INTRAPLEURAL PRESSURE

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Intrapleural pressure

Intrapleural pressure (Pip) is the pressure in the thin fluid-filled potential space between the visceral pleura covering the lung and the parietal pleura lining the thoracic wall.

It is normally negative relative to atmospheric pressure.

Why is it negative?

Two opposing elastic recoils act on the pleural space:

The lungs recoil inward and tend to collapse.
The chest wall recoils outward and tends to expand.

Their opposing pulls create subatmospheric pressure in the sealed pleural space. This negative pressure keeps the lungs expanded. Costanzo Physiology, 7th ed., pp. 207, 212.

Values during quiet breathing

Phase	Intrapleural pressure
End of normal expiration / at FRC	about -5 cm H₂O
Inspiration	Becomes more negative
End of quiet inspiration	about -8 cm H₂O
Forced expiration	May become positive

During inspiration, diaphragmatic contraction enlarges the thoracic cavity, lowering pleural pressure further. At the end of normal expiration, it returns to approximately -5 cm H₂O. Costanzo Physiology, 7th ed., p. 212-214.

Relationship to transpulmonary pressure

The pressure that distends the lung is the transpulmonary pressure:

[ P_{TP} = P_{Alveolar} - P_{Intrapleural} ]

At rest:

[ P_{TP} = 0 - (-5) = +5 \text{ cm H₂O} ]

This positive distending pressure counteracts lung elastic recoil and maintains alveolar expansion. Transpulmonary-pressure physiology describes the same pressure relationship.

Clinical importance: pneumothorax

If air enters the pleural space, intrapleural pressure equalizes with atmospheric pressure, approaching 0 cm H₂O. Transpulmonary pressure is then lost, so the affected lung recoils and collapses while the chest wall moves outward.

Normal pleural pressure and pneumothorax

One-line summary

Intrapleural pressure is normally negative, becomes more negative during inspiration, helps keep the lungs open, and is lost in pneumothorax.

GAS EXCHANGE IN THE LUNGS AND TISSUES. BLOOD GASES. Details notes in about 10 pages for physiology

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Intrapleural pressure

Intrapleural pressure (Pip) is the pressure in the thin fluid-filled potential space between the visceral pleura covering the lung and the parietal pleura lining the thoracic wall.

It is normally negative relative to atmospheric pressure.

Why is it negative?

Two opposing elastic recoils act on the pleural space:

The lungs recoil inward and tend to collapse.
The chest wall recoils outward and tends to expand.

Their opposing pulls create subatmospheric pressure in the sealed pleural space. This negative pressure keeps the lungs expanded. Costanzo Physiology, 7th ed., pp. 207, 212.

Values during quiet breathing

Phase	Intrapleural pressure
End of normal expiration / at FRC	about -5 cm H₂O
Inspiration	Becomes more negative
End of quiet inspiration	about -8 cm H₂O
Forced expiration	May become positive

Relationship to transpulmonary pressure

The pressure that distends the lung is the transpulmonary pressure:

[ P_{TP} = P_{Alveolar} - P_{Intrapleural} ]

At rest:

[ P_{TP} = 0 - (-5) = +5 \text{ cm H₂O} ]

This positive distending pressure counteracts lung elastic recoil and maintains alveolar expansion. Transpulmonary-pressure physiology describes the same pressure relationship.

Clinical importance: pneumothorax

One-line summary

**Intrapleural pressure is normally negative, becomes more negative during inspiration, helps keep the lungs open, and is lost in pneumothorax.**This is a broad physiology topic. I can structure it as a 10-page exam note, but it covers several distinct units.## Gas exchange in lungs and tissues, and blood gases: topic map

Basic principles of gas exchange
- Partial pressures and Dalton's law
- Diffusion and Fick's law
- Solubility of O₂ and CO₂
- Diffusing capacity of the lung
Alveolar gas exchange
- Composition of inspired, alveolar, and expired air
- Alveolar ventilation
- Alveolar gas equation
- Factors affecting alveolar (P_{O_2}) and (P_{CO_2})
Pulmonary capillary exchange
- Diffusion of O₂ from alveoli to blood
- Diffusion of CO₂ from blood to alveoli
- Perfusion-limited versus diffusion-limited transfer
- Ventilation-perfusion ratio and V/Q mismatch
- Physiological shunt and dead space
Oxygen transport in blood
- Dissolved O₂ and hemoglobin-bound O₂
- Oxyhemoglobin dissociation curve
- Right and left shifts
- Bohr effect, P50, oxygen content, and oxygen delivery
Gas exchange in tissues
- Tissue oxygen extraction
- Diffusion gradient between systemic capillaries and cells
- Bohr effect in tissue capillaries
- Role of myoglobin
Carbon dioxide transport
- Dissolved CO₂, bicarbonate, and carbamino compounds
- Carbonic anhydrase reaction
- Chloride shift
- Haldane effect
- CO₂ unloading in lungs
Blood gases and acid-base physiology
- Normal arterial and venous blood gas values
- ABG interpretation
- Respiratory and metabolic acidosis/alkalosis
- Compensation
- Anion gap and clinical correlations
Applied physiology
- Hypoxemia versus hypoxia
- Cyanosis
- High altitude
- Anemia and carbon monoxide poisoning
- COPD, pulmonary edema/fibrosis, shunt, and V/Q inequality

High-level overview

Gas exchange depends on diffusion down partial-pressure gradients. In the lungs, oxygen enters pulmonary capillary blood while carbon dioxide leaves it. In tissues, the direction reverses: oxygen moves from blood into cells and carbon dioxide enters blood.

