06 hypoxia

Dept. of PathologyDept. of Pathology

Medical 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 6Chapter 6

HypoxiaHypoxia（缺氧）（缺氧）

22

HypoxiaHypoxia

①① IntroductionIntroduction

②② Parameters of HypoxiaParameters of Hypoxia

③③ Classification, Etiology, and Classification, Etiology, and

MechanismMechanism

④④ Alterations of Metabolism and Alterations of Metabolism and

Function in the BodyFunction in the Body

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

TreatmentTreatment

Oxygen is one of the most important necessities in our life!

Important necessities of life①Oxygen②Water③Food④Vitamins

Normal Process of Oxygen Acquiring and Utilization

Air Lungs Blood Tissue utilization Ventilation Diffusion Transportation

Internal respirationExternal respiration

Oxygen usageOxygen supply

Deficiency in either the delivery or the Deficiency in either the delivery or the

utilization of oxygenutilization of oxygen at the tissue level, at the tissue level,

leading to leading to changes in functions, metabolisms changes in functions, metabolisms

and structuresand structures of cells and tissues of the body. of cells and tissues of the body.

Hypoxia: Definition

88

HypoxiaHypoxia




MechanismMechanism




TreatmentTreatment

Parameters for Evaluation of Hypoxia

PO2: Partial pressure of O2

C-O2max: O2 binding capacity

C-O2: Blood O2 content

SO2: O2 saturation

Da-vO2: Difference in arterio-venous O2

PO2: Partial Pressure of O2

Tension produced by the O2 molecules physically dissolved in plasma.

Normal PaO2: 80-110 mmHg (100 mmHg, 13.3 kPa)

PvO2: 37-40 mmHg (40 mmHg, 5.32 kPa)

1 kPa = 7.5 mmHg

Factors Affecting PO2

FiOFiO22: Fraction (percentage) of inspired oxygen: Fraction (percentage) of inspired oxygen

Normal FiONormal FiO22: 21% (0.21) : 21% (0.21)

Pulmonary functionPulmonary function•Ventilation problem Ventilation problem

Obstruction of airwayObstruction of airway

•Exchange (diffusion) problemExchange (diffusion) problem

Edema (inflammation)Edema (inflammation)

Venous-to-arterial shunt (shortcut)Venous-to-arterial shunt (shortcut)Venous-to-arterial shunt (shortcut)Venous-to-arterial shunt (shortcut)

Sketch Map of Normal Oxygen Pressure GradientSketch Map of Normal Oxygen Pressure Gradient

AlveolusAirAlveolar

capillaryArterial blood

Body

capillary

Venous

blood

mm

Hg

C-O2max:

Oxygen Oxygen binding capacitybinding capacity of hemoglobin of hemoglobin when fully oxygenated.when fully oxygenated. - Maximal amount of - Maximal amount of O2 that could be bound by that could be bound by Hb. (Ability of Hb to carry Hb. (Ability of Hb to carry O2.).)

Normal value: 20 ml/dl Normal value: 20 ml/dl (1.34 x 15)(1.34 x 15)

Affected by quantity and quality of Hb.Affected by quantity and quality of Hb.

C-O2: O2 Content

Oxygen that is Oxygen that is actually bound to actually bound to hemoglobinhemoglobin plus free O plus free O2 2 (0.3 ml/dl).(0.3 ml/dl).

- Sealed off from air. - Sealed off from air.

Normal value: Ca-ONormal value: Ca-O22: 19 ml/dl: 19 ml/dl

Cv-OCv-O22: 14 ml/dl: 14 ml/dl

Determined by PODetermined by PO22 and C-O and C-O22max.max.

Little but important

SO2: O2 Saturation

Percentage of Hb present as oxygenated Hb.

Normal value: SaO2: 93 ～ 98％ SvO2: 70 ～ 75 ％

Determined by: PO2. (SO2 vs. PO2: Oxygen Dissociation Curve)

Affected by: pH, Temp, PCO2, 2,3-DPG.

C-O2

C-O2max

SO2 = x 100%

Oxygen Dissociation Curve (ODC)Oxygen Dissociation Curve (ODC)

2,3-DPG: 2,3-diphosphoglycerate

20

40

60

80

100

0 20 40 60 80 100

PO

2 (%

)

PO2 (mmHg)

Oxygen Dissociation Curve

2,3-DPG ↑

[H+]↑ (pH ↓)

CO2 ↑

Temp ↑

2,3-DPG↓

[H+] ↓ (pH↑)

CO2↓

Temp ↓

Hb-O2 affinity?

