NEW SEPSIS AND SEPTIC SHOCK DEFINITIONS. Giorgio Tulli e Giulio Toccafondi 2016

Transcription

1 NEW SEPSIS AND SEPTIC SHOCK DEFINITIONS Giorgio Tulli e Giulio Toccafondi 2016

2 THE STORY STARTS MORE THAN 20 YEARS AGO FIRST AND SECOND DEFINITIONS OF SEPSIS AND SEPTIC SHOCK Bone RC et al American College of Chest Physicians/ Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis Crit Care Med 1992; 20: Levy MM et al SCCM/ESICM/ACCP/ATS/SIS 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference Crit Care Med 2003; 31: BUT THERE WAS SOMETHING IN THE AIR Vincent JL, Opal SM, Marshall JC, Tracey KJ Sepsis definitions: time for change Lancet 2013; 381:

3 The third international consensus definitions for sepsis and septic shock (Sepsis-3) Mervin Singer et al JAMA 2016; 315(8): Assessment of clinical criteria for sepsis For the third international consensus definitions for Sepsis and Septic Shock (Sepsis-3) Christopher W. Seymour and al. JAMA 2016; 315(8): Developing a new definition and assessing new clinical criteria for septic shock For the third international consensus definitions for sepsis and septic shock (Sepsis-3) Manu Shankar-Hari et al JAMA 2016; 315 (8):

4 Task Force Consensus Sepsis is much more than just INFECTION + SIRS The Host Response is more important than the bug Sepsis should now represent INFECTION THAT GOES BAD organ dysfunction and/or death SEVERE SEPSIS becomes a redundant term Septic Shock reflects sicker subset of septic patients

5 OLD 2 of 4 SIRS Organ dysfunction CV collapse not responding to fluids Infection Sepsis Severe Sepsis Septic Shock NEW Infection BAD SEPSIS SEPTIC SHOCK Organ dysfunction

6 The new definition Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection

7 The new definition key distictions Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection so SEPSIS now = the old SEVERE SEPSIS Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection and not the regulated host response that characterizes an appropriate non septic response to infection

8 The new definition So we now have a DEFINITION..but how do we measure ORGAN DYSFUNCTION at the bedside? ORGAN DYSFUNCTION characterized clinically by change in SOFA score 2 related to episode of new infection

9 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama n.b. assume SOFA =0 unless patient known to have abnormal score prior

10 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama n.b. assume SOFA = 0 unless patient known to have abnormal score prior

11 How the Task Force arrived to these definitions From: The third international consensus definitions for sepsis and septic shock (sepsis-3) Mervyn Singer et al JAMA 2016; 315(8): From: Assessment of clinical criteria for sepsis Christopher W. Seymour et al. JAMA 2016; 315(8):

12 Terminology and International Classification of Diseases Coding The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama

13 Variables for Candidate Sepsis Criteria Among Encounters With Suspected Infection Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama

14 Summary of Data Sets Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama

15 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Accrual of Encounters for Primary CohortED indicates emergency department; ICU, intensive care unit; PACU, postanesthesia care unit.

16 Characteristics of Encounters With Suspected Infection in the Primary Cohort at 12 UPMC Hospitals From 2010 to 2012 (N = ) a Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama

17 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Distribution of Patient Encounters Over SIRS Criteria and SOFA, LODS, and qsofa Scores Among ICU Patients and Non-ICU Patients With Suspected Infection in the UPMC Validation Cohort (N = )ICU indicates intensive care unit; LODS, Logistic Organ Dysfunction System; qsofa, quick Sequential [Sepsis-related] Organ Function Assessment; SIRS, systemic inflammatory response syndrome; SOFA, Sequential [Sepsis-related] Organ Function Assessment. The x-axis is the score range, with LODS truncated at 14 points (of 22 points) and SOFA truncated at 16 points (of 24 points) for illustration.

