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Sepsis Management at the
Hospital Point of Care
Mark J. Pamer, D.O. ABIM Board Certified in Pulmonary Diseases, Critical
Care, and Internal Medicine
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Goals
• Define sepsis
– Incidence/prevalence
– Manifestations
– Pathophysiology
• Surviving Sepsis Campaign
• Treatments
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Definitions
• Sterile
• Colonization
• Infection
• Inflammation
– Local
– Systemic
Bone RC, Balk RA, Cerra FB, et al. ACCP/SCCM Consensus Conference: Definitions for sepsis and organ
failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-1655
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Definitions
• Sterile
• Colonization
• Infection
• Inflammation
– Local
– Systemic
Absence of
microorganisms
ACCP/SCCP Consensus Conference Definitions
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Definitions
• Sterile
• Colonization
• Infection
• Inflammation
– Local
– Systemic
Small number of
microorganisms and
absence of significant
inflammatory response
to the presence of
microorganisms
ACCP/SCCP Consensus Conference Definitions
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Definitions
• Sterile
• Colonization
• Infection
• Inflammation
– Local
– Systemic
Inflammatory response
to the presence of
microorganisms or the
invasion of normally
sterile host tissue by
those organisms
ACCP/SCCP Consensus Conference Definitions
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Definitions
• Sterile
• Colonization
• Infection
• Inflammation
– Local
– Systemic
Calor
Dolor
Rubor
Tumor
ACCP/SCCP Consensus Conference Definitions
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Definitions
How do you define
“systemic”
inflammation?
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Systemic Inflammatory
Response Syndrome (SIRS)
• SIRS requires two of the following
– Temp < 36oC or > 38oC • < 96.8oF or >100.4oF
– Heart rate > 90 beats/min
– RR > 20 breaths/min or PaCO2 < 32 mm Hg
– WBC > 12,000 or < 4,000/mm3, or > 10%
band forms
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
• Sepsis = SIRS + Infection
– The body’s inflammatory response to infection
ACCP/SCCP Consensus Conference Definitions
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Diagnostic Criteria for Sepsis Infection (documented or suspected) and some of the following
• General variables – SIRS criteria
– Altered mental status
– Significant edema or positive fluid balance
– Hyperglycemia in the absence of diabetes
• Inflammatory variables – CRP > 2 SD above normal
– PCT > 2 SD above normal
• Hemodynamic variables – SBP < 90 or MAP < 60
• SBP decrease > 40 from baseline
– SVO2 > 70%
– Cardiac index > 3.5L/min/m2
• Organ dysfunction variables – Arterial hypoxemia
• PaO2/FiO2 < 300 mm Hg
– Acute oliguria • UOP < 0.5 ml/kg/hr > 2hrs
– Creatinine increase > 0.5 mg/dl
– Coagulation abnormalities • INR > 1.5 or aPTT > 60 sec
– Ileus
– Thrombocytopenia (<100K)
– Hyperbilirubinemia (>4 mg/dl)
• Tissue perfusion variables – Hyperlactatemia
– Decreased capillary refill or mottling
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
ACCP/SCCP Consensus Conference Definitions
SIRS Infection Sepsis
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ACCP/SCCM Definitions
SIRS Infection Sepsis
Bacteremia
Fungemia
Parasitemia
Viremia
Other
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
SIRS Infection Sepsis
Bacteremia
Fungemia
Parasitemia
Viremia
Other
Pancreatitis
Trauma
Burns
Other
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
SIRS Infection Sepsis
Bacteremia
Fungemia
Parasitemia
Viremia
Other
Pancreatitis
Trauma
Burns
Other
Severe
Sepsis
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
SIRS Infection Sepsis
Bacteremia
Fungemia
Parasitemia
Viremia
Other
Pancreatitis
Trauma
Burns
Other
Severe
Sepsis
Shock
Septic
