John Park, MD Assistant Professor of Medicine

John Park, MD Assistant Professor of Medicine Faculty photo will be placed here park.john@mayo.edu 2015 MFMER 3543652-1

Sepsis Out with the Old, In with the New Mayo School of Continuous Professional Development 2nd Annual Inpatient Medicine for NPs & Pas: Hospital Care from Admission to Discharge Wednesday-Saturday, October 19-22, 2016 Sawgrass Marriott Hotel Ponte Vedra Beach, Florida 2015 MFMER 3543652-2

Disclosure I have no relevant financial conflicts to disclose 2016 MFMER 3543652-3

Objectives To be able to recognize sepsis Understand the importance of early intervention Implement treatment guidelines in management of sepsis 2016 MFMER 3543652-4

Case 1 A 78 year-old male with history of HTN presents with fever and dysuria for 3 days. VS in the ED: BP = 125/65 (MAP 85), RR = 28, HR = 120, Temp = 38.9⁰C. Urine shows many WBCs, nitrite positive. Blood and urine were sent for cultures. Does this person have sepsis? A. Yes B. No C. Maybe 2016 MFMER 3543652-5

Case 1 A 78 year-old male with history of HTN presents with fever and dysuria for 3 days. VS in the ED: BP = 125/65 (MAP 85), RR = 28, HR = 120, Temp = 38.9⁰C. Urine shows many WBCs, nitrite positive. Blood and urine were sent for cultures. Does this person have sepsis? A. Yes B. No C. Maybe 2016 MFMER 3543652-6

Case 2 78 year old male presents with cough and dyspnea for one week. His vitals: temp 37.9, HR 90, RR 15, BP 110/48 (MAP 69). You hear some crackles in the lung fields. Pertinent laboratory findings include WBC of 9 K and lactate of 1.0. Bilirubin is 1.8 (normal < 1.2)and creatinine is 2.0 (normal < 1.2). Chest x-ray shows an infiltrate in the right lower lobe. Does this person have sepsis? A. Yes B. No C. Maybe 2016 MFMER 3543652-7

Case 2 78 year old male presents with cough and dyspnea for one week. His vitals: temp 37.9, HR 90, RR 15, BP 110/48 (MAP 69). You hear some crackles in the lung fields. Pertinent laboratory findings include WBC of 9 K and lactate of 1.0. Bilirubin is 1.8 (normal < 1.2)and creatinine is 2.0 (normal < 1.2). Chest x-ray shows an infiltrate in the right lower lobe. Does this person have sepsis? A. Yes B. No C. Maybe 2016 MFMER 3543652-8

Sepsis SIRS + infection (known or suspected) Systemic inflammatory response syndrome Infection Non-infectious Pancreatitis Criteria Temp > 38.3ºC or < 36ºC HR > 90/minute RR > 20/minute WBC > 12,000 or < 4,000/mm 3, or > 10% bands 2016 MFMER 3543652-9

Crit Care CCM Med 2013;41:580 2016 MFMER 3543652-10

In With the New 2016 MFMER 3543652-11

SEPSIS - 3 Life-threatening organ dysfunction caused by dysregulated host response to infection Organ dysfunction is identified by acute change in total SOFA (Sequential Organ Failure Assessment ) score of 2 points This criteria had in-hospital mortality risk of 10% Compared to 8.1% for STEMI JAMA 2016;315(8):801 2016 MFMER 3543652-12

SOFA JAMA 2016;315(8):801 2016 MFMER 3543652-13

Case 1 A 78 year-old male with history of HTN presents with fever and dysuria for 3 days. VS in the ED: BP = 125/65 (MAP 85), RR = 28, HR = 120, Temp = 38.9⁰C. Urine shows many WBCs, nitrite positive. Blood and urine were sent for cultures. Does this person have sepsis? A. Yes B. No C. Maybe 2016 MFMER 3543652-14

SEPSIS - 3 Severe Sepsis terminology is so yesterday! Septic shock: In those with sepsis, those needing vasopressors to maintain MAP 65 mmhg and lactate > 2 mmol/l (18 mg/dl) despite adequate volume resuscitation These patients have expected hospital mortality of 40%! JAMA 2016;315(8):801 2016 MFMER 3543652-15

qsofa (Quick SOFA) Having 2 of 3 criteria in those with infection should alert clinicians to further investigate for potential sepsis, escalate care/therapy, and/or transfer to higher level of care Also, having these criteria in those not previously known to have infection, should prompt clinician to look for possible infection JAMA 2016;315(8):801 2016 MFMER 3543652-16

