Special Article

Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 200...
S          evere sepsis (acute organ dys-     Table 1. Determination of the quality of evidence
           function second...
Critical Care Medicine. The great major-     ic-related search or recent trials. Quality   all discussions and deliberatio...
about these tradeoffs— either because           Table 3. Initial resuscitation and infection issues
some of the evidence i...
Table 4. Hemodynamic support and adjunctive therapy                                                   gets to be equivalen...
Table 5. Other supportive therapy of severe sepsis

Strength of recommendation and quality of evidence have been assessed ...
then dobutamine. This protocol was asso-       cular access device. Obtaining blood          Balancing risk and benefit is ...
the virulence and growing prevalence of        opment of antimicrobial resistance or to             sponse, undrainable fo...
4. We recommend that when intravas-               or crystalloids. There is no evidence-        volume deficit in patients ...
sor in septic shock (grade 2C). Vaso-      septic shock, but with continued shock        G. Inotropic Therapy
    pressin ...
ficiency (defined as postadrenocortico-          cortisol (protein-bound and free) while      (110). It remains uncertain wh...
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
Guia 2008 Sepsis Severa Y Shock Septico
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Guia 2008 Sepsis Severa Y Shock Septico

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Guia 2008 Sepsis Severa Y Shock Septico

  1. 1. Special Article Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008 R. Phillip Dellinger, MD; Mitchell M. Levy, MD; Jean M. Carlet, MD; Julian Bion, MD; Margaret M. Parker, MD; Roman Jaeschke, MD; Konrad Reinhart, MD; Derek C. Angus, MD, MPH; Christian Brun-Buisson, MD; Richard Beale, MD; Thierry Calandra, MD, PhD; Jean-Francois Dhainaut, MD; Herwig Gerlach, MD; Maurene Harvey, RN; John J. Marini, MD; John Marshall, MD; Marco Ranieri, MD; Graham Ramsay, MD; Jonathan Sevransky, MD; B. Taylor Thompson, MD; Sean Townsend, MD; Jeffrey S. Vender, MD; Janice L. Zimmerman, MD; Jean-Louis Vincent, MD, PhD; for the International Surviving Sepsis Campaign Guidelines Committee Objective: To provide an update to the original Surviving Sepsis Campaign pressure is identified to be poorly responsive to fluid and vasopressor therapy clinical management guidelines, “Surviving Sepsis Campaign Guidelines for Man- (2C); recombinant activated protein C in patients with severe sepsis and clinical agement of Severe Sepsis and Septic Shock,” published in 2004. assessment of high risk for death (2B except 2C for postoperative patients). In the Design: Modified Delphi method with a consensus conference of 55 interna- absence of tissue hypoperfusion, coronary artery disease, or acute hemorrhage, tional experts, several subsequent meetings of subgroups and key individuals, target a hemoglobin of 7–9 g/dL (1B); a low tidal volume (1B) and limitation of teleconferences, and electronic-based discussion among subgroups and among inspiratory plateau pressure strategy (1C) for acute lung injury (ALI)/acute respi- the entire committee. This process was conducted independently of any industry ratory distress syndrome (ARDS); application of at least a minimal amount of funding. positive end-expiratory pressure in acute lung injury (1C); head of bed elevation in Methods: We used the Grades of Recommendation, Assessment, Development mechanically ventilated patients unless contraindicated (1B); avoiding routine use and Evaluation (GRADE) system to guide assessment of quality of evidence from of pulmonary artery catheters in ALI/ARDS (1A); to decrease days of mechanical high (A) to very low (D) and to determine the strength of recommendations. A ventilation and ICU length of stay, a conservative fluid strategy for patients with strong recommendation (1) indicates that an intervention’s desirable effects established ALI/ARDS who are not in shock (1C); protocols for weaning and clearly outweigh its undesirable effects (risk, burden, cost) or clearly do not. Weak sedation/analgesia (1B); using either intermittent bolus sedation or continuous recommendations (2) indicate that the tradeoff between desirable and undesirable infusion sedation with daily interruptions or lightening (1B); avoidance of neuro- effects is less clear. The grade of strong or weak is considered of greater clinical muscular blockers, if at all possible (1B); institution of glycemic control (1B), importance than a difference in letter level of quality of evidence. In areas without targeting a blood glucose <150 mg/dL after initial stabilization (2C); equivalency complete agreement, a formal process of resolution was developed and applied. of continuous veno-veno hemofiltration or intermittent hemodialysis (2B); prophy- Recommendations are grouped into those directly targeting severe sepsis, rec- laxis for deep vein thrombosis (1A); use of stress ulcer prophylaxis to prevent ommendations targeting general care of the critically ill patient that are consid- upper gastrointestinal bleeding using H2 blockers (1A) or proton pump inhibitors ered high priority in severe sepsis, and pediatric considerations. (1B); and consideration of limitation of support where appropriate (1D). Recom- Results: Key recommendations, listed by category, include early goal-directed mendations specific to pediatric severe sepsis include greater use of physical resuscitation of the septic patient during the first 6 hrs after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly examination therapeutic end points (2C); dopamine as the first drug of choice for to confirm potential source of infection (1C); administration of broad-spectrum hypotension (2C); steroids only in children with suspected or proven adrenal antibiotic therapy within 1 hr of diagnosis of septic shock (1B) and severe sepsis insufficiency (2C); and a recommendation against the use of recombinant acti- without septic shock (1D); reassessment of antibiotic therapy with microbiology vated protein C in children (1B). and clinical data to narrow coverage, when appropriate (1C); a usual 7–10 days Conclusions: There was strong agreement among a large cohort of interna- of antibiotic therapy guided by clinical response (1D); source control with atten- tional experts regarding many level 1 recommendations for the best current care tion to the balance of risks and benefits of the chosen method (1C); administration of patients with severe sepsis. Evidenced-based recommendations regarding the of either crystalloid or colloid fluid resuscitation (1B); fluid challenge to restore acute management of sepsis and septic shock are the first step toward improved mean circulating filling pressure (1C); reduction in rate of fluid administration with outcomes for this important group of critically ill patients. (Crit Care Med rising filing pressures and no improvement in tissue perfusion (1D); vasopressor 2008; 36:296–327) preference for norepinephrine or dopamine to maintain an initial target of mean KEY WORDS: sepsis; severe sepsis; septic shock; sepsis syndrome; infection; arterial pressure >65 mm Hg (1C); dobutamine inotropic therapy when cardiac Grades of Recommendation, Assessment, Development and Evaluation criteria; output remains low despite fluid resuscitation and combined inotropic/vasopres- GRADE; guidelines; evidence-based medicine; Surviving Sepsis Campaign; sepsis sor therapy (1C); stress-dose steroid therapy given only in septic shock after blood bundles From Cooper University Hospital, Camden, NJ (RPD); Italy (MR); West Hertfordshire Health Trust, Hemel Hemp- Infection Society,* World Federation of Societies of Intensive Rhode Island Hospital, Providence, RI (MML); Hospital Saint- stead, UK (GR); The Johns Hopkins University School of and Critical Care Medicine.** Participation and endorsement Joseph, Paris, France (JMC); Birmingham University, Bir- Medicine, Baltimore, MD (JS); Massachusetts General Hos- by the German Sepsis Society and the Latin American Sepsis mingham, UK (JB); SUNY at Stony Brook, Stony Brook, NY pital, Boston, MA (BTT); Rhode Island Hospital, Providence, RI Institute. *Sponsor of 2004 guidelines. **Sponsors of 2008 (MMP); McMaster University, Hamilton, Ontario, Canada (RJ); (ST); Evanston Northwestern Healthcare, Evanston, IL (JSV); guidelines who did not participate formally in revision pro- Friedrich-Schiller-University of Jena, Jena, Germany (KR); The Methodist Hospital, Houston, TX (JLZ); Erasme University cess. Members of the 2008 SSC Guidelines Committee are University of Pittsburgh, Pittsburgh, PA (DCA); Hopital Henri Hospital, Brussels, Belgium (JLV). listed in Appendix I. Appendix J provides author disclosure Sponsoring organizations: American Association of Crit- information. Mondor, Créteil, France (CBB); Guy’s and St Thomas’ Hos- ical-Care Nurses,* American College of Chest Physicians,* Also published in Intensive Care Medicine (January pital Trust, London, UK (RB); Centre Hospitalier Universitaire 2008). Vaudois, Lausanne, Switzerland (TC); French Agency for American College of Emergency Physicians,* Canadian Crit- ical Care Society, European Society of Clinical Microbiology For information regarding this article, E-mail: Evaluation of Research and Higher Education, Paris, France Dellinger-Phil@CooperHealth.edu and Infectious Diseases,* European Society of Intensive Care (JFD); Vivantes-Klinikum Neukoelin, Berlin, Germany (HG); Medicine,* European Respiratory Society,* International Sep- Copyright © 2007 by the Society of Critical Care Consultants in Critical Care, Inc, Glenbrook, NV (MH); Univer- sis Forum,* Japanese Association for Acute Medicine, Jap- Medicine sity of Minnesota, St. Paul, MN (JJM); St. Michael’s Hospital, anese Society of Intensive Care Medicine; Society of Critical Toronto, Ontario, Canada (JM); Università di Torino, Torino, Care Medicine,* Society of Hospital Medicine,** Surgical DOI: 10.1097/01.CCM.0000298158.12101.41 296 Crit Care Med 2008 Vol. 36, No. 1
