PHYSIOLOGY
Respiration: gas transfer
Matthew Wayman
Dominic Errington
Abstract
The principles of gas transfer between the atmosphere and cell mitochon-
dria can be considered in a number of steps: inspired gases are humidified
in the upper airways and mix with expired gases in the alveoli. In perfused
alveoli, gases then diffuse passively down a partial pressure gradient into
pulmonary capillary blood. Gases are transported by the blood, in a dis-
solved state or by specific transport systems, to the systemic capillaries
from where they diffuse into cells. Efficient gas exchange between the atmo-
sphere and mitochondria requires the transfer of large volumes of gas with
minimal reduction in partial pressure. The nature of oxygen binding to hae-
moglobin and the transport of carbon dioxide as bicarbonate in the blood
improve the body’s ability to transfer these gases. An understanding of how
anaesthetic gases are transferred to their site of action and why side effects
occur is important to the safe conduct of anaesthesia.
Keywords carbon dioxide; diffusion; haemoglobin; mismatch; oxygen;
partial pressure; perfusion; saturation; ventilation
Cell function relies on the generation of energy substrates in
mitochondria, utilizing oxygen (O2) and producing carbon
dioxide (CO2). Unlike unicellular organisms, humans cannot
utilize diffusion alone for gas transfer. Instead, the respiratory
and circulatory systems interact to transfer gases between the
atmosphere and each cell’s mitochondria. The lungs provide the
major interface for gas transfer between the respiratory and
circulatory systems.
Principles of gas transfer1
Step 1: Atmosphere to alveoli
Inspiration generates a pressure gradient between the atmo-
sphere and alveoli, causing mass flow of gases to the bronchi-
oles, and thereafter diffusion to the alveoli. Inspired gases are
warmed and completely humidified in the upper airway, slightly
reducing the partial pressure of atmospheric inspired gases.
Matthew Wayman B Med Sci MBChB FRCA is a Specialist Registrar in
Anaesthetics in the Northern Deanery, Newcastle upon Tyne, UK. His
interests are intensive care medicine and medical education. Conflicts
of interest: none declared.
Dominic Errington B Med Sci BM BS MRCP FRCA is a Consultant in
Anaesthesia and Intensive Care Medicine at University Hospital of North
Durham, UK. He qualified from Nottingham University Medical School
before training in Anaesthetics and General Medicine at Nottingham,
Bristol and Newcastle upon Tyne (UK). He has clinical interests in
intensive care medicine and health care administration, and scientific
interests in tissue protection. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:11
Learning objectives
After reading this article you should be able to:
C describe quantitatively the stages of transfer of gases between
the atmosphere and cells, with particular reference to oxygen
and carbon dioxide
C explain the origins of ‘alveolar deadspace’ and ‘shunt’, and their
implications for lung function
C understand the basic difference in gas properties that lead to
their transfer at the alveoli between diffusion- or perfusion-
limited, and the use of these properties in assessing pulmonary
function
C apply the above principles to the uptake of anaesthetic gases
Dalton’s law of partial pressures states that the pressure
exerted by each gas in a mixture is the same as that which it
would exert if it alone occupied the container.2 As the pressure of
the gas mixture in the bronchi remains atmospheric, the partial
pressure of individual inspired gases can be calculated by:
PIG ¼ FIG$(PB  PH2O)
where PIG is the partial pressure of inspired gas, FIG is the
fraction of inspired gas, PB is the barometric pressure and PH2O is
the saturated vapour pressure of water vapour (6.3 kPa at 37  C).
Gases travel through around 16 generations of conducting
airways by bulk flow (mostly turbulent) before arrival at the
respiratory zone where gas transfer occurs. The respiratory zone
consists of respiratory bronchioles, alveolar ducts and alveoli.
Gases move by diffusion in the respiratory zone.
Inspired gases mix with expired gases in the alveoli, further
decreasing their partial pressures. Alveolar partial pressure of
oxygen can be estimated by the alveolar gas equation:
PAO2 ¼ PIO2  (PaCO2/R) þ F
where PAO2 is the alveolar partial pressure of oxygen, PIO2 is the
partial pressure of oxygen in inspired gas, PaCO2 is the arterial
partial pressure of carbon dioxide, R is the respiratory gas
quotient (CO2 produced/O2 consumed) and F is a correction
factor (often ignored as it is small).
Ventilationeperfusion matching: for efficiency it is important
that the gas flow to an alveolus correlates with the blood flow to
that alveolus. In vivo perfect matching does not occur, with some
alveoli overventilated relative to their perfusion and vice versa.
At extremes of ventilationeperfusion inequality, no gas
exchange occurs.
Shunt (venous admixture) occurs when alveoli are perfused but
not ventilated. Shunted blood is not supplemented by inspired gases
and mixes with blood from well-ventilated regions resulting in
a reduction in the partial pressure of inspired gases in arterial blood.
Dead-space ventilation describes ventilation to areas where
no gas exchange with blood occurs. This can be anatomical
(conducting airways) or physiological (unperfused ventilated
481 Ó 2011 Published by Elsevier Ltd.
 PHYSIOLOGY

