- For information regarding this article, E-mail:
cians,* American College of Emergency Physicians,* Ca- Dellinger-Phil@CooperHealth.edu
Mondor, Créteil, France (CBB); Guy’s and St Thomas’ Hos- nadian Critical Care Society, European Society of Clinical
pital Trust, London, UK (RB); Centre Hospitalier Universitaire Copyright © 2007 by the Society of Critical Care
Microbiology and Infectious Diseases,* European Society Medicine
Vaudois, Lausanne, Switzerland (TC); French Agency for of Intensive Care Medicine,* European Respiratory Soci-
Evaluation of Research and Higher Education, Paris, France ety,* Indian Society of Critical Care Medicine,** Interna- DOI: 10.1097/01.CCM.0000298158.12101.41

Crit Care Med 2008 Reprint 1


S evere sepsis (acute organ dys- Scheme 1. Diagnostic criteria for sepsis
function secondary to infec-
Infection, documented or suspected, and some of the following:
tion) and septic shock (severe
General variables
sepsis plus hypotension not re- Fever (⬎38.3°C)
versed with fluid resuscitation) are major Hypothermia (core temperature ⬍36°C)
healthcare problems, affecting millions of Heart rate ⬎90 min⫺1 or ⬎2 SD above the normal value for age
individuals around the world each year, Tachypnea
Altered mental status
killing one in four (and often more), and Significant edema or positive fluid balance (⬎20 mL/kg over 24 hrs)
increasing in incidence (1–5). Similar to Hyperglycemia (plasma glucose ⬎140 mg/dL or 7.7 mmol/L) in the absence of diabetes
polytrauma, acute myocardial infarction, Inflammatory variables
or stroke, the speed and appropriateness Leukocytosis (WBC count ⬎12,000 ␮L⫺1)
Leukopenia (WBC count ⬍4000 ␮L⫺1)
of therapy administered in the initial Normal WBC count with ⬎10% immature forms
hours after severe sepsis develops are Plasma C-reactive protein ⬎2 SD above the normal value
likely to influence outcome. In 2004, an Plasma procalcitonin ⬎2 SD above the normal value
international group of experts in the di- Hemodynamic variables
Arterial hypotension (SBP ⬍90 mm Hg; MAP ⬍70 mm Hg; or an SBP decrease ⬎40 mm Hg
agnosis and management of infection and
in adults or ⬍2 SD below normal for age)
sepsis, representing 11 organizations, Organ dysfunction variables
published the first internationally ac- Arterial hypoxemia (PaO2/FIO2 ⬍300)
cepted guidelines that the bedside clini- Acute oliguria (urine output ⬍0.5 mL/Kg hr or 45 mmol/L for at least 2 hrs, despite adequate
cian could use to improve outcomes in fluid resuscitation)
severe sepsis and septic shock (6, 7). Creatinine increase ⬎0.5 mg/dL or 44.2 ␮mol/L
Coagulation abnormalities (INR ⬎1.5 or a PTT ⬎60 secs)
These guidelines represented phase II of Ileus (absent bowel sounds)
the Surviving Sepsis Campaign (SSC), an Thrombocytopenia (platelet count, ⬍100,000 ␮L⫺1)
international effort to increase awareness Hyperbilirubinemia (plasma total bilirubin ⬎4 mg/dL or 70 ␮mol/L)
and improve outcomes in severe sepsis. Tissue perfusion variables
Hyperlactatemia (⬎ upper limit of lab normal)
Joined by additional organizations, the Decreased capillary refill or mottling
group met again in 2006 and 2007 to Diagnostic criteria for sepsis in the pediatric population are signs and symptoms of inflammation
update the guidelines document using a plus infection with hyper- or hypothermia (rectal temperature ⬎38.5°C or ⬍35°C),
new evidence-based methodology system tachycardia (may be absent in hypothermic patients), and at least one of the following
for assessing quality of evidence and indications of altered organ function: altered mental status, hypoxemia, increased serum
strength of recommendations (8 –11). lactate level, or bounding pulses.
These recommendations are intended
WBC, white blood cell; SBP, systolic blood pressure; MAP, mean arterial blood pressure; INR,
to provide guidance for the clinician car- international normalized ratio; a PTT, activated partial thromboplastin time.
ing for a patient with severe sepsis or Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS Interna-
septic shock. Recommendations from tional Sepsis Definitions Conference. Crit Care Med 2003; 31:1250 –1256
these guidelines cannot replace the clini-
cian’s decision-making capability when Scheme 2.
he or she is provided with a patient’s
unique set of clinical variables. Most of Severe sepsis ⫽ sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following
these recommendations are appropriate thought to be due to the infection)
Sepsis-induced hypotension
for the severe sepsis patient in both the
Lactate greater than the upper limits of normal laboratory results
intensive care unit (ICU) and non-ICU Urine output ⬍0.5 mL/kg hr for ⬎2 hrs, despite adequate fluid resuscitation
settings. In fact, the committee believes ALI with PaO2/FIO2 ⬍250 in the absence of pneumonia as infection source
that currently, the greatest outcome im- ALI with PaO2/FIO2 ⬍200 in the presence of pneumonia as infection source
provement can be made through educa- Creatinine ⬎2.0 mg/dL (176.8 ␮mol/L)
Bilirubin ⬎2 mg/dL (34.2 ␮mol/L)
tion and process change for those caring Platelet count ⬍100,000
for severe sepsis patients in the non-ICU Coagulopathy (INR ⬎1.5)
setting and across the spectrum of acute
care. It should also be noted that re- ALI, acute lung injury; INR, international normalized ratio.
source limitations in some institutions Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS Interna-
and countries may prevent physicians tional Sepsis Definitions Conference. Crit Care Med 2003; 31:1250 –1256. ACCP/SCCM Consensus
Conference Committee: American College of Chest Physicians/Society of Critical Care Medicine
from accomplishing particular recom-
Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative
mendations. therapies in sepsis. Crit Care Med 1992; 20:864 – 874

METHODS
threshold for this dysfunction has varied blood pressure (SBP) ⬍90 mm Hg or mean
Sepsis is defined as infection plus sys- somewhat from one severe sepsis research arterial pressure ⬍70 mm Hg or a SBP
temic manifestations of infection study to another. An example of typical decrease ⬎40 mm Hg or ⬍2 SD below nor-
(Scheme 1) (12). Severe sepsis is defined thresholds identification of severe sepsis is mal for age in the absence of other causes
as sepsis plus sepsis-induced organ dys- shown in Scheme 2 (12, 13). Sepsis- of hypotension. Septic shock is defined as
function or tissue hypoperfusion. The induced hypotension is defined as a systolic sepsis-induced hypotension persisting de-

2 Crit Care Med 2008 Reprint


spite adequate fluid resuscitation. Sepsis- ests; however, consensus as to thresh- (composed of a subset of the committee
induced tissue hypoperfusion is defined as old for exclusion could not be reached. members) at the 2007 SCCM (Orlando,
either septic shock, an elevated lactate, or Alternatively, the committee agreed to FL) and 2007 International Symposium
oliguria. ensure full disclosure and transparency on Intensive Care and Emergency Medi-
The current clinical practice guidelines of all committee members’ potential cine (Brussels) meetings with recircula-
build on the first and second editions from conflicts at time of publication. (See tion of deliberations and decisions to the
2001 (discussed subsequently) and 2004 (6, disclosures at the end of this docu- entire group for comment or approval. At
7, 14). The 2001 publication incorporated a ment.) the discretion of the chair and following
MEDLINE search for clinical trials in the The guidelines process included a adequate discussion, competing propos-
preceding 10 yrs, supplemented by a man- modified Delphi method, a consensus als for wording of recommendations or
ual search of other relevant journals (14). conference, several subsequent meetings assigning strength of evidence were re-
The 2004 publication incorporated the ev- of subgroups and key individuals, tele- solved by formal voting. On occasions,
idence available through the end of 2003. conferences and electronic-based discus- voting was performed to give the com-
The current publication is based on an up- sions among subgroups and members of mittee a sense of distribution of opinions
dated search into 2007 (see following meth- the entire committee, and two follow-up to facilitate additional discussion. The
ods and rules). nominal group meetings in 2007. manuscript was edited for style and form
The 2001 guidelines were coordinated Subgroups were formed, each charged by the writing committee with final ap-
by the International Sepsis Forum; the with updating recommendations in spe- proval by section leads for their respec-
2004 guidelines were funded by unre- cific areas, including corticosteroids, tive group assignment and then by the
stricted educational grants from industry blood products, activated protein C, renal entire committee.
and administered through the Society of replacement therapy, antibiotics, source The development of guidelines and
Critical Care Medicine (SCCM), the Eu- control, and glucose control. Each sub- grading of recommendations for the 2004
ropean Society of Intensive Care Medi- group was responsible for updating the guideline development process were
cine (ESICM), and the International Sep- evidence (into 2007, with major addi- based on a system proposed by Sackett
sis Forum. Two of the SSC administering tional elements of information incorpo- (15) in 1989, during one of the first
organizations receive unrestricted indus- rated into the evolving manuscript American College of Chest Physicians
try funding to support SSC activities (ES- throughout 2006 and 2007). A separate (ACCP) conferences on the use of anti-
ICM and SCCM), but none of this funding search was performed for each clearly de- thrombotic therapies. The revised guide-
was used to support the 2006/2007 com- fined question. The committee chair lines recommendations are based on the
mittee meetings. worked with subgroup heads to identify GRADE system, a structured system for
It is important to distinguish between pertinent search terms that always in- rating quality of evidence and grading
the process of guidelines revision and the cluded, at a minimum, sepsis, severe sep- strength of recommendation in clinical
SSC. The SSC is partially funded by un- sis, septic shock, and sepsis syndrome practice (8 –11). The SSC Steering Com-
restricted educational industry grants, crossed against the general topic area of mittee and individual authors collabo-
including those from Edwards Life- the subgroup as well as pertinent key rated with GRADE representatives to ap-
Sciences, Eli Lilly and Company, and words of the specific question posed. All ply the GRADE system to the SSC
Philips Medical Systems. SSC also re- questions of the previous guidelines pub- guidelines revision process. The mem-
ceived funding from the Coalition for lications were searched, as were pertinent bers of GRADE group were directly in-
Critical Care Excellence of the Society of new questions generated by general top- volved, either in person or via e-mail, in
Critical Care Medicine. The great major- ic-related search or recent trials. Quality all discussions and deliberations among
ity of industry funding has come from Eli of evidence was judged by predefined the guidelines committee members as to
Lilly and Company. Grades of Recommendation, Assessment, grading decisions. Subsequently, the SSC
Current industry funding for the SSC Development and Evaluation (GRADE) authors used written material prepared
is directed to the performance improve- criteria (discussed subsequently). Signif- by the GRADE group and conferred with
ment initiative. No industry funding was icant education of committee members GRADE group members who were avail-
used in the guidelines revision process. on the GRADE approach was performed able at the first committee meeting and
For both the 2004 and the 2006/2007 via e-mail before the first committee subsequent nominal group meetings.
efforts, there were no members of the meeting and at the first meeting. Rules GRADE representatives were also used as
committee from industry, no industry were distributed concerning assessing a resource throughout subgroup deliber-
input into guidelines development, and the body of evidence, and GRADE experts ation.
no industry presence at any of the were available for questions throughout The GRADE system is based on a se-
meetings. Industry awareness or com- the process. Subgroups agreed electroni- quential assessment of the quality of ev-
ment on the recommendations was not cally on draft proposals that were pre- idence, followed by assessment of the bal-
allowed. No member of the guideline sented to committee meetings for general ance between benefits vs. risks, burden,
committee received any honoraria for discussion. In January 2006, the entire and cost and, based on the preceding, de-
any role in the 2004 or 2006/2007 group met during the 35th SCCM Critical velopment and grading of a management
guidelines process. The committee con- Care Congress in San Francisco, Califor- recommendations (9 –11). Keeping the rat-
sidered the issue of recusement of indi- nia. The results of that discussion were ing of quality of evidence and strength of
vidual committee members during de- incorporated into the next version of rec- recommendation explicitly separate consti-
liberation and decision making in areas ommendations and again discussed using tutes a crucial and defining feature of the
where committee members had either electronic mail. Recommendations were GRADE approach. This system classifies
financial or academic competing inter- finalized during nominal group meetings quality of evidence as high (grade A), mod-

Crit Care Med 2008 Reprint 3


erate (grade B), low (grade C), or very low Table 1. Determination of the quality of evidence
(grade D). Randomized trials begin as high-
● Underlying methodology
quality evidence but may be downgraded
A. RCT
due to limitations in implementation, in- B. Downgraded RCT or upgraded observational studies
consistency or imprecision of the results, C. Well-done observational studies
indirectness of the evidence, and possible D. Case series or expert opinion
reporting bias (Table 1). Examples of indi- ● Factors that may decrease the strength of evidence
1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of
rectness of the evidence include population
bias
studied, interventions used, outcomes mea- 2. Inconsistency of results (including problems with subgroup analyses)
sured, and how these relate to the question 3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison)
of interest. Observational (nonrandomized) 4. Imprecision of results
studies begin as low-quality evidence, but 5. High likelihood of reporting bias
● Main factors that may increase the strength of evidence
the quality level may be upgraded on the 1. Large magnitude of effect (direct evidence, RR ⬎2 with no plausible confounders)
basis of large magnitude of effect. An exam- 2. Very large magnitude of effect with RR ⬎5 and no threats to validity (by two levels)
ple of this is the quality of evidence for early 3. Dose-response gradient
administration of antibiotics.
The GRADE system classifies recom- RCT, randomized controlled trial; RR, relative risk.
mendations as strong (grade 1) or weak
(grade 2). The grade of strong or weak is Table 2. Factors determining strong vs. weak recommendation
considered of greater clinical importance
than a difference in letter level of quality What Should Be Considered Recommended Process
of evidence. The committee assessed
Quality of evidence The lower the quality of evidence, the less likely a strong
whether the desirable effects of adherence
recommendation
will outweigh the undesirable effects, and Relative importance of the If values and preferences vary widely, a strong
the strength of a recommendation reflects outcomes recommendation becomes less likely
the group’s degree of confidence in that Baseline risks of outcomes The higher the risk, the greater the magnitude of benefit
assessment (Table 2). A strong recommen- Magnitude of relative risk, Larger relative risk reductions or larger increases in
dation in favor of an intervention reflects including benefits, harms, and relative risk of harm make a strong recommendation
burden more or less likely, respectively
that the desirable effects of adherence to
Absolute magnitude of the effect The larger the absolute benefits and harms, the greater or
a recommendation (beneficial health out- lesser likelihood, respectively, of a strong
comes, less burden on staff and patients, recommendation
and cost savings) will clearly outweigh Precision of the estimates of the The greater the precision, the more likely a strong
the undesirable effects (harms, more bur- effects recommendation
den, and greater costs). A weak recom- Costs The higher the cost of treatment, the less likely a strong
mendation in favor of an intervention in- recommendation
dicates that the desirable effects of
adherence to a recommendation probably
will outweigh the undesirable effects, but make the recommendation less applicable. a recommendation was as follows: 1) to
the panel is not confident about these Being a strong recommendation does not give a recommendation a direction (for or
tradeoffs— either because some of the ev- automatically imply standard of care. For against the given action), a majority of
idence is low quality (and thus there re- example, the strong recommendation for votes were to be in favor of that direction,
mains uncertainty regarding the benefits administering antibiotics within 1 hr of the with ⱕ20% preferring the opposite direc-
and risks) or the benefits and downsides diagnosis of severe sepsis, although desir- tion (there was a neutral vote allowed as
are closely balanced. While the degree of able, is not currently standard of care as well); 2) to call a given recommendation
confidence is a continuum and there is verified by current practice (M Levy, per- strong rather than weak, ⱖ70% “strong”
no precise threshold between a strong sonal communication, from first 8,000 pa- votes were required; 3) if ⬍70% of votes
and a weak recommendation, the pres- tients entered internationally into the SSC indicated “strong” preference, the recom-
ence of important concerns about one or performance improvement database). The mendation was assigned a weak category of
more of the preceding factors makes a implication of a weak recommendation is strength. We used a combination of modi-
weak recommendation more likely. A that although a majority of well-informed fied Delphi process and nominal (expert)
strong recommendation is worded as “we patients would accept it (but a substantial group techniques to ensure both depth and
recommend” and a weak recommenda- proportion would not), clinicians should breadth of review. The entire review group
tion as “we suggest.” consider its use according to particular cir- (together with their parent organizations
The implications of calling a recom- cumstance. as required) participated in the larger, iter-
mendation strong are that most well- Differences of opinion among commit- ative, modified Delphi process. The smaller
informed patients would accept that inter- tee members about interpretation of evi- working group meetings, which took place
vention and that most clinicians should use dence, wording of proposals, or strength of in person, functioned as the nominal
it in most situations. There may be circum- recommendations were resolved using a groups. If a clear consensus could not be
stances in which a strong recommendation specifically developed set of rules. We will obtained by polling within the nominal
cannot or should not be followed for an describe this process in detail in a separate group meetings, the larger group was spe-
individual patient because of that patient’s publication. In summary, the main ap- cifically asked to use the polling process.
preferences or clinical characteristics that proach for converting diverse opinions into This was only required for corticosteroids