Hb-O2 affinity?

20

40

60

80

100

0 20 40 60 80 100

[H+] ↓ (pH↑)

[H+]↑ (pH ↓)

Ox

yg

en s

atu

rati

on

(%

)

Oxygen pressure (mmHg)

Bohr effect:

When [H+]↑, ODC will right shift (the affinity ↓) ; When [H+] ↓, ODC will left shift (the affinity ↑).

Bohr effect:

When [H+]↑, ODC will right shift (the affinity ↓) ; When [H+] ↓, ODC will left shift (the affinity ↑).

Bohr effectBohr effect

The binding of 2,3-DPG prevents binding of O2. The binding of 2,3-DPG prevents binding of O2.

Effect of 2,3-DPG on O2 Binding

Glycerate

2,3-Diphosphoglycerate

Da-vO2:

Normal Value: Da-vO2=CaO2-CvO2=19-14=5 ml/dlNormal Value: Da-vO2=CaO2-CvO2=19-14=5 ml/dl

Difference in arterio-venous oxygen content.

- reflecting tissue oxygen usage (function of internal respiration).

Factors affecting Da-vO2:

PO2

Speed of blood flow

Metabolic rate

Hb-O2 affinity

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HypoxiaHypoxia




MechanismMechanism




TreatmentTreatment

Classification of Hypoxia

①Hypotonic (Hypoxic)

②Hemic (Hematogenous)

③Circulatory

④Histogenous (Dysoxidative)

④Histogenous (Dysoxidative)

Oxygen SupplyOxygen Supply

Oxygen UsageOxygen Usage

Types of Hypoxia

Air Lungs

① Hypotonic

Blood Tissue utilization

② Hemic ③ Circulatory

④ Histogenous

3.1 Hypotonic Hypoxia

Hypotonic hypoxia is characterized by the decrease of PaO2 (< 60 mmHg).

Also called Hypoxic Hypoxia.

Etiology and Mechanism

Decreased O2 level of inspired air

Hypoventilation

Diffusion abnormality

Venous-to-arterial shunt (tetralogy of Fallot)

O2

Diffusion abnormality

Venous-to-arterial

shunt

Hypo-ventilation

Relationship Between Altitude and Hypoxia

Altitude(km)

Air O2

(mmHg)PaO2

(mmHg)SaO2 Symptom

8

5

3

0

58

85

110

158

30

45

62

100

58%

75%

90%

95% -

±

++

Mostly dead

29

Defect in Defect in interventricular interventricular

septumseptum

Shunt from right to left

PaOPaO22

Venous-to-arterial Shunt (Tetralogy of Fallot)

Changes of Blood Oxygen Parameters

During Hypotonic Hypoxia

Changes of Blood Oxygen Parameters

During Hypotonic Hypoxia

Type PaO2 C-O2max Ca-O2 SaO2 Da-vO2Type PaO2 C-O2max Ca-O2 SaO2 Da-vO2

Hypotonic ↓ N ↓ ↓ ↓Hypotonic ↓ N ↓ ↓ ↓

3.2 Hemic Hypoxia

Refers to decreased Refers to decreased quantity of Hb in the blood quantity of Hb in the blood or altered affinity of Hb for or altered affinity of Hb for oxygen.oxygen.

Also called Also called HematogenousHematogenous or or IsotonicIsotonic Hypoxia. Hypoxia.

Etiology and Mechanism

Quantity of Hb changed (Anemia)Quantity of Hb changed (Anemia)

Quality of Hb changed Quality of Hb changed

→ ↓→ ↓ ability of Hb to bind Oability of Hb to bind O22

Carbon monoxide (CO) poisoningCarbon monoxide (CO) poisoning

form Carboxyhemoglobin (HbCO)form Carboxyhemoglobin (HbCO)

FeFe3+3+ poisoning poisoning

form Methemoglobin (HbFeform Methemoglobin (HbFe3+3+) )

34

Carbon Monoxide Carbon Monoxide PoisoningPoisoning

Hb+COHb+CO HbCOHbCO

↓ ↓ 2,3-DPG2,3-DPG ↓ ↓ OO22 releaserelease

↓ ↓ Ability to carry OAbility to carry O22

Methemoglobinemia

The ferrous state of iron (Fe2+) in Hb may be oxidized to the ferric state (Fe3+) under the action of oxidizers, e.g. nitrite and nitrobenzene.

HbFe3+ loses the ability to carry oxygen.

