surviving sepsis campaign guidelines for management of

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Surviving Sepsis Campaign guidelines for management of severesepsis and septic shock

R. Phillip Dellinger, MD; Jean M. Carlet, MD; Henry Masur, MD; Herwig Gerlach, MD, PhD;Thierry Calandra, MD; Jonathan Cohen, MD; Juan Gea-Banacloche, MD, PhD; Didier Keh, MD;John C. Marshall, MD; Margaret M. Parker, MD; Graham Ramsay, MD; Janice L. Zimmerman, MD;Jean-Louis Vincent, MD, PhD; Mitchell M. Levy, MD; for the Surviving Sepsis Campaign ManagementGuidelines Committee

Sponsoring Organizations: American Association of Critical-Care Nurses, American College of Chest Physicians, AmericanCollege of Emergency Physicians, American Thoracic Society, Australian and New Zealand Intensive Care Society,European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, EuropeanRespiratory Society, International Sepsis Forum, Society of Critical Care Medicine, Surgical Infection Society.

Copyright © 2004 by the Society of Critical Care Medicine

DOI: 10.1097/01.CCM.0000117317.18092.E4

Objective: In 2003, critical care and infectious disease expertsrepresenting 11 international organizations developed managementguidelines for severe sepsis and septic shock that would be ofpractical use for the bedside clinician, under the auspices of theSurviving Sepsis Campaign, an international effort to increase aware-ness and improve outcome in severe sepsis.

Design: The process included a modified Delphi method, a con-sensus conference, several subsequent smaller meetings of sub-groups and key individuals, teleconferences, and electronic-baseddiscussion among subgroups and among the entire committee.

Methods: We used a modified Delphi methodology for gradingrecommendations, built on a 2001 publication sponsored by theInternational Sepsis Forum. We undertook a systematic review of theliterature graded along five levels to create recommendation gradesfrom A to E, with A being the highest grade. Pediatric considerationswere provided to contrast adult and pediatric management.

Results: Key recommendations, listed by category and not byhierarchy, include early goal-directed resuscitation of the septicpatient during the first 6 hrs after recognition; appropriate diagnosticstudies to ascertain causative organisms before starting antibiotics;early administration of broad-spectrum antibiotic therapy; reassess-ment of antibiotic therapy with microbiology and clinical data tonarrow coverage, when appropriate; a usual 7–10 days of antibiotictherapy guided by clinical response; source control with attention tothe method that balances risks and benefits; equivalence of crystal-loid and colloid resuscitation; aggressive fluid challenge to restoremean circulating filling pressure; vasopressor preference for norepi-nephrine and dopamine; cautious use of vasopressin pending furtherstudies; avoiding low-dose dopamine administration for renal protec-tion; consideration of dobutamine inotropic therapy in some clinicalsituations; avoidance of supranormal oxygen delivery as a goal oftherapy; stress-dose steroid therapy for septic shock; use of recom-binant activated protein C in patients with severe sepsis and high risk

for death; with resolution of tissue hypoperfusion and in the absenceof coronary artery disease or acute hemorrhage, targeting a hemoglobinof 7–9 g/dL; appropriate use of fresh frozen plasma and platelets; a lowtidal volume and limitation of inspiratory plateau pressure strategy foracute lung injury and acute respiratory distress syndrome; application ofa minimal amount of positive end-expiratory pressure in acute lunginjury/acute respiratory distress syndrome; a semirecumbent bed posi-tion unless contraindicated; protocols for weaning and sedation/analge-sia, using either intermittent bolus sedation or continuous infusion se-dation with daily interruptions/lightening; avoidance of neuromuscularblockers, if at all possible; maintenance of blood glucose <150 mg/dLafter initial stabilization; equivalence of continuous veno-veno hemofil-tration and intermittent hemodialysis; lack of utility of bicarbonate usefor pH >7.15; use of deep vein thrombosis/stress ulcer prophylaxis; andconsideration of limitation of support where appropriate. Pediatric con-siderations included a more likely need for intubation due to low func-tional residual capacity; more difficult intravenous access; fluid resus-citation based on weight with 40–60 mL/kg or higher needed; decreasedcardiac output and increased systemic vascular resistance as the mostcommon hemodynamic profile; greater use of physical examinationtherapeutic end points; unsettled issue of high-dose steroids for therapyof septic shock; and greater risk of hypoglycemia with aggressiveglucose control.

Conclusion: Evidence-based recommendations can be made re-garding many aspects of the acute management of sepsis and septicshock that are hoped to translate into improved outcomes for thecritically ill patient. The impact of these guidelines will be formallytested and guidelines updated annually and even more rapidly assome important new knowledge becomes available. (Crit Care Med2004; 32:858–873)

KEY WORDS: sepsis; severe sepsis; septic shock; sepsis syndrome;infection; guidelines; evidence-based medicine; Surviving Sepsis Cam-paign

858 Crit Care Med 2004 Vol. 32, No. 3

T he mortality rate of severesepsis (infection-induced or-gan dysfunction or hypoper-fusion abnormalities) and

septic shock (hypotension not reversedwith fluid resuscitation and associatedwith organ dysfunction or hypoperfu-sion abnormalities) in most centers re-mains unacceptably high (1, 2). Similarto an acute myocardial ischemic attackand an acute brain attack, the speed andappropriateness of therapy administeredin the initial hours after the syndrome de-velops likely influence outcome. A group ofinternational critical care and infectiousdisease experts in the diagnosis and man-agement of infection and sepsis, represent-ing 11 organizations, came together to de-velop guidelines that the bedside cliniciancould use to improve outcome in severe

sepsis and septic shock. This process repre-sented phase II of the Surviving SepsisCampaign, an international effort to in-crease awareness and improve outcome insevere sepsis. Meeting expenses as well asstaff support for guidelines creation wereprovided by unrestricted industry educa-tional grants as listed. There were no in-dustry members of the committee. Therewas no industry input into guidelines de-velopment and no industry presence at anyof the meetings. Industry awareness orcomment on the recommendations wasnot allowed. The sponsors of the educa-tional grants did not see the recommenda-tions until the manuscript was peer re-viewed and accepted for publication in finalform. Phase I of the Surviving SepsisCampaign was initiated in October 2002with the Barcelona Declaration to improvesurvival in severe sepsis, and phase III willbe dedicated to the use of the managementguidelines to evaluate the impact on clini-cal outcome. A comprehensive documentcreated from the deliberations of the com-mittee will be submitted for publication asa supplement. This document representsan executive summary of the consensusprocess with presentation of key recom-mendations. These recommendations areintended to provide guidance for the clini-cian caring for a patient with severe sepsisor septic shock, but they are not applicablefor all patients. Recommendations fromthese guidelines cannot replace the clini-cian’s decision-making capability when heor she is provided with a patient’s uniqueset of clinical variables. Although these rec-ommendations are written primarily forthe patient in the intensive care unit (ICU)setting, many recommendations are appro-priate targets for the pre-ICU setting. Itshould also be noted that resource limita-tions may prevent physicians from accom-plishing a recommendation.

METHODS

The recommendations are graded based ona modified Delphi methodology with categori-zation as previously described (Table 1,adapted from Ref. 3). The methods for thisdocument build on a 2001 publication spon-sored by the International Sepsis Forum anduse the same method of grading recommen-dations (4). The supplement submission willinclude background material, questions posedthat led to the recommendation, and expandedrationale. This executive summary is targetedto be concise and user friendly for the bedsideclinician. The 2001 publication that was usedas a starting point for the current processincluded a MEDLINE search for clinical trialsin the preceding 10 yrs, supplemented by amanual search of other relevant journals. Sub-topics for each recommendation were cross-referenced to sepsis, severe sepsis, septicshock, sepsis syndrome, and infection. TheSurviving Sepsis Campaign guidelines consid-ered the evidence in the 2001 publication(through 1999) and repeated the process for2000 through 2003. The committee processbegan in June 2003 with a meeting featuringthe first presentations of data and recommen-dations. Recommendations were discussedand critiqued. Each clinical trial used to sup-port recommendations was graded based onthe methodology in Table 1 and included pres-ence or absence of important elements such asconcealed randomization, blinded outcomeadjudication, intention to treat analysis, andexplicit definition of primary outcome. All ar-ticles were initially reviewed based on sub-group assignments and typically by two orthree participants. Survival (28–30 days) wasthe standard outcome measure used to assessoutcome benefit, and when an alternative wasused this is stated in the rationale. Wherestrong trial evidence existed for outcome ben-efit in critically ill populations known to con-tain a larger number of sepsis patients, thesetrials were considered in determination of rec-ommendation grading. A strict evidence-basedmethodology with a scoring system was not