4 Crit Care Med 2008 Reprint


and glycemic control. The larger group had Table 3. Initial resuscitation and infection issues
the opportunity to review all outputs. In
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria,
this way the entire review combined in-
presented in parentheses after each guideline
tense focused discussion (nominal group) ● Indicates a strong recommendation, or “we recommend”
with broader review and monitoring using 䡩 Indicates a weak recommendation, or “we suggest”
the Delphi process. Initial resuscitation (first 6 hrs)
Note: Refer to Tables 3–5 for con- ● Begin resuscitation immediately in patients with hypotension or elevated serum lactate ⬎4
densed adult recommendations. mmol/L; do not delay pending ICU admission (1C)
● Resuscitation goals (1C)
CVP 8–12 mm Hga
I. MANAGEMENT OF SEVERE Mean arterial pressure ⱖ 65 mm Hg
Urine output ⱖ0.5 mL䡠kg⫺1䡠hr⫺1
SEPSIS Central venous (superior vena cava) oxygen saturation ⱖ70% or mixed venous ⱖ65%
䡩 If venous oxygen saturation target is not achieved (2C)
Consider further fluid
A. Initial Resuscitation Transfuse packed red blood cells if required to hematocrit of ⱖ30% and/or
Start dobutamine infusion, maximum 20 ␮g䡠kg⫺1䡠min⫺1
1. We recommend the protocolized re- Diagnosis
suscitation of a patient with sepsis- ● Obtain appropriate cultures before starting antibiotics provided this does not significantly
induced shock, defined as tissue hypo- delay antimicrobial administration (1C)
perfusion (hypotension persisting Obtain two or more BCs
One or more BCs should be percutaneous
after initial fluid challenge or blood
One BC from each vascular access device in place ⬎48 hrs
lactate concentration ⱖ4 mmol/L). Culture other sites as clinically indicated
This protocol should be initiated as ● Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)
soon as hypoperfusion is recognized Antibiotic therapy
and should not be delayed pending ● Begin intravenous antibiotics as early as possible and always within the first hour of
recognizing severe sepsis (1D) and septic shock (1B)
ICU admission. During the first 6 hrs
● Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with
of resuscitation, the goals of initial good penetration into presumed source (1B)
resuscitation of sepsis-induced hypo- ● Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity,
perfusion should include all of the fol- and minimize costs (1C)
lowing as one part of a treatment pro- 䡩 Consider combination therapy in Pseudomonas infections (2D)
tocol: 䡩 Consider combination empiric therapy in neutropenic patients (2D)
䡩 Combination therapy ⱕ3–5 days and de-escalation following susceptibilities (2D)
Central venous pressure 8 –12 mm ● Duration of therapy typically limited to 7–10 days; longer if response is slow or there are
Hg undrainable foci of infection or immunologic deficiencies (1D)
Mean arterial pressure (MAP) ⱖ65 ● Stop antimicrobial therapy if cause is found to be noninfectious (1D)
mm Hg Source identification and control
Urine output ⱖ0.5 mL·kg⫺1·hr ⫺1 ● A specific anatomic site of infection should be established as rapidly as possible (1C) and
within first 6 hrs of presentation (1D)
Central venous (superior vena
● Formally evaluate patient for a focus of infection amenable to source control measures (e.g.
cava) or mixed venous oxygen sat- abscess drainage, tissue debridement) (1C)
uration ⱖ70% or ⱖ65%, respec- ● Implement source control measures as soon as possible following successful initial
tively (grade 1C) resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is best
delayed) (2B)
Rationale. Early goal-directed resusci-
● Choose source control measure with maximum efficacy and minimal physiologic upset (1D)
tation has been shown to improve sur- ● Remove intravascular access devices if potentially infected (1C)
vival for emergency department patients
presenting with septic shock in a ran- GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ICU, intensive
domized, controlled, single-center study care unit; CVP, central venous pressure; BC, blood culture.
a
(16). Resuscitation directed toward the A higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical ventilation
previously mentioned goals for the initial or preexisting decreased ventricular compliance.
6-hr period of the resuscitation was able
to reduce 28-day mortality rate. The con- come in septic shock and MAP ⱖ65 mm
sensus panel judged use of central venous iment to filling (17). Similar consider- Hg as well as central venous oxygen sat-
and mixed venous oxygen saturation tar- ation may be warranted in circumstances uration (ScvO2, measured in superior
gets to be equivalent. Either intermittent of increased abdominal pressure or dia- vena cava, either intermittently or con-
or continuous measurements of oxygen stolic dysfunction (18). Elevated central tinuously) of ⱖ70% (19). Many recent
saturation were judged to be acceptable. venous pressures may also be seen with studies support the value of early proto-
Although blood lactate concentration preexisting clinically significant pulmo- colized resuscitation in severe sepsis and
may lack precision as a measure of tissue nary artery hypertension. Although the sepsis-induced tissue hypoperfusion (20 –
metabolic status, elevated levels in sepsis cause of tachycardia in septic patients 25). Studies of patients with shock indi-
support aggressive resuscitation. In me- may be multifactorial, a decrease in ele- cate that mixed venous oxygen saturation
chanically ventilated patients or patients vated pulse rate with fluid resuscitation is (SV̄O2) runs 5–7% lower than central ve-
with known preexisting decreased ven- often a useful marker of improving intra- nous oxygen saturation (ScvO2) (26) and
tricular compliance, a higher target cen- vascular filling. Recently published ob- that an early goal-directed resuscitation
tral venous pressure of 12–15 mm Hg is servational studies have demonstrated an protocol can be established in a nonre-
recommended to account for the imped- association between good clinical out- search general practice venue (27).

Crit Care Med 2008 Reprint 5


Table 4. Hemodynamic support and adjunctive therapy Rationale. The protocol used in the
study cited previously targeted an increase
Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, in ScvO2 to ⱖ70% (16). This was achieved
presented in parentheses after each guideline.
● Indicates a strong recommendation, or “we recommend” by sequential institution of initial fluid re-
䡩 Indicates a weak recommendation, or “we suggest” suscitation, packed red blood cells, and
Fluid therapy then dobutamine. This protocol was asso-
● Fluid-resuscitate using crystalloids or colloids (1B) ciated with an improvement in survival.
● Target a CVP of ⱖ8 mm Hg (ⱖ12 mm Hg if mechanically ventilated) (1C)
Based on bedside clinical assessment and
● Use a fluid challenge technique while associated with a hemodynamic improvement (1D)
● Give fluid challenges of 1000 mL of crystalloids or 300–500 mL of colloids over 30 mins. More personal preference, a clinician may deem
rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion (1D) either blood transfusion (if hematocrit is
● Rate of fluid administration should be reduced if cardiac filling pressures increase without ⬍30%) or dobutamine the best initial
concurrent hemodynamic improvement (1D) choice to increase oxygen delivery and
Vasopressors thereby elevate ScvO2, when fluid resusci-
● Maintain MAP ⱖ65 mm Hg (1C)
● Norepinephrine and dopamine centrally administered are the initial vasopressors of choice (1C) tation is believed to be already adequate.
䡩 Epinephrine, phenylephrine, or vasopressin should not be administered as the initial The design of the aforementioned trial did
vasopressor in septic shock (2C). Vasopressin 0.03 units/min may be subsequently added to not allow assessment of the relative contri-
norepinephrine with anticipation of an effect equivalent to norepinephrine alone bution of these two components (i.e., in-
䡩 Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly creasing oxygen content or increasing car-
responsive to norepinephrine or dopamine (2B). diac output) of the protocol on
● Do not use low-dose dopamine for renal protection (1A)
● In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D) achievement of improved outcome.
Inotropic therapy
● Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac B. Diagnosis
filling pressures and low cardiac output (1C)
● Do not increase cardiac index to predetermined supranormal levels (1B) 1. We recommend obtaining appropri-
Steroids ate cultures before antimicrobial
䡩 Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly therapy is initiated if such cultures
to adequate fluid resuscitation and vasopressors (2C)
do not cause significant delay in an-
䡩 ACTH stimulation test is not recommended to identify the subset of adults with septic shock
who should receive hydrocortisone (2B) tibiotic administration. To optimize
䡩 Hydrocortisone is preferred to dexamethasone (2B) identification of causative organisms,
䡩 Fludrocortisone (50 ␮g orally once a day) may be included if an alternative to hydrocortisone we recommend at least two blood
is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional if cultures be obtained before antibiot-
hydrocortisone is used (2C) ics with at least one drawn percuta-
䡩 Steroid therapy may be weaned once vasopressors are no longer required (2D)
neously and one drawn through each
● Hydrocortisone dose should be ⱕ300 mg/day (1A)
● Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s vascular access device, unless the de-
endocrine or corticosteroid history warrants it (1D) vice was recently (⬍48 hrs) inserted.
Recombinant human activated protein C Cultures of other sites (preferably
䡩 Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical quantitative where appropriate), such
assessment of high risk of death (typically APACHE II ⱖ25 or multiple organ failure) if there as urine, cerebrospinal fluid, wounds,
are no contraindications (2B, 2C for postoperative patients).
respiratory secretions, or other body
● Adult patients with severe sepsis and low risk of death (typically, APACHE II ⬍20 or one
organ failure) should not receive rhAPC (1A) fluids that may be the source of in-
fection should also be obtained be-
GRADE, Grades of Recommendation, Assessment, Development and Evaluation; CVP, central fore antibiotic therapy if not associ-
venous pressure; MAP, mean arterial pressure; ACTH, adrenocorticotropic hormone; rhAPC, recom- ated with significant delay in
binant human activated protein C; APACHE, Acute Physiology and Chronic Health Evaluation. antibiotic administration (grade 1C).
Rationale. Although sampling should
not delay timely administration of antibi-
otics in patients with severe sepsis (e.g.,
There are recognized limitations to riod and research to validate utility. lumbar puncture in suspected meningi-
ventricular filling pressure estimates as These technologies are already available tis), obtaining appropriate cultures be-
surrogates for fluid resuscitation (28, for early ICU resuscitation. fore administration of antibiotics is es-
29). However, measurement of central sential to confirm infection and the
2. We suggest that during the first 6 hrs of
venous pressure is currently the most responsible pathogens and to allow de-
resuscitation of severe sepsis or septic
readily obtainable target for fluid resus- escalation of antibiotic therapy after re-
citation. There may be advantages to shock, if ScvO2 or SV̄O2 of 70% or 65%, ceipt of the susceptibility profile. Samples
targeting fluid resuscitation to flow and respectively, is not achieved with fluid can be refrigerated or frozen if processing
perhaps to volumetric indices (and even resuscitation to the central venous pres- cannot be performed immediately. Im-
to microcirculation changes) (30 –33). sure target, then transfusion of packed mediate transport to a microbiological
Technologies currently exist that allow red blood cells to achieve a hematocrit lab is necessary. Because rapid steriliza-
measurement of flow at the bedside (34, of ⱖ30% and/or administration of a do- tion of blood cultures can occur within a
35). Future goals should be making butamine infusion (up to a maximum of few hours after the first antibiotic dose,
these technologies more accessible dur- 20 ␮g·kg⫺1·min⫺1) be used to achieve obtaining those cultures before starting
ing the critical early resuscitation pe- this goal (grade 2C). therapy is essential if the causative organ-

6 Crit Care Med 2008 Reprint


Table 5. Other supportive therapy of severe sepsis

Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in parentheses after each guideline
● Indicates a strong recommendation, or “we recommend”
䡩 Indicates a weak recommendation, or “we suggest”
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 hemorrhage, cyanotic heart
disease, or lactic acidosis)
● Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons (1B)
䡩 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)
䡩 Administer platelets when (2D)
Counts are ⬍5000/mm3 (5 ⫻ 109/L) regardless of bleeding
Counts are 5000–30,000/mm3 (5–30 ⫻ 109/L) and there is significant bleeding risk
Higher platelet counts (ⱖ50,000/mm3 [50 ⫻ 109/L]) are required for surgery or invasive procedures
Mechanical ventilation of sepsis-induced 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 ⱕ30 cm H2O. 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)
● Set PEEP to avoid extensive lung collapse at end-expiration (1C)
䡩 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 semirecumbent position (head of the bed raised to 45°) unless contraindicated (1B), between 30°
and 45° (2C)
䡩 Noninvasive ventilation may be considered in the minority of ALI/ARDS patients with mild to 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 an SBT regularly to evaluate the potential for discontinuing mechanical ventilation (1A)
● SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T piece
● Before the SBT, patients should
be arousable
be hemodynamically 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 (1A)
● 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 where possible. Monitor depth of block with train-of-four when using continuous infusions (1B)
Glucose control
● Use intravenous insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B)
䡩 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
䡩 Intermittent hemodialysis and CVVH are considered equivalent (2B)
䡩 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 ⱖ7.15 (1B)
Deep vein thrombosis prophylaxis
● Use either low-dose UFH or LMWH, unless contraindicated (1A)
● Use a mechanical prophylactic device, such as compression stockings or an intermittent compression device, when heparin is contraindicated (1A)
䡩 Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for deep vein thrombosis (2C)
䡩 In patients at very high risk, LMWH should be used rather than UFH (2C)
Stress ulcer prophylaxis
● Provide stress ulcer prophylaxis using H2 blocker (1A) or proton pump inhibitor (1B). Benefits of prevention of upper gastrointestinal bleed must
be weighed against the potential for development of ventilator-acquired pneumonia
Consideration for limitation of support
● Discuss advance care planning with patients and families. Describe likely outcomes and set realistic expectations (1D)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ALI, acute lung injury; ARDS, acute respiratory distress syndrome;
PEEP, positive end-expiratory pressure; SBT, spontaneous breathing trial; ICU, intensive care unit; CVVH, continuous veno-venous hemofiltration; UFH,
unfractionated heparin; LMWH, low-molecular weight heparin.

ism is to be identified. Two or more blood cular access device. Obtaining blood that the organism is causing the severe
cultures are recommended (36). In pa- cultures peripherally and through a sepsis is enhanced. In addition, if the
tients with indwelling catheters (for ⬎48 vascular access device is an important culture drawn through the vascular ac-
hrs), at least one blood culture should be strategy. If the same organism is recov- cess device is positive much earlier than
drawn through each lumen of each vas- ered from both cultures, the likelihood the peripheral blood culture (i.e., ⬎2 hrs

