Sepsis or Severe Sepsis? Is there a right thing, and how do we do it?

Sepsis or Severe Sepsis? Is there a right thing, and how do we do it? Steven Q Simpson, MD, FCCP, FACP Professor of Medicine Division of Pulmonary and Critical Care University of Kansas

Disclosures No commercial interests to disclose Founder of Midwest Critical Care Collaborative Founder of the Kansas Sepsis Project Participant 2016 update, Surviving Sepsis Campaign Guidelines Dissenting opinion on Sepsis-3 in CHEST

Kansas: Exemplar of Rural America

Objectives 1. Discuss definitions of sepsis and what they mean 2. Discuss the role of Early Goal Directed Therapy in sepsis 3. Discuss CMS measures and their role in improving sepsis care

21 st Century Sepsis Teaching? as the physicians say it happens in hectic fever, that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure Niccolò Machiavelli The Prince 1513 or 1532

What is Sepsis? Life threatening organ dysfunction due to a dysregulated host response to infection

Hospital Case 72 y.o. man, 3 days post-op from ureteral stent placement; Foley in place Nurse finds him with flank pain and fever, mild confusion (previously oriented x 4) Hx of CAD, HTN Meds include terazosin, atorvastatin, metoprolol BP 105/43, P 117, R 21, T 39.1 o, SpO2 87% Exam: left CVA tenderness, BPH

ACCP/SCCM Consensus Definitions Infection - Inflammatory response to microorganisms, or - Invasion of normally sterile tissues Systemic Inflammatory Response Syndrome (SIRS) - Systemic response to a variety of processes - 2 or more SIRS criteria Sepsis Infection plus 2 or more SIRS criteria Severe Sepsis Sepsis Organ dysfunction Septic shock Sepsis Hypotension despite fluid resuscitation Bone RC et al. Chest. 1992;101:1644-55.

SIRS: Systemic Inflammatory Response Syndrome SIRS: nonspecific insult 2 of the following: Temperature > 38 o C or < 36 o C HR > 90 beats/min Respirations > 20/min WBC > 12,000/µL, < 4,000/µL, or >10% immature neutrophils (bands) SIRS Adapted from: Bone RC et al. Chest. 1992;101:1644-55. Opal SM et al. Crit Care Med. 2000;28:S81-2.

Acute Organ Dysfunction as the Hallmark of Severe Sepsis Altered Consciousness Confusion Psychosis Hypotension SBP < 90 MAP < 65 Tachypnea PaO2 <70 mm Hg SaO2 <90% PaO2/FiO2 < 300 Oliguria - < 20 ml/hr Anuria Creatinine (>0.5 mg/dl) T. Bilirubin > 4 mg/dl Lactic acidosis Platelets (< 100k) (INR>1.5, PTT>60 sec) D-dimer

Sepsis: What Are We Talking About? ICD-9: septicemia Positive blood cultures Multiple positive blood cultures Roger C. Bone, MD Positive blood cultures + hypotension Syndrome: how shall we define it?

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Definition: Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection Drops the term severe sepsis Drops the use of SIRS and infection + SIRS

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Condition Sepsis-2 Sepsis-3 Sepsis Infection + SIRS Infection + SOFA 2 Severe Sepsis Infection + SIRS + organ dysfunction Septic Shock Infection + Unresponsive Hypotension* NON-EXISTENT Infection + Unresponsive Hypotension* + Serum Lactate > 2 mmol/l *Hypotension that does not respond to volume infusion and requires vasopressor administration

SOFA Score 1 2 3 4 Respiration PaO 2 /FiO 2 < 400 < 300 < 200 With respiratory support < 100 with respiratory support Cardiovascular Hypotension MAP < 70 mm Hg Dopamine 5 or dobutamine, any dose Dopamine > 5 or epinephrine or norepinephrine 0.1 Dopamine > 15 or epinephrine or norepinephrine > 0.1 Liver Bilirubin (mg/dl) 1.2 1.9 2.0 5.9 6.0 11.9 > 12.0 Renal Creatinine (mg/dl) or urine output 1.2 1.9 2.0 3.4 3.5 4.9 or < 500 ml/24 hr 5.0 or < 200 ml/24 hr Coagulation Platelets x 10 3 /mm 3 < 150 < 100 < 50 < 25 CNS Glasgow Coma Scale 13-14 10-12 6-9 < 6

Quick SOFA Also known as qsofa Any two of: - Glasgow Coma Scale < 15 - Respiratory rate 22/min - Systolic blood pressure 100 mm Hg

ROC Results

Sensitivity (True Positive Rate) ROC Curves & Diagnostic Accuracy This is NOT the probability Excellent of the OUTCOME, if the TEST is positive. It is the probability that the TEST is positive in someone who had the OUTCOME and negative in someone without it. Fair-Good i.e. Worthless This is NOT the probability of death if qsofa or SIRS is positive. It is the probability that qsofa or SIRS was present in those who died and not present in those who survived. 1 specificity (False Positive Rate)

SIRS is too non-specific I make love to my wife and I get SIRS Hopefully, more than once! Jean-Louis Vincent

Bayes Theorem P(D T) = P(T D)P(D) P(T D)P(D) + P(T D )P(D ) P sepsis SIRS P SIRS sepsis x P sepsis in group

Bayes Theorem P sepsis SIRS P SIRS sepsis x P sepsis in group P SIRS

Likelihood Ratio / Fagan Nomogram The essence of the Bayesian approach is to provide a mathematical rule explaining how you should change your existing beliefs in the light of new evidence. Post-test probability of a disease is dependent on: 1. the pre-test probability of disease 2. characteristics of the test (likelihood ratio) LR + = sensitivity / (1 specificity) LR - = (1 sensitivity) / specificity Treatment threshold Test threshold Fagan TJ. N Engl J Med 1975;293:257.

