Presented by:

Dr. Md. Zareer Tafadar Post Graduate Student

Deptt. Of Anaesthesiology &Critical Care

Silchar Medical College & Hospital.

OXYGEN TRANSPORT & OXYGEN DISSOCIATION

CURVE

Components of the Oxygen Transport System

•Mass Transport from Environment to Alveolar Space

•Diffusion from Alveolar Air to Blood in the Pulmonary Capillary

•Mass Transport from the Pulmonary to the Systemic Capillaries

• Diffusion of Oxygen from Capillary Blood to Metabolizing Cells and Within the Cell to the Site of Consumption, the Mitochondria

The First Step Environment Alveolar Space

ATMOSPHERIC OXYGEN TENSION (PiO2 )

Atmospheric air containing 21 % oxygen at a total atmospheric pressure of 760 mm Hg at sea level has a pO2 of approximately 160 mm Hg.

ALVEOLAR OXYGEN TENSION With every breath, the inspired gas is humidified at 37°C in the upper

airway. The inspired tension of oxygen (PIO2) is therefore reduced by

the added water vapor. Water vapor pressure is 47 mm Hg at 37°C. In humidified air, in the trachea the normal partial pressure of O2 at sea

level is 149.7 mm Hg:(760-47)0.21

Pulmonary Ventilation

Respiratory muscle activity of inspiration/expiration cycling maintains two–way airflow and averaged over several cycles, maintains a partial pressure of oxygen and carbon dioxide in the alveolar air of 100 and 40 mm Hg respectively

Alveolar pO2 and pCO2 are maintained remarkably constant by complex neural regulation of the total and alveolar ventilation.

In order to generate airflow into the lung, inspiratory muscle contraction overcomes three forces:1. The elastic recoil of the lung and chest wall complex

2.The frictional resistance to airflow in the airways and the frictional resistances between lung and thorax; and

3. Inertial airflow resistance

The Second Step Alveoli Pulmonary Capillary

Factors important in efficient respiratory exchange between alveolar air and capillary blood in the lung

1. A large PO2 gradient of approximately 100- 40 mm Hg.

2. A large surface area available for gas exchange with a thin diffusion barrier.

3. A favorable diffusion coefficient for oxygen. 4. Efficient binding of O2 to Hb in blood.

O2 moves across the alveolar membranes into the

pulmonary capillaries by passive diffusion , across the alveolo capillary membrane, through the plasma and across the erythrocyte membrane and binds to Hb.

This is ‘‘driven’’ by a partial-pressure gradient for oxygen (pAO2 – pO2)

Alveolar Gas Equation

PAO2 = PiO2 ‒ PA CO2/R

where PIO2 is inspired oxygen tension, PACO2 is alveolar CO2 tension (assumed to equal arterial PCO2), R is the respiratory exchange ratio (normally in the range of 0.8 to 1.0),

The alveolar oxygen tension is approximately 104mm of Hg The factors that determine the precise value of alveolar PO2 are

(1) the PO2 of atmospheric air,

(2) the rate of alveolar ventilation, and

(3) the rate of total body oxygen consumption

Arterial Oxygen Tension

PaO2 cannot be calculated like PAO2 but must be measured at room air.

Arterial O2 tension can be approximated by the following formula (in mm

Hg):

PaO2=102-age/3.

The normal PaO2: 97mm Hg

Alveolar–arterial gradient (PAO2 – PaO2)

The Alveolar–arterial gradient is a measure of the difference between the alveolar concentration (A) and the arterial (a) concentration of oxygen. It is used in diagnosing the source of hypoxemia. It helps to assess the integrity of alveolar capillary unit

normally about 5–10 mm Hg, but progressively increases with age up to 25 mm Hg

A high A–a gradient could indicate a patient breathing hard to achieve normal oxygenation.If lack of oxygenation is proportional to low respiratory effort, then the A–a gradient is not increased

Exchange of Gases in Alveoli – Henry’s Law When a liquid is exposed to air containing a particular

gas, molecules of the gas will enter the liquid and dissolve in it.

Henry’s law states that “the amount of gas dissolved in a liquid will be directly proportional to the partial pressure of the gas in the liquid-gas interface”.

