Hypoxia

Department of pathphysiology
Han Song
 Why we need oxygen?

Aerobic metabolism

＋
NADH NAD
Cytb1 Cytc1
-
FMNH2 2e CoQH 2e CoQH 2e
2e
2O ATP
Cytc Cyca-a3
X
2H
＋
2H
＋
2H
＋
2H
＋ Pi
NADH dehydrogenase Cytb-c1 Cyt oxidase
ADP
 Content
 General Introduction
 Classification, Etiology and
Mechanisms
 Functional and Metabolic Changes
 Factors Involved in Tolerance to
Hypoxia
 Oxygen Treatment and Oxygen Toxicity
 External respiration

Circulation Tissue cells

Bound to haemoglobin

Oxygen supply Oxygen utilization

 Concept
Hypoxia is referred to a pathological process
in which oxygen supply to tissues or organs is
inadequate to meet the demand of cells, or
there is adequate delivery to tissue but the
tissue cells cannot make use of oxygen,
leading to changes in functions, metabolisms

and structures of cells and tissues of the body.

 Hypotonic
Histogenous

Hemic Circulatory

Oxygen Oxygen
supply↓ Hypoxia utilization ↓
Parameters of blood oxygen
 Partial pressure of oxygen, PO2

 Oxygen binding capacity,CO2max

 Oxygen content, CO2

 A-VdO2

 Oxygen saturation(SO2) and P50

 Partial pressure of oxygen, PO2
PO2 is the pressure or tension caused by
oxygen physically dissolved in the blood.

Normal value ：
PO2 of inspired air
PaO2 13.3kPa(100mmHg)
External respiration

PvO2 5. 33kPa(40mmHg) Internal respiration

Oxygen binding capacity, C-O2max
CO2 max is the maximum amount of oxygen
combined by Hb in 100ml blood under fully
saturated condition ：
PO2 150 mmHg、PCO2 40 mmHg 、 38 ℃
Normal value：
1.34ml/g x 15g/dl = 20ml/dl (8.92mmol/L )
Influence：
Quality (binding affinity with O2) and quantity
of Hb
Oxygen content, C-O2
The total amount of oxygen contained actually
in 100 ml blood sample, including the part
combined with Hb and the part physically
dissolved in plasma （0.3ml/dl).
Normal value：
CaO2 19ml/dl
CvO2 14ml/dl
Influence：
Hb quality and quantity
PO2
 A-VdO2 (CaO2-CvO2)
The difference value is between arterial
and venous blood oxygen content.
19ml/dl 14ml/dl
A O2 O2 O2 O2 O2 V

5ml/dl
Meaning
A-VdO2= volume of O2 tissue uptake = CaO2-CvO2
 Oxygen saturation, SO2
The percentage of hemoglobin present as oxyhemoglobin.

CO2 –O2 dissolved physically in plasma

SO2 = 100%
CO2max
Normal value：
SaO2 93％～98％
SvO2 70％～75％
Influence ：
PO2
＋
H (pH)，2,3-DPG，PaCO2 ，temperature
 Oxygen-hemoglobin dissociation curve
100
2,3-DPG↓
＋
H ↓
CO2↓
80
Temperature↓
SO2 (%)

60 2,3-DPG ↑
＋
H ↑
CO2 ↑
40 Temperature ↑

20

0
0 20 40 60 80 100

PO2 (mmHg)
 P50
One measure of the position of the curve is the
PO2 at the 50% SO2.

Normal value：
3.47～3.6kPa
(26 ～ 28mmHg)

Significance
The P50 indicates affinity
of hemoglobin for oxygen
Classification, Etiology and Mechanisms

 Hypotonic Hypoxia (Hypoxic Hypoxia)

 Hemic Hypoxia (Isotonic Hypoxia)

 Circulatory Hypoxia(Hypokinetic Hypoxia)

 Histogenous Hypoxia(Histotoxic Hypoxia)

 Hypotonic
Histogenous

Hemic Circulatory

Oxygen Oxygen
supply↓ Hypoxia utilization ↓
Hypotonic hypoxia (Hypoxic hypoxia)

Oxygen tension in arterial

blood is lower than normal,
which resulted in lack of oxygen
from blood to tissues.
Causes
 Decreased PO2 of inspired air
 High altitude、 In mines
 Breathe in air with low O2