Criticizing SIRS for being too sensitive a test to diagnose sepsis in all comers is like criticizing a hammer for being the only tool in your toolbox.

SEPSIS SIRS Suspect Infection

SEPSIS qsofa Suspect Infection

Infection Syndromes Pneumonia cough, purulent sputum, pleuritic chest pain, consolidation Cellulitis redness, tenderness, advancing margin Pyelonephritis flank pain, costophrenic angle tenderness, urinary leukocytosis Peritonitis abdominal pain, ileus, rebound tenderness, rigidity Possible BSI from indwelling catheter

Early Goal Directed Therapy Wanted Dead or Alive?

Primary Endpoint: In hospital mortality; single center Secondary Endpoints: - Resuscitation endpoints - Organ dysfunctions - Coagulation endpoints - Healthcare resources Rivers E, et al. N Engl J Med 345:1368 1377, 2001.

EGDT Lactate > 4 mmol/l or Septic Shock NEJM 345:1368 77, 2001.

EGDT Initial Results Rivers E, et al. N Engl J Med 345:1368 1377, 2001.

EGDT NEJM 345:1368 77, 2001.

ProCESS ProCESS ARISE ARISE ProMISE

HOWEVER I 2 = 57% SUBSTANTIAL HETEROGENEITY

Cut and Dried?

Rivers, et al. ProCESS ARISE ProMISe # per group 130, 130 445, 448, 458 792, 796 625, 626 Standard Rx Mortality EGDT Mortality 46.5% 18.9% 18.8% 29.2% 30.5% 21.0% 18.6% 29.5% APACHE II 20.4 20.7 15.8 18.0 ScvO 2 % 48.6 ± 11.2 71 ± 13 72.7 ± 10.5 70 ± 12 ScvO 2 > 70% 3, 3 222, 224, 229 346, 348 312, 313 Antibiotic Time 92.4% in 6 hours 75% in 72 minutes median 91 minutes 100% in 2.5 hours Fluids Before Randomizing 20-30 ml/kg, if hypotensive > 29 ml/kg > 30 ml/kg > 1.95 L in 2.5 hours

Two Concepts to Remember Power of randomization Properties of the normal distribution

Intention to Treat Analysis Inclusion of all randomized patients in each group Helps overcome Protocol non-compliance Missing data Not intended for Patients who already meet endpoint at inclusion Perspect Clin Res. 2011 Jul-Sep; 2(3): 109 112.

ProCESS, ARISE, ProMISe EGDT, as originally defined, applied to patients who meet the original criteria, does not add survival benefit in centers adept at sepsis management when patients are identified early, given antibiotics and fluid boluses early.

EGDT vs Control: Benefit Depends on Control Group Mortality Benefit when Control Mortality >35% EGDT inferior to Lactate/CVP directed therapy

Remaining Scientific Questions How important is low ScvO 2 in determining MORTALITY from septic shock? Should all patients with septic shock be assessed for low ScvO 2? (this means central access in all) For patients who actually have low ScvO 2, is some form of systematic approach desirable? Time will tell!

CMS Measures and Quality Sepsis Care We re from the Government We re here to help

Surviving Sepsis Campaign Bundles To be completed within 3 hours: 1. Measure serum lactate level 2. Obtain blood cultures prior to administration of antibiotics (1C) 3. Administer broad spectrum antibiotics (1B, 1C) 4. Administer 30 ml/kg crystalloid for hypotension or lactate 4 mmol/l

Surviving Sepsis Campaign Bundles To be completed within 6 hours 1. Apply vasopressors (for hypotension that does not respond to initial fluid resuscitation) to maintain a mean arterial pressure (MAP) 65 mm Hg 2. In the event of persistent arterial hypotension despite volume resuscitation (septic shock) or initial lactate 4 mmol/l (36 mg/dl) Measure central venous pressure (CVP)* Measure central venous oxygen saturation (ScvO2)* 3. Re-measure lactate if initial lactate was elevated* *Targets are: CVP 8 mm Hg, ScvO2 > 70%, lactate normal

CMS Core Measures: Simply Complicated Within 3 hours of Presentation of Severe Sepsis 1. Initial lactate level measurement 2. Broad spectrum antibiotics administered 3. Blood cultures drawn prior to antibiotics 4. Crystalloid fluid initiated Did hypotension persist after fluid given? NO YES, continue on Core Measure goals met, re-measure lactate within 6hrs Within 3 hours of Presentation of Septic Shock 1. Resuscitation with 30ml/kg crystalloid fluids 2. Evaluate the need for vasopressors After fluid resuscitation, but within 6 hours of Presentation of Septic Shock Re-assessment of volume status and tissue perfusion A focused exam including Vital signs Cardiopulmonary exam Capillary refill evaluation Peripheral pulse evaluation Skin examination Must be performed and documented by a Physician, ARNP, or PA 2 out of 4 from the following: CVP Bedside Cardio US ScvO 2 Passive Leg Raise or Fluid Challenge

www.mwcritcare.org

www.kansassepsisproject.org

Thank you! ssimpson3@kumc.edu