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~ Sepsis ~ A Practical Predictive Paradigm

~ Sepsis ~ A Practical Predictive Paradigm. Jeremy Barnett MD ~ Department of Critical Care Amy Gutman MD ~ Director, Department of Emergency Medicine Amy.Gutman@HAHV.org; jdbarnettmd@yahoo.com. Objectives. Not teaching “sepsis”

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~ Sepsis ~ A Practical Predictive Paradigm

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  1. ~ Sepsis ~A Practical Predictive Paradigm Jeremy Barnett MD ~ Department of Critical Care Amy Gutman MD ~ Director, Department of Emergency Medicine Amy.Gutman@HAHV.org; jdbarnettmd@yahoo.com

  2. Objectives • Not teaching “sepsis” • Importance of predictive testing, early identification & aggressive management • Understand key concepts of the disease process & pathophysiology behind management decisions

  3. Sepsis…New Paradigm, Old “Disease” • Mortality increases 8% for every hour treatment delayed • >80%sepsis deaths preventable with rapid diagnosis & treatment • 26 million people worldwide annually • Leading cause of death in US hospitals • Disease with highest 30 day readmission rate • #1 cost of hospitalization in the US (>$20 billion annually) • One person dies every 2 minutes from sepsis • More than prostate cancer, breast cancer & AIDS combined • >75,000 maternal deaths annually worldwide jama.jamanetwork.com; www.hcup-us.ahrq.gov/reports/statbriefs/sb196-Readmissions-Trends-High-Volume-Conditions.jsp; www.ncbi.nlm.nih.gov/pubmed/20375891; www.hcup-us.ahrq.gov/reports/statbriefs/sb160.jsp

  4. Forget (Almost) Everything You Know

  5. Sepsis Pathophysiology • Sepsis not simply infection + two or more SIRS criteria, but infection leading to organ dysfunction • Importance of host response as dysregulation leads to sepsis cascade Clinicalmonster.com

  6. Bye Bye SIRS…. • Appropriate, but not dysregulated host response to infection • Has its place though not for diagnosing sepsis • Parameters useful in forming provisional diagnosis of inflammation or infection

  7. “Sepsis” ~ Updated Definition • Life-threatening organ dysfunction caused by a dysregulated host response to infection • “Sepsis” = old “Severe Sepsis” • Infection often confirmed late in presentation • Or never in 30-50% • Patients usually treated if infection suspected • Identifying patient as ‘septic’ = high risk for a poor outcome

  8. What Is Septic Shock? • Profound circulatory, cellular & metabolic abnormalities with greater mortality risk than sepsis alone • Dysfunctional “organ” is “cellular” • Despite adequate fluid resuscitation, vasopressors needed to maintain MAP ≥65 mmHg & elevated lactate

  9. “Spiraling Sepsis Cascade” www.researchgate.net

  10. This Is Why I Do Not Exercise! physrev.physiology.org

  11. 2001 Rivers EGDT Protocol • Among patients with severe sepsis or septic shock, mortality lower if received a 6 hour EGDT protocol (31% vs 47%) • Central catheterization monitored CVP & SCVO2, guiding use of IVFs, vasopressors, transfusions & dobutamine to achieve physiological targets  • Recent EBM shows not all protocol elements required to improve survival Rivers E, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001; 345:1368-1377

  12. Literature Review • Multiple criteria to identify septic shock • Wide variations in diagnostic criteria = 4-fold mortality variation • Cannot treat a disease until you can describe it • And…everyone uses the same definition

  13. Variable “Variables” • Hypotension (SAP <90, MAP <60 or <70, fall in SAP >40) • AND/OR • Persists despite adequate fluid resuscitation (unspecified, 20 ml/kg, 30ml/kg, or 1000 ml) • AND/OR • Biochemical variables (i.e. lactate >2 or >4, base deficit >5) • AND/OR • Use of inotropes &/or vasopressors (type / dose varies) • AND/OR • New onset organ dysfunction (APACHE II, APACHE III, or SOFA)