alveoli). Like shunting, this decreases the area over which gas
exchange can occur. Unlike shunting, there is less effect on Partial pressure of gases in blood during
arterial partial pressures of inspired gases and more effect on the transit through a pulmonary capillary
removal of expired waste gases (increased ventilation required Alveolar
for same degree of removal). partial
In an upright lung, gradients of ventilation and perfusion exist pressure
resulting in ventilationeperfusion mismatch. At the apex, there
Oxygen (under normal
is a constant negative intrapleural pressure, holding lung units in

Partial pressure
conditions) – perfusion
expansion. Gravity causes the basal intrapleural pressure to be limited uptake
less negative with less expanded alveoli. Basal units are more
compliant, receiving a greater proportion of tidal ventilation.
Nitrous oxide – perfusion
Gravity results in increased perfusion to lung bases. This perfu- limited uptake
sion gradient is more marked than the ventilation gradient, Carbon monoxide –
diffusion limited uptake
resulting in apical lung units being relatively overventilated and
basal units relatively overperfused.
Pulmonary arterioles vasoconstrict in response to a low 0
alveolar partial pressure of oxygen (hypoxic pulmonary vaso- Start of End of
constriction), reducing intrapulmonary shunting. capillary capillary
Transit through pulmonary capillary

Step 2: Alveoli to blood Figure 1

Fick’s law: most gases cross biological membranes by simple
diffusion with the rate of transfer determined by Fick’s law:
flow of gas f (A/T )$D$(P1  P2)
where A is the surface area of the membrane, T is the thickness
of the membrane, D is the diffusion constant of the gas (f
solubility/Omol wt) and P1  P2 is the pressure gradient across
the membrane.
Pulmonary capillaries form a dense, sheet-like network in the
walls of alveoli, resulting in a thin (0.3 mm) bloodegas barrier with
a large surface area (50e100 m2) suited to efficient gas exchange.
Diffusion and perfusion limitation: gas exchange between
alveoli and blood may be diffusion or perfusion limited depen-
dent upon gas and membrane characteristics as well as the rate
of blood flow. Diffusion limitation occurs with gases that are
highly soluble in blood or bind rapidly to carrier molecules (e.g.
carbon monoxide with haemoglobin). The partial pressure of gas
in the blood remains minimal throughout the transit of blood
along the pulmonary capillary (Figure 1). The pressure gradient
across the bloodegas barrier is maintained and the amount of
gas transferred is limited by the diffusion properties of the
membrane.
Perfusion limitation occurs with poorly soluble gases without
Step 4: Blood to tissues
Gas transfer from blood to tissues is by simple diffusion and
therefore follows Fick’s law. As the distances travelled by gases
from the blood to their site of action (or site of production to the
blood) are much greater than the thickness of the alveolar
membrane, the partial pressure gradients involved are larger.
Part 2: Specific gases
Oxygen1
At rest 250 ml/minute oxygen is transferred from the atmosphere
to cell mitochondria where it is used to produce energy
substrates.
The oxygen cascade: Figure 2 shows how the partial pressure of
oxygen decreases from the atmosphere to mitochondria. The
atmosphere contains 21% oxygen and, as atmospheric pressure
(sea level) is 101.3 kPa, the partial pressure of oxygen (PO2) is
approximately 21 kPa. Humidification of inspired gases reduces
the partial pressure in the bronchi to 20 kPa. Mixing in the alveoli
Oxygen cascade
20
Interstitium and cytoplasm

carrier molecules in the blood (e.g. nitrous oxide) or those with

slow reactions with carrier molecules (e.g. oxygen). As gas
molecules diffuse from alveoli to blood the partial pressure of the 15
Humidified gas in bronchi

gas in the blood increases and the pressure gradient for diffusion
PaO2 (kPa)

is lost before the transit of blood through a pulmonary capillary is

Dry atmospheric air

10
complete. The amount of gas transferred is therefore limited by
Gas in alveolus

Arterial blood

Mitochondria

the delivery of new blood.