Surviving Sepsis Campaign Management Guide-lines Committee. Chairs: R. Phillip Dellinger, MD*;Henry Masur, MD; Jean M. Carlet, MD; Herwig Gerlach,MD, PhD**. Committee Members: Richard J. Beale,MD**; Marc Bonten, MD; Christian Brun-Buisson, MD;Thierry Calandra, MD; Joseph A. Carcillo, MD;Jonathan Cohen, MD**; Catherine Cordonnier, MD; E.Patchen Dellinger, MD; Jean-Francois Dhainaut, MD,PhD; Roger G. Finch, MD; Simon Finfer, MD; FrancoisA. Fourrier, MD; Juan Gea-Banacloche, MD; MaureneA. Harvey, RN, MPH**; Jan A. Hazelzet, MD; Steven M.Hollenberg, MD; James H. Jorgensen, PhD; Didier Keh,MD; Mitchell M. Levy, MD*; Ronald V. Maier, MD;Dennis G. Maki, MD; John J. Marini, MD; John C.Marshall, MD; Steven M. Opal, MD; Tiffany M. Osborn,MD; Margaret M. Parker, MD**; Joseph E. Parrillo, MD;Graham Ramsay, MD*; Andrew Rhodes, MD; JonathanE. Sevransky, MD; Charles L. Sprung, MD, JD**; AntoniTorres, MD; Jeffery S. Vender, MD; Jean-Louis Vin-cent, MD, PhD**; Janice L. Zimmerman, MD. AssociateMembers: E. David Bennett, MD; Pierre-Yves Bochud,MD; Alain Cariou, MD; Glenn S. Murphy, MD; MartinNitsun, MD; Joseph W. Szokol, MD; Stephen Trzeciak,MD; Christophe Vinsonneau, MD. *Executive Commit-tee, Surviving Sepsis Campaign. **Steering Commit-tee, Surviving Sepsis Campaign. The Surviving SepsisCampaign is administered jointly by the European So-ciety of Intensive Care Medicine, International SepsisForum, and the Society of Critical Care Medicine and issupported in part by unrestricted educational grantsfrom Baxter Bioscience, Edwards Lifesciences, and EliLilly and Company (majority sponsor).

Use of trade names or names of commercialsources is for information only and does not implyendorsement by the Society of Critical Care Medicine.

The authors and the publisher have exercisedgreat care to ensure that drug dosages, formulas, andother information presented in this publication areaccurate and in accord with the professional standardsin effect at the time of publication. Readers are, how-ever, advised to always check the manufacturer’sproduct information sheet that is packaged with therespective products to be fully informed of changes inrecommended dosages, contraindications, and the likebefore prescribing or administering any drug.

Also published in Intensive Care Medicine (May).Address requests for reprints to: R. Phillip Del-

linger, MD, Cooper Health Systems, One Cooper Plaza,393 Dorrance, Camden, NJ 08103.

Table 1. Grading system

Grading of recommendationsA. Supported by at least two level I investigationsB. Supported by one level I investigationC. Supported by level II investigations onlyD. Supported by at least one level III investigationE. Supported by level IV or V evidence

Grading of evidenceI. Large, randomized trials with clear-cut results; low risk of false-positive (alpha) error of

false-negative (beta) errorII. Small, randomized trials with uncertain results; moderate-to-high risk of false-positive

(alpha) and/or false-negative (beta) errorIII. Nonrandomized, contemporaneous controlsIV. Nonrandomized, historical controls and expert opinionV. Case series, uncontrolled studies, and expert opinion

859Crit Care Med 2004 Vol. 32, No. 3

used. The goal was total consensus, which wasreached in all recommendations except two. Inthose circumstances (recommendations C3 andH1), the solution was achieved with the inclu-sion of subrecommendations that expressedsome difference in expert opinion. When therewas difference of opinion about grading of aclinical trial, an outside epidemiologist was con-sulted. This occurred in one circumstance withresolution of differences. Each participant com-pleted a conflict of interest form, and individualswere not assigned to a subgroup topic if they hada potential conflict of interest. A full listing of allpotential conflicts of interest is included withthis article. Following that meeting, the processcontinued with further refinement of recom-mendations through electronic communicationamong committee members. A second meetingof core members of the committee occurred inearly October 2003. The document was finalizedand approved by the consensus committee andby sponsoring organizations in December 2003.

Evidence-based approaches are morereadily applied to data from therapeutic trials.Evaluation of diagnostic techniques is lesswell suited to this approach. Readers will notethat the majority of the recommendations arenot supported by high-level evidence. Most aresupported by expert opinion only. In order fora general recommendation to carry a higherlevel of evidence (grades A, B, C, or D), asupporting study or studies must have shown aclinical outcome difference. Studies showingphysiologic changes that could be potential sur-rogates of clinical outcome benefit were notused by themselves as pivotal studies but wereused to support the validity of studies showingan outcome in a clinically important variablesuch as survival or length of ICU stay. A grade ofA, B, or C required randomized trials. Recom-mendations are graded and followed with ratio-nale. References are provided to support gradesA–D. In the committee’s deliberations, the grad-ing of a recommendation did not establish thelevel of priority or importance of a specific in-tervention, only the degree of literature support.Pediatric considerations are provided at the endof the document for aspects of management thatdiffer from adults. Recommendations aregrouped by category and not by hierarchy.

A. Initial Resuscitation

1. The resuscitation of a patient in severesepsis or sepsis-induced tissue hypoperfu-sion (hypotension or lactic acidosis)should begin as soon as the syndrome isrecognized and should not be delayedpending ICU admission. An elevated se-rum lactate concentration identifies tis-sue hypoperfusion in patients at risk whoare not hypotensive. During the first 6 hrsof resuscitation, the goals of initial resus-citation of sepsis-induced hypoperfusionshould include all of the following as onepart of a treatment protocol:

Central venous pressure: 8–12 mm Hg

Mean arterial pressure �65 mm Hg

Urine output �0.5 mL·kg�1·hr�1

Central venous (superior vena cava) or mixedvenous oxygen saturation �70%

Grade B

Rationale. Early goal-directed therapy hasbeen shown to improve survival for emergencydepartment patients presenting with septicshock in a randomized, controlled, single--center study (5). Resuscitation directed to-ward the previously mentioned goals for theinitial 6-hr period of the resuscitation was ableto reduce 28-day mortality rate. The consen-sus panel judged central venous and mixedvenous oxygen saturation to be equivalent.Either intermittent or continuous measure-ments of oxygen saturation are judged to beacceptable. Although lactate measurementmay be useful, it lacks precision as a measureof tissue metabolic status. In mechanicallyventilated patients, a higher target central ve-nous pressure of 12–15 mm Hg is recom-mended to account for the increased intratho-racic pressure. Similar consideration may bewarranted in circumstances of increased ab-dominal pressure. Although the cause oftachycardia in septic patients may be multi-factorial, a decrease in elevated pulse withfluid resuscitation is often a useful marker ofimproving intravascular filling.

2. During the first 6 hrs of resuscitation ofsevere sepsis or septic shock, if central ve-nous oxygen saturation or mixed venousoxygen saturation of 70% is not achievedwith fluid resuscitation to a central venouspressure of 8–12 mm Hg, then transfusepacked red blood cells to achieve a hemat-ocrit of �30% and/or administer a dobut-amine infusion (up to a maximum of 20�g·kg�1·min�1) to achieve this goal.

Grade B

Rationale. The protocol used in the studycited previously targeted an increase in mixedvenous oxygen saturation to �70%. This wasachieved by sequential institution of initial fluidresuscitation, then packed red blood cells, andthen dobutamine. This protocol was associatedwith an improvement in survival (5).

B. Diagnosis

1. Appropriate cultures should always be ob-tained before antimicrobial therapy is ini-tiated. To optimize identification of caus-ative organisms, at least two bloodcultures should be obtained with at leastone drawn percutaneously and one drawnthrough each vascular access device, un-less the device was recently (�48 hrs)inserted. Cultures of other sites such asurine, cerebrospinal fluid, wounds, respi-ratory secretions, or other body fluidsshould be obtained before antibiotic ther-

apy is initiated as the clinical situationdictates.

Grade D

Rationale. Two or more blood cultures arerecommended (6). Ideally, at least one bloodculture should be drawn through each lumenof each vascular access device. Obtainingblood cultures peripherally and through a vas-cular access device is an important strategy. Ifthe same organism is recovered from bothcultures, the likelihood that the organism iscausing the severe sepsis is enhanced. In ad-dition, if the culture drawn through the vas-cular access device is positive much earlierthan the peripheral blood culture (i.e., �2 hrsearlier), it may offer support that the vascularaccess device is the source of the infection (7).Volume of blood may also be important (8).

2. Diagnostic studies should be performedpromptly to determine the source of theinfection and the causative organism.Imaging studies and sampling of likelysources of infection should be per-formed; however, some patients may betoo unstable to warrant certain invasiveprocedures or transport outside of theICU. Bedside studies, such as ultrasound,may be useful in these circumstances.