Oxygen is carried predominantly by hemoglobin, whereas carbon dioxide is transported mainly as bicarbonate. Arterial blood-gas measurements assess ventilation, oxygenation, and acid-base status, making them central to respiratory physiology and clinical diagnosis.

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Gas Exchange in the Lungs and Tissues. Blood Gases

Detailed Physiology Note

1. Introduction

Respiration has four linked processes:

Pulmonary ventilation: movement of air between atmosphere and alveoli.
Diffusion: movement of O₂ and CO₂ across the alveolar-capillary membrane.
Transport of gases in blood: carriage of O₂ from lungs to tissues and CO₂ from tissues to lungs.
Tissue gas exchange: diffusion of O₂ into cells and CO₂ out of cells.

The overall sequence is:

[ \text{Atmosphere} \rightarrow \text{Alveoli} \rightarrow \text{Blood} \rightarrow \text{Tissues} ]

for oxygen, and the reverse for carbon dioxide.

At rest, the body consumes approximately 250 mL O₂/min and produces approximately 200 mL CO₂/min. Thus, the respiratory quotient:

[ R = \frac{\dot V_{CO_2}}{\dot V_{O_2}} ]

is approximately:

[ R = \frac{200}{250} = 0.8 ]

2. Basic Concepts in Gas Exchange

2.1 Partial pressure

A gas mixture exerts a total pressure equal to the sum of the partial pressures of its component gases. This is Dalton's law.

[ P_{Total} = P_{O_2} + P_{CO_2} + P_{N_2} + P_{H_2O} ]

The partial pressure of any gas is:

[ P_{gas} = F_{gas} \times P_{total} ]

where (F_{gas}) is the fractional concentration of the gas.

At sea level:

[ P_B = 760 \text{ mm Hg} ]

Atmospheric air contains approximately 21% O₂:

[ P_{IO_2} = 0.21 \times 760 = 160 \text{ mm Hg} ]

Thus, the (P_{O_2}) of dry atmospheric air is approximately 160 mm Hg.

2.2 Humidification of inspired air

Inspired air becomes saturated with water vapor as it passes through the upper airway. At body temperature, water vapor pressure is:

[ P_{H_2O} = 47 \text{ mm Hg} ]

Therefore, the partial pressure of inspired oxygen after humidification is:

[ P_{IO_2} = F_{IO_2}(P_B - P_{H_2O}) ]

At sea level:

[ P_{IO_2} = 0.21(760 - 47) ]

[ P_{IO_2} \approx 150 \text{ mm Hg} ]

Thus:

Site	(P_{O_2})
Dry atmospheric air	160 mm Hg
Humidified tracheal air	150 mm Hg
Alveolar air	about 100 mm Hg
Systemic arterial blood	about 95-100 mm Hg
Mixed venous blood	about 40 mm Hg

Costanzo Physiology, 7th ed., p. 218.

2.3 Diffusion of gases

Gases move by simple diffusion from a region of higher partial pressure to a region of lower partial pressure.

The rate of diffusion is described by Fick's law:

[ \dot V_{gas} = \frac{A}{T} \times D \times (P_1-P_2) ]

Where:

(\dot V_{gas}) = rate of gas transfer
(A) = surface area available for diffusion
(T) = thickness of the diffusion barrier
(D) = diffusion coefficient of the gas
(P_1 - P_2) = partial-pressure gradient

Therefore, diffusion increases with:

Increased surface area
Increased partial-pressure gradient
Higher solubility of the gas

Diffusion decreases with:

Increased membrane thickness
Reduced surface area
Reduced partial-pressure gradient

2.4 Diffusion coefficient

The diffusion coefficient is proportional to:

[ D \propto \frac{\text{Solubility}}{\sqrt{\text{Molecular weight}}} ]

CO₂ is much more soluble than O₂. Therefore, despite its smaller pressure gradient, CO₂ diffuses approximately 20 times more rapidly than O₂ across the respiratory membrane.

Guyton and Hall Textbook of Medical Physiology, p. 522.

Clinical significance

Pulmonary fibrosis increases diffusion distance.
Pulmonary edema adds fluid between alveolar air and capillary blood.
Emphysema reduces surface area by destroying alveolar septa.
O₂ transfer is affected earlier and more severely than CO₂ transfer in diffusion disorders.