Capillary

5
blood

Step 3: Transport of gases in blood

Gases can be carried in the blood in a dissolved state or by
specific transport mechanisms. The amount of a given gas 0
dissolved in a liquid is directly proportional to the partial pres-
sure of the gas in equilibrium with the liquid (Henry’s law). Figure 2

ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:11 482 Ó 2011 Published by Elsevier Ltd.

reduces this to around 13.5 kPa (alveolar gas equation). A small
diffusion gradient combined with a degree of ventilatione
perfusion mismatch results in an arterial partial pressure (PaO2)
of around 12.5 kPa.
As oxygen is extracted by tissues, the partial pressure falls
further. The po2 of venous blood is around 5.3 kPa. Mitochon-
drial po2 is lower than venous PO2 with an oxygen gradient
between the capillaries and the mitochondria.
Oxygen diffusion across the bloodegas barrier: normally,
transfer of oxygen across the bloodegas barrier is perfusion
limited (Figure 1). Equilibration of pressures between an alveolus
and blood occurs within one-third of the time taken for blood to
transit a pulmonary capillary. Diffusion limitation can occur if the
bloodegas barrier becomes thickened by fibrosis or oedema, and
during exercise when capillary transit time is reduced.
Oxygen transport in the blood: 100 ml arterial blood contains
around 21 ml oxygen; a small proportion is transported as dis-
solved gas, but most is carried by haemoglobin. Loading of
oxygen onto haemoglobin molecules relies on a partial pressure
gradient illustrated by the oxygen dissociation curve (Figure 3).
Oxygen saturation is more relevant than PaO2 (although they are
interrelated) when considering oxygen content of the blood. This
is calculated as:
O2 content (ml/dl) ¼ ((SaO2/100)$1.39: ‘1.39.46 ‘Hb)
þ 0.0225$PaO2
where Hb is the haemoglobin concentration in g/dl, PaO2 is the
arterial partial pressure of O2 in kPa and SaO2 is oxygen satura-
tion of arterial blood.
If haemoglobin becomes 100% saturated with oxygen,
increasing the alveolar partial pressure of oxygen has little effect
on blood oxygen content. In shunt, increasing the partial pres-
sure of oxygen in ventilated alveoli does not compensate for the
reduction in oxygen content of shunted blood.
Oxygen dissociation curve
100
Percentage saturation of haemoglobin
75
50
Venous Arterial
blood blood
25
0
0 5 10 15
Partial pressure of oxygen (PO2)
Figure 3
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:11
PHYSIOLOGY
The oxygen dissociation curve (Figure 3): the sigmoid shape
confers several advantages. The steep portion of the curve
corresponds to pressures in the pulmonary capillaries, with the
majority of oxygen loading occurring while the capillary PO2
remains low, allowing the pressure gradient between the alveoli
and blood to be maintained and oxygen transfer to continue. It is
also of advantage when it comes to the unloading of oxygen in
the tissues as oxygen is unloaded while PO2, and therefore the
diffusion gradient, is relatively maintained. The flat portion at the
top of the curve acts as a buffer so that as PAO2 drops oxygen
loading will be affected only minimally until PAO2 drops below
around 8 kPa.
The affinity of haemoglobin for oxygen is reduced by a number
of factors which aid oxygen unloading in the tissues and result in
a right shift of the oxygen dissociation curve. This includes
increased temperature, increased 2,3-diphosphoglycerate (DPG;
a product of red cell metabolism), decreased pH and increased
PCO2 (Bohr effect), all of which occur in metabolizing tissue.
Carbon dioxide1
Carbon dioxide is a product of aerobic respiration in mitochon-
dria. Around 200 ml is excreted via the lungs per minute. It is
also important in acidebase balance, combining with water to
produce carbonic acid and acting as part of the bicarbonate
buffer system.
Carbon dioxide transport in the blood: venous blood contains
approximately 50 ml carbon dioxide per 100 ml. The majority of
CO2 is transported as bicarbonate with smaller quantities dis-
solved and as carbamino compounds.
Most bicarbonate is produced in erythrocytes which contain
carbonic anhydrase. This enzyme catalyses the formation of
carbonic acid, which dissociates in the erythrocytes to hydrogen
and bicarbonate ions. Hydrogen ions are buffered by haemo-