  2. 2. S evere sepsis (acute organ dys- Table 1. Determination of the quality of evidence function secondary to infec- ● Underlying methodology tion) and septic shock (severe A. RCT sepsis plus hypotension not re- B. Downgraded RCT or upgraded observational studies versed with fluid resuscitation) are major C. Well-done observational studies healthcare problems, affecting millions of D. Case series or expert opinion individuals around the world each year, ● Factors that may decrease the strength of evidence 1. Poor quality of planning and implementation of available RCTs, suggesting high likelihood of killing one in four (and often more), and bias increasing in incidence (1–5). Similar to 2. Inconsistency of results (including problems with subgroup analyses) polytrauma, acute myocardial infarction, 3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison) or stroke, the speed and appropriateness 4. Imprecision of results 5. High likelihood of reporting bias of therapy administered in the initial ● Main factors that may increase the strength of evidence hours after severe sepsis develops are 1. Large magnitude of effect (direct evidence, RR 2 with no plausible confounders) likely to influence outcome. In 2004, an 2. Very large magnitude of effect with RR 5 and no threats to validity (by two levels) international group of experts in the di- 3. Dose-response gradient agnosis and management of infection and RCT, randomized controlled trial; RR, relative risk. sepsis, representing 11 organizations, published the first internationally ac- cepted guidelines that the bedside clini- Table 2. Factors determining strong vs. weak recommendation cian could use to improve outcomes in What Should Be Considered Recommended Process severe sepsis and septic shock (6, 7). These guidelines represented phase II of Quality of evidence The lower the quality of evidence, the less likely a strong the Surviving Sepsis Campaign (SSC), an recommendation international effort to increase awareness Relative importance of the If values and preferences vary widely, a strong and improve outcomes in severe sepsis. outcomes recommendation becomes less likely Baseline risks of outcomes The higher the risk, the greater the magnitude of benefit Joined by additional organizations, the Magnitude of relative risk, Larger relative risk reductions or larger increases in group met again in 2006 and 2007 to including benefits, harms, and relative risk of harm make a strong recommendation update the guidelines document using a burden more or less likely, respectively new evidence-based methodology system Absolute magnitude of the effect The larger the absolute benefits and harms, the greater or for assessing quality of evidence and lesser likelihood, respectively, of a strong strength of recommendations (8 –11). recommendation These recommendations are intended Precision of the estimates of the The greater the precision, the more likely a strong effects recommendation to provide guidance for the clinician car- Costs The higher the cost of treatment, the less likely a strong ing for a patient with severe sepsis or recommendation septic shock. Recommendations from these guidelines cannot replace the clini- cian’s decision-making capability when he or she is provided with a patient’s this dysfunction has varied somewhat from dated search into 2007 (see following meth- unique set of clinical variables. Most of one severe sepsis research study to another. ods and rules). these recommendations are appropriate An example of typical thresholds identifica- The 2001 guidelines were coordinated for the severe sepsis patient in both the tion of severe sepsis is shown in Table 2 by the International Sepsis Forum; the intensive care unit (ICU) and non-ICU (13). Sepsis-induced hypotension is defined 2004 guidelines were funded by unre- settings. In fact, the committee believes as a systolic blood pressure (SBP) 90 mm stricted educational grants from industry that currently, the greatest outcome im- Hg or mean arterial pressure 70 mm Hg and administered through the Society of provement can be made through educa- or a SBP decrease 40 mm Hg or 2 SD Critical Care Medicine (SCCM), the Eu- tion and process change for those caring below normal for age in the absence of ropean Society of Intensive Care Medi- for severe sepsis patients in the non-ICU other causes of hypotension. Septic shock cine (ESICM), and the International Sep- setting and across the spectrum of acute is defined as sepsis-induced hypotension sis Forum. Two of the SSC administering care. It should also be noted that re- persisting despite adequate fluid resuscita- organizations receive unrestricted indus- source limitations in some institutions tion. Sepsis-induced tissue hypoperfusion try funding to support SSC activities (ES- and countries may prevent physicians is defined as either septic shock, an elevated ICM and SCCM), but none of this funding from accomplishing particular recom- lactate, or oliguria. was used to support the 2006/2007 com- mendations. The current clinical practice guidelines mittee meetings. build on the first and second editions from It is important to distinguish between 2001 (discussed subsequently) and 2004 (6, the process of guidelines revision and the METHODS 7, 14). The 2001 publication incorporated a SSC. The SSC is partially funded by un- MEDLINE search for clinical trials in the restricted educational industry grants, Sepsis is defined as infection plus sys- preceding 10 yrs, supplemented by a man- including those from Edwards Life- temic manifestations of infection (Table ual search of other relevant journals (14). Sciences, Eli Lilly and Company, and 1) (12). Severe sepsis is defined as sepsis The 2004 publication incorporated the ev- Philips Medical Systems. SSC also re- plus sepsis-induced organ dysfunction or idence available through the end of 2003. ceived funding from the Coalition for tissue hypoperfusion. The threshold for The current publication is based on an up- Critical Care Excellence of the Society of Crit Care Med 2008 Vol. 36, No. 1 297
  3. 3. Critical Care Medicine. The great major- ic-related search or recent trials. Quality all discussions and deliberations among ity of industry funding has come from Eli of evidence was judged by predefined the guidelines committee members as to Lilly and Company. Grades of Recommendation, Assessment, grading decisions. Subsequently, the SSC Current industry funding for the SSC Development and Evaluation (GRADE) authors used written material prepared is directed to the performance improve- criteria (discussed subsequently). Signif- by the GRADE group and conferred with ment initiative. No industry funding was icant education of committee members GRADE group members who were avail- used in the guidelines revision process. on the GRADE approach was performed able at the first committee meeting and For both the 2004 and the 2006/2007 via e-mail before the first committee subsequent nominal group meetings. efforts, there were no members of the meeting and at the first meeting. Rules GRADE representatives were also used as committee from industry, no industry were distributed concerning assessing a resource throughout subgroup deliber- input into guidelines development, and the body of evidence, and GRADE experts ation. no industry presence at any of the were available for questions throughout The GRADE system is based on a se- meetings. Industry awareness or com- the process. Subgroups agreed electroni- quential assessment of the quality of ev- ment on the recommendations was not cally on draft proposals that were pre- idence, followed by assessment of the bal- allowed. No member of the guideline sented to committee meetings for general ance between benefits vs. risks, burden, committee received any honoraria for discussion. In January 2006, the entire and cost and, based on the preceding, de- any role in the 2004 or 2006/2007 group met during the 35th SCCM Critical velopment and grading of a management guidelines process. The committee con- Care Congress in San Francisco, Califor- recommendations (9 –11). Keeping the rat- sidered the issue of recusement of indi- nia. The results of that discussion were ing of quality of evidence and strength of vidual committee members during de- incorporated into the next version of rec- recommendation explicitly separate consti- liberation and decision making in areas ommendations and again discussed using tutes a crucial and defining feature of the where committee members had either