HbFeHbFe2+2+ HbFeHbFe3+3+

NitriteNitrite


Anemia N ↓ ↓ N ↓Anemia N ↓ ↓ N ↓

Changes of blood oxygen parametersChanges of blood oxygen parameters

3.3 Circulatory Hypoxia

Circulatory hypoxia refers to inadequate Circulatory hypoxia refers to inadequate

blood flow leading to inadequate blood flow leading to inadequate

oxygenation of the tissues.oxygenation of the tissues.

Also called Hypokinetic Hypoxia.Also called Hypokinetic Hypoxia.

Etiology and mechanism

Systemic circulation obstacleShock

Local circulation obstacleLeft heart failure

Thrombosis

Arterial stenosis (narrowing)

Tissue congestion, tissue ischemia

Changes of Blood Oxygen Parameters During Circulatory

Hypoxia

Changes of Blood Oxygen Parameters During Circulatory

Hypoxia


Circ. Hyp. N N N N ↑Circ. Hyp. N N N N ↑

3.4 Histogenous hypoxia

Even though the amount of oxygen Even though the amount of oxygen delivered to tissue is adequate, the tissue delivered to tissue is adequate, the tissue cells can not make use of the oxygen cells can not make use of the oxygen supplied to them.supplied to them.

Also called Dysoxidative Hypoxia.Also called Dysoxidative Hypoxia.

Mitochondrial injuryMitochondrial injuryCyanide poisoningCyanide poisoningArsenideArsenideRadiationRadiationBacterial toxinsBacterial toxinsOxygen free radicalOxygen free radical

inhibit the function of the mitochondriainhibit the function of the mitochondria

Deficiency of B group vitamins (BDeficiency of B group vitamins (B2 2 or PP)or PP)

Coenzymes required for oxidative phosphorylation.Coenzymes required for oxidative phosphorylation.

Causes of Histogenous Hypoxia

Changes of Blood Oxygen Parameters During Histogenous

Hypoxia

Changes of Blood Oxygen Parameters During Histogenous

Hypoxia


Histo. Hyp. N N N N ↓Histo. Hyp. N N N N ↓

Characteristic Changes of Different Types of Hypoxia

Characteristic Changes of Different Types of Hypoxia

Type PaO2 C-O2max Ca-O2 SaO2 Da-vO2

Hypotonic ↓ N ↓ ↓ ↓

Hemic N ↓ ↓ N ↓

Circulatory N N N N ↑

Histogenous N N N N ↓

Changes of Blood Oxygen Parameters in Different Types of

Hypoxia

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HypoxiaHypoxia




MechanismMechanism




TreatmentTreatment

Section 4. Alterations of Metabolism and Function

Respiratory system

Circulatory system

Hematologic system

Central nervous system

Tissues and cells

Central respiratory failureCentral respiratory failure

- Periodic breathing- Periodic breathing

Cheyne-Stoke respirationCheyne-Stoke respiration

Biot’s breathingBiot’s breathing

High altitude pulmonary edema (HAPE)High altitude pulmonary edema (HAPE)

Clinical Manifestations

Biot’s breathingBiot’s breathing

Cheyne-StokeCheyne-Stoke

4.1 Respiratory system

High Altitude Pulmonary Edema (HAPE)

A life-threatening form of pulmonary edema (fluid A life-threatening form of pulmonary edema (fluid accumulation in the lungs) that occurs at altitudes accumulation in the lungs) that occurs at altitudes typically above 2.5 km.typically above 2.5 km.

The major cause of death related to high-altitude The major cause of death related to high-altitude exposure.exposure.

Mechanisms of HAPE:Mechanisms of HAPE:Excitement of the sympathetic nerveExcitement of the sympathetic nerve↑ ↑ lung artery pressure lung artery pressure (due to (due to Hypoxic Pulmonary Hypoxic Pulmonary Vasoconstriction (Vasoconstriction (HPV)) HPV)) → Exudation of fluid→ Exudation of fluid↑↑ permeability of the vascular endotheliumpermeability of the vascular endothelium

4.2 Circulatory systemIncreased cardiac output (CO) and heart rate (HR)Increased cardiac output (CO) and heart rate (HR)

Redistribution of blood flowRedistribution of blood flow

Dilation of heart and brain vesselsDilation of heart and brain vessels

Hypoxic Pulmonary Vasoconstriction (Hypoxic Pulmonary Vasoconstriction (HPV)HPV)

