Early Goal Directed Therapy in Severe Sepsis and Septic Shock: Where Are We 10 Years Later

Early Goal Directed Therapy in Severe Sepsis and Septic Shock: Where are we 10 years later

Emanuel P. Rivers, MD, MPH, IOM Vice Chair and Research Director Senior Staff in Emergency Medicine and Critical Care Henry Ford Hospital Clinical Professor, Wayne State University Detroit, Michigan Why Should You Bother with Early Sepsis Intervention? Time Sensitive Diseases Changing the Paradigm of Practice

AMI Stroke Trauma

< 10% 7% < 5% Acute Myocardial Liver Transplant Infarction Mortality - 10% Mortality - 5%

Trauma Mortality - 5% Cardiac Surgery Mortality - 5%

Septic Shock Mortality– 50-55% 10% of Hospital Admissions – 40% of Hospital Deaths $100 million in total hospital costs per year 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.

Early Detection of High Risk Patients

Collaboration is Fun

Inflammation Microcirculation

Appropriate Disposition The LectureEarly Goal Directed Goals HemodynamicICU Optimization

Organ Dysfunction Decrease Health Care Resource Consumption Decrease Mortality The First Step: Understanding the Pathogenesis and Expanding the Landscape of Sepsis Sepsis: A Complex and Dynamic Landscape

Systemic Inflammation Source Sepsis or Inflammatory Response Organism Systemic Inflammatory Response Syndrome (SIRS) A clinical response arising from a nonspecific insult, including 2 of the following:

Diffuse endothelial o odisruption and • Temperature ≥38 C or ≤36microcirculationC defects • HR ≥90 beats/minGeneralIntensiveEmergencyAtOut HomeOR Patient Practice Care or Global Tissue andDepartmentResidenceSettingFloors RecoveryUnit • RespirationsHypoxia and ≥20/min Organ 3 Severe Sepsis • WBCDysfunction count ≥12,000/mm or ≤4,000/mm3 or >10% bands • PaCO2 < 32mmHg

Septic Shock

Multiple Organ Dysfunction and Refractory Hypotension Pre-Hospital

ICU General IPD Floors and Post Op

• After ICU Admission: • 67 minute delay to – > 6 hour total delay for ICU arrival.# hemodynamic optimization. • 3 fold increase in – ICU is poor • 115 million visits/year. mortality. • 2.9% of hospital admits are • Shock mortality rate: severe sepsis and septic shock. – ICU - 24% to 70%. – 600,000 admissions per year through the ED. • ED waiting times (5-6 hours) approaching 24 hours. McCaig: MMWR, 2001, Angus DC et al. CCM, 2001, Varon, CCM, 1997, Lundberg, 1998, CCM, Lefrant, 2000*, CCM A Systems Approach and A Resuscitation Golden Hours

Bundles

Silver Day The Evidence behind the Resuscitation Bundle The Role of Antibiotics • 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.

The Importance of Source Control • 54 y/o high school principle presents with pyelonephritis, receives antibiotics.

Crit Care Med, 2004

• Radiography

• Remove infected devices

• Early Surgical Intervention Sepsis is the friend of the elderly ……. Greg Henry Miss World Finalist Mariana Bridi da Costa Age 20, Dies From septic shock

“Doctors diagnosed her with a urinary track infection, her condition worsened and doctors then diagnosed her with kidney stone and urinary tract infection spread”

“She was hospitalized, required dialysis and had her hands and feet amputated in a bid to save her from a deadly and little-known illness” The Diagnosis of Sepsis is Imperfect StephenStephen Hales Hales -- 17331733

Outcome Implication of Not Recognizing A Subtle but Deadly Disease Transition

ER or Ward ICU

MAP ~ SVR X CO The Physiology of Oxygen Transport:

Defining Tissue Hypoperfusion SvO2 = 65-75% Hgb x SaO2 + PaO2 x 0.003 = 20 volume %

Cardiac Output 5 liters/min.

25%

250 ml/min 1000 ml/min Global Tissue Hypoxia: A More Sensitive Measure of Shock

OXY GEN DEM AND OXYGEN OXYGEN Global Tissue DEMAND DELIVERYO XYG D EN Hypoxia ELIV ERY

OXYGEN BALANCE

Lactic Acid > 4 mM/L ScvO2 SvO2

70-75% - +

VO2 DO2

• Stress • SaO2/PaO2 • Pain • Hgb • Hyperthermia • Cardiac Output • Shivering • Work of breathing Pope, Annals of Emerg Med, 2009

619 Patients received EGDT in 4 centers Pope, Annals of Emerg Med, 2009

< 70% 70 - 90% > 90% Risk Stratification or Early Detection of High Risk Patients:

The Use of Lactate

Diagnostic and Therapeutic Markers

<2mM/L4 mM/L SvO2 38- 40% Diagnostic and Therapeutic Markers

4 mM/L SvO2 The Implications of Lactate Clearance  Lactate (ED or ICU Admission – (ED or ICU @ 6 hours) ED or ICU Length of Stay (hrs)

80 70 60 50 Lactate 40 30 Clearance 20 % 10 0 -10 -20 -30 1 2 3 4

Quartiles of Lactate Clearance 11 No Clearance 10 Intermediate Clearance High Clearance Early Lactate 9

S Clearance

8D 7O M 6 5 4 3 0 6 12 24 36 48 60 72 Time (hr) p<0.05

60 53 50 42 Debaker, 2006 )

% 40 (

t 29 i l 30 a t r o 20 16 M 10

0 1 2 3 4 JAMA EGDT Lactate 3.8 7.7 SAPS II 44.8 51.2 Predicted Mortality 34.8% 48.4%

ScvO2 74 48.6 Central Venous Pressure 11 5.3 ) 2 m / Lactate SvO n 2 i m / l m (

n o i t p m

u EGDT JAMA Critical O Delivery s 2

n Threshold o C 2 O

c i m e t

s JAMA EGDT y

S Lactate 3.8 7.7 2 Systemic O2 Delivery (ml/min/m ) SAPS 44.8 51.2

ScvO2 74 48.6 CVP 11 5.3 50% of vasopressor-dependent septic shock patients do not express lactic acidosis and have higher mortalities

Crit Care, 2009 The Hemodynamic Perturbations of Early Sepsis 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 Goal Directed Septic Shock

DO CNS and Systemic VO2 2 - Stress - PaO2 - Pain - Hemoglobin - Hyperthermia - Cardiac Output - Shivering - Work of breathing Cardiac Optimization - Preload (CVP, PCWP, SVV) - Afterload (MAP, SVR) Contractility (SV) Endpoints of Resuscitation - Heart Rate (BPM) - Coronary Perfusion Pressure

SvO2 Lactate Microcirculation (a-v)CO2

Happy Base Cell Deficit

pHi

StO2 VO2 Excellence is performing common things in uncommon places….

George Washington Carver Task Force of the American College of Critical Care Medicine Fluids Vasopressors Inotropes Lactate Practice parameters for hemodynamic support of sepsis in adult patients in Hematocrit of 30% sepsis. SvO2 Crit Care Med 1999 ;27:639-60 Sepsis is a Spectrum of Disease

CVP Treatment and MAP FTc Lactate ScvO2 Comments PPV

Hypovolemia Variable ↓ ↓ ↑ Volume Compensated and Vasopressors ↓ Normal Variable vasodilatory ↑ Adrenal Dysf.

Myocardial Correct anemia Variable ↑ Suppression ↓ ↑ Inotropic Therapy

Impairment of Vasodilators, Variable Normal ↑ ↑ tissue O2 utilization r-APC • 62 year presents with sepsis after a prostate biopsy. • He also complains of SIRS, SOB and disorientation. • WBC of 25,000 and Lactate of 9 mM/L • Blood cultures and Antibiotics • 7 liters of fluid May, 2006 93 years old Perforated Ulcer 7 liters of fluids in first 6 hours and off vasopressors Before Surgery

Day 2 – Extubated in the Recovery Room 10 liters of fluid in 10 hours

Levophed – 10 ug/min Day 3 – Mobilization Although no difference in mortality at 60 days between the two treatment groups, patients treated according to a conservative strategy of fluid management (47 hours after ICU adm) had:

1. Significantly improved lung function and central nervous system function

2. Decreased need for sedation, mechanical ventilation, and intensive care.

3. A small (0.3 day) increase in the number of cardiovascular-failure–free days during the first 7 days with the liberal strategy.

These salutary effects were achieved without an increase in the frequency of non-pulmonary organ failure or shock. PaO2/FIO2 Ratio

350 Standard EGDT o i 300 t a R

2 O i F / 2 O a

P 250

200 0 3 6 12 24 36 48 60 72 Hours after start of treatment

Sepsis is a Spectrum of Disease

Treatment and MAP CVP Lactate ScvO2 Comments

Hypovolemia Variable ↓ ↓ ↑ Volume Compensated and Vasopressors ↓ Normal Variable vasodilatory ↑ Adrenal Dysf.