 External respiratory dysfunction

 Ventilation or gas exchange dysfunction,
PaO2 ↓ CaO2 ↓
 Respiratory hypoxia

 Venous-to-arterial shunt
 Congenital heart disease，right to left
shunt
 Increase shunt in pulmonary
Altitude Air P Air PO2 Alveoli PO2
(m) (mmHg) (mmHg) (mmHg)
Sea level 760 159 105
1000 680 140 90
2000 600 125 70
3000 530 110 62
5000 405 85 45
6000 366 74 40
8000 270 56 30
 Tetralogy of Fallot

Normal Right to left shunt

Characteristics of blood oxygen

Hypotonic PO2 SaO2 CO2max CO2 Ca-vO2

Acute ↓ ↓ N ↓ ↓

Chronic ↓ ↓ ↑ ↓ N
 Characteristics of blood oxygen

Type PaO2 CO2max CaO2 SaO2 CO2 Skin color

(a-v)
Hypotonic cyanosis
Cyanosis
The bluish color of skin, nails, lips and mucous
membranes when the deoxyhemoglobin
concentration of the blood in the capillaries is
more than 5g/dl.

2.6g/dl HHb
≥5g/dl

HbO2

Normal Hypoxia
 Hypoxia and Cyanosis are not consistent
while Hb is too much or too little
 Serious anemia,Hb <50g/L(5g/dl),hypoxia but
not cyanosis
 RBC increase, deoxyHb>50g/L(5g/dl),
Cyanosis but not hypoxia
Hemic hypoxia

 Hemic hypoxia refers to the altered

affinity of Hb for oxygen or decrease
in amount of Hb in the blood
 PaO2 normal, also called isotonic
hypoxia
Causes

 Hb amount decrease
 Anemia

 Hb alteration
 Carbon monoxide poisoning
 Methemoglobinemia, MHb
 Higher affinity of Hb to oxygen
Sickle Cell Anemia

Glu Val

Skin color Pallor

Carbon monoxide poisoning
 Carbon monoxide poisoning
 Affinityof CO for Hb is 210 times as
its affinity for O2

Hb＋CO—HbCO

 COinhibits glycolysis in RBC, 2,3-DPG

reduced，Oxygen dissociation curve
shift ot left,decrease the amount of
oxygen released.

Skin color HbCO Cherry-red

 Methemoglobinemia
The ferrous state iron in Hb is oxidized to the
ferric state under the action of oxidizers,e.g.
nitrite,nitrobenzene,to form methemoglobin( HbFe3+OH）
oxidizers
HbFe2+ HbFe3+OH
nitrite （coffee color）
nitrite

HbFe3+OH > 1.5 g/dl， skin appears to coffee color ，

called enterogenous cyanosis.
HbFe3+OH Fe3+ unable to Fe2+-O2+ unable
carry O2 to dissociate

Methemoglobinemia
 High affinity of Hb for O2
Hb-O2 affinity ↑：ODC shift to left

100 2,3-DPG↓
＋
H ↓

80 CO2↓ Depot blood ：

SO2 (%)

Temperature↓ RBC 2,3-DPG↓

60 2,3-DPG ↑
＋
H ↑ Alkaline solution：
40 CO2 ↑ pH↑, Hb-O2 affinity ↑ by
Temperature ↑ Bohr effect
20

0
0 20 40 60 80 100

PO2 (mmHg)
Characteristics of blood oxygen

Hemic PO2 SaO2 CO2max CaO2 Ca-vO2

Anemia N N ↓ ↓ ↓
CO
N ↓ N ↓ ↓
poisoning
MHb N N ↓ ↓ ↓
High
affinity of N N N N ↓
Hb for O2
 Characteristics of blood oxygen

Type PaO2 CO2max CaO2 SaO2 CO2 Skin color

(a-v)

Hypotonic Cyanosis

Pallor
Hemic Coffee color
Cherry-red
Circulatory hypoxia (hypokinetic hypoxia)
 Circulatory hypoxia refers to inadequate
blood flow leading to inadequate
oxygenation of the tissues, which is also
called hypokinetic hypoxia.
 Etiology ：
Ischemic hypoxia ：shock, left heart
failure, thrombosis, arterial stenosis
Congestive hypoxia： right heart
failure,venous embolism, phlebitis
Mechanisms
 Ischemic hypoxia

Artery Vein
Capillary
pressure↓

 Congestive hypoxia
Artery Vein
Capillary
pressure ↑
 19ml/dl 12ml/dl

A O2 O2 O2 O2 O2 O 2 O2 O2 V

7ml/dl

Blood flow to tissues  Total oxygen 

 Characteristics of blood oxygen

Type PaO2 CO2max CaO2 SaO2 CO2 Skin color

(a-v)

