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

The Sunshine Act of Medical Transparency

I have no disclosures

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.

Golden Hours

Bundles

What do you think of prehospital empiric antibiotic therapy?

 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.

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Crit Care, 2008

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

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What is your take on serial lactate (Allan Joness study)?

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Initial Lactate minus Later Lactate Initial Lactate

80 70 60 50 Lactate 40 30 Clearance 20 % 10 0 -10 -20 -30

Quartiles of Lactate Clearance

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11 10 9 8 7 6 5 4 3 0 6 12
60 50 Mortality (%) 40 30 20 10 0 1 2 3

No Clearance Intermediate Clearance High Clearance

MODS

Early Lactate Clearance

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36

48

60

Time (hr)
53 42 29

72 p<0.05

Debaker, 2006

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 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.

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Lactate SAPS II Predicted Mortality ScvO2

Central Venous Pressure

JAMA 3.8 44.8 34.8% 74 11

EGDT 7.7 51.2 48.4% 48.6 5.3

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Systemic O2 Consumption (ml/min/m2)

Lactate

SvO2

EGDT

JAMA

Critical O2 Delivery Threshold

JAMA Lactate 3.8 44.8 74 11

EGDT 7.7 51.2 48.6 5.3

Systemic O2 Delivery (ml/min/m2)

SAPS ScvO2 CVP

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A Lack of Interventions to Show Non-Inferiority Underpowered Beyond the Study Conditions

Jones, JAMA Lactate Clearance p-value Red blood cell transfusions,% Vasopressors,% Inotropes,% Mechanical Ventilation,% Sudden cardiopulmonary collapse,% 7 0.2 72 0.6 3 0.57 27 0.99 Not addressed ScvO2 Guided 3 75 5 26 Not addressed Rivers, NEJM Standard Therapy p-value 18.5 <0.001 30.3 0.62 0.8 <0.001 53.8 0.90 21.0% 0.02

EGDT 64.1 27.4 13.7 53.0 10.3%

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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; 21:18681875. 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; 29:256261. Oud L, Haupt MT: Persistent gastric intramucosal ischemia in patients with sepsis following resuscitation from shock. Chest 1999; 115:13901396.

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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.

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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.

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Crit Care, 2009

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50% of vasopressor-dependent septic shock patients do not express lactic acidosis and have higher mortalities

Crit Care, 2009

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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

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

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Goal Directed

Septic Shock
CNS and Systemic VO2 - Stress - Pain - Hyperthermia - Shivering - Work of breathing

DO2
- PaO2 - Hemoglobin - Cardiac Output Cardiac Optimization - Preload (CVP, PCWP, SVV, IVC) - Afterload (MAP, SVR) Contractility (SV) - Heart Rate (BPM) - Coronary Perfusion Pressure

Endpoints of Resuscitation
SvO2
Lactate

(a-v)CO2

Microcirculation

Happy Cell

Base Deficit

pHi

P.E.

VO2

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Sepsis is a Spectrum of Disease

MAP SVR Hypovolemia Compensated and vasodilatory Myocardial Suppression Impairment of tissue O2 utilization
Variable

Volume CVP, SVV Normal

Flow CO, ScvO2

Lactate

Treatment and Comments Volume Vasopressors Adrenal Dysf. Correct anemia Inotropic Therapy Vasodilators, r-APC

Variable

Variable

Variable

Normal

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

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No outcome difference

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Cardiac Output

Right Atrial Pressure

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Mortality Prediction at 48 hours

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

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How much fluid resuscitation should an ESRD patient receive?

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Baseline Characteristics
Control
(n = 10)

Treatment
(n = 7)

p-value 0.91 0.79 0.44 0.26 0.25 0.64 0.67 0.38 0.74

Age APACHE MODS SAPS Lactate ScvO2 CVP Heart Rate MAP

65 + 15 24.6 + 4.1 10.0 + 3.2 48.5 + 5.5 9.9 + 5.2 46.3 + 14 5.0 + 4.2 103 + 25 78 + 31

65 + 17 25.1 + 1 8.9 + 2.5 45.4 + 5.0 7.0 + 4.2 40.5 + 16 8.2 + 13.0 108 + 35 84 + 41

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Mechanical Ventilation

Control = 5/10 (50%)

Treatment = 2/7 (29%)

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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

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

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Steroids in shock?

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What is the deal with stress dose hormones?

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What is your take on the etomidate controversy?

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

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Patients Receiving Vasopressors Septic Shock

5 day therapy instead of 7 days

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No Outcome Benefit

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Now what should I do about steroids?

The Original Trial 8 hour time frame Minimal steroid use 56% mortality The Corticus Trial 72 hour time frame Excluded patients treated over 50% Less severe patients 30 - 40% mortality Similar benefit with higher mortality

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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)

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Timing of echo does it matter?

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Global Tissue Hypoxia

Parillo, JClin.Invest, 1985

Inflammatory Mediators

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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.

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Sepsis Data Base of 1287 Patients

183 with echo documented systolic dysfunction (EF< 50%) 135 patients did not meet EGDT Mortality 36.3% 48 patients met EGDT Mortality 17%

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Ms. Peterson
Infected foot clostridium Perf (anaerobe) Lactate of 10 and oliguric BNP -3467 BUN-77 and creatinine 4.3 CXR Ultrasound

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Is there any role for Protein C for severe sepsis in 2011?

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Activated Protein C Modulates Multiple Mechanisms in Severe Sepsis

Endothelial Dysfunction and Microvascular Thrombosis

Activated Protein C

Activated Protein C

Coagulation Inflammation

Fibrinolysis

Hypoperfusion/Ischemia

Acute Organ Dysfunction (Severe Sepsis) Homeostasis Death

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CCM, 2010

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Among patients presenting with septic shock, early treatment with activated protein C may be associated with reduced hospital mortality.

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Bernard, NEJM, 2001

< 6 hours

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How do you implement EGDT in a community hospital with single ED coverage where you cant spend 6 hrs with one patient, and dont have central lines with ScvO2?

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Multi-center Severe Sepsis & Septic Shock Collaborative

St. Cloud Hospital Henry Ford Hospital Northwest Community Detroit Hospital St. Joseph Mercy Hospital

Christiana Care Health System

California Pacific Medical Center University of Kansas Hospital University Medical Center at Brackenridge Barnes Jewish Hospital

Porter Memorial Hospital

Henry Ford Hospital Wyandotte

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The Multi-Center Severe Sepsis and Septic Shock Collaborative Group 11 Medical Centers (5 Community / 6 Tertiary ) 9 States

2003 2005
to

(Historical Control Group)

Pre-Sepsis Quality Initiative Group

Post-Sepsis Quality Initiative Group

(Treatment Group)

2005 2008
to

1446 Control Patients

4021 Treatment Patients

Severe Sepsis 44.2%

Septic Shock 55.8%

Severe Sepsis 36.2%

Septic Shock 63.8%

In this intention-to-treat evaluation, all patients including DNR were examined.

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16% ARR

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The Future of Sepsis Management

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12000 10000 IL-1ra pg/ml 8000 6000 4000 2000 0 0 3 6 12 24 36 48 60 72 Hours after the start of treatment

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60 TNF- pg/ml 50 40 30 20 0 3 6 12 24 36 48 60 72 Hours after the start of treatment

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Statins in shock?

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