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

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

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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

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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

Diagnosis and Management

  • f Severe Sepsis and

Septic Shock

A Decade of Evidence

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The Sunshine Act of Medical Transparency

I have no disclosures

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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.

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Golden Hours

Bundles

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

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  • 2,154 septic shock patients
  • Received antibiotics after the
  • nset 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 Jones’s study)?

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  • 30
  • 20
  • 10

10 20 30 40 50 60 70 80 Lactate Clearance % 1 2 3 4

Quartiles of Lactate Clearance

Initial Lactate minus Later Lactate Initial Lactate

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Early Lactate Clearance

12 24 36 48 60 72 6 3 4 5 6 7 8 9 10 11

No Clearance Intermediate Clearance High Clearance

Time (hr)

p<0.05

MODS

53 42 29 16 10 20 30 40 50 60 Mortality (%) 1 2 3 4

Debaker, 2006

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  • Its primary focus was on individually randomized trials

with 2 parallel groups that assess the possible superiority

  • f 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
  • ften inadequate.
  • CONSORT checklist. The intent is to improve reporting
  • f noninferiority and equivalence trials, enabling readers

to assess the validity of their results and conclusions.

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7.7 3.8 Lactate 5.3 11

Central Venous Pressure

48.6 74 ScvO2 51.2 44.8 SAPS II EGDT JAMA 48.4% 34.8% Predicted Mortality

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Systemic O2 Delivery (ml/min/m2) SvO2 Lactate

Critical O2 Delivery Threshold

Systemic O2 Consumption (ml/min/m2)

EGDT JAMA 7.7 3.8 Lactate 5.3 11 CVP 48.6 74 ScvO2 51.2 44.8 SAPS EGDT JAMA

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10.3% 21.0% 0.02 Not addressed Not addressed Sudden cardiopulmonary collapse,% 64.1 18.5 <0.001 3 7 0.2 Red blood cell transfusions,% 27.4 30.3 0.62 75 72 0.6 Vasopressors,% 13.7 0.8 <0.001 5 3 0.57 Inotropes,% 53.0 53.8 0.90 26 27 0.99 Mechanical Ventilation,% EGDT Standard Therapy p-value ScvO2 Guided Lactate Clearance p-value Rivers, NEJM Jones, JAMA

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

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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; 21:1868–1875. De Backer D, Creteur J, Silva E, et al: The hepatosplanchnic area is not a common source

  • f 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.

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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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Crit Care, 2009

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

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Increased Metabolic Demands: Fever, Tachypnea Hypovolemia,Vasodilation & Myocardial Depression Microvascular Alterations: Impaired Tissue Oxygen Utilization

Inflammatory Mediators Produce Cardiovascular Insufficiency 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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Septic Shock

Goal Directed

DO2

  • PaO2
  • Hemoglobin
  • Cardiac Output

Cardiac Optimization

  • Preload (CVP, PCWP, SVV, IVC)
  • Afterload (MAP, SVR)

Contractility (SV)

  • Heart Rate (BPM)
  • Coronary Perfusion Pressure

Microcirculation

CNS and Systemic VO2

  • Stress
  • Pain
  • Hyperthermia
  • Shivering
  • Work of breathing

Endpoints of Resuscitation

Lactate

Happy Cell

Base Deficit (a-v)CO2

SvO2

pHi VO2

P.E.

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Sepsis is a Spectrum of Disease

↑ ↑

Normal

Variable

Impairment of tissue O2 utilization

↑ ↓

↑

Variable

Myocardial Suppression Variable

↑

Normal ↓ Compensated and vasodilatory

↑ ↓

↓

Variable

Hypovolemia Lactate Flow CO, ScvO2 Volume CVP, SVV MAP SVR Vasodilators, r-APC Correct anemia Inotropic Therapy Vasopressors Adrenal Dysf. Volume Treatment and Comments

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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 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 ScvO2 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

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

Mechanical Ventilation

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Control (n= 10) EGDT (n = 7) p-value In-Hosp 70 % 14 %

0.0498

30-Day 70 % 14 %

0.0498

60-Day 80 % 14 %

0.0150

Mortality

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What do you think about pre-hospital use

  • f 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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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 Effect of Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock

(Annane JAMA 2002)

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 Inflammatory Mediators

Parillo, JClin.Invest, 1985

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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

Homeostasis

  • Fibrinolysis

Fibrinolysis

  • Coagulation

Coagulation

  • Inflammation

Inflammation Activated Protein C Activated Protein C Endothelial Dysfunction and Microvascular Thrombosis Hypoperfusion/Ischemia Acute Organ Dysfunction (Severe Sepsis) 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 can’t spend 6 hrs with one patient, and don’t have central lines with ScvO2?

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Barnes Jewish Hospital California Pacific Medical Center Christiana Care Health System

  • St. Cloud Hospital

Porter Memorial Hospital Henry Ford Hospital Detroit University Medical Center at Brackenridge Northwest Community Hospital

  • St. Joseph Mercy

Hospital University of Kansas Hospital Henry Ford Hospital Wyandotte

Multi-center Severe Sepsis & Septic Shock Collaborative

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The Multi-Center Severe Sepsis and Septic Shock Collaborative Group 1 1 Medical Centers ( 5 Com m unity / 6 Tertiary ) 9 States Post-Sepsis Quality I nitiative Group

( Treatm ent Group)

4 0 2 1 Treatm ent Patients Pre-Sepsis Quality I nitiative Group

( Historical Control Group)

1 4 4 6 Control Patients Severe Sepsis 4 4 .2 % Septic Shock 5 5 .8 % Severe Sepsis 3 6 .2 % Septic Shock 6 3 .8 %

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

2 0 0 3 2 0 0 5

to

2 0 0 5 2 0 0 8

to

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16% ARR

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The Future of Sepsis Management

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84 2000 4000 6000 8000 10000 12000 0 3 6 12 24 36 48 60 72 Hours after the start of treatment IL-1ra pg/ml

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85 20 30 40 50 60 0 3 6 12 24 36 48 60 72 Hours after the start of treatment TNF-α pg/ml

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Statins in shock?

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