Sobreviviendo a La Sepsis Bueno

8/2/2019 Sobreviviendo a La Sepsis Bueno

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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

From Cooper University Hospital, Camden, NJ (RPD);

Rhode Island Hospital, Providence, RI (MML); Hospital Saint-Joseph, Paris, France (JMC); Birmingham University, Bir-mingham, UK (JB); SUNY at Stony Brook, Stony Brook, NY(MMP); McMaster University, Hamilton, Ontario, Canada (RJ);Friedrich-Schiller-University of Jena, Jena, Germany (KR);University of Pittsburgh, Pittsburgh, PA (DCA); Hopital HenriMondor, Crteil, France (CBB); Guys and St Thomas Hos-pital Trust, London, UK (RB); Centre Hospitalier Universitaire

Vaudois, Lausanne, Switzerland (TC); French Agency forEvaluation of Research and Higher Education, Paris, France(JFD); Vivantes-Klinikum Neukoelin, Berlin, Germany (HG);Consultants in Critical Care, Inc, Glenbrook, NV (MH); Univer-sity of Minnesota, St. Paul, MN (JJM); St. Michaels Hospital,Toronto, Ontario, Canada (JM); Universit di Torino, Torino,

Italy (MR); West Hertfordshire Health Trust, Hemel Hemp-

stead, UK (GR); The Johns Hopkins University School ofMedicine, Baltimore, MD (JS); Massachusetts General Hos-pital, Boston, MA (BTT); Rhode Island Hospital, Providence, RI(ST); Evanston Northwestern Healthcare, Evanston, IL (JSV);The Methodist Hospital, Houston, TX (JLZ); Erasme UniversityHospital, Brussels, Belgium (JLV).

Sponsoring organizations: American Association of Crit-ical-Care Nurses,* American College of Chest Physicians,*

American College of Emergency Physicians,* Canadian Crit-ical Care Society, European Society of Clinical Microbiologyand Infectious Diseases,* European Society of Intensive CareMedicine,* European Respiratory Society,* International Sep-sis Forum,* Japanese Association for Acute Medicine, Jap-anese Society of Intensive Care Medicine; Society of CriticalCare Medicine,* Society of Hospital Medicine,** Surgical

Infection Society,* World Federation of Societies of Intensive

and Critical Care Medicine.** Participation and endorsementby theGerman Sepsis Society andthe Latin AmericanSepsisInstitute. *Sponsor of 2004 guidelines. **Sponsors of 2008guidelines who did not participate formally in revision pro-cess. Members of the 2008 SSC Guidelines Committee arelisted in Appendix I. Appendix J provides author disclosureinformation.

Also published in Intensive Care Medicine(January2008).

For information regarding this article, E-mail:[email protected]

Copyright 2007 by the Society of Critical Care

Medicine

DOI: 10.1097/01.CCM.0000298158.12101.41

Objective: To provide an update to the original Surviving Sepsis Campaign

clinical management guidelines, Surviving Sepsis Campaign Guidelines for Man-

agement of Severe Sepsis and Septic Shock, published in 2004.

Design: Modified Delphi method with a consensus conference of 55 interna-

tional experts, several subsequent meetings of subgroups and key individuals,

teleconferences, and electronic-based discussion among subgroups and among

the entire committee. This process was conducted independently of any industry

funding.

Methods:We used the Grades of Recommendation, Assessment, Development

and Evaluation (GRADE) system to guide assessment of quality of evidence from

high (A) to very low (D) and to determine the strength of recommendations. A

strong recommendation (1) indicates that an interventions desirable effects

clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak

recommendations (2) indicate that the tradeoff between desirable and undesirable

effects is less clear. The grade of strong or weak is considered of greater clinical

importance than a difference in letter level of quality of evidence. In areas without

complete agreement, a formal process of resolution was developed and applied.

Recommendations are grouped into those directly targeting severe sepsis, rec-

ommendations targeting general care of the critically ill patient that are consid-

ered high priority in severe sepsis, and pediatric considerations.

Results:Key recommendations, listed by category, include early goal-directed

resuscitation of the septic patient during the first 6 hrs after recognition (1C);

blood cultures before antibiotic therapy (1C); imaging studies performed promptly

to confirm potential source of infection (1C); administration of broad-spectrum

antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsiswithout septic shock (1D); reassessment of antibiotic therapy with microbiology

and clinical data to narrow coverage, when appropriate (1C); a usual 710 days

of antibiotic therapy guided by clinical response (1D); source control with atten-

tion to the balance of risks and benefits of the chosen method (1C); administration

of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore

mean circulating filling pressure (1C); reduction in rate of fluid administration with

rising filing pressures and no improvement in tissue perfusion (1D); vasopressor

preference for norepinephrine or dopamine to maintain an initial target of mean

arterial pressure >65 mm Hg (1C); dobutamine inotropic therapy when cardiac

output remains low despite fluid resuscitation and combined inotropic/vasopres-

sor therapy (1C); stress-dose steroid therapy given only in septic shock after blood

pressure is identified to be poorly responsive to fluid and vasopressor therapy

(2C); recombinant activated protein C in patients with severe sepsis and clinical

assessment of high risk for death (2B except 2C for postoperative patients). In the

absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage,

target a hemoglobin of 79 g/dL (1B); a low tidal volume (1B) and limitation of

inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respi-

ratory distress syndrome (ARDS); application of at least a minimal amount of

positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in

mechanically ventilated patients unless contraindicated (1B); avoiding routine use

of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanicalventilation and ICU length of stay, a conservative fluid strategy for patients with

established ALI/ARDS who are not in shock (1C); protocols for weaning and

sedation/analgesia (1B); using either intermittent bolus sedation or continuous

infusion sedation with daily interruptions or lightening (1B); avoidance of neuro-

muscular blockers, if at all possible (1B); institution of glycemic control (1B),

targeting a blood glucose


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Severe sepsis (acute organ dys-function secondary to infec-tion) and septic shock (severesepsis plus hypotension not re-

versed with fluid resuscitation) are majorhealthcare problems, affecting millions ofindividuals around the world each year,killing one in four (and often more), andincreasing in incidence (15). Similar topolytrauma, acute myocardial infarction,

or stroke, the speed and appropriatenessof therapy administered in the initialhours after severe sepsis develops arelikely to influence outcome. In 2004, aninternational group of experts in the di-agnosis and management of infection andsepsis, representing 11 organizations,published the first internationally ac-cepted guidelines that the bedside clini-cian could use to improve outcomes insevere sepsis and septic shock (6, 7).These guidelines represented phase II ofthe Surviving Sepsis Campaign (SSC), an

international effort to increase awarenessand improve outcomes in severe sepsis.Joined by additional organizations, thegroup met again in 2006 and 2007 toupdate the guidelines document using anew evidence-based methodology systemfor assessing quality of evidence andstrength of recommendations (811).

These recommendations are intendedto provide guidance for the clinician car-ing for a patient with severe sepsis orseptic shock. Recommendations fromthese guidelines cannot replace the clini-cians decision-making capability whenhe or she is provided with a patientsunique set of clinical variables. Most ofthese recommendations are appropriatefor the severe sepsis patient in both theintensive care unit (ICU) and non-ICUsettings. In fact, the committee believesthat currently, the greatest outcome im-provement can be made through educa-tion and process change for those caringfor severe sepsis patients in the non-ICUsetting and across the spectrum of acutecare. It should also be noted that re-source limitations in some institutions

and countries may prevent physiciansfrom accomplishing particular recom-mendations.

METHODS

Sepsis is defined as infection plus sys-temic manifestations of infection (Table1) (12). Severe sepsis is defined as sepsisplus sepsis-induced organ dysfunction ortissue hypoperfusion. The threshold for

this dysfunction has varied somewhat fromone severe sepsis research study to another.

An example of typical thresholds identifica-tion of severe sepsis is shown in Table 2(13). Sepsis-induced hypotension is definedas a systolic blood pressure (SBP)90 mmHg or mean arterial pressure 70 mm Hgor a SBP decrease 40 mm Hg or 2 SDbelow normal for age in the absence ofother causes of hypotension. Septic shockis defined as sepsis-induced hypotensionpersisting despite adequate fluid resuscita-tion. Sepsis-induced tissue hypoperfusion

is defined as either septic shock, an elevatedlactate, or oliguria.

The current clinical practice guidelinesbuild on the first and second editions from2001 (discussed subsequently) and 2004 (6,7, 14). The 2001 publication incorporated aMEDLINE search for clinical trials in thepreceding 10 yrs, supplemented by a man-ual search of other relevant journals (14).The 2004 publication incorporated the ev-idence available through the end of 2003.The current publication is based on an up-

dated search into 2007 (see following meth-ods and rules).