Grade E

Rationale. Diagnostic studies may identify asource of infection that must be drained to max-imize the likelihood of a satisfactory response totherapy. However, even in the most organizedand well-staffed healthcare facilities, transport ofpatients can be dangerous, as can placing pa-tients in outside-unit imaging devices that aredifficult to access and monitor.

C. Antibiotic Therapy

1. Intravenous antibiotic therapy shouldbe started within the first hour of rec-ognition of severe sepsis, after appropri-ate cultures have been obtained.

Grade E

Rationale. Establishing vascular access andinitiating aggressive fluid resuscitation is thefirst priority when managing patients with se-vere sepsis or septic shock. However, promptinfusion of antimicrobial agents is also a logicalstrategy and may require additional vascular ac-cess ports. Establishing a supply of premixedantibiotics in an emergency department or crit-ical care unit for such urgent situations is anappropriate strategy for enhancing the likeli-hood that antimicrobial agents will be infusedpromptly. Staff should be cognizant that someagents require more lengthy infusion timewhereas others can be rapidly infused or evenadministered as a bolus.

2. Initial empirical anti-infective therapyshould include one or more drugs that


have activity against the likely pathogens(bacterial or fungal) and that penetrateinto the presumed source of sepsis. Thechoice of drugs should be guided by thesusceptibility patterns of microorganismsin the community and in the hospital.

Grade D

Rationale. The choice of empirical antibi-otics depends on complex issues related to thepatient’s history (including drug intolerance),underlying disease, the clinical syndrome, andsusceptibility patterns in the patient’s com-munity and in the healthcare facility.

The initial selection of an empirical anti-microbial regimen should be broad enough,according to these criteria, covering all likelypathogens since there is little margin for errorin critically ill patients. There is ample evi-dence that failure to initiate appropriate ther-apy promptly (i.e., therapy that is activeagainst the causative pathogen) has adverseconsequences on outcome (9–12).

Although restricting the use of antibiotics,and particularly broad-spectrum antibiotics, isimportant for limiting superinfection and fordecreasing the development of antibiotic-resistant pathogens, patients with severe sep-sis or septic shock warrant broad-spectrumtherapy until the causative organism and itsantibiotic susceptibilities are defined. At thatpoint, restriction of the number of antibioticsand narrowing the spectrum of antimicrobialtherapy is an important and responsible strat-egy for minimizing the development of resis-tant pathogens and for containing costs.

All patients should receive a full loadingdose of each antimicrobial. However, patientswith sepsis or septic shock often have abnor-mal renal or hepatic function and may haveabnormal volumes of distribution due to ag-gressive fluid resuscitation. The ICU pharma-cist should be consulted to ensure that serumconcentrations are attained that maximize ef-ficacy and minimize toxicity, (13–16).

3. The antimicrobial regimen should al-ways be reassessed after 48–72 hrs onthe basis of microbiological and clinicaldata with the aim of using a narrow-spectrum antibiotic to prevent the devel-opment of resistance, to reduce toxicity,and to reduce costs. Once a causativepathogen is identified, there is no evi-dence that combination therapy is moreeffective than monotherapy. The dura-tion of therapy should typically be 7–10days and guided by clinical response.

Grade E

a. Some experts prefer combination therapyfor patients with Pseudomonas infections.

Grade E

b. Most experts would use combination ther-apy for neutropenic patients with severe sepsisor septic shock. For neutropenic patients,

broad-spectrum therapy usually must be con-tinued for the duration of the neutropenia.

Grade E

Rationale. Use of antimicrobial agents witha more narrow spectrum and reducing theduration of therapy will reduce the likelihoodthat the patient will develop superinfectionwith pathogenic or resistant organisms suchas Candida species, Clostridium difficile, orvancomycin-resistant Enterococcus faecium.However, the desire to minimize superinfec-tions and other complications should not takeprecedence over the need to give the patientan adequate course of potent antimicrobials.

4. If the presenting clinical syndrome isdetermined to be due to a noninfec-tious cause, antimicrobial therapyshould be stopped promptly to mini-mize the development of resistantpathogens and superinfection withother pathogenic organisms.

Grade E

Rationale. Clinicians should be cognizantthat blood cultures will be negative in themajority of cases of sepsis or septic shock.Thus, the decision to continue, narrow, orstop antimicrobial therapy must be made onthe basis of clinician judgment and other cul-ture results.

D. Source Control

1. Every patient presenting with severesepsis should be evaluated for the pres-ence of a focus on infection amenable tosource control measures, specificallythe drainage of an abscess or local focuson infection, the debridement of in-fected necrotic tissue, the removal of apotentially infected device, or the defin-itive control of a source of ongoing mi-crobial contamination (17). (See Appen-dix A for examples of potential sitesneeding source control.)

Grade E

Rationale. Healthcare professionals shouldengage specialists in other disciplines such asradiology, surgery, pulmonary medicine, andgastroenterology to obtain diagnostic samplesand to drain, debride, or remove the infectionsource as appropriate.

2. The selection of optimal source controlmethods must weigh benefits and risksof the specific intervention. Source con-trol interventions may cause furthercomplications such as bleeding, fistulas,or inadvertent organ injury; in general,the intervention that accomplishes thesource control objective with the leastphysiologic upset should be employed,for example, consideration of percutane-ous rather than surgical drainage of anabscess (18).

Grade E

3. When a focus of infection amenable tosource control measures such as anintra-abdominal abscess, a gastrointes-tinal perforation, cholangitis, or intes-tinal ischemia has been identified asthe cause of severe sepsis or septicshock, source control measures shouldbe instituted as soon as possible follow-ing initial resuscitation.

Grade E

Rationale. Case series and expert opinionsupport the principle that rapid correction of asource of microbial contamination is essentialto maximize survival of the severely septicpatient with acute physiologic deterioration.Intervention should only be undertaken fol-lowing adequate resuscitation. Timely andemergent intervention is particularly impor-tant for patients with necrotizing soft tissueinfection or intestinal ischemia (19).

4. If intravascular access devices are poten-tially the source of severe sepsis or septicshock, they should be promptly removedafter establishing other vascular access.

Grade E

Rationale. Intravascular access devices arethought to be the source of the majority ofnosocomial bloodstream infections. When pa-tients develop sepsis of unknown source, itmay be reasonable to leave vascular accessdevices in place until the source of infectioncan be determined. However, when patientshave severe sepsis or septic shock of unknownsource, clinicians should consider removaland replacement of vascular access devices tobe a priority, even if the device is tunneled orsurgically implanted (20, 21).

E. Fluid Therapy

See initial resuscitation recommendations(A1–2) for timing of resuscitation.

1. Fluid resuscitation may consist of natu-ral or artificial colloids or crystalloids.There is no evidence-based support forone type of fluid over another.

Grade C

Rationale. Although prospective studies ofchoice of fluid resuscitation in patients withseptic shock only are lacking, meta-analysis ofclinical studies comparing crystalloid and col-loid resuscitation in general and surgical pa-tient populations indicate no clinical outcomedifference between colloids and crystalloidsand would appear to be generalizable to sepsispopulations (22–24). As the volume of distri-bution is much larger for crystalloids than forcolloids, resuscitation with crystalloids re-quires more fluid to achieve the same endpoints and results in more edema.


2. Fluid challenge in patients with sus-pected hypovolemia (suspected inade-quate arterial circulation) may be givenat a rate of 500–1000 mL of crystalloidsor 300–500 mL of colloids over 30 minsand repeated based on response (increasein blood pressure and urine output) andtolerance (evidence of intravascular vol-ume overload).

Grade E

Rationale. Fluid challenge must be clearlyseparated from an increase in maintenancefluid administration. Fluid challenge is a termused to describe the initial volume expansionperiod in which the response of the patient tofluid administration is carefully evaluated.During this process, large amounts of fluidsmay be administered over a short period oftime under close monitoring to evaluate thepatient’s response and avoid the developmentof pulmonary edema. The degree of intravas-cular volume deficit in patients with severesepsis varies. With venodilation and ongoingcapillary leak, most patients require continu-ing aggressive fluid resuscitation during thefirst 24 hrs of management. Input is typicallymuch greater than output, and input/outputratio is of no utility to judge fluid resuscitationneeds during this time period.

F. Vasopressors

1. When an appropriate fluid challengefails to restore adequate blood pres-sure and organ perfusion, therapywith vasopressor agents should bestarted. Vasopressor therapy may alsobe required transiently to sustain lifeand maintain perfusion in the face oflife-threatening hypotension, evenwhen a fluid challenge is in progressand hypovolemia has not yet been cor-rected.

Grade E

Rationale. Below a certain mean arterialpressure, autoregulation in various vascularbeds can be lost, and perfusion can become lin-early dependent on pressure. Thus, some pa-tients may require vasopressor therapy toachieve a minimal perfusion pressure and main-tain adequate flow. It is important to supple-ment goals such as blood pressure with assess-ment of global perfusion such as blood lactateconcentrations. Adequate fluid resuscitation is afundamental aspect of the hemodynamic man-agement of patients with septic shock andshould ideally be achieved before vasopressorsare used, but it is frequently necessary to employvasopressors early as an emergency measure inpatients with severe shock (25, 26).

