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Dept. of PathologyDept. of PathologyMedical CollegeMedical College
Hunan Normal UniversityHunan Normal University(( 湖南师范大学医学院病理学教研室湖南师范大学医学院病理学教研室 )) 1
Chapter 7Chapter 7
ShockShock(休克)(休克)
22
ShockShock
①① IntroductionIntroduction②② Pathogenesis of ShockPathogenesis of Shock③③ Alterations of Metabolism Alterations of Metabolism
and Functionand Function④④ Pathophysiological Basis of Pathophysiological Basis of
TreatmentTreatment
Apoptosis Oxygen Society Education Program Tome & Briehl 4
Introduction of Shock
I: Definition of ShockI: Definition of Shock
II: Classification of ShockII: Classification of Shock
Definition
A dangerous systemic pathologic process
under the effect of various drastic etiological
factors, characterized by acute circulatory
failure, leading to inadequate tissue
perfusion, cellular metabolism impediment
and dysfunction of multiple organs.
Etiological factorsEtiological factors
Microcirculation failureMicrocirculation failure
Shock
Cell injury and organ dysfunctionsCell injury and organ dysfunctions
Effective circulatory volume Effective circulatory volume ↓↓
Blood volume
Three Factors Determining Effective circulatory
volumeHeart function
Blood vessel tone
Apoptosis Oxygen Society Education Program Tome & Briehl 8
Introduction of Shock
I: Definition of ShockI: Definition of Shock
II: Classification of ShockII: Classification of Shock
↓↓Blood volume Blood volume
Heart failureHeart failure
↑↑Blood vessel Blood vessel capacitycapacity
HypovolemHypovolemicic
CardiogeCardiogenicnic
VasogeniVasogenicc
Effective Effective
circulatory circulatory
volume↓volume↓
ShocShockk
General Categories of General Categories of ShockShock
Classification According to CausesClassification According to Causes
Loss of Loss of blood and blood and
fluidfluidBurnBurn
TraumaTrauma
InfectionInfection
AnaphylaAnaphylaxisxis
(Allergy)(Allergy)
Nerve Nerve stimulatiostimulatio
nnHeart Heart failurefailure
HypovoleHypovolemicmic
VasogeVasogenicnic
CardiogeCardiogenicnic
①①Hemorrhagic shockHemorrhagic shock②②Burn shockBurn shock③③Traumatic shockTraumatic shock④④Anaphylactic shockAnaphylactic shock⑤⑤Infectious shock Infectious shock
(Septic shock)(Septic shock)⑥⑥Neurogenic shockNeurogenic shock⑦⑦Cardiogenic shockCardiogenic shock
1111
ShockShock
①① IntroductionIntroduction②② Pathogenesis of ShockPathogenesis of Shock③③ Alterations of Metabolism Alterations of Metabolism
and Functionand Function④④ Pathophysiological Basis of Pathophysiological Basis of
TreatmentTreatment
1. 1. Sympathetic activationSympathetic activation rather than rather than sympathetic failure during shocksympathetic failure during shock
2. Essential issue of shock 2. Essential issue of shock - - Not: Not: BP↓BP↓- - But: But: Blood flow↓ → Tissue perfusion↓Blood flow↓ → Tissue perfusion↓
Microcirculation TheoryMicrocirculation Theory
The circulation between arterioles and venules.The circulation between arterioles and venules.
The location The location where fluids, gasses, nutrients, anwhere fluids, gasses, nutrients, an
d wastes are exchanged between the blood and d wastes are exchanged between the blood and
body cells.body cells.