18 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Area Under the Receiver Operating Characteristic Curve and 95% Confidence Intervals for In-Hospital Mortality of Candidate Criteria (SIRS, SOFA, LODS, and qsofa) Among Suspected Infection Encounters in the UPMC Validation Cohort (N = )ICU indicates intensive care unit; LODS, Logistic Organ Dysfunction System; qsofa, quick Sequential [Sepsis-related] Organ Function Assessment; SIRS, systemic inflammatory response syndrome; SOFA, Sequential [Sepsis-related] Organ Function Assessment. The area under the receiver operating characteristic curve (AUROC) data in the blue-shaded diagonal cells derive from models that include baseline variables plus candidate criteria. For comparison, the AUROC of the baseline model alone is 0.58 (95% CI, ) in the ICU and 0.69 (95% CI, ) outside of the ICU. Below the AUROC data cells are P values for comparisons between criteria, while above the AUROC data cells are Cronbach α data (with bootstrap 95% confidence intervals), a measure of agreement.

19 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Fold Change in Rate of In-Hospital Mortality (Log Scale) Comparing Encounters With 2 vs <2 Criteria for Each Decile of Baseline Risk in the UPMC Validation Cohort (N = )ICU indicates intensive care unit; LODS, Logistic Organ Dysfunction System; qsofa, quick Sequential [Sepsis-related] Organ Function Assessment; SIRS, systemic inflammatory response syndrome; SOFA, Sequential [Sepsis-related] Organ Function Assessment. Panel A shows ICU encounters comparing fold change for SIRS, SOFA, LODS, and qsofa. Panel B shows non-icu encounters. Medians and ranges of baseline risk of in-hospital mortality within decile shown are below the x-axis. Interpretive example: The x-axis divides the cohort into deciles of baseline risk, determined by age, sex, comorbidities, and race/ethnicity. For a young woman with no comorbidities (panel A, decile 2) admitted to the ICU with pneumonia, her chance of dying in the hospital is 10-fold greater if she has 3 SOFA points compared with 1 SOFA point. On the other hand, she has only a small increase in the chance of dying if she has 3 SIRS criteria compared with 1 SIRS criterion. For an older woman with chronic obstructive pulmonary disease admitted to the ward with pneumonia (panel B, decile 6), her chance of dying in the hospital is 7- fold higher if she has 3 qsofa points compared with 1 qsofa point. On the other hand, she has only a 3-fold increase in odds of dying if she has 3 SIRS criteria compared with 1 SIRS criterion. JAMA. 2016;315(8): doi: /jama

20 Why a change of 2 from baseline SOFA? Many patients have existing (new/old) comorbidities pre-onset of possible sepsis, thus already score SOFA points at baseline Most of these SOFA scorers well already be known.so look for change in SOFA 2 related to pre-infection baseline Assume 0 SOFA score if previously healthy

21 The new definition of SEPTIC SHOCK Septic shock is a subset of sepsis in which profound circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone

22 How do we operationalize this definition at the bedside i.e what clinical criteria describe septic shock? Derivation cohort SSC data base (SSC) ; n= 28,150 Validation cohort 12 hospitals in Pennsylvania (UPMC) ; n= 1,309, hospital Kaiser Permanente Norther California (KPNC) ; n= 1,847,165

23 VARIABLES and OUTCOME Variable Circulatory dysfunction Hypotension after adequate fluid resuscitation Vasopressors needed to maintain MAP 65 mmhg Metabolic and cellular Serum lactate Outcome Acute hospital mortality

24 Derivation of clinical criteria (SSC database) 45 42,3 Crude mortality% in six different groups ,1 28,7 25,7 29, , crude mortality % group 1 group 2 group 3 group 4 group 5 group 6 Group1 : hypotensive after fluid and vasopressor therapy and serum lactate levels 2 mmol/l Group 2: hypotensive after fluid and vasopressor therapy and serum lactate levels 2 mmol/l Group 3: hypotensive after fluids and no vasopressors and serum lactate levels 2mmol/L Group 4: serum lactate levels 2 mmol/l and no hypotension after fluids and no vasopressors Group 5: serum lactate levels 2mmol/L and no hypotension before fluids and no vasopressors Group 6: hypotensive after fluids and no vasopressors and serum lactate 2 mmol/l

