section of critical care medicine section of infectious diseases

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


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


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


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


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.

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