3. The Alveolar-Capillary Membrane

The respiratory membrane separates alveolar gas from pulmonary capillary blood. It includes:

Alveolar lining fluid and surfactant
Type I alveolar epithelial cell
Epithelial basement membrane
Thin interstitial space
Capillary basement membrane
Capillary endothelial cell
Plasma
Red blood cell membrane

It is extremely thin, approximately 0.2 to 0.6 µm in many areas, allowing rapid diffusion.

Mixed venous blood enters the pulmonary capillary from the right ventricle. It gains O₂ and loses CO₂. The blood leaving the capillary becomes oxygenated arterial blood and returns to the left heart. Costanzo Physiology, 7th ed., p. 218.

4. Alveolar Ventilation

4.1 Minute ventilation

Minute ventilation is the total volume of air inspired or expired per minute:

[ \dot V_E = V_T \times f ]

Where:

(\dot V_E) = minute ventilation
(V_T) = tidal volume
(f) = respiratory rate

Example:

[ \dot V_E = 500 \text{ mL} \times 12/\text{min} ]

[ \dot V_E = 6000 \text{ mL/min} = 6 \text{ L/min} ]

However, not all inspired air reaches alveoli for gas exchange.

4.2 Dead space

Dead space is the volume of inspired air that does not take part in gas exchange.

A. Anatomical dead space

It is the volume in conducting airways:

Nose
Pharynx
Larynx
Trachea
Bronchi
Terminal bronchioles

In an average adult:

[ V_D \approx 150 \text{ mL} ]

B. Alveolar dead space

Alveoli may be ventilated but receive little or no blood flow. Such ventilation is wasted.

This occurs in conditions such as:

Pulmonary embolism
Low cardiac output
Destruction of pulmonary capillary bed in emphysema

C. Physiological dead space

[ \text{Physiological dead space} = \text{Anatomical dead space} + \text{Alveolar dead space} ]

Normally, alveolar dead space is very small, so physiological dead space is nearly equal to anatomical dead space.

4.3 Alveolar ventilation

Only air reaching the alveoli participates in gas exchange.

[ \dot V_A = (V_T - V_D) \times f ]

Where:

(\dot V_A) = alveolar ventilation
(V_T) = tidal volume
(V_D) = dead-space volume
(f) = respiratory rate

Example:

[ \dot V_A = (500 - 150) \times 12 ]

[ \dot V_A = 4200 \text{ mL/min} = 4.2 \text{ L/min} ]

Importance of tidal volume

Compare two breathing patterns:

Pattern	Tidal volume	Respiratory rate	Minute ventilation	Alveolar ventilation
Normal	500 mL	12/min	6 L/min	4.2 L/min
Rapid, shallow	250 mL	24/min	6 L/min	2.4 L/min

Although minute ventilation is equal, rapid shallow breathing is less efficient because a greater fraction of each breath enters dead space.

4.4 Alveolar ventilation equation

Alveolar (P_{CO_2}) is inversely related to alveolar ventilation:

[ P_{A CO_2} = \frac{\dot V_{CO_2} \times K}{\dot V_A} ]

Clinically:

[ P_{a CO_2} \approx P_{A CO_2} ]

Therefore:

[ P_{a CO_2} = \frac{\dot V_{CO_2} \times 0.863}{\dot V_A} ]

Where:

(P_{aCO_2}) = arterial carbon dioxide tension
(\dot V_{CO_2}) = rate of CO₂ production
(\dot V_A) = alveolar ventilation
0.863 = conversion constant

Consequences

Change	Alveolar ventilation	PaCO₂
Hypoventilation	Decreases	Increases
Hyperventilation	Increases	Decreases
Increased CO₂ production	Unchanged	Increases
Decreased CO₂ production	Unchanged	Decreases

Thus, hypercapnia usually indicates alveolar hypoventilation.

Costanzo Physiology, 7th ed., pp. 211-212.

5. Alveolar Gas Equation

The alveolar gas equation estimates alveolar oxygen tension:

[ P_{A O_2} = P_{I O_2} - \frac{P_{a CO_2}}{R} ]

At sea level while breathing room air:

[ P_{A O_2} = F_{IO_2}(P_B-P_{H_2O}) - \frac{P_{aCO_2}}{R} ]

With:

(F_{IO_2} = 0.21)
(P_B = 760) mm Hg
(P_{H_2O} = 47) mm Hg
(P_{aCO_2} = 40) mm Hg
(R = 0.8)

[ P_{A O_2} = 0.21(760-47) - \frac{40}{0.8} ]

[ P_{A O_2} = 150 - 50 ]

[ P_{A O_2} = 100 \text{ mm Hg} ]

Factors reducing alveolar (P_{O_2})

Low inspired oxygen concentration
Reduced barometric pressure at high altitude
Hypoventilation with increased PaCO₂
Increased oxygen consumption, if not matched by ventilation

Costanzo Physiology, 7th ed., p. 214.

6. Gas Exchange in the Lungs

6.1 Oxygen transfer

Mixed venous blood entering pulmonary capillaries has:

[ P_{vO_2} \approx 40 \text{ mm Hg} ]

Alveolar gas has:

[ P_{AO_2} \approx 100 \text{ mm Hg} ]

Thus, there is a diffusion gradient of about:

[ 100 - 40 = 60 \text{ mm Hg} ]

O₂ diffuses from alveoli into pulmonary capillary blood until blood (P_{O_2}) equilibrates with alveolar (P_{O_2}).

