BJA Education, 16 (10): 34–1348 (2016)

doi: 10.1093/bjaed/mkw012
Advance Access Publication Date: 17 May 2016
Matrix reference
1A01, 1A03, 3C00

Physiology of oxygen transport

J-OC Dunn MB ChB BAO FRCA1, MG Mythen MBBS MD FRCA FFICM FCAI (Hon)2, Do
wn
and MP Grocott BSc MBBS MD FRCA FRCP FFICM3,4,* loa
de
1
d
PhD Research Fellow and Specialty Registrar in Anaesthesia and Critical Care Medicine, Critical Care Research fro
Area, NIHR Southampton Respiratory Biomedical Research Unit, University Hospital Southampton NHS m
htt
Foundation Trust, Southampton, UK, 2Smiths Medical Professor of Anaesthesia and Critical Care, UCL Director,
ps:
UCLH/UCL/RFH Research Support Centre, Director of Research & Development and National Clinical Adviser, //a
Department of Health Enhanced Recovery Partnership, UK, 3Professor of Anaesthesia and Critical Care Medicine, ca
de
Integrative Physiology and Critical Illness Group, Faculty of Medicine, University of Southampton, Southampton, mi
UK, and 4Consultant in Critical Care Medicine, University Hospital Southampton NHS Foundation Trust, CE.93, c.o
up
Mailpoint 24, E Level, Centre Block, Tremona Road, Southampton SO16 6YD, UK
.co
*To whom correspondence should be addressed. Tel: +44 2381 208449/5308; Fax: +44 2381 204295; E-mail: mike.grocott@soton.ac.uk m/
bja
ed/
art
the coenzyme that supplies energy to all active metabolic pro- icl
Key points cesses. This article will discuss the key physiological concepts e/1
6/
underpinning the movement of oxygen within the human body
• The transport of oxygen is fundamental to aerobic 10
and also highlight some clinical applications that serve as /3
respiration.
exam- ples of these concepts. 41
• Oxygen transport within the human body occurs /2
through both convection and diffusion. 28
Convective vs diffusive oxygen transport1–4 86
• Within the pulmonary capillaries, one With respect to human physiology, oxygen transport can be di- 29
haemoglobin molecule binds up to four oxygen vided into that occurring through convection and that by
molecules in a co- operative manner. occurring by diffusion. In this context, convection describes the
gu
est
• Global oxygen delivery, or oxygen dispatch, de- movement of oxygen within the circulation, occurring through
on
scribes the total amount of oxygen delivered to bulk trans- port. This is an active process requiring energy, in 20
the tissues each minute, and is a product of the this case derived from the pumping of the heart. On the other Ju
car- diac output and arterial oxygen content. hand, diffu- sion describes the passive movement of oxygen ne
down a concen- tration gradient, for example, from the 20
• Oxygen diffuses from both the alveoli into the pul- microcirculation into the tissues (and ultimately the 21
monary capillaries and the systemic capillaries mitochondria).
into the tissues, according to Fick’s laws of diffusion
and the random walk of the diffusing particles.
Section 1: convective oxygen transport
Oxygen uptake into the blood

Deoxygenated venous blood becomes oxygenated in the pul-

Oxygen is vital for life-sustaining aerobic respiration in humans
and is arguably the most commonly administered drug in
anaes- thesia and critical care medicine. Within the
mitochondrial inner membrane, oxygen acts as the terminal
electron acceptor at the end of the electron transport chain
whereby oxidative phosphor- ylation results in the synthesis of
adenosine triphosphate (ATP),
monary capillaries after diffusion down a concentration gradient
across the alveolar capillary membrane (see Section 2: diffusive
oxygen transport). The physiology of control of ventilation and
the determinants of alveolar oxygen partial pressure, ventila-
tion–perfusion matching, and diffusion within the alveolar–
capillary unit are dealt with elsewhere.1,5

© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights
reserved. For Permissions, please email: journals.permissions@oup.com