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
• Severe sepsis – pathophysiology
– Endothelial dysfunction
– Activation of coagulation cascade
– Microvascular thrombosis
– End-organ dysfunction
ACCP/SCCP Consensus Conference Definitions
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Sublingual Circulation
Normal subject Septic shock
De Backer D, et al. Am J Respir Crit Care Med 2002; 106: 98-104
http://ajrccm.atsjournals.org/cgi/content/full/166/1/98/DC1
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ACCP/SCCM Definitions
• Severe sepsis – clinical manifestations
– Hypoperfusion
– Hypotension
– Organ dysfunction
ACCP/SCCP Consensus Conference Definitions
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• Severe sepsis
– Hypoperfusion
– Hypotension
– Organ dysfunction
Altered mental status
Urine output < 0.5 cc/kg/hr
Lactic acid production
ACCP/SCCM Definitions
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ACCP/SCCM Definitions
• Severe sepsis
– Hypoperfusion
– Hypotension
– Organ dysfunction
Altered mental status
Urine output < 0.5 cc/kg/hr
Lactic acid production
SBP < 90 mm Hg
or decrease of > 40 mm Hg
from baseline
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ACCP/SCCM Definitions
• Severe sepsis
– Hypoperfusion
– Hypotension
– Organ dysfunction
Altered mental status
Urine output < 0.5 cc/kg/hr
Lactic acid production
Alteration in function of any
organ or system
SBP < 90 mm Hg
or decrease of > 40 mm Hg
from baseline
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ACCP/SCCM Definitions
• Septic Shock
– Sepsis-induced hypotension despite adequate
fluid resuscitation
• Perfusion abnormalities
– Lactic acidosis
– Oliguria
– Acute alteration in mental status
ACCP/SCCP Consensus Conference Definitions
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ACCP/SCCM Definitions
• Septic Shock
– Sepsis-induced hypotension despite adequate
fluid resuscitation
• Perfusion abnormalities
– Lactic acidosis
– Oliguria
– Acute alteration in mental status
Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ
dysfunction, yet they are still considered to have septic shock
ACCP/SCCP Consensus Conference Definitions
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Wenzel R. N Engl J Med 2002;347:966-967
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Pathophysiology of
Sepsis
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Russell J. N Engl J Med 2006;355:1699-1713
Inflammatory Responses to Sepsis
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Procoagulant Response in Sepsis
Russell J. N Engl J Med 2006;355:1699-1713
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Landry D. N Engl J Med 2001;345:588-595
Regulation of Vascular Smooth-Muscle Tone
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Landry D. N Engl J Med 2001;345:588-595
Effect of Membrane
Potential on the Regulation of Vascular Tone
Effect of Lactic Acidosis
on Vascular Tone
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Mechanisms of Vasodilatory Shock
Landry D. N Engl J Med 2001;345:588-595
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Landry D. N Engl J Med 2001;345:588-595
Vasopressin immunoreactivity in the neurohypophysis after severe hemorrhagic hypotension (MAP 40 mm Hg) for one hour
Normal Dog After Shock for One Hour
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Stages of Sepsis
From tissue insult to SIRS to Sepsis
to Severe Sepsis to MODS to Death
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From the Dogs of War to the
Doves of Peace
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Compensatory Anti-Inflammatory
Response Syndrome (CARS)
• Follows SIRS; may be as large or larger
– Downregulation of inflammatory cytokines – TNF-g and IL-2
– Upregulation of anti-inflammatory cytokines – IL-4, 6, 10, 11, 13, TNF-a, IL-1 ra, TFG-b
– Impaired Antigen presenting activity – Diminished MHC-2 expression