  14. Sepsis Scoring Systems

  15. Different Criteria, Different Mortality From Septic Shock • Australia 22% • Kaukonen et al, 2014 • Germany 61% • Heublein et al, 2015 • Netherlands 60% • Klein-Klouwenberg et al, 2012 Am J Respir Crit Care Med 2015; 192:958-964; Crit Care Med 2013; 41: 1167-1174; SCCM.org

  16. Definition Changes Therefore Are Not Simply Semantics

  17. EGDT vs “Usual” Care • 3 recent trials not only redefined sepsis, but changed the EGDT paradigm • Protocolized Care for Early Septic Shock (ProCESS) • Australasian Resuscitation in Sepsis Evaluation (ARISE) • ProtocolisedManagement in Sepsis (ProMISe) Trial • Concept: • If patients identified EARLY, given IVF EARLY, &antibiotics EARLY, then the management pathway used after (EGDT vs “Usual Care”) is less important than the quality of the resuscitation RebelEM.com

  18. ProCESSTrialProtocolized Care for Early Septic Shock • Multicenter, RCT • 1341 patients in 31 US EDs • EGDT • “Usual care” without CVC, inotropes, transfusions • Conclusions: • If patients in septic shock identified early, given early IVF & antibiotics, then CVC & monitoring do not matter • No single resuscitative pathway preferred, allowing management variability • “Usual care” now more aggressive, which may explain lower mortality rates A Randomized Trial of Protocol-Based Care for Early Septic Shock. The ProCESS Investigators; Protocolized Care for Early Septic Shock. N Engl J Med 2014; 370:1683-1693

  19. ARISE TrialAustralasian Resuscitation in Sepsis Evaluation • Prospective, Multicenter, Unblinded RCT • 1600 ED patients (Australia, New Zealand, Finland, Japan, Ireland) • EGDT vs Standard Care • Conclusion:  • EGDT did not reduce 90 day mortality • Early, aggressive identification & treatment improves outcomes • Pathway less important than decisive management & resuscitation Goal-Directed Resuscitation for Patients with Early Septic Shock The ARISE Investigators & ANZICS Clinical Trials Group (The Australasian Resuscitation in Sepsis Evaluation) N Engl J Med 2014;371:1496-506.

  20. ProMISe TrialProtocolised Management in Sepsis • Multi-center, unblinded RCT • 1260 patients, 56 EDs (United Kingdom) • EGDT (6-hour resuscitation protocol) vs “usual” care • Conclusions: • More EGDT patients required advanced CV support (37% vs 31%) • # ICU days higher in EGDT group (2.6 vs 2.2) • Average cost of EGDT care higher • If septic shock identified early, the use of EGDT vs “usual” care did not improve 90 day mortality *Not statistically significant;Mouncey PR, et al. ProtocolisedManagement In Sepsis (ProMISe): a multicentrerandomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock. Health Technol Assess. 2015 Nov;19(97):i-xxv, 1-150.

  21. What Is The “Take-Away” Message? • EGDT: 31-47% 90 day mortality • ProCESS: 18-21% 60 day mortality • ARISE: 18-19% 90 day mortality • ProMISe: 19-29% 90 day mortality • If patients identified EARLY, given IVF EARLY, antibiotics EARLY…then the pathway used afterwards is less important then the quality of the resuscitation of patients with severe sepsis & septic shock Social Media & Critical Care. intensivecarenetwork.com

  22. Sepsis “6 (ish)” • 0 - 60 minutes • Check Lactic Acid • Send Blood Cultures • Give Antibiotics • 30mL/kg IVF • 61 – 180 minutes • Vasopressors if MAP <65mmHg • Re-assess volume status & tissue perfusion • Re-check Lactic Acid BJM. 2001;345:1368-77