Myocardial Correct anemia Variable ↑ Suppression ↓ ↑ Inotropic Therapy

Impairment of Vasodilators, Variable Normal ↑ ↑ tissue O2 utilization r-APC

The Choice of a Vasopressor

Hypotensive Tachycardic Patient

Hypotensive Bradycardic Patient

60 58% 54% )

% 40 37% ( y t i l a t r

o 20% 20 M

0 No No Vasopressor No Vasopressor Low Dose Vasopressor to Low Dose to High Dose to High Dose Vasopressor Vasopressor Vasopressor What do these individuals have in common? Adrenal Insufficiency

Effect of Low Doses of Hydrocortisone and Fludrocortisone on Mortality in

(Annane JAMA 2002) Patients with Septic Shock

Design: Randomized, double-blind, 229 Non-responders multi-center Randomized

Patients: Septic shock 115 Treatment & 114 controls Intervention: Hydrocortisone (50 mg every six hours) 10% decrease in Fludrocortisone (50 ug once per day) 28-day mortality

Main Outcome: 28-day survival in 17% reduction in nonresponders to CST vasopressors use

Patients Receiving Vasopressors – Septic Shock No Outcome Benefit 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 • 56% mortality treated – over 50% • Less severe patients – 30 - 40% mortality • Similar benefit with higher mortality

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) Sepsis is a Spectrum of Disease

CVP Treatment and MAP FTc Lactate ScvO2 Comments PPV

Hypovolemia Variable ↓ ↓ ↑ Volume Compensated and Vasopressors ↓ Normal Variable vasodilatory ↑ Adrenal Dysf.

Myocardial ↑ and Correct anemia Variable Suppression BNP ↓ ↑ Inotropic Therapy

Impairment of Vasodilators, Variable Normal ↑ ↑ tissue O2 utilization r-APC Global Tissue Hypoxia

Parillo, JClin.Invest, 1985 Inflammatory Mediators

Ms. Peterson

• Infected foot – clostridium Perf (anaerobe) • Lactate of 10 and oliguric • BNP -3467 • BUN-77 and creatinine 4.3 • CXR • Ultrasound Sepsis is a Spectrum of Disease

CVP Treatment and MAP FTc Lactate ScvO2 Comments PPV

Hypovolemia Variable ↓ ↓ ↑ Volume Compensated and Vasopressors ↓ Normal Variable vasodilatory ↑ Adrenal Dysf.

Myocardial Correct anemia Variable ↑ Suppression ↓ ↑ Inotropic Therapy

Impairment of Vasodilators, Variable Normal ↑ ↑ ↑ tissue O2 utilization r-APC Venous Hyperoxia in Sepsis Pope, Annals of Emerg Med, 2009

< 70% 70 - 90% > 90%

Developing a sepsis quality improvement program is not as painful as it appears! The Devil is in the Details of a Sepsis Program

Understanding 3 Concepts 6 hour Quality Epidemiology theDocumentation andof Pathogenesis Bundle Teams Assurance Standard Operating Procedures

Recognizing Early Staging Timely Definitive Improved one has a of Illness Interventions Care Outcomes problem? Severity Upon Arrival ED or ICU? And Costs

CME Current Sepsis 24 hour Documentation and Early Markers Management Bundle And Orders Peer Uniformity Early Sepsis Intervention Saves Hospital Costs 54.336 Billion 183% Increase over 8 years 20% Reduction in Sepsis Related Costs Or $10 Billion of the $500 Billion in National Health Care Savings Roberta Mooney Sepsis Coordinator at HFHS

Daily Monthly Assessment of Meetings and all admitted Reports for all sepsis patients ICU’s and ED

Feed back to all clinicians EGDT after a Decade NEJM, 2001 % y t i l

a 51% t r

o 46%

M 30%

November 8, 2001

Pre-EGDT Control EGDT 2009

2008 November, 2009 Abstracts (4298 Patients) Crowe, 2010 16-18% Lefrant, 2010 Mortality Reduction Cardoso, 2010 Castellanos-Ortega, 2010 Puskarich, 2009 Moore, 2009 Focth, 2009 Zambon, 2008 Zubrow, 2008 El Sohl, 2007 Sebat, 2007 Jones, 2007 6125 Before Chen, 2007 5328 Before Nguyen, 2007 Qu, 2006 Shu-Min Lin, 2006 Micek, 2006 Trzeciak, 2006 Shapiro, 2006 Kortgen, 2006 Sebat, 2005 Gao, 2005 Rivers, 2001 0 10 20 30 40 50

Absolute Risk Reduction Abstracts and Publications

Rivers, 2001

1 of every 6 Publications Patients

Abstracts

0.0 2.5 5.0 7.5 10.0

Number Need To Treat

5125 Before 4328 After Which component of the sepsis bundle actually works?

The Future of Sepsis Management What should I target for my next septic patient? Vasopressin

Steroids

Lactate, Cultures, Antibiotics Source Control EGDT, r-APC

Norm Glycemic Control

Tight Glycemic Control