Crit Care Med 2008 Reprint 7


earlier), the data support the concept that obtained before initiating antibiotic gen when choosing initial therapy. When
the vascular access device is the source of therapy but should not prevent deemed warranted, the selection of empir-
the infection (37). Quantitative cultures prompt administration of antimicro- ical antifungal therapy (e.g., fluconazole,
of catheter and peripheral blood are also bial therapy (grade 1D). amphotericin B, or echinocandin) will be
useful for determining whether the cath- Rationale. Establishing vascular ac- tailored to the local pattern of the most
eter is the source of infection. Volume of prevalent Candida species and any prior
cess and initiating aggressive fluid resus-
blood drawn with the culture tube should administration of azoles drugs (44). Risk
citation are the first priority when man-
be ⱖ10 mL (38). Quantitative (or semi- factors for candidemia should also be con-
aging patients with severe sepsis or septic
quantitative) cultures of respiratory tract sidered when choosing initial therapy.
shock. However, prompt infusion of anti-
secretions are recommended for the di- Because patients with severe sepsis
microbial agents should also be a priority
agnosis of ventilator-associated pneumo- or septic shock have little margin for
and may require additional vascular ac-
nia (39). Gram-negative stain can be use- error in the choice of therapy, the ini-
cess ports (42, 43). In the presence of
ful, in particular for respiratory tract tial selection of antimicrobial therapy
septic shock, each hour delay in achiev-
specimens, to help decide the micro- should be broad enough to cover all
ing administration of effective antibiotics
organisms to be targeted. The potential likely pathogens. There is ample evi-
role of biomarkers for diagnosis of in- is associated with a measurable increase
in mortality (42). If antimicrobial agents dence that failure to initiate appropri-
fection in patients presenting with se- ate therapy (i.e., therapy with activity
vere sepsis remains undefined. The pro- cannot be mixed and delivered promptly
from the pharmacy, establishing a supply against the pathogen that is subse-
calcitonin level, although often useful, quently identified as the causative
is problematic in patients with an acute of premixed antibiotics for such urgent
situations is an appropriate strategy for agent) correlates with increased mor-
inflammatory pattern from other
ensuring prompt administration. In bidity and mortality (45– 48).
causes (e.g., postoperative, shock) (40).
choosing the antimicrobial regimen, cli- Patients with severe sepsis or septic
In the near future, rapid diagnostic
nicians should be aware that some anti- shock warrant broad-spectrum therapy
methods (polymerase chain reaction,
microbial agents have the advantage of until the causative organism and its an-
micro-arrays) might prove extremely
bolus administration, while others re- tibiotic susceptibilities are defined. Re-
helpful for a quicker identification of
quire a lengthy infusion. Thus, if vascular striction of antibiotics as a strategy to
pathogens and major antimicrobial re-
sistance determinants (41). access is limited and many different reduce the development of antimicrobial
agents must be infused, bolus drugs may resistance or to reduce cost is not an
2. We recommend that imaging studies appropriate initial strategy in this patient
offer an advantage.
be performed promptly in attempts population.
to confirm a potential source of in- 2a. We recommend that initial empirical
All patients should receive a full load-
fection. Sampling of potential anti-infective therapy include one or
ing dose of each antimicrobial. However,
sources of infection should occur as more drugs that have activity against
patients with sepsis or septic shock often
they are identified; however, some all likely pathogens (bacterial and/or
have abnormal renal or hepatic function
patients may be too unstable to war- fungal) and that penetrate in ade-
and may have abnormal volumes of dis-
rant certain invasive procedures or quate concentrations into the pre-
tribution due to aggressive fluid resusci-
transport outside of the ICU. Bedside sumed source of sepsis (grade 1B).
tation. Drug serum concentration moni-
studies, such as ultrasound, are use- Rationale. The choice of empirical an- toring can be useful in an ICU setting for
ful in these circumstances (grade tibiotics depends on complex issues re- those drugs that can be measured
1C). lated to the patient’s history, including promptly. An experienced physician or
Rationale. Diagnostic studies may drug intolerances, underlying disease, clinical pharmacist should be consulted
identify a source of infection that re- the clinical syndrome, and susceptibility to ensure that serum concentrations are
quires removal of a foreign body or drain- patterns of pathogens in the community, attained that maximize efficacy and min-
age to maximize the likelihood of a sat- in the hospital, and that previously have imize toxicity (49 –52).
isfactory response to therapy. However, been documented to colonize or infect
even in the most organized and well- 2b. We recommend that the antimicro-
the patient. There is an especially wide
staffed healthcare facilities, transport of bial regimen be reassessed daily to
range of potential pathogens for neutro-
patients can be dangerous, as can placing optimize activity, to prevent the de-
penic patients.
patients in outside-unit imaging devices velopment of resistance, to reduce
Recently used antibiotics should gener-
that are difficult to access and monitor. ally be avoided. When choosing empirical toxicity, and to reduce costs (grade
Balancing risk and benefit is therefore therapy, clinicians should be cognizant of 1C).
mandatory in those settings. the virulence and growing prevalence of Rationale. Although restriction of an-
oxacillin (methicillin)-resistant Staphylo- tibiotics as a strategy to reduce the devel-
C. Antibiotic Therapy coccus aureus (ORSA or MRSA) in some opment of antimicrobial resistance or to
communities and healthcare settings (espe- reduce cost is not an appropriate initial
1. We recommend that intravenous an- cially in the United States). If the preva- strategy in this patient population, once
tibiotic therapy be started as early as lence is significant, and in consideration of the causative pathogen has been identi-
possible and within the first hour of the virulence of this organism, empirical fied, it may become apparent that none of
recognition of septic shock (1B) and therapy adequate for this pathogen would the empirical drugs offers optimal ther-
severe sepsis without septic shock be warranted. Clinicians should also con- apy; that is, there may be another drug
(1D). Appropriate cultures should be sider whether candidemia is a likely patho- proven to produce superior clinical out-

8 Crit Care Med 2008 Reprint


come that should therefore replace em- patient will become infected with an clude a rapid diagnosis of the specific site
pirical agents. antibiotic-resistant pathogen or will of infection and identification of a focus
Narrowing the spectrum of antibiotic develop a drug-related adverse effect on infection amenable to source control
coverage and reducing the duration of (grade 1D). measures (specifically the drainage of an
antibiotic therapy will reduce the likelihood Rationale. Clinicians should be cogni- abscess, debridement of infected necrotic
that the patient will develop superinfection zant that blood cultures will be negative tissue, removal of a potentially infected
with pathogenic or resistant organisms, in ⬎50% of cases of severe sepsis or sep- device, and definitive control of a source
such as Candida species, Clostridium diffi- tic shock, yet many of these cases are very of ongoing microbial contamination)
cile, or vancomycin-resistant Enterococcus likely caused by bacteria or fungi. Thus, (58). Foci of infection readily amenable to
faecium. However, the desire to minimize the decisions to continue, narrow, or stop source control measures include an in-
superinfections and other complications antimicrobial therapy must be made on tra-abdominal abscess or gastrointestinal
should not take precedence over the need the basis of clinician judgment and clin- perforation, cholangitis or pyelonephri-
to give the patient an adequate course of ical information. tis, intestinal ischemia or necrotizing soft
therapy to cure the infection that caused tissue infection, and other deep space in-
the severe sepsis or septic shock. fection, such as an empyema or septic
D. Source Control arthritis. Such infectious foci should be
2c. We suggest combination therapy for controlled as soon as possible following
patients with known or suspected 1a. We recommend that a specific ana- successful initial resuscitation (59), ac-
Pseudomonas infections as a cause of tomical diagnosis of infection requir- complishing the source control objective
severe sepsis (grade 2D). ing consideration for emergent with the least physiologic upset possible
2d. We suggest combination empirical source control (e.g., necrotizing fas- (e.g., percutaneous rather than surgical
therapy for neutropenic patients with ciitis, diffuse peritonitis, cholangitis, drainage of an abscess [60], endoscopic
severe sepsis (grade 2D). intestinal infarction) be sought and rather than surgical drainage of biliary
2e. When used empirically in patients diagnosed or excluded as rapidly as tree), and removing intravascular access
with severe sepsis, we suggest that possible (grade 1C) and within the devices that are potentially the source of
combination therapy should not be first 6 hrs following presentation severe sepsis or septic shock promptly
administered for ⬎3–5 days. De- (grade 1D). after establishing other vascular access
escalation to the most appropriate 1b. We further recommend that all pa- (61, 62). A randomized, controlled trial
single therapy should be performed tients presenting with severe sepsis comparing early vs. delayed surgical in-
as soon as the susceptibility profile is be evaluated for the presence of a tervention for peripancreatic necrosis
known (grade 2D). focus on infection amenable to showed better outcomes with a delayed
source control measures, specifically approach (63). However, areas of uncer-
Rationale. Although no study or meta-
the drainage of an abscess or local tainty exist, such as definitive docu-
analysis has convincingly demonstrated focus on infection, the debridement
that combination therapy produces a supe- mentation of infection and appropriate
of infected necrotic tissue, the re- length of delay. The selection of optimal
rior clinical outcome for individual patho- moval of a potentially infected device,
gens in a particular patient group, combi- source control methods must weigh
or the definitive control of a source benefits and risks of the specific inter-
nation therapies do produce in vitro of ongoing microbial contamination
synergy against pathogens in some models vention as well as risks of transfer (64).
(grade 1C). (Appendix A provides ex- Source control interventions may cause
(although such synergy is difficult to define amples of potential sites needing
and predict). In some clinical scenarios, further complications, such as bleed-
source control.) ing, fistulas, or inadvertent organ in-
such as the two preceding, combination 2. We suggest that when infected
therapies are biologically plausible and are jury. Surgical intervention should be
peripancreatic necrosis is identified as considered when lesser interventional
likely clinically useful even if evidence has a potential source of infection, defini-
not demonstrated improved clinical out- approaches are inadequate or when di-
tive intervention is best delayed until agnostic uncertainty persists despite ra-
come (53–56). Combination therapy for adequate demarcation of viable and
suspected known Pseudomonas pending diologic evaluation. Specific clinical sit-
nonviable tissues has occurred (grade uations require consideration of
sensitivities increases the likelihood that at 2B). available choices, patient’s preferences,
least one drug is effective against that 3. We recommend that when source con- and clinician’s expertise.
strain and positively affects outcome (57). trol is required, the effective intervention
3. We recommend that the duration of associated with the least physiologic in-
E. Fluid Therapy
therapy typically be 7–10 days; longer sult be employed (e.g., percutaneous
courses may be appropriate in pa- rather than surgical drainage of an 1. We recommend fluid resuscitation
tients who have a slow clinical re- abscess (grade 1D). with either natural/artificial colloids
sponse, undrainable foci of infection, 4. We recommend that when intravas- or crystalloids. There is no evidence-
or immunologic deficiencies, includ- cular access devices are a possible based support for one type of fluid
ing neutropenia (grade 1D). source of severe sepsis or septic over another (grade 1B).
4. We recommend that if the presenting shock, they be promptly removed af- Rationale. The SAFE study indicated
clinical syndrome is determined to be ter other vascular access has been that albumin administration was safe and
due to a noninfectious cause, antimi- established (grade 1C). equally as effective as crystalloid (65). There
crobial therapy be stopped promptly Rationale. The principals of source was an insignificant decrease in mortality
to minimize the likelihood that the control in the management of sepsis in- rates with the use of colloid in a subset

Crit Care Med 2008 Reprint 9


analysis of septic patients (p ⫽ .09). Previ- F. Vasopressors Rationale. There is no high-quality
ous meta-analyses of small studies of ICU primary evidence to recommend one cat-
patients had demonstrated no difference 1. We recommend that mean arterial echolamine over another. Much litera-
between crystalloid and colloid fluid resus- pressure (MAP) be maintained ⱖ65 ture exists that contrasts the physiologic
citation (66 – 68). Although administration mm Hg (grade 1C). effects of choice of vasopressor and com-
of hydroxyethyl starch may increase the Rationale. Vasopressor therapy is re- bined inotrope/vasopressors in septic
risk of acute renal failure in patients with quired to sustain life and maintain perfu- shock (73– 85). Human and animal stud-
sepsis, variable findings preclude definitive sion in the face of life-threatening hypo- ies suggest some advantages of norepi-
recommendations (69, 70). As the volume tension, even when hypovolemia has not nephrine and dopamine over epinephrine
of distribution is much larger for crystal- yet been resolved. Below a certain mean (the latter with the potential for tachy-
loids than for colloids, resuscitation with arterial pressure, autoregulation in vari- cardia as well as disadvantageous effects
crystalloids requires more fluid to achieve ous vascular beds can be lost, and perfu- on splanchnic circulation and hyper-
the same end points and results in more sion can become linearly dependent on lactemia) and phenylephrine (decrease in
edema. Crystalloids are less expensive. pressure. Thus, some patients may re- stroke volume). There is, however, no
quire vasopressor therapy to achieve a clinical evidence that epinephrine results
2. We recommend that fluid resuscita-
minimal perfusion pressure and maintain in worse outcomes, and it should be the
tion initially target a central venous
first chosen alternative to dopamine or
pressure of ⱖ8 mm Hg (12 mm Hg in adequate flow (71, 72). The titration of
norepinephrine to as low as MAP 65 mm norepinephrine. Phenylephrine is the ad-
mechanically ventilated patients).
Hg has been shown to preserve tissue renergic agent least likely to produce
Further fluid therapy is often re-
perfusion (72). In addition, preexisting tachycardia but as a pure vasopressor
quired (grade 1C).
comorbidities should be considered as to would be expected to decrease stroke vol-
3a. We recommend that a fluid challenge
most appropriate MAP target. For exam- ume. Dopamine increases mean arterial
technique be applied wherein fluid
ple, a MAP of 65 mm Hg might be too low pressure and cardiac output, primarily
administration is continued as long
in a patient with severe uncontrolled hy- due to an increase in stroke volume and
as the hemodynamic improvement
pertension, and in a young previously heart rate. Norepinephrine increases
(e.g., arterial pressure, heart rate,
normotensive, a lower MAP might be mean arterial pressure due to its vasocon-
urine output) continues (grade 1D).
adequate. Supplementing end points, strictive effects, with little change in
3b. We recommend that fluid challenge
heart rate and less increase in stroke vol-
in patients with suspected hypovole- such as blood pressure, with assess-
ume compared with dopamine. Either
mia be started with ⱖ1000 mL of ment of regional and global perfusion,
may be used as a first-line agent to correct
crystalloids or 300 –500 mL of col- such as blood lactate concentrations
hypotension in sepsis. Norepinephrine is
loids over 30 mins. More rapid ad- and urine output, is important. Ade-
more potent than dopamine and may be
ministration and greater amounts of quate fluid resuscitation is a fundamen-
more effective at reversing hypotension in
fluid may be needed in patients with tal aspect of the hemodynamic manage-
patients with septic shock. Dopamine may
sepsis-induced tissue hypoperfusion ment of patients with septic shock and
be particularly useful in patients with com-
(see Initial Resuscitation recommen- should ideally be achieved before vaso-
promised systolic function but causes more
dations) (grade 1D). pressors and inotropes are used, but
tachycardia and may be more arrhythmo-
3c. We recommend that the rate of fluid using vasopressors early as an emer-
genic (86). It may also influence the endo-
administration be reduced substan- gency measure in patients with severe
crine response via the hypothalamic-
tially when cardiac filling pressures shock is frequently necessary. When
pituitary axis and have immunosuppressive
(central venous pressure or pulmo- that occurs, great effort should be di-
effects.
nary artery balloon-occluded pres- rected to weaning vasopressors with
Vasopressin levels in septic shock have
sure) increase without concurrent continuing fluid resuscitation.
been reported to be lower than antici-
hemodynamic improvement (grade 2. We recommend either norepineph- pated for a shock state (87). Low doses of
1D). rine or dopamine as the first choice vasopressin may be effective in raising
Rationale. Fluid challenge must be vasopressor agent to correct hypo- blood pressure in patients refractory to
clearly separated from simple fluid ad- tension in septic shock (administered other vasopressors and may have other
ministration; it is a technique in which through a central catheter as soon as potential physiologic benefits (88 –93).
large amounts of fluids are administered one is available) (grade 1C). Terlipressin has similar effects but is long
over a limited period of time under close 3a. We suggest that epinephrine, phenyl- lasting (94). Studies show that vasopres-
monitoring to evaluate the patient’s re- ephrine, or vasopressin should not be sin concentrations are elevated in early
sponse and avoid the development of pul- administered as the initial vasopres- septic shock, but with continued shock
monary edema. The degree of intravascular sor in septic shock (grade 2C). Vaso- the concentration decreases to normal
volume deficit in patients with severe sepsis pressin 0.03 units/min may be added range in the majority of patients between
varies. With venodilation and ongoing cap- to norepinephrine subsequently with 24 and 48 hrs (95). This has been called
illary leak, most patients require continu- anticipation of an effect equivalent to relative vasopressin deficiency because in
ing aggressive fluid resuscitation during that of norepinephrine alone. the presence of hypotension, vasopressin
the first 24 hrs of management. Input is 3b. We suggest that epinephrine be the would be expected to be elevated. The
typically much greater than output, and first chosen alternative agent in sep- significance of this finding is unknown.
input/output ratio is of no utility to judge tic shock that is poorly responsive to The recent VASST trial, a randomized,
fluid resuscitation needs during this time norepinephrine or dopamine (grade controlled trial comparing norepineph-
period. 2B). rine alone to norepinephrine plus vaso-