  23. EBM Guidelines • Administration of IV antimicrobials within 1st hour of septic shock recognition (Grade 1B) & severe sepsis without septic shock (Grade 1C) • Initial empiric / appropriate anti-infective therapy of >1 drugs with activity against all likely pathogens (Grade 1B) Crit Care Med 2013;41:580-637

  24. Fluid Resuscitation • Rapid 30 mL/kg crystalloids, followed by response assessment • >4-6 liters often required • Crystalloids titrated to adequate tissue perfusion • CVP increases >2 mmHg, CVP >8-12 mmHg, or signs of volume overload • Non-invasive CVP estimation • Ultrasonography • IVC diameter as a surrogate for volume status • 50% difference predicts CVP <8 mmHg with >92% sensitivity & specificity • UOP • <30-50 mL/hr should prompt measures to increase cardiac output www.swjpcc.com

  25. Crystalloid IVF Resuscitation • Risk from “excessive” IVF administration • Meta-analysis of 4 RCTs at 20-40ml/kg bolus: • No mortality reduction • 18 trials with historical controls showed a significant increase in survival • Although most septic patients are “functionally hypovolemic” careful monitoring of right ventricular volume status essential to avoid inducing acute corpulmonale

  26. Rationale for Early Antibiotics • “For the greatest survival benefit, give antibiotics as early as possible & always within 1 hour of presentation … or recognition”* • Early antibiotics may: • Limit injury caused by microbial activity & toxin production • Limit harmful host responses to infection • Many studies of antibiotic timing suffer from confounders: • Failure to correct for illness severity • Failure to determine if antibiotic choice appropriate ~Australian Therapeutic Guidelines (2014); LITFL.com

  27. Rationale for Early Antibiotics • Strong association between early antibiotics & improved survival • Antibiotics kill organisms, halting / slowing MODS physiologic progression • Mortality from physiologic response to infection & resultants MODS • Antibiotics ideally given before severe sepsis with hypotension occurs, as irreversible injury may result • Microbial load increases as infection progresses • Cytokine release that occurs when antibiotics are given may be more severe & increase the likelihood of progression to MODS LITFL.com

  28. Quick SOFASequential Organ Failure Assessment • Tool for identifying patients at risk of sepsis • Predictive • Does not define sepsis • 2 qSOFA criteria predict increased mortality & prolonged ICU stays

  29. SOFA vs qSOFA EPmonthly.com

  30. In the ICU, SOFA has greater predictive validity than qSOFA • Outside the ICU, qSOFA has similar predictive validity to more complex scores • Focus on timeliness, ease of use • 21 variables from Sepsis-2 • Multivariable logistic regression for in-hospital mortality • Most predictive: Infection plus >2 SOFA points (above baseline) www.qsofa.org

  31. Hyperlactemia • Marker of cellular/metabolic stress & organ dysfunction not necessarily tissue hypoperfusion • Independent predictor of mortality • Management tool guides therapeutic response & indicator of severity Derangedphysiology.com

  32. Lactate & qSOFA • Lactate added only small improvement to predictive validity vs qSOFA alone • Utility in intermediate risk patients (qSOFA = 1) • Important Point: • 3 recent trials showed lactate-guided therapy had no impact on survival • However, lactate levels parallel septic shock severity with prognostic implications

  33. Lactate & Hypotension In Septic Shock? Shankar-Hari et al. JAMA 2016

  34. So…Sepsis 6 “ish” • 0-60 minutes • Check Lactic Acid • Send Blood Cultures • Give Antibiotics • 30mL/kg IVF • 61 – 180 minutes • Vasopressors if MAP <65mmHg • Re-assess Volume Status & Tissue Perfusion • Re-Check Lactic Acid