The 2001 guidelines were coordinatedby the International Sepsis Forum; the2004 guidelines were funded by unre-stricted educational grants from industryand administered through the Society ofCritical Care Medicine (SCCM), the Eu-ropean Society of Intensive Care Medi-cine (ESICM), and the International Sep-sis Forum. Two of the SSC administeringorganizations receive unrestricted indus-try funding to support SSC activities (ES-

ICM and SCCM), but none of this fundingwas used to support the 2006/2007 com-mittee meetings.

It is important to distinguish betweenthe process of guidelines revision and theSSC. The SSC is partially funded by un-restricted educational industry grants,including those from Edwards Life-Sciences, Eli Lilly and Company, andPhilips Medical Systems. SSC also re-ceived funding from the Coalition forCritical Care Excellence of the Society of

Table 1. Determination of the quality of evidence

Underlying methodologyA. RCTB. Downgraded RCT or upgraded observational studiesC. Well-done observational studiesD. Case series or expert opinion

Factors that may decrease the strength of evidence1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of

bias2. Inconsistency of results (including problems with subgroup analyses)3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison)4. Imprecision of results5. High likelihood of reporting bias

Main factors that may increase the strength of evidence1. Large magnitude of effect (direct evidence, RR 2 with no plausible confounders)2. Very large magnitude of effect with RR 5 and no threats to validity (by two levels)3. Dose-response gradient

RCT, randomized controlled trial; RR, relative risk.

Table 2. Factors determining strong vs. weak recommendation

What Should Be Considered Recommended Process

Quality of evidence The lower the quality of evidence, the less likely a strong

recommendationRelative importance of the

outcomes

If values and preferences vary widely, a strong

recommendation becomes less likelyBaseline risks of outcomes The higher the risk, the greater the magnitude of benefitMagnitude of relative risk,

including benefits, harms, and

burden

Larger relative risk reductions or larger increases in

relative risk of harm make a strong recommendation

more or less likely, respectivelyAbsolute magnitude of the effect The larger the absolute benefits and harms, the greater or

lesser likelihood, respectively, of a strong

recommendationPrecision of the estimates of the

effects

The greater the precision, the more likely a strong

recommendationCosts The higher the cost of treatment, the less likely a strong

recommendation

297Crit Care Med 2008 Vol. 36, No. 1


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about these tradeoffs either becausesome of the evidence is low quality (andthus there remains uncertainty regardingthe benefits and risks) or the benefits anddownsides are closely balanced. While thedegree of confidence is a continuum andthere is no precise threshold between astrong and a weak recommendation, thepresence of important concerns aboutone or more of the preceding factors

makes a weak recommendation morelikely. A strong recommendation isworded as we recommend and a weakrecommendation as we suggest.

The implications of calling a recom-mendation strong are that most well-informed patients would accept that inter-

vention and that most clinicians should useit in most situations. There may be circum-stances in which a strong recommendationcannot or should not be followed for anindividual patient because of that patientspreferences or clinical characteristics thatmake the recommendation less applicable.Being a strong recommendation does notautomatically imply standard of care. Forexample, the strong recommendation foradministering antibiotics within 1 hr of thediagnosis of severe sepsis, although desir-able, is not currently standard of care as

verified by current practice (M Levy, per-sonal communication, from first 8,000 pa-tients entered internationally into the SSCperformance improvement database). Theimplication of a weak recommendation isthat although a majority of well-informedpatients would accept it (but a substantial

proportion would not), clinicians shouldconsider its use according to particular cir-cumstance.

Differences of opinion among commit-tee members about interpretation of evi-dence, wording of proposals, or strength ofrecommendations were resolved using aspecifically developed set of rules. We willdescribe this process in detail in a separatepublication. In summary, the main ap-proach for converting diverse opinions intoa recommendation was as follows: 1) togive a recommendation a direction (for or

against the given action), a majority ofvotes were to be in favor of that direction,with 20% preferring the opposite direc-tion (there was a neutral vote allowed as

well); 2) to call a given recommendationstrong rather than weak, 70% strong

votes were required; 3) if70% of votesindicated strong preference, the recom-mendation was assigned a weak category ofstrength. We used a combination of modi-fied Delphi process and nominal (expert)group techniques to ensure both depth and

breadth of review. The entire review group(together with their parent organizations

as required) participated in the larger, iter-ative, modified Delphi process. The smaller

working group meetings, which took placein person, functioned as the nominalgroups. If a clear consensus could not beobtained by polling within the nominalgroup meetings, the larger group was spe-cifically asked to use the polling process.This was only required for corticosteroidsand glycemic control. The larger group hadthe opportunity to review all outputs. Inthis way the entire review combined in-

tense focused discussion (nominal group)with broader review and monitoring using

the Delphi process.Note: Refer to Tables 35 for con-

densed adult recommendations.

I. MANAGEMENT OF SEVERE

SEPSIS

A. Initial Resuscitation

1. We recommend the protocolized re-suscitation of a patient with sepsis-

Table 3. Initial resuscitation and infection issues

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 Indicates a weak recommendation, or we suggest

Initial resuscitation (first 6 hrs) Begin resuscitation immediately in patients with hypotension or elevated serum lactate 4

mmol/L; do not delay pending ICU admission (1C) Resuscitation goals (1C)

CVP 812 mm Hga

Mean arterial pressure 65 mm Hg

Urine output

0.5 mL

kg

1

hr

1

Central venous (superior vena cava) oxygen saturation 70% or mixed venous 65% If venous oxygen saturation target is not achieved (2C)

Consider further fluidTransfuse packed red blood cells if required to hematocrit of30% and/orStart dobutamine infusion, maximum 20 gkg1min1

Diagnosis Obtain appropriate cultures before starting antibiotics provided this does not significantly

delay antimicrobial administration (1C)Obtain two or more BCsOne or more BCs should be percutaneousOne BC from each vascular access device in place 48 hrsCulture other sites as clinically indicated

Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C)Antibiotic therapy

Begin intravenous antibiotics as early as possible and always within the first hour of

recognizing severe sepsis (1D) and septic shock (1B) Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with

good penetration into presumed source (1B) Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity,

and minimize costs (1C) Consider combination therapy in Pseudomonas infections (2D) Consider combination empiric therapy in neutropenic patients (2D) Combination therapy 35 days and de-escalation following susceptibilities (2D) Duration of therapy typically limited to 710 days; longer if response is slow or there are

undrainable foci of infection or immunologic deficiencies (1D) Stop antimicrobial therapy if cause is found to be noninfectious (1D)

Source identification and control A specific anatomic site of infection should be established as rapidly as possible (1C) and

within first 6 hrs of presentation (1D) Formally evaluate patient for a focus of infection amenable to source control measures (e.g.

abscess drainage, tissue debridement) (1C)

Implement source control measures as soon as possible following successful initialresuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is best

delayed) (2B) Choose source control measure with maximum efficacy and minimal physiologic upset (1D) Remove intravascular access devices if potentially infected (1C)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ICU, intensive

care unit; CVP, central venous pressure; BC, blood culture.aA higher target CVP of 1215 mm Hg is recommended in the presence of mechanical ventilation

or preexisting decreased ventricular compliance.



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induced shock, defined as tissue hypo-perfusion (hypotension persistingafter initial fluid challenge or bloodlactate concentration 4 mmol/L).This protocol should be initiated as

soon as hypoperfusion is recognizedand should not be delayed pendingICU admission. During the first 6 hrsof resuscitation, the goals of initialresuscitation of sepsis-induced hypo-perfusion should include all of the fol-lowing as one part of a treatment pro-tocol:

Central venous pressure 812 mmHgMean arterial pressure (MAP) 65mm Hg

Urine output 0.5 mLkg1hr 1

Central venous (superior vena

cava) or mixed venous oxygen sat-

uration 70% or 65%, respec-

tively (grade 1C)

Rationale. Early goal-directed resusci-

tation has been shown to improve sur-

vival for emergency department patients

presenting with septic shock in a ran-

domized, controlled, single-center study

(16). Resuscitation directed toward the

previously mentioned goals for the initial

6-hr period of the resuscitation was able

to reduce 28-day mortality rate. The con-

sensus panel judged use of central venous

and mixed venous oxygen saturation tar-

gets to be equivalent. Either intermittentor continuous measurements of oxygensaturation were judged to be acceptable.