As long as the PO2 in the gas phase is higher than the PO2 in the liquid phase, there will be a net diffusion of O2 into the blood. Diffusion equilibrium will be reached only when the PO2 in the liquid phase is equal to the PO2 in the gas phase.

Partial pressures of carbon dioxide and oxygen in inspired air at sea level and various places in the body

Diffusion of Gases Through the Respiratory Membrane

Respiratory Unit is composed of a respiratory bronchiole, alveolar ducts, atria, and alveoli.

The alveolar walls are extremely thin, and between the alveoli is an almost solid network of interconnecting capillaries & the alveolar gases are in very close proximity to the blood of the pulmonary capillaries

Respiratory Membrane: Gas exchange between the alveolar air and the pulmonary blood occurs through the membranes of all the terminal portions of the lungs. All these membranes are collectively known as the respiratory membrane, also called the pulmonary membrane.

The following are the different layers of the respiratory membrane:

1. A layer of fluid lining the alveolus and containing surfactant that reduces the surface tension of the alveolar fluid.

2. The alveolar epithelium composed of thin epithelial cells.

3. An epithelial basement membrane.

4. A thin interstitial space between the alveolar epithelium and the capillary membrane.

5. A capillary basement membrane that in many places fuses with the alveolar epithelial basement membrane.

6. The capillary endothelial membrane.

Factors That Affect the Rate of Gas Diffusion Through the Respiratory Membrane

The thickness of the respiratory membrane :The rate of diffusion through the membrane is inversely proportional to the thickness of the membrane and any factor that increases the thickness (eg. Fibrosis, oedema fluid) can interfere significantly with normal respiratory exchange of gases.

The surface area of the respiratory membrane: Greater the surface area greaater is the rate of diffusion. In emphysema, the total surface area of the respiratory membrane is often decreased because of loss of the alveolar walls and respiratory exchange of gases is impeded.

The diffusion coefficient for transfer of each gas through the respiratory membrane depends on the gas’s solubility in the membrane and, inversely, on the square root of the gas’s molecular weight.

The  Alveolar–arterial gas gradient.

Diffusion from Alveoli to pulmonary capillary

Rate of gas diffusion = Diffusion coefficient X Pressure gradient x Surface area of the membrane

Thickness of the membrane

The volume of gas transfer across the alveolar-capillary membrane per unit time is:

Directly proportional to:- The difference in the partial pressure of gas between alveoli and

capillary blood.- The surface area of the membrane.- The solubility of the gas.Inversely proportional to:- Thickness of the membrane.- Molecular weight of the gas.

Diffusing Capacity of the Respiratory Membrane

the volume of a gas that will diffuse through the membrane each minute for a partial pressure difference of 1 mm Hg.

In the average young man, the diffusing capacity for oxygen under resting conditions averages 21 ml/min/mm Hg.

The mean oxygen pressure difference across the respiratory membrane during normal, quiet breathing is about 11 mm Hg. Multiplication of this pressure by the diffusing capacity (11 × 21) gives a total of about 230 milliliters of oxygen diffusing through the respiratory membrane each minute

this is equal to the rate at which the resting body uses oxygen.

The Third Step Pulmonary Systemic Capillaries

Transport of Oxygen in Blood

Each liter normally contains the number of oxygen molecules equivalent to 200 ml of pure gaseous oxygen at atmospheric pressure.

The oxygen is present in two forms:

(1) dissolved in the plasma

(2) reversibly combined with hemoglobin molecules in the RBCs. O2 is relatively insoluble in water, only 3 ml can be dissolved in 1 L of

blood at the normal arterial PO2 of 100 mmHg. The other 197 ml of oxygen in a liter of arterial blood, more than 98 percent of the oxygen content in the liter, is transported in the erythrocytes reversibly combined with hemoglobin.

Physically dissolved O2

Only 1.5 % of total O2 in blood.

Dissolved in plasma and water of RBC. (because solubility of O2 is very low)

It is about 0.3ml of O2 dissolved in 100ml arterial blood (at PO2 100 mmHg).

Its amount is directly proportional to blood PO2.

Can not satisfy tissue needs.

Chemically combined O2

98.5 % of total O2 in blood.

Transported in combination with Hb.

It is about 19.5 ml of O2 in 100 ml arterial blood.