25 The new definition of SEPTIC SHOCK Septic shock is a subset of sepsis in which profound circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone THE CLINICAL CRITERIA TO DESCRIBE SEPTIC SHOCK Despite adequate fluid resuscitation Vasopressors needed to maintain MAP 65 mmhg AND Lactate 2 mmol/l

26 How the Task Force arrived to these definitions From: Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Manu Shankar-Hari et al JAMA 2016; 315(8):

27 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3 Study Identification and Selection Process Used in the Systematic Review a Nonduplicate references from other sources included review articles. See emethods 1 in the Supplement for further details of search strategy. b Refers to records that were excluded after reference screening of full text articles. The screening criteria for full text inclusion were reporting of all case sepsis epidemiology in adult populations without specific assessment of interventions. The qualitative review assessed sepsis and septic shock definitions and criteria. The records included in the qualitative review (92 studies) are presented in etable 2 in the Supplement. The quantitative review assessed septic shock criteria and mortality. c Refers to the records included for quantitative assessment of septic shock mortality and the heterogeneity by criteria using random-effects metaanalysis (44 studies) (etable 2 in the Supplement). JAMA. 2016;315(8): doi: /jama

28 From: Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Summary of Septic Shock Definitions and Criteria Reported in the Studies Identified by the Systematic Review a

29 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Random-Effects Meta-analysis of Studies Identified in the Systematic Review, Reporting Septic Shock MortalityFortyfour studies report septic shock associated mortality and were included in the quantitative synthesis using randomeffects meta-analysis. The Surviving Sepsis Campaign (SSC) database analyses with similar data are reported in 2 studies; therefore, only one of these was used in the metaanalysis reported. Levy et al report 3 septic shock subsets, Klein Klowenberg et al report 2 (restrictive and liberal), Zahar et al report 3 (community-acquired, ICU-acquired, and nosocomial infection associated septic shock), and Phua et al report 2 groups, which were treated as separate data points in the meta-analysis. Studies under consensus definition cite the Sepsis Consensus Definitions. The categorization used to assess heterogeneity does not fully account for septic shock details in individual studies. SI conversion factor: To convert serum lactate values to mg/dl, divide by a Data obtained from GiViTI database provided by Bertolini et al (published 2015). b The mortality data of Group 1 patients (new septic shock population) and the overall potential septic shock patient populations (n = ) described in the manuscript from the current study using the Surviving SSC database are also included in the meta-analysis. Septic shock specific data were obtained from Australian & New Zealand Intensive Care Society Adult Patient Database (ANZICS), from a previously published report. This results in 52 data points for random-effects meta-analysis.

30 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Random Effects Meta-Analysis by Septic Shock Criteria Groups

31 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Distribution of Septic Shock Cohorts and Crude Mortality From Surviving Sepsis Campaign Database (n = patients)

32 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Selection of Surviving Sepsis Campaign Database CohortHypotension was defined as mean arterial pressure less than 65 mm Hg. Vasopressor therapy to maintain mean arterial pressure of 65 mm Hg or higher is treated as a binary variable. Serum lactate level greater than 2 mmol/l (18 mg/dl) is considered abnormal. The after fluids field in the Surviving Sepsis Campaign (SSC) database was considered equivalent to adequate fluid resuscitation. Before fluids refers to patients who did not receive fluid resuscitation. Serum lactate level greater than 2 mmol/l after fluid resuscitation but without hypotension or need for vasopressor therapy (group 4) is defined as cryptic shock. Missing serum lactate level measurements (n = 4419 [15.7%]) and patients with serum lactate levels greater than 4 mmol/l (36 mg/dl) who did not receive fluids as per SSC guidelines (n = 790 [2.8%]) were excluded from full case analysis. Of the patients, 4101 who were coded as having severe sepsis were excluded. Thus, the remaining patients were categorized within septic shock groups 1 to 6. a Patients with screening serum lactate levels coded as greater than 2 mmol/l (n=3342) were included in the missing-data analysis. JAMA. 2016;315(8): doi: /jama