Although blood lactate concentratio nmay lack precision as a measure of tissuemetabolic status, elevated levels in sepsissupport aggressive resuscitation. In me-chanically ventilated patients or patients

with known preexisting decreased ven-tricular compliance, a higher target cen-

tral venous pressure of 1215 mm Hg isrecommended to account for the imped-iment to filling (17). Similar consider-ation may be warranted in circumstancesof increased abdominal pressure or dia-stolic dysfunction (18). Elevated central

venous pressures may also be seen withpreexisting clinically significant pulmo-nary artery hypertension. Although thecause of tachycardia in septic patientsmay be multifactorial, a decrease in ele-

vated pulse rate with fluid resuscitation isoften a useful marker of improving intra-

vascular filling. Recently published ob-servational studies have demonstrated anassociation between good clinical out-come in septic shock and MAP 65 mmHg as well as central venous oxygen sat-uration (ScvO2, measured in superior

vena cava, either intermittently or con-tinuously) of 70% (19). Many recentstudies support the value of early proto-colized resuscitation in severe sepsis andsepsis-induced tissue hypoperfusion (2025). Studies of patients with shock indi-cate that mixed venous oxygen saturation(SVO

2) runs 57% lower than central ve-

nous oxygen saturation (ScvO2) (26) andthat an early goal-directed resuscitationprotocol can be established in a nonre-search general practice venue (27).

There are recognized limitations toventricular filling pressure estimates assurrogates for fluid resuscitation (28, 29).However, measurement of central venouspressure is currently the most readily ob-tainable target for fluid resuscitation.There may be advantages to targetingfluid resuscitation to flow and perhaps to

volumetric indices (and even to microcir-culation changes) (3033). Technologiescurrently exist that allow measurementof flow at the bedside (34, 35). Futuregoals should be making these technolo-gies more accessible during the criticalearly resuscitation period and research to

validate utility. These technologies arealready available for early ICU resuscita-tion.

2. We suggest that during the first 6 hrsof resuscitation of severe sepsis or sep-

Table 4. Hemodynamic support and adjunctive therapy

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 Indicates a weak recommendation, or we suggest

Fluid therapy Fluid-resuscitate using crystalloids or colloids (1B) Target a CVP of8 mm Hg (12 mm Hg if mechanically ventilated) (1C) Use a fluid challenge technique while associated with a hemodynamic improvement (1D) Give fluid challenges of 1000 mL of crystalloids or 300500 mL of colloids over 30 mins. More

rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion (1D)

Rate of fluid administration should be reduced if cardiac filling pressures increase withoutconcurrent hemodynamic improvement (1D)Vasopressors

Maintain MAP 65 mm Hg (1C) Norepinephrine and dopamine centrally administered are the initial vasopressors of choice (1C) Epinephrine, phenylephrine, or vasopressin should not be administered as the initial

vasopressor in septic shock (2C). Vasopressin 0.03 units/min may be subsequently added to

norepinephrine with anticipation of an effect equivalent to norepinephrine alone Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly

responsive to norepinephrine or dopamine (2B). Do not use low-dose dopamine for renal protection (1A) In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D)

Inotropic therapy Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac

filling pressures and low cardiac output (1C) Do not increase cardiac index to predetermined supranormal levels (1B)

Steroids Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly

to adequate fluid resuscitation and vasopressors (2C) ACTH stimulation test is not recommended to identify the subset of adults with septic shock

who should receive hydrocortisone (2B) Hydrocortisone is preferred to dexamethasone (2B) Fludrocortisone (50 g orally once a day) may be included if an alternative to hydrocortisone

is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional if

hydrocortisone is used (2C) Steroid therapy may be weaned once vasopressors are no longer required (2D) Hydrocortisone dose should be 300 mg/day (1A) Do not use corticosteroids to treat sepsis in the absence of shock unless the patients

endocrine or corticosteroid history warrants it (1D)Recombinant human activated protein C

Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical

assessment of high risk of death (typically APACHE II 25 or multiple organ failure) if there

are no contraindications (2B, 2C for postoperative patients). Adult patients with severe sepsis and low risk of death (typically, APACHE II 20 or one

organ failure) should not receive rhAPC (1A)

GRADE, Grades of Recommendation, Assessment, Development and Evaluation; CVP, central

venous pressure; MAP, mean arterial pressure; ACTH, adrenocorticotropic hormone; rhAPC, recom-

binant human activated protein C; APACHE, Acute Physiology and Chronic Health Evaluation.

300 Crit Care Med 2008 Vol. 36, No. 1


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tic shock, if ScvO2 or SVO2 of 70% or65%, respectively, is not achieved withfluid resuscitation to the central ve-nous pressure target, then transfusionof packed red blood cells to achieve a

hematocrit of30% and/or adminis-tration of a dobutamine infusion (upto a maximum of 20 gkg1min1)be used to achieve this goal (grade2C).

Rationale. The protocol used in thestudy cited previously targeted an increasein ScvO2 to 70% (16). This was achievedby sequential institution of initial fluid re-suscitation, packed red blood cells, and

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 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 7.09.0 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) Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures (2D) Do not use antithrombin therapy (1B) Administer platelets when (2D)

Counts are 5000/mm3 (5 109/L) regardless of bleedingCounts are 500030,000/mm3 (530 109/L) and there is significant bleeding riskHigher platelet counts (50,000/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 30 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) Consider using the prone position for ARDS patients requiring potentially injurious levels of F IO2 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) 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 H 2O or a T piece

Before the SBT, patients shouldbe arousablebe hemodynamically stable without vasopressorshave no new potentially serious conditionshave low ventilatory and end-expiratory pressure requirementrequire 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) 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 12 hrs (4 hrs when stable) in patients receiving intravenous insulin (1C) Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood or plasma

glucose values (1B)Renal replacement

Intermittent hemodialysis and CVVH are considered equivalent (2B) CVVH offers easier management in hemodynamically unstable patients (2D)

Bicarbonate therapy Do not use bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-

induced lactic acidemia with pH 7.15 (1B)Deep vein thrombosis 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) Use a combination of pharmacologic and mechanical therapy for patients who are at very high risk for deep vein thrombosis (2C) In patients at very high risk, LMWH should be used rather than UFH (2C)

Stress ulcer prophylaxis Provide stress ulcer prophylaxis using H2 blocker (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.



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then dobutamine. This protocol was asso-ciated with an improvement in survival.Based on bedside clinical assessment andpersonal preference, a clinician may deemeither blood transfusion (if hematocrit is30%) or dobutamine the best initialchoice to increase oxygen delivery andthereby elevate ScvO2, when fluid resusci-tation is believed to be already adequate.The design of the aforementioned trial did

not allow assessment of the relative contri-bution of these two components (i.e., in-creasing oxygen content or increasing car-di ac outp ut ) o f the p ro to co l o nachievement of improved outcome.

B. Diagnosis

1. We recommend obtaining appropri-ate cultures before antimicrobialtherapy is initiated if such culturesdo not cause significant delay in an-tibiotic administration. To optimizeidentification of causative organisms,

we recommend at least two bloodcultures be obtained before antibiot-ics with at least one drawn percuta-neously and one drawn through each

vascular access device, unless the de-vice was recently (48 hrs) inserted.Cultures of other sites (preferablyquantitative where appropriate), suchas urine, cerebrospinal fluid, wounds,respiratory secretions, or other bodyfluids that may be the source of in-fection should also be obtained be-fore antibiotic therapy if not associ-

a te d wit h s ig ni fic ant d el ay i nantibiotic administration (grade 1C).

Rationale. Although sampling shouldnot delay timely administration of antibi-otics in patients with severe sepsis (e.g.,lumbar puncture in suspected meningi-tis), obtaining appropriate cultures be-fore administration of antibiotics is es-sential to confirm infection and theresponsible pathogens and to allow de-escalation of antibiotic therapy after re-ceipt of the susceptibility profile. Samplescan be refrigerated or frozen if processing

cannot be performed immediately. Im-mediate transport to a microbiologicallab is necessary. Because rapid steriliza-tion of blood cultures can occur within afew hours after the first antibiotic dose,obtaining those cultures before startingtherapy is essential if the causative organ-ism is to be identified. Two or more bloodcultures are recommended (36). In pa-tients with indwelling catheters (for 48hrs), at least one blood culture should bedrawn through each lumen of each vas-

cular access device. Obtaining blood

cultures peripherally and through avascular access device is an important

strategy. If the same organism is recov-

ered from both cultures, the likelihoodthat the organism is causing the severe

sepsis is enhanced. In addition, if the

culture drawn through the vascular ac-cess device is positive much earlier than

the peripheral blood culture (i.e., 2 hrs

earlier), the data support the concept thatthe vascular access device is the source of

the infection (37). Quantitative culturesof catheter and peripheral blood are also

useful for determining whether the cath-

eter is the source of infection. Volume ofblood drawn with the culture tube should

be 10 mL (38). Quantitative (or semi-

quantitative) cultures of respiratory tractsecretions are recommended for the di-

agnosis of ventilator-associated pneumo-

nia (39). Gram-negative stain can be use-ful, in particular for respiratory tract

specimens, to help decide the micro-organisms to be targeted. The potentialrole of biomarkers for diagnosis of in-

fection in patients presenting with se-vere sepsis remains undefined. The pro-

calcitonin level, although often useful,

is problematic in patients with an acutei nflam m at o ry p a tt e rn f r om o t her

causes (e.g., postoperative, shock) (40).