electronic mail. Recommendations were GRADE approach. This system classifies financial or academic competing inter- finalized during nominal group meetings quality of evidence as high (grade A), mod- ests; however, consensus as to thresh- (composed of a subset of the committee erate (grade B), low (grade C), or very low old for exclusion could not be reached. members) at the 2007 SCCM (Orlando, (grade D). Randomized trials begin as high- Alternatively, the committee agreed to FL) and 2007 International Symposium quality evidence but may be downgraded ensure full disclosure and transparency on Intensive Care and Emergency Medi- due to limitations in implementation, in- of all committee members’ potential cine (Brussels) meetings with recircula- consistency or imprecision of the results, conflicts at time of publication. (See tion of deliberations and decisions to the indirectness of the evidence, and possible disclosures at the end of this docu- entire group for comment or approval. At reporting bias (Table 1). Examples of indi- ment.) the discretion of the chair and following rectness of the evidence include population The guidelines process included a adequate discussion, competing propos- studied, interventions used, outcomes mea- modified Delphi method, a consensus als for wording of recommendations or sured, and how these relate to the question conference, several subsequent meetings assigning strength of evidence were re- of interest. Observational (nonrandomized) of subgroups and key individuals, tele- solved by formal voting. On occasions, studies begin as low-quality evidence, but conferences and electronic-based discus- voting was performed to give the com- the quality level may be upgraded on the sions among subgroups and members of mittee a sense of distribution of opinions basis of large magnitude of effect. An exam- the entire committee, and two follow-up to facilitate additional discussion. The ple of this is the quality of evidence for early nominal group meetings in 2007. manuscript was edited for style and form administration of antibiotics. Subgroups were formed, each charged by the writing committee with final ap- The GRADE system classifies recom- with updating recommendations in spe- proval by section leads for their respec- mendations as strong (grade 1) or weak cific areas, including corticosteroids, tive group assignment and then by the (grade 2). The grade of strong or weak is blood products, activated protein C, renal entire committee. considered of greater clinical importance replacement therapy, antibiotics, source The development of guidelines and than a difference in letter level of quality control, and glucose control. Each sub- grading of recommendations for the 2004 of evidence. The committee assessed group was responsible for updating the guideline development process were whether the desirable effects of adher- evidence (into 2007, with major addi- based on a system proposed by Sackett ence will outweigh the undesirable ef- tional elements of information incorpo- (15) in 1989, during one of the first fects, and the strength of a recommenda- rated into the evolving manuscript American College of Chest Physicians tion reflects the group’s degree of throughout 2006 and 2007). A separate (ACCP) conferences on the use of anti- confidence in that assessment. A strong search was performed for each clearly de- thrombotic therapies. The revised guide- recommendation in favor of an interven- fined question. The committee chair lines recommendations are based on the tion reflects that the desirable effects of worked with subgroup heads to identify GRADE system, a structured system for adherence to a recommendation (benefi- pertinent search terms that always in- rating quality of evidence and grading cial health outcomes, less burden on staff cluded, at a minimum, sepsis, severe sep- strength of recommendation in clinical and patients, and cost savings) will sis, septic shock, and sepsis syndrome practice (8 –11). The SSC Steering Com- clearly outweigh the undesirable effects crossed against the general topic area of mittee and individual authors collabo- (harms, more burden, and greater costs). the subgroup as well as pertinent key rated with GRADE representatives to ap- A weak recommendation in favor of an words of the specific question posed. All ply the GRADE system to the SSC intervention indicates that the desirable questions of the previous guidelines pub- guidelines revision process. The mem- effects of adherence to a recommendation lications were searched, as were pertinent bers of GRADE group were directly in- probably will outweigh the undesirable new questions generated by general top- volved, either in person or via e-mail, in effects, but the panel is not confident 298 Crit Care Med 2008 Vol. 36, No. 1
  4. 4. about these tradeoffs— either because Table 3. Initial resuscitation and infection issues some of the evidence is low quality (and Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, thus there remains uncertainty regarding presented in parentheses after each guideline the benefits and risks) or the benefits and ● Indicates a strong recommendation, or “we recommend” downsides are closely balanced. While the Indicates a weak recommendation, or “we suggest” degree of confidence is a continuum and Initial resuscitation (first 6 hrs) there is no precise threshold between a ● Begin resuscitation immediately in patients with hypotension or elevated serum lactate 4 strong and a weak recommendation, the mmol/L; do not delay pending ICU admission (1C) ● Resuscitation goals (1C) presence of important concerns about CVP 8–12 mm Hga one or more of the preceding factors Mean arterial pressure 65 mm Hg makes a weak recommendation more Urine output 0.5 mL kg 1 hr 1 likely. A strong recommendation is Central venous (superior vena cava) oxygen saturation 70% or mixed venous 65% If venous oxygen saturation target is not achieved (2C) worded as “we recommend” and a weak Consider further fluid recommendation as “we suggest.” Transfuse packed red blood cells if required to hematocrit of 30% and/or The implications of calling a recom- Start dobutamine infusion, maximum 20 g kg 1 min 1 mendation strong are that most well- Diagnosis informed patients would accept that inter- ● Obtain appropriate cultures before starting antibiotics provided this does not significantly delay antimicrobial administration (1C) vention and that most clinicians should use Obtain two or more BCs it in most situations. There may be circum- One or more BCs should be percutaneous stances in which a strong recommendation One BC from each vascular access device in place 48 hrs cannot or should not be followed for an Culture other sites as clinically indicated individual patient because of that patient’s ● Perform imaging studies promptly to confirm and sample any source of infection, if safe to do so (1C) Antibiotic therapy preferences or clinical characteristics that ● Begin intravenous antibiotics as early as possible and always within the first hour of make the recommendation less applicable. recognizing severe sepsis (1D) and septic shock (1B) Being a strong recommendation does not ● Broad-spectrum: one or more agents active against likely bacterial/fungal pathogens and with automatically imply standard of care. For good penetration into presumed source (1B) example, the strong recommendation for ● Reassess antimicrobial regimen daily to optimize efficacy, prevent resistance, avoid toxicity, administering antibiotics within 1 hr of the and minimize costs (1C) Consider combination therapy in Pseudomonas infections (2D) diagnosis of severe sepsis, although desir- Consider combination empiric therapy in neutropenic patients (2D) able, is not currently standard of care as Combination therapy 3–5 days and de-escalation following susceptibilities (2D) verified by current practice (M Levy, per- ● Duration of therapy typically limited to 7–10 days; longer if response is slow or there are sonal communication, from first 8,000 pa- undrainable foci of infection or immunologic deficiencies (1D) tients entered internationally into the SSC ● Stop antimicrobial therapy if cause is found to be noninfectious (1D) Source identification and control performance improvement database). The ● A specific anatomic site of infection should be established as rapidly as possible (1C) and implication of a weak recommendation is within first 6 hrs of presentation (1D) that although a majority of well-informed ● Formally evaluate patient for a focus of infection amenable to source control measures (e.g. patients would accept it (but a substantial abscess drainage, tissue debridement) (1C) proportion would not), clinicians should ● Implement source control measures as soon as possible following successful initial consider its use according to particular cir- resuscitation (1C) (exception: infected pancreatic necrosis, where surgical intervention is best delayed) (2B) cumstance. ● Choose source control measure with maximum efficacy and minimal physiologic upset (1D) Differences of opinion among commit- ● Remove intravascular access devices if potentially infected (1C) tee members about interpretation of evi- dence, wording of proposals, or strength of GRADE, Grades of Recommendation, Assessment, Development and