2. Either norepinephrine or dopamine(through a central catheter as soon as avail-able) is the first-choice vasopressor agent tocorrect hypotension in septic shock.

Grade D

Rationale. Although there is no high-quality primary evidence to recommend onecatecholamine over another, human and an-imal studies suggest some advantages ofnorepinephrine and dopamine over epineph-rine (potential tachycardia, possibly disad-vantageous effects on splanchnic circula-tion) and phenylephrine (decrease in strokevolume). Phenylephrine is the adrenergicagent least likely to produce tachycardia.Dopamine increases mean arterial pressureand cardiac output, primarily due to an in-crease in stroke volume and heart rate. Nor-epinephrine increases mean arterial pres-sure due to its vasoconstrictive effects, withlittle change in heart rate and less increasein stroke volume compared with dopamine.Either may be used as a first-line agent tocorrect hypotension in sepsis. Norepineph-rine is more potent than dopamine and maybe more effective at reversing hypotensionin patients with septic shock. Dopamine maybe particularly useful in patients with com-promised systolic function but causes moretachycardia and may be more arrhythmo-genic (25, 27–30).

3. Low-dose dopamine should not be usedfor renal protection as part of the treat-ment of severe sepsis.

Grade B

Rationale. A large randomized trial and ameta-analysis comparing low-dose dopamineto placebo in critically ill patients found nodifference in either primary outcomes (peakserum creatinine, need for renal replacementtherapy, urine output, time to recovery of nor-mal renal function) or secondary outcomes(survival to either ICU or hospital discharge,ICU stay, hospital stay, arrhythmias). Thus,the available data do not support administra-tion of low doses of dopamine to maintain orimprove renal function (31, 32).

4. All patients requiring vasopressorsshould have an arterial catheter placed assoon as practical if resources are available.

Grade E

Rationale. In shock states, measurementof blood pressure using a cuff is commonlyinaccurate, whereas use of an arterial cath-eter provides a more accurate and reproduc-ible measurement of arterial pressure. Mon-itoring with these catheters also allows beat-to-beat analysis so that decisions regardingtherapy can be based on immediate bloodpressure information (25). Placement of anarterial catheter in the emergency depart-ment is typically not possible or practical. Itis important to appreciate the complicationsof arterial catheter placement, which in-clude hemorrhage and damage to arterialvessels.

5. Vasopressin use may be considered inpatients with refractory shock despiteadequate fluid resuscitation and high-dose conventional vasopressors. Pendingthe outcome of ongoing trials, it is notrecommended as a replacement for nor-epinephrine or dopamine as a first-lineagent. If used in adults, it should beadministered at infusion rates of 0.01–0.04 units/min. It may decrease strokevolume.

Grade E

Rationale. Low doses of vasopressin maybe effective in raising blood pressure in pa-tients refractory to other vasopressors, al-though no outcome data are available. Un-like dopamine and epinephrine, vasopressinis a direct vasoconstrictor without inotropicor chronotropic effects and may result indecreased cardiac output and hepato-splanchnic flow. Most published reports ex-clude patients from treatment with vaso-pressin if the cardiac index is �2 or 2.5L·min�1·m�2, and it should be used withcaution in patients with cardiac dysfunction.Studies show that vasopressin concentra-tions are elevated in early septic shock, butwith continued shock, concentrations de-crease to normal range in the majority ofpatients between 24 and 48 hrs (33). Thishas been called “relative vasopressin defi-ciency” since in the presence of hypoten-sion, vasopressin would be expected to beelevated. The significance of this finding isunknown. Doses of vasopressin �0.04 units/min have been associated with myocardialischemia, significant decreases in cardiacoutput, and cardiac arrest (34 –36).

G. Inotropic Therapy

1. In patients with low cardiac output de-spite adequate fluid resuscitation, dobu-tamine may be used to increase cardiacoutput. If used in the presence of lowblood pressure, it should be combinedwith vasopressor therapy.

Grade E

Rationale. Dobutamine is the first-choiceinotrope for patients with measured or sus-pected low cardiac output in the presence ofadequate left ventricular filling pressure (or clin-ical assessment of adequate fluid resuscitation)and adequate mean arterial pressure. In the ab-sence of measurements of cardiac output, hypo-tensive patients with severe sepsis may have low,normal, or increased cardiac outputs. Therefore,treatment with a combined inotrope/vasopressorsuch as norepinephrine or dopamine is recom-mended. When the capability exists for monitor-ing cardiac output in addition to blood pressure,a vasopressor such as norepinephrine and aninotrope such as dobutamine may be used sep-arately to target specific levels of mean arterialpressure and cardiac output.


2. A strategy of increasing cardiac index toachieve an arbitrarily predefined elevatedlevel is not recommended.

Grade A

Rationale. Two large prospective clinicaltrials that included critically ill ICU patientswho had severe sepsis failed to demonstratebenefit from increasing oxygen delivery to su-pranormal levels by use of dobutamine (37,38). The goal of resuscitation should insteadbe to achieve adequate levels of oxygen deliv-ery or avoid flow-dependent tissue hypoxia.

H. Steroids

1. Intravenous corticosteroids (hydrocortisone200–300 mg/day, for 7 days in three orfour divided doses or by continuous infu-sion) are recommended in patients withseptic shock who, despite adequate fluidreplacement, require vasopressor therapyto maintain adequate blood pressure.

Grade C

Rationale. One multiple-center, random-ized, controlled trial (RCT) with patients in se-vere septic shock showed a significant shockreversal and reduction of mortality rate in pa-tients with relative adrenal insufficiency (definedas post-adrenocorticotropic hormone [ACTH]cortisol increase �9 �g/dL) (39). Two additionalsmaller RCTs showed significant effects onshock reversal (40, 41). In the first study, pa-tients had more severe septic shock (systolicblood pressure �90 mm Hg despite vasopres-sors) than in the latter two studies (systolicblood �90 mm Hg with vasopressors).

a. Some experts would use a 250-�g ACTHstimulation test to identify responders (�9�g/dL increase in cortisol 30–60 mins post-ACTH administration) and discontinuetherapy in these patients. Clinicians shouldnot wait for ACTH stimulation results toadminister corticosteroids.

Grade E

Rationale. One study demonstrated that anincremental increase of �9 �g/dL after 250-�gACTH stimulation test (responders) identifiessurvivors of septic shock (42). A subsequent trialdemonstrated that stress dose steroids improvedsurvival in those patients who failed to producethis increase in cortisol with ACTH (nonre-sponders). Treatment with corticosteroids wasineffective in responders (39). Recommenda-tions for the identification of relative adrenalinsufficiency vary based on different cutoff levelsof random cortisol, peak cortisol after stimula-tion, incremental cortisol increase after stimu-lation, and combinations of these criteria (43–45). In patients with septic shock, cliniciansshould consider administering a dose of dexa-methasone until such time that an ACTH stim-ulation test can be administered because dexa-methasone, unlike hydrocortisone, does notinterfere with the cortisol assay.

b. Some experts would decrease dosage ofsteroids after resolution of septic shock.

Grade E

Rationale. There has been no comparativestudy between a fixed duration and clinicallyguided regimen. Two RCTs used a fixed dura-tion protocol for treatment (39, 41), and inoneRCT, therapy was decreased after shock reso-lution and discontinued after 6 days (40).

c. Some experts would consider tapering thedose of corticosteroids at the end of therapy.

Grade E

Rationale. One study showed hemody-namic and immunologic rebound effects afterabrupt cessation of corticosteroids (46).

d. Some experts would add fludrocortisone (50�g orally four times per day) to this regimen.

Grade E

Rationale. One study added 50 �g offludrocortisone orally (39). Since hydrocorti-sone has intrinsic mineralocorticoid activity,there is controversy as to whether fludrocor-tisone should be added.

2. Doses of corticosteroids �300 mg hydro-cortisone daily should not be used insevere sepsis or septic shock for the pur-pose of treating septic shock.

Grade A

Rationale. Two randomized prospectiveclinical trials and two meta-analyses concludedthat for therapy of severe sepsis or septic shock,high-dose corticosteroid therapy is ineffective orharmful (47–50). There may be reasons to main-tain higher doses of corticosteroid for medicalconditions other than septic shock.

3. In the absence of shock, corticosteroidsshould not be administered for the treat-ment of sepsis. There is, however, nocontraindication to continuing mainte-nance steroid therapy or to using stressdose steroids if the patient’s history ofcorticosteroid administration or the pa-tient’s endocrine history warrants.

Grade E

Rationale. There are no studies document-ing that stress doses of steroids improve theoutcome of sepsis in the absence of shockunless the patient requires stress dose replace-ment due to a prior history of steroid therapyor adrenal dysfunction.