Microcirculation (MC)
①① ArterioleArteriole②② Post-arteriolePost-arteriole③③ Pre-capillary Pre-capillary
sphinterssphinters④④ True capillaries; True capillaries;
Straight pathStraight path⑤⑤ VenuleVenule⑥⑥ A-V shunt A-V shunt
Pre-cap sphincter & Pre-cap sphincter & arteriole constrictionarteriole constriction → Capillary
perfusion → Local metabolites& histamine
↓VSM response to constrictive substance
↓
↑
Pre-cap sphincter & Pre-cap sphincter & arteriole dilationarteriole dilation
Capillary perfusion ←←
↑
Local Feedback Regulation of Capillary Perfusion
Local metabolites& histamine
VSM response to con- strictive substance
Apoptosis Oxygen Society Education Program Tome & Briehl 15
Pathogenesis of Shock
Microcirculation Changes
Cellular Mechanisms
Humoral Mechanisms
Apoptosis Oxygen Society Education Program Tome & Briehl 16
Microcirculation Changes
Three Stages of Microcirculation Changes
Stage I: Ischemic hypoxia stageStage I: Ischemic hypoxia stage
Stage II: Stagnant hypoxia stageStage II: Stagnant hypoxia stage
Stage III: Refractory stageStage III: Refractory stage
Compensatory stage
Stage of vasoconstriction
1. Ischemic Hypoxia Stage
Main driver:
Excitation of sympathetic nerve-
adrenomedullary system ++
Mechanism of microcirculatory changesActivation of sympathetic nerve-
adrenomedullary system
Vasoconstrictive substances ↑ ↑(Catecholamines, angiotension , vasopressin, endothelin)Ⅱ
α -receptors
Constriction of microvessel
β -receptors
Opening of A-V shunts
Ischemic Hypoxia Stage
Redistribution of Blood Flow During Redistribution of Blood Flow During Stage IStage I
α-receptorα-receptor
Catecholamines
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Sympathetic-adrenal system
excited
β-receptorβ-receptor
Normal Ischemic hypoxia stage
Ischemic Hypoxia Stage
Microcirculatory changes
Arteriole +++Sphincter ++++
Venule +
Inflow ↓ ↓ & outflow ↓
Characteristics of MC perfusionArteriole +++Sphincter ++++
Venule +
Ischemic Hypoxia Stage
Inflow < outflow
↓ Opening of true capillaries
Compensatory significance
①①Maintenance of blood volumeMaintenance of blood volume•Auto Auto bloodblood transfusion transfusion•Auto Auto fluidfluid transfusion transfusion
②②Maintenance of BPMaintenance of BP•↑ ↑ returned bloodreturned blood•↑ ↑ cardiac outputcardiac output•↑ ↑ peripheral resistance peripheral resistance
③③Blood supply to heart and brainBlood supply to heart and brain - Redistribution of blood flow- Redistribution of blood flow
Ischemic hypoxia stage
23
Auto Auto BloodBlood Transfusion During Stage I Transfusion During Stage I
The “first defense line” in shockThe “first defense line” in shock
Capillary hydrostatic pressure ↓Capillary hydrostatic pressure ↓
Absorption of fluid into blood vessels ↑Absorption of fluid into blood vessels ↑
Auto Auto FluidFluid Transfusion Transfusion
Auto Auto FluidFluid Transfusion During Stage ITransfusion During Stage I
↓ ↓ Opening of true capillariesOpening of true capillaries
The “second defense line” in shockThe “second defense line” in shock
Excitation of sympathetic-adrenomedullay system
Catecholamines ↑
Vasoconstriction
Renal ischemia
Skin ischemia
Urine↓ Pallor faceCool limbs
Sweat gland secretion ↑
Sweating
Excitation of CNS
AgitationRestless
Heart rate ↑Contractility ↑
Peripheral resistances↑
BP(-)Thread pulse
Ischemic hypoxia stageClinical Manifestations
Apoptosis Oxygen Society Education Program Tome & Briehl 26
Three Stages of Microcirculation Changes
Stage I: Ischemic hypoxia stageStage I: Ischemic hypoxia stage
Stage II: Stagnant hypoxia stageStage II: Stagnant hypoxia stage
Stage III: Refractory stageStage III: Refractory stage
Microcirculation Changes
2. Stagnant Hypoxia Stage
Decompensatory stage
Stage of shock
Main driver:Main driver:
Over excitation of sympathetic Over excitation of sympathetic
nerve-adrenomedulla system nerve-adrenomedulla system ++++++++
Change of microcirculation
Normal Stagnant hypoxia stage
Stagnant Hypoxia Stage
Arteriole +Sphincter -
Venule +++
Precapillary vessel and sphincter dilation
Mechanism of Microcirculatory Stasis
Acidosis:Acidosis: Anaerobic glycolysis ↑Anaerobic glycolysis ↑ →lactate ↑→lactate ↑
↓ ↓ blood perfusion → COblood perfusion → CO22 removal ↓ → H removal ↓ → H22COCO33 ↑ ↑
Effects of humoral factorsEffects of humoral factors Nitric oxide (NO), histamine, kinin, etcNitric oxide (NO), histamine, kinin, etc