33 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Serum Lactate Level AnalysisAdjusted odds ratio for actual serum lactate levels for the entire septic shock cohort (N = ). The covariates used in the regression model include region (United States and Europe), location where sepsis was suspected (emergency department, ward, or critical care unit), antibiotic administration, steroid use, organ failures (pulmonary, renal, hepatic, and acutely altered mental state), infection source (pneumonia, urinary tract infection, abdominal, meningitis, and other), hyperthermia (>38.3 C), hypothermia (20/min), leukopenia (120 mg/dl [6.7 mmol/l]), platelet count < /μl, and coagulopathy (emethods 3 in the Supplement). The adjusted odds ratio (OR) for the 6 groups presented in etable 7 in the Supplement and the adjusted OR for the individual variables (lactate, vasopressor therapy, and fluids) are reported in etable 8 in the Supplement. To convert serum lactate values to mg/dl, divide by

34 Characteristics of Serum Lactate Level Cutoff Values for Complete Case Analysis and Imputation Analysis Using Surviving Sepsis Campaign Database Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama

35 Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Crude Mortality in Septic Shock Groups From UPMC and KPNC Data sets

36 WHY LACTATE 2 mmol/l test performance (receiver operator characteristics) LACTATE SENSITIVITY 90 83, ,1 70,4 69, , , sensitivity NPV >2mmol/L >3mmol/L >4mmol/L

37 Quick SOFA Can we offer evidence based bedside sniffer to rapidly identify patients at risk of having sepsis?

38 Developing the prompt qsofa ( quick SOFA) Focus on timeliness, ease of use Studied 21 variables from SEPSIS-2 Multivariable logistic regression for in hospital mortality RESPIRATORY RATE 22bpm ALTERED MENTATION SYSTOLIC BLOOD PRESSURE 100 mmhg SO q FA

39 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Area Under the Receiver Operating Characteristic Curve and 95% Confidence Intervals for In-Hospital Mortality of Candidate Criteria (SIRS, SOFA, LODS, and qsofa) Among Suspected Infection Encounters in the UPMC Validation Cohort (N = )ICU indicates intensive care unit; LODS, Logistic Organ Dysfunction System; qsofa, quick Sequential [Sepsisrelated] Organ Function Assessment; SIRS, systemic inflammatory response syndrome; SOFA, Sequential [Sepsisrelated] Organ Function Assessment. The area under the receiver operating characteristic curve (AUROC) data in the blue-shaded diagonal cells derive from models that include baseline variables plus candidate criteria. For comparison, the AUROC of the baseline model alone is 0.58 (95% CI, ) in the ICU and 0.69 (95% CI, ) outside of the ICU. Below the AUROC data cells are P values for comparisons between criteria, while above the AUROC data cells are Cronbach α data (with bootstrap 95% confidence intervals), a measure of agreement.

40 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Odds Ratios for Baseline Model and qsofa Variables for In-Hospital Mortality in the UPMC Derivation Cohort (N = )

41 Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama AUROCs for In-Hospital Mortality for qsofa in External Data Sets Adequate predictive validity (AUC range 0.7 to 0.8) Hospital acquired infections Ward and ICU encounters Pre-hospital records