Evaluation; ICU, intensive recommendations were resolved using a care unit; CVP, central venous pressure; BC, blood culture. a specifically developed set of rules. We will A higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical ventilation describe this process in detail in a separate or preexisting decreased ventricular compliance. publication. In summary, the main ap- proach for converting diverse opinions into a recommendation was as follows: 1) to breadth of review. The entire review group tense focused discussion (nominal group) give a recommendation a direction (for or (together with their parent organizations with broader review and monitoring using against the given action), a majority of as required) participated in the larger, iter- the Delphi process. votes were to be in favor of that direction, ative, modified Delphi process. The smaller Note: Refer to Tables 3–5 for con- with 20% preferring the opposite direc- working group meetings, which took place densed adult recommendations. tion (there was a neutral vote allowed as in person, functioned as the nominal well); 2) to call a given recommendation groups. If a clear consensus could not be strong rather than weak, 70% “strong” obtained by polling within the nominal I. MANAGEMENT OF SEVERE votes were required; 3) if 70% of votes group meetings, the larger group was spe- SEPSIS indicated “strong” preference, the recom- cifically asked to use the polling process. mendation was assigned a weak category of This was only required for corticosteroids A. Initial Resuscitation strength. We used a combination of modi- and glycemic control. The larger group had fied Delphi process and nominal (expert) the opportunity to review all outputs. In 1. We recommend the protocolized re- group techniques to ensure both depth and this way the entire review combined in- suscitation of a patient with sepsis- Crit Care Med 2008 Vol. 36, No. 1 299
  5. 5. Table 4. Hemodynamic support and adjunctive therapy gets to be equivalent. Either intermittent or continuous measurements of oxygen Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, saturation were judged to be acceptable. presented in parentheses after each guideline. ● Indicates a strong recommendation, or “we recommend” Although blood lactate concentration Indicates a weak recommendation, or “we suggest” may lack precision as a measure of tissue Fluid therapy metabolic status, elevated levels in sepsis ● Fluid-resuscitate using crystalloids or colloids (1B) support aggressive resuscitation. In me- ● Target a CVP of 8 mm Hg ( 12 mm Hg if mechanically ventilated) (1C) ● Use a fluid challenge technique while associated with a hemodynamic improvement (1D) chanically ventilated patients or patients ● Give fluid challenges of 1000 mL of crystalloids or 300–500 mL of colloids over 30 mins. More with known preexisting decreased ven- rapid and larger volumes may be required in sepsis-induced tissue hypoperfusion (1D) tricular compliance, a higher target cen- ● Rate of fluid administration should be reduced if cardiac filling pressures increase without tral venous pressure of 12–15 mm Hg is concurrent hemodynamic improvement (1D) recommended to account for the imped- Vasopressors ● Maintain MAP 65 mm Hg (1C) iment to filling (17). Similar consider- ● Norepinephrine and dopamine centrally administered are the initial vasopressors of choice (1C) ation may be warranted in circumstances Epinephrine, phenylephrine, or vasopressin should not be administered as the initial of increased abdominal pressure or dia- vasopressor in septic shock (2C). Vasopressin 0.03 units/min may be subsequently added to stolic dysfunction (18). Elevated central norepinephrine with anticipation of an effect equivalent to norepinephrine alone venous pressures may also be seen with Use epinephrine as the first alternative agent in septic shock when blood pressure is poorly preexisting clinically significant pulmo- responsive to norepinephrine or dopamine (2B). ● Do not use low-dose dopamine for renal protection (1A) nary artery hypertension. Although the ● In patients requiring vasopressors, insert an arterial catheter as soon as practical (1D) cause of tachycardia in septic patients Inotropic therapy may be multifactorial, a decrease in ele- ● Use dobutamine in patients with myocardial dysfunction as supported by elevated cardiac vated pulse rate with fluid resuscitation is filling pressures and low cardiac output (1C) often a useful marker of improving intra- ● Do not increase cardiac index to predetermined supranormal levels (1B) Steroids vascular filling. Recently published ob- Consider intravenous hydrocortisone for adult septic shock when hypotension responds poorly servational studies have demonstrated an to adequate fluid resuscitation and vasopressors (2C) association between good clinical out- ACTH stimulation test is not recommended to identify the subset of adults with septic shock come in septic shock and MAP 65 mm who should receive hydrocortisone (2B) Hg as well as central venous oxygen sat- Hydrocortisone is preferred to dexamethasone (2B) Fludrocortisone (50 g orally once a day) may be included if an alternative to hydrocortisone uration (ScvO2, measured in superior is being used that lacks significant mineralocorticoid activity. Fludrocortisone if optional if vena cava, either intermittently or con- hydrocortisone is used (2C) tinuously) of 70% (19). Many recent Steroid therapy may be weaned once vasopressors are no longer required (2D) studies support the value of early proto- ● Hydrocortisone dose should be 300 mg/day (1A) colized resuscitation in severe sepsis and ● Do not use corticosteroids to treat sepsis in the absence of shock unless the patient’s sepsis-induced tissue hypoperfusion (20 – endocrine or corticosteroid history warrants it (1D) Recombinant human activated protein C 25). Studies of patients with shock indi- Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical cate that mixed venous oxygen saturation assessment of high risk of death (typically APACHE II 25 or multiple organ failure) if there ¯ (SVO2) runs 5–7% lower than central ve- are no contraindications (2B, 2C for postoperative patients). nous oxygen saturation (ScvO2) (26) and ● Adult patients with severe sepsis and low risk of death (typically, APACHE II 20 or one that an early goal-directed resuscitation organ failure) should not receive rhAPC (1A) protocol can be established in a nonre- GRADE, Grades of Recommendation, Assessment, Development and Evaluation; CVP, central search general practice venue (27). venous pressure; MAP, mean arterial pressure; ACTH, adrenocorticotropic hormone; rhAPC, recom- There are recognized limitations to binant human activated protein C; APACHE, Acute Physiology and Chronic Health Evaluation. ventricular filling pressure estimates as surrogates for fluid resuscitation (28, 29). However, measurement of central venous induced shock, defined as tissue hypo- Urine output 0.5 mL·kg 1·hr 1 pressure is currently the most readily ob- perfusion (hypotension persisting Central venous (superior vena tainable target for fluid resuscitation. after initial fluid challenge or blood cava) or mixed venous oxygen sat- There may be advantages to targeting lactate concentration 4 mmol/L). uration 70% or 65%, respec- fluid resuscitation to flow and perhaps to This protocol should be initiated as tively (grade 1C) volumetric indices (and even to microcir- soon as hypoperfusion is recognized Rationale. Early goal-directed resusci- culation changes) (30 –33). Technologies and should not be delayed pending tation has been shown to improve sur- currently exist that allow measurement ICU admission. During the first 6 hrs vival for emergency department patients of flow at the bedside (34, 35). Future of resuscitation, the goals of initial presenting with septic shock in a ran- goals should be making these technolo- resuscitation of sepsis-induced hypo- perfusion should include all of the fol- domized, controlled, single-center study gies more accessible during the critical lowing as one part of a treatment pro- (16). Resuscitation directed toward the early resuscitation period and research to tocol: previously mentioned goals for the initial validate utility. These technologies are Central venous pressure 8 –12 mm 6-hr period of the resuscitation was able already available for early ICU resuscita- Hg to reduce 28-day mortality rate. The con- tion. Mean arterial pressure (MAP) 65 sensus panel judged use of central venous 2. We suggest that during the first 6 hrs mm Hg and mixed venous oxygen saturation tar- of resuscitation of severe sepsis or sep- 300 Crit Care Med 2008 Vol. 36, No. 1
