Introduction 1 5 6 7 8 11 These recommendations are intended to provide guidance for the clinician caring for a patient with severe sepsis or septic shock. Recommendations from these guidelines cannot replace the clinician's decision-making capability when he or she is provided with a patient's unique set of clinical variables. Most of these recommendations are appropriate for the severe sepsis patient in both the intensive care unit (ICU) and non-ICU settings. In fact the committee believes that, currently, the greatest outcome improvement can be made through education and process change for those caring for severe sepsis patients in the non-ICU setting and across the spectrum of acute care. It should also be noted that resource limitations in some institutions and countries may prevent physicians from accomplishing particular recommendations. Methods 1 12 2 13 Table 1 Determination of the Quality of Evidence • Underlying methodology A RCT B Downgraded RCT or upgraded observational studies C Well-done observational studies D Case series or expert opinion • Factors that may decrease the strength of evidence 1. Poor quality of planning and implementation of available RCTs suggesting high likelihood of
    bias 2. Inconsistency of results (including problems with subgroup analyses) 3. Indirectness of evidence (differing population, intervention, control, outcomes, comparison) 4. Imprecision of results 5. High likelihood of reporting bias • Main factors that may increase the strength of evidence 1. Large magnitude of effect (direct evidence, relative risk (RR) > 2 with no plausible
    confounders) 2. Very large magnitude of effect with RR > 5 and no threats to validity (by two levels) 3. Dose response gradient RCT RR 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 recommendation Relative importance of the outcomes If values and preferences vary widely, a strong recommendation becomes less likely Baseline risks of outcomes The higher the risk, the greater the magnitude of benefit Magnitude 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 respectively Absolute magnitude of the effect The larger the absolute benefits and harms, the greater or lesser likelihood respectively
    of a strong recommendation Precision of the estimates of the effects The greater the precision the more likely is a strong recommendation Costs The higher the cost of treatment, the less likely a strong recommendation 6 7 14 14 The 2001 guidelines were coordinated by the International Sepsis Forum (ISF); the 2004 guidelines were funded by unrestricted educational grants from industry and administered through the Society of Critical Care Medicine (SCCM), the European Society of Intensive Care Medicine (ESICM), and ISF. Two of the SSC administering organizations receive unrestricted industry funding to support SSC activities (ESICM and SCCM), but none of this funding was used to support the 2006–2007 committee meetings. It is important to distinguish between the process of guidelines revision and the Surviving Sepsis Campaign. The Surviving Sepsis Campaign (SSC) is partially funded by unrestricted educational industry grants, including those from Edwards LifeSciences, Eli Lilly and Company, and Philips Medical Systems. SSC also received funding from the Coalition for Critical Care Excellence of the Society of Critical Care Medicine. The great majority of industry funding has come from Eli Lilly and Company. Current industry funding for the Surviving Sepsis Campaign is directed to the performance improvement initiative. No industry funding was used in the guidelines revision process. For both the 2004 and the 2006/2007 efforts there were no members of the committee from industry, no industry input into guidelines development, and no industry presence at any of the meetings. Industry awareness or comment on the recommendations was not allowed. No member of the guideline committee received any honoraria for any role in the 2004 or 2006/2007 guidelines process. The committee considered the issue of recusement of individual committee members during deliberation and decision making in areas where committee members had either financial or academic competing interests; however, consensus as to threshold for exclusion could not be reached. Alternatively, the committee agreed to ensure full disclosure and transparency of all committee members' potential conflicts at time of publication (see disclosures at the end of this document). The guidelines process included a modified Delphi method, a consensus conference, several subsequent meetings of subgroups and key individuals, teleconferences and electronically