IAFP Conference McCall, Idaho May 20, 2017 Ann Lima, MD MPH Sepsis Update IAFP Conference McCall, Idaho May 20, 2017 Ann Lima, MD MPH

Objectives Understand history of sepsis definitions and guidelines Familiarize with most recent literature regarding sepsis Recognize different tools used for screening and monitoring of sepsis Familiarize with Sepsis 3 recommendations and Surviving Sepsis 2016 guidelines Identify areas for clinical improvement and future research

Sepsis Timeline SIRS criteria 1991 1991 Sepsis Task Force (1) Rivers et al 2001 2001 Sepsis Task Force (2) Surviving Sepsis Campaign 2002 ProCESS, ARISE, ProMISe 2014-2015 2016 Sepsis Task Force (3)

Sepsis Identification SIRS – Systemic Inflammatory Response Syndrome LODS – Logistic Organ Dysfunction Score SOFA – Sequential (Sepsis-related) Organ Dysfunction Assessment qSOFA – Quick Sequential (Sepsis-related) Organ Dysfunction Assessment NEWS – National Early Warning Score MEWS – Modified Early Warning Score RFS – Red Flag Sepsis

Surviving Sepsis Campaign Started in 2002 at European Society of Intensive Care Medicine annual meeting 2012 guidelines came out Sepsis care bundles Within 3 hours of presentation Lactate measurement Blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30ml/kg crystalloid for hypotension or lactate >4 Within 6 hours Measure CVP, MAP, urine output, ScvO2

Surviving Sepsis Campaign Update in April 2015 (after ProCESS, ARISE, ProMISe) Within 3 hours of presentation (no change) Lactate measurement Blood cultures prior to administration of antibiotics Administer broad spectrum antibiotics Administer 30ml//kg crystalloid for hypotension or lactate >4

Surviving Sepsis Campaign Update in April 2015 (after trials) Within 3 hours of presentation (no change) Within 6 hours Vasopressors for hypotension, that does not respond to initial fluid resuscitation, to maintain a mean arterial pressure (MAP) > 65mmHg If persistent hypotension after initial fluid administration, or if initial lactate was >4mmol/L, reassess volume status and tissue perfusion Re-measure lactate if initial lactate elevated

Sepsis 3.0 Sepsis is not simply infection + two or more SIRS criteria The host response is of key importance Sepsis represents bad infection where bad = infection leading to organ dysfunction “Severe sepsis” is not helpful and should be eliminated

Sepsis 3.0 Redefined sepsis as life-threatening organ dysfunction caused by a dysregulated response to infection Organ dysfunction identified by change in SOFA score >2 points due to the infection. GCS P:F ratio (PaO2:FiO2) BP (MAP and/or pressors) Platelets Total Bilirubin Creatinine

Sepsis 3.0 Screening for sepsis, recommend qSOFA >2 Altered mental status SBP <100mmHG RR >22/min Not suggesting not treating until this threshold reached, but offering alternative to SIRS

Sepsis 3.0 Lactate? Marker of cellular and/or metabolic stress Not necessarily tissue hypoperfusion Independent predictor of mortality Additional tool Septic shock is more than hypotension alone

Sepsis 3.0 Conclusions Definition Clinical criteria Septic shock is defined as a subset of sepsis in which underlying circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone Clinical criteria Hypotension requiring use of vasopressors to maintain MAP ≥65 mmHg and having a serum lactate >2 mmol/l persisting despite adequate fluid resuscitation

Sepsis 3.0

Response to Sepsis 3.0 Churpek et al sought to compare qSOFA with other scores – SIRS, MEWS, NEWS Retrospective 30,677 patients NEWS > MEWS > qSOFA > SIRS Predicting death and ICU transfer in non-ICU patients Using the highest non-ICU score of patients (combined outcome of death, ICU transfer): sensitivity of 91% and specificity of 13% for ≥2 SIRS 54% and 67% for qSOFA ≥2, 59% and 70% for MEWS ≥5, 67% and 66% for NEWS ≥8. Most patients met ≥2 SIRS criteria 17 hours before the combined outcome compared with 5 hours for ≥2 and 17 hours for ≥1 qSOFA criteria.

Response to Sepsis 3.0

Response to Sepsis 3.0 Price and Sivayoham aimed to identify the most sensitive sepsis screening tool Retrospective 178 patients SIRS > RFS > qSOFA for identification of septic patients at triage (in ED) RFS > SIRS > qSOFA for mortality sensitivity qSOFA > RFS > SIRS for mortality specificity Red Flag Sepsis

Response to Sepsis 3.0 Red Flag Sepsis (RFS)

Response to Sepsis 3.0 UK Sepsis Trust, advised waiting until qSOFA validated, continue RFS and NEWS Moskowitz et al 2016 Cortes-Puch et al 2016 American College of Chest Physicians Multiple emergency medicine and critical care blogs have criticized qSOFA and Sepsis 3.0 http://sepsistrust.org/wp-content/uploads/2016/02/Interim-statement-new-definitions-3.pdf http://sepsistrust.org/wp-content/uploads/2016/02/Interim-statement-new-definitions-3.pdf

Response to Sepsis 3.0 Freund et al, JAMA Jan 2017 Prospectively validate qSOFA as mortality predictor 1088 patients qSOFA had greater prognostic accuracy for in- hospital mortality than SIRS or severe sepsis