42 SERUM LACTATE Not retained during qsofa model build Serum lactate at various threshoulds added to qsofa

43 SERUM LACTATE During model building in UPMC data, serum lactate did not meet prespecified statistical thresholds for inclusion in qsofa. In KPNC data, the post hoc addition of serum lactate levels of 2.0 mmol/l (18mg/dL) or more to qsofa (revised to a 4 point score with 1 added point for elevated serum lactate level) statistically changed the predictive validity of qsofa (AUROC with lactate=0.80; 95%CI, vs AUROC without lactate = 0.79; 95%CI, ; P<0.001). This was consistent for higher thresholds of lactate(3.0mmol/l, 4.0 mmol/l) or using a continuousdistribution (P<0.001) However the clinical relevance was small as the rates of in hospital mortality comparing encounters with 2 or more versus less than 2 points across deciles of risk were numerically similar wheter or not serum lactate was included in qsofa Among encounters with 1 qsofa point but also a serum lactate level of 2.0 mmol/l or more, in hospital mortality was higher than that for the encounters with serum lactate levels of less than 2.0 mmol/l across the range of baseline risk. The rate of in hospital mortality was numerically similar to that for encounters with 2 qsofa points using the model without serum lactate Because serum lactate levels are widely used for screening in many centers, the distribution of qsofa scores over strata of serum lactate level was investigated The qsofa consistently identified higher risk encounters even at varying serum lactate levels

44 Clinical criteria for sepsis INFECTION plus 2 SOFA points (above baseline) Prompt outside the ICU to consider sepsis INFECTION plus 2 qsofa points

45 Controversies and limitations There are inherent challenges in defining sepsis and septic shock. First and foremost sepsis is a broad term applied to an incompletely understood process. There are, as yet, no simple and unambiguous clinical criteria or biological imaging, or laboratory features that uniquely identify a septic patient

46 Is there still a place for SIRS, lactate.? YES! SIRS may help towards making an initial presumptive diagnosis of infection YES! Many find lactate useful for guiding management but we were focused purely on definitions but they are not needed for the diagnosis of sepsis Lactate is needed for diagnosing septic shock as it is the best readily available marker of cellular/metabolic stress

47 Should I not treat patients until they hit qsofa 2 or ΔSOFA 2? ABSOLUTELY NOT! If they need antibiotic for their infection, treat If they need fluid for their oliguria or oxygen for their hyperaemia, treat

48 SEPSIS IS A SYNDROME, A LABEL Like infection often diagnosed retrospectively So treat the patient in front of you regardless of the label but hitting qsofa 2 or ΔSOFA 2 or septic shock criteria does identify patients at greater risk of doing badly

49 What do the new definitions/criteria bring? Objectivity, reproducibility and generalizability to aid research, for coding, for epidemiology Ease of use in clinical practice qsofa rapid bedside measure SOFA clinical measure and lab tests performed routinely in any sick patients

50 What about children? Definitions still hold true Task Force lacked expertise to derive clinical citeria for children at differing age ranges Paediatric initiatives underway

51 Developing world May lack ability to measure lactate or SOFA criteria? Use qsofa as surrogate for sepsis (post-validation) For septic shock, use clinical markers of tissue perfusion if lactate not available ( e.g capillary refill) PoC testing increasingly available and cheap

52 What next? Prospective validation of qsofa in different healthcare settings ( non- US, developed and developing world) More work to eventually improve on SOFA

53 FINAL THOUGHTS The new criteria offer objectivity, reproducibility and generalizability for research, for coding, for epidemiology.and hopefully offer a useful bedside prompt to highlight at risk patients Need prospective validation ( especially qsofa) NOT the final word..it is an iterative process SEPSIS-4 will improve on SEPSIS-3

54 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA. 2016;315(8): doi: /jama Operationalization of Clinical Criteria Identifying Patients With Sepsis and Septic Shock The baseline Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score should be assumed to be zero unless the patient is known to have preexisting (acute or chronic) organ dysfunction before the onset of infection. qsofa indicates quick SOFA; MAP, mean arterial pressure.