based discussions among subgroups and members of the entire committee and two follow-up nominal group meetings in 2007. Subgroups were formed, each charged with updating recommendations in specific areas, including corticosteroids, blood products, activated protein C, renal replacement therapy, antibiotics, source control, and glucose control, etc. Each subgroup was responsible for updating the evidence (into 2007, with major additional elements of information incorporated into the evolving manuscript throughout 2006 and 2007). A separate search was performed for each clearly defined question. The committee chair worked with subgroup heads to identify pertinent search terms that always included, at a minimum, sepsis, severe sepsis, septic shock and sepsis syndrome crossed against the general topic area of the subgroup as well as pertinent key words of the specific question posed. All questions of the previous guidelines publications were searched, as were pertinent new questions generated by general topic related search or recent trials. Quality of evidence was judged by pre-defined Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria (see below). Significant education of committee members on the GRADE approach was performed via email prior to the first committee meeting and at the first meeting. Rules were distributed concerning assessing the body of evidence and GRADE experts were available for questions throughout the process. Subgroups agreed electronically on draft proposals that were presented to committee meetings for general discussion. In January 2006, the entire group met during the 35th SCCM Critical Care Congress in San Francisco, California, USA. The results of that discussion were incorporated into the next version of recommendations and again discussed using electronic mail. Recommendations were finalized during nominal group meetings (composed of a subset of the committee members) at the 2007 SCCM (Orlando) and 2007 International Symposium on Intensive Care and Emergency Medicine (Brussels) meetings with recirculation of deliberations and decisions to the entire group for comment or approval. At the discretion of the chair and following adequate discussion, competing proposals for wording of recommendations or assigning strength of evidence were resolved by formal voting. On occasions, voting was performed to give the committee a sense of distribution of opinions to facilitate additional discussion. The manuscript was edited for style and form by the writing committee with final approval by section leads for their respective group assignment and then by the entire committee. 15 8 11 9 11 1 The GRADE system classifies recommendations as strong (Grade 1) or weak (Grade 2). The grade of strong or weak is considered of greater clinical importance than a difference in letter level of quality of evidence. The committee assessed whether the desirable effects of adherence will outweigh the undesirable effects, and the strength of a recommendation reflects the group's degree of confidence in that assessment. A strong recommendation in favor of an intervention reflects that the desirable effects of adherence to a recommendation (beneficial health outcomes, less burden on staff and patients, and cost savings) will clearly outweigh the undesirable effects (harms, more burden and greater costs). A weak recommendation in favor of an intervention indicates that the desirable effects of adherence to a recommendation probably will outweigh the undesirable effects, but the panel is not confident about these tradeoffs – either because some of the evidence is low-quality (and thus there remains uncertainty regarding the benefits and risks) or the benefits and downsides are closely balanced. While the degree of confidence is a continuum and there is a lack of a precise threshold between a strong and a weak recommendation, the presence of important concerns about one or more of the above factors makes a weak recommendation more likely. A “strong” recommendation is worded as “we recommend” and a weak recommendation as “we suggest.” The implications of calling a recommendation “strong” are that most well-informed patients would accept that intervention, and that most clinicians should use it in most situations. There may be circumstances in which a “strong” recommendation cannot or should not be followed for an individual patient because of that patient's preferences or clinical characteristics which make the recommendation less applicable. It should be noted that being a “strong” recommendation does not automatically imply standard of care. For example, the strong