Updates in Sepsis 2017

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1 Mortality Cases Total U.S. Population/1,000 Updates in 2017 Joshua Solomon, M.D. Associate Professor of Medicine National Jewish Health University of Colorado Denver Background New Definition of New Trials of EGDT Transfusions New sepsis bundle Outline Survivors of sepsis Epidemiology of sepsis is a devastating medical condition Incidence has risen dramatically over the past 20 years (3/1000 population) While in hospital mortality is improving, 10 th leading cause of death in the United States mortality ranges from 30-50% >210,000 deaths/year Considerable impact on quality of life among survivors post critical illness syndrome Mortality of by Age in the US Projected Incidence of in US % 40% 35% Without Co-morbidity With Co-morbidity Overall 1,800,000 1,600,000 1,400,000 Cases US Population 600, ,000 30% 1,200, ,000 25% 20% 1,000, , ,000 15% 600, ,000 10% 5% 400, , ,000 0% Age Year Angus DC, et al. Crit Care Med Angus DC, et al. Crit Care Med

2 Bone et al. Chest 1992 Nidus of Infection Abscess Pneumonia Peritonitis Pyelonephritis Cellulitis Complement Pathogenesis of Coagulation - Extrinsic / intrinsic pathways - Protein C; S - TFPI Organism -Kinins Leukocyte aggregation Cytokines - Endothelial cell - TNF dysfunction - Interleukins Exotoxin TSST-1 Toxin-A Gut release of endotoxin Structural Component Cellular Dysfunction Teichoic Acid Antigen Peptidoglycan, Endotoxin (LPS) Bacterial nucleic acids Vasculature Organs Myocardium Plasma Monocyte-Macrophage Endothelial Cells Neutrophils - Vasodilation - Dysfunction - Depression - Vasoconstriction - Metabolic abnormalities - Dilatation - Interferons - MIF - HMGB1 Selectins, Icams Lysosomes Renin-angiotensin systemoxygen free radicals Prostaglandins (superoxides) Leukotrienes Granulocyte Colony Prostacyclin ShockThromboxane Platelet Activating Factor Endothelin Nitric Oxide Refractory Hypotension Tissue Factor Multiple Organ Dysfunction Recovery Stimulating Factor (G-CSF) What is the patient s diagnosis? A. B. C. Severe sepsis D. Septic shock DeathCellular Dysfunction Old Definitions Old Definitions Systemic Inflammatory Response Syndrome 2 or more of: Temperature >38 0 or <36 0 Heart rate >90 beats/min Respiratory rate >20 or PaCO2 < 32 mmhg WBC >12,000, <4,000, or left-shift (>10%) * Can result from a variety of insults (infection, trauma, pancreatitis, etc) 2

3 Old Definitions Old Definitions + Suspected Infection All 3 criteria met within 6 hrs of each other 1.Documentation of suspected source of infection ( possible ) 2. 3.Organ dysfunction (need only one) SBP < 90 or MAP < 65 mm Hg within 1 st hr Creatinine > 2 or urine output <.5 ml/kg/hr for > 2hr Bilirubin > 2 mg/dl Platelets < 100,000 Coagulopathy (INR > 1.5 or PTT > 60 sec) Lactate > 2 mmol/l Old Definitions Definition 2017 ( 3) with: Hypoperfusion despite adequate fluid resuscitation (SBP < 90 or MAP < 65 mm Hg or 40% reduction from baseline) OR Lactate > 4.0 mmol/l Quick SOFA 2 or more of Resp Rate 22 Altered Mentation (GCS 13) Systolic BP 100 mmhg Definition 2016 Clinical Handbook of Interstitial Lung Disease Clinical Handbook of Interstitial Lung Disea SEPSIS Evidence of Infection + Change in baseline SOFA score of 2 (assume baseline of 0) Sequential Organ Failure Assessment (SOFA) Score 3