I. Recombinant HumanActivated Protein C (rhAPC)

1. rhAPC is recommended in patients at highrisk of death (Acute Physiology and ChronicHealth Evaluation II �25, sepsis-inducedmultiple organ failure, septic shock, orsepsis-induced acute respiratory distress

syndrome [ARDS]) and with no absolutecontraindication related to bleeding risk orrelative contraindication that outweighsthe potential benefit of rhAPC (see Appen-dix B for absolute contraindications andprescription information for warnings).

Grade B

Rationale. The inflammatory response insevere sepsis is integrally linked to procoagu-lant activity and endothelial activation. Theinflammatory response in sepsis is procoagu-lant in the early stages. rhAPC, an endogenousanticoagulant with anti-inflammatory proper-ties, has been shown, in a large, multiple-center, randomized, controlled trial (50), toimprove survival in patients with sepsis-induced organ dysfunction.

At present, risk assessment is best deter-mined by bedside clinical evaluation and judg-ment. Given the uncertainty of risk assess-ment and the potential for rapid deteriorationof patients with severe sepsis and septic shock,once a patient has been identified as at highrisk of death, treatment should begin as soonas possible.

J. Blood Product Administration

1. Once tissue hypoperfusion has resolvedand in the absence of extenuating circum-stances, such as significant coronary arterydisease, acute hemorrhage, or lactic acido-sis (see recommendations for initial resus-citation), red blood cell transfusion shouldoccur only when hemoglobin decreases to�7.0 g/dL (�70 g/L) to target a hemoglo-bin of 7.0–9.0 g/dL.

Grade B

Rationale. Although the optimum hemo-globin for patients with severe sepsis has notbeen specifically investigated, the TransfusionRequirements in Critical Care trial suggestedthat a hemoglobin of 7–9 g/dL (70–90 g/L) isadequate for most critically ill patients. Atransfusion threshold of 7.0 g/dL (70 g/L) wasnot associated with increased mortality rate.Red blood cell transfusion in septic patientsincreases oxygen delivery but does not usuallyincrease oxygen consumption (51–53). Thistransfusion threshold contrasts with the tar-get of a hematocrit of 30% in patients with lowcentral venous oxygen saturation during thefirst 6 hrs of resuscitation of septic shock.

2. Erythropoietin is not recommended as aspecific treatment of anemia associatedwith severe sepsis but may be used whenseptic patients have other accepted rea-sons for administration of erythropoietinsuch as renal failure induced compro-mise of red blood cell production.

Grade B

Rationale. No specific information regard-ing erythropoietin use in septic patients is avail-able, but clinical trials in critically ill patients


show some decrease in red cell transfusion re-quirement with no effect on clinical outcome(54, 55). Patients with severe sepsis and septicshock may have coexisting conditions that dowarrant use of erythropoietin.

3. Routine use of fresh frozen plasma to cor-rect laboratory clotting abnormalities inthe absence of bleeding or planned invasiveprocedures is not recommended.

Grade E

Rationale. Although clinical studies havenot assessed the impact of transfusion of freshfrozen plasma on outcomes in critically illpatients, professional organizations have rec-ommended fresh frozen plasma for coagulopa-thy when there is a documented deficiency ofcoagulation factors (increased prothrombintime, international normalized ratio, or partialthromboplastin time) and the presence of ac-tive bleeding or before surgical or invasiveprocedures (56–58).

4. Antithrombin administration is not rec-ommended for the treatment of severesepsis and septic shock.

Grade B

Rationale. A phase III clinical trial of high-dose antithrombin did not demonstrate anybeneficial effect on 28-day all-cause mortalityin adults with severe sepsis and septic shock.High-dose antithrombin was associated withan increased risk of bleeding when adminis-tered with heparin (59).

5. In patients with severe sepsis, plateletsshould be administered when counts are�5000/mm3 (5 � 109/L) regardless ofapparent bleeding. Platelet transfusionmay be considered when counts are5000–30,000/mm3 (5–30 � 109/L) andthere is a significant risk of bleeding.Higher platelet counts (�50,000/mm3

[50 � 109/L]) are typically required forsurgery or invasive procedures.

Grade E

Rationale. Guidelines for transfusion ofplatelets are derived from consensus opinionand experience in patients undergoing chemo-therapy. Recommendations take into accountthe etiology of thrombocytopenia, platelet dys-function, risk of bleeding, and presence ofconcomitant disorders (56, 58).

K. Mechanical Ventilation ofSepsis-Induced Acute LungInjury (ALI)/ARDS

1. High tidal volumes that are coupled withhigh plateau pressures should be avoidedin ALI/ARDS. Clinicians should use as astarting point a reduction in tidal vol-umes over 1–2 hrs to a “low” tidal vol-ume (6 mL per kilogram of predictedbody weight) as a goal in conjunction

with the goal of maintaining end-inspiratory plateau pressures �30 cmH2O. (See Appendix C for a formula tocalculate predicted body weight.)

Grade B

Rationale. Over the past 10 yrs, severalmultiple-center randomized trials have beenperformed to evaluate the effects of limitinginspiratory pressure through modulations intidal volume (60–63). These studies showeddiffering results that may have been caused bydifferences between airway pressures in thetreatment and control groups (64, 65). Thelargest trial of a volume- and pressure-limitedstrategy showed a 9% decrease of all-causemortality in patients ventilated with tidal vol-umes of 6 mL/kg of predicted body weight(as opposed to 12 mL/kg) while aiming for aplateau pressure �30 cm H2O (66).

2. Hypercapnia (allowing PaCO2 to increaseabove normal, so-called permissive hy-percapnia) can be tolerated in patientswith ALI/ARDS if required to minimizeplateau pressures and tidal volumes.

Grade C

Rationale. An acutely elevated PaCO2 mayhave physiologic consequences that includevasodilation as well as an increased heart rate,blood pressure, and cardiac output. Allowingmodest hypercapnia in conjunction with lim-iting tidal volume and minute ventilation hasbeen demonstrated to be safe in small nonran-domized series (67, 68). Patients treated inlarger trials that have the goal of limiting tidalvolumes and airway pressures have demon-strated improved outcomes, but permissivehypercapnia was not a primary treatment goalin these studies (66). The use of hypercarbia islimited in patients with preexisting metabolicacidosis and is contraindicated in patientswith increased intracranial pressure. Sodiumbicarbonate infusion may be considered in se-lect patients to facilitate use of permissivehypercarbia.

3. A minimum amount of positive end-expiratory pressure should be set to pre-vent lung collapse at end-expiration. Set-ting positive end-expiratory pressurebased on severity of oxygenation deficitand guided by the FIO2 required to main-tain adequate oxygenation is one accept-able approach. (See Appendix C.) Someexperts titrate positive end-expiratorypressure according to bedside measure-ments of thoracopulmonary compliance(to obtain the highest compliance, re-flecting lung recruitment).

Grade E

Rationale. Raising end-expiratory pressurein ALI/ARDS keeps lung units open to partic-ipate in gas exchange (69–71). This will in-

crease PaO2 when positive end-expiratory pres-sure is applied through either an endotrachealtube or a face mask.

4. In facilities with experience, prone posi-tioning should be considered in ARDSpatients requiring potentially injuriouslevels of FIO2 or plateau pressure who arenot at high risk for adverse conse-quences of positional changes.

Grade E

Rationale. Several smaller studies and onelarger study have shown that a majority ofpatients with ALI/ARDS respond to the proneposition with improved oxygenation (72–76).The large multiple-center trial of prone posi-tioning for �7 hrs/day did not show improve-ment in mortality rates in patients with ALI/ARDS; however, a post hoc analysis suggestedimprovement in those patients with the mostsevere hypoxemia by PaO2/FIO2 ratio (75).Prone positioning may be associated with po-tentially life-threatening complications, in-cluding accidental dislodgment of the endo-tracheal tube and central venous catheters,but these complications can usually beavoided with proper precautions.

5. Unless contraindicated, mechanicallyventilated patients should be maintainedsemirecumbent, with the head of the bedraised to 45° to prevent the developmentof ventilator-associated pneumonia.

Grade C

Rationale. The semirecumbent positionhas been demonstrated to decrease the inci-dence of ventilator-required pneumonia (77).Patients are laid flat for procedures, hemody-namic measurements, and during episodes ofhypotension. Consistent return to semirecum-bent position should be viewed as a qualityindicator in patients receiving mechanicalventilation.

6. A weaning protocol should be in placeand mechanically ventilated patientsshould undergo a spontaneous breathingtrial to evaluate the ability to discon-tinue mechanical ventilation when theysatisfy the following criteria: a) arous-able; b) hemodynamically stable (with-out vasopressor agents); c) no new po-tentially serious conditions; d) lowventilatory and end-expiratory pressurerequirements; and e) requiring levels ofFIO2 that could be safely delivered with aface mask or nasal cannula. If the spon-taneous breathing trial is successful,consideration should be given for extu-bation (see Appendix D). Spontaneousbreathing trial options include a lowlevel of pressure support with continu-ous positive airway pressure 5 cm H2O ora T-piece.