  6. 6. 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 7.0–9.0 g/dL in adults (1B). A higher hemoglobin level may be required in special circumstances (e.g., myocardial ischaemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis) Do not use erythropoietin to treat sepsis-related anemia. Erythropoietin may be used for other accepted reasons (1B) Do not use fresh frozen plasma to correct laboratory clotting abnormalities unless there is bleeding or planned invasive procedures (2D) ● Do not use antithrombin therapy (1B) Administer platelets when (2D) Counts are 5000/mm3 (5 109/L) regardless of bleeding Counts are 5000–30,000/mm3 (5–30 109/L) and there is significant bleeding risk Higher platelet counts ( 50,000/mm3 [50 109/L]) are required for surgery or invasive procedures Mechanical ventilation of sepsis-induced 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 FIO2 or plateau pressure, provided they are not put at risk from positional changes (2C) ● Maintain mechanically ventilated patients in a semirecumbent position (head of the bed raised to 45°) unless contraindicated (1B), between 30° and 45° (2C) Noninvasive ventilation may be considered in the minority of ALI/ARDS patients with mild to moderate hypoxemic respiratory failure. The patients need to be hemodynamically stable, comfortable, easily arousable, able to protect/clear their airway, and expected to recover rapidly (2B) ● Use a weaning protocol and an SBT regularly to evaluate the potential for discontinuing mechanical ventilation (1A) ● SBT options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T piece ● Before the SBT, patients should be arousable be hemodynamically stable without vasopressors have no new potentially serious conditions have low ventilatory and end-expiratory pressure requirement require FIO2 levels that can be safely delivered with a face mask or nasal cannula ● Do not use a pulmonary artery catheter for the routine monitoring of patients with ALI/ARDS (1A) ● Use a conservative fluid strategy for patients with established ALI who do not have evidence of tissue hypoperfusion (1C) Sedation, analgesia, and neuromuscular blockade in sepsis ● Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients (1B) ● Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily interruption/lightening to produce awakening. Re-titrate if necessary (1B) ● Avoid neuromuscular blockers where possible. Monitor depth of block with train-of-four when using continuous infusions (1B) Glucose control ● Use intravenous insulin to control hyperglycemia in patients with severe sepsis following stabilization in the ICU (1B) ● Aim to keep blood glucose 150 mg/dL (8.3 mmol/L) using a validated protocol for insulin dose adjustment (2C) ● Provide a glucose calorie source and monitor blood glucose values every 1–2 hrs (4 hrs when stable) in patients receiving intravenous insulin (1C) ● Interpret with caution low glucose levels obtained with point of care testing, as these techniques may overestimate arterial blood or plasma glucose values (1B) Renal replacement Intermittent hemodialysis and 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. ¯ tic shock, if ScvO2 or SVO2 of 70% or hematocrit of 30% and/or adminis- Rationale. The protocol used in the 65%, respectively, is not achieved with tration of a dobutamine infusion (up study cited previously targeted an increase fluid resuscitation to the central ve- to a maximum of 20 g·kg 1·min 1) in ScvO2 to 70% (16). This was achieved nous pressure target, then transfusion be used to achieve this goal (grade by sequential institution of initial fluid re- of packed red blood cells to achieve a 2C). suscitation, packed red blood cells, and Crit Care Med 2008 Vol. 36, No. 1 301
  7. 7. then dobutamine. This protocol was asso- cular access device. Obtaining blood Balancing risk and benefit is therefore ciated with an improvement in survival. cultures peripherally and through a mandatory in those settings. Based on bedside clinical assessment and vascular access device is an important personal preference, a clinician may deem strategy. If the same organism is recov- C. Antibiotic Therapy either blood transfusion (if hematocrit is ered from both cultures, the likelihood 30%) or dobutamine the best initial that the organism is causing the severe 1. We recommend that intravenous an- choice to increase oxygen delivery and sepsis is enhanced. In addition, if the tibiotic therapy be started as early as thereby elevate ScvO2, when fluid resusci- culture drawn through the vascular ac- possible and within the first hour of tation is believed to be already adequate. cess device is positive much earlier than recognition of septic shock (1B) and The design of the aforementioned trial did the peripheral blood culture (i.e., 2 hrs severe sepsis without septic shock not allow assessment of the relative contri- earlier), the data support the concept that (1D). Appropriate cultures should be bution of these two components (i.e., in- the vascular access device is the source of obtained before initiating antibiotic creasing oxygen content or increasing car- the infection (37). Quantitative cultures therapy but should not prevent diac output) of the protocol on of catheter and peripheral blood are also prompt administration of antimicro- achievement of improved outcome. useful for determining whether the cath- bial therapy (grade 1D). eter is the source of infection. Volume of Rationale. Establishing vascular ac- B. Diagnosis blood drawn with the culture tube should cess and initiating aggressive fluid resus- 1. We recommend obtaining appropri- be 10 mL (38). Quantitative (or semi- citation are the first priority when man- ate cultures before antimicrobial quantitative) cultures of respiratory tract aging patients with severe sepsis or septic therapy is initiated if such cultures secretions are recommended for the di- shock. However, prompt infusion of anti- do not cause significant delay in an- agnosis of ventilator-associated pneumo- microbial agents should also be a priority tibiotic administration. To optimize nia (39). Gram-negative stain can be use- and may require additional vascular ac- identification of causative organisms, ful, in particular for respiratory tract cess ports (42, 43). In the presence of we recommend at least two blood specimens, to help decide the micro- septic shock, each hour delay in achiev- cultures be obtained before antibiot- organisms to be targeted. The potential ing administration of effective antibiotics ics with at least one drawn percuta- role of biomarkers for diagnosis of in- is associated with a measurable increase neously and one drawn through each fection in patients presenting with se- in mortality (42). If antimicrobial agents vascular access device, unless the de- vere sepsis remains undefined. The pro- cannot be mixed and delivered promptly vice was recently ( 48 hrs) inserted. calcitonin level, although often useful, from the pharmacy, establishing a supply Cultures of other sites (preferably is problematic in patients with an acute of premixed antibiotics for such urgent quantitative where appropriate), such inflammatory pattern from other situations is an appropriate strategy for as urine, cerebrospinal fluid, wounds, causes (e.g., postoperative, shock) (40). ensuring prompt administration. In respiratory secretions, or other body In the near future, rapid diagnostic choosing the antimicrobial regimen, cli- fluids that may be the source of in- nicians should be aware that some anti- methods (polymerase chain reaction, fection should also be obtained be- microbial agents have the advantage of micro-arrays) might prove extremely fore antibiotic therapy if not associ- bolus administration, while others re- helpful for a quicker identification of ated with significant delay in quire a lengthy infusion. Thus, if vascular pathogens and major antimicrobial re- antibiotic administration (grade 1C). access is limited and many different sistance determinants (41). agents must be infused, bolus drugs may Rationale. Although sampling should 2. We recommend that imaging studies offer an advantage. not delay timely administration of antibi- be performed promptly in attempts otics in patients with severe sepsis (e.g., 2a. We recommend that initial empirical to confirm a potential source of in- anti-infective therapy include one or lumbar puncture in suspected meningi- fection. Sampling of potential tis), obtaining appropriate cultures be- more drugs that have activity against sources of infection should occur as all likely pathogens (bacterial and/or fore administration of antibiotics is es- they are identified; however, some sential to confirm infection and the fungal) and that penetrate in ade- patients may be too unstable to war- quate concentrations into the pre- responsible pathogens and to allow de- rant certain invasive procedures or escalation of antibiotic therapy after re- sumed source of sepsis (grade 1B). transport outside of the ICU. Bedside ceipt of the susceptibility profile. Samples studies, such as ultrasound, are use- Rationale. The choice of empirical an- can be refrigerated or frozen if processing ful in these circumstances (grade tibiotics depends on complex issues re- cannot be performed immediately. Im- 1C). lated to the patient’s history, including mediate transport to a microbiological drug intolerances, underlying disease, lab is necessary. Because rapid steriliza- Rationale. Diagnostic studies may the clinical syndrome, and susceptibility tion of blood cultures can occur within a identify a source of infection that re- patterns of pathogens in the community, few hours after the first antibiotic dose, quires removal of a foreign body or drain- in the hospital, and that previously have obtaining those cultures before starting age to maximize the likelihood of a sat- been documented to colonize or infect therapy is essential if the causative organ- isfactory response to therapy. However, the patient. There is an especially wide ism is to be identified. Two or more blood even in the most organized and well- range of potential pathogens for neutro- cultures are recommended (36). In pa- staffed healthcare facilities, transport of penic patients. tients with indwelling catheters (for 48 patients can be dangerous, as can placing Recently used antibiotics should gener- hrs), at least one blood culture should be patients in outside-unit imaging devices ally be avoided. When choosing empirical drawn through each lumen of each vas- that are difficult to access and monitor. therapy, clinicians should be cognizant of 302 Crit Care Med 2008 Vol. 36, No. 1