In the near future, rapid diagnosticmethods (polymerase chain reaction,

micro-arrays) might prove extremely

helpful for a quicker identification of

pathogens and major antimicrobial re-sistance determinants (41).

2. We recommend that imaging studies

be performed promptly in attempts

to confirm a potential source of in-fection. Sampling of potential

sources of infection should occur as

they are identified; however, somepatients may be too unstable to war-

rant certain invasive procedures or

transport outside of the ICU. Bedsidestudies, such as ultrasound, are use-

ful in these circumstances (grade

1C).

Rationale. Diagnostic studies mayidentify a source of infection that re-quires removal of a foreign body or drain-

age to maximize the likelihood of a sat-isfactory response to therapy. However,

even in the most organized and well-staffed healthcare facilities, transport of

patients can be dangerous, as can placing

patients in outside-unit imaging devicesthat are difficult to access and monitor.

Balancing risk and benefit is thereforemandatory in those settings.

C. Antibiotic Therapy

1. We recommend that intravenous an-tibiotic therapy be started as early aspossible and within the first hour ofrecognition of septic shock (1B) andsevere sepsis without septic shock

(1D). Appropriate cultures should beobtained before initiating antibiotictherapy but should not preventprompt administration of antimicro-bial therapy (grade 1D).

Rationale. Establishing vascular ac-cess and initiating aggressive fluid resus-citation are the first priority when man-aging patients with severe sepsis or septicshock. However, prompt infusion of anti-microbial agents should also be a priorityand may require additional vascular ac-cess ports (42, 43). In the presence of

septic shock, each hour delay in achiev-ing administration of effective antibioticsis associated with a measurable increasein mortality (42). If antimicrobial agentscannot be mixed and delivered promptlyfrom the pharmacy, establishing a supplyof premixed antibiotics for such urgentsituations is an appropriate strategy forensuring prompt administration. Inchoosing the antimicrobial regimen, cli-nicians should be aware that some anti-microbial agents have the advantage ofbolus administration, while others re-quire a lengthy infusion. Thus, if vascularaccess is limited and many differentagents must be infused, bolus drugs mayoffer an advantage.

2a. We recommend that initial empiricalanti-infective therapy include one ormore drugs that have activity againstall likely pathogens (bacterial and/orfungal) and that penetrate in ade-quate concentrations into the pre-sumed source of sepsis (grade 1B).

Rationale. The choice of empirical an-tibiotics depends on complex issues re-

lated to the patients history, includingdrug intolerances, underlying disease,the clinical syndrome, and susceptibilitypatterns of pathogens in the community,in the hospital, and that previously havebeen documented to colonize or infectthe patient. There is an especially widerange of potential pathogens for neutro-penic patients.

Recently used antibiotics should gener-ally be avoided. When choosing empiricaltherapy, clinicians should be cognizant of



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the virulence and growing prevalence ofoxacillin (methicillin)-resistant Staphylo-coccus aureus (ORSA or MRSA) in somecommunities and healthcare settings (espe-cially in the United States). If the preva-lence is significant, and in consideration ofthe virulence of this organism, empiricaltherapy adequate for this pathogen wouldbe warranted. Clinicians should also con-sider whether candidemia is a likely patho-

gen when choosing initial therapy. Whendeemed warranted, the selection of empir-ical antifungal therapy (e.g., fluconazole,amphotericin B, or echinocandin) will betailored to the local pattern of the mostprevalent Candida species and any prioradministration of azoles drugs (44). Riskfactors for candidemia should also be con-sidered when choosing initial therapy.

Because patients with severe sepsis orseptic shock have little margin for errorin the choice of therapy, the initial selec-tion of antimicrobial therapy should bebroad enough to cover all likely patho-gens. There is ample evidence that failureto initiate appropriate therapy (i.e., ther-apy with activity against the pathogenthat is subsequently identified as thecausative agent) correlates with increasedmorbidity and mortality (4548).

Patients with severe sepsis or septicshock warrant broad-spectrum therapyuntil the causative organism and its an-tibiotic susceptibilities are defined. Re-striction of antibiotics as a strategy toreduce the development of antimicrobialresistance or to reduce cost is not an

appropriate initial strategy in this patientpopulation.

All patients should receive a full load-ing dose of each antimicrobial. However,patients with sepsis or septic shock oftenhave abnormal renal or hepatic functionand may have abnormal volumes of dis-tribution due to aggressive fluid resusci-tation. Drug serum concentration moni-toring can be useful in an ICU setting forthose drugs that can be measuredpromptly. An experienced physician orclinical pharmacist should be consulted

to ensure that serum concentrations areattained that maximize efficacy and min-imize toxicity (4952).

2b. We recommend that the antimicro-bial regimen be reassessed daily tooptimize activity, to prevent the de-

velopment of resistance, to reducetoxicity, and to reduce costs (grade1C).

Rationale. Although restriction of an-tibiotics as a strategy to reduce the devel-

opment of antimicrobial resistance or toreduce cost is not an appropriate initialstrategy in this patient population, oncethe causative pathogen has been identi-

fied, it may become apparent that none ofthe empirical drugs offers optimal ther-apy; that is, there may be another drugproven to produce superior clinical out-come that should therefore replace em-pirical agents.

Narrowing the spectrum of antibioticcoverage and reducing the duration of

antibiotic therapy will reduce the likelihoodthat the patient will develop superinfection

with pathogenic or resistant organisms,such as Candida species, Clostridium diffi-cile, or vancomycin-resistant Enterococcus

faecium. However, the desire to minimizesuperinfections and other complicationsshould not take precedence over the needto give the patient an adequate course of

therapy to cure the infection that causedthe severe sepsis or septic shock.

2c. We suggest combination therapy forpatients with known or suspected

Pseudomonas infections as a cause ofsevere sepsis (grade 2D).

2d. We suggest combination empiricaltherapy for neutropenic patients withsevere sepsis (grade 2D).

2e. When used empirically in patients

with severe sepsis, we suggest thatcombination therapy should not beadministered for 35 days. De-escalation to the most appropriatesingle therapy should be performed

as soon as the susceptibility profile isknown (grade 2D).

Rationale. Although no study or meta-analysis has convincingly demonstratedthat combination therapy produces a supe-

rior clinical outcome for individual patho-gens in a particular patient group, combi-nation therapies do produce in vitrosynergy against pathogens in some models(although such synergy is difficult to defineand predict). In some clinical scenarios,such as the two preceding, combinationtherapies are biologically plausible and are

likely clinically useful even if evidence hasnot demonstrated improved clinical out-come (5356). Combination therapy forsuspected known Pseudomonas pendingsensitivities increases the likelihood that atleast one drug is effective against thatstrain and positively affects outcome (57).

3. We recommend that the duration oftherapy typically be 710 days; longercourses may be appropriate in pa-tients who have a slow clinical re-

sponse, undrainable foci of infection,or immunologic deficiencies, includ-ing neutropenia (grade 1D).

4. We recommend that if the presentingclinical syndrome is determined to bedue to a noninfectious cause, antimi-crobial therapy be stopped promptlyto minimize the likelihood that thepatient will become infected with anantibiotic-resistant pathogen or will

develop a drug-related adverse effect(grade 1D).

Rationale. Clinicians should be cogni-zant that blood cultures will be negativein 50% of cases of severe sepsis or sep-tic shock, yet many of these cases are verylikely caused by bacteria or fungi. Thus,the decisions to continue, narrow, or stopantimicrobial therapy must be made onthe basis of clinician judgment and clin-ical information.

D. Source Control

1a. We recommend that a specific ana-tomical diagnosis of infection requir-ing consideration for emergentsource control (e.g., necrotizing fas-ciitis, diffuse peritonitis, cholangitis,intestinal infarction) be sought anddiagnosed or excluded as rapidly aspossible (grade 1C) and within thefirst 6 hrs following presentation(grade 1D).

1b. We further recommend that all pa-tients presenting with severe sepsis

be evaluated for the presence of afocus on infection amenable tosource control measures, specificallythe drainage of an abscess or localfocus on infection, the debridementof infected necrotic tissue, the re-moval of a potentially infected device,or the definitive control of a sourceof ongoing microbial contamination(grade 1C). (Appendix A provides ex-amples of potential sites needingsource control.)

2. We suggest that when infected

peripancreatic necrosis is identified asa potential source of infection, defini-tive intervention is best delayed untiladequate demarcation of viable andnonviable tissues has occurred (grade2B).

3. We recommend that when source con-trol is required, the effective interventionassociated with the least physiologic in-sult be employed (e.g., percutaneousrather than surgical drainage of anabscess (grade 1D).



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4. We recommend that when intravas-cular access devices are a possiblesource of severe sepsis or septicshock, they be promptly removed af-ter other vascular access has beenestablished (grade 1C).