341
Physiology of oxygen
transport

Haemoglobin and the oxygen dissociation curve1,5–7 Haemoglobin has a maximum theoretical oxygen-carrying
Oxygen is carried in the blood bound to haemoglobin and dis- capacity of 1.39 ml O2 g−1 Hb (known as Hü fner’s constant), and
solved in plasma (and intracellular fluid). Haemoglobin, an allo- therefore, a theoretical maximum oxygen capacity of 20.85 ml
steric protein, consists of four protein (globin) chains, to each O2 100 ml−1 blood at a ‘normal’ haemoglobin concentration of
of which is attached a haem moiety, an iron-porphyrin 15 g dl−1 (range 13.5–18.0 in men, 11.5–16.0 in women). However,
compound. Two pairs of globin chains exist within each due in part to the existence of abnormal forms of haemoglobin
haemoglobin mol- ecule. Haemoglobin A consists of two α and such as methaemoglobin and carboxyhaemoglobin, which re-
two β chains (denoted α2β2), and accounts for more than 95% of duce the oxygen-carrying capacity of haemoglobin, empirically
normal adult haemoglo- bin. Mutations in the amino acid this value seems to be closer to 1.31 ml O2 g−1 Hb.5,11 Haemoglo-
sequences in the globin chains give increase to both bin oxygen saturation is a percentage expression of the number
pathological [e.g. haemoglobin S (α2βs2), sickle-cell disease] and of oxygen binding sites occupied out of the maximum number
non-pathological haemoglobin variants [such as haemoglobin of oxygen binding sites available.
A2 (α2δ2)]. Fetal haemoglobin is denoted haemoglobin F (α2γ2)
and is replaced by haemoglobin A during the first year of life. 1,6,12
P50 Do
Once oxygen has diffused across the alveolar membrane, it
binds reversibly to haemoglobin within the pulmonary capillar- The P50 is the partial pressure of oxygen at which haemoglobin is wn
50% saturated. It is a marker of haemoglobin’s affinity for oxygen loa
ies in a cooperative manner forming oxyhaemoglobin. Up to
de
four molecules of oxygen can be carried simultaneously by one and is used to compare changes in the position of the curve. The
d
haemoglobin molecule. When a molecule of oxygen binds to ODC position changes in the face of various chemical and fro
haem, the shape of the globin chain is altered, leading an overall physio- logical factors, and also with different haemoglobin m
change in the quaternary structure of haemoglobin. Subsequent species. The various factors and their effects on the curve are htt
oxygen molecules are then bound with greater affinity. This rela- described in Table 1, and also the effects of a change in position ps:
tionship is best described by the sigmoid-shaped oxyhaemoglo- of the curve on oxygen loading and unloading. //a
bin dissociation curve (ODC, Fig. 1). ca
de
Haemoglobin exists in two forms: taut (T), which has a low af- 2,3-Diphosphoglycerate6,12,13 mi
finity for oxygen; and relaxed (R), which has a high affinity for oxy- c.o
2,3-Diphosphoglycerate (2,3-DPG) is an organic phosphate pro-
gen. The taut form predominates in the tissues (a high carbon up
duced during glycolysis and found in the red blood cell, promot-
dioxide, low pH environment) promoting oxygen release, .co
ing haemoglobin oxygen release. Of clinical relevance: m/
where- as the relaxed form binds oxygen more avidly in areas of
high pH, low carbon dioxide tension, and high partial pressures bja
• Increased 2,3-DPG production is seen in anaemia, which ed/
of oxygen (such as in the alveoli). This relationship between
may minimize tissue hypoxia by right-shifting the ODC and art
haemoglobin, oxygen binding, carbon dioxide tension, and pH is
in- creasing tissue oxygen release. icl
known as the Bohr effect.
• 2,3-DPG undergoes metabolism in banked donor blood caus- e/1
Carbon dioxide is returned to the lungs from the tissues dis- 6/
ing reduced oxygen unloading capacity after transfusion.
solved in the plasma, either directly or as bicarbonate, and 10
• Inorganic phosphate is a substrate for the production of 2,3-
through the formation of carbaminohaemoglobin species /3
DPG and thus capillary haemoglobin oxygen release may 41
within the erythrocyte. Deoxygenated blood has a greater
be impaired if hypophosphataemia is not corrected. Causes /2
ability to transport carbon dioxide when compared with
oxygenated blood, and this is known as the Haldane effect. In
of hypophosphataemia can be divided into: decreased 28
intestinal absorption (e.g. malnutrition); internal 86
combination therefore, the Bohr and Haldane effects promote
redistribution (e.g. in acute leukaemia and recovery from 29
oxygen binding and carbon dioxide release in the pulmonary
diabetic ketoacidosis); or increased renal excretion (e.g. by
capillaries, with the reverse occurring in the tissues. gu
following corticosteroid use and volume expansion). In
est
critical care, hypophosphataemia is often seen in sepsis,
on
after operation, in refeeding syndrome, in diabetic 20
ketoacidosis (due to increased urinary phosphate Ju
excretion), and during renal replacement therapy. Hypopho- ne
sphataemia is also noted after an acute liver injury caused 20
by, for example, paracetamol overdose and after hepatic 21
resection.

