Transcript PowerPoint Sunusu - Thomas Jefferson University

Septic Shock: Current
Management and New
Therapeutic Frontiers
R. Phillip Dellinger, MD
Professor of Medicine
Robert Wood Johnson Medical School/UMDNJ
Director Critical Care Medicine
Cooper University Hospital
Camden, New Jersey
Personal Financial Disclosures
• None relevant to presentation today
Background - Basic Definitions
• Sepsis = known or suspected infection plus
systemic manifestations of infection (SIRS
and others)
• Severe Sepsis = Sepsis + either
– Acute organ dysfunction thought to be due to
sepsis
– Acute tissue hypoperfusion thought to be due to
sepsis
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Hypotension
Elevated lactate
Oliguria
(Altered mental status)
Background - Basic Definitions
• Severe Sepsis Organ Dysfunctions
– Acute lung injury
– Acute kidney injury
– Coagulopathy
• Thrombocytopenia
• Increased INR
– Liver Dysfunction
– (Cardiovascular)
• Septic Shock
– Vasopressors +/- organ dysfunction
Surviving Sepsis Campaign (SSC)
guidelines for management of severe
sepsis and septic shock
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,
Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM
and the SSC Management Guidelines Committee
Crit Care Med 2004;32:858-873
Intensive Care Med 2004;30:536-555
Surviving Sepsis Campaign: International guidelines for
management of severe sepsis and septic shock: 2008
Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM,
Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale
R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ,
Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson
BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL.
Crit Care Med 2008; 36:296-327
Intensive Care Med 2008;30:536-555
Sponsoring Organizations
2008 Guidelines
•American Association of Critical
Care Nurses
•American College of Chest
Physicians
•American College of Emergency
Physicians
•Canadian Critical Care Society
•European Respiratory Society
•European Society of Clinical
Microbiology and Infectious
Diseases
•European Society of Intensive Care
Medicine
•Indian Society of Critical Care
Medicine
• International Sepsis Forum
• Japanese Society of Intensive
Care Medicine
• Japanese Association of Acute
Medicine
• Society of Hospital Medicine
• Society of Critical Care Medicine
• Surgical Infection Society
• World Federation of Critical Care
Nurses
• World Federation of Societies of
Intensive and Critical Care
Medicine
SSC Update 2010/2011
Current Surviving Sepsis Campaign Guideline Sponsors
(2010/11 Update)
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American Association of Critical-Care
Nurses
American College of Chest Physicians
American College of Emergency
Physicians
Australian and New Zealand Intensive
Care Society
Asia Pacific Association of Critical Care
Medicine
American Thoracic Society
Brazilian Society of Critical Care(AIMB)
Canadian Critical Care Society
European Respiratory Society
European Society of Clinical Microbiology
and Infectious Diseases
European Society of Intensive Care
Medicine
European Society of Pediatric and
Neonatal Intensive Care
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German Sepsis Society
Infectious Diseases Society of America
Indian Society of Critical Care Medicine
Japanese Association for Acute Medicine
Japanese Society of Intensive Care Medicine
Latin American Sepsis Institute
Pan Arab Critical Care Medicine Society
Pediatric Acute Lung Injury and Sepsis
Investigators
Society Academic Emergency Medicine
Society of Critical Care Medicine
Society of Hospital Medicine
Surgical Infection Society
World Federation of Critical Care Nurses
World Federation of Societies of Intensive
and Critical Care Medicine
Evidence Based Medicine
Grading System
Grades of Recommendation,
Assessment, Development
and Evaluation (GRADE)
Grading Quality
of Evidence
• A- high quality
– Randomized controlled trial (RCT)
• B- intermediate
– Downgraded RCT or upgraded observational
• C- low
– Observational or cohort
• D- very low
– Case series or expert opinion
• Upgrade capability
Grading Strength of Recommendation
• 1- strong recommendation – Do it
– We recommend
• 2- weak recommendation – Probably do it
– We suggest
• Determinants of strength
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Quality of evidence
Relative importance of outcomes
Risks and costs
Absolute magnitude and precision of effect
Kumar A, et al. Crit Care Med 2006; 34:1589-1596
Antibiotic Therapy
 We recommend beginning intravenous
antibiotics within first hour of recognition
of severe sepsis
1B
• Broad antibiotic coverage initially
• Narrow coverage after return of cultures
• Source control as soon as possible and within
6 hours
Initial Resuscitation
Resuscitation of Sepsis Induced
Tissue Hypoperfusion
• Recommend MAP 65 mm Hg
• Recommend urine output .5 ml/kg/hr
Grade 1C
Fluid Therapy
•
Recommend fluid resuscitation may
consist of natural or artificial colloids or
crystalloids.