– HLA-DR monocyte expression reduced to < 30% – Diminished ability to produce inflammatory cytokines
Bone RC. Chest 1997; 112:235-243
Fisher CJ. Crit Care Med 1993; 21:318-27
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Stages after Initial Insult
• Local inflammation/CARS
• Systemic inflammation/CARS
• Loss of inflammatory regulation
• Excessive anti-inflammatory reaction
• Immunologic dissonance
Bone RC. Chest 1997; 112:235-43
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Hotchkiss R and Karl I. N Engl J Med 2003;348:138-150
Immunologic Response of Three Hypothetical Patients with Sepsis
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Hotchkiss Nature Reviews Immunology 2006; 6:813-22
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Hotchkiss Nature Reviews Immunology 2006; 6:813-22
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Hotchkiss Nature Reviews Immunology 2006; 6:813-22
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All Organ Systems
Can Be Affected in
Severe
Sepsis/Septic
Shock
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Respiratory Dysfunction
Failure of oxygenation
Need for Mechanical Ventilation
Cardiovascular Dysfunction
Hypotension
Arrythmia
Use of inotropic or vasopressor support
Elevated CVP or PCWP
Changes in heart rate
Cardiac arrest
Hepatic Dysfunction
Elvevated serum aminotransferases
Elevated LDH
Elevated alkaline phosphatase
Jaundice/hyperbilirubinemia
Hypoalbuminemia
Elevated Prothrombin time (PT)
Renal Dysfunction Increased serum creatinine
Decreased urine output
Need for renal replacement therapy
Neurologic Dysfunction
Altered mental status
Deceased GCS, delirium,
obtundation, coma
GI Dysfunction
GI Bleeding
Acalculous cholecystitis
Pancreatitis
Ileus
Intolerance of enteral nutrition
Intestinal ischemia or infarction
Development of GI perforation
Hematologic Dysfunction
Coagulopathy with high PT, PTT, DIC
Thrombocytopenia
Leukocytosis/leukopenia
Endocrine Dysfunction
Hyperglycemia (insulin resistance)
Thyroid dysfunction
Hypertriglyceridemia
Hypoalbuminemia
Hypercatabolism
Weight loss
Immune System Dysfunction
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Epidemiology of Sepsis
More cases, worse bugs
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Angus DC, et al. Crit Care Med. 2001.
Age-Specific Number and Incidence of Severe
Sepsis in the United States
Age (y)
<1
1-4
5-9
10-1
415-1
920-2
425-2
930-3
435-3
940-4
445-4
950-5
455-5
960-6
465-6
970-7
475-7
980-8
485
Incid
en
ce (
per
1000 p
op
)
0
5
10
15
20
25
30
Cases
Incidence
0
20,000
40,000
60,000
80,000
100,000
120,000
No
. o
f C
ases
>
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Increasing Incidence of Sepsis
• New cases increase by 1.5% per year
– More elderly
– More invasive/diagnostic procedures
– More immunocompromised patients
– More immunosuppressive & cytotoxic therapy
– More microorganism resistance
– More awareness
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Characteristics of Patients with Sepsis from 1979 - 2000
Martin, G. et al. N Engl J Med 2003;348:1546-1554
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Population-Adjusted Incidence of Sepsis, According to Sex, 1979-2000
Martin, G. et al. N Engl J Med 2003;348:1546-1554
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Population-Adjusted Incidence of Sepsis, According to Race, 1979-2000
Martin, G. et al. N Engl J Med 2003;348:1546-1554
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Numbers of Cases of Sepsis in the United States, According to the Causative Organism, 1979-2000
Martin, G. et al. N Engl J Med 2003;348:1546-1554
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Overall In-Hospital Mortality Rate among Patients Hospitalized for Sepsis, 1979-2000
Martin, G. et al. N Engl J Med 2003;348:1546-1554
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Angus DC, et al. Crit Care Med. 2001.