Under normal conditions, equilibrium occurs during the first one-third of capillary transit time. Thus, the normal lung has a substantial diffusion reserve.

6.2 Carbon dioxide transfer

Mixed venous blood has:

[ P_{vCO_2} \approx 46 \text{ mm Hg} ]

Alveolar gas has:

[ P_{ACO_2} \approx 40 \text{ mm Hg} ]

The CO₂ pressure gradient is only about 6 mm Hg. Yet CO₂ diffuses rapidly because of its much greater solubility.

[ P_{vCO_2} - P_{ACO_2} = 46 - 40 = 6 \text{ mm Hg} ]

CO₂ moves from blood to alveoli and is then removed by expiration.

6.3 Diffusion-limited and perfusion-limited gas transfer

Perfusion-limited transfer

Gas equilibrates completely between alveolar air and capillary blood early in the capillary. Further uptake depends on delivery of more blood.

Examples:

Nitrous oxide
O₂ under normal resting conditions
CO₂ under normal conditions

O₂ is normally perfusion limited because its capillary partial pressure rapidly reaches alveolar partial pressure.

Diffusion-limited transfer

The gas does not equilibrate between alveolar air and capillary blood by the end of the capillary. Transfer is limited by diffusion across the membrane.

Classic example:

Carbon monoxide

CO binds strongly to hemoglobin, maintaining capillary (P_{CO}) close to zero. Therefore, a diffusion gradient persists along the whole capillary.

O₂ can become diffusion limited in:

Interstitial fibrosis
Pulmonary edema
Severe emphysema
Strenuous exercise
High altitude

Costanzo Physiology, 7th ed., pp. 220-222.

6.4 Diffusing capacity of the lungs

Diffusing capacity is the volume of gas crossing the respiratory membrane each minute for a pressure gradient of 1 mm Hg.

[ D_L = \frac{\dot V_{gas}}{\Delta P} ]

The approximate diffusing capacity for O₂ at rest is:

[ D_{LO_2} \approx 21 \text{ mL/min/mm Hg} ]

It increases substantially during exercise because:

More pulmonary capillaries are recruited.
Existing capillaries dilate.
Surface area for diffusion increases.
Ventilation-perfusion matching improves.

Guyton and Hall Textbook of Medical Physiology, pp. 522-523.

DLCO

Diffusing capacity is commonly assessed clinically by measuring carbon monoxide uptake, called DLCO.

DLCO is reduced in:

Emphysema
Interstitial lung disease
Pulmonary edema
Pulmonary vascular disease
Anemia

DLCO may be increased in:

Exercise
Polycythemia
Pulmonary hemorrhage

7. Ventilation-Perfusion Relationship

7.1 Definition

For effective gas exchange, alveolar ventilation and pulmonary blood flow must be matched.

[ \frac{\dot V_A}{\dot Q} ]

Where:

(\dot V_A) = alveolar ventilation
(\dot Q) = pulmonary perfusion

Normal total values are approximately:

[ \dot V_A = 4.2 \text{ L/min} ]

[ \dot Q = 5 \text{ L/min} ]

Therefore:

[ \frac{\dot V_A}{\dot Q} = \frac{4.2}{5} \approx 0.8 ]

7.2 Regional V/Q differences

Due to gravity, both ventilation and perfusion are greater at the base of the upright lung. Perfusion increases more than ventilation toward the base.

Region	Ventilation	Perfusion	V/Q ratio
Apex	Low	Very low	High
Base	High	Very high	Low
Average lung	Normal	Normal	0.8

Apex

High V/Q means relatively more ventilation than perfusion.

Higher alveolar (P_{O_2})
Lower alveolar (P_{CO_2})

Base

Low V/Q means relatively more perfusion than ventilation.

Lower alveolar (P_{O_2})
Higher alveolar (P_{CO_2})

7.3 V/Q = 0: shunt-like unit

When:

[ \dot V_A = 0 ]

but blood flow remains present:

[ \frac{\dot V_A}{\dot Q} = 0 ]

No fresh gas reaches the alveolus. Blood passing through it remains poorly oxygenated.

Examples:

Atelectasis
Alveolar flooding in pulmonary edema
Consolidation in pneumonia
Mucus plugging

This behaves as a right-to-left shunt.

7.4 V/Q = infinity: dead-space unit

When ventilation occurs but there is no perfusion:

[ \dot Q = 0 ]

[ \frac{\dot V_A}{\dot Q} = \infty ]

No gas exchange occurs because there is no blood to receive O₂ or deliver CO₂.

Examples:

Pulmonary embolism
Severe reduction in pulmonary blood flow
Destruction of capillary bed in emphysema

7.5 V/Q mismatch

V/Q mismatch is the most common cause of hypoxemia in lung disease.