Grade 1B
Probability of Survival
The SAFE Study Investigators, N Engl J Med 2004;350:2247
Relative Risk of Death from Any Cause
among All the Patients and among the
Patients in the Six Predefined Subgroups of Survival
The SAFE Study Investigators, N Engl J Med 2004;350:2247
Sepsis Induced Hypotension
• Fluid challenge
– Minimum of 20 ml/kg crystalloid or colloid
equivalent
Sepsis Induced Tissue
Hypoperfusion
 Requirement for Vasopressors after
initial fluid challenge
Lactate ≥ 4 mg/dL
Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.
Which two adrenergic agents are most appropriate to
maintain acceptable blood pressure in a patient with
septic shock?
A.
B.
C.
D.
Dopamine or epinephrine
Epinephrine or vasopressin
Vasopressin or norepinephrine
Norepinephrine or dopamine
Which two adrenergic agents are most appropriate to
maintain acceptable blood pressure in a patient with
septic shock?
A.
B.
C.
D.
Dopamine or epinephrine
Epinephrine or vasopressin
Vasopressin or norepinephrine
Norepinephrine or dopamine
During Septic Shock
Diastole
Systole
10 Days Post Shock
Diastole
Systole
Images used with permission from Joseph E. Parrillo, MD
Effects of Dopamine, Norepinephrine,
and Epinephrine on the Splanchnic
Circulation in Septic Shock
Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent JL. Effects of
dopamine, norepinephrine, and epinephrine on the splanchnic circulation in septic shock: Which is best?
Crit Care Med 2003; 31:1659-1667
Norepinephrine vs. Dopamine
28-day Survival
De Backer D, et al. N Engl J Med 2010, 362;9:779-789
Predefined subgroup analysis by type
of shock
De Backer D, et al. N Engl J Med 2010, 362;9:779-789
Phenylephrine
• Pure vasoconstrictor in general should be
avoided
– Decreases cardiac output
• Rare exceptions
– Cardiac output measured and high and difficulty
with maintaining MAP with other vasopressor
agents
– Profound tachycardia or severe ventricular
arrhythmias with norepinephrine
Initial Resuscitation of Persistent
Hypotension or Lactate >4
Recommend
Insertion central venous catheter
Recommended goals :
• Central venous pressure: 8–12 mm Hg
• Higher with altered ventricular compliance or
increased intrathoracic pressure
• ScvO2 saturation (SVC)  70%
Grade 1C
The Early Bird Gets the Worm
The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
NNT to prevent 1 event (death) = 6-8
Mortality (%)
60
50
Standard therapy
EGDT
40
30
20
10
0
In-hospital
mortality
(all
patients)
28-day
mortality
60-day
mortality
Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al. Early goaldirected therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377
Trials of Late Hemodynamic Optimization
with Control Group Mortality > 20%
After onset of organ failure
Alia et al. 1999
Favors
Optimization
Favors
Control
Yu et al. 1998
Yu et al. 1998
Gattinoni et al. 1995
Hayes et al. 1994
Yu et al. 1993
OVERALL RESULT
-0.4
Kern and Shoemaker Crit Care Med 2002
0.0
0.4
Role of Collaboration
ED
ICU
Jones AE, Shapiro NI, Trzeciak S, et al. Lactate
clearance vs central venous oxygen saturation as
goals of early sepsis therapy: a randomized
clinical trial. JAMA. 2010;303(8):739-46.
Hospital Mortality
and Length of Stay
Jones, A. E. et al. JAMA 2010;303:739-746.
Copyright restrictions may apply.
Vasopressin
• Continue to recommend against using high
doses of vasopressin (unless salvage
therapy)
• Vasopressin .03 units per min plus NE
equivalent to norepinephrine alone
– VASST trial
Steroid Therapy
Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al. Effect of
treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.