Rationale. The principals of sourcecontrol in the management of sepsis in-clude a rapid diagnosis of the specific siteof infection and identification of a focus

on infection amenable to source controlmeasures (specifically the drainage of anabscess, debridement of infected necrotictissue, removal of a potentially infecteddevice, and definitive control of a sourceof ongoing microbial contamination)(58). Foci of infection readily amenable tosource control measures include an in-tra-abdominal abscess or gastrointestinalperforation, cholangitis or pyelonephri-tis, intestinal ischemia or necrotizing softtissue infection, and other deep space in-fection, such as an empyema or septic

arthritis. Such infectious foci should becontrolled as soon as possible followingsuccessful initial resuscitation (59), ac-complishing the source control objective

with the least physiologic upset possible(e.g., percutaneous rather than surgicaldrainage of an abscess [60], endoscopicrather than surgical drainage of biliarytree), and removing intravascular accessdevices that are potentially the source ofsevere sepsis or septic shock promptlyafter establishing other vascular access(61, 62). A randomized, controlled trialcomparing early vs. delayed surgical in-tervention for peripancreatic necrosisshowed better outcomes with a delayedapproach (63). However, areas of uncer-tainty exist, such as definitive docu-mentation of infection and appropriatelength of delay. The selection of optimalsource control methods must weighbenefits and risks of the specific inter-

vention as well as risks of transfer (64).Source control interventions may causefurther complications, such as bleed-ing, fistulas, or inadvertent organ in-

jury. Surgical intervention should be

considered when lesser interventionalapproaches are inadequate or when di-agnostic uncertainty persists despite ra-diologic evaluation. Specific clinical sit-ua ti o ns r e qui r e c o nsi d er a ti o n o f available choices, patients preferences,and clinicians expertise.

E. Fluid Therapy

1. We recommend fluid resuscitationwith either natural/artificial colloids

or crystalloids. There is no evidence-based support for one type of fluidover another (grade 1B).

Rationale. The SAFE study indicatedthat albumin administration was safe and

equally as effective as crystalloid (65). Therewas an insignificant decrease in mortalityrates with the use of colloid in a subsetanalysis of septic patients (p .09). Previ-ous meta-analyses of small studies of ICU

patients had demonstrated no differencebetween crystalloid and colloid fluid resus-citation (6668). Although administrationof hydroxyethyl starch may increase the

risk of acute renal failure in patients withsepsis, variable findings preclude definitiverecommendations (69, 70). As the volumeof distribution is much larger for crystal-loids than for colloids, resuscitation withcrystalloids requires more fluid to achievethe same end points and results in moreedema. Crystalloids are less expensive.

2. We recommend that fluid resuscita-tion initially target a central venous

pressure of8 mm Hg (12 mm Hg inmechanically ventilated patients).Further fluid therapy is often re-quired (grade 1C).

3a. We recommend that a fluid challengetechnique be applied wherein fluidadministration is continued as longas the hemodynamic improvement(e.g., arterial pressure, heart rate,

urine output) continues (grade 1D).3b. We recommend that fluid challenge

in patients with suspected hypovole-mia be started with 1000 mL ofcrystalloids or 300500 mL of col-loids over 30 mins. More rapid ad-ministration and greater amounts offluid may be needed in patients with

sepsis-induced tissue hypoperfusion(see Initial Resuscitation recommen-dations) (grade 1D).

3c. We recommend that the rate of fluidadministration be reduced substan-tially when cardiac filling pressures(central venous pressure or pulmo-nary artery balloon-occluded pres-

sure) increase without concurrenthemodynamic improvement (grade1D).

Rationale. Fluid challenge must beclearly separated from simple fluid ad-ministration; it is a technique in whichlarge amounts of fluids are administeredover a limited period of time under closemonitoring to evaluate the patients re-sponse and avoid the development of pul-monary edema. The degree of intravascular

volume deficit in patients with severe sepsisvaries. With venodilation and ongoing cap-illary leak, most patients require continu-ing aggressive fluid resuscitation duringthe first 24 hrs of management. Input istypically much greater than output, andinput/output ratio is of no utility to judgefluid resuscitation needs during this timeperiod.

F. Vasopressors

1. We recommend that mean arterialpressure (MAP) be maintained 65mm Hg (grade 1C).

Rationale. Vasopressor therapy is re-quired to sustain life and maintain perfu-sion in the face of life-threatening hypo-tension, even when hypovolemia has not

yet been resolved. Below a certain meanarterial pressure, autoregulation in vari-ous vascular beds can be lost, and perfu-sion can become linearly dependent on

pressure. Thus, some patients may re-quire vasopressor therapy to achieve aminimal perfusion pressure and maintainadequate flow (71, 72). The titration ofnorepinephrine to as low as MAP 65 mmHg has been shown to preserve tissueperfusion (72). In addition, preexistingcomorbidities should be considered as tomost appropriate MAP target. For exam-ple, a MAP of 65 mm Hg might be too lowin a patient with severe uncontrolled hy-pertension, and in a young previouslynormotensive, a lower MAP might be

adequate. Supplementing end points,such as blood pressure, with assess-ment of regional and global perfusion,such as blood lactate concentrationsand urine output, is important. Ade-quate fluid resuscitation is a fundamen-tal aspect of the hemodynamic manage-ment of patients with septic shock andshould ideally be achieved before vaso-pressors and inotropes are used, butusing vasopressors early as an emer-gency measure in patients with severeshock is frequently necessary. Whenthat occurs, great effort should be di-rected to weaning vasopressors withcontinuing fluid resuscitation.

2. We recommend either norepineph-rine or dopamine as the first choice

vasopressor agent to correct hypo-tension in septic shock (administeredthrough a central catheter as soon asone is available) (grade 1C).

3a. We suggest that epinephrine, phenyl-ephrine, or vasopressin should not beadministered as the initial vasopres-



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sor in septic shock (grade 2C). Vaso-pressin 0.03 units/min may be addedto norepinephrine subsequently withanticipation of an effect equivalent tothat of norepinephrine alone.

3b. We suggest that epinephrine be thefirst chosen alternative agent in sep-tic shock that is poorly responsive tonorepinephrine or dopamine (grade2B).

Rationale. There is no high-qualityprimary evidence to recommend one cat-echolamine over another. Much litera-ture exists that contrasts the physiologiceffects of choice of vasopressor and com-bined inotrope/vasopressors in septicshock (7385). Human and animal stud-ies suggest some advantages of norepi-nephrine and dopamine over epinephrine(the latter with the potential for tachy-cardia as well as disadvantageous effectson splanchnic circulation and hyper-lactemia) and phenylephrine (decrease in

stroke volume). There is, however, noclinical evidence that epinephrine resultsin worse outcomes, and it should be thefirst chosen alternative to dopamine ornorepinephrine. Phenylephrine is the ad-renergic agent least likely to producetachycardia but as a pure vasopressor

would be expected to decrease stroke vol-ume. Dopamine increases mean arterialpressure and cardiac output, primarilydue to an increase in stroke volume andheart rate. Norepinephrine increasesmean arterial pressure due to its vasocon-

strictive effects, with little change inheart rate and less increase in stroke vol-ume compared with dopamine. Eithermay be used as a first-line agent to correcthypotension in sepsis. Norepinephrine ismore potent than dopamine and may bemore effective at reversing hypotension inpatients with septic shock. Dopamine maybe particularly useful in patients with com-promised systolic function but causes moretachycardia and may be more arrhythmo-genic (86). It may also influence the endo-crine response via the hypothalamic-

pituitary axis and have immunosuppressiveeffects.Vasopressin levels in septic shock have

been reported to be lower than antici-pated for a shock state (87). Low doses of

vasopressin may be effective in raisingblood pressure in patients refractory toother vasopressors and may have otherpotential physiologic benefits (8893).Terlipressin has similar effects but is longlasting (94). Studies show that vasopres-sin concentrations are elevated in early

septic shock, but with continued shockthe concentration decreases to normalrange in the majority of patients between24 and 48 hrs (95). This has been called

relative vasopressin deficiency because inthe presence of hypotension, vasopressin

would be expected to be elevated. Thesignificance of this finding is unknown.The recent VASST trial, a randomized,controlled trial comparing norepineph-

rine alone to norepinephrine plus vaso-pressin at 0.03 units/min, showed no dif-ference in outcome in the intent to treatpopulation. An a priori defined subgroupanalysis showed that the survival of pa-tients receiving15 g/min norepineph-rine at the time of randomization wasbetter with vasopressin. However, thepretrial rationale for this stratification

was based on exploring potential benefitin the 15 g norepinephrine require-ment population. Higher doses of vaso-pressin have been associated with car-

diac, digital, and splanchnic ischemia andshould be reserved for situations wherealternative vasopressors have failed (96).Cardiac output measurement to allowmaintenance of a normal or elevated flowis desirable when these pure vasopressorsare instituted.