Can satisfy tissue needs.

Hemoglobin

. Each hemoglobin molecule is a protein made up of four subunits bound together. Each subunit consists of a molecular group known as heme and a polypeptide attached to the hemeThe four polypeptides of a hemoglobin molecule are,collectively called globin. Heme is an iron–porphyrin compound that is an essential part of the O2-binding sites; only the

divalent form (+2 charge) of iron can bind O2.

Each of the four heme groups in a hemoglobin molecule contains one atom of iron (Fe), to which oxygen binds.

Thus this chain can exist in one of two forms—deoxyhemoglobin (Hb) and oxyhemoglobin (HbO2).

In a blood sample containing many Hb molecules, the fraction of all the Hb in the form of OxyHb is expressed as the percent Hb saturation

Effect of PO2 on Hemoglobin Saturation: The O2-Hb Dissociation Curve

The oxygen–hemoglobin dissociation curve plots the proportion of Hb in its saturated form on the vertical axis against the prevailing O2 tension on the horizontal axis.

 Important tool for understanding how blood carries and releases oxygen. More specifically it relates between the percentage of O2 carrying capacity

of Hb and PaO2

It is an S-shaped curve that has 2 parts:- upper flat (plateau) part.- lower steep part.

Oxygen-hemoglobin dissociation curve

The curve is S-shaped because each Hb molecule contains four subunits;

each binding of O2 to each subunit facilites the binding of the next one.

This combination of oxygen with hemoglobin is an example of cooperativity,

Explanation The globin units of DeoxyHb are tightly held by electrostatic bonds in a

conformation with a relatively low affinity for oxygen. The binding of oxygen to a heme molecule breaks some of these bonds

between the globin units, leading to a conformation change such that the remaining oxygen-binding sites are more exposed.

Thus, the binding of one O2 molecule to DeoxyHb increases the affinity of the remaining sites on the same hemoglobin molecule, and so on.

The upper flat (plateau) part of the curve

POPO22

% H

b s

atu

rati

on%

Hb

sat

ura

tion

1001006060

97 %97 %

90 %90 %

In the pulmonary capillaries (lung, POIn the pulmonary capillaries (lung, PO22 range of 100-60 mmHg). range of 100-60 mmHg). - At PO2 100 mmHg 97% of Hb is saturated with O2.- At PO2 60 mmHg 90% of Hb is saturated with O2 (small change in % Hb saturation).

Physiologic significance:

- Drop of arterial PO2 from 100 to 60 mmHg little decrease in Hb saturation to 90 % which will be sufficient to meet the body needs.

This provides a good margin of safety against blood PO2 changes in pathological conditions and in abnormal situations.

- Increase arterial PO2 (by breathing pure O2)

little increase in % Hb saturation (only 2.5%) and in total O2 content of blood.

The steep lower part of the curve

POPO22

% H

b s

atu

rati

on%

Hb

sat

ura

tion

1001006060

97 %97 %

90 %90 %

In the systemic capillaries (tissue, POIn the systemic capillaries (tissue, PO22 range of 0-60 mm Hg). range of 0-60 mm Hg).- At PO2 40 mmHg (venous blood) 70% of Hb is saturated with O2 (large change in % Hb saturation).At PO2 20 mmHg (exercise) 30% of Hb is saturated with O2.

30 %30 %

70 %70 %

2020 4040

The P50: The PaO2 in the blood at which the hemoglobin is 50% saturated, typically about 26.6 mmHg for a healthy person.

Increased P50 indicates a rightward shift of the standard curve, which means that a larger partial pressure is necessary to maintain a 50% oxygen saturation. This indicates a decreased affinity

Conversely, a lower P50 indicates a leftward shift and a higher affinity

SHIFT TO THE LEFT As In Pulmonary Capillaries

High pH

Decreased Temp.

Decreased Co2

Fetal Hb

Methaemoglobinemia

Increased Affinity Of Hb To Oxygen –Less Release Of Oxygen

SHIFT TO THE RIGHT As In Placenta And Muscles

Low pH

Increased Temp.

Increased CO2

Increased 2,3 DPG

Decreased Affinity Of Hb To Oxygen- More Release Of Oxygen From Hb

OOXXYYGGEENN--HHBB

CCUURRVVEE

Clinically important factors altering O2 binding include

1.Hydrogen ion concentration,

2.CO2 tension.