Common causes include:

Chronic obstructive pulmonary disease
Asthma
Pneumonia
Pulmonary edema
Pulmonary embolism
Interstitial lung disease

Hypoxemia from V/Q mismatch generally improves with supplemental O₂, because oxygen can enter well-ventilated alveoli and increase oxygen content in blood leaving them.

7.6 Physiological shunt

A small normal physiological shunt is present because some venous blood enters systemic arterial blood without complete oxygenation.

Sources include:

Bronchial venous blood draining into pulmonary veins
Thebesian veins draining directly into the left heart

Therefore, systemic arterial (P_{O_2}) is slightly less than alveolar (P_{O_2}).

[ P_{AO_2} \approx 100 \text{ mm Hg} ]

[ P_{aO_2} \approx 95 \text{ mm Hg} ]

Costanzo Physiology, 7th ed., pp. 218-219.

8. Oxygen Transport in Blood

O₂ exists in blood in two forms:

Dissolved in plasma
Bound reversibly to hemoglobin

8.1 Dissolved oxygen

The amount of dissolved O₂ follows Henry's law:

[ \text{Dissolved O₂} = P_{aO_2} \times 0.003 ]

At (P_{aO_2} = 100) mm Hg:

[ 100 \times 0.003 = 0.3 \text{ mL O₂/dL blood} ]

This represents only about 1.5% to 2% of total arterial O₂ content.

Dissolved O₂ is important because it determines:

PaO₂
The gradient for diffusion into tissues
Oxygen tension measured on ABG analysis

8.2 Hemoglobin-bound oxygen

Approximately 98% of O₂ is carried bound to hemoglobin.

One gram of hemoglobin binds approximately:

[ 1.34 \text{ mL O₂} ]

The oxygen content of arterial blood is:

[ C_{aO_2} = (1.34 \times Hb \times S_{aO_2}) + (0.003 \times P_{aO_2}) ]

Where:

(C_{aO_2}) = arterial oxygen content, mL O₂/dL
Hb = hemoglobin concentration, g/dL
(S_{aO_2}) = arterial oxygen saturation as a decimal
(P_{aO_2}) = arterial oxygen tension

Example

For a person with:

Hb = 15 g/dL
SaO₂ = 98% = 0.98
PaO₂ = 100 mm Hg

[ C_{aO_2} = (1.34 \times 15 \times 0.98) + (0.003 \times 100) ]

[ C_{aO_2} = 19.7 + 0.3 ]

[ C_{aO_2} \approx 20 \text{ mL O₂/dL} ]

Costanzo Physiology, 7th ed., pp. 223-224.

8.3 Oxygen delivery

The rate of oxygen delivery to tissues is:

[ D_{O_2} = Cardiac\ Output \times C_{aO_2} ]

More precisely:

[ D_{O_2} = CO \times C_{aO_2} \times 10 ]

For:

Cardiac output = 5 L/min
CaO₂ = 20 mL/dL

[ D_{O_2} = 5 \times 20 \times 10 ]

[ D_{O_2} = 1000 \text{ mL O₂/min} ]

At rest, body oxygen consumption is about 250 mL/min. Therefore, only approximately 25% of delivered O₂ is extracted at rest.

9. Oxyhemoglobin Dissociation Curve

The oxyhemoglobin dissociation curve relates (P_{O_2}) to hemoglobin saturation.

It is sigmoid-shaped because hemoglobin binds O₂ cooperatively. Binding of one O₂ molecule increases affinity for subsequent O₂ molecules.

9.1 Functional importance of the curve

Plateau portion

At PaO₂ between approximately 60 and 100 mm Hg, hemoglobin saturation remains relatively high.

This protects arterial oxygen content from moderate reductions in alveolar PO₂.

Typical values:

PaO₂	SaO₂
100 mm Hg	about 97-98%
60 mm Hg	about 90%
40 mm Hg	about 75%

Steep portion

At tissue PO₂ values, small decreases in PO₂ produce large decreases in hemoglobin saturation. This facilitates oxygen unloading.

At rest:

[ P_{vO_2} \approx 40 \text{ mm Hg} ]

[ S_{vO_2} \approx 75% ]

Thus, approximately 25% of hemoglobin-bound O₂ is extracted by tissues at rest.

9.2 P50

P50 is the PO₂ at which hemoglobin is 50% saturated.

For adult hemoglobin A:

[ P50 \approx 26-27 \text{ mm Hg} ]

An increased P50 indicates decreased affinity for O₂ and a right shift.

A decreased P50 indicates increased affinity for O₂ and a left shift.

9.3 Right shift

A right shift means hemoglobin has reduced affinity for O₂ and releases O₂ more readily to tissues.

Causes:

Increased H⁺ concentration, decreased pH
Increased PCO₂
Increased temperature
Increased 2,3-bisphosphoglycerate, 2,3-BPG
Exercise
Chronic hypoxemia

Mnemonic: CADET, face Right

CO₂ increased
Acid increased
DPG, 2,3-BPG increased
Exercise
Temperature increased

9.4 Left shift

A left shift means hemoglobin has increased affinity for O₂ and holds O₂ more tightly.

