Sepsis And Septic Shock
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Transcript of Sepsis And Septic Shock
Section of Critical Care MedicineSection of Infectious Diseases
University of Manitoba, Winnipeg, CanadaUMDNJ-Robert Wood Johnson Medical School
Cooper Hospital, NJ
Anand Kumar, MDAnand Kumar, MD
Sepsis and Septic Sepsis and Septic ShockShock
Old Concepts, New PreceptsOld Concepts, New Precepts
Incidence of Severe Sepsis/Septic ShockIncidence of Severe Sepsis/Septic Shock
Approximate Cases/Year800,000
600,000
400,000
200,000
0
Severe sepsis800,000
Septic shock400,000
Deaths from septic shock200,000
Sepsis and sequelae are a leading cause of death in ICUMortality in septic shock remains at 35 - 50%
-unchanged since advent of antibiotics (from 55 - 75%)
Bacterial SepsisBacterial Sepsis
Death Rate in the United States5.0
Chart adapted from CDC/National Center for Health Statistics, 1992.
4.0
3.0
2.0
1.00.00.80.7
0.5
0.4
0.6
0.2
0.1
0.3
1960 1965 1970 1975 1980 1985 1990
Rat
e p
er 1
00,0
00 P
op
ula
tio
n
4.1
Severe Sepsis: Severe Sepsis: Comparative Incidence and MortalityComparative Incidence and Mortality
Angus DC, et al. Crit Care Med. 2001; ACS.
0
50
100
150
200
250
300
AIDS BreastCancer
1st MI SevereSepsis
Incidence
Cas
es/1
00,0
00
0
50000
100000
150000
200000
250000
AIDS BreastCancer
AMI SevereSepsis
Mortality
Dea
ths/
Yea
r
Mortality of Severe Sepsis by Age in the Mortality of Severe Sepsis by Age in the United StatesUnited States
Angus DC, et al. Crit Care Med. 2001.
•0%
•5%
•10%
•15%
•20%
•25%
•30%
•35%
•40%
•45%
•0 •1 •5 •10 •15 •20 •25 •30 •35 •40 •45 •50 •55 •60 •65 •70 •75 •80 •85
Age
Mo
rtal
ity
•Without Co-morbidity
•With Co-morbidity
•Overall
Projected Incidence of Severe Sepsis in the Projected Incidence of Severe Sepsis in the US: 2001 - 2050US: 2001 - 2050
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
1,800,000
2001 2025 2050
Year
100,000
200,000
300,000
400,000
500,000
600,000Severe Sepsis CasesUS Population
Sep
sis
Cas
es
To
tal
U.S
. P
op
ula
tio
n/1
,000
Angus DC, et al. Crit Care Med. 2001.
Systemic Inflammatory Response Syndrome Systemic Inflammatory Response Syndrome (SIRS)(SIRS)
Systemic inflammatory response to a variety of severe clinical insults. Manifested by two or more of the
following:
Temperature > 38oC or < 36oC
Heart rate > 90 beats/min
Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg
WBC > 12,000/mm3, < 4000/mm3, or > 10% immature (band) forms
ACCP/SCCM Consensus Statement Chest. 1992;1644-1655.
Sepsis: ACCP/SCCM DefinitionsSepsis: ACCP/SCCM Definitions
Infection• Inflammatory response to microorganisms or invasion of normally sterile
tissues
Sepsis• The systemic response to infection – i.e., confirmed or suspected
infection plus 2 SIRS criteria
Severe Sepsis• Sepsis associated with organ dysfunction, hypoperfusion, or hypotension• Hypoperfusion abnormalities may include but are not limited to lactic
acidosis, oliguria, acute alteration in mental status
ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-55.
Sepsis - ACCP/SCCM Definitions: Sepsis - ACCP/SCCM Definitions: The UpdateThe Update
Altered mental status
Edema or increased fluid balance
Hyperglycemia (absent diabetes)
Increased CRP or procalcitonin
Hypotension
Increased SvO2
CI > 3.5 L/min/m2
Arterial hypoxemia (PaO2/FiO2 < 300)
Acute oliguria (> 2 hours)
Increased serum Cr (> 0.5 mg/dL)
Coagulopathy (INR > 1.5)
Ileus (absent bowel sounds)
Thrombocytopenia (< 100,000/uL)
Hyperbilirubinemia (> 40 mg/dL or 70 mmol/L)
Hyperlactatemia (> 1 mmol/L)
Decreased capillary refill or mottling
Levy MM, et al. Crit Care Med. 2003.