recommendation for administering antibiotics within one hour of the diagnosis of severe sepsis, although desirable, is not currently standard of care as verified by current practice (personal communication, Mitchell Levy from first 8,000 patients entered internationally into the SSC performance improvement data base). The implication of a “weak” recommendation is that although a majority of well-informed patients would accept it (but a substantial proportion would not), clinicians should consider its use according to particular circumstance. Differences of opinion among committee members about interpretation of evidence, wording of proposals, or strength of recommendations were resolved using a specifically developed set of rules. We will describe this process in detail in a separate publication. In summary, the main approach for converting diverse opinions into a recommendation was: 1. to give a recommendation a direction (for or against the given action). a majority of votes were to be in favor of that direction, with no more than 20% preferring the opposite direction (there was a neutral vote allowed as well); 2. to call a given recommendation “strong” rather than “weak” at least 70% “strong” votes were required; 3. if fewer than 70% of votes indicated “strong” preference, the recommendation was assigned a “weak” category of strength. We used a combination of modified Delphi Process and Nominal (Expert) Group techniques to ensure both depth and breadth of review. The entire review group (together with their parent organizations as required) participated in the larger, iterative, modified Delphi process. The smaller working group meetings which took place in person functioned as the Nominal Groups. If a clear consensus could not be obtained by polling within the Nominal Group meetings, the larger group was specifically asked to use the polling process. This was only required for corticosteroids and glycemic control. The larger group had the opportunity to review all outputs. In this way the entire review combined intense focused discussion (Nominal Group) with broader review and monitoring using the Delphi process. Note: Refer to Tables 3 4 , and 5 for condensed adult recommentations. Table 3 Initial Resuscitation and Infection Issues Initial resuscitation (first 6 hours) Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” C C – Central venous pressure (CVP) 8–12 mm Hg* – Mean arterial pressure ≥ 65 mm Hg – Urine output ≥ 0.5 mL.kg-1.hr-1 – Central venous (superior vena cava) oxygen saturation ≥ 70%, or mixed
    venous ≥ 65% 2 C – consider further fluid – transfuse packed red blood cells if required to hematocrit of ≥ 30%
    and/or -1 -1 * A higher target CVP of 12–15 mm Hg is recommended in the presence of mechanical
    ventilation or pre-existing decreased ventricular compliance. Diagnosis C – Obtain two or more blood cultures (BCs) – One or more BCs should be percutaneous – One BC from each vascular access device in place > 48 h – Culture other sites as clinically indicated C Antibiotic therapy D B B C D D D D D Source identification and control C D C C B D C Table 4 Hemodynamic Support and Adjunctive Therapy Fluid therapy Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” B C D D D Vasopressors C C C – Vasopressin 0.03 units/min maybe subsequently added to norepinephrine with anticipation
    of an effect equivalent to norepinephrine alone. B A D Inotropic therapy C B Steroids C B B C D A D Recombinant human activated protein C (rhAPC) ○ Consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical
    assessment of high risk of death (typically APACHE II ≥ 25 or multiple organ failure) if there
    are no contraindications.(2B,2Cforpost-operativepatients) A Table 5 Other Supportive Therapy of Severe Sepsis Blood product administration Strength of recommendation and quality of evidence have been assessed using the GRADE criteria, presented in brackets after each guideline. For added clarity: • Indicates a strong recommendation or “we recommend”; ○ indicates a weak recommendation or “we suggest” B – A higher hemoglobin level may be required in special circumstances (e. g.: myocardial