↓ response of SMC to catecholaminesresponse of SMC to catecholamines
31
Constriction Constriction of Arteriolesof Arterioles
Constriction Constriction of Venulesof Venules
DilationDilation of of ArteriolesArterioles
ConstrictionConstriction of Venulesof Venules
Stage IIStage IIStage IStage I
Cell Adhesion Molecules
Stagnant Hypoxia Stage
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Calcium-dependentCalcium-dependentIntegrinsIntegrinsCadherinsCadherinsSelectinsSelectins
Calcium-independentCalcium-independentImmunoglobulin superfamily (IgSF) CAMsImmunoglobulin superfamily (IgSF) CAMsLymphocyte homing receptorsLymphocyte homing receptors
Families of Cell Adhesion Molecules (CAMs)
Inflow ↑ & outflow ↓
Characteristics of MC perfusionVenule +++ ↑ CAMs
Inflow > outflow
Stagnant Hypoxia Stage
↑ Opening of capillary
Arteriole +Sphincter -
Vicious cycleVicious cycle
Opening of CapillariesOpening of Capillaries
Returned bloodReturned blood↓↓
CO, BP CO, BP ↓↓
Tissue perfusionTissue perfusion↓↓
Ischemia, Hypoxia, AcidosisIschemia, Hypoxia, Acidosis
34
Consequences of MC Consequences of MC Changes Changes
Sympathetic nerve +Sympathetic nerve +
Stagnant Hypoxia Stage
Microcirculation stasis
Cardiac output ↓
Renal blood flow ↓
Returned blood volume ↓
Oliguria or anuria
Blood pressure ↓↓
Brain ischemia
Dull or coma
Stasis in kidney
Cyanosis or maculation
Stasis in skin
Clinical ManifestationsStagnant Hypoxia Stage
Treatment principlesTreat microcirculatory stasis
Stagnant Hypoxia Stage
②. Volume replacement “ Infusion as much as required”
①. Acidosis correction
③. Vasoactive drugs Vasodilators vs. Vasoconstrictors
Apoptosis Oxygen Society Education Program Tome & Briehl 37
Three Stages of Microcirculation Changes
Stage I: Ischemic hypoxia stageStage I: Ischemic hypoxia stage
Stage II: Stagnant hypoxia stageStage II: Stagnant hypoxia stage
Stage III: Refractory stageStage III: Refractory stage
Microcirculation Changes
Terminal stage of shock
Microcirculatory failure stage
Irreversible stage
3. Refractory stage
Also called:
Damage of EC + HemoconcentrationDamage of EC + Hemoconcentration
Aggregation of RBCs, platelets → CoagulationAggregation of RBCs, platelets → Coagulation
Consumption of coagulation factors → Consumption of coagulation factors → Bleeding, hemolysisBleeding, hemolysis
Congestion, Hypoxia, AcidosisCongestion, Hypoxia, Acidosis
39
Disseminated Intravascular Coagulation Disseminated Intravascular Coagulation (DIC)(DIC)
Refractory Stage
Blood volume Blood volume ↓↓ ↓↓
Changes of MicrocirculationChanges of Microcirculation
Paralytic dilation of microvesselsParalytic dilation of microvessels
Microthrombosis Microthrombosis → → DICDIC
Characteristics of MC PerfusionCharacteristics of MC Perfusionno inflow and no outflowno inflow and no outflow
Refractory Stage
Microcirculatory Changes - paralyzed and collapsed
Normal Stage III
Refractory Stage
Extracellular [K+] ↑
Refractory phase
Membrane hyperpolarization
K+ Channel activationNO↑
Vasoconstrictive response ↓
Mechanism for Progressive Hypotension
Ischemia, Hypoxia → ATP↓
cGMP↑
Intracellular H+↑
H+-Ca2+
compete
Calcium influx ↓
iNOS
Mechanism for DIC Development
1) Increased blood viscosity
2) Coagulation system activated
3) Platelet aggregation and adhesion
1) MC blocked by microthrombi1) MC blocked by microthrombi
2) Hemorrhage2) Hemorrhage
3) Increased capillary permeability3) Increased capillary permeability
4) Organ infarction (and failure)4) Organ infarction (and failure)
Consequences of DIC
Refractory Stage
1) Circulatory collapse1) Circulatory collapse
Progressive refractory BP Progressive refractory BP ↓↓
2) Development of DIC2) Development of DIC
3) Failure of vital organs3) Failure of vital organs
Lung, kidney, liver, heart and brainLung, kidney, liver, heart and brain
Caused by hypoperfusionCaused by hypoperfusion
Clinical Manifestations
Refractory Stage
Refractory Mechanisms
1) DIC1) DIC
2) Failure of vital organs2) Failure of vital organs
3) No-reflow phenomenon3) No-reflow phenomenon
Refractory Stage
No-Reflow Phenomenon
The failure of blood to reperfuse an ischemic area after the The failure of blood to reperfuse an ischemic area after the
physical obstruction has been removed.physical obstruction has been removed.