5. We recommend that low-dose dopa-mine not be used for renal protection(grade 1A).

Rationale. A large randomized trialand meta-analysis comparing low-dosedopamine to placebo found no difference

in either primary outcomes (peak serumcreatinine, need for renal replacement,urine output, time to recovery of normalrenal function) or secondary outcomes(survival to either ICU or hospital dis-charge, ICU stay, hospital stay, arrhyth-mias) (97, 98). Thus, the available data donot support administration of low dosesof dopamine solely to maintain renalfunction.

6. We recommend that all patients re-quiring vasopressors have an arterialcatheter placed as soon as practical ifresources are available (grade 1D).

Rationale. In shock states, estimationof blood pressure using a cuff is com-monly inaccurate; use of an arterial can-nula provides a more appropriate and re-producible measurement of arterialpressure. These catheters also allow con-tinuous analysis so that decisions regard-ing therapy can be based on immediateand reproducible blood pressure informa-tion.

G. Inotropic Therapy

1. We recommend that a dobutamine in-fusion be administered in the presenceof myocardial dysfunction as sug-gested by elevated cardiac filling pres-sures and low cardiac output (grade1C).

2. We recommend against the use of astrategy to increase cardiac index topredetermined supranormal levels(grade 1B).

Rationale. Dobutamine is the first-choice inotrope for patients with mea-sured or suspected low cardiac output inthe presence of adequate left ventricularfilling pressure (or clinical assessment ofadequate fluid resuscitation) and ade-quate mean arterial pressure. Septic pa-tients who remain hypotensive after fluidresuscitation may have low, normal, orincreased cardiac outputs. Therefore,treatment with a combined inotrope/

vasopressor, such as norepinephrine ordopamine, is recommended if cardiacoutput is not measured. When the capa-bility exists for monitoring cardiac out-put in addition to blood pressure, a vaso-pressor, such as norepinephrine, may beused separately to target specific levels ofmean arterial pressure and cardiac out-put. Two large prospective clinical trialsthat included critically ill ICU patients

who had severe sepsis failed to demon-strate benefit from increasing oxygen de-livery to supranormal targets by use ofdobutamine (99, 100). These studies did

not specifically target patients with se-vere sepsis and did not target the first 6hrs of resuscitation. The first 6 hrs ofresuscitation of sepsis-induced hypoper-fusion need to be treated separately fromthe later stages of severe sepsis (see Ini-tial Resuscitation recommendations).

H. Corticosteroids

1. We suggest that intravenous hydro-cortisone be given only to adult septicshock patients after it has been con-firmed that their blood pressure ispoorly responsive to fluid resuscita-tion and vasopressor therapy (grade2C).

Rationale. One French multicenter,randomized controlled trial (RCT) of pa-tients in vasopressor-unresponsive septicshock (hypotension despite fluid resuscita-tion and vasopressors) showed a significantshock reversal and reduction of mortalityrate in patients with relative adrenal insuf-



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ficiency (defined as postadrenocortico-tropic hormone [ACTH] cortisol increase9 g/dL) (101). Two additional smallerRCTs also showed significant effects onshock reversal with steroid therapy (102,103). However, a recent large, Europeanmulticenter trial (CORTICUS), which hasbeen presented in abstract form but not yetpublished, failed to show a mortality benefit

with steroid therapy of septic shock (104).

CORTICUS did show a faster resolution ofseptic shock in patients who received ste-roids. The use of the ACTH test (respondersand nonresponders) did not predict thefaster resolution of shock. Importantly, un-like the French trial, which only enrolledshock patients with blood pressure unre-sponsive to vasopressor therapy, the COR-TICUS study included patients with septicshock, regardless of how the blood pressureresponded to vasopressors. Although corti-costeroids do appear to promote shock re-

versal, the lack of a clear improvement inmortalitycoupled with known side ef-fects of steroids, such as increased risk ofinfection and myopathygenerally tem-pered enthusiasm for their broad use. Thus,there was broad agreement that the recom-mendation should be downgraded from theprevious guidelines (Appendix B). There

was considerable discussion and consider-ation by the committee on the option ofencouraging use in those patients whoseblood pressure was unresponsive to fluidsand vasopressors, while strongly discourag-ing use in subjects whose shock responded

well to fluids and pressors. However, this

more complex set of recommendations wasrejected in favor of the preceding singlerecommendation (Appendix B).

2. We suggest that the ACTH stimulationtest not be used to identify the subsetof adults with septic shock who shouldreceive hydrocortisone (grade 2B).

Rationale. Although one study sug-gested those who did not respond to

ACTH with a brisk surge in cortisol (fail-ure to achieve or 9 g/dL increase incortisol 3060 mins after ACTH admin-

istration) were more likely to benefitfrom steroids than those who did re-spond, the overall trial population ap-peared to benefit regardless of ACTH re-sult, and the observation of a potentialinteraction between steroid use and

ACTH test was not statistically significant(101). Furthermore, there was no evi-dence of this distinction between re-sponders and nonresponders in a recentmulticenter trial (104). Commonly usedcortisol immunoassays measure total

cortisol (protein-bound and free) while

free cortisol is the pertinent measure-

ment. The relationship between free and

total cortisol varies with serum protein

concentration. When compared with a

reference method (mass spectrometry),

cortisol immunoassays may over- or un-

derestimate the actual cortisol level, af-

fecting the assignment of patients to re-

sponders or nonresponders (105).

Although the clinical significance is notclear, it is now recognized that etomi-

date, when used for induction for intuba-

tion, will suppress the hypothalamic-

pituitary-adrenal axis (106).

3. We suggest that patients with septic

shock should not receive dexametha-

sone if hydrocortisone is available

(grade 2B).

Rationale. Although often proposedfor use until an ACTH stimulation test

can be administered, we no longer sug-

gest an ACTH test in this clinical situa-tion (see the preceding point 3). Further-

more, dexamethasone can lead to

immediate and prolonged suppression of

the hypothalamic-pituitary-adrenal axis

after administration (107).

4. We suggest the daily addition of oral

fludrocortisone (50 g) if hydrocorti-

sone is not available and the steroid

that is substituted has no significant

mineralocorticoid activity. Fludrocor-

tisone is considered optional if hydro-

cortisone is used (grade 2C).

Rationale. One study added 50 g offludrocortisone orally (101). Since hydro-

cortisone has intrinsic mineralocorticoid

activity, there is controversy as to

whether fludrocortisone should be added.

5. We suggest that clinicians wean the

patient from steroid therapy when va-

sopressors are no longer required

(grade 2D).

Rationale. There has been no compar-

ative study between a fixed-duration and

clinically guided regimen or between ta-

pering and abrupt cessation of steroids.

Three RCTs used a fixed-duration proto-

col for treatment (101, 103, 104), and in

two RCTs, therapy was decreased after

shock resolution (102, 108). In four RCTs

steroids were tapered over several days

(102104, 108), and in two RCTs (101,

109) steroids were withdrawn abruptly.

One crossover study showed hemody-

namic and immunologic rebound effects

after abrupt cessation of corticosteroids

(110). It remains uncertain whether out-come is affected by tapering of steroids.

6. We recommend that doses of cortico-steroids comparable to 300 mg ofhydrocortisone daily not be used insevere sepsis or septic shock for thepurpose of treating septic shock(grade 1A).

Rationale. Two randomized prospec-tive clinical trials and a meta-analysesconcluded that for therapy of severe sep-sis or septic shock, high-dose corticoste-roid therapy is ineffective or harmful(111113). Reasons to maintain higherdoses of corticosteroid for medical condi-tions other than septic shock may exist.

7. We recommend that corticosteroidsnot be administered for the treatmentof sepsis in the absence of shock.There is, however, no contraindicationto continuing maintenance steroidtherapy or to using stress-dose ste-roids if the patients endocrine or cor-ticosteroid administration history

warrants (grade 1D).

Rationale. No studies exist that specif-ically target severe sepsis in the absence ofshock and offer support for use of stressdoses of steroids in this patient population.Steroids may be indicated in the presenceof a history of steroid therapy or adrenaldysfunction. A recent preliminary study ofstress-dose level steroids in community-acquired pneumonia is encouraging butneeds confirmation (114).

I. Recombinant Human

Activated Protein C (rhAPC)

1. We suggest that adult patients with sep-sis-induced organ dysfunction associ-ated with a clinical assessment of highrisk of death, most of whom will have

Acute Physiology and Chronic HealthEvaluation (APACHE) II 25 or multi-ple organ failure, receive rhAPC if thereare no contraindications (grade 2B ex-cept for patients within 30 days of sur-gery, for whom it is grade 2C). Relativecontraindications should also be consid-ered in decision making.

2. We recommend that adult patientswith severe sepsis and low risk ofd ea th, m os t o f who m wil l hav e

APACHE II 20 or one organ failure,do not receive rhAPC (grade 1A).