    ischaemia, severe hypoxemia, acute haemorrhage, cyanotic heart disease or lactic acidosis) B D B D 3 9 3 9 3 9 Mechanical ventilation of sepsis-induced acute lung injury (ALI)/ARDS B 2 C 2 C C 2 C B     C B A 2 – Before the SBT, patients should:  – be arousable  – be haemodynamically stable without vasopressors  – have no new potentially serious conditions  – have low ventilatory and end-expiratory pressure requirement 2 A C Sedation, analgesia, and neuromuscular blockade in sepsis B B B Glucose control B C C B Renal replacement B D Bicarbonate therapy B Deep vein thrombosis (DVT) prophylaxis A A C C Stress ulcer prophylaxis 2 A B Consideration for limitation of support D I. Management of Severe Sepsis A. Initial Resuscitation recommend Central venous pressure (CVP): 8–12 mm Hg Mean arterial pressure (MAP) ≥ 65 mm Hg −1 −1 Central venous (superior vena cava) or mixed venous oxygen saturation ≥ 70% or ≥ 65%, respectively (Grade 1C) Rationale. 16 17 18 2 19 20 25 2 2 26 27 28 29 30 33 34 35 suggest CV 2 2 −1 −1 Rationale. CV 2 16 CV 2 2 B. Diagnosis recommend Rationale. 36 37 38 39 40 41 recommend Rationale. C. Antibiotic Therapy recommend Rationale. 42 43 42 recommend Rationale. 44 45 48 Patients with severe sepsis or septic shock warrant broad-spectrum therapy until the causative organism and its antibiotic susceptibilities are defined. Restriction of antibiotics as a strategy to reduce the development of antimicrobial resistance or to reduce cost is not an appropriate initial strategy in this patient population. 49 52 recommend Rationale. Candida Clostridium difficile Enterococcus faecium suggest Pseudomonas suggest When used empirically in patients with severe sepsis, we suggest that combination therapy should not be administered for more than 3 to 5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known. (Grade 2D). Rationale. 53 56 Pseudomonas 57 recommend recommend Rationale. D. Source Control recommend recommend suggest recommend recommend Rationale. 58 59 60 61 62 63 64 E. Fluid Therapy recommend Rationale. 65 p 66 68 69 70 recommend recommend recommend initial resuscitation recommend Rationale. F. Vasopressors recommend Rationale. 71 72 72 recommend suggest suggest Rationale. 73 85 86 87 88 93 94 95 a priori 96 recommend Rationale. 97 98 recommend Rationale. G. Inotropic Therapy recommend recommend Rationale. 99 100 H. Corticosteroids suggest only Rationale. 101 102 103 104 suggest not Rationale. 101 104 105 106 suggest not Rationale. 107 suggest Rationale. 101 suggest Rationale. 101 103 104 102 108 102 104 108 101 109 110 recommend not Rationale. 111 113 recommend not Rationale. 114 I. Recombinant Human Activated Protein C (rhAPC) suggest recommend do not Rationale. 115 116 117 115 118 119 116 n 119 115 116 115 117 p 115 p 116 117 106 116 108 120 121 The two RCTs in adult patients were methodologically strong, precise, and provide direct evidence regarding death rates. The conclusions are limited, however, by inconsistency that is not adequately resolved by subgroup analyses (thus the designation of moderate quality evidence). Results, however, consistently fail to show benefit for the subgroup of patients at lower risk of death, and consistently show increases in serious bleeding. The RCT in pediatric severe sepsis failed to show benefit and has no important limitations. Thus, for low risk and pediatric patients, we rate the evidence as high quality. 122 J. Blood Product Administration recommend Rationale. 123 124 126 CV 2 recommend not Rationale. 127 128 suggest not Rationale. 129 131 132 recommend against Rationale. 133 post hoc 134 suggest 3 9 3 9 3 9 Rationale. 129 131 II. Supportive Therapy of Severe Sepsis A. Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). recommend recommend 2 Rationale. 135 139 135 140 2 135 2 141 142 2 2 143 2 144 135 2 No single mode of ventilation (pressure control, volume control, airway pressure release ventilation, high frequency ventilation, etc.) has been consistently shown advantageous when compared with any other that respects the same principles of lung protection. recommend 2 Rationale. 2 145 146 135 ® 147 148 recommend Rationale. 2 149 151 152 153 154 I 2 135 2 155 suggest I 2 Rationale. 156 159 post hoc 2 I 2 2 159 160 161 recommend suggest Rationale. 164 162 162 163 163 suggest Rationale. 164 165 recommend I 2 2 Rationale. 166 169 recommend against Rationale. 170 172 173 174 175 176 177 179 recommend Rationale. 180 181 182 183 184 185 B. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis recommend Rationale. 186 188 186 187 188 186 189 recommend Rationale. 186 189 190 191 192 186 193 recommend Rationale. 194 195 196 197 195 198 201 195 202 203 204 Benefits to neuromuscular monitoring, including faster recovery of neuromuscular function and, shorter intubation times, appear to exist. A potential for cost savings (reduced total dose of NMBAs and shorter intubation times) also may exist, although this has not been studied formally. C. Glucose Control recommend suggest recommend recommend Rationale. 