Grade A

Rationale. Recent studies demonstratethat daily spontaneous breathing trials re-duce the duration of mechanical ventilation(78 – 80). Although these studies had limitednumbers of patients with documented ALI/ARDS, there is no reason to believe thatALI/ARDS patients would have different out-comes from other critically ill patients. Suc-cessful completion of spontaneous breath-ing trials leads to a high likelihood ofsuccessful discontinuation of mechanicalventilation.

L. Sedation, Analgesia, andNeuromuscular Blockade inSepsis

1. Protocols should be used when sedationof critically ill mechanically ventilatedpatients is required. The protocol shouldinclude the use of a sedation goal, mea-sured by a standardized subjective seda-tion scale.

Grade B

2. Either intermittent bolus sedation orcontinuous infusion sedation to prede-termined end points (e.g., sedationscales) with daily interruption/lighten-ing of continuous infusion sedation withawakening and retitration, if necessary,are recommended methods for sedationadministration.

Grade B

Rationale (L1 and L2). Mechanically ven-tilated patients receiving continuous sedationmay have a significantly longer duration ofmechanical ventilation as well as ICU and hos-pital length of stay (81). A daily interruption orlightening of a “continuous” sedative infusionuntil the patient is awake may decrease theduration of mechanical ventilation and ICUstay (82). The use of sedation protocols inmechanically ventilated patients has shown areduced duration of mechanical ventilation,length of stay, and tracheostomy rates (83).

3. Neuromuscular blockers should beavoided if at all possible in the septicpatient due to the risk of prolonged neu-romuscular blockade following discon-tinuation. If neuromuscular blockersmust be used for longer than the firsthours of mechanical ventilation, eitherintermittent bolus as required or contin-uous infusion with monitoring of depthof block with train of four monitoringshould be used.

Grade E

Rationale. Prolonged skeletal muscleweakness has been reported in critically illpatients following the use of intermediate- andlong-acting neuromuscular blockers (84–91).The risk of prolonged paralysis may be re-

duced if an intermittent assessment of thedepth of neuromuscular blockade is per-formed (92, 93).

M. Glucose Control

1. Following initial stabilization of patientswith severe sepsis, maintain blood glu-cose �150 mg/dL (8.3 mmol/L). Studiessupporting the role of glycemic controlhave used continuous infusion of insulinand glucose. With this protocol, glucoseshould be monitored frequently after ini-tiation of the protocol (every 30 – 60mins) and on a regular basis (every 4 hrs)once the blood glucose concentrationhas stabilized.

Grade D

Rationale. A large single-center trial ofpostoperative surgical patients showed signif-icant improvement in survival when continu-ous infusion insulin was used to maintainglucose between 80 and 110 mg/dL (4.4–6.1mmol/L) (94). Exogenous glucose was begunsimultaneously with insulin with frequentmonitoring of glucose (every 1 hr) and inten-sity of monitoring greatest at the time of ini-tiation of insulin. Hypoglycemia may occur.There is no reason to think that these data arenot generalizable to all severely septic pa-tients. Post hoc data analysis of the trial datarevealed that although best results were ob-tained when glucose was maintained between80 and 110 mg/dL (4.4 and 6.1 mmol/L),achieving a goal of �150 mg/dL (8.3 mmol/L)also improved outcome when compared withhigher concentrations. This goal will likelyreduce the risk of hypoglycemia. The controlof the blood glucose concentration appears tobe more important than the amount of insulininfused (95, 96). The frequency of blood glu-cose determinations may require the use ofcentral or arterial catheters for blood sam-pling.

2. In patients with severe sepsis, a strategyof glycemic control should include a nu-trition protocol with the preferential useof the enteral route.

Grade E

Rationale. When a glycemic control strat-egy is initiated, hypoglycemia is minimized byproviding a continuous supply of glucose sub-strate. Initially, unless the patient is alreadyprofoundly hyperglycemia, this is accom-plished with 5% or 10% dextrose infusion andfollowed by initiation of feeding, preferably bythe enteral route, if tolerated (97).

N. Renal Replacement

1. In acute renal failure, and in the absenceof hemodynamic instability, continuousvenovenous hemofiltration and intermit-tent hemodialysis are considered equiva-lent. Continuous hemofiltration offers eas-

ier management of fluid balance inhemodynamically unstable septic patients.

Grade B

Rationale. Studies support the equivalenceof continuous and intermittent renal replace-ment therapies for the treatment of acute re-nal failure in critically ill patients (98, 99).In-termittent hemodialysis may be poorlytolerated in hemodynamically unstable pa-tients. There is no current evidence to supportthe use of continuous venovenous hemofiltra-tion for the treatment of sepsis independent ofrenal replacement needs.

O. Bicarbonate Therapy

1. Bicarbonate therapy for the purpose ofimproving hemodynamics or reducingvasopressor requirements is not recom-mended for treatment of hypoperfusion-induced lactic acidemia with pH �7.15.The effect of bicarbonate administrationon hemodynamics and vasopressor re-quirement at lower pH as well as theeffect on clinical outcome at any pH hasnot been studied.

Grade C

Rationale. There is no evidence to supportthe use of bicarbonate therapy in the treat-ment of hypoperfusion-induced acidemia as-sociated with sepsis. Two studies comparingsaline and bicarbonate in patients with pH�7.13–7.15 failed to reveal any difference inhemodynamic variables or vasopressor re-quirements between equimolar concentra-tions of bicarbonate and normal saline witheither therapy (100, 101).

P. Deep Vein ThrombosisProphylaxis

1. Severe sepsis patients should receivedeep vein thrombosis (DVT) prophylaxiswith either low-dose unfractionated hep-arin or low-molecular weight heparin.For septic patients who have a contrain-dication for heparin use (i.e., thrombo-cytopenia, severe coagulopathy, activebleeding, recent intracerebral hemor-rhage), the use of a mechanical prophy-lactic device (graduated compressionstockings or intermittent compressiondevice) is recommended (unless contra-indicated by the presence of peripheralvascular disease). In very high-risk pa-tients such as those who have severesepsis and history of DVT, a combinationof pharmacologic and mechanical ther-apy is recommended.

Grade A

Rationale. Although no study has beenperformed specifically in patients with severesepsis, large trials confirming the benefit ofDVT prophylaxis in general ICU populationshave included significant numbers of septicpatients (102–104). This benefit should be ap-


plicable to patients with severe sepsis and sep-tic shock.

Q. Stress Ulcer Prophylaxis

1. Stress ulcer prophylaxis should be givento all patients with severe sepsis. H2 re-ceptor inhibitors are more efficaciousthan sucralfate and are the preferredagents. Proton pump inhibitors have notbeen assessed in a direct comparisonwith H2 receptor antagonists and, there-fore, their relative efficacy is unknown.They do demonstrate equivalency in abil-ity to increase gastric pH.

Recommendation: Grade A

Rationale. Although no study has beenperformed specifically in patients with severesepsis, large trials confirming the benefit ofstress ulcer prophylaxis in general ICU popu-lations have included significant numbers ofseptic patients (105–108). This benefit shouldbe applicable to patients with severe sepsis andseptic shock. In addition, the conditionsshown to benefit from stress ulcer prophylaxis(coagulopathy, mechanical ventilation, hypo-tension) are frequently present in patientswith severe sepsis and septic shock.

R. Consideration for Limitationof Support

1. Advance care planning, including thecommunication of likely outcomes andrealistic goals of treatment, should bediscussed with patients and families. De-cisions for less aggressive support orwithdrawal of support may be in the pa-tient’s best interest.

Grade E

Rationale. It is too frequent that inade-quate physician/family communication char-acterizes end-of-life care in the ICU. The levelof life support given to ICU patients may notbe consistent with their wishes. Early and fre-quent caregiver discussions with patients whoface death in the ICU and their loved ones mayfacilitate appropriate application and with-drawal of life-sustaining therapies.

S. Pediatric Considerations

1. Mechanical Ventilation. Due to lowfunctional residual capacity, young infantsand neonates with severe sepsis may requireearly intubation (109). The principles of lung-protective strategies are applied to children asthey are to adults. In premature infants, addi-tional attention is paid to avoiding hyperox-emia to prevent retinopathy.