55 SOME CRITICISMS

56 Editorial New definitions for sepsis and septic shock continuing evolution but with much still to be done Edward Abraham JAMA 2016; 315(8): Patients with infections and organ dysfunction are exceptionally heterogeneous in term of demographic characteristics, underlying conditions, microbiology, and other clinically relevant factors (Cohen J et al Sepsis : a roadmap for future research Lancet Infect Dis 2015 ; 15 : ) The updated definition for sepsis, like the previous versions, is broad with respect to diagnostic criteria and will not help in segmenting patients into subgroups based on underlying microbiology, pathophysiology or cellular alterations. For example, a previously healthy 18-year-old with meningococcemia, coagulopathy and hypoxemia; a 45-year-old tourist returning from Southeast Asia with malaria, new onset renal dysfunction, and hyperbilirubinemia; a 90-year-old with a medical history of Alzheimer disease, diabetes and congestive heart failure who present with worsening mental status, decreased urinary output and a urinary tract infection related to an indwelling bladder catheter will all be categorized as septic, and all will have septic shock if they demonstrate an elevated serum lactate level and require vasopressors to maintain blood pressure. The inclusion of such a wide variety of patients with suspected, but not necessarily proven, infection, organ system dysfunction of multiple types and a variety of underlying medical conditions ensures that even though the new definitions may be helpful in evaluating the epidemiology and economics relating to sepsis, they will be limited in their utility to strengthen the design of clinical trials and, most importantly, in directing care for individual patients

57 Although the use of large databases provides support for the new consensus definitions of sepsis and septic shock, there remain concerns with the information used to generate the updated criteria. In particular, the patient data are all almost exclusively from adults in high income countries and primarily contain information from patients in the United States, so the utility of these definitions in other geographic regions in settings that are less resource replete and among paediatric populations is presently unknown. As noted by the authors of these articles, the ability of the new definitions to predict morbidity and mortality in low and middle income countries, where levels of patient monitoring and supportive care commonly used in the United States and developed world are often not available, remain an unanswered question. An additional concern relates to the inclusion of serum lactate levels in the definition of septic shock, because such measurements may not be available in resource limited settings

58 The consensus document also introduces a new bedside index, called the qsofa, which is proposed to help identify patients with suspected infection who are being treated outside of critical care units and likely to develop complications of sepsis. The qsofa requires at least 2 of the following 3 risk variables: respiratory rate of 22 or more breath per minute, systolic blood pressure of 100 mmhg or less and altered mental status. However, because this index was retrospectively, derived from databases that had substantial gaps in clinical information for patients treated outside of ICUs, qsofa will require prospective, real world validation before it can enter routine clinical practice. In addition, because analysis of the Veterans Affairs database appeared to show little additional predictive value in qsofa from the inclusion of mental status changes, further simplification of this index may be possible

59 A fundamental component of the new definitions for sepsis and septic shock remains the presence of infection. Yet negative microbiologic cultures from blood or relevant anatomic sites are frequent in patients clinically identified as being septic (Cohen J et al Sepsis : a roadmap for future research Lancet Infect Dis 2015 ; 15 : ). While new techniques, such as those using matrix associated laser desorption ionization time to flight (MALDI-TOF) or polymerase chain reaction (PCR) are likely to enhance the current ability to diagnose infections (Cohen J et al Sepsis : a roadmap for future research Lancet Infect Dis 2015 ; 15 : ; Buehler SS et al Effectiveness of practices to increase timeliness of providing targeted therapy for inpatients with bloodstream infections: a laboratory medicine best practice systematic review and meta-analysis Clin Microbiol Rev 2016; 29: ), a major limitation continues to be the identification of patients whose organ system dysfunction is truly secondary to an underlying infection rather than other causes. This is a particularly important issue in critical care, where many noninctious conditions, such as trauma and pancreatitis, are accompanied by the acute onset of organ failure, with the contributory role of concomitant infection often being extremely difficult to determine

60 In the same way that patients with sepsis are heterogeneous in terms of their underlying microbiology, medical history and clinical characteristics, so are the alterations in cellular function that accompany this condition (Deutschman CS, Tracey KJ Sepsis: current dogma and new perspectives Immunity 2014; 40: ; Delano MJ, Ward PA Sepsis-induced immune dysfunction: can immune therapies reduce mortality? J Clin Invest 2016; 126:23-31). Development in genetics, genomics, immunology and cellular biology have led to increased understanding of the derangements that contribute to organ dysfunction and death in experimental models and patients with severe infections. Pathways involving inflammatory and anti-inflammatory signalling, innate and adaptive immune response, apoptosis, mitochondrial function, translational and transcriptional regulation and oxidative biology, as well as additional intracellular and extracellular events, are activated with differing kinetics in individual with sepsis. Enhanced understanding of the range of underlying cellular events contributing to organ dysfunction associated with severe infection has highlighted the need to develop biomarkers that identify the alterations present in patients with sepsis so specific therapies can be used in an appropriate manner