Rationale. The evidence concerninguse of rhAPC in adults is primarily based ontwo RCTs: PROWESS (1,690 adult patients,stopped early for efficacy) (115) and AD-



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DRESS (stopped early for futility) (116).Additional safety information comes froman open-label observational study, EN-HANCE (117). The ENHANCE trial alsosuggested that early administration ofrhAPC was associated with better out-comes.

PROWESS involved 1,690 patients anddocumented 6.1% in absolute total mor-tality reduction with a relative risk reduc-

tion of 19.4%, 95% confidence interval6.630.5%, and number needed to treat16 (115). Controversy associated with theresults focused on a number of subgroupanalyses. Subgroup analyses have the po-tential to mislead due to the absence ofan intent to treat, sampling bias, andselection error (118). The analyses sug-gested increasing absolute and relativerisk reduction with greater risk of deathusing both higher APACHE II scores andgreater number of organ failures (119).This led to drug approval for patients

with high risk of death (such as APACHEII 25) and more than one organ failurein Europe.

The ADDRESS trial involved 2,613 pa-tients judged to have a low risk of deathat the time of enrollment. The 28-daymortality rate from all causes was 17% onplacebo vs. 18.5% on APC, relative risk1.08, 95% confidence interval 0.921.28(116). Again, debate focused on subgroupanalyses; analyses were restricted tosmall subgroups of patients with

APACHE II score 25 or more than oneorgan failure, which failed to show bene-

fit. However, these patient groups alsohad a lower mortality than in PROWESS.

Relative risk reduction of death wasnumerically lower in the subgroup of pa-tients with recent surgery (n 502) inthe PROWESS trial (30.7% placebo vs.27.8% APC) (119) when compared withthe overall study population (30.8% pla-cebo vs. 24.7% APC) (115). In the AD-DRESS trial, patients with recent surgeryand single organ dysfunction who re-ceived APC had significantly higher 28-day mortality rates (20.7% vs. 14.1%, p

.03, n 635) (116).Serious adverse events did not differ in

the studies (115117) with the exceptionof serious bleeding, which occurred moreoften in the patients treated with APC:2% vs. 3.5% (PROWESS; p .06) (115);2.2% vs. 3.9% (ADDRESS; p .01) (116);6.5% (ENHANCE, open label) (117). Thepediatric trial and implications are dis-cussed in the pediatric consideration sec-tion of this article. (Appendix C providesabsolute contraindications to use of

rhAPC and prescribing information forrelative contraindications.)

Intracranial hemorrhage (ICH) oc-curred in the PROWESS trial in 0.1%(placebo) and 0.2% (APC) (not signifi-cant) (106); in the ADDRESS trial 0.4%(placebo) vs. 0.5 % (APC) (not significant)(116); and in ENHANCE 1.5% (108). Reg-istry studies of rhAPC report higherbleeding rates than randomized con-

trolled trials, suggesting that the risk ofbleeding in actual practice may be greaterthan reported in PROWESS and AD-DRESS (120, 121).

The two RCTs in adult patients weremethodologically strong and precise andprovided direct evidence regarding deathrates. The conclusions are limited, how-ever, by inconsistency that is not ade-quately resolved by subgroup analyses(thus the designation of moderate-qualityevidence). Results, however, consistentlyfail to show benefit for the subgroup ofpatients at lower risk of death and con-sistently show increases in serious bleed-ing. The RCT in pediatric severe sepsisfailed to show benefit and has no impor-tant limitations. Thus, for low-risk andpediatric patients, we rate the evidence ashigh quality.

For adult use there is probable mor-tality reduction in patients with clinicalassessment of high risk of death, most of

whom will have APACHE II 25 or mul-tiple organ failure. There is likely no ben-efit in patients with low risk of death,most of whom will have APACHE II 20

or single organ dysfunction. The effectsin patients with more than one organfailure but APACHE II 25 are unclear,and in that circumstance one may useclinical assessment of the risk of deathand number of organ failures to supportdecision. There is a certain increasedrisk of bleeding with administration ofrhAPC, which may be higher in surgicalpatients and in the context of invasiveprocedures. Decision on utilization de-pends on assessing likelihood of mor-tality reduction vs. increases in bleed-

ing and cost. (Appendix D provides thenominal committee vote on recommen-dation for rhAPC.) A European regula-tory mandated RCT of rhAPC vs. pla-cebo in patients with septic shock isnow ongoing (122).

J. Blood Product Administration

1. Once tissue hypoperfusion has resolvedand in the absence of extenuating cir-cumstances, such as myocardial isch-

emia, severe hypoxemia, acute hemor-rhage, cyanotic heart disease, or lacticacidosis (see recommendations for ini-tial resuscitation), we recommend thatred blood cell transfusion occur whenhemoglobin decreases to 7.0 g/dL(70 g/L) to target a hemoglobin of7.09.0 g/dL (70 90 g/L) in adults(grade 1B).

Rationale. Although the optimum he-

moglobin for patients with severe sepsishas not been specifically investigated, theTransfusion Requirements in CriticalCare trial suggested that a hemoglobin of79 g/dL (7090 g/L) when compared

with 10 12 g/dL (100 200 g/L) was notassociated with increased mortality inadults (123). Red blood cell transfusion inseptic patients increases oxygen deliverybut does not usually increase oxygen con-sumption (124126). This transfusionthreshold of 7 g/dL (70 g/L) contrasts

with the early goal-directed resuscitation

protocol that uses a target hematocrit of30% in patients with low ScvO2 (mea-sured in superior vena cava) during thefirst 6 hrs of resuscitation of septic shock.

2. We recommend that erythropoietinnot be used as a specific treatment ofanemia associated with severe sepsisbut may be used when septic patientshave other accepted reasons for ad-ministration of erythropoietin, such asrenal failure-induced compromise ofred blood cell production (grade 1B).

Rationale. No specific information re-

garding erythropoietin use in septic pa-tients is available, but clinical trials incritically ill patients show some decreasein red cell transfusion requirement withno effect on clinical outcome (127, 128).The effect of erythropoietin in severe sep-sis and septic shock would not be ex-pected to be more beneficial than in othercritical conditions. Patients with severesepsis and septic shock may have coexist-ing conditions that do warrant use oferythropoietin.

3. We suggest that fresh frozen plasmanot be used to correct laboratory clot-ting abnormalities in the absence ofbleeding or planned invasive proce-dures (grade 2D).

Rationale. Although clinical studieshave not assessed the impact of transfu-sion of fresh frozen plasma on outcomesin critically ill patients, professional or-ganizations have recommended fresh fro-zen plasma for coagulopathy when thereis a documented deficiency of coagulation



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factors (increased prothrombin time, in-ternational normalized ratio, or partialthromboplastin time) and the presence ofactive bleeding or before surgical or in-

vasive procedures (129 131). In addition,transfusion of fresh frozen plasma innonbleeding patients with mild abnor-malities of prothrombin time usually failsto correct the prothrombin time (132).There are no studies to suggest that cor-

rection of more severe coagulation ab-normalities benefits patients who are notbleeding.

4. We recommend against antithrombinadministration for the treatment of se-

vere sepsis and septic shock (grade 1B).

Rationale. A phase III clinical trial ofhigh-dose antithrombin did not demon-strate any beneficial effect on 28-day all-cause mortality in adults with severe sepsisand septic shock. High-dose antithrombin

was associated with an increased risk ofbleeding when administered with heparin

(133). Although a post hoc subgroup anal-ysis of patients with severe sepsis and highrisk of death showed better survival in pa-tients receiving antithrombin, antithrom-bin cannot be recommended until furtherclinical trials are performed (134).

5. In patients with severe sepsis, we sug-gest that platelets be administered

when counts are 5000/mm3 (5 109/L) regardless of apparent bleeding.Platelet transfusion may be considered

when counts are 5000 30,000/mm3

(530 109/L) and there is a signifi-

cant risk of bleeding. Higher plateletcounts (50,000/mm3 [50 109/L])are typically required for surgery orinvasive procedures (grade 2D).

Rationale. Guidelines for transfusionof platelets are derived from consensusopinion and experience in patients under-going chemotherapy. Recommendationstake into account the etiology of throm-bocytopenia, platelet dysfunction, risk ofbleeding, and presence of concomitantdisorders (129, 131).

II. SUPPORTIVE THERAPY OFSEVERE SEPSIS

A. Mechanical Ventilation of

Sepsis-Induced Acute Lung

Injury (ALI)/Acute Respiratory

Distress Syndrome (ARDS)

1. We recommend that clinicians targeta tidal volume of 6 mL/kg (predicted)body weight in patients with ALI/

ARDS (grade 1B).

2. We recommend that plateau pressures

be measured in patients with ALI/

ARDS and that the initial upper limit

goal for plateau pressures in a pas-

sively inflated patient be 30 cm H2O.

Chest wall compliance should be con-

sidered in the assessment of plateau

pressure (grade 1C).