10 Crit Care Med 2008 Reprint


pressin at 0.03 units/min, showed no dif- predetermined supranormal levels CORTICUS did show a faster resolution of
ference in outcome in the intent to treat (grade 1B). septic shock in patients who received ste-
population. An a priori defined subgroup Rationale. Dobutamine is the first- roids. The use of the ACTH test (responders
analysis showed that the survival of pa- choice inotrope for patients with mea- and nonresponders) did not predict the
tients receiving ⬍15 ␮g/min norepineph- sured or suspected low cardiac output in faster resolution of shock. Importantly, un-
rine at the time of randomization was the presence of adequate left ventricular like the French trial, which only enrolled
better with vasopressin. However, the filling pressure (or clinical assessment of shock patients with blood pressure unre-
pretrial rationale for this stratification adequate fluid resuscitation) and ade- sponsive to vasopressor therapy, the COR-
was based on exploring potential benefit quate mean arterial pressure. Septic pa- TICUS study included patients with septic
in the ⱖ15 ␮g norepinephrine require- tients who remain hypotensive after fluid shock, regardless of how the blood pressure
ment population. Higher doses of vaso- resuscitation may have low, normal, or responded to vasopressors. Although corti-
pressin have been associated with car- increased cardiac outputs. Therefore, costeroids do appear to promote shock re-
diac, digital, and splanchnic ischemia and treatment with a combined inotrope/ versal, the lack of a clear improvement in
should be reserved for situations where vasopressor, such as norepinephrine or mortality— coupled with known side ef-
alternative vasopressors have failed (96). dopamine, is recommended if cardiac fects of steroids, such as increased risk of
Cardiac output measurement to allow output is not measured. When the capa- infection and myopathy— generally tem-
maintenance of a normal or elevated flow bility exists for monitoring cardiac out- pered enthusiasm for their broad use. Thus,
is desirable when these pure vasopressors put in addition to blood pressure, a vaso- there was broad agreement that the recom-
are instituted. pressor, such as norepinephrine, may be mendation should be downgraded from the
5. We recommend that low-dose dopa- used separately to target specific levels of previous guidelines (Appendix B). There
mine not be used for renal protection mean arterial pressure and cardiac out- was considerable discussion and consider-
(grade 1A). put. Two large prospective clinical trials ation by the committee on the option of
that included critically ill ICU patients encouraging use in those patients whose
Rationale. A large randomized trial blood pressure was unresponsive to fluids
and meta-analysis comparing low-dose who had severe sepsis failed to demon-
strate benefit from increasing oxygen de- and vasopressors, while strongly discourag-
dopamine to placebo found no difference ing use in subjects whose shock responded
in either primary outcomes (peak serum livery to supranormal targets by use of
dobutamine (99, 100). These studies did well to fluids and pressors. However, this
creatinine, need for renal replacement, more complex set of recommendations was
urine output, time to recovery of normal not specifically target patients with se-
vere sepsis and did not target the first 6 rejected in favor of the preceding single
renal function) or secondary outcomes recommendation (Appendix B).
(survival to either ICU or hospital dis- hrs of resuscitation. The first 6 hrs of
charge, ICU stay, hospital stay, arrhyth- resuscitation of sepsis-induced hypoper- 2. We suggest that the ACTH stimulation
mias) (97, 98). Thus, the available data do fusion need to be treated separately from test not be used to identify the subset
not support administration of low doses the later stages of severe sepsis (see Ini- of adults with septic shock who should
of dopamine solely to maintain renal tial Resuscitation recommendations). receive hydrocortisone (grade 2B).
function. Rationale. Although one study sug-
6. We recommend that all patients re- H. Corticosteroids gested those who did not respond to
quiring vasopressors have an arterial ACTH with a brisk surge in cortisol (fail-
1. We suggest that intravenous hydro- ure to achieve or ⬎9 ␮g/dL increase in
catheter placed as soon as practical if
cortisone be given only to adult septic cortisol 30 – 60 mins after ACTH admin-
resources are available (grade 1D).
shock patients after it has been con- istration) were more likely to benefit
Rationale. In shock states, estimation firmed that their blood pressure is from steroids than those who did re-
of blood pressure using a cuff is com- poorly responsive to fluid resuscita- spond, the overall trial population ap-
monly inaccurate; use of an arterial can- tion and vasopressor therapy (grade peared to benefit regardless of ACTH re-
nula provides a more appropriate and re- 2C). sult, and the observation of a potential
producible measurement of arterial
Rationale. One French multicenter, interaction between steroid use and
pressure. These catheters also allow con-
randomized controlled trial (RCT) of pa- ACTH test was not statistically significant
tinuous analysis so that decisions regard-
tients in vasopressor-unresponsive septic (101). Furthermore, there was no evi-
ing therapy can be based on immediate
shock (hypotension despite fluid resuscita- dence of this distinction between re-
and reproducible blood pressure informa-
tion and vasopressors) showed a significant sponders and nonresponders in a recent
tion.
shock reversal and reduction of mortality multicenter trial (104). Commonly used
rate in patients with relative adrenal insuf- cortisol immunoassays measure total
G. Inotropic Therapy ficiency (defined as postadrenocortico- cortisol (protein-bound and free) while
tropic hormone [ACTH] cortisol increase free cortisol is the pertinent measure-
1. We recommend that a dobutamine in- ⱕ9 ␮g/dL) (101). Two additional smaller ment. The relationship between free and
fusion be administered in the presence RCTs also showed significant effects on total cortisol varies with serum protein
of myocardial dysfunction as sug- shock reversal with steroid therapy (102, concentration. When compared with a
gested by elevated cardiac filling pres- 103). However, a recent large, European reference method (mass spectrometry),
sures and low cardiac output (grade multicenter trial (CORTICUS), which has cortisol immunoassays may over- or un-
1C). been presented in abstract form but not yet derestimate the actual cortisol level, af-
2. We recommend against the use of a published, failed to show a mortality benefit fecting the assignment of patients to re-
strategy to increase cardiac index to with steroid therapy of septic shock (104). sponders or nonresponders (105).

Crit Care Med 2008 Reprint 11


Although the clinical significance is not sis or septic shock, high-dose corticoste- 16 (115). Controversy associated with the
clear, it is now recognized that etomi- roid therapy is ineffective or harmful results focused on a number of subgroup
date, when used for induction for intuba- (111–113). Reasons to maintain higher analyses. Subgroup analyses have the po-
tion, will suppress the hypothalamic- doses of corticosteroid for medical condi- tential to mislead due to the absence of
pituitary-adrenal axis (106). tions other than septic shock may exist. an intent to treat, sampling bias, and
3. We suggest that patients with septic 7. We recommend that corticosteroids selection error (118). The analyses sug-
shock should not receive dexametha- not be administered for the treatment gested increasing absolute and relative
sone if hydrocortisone is available of sepsis in the absence of shock. risk reduction with greater risk of death
(grade 2B). There is, however, no contraindication using both higher APACHE II scores and
to continuing maintenance steroid greater number of organ failures (119).
Rationale. Although often proposed This led to drug approval for patients
for use until an ACTH stimulation test therapy or to using stress-dose ste-
roids if the patient’s endocrine or cor- with high risk of death (such as APACHE
can be administered, we no longer sug- II ⱖ25) and more than one organ failure
gest an ACTH test in this clinical situa- ticosteroid administration history
warrants (grade 1D). in Europe.
tion (see the preceding point 3). Further- The ADDRESS trial involved 2,613 pa-
more, dexamethasone can lead to Rationale. No studies exist that specif- tients judged to have a low risk of death
immediate and prolonged suppression of ically target severe sepsis in the absence of at the time of enrollment. The 28-day
the hypothalamic-pituitary-adrenal axis shock and offer support for use of stress mortality rate from all causes was 17% on
after administration (107). doses of steroids in this patient population. placebo vs. 18.5% on APC, relative risk
4. We suggest the daily addition of oral Steroids may be indicated in the presence 1.08, 95% confidence interval 0.92–1.28
fludrocortisone (50 ␮g) if hydrocorti- of a history of steroid therapy or adrenal (116). Again, debate focused on subgroup
sone is not available and the steroid dysfunction. A recent preliminary study of analyses; analyses were restricted to
that is substituted has no significant stress-dose level steroids in community- small subgroups of patients with
mineralocorticoid activity. Fludrocor- acquired pneumonia is encouraging but APACHE II score ⬎25 or more than one
tisone is considered optional if hydro- needs confirmation (114). organ failure, which failed to show bene-
cortisone is used (grade 2C). fit. However, these patient groups also
I. Recombinant Human had a lower mortality than in PROWESS.
Rationale. One study added 50 ␮g of
Activated Protein C (rhAPC) Relative risk reduction of death was
fludrocortisone orally (101). Since hydro-
numerically lower in the subgroup of pa-
cortisone has intrinsic mineralocorticoid 1. We suggest that adult patients with sep- tients with recent surgery (n ⫽ 502) in
activity, there is controversy as to sis-induced organ dysfunction associ- the PROWESS trial (30.7% placebo vs.
whether fludrocortisone should be added. ated with a clinical assessment of high 27.8% APC) (119) when compared with
5. We suggest that clinicians wean the risk of death, most of whom will have the overall study population (30.8% pla-
patient from steroid therapy when va- Acute Physiology and Chronic Health cebo vs. 24.7% APC) (115). In the AD-
sopressors are no longer required Evaluation (APACHE) II ⱖ25 or multi- DRESS trial, patients with recent surgery
(grade 2D). ple organ failure, receive rhAPC if there and single organ dysfunction who re-
are no contraindications (grade 2B ex- ceived APC had significantly higher 28-
Rationale. There has been no compar- cept for patients within 30 days of sur-
ative study between a fixed-duration and day mortality rates (20.7% vs. 14.1%, p ⫽
gery, for whom it is grade 2C). Relative .03, n ⫽ 635) (116).
clinically guided regimen or between ta- contraindications should also be consid-
pering and abrupt cessation of steroids. Serious adverse events did not differ in
ered in decision making. the studies (115–117) with the exception
Three RCTs used a fixed-duration proto- 2. We recommend that adult patients
col for treatment (101, 103, 104), and in of serious bleeding, which occurred more
with severe sepsis and low risk of often in the patients treated with APC:
two RCTs, therapy was decreased after death, most of whom will have
shock resolution (102, 108). In four RCTs 2% vs. 3.5% (PROWESS; p ⫽ .06) (115);
APACHE II ⬍20 or one organ failure, 2.2% vs. 3.9% (ADDRESS; p ⬍ .01) (116);
steroids were tapered over several days do not receive rhAPC (grade 1A).
(102–104, 108), and in two RCTs (101, 6.5% (ENHANCE, open label) (117). The
109) steroids were withdrawn abruptly. Rationale. The evidence concerning pediatric trial and implications are dis-
One crossover study showed hemody- use of rhAPC in adults is primarily based on cussed in the pediatric consideration sec-
namic and immunologic rebound effects two RCTs: PROWESS (1,690 adult patients, tion of this article. (Appendix C provides
after abrupt cessation of corticosteroids stopped early for efficacy) (115) and AD- absolute contraindications to use of
(110). It remains uncertain whether out- DRESS (stopped early for futility) (116). rhAPC and prescribing information for
come is affected by tapering of steroids. Additional safety information comes from relative contraindications.)
an open-label observational study, EN- Intracranial hemorrhage (ICH) oc-
6. We recommend that doses of cortico- HANCE (117). The ENHANCE trial also curred in the PROWESS trial in 0.1%
steroids comparable to ⬎300 mg of suggested that early administration of (placebo) and 0.2% (APC) (not signifi-
hydrocortisone daily not be used in rhAPC was associated with better out- cant) (106); in the ADDRESS trial 0.4%
severe sepsis or septic shock for the comes. (placebo) vs. 0.5 % (APC) (not significant)
purpose of treating septic shock PROWESS involved 1,690 patients and (116); and in ENHANCE 1.5% (108). Reg-
(grade 1A). documented 6.1% in absolute total mor- istry studies of rhAPC report higher
Rationale. Two randomized prospec- tality reduction with a relative risk reduc- bleeding rates than randomized con-
tive clinical trials and a meta-analyses tion of 19.4%, 95% confidence interval trolled trials, suggesting that the risk of
concluded that for therapy of severe sep- 6.6 –30.5%, and number needed to treat bleeding in actual practice may be greater

12 Crit Care Med 2008 Reprint


than reported in PROWESS and AD- Transfusion Requirements in Critical normalities benefits patients who are not
DRESS (120, 121). Care trial suggested that a hemoglobin of bleeding.
The two RCTs in adult patients were 7–9 g/dL (70 –90 g/L) when compared 4. We recommend against antithrombin
methodologically strong and precise and with 10 –12 g/dL (100 –200 g/L) was not administration for the treatment of se-
provided direct evidence regarding death associated with increased mortality in vere sepsis and septic shock (grade 1B).
rates. The conclusions are limited, how- adults (123). Red blood cell transfusion in
ever, by inconsistency that is not ade- septic patients increases oxygen delivery Rationale. A phase III clinical trial of
quately resolved by subgroup analyses high-dose antithrombin did not demon-
but does not usually increase oxygen con-
(thus the designation of moderate-quality strate any beneficial effect on 28-day all-
sumption (124 –126). This transfusion
evidence). Results, however, consistently cause mortality in adults with severe sepsis
threshold of 7 g/dL (70 g/L) contrasts
fail to show benefit for the subgroup of and septic shock. High-dose antithrombin
with the early goal-directed resuscitation
patients at lower risk of death and con- was associated with an increased risk of
protocol that uses a target hematocrit of
sistently show increases in serious bleed- bleeding when administered with heparin
30% in patients with low ScvO2 (mea- (133). Although a post hoc subgroup anal-
ing. The RCT in pediatric severe sepsis sured in superior vena cava) during the
failed to show benefit and has no impor- ysis of patients with severe sepsis and high
first 6 hrs of resuscitation of septic shock. risk of death showed better survival in pa-
tant limitations. Thus, for low-risk and
pediatric patients, we rate the evidence as 2. We recommend that erythropoietin tients receiving antithrombin, antithrom-
high quality. not be used as a specific treatment of bin cannot be recommended until further
For adult use there is probable mor- anemia associated with severe sepsis clinical trials are performed (134).
tality reduction in patients with clinical but may be used when septic patients 5. In patients with severe sepsis, we sug-
assessment of high risk of death, most of have other accepted reasons for ad- gest that platelets be administered
whom will have APACHE II ⱖ25 or mul- ministration of erythropoietin, such as when counts are ⬍5000/mm3 (5 ⫻
tiple organ failure. There is likely no ben- renal failure-induced compromise of 109/L) regardless of apparent bleeding.
efit in patients with low risk of death, red blood cell production (grade 1B). Platelet transfusion may be considered
most of whom will have APACHE II ⬍20 Rationale. No specific information re- when counts are 5000 –30,000/mm3
or single organ dysfunction. The effects garding erythropoietin use in septic pa- (5–30 ⫻ 109/L) and there is a signifi-
in patients with more than one organ tients is available, but clinical trials in cant risk of bleeding. Higher platelet
failure but APACHE II ⬍25 are unclear, critically ill patients show some decrease counts (ⱖ50,000/mm3 [50 ⫻ 109/L])
and in that circumstance one may use are typically required for surgery or
in red cell transfusion requirement with
clinical assessment of the risk of death invasive procedures (grade 2D).
no effect on clinical outcome (127, 128).
and number of organ failures to support
The effect of erythropoietin in severe sep- Rationale. Guidelines for transfusion
decision. There is a certain increased
sis and septic shock would not be ex- of platelets are derived from consensus
risk of bleeding with administration of
pected to be more beneficial than in other opinion and experience in patients under-
rhAPC, which may be higher in surgical
critical conditions. Patients with severe going chemotherapy. Recommendations
patients and in the context of invasive
sepsis and septic shock may have coexist- take into account the etiology of throm-
procedures. Decision on utilization de-
ing conditions that do warrant use of bocytopenia, platelet dysfunction, risk of
pends on assessing likelihood of mor-
erythropoietin. bleeding, and presence of concomitant
tality reduction vs. increases in bleed-
disorders (129, 131).
ing and cost. (Appendix D provides the 3. We suggest that fresh frozen plasma
nominal committee vote on recommen- not be used to correct laboratory clot-
dation for rhAPC.) A European regula- ting abnormalities in the absence of
tory mandated RCT of rhAPC vs. pla- bleeding or planned invasive proce- II. SUPPORTIVE THERAPY OF
cebo in patients with septic shock is dures (grade 2D). SEVERE SEPSIS
now ongoing (122).
Rationale. Although clinical studies
have not assessed the impact of transfu- A. Mechanical Ventilation of
J. Blood Product Administration
sion of fresh frozen plasma on outcomes Sepsis-Induced Acute Lung
1. Once tissue hypoperfusion has resolved in critically ill patients, professional or- Injury (ALI)/Acute Respiratory
and in the absence of extenuating cir- ganizations have recommended fresh fro-
Distress Syndrome (ARDS)
cumstances, such as myocardial isch- zen plasma for coagulopathy when there
emia, severe hypoxemia, acute hemor- is a documented deficiency of coagulation 1. We recommend that clinicians target
rhage, cyanotic heart disease, or lactic factors (increased prothrombin time, in- a tidal volume of 6 mL/kg (predicted)
acidosis (see recommendations for ini- ternational normalized ratio, or partial body weight in patients with ALI/
tial resuscitation), we recommend that thromboplastin time) and the presence of ARDS (grade 1B).
red blood cell transfusion occur when active bleeding or before surgical or in- 2. We recommend that plateau pressures
hemoglobin decreases to ⬍7.0 g/dL vasive procedures (129 –131). In addition, be measured in patients with ALI/
(⬍70 g/L) to target a hemoglobin of transfusion of fresh frozen plasma in ARDS and that the initial upper limit
7.0 –9.0 g/dL (70 –90 g/L) in adults nonbleeding patients with mild abnor- goal for plateau pressures in a pas-
(grade 1B). malities of prothrombin time usually fails sively inflated patient be ⱕ30 cm H2O.
Rationale. Although the optimum he- to correct the prothrombin time (132). Chest wall compliance should be con-
moglobin for patients with severe sepsis There are no studies to suggest that cor- sidered in the assessment of plateau
has not been specifically investigated, the rection of more severe coagulation ab- pressure (grade 1C).