3.Temperature,

4.2,3-diphosphoglycerate (2,3-DPG) concentration.

Effect Of pH

H+ decreases the affinity of Hb molecule for O2 . It does so by combining with the globin portion of hemoglobin and altering the conformation of the Hb molecule.

H+ and O2 both compete for binding to the hemoglobin molecule. Therefore, with increased acidity, the hemoglobin binds less O2 for a given PO2 (and more H+)

Thus, these effects are a form of allosteric modulation.

Effect of CO2 :

CO2 affects the curve in two ways:

Most of the CO2 content (80–90%) is transported as bicarbonate ions. The formation of a bicarbonate ion will release a proton into the plasma. Hence, the elevated CO2 content creates a respiratory acidosis and shifts the oxygen–hemoglobin dissociation curve to the right.

About 5–10% of the total CO2 content of blood is transported as carbamino compounds which bind to Hb forming CarbaminoHb. Levels of carbamino compounds have the effect of shifting the curve to the left.

Bohr's Effect

The Bohr effect is a physiological phenomenon first described in 1904 by the Danish physiologist Christian Bohr, stating that the “oxygen binding affinity of Hb is inversely related to the concentration of carbon dioxide & H+ concentration.”

- At tissues: Increased PCO2 & H+ conc. shift of O2-Hb curve to the right.

- At lungs: Decreased PCO2 & H+ conc. shift of O2-Hb

curve to the left. So, Bohr's effect facilitates i) O2 release from Hb at tissues.ii) O2 uptake by Hb at lungs.

Effect of 2,3DPG to Shift the O2-Hb Dissociation Curve.

2,3-Bisphosphoglyceric acid (isomer of the glycolytic intermediate 1,3-bisphosphoglyceric acid (1,3-BPG). 2,3-BPG is present in human RBC.

It interacts with deoxygenated Hb beta subunits by decreasing their affinity for O2, so it allosterically promotes the release of the remaining oxygen molecules bound to the hemoglobin, thus enhancing the ability of RBCs to release oxygen near tissues that need it most.

Increased by: exercise, at high altitude, thyroid hormone, growth hormone and androgens.

Decreased by: acidosis and in stored blood.

O2 Dissociation Curve Of Fetal Hb

Fetal Hb (HbF) contains 2 and 2 polypeptide chains and has no chain which is found in adult Hb (HbA).

So, it cannot combine with 2, 3 DPG that binds only to chains. So, fetal Hb has a dissociation curve to the left of that of adult Hb.

So, its affinity to O2 is high increased O2 uptake by the fetus from the mother.

Fetal haemoglobin

O2 Dissociation Curve Of Myoglobin

One molecule of myoglobin has one ferrous atom (Hb has 4 ferrous atoms).

One molecule of myoglobin can combine with only one molecule of O2 .

The O2–myoglobin curve is rectangular in shape and to the left of the O2-Hb dissociation curve.

So, it gives its O2 to the tissue at very low PO2. So, it acts as O2 store used in severe muscular exercise when PO2 becomes

very low.

The myoglobin dissociation curve is a long way to the left of Hb.

At each partial pressure of oxygen, myoglobin holds onto much more oxygen than Hb.

The Fourth Step Capillary Blood Within the Cell

The blood entering the capillary with a high PO2 begins to surrender its oxygen because it is surrounded by an immediate environment of lower PO2, initially giving off oxygen dissolved in plasma, and followed by release of oxygen bound to Hb.

The principal force driving diffusion is the gradient in pO2 from blood to the cells

The oxygen dissociation characteristics of Hb facilitate the rapid and efficient unloading of oxygen within the capillary.

The O2 ultimately diffuses from the microcirculation into the cells and finally into the mitochondria.

