Sepsis A Practical Predictive Paradigm Jeremy Barnett MD

~ 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” • Importance of predictive testing, early identification & aggressive management • Understand key concepts of the disease process & pathophysiology behind management decisions

Sepsis…New Paradigm, Old “Disease” • 26 million people worldwide annually • Leading cause of death in US hospitals • Mortality increases 8% for every hour 8% • Disease with highest 30 day readmission rate treatment delayed • #1 cost of hospitalization in the US (>$20 billion annually) • >80% sepsis deaths preventable with • One person dies every 2 minutes from sepsis rapid diagnosis & treatment • More than prostate cancer, breast cancer & AIDS combined • >75, 000 maternal deaths annually worldwide jamanetwork. com; www. hcup-us. ahrq. gov/reports/statbriefs/sb 196 -Readmissions-Trends-High-Volume-Conditions. jsp; www. ncbi. nlm. nih. gov/pubmed/20375891; www. hcup-us. ahrq. gov/reports/statbriefs/sb 160. jsp

Forget (Almost) Everything You Know

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

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

“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

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 mm. Hg & elevated lactate

“Spiraling Sepsis Cascade” www. researchgate. net

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

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 & SCVO 2, 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

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

Variable “Variables” • Hypotension (SAP <90, MAP <60 or <70, fall in SAP >40) • AND/OR • Persists despite adequate fluid resuscitation (unspecified, 20 ml/kg, 30 ml/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)

Sepsis Scoring Systems

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

Definition Changes Therefore Are Not Simply Semantics

EGDT vs “Usual” Care • 3 recent trials not only redefined sepsis, but changed the EGDT paradigm • Protocolized Care for Early Septic Shock (Pro. CESS) • Australasian Resuscitation in Sepsis Evaluation (ARISE) • Protocolised Management in Sepsis (Pro. MISe) 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 Rebel. EM. com

Pro. CESS Trial Protocolized 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 Pro. CESS Investigators; Protocolized Care for Early Septic Shock. N Engl J Med 2014; 370: 1683 -1693

ARISE Trial Australasian 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.

Pro. MISe Trial Protocolised 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. Protocolised Management In Sepsis (Pro. MISe): a multicentre randomised 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.

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

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

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

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

Crystalloid IVF Resuscitation • Risk from “excessive” IVF administration • Meta-analysis of 4 RCTs at 20 -40 ml/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 cor pulmonale

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

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

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

SOFA vs q. SOFA EPmonthly. com

• In the ICU, SOFA has greater predictive validity than q. SOFA • Outside the ICU, q. SOFA 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

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

Lactate & q. SOFA • Lactate added only small improvement to predictive validity vs q. SOFA alone • Utility in intermediate risk patients (q. SOFA = 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

Lactate & Hypotension In Septic Shock? Criteria Hospital Mortality (%) Hypotension + Elevated Lactate 42% Hypotension Alone 30% Elevated Lactate Alone 26% Normal BP & Lactate 19% Shankar-Hari et al. JAMA 2016

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

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 1 C) • Antibiotic stewardship & planned de-escalation

Vasopressors • Septic shock unresponsive to 30 ml/kg IVF (1. 5 -3 liters) (Grade 1 C) • Promptly begun & continued simultaneously with fluid resuscitation • Targeting MAP >65 mm Hg (Grade 1 C) • Norepinephrine (Levophed) • 1 st line vasopressor (Grade 1 B) • Increases MAP via vasoconstriction, little effect on HR, SV, & CO • Epinephrine • When norepinephrine insufficient to maintain MAP >65 mm. Hg (Grade 2 B) • Vasopressin • Use with norephinephrine to improve perfusion • Dopamine • Increases MAP through increasing CO (increasing HR & SV) • More likely than norepinephrine to cause tachyarrhythmias

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

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

Rebel. EM. com…Oh Snap! Guess What…We Do it Better Here!

References • • • • Conservative fluid therapy in septic shock: an example of targeted therapeutic minimization. Crit Care. 2014; 18(4): 481. SCCM/ESICM: The 3 rd International Consensus Definitions for Sepsis & Septic Shock. The Sepsis Definitions Task Force. New definitions: Why, How & What. Query September 2016. 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. 3 rd International 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 3 rd 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): e 122 -e 130. 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/Pro. MISe Methodology Writing Committee. Harmonizing international trials of early goaldirected resuscitation for severe sepsis and septic shock: Methodology of Pro. CESS, ARISE, and Pro. MISe. Intensive Care Med. 2013 Oct; 39(10): 1760 -75. The Pro. CESS Investigators. A Randomized Trial of Protocol-Based Care for Early Septic Shock. NEJM. 2014; 370: 1683 -1693

Conclusions Amy. 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