Hypotonic Cyanosis

Pallor
Hemic Coffee color
Cherry-red

Pallor
Circulator
y Cyanosis
Histogenous hypoxia
Histogenous hypoxia refers to the tissue cells can
not make use of the oxygen supplied to them, though
the amount of oxygen delivered to them is adequate.
 Etiology and mechanism
 Inhibition of oxidative phosphorylation - tissue intoxicity
cyanides, sulphuret, rotenone
cyanides cytochrome oxidase↓ hypoxia

 Mitochondria injury
bacteriotoxin, radiation, free radical

 Absence of Vitamin
VB1，VB2，VPP, co-enzyme
The mitochondrial respiratory chain and its inhibitors

Rotenone
amytal

antimycin
↓ Cyanide
NADH → FMN
↓ ↓
CoQ → cyt b→ cyt c1→ cyt c → cyt aa→
3 O2

Succinate → FAD
 Characteristics of blood oxygen

Type PaO2 CO2max CaO2 SaO2 CO2 Skin color

(a-v)

Hypotonic Cyanosis

Pallor
Hemic Coffee color
Cherry-red

Pallor
Circulator
y Cyanosis

Histogenous Red
Multiple types of hypoxia occurs in clinical

Blood lost Hemic

Ischemic Shock

Circulation
Circulatory
dysfunction

Lung failure Hypotonic

Endotoxemia Histogenous
 Changes of function and metabolism

• Respiratory system
Compensatory
• Circulatory system
Responses
• Hematologic system
• Central nervous system
Injurious responses
• Tissues and cells
 Respiratory system
Hypotonic hypoxia

Early stage PaO2↓ Ventilation↑ Compensatory

response

Severe hypoxia PaO2↓↓ Respiratory

center ↓
Pulmonary Decompensatory
Acute effects
edema
Chronic Sensibility of peripheral
chemorecepter↓
 Compensatory Reaction
PaO2↓
(<60mmHg)
Meaning：
Chemoreceptor in PaO2 ↑
carotid and aortic body
Blood volume
Stimulate respiratory returning to heart ↑
center

Respiration ↑
Ventilation↑
 Injury Manifestation
High altitude pulmonary edema (HAPE )
When people first arrive at a high altitude above
3000 m, many individuals develop “mountain
sickness” after 1-4 days.
Clinical characteration：headache, irritability,
insomnia, cyanosis, breathlessness, vomiting and
loss of consciousness.
Mechanisms：
1. Pulmonary hypertension
2. Permeability of pulmonary endothelial cell
3. Sympathetic tone 
 Central respiratory failure
PaO2<30mmHg→Respiratory center inhibition
→Central respiratory failure
Circulatory system

Compensatory response
1. Cardiac output↑

2. Redistribution of blood flow

3. Pulmonary vasoconstriction

4.Capillary hyperplasia
1. Cardiac output ↑

Cardiac contractility↑

PaO2↓ Heart rate ↑

CO2↑

Venous return↑
2. Redistribution of blood flow
Hypoxia

Increased sympathetic Hypoxia metabolites:

tone adenosine, lactic acid

vasoconstriction vasodilation

Skin, viscus Heart, brain

3. Pulmonary vasoconstriction
Maintain the normal ratio of V/Q， PaO2↑
O2

O2 O2
PO2 PO2 O2
PO2 PaO2
PaO2 PaO2

PaO2
V/Q＝0.8 V /Q＜0.8 V /Q ＝ 0.8
Mechanisms

 Direct effect of O2 on lung arterial smooth

muscle

Humoral factors ：TXA2,ET  

PGI2, Histamine, NO 

 Sympathetic nerve
4.Capillary Hyperplasia
Capillary proliferation facilitate
oxygen diffusion into cells

brain，heart， skeletal muscle

High expression of VEGF,

Increased adenosine

In chronic hypoxia
 Injury Manifestation

1. Pulmonary hypertension：right heart failure

2. Decreased diastolic and systolic myocardial
function
3. Arrhythmia：bradycardia, premature beats
and ventricular fibrillation
4. Decrease in venous return to the heart：
Increased adenosine and lactic acid lead to
vasodilation
 Hematologic system