Capillary proliferationCapillary proliferation

Hypoxia → HIF (hypoxia-inducible factor) → Hypoxia → HIF (hypoxia-inducible factor) → VEGF → Capillary growthVEGF → Capillary growth

Injury Manifestations

•Pulmonary hypertensionPulmonary hypertension

•Arrhythmia Arrhythmia

- Vagus Nerve- Vagus Nerve- K- K++/Ca/Ca2+2+ disturbance disturbance

•Decreased myocardial function Decreased myocardial function

•Decreased venous return to heart Decreased venous return to heart

•Hypertension Hypertension

4.3 Hematologic System

Increase in RBCs and HbIncrease in RBCs and Hb

Hypoxia → HIF → EPOHypoxia → HIF → EPO

↑ ↑ 2,3-DPG 2,3-DPG (produced from glycolysis)(produced from glycolysis)

→→ ODC shift (left or right?)ODC shift (left or right?)

• goodgood for O for O22 release in the tissue; release in the tissue;

• badbad for O for O22 binding in the lungs binding in the lungs

Plasma viscosity↑ Plasma viscosity↑ → → blood flow resistance ↑ blood flow resistance ↑ → → afterload of heart ↑afterload of heart ↑

Affinity between Hb and oxygen Affinity between Hb and oxygen ↓↓- Due to - Due to ↑ ↑ 2,3-DPG2,3-DPG


4.4 Central nervous systemAcute hypoxiaAcute hypoxia

HeadacheHeadachePoor memoryPoor memoryInability to make judgmentInability to make judgmentDepressionDepression

Chronic hypoxiaChronic hypoxiaUnable to concentrateUnable to concentrateFatigueFatigueDrowsinessDrowsinessCerebral edema and neuron injury → Cerebral edema and neuron injury → worsen hypoxia → deathworsen hypoxia → death

↑ ↑ Ability to use of oxygenAbility to use of oxygen

(All types except histogenous hypoxia)(All types except histogenous hypoxia)

↑ ↑ Number and density of mitochondriaNumber and density of mitochondria

↑ ↑ Activity of mitochondrial enzymesActivity of mitochondrial enzymes

↑ ↑ Glycolysis Glycolysis

↑ ↑ Capillary density Capillary density

↓ ↓ Metabolic state Metabolic state

↑ ↑ Myoglobin (OMyoglobin (O22 reservoir) reservoir)

4.5 Tissues and Cells

Enhanced MyoglobinEnhanced Myoglobin

2020 4040 6060 8080

SO2SO2

2020

4040

6060

8080

(mmHg)(mmHg)

(%)(%)


Mitochondria injuryMitochondria injury↓ ↓ ATPATP

Cell membrane injuryCell membrane injury↑↑ NaNa++ and Ca and Ca2+2+ inflow inflow↑↑ KK++ outflow outflow

Lysosome injury Lysosome injury Autocytosis (necrosis)Autocytosis (necrosis)

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HypoxiaHypoxia




MechanismMechanism




TreatmentTreatment

5.Pathophysiological Basis of Prevention and Treatment

Eliminating causesEliminating causes

Oxygen therapy: Oxygen therapy:

Increase the concentration of OIncrease the concentration of O22. .

- Usually not exceeding 60% O- Usually not exceeding 60% O22 (FiO (FiO22 0.6).0.6).

Increase the pressure of OIncrease the pressure of O2.2.

- Not exceeding 3 atmosphere. - Not exceeding 3 atmosphere.

O2 Therapy

All patients with hypoxia can be treated All patients with hypoxia can be treated with inhalation of oxygen, but the efficiency with inhalation of oxygen, but the efficiency is quite different to every type of hypoxia.is quite different to every type of hypoxia.

Effectiveness of OEffectiveness of O22 Therapy: Therapy: The best — Hypotonic hypoxia The best — Hypotonic hypoxia The worst — Histogenous hypoxiaThe worst — Histogenous hypoxia

When the patient inhales high pressure of oxygen, When the patient inhales high pressure of oxygen, a series of toxic signs and symptoms will appear, a series of toxic signs and symptoms will appear, this condition is termed as this condition is termed as oxygen toxicationoxygen toxication..

Cerebral oxygen toxication (Acute)Cerebral oxygen toxication (Acute)

Pulmonary oxygen toxication (Chronic)Pulmonary oxygen toxication (Chronic)

The mechanisms of oxygen toxicity.The mechanisms of oxygen toxicity.

Reactive oxygen species or oxygen free radicals.Reactive oxygen species or oxygen free radicals.

Oxygen Toxication (OT)

06 hypoxia

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