Causes:

Reduced H⁺ concentration, alkalosis
Reduced PCO₂
Reduced temperature
Reduced 2,3-BPG
Fetal hemoglobin
Carbon monoxide poisoning
Stored blood

A left shift improves hemoglobin loading in the lungs but can reduce oxygen unloading in tissues.

9.5 Bohr effect

The Bohr effect is the reduction in hemoglobin affinity for O₂ caused by increased PCO₂ and H⁺ concentration.

In tissues

Metabolically active tissues produce CO₂ and H⁺:

[ CO_2 + H_2O \leftrightarrow H_2CO_3 \leftrightarrow H^+ + HCO_3^- ]

Increased H⁺ and CO₂ shift the oxyhemoglobin curve to the right. This promotes O₂ unloading where it is most needed.

In lungs

CO₂ leaves blood and enters alveoli. Blood PCO₂ and H⁺ concentration decrease, shifting the curve left and promoting O₂ loading onto hemoglobin.

Guyton and Hall Textbook of Medical Physiology, p. 526.

10. Oxygen Exchange in Tissues

Systemic arterial blood enters tissue capillaries with:

[ P_{aO_2} \approx 95-100 \text{ mm Hg} ]

Intracellular PO₂ is much lower because O₂ is continuously used in mitochondria for oxidative phosphorylation.

Thus, O₂ moves down its partial-pressure gradient:

[ \text{Capillary blood} \rightarrow \text{Interstitial fluid} \rightarrow \text{Cells} \rightarrow \text{Mitochondria} ]

Mitochondrial PO₂ is very low, often approximately 1 to 3 mm Hg.

The amount of O₂ extracted depends on:

Tissue metabolic rate
Local blood flow
Hemoglobin concentration
Arterial oxygen content
Capacity of tissues to use O₂

Oxygen extraction ratio

[ OER = \frac{C_{aO_2}-C_{vO_2}}{C_{aO_2}} ]

At rest, the oxygen extraction ratio is approximately 25%.

During exercise, tissues increase O₂ extraction. Mixed venous PO₂ and venous oxygen saturation decrease.

11. Carbon Dioxide Transport

CO₂ produced by tissue metabolism is carried to the lungs in three forms:

Form of CO₂ transport	Approximate proportion
Bicarbonate, HCO₃⁻	60-70%
Carbamino compounds	20-30%
Dissolved CO₂	5-10%

11.1 Dissolved CO₂

A small amount of CO₂ is physically dissolved in plasma.

Because CO₂ is relatively soluble, dissolved CO₂ contributes significantly to PCO₂.

Venous PCO₂ is normally approximately 45-46 mm Hg, while arterial PCO₂ is approximately 40 mm Hg.

Guyton and Hall Textbook of Medical Physiology, p. 529.

11.2 Transport as bicarbonate

Most CO₂ is transported as bicarbonate.

In tissue capillaries:

[ CO_2 + H_2O \leftrightarrow H_2CO_3 \leftrightarrow H^+ + HCO_3^- ]

The enzyme carbonic anhydrase, abundant in red blood cells, accelerates the first reaction.

Events in systemic capillaries

CO₂ diffuses from tissue cells into plasma and red blood cells.
CO₂ combines with water in RBCs.
Carbonic anhydrase forms carbonic acid.
Carbonic acid dissociates into H⁺ and HCO₃⁻.
H⁺ is buffered mainly by deoxyhemoglobin.
HCO₃⁻ leaves the RBC and enters plasma.
Cl⁻ enters the RBC to maintain electrical neutrality.

The exchange of bicarbonate out of RBCs for chloride into RBCs is called the chloride shift or Hamburger phenomenon.

[ HCO_3^- \text{ out} \quad \leftrightarrow \quad Cl^- \text{ in} ]

Guyton and Hall Textbook of Medical Physiology, pp. 528-529.

11.3 Carbaminohemoglobin

CO₂ can bind directly to terminal amino groups on globin chains of hemoglobin:

[ CO_2 + Hb-NH_2 \leftrightarrow Hb-NHCOO^- + H^+ ]

This forms carbaminohemoglobin.

Deoxygenated hemoglobin binds CO₂ more readily than oxygenated hemoglobin. This promotes CO₂ uptake in tissues, where hemoglobin releases O₂.

11.4 Haldane effect

The Haldane effect describes the effect of O₂ on CO₂ transport.

In tissues

As hemoglobin releases O₂ and becomes deoxygenated:

Its capacity to bind CO₂ increases.
Its capacity to buffer H⁺ increases.
More CO₂ is carried as carbaminohemoglobin and bicarbonate.

In lungs

When O₂ binds to hemoglobin:

Hemoglobin becomes less able to bind CO₂.
Hemoglobin releases H⁺.
H⁺ combines with HCO₃⁻ to form CO₂ and H₂O.
CO₂ diffuses into alveoli and is expired.