61 The epidemiologic strengths of the new consensus conference definitions of sepsis and septic shock are accompanied by weaknesses in their ability to be used in the treatment of individual patients or in clinical trials. Although the new definitions provide a broad view of the universe of sepsis and may help in facilitating early identification of patients with this condition, they will be of only limited help in directing specific therapies to individual patients or in designing clinical trials focused on specific mechanisms of sepsis-induced organ dysfunction

62 Precision medicine, in which individualized therapies are provided to patients based on the specific genomic and cellular alterations accompanying their disease process, is revolutionizing the treatment of cancer and other conditions (Jameson JL, Longo DL Precision Medicine- personalized, problematic and promising N Engl J Med 2015 ; 372: ). Such targeted treatment has been shown to be associated with enhanced clinical response among patients with cancer, often with diminished toxicity. There would appear to be substantial potential for a similarly tailored approach to sepsis, given the heterogeneity of cellular responses associated with this condition. However, the lack of molecular components in the new consensus definitions does not advance this exicing possibility

63 An ongoing issue, discussed in the articles in this issue of JAMA, is that sepsis is a syndrome and not a specific disease. The new definitions do not alleviate this concern. Other conditions, most notably cancer, were previously described in a similar manner but are now further characterized based not just on anatomic location and cell type but most recently on expression of specific biomarkers, including cellular receptors, activation of intracellular pathways and genomic alterations. Such characterization has enabled development of therapies targeted to specific patients, with remarkable improvements in outcome. Although the present definition for sepsis provides needed evolution in categorization of this syndrome, incorporation of more information about the molecular and cellular characterization of sepsis may have been helpful. Hopefully, the next iteration of this consensus process will take full advantage of the rapidly advancing understanding of molecular processes that lead from infection to organ failure and death so that sepsis and septic shock will no longer need to be defined as a syndrome but rather as a group of identifiable diseases, each characterized by specific cellular alterations and linked biomarkers. Such evolution will be required to truly transform care for the millions of patients worldwide who develop these life-threatening conditions

64 A framework for the development and interpretation of different sepsis definitions and clinical criteria Derek C Angus et al Crit Care Med 2016; 44:e113-e121

65 Abstract Although sepsis was described more than 2,000 years ago, and clinicians still struggle to define it, there is no gold standard and multiple competing approaches and terms exist. Challenges include the ever-changing knowledge base that informs our understanding of sepsis, competing views on which aspects of any potential definition are most important, and the tendency of most potential criteria to be distributed in at-risk populations in such a way as to hinder separation into discrete sets of patients. We propose that the development and evaluation of any definition or diagnostic criteria should follow four steps: 1) define the epistemologic underpinning, 2) agree on all relevant terms used to frame the exercise, 3) state the intended purpose for any proposed set of criteria and 4) adopt a scientific approach to inform on their usefulness with regard to the intended purpose. Usefulness can be measured across six domains: 1) reliability (stability of criteria during retesting, between raters, over time, and across stings), 2) content validity ( similar to face validity), 3) construct validity (whether criteria measure what they purport to measure), 4) criterion validity (how new criteria fare compared to standards, 5) measurement burden ( cost, safety, and complexity) and 6) timeliness ( whether criteria are available concurrent with care decisions). The relative importance of these domains of usefulness depends on the intended purpose, of which are four broad categories: 1) clinical care, 2) research, 3) surveillance, and 4) quality improvement and audit. This proposed methodologic framework is intended to aid understanding of the strengths and weaknesses of different approaches, provide a mechanism for explaining differences in epidemiologic estimates generated by different approaches and guide the development of future definitions and diagnostic criteria