Table 1 Factors that affect the standard human oxygen dissociation

curve. Adapted from Thomas and Lumb6 and Leach and Treacher12

Left-shifted ODC (↓P50) Right-shifted ODC (↑P50)

Causes ↑pH (↓H+) ↓pH (↑H+)

↓PaCO2
↓2,3-diphosphoglycerate
↓Temperature
Effect Increased haemoglobin
oxygen affinity,
enhanced oxygen binding
1 atmosphere. Drawn from equations described by Roughton and Severinghaus 8,9
(subsequently validated).10
Fig 1 The standard human ODC at pH 7.4, base excess zero, temperature 37°C, and
↑PaCO2
↑2,3-diphosphoglycerate
↑Temperature
Decreased haemoglobin
oxygen affinity, enhanced
release of oxygen in the
tissues
 Physiology of oxygen
transport
Others Fetal haemoglobin Adult
haemoglobin Carbon monoxide
poisoning
Methaemoglobinaemi
a
Oxygen content1,11,12
The oxygen content of arterial blood is the sum of the oxygen
bound to haemoglobin and oxygen dissolved in plasma (where
the amount of oxygen dissolved is proportional to the partial
pressure exerted by oxygen on the plasma at a given tempera-
ture, obeying Henry’s law). It is the amount of oxygen in each
100 ml of blood and is calculated by the equation:
Arterial oxygen content ¼ bound oxygen þ dissolved oxygen
CaO2 ¼ ð1:31 × Hb × SaO2 × 0:01Þ þ ð0:0225 × PaO2 Þ
where 1.31 is Hü fner’s constant, the directly measured
maximum oxygen-carrying capacity per gram of haemoglobin
[ml O2 g−1 Hb, reduced from the theoretical maximum binding
capacity of 1.39 ml O2 g−1 Hb due to the presence of abnormal
Factors affecting oxygen delivery5,11,14
As can be seen from the above equation, alterations in cardiac
out- put, arterial oxygen saturation, and haemoglobin
concentration will affect oxygen delivery. Sir Joseph Barcroft
first presented the causes of reduced oxygen delivery in 1920,15
classically describing ‘stagnant anoxia’ (reduced CO or reduced
regional blood flow), ‘an-
oxic anoxia’ (arterial hypoxaemia), and ‘anaemic anoxia’ (reduced
haemoglobin). Latterly, ‘cytopathic hypoxia’ (e.g. secondary to
sepsis and inflammation) and ‘histotoxic hypoxia’ (e.g. cyanide
poisoning) have been recognized. Under these circumstances,
cells have a relative or absolute failure of the capacity to utilize
oxygen and increasing D O will have little effect in correcting the
2