[ H^+ + HCO_3^- \leftrightarrow H_2CO_3 \leftrightarrow CO_2 + H_2O ]

The Haldane effect promotes CO₂ loading in systemic capillaries and CO₂ unloading in pulmonary capillaries.

It is quantitatively more important for CO₂ transport than the Bohr effect is for O₂ transport. Guyton and Hall Textbook of Medical Physiology, p. 530.

12. Normal Blood Gas Values

12.1 Normal arterial blood gas values

Variable	Typical normal value
pH	7.35-7.45
PaO₂	80-100 mm Hg
PaCO₂	35-45 mm Hg
HCO₃⁻	22-26 mEq/L
Base excess	-2 to +2 mEq/L
SaO₂	95-100%

Normal values vary with age, altitude, temperature, and inspired oxygen concentration.

12.2 Normal mixed venous blood values

Variable	Typical mixed venous value
PvO₂	about 40 mm Hg
SvO₂	about 75%
PvCO₂	about 46 mm Hg
pH	about 7.36

The arterial-venous difference reflects tissue oxygen consumption and carbon dioxide production.

12.3 Arterial oxygen content versus PaO₂

PaO₂ and oxygen content are not equivalent.

PaO₂ measures oxygen dissolved in plasma.
CaO₂ measures total oxygen carried in arterial blood, mainly hemoglobin-bound O₂.

Anemia

Anemia may cause severe reduction in CaO₂ even if PaO₂ and SaO₂ are normal.

Carbon monoxide poisoning

PaO₂ may be normal because dissolved oxygen is normal. However, hemoglobin oxygen-carrying capacity is reduced, resulting in low CaO₂ and tissue hypoxia.

Polycythemia

PaO₂ may be normal, but CaO₂ is increased because hemoglobin concentration is higher.

13. Acid-Base Relationship to Blood Gases

The Henderson-Hasselbalch equation for blood is:

[ pH = 6.1 + \log \left(\frac{[HCO_3^-]}{0.03 \times P_{aCO_2}}\right) ]

Thus, pH depends on the ratio of:

[ \frac{HCO_3^-}{P_{aCO_2}} ]

Bicarbonate is mainly controlled by the kidneys.
PaCO₂ is mainly controlled by ventilation.

Normal values:

[ pH = 7.40 ]

[ HCO_3^- = 24 \text{ mEq/L} ]

[ P_{aCO_2} = 40 \text{ mm Hg} ]

13.1 Respiratory acidosis

Primary abnormality:

[ \uparrow P_{aCO_2} ]

Cause: hypoventilation.

Examples:

CNS depression from sedative drugs
Opioid toxicity
Neuromuscular disease
Severe COPD
Severe airway obstruction
Obesity hypoventilation syndrome

Compensation: kidneys retain bicarbonate and excrete H⁺.

13.2 Respiratory alkalosis

Primary abnormality:

[ \downarrow P_{aCO_2} ]

Cause: hyperventilation.

Examples:

Anxiety
Pain
Hypoxemia
High altitude
Pulmonary embolism
Pregnancy
Sepsis

Compensation: kidneys excrete bicarbonate.

13.3 Metabolic acidosis

Primary abnormality:

[ \downarrow HCO_3^- ]

Compensatory response: hyperventilation causes a fall in PaCO₂.

Examples:

Diabetic ketoacidosis
Lactic acidosis
Renal failure
Severe diarrhea
Toxin ingestion

13.4 Metabolic alkalosis

Primary abnormality:

[ \uparrow HCO_3^- ]

Compensatory response: hypoventilation raises PaCO₂, though compensation is limited by hypoxemia.

Examples:

Vomiting
Nasogastric suction
Diuretics
Mineralocorticoid excess

14. Alveolar-Arterial Oxygen Gradient

The alveolar-arterial oxygen gradient is:

[ A-a\ gradient = P_{AO_2} - P_{aO_2} ]

At sea level in a young healthy adult, it is usually approximately:

[ 5-15 \text{ mm Hg} ]

The A-a gradient increases with age.

14.1 Causes of hypoxemia with normal A-a gradient

A normal A-a gradient indicates that oxygen transfer from alveoli to arterial blood is relatively preserved.

Causes:

Hypoventilation
Low inspired oxygen tension, especially high altitude

14.2 Causes of hypoxemia with increased A-a gradient

An increased A-a gradient indicates impaired transfer of oxygen from alveoli to blood.

Causes:

V/Q mismatch
Right-to-left shunt
Diffusion limitation
Reduced alveolar-capillary surface area or pulmonary capillary blood flow

15. Hypoxemia and Hypoxia

15.1 Definitions

Hypoxemia means low arterial oxygen tension:

[ \downarrow P_{aO_2} ]

Hypoxia means inadequate oxygen availability or utilization by tissues.

Hypoxemia can cause hypoxia, but hypoxia can occur with normal PaO₂.