Following treatment of shock with blood transfusion or Following treatment of shock with blood transfusion or
fluid infusion:fluid infusion:BP could be restored temporally;BP could be restored temporally;Microcirculatory perfusion is not improved obviously;Microcirculatory perfusion is not improved obviously;Blood flow in capillary is not recovered. Blood flow in capillary is not recovered.
No-Reflow Phenomenon
A: Microvascular injury A: Microvascular injury B: Interstitial edemaB: Interstitial edemaC: RBC lineup C: RBC lineup D: WBC adhesion on endothelial cellsD: WBC adhesion on endothelial cellsE: Capillary narrowing E: Capillary narrowing F: Platelets F: Platelets G: ThrombosisG: Thrombosis
Initial Cause
Effective Circulatory Volume ↓
MC Ischemia
MC Stasis
MC Failure
Cell damage
Organ failure
Compensatory
Decompensatory
Refractory MODS
Stage I Stage II Stage III
Shock Pathogenesis - Summary
NormalNormal Stage IStage I
Stage IIIStage IIIStage IIStage II
Apoptosis Oxygen Society Education Program Tome & Briehl 51
Pathogenesis of Shock
Microcirculation Changes
Cellular Mechanisms
Humoral Mechanisms
Cell Damage
1) Cell membrane damage1) Cell membrane damage
2) Mitochondrial swelling2) Mitochondrial swelling
3) Lysosome swelling and vacuole 3) Lysosome swelling and vacuole formationformation→→ Cell necrosisCell necrosis
Cell DamageCell Damage
Cell Membrane DamageCell Membrane DamageNaNa++/Ca/Ca2+2+ pump dysfunctionpump dysfunctionNaNa++/Ca/Ca2+2+ inflowinflow ,, KK++ outflowoutflowCellular edemaCellular edema
Lysosomal DamageSwelling and vacuole formationLysosomal enzyme releaseCell autolysis
Mitochondrial DamageMitochondrial DamageAcidosisAcidosis→→Respiratory enzymes Respiratory enzymes ↓ ↓ HypoxiaHypoxia→→ATPATP↓↓
53
Apoptosis Oxygen Society Education Program Tome & Briehl 54
Pathogenesis of Shock
Microcirculation Changes
Cellular Mechanisms
Humoral Mechanisms
Apoptosis Oxygen Society Education Program Tome & Briehl 55
Humoral Mechanisms
Vasoactive Substances
Inappropriate Inflammatory Response
Vasoactive SubstancesVasoactive SubstancesVasoconstrictorsVasoconstrictors VasodilatorsVasodilators
57
Endothelin
Angiotensin
ADH (Vasopressin)
ANP
CAs
Histamine
5-Hydroxytryptamine
NO
PGE2PGI2TXA2
Bradykinin
-endorphin
Apoptosis Oxygen Society Education Program Tome & Briehl 59
Humoral Mechanisms
Vasoactive Substances
Inappropriate Inflammatory Response- Systemic Inflammatory Response Syndrome
An inflammatory state affecting the whole body, An inflammatory state affecting the whole body,
frequently a response of the immune system to an frequently a response of the immune system to an
infectious or noninfectious insult. infectious or noninfectious insult.