globin, and bicarbonate ions are exchanged for Cl across the red
cell membrane.
The ability of haemoglobin to form carbaminohaemoglobin
and to buffer Hþ ions is increased by the unloading of oxygen
(Haldane effect), this assists with CO2 transport at the tissues and
CO2 release in the pulmonary circulation.
The CO2 dissociation curve is much more linear than the O2
curve, with much less difference between arterial and venous
PCO2 than seen with PO2.
Carbon dioxide exchange in the lungs: CO2 is around 20 times
more soluble in the bloodegas barrier than oxygen; transfer is
therefore rarely diffusion limited. In the majority of situations, it
is reasonable to assume that PaCO2 is equal to PACO2 (as in the
alveolar gas equation).
Ventilationeperfusion mismatch has less effect on PaCO2 than
on PaO2. This is due to the smaller difference in PCO2 between
arterial and venous blood and also the fact that respiratory drive
is determined by CO2 so conscious patients will compensate for
a raised PaCO2 by increasing their minute ventilation.
20 Anaesthetic agents
Nitrous oxide1,3: nitrous oxide (N2O) is used as a carrier gas for
volatile anaesthetics and is pre-mixed with oxygen as an anal-
gesic. It has low blood:gas solubility and no specific carrier
483 Ó 2011 Published by Elsevier Ltd.
 PHYSIOLOGY
system in the blood; transfer across the bloodegas barrier is
therefore perfusion limited (Figure 1).
Despite low blood solubility N2O is around 20 times more
soluble than nitrogen (N2). This means that at the same partial
pressure 20 times more molecules of N2O than N2 are dissolved
in blood and explains several side effects of using N2O as
a carrier gas:
 Concentration effect: in the initial phase of N2O adminis-
tration the amount of N2O passing from alveolus to blood
exceeds the amount of N2 travelling in the opposite
direction. More gas molecules leave the alveolus than
enter; therefore, the fractional concentrations of remaining
gases increase.
 Closed air spaces: for the same change in partial pressure
more N2O enters a closed air space than N2 leaves. The
number of gas molecules (n) in the space increases and
volume (V), pressure (P) or both will increase (PV ¼ nRT;
where R is the universal gas constant and T is
temperature).
 Diffusion hypoxia: when the administration of N2O ceases,
dissolved N2O passes from blood to the alveolus. More
N2O leaves the circulation than N2 enters; therefore, the
number of N2O molecules in the alveolus increases and the
fractional concentration of other gases decreases. This
results in hypoxia if the inspired gas mixture has a low
concentration of oxygen.
Volatile agents: as with other gases, volatile anaesthetics depend
on a partial pressure gradient to cross biological membranes. The
limiting factor to their diffusion across the bloodegas barrier
ANAESTHESIA AND INTENSIVE CARE MEDICINE 12:11
(and also the bloodebrain barrier) remains debated, with some
authors arguing for the occurrence of diffusion limitation and
others arguing against this theory.4
Less blood-soluble agents require smaller numbers of mole-
cules to diffuse from the alveolus via blood to brain tissue to
achieve partial pressure equilibration. They therefore have more
rapid onset. Rate of onset is also influenced by cardiac output,
but this effect is probably due more to redistribution of agent to
fatty tissues than to the effects on gas transfer at the bloodegas
barrier.
The potency of volatile agents is determined by solubility in
brain tissue because it is concentration and not partial pressure
which is important for the anaesthetic effect (this holds true for
a receptor-based as well as more traditional theories of anaes-
thesia). Less soluble drugs require a higher partial pressure to
achieve the same dissolved concentration and therefore have
higher minimum alveolar concentration (MAC) values. A
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2 Davis PD, Kenny GNC. Basic physics and measurement in anaesthesia.
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3 Pharmacokinetics of inhalational anaesthetic agents. Available at:
http://www.frca.co.uk/article.aspx?articleid¼100339 (accessed 20
August 2008).
4 Mapleson WW, Drummond GB. Uptake of volatile agents. Anaesthesia
2004; 59: 915e7.
484 Ó 2011 Published by Elsevier Ltd.