Response to Sepsis 3.0 Forward et al, Intensive Care Med, March 2017 161 hospitalized (non-ICU) patients Higher specificity for sepsis, in-hospital mortality, ICU admission and blood culture positivity with qSOFA, than SIRS or Sepsis Kills (SK) criteria Similar sensitivity for sepsis

Response to Sepsis 3.0 Finkelsztein et al 2017 Kim et al 2017 Prospective 152 patients qSOFA more accurate than SIRS for predicting mortality and ICU-free days Kim et al 2017 615 patients qSOFA with low sensitivity and high specificity for sepsis, 28-day mortality and ICU admission

Surviving Sepsis Campaign Update No comment on sepsis criteria (qSOFA), but did use much of sepsis 3 recommendations No more EGDT Use crystalloid, can consider albumin if using large amounts of crystalloid Dynamic reassessment, eg passive leg raise Use norepi first, then epi, then vasopressin (no more dopamine)

Surviving Sepsis Campaign Update Start resuscitation early with source control, ivf, and antibiotics Guide resuscitation to normalize lactate in patients with elevated lactate levels Hospitals have a performance improvement program for sepsis including sepsis screening for acutely ill, high-risk patients.

Surviving Sepsis Campaign Update Routine microbiologic cultures, including 2 sets of blood cultures, be obtained before starting antimicrobial therapy in patients with suspected sepsis and septic shock if doing so results in no substantial delay in the start of antimicrobial therapy. For the initial management of septic shock, use at least two antibiotics of different antimicrobial classes aimed at the most likely bacterial pathogen for empiric combination therapy.

Surviving Sepsis Campaign Update Combination therapy (ie double-covering pseudomonas or acinetobacter) not to be used: Ongoing treatment of most other serious infections, including bacteremia and sepsis without shock. Routine treatment of neutropenic sepsis/bacteremia. Daily assessment of de-escalation of antimicrobial therapy Narrow antimicrobial therapy once pathogen identification and/or clinical improvement

Surviving Sepsis Campaign Update Goals of care and prognosis be discussed with patients and families. Goals of care be incorporated into treatment and end-of-life care planning, utilizing palliative care principles where appropriate. 7-10 days is adequate for most serious infections associated with sepsis and septic shock Procalcitonin levels can be used to support shortening duration of antimicrobial therapy in sepsis

Surviving Sepsis Campaign Update More guidelines Steroids Mechanical ventilation Nutrition Glucose Control Renal replacement therapy

Screening, Monitoring Tools SIRS SOFA qSOFA NEWS MEWS RFS Temperature X Heart Rate Blood Pressure Respiratory Rate Oxygen Saturation Use of supplemental oxygen PaO2:FiO2 Mental status Leukocyte count Urine output Lactate Purpuric rash Platelets Creatinine Bilirubin

Objectives Understand history of sepsis definitions and guidelines Familiarize with most recent literature regarding sepsis Recognize different tools used for screening and monitoring of sepsis Familiarize with Sepsis 3 recommendations and Surviving Sepsis 2016 guidelines Identify areas for clinical improvement and future research

References Bone RC, Balk RA, Cerra FB, 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(6):864–874. Dellinger  RP, Levy  MM, Rhodes  A,  et al; Surviving Sepsis Campaign Guidelines Committee Including the Pediatric Subgroup.  Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012.  Crit Care Med. 2013;41(2):580-637. Levy  MM, Fink  MP, Marshall  JC,  et al; International Sepsis Definitions Conference.  2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.  Intensive Care Med. 2003;29(4):530-538. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M et al. Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA 2016; 315: 801-10. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M, Sepsis Definitions Task Force. 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;315:775–87. ProCESS Investigators, Yealy DM, Kellum JA, Juang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370(18):1683- 1693 The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496-1506 Mouncey PR, Osborn TM, Power GS, et al for the ProMISe trial investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015: DOI: 10.1056/NEJMoa1500896 Churpek MM, Zadravecz FJ, Winslow C, Howell MD, Edelson DP. Incidence and prognostic value of the systemic inflammatory response syndrome and organ dysfunctions in ward patients. Am J Respir Crit Care Med. 2015;192:958–64. Freund, Lemachatti, Krastinova et al. Prognostic accuracy of sepsis-3 criteria for in0hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017 Jan 17;317(3):301-308. Kim, Ahn, Kim et al. Predictive performance of the quick sequential organ failur assessment score as a screening tool for sepsis, mortality, and intensive care unit admission in patients with febrile neutropenia. Support Care Cacner. 2017 May;25 (5):1557-1562. Finkelsztein, Jones, Ma et al. Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Cit Care. 2017 Mar 26;21(1):73. Forward, Konency, , Bursont, et al. Predictive validity of the qSOFA criteria for speis in non-ICU inpatients. Intensive Care Med.

References http://sepsistrust.org/wp- content/uploads/2016/02/Interim-statement-new- definitions-3.pdf http://rebelem.com/sepsis-3-0/ https://emcrit.org/pulmcrit/sepsis-3-sofa-validation- news/ http://embasic.org/sepsis-3-0/ https://lifeinthefastlane.com/ccc/sepsis-definitions/ https://first10em.com/2016/02/25/sepsis-3-0/ http://sinaiem.org/sepsis-2-0-vs-3-0/