Diagnosis and Management of Severe Sepsis and Septic Shock A - PDF document

Diagnosis and Management of Severe Sepsis and Septic Shock A Decade of Evidence Emanuel P. Rivers, MD, MPH, IOM Vice Chairman and Research Director Emergency and Surgical Critical Care Medicine Henry Ford Hospital Clinical Professor, Wayne State University Detroit, Michigan 1

The Sunshine Act of Medical Transparency I have no disclosures 2

HealthGrades analyzed over 5 million Medicare records of patients admitted through the emergency department at 4,907 hospitals from 2006 through 2008, to identify the top 5% of the best-performing hospitals in emergency medicine. 3

4

Golden Hours Bundles 5

What do you think of pre- hospital empiric antibiotic therapy? 6

• 2,154 septic shock patients • Received antibiotics after the onset of recurrent or persistent hypotension • Each hour of delay over 6 hrs was associated with 7.6% decrease in survival. 7

8

9

10

2 11

12

Crit Care, 2008 13

14

Can you describe the evidence and benefit associated with lactate clearance and the importance of repeating within 4 hours? 15

What is your take on serial lactate (Allan Jones’s study)? 16

Initial Lactate minus Later Lactate Initial Lactate 80 70 60 50 40 Lactate 30 Clearance 20 % 10 0 -10 -20 -30 1 2 3 4 Quartiles of Lactate Clearance 17

11 No Clearance Early Lactate Intermediate Clearance 10 High Clearance Clearance 9 MODS 8 7 6 5 4 3 0 6 12 24 36 48 60 72 p<0.05 Time (hr) 60 53 50 Debaker, 2006 42 Mortality (%) 40 29 30 20 16 10 0 1 2 3 4 18

• Its primary focus was on individually randomized trials with 2 parallel groups that assess the possible superiority of one treatment compared with another but is now being extended to other trial designs. • Noninferiority and equivalence trials have methodological features that differ from superiority trials and present particular difficulties in design, conduct, analysis, and interpretation. • The quality of reporting of those that are published is often inadequate. • CONSORT checklist. The intent is to improve reporting of noninferiority and equivalence trials, enabling readers to assess the validity of their results and conclusions. 19

20

JAMA EGDT Lactate 3.8 7.7 SAPS II 44.8 51.2 34.8% 48.4% Predicted Mortality ScvO 2 74 48.6 11 5.3 Central Venous Pressure 21

Systemic O 2 Consumption (ml/min/m 2 ) Lactate SvO 2 EGDT JAMA Critical O 2 Delivery Threshold JAMA EGDT Lactate 3.8 7.7 Systemic O 2 Delivery (ml/min/m 2 ) SAPS 44.8 51.2 ScvO 2 74 48.6 CVP 11 5.3 22

A Lack of Interventions to Show Non-Inferiority Underpowered Beyond the Study Conditions Jones, JAMA Rivers, NEJM Lactate Clearance ScvO 2 Standard Therapy EGDT p-value Guided p-value 7 18.5 Red blood cell transfusions,% 3 64.1 0.2 <0.001 72 30.3 Vasopressors,% 75 27.4 0.6 0.62 3 0.8 Inotropes,% 5 13.7 0.57 <0.001 27 53.8 Mechanical Ventilation,% 26 53.0 0.99 0.90 Sudden cardiopulmonary Not Not 21.0% 10.3% collapse,% addressed addressed 0.02 23

It is common knowledge, however, that many septic patients develop multiple organ failure and die despite normal blood lactate levels. Vallet B, Chopin C, Curtis S E, et al: Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: A prospective, multicenter study. Crit Care Med 1993; 21:1868–1875. De Backer D, Creteur J, Silva E, et al: The hepatosplanchnic area is not a common source of lactate in patients with severe sepsis. Crit Care Med 2001; 29:256–261. Oud L, Haupt MT: Persistent gastric intramucosal ischemia in patients with sepsis following resuscitation from shock. Chest 1999; 115:1390–1396. 24

Alactemic Sepsis • Multicenter Study (2,424 lactates) – 11.6% have Lactate < 2 and SBP < 90 (vasopressors) – 16% have Lactate < 2.5 and SBP < 90 (vasopressors) – 25% have Lactate < 4.0 and SBP < 90 (vasopressors) Cannon CM, for the Multicenter Severe S, Septic Shock Collaborative G. The GENESIS Project (GENeralization of Early Sepsis InterventionS): A Multicenter Quality Improvement Collaborative. Acad Emerg Med 2010;17:1258. 25

Alactemic Sepsis – Nguyen, East Asian Study (512 lactates) – 9.1% with LA < 2 and SBP < 90 (vasopressors) – 24.2% have LA < 4 and SBP < 90 (vasopressors) Na S, Joshi M, Li C-h, et al. Implementation of a 6-hour severe sepsis bundle in multiple asian countries is associated with decrease mortality. Chest 2009;136:20S. 26