Crit Care Med 2008 Reprint 13


Rationale. Over the past 10 yrs, sev- pressure ⱕ30 cm H2O. If plateau pressure with lower PEEP levels (152). Neither the
eral multicenter randomized trials have remains ⬎30 after reduction of tidal vol- control nor experimental group in that
been performed to evaluate the effects of ume to 6 mL/kg PBW, tidal volume should study, however, was clearly exposed to
limiting inspiratory pressure through be reduced further to as low as 4 mL/kg hazardous plateau pressures. A recent
moderation of tidal volume (135–139). PBW. (Appendix E provides ARDSNet ven- multicenter Spanish trial compared a
These studies showed differing results tilator management and formulas to calcu- high PEEP, low-moderate tidal volume
that may have been caused by differences late predicted body weight.) approach to one that used conventional
between airway pressures in the treat- No single mode of ventilation (pres- tidal volumes and the least PEEP achiev-
ment and control groups (135, 140). The sure control, volume control, airway ing adequate oxygenation. A marked sur-
largest trial of a volume- and pressure- pressure release ventilation, high-fre- vival advantage favored the former ap-
limited strategy showed a 9% decrease of quency ventilation) has been consistently proach in high-acuity patients with ARDS
all-cause mortality in patients with ALI or shown advantageous when compared (153). Two options are recommended for
ARDS ventilated with tidal volumes of 6 with any other that respects the same PEEP titration. One option is to titrate
mL/kg of predicted body weight (PBW), principles of lung protection. PEEP (and tidal volume) according to
as opposed to 12 mL/kg, and aiming for a bedside measurements of thoracopulmo-
3. We recommend that hypercapnia (al-
plateau pressure ⱕ30 cm H2O (135). The nary compliance with the objective of ob-
lowing PaCO2 to increase above its pre-
use of lung-protective strategies for pa- taining the best compliance, reflecting a
morbid baseline, so-called permissive
tients with ALI is supported by clinical favorable balance of lung recruitment
hypercapnia) be allowed in patients
trials and has been widely accepted, but and overdistension (154). The second op-
with ALI/ARDS if needed to minimize
the precise choice of tidal volume for an tion is to titrate PEEP based on severity
plateau pressures and tidal volumes
individual patient with ALI may require of oxygenation deficit and guided by the
(grade 1C).
adjustment for such factors as the plateau FIO2 required to maintain adequate oxy-
pressure achieved, the level of positive Rationale. An acutely elevated PaCO2 genation (135) (Appendix D). Whichever
end-expiratory pressure chosen, the com- may have physiologic consequences that the indicator— compliance or oxygen-
pliance of the thoracoabdominal com- include vasodilation as well as an in- ation—recruiting maneuvers are reason-
partment, and the vigor of the patient’s creased heart rate, blood pressure, and able to employ in the process of PEEP
breathing effort. Some clinicians believe cardiac output. Allowing modest hyper- selection. Blood pressure and oxygen-
it may be safe to ventilate with tidal vol- capnia in conjunction with limiting tidal ation should be monitored and recruit-
umes ⬎6 mL/kg PBW as long as the pla- volume and minute ventilation has been ment discontinued if deterioration in
teau pressure can be maintained ⱕ30 cm demonstrated to be safe in small, nonran- these variables is observed. A PEEP ⬎5
H2O (141, 142). The validity of this ceil- domized series (145, 146). Patients cm H20 is usually required to avoid lung
ing value will depend on breathing effort, treated in larger trials that have the goal collapse (155).
as those who are actively inspiring gen- of limiting tidal volumes and airway pres-
5. We suggest prone positioning in ARDS
erate higher transalveolar pressures for a sures have demonstrated improved out-
patients requiring potentially injurious
given plateau pressure than those who comes, but permissive hypercapnia was
levels of FIO2 or plateau pressure who
are passively inflated. Conversely, pa- not a primary treatment goal in these stud-
are not at high risk for adverse conse-
tients with very stiff chest walls may re- ies (135). The use of hypercapnia is limited
quences of positional changes in facili-
quire plateau pressures ⬎30 cm H2O to in patients with preexisting metabolic aci-
ties that have experience with such
meet vital clinical objectives. One retro- dosis and is contraindicated in patients
practices (grade 2C).
spective study suggested that tidal vol- with increased intracranial pressure. So-
umes should be lowered even with pla- dium bicarbonate or tromethamine Rationale. Several small studies and
teau pressures ⱕ30 cm H2O (143). An (THAM) infusion may be considered in se- one larger study have shown that a ma-
additional observational study suggested lected patients to facilitate use of permis- jority of patients with ALI/ARDS respond
that knowledge of the plateau pressures sive hypercarbia (147, 148). to the prone position with improved ox-
was associated with lower plateau pres- ygenation (156 –159). One large multi-
4. We recommend that positive end-
sures; however, in that trial plateau pres- center trial of prone positioning for approx-
expiratory pressure (PEEP) be set so
sure was not independently associated imately 7 hrs/day did not show
as to avoid extensive lung collapse at improvement in mortality rates in patients
with mortality rates across a wide range
end-expiration (grade 1C). with ALI/ARDS; however, a post hoc anal-
of plateau pressures that bracketed 30 cm
H2O (144). The largest clinical trial em- Rationale. Raising PEEP in ALI/ARDS ysis suggested improvement in those pa-
ploying a lung-protective strategy cou- keeps lung units open to participate in tients with the most severe hypoxemia by
pled limited pressure with limited tidal gas exchange. This will increase PaO2 PaO2/FIO2 ratio, in those exposed to high
volumes to demonstrate a mortality ben- when PEEP is applied through either an tidal volumes, and in those who improved
efit (135). endotracheal tube or a face mask (149 – CO2 exchange as a result of proning (159).
High tidal volumes that are coupled 151). In animal experiments, avoidance of A second large trial of prone positioning,
with high plateau pressures should be end-expiratory alveolar collapse helps conducted for an average of approximately
avoided in ALI/ARDS. Clinicians should use minimize ventilator-induced lung injury 8 hrs/day for 4 days in adults with hypox-
as a starting point the objective of reducing when relatively high plateau pressures emic respiratory failure of low-moderate
tidal volume over 1–2 hrs from its initial are in use. One large multicenter trial of acuity, confirmed improvement in oxygen-
value toward the goal of a “low” tidal vol- the protocol-driven use of higher PEEP ation but also failed to show a survival ad-
ume (⬇6 mL/kg PBW) achieved in con- in conjunction with low tidal volumes did vantage (160). However, a randomized
junction with an end-inspiratory plateau not show benefit or harm when compared study that extended the length of time for

14 Crit Care Med 2008 Reprint


proning each day to a mean of 17 hrs for a for airway intubation should be main- (175) and one in patients with acute lung
mean of 10 days supported benefit of pron- tained (grade 2B). injury (176), failed to show benefit with
ing, with randomization to supine position Rationale. Obviating the need for air- the routine use of pulmonary artery cath-
an independent risk factor for mortality by way intubation confers multiple advan- eters in patients with acute lung injury.
multivariate analysis (161). Prone position- tages: better communication, lower inci- In addition, other studies in different
ing may be associated with potentially life- dence of infection, reduced requirements types of critically ill patients have failed
threatening complications, including acci- for sedation. Two RCTs demonstrate im- to show definitive benefit with routine
dental dislodgment of the endotracheal proved outcome with the use of NIV when use of the pulmonary artery catheter
tube and central venous catheters, but it can be employed successfully (162, (177–179). Well-selected patients remain
these complications can usually be avoided 165). Unfortunately, only a small percent- appropriate candidates for pulmonary ar-
with proper precautions. age of patients with life-threatening hy- tery catheter insertion when the answers
poxemia can be managed in this way. to important management decisions de-
6a. Unless contraindicated, we recom- pend on information only obtainable
mend that mechanically ventilated 8. We recommend that a weaning proto- from direct measurements made within
patients be maintained with the head col be in place and that mechanically the pulmonary artery.
of the bed elevated to limit aspiration ventilated patients with severe sepsis
undergo spontaneous breathing trials 10. To decrease days of mechanical ven-
risk and to prevent the development
regularly to evaluate the ability to dis- tilation and ICU length of stay we
of ventilator-associated pneumonia
continue mechanical ventilation when recommend a conservative fluid
(grade 1B).
they satisfy the following criteria: a) strategy for patients with established
6b. We suggest that the head of bed be acute lung injury who do not have
elevated approximately 30 – 45° They are arousable; b) they are hemo-
dynamically stable (without vasopres- evidence of tissue hypoperfusion
(grade 2C). (grade 1C).
sor agents); c) they have no new po-
Rationale. The semirecumbent posi- tentially serious conditions; d) they Rationale. Mechanisms for the devel-
tion has been demonstrated to decrease have low ventilatory and end-expira- opment of pulmonary edema in patients
the incidence of ventilator-associated tory pressure requirements; and e) with acute lung injury include increased
pneumonia (VAP) (162). Enteral feeding their F IO 2 requirements could be capillary permeability, increased hydro-
increased the risk of developing VAP; safely delivered with a face mask or static pressure, and decreased oncotic
50% of the patients who were fed enter- nasal cannula. If the spontaneous pressure (180, 181). Small prospective
ally in the supine position developed VAP breathing trial is successful, consider- studies in patients with critical illness
(163). However, the bed position was only ation should be given for extubation and acute lung injury have suggested that
monitored once a day, and patients who (Appendix E). Spontaneous breathing less weight gain is associated with im-
did not achieve the desired bed elevation trial options include a low level of proved oxygenation (182) and fewer days
were not included in the analysis (163). A pressure support, continuous positive of mechanical ventilation (183, 184). Use
recent study did not show a difference in airway pressure (⬇5 cm H2O), or a of a fluid-conservative strategy directed at
incidence of VAP between patients main- T-piece (grade 1A). minimizing fluid infusion and weight
tained in supine and semirecumbent po- Rationale. Recent studies demon- gain in patients with acute lung injury
sitions (164). In this study, patients in the strate that daily spontaneous breathing based on either a central venous catheter
semirecumbent position did not consis- trials in appropriately selected patients or a pulmonary artery catheter along
tently achieve the desired head of the bed reduce the duration of mechanical venti- with clinical variables to guide treatment
elevation, and the head of bed elevation lation (166 –169). Successful completion strategies led to fewer days of mechanical
in the supine group approached that of of spontaneous breathing trials leads to a ventilation and reduced length of ICU
the semirecumbent group by day 7 (164). high likelihood of successful discontinu- stay without altering the incidence of re-
When necessary, patients may be laid flat ation of mechanical ventilation. nal failure or mortality rates (185). Of
for procedures, hemodynamic measure- note, this strategy was only used in pa-
9. We recommend against the routine tients with established acute lung injury,
ments, and during episodes of hypoten- use of the pulmonary artery catheter some of whom had shock present. Active
sion. Patients should not be fed enterally for patients with ALI/ARDS (grade attempts to reduce fluid volume were
with the head of the bed at 0°. 1A). conducted only during periods free from
7. We suggest that noninvasive mask Rationale. While insertion of a pulmo- shock.
ventilation (NIV) only be considered in nary artery catheter may provide useful
that minority of ALI/ARDS patients information on a patient’s volume status B. Sedation, Analgesia, and
with mild-moderate hypoxemic respi- and cardiac function, potential benefits of Neuromuscular Blockade in
ratory failure (responsive to relatively such information may be confounded by Sepsis
low levels of pressure support and differences in interpretation of results
PEEP) with stable hemodynamics who (170 –172), lack of correlation of pulmo- 1. We recommend sedation protocols
can be made comfortable and are eas- nary artery occlusion pressures with clin- with a sedation goal when sedation of
ily arousable; who are able to protect ical response (173), and absence of a critically ill mechanically ventilated
the airway and spontaneously clear proven strategy to use catheter results to patients with sepsis is required (grade
the airway of secretions; and who are improve patient outcomes (174). Two 1B).
anticipated to recover rapidly from the multicenter randomized trials, one in pa- Rationale. A growing body of evidence
precipitating insult. A low threshold tients with shock or acute lung injury indicates that the use of protocols for

Crit Care Med 2008 Reprint 15


sedation of critically ill ventilated pa- tional study of mechanically ventilated ing the work of breathing and respiratory
tients can reduce the duration of me- patients showed that patients receiving muscle blood flow (196). However, a ran-
chanical ventilation and ICU and hospital continuous sedation had significantly domized, placebo-controlled clinical trial
length of stay (186 –188). A randomized, longer durations of mechanical ventila- in patients with severe sepsis demon-
controlled clinical trial found that proto- tion and ICU and hospital length of stay strated that oxygen delivery, oxygen con-
col use reduced duration of mechanical (191). sumption, and gastric intramucosal pH
ventilation, lengths of stay, and tracheos- Similarly, a prospective, controlled were not improved during profound neu-
tomy rates (186). study in 128 mechanically ventilated romuscular blockade (197).
A report describing the implementa- adults receiving continuous intravenous An association between NMBA use and
tion of protocols, including sedation and sedation demonstrated that a daily inter- myopathies and neuropathies has been
analgesia, using a short-cycle improve- ruption in the continuous sedative infu- suggested by case studies and prospective
ment methodology in the management of sion until the patient was awake de- observational studies in the critical care
critically ill patients demonstrated a de- creased the duration of mechanical population (195, 198 –201). The mecha-
crease in the cost per patient-day and a ventilation and ICU length of stay (192). nisms by which NMBAs produced or con-
decrease of ICU length of stay (187). Fur- Although the patients did receive contin- tribute to myopathies and neuropathies
thermore, a prospective before-and-after uous sedative infusions in this study, the in critically ill patients are presently un-
study on the implementation of a seda- daily interruption and awakening allowed known. There appears to be an added
tion protocol demonstrated enhanced for titration of sedation, in effect making association with the concurrent use of
quality of sedation with reduced drug the dosing intermittent. Systematic (pro- NMBAs and steroids. Although no studies
costs. Although this protocol also may tocolized) titration to a predefined end exist specific to the septic patient popu-
have contributed to a longer duration of point has also been shown to alter out- lation, it seems clinically prudent based
mechanical ventilation, ICU discharge come (186). Additionally, a randomized on existent knowledge that NMBAs not be
was not delayed (188). Despite the lack of prospective blinded observational study administered unless there is a clear indi-
evidence regarding the use of subjective demonstrated that although myocardial cation for neuromuscular blockade that
methods of evaluation of sedation in sep- ischemia is common in critically ill ven- cannot be safely achieved with appropri-
tic patients, the use of a sedation goal has tilated patients, daily sedative interrup- ate sedation and analgesia (195).
been shown to decrease the duration of tion is not associated with an increased Only one prospective, randomized
mechanical ventilation in critically ill pa- occurrence of myocardial ischemia (193). clinical trial has evaluated peripheral
tients (186). Several subjective sedation Thus, the benefits of daily interruption of nerve stimulation vs. standard clinical as-
scales have been described in the medical sedation appear to outweigh the risks. sessment in ICU patients. Rudis et al.
literature. Currently, however, there is These benefits include potentially shorter (202) randomized 77 critically ill patients
not a clearly superior sedation evaluation duration of mechanical ventilation and requiring neuromuscular blockade in the
methodology against which these seda- ICU stay, better assessment of neurologic ICU to receive dosing of vecuronium
tion scales can be evaluated (189). The function, and reduced costs. based on train-of-four stimulation or
benefits of sedation protocols appear to clinical assessment (control). The periph-
3. We recommend that NMBAs be
outweigh the risks. eral nerve stimulation group received less
avoided if possible in the septic patient
drug and recovered neuromuscular func-
2. We recommend intermittent bolus se- due to the risk of prolonged neuro-
tion and spontaneous ventilation faster
dation or continuous infusion seda- muscular blockade following discon-
than the control group. Nonrandomized
tion to predetermined end points (e.g., tinuation. If NMBAs must be main-
observational studies have suggested that
sedation scales) with daily interrup- tained, either intermittent bolus as
peripheral nerve monitoring reduces or
tion/lightening of continuous infusion required or continuous infusion with
has no effect on clinical recovery from
sedation with awakening and retitra- monitoring the depth of blockade with
NMBAs in the ICU (203, 204).
tion if necessary for sedation adminis- train-of-four monitoring should be
Benefits to neuromuscular monitor-
tration to septic mechanically venti- used (grade 1B).
ing, including faster recovery of neuro-
lated patients (grade 1B). Rationale. Although NMBAs are often muscular function and shorter intuba-
Rationale. Although not specifically administered to critically ill patients, tion times, appear to exist. A potential for
studied in patients with sepsis, the ad- their role in the ICU is not well defined. cost savings (reduced total dose of
ministration of intermittent sedation, No evidence exists that maintaining neu- NMBAs and shorter intubation times)
daily interruption, and retitration or sys- romuscular blockade in this patient pop- also may exist, although this has not been
temic titration to a predefined end point ulation reduces mortality or major mor- studied formally.
have been demonstrated to decrease the bidity. In addition, no studies have been
duration of mechanical ventilation (186, published that specifically address the use C. Glucose Control
189, 190). Patients receiving neuromus- of NMBAs in septic patients.
cular blocking agents (NMBAs) must be The most common indication for 1. We recommend that following initial
individually assessed regarding discontin- NMBA use in the ICU is to facilitate me- stabilization, patients with severe sep-
uation of sedative drugs because neuro- chanical ventilation (194). When appro- sis and hyperglycemia who are admit-
muscular blocking drugs must also be priately used, NMBAs may improve chest ted to the ICU receive intravenous in-
discontinued in that situation. The use of wall compliance, prevent respiratory dys- sulin therapy to reduce blood glucose
intermittent vs. continuous methods for synchrony, and reduce peak airway pres- levels (grade 1B).
the delivery of sedation in critically ill sures (195). Muscle paralysis may also 2. We suggest use of a validated protocol
patients has been examined. An observa- reduce oxygen consumption by decreas- for insulin dose adjustments and tar-