Septic Shock : ACCP/SCCM DefinitionSeptic Shock : ACCP/SCCM Definition
Sepsis-induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration of mental status; patients receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.
ACCP/SCCM Consensus Statement. Chest. 1992;101:1644-55.
Relationship of Sepsis, SevereRelationship of Sepsis, SevereSepsis, and Septic ShockSepsis, and Septic Shock
Sepsis
Severe Sepsis
Septic shock
MODS
Death
Sepsis and organdysfunction, hypoperfusion,or hypotension
Sepsis-inducedhypotension
Nosocomial Infection vs. Nosocomial Infection vs. Severe Sepsis in MICUSevere Sepsis in MICU
Reinhart, et al. Crit Care Med. 2001; Bernard et al (aPC). N Engl J Med. 2001; Fisher et al (IL-1ra). JAMA. 1994;
Abraham et al (TNF Mab). JAMA 1995; Bernard et al (Ibuprofen). N Engl J Med. 1997.
UTI 15%(8 - 20%)
GI 25% (15 - 30%)
Skin/soft tissue 10% (5 - 15%)
Primary bloodstream Infections 5%
(2.5 - 7.5%)
Pneumonia 45%(37 - 54%)
Richards MJ, et al. Crit Care Med. 1999;27:887-92.
Urinary Tract Infection
31%
Primary Bloodstream
Infections19%
Gastrointestinal Infections
5%
Cardiovascular System
4%
Eye, Ear, Nose and Throat
4%
Lower Respiratory Tract Infections
4% Other6%
Pneumonia27%
Nosocomial Infection (NNIS 92-97)
Severe Sepsis
Nidus of InfectionAbscessPneumoniaPeritonitisPyelonephritisCellulitis
Organism
ExotoxinTSST-1Toxin-A
Structural ComponentTeichoic Acid AntigenPeptidoglycan, Endotoxin (LPS)Bacterial nucleic acids
Gut release of endotoxin
Plasma
- Extrinsic / intrinsic pathways- Protein C; S- TFPI
Complement Kinins
Coagulation
Monocyte-Macrophage
- TNF- Interleukins- Interferons- MIF- HMGB1
Cytokines
Endothelial Cells
Selectins, IcamsRenin-angiotensin systemProstaglandinsLeukotrienesProstacyclinThromboxaneEndothelin
Neutrophils
LysosomesOxygen free radicals (superoxides)Granulocyte Colony Stimulating Factor (G-CSF)
Cellular DysfunctionContinued...
Pathogenesis of Septic ShockPathogenesis of Septic Shock
Platelet Activating FactorNitric OxideTissue Factor
Vasculature- Vasodilation- Vasoconstriction- Leukocyte aggregation- Endothelial cell dysfunction
Cellular Dysfunction
Organs- Dysfunction- Metabolic abnormalities
Myocardium- Depression- Dilatation
Shock
Refractory Hypotension Multiple Organ Dysfunction Recovery
Death
Nucleus
LysosomeMitochondria Actin/Myosin
Membranechannel
Membranereceptor
Pathogenesis of Septic ShockPathogenesis of Septic Shock
Pili
Adapted from Young, et al. Ann Intern Med. 1977;86:456-71.
Capsule(K antigen)
Outermembrane
Solidmembrane(peptidoglycan)
Flagellum(H antigen)
LPS (endotoxin: O antigen)
Oligosaccharideside chains
Core polysaccharide
Lipid A
Inner cytoplasmic membrane
Endotoxin (LPS): A Component of the Endotoxin (LPS): A Component of the Gram-negative Bacterial Cell WallGram-negative Bacterial Cell Wall
LPS LBP
LBP
LPS LBP
Extra-cellularspace
Extra-cellularspace
MacrophageMacrophage
Extra-cellularspace
Extra-cellularspace
LPS
CD14
TNFTNF
PAFPAFIL-6IL-6 IL-1IL-1
LPS Signaling Pathways, 1990LPS Signaling Pathways, 1990
Signaling Pathways Related to CD14 and TLRSignaling Pathways Related to CD14 and TLR
LPS LBP
LBP
LPS LBP
Toll4 Toll2
MYD88
IRAK
MYD88
IRAK
TRAF 6
NIK IKK
IB
NFBIB
NFB
Extra-cellularspace
Extra-cellularspace
CytoplasmCytoplasm
NucleusNucleus
LPS
CD14
NFB
HDLElimination
LPSHDL
HDL
STATs? IRFs? HMGs? MAP kinases?