205 206 p 205 206 207 p 208 209 n 210 211 212 213 214 2 215 216 217 205 207 212 213 The finding of reduced morbidity and mortality within the longer ICU length of stay subsets along with acceptable cost weighed heavily on our recommendation to attempt glucose control after initial stabilization of the patient with hyperglycemia and severe sepsis. However, the mortality benefit and safety of intensive insulin therapy (goal to normalize blood glucose) has been questioned by 2 recent trials and we recommend maintaining glucose levels < 150 mg/dl until recent and ongoing trials are published or completed. Further study of protocols that have been validated to be safe and effective for controlling blood glucose concentrations and blood glucose variation in the severe sepsis population are needed. D. Renal Replacement suggest suggest Rationale. 218 225 226 227 227 228 232 229 232 228 228 232 230 233 233 230 229 231 232 234 228 230 235 238 235 237 238 236 E. Bicarbonate Therapy recommend against Rationale. 239 240 2 F. Deep Vein Thrombosis Prophylaxis recommend recommend suggest suggest Rationale. 241 242 250 251 252 253 The cost of LMWH is greater and the frequency of injection is less. UFH is preferred over LMWH in patients with moderate to severe renal dysfunction. 254 256 257 259 G. Stress Ulcer Prophylaxis (SUP) recommend 2 Rationale. 260 263 264 265 266 269 270 2 271 272 2 273 274 H. Selective Digestive Tract Decontamination (SDD) The guidelines group was evenly split on the issue of SDD, with equal numbers weakly in favor and against recommending the use of SDD (see appendix H). The committee therefore chose not to make a recommendation for the use of SDD specifically in severe sepsis at this time. The final consensus on use of SDD in severe sepsis was achieved at the last nominal committee meeting and subsequently approved by the entire committee (see Appendix H for committee vote). Rationale. 275 286 Post hoc 287 288 289 290 268 288 291 292 293 I. Consideration for Limitation of Support recommend Rationale. 294 296 297 III. Pediatric Considerations in Severe Sepsis 298 299 or or 299 A. Antibiotics recommend B. Mechanical Ventilation No graded recommendations. 300 301 C. Fluid Resuscitation suggest 302 303 308 303 307 308 304 308 D. Vasopressors/Inotropes (should be used in volume loaded patients with fluid refractory shock) suggest 309 suggest 310 311 313 314 315 E. Therapeutic End Points suggest −1 −1 290 2 2 −1 −2 290 305 316 F. Approach to Pediatric Septic Shock 1 317 Fig. 1 Approach to Pediatric Shock  G. Steroids suggest 318 319 2 320 321 321 H. Protein C and Activated Protein C recommend against 322 323 324 I. DVT Prophylaxis suggest 325 326 J. Stress Ulcer Prophylaxis No graded recommendations. 327 328 2 K. Renal Replacement Therapy No graded recommendations. 329 L. Glycemic Control No graded recommendations. −1 −1 330 331 M. Sedation/Analgesia recommend 332 333 N. Blood Products No graded recommendations. 334 O. Intravenous Immunoglobulin suggest 335 ECMO suggest 336 337 Although the pediatric considerations section of this manuscript offers important information to the practicing pediatric clinician for the management of critically ill children with sepsis, the reader is referred to the references at the end of the document for more in-depth descriptions of appropriate management of pediatric septic patients. Summary and Future Directions The reader is reminded that although this document is static, the optimum treatment of severe sepsis and septic shock is a dynamic and evolving process. New interventions will be proven and established interventions, as stated in the current recommendations, may need modification. This publication represents an ongoing process. The Surviving Sepsis Campaign and the consensus committee members are committed to updating the guidelines on a regular basis as new interventions are tested and published in the literature. 338 20 24 25 339 www.survivingsepsis.org Engendering evidence-based change in clinical practice through multi-faceted strategies while auditing practice and providing feedback to healthcare practitioners is the key to improving outcomes in severe sepsis. Nowhere is this more evident than in the worldwide enthusiasm for Phase III of the Campaign, a performance improvement program using SSC guideline-based sepsis bundles. Using the guidelines as the basis, the bundles have established a global best practice for the management of critically ill patients with severe sepsis. As of November 2007, over 12,000 patients have been entered into the SSC central database, representing the efforts of 239 hospitals in 17 countries. Change in practice and potential effect on survival are being measured.