16 Crit Care Med 2008 Reprint


geting glucose levels to the ⬍150 tality reduction of 27% and a relative feeding, intravenous dextrose) in the en-
mg/dL range (grade 2C). reduction of 45% (p ⫽ .02). Two addi- vironments in which these protocols
3. We recommend that all patients re- tional observational studies reported an were developed and tested. Alternatively,
ceiving intravenous insulin receive a association of mean glucose levels with some protocols may be more effective
glucose calorie source and that reductions in mortality, polyneuropathy, than others. This conclusion is supported
blood glucose values be monitored acute renal failure, nosocomial bactere- by the wide variability in hypoglycemia
every 1–2 hrs until glucose values mia, and number of transfusions, and rates reported with protocols (205–207,
and insulin infusion rates are stable they suggested that a glucose threshold 212, 213). Thus, the use of a validated and
and then every 4 hrs thereafter for improved mortality lies somewhere safe intensive insulin protocol is impor-
(grade 1C). between 145 and 180 mg/dL (208, 209). tant not only for clinical care but also for
4. We recommend that low glucose lev- However, a large observational study the conduct of clinical trials to avoid hy-
els obtained with point-of-care testing (n ⫽ 7,049) suggested that both a lower poglycemia, adverse events, and prema-
of capillary blood be interpreted with mean glucose and less variation of blood ture termination of these trials before the
caution, as such measurements may glucose may be important (210). A meta- efficacy signal, if any, can be determined.
overestimate arterial blood or plasma analysis of 35 trials on insulin therapy in The finding of reduced morbidity and
glucose values (grade 1B). critically ill patients, including 12 ran- mortality within the longer ICU length of
domized trials, demonstrated a 15% re- stay subsets along with acceptable cost
Rationale. The consensus on glucose
duction in short-term mortality (relative weighed heavily on our recommendation
control in severe sepsis was achieved at
risk 0.85, 95% confidence interval 0.75– to attempt glucose control after initial
the first committee meeting and subse-
0.97) but did not include any studies of stabilization of the patient with hypergly-
quently approved by the entire commit- insulin therapy in medical ICUs (211). cemia and severe sepsis. However, the
tee. (Appendix G presents the committee Two additional multicenter RCTs of mortality benefit and safety of intensive
vote.) One large randomized single- intensive insulin therapy, one focusing insulin therapy (goal to normalize blood
center trial in a predominantly cardiac on patients with severe sepsis (VISEP) glucose) have been questioned by two re-
surgical ICU demonstrated a reduction in and the second on medical and surgical cent trials, and we recommend maintain-
ICU mortality with intensive intravenous ICU patients, failed to demonstrate im- ing glucose levels ⬍150 mg/dL until re-
insulin (Leuven protocol) targeting blood provement in mortality but are not yet cent and ongoing trials are published or
glucose to 80 –110 mg/dL (for all pa- published (212, 213). Both were stopped completed. Further study of protocols
tients, a relative 43% and absolute 3.4% earlier than planned because of high rates that have been validated to be safe and
mortality reduction; for those with ⬎5 of hypoglycemia and adverse events in effective for controlling blood glucose
days in the ICU, a 48% relative and 9.6% the intensive insulin groups. A large RCT concentrations and blood glucose varia-
absolute mortality reduction) (205). A re- that is planned to compare targeting 80 – tion in the severe sepsis population is
duction in organ dysfunction and ICU 110 mg/dL (4.5– 6.0 mmol/L) vs. 140 –180 needed.
length of stay (LOS) (from a median of 15 mg/dL (8 –10 mmol/L) and recruit
to 12 days) was also observed in the sub- ⬎6,000 patients (Normoglycemia in In- D. Renal Replacement
set with ICU LOS ⬎5 days. A second ran- tensive Care Evaluation and Survival Us-
domized trial of intensive insulin therapy ing Glucose Algorithm Regulation, or 1. We suggest that continuous renal re-
using the Leuven protocol enrolled med- NICE-SUGAR) is ongoing (214). placement therapies and intermittent
ical ICU patients with an anticipated ICU Several factors may affect the accuracy hemodialysis are equivalent in pa-
LOS of ⬎3 days in three medical ICUs and reproducibility of point-of-care test- tients with severe sepsis and acute re-
(206). Overall mortality was not reduced, ing of blood capillary blood glucose, in- nal failure (grade 2B).
but ICU and hospital LOS were reduced cluding the type and model of the device 2. We suggest the use of continuous
associated with earlier weaning from me- used, user expertise, and patient factors, therapies to facilitate management of
chanical ventilation and less acute kidney including hematocrit (false elevation fluid balance in hemodynamically un-
injury. In patients with a medical ICU with anemia), PaO2, and drugs (215). One stable septic patients (grade 2D).
LOS ⬎3 days, hospital mortality was re- report showed overestimation of arterial Rationale. Although numerous non-
duced with intensive insulin therapy plasma glucose values by capillary point- randomized studies have reported a non-
(43% vs. 52.5%; p ⫽ .009). However, in- of-care testing sufficient to result in dif- significant trend toward improved sur-
vestigators were unsuccessful in predict- ferent protocol-specified insulin dose ti- vival using continuous methods (218 –
ing ICU LOS, and 433 patients (36%) had tration. The disagreement between 225), two meta-analyses (226, 227)
an ICU LOS of ⬍3 days. Furthermore, use protocol-recommended insulin doses was reported the absence of significant differ-
of the Leuven protocol in the medical ICU largest when glucose values were low ence in hospital mortality between pa-
resulted in a nearly three-fold higher rate (216). A recent review of 12 published tients who receive continuous and inter-
of hypoglycemia than in the original ex- insulin infusion protocols for critically ill mittent renal replacement therapies. This
perience (18% vs. 6.2% of patients) (205, patients showed wide variability in insu- absence of apparent benefit of one modal-
206). lin dose recommendations and variable ity over the other persists even when the
One large before-and-after observa- glucose control during simulation (217). analysis is restricted to only randomized
tional trial showed a 29% relative and This lack of consensus about optimal dos- studies (227). To date, five prospective
6.1% absolute reduction in mortality and ing of intravenous insulin may reflect randomized studies have been published
a 10.8% reduction in median ICU LOS variability in patient factors (severity of (228 –232). Four of them found no signif-
(207). In a subgroup of 53 patients with illness, surgical vs. medical settings) or icant difference in mortality (229 –232).
septic shock, there was an absolute mor- practice patterns (e.g., approaches to One study found significantly higher

Crit Care Med 2008 Reprint 17


mortality in the continuous treatment States and RENAL in Australia and New apy be used unless contraindicated or
group (228), but imbalanced randomiza- Zealand) will be available in 2008 and will not practical (grade 2C).
tion had led to a higher baseline severity greatly inform practice. 4. We suggest that in patients at very
of illness in this group. When a multiva- high risk, LMWH be used rather than
riable model was used to adjust for sever- E. Bicarbonate Therapy UFH as LMWH is proven superior in
ity of illness, no difference in mortality other high-risk patients (grade 2C).
was apparent between the groups (228). 1. We recommend against the use of so-
dium bicarbonate therapy for the pur- Rationale. ICU patients are at risk for
Most studies comparing modes of renal DVT (241). Significant evidence exists for
replacement in the critically ill have in- pose of improving hemodynamics or
reducing vasopressor requirements in benefit of DVT prophylaxis in ICU pa-
cluded a small number of patients and tients in general. No reasons suggest that
some major weaknesses (randomization patients with hypoperfusion-induced
lactic acidemia with pH ⱖ7.15 (grade severe sepsis patients would be different
failure, modifications of therapeutic pro- from the general patient population.
tocol during the study period, combina- 1B).
Nine randomized placebo-controlled
tion of different types of continuous renal Rationale. No evidence supports the clinical trials of DVT prophylaxis in gen-
replacement therapies, small number of use of bicarbonate therapy in the treat- eral populations of acutely ill patients ex-
heterogenous groups of patients en- ment of hypoperfusion-induced lactic aci- ist (242–250). All nine trials showed re-
rolled). The most recent and largest ran- demia associated with sepsis. Two ran- duction in DVT or pulmonary embolism.
domized study (232) enrolled 360 pa- domized, blinded, crossover studies that The prevalence of infection/sepsis was
tients and found no significant difference compared equimolar saline and bicarbon- 17% in all studies in which this was as-
in survival between the two groups. ate in patients with lactic acidosis failed certainable, with a 52% prevalence of in-
Moreover, there is no current evidence to to reveal any difference in hemodynamic fection/sepsis patients in the study that
support the use of continuous therapies variables or vasopressor requirements included ICU patients only. Benefit of
in sepsis independent of renal replace- (239, 240). The number of patients with DVT prophylaxis is also supported by
ment needs. pH ⬍7.15 in these studies was small. meta-analyses (251, 252). With that in
Concerning the hemodynamic toler- Bicarbonate administration has been as- mind, DVT prophylaxis would appear to
ance of each method, no current evidence sociated with sodium and fluid overload, have a high grade for quality of evidence
exists to support a better tolerance with an increase in lactate and PCO2, and a (A). Because the risk of administration to
continuous treatments. Only two pro- decrease in serum ionized calcium, but the patient is small, the gravity of the
spective studies (230, 233) have reported the relevance of these variables to out- potential result of not administering is
a better hemodynamic tolerance with come is uncertain. The effect of bicarbon- great, and the cost is low, the grading of
continuous treatment, with no improve- ate administration on hemodynamics and the strength of the recommendation is
ment in regional perfusion (233) and no vasopressor requirements at lower pH as strong. The evidence supports equiva-
survival benefit (230). Four other pro- well as the effect on clinical outcomes at lency of LMWH and UFH in general med-
spective studies did not find any signifi- any pH is unknown. No studies have ex- ical populations. A recent meta-analysis
cant difference in mean arterial pressure amined the effect of bicarbonate admin- comparing UFH twice daily and three
or drop in systolic pressure between the istration on outcomes. times daily demonstrated that UFH three
two methods (229, 231, 232, 234). Con- times daily produced better efficacy and
cerning fluid balance management, two F. Deep Vein Thrombosis twice daily produced less bleeding (253).
studies reported a significant improve- Prophylaxis Practitioners should use underlying risk
ment in goal achievement with continu- for VTE and bleeding to individualize
ous methods (228, 230). In summary, 1. We recommend that patients with se- choice of twice daily vs. three times daily.
current evidence is insufficient to draw vere sepsis receive deep vein thrombosis The cost of LMWH is greater and the
strong conclusions regarding the mode of (DVT) prophylaxis with either a) low- frequency of injection is less. UFH is pre-
replacement therapy for acute renal fail- dose unfractionated heparin (UFH) ad- ferred over LMWH in patients with mod-
ure in septic patients. ministered twice or three times per day; erate to severe renal dysfunction.
Four randomized controlled trials or b) daily low-molecular weight hepa- Mechanical methods (intermittent com-
have addressed whether the dose of con- rin (LMWH) unless there are contrain- pression devices and graduated compres-
tinuous renal replacement affects out- dications (i.e., thrombocytopenia, severe sion stockings) are recommended when an-
comes in patients with acute renal failure coagulopathy, active bleeding, recent in- ticoagulation is contraindicated or as an
(235–238). Three found improved mor- tracerebral hemorrhage) (grade 1A). adjunct to anticoagulation in very high-risk
tality in patients receiving higher doses of 2. We recommend that septic patients patients (254 –256). In very high-risk pa-
renal replacement (235, 237, 238), while who have a contraindication for hepa- tients, LMWH is preferred over UFH (257–
one (236) did not. None of these trials rin use receive mechanical prophylac- 259). Patients receiving heparin should be
was conducted specifically in patients tic device, such as graduated compres- monitored for development of heparin-
with sepsis. Although the weight of cur- sion stockings or intermittent induced thrombocytopenia.
rent evidence suggests that higher doses compression devices, unless contrain-
of renal replacement may be associated dicated (grade 1A).
G. Stress Ulcer Prophylaxis
with improved outcomes, these results 3. We suggest that in very high-risk pa-
may not be easily generalizable. The re- tients, such as those who have severe 1. We recommend that stress ulcer pro-
sults of two very large multicenter ran- sepsis and history of DVT, trauma, or phylaxis using H2 blocker (grade 1A)
domized trials comparing the dose of re- orthopedic surgery, a combination of or proton pump inhibitor (grade 1B)
nal replacement (ATN in the United pharmacologic and mechanical ther- be given to patients with severe sepsis

18 Crit Care Med 2008 Reprint


to prevent upper gastrointestinal (GI) recommendation for the use of SDD spe- life-sustaining therapies. A recent RCT
bleed. The benefit of prevention of up- cifically in severe sepsis at this time. The demonstrated reduction of anxiety and
per GI bleed must be weighed against final consensus on use of SDD in severe depression in family members when end-
the potential effect of an increased sepsis was achieved at the last nominal of-life meetings were carefully planned
stomach pH on development of venti- committee meeting and subsequently ap- and conducted, included advance care
lator-associated pneumonia. proved by the entire committee (Appen- planning, and provided relevant informa-
Rationale. Although no study has been dix H provides the committee vote). tion about diagnosis, prognosis, and
performed specifically in patients with se- treatment (297).
Rationale. The cumulative conclusion
vere sepsis, trials confirming the benefit from the literature demonstrates that
of stress ulcer prophylaxis in reducing prophylactic use of SDD (enteral nonab- III. Pediatric Considerations in
upper GI bleeds in general ICU popula- sorbable antimicrobials and short-course Severe Sepsis
tions would suggest that 20% to 25% of intravenous antibiotics) reduces infec-
patients enrolled in these types of trials While sepsis in children is a major
tions, mainly pneumonia, and mortality cause of mortality, the overall mortality
have sepsis (260 –263). This benefit in the general population of critically ill
should be applicable to patients with se- from severe sepsis in children is much
and trauma patients (275–286) without lower that that in adults, estimated at
vere sepsis and septic shock. In addition, promoting emergence of resistant Gram-
the conditions shown to benefit from about 10% (298). The definitions for se-
negative bacteria. Post hoc subgroup vere sepsis and septic shock in children
stress ulcer prophylaxis (coagulopathy, analyses (287, 288) of two prospective
mechanical ventilation, hypotension) are are similar but not identical to the defi-
blinded studies (289, 290) suggest that nitions in adults (299). In addition to
frequently present in patients with severe SDD reduces nosocomial (secondary) in-
sepsis and septic shock (264, 265). age-appropriate differences in vital signs,
fections in ICU patients admitted with the definition of systemic inflammatory
Although there are individual trials primary infections (268) and may reduce
that have not shown benefit from stress response syndrome requires the presence
mortality (288). No studies of SDD spe- of either temperature or leukocyte abnor-
ulcer prophylaxis, numerous trials and a cifically focused on patients with severe
meta-analysis show reduction in clini- malities. The presence of severe sepsis
sepsis or septic shock. The use of SDD in requires sepsis plus cardiovascular dys-
cally significant upper GI bleeding, which severe sepsis patients would be targeted
we consider significant even in the ab- function or ARDS or two or more other
toward preventing secondary infection. organ dysfunctions (299).
sence of proven mortality benefit (266 – As the main effect of SDD is in preventing
269). The benefit of prevention of upper ventilator-associated pneumonia (VAP),
GI bleed must be weighed against the studies comparing SDD with nonantimi- A. Antibiotics
potential effect of increased stomach pH crobial interventions, such as ventilator 1. We recommend that antibiotics be ad-
on greater incidence of ventilator- bundles for reducing VAP, are needed. ministered within 1 hr of the identifi-
associated pneumonia (270). Those se- Further investigation is required to de- cation of severe sepsis, after appropri-
vere sepsis patients with the greatest risk termine the comparative efficacy of these ate cultures have been obtained (grade
of upper GI bleeding are likely to benefit two interventions, separately or in com- 1D).
most from stress ulcer prophylaxis. The bination. Although studies incorporating
rationale for preferring suppression of enteral vancomycin in the regimen ap- Early antibiotic therapy is as critical
acid production over sulcrafate was based pear to be safe (291–293), concerns per- for children with severe sepsis as it is for
on the study of 1,200 patients by Cook et sist about the potential for emergence of adults.
al. (271, 272) comparing H2 blockers and resistant Gram-positive infections.
sulcrafate and a meta-analysis. Two stud- B. Mechanical Ventilation
ies support equivalency between H2
I. Consideration for Limitation No graded recommendations.
blockers and proton pump inhibitors.
One study included very ill ICU patients; of Support Due to low functional residual capac-
the second study was larger and demon- ity, young infants and neonates with se-
1. We recommend that advance care
strated noninferiority of omeprazole sus- vere sepsis may require early intubation
planning, including the communica-
pension for clinically significant stress ul- (300). Drugs used for intubation have im-
tion of likely outcomes and realistic
cer bleeding (273, 274). No data relating portant side effects in these patients; for
goals of treatment, be discussed with
to utility of enteral feeding in stress ulcer example, concerns have been raised
patients and families (grade 1D).
prophylaxis exist. Patients should be pe- about the safety of using etomidate in
riodically evaluated for continued need Rationale. Decisions for less aggres- children with meningococcal sepsis be-
for prophylaxis. sive support or withdrawal of support cause of adrenal suppression effect (301).
may be in the patient’s best interest The principles of lung-protective strategies
(294 –296). Too frequently, inadequate are applied to children as they are to adults.
H. Selective Digestive Tract physician/family communication charac-
Decontamination (SDD) terizes end-of-life care in the ICU. The C. Fluid Resuscitation
level of life support given to ICU patients
The guidelines group was evenly split may not be consistent with their wishes. 1. We suggest that initial resuscitation
on the issue of SDD, with equal numbers Early and frequent caregiver discussions begin with infusion of crystalloids
weakly in favor and against recommend- with patients who face death in the ICU with boluses of 20 mL/kg over 5–10
ing the use of SDD (Appendix H). The and with their loved ones may facilitate mins, titrated to clinical monitors of
committee therefore chose not to make a appropriate application and withdrawal of cardiac output, including heart rate,