Age-Specific Mortality for Severe Sepsis in the
United States
Age (y)
<1 1-4
5-9
10-1
415
-19
20-2
425
-29
30-3
435
-39
40-4
445
-49
50-5
455
-59
60-6
465
-69
70-7
475
-79
80-8
4 85
Mo
rtality
(%
)
0
5
10
15
20
25
30
35
40
45
No comorbidity
Overall
Comorbidity
>
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Fluid Management
in Sepsis
A drop in the bucket
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This is NOT a Good Idea
Excessive
Fluids
Fluids
Fluids
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Positive Fluid Balance
One of the strongest predictors
of death
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Comparing Methods of Determining
Fluid Responsiveness
ROC curves comparing DPp, DPs, RAP, and PAOP to discriminate responders
(CI increase > 15%) and non-responders to volume expansion
Michard F. Am J Respir Crit Care Med 2000; 162:134-138
Se
ns
itiv
ity (
%)
1 - Specificity (%)
DPP
DSP
RAP
PAOP
0
20
40
60
80
100
0 20 40 60 80 100
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Relationship between CVP and PAOP before fluid loading in the overall population
reveals a large overlap. Linear correlation r2 = 0.547, r= 0.740, p< 0.0001
Individual values (open circles) and mean values + SD (closed circles) of pre-infusion CVP and PAOP in responders (R) and
nonresponders (NR)
5 10 18
8
15
12
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Influence of Colloid and
Crystalloid Fluids on Volume
1000
1000
1000
1000
500
500
500
500
0
0
D5W (1 L)
0.9% NaCl (1 L)
5% Albumin (1 L)
Increase in Plasma Volume Increase in Interstitial Volume
(mL)
Imm A, Carlson RW. Crit Care Clin 1993; 9:313
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Kellum, J. A. Chest 2006;130:962-967
Hyperchloremic Acidosis is Associated with Increased Serum Cytokine Levels
7
7.1
7.2
7.3
7.4
0 4 8
Control SBE -5 to -10 SBE -10 to -15
0
2
4
0 4 8
-14
-12
-10
-8
-6
-4
-2
0 4 8
pH
L
ac
tate
(m
mo
l/L
) S
BE
(m
Eq
/L)
Time (hours)
20
40
60
80
100
120
140
0 4 8
Ch
lori
de
(mm
ol/L
)
PC
O2
(mm
H
g)
Time (hours)
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Hyperchloremic Acidosis induces changes in plasma IL-6, IL-10, and TNF
Kellum, J. A. Chest 2006;130:962-967
0
200
400
600
800
0 4 8
Control SBE -5 to -10 SBE -10 to -15
0
20
40
60
80
100
120
140
0 4 8
pg
/ml
IL-6
IL-10
pg
/ml
Time (hours)
0
100
200
300
400
0 4 8
Time (hours)
TNF
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The SAFE Study Investigators. N Engl J Med 2004;350:2247-2256
SAFE Study: Colloid vs. Crystalloid
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The SAFE Study Investigators. N Engl J Med 2004;350:2247-2256
Kaplan-Meier Estimates of the Probability of Survival
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Critical Care Medicine - Volume 34, Issue 10 (October 2006)
Albumin administration improves organ function in
critically ill hypoalbuminemic patients
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The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. N Engl J Med 2006;354:2564-2575
Mortality in ARDS with Liberal or Conservative Fluid Management
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Norepinephrine plus Dobutamine versus
Epinephrine for Management of Septic Shock
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9
Epinephrine Norepinephrine plus dobutamine
Annane D. Lancet 2007;370:676-684.
Su
rviv
al
pro
bab
ilit
y (
%)
Time (days)
Mortality at 3 months
Epinephrine: 84/161 (52%)
Norepinephrine plus Dobtamine 85/169 (50%)
p=0.73
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Surviving Sepsis www.survivingsepsis.org
What works?