Case 3 An 85 y/o nursing home resident is admitted to the floor for altered mental status. GCS = 14. He was recently treated for healthcare associated pneumonia with broad spectrum antibiotics. He has had diarrhea and decreased oral intake for 5 days. His BP is 92/50 mm Hg (MAP 64), RR 20/min, HR 120/min, T 37.6 ⁰ C. His C. diff toxin was negative. He has poor skin turgor, and dry skin and oral mucosa. His urine output has been 10 ml for the last 4 hours, and his Cr is 1.9. His serum lactate is 5 mmol/l. Does he have sepsis? A. Yes B. No 2016 MFMER 3543652-17

Case 3 An 85 y/o nursing home resident is admitted to the floor for altered mental status. GCS = 14. He was recently treated for healthcare associated pneumonia with broad spectrum antibiotics. He has had diarrhea and decreased oral intake for 5 days. His BP is 92/50 mm Hg (MAP 64), RR 20/min, HR 120/min, T 37.6 ⁰ C. His C. diff toxin was negative. He has poor skin turgor, and dry skin and oral mucosa. His urine output has been 10 ml for the last 4 hours, and his Cr is 1.9. His serum lactate is 5 mmol/l. Does he have sepsis? A. Yes B. No 2016 MFMER 3543652-18

Case 3 An 85 y/o nursing home resident is admitted to the floor for altered mental status. GCS = 14. He was recently treated for healthcare associated pneumonia with broad spectrum antibiotics. He has had diarrhea and decreased oral intake for 5 days. His BP is 92/50 mm Hg (MAP 64), RR 20/min, HR 120/min, T 37.6 ⁰ C. His C. diff toxin was negative. He has poor skin turgor, and dry skin and oral mucosa. His urine output has been 10 ml for the last 4 hours, and his Cr is 1.9. His serum lactate is 5 mmol/l. Does he have sepsis? A. Yes B. No 2016 MFMER 3543652-19

Case 3 An 85 y/o nursing home resident is admitted to the floor for altered mental status. GCS = 14. He was recently treated for healthcare associated pneumonia with broad spectrum antibiotics. He has had diarrhea and decreased oral intake for 5 days. His BP is 92/50 mm Hg (MAP 64), RR 20/min, HR 120/min, T 37.6 ⁰ C. His C. diff toxin was negative. He has poor skin turgor, and dry skin and oral mucosa. His urine output has been 10 ml for the last 4 hours, and his Cr is 1.9. His serum lactate is 5 mmol/l. Does he have sepsis? A. Yes B. No 2016 MFMER 3543652-20

Case 3 An 85 y/o nursing home resident is admitted to the floor for altered mental status. GCS = 14. He was recently treated for healthcare associated pneumonia with broad spectrum antibiotics. He has had diarrhea and decreased oral intake for 5 days. His BP is 92/50 mm Hg (MAP 64), RR 20/min, HR 120/min, T 37.6 ⁰ C. His C. diff toxin was negative. He has poor skin turgor, and dry skin and oral mucosa. His urine output has been 10 ml for the last 4 hours, and his Cr is 1.9. His serum lactate is 5 mmol/l. Does he have sepsis? A. Yes B. No 2016 MFMER 3543652-21

Sepsis Starts with infection, either suspected or documented Then look for any additional signs of organ dysfunction and hypoperfusion Need: ABG CBC Bilirubin Creatinine GCS assessment Lactate 2016 MFMER 3543652-22

Operationalization of Sepsis Identification JAMA 2016;315(8):801 2016 MFMER 3543652-23

Importance of Early Intervention N = 9190 Each 10% increase in lactate was associated with 9.4% increase in odds of hospital death Each 7.5 ml/kg increase in fluids was associated with 1.3% decrease in lactate Ann Am Thorac Soc 2013;10:466 2016 MFMER 3543652-24

Too Much of a Good Thing Ann Am Thorac Soc 2013;10:466 2016 MFMER 3543652-25

Sepsis: Management Early appropriate antibiotics Crit Care Med 2006;34:1589 2016 MFMER 3543652-26

Sepsis Management Fluids If they are hypotensive, have elevated lactate, have reduced urine output Recall tachycardia may also be due to fever 250 ml is NOT a bolus Bolus is not 100 cc/hr Bolus is given within 15 minutes 500 to 1000 ml at a time 2016 MFMER 3543652-27

The Volume Properties of 1-L Fluid Infusion Fluid Volume (ml) Intracellular Extra-cellular Intravascular Interstitial D 5 W 660 255 85 NS or LR -100 825 275 3% NaCl -2950 2690 990 5% Albumin 0 500 500 Whole blood 0 0 1000 Courtesy: Dr. Afessa 2016 MFMER 3543652-28

Meta-analysis of Albumin in Sepsis Crit Care Med 2011;39:386 2016 MFMER 3543652-29