15.2 Types of hypoxia

Type	Main defect	PaO₂	CaO₂	Example
Hypoxemic hypoxia	Low arterial PO₂	Low	Low	High altitude, pneumonia
Anemic hypoxia	Low hemoglobin	Normal	Low	Severe anemia
Stagnant hypoxia	Low tissue blood flow	Normal	Usually normal	Heart failure, shock
Histotoxic hypoxia	Cells cannot use O₂	Normal	Normal	Cyanide poisoning

15.3 Causes of hypoxemic hypoxia

The major mechanisms are:

Low inspired oxygen tension
Hypoventilation
Diffusion limitation
V/Q mismatch
Right-to-left shunt

Mechanism	PaCO₂	A-a gradient	Response to supplemental O₂
Low inspired O₂	Normal or low	Normal	Good
Hypoventilation	High	Normal	Good
Diffusion limitation	Normal or low	Increased	Good
V/Q mismatch	Normal or low	Increased	Usually good
Right-to-left shunt	Variable	Increased	Limited

16. Cyanosis

Cyanosis is bluish discoloration due to increased concentration of deoxygenated hemoglobin in blood.

It is usually clinically apparent when deoxygenated hemoglobin exceeds approximately:

[ 5 \text{ g/dL} ]

Important implications

A severely anemic patient may have profound hypoxemia without obvious cyanosis because total hemoglobin is low.
A polycythemic patient may appear cyanosed at a relatively higher PaO₂ because total hemoglobin is high.
Cyanosis is not a reliable measure of arterial oxygenation.

17. Effects of Exercise on Gas Exchange

During exercise:

O₂ consumption increases.
CO₂ production increases.
Cardiac output increases.
Pulmonary blood flow increases.
Alveolar ventilation increases.
Diffusing capacity increases.
More pulmonary capillaries are recruited.
V/Q matching improves.

In healthy persons, arterial PO₂ and PaCO₂ remain near normal during moderate exercise because ventilation and perfusion increase in a coordinated manner.

At active tissues:

Temperature rises.
CO₂ production rises.
H⁺ rises.
2,3-BPG may rise over time.

These changes cause a right shift of the oxyhemoglobin dissociation curve and enhance O₂ unloading.

18. High Altitude Physiology

At high altitude, barometric pressure falls. The percentage of oxygen remains approximately 21%, but inspired PO₂ decreases.

[ P_{IO_2} = F_{IO_2}(P_B-P_{H_2O}) ]

As (P_B) falls:

[ P_{IO_2} \downarrow ]

[ P_{AO_2} \downarrow ]

[ P_{aO_2} \downarrow ]

The immediate response to altitude is hyperventilation, which:

Raises alveolar PO₂
Lowers PaCO₂
Produces respiratory alkalosis

Over time, acclimatization includes:

Renal bicarbonate excretion
Increased erythropoietin and RBC mass
Increased 2,3-BPG
Increased pulmonary diffusing capacity
Increased capillary density in some tissues

At high altitude, O₂ transfer may become partly diffusion limited because the alveolar-to-capillary PO₂ gradient is reduced. Costanzo Physiology, 7th ed., p. 222.

19. Summary Table

Feature	Oxygen	Carbon dioxide
Direction in lungs	Alveolus to blood	Blood to alveolus
Direction in tissues	Blood to tissues	Tissues to blood
Alveolar partial pressure	about 100 mm Hg	about 40 mm Hg
Arterial partial pressure	about 95-100 mm Hg	about 40 mm Hg
Mixed venous partial pressure	about 40 mm Hg	about 46 mm Hg
Major form in blood	Hemoglobin-bound	Bicarbonate
Main effect facilitating tissue transfer	Bohr effect	Haldane effect
Diffusion across lung membrane	Normally perfusion limited	Normally perfusion limited
Relative diffusibility	Lower	About 20 times greater than O₂

20. Key Examination Points

O₂ moves from alveoli to blood, whereas CO₂ moves from blood to alveoli.
Normal alveolar values are approximately: [ P_{AO_2}=100 \text{ mm Hg}, \quad P_{ACO_2}=40 \text{ mm Hg} ]
Normal mixed venous values are approximately: [ P_{vO_2}=40 \text{ mm Hg}, \quad P_{vCO_2}=46 \text{ mm Hg} ]
Alveolar ventilation, not minute ventilation, determines PaCO₂.
The alveolar gas equation estimates PAO₂.
V/Q mismatch is the most common cause of hypoxemia.
Shunt produces hypoxemia that responds poorly to oxygen.
Most O₂ is transported bound to hemoglobin.
Most CO₂ is transported as bicarbonate.
The Bohr effect promotes O₂ unloading in tissues.
The Haldane effect promotes CO₂ transport and unloading in lungs.
PaO₂ reflects dissolved oxygen, whereas CaO₂ reflects total oxygen carried in blood.
Severe anemia may cause tissue hypoxia with normal PaO₂.
Carbon monoxide poisoning may show normal PaO₂ despite reduced oxygen content.
An increased A-a gradient suggests V/Q mismatch, shunt, or diffusion impairment.

Textbook references

Costanzo Physiology, 7th ed., pp. 211-224, 223-230.
Guyton and Hall Textbook of Medical Physiology, pp. 522-530.

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