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Russell J. N Engl J Med 2006;355:1699-1713
Results of Positive RCTs
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Treatment goal:
Optimize Oxygen Delivery (DO2)
DO2 = CO x CaO2
CO = SV x HR (or MAP ÷ SVR)
CaO2 = Hb X 1.34 x SaO2
Rivers E , et al. N Engl J Med 2001;345:1368-1377
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Rivers E , et al. N Engl J Med 2001;345:1368-1377
Early Goal Directed Therapy (EGDT) in Severe Sepsis and Septic Shock
Venous Blood Gas
from Internal Jugular
or Subclavian Vein
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Rivers E et al. N Engl J Med 2001;345:1368-1377
Protocol for EGDT in Severe Sepsis and Septic Shock
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Mortality and Causes of In-Hospital Death
Rivers E et al. N Engl J Med 2001;345:1368-1377
16% Absolute Risk Reduction
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Kumar A. Crit Care Med, 2006; 34: 1589-1596
Mortality increases proportionally to the delay in
initiation of effective antimicrobial therapy
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Kumar A: Crit Care Med, 2006; 34: 1589-1596
8% Per Hour
Mortality increases proportionally to the delay in
initiation of effective antimicrobial therapy
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Acute Respiratory Distress
Syndrome (ARDS)
Low Tidal Volumes
Corticosteroids
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Malhotra A. N Engl J Med 2007;357:1113-1120
Lung Injury Induced by High-Pressure Mechanical Ventilation (Peak Airway Pressure of 45 cm H2O)
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Conventional Ventilation (12 cc/kg of IBW) vs. Protective Lung Ventilation (6 cc/kg of IBW)
Malhotra A. N Engl J Med 2007;357:1113-1120
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Lung Protective Strategy Improves Survival and Probability
of Being Discharged Home and Breathing without Assistance
The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308
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The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308
Main Outcome Variables
9% ARR
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Suter P. N Engl J Med 2006;354:1739-1742
Pathways of the Inhibition of
Inflammation by Corticosteroids
in ARDS
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The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. N Engl J Med 2006;354:1671-1684
In persistent ARDS, corticosteroid therapy started 2 weeks after refractory hypoxia did not improve outcomes
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Low Dose Corticosteroids in
Early ARDS
• Action at low doses • Anti-inflammatory without immune suppression
• Duration • Lower doses over longer time are superior to higher doses
for shorter periods of time
• Early withdrawal negates effect!!!
• Dosing of methylprednisolone • 2 weeks: 1 mg/kg
• 1 week: 0.5 mg/kg
• ½ week: 0.25 mg/kg
• ½ week: 0.125 mg/kg
Meduri GU. Chest 2007; 132:1097-1100
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Meduri GU. Chest 2007; 132:1097-1100
Low Dose Corticosteroids in
Early ARDS
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Russell J. N Engl J Med 2006;355:1699-1713
Results of Positive RCTs
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Bernard G. N Engl J Med 2001;344:699-709
Proposed Actions of Activated Protein C
Anti-
inflammatory:
Inhibits production
of TNF-a, IL-1, and
IL-6
Limits rolling of
macrophages and
PMNs
Limits
thrombin
generation:
Inactivates
Factors Va
and VIIIa
Increases
fibrinolytic
activity:
Inhibits PAI
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Dretrocogin Alpha rhAPC
• PROWESS
– Severe sepsis
– High risk of death
• APACHE > 25 or
• Multiorgan failure
• ADDRESS
– Severe sepsis
– Low risk of death
• APACHE < 25
• Single organ failure
Bernard G et al. N Engl J Med 2001;344:699-709 Abraham E et al. N Engl J Med 2005;353:1332-1341
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Incidence of Serious Adverse Events
Bernard G et al. N Engl J Med 2001;344:699-709 Abraham E et al. N Engl J Med 2005;353:1332-1341
PROWESS ADDRESS
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Survival vs. Placebo
Bernard G et al. N Engl J Med 2001;344:699-709 Abraham E et al. N Engl J Med 2005;353:1332-1341
PROWESS ADDRESS
6% Absolute risk reduction
Stopped Early
No Difference
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Current Recommendations for
rhAPC
• Severe sepsis with high risk of death • APACHE II score > 25
• Sepsis-induced multi-organ failure
• Septic shock
• Sepsis-induced ARDS
– No absolute contraindications related to bleeding risk
– No relative contraindication that outweighs potential
benefit
Dellinger RP, et al. Surviving Sepsis Campaign Guidelines. Crit Care Med 2004; 32:858873
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Russell J. N Engl J Med 2006;355:1699-1713
Results of Positive RCTs
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Annane D. JAMA 2000;283:1038-45.