  8. 8. the virulence and growing prevalence of opment of antimicrobial resistance or to sponse, undrainable foci of infection, oxacillin (methicillin)-resistant Staphylo- reduce cost is not an appropriate initial or immunologic deficiencies, includ- coccus aureus (ORSA or MRSA) in some strategy in this patient population, once ing neutropenia (grade 1D). communities and healthcare settings (espe- the causative pathogen has been identi- 4. We recommend that if the presenting cially in the United States). If the preva- fied, it may become apparent that none of clinical syndrome is determined to be lence is significant, and in consideration of the empirical drugs offers optimal ther- due to a noninfectious cause, antimi- the virulence of this organism, empirical apy; that is, there may be another drug crobial therapy be stopped promptly therapy adequate for this pathogen would proven to produce superior clinical out- to minimize the likelihood that the be warranted. Clinicians should also con- come that should therefore replace em- patient will become infected with an sider whether candidemia is a likely patho- pirical agents. antibiotic-resistant pathogen or will gen when choosing initial therapy. When Narrowing the spectrum of antibiotic develop a drug-related adverse effect deemed warranted, the selection of empir- coverage and reducing the duration of (grade 1D). ical antifungal therapy (e.g., fluconazole, antibiotic therapy will reduce the likelihood Rationale. Clinicians should be cogni- amphotericin B, or echinocandin) will be that the patient will develop superinfection zant that blood cultures will be negative tailored to the local pattern of the most with pathogenic or resistant organisms, in 50% of cases of severe sepsis or sep- prevalent Candida species and any prior such as Candida species, Clostridium diffi- tic shock, yet many of these cases are very administration of azoles drugs (44). Risk cile, or vancomycin-resistant Enterococcus likely caused by bacteria or fungi. Thus, factors for candidemia should also be con- faecium. However, the desire to minimize the decisions to continue, narrow, or stop sidered when choosing initial therapy. superinfections and other complications antimicrobial therapy must be made on Because patients with severe sepsis or should not take precedence over the need the basis of clinician judgment and clin- septic shock have little margin for error to give the patient an adequate course of ical information. in the choice of therapy, the initial selec- therapy to cure the infection that caused tion of antimicrobial therapy should be the severe sepsis or septic shock. broad enough to cover all likely patho- D. Source Control gens. There is ample evidence that failure 2c. We suggest combination therapy for to initiate appropriate therapy (i.e., ther- patients with known or suspected 1a. We recommend that a specific ana- apy with activity against the pathogen Pseudomonas infections as a cause of tomical diagnosis of infection requir- that is subsequently identified as the severe sepsis (grade 2D). ing consideration for emergent causative agent) correlates with increased 2d. We suggest combination empirical source control (e.g., necrotizing fas- morbidity and mortality (45– 48). therapy for neutropenic patients with ciitis, diffuse peritonitis, cholangitis, Patients with severe sepsis or septic severe sepsis (grade 2D). intestinal infarction) be sought and shock warrant broad-spectrum therapy 2e. When used empirically in patients diagnosed or excluded as rapidly as until the causative organism and its an- with severe sepsis, we suggest that possible (grade 1C) and within the tibiotic susceptibilities are defined. Re- combination therapy should not be first 6 hrs following presentation striction of antibiotics as a strategy to administered for 3–5 days. De- (grade 1D). reduce the development of antimicrobial escalation to the most appropriate 1b. We further recommend that all pa- resistance or to reduce cost is not an single therapy should be performed tients presenting with severe sepsis appropriate initial strategy in this patient as soon as the susceptibility profile is be evaluated for the presence of a population. known (grade 2D). focus on infection amenable to All patients should receive a full load- Rationale. Although no study or meta- source control measures, specifically ing dose of each antimicrobial. However, analysis has convincingly demonstrated the drainage of an abscess or local patients with sepsis or septic shock often that combination therapy produces a supe- focus on infection, the debridement have abnormal renal or hepatic function rior clinical outcome for individual patho- of infected necrotic tissue, the re- and may have abnormal volumes of dis- gens in a particular patient group, combi- moval of a potentially infected device, tribution due to aggressive fluid resusci- nation therapies do produce in vitro or the definitive control of a source tation. Drug serum concentration moni- synergy against pathogens in some models of ongoing microbial contamination toring can be useful in an ICU setting for (grade 1C). (Appendix A provides ex- (although such synergy is difficult to define those drugs that can be measured amples of potential sites needing and predict). In some clinical scenarios, promptly. An experienced physician or source control.) such as the two preceding, combination clinical pharmacist should be consulted 2. We suggest that when infected therapies are biologically plausible and are to ensure that serum concentrations are peripancreatic necrosis is identified as likely clinically useful even if evidence has attained that maximize efficacy and min- a potential source of infection, defini- not demonstrated improved clinical out- imize toxicity (49 –52). tive intervention is best delayed until come (53–56). Combination therapy for adequate demarcation of viable and 2b. We recommend that the antimicro- suspected known Pseudomonas pending nonviable tissues has occurred (grade bial regimen be reassessed daily to sensitivities increases the likelihood that at 2B). optimize activity, to prevent the de- least one drug is effective against that 3. We recommend that when source con- velopment of resistance, to reduce strain and positively affects outcome (57). trol is required, the effective intervention toxicity, and to reduce costs (grade 3. We recommend that the duration of associated with the least physiologic in- 1C). therapy typically be 7–10 days; longer sult be employed (e.g., percutaneous Rationale. Although restriction of an- courses may be appropriate in pa- rather than surgical drainage of an tibiotics as a strategy to reduce the devel- tients who have a slow clinical re- abscess (grade 1D). Crit Care Med 2008 Vol. 36, No. 1 303
  9. 9. 4. We recommend that when intravas- or crystalloids. There is no evidence- volume deficit in patients with severe sepsis cular access devices are a possible based support for one type of fluid varies. With venodilation and ongoing cap- source of severe sepsis or septic over another (grade 1B). illary leak, most patients require continu- shock, they be promptly removed af- Rationale. The SAFE study indicated ing aggressive fluid resuscitation during ter other vascular access has been that albumin administration was safe and the first 24 hrs of management. Input is established (grade 1C). typically much greater than output, and equally as effective as crystalloid (65). There Rationale. The principals of source input/output ratio is of no utility to judge was an insignificant decrease in mortality control in the management of sepsis in- fluid resuscitation needs during this time rates with the use of colloid in a subset clude a rapid diagnosis of the specific site period. analysis of septic patients (p .09). Previ- of infection and identification of a focus ous meta-analyses of small studies of ICU on infection amenable to source control patients had demonstrated no difference F. Vasopressors measures (specifically the drainage of an between crystalloid and colloid fluid resus- abscess, debridement of infected necrotic citation (66 – 68). Although administration 1. We recommend that mean arterial tissue, removal of a potentially infected of hydroxyethyl starch may increase the pressure (MAP) be maintained 65 device, and definitive control of a source risk of acute renal failure in patients with mm Hg (grade 1C). of ongoing microbial contamination) sepsis, variable findings preclude definitive Rationale. Vasopressor therapy is re- (58). Foci of infection readily amenable to recommendations (69, 70). As the volume quired to sustain life and maintain