JAMA 2002; 288:862-871
CORTICUS: Results
• No benefit in intent to treat
– Mortality
– Shock reversal
• Earlier reversal of shock with steroids in
those that had shock reversal
FRENCH TRIAL
CORTICUS
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< 8 hrs
< 72 hrs
Degree of Hypotension
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Potential for Selection Bias
Unlikely
Yes
Overall Severity of Illness
Duration of Shock
Steroids
Suggest intravenous hydrocortisone be
given only to adult septic shock patients
after blood pressure is identified to be
poorly responsive to fluid resuscitation and
vasopressor therapy
Grade 2C
Recombinant Human
Activated Protein C (rhAPC)
• Suggest use in patients with clinical
assessment of high risk of death due to
sepsis induced organ dysfunction typically
with APACHE II 25 or greater or multiple organ
failure
• No absolute contraindications
• Weigh relative contraindications
Grade 2B
PROWESS SHOCK
As to Guidelines Publications
• “Knowledge is Good”
“Knowledge is Good”
Guidelines Are Not Enough
• Protocols
• Performance Improvement Programs
Severe Sepsis Resuscitation Bundle
Complete tasks within 6 hours of identifying severe sepsis.
1. Measure serum lactate.
2. Obtain blood cultures prior to antibiotic administration.
3. Administer broad-spectrum antibiotic within 3 hours of ED admission
and within 1 hour of non-ED admission.
4. In the event of hypotension and/or serum lactate > 4 mmol/L:
a. Deliver an initial minimum of 20 mL/kg of crystalloid or equivalent.
b. Begin vasopressors for hypotension not responding to initial fluid
resuscitation to maintain MAP > 65 mm Hg.
5. In the event of persistent hypotension despite fluid resuscitation (septic
shock) and/or lactate > 4 mmol/L:
a. Achieve a central venous pressure (CVP) of > 8 mm Hg
b. Achieve a central venous oxygen saturation (ScvO2) > 70% or mixed
venous oxygen saturation (ScvO2) > 65%
Implement the 6-hour bundle. Available at: http://ssc.sccm.org/6hr_bundles.
SSC Interactive Database
Surviving Sepsis Campaign:
Phase III
• A global, multi-center, 2-year trial
–Multiple hospital networks
–166 sites
–15,022 patients
• Primary outcome
–The impact of a model for changing
bedside management of sepsis
• Secondary outcome
–Mortality
Findings
• Primary outcome of SSC: behavior change
– 20% increase in bundle compliance over 24
months
• Secondary outcome - Mortality
-- 7.0% ARR, 19% RRR
-- 5.4% ARR after severity adjustment
Septic Shock Research at Cooper
Intrathoracic Pressure Regulation (ITPR) in Porcine
Peritonitis Septic Shock
Peak Changes in Stroke Volume
Stroke Volume (mL)
p<0.001
5.0
4.0
3.0
2.0
n=28
1.0
n=28
0.0
ITPR ON
ITPR OFF
Peak Changes in Mean Arterial Pressure
30
Mean Arterial Pressure
(mmHg)
25
20
p<0.001
15
10
5
n=28
n=28
0
1
ITPR ON
2
ITPR OFF
: ITPR application and duration
FE202158
•Vasopressin A1 receptor agonist
Septic sheep – Traber et al.
V1a Receptor Agonist in a Rat Model of PAFInduced Hypotension & Vascular Leak
Syndrome
100
Survival (%)
80
60
40
VEHICLE-VEHICLE (n=3)
PAF-VEHICLE (n=14)
PAF-AVP (n=9)
PAF-FE 202158 (n=10)
20
0
0
15
30
45
60
75
90
105 120 135 150 165 180
Resuscitation Period (min)
The EUPHRATES Trial
Evaluating the Use of
Polymyxin B Hemoperfusion
in a Randomized controlled trial of
Adults Treated for Endotoxemia and
Septic shock
Sources of Endotoxin
Endotoxemia
Endotoxin shed from local
bacterial infection
Endotoxin translocation
from GI Tract
 Every
human has 25-30 grams
of Endotoxin in their GI tract
 Less than 0.001 grams of Endotoxin
is enough to kill a person
Sepsis and Endotoxin
Opal SM, et al. Infect Dis, 1999
Intervention
DIRECT HEMOPERFUSION WITH ADSORBENT COLUMN
USING POLYMYXIN B IMMOBILIZED FIBER
BLOOD TUBE
Duration: 2 hours
FEMORAL or IJ VEIN
FEMORAL or IJ VEIN
BLOOD PUMP
Perfusion rate 80-120 ml/min
P
ANTICOAGULANT
73
EUPHAS: 10 centres, Italy, randomized, unblinded
Groups were equal at baseline
Endotoxin Activity Assay
EAA™
The only FDA cleared test for detection of Endotoxin
Spectral Diagnostics Inc. 76
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