Survival in Severe Sepsis and Septic Shock Baseline Cortisol and Post-ACTH
Basal Plasma Cortisol Level 34 g/dL, Dmax >9 g/dL
Basal Plasma Cortisol Level 34 g/dL, Dmax 9 g/dL or
Basal Plasma Cortisol Level >34 g/dL, Dmax 9 g/dL
Pro
bab
ilit
y o
f S
urv
ival
100%
80%
60%
40%
20%
0
0 7 14 21 28
Time (days)
Basal Plasma Cortisol Level >34 g/dL, Dmax >9 g/dL
ACTH Responders
ACTH Non-responders
Mortality increased in higher baseline cortisol levels and with
relative adrenal insufficiency
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Low Dose Steroid Treatment in Septic Shock: 28 Day Mortality (Non-responders vs. Responders)
Low-dose Steroids Placebo
Relative Adrenal Insufficiency (ACTH Test Non-responders)
No Adrenal Insufficiency (ACTH Test Responders)
P=0.04 P=0.96
N=114 N=36 N=34 N=115
28-d
ay M
ort
ali
ty
Annane, D. JAMA, 2002; 288: 868.
10% Absolute risk reduction
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Russell J. N Engl J Med 2006;355:1699-1713
Results of Positive RCTs
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Van den Berghe G et al. N Engl J Med 2006;354:449-461
Intensive Insulin Treatment Improved Mortality in Surgical ICU Patients
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Enteral Feeding with Eicosapentanoic Acid, g-linolenic
acid, and Antioxidants in Mechanically Ventilated
Patients with Severe Sepsis and Septic Shock
Pontes-Arruda A. Crit Care Med 2006;34:2325-2333
Improvement in Mortality Improvement in Oxygenation
7.6 more ventilator-free days
(p < .001)
6.2 more ICU-free days
(p < .001)
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Pontes-Arruda A. Crit Care Med 2006;34:2325-2333
Enteral Feeding with Eicosapentanoic Acid, g-linolenic
acid, and Antioxidants in Mechanically Ventilated
Patients with Severe Sepsis and Septic Shock
Less organ dysfunction
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Corwin H et al. N Engl J Med 2007;357:965-976
Efficacy and Safety of Epoetin Alfa in Critically Ill Patients
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Corwin H et al. N Engl J Med 2007;357:965-976
No Difference
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Micek ST. et al. Crit Care Med 2006;34:2707-2713.
Process of Care Order Sets For Septic Shock
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Evidence-based sepsis protocols
Protocol Use:
•↑ Survival (70% vs. 50%)
•↓ LOS by 5 days
•↓ Cost ($16K vs. $22K)
Shorr AF. Crit Care Med 2007;35:1257-1262.
Before & After study of 120 ER Septic Shock Patients
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Sepsis Bundles Save Lives
Prospective,observational study in 101 consecutive adult
pts with severe sepsis or shock at 2 UK hospitals.
Hospital Mortality
Bundle Comp Non-Comp p-value
6hr 23% 49% 0.01
24h 29% 50% 0.16
Gao et al. Crit Care Med 2005; 9:R764
Retrospective Study of 60 Septic Shock Patients before
and after sepsis bundles
Standard therapy with EGDT, Insulin, Steroids, rhAPC
28 day Mortality Rate: 53% vs. 27%
[RR 0.5 (0.253-0.9880), p<0.05]
Kortgen et al Crit Care Med 2006;34:943-949.
Up to 30%
Reduction in
Mortality!
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Bang For The Buck Absolute Risk Reduction in Mortality by Intervention
Early Goal Directed Therapy (EGDT) 16%
Low Tidal Volume Ventilation 9%
Corticosteroids for Early ARDS* < 10%
Corticosteroids for Adrenal Insufficiency 10%
Intensive Insulin Therapy 10%
rhAPC in high risk of death 6%
Tube feeds with Eicosapentanoic Acid,
g-linolenic acid, and Antioxidants
20%
Sepsis bundles < 30%
*Requires further studies
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Improving Mortality
with POC Testing • Arterial Blood Gas (ABG)
• pH, PCO2, PO2
• Electrolytes (Potassium, Chloride, HCO3-)
• Renal function: BUN, Creatinine
• Lactate
• Venous Blood Gas (VBG) • pH, PCO2, PO2
• ScvO2 (central venous O2 saturation)
• Blood Glucometer • Glucose measurement
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Thank You
• Questions