Rationale. Over the past 10 yrs, sev-eral multicenter randomized trials have

been performed to evaluate the effects oflimiting inspiratory pressure through

moderation of tidal volume (135139).

These studies showed differing results

that may have been caused by differences

between airway pressures in the treat-

ment and control groups (135, 140). The

largest trial of a volume- and pressure-

limited strategy showed a 9% decrease of

all-cause mortality in patients with ALI or

ARDS ventilated with tidal volumes of 6

mL/kg of predicted body weight (PBW),

as opposed to 12 mL/kg, and aiming for a

plateau pressure 30 cm H2O (135). The

use of lung-protective strategies for pa-

tients with ALI is supported by clinical

trials and has been widely accepted, but

the precise choice of tidal volume for an

individual patient with ALI may require

adjustment for such factors as the plateau

pressure achieved, the level of positive

end-expiratory pressure chosen, the com-

pliance of the thoracoabdominal com-

partment, and the vigor of the patients

breathing effort. Some clinicians believe

it may be safe to ventilate with tidal vol-

umes 6 mL/kg PBW as long as the pla-

teau pressure can be maintained 30 cm

H2O (141, 142). The validity of this ceil-

ing value will depend on breathing effort,

as those who are actively inspiring gen-

erate higher transalveolar pressures for a

given plateau pressure than those who

are passively inflated. Conversely, pa-

tients with very stiff chest walls may re-

quire plateau pressures 30 cm H2O to

meet vital clinical objectives. One retro-

spective study suggested that tidal vol-

umes should be lowered even with pla-

teau pressures 30 cm H2O (143). An

additional observational study suggested

that knowledge of the plateau pressures

was associated with lower plateau pres-

sures; however, in that trial plateau pres-

sure was not independently associated

with mortality rates across a wide range

of plateau pressures that bracketed 30 cm

H2O (144). The largest clinical trial em-

ploying a lung-protective strategy cou-

pled limited pressure with limited tidal

volumes to demonstrate a mortality ben-efit (135).

High tidal volumes that are coupledwith high plateau pressures should beavoided in ALI/ARDS. Clinicians should useas a starting point the objective of reducingtidal volume over 12 hrs from its initial

value toward the goal of a low tidal vol-ume (6 mL/kg PBW) achieved in con-

junction with an end-inspiratory plateau

pressure

30 cm H2O. If plateau pressureremains 30 after reduction of tidal vol-ume to 6 mL/kg PBW, tidal volume shouldbe reduced further to as low as 4 mL/kgPBW. (Appendix E provides ARDSNet ven-tilator management and formulas to calcu-late predicted body weight.)

No single mode of ventilation (pres-sure control, volume control, airwaypressure release ventilation, high-fre-quency ventilation) has been consistentlyshown advantageous when compared

with any other that respects the same

principles of lung protection.3. We recommend that hypercapnia (al-

lowing PaCO2 to increase above its pre-morbid baseline, so-called permissivehypercapnia) be allowed in patients

with ALI/ARDS if needed to minimizeplateau pressures and tidal volumes(grade 1C).

Rationale. An acutely elevated PaCO2may have physiologic consequences thatinclude vasodilation as well as an in-creased heart rate, blood pressure, andcardiac output. Allowing modest hyper-

capnia in conjunction with limiting tidalvolume and minute ventilation has beendemonstrated to be safe in small, nonran-domized series (145, 146). Patientstreated in larger trials that have the goalof limiting tidal volumes and airway pres-sures have demonstrated improved out-comes, but permissive hypercapnia wasnot a primary treatment goal in these stud-ies (135). The use of hypercapnia is limitedin patients with preexisting metabolic aci-dosis and is contraindicated in patients

with increased intracranial pressure. So-

dium bicarbonate or tromethamine(THAM) infusion may be considered in se-lected patients to facilitate use of permis-sive hypercarbia (147, 148).

4. We recommend that positive end-expiratory pressure (PEEP) be set soas to avoid extensive lung collapse atend-expiration (grade 1C).

Rationale. Raising PEEP in ALI/ARDSkeeps lung units open to participate ingas exchange. This will increase PaO2



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when PEEP is applied through either anendotracheal tube or a face mask (149151). In animal experiments, avoidance ofend-expiratory alveolar collapse helpsminimize ventilator-induced lung injury

when relatively high plateau pressuresare in use. One large multicenter trial ofthe protocol-driven use of higher PEEPin conjunction with low tidal volumes didnot show benefit or harm when compared

with lower PEEP levels (152). Neither thecontrol nor experimental group in thatstudy, however, was clearly exposed tohazardous plateau pressures. A recentmulticenter Spanish trial compared ahigh PEEP, low-moderate tidal volumeapproach to one that used conventionaltidal volumes and the least PEEP achiev-ing adequate oxygenation. A marked sur-

vival advantage favored the former ap-proach in high-acuity patients with ARDS(153). Two options are recommended forPEEP titration. One option is to titratePEEP (and tidal volume) according tobedside measurements of thoracopulmo-nary compliance with the objective of ob-taining the best compliance, reflecting afavorable balance of lung recruitmentand overdistension (154). The second op-tion is to titrate PEEP based on severityof oxygenation deficit and guided by theFIO2 required to maintain adequate oxy-genation (135) (Appendix D). Whicheverthe indicatorcompliance or oxygen-ationrecruiting maneuvers are reason-able to employ in the process of PEEPselection. Blood pressure and oxygen-

ation should be monitored and recruit-ment discontinued if deterioration inthese variables is observed. A PEEP 5cm H20 is usually required to avoid lungcollapse (155).

5. We suggest prone positioning in ARDSpatients requiring potentially injuriouslevels of FIO2 or plateau pressure whoare not at high risk for adverse conse-quences of positional changes in facili-ties that have experience with suchpractices (grade 2C).

Rationale. Several small studies andone larger study have shown that a ma-

jority of patients with ALI/ARDS respondto the prone position with improved ox-

ygenation (156 159). One large multi-center trial of prone positioning for approx-imately 7 hrs/day did not showimprovement in mortality rates in patients

with ALI/ARDS; however, a post hoc anal-ysis suggested improvement in those pa-tients with the most severe hypoxemia byPaO2/FIO2 ratio, in those exposed to high

tidal volumes, and in those who improvedCO2 exchange as a result of proning (159).

A second large trial of prone positioning,conducted for an average of approximately

8 hrs/day for 4 days in adults with hypox-emic respiratory failure of low-moderateacuity, confirmed improvement in oxygen-ation but also failed to show a survival ad-

vantage (160). However, a randomizedstudy that extended the length of time for

proning each day to a mean of 17 hrs for amean of 10 days supported benefit of pron-

ing, with randomization to supine positionan independent risk factor for mortality bymultivariate analysis (161). Prone position-ing may be associated with potentially life-threatening complications, including acci-dental dislodgment of the endotrachealtube and central venous catheters, butthese complications can usually be avoided

with proper precautions.

6a. Unless contraindicated, we recom-mend that mechanically ventilated

patients be maintained with the headof the bed elevated to limit aspirationrisk and to prevent the developmentof ventilator-associated pneumonia(grade 1B).

6b. We suggest that the head of bed beelevated approximately 30 45(grade 2C).

Rationale. The semirecumbent posi-tion has been demonstrated to decrease

the incidence of ventilator-associatedpneumonia (VAP) (162). Enteral feedingincreased the risk of developing VAP;50% of the patients who were fed enter-ally in the supine position developed VAP(163). However, the bed position was onlymonitored once a day, and patients whodid not achieve the desired bed elevation

were not included in the analysis (163). Arecent study did not show a difference inincidence of VAP between patients main-tained in supine and semirecumbent po-sitions (164). In this study, patients in thesemirecumbent position did not consis-tently achieve the desired head of the bedelevation, and the head of bed elevation

in the supine group approached that ofthe semirecumbent group by day 7 (164).

When necessary, patients may be laid flatfor procedures, hemodynamic measure-ments, and during episodes of hypoten-sion. Patients should not be fed enterally

with the head of the bed at 0.

7. We suggest that noninvasive maskventilation (NIV) only be considered inthat minority of ALI/ARDS patients

with mild-moderate hypoxemic respi-

ratory failure (responsive to relativelylow levels of pressure support and

PEEP) with stable hemodynamics whocan be made comfortable and are eas-ily arousable; who are able to protectthe airway and spontaneously clear

the airway of secretions; and who areanticipated to recover rapidly from theprecipitating insult. A low threshold

for airway intubation should be main-

tained (grade 2B).Rationale. Obviating the need for air-

way intubation confers multiple advan-

tages: better communication, lower inci-dence of infection, reduced requirementsfor sedation. Two RCTs demonstrate im-proved outcome with the use of NIV when

it can be employed successfully (162,165). Unfortunately, only a small percent-age of patients with life-threatenin

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