4 Definition 2016 Vasopressors to maintain MAP 65 mmhg What is the patient s diagnosis (old definition)? A. B. C. Severe sepsis D. Septic shock And Lactate > 2 mmol/l despite volume resuscitation What is the patient s diagnosis (old definition)? A. B. C. Severe sepsis D. Septic shock What is the patient s diagnosis (new definition)? A. Not Septic B. C. Septic shock What is the patient s diagnosis (new definition)? A. Not Septic B. C. Septic shock 1.5 L of saline but remains hypotensive (She weighs 75 kg) What are the next best steps? A. Get blood cultures B. Give broad spectrum antibiotics C. Place a central line to measure CVP 4

5 Mortality % Surviving % Surviving Prompt Administration of Antibiotics Saves Lives Prompt Administration of Antibiotics Saves Lives N = 2731 patients 10 hospitals, 14 ICUs Each hour of delay is associated with an 8% decrease in survival < < Time to Antibiotic Administration (hrs) Time to Antibiotic Administration (hrs) Kumar. Crit Care Med 2006 Kumar. Crit Care Med 2006 or Early Goal Directed Therapy CVP < 8 mm Hg IV Fluids Has become a de facto standard of care for the last 14 years for how to resuscitate patients in severe sepsis and septic shock. Has led to sepsis bundles of care 3 hour bundle 6 hour bundle 8-12 mm Hg MAP > 65 mm Hg SvO 2 > 70% No Goals Met? < 65 mm Hg < 70% Vasopressors Transfuse blood until Hct > 30% Dobutamine > 70% < 70% NEJM November 8, 2001; 345: Yes ICU Admission Rivers. NEJM 345: ,2001 Early Goal Directed Therapy - Mortality 60 * p<0.05 PROCESS TRIAL ** p< ** ** * Control PROMISE TRIAL 30 EGDT ARISE TRIAL In-hospital 28 Day 60 Day Rivers. NEJM 345: , UPDATE 3 major large randomized trials Looking to determine if there REALLY is any benefit to using the approach of EGDT vs. usual care in patients with septic shock 5

6 ProCESS Trial ProCESS trial In 31 EDs across USA, randomly assigned patients with septic shock to one of three groups for 6 hr of resuscitation (1341 patients): Protocol-based EGDT Protocol-based standard therapy that did not require placement of CVP, inotropes, or blood transfusions Usual care N Engl J Med 2014;370: Early Goal Directed Therapy or CVP < 8 mm Hg IV Fluids Shock index = HR/SBP Values 0.8 suggestive of shock 8-12 mm Hg MAP < 65 mm Hg Vasopressors > 65 mm Hg > 70% SvO 2 < 70% Transfuse blood until Hct > 30% < 70% > 70% Dobutamine No Goals Met? Yes ICU Admission Rivers. NEJM 345: , day mortality Protocol EGDT: 21% Protocol standard therapy: 18.2% Usual care: 18.9% Relative Risk of death: Protocol v. usual care: 1.04 ( , p=0.83) EGDT v. prot. standard: 1.15 ( , p=0.31) ProCESS: Conclusions In our multicenter, randomized trial, in which patients were identified early in the ED as having septic shock and received abx and other non-resuscitation aspects of care promptly, we found no significant advantage, with respect to mortality or morbidity, of protocolbased resuscitation over bedside care provided according to the treating physician's judgment. We also found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients. 6