perfu- source control measures include an in- of distribution is much larger for crystal- sion in the face of life-threatening hypo- tra-abdominal abscess or gastrointestinal loids than for colloids, resuscitation with tension, even when hypovolemia has not perforation, cholangitis or pyelonephri- crystalloids requires more fluid to achieve yet been resolved. Below a certain mean tis, intestinal ischemia or necrotizing soft the same end points and results in more arterial pressure, autoregulation in vari- tissue infection, and other deep space in- edema. Crystalloids are less expensive. ous vascular beds can be lost, and perfu- fection, such as an empyema or septic sion can become linearly dependent on arthritis. Such infectious foci should be 2. We recommend that fluid resuscita- pressure. Thus, some patients may re- controlled as soon as possible following tion initially target a central venous quire vasopressor therapy to achieve a successful initial resuscitation (59), ac- pressure of 8 mm Hg (12 mm Hg in minimal perfusion pressure and maintain complishing the source control objective mechanically ventilated patients). adequate flow (71, 72). The titration of with the least physiologic upset possible Further fluid therapy is often re- norepinephrine to as low as MAP 65 mm (e.g., percutaneous rather than surgical quired (grade 1C). Hg has been shown to preserve tissue drainage of an abscess [60], endoscopic 3a. We recommend that a fluid challenge perfusion (72). In addition, preexisting rather than surgical drainage of biliary technique be applied wherein fluid comorbidities should be considered as to tree), and removing intravascular access administration is continued as long most appropriate MAP target. For exam- devices that are potentially the source of as the hemodynamic improvement ple, a MAP of 65 mm Hg might be too low severe sepsis or septic shock promptly (e.g., arterial pressure, heart rate, in a patient with severe uncontrolled hy- after establishing other vascular access urine output) continues (grade 1D). pertension, and in a young previously (61, 62). A randomized, controlled trial 3b. We recommend that fluid challenge normotensive, a lower MAP might be comparing early vs. delayed surgical in- in patients with suspected hypovole- adequate. Supplementing end points, tervention for peripancreatic necrosis mia be started with 1000 mL of such as blood pressure, with assess- showed better outcomes with a delayed crystalloids or 300 –500 mL of col- ment of regional and global perfusion, approach (63). However, areas of uncer- loids over 30 mins. More rapid ad- such as blood lactate concentrations tainty exist, such as definitive docu- ministration and greater amounts of and urine output, is important. Ade- mentation of infection and appropriate fluid may be needed in patients with quate fluid resuscitation is a fundamen- length of delay. The selection of optimal sepsis-induced tissue hypoperfusion tal aspect of the hemodynamic manage- source control methods must weigh (see Initial Resuscitation recommen- ment of patients with septic shock and benefits and risks of the specific inter- dations) (grade 1D). should ideally be achieved before vaso- vention as well as risks of transfer (64). 3c. We recommend that the rate of fluid pressors and inotropes are used, but Source control interventions may cause administration be reduced substan- using vasopressors early as an emer- further complications, such as bleed- tially when cardiac filling pressures gency measure in patients with severe ing, fistulas, or inadvertent organ in- (central venous pressure or pulmo- shock is frequently necessary. When jury. Surgical intervention should be nary artery balloon-occluded pres- that occurs, great effort should be di- considered when lesser interventional sure) increase without concurrent rected to weaning vasopressors with approaches are inadequate or when di- hemodynamic improvement (grade continuing fluid resuscitation. agnostic uncertainty persists despite ra- 1D). diologic evaluation. Specific clinical sit- 2. We recommend either norepineph- Rationale. Fluid challenge must be rine or dopamine as the first choice uations require consideration of clearly separated from simple fluid ad- vasopressor agent to correct hypo- available choices, patient’s preferences, ministration; it is a technique in which tension in septic shock (administered and clinician’s expertise. large amounts of fluids are administered through a central catheter as soon as over a limited period of time under close one is available) (grade 1C). E. Fluid Therapy monitoring to evaluate the patient’s re- 3a. We suggest that epinephrine, phenyl- 1. We recommend fluid resuscitation sponse and avoid the development of pul- ephrine, or vasopressin should not be with either natural/artificial colloids monary edema. The degree of intravascular administered as the initial vasopres- 304 Crit Care Med 2008 Vol. 36, No. 1
  10. 10. sor in septic shock (grade 2C). Vaso- septic shock, but with continued shock G. Inotropic Therapy pressin 0.03 units/min may be added the concentration decreases to normal to norepinephrine subsequently with range in the majority of patients between 1. We recommend that a dobutamine in- anticipation of an effect equivalent to 24 and 48 hrs (95). This has been called fusion be administered in the presence that of norepinephrine alone. relative vasopressin deficiency because in of myocardial dysfunction as sug- 3b. We suggest that epinephrine be the the presence of hypotension, vasopressin gested by elevated cardiac filling pres- first chosen alternative agent in sep- would be expected to be elevated. The sures and low cardiac output (grade tic shock that is poorly responsive to significance of this finding is unknown. 1C). norepinephrine or dopamine (grade The recent VASST trial, a randomized, 2. We recommend against the use of a 2B). controlled trial comparing norepineph- strategy to increase cardiac index to rine alone to norepinephrine plus vaso- predetermined supranormal levels Rationale. There is no high-quality (grade 1B). primary evidence to recommend one cat- pressin at 0.03 units/min, showed no dif- echolamine over another. Much litera- ference in outcome in the intent to treat Rationale. Dobutamine is the first- ture exists that contrasts the physiologic population. An a priori defined subgroup choice inotrope for patients with mea- effects of choice of vasopressor and com- analysis showed that the survival of pa- sured or suspected low cardiac output in bined inotrope/vasopressors in septic tients receiving 15 g/min norepineph- the presence of adequate left ventricular shock (73– 85). Human and animal stud- rine at the time of randomization was filling pressure (or clinical assessment of ies suggest some advantages of norepi- better with vasopressin. However, the adequate fluid resuscitation) and ade- nephrine and dopamine over epinephrine pretrial rationale for this stratification quate mean arterial pressure. Septic pa- (the latter with the potential for tachy- was based on exploring potential benefit tients who remain hypotensive after fluid cardia as well as disadvantageous effects in the 15 g norepinephrine require- resuscitation may have low, normal, or on splanchnic circulation and hyper- ment population. Higher doses of vaso- increased cardiac outputs. Therefore, lactemia) and phenylephrine (decrease in pressin have been associated with car- treatment with a combined inotrope/ stroke volume). There is, however, no diac, digital, and splanchnic ischemia and vasopressor, such as norepinephrine or clinical evidence that epinephrine results should be reserved for situations where dopamine, is recommended if cardiac in worse outcomes, and it should be the alternative vasopressors have failed (96). output is not measured. When the capa- first chosen alternative to dopamine or Cardiac output measurement to allow bility exists for monitoring cardiac out- maintenance of a normal or elevated flow put in addition to blood pressure, a vaso- norepinephrine. Phenylephrine is the ad- is desirable when these pure vasopressors pressor, such as norepinephrine, may be renergic agent least likely to produce are instituted. used separately to target specific levels of tachycardia but as a pure vasopressor 5. We recommend that low-dose dopa- mean arterial pressure and cardiac out- would be expected to decrease stroke vol- mine not be used for renal protection put. Two large prospective clinical trials ume. Dopamine increases mean arterial that included critically ill ICU patients pressure and cardiac output, primarily (grade 1A). who had severe sepsis failed to demon- due to an increase in stroke volume and Rationale. A large randomized trial strate benefit from increasing oxygen de- heart rate. Norepinephrine increases and meta-analysis comparing low-dose livery to supranormal targets by use of mean arterial pressure due to its vasocon- dopamine to placebo found no difference dobutamine (99, 100). These studies did strictive effects, with little change in in either primary outcomes (peak serum not specifically target patients with se- heart rate and less increase in stroke vol- creatinine, need for renal replacement, vere sepsis and did not target the first 6 ume compared with dopamine. Either urine output, time to