2. Fluid Resuscitation. Intravenous accessfor fluid resuscitation and inotrope/vasopres-sor infusion is more difficult to attain in chil-dren than in adults. The American Heart As-sociation has developed pediatric advanced lifesupport guidelines for emergency establish-

ment of intravascular support (110). On thebasis of a number of studies, it is accepted thataggressive fluid resuscitation with crystalloidsor colloids is of fundamental importance tosurvival of septic shock in children (111, 112).There is only one randomized, controlled trialcomparing the use of colloid to crystalloidresuscitation (dextran, gelatin, lactated Ring-er’s solution, or saline) in children with den-gue shock (111). All these children survivedregardless of the fluid used, but the longesttime to recovery from shock occurred in chil-dren who received lactated Ringer’s solution.Among patients with the narrowest pulse pres-sure, there was a suggestion that colloids weremore effective than crystalloids in restoringnormal pulse pressure. Fluid infusion is bestinitiated with boluses of 20 mL/kg over 5–10mins, titrated to clinical monitors of cardiacoutput, including heart rate, urine output,capillary refill, and level of consciousness.Children normally have a lower blood pressurethan adults and can prevent reduction inblood pressure by vasoconstriction and in-creasing heart rate. Therefore, blood pressureby itself is not a reliable end point for assess-ing the adequacy of resuscitation. However,once hypotension occurs, cardiovascular col-lapse may soon follow. Hepatomegaly occursin children who are fluid overloaded and canbe a helpful sign of the adequacy of fluidresuscitation. Large fluid deficits typically ex-ist, and initial volume resuscitation usuallyrequires 40 – 60 mL/kg but can be muchhigher (112–114).

3. Vasopressors/Inotropes (Should Only BeUsed After Appropriate Volume Resuscita-tion). Children with severe sepsis can presentwith low cardiac output and high systemicvascular resistance, high cardiac output andlow systemic vascular resistance, or low car-diac output and low systemic vascular resis-tance shock. Depending on which situationexists, inotropic support should be started inthe case of fluid refractory shock or a combi-nation of an inotrope together with a vaso-pressor or a vasodilator. Dopamine is the firstchoice of support for the pediatric patient withhypotension refractory to fluid resuscitation.The choice of vasoactive agent is determinedby the clinical examination. Dopamine-refractory shock may reverse with epinephrineor norepinephrine infusion (114). Pediatricpatients with low cardiac output states maybenefit from use of dobutamine. The use ofvasodilators can reverse shock in pediatric pa-tients who remain hemodynamically unstablewith a high systemic vascular resistance state,despite fluid resuscitation and implementa-tion of inotropic support (114, 115). Nitroso-vasodilators with a very short half-life (nitro-prusside or nitroglycerin) are used as first-linetherapy for children with epinephrine-resis-tant low cardiac output and elevated systemicvascular-resistance shock. Inhaled nitric oxidereduced extracorporeal membrane oxygen-ation (ECMO) use when given to term neo-nates with persistent pulmonary artery hyper-

tension of the newborn and sepsis in arandomized controlled trial (116). When pedi-atric patients remain in a normotensive lowcardiac output and high vascular resistancestate, despite epinephrine and nitrosovasodi-lator therapy, then the use of a phosphodies-terase inhibitor should be strongly considered(117–119). Pentoxifylline (not available in theUnited States) improved outcome in prema-ture neonates with sepsis when given for 6hrs/day for 5 days in a randomized, controlledtrial (120).

4. Therapeutic End Points. Therapeuticend points are capillary refill of �2 secs, nor-mal pulses with no differential between pe-ripheral and central pulses, warm extremities,urine output �1 mL·kg�1·hr�1, normal men-tal status, decreased lactate and increased basedeficit, and superior vena cava or mixed ve-nous oxygen saturation �70%. When employ-ing measurements to assist in identifying ac-ceptable cardiac output in children withsystemic arterial hypoxemia such as cyanoticcongenital heart disease or severe pulmonarydisease, arterial-venous oxygen content differ-ence is a better marker than mixed venoushemoglobin saturation with oxygen. Optimiz-ing preload optimizes cardiac index. As notedpreviously, blood pressure by itself is not areliable end point for resuscitation. If a pul-monary artery catheter is used, therapeuticend points are cardiac index �3.3 and �6.0L·min�1·m�2 with normal perfusion pressure(mean arterial pressure/central venous pres-sure) for age.

5. Approach to Pediatric Septic Shock. Fig-ure 1 shows a flow diagram summarizing anapproach to pediatric septic shock (121).

6. Steroids. Hydrocortisone therapy shouldbe reserved for use in children with catechol-amine resistance and suspected or proven ad-renal insufficiency. Patients at risk includechildren with severe septic shock and purpura(122, 123), children who have previously re-ceived steroid therapies for chronic illness,and children with pituitary or adrenal abnor-malities. There are no strict definitions, butadrenal insufficiency in the case of cate-cholamine-resistant septic shock is assumedat a random total cortisol concentration �18�g/dL (496 nmol/L). There is no clear consen-sus for the role of steroids or best dose ofsteroids in children with septic shock. A post30- or 60-min ACTH stimulation test increasein cortisol of �9 �g/dL (248 nmol/L) also makesthat diagnosis. Two randomized controlled trialsused “shock dose” hydrocortisone (25 timeshigher than the stress dose) in children, both indengue fever. The results were conflicting (124,125). Dose recommendations vary from 1–2mg/kg for stress coverage (based on clinical di-agnosis of adrenal insufficiency) to 50 mg/kg forempirical therapy of shock followed by the samedose as a 24-hr infusion.

7. Protein C and Activated Protein C. Pro-tein C concentrations in children reach adultvalues at the age of 3 yrs. This might indicatethat the importance of protein C supplemen-


tation either as protein C concentrate or asrhAPC is even greater in young children thanin adults. There has been one dose finding,placebo-controlled study performed using pro-tein C concentrate. This study was not pow-ered to show an effect on mortality rate butdid show a positive effect on sepsis-inducedcoagulation disturbances (126, 127). No ran-domized studies using rhAPC have been per-formed.

8. Granulocyte Macrophage Colony Stim-ulating Factor. Growth factors or white bloodcell transfusions are given to patients withneutropenic sepsis secondary to chemother-apy or white blood cell primary immune defi-ciency. A randomized, controlled trial showedimproved outcomes in neonates with sepsisand an absolute neutrophil count �1500/�L(1.5 � 109/L) treated with a 7-day course ofgranulocyte macrophage colony stimulatingfactor (128, 129).

9. DVT Prophylaxis. Most DVTs in youngchildren are associated with central venouscatheters. Femoral venous catheters are com-monly used in children, and central venouscatheter-associated DVT occurs in approximately25% of children with a femoral central venouscatheter. There are no data on use of heparinprophylaxis to prevent DVT in children.

10. Stress Ulcer Prophylaxis. No studieshave been performed in children analyzing theeffect of stress ulcer prophylaxis. Studies haveshown that the rate of clinically importantgastrointestinal bleeding in children occurs atrates similar to adults (130, 131). As in adults,coagulopathy and mechanical ventilation arerisk factors for clinically important gastroin-testinal bleeding. Stress ulcer prophylaxisstrategy is commonly used in mechanicallyventilated children, usually with H2 blockers.Its effect is not known.

11. Renal Replacement Therapy. Continu-ous venovenous hemofiltration may be clini-cally useful in children with anuria/severe ol-iguria and fluid overload, but no large RCTshave been performed.

12. Glycemic Control. In general, infantsare at risk for developing hypoglycemiawhen they depend on intravenous fluids.This means that a glucose intake of 4 – 6mg·kg�1·min�1 or maintenance fluid intakewith glucose 10% in NaCl 0.45% is advised.There are no studies in pediatric patientsanalyzing the effect of rigid glycemic con-trol using insulin. This should only be donewith frequent glucose monitoring in view ofthe risks for hypoglycemia.

13. Sedation/Analgesia. Appropriate seda-tion and analgesia for children who are me-chanically ventilated are the standard of care,although there are no data supporting anyparticular drugs or drug regimens.

14. Blood Products. In the absence of data,it is reasonable to maintain hemoglobin con-centration within the normal range for age inchildren with severe sepsis and septic shock(�10 g/dL [100 g/L]).

15. Intravenous Immunoglobulin. Poly-clonal intravenous immunoglobulin hasbeen reported to reduce mortality rate and isa promising adjuvant in the treatment ofsepsis and septic shock. In children, how-ever, all the trials have been small, and thetotality of the evidence is insufficient tosupport a robust conclusion of benefit. Ad-junctive therapy with monoclonal intrave-nous immunoglobulins remains experimen-tal (132).

16. ECMO. ECMO has been used in septicshock in children, but its impact is not clear.Survival from refractory shock or respiratoryfailure associated with sepsis is 80% in neo-nates and 50% in children. There is one studyanalyzing 12 patients with meningococcal sep-

sis on ECMO; eight of the 12 patients survived,with six leading functionally normal lives at amedian of 1 yr (range, 4 months to 4 yrs) offollow-up. Children with sepsis on ECMO donot perform worse than children without sep-sis at long-term follow-up (133–135).

