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Practical Insights: Early Sepsis Identification and Management Paradigm

Learn the importance of predictive testing, early sepsis identification, and aggressive management, understanding key disease concepts and pathophysiology for improved outcomes. Mortality increases with treatment delays, highlighting the need for rapid diagnosis and preventive measures against sepsis. Explore the updated definitions of sepsis and septic shock, with insights on the evolving management strategies. Discover the impact of timely interventions and the shift towards quality resuscitation in sepsis care.

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Practical Insights: Early Sepsis Identification and Management 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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