Crit Care, 2009 27

50% of vasopressor-dependent septic shock patients do not express lactic acidosis and have higher mortalities Crit Care, 2009 28

Inflammatory Mediators Produce Cardiovascular Insufficiency Increased Metabolic Demands: Fever, Tachypnea Hypovolemia,Vasodilation & Myocardial Depression Microvascular Alterations: Impaired Tissue Oxygen Utilization Cytopathic Tissue Hypoxia Fink, Crit Care Clin, 2002 29

What are your markers of severe sepsis and goals of resuscitation? 30

Goal Directed Septic Shock DO 2 CNS and Systemic VO 2 - PaO 2 - Stress - Hemoglobin - Pain - Cardiac Output - Hyperthermia - Shivering Cardiac Optimization - Work of breathing - Preload (CVP, PCWP, SVV, IVC) - Afterload (MAP, SVR) Contractility (SV) Endpoints of Resuscitation - Heart Rate (BPM) - Coronary Perfusion Pressure SvO 2 Lactate Microcirculation (a-v)CO 2 Happy Base Deficit Cell pHi P.E. VO 2 31

Sepsis is a Spectrum of Disease Volume Flow MAP Treatment and CVP, CO, Lactate SVR Comments SVV ScvO 2 ↓ ↑ Hypovolemia Variable ↓ Volume Compensated and Vasopressors ↑ ↓ Normal Variable vasodilatory Adrenal Dysf. Myocardial Correct anemia ↓ ↑ Variable ↑ Suppression Inotropic Therapy Impairment of Vasodilators, ↑ ↑ Variable Normal tissue O 2 utilization r-APC 32

What is your take determining fluid responsiveness (Marik meta-analysis from Chest 2008)? 33

34

No outcome difference 35

Cardiac Output Right Atrial Pressure 36

Mortality Prediction at 48 hours 37

Are the things that the SAFE trial provides enough data to suggest using albumin? 38

39

40

41

42

43

How much fluid resuscitation should an ESRD patient receive? 44

Baseline Characteristics Control Treatment p-value (n = 10) (n = 7) Age 65 + 15 65 + 17 0.91 APACHE 24.6 + 4.1 25.1 + 1 0.79 MODS 10.0 + 3.2 8.9 + 2.5 0.44 SAPS 48.5 + 5.5 45.4 + 5.0 0.26 Lactate 9.9 + 5.2 7.0 + 4.2 0.25 ScvO 2 46.3 + 14 40.5 + 16 0.64 CVP 5.0 + 4.2 8.2 + 13.0 0.67 Heart Rate 103 + 25 108 + 35 0.38 MAP 78 + 31 84 + 41 0.74 45

Mechanical Ventilation Control = 5/10 (50%) Treatment = 2/7 (29%) 46

Mortality Control EGDT p-value (n= 10) (n = 7) In-Hosp 70 % 14 % 0.0498 30-Day 70 % 14 % 0.0498 60-Day 80 % 14 % 0.0150 47

48

What do you think about pre-hospital use of low dose vasopressin in moderate to severe sepsis to replenish the reserves? 49

50

51

52

Steroids in shock? 53

What is the deal with stress dose hormones? 54

What is your take on the etomidate controversy? 55

56

57

Effect of Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock (Annane JAMA 2002) Design: Randomized, double-blind, 229 Non-responders Randomized multi-center 115 Treatment & Patients: Septic shock 114 controls Intervention: 10% decrease in Hydrocortisone (50 mg every six hours) 28-day mortality Fludrocortisone (50 ug once per day) 17% reduction in Main Outcome: 28-day survival in vasopressors use nonresponders to CST 58

59

Patients Receiving Vasopressors – Septic Shock 5 day therapy instead of 7 days 60

No Outcome Benefit 61

Now what should I do about steroids? The Original Trial The Corticus Trial • 8 hour time frame • 72 hour time frame • Minimal steroid use • Excluded patients treated – over 50% • 56% mortality • Less severe patients – 30 - 40% mortality • Similar benefit with higher mortality 62

63

14.5% Reduction in Vasopressor Use if Optimized with EGDT Hold steroid use until the patient has been resuscitated and endpoints met (6-8 hours) 64

Timing of echo – does it matter? 65

Global Tissue Hypoxia Parillo, JClin.Invest, 1985 Inflammatory Mediators 66

67

Early Goal-Directed Therapy for Sepsis in Patients With Preexisting Left Ventricular Dysfunction: A Retrospective Comparison of Outcomes Based Upon Protocol Adherence Shah S, Ouellette DR. Chest 2010;138:897A. 68

Sepsis Data Base of 1287 Patients 183 with echo documented systolic dysfunction (EF< 50%) 135 patients 48 patients did not meet EGDT met EGDT Mortality 36.3% Mortality 17% 69