66 SEPSIS= f (threat to life organ dysfunction dysregulated host response infection ) A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria Angus, Derek C.; Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Klompas, Michael; Levy, Mitchell M.; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Watson, R. Scott Critical Care Medicine. 44(3):e113-e121, March doi: /CCM

67 A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria Angus, Derek C.; Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Klompas, Michael; Levy, Mitchell M.; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Watson, R. Scott Critical Care Medicine. 44(3):e113-e121, March doi: /CCM Figure 1. The zone of rarity problem: ideal and typical distributions of surface phenomena (clinical and biologic features) among patients with and without disease. Panels A and B illustrate situations in which a surface phenomenon (e.g., a single blood test) or set of phenomena (e.g., a combination of clinical features and blood tests) is used to separate a population into those who do and those who do not have a particular disease. Ideally (Panel A), there would be a large zone of rarity where few individuals would exhibit the test result or constellation of features at the border between health and disease. However (Panel B), most tests or combinations of tests and features are expressed on a continuum, with no zone of rarity. For example, the distribution of white blood cell count values across a population of hospitalized patients will not exhibit a zone of rarity near the upper limit of normal. Rather, many patients will have borderlineelevated values. Panel C and D show the corresponding distributions for sepsis, where surface phenomena classify patients with both infection and organ dysfunction. Although the ideal criteria (Panel C) for both infection and organ dysfunction would have clear zones of rarity, neither domains have such criteria (Panel D). For example, most organ dysfunction measures, like measures of infection, are expressed on a continuum with many patients exhibiting borderline values.

68 A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria Angus, Derek C.; Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Klompas, Michael; Levy, Mitchell M.; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Watson, R. Scott Critical Care Medicine. 44(3):e113-e121, March doi: /CCM Methodological Considerations for Any Disease or Syndrome Classification Exercise

69 A Framework for the Development and Interpretation of Different Sepsis Definitions and Clinical Criteria Angus, Derek C.; Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Klompas, Michael; Levy, Mitchell M.; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Watson, R. Scott Critical Care Medicine. 44(3):e113-e121, March doi: /CCM Six Domains of Usefulness for Potential Criteria for the Definition of Sepsis

70 Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Gesten, Foster; Klompas, Michael; Levy, Mitchell; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Warren, David K.; Watson, R. Scott; Angus, Derek C. Critical Care Medicine. 44(3):e122-e130, March doi: /CCM Domains of Usefulness (and Subdomains) for Potential Sepsis Diagnostic Criteria and their Priority by Purpose

71 Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Gesten, Foster; Klompas, Michael; Levy, Mitchell; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Warren, David K.; Watson, R. Scott; Angus, Derek C. Critical Care Medicine. 44(3):e122-e130, March doi: /CCM Examples of Alternative Sepsis Diagnostic Criteria by Purpose

72 Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Gesten, Foster; Klompas, Michael; Levy, Mitchell; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Warren, David K.; Watson, R. Scott; Angus, Derek C. Critical Care Medicine. 44(3):e122-e130, March doi: /CCM Sepsis Case Identification by Alternative Criteria in a 12-Hospital Regional Health System (n = 396,241)

73 Application of a Framework to Assess the Usefulness of Alternative Sepsis Criteria Seymour, Christopher W.; Coopersmith, Craig M.; Deutschman, Clifford S.; Gesten, Foster; Klompas, Michael; Levy, Mitchell; Martin, Gregory S.; Osborn, Tiffany M.; Rhee, Chanu; Warren, David K.; Watson, R. Scott; Angus, Derek C. Critical Care Medicine. 44(3):e122-e130, March doi: /CCM Modified multimethod matrix for various sepsis criteria.below-the-diagonal cells contain the correlation coefficient between dichotomized criteria (with bootstrapped 95% CI). The above diagonal cells illustrate the 2 2 distribution of patients across criteria (either present or absent). Color scale corresponds to the number of patients in each group in the respective 2 2 table (red = many patients in that cell, blue = fewer patients in that cell). SOFA = Sepsis-Related Organ Failure Assessment, qsofa = quick SOFA, CMS = Centers for Medicare & Medicaid Services.