Key IssuesKey Issues
▲ ▲ Disseminated activation of inflammatory cellsDisseminated activation of inflammatory cells
▲ ▲ Inflammatory mediator spilloverInflammatory mediator spillover
Systemic Inflammatory Response Systemic Inflammatory Response SyndromeSyndrome
(SIRS)(SIRS)
60
Development of SIRS
Causative Factor
Inflammatory Cells
Inflammatory mediators
Cascade
Pro-inflammatory mediatorsPro-inflammatory mediatorsTNFαTNFα 、、 IL-1IL-1 、、 IL-2IL-2 、、 IL-6IL-6 、、 IL-8IL-8 、、 IFNIFN 、 、 LTsLTs 、、 PAFPAF 、、 TXATXA22
Anti-inflammatory mediatorsAnti-inflammatory mediatorsIL-4IL-4 、、 IL-10IL-10 、、 IL-13IL-13 、、 PGEPGE22 、、 PGIPGI22
Inflammatory MediatorsInflammatory Mediators
62
Inflammatory CellsInflammatory Cells
63
MacrophagesMacrophagesTNFTNFαα 、、 IL-1IL-1 、、 IL-6IL-6 、、 IL-8IL-8 、、 IFNIFN 、、
IL-10IL-10 、、 IL-4IL-4
NeutrophilsNeutrophilsLTsLTs (( LeukotrieneLeukotriene
ss ))PlateletsPlatelets
PGGPGG22 、、 PGHPGH22 、、 TXATXA22 (( Thromboxane AThromboxane A22 ))Endothelial cellsEndothelial cells
IL-1IL-1 、、 GM-CSFGM-CSF 、、 ROSROS 、、 PGIPGI22
Compensatory Anti-inflammatory Compensatory Anti-inflammatory Response Syndrome (CARS)Response Syndrome (CARS)
64
With the increase of pro-inflammatory With the increase of pro-inflammatory mediators during SIRS, anti-inflammatory mediators during SIRS, anti-inflammatory factors begin to emerge. Overload of these factors begin to emerge. Overload of these anti-inflammatory factors will inhibit immune anti-inflammatory factors will inhibit immune system increase the chance of infection. system increase the chance of infection.
This is called Compensatory Anti-This is called Compensatory Anti-inflammatory Response Syndrome (CARS).inflammatory Response Syndrome (CARS).
SIRS vs. CARSSIRS vs. CARS
65
• SIRS > CARS:
Cell death, Organ dysfunction
• CARS > SIRS:
Immunosuppression, increase of infection
• SIRS ↑CARS↑:
- Disturbance of inflammation and immunity
- Mixed antagonist response syndrome
(MARS)
6666
ShockShock
①① IntroductionIntroduction②② Pathogenesis of ShockPathogenesis of Shock③③ Alterations of Metabolism Alterations of Metabolism
and Functionand Function④④ Pathophysiological Basis of Pathophysiological Basis of
TreatmentTreatment
Apoptosis Oxygen Society Education Program Tome & Briehl 67
Alterations of Metabolism and
FunctionMetabolic Disorders
Water, Electrolytes and Acid-Base Disturbance
Multiple Organ Dysfunction Syndrome
Organ Dysfunction During Shock
0102030405060708090
100
Lung Liver Kidney GI Heart
Inci
denc
e
Multiple Organ Dysfunction Multiple Organ Dysfunction Syndrome (MODS)Syndrome (MODS)
Pathogenesis of MODS:Pathogenesis of MODS: Ischemia Ischemia HypoxiaHypoxia Acidosis Acidosis Uncontrolled inflammatory responseUncontrolled inflammatory response
- SIRS- SIRS
69
7070
ShockShock
①① IntroductionIntroduction②② Pathogenesis of ShockPathogenesis of Shock③③ Alterations of Metabolism Alterations of Metabolism
and Functionand Function④④ Pathophysiological Basis of Pathophysiological Basis of
TreatmentTreatment
Etiology control
Eliminate or control the Eliminate or control the primary cause (disease) of primary cause (disease) of the shockthe shock
2) Prevent cell damage and protect cell function
3) Block the effect of inflammatory mediators
4) Prevent onset of DIC and MOSF
1) Improve MC
Prevention & treatment according to Pathogenesis
Treatment principlesTreat microcirculatory stasis
Stagnant Hypoxia Stage
②. Volume replacement “Infusion as much as required”
①. Acidosis correction
③. Vasoactive drugs (Vasodilators vs. Vasoconstrictors)