Hydroxyethyl Starch (HES) NEJM 2012;367:124 2016 MFMER 3543652-30

CRISTAL Trial JAMA 2013;310:1809 2016 MFMER 3543652-31

Albumin Supplementation: ALBIOS NEJM 2014;350:2247 2016 MFMER 3543652-32

Contents of Crystalloids and Colloid NS LR 5% Alb Na 154 130 130-160 Cl 154 109 130-160 Osm 310 275 310 Lactate 0 28 0 Potassium 0 4 0 Calcium 0 3 0 ph 5 6.5 6.9 Cost 0.6 0.75 80 2016 MFMER 3543652-33

Type of fluid matters Balanced fluid (lactated ringer) appears to be better than normal saline Crit Care Med 2014;42:1585 2016 MFMER 3543652-34

Type of fluid matters Chloride restrictive fluids (LR or Plasma-Lyte) reduces renal injury JAMA 2012;308:1566 2016 MFMER 3543652-35

Amount of fluid matters Giving too much may be harmful Adjusted for age, APACHE II score, dose of norepinephrine +710 +2880- +4900 +8150 Crit Care Med 2011;39:259 2016 MFMER 3543652-36

Issues Regarding Fluids Watch out for hyperchloremic metabolic acidosis with too much NS Crystalloid should be the initial resuscitative fluid 5% albumin is iso-oncotic whereas 25% albumin is hyper-oncotic Chloride-restrictive fluid may have better outcomes Too much fluid may be harmful 2016 MFMER 3543652-37

Sepsis Management Early identification Initially based on suspicion, but adjust accordingly Procalcitonin Not for diagnosis of sepsis Misses fungal and possibly viral 2016 MFMER 3543652-38

Sepsis Management Early appropriate antibiotics Targeting suspecting organism Considering potential resistance Sufficient fluid administered Crystalloid first Consider chloride-restrictive or balanced fluid 2016 MFMER 3543652-39

What next? 2016 MFMER 3543652-40

Early Goal Directed Therapy NEJM 2001;345:1368 2016 MFMER 3543652-41

Surviving Sepsis Guideline Crit Care Med 2013;41:580 2016 MFMER 3543652-42

CCM 2013;41:580 2016 MFMER 3543652-43

Crit Care Med 2013;41:580 2016 MFMER 3543652-44

ProCESS Trial NEJM 2014;370:1683 2016 MFMER 3543652-45

ARISE Trial NEJM 2014;371:1496 2016 MFMER 3543652-46

ProMISe Trial NEJM 2015;372:1301 2016 MFMER 3543652-47

Adapted from NEJM 2014;370:1683 2016 MFMER 3543652-48

Adapted from NEJM 2014;370:1683 2016 MFMER 3543652-49

Vasopressors Norepinephrine is the first line Vasopressin can be added 0.03 or 0.04 u/min NOT titrated If still hypotensive, add steroids Hydrocortisone 50 mg Q6 hr Next choice of pressors depends Inotrope Epinephrine Phenylephrine Dopamine has been associated with worse outcomes! 2016 MFMER 3543652-50

Vasopressors α - vasoconstriction β 1 increase HR and myocardial contractility β 2 - vasodilation Chest 2007;132:1678 2016 MFMER 3543652-51

Mayo MICU Sepsis Management Within the first 3 hours: Lactate POC in MICU. If elevated, repeat in 3 hours. If normal, no further testing Cultures before antibiotics Antibiotics 30 ml/kg IVF bolus Noticed: De-emphasized: CVP, SCVO 2, RBC transfusion! 2016 MFMER 3543652-52

CMS!!!!! 2016 MFMER 3543652-53

CMS!!!! 2016 MFMER 3543652-54

Sepsis - Summary Early identification Starts with infection suspected or documented! SOFA qsofa But for CMS SIRS 2016 MFMER 3543652-55

Sepsis - Summary Early management Lactate Make sure its repeated if > 2 mmol/l, within 6 hours Cultures before antibiotics Appropriate antibiotics Fluids 30 ml/kg crystalloid 2016 MFMER 3543652-56

Sepsis - Summary Crystalloids Balanced or chloride-restrictive fluid may be better 30 ml/kg Control the source of infection Repeat lactate, if initial was elevated, should guide 2016 MFMER 3543652-57

Sepsis - Summary Consider adjunctive therapies Vasopressors Hydrocortisone Consider cardiogenic issues Demand ischemia Stress cardiomyopathy Consider transfer to higher level of care Only if I am not covering the MICU! 2016 MFMER 3543652-58

Thanks for your attention 2016 MFMER 3543652-59

Questions & Discussion 2016 MFMER 3543652-60

GCS www.glasgowcomascale.org 2016 MFMER 3543652-61