?
CD14
MD-2
Toll-like Receptor (TLR) Receptors and Toll-like Receptor (TLR) Receptors and LigandsLigands
Bochud P, Calandra T. BMJ. 2003.
50
Pat
ien
ts (
%)
0
10
20
30
40
Modified from Danner RL, et al. Chest. 1991;99:172.
Hours
0 4 8 12 16 20 >24
Cumulative Percentage of Clinically Septic Cumulative Percentage of Clinically Septic Patients with Detectable Endotoxemia Patients with Detectable Endotoxemia (N = 100)
150,000
TN
F u
nit
s/m
L s
eru
m
10
400
600
1,000
1,200
Waage A, Halstensen A, Espevick T. Lancet. 1987.
Serum from patientswho died
Serum Concentrations in Survivors and Nonsurvivors of Septic Shock
Serum from patientswho survived
Detection limitfor TNF
100,0001,400
1,000
200
Tumor Necrosis Factor (TNF)Tumor Necrosis Factor (TNF)
Putative
Mediator
Arterial
Pressure
Cardiac
Output
Systemic
Vascular
Resistance
Ejection
Fraction
Miscellaneous
Effects
Endotoxin Decreased
(human, canine)
Increased
(human, canine)
Decreased
(human, canine)
Decreased
(human, canine)
WBC, pyrexia
TNF, IL - 1, IL - 6
TNF Decreased
(human, canine)
Increased
(human, canine)
Decreased
(human, canine)
Decreased
(canine)
Lactic acidosis,
pulmonary edema,
WBC, pyrexia
DIC, platelets
IL - 1 Decreased
(human, canine)
Increased
(human, canine)
Decreased
(human, canine)
Decreased
(canine)
Pyrexia,
platelets
IL - 6No change
(canine)
No change
(canine)
No change
(canine)?
Hepatic acute phase
response
Kumar, et al. J Cardiovasc Thor Anes. 2001.
Hemodynamic Effects of Putative Septic Hemodynamic Effects of Putative Septic Shock MediatorsShock Mediators
PathogenPathogen
InflammationInflammation CoagulationCoagulation
MonocyteMonocyte
Pathophysiology of Sepsis - Pathophysiology of Sepsis - A New ParadigmA New Paradigm
Tissue FactorCytokines
Modern View of the Coagulation CascadeModern View of the Coagulation Cascade
Steps in coagulation
Coagulationcascade
Initiation TF/VIIa
Propagation VIIIa
Thrombin activity
Fibrinogen Fibrin
IXa
IXX
Xa
IIVa
IIa
II indicates prothrombin; IIa, thrombin; IX, factor IX; IXa, activated factor IX; TF, tissue factor; Va, activated factor V; VIIa, activated factor VII; VIIIa, activated factor VIII; X, factor X; Xa, activated factor X.
Weitz JI, et al. Chest. 2001.
Coagulation in SepsisCoagulation in Sepsis
Bernard GR, et al. New Engl J Med, 2001;344:699-709.
Inflammatory Responseto Infection
Thrombotic Responseto Infection
Fibrinolytic Responseto Infection
Endothelium
TAFI
PAI-1
Suppressedfibrinolysis
Neutrophil
Monocyte
IL-6IL-1TNF
Bacterial, viral, fungal or parasitic infection/endotoxin
Bacterial, viral, fungal or parasitic infection/endotoxin
IL-6
Tissue Factor
Tissue Factor
COAGULATION CASCADE
Factor Va
Factor VIIIa
THROMBIN
FibrinFibrin clot
Activation of Coagulation in Severe SepsisActivation of Coagulation in Severe Sepsis
Data from: Bernard et al. The Ibuprofen in Sepsis Trial (In Press).
0
20
40
60
80
100
Platelets
PTT PT
Any One
Any Two
All Three Protein C
D-Dimers
Per
cen
tag
e o
f P
atie
nts
Markers of DIC
Protein C Levels Decrease Before the Protein C Levels Decrease Before the Clinical Diagnosis of Severe SepsisClinical Diagnosis of Severe Sepsis
Mesters et al. Crit Care Med. 2000;28:2209-16.