Oxygen movement in the lungs and tissues

Oxygen content (CaO2)

Total amount of O2 present in 100 ml of Arterial BloodCaO2=Hb. Bound O2+ dissolved Hb = [1.34 x Hb x SaO2] + 0.003 x PO2  = [1.34×15×97.5] +0.003×100 =19.9=20ml /dl approx

. =200ml/L

Similarly for Venous blood CvO2=1.34 × Hb × SvO2 + 0.003 × PvO2replacing with values we have CvO2=15 ml/dl

=150 ml/LTotal oxygen content

200 × arterial blood vol. + 150 × venous blood vol.= 200 × 0.25 × 5+150 × 0.75 × 5= 250 + 562.5

= 812ml

Oxygen delivery (DO2)

Quantity of O2 made available to body in one minute – O2 delivery or flux

DO2= Q × CaO2 × 10= Q × 1.34 × Hb × SaO2 × 10

Q - cardiac output CaO2-arterial oxygen contentMultiplier 10 is used to convert CaO2 from

ml/dl to ml/L

Normal DO2 in adults at rest is 900-1,100 ml/min

Oxygen consumption (VO2)

Total amount of O2 consumed by the tissues per unit of time

VO2=Q × (CaO2- CvO2) × 10rearranging, VO2=Q × 1.34 × Hb × (SaO2-SvO2)

Substituting the values

Normal resting O2 consumption ~ 200 to 300 ml/minin adult humans

The fraction of the oxygen delivered to the capillaries that is taken up into the tissues is an index of the efficiency of oxygen transport. This is monitored with a parameter called the oxygen extraction ratio (O2ER), which is the ratio of O2 uptake to O2 delivery.

O2ER=VO2/DO2

The O2ER is normally about 0.25 (range = 0.2–0.3), . This meansthat only 25% of the oxygen delivered to the systemic capillaries is taken up into the tissues.

Oxygen extraction ratio

The DO2–VO2 Relationship• As O2 delivery (DO2) begins to decrease below normal, the O2 uptake (VO2) initially remains constant, indicating that the O2 extraction (O2ER) is increasing as the DO2 decreases. Further decreases in DO2 eventually leads to a point where the VO2 begins to decrease.

• The transition from a constant to a varying VO2 occurs when the O2 extraction increases to a maximum level of 50% to 60% (O2ER = 0.5 to 0.6). Once the O2ER is maximal, further decreases in DO2 will result in equivalent decreases in VO2 because the O2ER is fixed and cannot increase further.

• When this occurs, the VO2 is referred to as being supply-dependent, and the rate of aerobic metabolism is limited by the supply of oxygen. This condition is known as dysoxia .

• As aerobic metabolism (VO2) begins to decrease, the oxidative production of high energy phosphates (ATP) begins to decline, resulting in impaired cell function and eventual cell death. The clinical expression of this process is clinical shock and progressive multiorgan failure …

The Critical DO2

•The DO2 at which the VO2 becomes supply-dependent is called the critical oxygen delivery (critical DO2). It is the lowest DO2 that is capable of fully supporting aerobic metabolism .• It is identified by the bend in the DO2–VO2 curve .

• Despite the ability to identify the anaerobic threshold, the critical DO2 has limited clinical value.• First, the critical DO2 has varied widely in studies of critically ill patient, and it is not possible to predict the critical DO2 in any individual patient in the ICU.

•Second, the DO2–VO2 curve can be curvilinear (i.e., without a single transition point from constant to changing VO2) , and in these cases, it is not possible to identify a critical DO2.

DO2 – VO2 relationship in critically illSlope of maximum OER isless steep

↓Reduced extraction ofoxygen by tissues

↓Does not plateau(consumption remainssupply dependent evenat “supranormal” levelsof DO2)

Ultimate Fate of Oxygen The oxygen-consuming process in the mitochondrion is localized in the five

sequential enzyme complexes embedded in the inner membrane, comprising the mitochondrial respiratory chain.

Four of the five complexes provide reduced NADH transporting free electrons to the fifth complex, ATP synthase,where oxidative phosphorylation of ADP takes place.

In the process oxygen is used to generate water and CO2.

The Oxygen Cascade

The oxygen cascade describes the process of declining oxygen tension from atmosphere to mitochondria.

At sea level:159mmHg PIO2 : 149mmHg

PAO2 : 105 mmHg

PaO2 : 98 mmHg

PvO2 : 47mmHg

Intracellular : < 40 mmHg Mitochondria: < 5 mmHg

*Any interference to the delivery of oxygen at any point in the cascade, significant injury can occur downstream. The most graphic example of this is ascension to altitude.

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