  35. Blood Cultures • Clinical & lab parameters independently correlate with bacteremia • Hypoalbuminemia, AKI, UTI • Chills, fever, hypothermia, leukocytosis, neutrophil left shift, neutropenia, shock • Peaking fever more sensitive than leukocytosis to predict bacteremia • Obtain cultures before antimicrobial therapy initiated if does delay administration (Grade 1C) • Antibiotic stewardship & planned de-escalation

  36. Vasopressors • Septic shock unresponsive to 30 ml/kg IVF (1.5-3 liters) (Grade 1C) • Promptly begun & continued simultaneously with fluid resuscitation • Targeting MAP >65 mm Hg (Grade 1C) • Norepinephrine (Levophed)  • 1st line vasopressor (Grade 1B) • Increases MAP via vasoconstriction, little effect on HR, SV, & CO • Epinephrine • When norepinephrine insufficient to maintain MAP >65mmHg (Grade 2B) • Vasopressin  • Use with norephinephrine to improve perfusion • Dopamine • Increases MAP through increasing CO (increasing HR & SV) • More likely than norepinephrine to cause tachyarrhythmias

  37. Overcoming Identification & Management Barriers • Multidisciplinary approach to healthcare professionals education • Early identification = early suspicion • Update policies to minimize delays • Antibiotics prior to transfer • Order initial IV antibiotics “STAT” • Standardized treatment approach using protocols & order sets Crit Care Clin 2011;27:53-76; Crit Care Med 2007;35:2568-75

  38. More Than Metrics sydney.edu.au; radiometer.com; www.biomerieux.com

  39. RebelEM.com…Oh Snap!Guess What…We Do it Better Here!

  40. References • Conservative fluid therapy in septic shock: an example of targeted therapeutic minimization. Crit Care. 2014; 18(4): 481. • SCCM/ESICM: The 3rdInternational Consensus Definitions for Sepsis & Septic Shock. The Sepsis Definitions Task Force. New definitions: Why, How & What. Query September2016. • CRISMA Center. University of Pittsburgh Departments of Critical Care &Emergency Medicine • www.sccm.org/sepsisredefined. Queried September 2016 • Surviving Sepsis Campaign. www.survivingsepsis.org. Queried September 2016. • Singer M, et al. 3rdInternational Consensus Definitions for Sepsis & Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-810. • Seymour CW, et al. Assessment of clinical criteria for sepsis: for the 3rd international consensus definition for sepsis &septic shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):762-774. • Seymour CW, et al. Application of a framework to assess the usefulness of alternative sepsis criteria. Crit Care Med. 2016 Mar; 44(3):e122-e130. • Levy MM, et al. Surviving Sepsis Campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015 Jan;43(1):3-12. • Wells D. Appropriate timing &dosing of antibiotics in sepsis. Auburn University Harrison School of Pharmacy. Queried September 2016. • Fish, J. University of Wisconsin Hospital. Trauma and Life Center. Appropriate timing and dosing of antibiotics in sepsis. Queried Sept 2016 • Kumar A, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006 Jun;34(6):1589-96. • Rivers E, Nguyen B, et al. Early Goal-Directed Therapy Collaborative Group. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. NEJM. 2001; 345:1368-1377 • Process/ARISE/ProMISe Methodology Writing Committee. Harmonizing international trials of early goal-directed resuscitation for severe sepsis and septic shock: Methodology of ProCESS, ARISE, and ProMISe. Intensive Care Med. 2013 Oct;39(10):1760-75. • The ProCESSInvestigators.A Randomized Trial of Protocol-Based Care for Early Septic Shock. NEJM. 2014; 370:1683-1693

  41. ConclusionsAmy.Gutman@hahv.org; jdbarnettmd@yahoo.com • No more “SIRS” • “Sepsis” is now “Severe Sepsis” • “Septic shock” is a subset of sepsis in which underlying circulatory, cellular and metabolic abnormalities are associated with a greater risk of mortality than sepsis alone • Treat the patient in front of you & do not wait until criteria met as early identification & management key to survival • Understand the “why” of what we do, not just the metrics

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