7 Enrolled 1600 patients at 51 centers to EGDT vs usual care in Australia and New Zealand Primary outcome: 90-day mortality 90-day mortality: EGDT: 18.6% Usual care: 18.8% ( P=0.90 ) EGTD had more vasopressors, RBC transfusions and dobutamine Pragmatic randomized trial of 1260 patients in 56 hospitals in England Patients with early septic shock were randomized to receive either: 6 hours of Early Goal-directed Therapy (EGDT) 6 hours of usual care 90 day mortality the same (29.5% vs 29.2%) EGDT had more IVF, vasoactive drugs, RBC EGDT had worse organ failure scores, more days with CV support, longer ICU stays Study Setting Patients EGDT Usual Care Protocol Based Rivers Single Center ProCESS ARISE ProMISE % Mortality % Mortality Study Setting Patients EGDT Usual Care Protocol Based Rivers Single Center ProCESS USA (31) ARISE Aus/NZ (51) ProMISE England (56) CVP is useless for assessing volume status % on Pressors % with CVC Study EGDT Usual Care EGDT Usual Care Rivers NA ProCESS ARISE ProMISE Shippy CR. Crit Care Med : Marik P. Chest. 2008;134(1):

8 CVP is useless for assessing volume status 1.5 L of saline but remains hypotensive (She weighs 70 kg) Shippy CR. Crit Care Med : What are the next best steps? A. Get blood cultures B. Give broad spectrum antibiotics C. Place a central line to measure CVP 1.5 L of saline but remains hypotensive (She weighs 70 kg) What are the next best steps? A. Get blood cultures B. Give broad spectrum antibiotics C. Place a central line to measure CVP, Hgb L of saline but remains hypotensive (She weighs 70 kg) What should we do about fluids? A. Give saline 30cc/kg based on CMS guidelines B. Give fluids until you think she s had enough C. Give blood to volume expand and improve oxygenation Fluid Administration After enrollment (L) Study Setting EGDT Usual Care Rivers Single Center ProCESS USA (31) ARISE Aus/NZ (51) ProMISE England (56) Fluid Administration After enrollment (L) Total in 6hrs (L) Study Setting EGDT Usual Care EGDT Usual Care Rivers Single Center ProCESS USA (31) ARISE Aus/NZ (51) ProMISE England (56)

9 % Transfused Study EGDT Usual Care Rivers ProCESS ARISE ProMISE Blood Administration TRISS Study Multicenter randomized controlled trial 998 patients with septic shock Transfused for Hgb < 9 or Hgb < 7 No benefit to higher Hgb Fluid Administration Summary and Additional Notes Starch is bad leads to renal failure and increased mortality Albumin appears to be safe but no benefit over crystalloid (ALBIOS and SAFE studies) Don t use blood to volume expand Crystalloids are best studied Give a minimum of 30 cc/kg in first 6 hrs (CMS guidelines) Most patients needed at least 4L in multicenter trials Use your clinical skills to determine the optimum amount LR may be better than saline (ph 3-6, chloride 150), Hgb L of saline but remains hypotensive (She weighs 70 kg) What should we do about fluids? A. Give saline 30cc/kg based on guidelines B. Give fluids until you think she s had enough C. Give blood to volume expand and improve oxygenation, Hgb L of saline but remains hypotensive (She weighs 70 kg) What should we do about fluids? A. Give saline 30cc/kg based on guidelines B. Give fluids until you think she s had enough C. Give blood to volume expand and improve oxygenation Bundle 0 3 hr 6 hr 1. measure lactate level 2. obtain blood cultures prior to antibiotics 3. administer broad spectrum antibiotics cc/kg crystalloid for hypotension or lactate 4 Physical exam or 2 of CVP ScVO2 Echo Dynamic assessment 1. apply vasopressors for hypotension that does not respond to initial fluid resuscitation (MAP 65) 2. re-assess volume status and tissue perfusion and document findings.* 3. Re-measure lactate if initial level was elevated 9

10 Survivors Of those who lived independently prior to sepsis: 1/3 die by 6 months 1/3 of 6 month survivors have not returned to independence 45% of those with problems at 6 m die or continue with problems at 1y Yendi et al. Crit Care 2016 New definitions of sepsis and septic shock No need for routine CVL and CVP Less transfusion (target hg > 7) Conclusions? Protocol to use but EGDT is not necessary Crucial points early recognition, early antibiotics, lot of fluid Survivors of sepsis have a tough road ahead of them Jutte et al. SRCCM