hypoxia. Any cause of microcirculatory dysfunction will affect Do

haemoglobin species in vivo (e.g. carboxyhaemoglobin and oxygen delivery,16 for example, sepsis where nitric oxide wn
methaemoglobin)], Hb the
produc- tion is increased leading to disorders of autoregulation loa
amount of haemoglobin in grams per decilitre (g dl −1), SaO2 the de
(matching of supply with demand within the tissues) along with
arterial haemoglobin saturation in per cent, 0.0225 the solubility d
the de- creased vascular tone that manifests clinically as fro
coefficient of oxygen at body temperature; the number of
hypotension. m
millilitres of oxygen dissolved per 100 ml of plasma per
Manipulation of global oxygen delivery to improve patient htt
kilopascal (ml O2 ps:
outcome has been the focus of goal-directed haemodynamic
100 ml−1 plasma kPa−1), and PaO2 the partial pressure of oxygen //a
therapy (GDT) since its inception in the 1980s. Given that con-
in arterial blood in kilopascals (kPa).
tinuing evidence supports equivalent outcome with low blood ca
Therefore, inserting average figures for a ‘normal’ adult male transfusion triggers in many clinical contexts (haemoglobin
de
breathing air at sea level at rest [FI 2 0.21, 1 atm (101.325 kPa), SaO2 mi
O

100%, Hb 15 g 100 ml−1, PaO 13.3 kPa], the arterial oxygen con-
c.o
content centrations 7.0–9.0 g 100 ml−1),17 and the increasing interest in up
limiting hyperoxia,1 8 it is clear that the greatest changes in DO 2 .co
2
(convective oxygen delivery) will be achieved through the ma- m/
can be calculated as 19.95 ml 100 blood.
nipulation of cardiac output. 14 Diffusive oxygen transport will bja
ml−1 be discussed later. ed/
art
Oxygen delivery5,11,14 icl
e/1
Traditionally, in anaesthesia and critical care medicine, the 6/
Oxygen consumption11,12,14 10
prod- uct of cardiac output and oxygen content has been
referred to as ‘oxygen delivery’, despite the fact that this is Oxygen consumption (VO ) is the amount of oxygen consumed by /3
2

inherently incor- rect. First of all, the word delivery implies that the tissues per minute and can be calculated either through dir- 41
/2
all the oxygen so described is delivered to, and utilized by, ect analysis of respiratory gases or indirectly, using Fick’s
28
metabolizing cells. principle, by measuring the oxygen content of mixed venous 86
This is clearly inaccurate, as we know that the oxygen blood (i.e. blood in the pulmonary arteries), Cv O , and using the
2 29
extraction ratio at rest is ∼25%, and that this ratio rarely if ever equations: by
exceeds 75%, even under conditions of exceptional metabolic gu
stress. The term ‘oxygen dispatch’ has sometimes been preferred est
CvO2 ¼ ð1:31 × Hb × SvO2 × 0:01Þ þ ð0:0225 × PvO2 Þ
for this reason. Secondly, the word delivery implies an active on
external process re- 20
VO2 ¼ CO × ðCaO2 — CvO2 Þ Ju
sponsible for ensuring arrival of oxygen at the cell. However, this
ne
set of processes can just as easily be viewed from the
Again inserting ‘normal’ values for an adult male breathing air 20
perspective of the cell ‘sucking in’ oxygen to meet 21
at sea level at rest [FI 2 0.21, 1 atm (101.325 kPa), SvO2 75%,
O

requirements. Notwith- Hb 15 g 100 ml−1, PvO2 5.3 kPa, CaO 19.95 ml 100 ml−1, CO 5 litre
standing these comments, we will continue with oxygen 2

delivery min−1], the mixed venous oxygen content can be calculated as

within the context of this article in order to remain consistent
with common custom and usage.
Global oxygen delivery describes the amount of oxygen deliv-
ered to the tissues in each minute and is a product of the
cardiac output and arterial oxygen content.
14.86 ml 100 ml−1 blood, and therefore the oxygen
consumption as 254.5 ml min−1.
Oxygen delivery (oxygen flux) and oxygen consumption are
glo- bal measures. At tissue level, blood flow is denoted as Q,
[O2]In de- scribes the oxygen content of the afferent blood 2