SUMMARY AND FUTUREDIRECTIONS

Although evidence-based recommenda-tions have been frequently published in themedical literature, documentation of im-pact on patient outcome is limited. Thenext phase of the Surviving Sepsis Cam-paign is targeted to implement a core set of

Figure 1. Resuscitation of pediatric septic shock. Adapted from Ref. 121. *Normalization of bloodpressure and tissue perfusion; **hypotension, abnormal capillary refill, or extremity coolness.


the previous recommendations in hospitalenvironments where change in behaviorand clinical impact can be measured. Thefirst step in this next phase will be a jointeffort with the Institute of Healthcare Im-provement to deploy a “change bundle”based on a core set of the previous recom-mendations into the Institute of HealthcareImprovement collaborative system. Chartreview will identify and track change inpractice and clinical outcome. Engender-ing evidence-based change through moti-vational strategies while monitoring andsharing impact with healthcare practitio-ners is the key to improving outcome insevere sepsis.

The reader is reminded that althoughthis document is static, the optimumtreatment of severe sepsis and septicshock is a dynamic and evolving process.New interventions will be proven and es-tablished interventions, as stated in thecurrent recommendations, may needmodification. This publication representsthe start of what will be an ongoing pro-cess. The Surviving Sepsis Campaign andthe consensus committee members arecommitted to creating a dynamic, elec-tronic, Web-based guideline process. Weforesee that as new evidence becomesavailable, revisions will be channeledthrough the committee and, followingsponsoring organization approval,changes will be noted on the electronicguidelines, which are available for post-ing on all sponsoring organization Websites. We anticipate a formal updatingprocess annually.

Acknowledgment

The ESICM, SCCM, and International SepsisForum have established the Surviving SepsisCampaign with the aim of improving the care ofseptic patients. The first phase of the Campaignwas built around the Barcelona ESICM meetingin 2002 and included the initial Barcelona Dec-laration, a medical campaign that identified sep-sis as a killer and the need to make progress inpublic awareness and to reduce mortality, andtwo surveys performed among physicians. Thecost of phase I was approximately $702,598, andwas supported by unrestricted educational grantsfrom Eli Lilly (94%), Edwards (3%), and Baxter(3%). Producing the present guidelines docu-ment was phase II of the Campaign. For this, thesponsor companies have been entirely separatedfrom the process by which the guidelines weredeveloped by the many contributors, whose con-flicts of interest have been collected in accor-dance with SCCM guidance (see below). The costsfor this phase mainly included the meeting, tele-

conferences, and website update and amountedto approximately $158,758, and were borne byunrestricted educational grants from Eli Lilly(90%) and Edwards (10%). Most of the expensefor this effort has been time by the committeewho received no reimbursement.

Faculty Disclosures—PotentialConflicts of Interest

Speakers bureau, consultant fees, or researchgrants; Richard J. Beale, MD (Eli Lilly, FreseniusHemocare and Fresenius Kabi); E. David Bennett,MD (Deltex, Ltd.); Pierre-Yves Bochud, MD(Swiss National Science Foundation); ChristianBrun-Buisson, MD (Arrow Int’l, Eli Lilly, Glaxo-Smith-Kline, Roche, Wyeth-Lederle); Thierry Ca-landra, MD (Pfizer, Merck, NatImmune); Jean M.Carlet, MD (Eli Lilly, Anbics, Novo Nordisk,Wyeth Lederle, Fujisawa, Glaxo-Smith-Kline,Bayer, Abbott, Intrabiotics); Jonathan Cohen, MD(Glaxo-Smith-Kline); Catherine Cordonnier, MD(Gilead Science, Merck, Pfizer, Fujisawa); E.Patchen Dellinger, MD (Glaxo-Smith-Kline,Bayer, Eli Lilly, Merck, Wyeth-Ayerst, Pfizer, Or-tho-McNeil, Chiron, Versicor, InterMune, Penin-sula); R. Phillip Dellinger, MD (Aventis, Bayer,Cubist, Edwards, Eli Lilly, Ortho Biotech, Wyeth-Ayerst); Roger G. Finch, MD (Cubist, Bayer,Glaxo-Smith-Kline, AstraZeneca, Bristol MyersSquibb, Aventis); Francois A. Fourrier, MD(Laboratoire Francais du fractionnement et desbiotechnologies [LFB]); Jan A. Hazelzet, MD(Baxter, Eli Lilly); James H. Jorgensen, PhD (bio-Merieux Inc., Becton-Dickinson); Didier Keh, MD(Deutsche Forschungsgemeinschaft [DFG]);Mitchell M. Levy, MD (Eli Lilly, Edwards Life-sciences, OrthoBiotech); Dennis G. Maki, MD (EliLilly, Becton Dickinson, Johnson and Johnson);John C. Marshall, MD (Glaxo-Smith-Kline, EliLilly, Wyeth-Ayerst, Eisai, Centocor, Boehringer-Ingelheim); Henry Masur, MD (Cubist); Glenn S.Murphy, MD (Organon, Inc.); Steven M. Opal, MD(Genetics Institute, Chiron, Eli Lilly); MargaretM. Parker, MD (Johnson & Johnson [Ortho Bio-tech] – member of Independent Data MonitoringCommittee for epo trial); Joseph E. Parrillo, MD(Eisai American, Inc., Schering-Plough Co., Gl-axo-Smith-Kline, Medinox, Inc., Chiron Corp.,Edwards Lifesciences, Ortho Biotech); AndrewRhodes, MD (Edwards Lifesciences); Charles L.Sprung, MD, JD (AstraZeneca, European Com-mission, Eli Lilly); Antoni Torres, MD (Aventis,Abbott, Bayer); Stephen Trzeciak, MD (Aventis,Eli Lilly, Edwards Lifesciences); Jeffery S. Vender,MD (Abbott Pharmaceuticals); Jean-Louis Vin-cent, MD, PhD (Baxter, Brahms, BMS, Eli Lilly,Glaxo-Smith-Kline, Edwards, Pfizer); Janice L.Zimmerman, MD (Glaxo-Smith-Kline, Cubist).Direct financial interest – stock ($10,000 ormore) or partial ownership; None. Faculty withno relationship to disclose; Marc Bonten, MD;

Joseph A. Carcillo, MD; Alain Cariou, MD; Jean-Francois Dhainaut, MD, PhD; Simon Finfer, MD;Juan Gea-Banacloche, MD; Herwig Gerlach, MD,PhD; Maurene A. Harvey, RN, MPH; Steven M.Hollenberg, MD; Ronald V. Maier, MD; John J.Marini, MD; Martin Nitsun, MD; Graham Ramsay,MD; Jonathan E. Sevransky, MD; Joseph W. Szokol,MD; Christophe Vinsonneau, MD.

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Appendix A. Source control

Source Control Technique Examples

Drainage ● Intra-abdominal abscess● Thoracic empyema● Septic arthritis● Pyelonephritis, cholangitis

Debridement ● Necrotizing fasciitis● Infected pancreatic necrosis● Intestinal infarction● Mediastinitis

Device removal ● Infected vascular catheter● Urinary catheter● Colonized endotracheal tube● Infected intrauterine contraceptive device

Definitive control ● Sigmoid resection for diverticulitis● Cholecystectomy for gangrenous cholecystitis● Amputation for clostridial myonecrosis

Appendix B. Contraindications to use of recombinant human activated protein C (rhAPC)a

rhAPC increases the risk of bleeding. rhAPC is contraindicated in patients with the followingclinical situations in which bleeding could be associated with a high risk of death or significantmorbidity.

● Active internal bleeding● Recent (within 3 months) hemorrhagic stroke● Recent (within 2 months) intracranial or intraspinal surgery, or severe head trauma● Trauma with an increased risk of life-threatening bleeding● Presence of an epidural catheter● Intracranial neoplasm or mass lesion or evidence of cerebral herniation

See labeling instructions for relative contraindications.aThe committee recommends that platelet count be maintained at �30,000 during infusion of

rhAPC.Physicians’ Desk Reference. 57th Edition. Montvale, NJ, Thompson PDR, 2003, pp 1875–1876.

Appendix C. ARDSNET Ventilator Management (66)

● Assist control mode—volume ventilation● Reduce tidal volume to 6 mL/kg predicted body weight● Keep Pplat �30 cm H2O

—Reduce Tv as low as 4 mL/kg predicted body weight* to limit Pplat● Maintain SaO2/SpO2 88–95%● Anticipated PEEP settings at various FIO2 requirements

FIO2 0.3 0.4 0.4 0.5 0.5 0.6 0.7 0.7 0.7 0.8 0.9 0.9 0.9 1.0PEEP 5 5 8 8 10 10 10 12 14 14 14 16 18 20–24

*Predicted Body Weight Calculation

● Male—50 � 2.3 [height (inches) � 60] or 50 � 0.91 [height (cm) � 152.4]● Female—45.5 � 2.3 [height (inches) � 60] or 45.5 � 0.91 [height (cm) � 152.4]

Tv, tidal volume; SaO2, arterial oxygen saturation; PEEP, positive end-expiratory pressure.


Appendix D. Use of spontaneous breathing trial in weaning ARDS patients


surviving sepsis campaign guidelines for management of

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