Crit Care Med 2008 Reprint 19


urine output, capillary refill, and level temic vascular resistance shock. At vari- ference is a better marker than mixed
of consciousness (grade 2C). ous stages of sepsis or the treatment venous hemoglobin saturation with oxy-
Intravenous access for fluid resuscita- thereof, a child may move from one he- gen. As noted previously, blood pressure
tion and inotrope/vasopressor infusion is modynamic state to another. Vasopressor by itself is not a reliable end point for
more difficult to attain in children than or inotrope therapy should be used ac- resuscitation. If a thermodilution catheter is
in adults. The American Heart Associa- cording to the clinical state of the child. used, therapeutic end points are cardiac index
tion and the American Academy of Pedi- Dopamine-refractory shock may re- ⬎3.3 and ⬍6.0 L·min⫺1·m⫺2 with normal
atrics have developed pediatric advanced verse with epinephrine or norepinephrine coronary perfusion pressure (mean arterial
life support guidelines for emergency es- infusion (309). pressure minus central venous pressure) for
tablishment of intravascular support en- 2. We suggest that patients with low age (290). Using clinical end points, such as
couraging early intraosseous access cardiac output and elevated systemic reversal of hypotension and restoration of
(302). On the basis of a number of stud- vascular resistance states (cool ex- capillary refill, for initial resuscitation at the
ies, it is accepted that aggressive fluid tremities, prolonged capillary refill, community hospital level before transfer to a
resuscitation with crystalloids or colloids decreased urine output but normal tertiary center was associated with signifi-
is of fundamental importance to survival blood pressure following fluid resus- cantly improved survival rates in children
of septic shock in children (303–308). citation) be given dobutamine (grade with septic shock (305). Development of a
Three randomized controlled trials com- 2C). transport system including publicizing to lo-
pared the use of colloid to crystalloid cal hospitals and transport with mobile inten-
The choice of vasoactive agent is de- sive care services significantly decreased the
resuscitation in children with dengue termined by the clinical examination. For
shock (303, 307, 308). No difference in case fatality rate from meningococcal disease
the child with a persistent low cardiac in the United Kingdom (316).
mortality between colloid or crystalloid output state with high systemic vascular
resuscitation was shown. resistance despite fluid resuscitation and
Children normally have a lower blood inotropic support, vasodilator therapy F. Approach to Pediatric Septic
pressure than adults, and fall in blood may reverse shock (310). When pediatric Shock
pressure can be prevented by vasocon- patients remain in a normotensive low
striction and increasing heart rate. cardiac output and high vascular resis- Figure 1 shows a flow diagram sum-
Therefore, blood pressure by itself is not a tance state despite epinephrine and vaso- marizing an approach to pediatric septic
reliable end point for assessing the ade- dilator therapy, the use of a phosphodies- shock (317).
quacy of resuscitation. However, once hy- terase inhibitor may be considered (311–
potension occurs, cardiovascular collapse 313). In the case of extremely low
may soon follow. Hepatomegaly occurs in G. Steroids
systemic vascular resistance despite the
children who are fluid overloaded and can use of norepinephrine, vasopressin use 1. We suggest that hydrocortisone ther-
be a helpful sign of adequacy of fluid has been described in a number of case apy be reserved for use in children
resuscitation. Large fluid deficits typi- reports. There is no clear evidence for the with catecholamine resistance and
cally exist, and initial volume resuscita- use of vasopressin in pediatric sepsis suspected or proven adrenal insuffi-
tion usually requires 40 – 60 mL/kg but (314, 315). ciency (grade 2C).
can be much higher (304 –308). However,
the rate of fluid administration should be Patients at risk for adrenal insuffi-
reduced substantially when there are E. Therapeutic End Points ciency include children with severe septic
(clinical) signs of adequate cardiac filling shock and purpura (318, 319), children
1. We suggest that the therapeutic end who have previously received steroid
without hemodynamic improvement. points of resuscitation of septic shock therapies for chronic illness, and children
be normalization of the heart rate, cap- with pituitary or adrenal abnormalities.
illary refill of ⬍2 secs, normal pulses Children who have clear risk factors for
D. Vasopressors/Inotropes with no differential between peripheral adrenal insufficiency should be treated
(Should Be Used in and central pulses, warm extremities, with stress-dose steroids (hydrocortisone
Volume-Loaded Patients With urine output ⬎1 mL·kg⫺1·hr⫺1, and 50 mg/m2/24 hrs).
Fluid Refractory Shock) normal mental status (290) (grade 2C). Adrenal insufficiency in pediatric se-
Capillary refill may be less reliable in a vere sepsis is associated with a poor prog-
1. We suggest dopamine as the first cold environment. Other end points that nosis (320). No strict definitions exist,
choice of support for the pediatric pa- have been widely used in adults and may but absolute adrenal insufficiency in the
tient with hypotension refractory to logically apply to children include de- case of catecholamine-resistant septic
fluid resuscitation (grade 2C). creased lactate and improved base deficit, shock is assumed at a random total cor-
In the initial resuscitation phase, va- ScvO2 ⱖ70% or SV̄O2 ⱖ65%, central ve- tisol concentration ⬍18 ␮g/dL (496
sopressor therapy may be required to sus- nous pressure of 8 –12 mm Hg, or other nmol/L). A post 30- or 60-min ACTH
tain perfusion pressure, even when hypo- methods to analyze cardiac filling. Opti- stimulation test increase in cortisol of ⱕ9
volemia has not yet been resolved. mizing preload optimizes cardiac index. ␮g/dL (248 mmol/L) has been used to
Children with severe sepsis can present In terms of identifying acceptable cardiac define relative adrenal insufficiency. The
with low cardiac output and high sys- output in children with systemic arterial treatment of relative adrenal insuffi-
temic vascular resistance, high cardiac hypoxemia, such as cyanotic congenital ciency in children with septic shock is
output and low systemic vascular resis- heart disease or severe pulmonary dis- controversial. A retrospective study from
tance, or low cardiac output and low sys- ease, arterial-venous oxygen content dif- a large administrative database recently

20 Crit Care Med 2008 Reprint


effect on mortality rate but did show a
positive effect on sepsis-induced coagula-
tion disturbances (323). An RCT of rhAPC
in pediatric severe sepsis patients was
stopped by recommendation of the Data
Monitoring Committee for futility after
enrollment of 399 patients: 28-day all
cause mortality was 18% placebo group
vs. 17% APC group. Major amputations
occurred in 3% of the placebo group vs.
2% in the APC group (324). Due to the
increased risk of bleeding (7% vs. 6% in
the pediatric trial) and lack of proof of
efficacy, rhAPC is not recommended for
use in children.

I. DVT Prophylaxis
1. We suggest the use of DVT prophylaxis
in postpubertal children with severe
sepsis (grade 2C).
Most DVTs in young children are as-
sociated with central venous catheters.
Femoral venous catheters are commonly
used in children, and central venous
catheter-associated DVTs occur in ap-
proximately 25% of children with a fem-
oral central venous catheter. Heparin-
bonded 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 UFH or LMWH prophylaxis to prevent
catheter-related DVT in children in the
ICU exist.

J. Stress Ulcer Prophylaxis


No graded recommendations.
Studies have shown that the rate of
clinically important gastrointestinal
Figure 1. Approach to pediatric shock. *Normalization of blood pressure and tissue perfusion; bleeding in children occurs at rates sim-
**hypotension, abnormal capillary refill or extremity coolness. PALS, Pediatric Advanced Life Support; ilar to adults (327, 328). As in adults,
PICU, pediatric intensive care unit; CI, cardiac index; ECMO, extracorporeal membrane oxygenation. coagulopathy and mechanical ventilation
are risk factors for clinically important
gastrointestinal bleeding. Stress ulcer
reported that the use of any corticoste- H. Protein C and Activated prophylaxis strategy is commonly used in
roids in children with severe sepsis was mechanically ventilated children, usually
Protein C
associated with increased mortality (odds with H2 blockers. Its effect is not known.
ratio 1.9, 95% confidence interval 1.7– 1. We recommend against the use rhAPC
2.2) (321). While steroids may have been in children (grade 1B). K. Renal Replacement Therapy
given preferentially to more severely ill Protein C concentrations in children No graded recommendations.
children, the use of steroids was an inde- reach adult values at the age of 3 yrs. This Continuous veno-venous hemofiltration
pendent predictor of mortality in multi- might indicate that the importance of (CVVH) may be clinically useful in children
variable analysis (321). Given the lack of protein C supplementation either as pro- with anuria/severe oliguria and fluid over-
data in children and potential risk, ste- tein C concentrate or as rhAPC is even load, but no large RCTs have been per-
roids should not be used in children who greater in young children than in adults formed comparing CVVH with intermittent
do not meet minimal criteria for adrenal (322). There has been one dose-finding, dialysis. A retrospective study of 113 criti-
insufficiency. A randomized, controlled randomized, placebo-controlled study cally ill children reported that children
trial in children with septic shock is very performed using protein C concentrate. with less fluid overload before CVVH had
much needed. This study was not powered to show an better survival, especially in those children

Crit Care Med 2008 Reprint 21


with dysfunction of three or more organs old of 9.5 g/dL (334). Whether a lower dations, established interventions may
(329). CVVH or other renal replacement transfusion trigger is safe or appropriate need modification. This publication rep-
therapy should be instituted in children in the initial resuscitation of septic shock resents an ongoing process. The Surviv-
with anuria/severe oliguria before signifi- has not been determined. ing Sepsis Campaign and the consensus
cant fluid overload occurs. committee members are committed to
O. Intravenous Immunoglobulin updating the guidelines regularly as new
L. Glycemic Control interventions are tested and published.
1. We suggest that immunoglobulin be Although evidence-based recommen-
No graded recommendations. considered in children with severe dations have been published frequently in
In general, infants are at risk for de- sepsis (grade 2C). the medical literature, documentation of
veloping hypoglycemia when they depend impact on patient outcome is limited
Administration of polyclonal intrave-
on intravenous fluids. This means that a (338). However, there is growing evi-
nous immunoglobulin has been reported
glucose intake of 4 – 6 mg·kg⫺1·min⫺1 or dence that protocol implementation as-
to reduce mortality rate and is a promis-
maintenance fluid intake with glucose sociated with education and performance
ing adjuvant in the treatment of sepsis
10%/NaCl-containing solution is advised. feedback does change clinician behavior
and septic shock in neonates. A recent
Associations have been reported between and may improve outcomes and reduce
randomized controlled study of poly-
hyperglycemia and an increased risk of costs in severe sepsis (20, 24, 25). Phase
clonal immunoglobulin in pediatric sep-
death and longer length of stay (330). A III of the Surviving Sepsis Campaign tar-
sis syndrome patients (n ⫽ 100) showed a
recent retrospective pediatric ICU study gets the implementation of a core set of
significant reduction in mortality and
reported associations of hyperglycemia, the previous recommendations in hospi-
LOS and less progress to complications,
hypoglycemia, and glucose variability tal environments where change in behav-
especially disseminated intravascular co-
with length of stay and mortality rates ior and clinical impact are being mea-
agulation (335).
(331). No studies in pediatric patients sured. The sepsis bundles were developed
(without diabetes mellitus) analyzing the in collaboration with the Institute of
effect of strict glycemic control using in- P. Extracorporeal Membrane Healthcare Improvement (339). Concur-
sulin exist. In adults, the recommenda- Oxygenation (ECMO) rent or retrospective chart review will
tion is to maintain serum glucose ⬍150 identify and track changes in practice and
mg/dL. Insulin therapy to avoid long pe- 1. We suggest that use of ECMO be lim-
clinical outcome. Software and software
riods of hyperglycemia seems sensible in ited to refractory pediatric septic
support are available at no cost in seven
children as well, but the optimal goal shock and/or respiratory failure that
languages, allowing bedside data entry
glucose is not known. However, continu- cannot be supported by conventional
and allowing creation of regular reports
ous insulin therapy should only be con- therapies (grade 2C).
for performance feedback. The SSC also
ducted with frequent glucose monitoring ECMO has been used in septic shock offers significant program support and
in view of the risks for hypoglycemia. in children, but its impact is not clear. educational materials at no cost to the
Survival from refractory shock or respi- user (www.survivingsepsis.org).
M. Sedation/Analgesia ratory failure associated with sepsis is Engendering evidence-based change
80% in neonates and 50% in children. In in clinical practice through multifaceted
1. We recommend sedation protocols one study analyzing 12 patients with me- strategies while auditing practice and
with a sedation goal when sedation of ningococcal sepsis in ECMO, eight of the providing feedback to healthcare practi-
critically ill mechanically ventilated 12 patients survived, with six leading tioners is the key to improving outcomes
patients with sepsis is required (grade functionally normal lives at a median of 1 in severe sepsis. Nowhere is this more
1D). yr (range, 4 months to 4 yrs) of follow-up. evident than in the worldwide enthusi-
Appropriate sedation and analgesia are Children with sepsis on ECMO do not asm for phase III of the SSC, a perfor-
the standard of care for children who are perform worse than children without sep- mance improvement program using SSC
mechanically ventilated. Although there sis at long-term follow-up (336, 337). guideline-based sepsis bundles. Using the
are no data supporting any particular Although the pediatric considerations guidelines as the basis, the bundles have
drugs or regimens, it should be noted section of this article offers important established a global best practice for the
that propofol should not be used for long- information to the practicing pediatric management of critically ill patients with
term sedation in children because of the clinician for the management of critically severe sepsis. As of November 2007,
reported association with fatal metabolic ill children with sepsis, the reader is re- nearly 12,000 patients had been entered
acidosis (332, 333). ferred to the reference list for more in- into the SSC central database, represent-
depth descriptions of appropriate man- ing efforts of 239 hospitals in 17 coun-
agement of pediatric septic patients. tries. Changes in practice and potential
N. Blood Products
effects on survival are being measured.
No graded recommendations. SUMMARY AND FUTURE
The optimal hemoglobin for a criti- DIRECTIONS ACKNOWLEDGMENTS
cally ill child with severe sepsis is not
known. A recent multicenter trial re- Although this document is static, the As mentioned previously, the Surviv-
ported similar outcomes in stable criti- optimum treatment of severe sepsis and ing Sepsis Campaign (SSC) is partially
cally ill children managed with a transfu- septic shock is a dynamic and evolving funded by unrestricted educational in-
sion threshold of 7 g/dL compared with process. New interventions will be proven dustry grants, including those from Ed-
those managed with a transfusion thresh- and, as stated in the current recommen- wards LifeSciences, Eli Lilly and Com-