20
40
60
80
100
120
PC HEM
WBC
Fever
6 hr12 hr
18 hr
24 hr
36 hr
48 hr
60 hr
72 hr
PC
Ant
igen
(%
)
Severe Sepsis Patients
Septic Shock Patients
Average Time to Diagnose Severe Sepsis
GTP cGMP
BloodBlood EndotheliumEndothelium SmoothMuscle
SmoothMuscle
GTPGTP
cGMPcGMP
GC
L-ArgL-Arg
O2O2
L-citrullineL-citrulline
GCGCNONO..
cNOSPlateletsPlatelets
Nitric Oxide in the VasculatureNitric Oxide in the Vasculature
GTP cGMP
BloodBlood EndotheliumEndothelium SmoothMuscle
SmoothMuscle
GTPGTP
cGMPcGMP
GC
L-ArgL-Arg
O2O2
L-citrullineL-citrullineGCGC
NONO
iNOSPlateletsPlatelets
iNOS
cNOS
EndotoxinCytokinesEndotoxinCytokines
NONO
Nitric Oxide in SepsisNitric Oxide in Sepsis
Septic Shock HemodynamicsSeptic Shock Hemodynamics
Warm (hyperdynamic) shock
hypotensive
tachycardia
tachypnea
bounding pulse
warm, well perfused extremities
skin flushed, moist
Cold (hypodynamic) shock
hypotensive
tachycardia
tachypnea
narrow, thready pulse
cold, poorly perfused extremities
skin pale, dry
Septic Shock HemodynamicsSeptic Shock Hemodynamics
CVP does not accurately estimate ventricular filling pressures in the critically ill.
When PWP is appropriately elevated to 12 - 15 mm Hg with fluid resuscitation, 90% of patients with septic shock exhibit a hyperdynamic circulatory state.
Hyperdynamic state persists to death
1
0
2
5
6
Car
dia
c In
dex
(L
/min
/m2)
3
4
1 2 4 7 10 1 2 4 7 10
Time (days)
7
SurvivorsNonsurvivorsAll Patients
Parker et al. Ann Intern Med. 1984.
Cardiac Index in Septic Shock (post - 1980)Cardiac Index in Septic Shock (post - 1980)
Hypovolemia in Septic Shock: CausesHypovolemia in Septic Shock: Causes
Venous pooling
Interstitial “third-spacing”
insensible losses (fever, RR)
oral intake
Septic Shock HemodynamicsSeptic Shock Hemodynamics
Hypodynamic septic shock in humans = inadequately fluid resuscitated septic shock (until PWP shows filling pressures between 12 - 15 mm Hg).
Mizock BA. Crit Care Med. 1992;20:80-93.
Oxy
gen
Co
nsu
mp
tio
n
Oxygen Delivery
Critical DeliveryThreshold
Lactic
Aci
dosis
Physiologic Oxygen Supply Dependency Physiologic Oxygen Supply Dependency Indicating a Critical Delivery Threshold Below Indicating a Critical Delivery Threshold Below
Which Lactic Acidosis EnsuesWhich Lactic Acidosis Ensues
Mizock BA. Crit Care Med. 1992;20:80-93.
Oxy
gen
Co
nsu
mp
tio
n
Oxygen Delivery
Pathologic
Physiologic
Relationship Between Oxygen Delivery and Relationship Between Oxygen Delivery and Consumption Under Physiologic and Consumption Under Physiologic and
Pathologic ConditionsPathologic Conditions
Capillary
Vascular Abnormality
Arteriole
NeutrophilAggregation
VasoconstrictionVasodilation
Endothelial CellDestruction
Venule
Cell
Pathogenesis of Septic ShockPathogenesis of Septic Shock
Metabolic Derangements in Sepsis: Metabolic Derangements in Sepsis: Lactate, MVOLactate, MVO22
Micro-anatomic shunts (non-nutrient capillaries)
Functional shunts (impaired micro-circulatory vasomotor control)
Citric acid (Kreb’s) cycle defect with anaerobic glycolysis
Aerobic glycolysis with lactate production
ReferencesReferences
1. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet. 2005;365:63-78.
2. Aird WC. Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med. 2001;29:S28-S34.
3. Kumar A, Haery C, Parrillo JE. Myocardial dysfunction in septic shock. Crit Care Clin. 2000;16;251-287.