recovery of normal hrs of resuscitation. The first 6 hrs of may be used as a first-line agent to correct renal function) or secondary outcomes resuscitation of sepsis-induced hypoper- hypotension in sepsis. Norepinephrine is (survival to either ICU or hospital dis- fusion need to be treated separately from more potent than dopamine and may be charge, ICU stay, hospital stay, arrhyth- the later stages of severe sepsis (see Ini- more effective at reversing hypotension in mias) (97, 98). Thus, the available data do tial Resuscitation recommendations). patients with septic shock. Dopamine may not support administration of low doses be particularly useful in patients with com- of dopamine solely to maintain renal promised systolic function but causes more function. H. Corticosteroids tachycardia and may be more arrhythmo- genic (86). It may also influence the endo- 6. We recommend that all patients re- 1. We suggest that intravenous hydro- crine response via the hypothalamic- quiring vasopressors have an arterial cortisone be given only to adult septic pituitary axis and have immunosuppressive catheter placed as soon as practical if shock patients after it has been con- effects. resources are available (grade 1D). firmed that their blood pressure is Vasopressin levels in septic shock have Rationale. In shock states, estimation poorly responsive to fluid resuscita- been reported to be lower than antici- of blood pressure using a cuff is com- tion and vasopressor therapy (grade pated for a shock state (87). Low doses of monly inaccurate; use of an arterial can- 2C). vasopressin may be effective in raising nula provides a more appropriate and re- Rationale. One French multicenter, blood pressure in patients refractory to producible measurement of arterial randomized controlled trial (RCT) of pa- other vasopressors and may have other pressure. These catheters also allow con- tients in vasopressor-unresponsive septic potential physiologic benefits (88 –93). tinuous analysis so that decisions regard- shock (hypotension despite fluid resuscita- Terlipressin has similar effects but is long ing therapy can be based on immediate tion and vasopressors) showed a significant lasting (94). Studies show that vasopres- and reproducible blood pressure informa- shock reversal and reduction of mortality sin concentrations are elevated in early tion. rate in patients with relative adrenal insuf- Crit Care Med 2008 Vol. 36, No. 1 305
  11. 11. ficiency (defined as postadrenocortico- cortisol (protein-bound and free) while (110). It remains uncertain whether out- tropic hormone [ACTH] cortisol increase free cortisol is the pertinent measure- come is affected by tapering of steroids. 9 g/dL) (101). Two additional smaller ment. The relationship between free and 6. We recommend that doses of cortico- RCTs also showed significant effects on total cortisol varies with serum protein steroids comparable to 300 mg of shock reversal with steroid therapy (102, concentration. When compared with a hydrocortisone daily not be used in 103). However, a recent large, European reference method (mass spectrometry), severe sepsis or septic shock for the multicenter trial (CORTICUS), which has cortisol immunoassays may over- or un- purpose of treating septic shock been presented in abstract form but not yet derestimate the actual cortisol level, af- (grade 1A). published, failed to show a mortality benefit fecting the assignment of patients to re- with steroid therapy of septic shock (104). Rationale. Two randomized prospec- sponders or nonresponders (105). CORTICUS did show a faster resolution of tive clinical trials and a meta-analyses Although the clinical significance is not concluded that for therapy of severe sep- septic shock in patients who received ste- clear, it is now recognized that etomi- roids. The use of the ACTH test (responders sis or septic shock, high-dose corticoste- date, when used for induction for intuba- roid therapy is ineffective or harmful and nonresponders) did not predict the tion, will suppress the hypothalamic- faster resolution of shock. Importantly, un- (111–113). Reasons to maintain higher pituitary-adrenal axis (106). doses of corticosteroid for medical condi- like the French trial, which only enrolled shock patients with blood pressure unre- 3. We suggest that patients with septic tions other than septic shock may exist. sponsive to vasopressor therapy, the COR- shock should not receive dexametha- 7. We recommend that corticosteroids TICUS study included patients with septic sone if hydrocortisone is available not be administered for the treatment shock, regardless of how the blood pressure (grade 2B). of sepsis in the absence of shock. responded to vasopressors. Although corti- Rationale. Although often proposed There is, however, no contraindication costeroids do appear to promote shock re- for use until an ACTH stimulation test to continuing maintenance steroid versal, the lack of a clear improvement in can be administered, we no longer sug- therapy or to using stress-dose ste- mortality— coupled with known side ef- gest an ACTH test in this clinical situa- roids if the patient’s endocrine or cor- fects of steroids, such as increased risk of tion (see the preceding point 3). Further- ticosteroid administration history infection and myopathy— generally tem- more, dexamethasone can lead to warrants (grade 1D). pered enthusiasm for their broad use. Thus, immediate and prolonged suppression of Rationale. No studies exist that specif- there was broad agreement that the recom- the hypothalamic-pituitary-adrenal axis ically target severe sepsis in the absence of mendation should be downgraded from the shock and offer support for use of stress after administration (107). previous guidelines (Appendix B). There doses of steroids in this patient population. was considerable discussion and consider- 4. We suggest the daily addition of oral Steroids may be indicated in the presence ation by the committee on the option of fludrocortisone (50 g) if hydrocorti- of a history of steroid therapy or adrenal encouraging use in those patients whose sone is not available and the steroid dysfunction. A recent preliminary study of blood pressure was unresponsive to fluids that is substituted has no significant stress-dose level steroids in community- and vasopressors, while strongly discourag- mineralocorticoid activity. Fludrocor- acquired pneumonia is encouraging but ing use in subjects whose shock responded tisone is considered optional if hydro- needs confirmation (114). well to fluids and pressors. However, this cortisone is used (grade 2C). more complex set of recommendations was Rationale. One study added 50 g of rejected in favor of the preceding single I. Recombinant Human fludrocortisone orally (101). Since hydro- Activated Protein C (rhAPC) recommendation (Appendix B). cortisone has intrinsic mineralocorticoid 2. We suggest that the ACTH stimulation activity, there is controversy as to 1. We suggest that adult patients with sep- test not be used to identify the subset whether fludrocortisone should be added. sis-induced organ dysfunction associ- of adults with septic shock who should ated with a clinical assessment of high 5. We suggest that clinicians wean the receive hydrocortisone (grade 2B). risk of death, most of whom will have patient from steroid therapy when va- Rationale. Although one study sug- Acute Physiology and Chronic Health sopressors are no longer required gested those who did not respond to Evaluation (APACHE) II 25 or multi- (grade 2D). ACTH with a brisk surge in cortisol (fail- ple organ failure, receive rhAPC if there ure to achieve or 9 g/dL increase in Rationale. There has been no compar- are no contraindications (grade 2B ex- cortisol 30 – 60 mins after ACTH admin- ative study between a fixed-duration and cept for patients within 30 days of sur- istration) were more likely to benefit clinically guided regimen or between ta- gery, for whom it is grade 2C). Relative from steroids than those who did re- pering and abrupt cessation of steroids. contraindications should also be consid- spond, the overall trial population ap- Three RCTs used a fixed-duration proto- ered in decision making. peared to benefit regardless of ACTH re- col for treatment (101, 103, 104), and in 2. We recommend that adult patients sult, and the observation of a potential two RCTs, therapy was decreased after with severe sepsis and low risk of interaction between steroid use and shock resolution (102, 108). In four RCTs death, most of whom will have ACTH test was not statistically significant steroids were tapered over several days APACHE II 20 or one organ failure, (101). Furthermore, there was no evi- (102–104, 108), and in two RCTs (101, do not receive rhAPC (grade 1A). dence of this distinction between re- 109) steroids were withdrawn abruptly. Rationale. The evidence concerning sponders and nonresponders in a recent One crossover study showed hemody- use of rhAPC in adults is primarily based on multicenter trial (104). Commonly used namic and immunologic rebound effects two RCTs: PROWESS (1,690 adult patients, cortisol immunoassays measure total after abrupt cessation of corticosteroids stopped early for efficacy) (115) and AD- 306 Crit Care Med 2008 Vol. 36, No. 1

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