22 Crit Care Med 2008 Reprint


pany, and Philips Medical Systems. The et al: Rapid increase in hospitalization and in septic shock. Intensive Care Med 2005;
SSC also received funding from the Coa- mortality rates for severe sepsis in the 31:1066 –1071
lition for Critical Care Excellence of the United States: A trend analysis from 1993 to 20. Kortgen A, Niederprum P, Bauer M: Imple-
Society of Critical Care Medicine. The 2003. Crit Care Med 2007; 35:1414 –1415 mentation of an evidence-based “standard
6. Dellinger RP, Carlet JM, Masur H, et al: operating procedure” and outcome in septic
great majority of industry funding has
Surviving Sepsis Campaign guidelines for shock. Crit Care Med 2006; 34:943–949
come from Eli Lilly and Company. management of severe sepsis and septic 21. Sebat F, Johnson D, Musthafa AA, et al: A
Current industry funding for the Sur- shock. Crit Care Med 2004; 32:858 – 873 multidisciplinary community hospital pro-
viving Sepsis Campaign is directed to the 7. Dellinger RP, Carlet JM, Masur H, et al: gram for early and rapid resuscitation of
performance improvement initiative. No Surviving Sepsis Campaign guidelines for shock in nontrauma patients. Chest 2005;
industry funding was used for committee management of severe sepsis and septic 127:1729 –1743
meetings. No honoraria were provided to shock. Intensive Care Med 2004; 30: 22. Shapiro NI, Howell MD, Talmor D, et al:
committee members. The revision pro- 536 –555 Implementation and outcomes of the Mul-
cess was funded primarily by the Society 8. Guyatt G, Schünemann H, Cook D, et al: tiple Urgent Sepsis Therapies (MUST) pro-
of Critical Care Medicine, with the spon- Applying the grades of recommendations tocol. Crit Care Med 2006; 34:1025–1032
for antithrombotic and thrombolytic ther- 23. Micek SST, Roubinian N, Heuring T, et al:
soring professional organizations provid-
apy: The seventh ACCP conference of anti- Before-after study of a standardized hospital
ing travel expenses for their designated thrombotic and thrombolytic therapy. order set for the management of septic
delegate to the guidelines revision meet- Chest 2004; 126:179S–187S shock. Crit Care Med 2006; 34:2707–2713
ing where needed. 9. GRADE working group: Grading quality of 24. Nguyen HB, Corbett SW, Steele R, et al:
evidence and strength of recommendations. Implementation of a bundle of quality indi-
OTHER ACKNOWLEDGMENTS BMJ 2004; 328:1490 –1498 cators for the early management of severe
10. Guyatt G, Gutterman D, Baumann MH, et sepsis and septic shock is associated with
In addition, we acknowledge Toni al: Grading strength of recommendations decreased mortality. Crit Care Med 2007;
Piper and Rae McMorrow for their assis- and quality of evidence in clinical guide- 35:1105–1112
tance in bringing the manuscripts to- lines: Report from an American College of 25. Shorr AF, Micek ST, Jackson WL Jr, et al:
gether; and Gordon Guyatt and Henry Chest Physicians task force. Chest 2006; Economic implications of an evidence-
Masur, MD, for their guidance on grading 129:174 –181 based sepsis protocol: Can we improve out-
of evidence and antibiotic recommenda- 11. Schünemann HJ, Jaeschke R, Cook DJ, et comes and lower costs? Crit Care Med 2007;
al, on behalf of the ATS Documents Devel- 35:1257–1262
tions, respectively.
opment and Implementation Committee: 26. Reinhart K, Kuhn HJ, Hartog C, et al: Con-
Nine of the 11 organizations that
An official ATS statement: Grading the tinuous central venous and pulmonary ar-
sponsored the first guidelines are spon- quality of evidence and strength of recom- tery oxygen saturation monitoring in the
sors of the revision. Four additional na- mendations in ATS guidelines and recom- critically ill. Intensive Care Med 2004; 30:
tional organizations (Canadian Critical mendations. Am J Respir Crit Care Med 1572–1578
Care Society, Japanese Association for 2006; 174:605– 614 27. Trzeciak S, Dellinger RP, Abate N, et al:
Acute Medicine, Japanese Society of In- 12. Levy MM, Fink MP, Marshall JC, et al: 2001 Translating research to clinical practice: A
tensive Care Medicine, and Society of SCCM/ESICM/ACCP/ATS/SIS International 1-year experience with implementing early
Hospital Medicine), the World Federation Sepsis Definitions Conference. Crit Care goal-directed therapy for septic shock in the
of Intensive and Critical Care Societies, Med 2003; 31:1250 –1256 emergency department. Chest 2006; 129:
and two sepsis organizations (German 13. Bone RC, Balk RA, Cerra FB, et al, and 225–232
members of the ACCP/SCCM Consensus 28. Magder S: Central venous pressure: A useful
Sepsis Society and the Latin American
Conference: Definitions for sepsis and or- but not so simple measurement. Crit Care
Sepsis Institute) have also come on board gan failure and guidelines for the use of Med 2006; 34:2224 –2227
as sponsors. Two organizations that innovative therapies in sepsis. Chest 1992; 29. Bendjelid K: Right arterial pressure: Deter-
sponsored the first guidelines (American 101:1644 –1655 and Crit Care Med 1992; minant or result of change in venous re-
Thoracic Society and Australian and New 20:864 – 874 turn? Chest 2005; 128:3639 –3640
Zealand Intensive Care Society) elected 14. Sprung CL, Bernard GR, Dellinger RP 30. Vincent JL, Weil MH: Fluid challenge revis-
not to sponsor the revision. (Eds): Guidelines for the management of ited. Crit Care Med 2006; 34:1333–1337
severe sepsis and septic shock. Intensive 31. Trzeciak S, Dellinger RP, Parrillo JE, et al:
Care Med 2001; 27(Suppl 1):S1–S134 Early microcirculatory perfusion derange-
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28 Crit Care Med 2008 Reprint


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30 Crit Care Med 2008 Reprint


338. Cinel I, Dellinger RP: Guidelines for severe a single recommendation suggested to APPENDIX C
infections: Are they useful. Curr Opin Crit some that this approach might lead to
Care 1006; 12:483– 488 excessive use of steroids and increased
339. Levy MM, Pronovost PJ, Dellinger RP, et al: Contraindications to Use of
incidence of superinfections, citing the
Sepsis change bundles: Converting guide- Recombinant Human Activated
sepsis and septic shock adverse events in
lines into meaningful change in behavior Protein C (rhAPC)
and clinical outcome. Crit Care Med 2004; the steroid-treated patients in the
32(Suppl):S595–S597 CORTICUS trial. Those who argued for rhAPC increases the risk of bleeding
340. Meduri GU, Golden E, Freire AX, et al: one recommendation pointed to prob- and is contraindicated in patients with
Methylprednisolone infusion in early severe lems with two different recommenda- the following clinical situations in which
ARDS: Results of a randomized controlled tions that would require the bedside cli- bleeding could be associated with a high
trial. Chest 2007; 131:1954 –1963 nician to choose a time point for risk of death or significant morbidity:
341. The National Heart, Lung, and Book Insti- classification of one or the other as well
tute Acute Respiratory Distress Syndrome as a distinct blood pressure cutoff with Active internal bleeding
(ARDS) Clinical Trials Network: Efficacy
the potential for the blood pressure to Recent (within 3 months) hemor-
and safety of corticosteroids for persistent rhagic stroke
vary over time. In addition, there are in-
acute respiratory distress syndrome. N Engl Recent (within 2 months) intracra-
J Med 2006; 354:1671–1684 adequate data to provide standardization
of how much fluids and vasopressors nial or intraspinal surgery, or severe
should be in place to call the blood pres- head trauma
APPENDIX A Trauma with an increased risk of life-
sure unresponsive or poorly responsive.
These members also pointed to the fact threatening bleeding
Source Control that the increased superinfection/sepsis/ Presence of an epidural catheter
septic shock adverse events in CORTICUS Intracranial neoplasm or mass lesion
Source Control are contrary to the results of other stress- or evidence of cerebral herniation
Technique Examples dose steroid trials, such as early ARDS Known hypersensitivity to rhAPC or
(lower incidence of infections) (341), late any component of the product
Drainage Intra-abdominal abscess
ARDS (decreased development of septic See labeling instructions for relative
Thoracic empyema
Septic arthritis
shock), and community-acquired pneu- contraindications. The committee rec-
Debridement Pyelonephritis, cholangitis monia (decreased development of septic ommends that platelet count be main-
Infected pancreatic shock) (114). Based on GRADE adjudica- tained at ⱖ30,000 during infusion of
necrosis tion guidelines, a secret ballot vote was rhAPC. (Physicians’ Desk Reference, 61st
Intestinal infarction conducted to resolve the issue. Edition. Montvale, NJ, Thompson PDR,
Mediastinitis The two options put to vote were: 2007, p 1829).
Device removal Infected vascular catheter
Urinary catheter
Infected intrauterine Two-Recommendation Option APPENDIX D
contraceptive device
Definitive control Sigmoid resection for 1. We suggest that intravenous hydro-
diverticulitis cortisone be given to adult septic Recombinant Activated Protein
Cholecystectomy for shock patients if blood pressure is in- C Nominal Group Vote
gangrenous adequate with appropriate fluid resus- Strong for use, 6
cholecystitis citation and vasopressor therapy Weak for use, 15
Amputation for clostridial (grade 2B).
myonecrosis Neutral, 1
2. We suggest intravenous hydrocorti- Weak for not using, 0
sone not be given to adult septic shock Strong for not using, 0
patients if blood pressure is adequate
APPENDIX B with appropriate fluid resuscitation
and vasopressor therapy (grade 2B). APPENDIX E
Steroids
One-Recommendation Option ARDSNet Ventilator
Considerable difference of opinion ex- Management
isted among committee members as to 1. We suggest that intravenous hydrocor-
the best option for the style of the rec- tisone be given only to adult septic
ommendations for steroid use in septic shock patients with blood pressure Assist control mode—volume venti-
shock. Some committee members argued poorly responsive to fluid resuscitation lation (96)
for two recommendations and pointed to and vasopressor therapy (grade 2C). Reduce tidal volume to 6 mL/kg lean
the two distinct patient populations of body weight
the French Trial (enrollment early in sep- The committee vote that determined Keep inspiratory plateau pressure
tic shock and blood pressure unrespon- the current recommendation was: (Pplat) ⱕ30 cm H2O
sive to vasopressors) and the CORTICUS Favor two-recommendation op- Reduce tidal volume as low as 4 mL/kg
trial (enrollment allowed up to 72 hrs and tion—19 predicted body weight to limit Pplat
did not target patients with blood pres- Favor one-recommendation op- Maintain arterial oxygen saturation/
sure unresponsive to vasopressin), lead- tion—31 pulse oximetry oxyhemoglobin satu-
ing to two distinct results. Furthermore, Abstain—1 ration (SpO2) 88% to 95%

Crit Care Med 2008 Reprint 31


Anticipated PEEP settings at various APPENDIX G
FIO2 requirements
FIO2 0.3, 0.4, 0.4, 0.5, 0.5, 0.6, 0.7, Glycemic Control Committee Vote
0.7, 0.7, 0.8, 0.9, 0.9, 0.9, 1.0 Glycemic control—90%
PEEP 5, 5, 8, 8, 10, 10, 10, 12, 14, 14, Total votes ⫽ 51
14, 16, 18, 20 –24 Agree—34
Predicted Body Weight Calculation Too conservative, but accept— 4
Male—50 ⫹ 2.3 (height [inches] ⫺ Too liberal, but accept— 8
60) or 50 ⫹ 0.91 (height [cm] ⫺ Disapprove, too conservative— 0
152.4) Disapprove, too liberal—5
Female— 45.5 ⫹ 2.3 (height Disapprove, other— 0
[inches] ⫺ 60) or 45.5 ⫹ 0.91
(height [cm] ⫺ 152.4)

APPENDIX F

32 Crit Care Med 2008 Reprint


Appendix H. Selective Digestive Decontamination Nominal Group Vote support from GlaxoSmithKline, Ortho-
Biotech, and Amgen.
Strong Weak Weak Strong
Dr. Brun-Buisson has not disclosed
Antibiotics for Use for Use Neutral for Not Using for Not Using
any potential conflicts of interest.
Systemic — 9 4 8 1 Dr. Beale has received honoraria from
and oral Eisai and speaking fees (paid to university)
Systemic — 2 7 5 3 from Lilly UK, Philips, Lidco, and Chiron.
alone Dr. Calandra has consulted for Baxter,
received honoraria from Roche Diagnos-
tics, and received grant support from
Baxter and Roche Diagnostics. He also
served on the advisory board for Biosite.
of Chest Physicians; n International
APPENDIX I Dr. Dhainaut has consulted for Eli
Sepsis Forum; oEuropean Respiratory
Lilly and Novartis. He has also received
Society.
2008 SSC Guidelines Committee honoraria from Eli Lilly.
Dr. Gerlach has not disclosed any po-
R. Phillip Dellinger (Chair), Tom APPENDIX J tential conflicts of interest.
Ahrens,a Naoki Aikawa,b Derek Angus, Ms. Harvey has not disclosed any po-
Djillali Annane, Richard Beale, Gordon Author Disclosure Information tential conflicts of interest.
R. Bernard, Julian Bion,c Christian Brun- 2006 –2007 Dr. Marini has consulted for KCI and
Buisson, Thierry Calandra, Joseph Carcillo, received honoraria from Maquet.
Jean Carlet, Terry Clemmer, Jonathan Dr. Dellinger has consulted for Astra- Dr. Marshall has consulted for Becton
Cohen, Edwin A. Deitch,d Jean-Francois Zeneca, Talecris, and B Braun. He has Dickinson, Takeda, Pfizer, Spectral Diagnos-
Dhainaut, Mitchell Fink, Satoshi Gando,b received honoraria from Eli Lilly (2), tics, Eisai, and Leo-Pharma. He has also re-
Herwig Gerlach, Gordon Guyatt,e Maurene Brahms (2), INO Therapeutics (1), Pul- ceived honoraria from Spectral Diagnostics.
Harvey, Jan Hazelzet, Hiroyuki Hirasawa,f sion (1), and bioMerieux (1). He has also Dr. Ranieri has served on the advisory
Steven M. Hollenberg, Michael Howell, Ro- received grant support from AstraZeneca board for Maquet and received support
man Jaeschke,e Robert Kacmarek, Didier and Artisan. for a sponsored trial from Eli Lilly. He
Keh, Mitchell M. Levy,g Jeffrey Lipman, Dr. Levy has received honoraria from has also received grant support from
John J. Marini, John Marshall, Claude Mar- Eli Lilly and Edwards Lifesciences. He Tyco, Draeger, and Hamilton.
tin, Henry Masur, Steven Opal, Tiffany M. has also received grant support from Dr. Ramsay has consulted for Edwards
Osborn,h Giuseppe Pagliarello,i Margaret Philips Medical Systems, Edwards Life- Lifesciences and Respironics.
Parker, Joseph Parrillo, Graham Ramsay, sciences, Philips Medical Systems, Novar- Dr. Sevransky has not disclosed any
Adrienne Randolph, Marco Ranieri, Robert tis, Biosite, and Eisai. potential conflicts of interest.
C. Read,j Konrad Reinhart,k Andrew Dr. Carlet has consulted for Forrest, Dr. Thompson has consulted for Eli
Rhodes, Emmanuel Rivers,h Gordon Wyeth, Chiron, bioMerieux, and Glaxo- Lilly, Abbott, and AstraZeneca. He has
Rubenfeld, Jonathan Sevransky, Eliezer Sil- SmithKline. He has also received hono- also received grant support from the NIH
va,l Charles L. Sprung, B. Taylor Thomp- raria from Eli Lilly, Becton Dickinson, for a study on computerized glucose
son, Sean R. Townsend, Jeffery Vender,m Jansen, Cook, AstraZeneca, Hutchinson, control.
Jean-Louis Vincent,n Tobias Welte,o Janice Bayer, Gilead, MSD, and Targanta. Dr. Townsend has not disclosed any
Zimmerman. Dr. Bion has not disclosed any poten- potential conflicts of interest.
a
American Association of Critical- tial conflicts of interest. Dr. Vender has consulted and received
Care Nurses; bJapanese Association for Dr. Parker has consulted for Johnson honoraria from Eli Lilly.
Acute Medicine; cEuropean Society of & Johnson. Dr. Zimmerman has not disclosed any
Intensive Care Medicine; dSurgical In- Dr. Jaeschke has received honoraria potential conflicts of interest.
fection Society; eGrades of Recommen- from AstraZeneca, Boehringer, Eli Lilly, Dr. Vincent has consulted for Astra-
dation, Assessment, Development and GlaxoSmithKline, and MSD. Zeneca, Biosite, bioMerieux, Edwards Life-
Evaluation (GRADE) Group; fJapanese Dr. Reinhart has consulted for Eli Lilly sciences, Eli Lilly, Eisai, Ferring, Glaxo-
Society of Intensive Care Medicine; and Edwards Lifesciences. He has also SmithKline, Intercell, Merck, Novartis,
g
Society of Critical Care Medicine; received honoraria from B Braun and NovoNordisk, Organon, Pfizer, Philips
h
American College of Emergency Phy- royalties from Edwards Lifesciences. Medical Systems, Roche Diagnostics, Spec-
sicians; iCanadian Critical Care Society; Dr. Angus has consulted for or re- tral Diagnostics, Takeda, and Wyeth-
j
European Society of Clinical Micro- ceived speaking fees from AstraZeneca, Lederle. He has also received honoraria
biology and Infectious Diseases; kGer- Brahms Diagnostica, Eisai, Eli Lilly, Glaxo- from Eli Lilly, Edwards Lifesciences, Eisai,
man Sepsis Society; lLatin American SmithKline, OrthoBiotech, Takeda, and GlaxoSmithKline, Novartis, NovoNordisk,
Sepsis Institute; m American College Wyeth-Ayerst. He has also received grant and Pfizer.

Crit Care Med 2008 Reprint 33

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