Compensatory response
1. Increase in the amount of RBCs and Hb
More EPO produced and released by kidney
2. Right shift of O2-Hb dissociation curve
More 2,3-DPG produced from glycolysis process
 1. RBC↑ Hb ↑
Acute hypoxia：Sympathetic nerve
excitement， Redistribution of
blood flow →Blood in liver
Chronic and spleen
RBCreleases CO2↑
EPO↑
hypoxia generation
in blood↑ Plasma
 Meaning viscosity ↑
Increase CO2max and CO2
 Defects
Increase plasma viscosity and obstruction of circulation
2.Right shift of ODC →Hb release O2↑

2,3-DPG binds to HHb at the central cavity

 6-P-F 6-P-G G
- DPGP ATP
pH↑ +
Hyperventilation PFK
ADP
- 1,6-DPF

HHb ↑
- G3P Phosphodihydroxyacetone

DPGM
2,3DPG-Hb↑ 1,3- DPG
- 2,3- DPGP
3-PGA
DPG
DPGP
2-PGA

2-PEP Pyruvate Lactic acid

Mechanism-
of increasing 2,3-DPG production
from glycolysis process caused by hypoxia
 Injury Manifestation

RBC↑ Plasma viscosity↑, blood flow

resistance ↑, afterload of heart ↑

When PO2 <60mmHg, 2,3-DPG ↑

Binding affinity of Hb for O2 in alveoli 
CaO2 
 Central nervous system
CNS is very sensitive to hypoxia

Compensation：
Mild hypoxia or early stage： Redistribution of
cerebral blood flow
Decompensation：
Severe or prolonged hypoxia：
CNS dysfunction, Cerebral edema and neuron injury
 Dysfunction of CNS

 Acute hypoxia:
headache, agitation, poor faculty of
memory, inability to make judgment,
depress or loss of coordination
 Chronic hypoxia:
impaired concentration, fatigue, drowsiness
 Cerebral edema and neuron injury
Tissue and cellular alteration
Compensatory response
 Enhanced cell capacity for use of oxygen :
number and membrane surface of mitochondria↑
activity of succinic dehydrogenase and cyt-oxidase ↑

 Enhanced anaerobic glycolysis ↑

 Low metabolic states
 Myoglobin and other protein carried oxygen↑
1. Enhanced cell capacity for use of oxygen
 number and membrane surface of
mitochondria ↑

 Enzymes in the respiratory increase

 Succinate dehydrogenase
 cytochrome oxidase
2. Enhanced anaerobic glycolysis ↑
 Enhanced glucose uptake
 Enhanced glycolysis
ATP↓ ATP/ADP ↓ →
phosphofructokinase ↑

3. Low metabolic states

 Metabolism Energy consumption 
Ion pump function
4.Inrease of myoglobin
 Injury Manifestation

 Cell membrane injury

 Mitochondria injury
 Lysosome injury
 Apoptosis
Cell membrane injury
膜电位下降，能量不足

Na+ influx :
ATP ↓ cell swelling
Na＋
Ca2＋ H2O
K+ efflux :
K＋ synthetic disorder

Ca2+ influx:
phospholipase
Ca2+ -dependent
protein kinase
Mitochondria injury
Mild or early phase hypoxia:
Function of mitochondria ↑
Severe hypoxia:
decrease cell respiratory function, ATP ↓
Alteration： swelling， mitochondrial crista crack，
mebrane broken，content leak
Lysosome injury
Acidosis，increased free Ca2+ : phospholipase activity ↑
permeability of lysosome mebrane ↑ ，hydrolase released
 Factors involved in
Torlerance to hypoxia

 Oxygen stores
 Metabolism rate
 Differences between individuals
 Adaptive exercise
 Pre-hypoxia stimulation
 Pathophysiological basis of
prevention and treatment

Eliminating causes
Pulmonary ventilation, gas exchange,
antitoxic treatment

Oxygen treatment
Main method of hypoxia treatment
 Home oxygen therapy

Chronic respiratory or
circulatory diseases:
COPD, respiratory failure,
heart failure
 Hyperbaric oxygen therapy

Pure oxygen is given under hyperbaric conditions.

(2-3 atmospheres)
 Oxygen Toxity
 High PIO2（>0.5 atmosphere）may cause cell
injury, organs and tissues dysfuction，called
oxygen intoxication.
 Oxygen Toxity depend on the partial pressure of
inspired air:
PiO2=(PB-47) FiO2
 Classifiction
 Acute：oxygen pressure > 2 ATM,CNS effects
 Chronic：Inhalation of high concentration of
oxygen for more than 12h, cough, sore throat,
nasal congestion