Thus: (analogous to CaO globally), and [O2]Out describes the oxygen

content of the efferent blood (analogous to CvO globally).
2

Oxygen delivery ¼ cardiac output × arterial oxygen content Therefore, at tissue level:
DO2 ¼ CO × CaO2

or

DO2 ¼ CO × fð1:31 × Hb × SaO2 × 0:01Þ þ ð0:0225 × PaO2 Þg figures as before), a ‘normal’ adult male has an oxygen delivery of
997.5 ml min−1. It is important to note that this is clearly an over-
With a resting cardiac output of 5 litre min−1 (and using the same all measure of oxygen delivery and does not describe regional

BJA Education | Volume 16, Number 10, 475635

differences—oxygen flux to each tissue bed is not constant
throughout the body, rather the microcirculation responds to
al-
tering tissue metabolic demands by varying the regional and
local blood flow.
VO2 ¼ Q × ð½O2 ]In — ½O2 ]Out Þ
Factors affecting oxygen consumption14
The rate of oxygen consumption depends on cellular metabolic
demand and can be manipulated. For example, the use of thera-
peutic hypothermia to reduce cerebral metabolic demand post-
cardiac arrest in order to improve neurological outcome is well
documented.19 Commonly encountered factors that affect V O 2

are documented in Table 2.

4756 BJA Education | Volume 16, Number 10, 2016

4
 Table 2 Factors that affect oxygen consumption. Adapted from
McLellan and Walsh11

Factors that increase VO2 Factors that decrease VO2

Exercise Sedation/analgesia/neuromuscular
blocking agents/antipyretics
Trauma (including surgery Hypovolaemia/shock states
and burns)
Inflammation/sepsis/pyrexia Mechanical ventilation
Shivering Hypothermia
Pain
Agitation
Physiotherapy (quoad
patients in critical care)

Do
Fig 2 A graph depicting the relationship between VO and DO . Taken from Leach
2 2
wn
Oxygen extraction ratio2,11,12,14,18,20 and Treacher14 with kind permission from BMJ Publishing Group Ltd. loa
de
This is the fraction of oxygen delivered via the cardiovascular d
system that is actually utilized by the tissues, and is therefore fro
continue to increase, even with increasing D O (demonstrated m
the ratio of oxygen consumption to oxygen delivery: 2

by the line EF), and DO crit may be greater than in health. This
2 htt
is termed a ‘pathological DO dependency’ and O2ER may not in- ps:
VO 2

O2 ER ¼ D 2 ðgloballyÞ crease proportionately with VO . Slopes AB and DE represent

2
//a
O2
the ca
maximum O2ER. The gradient of slope DE is reduced in critical ill- de
mi
CaO2 — CvO2 ness as the tissues are less able to extract oxygen.
O ER ¼ CaO2
c.o
Þ2 Another method used clinically to assess DO is to measure 2 up
or pulmonary artery mixed venous blood saturation (SvO2 ) using a .co
pulmonary artery catheter (PAC) as this represents unused oxy- m/
ð½O2 ]In — ½O2 ]Out Þ gen returned to the lungs from the tissues. Targeting an SvO2 of bja
O ¼ER ð at tissue level
Þ2 ed/
½O ]
2 In
>70% suggests adequate resuscitation of a critically unwell pa-
tient has been performed and DO optimized. However, under art
icl
2

these circumstances, consideration should be given to the

possi- bility that a ‘normal’ SvO2 may be an indication of e/1
In health, only 20–30% of the oxygen delivered to the tissues is 6/
inadequate oxygen utilization, be it through microcirculatory
utilized (an O2ER 0.2–0.3) and it can be seen that by 10
dysfunction
/3
substituting the figures presented earlier (namely V O 254.5 ml or altered cellular oxygen uptake, rather than adequate oxygen
2
41
min−1 and DO 997.5 ml min−1), an adult male has an O 2ER 0.26 delivery. In the absence of a PAC, central venous saturations
2 /2
at rest. Under these circumstances, oxygen consumption is said can be used as a surrogate (ScvO2 ), with the normal range only 28
to be ‘supply independent’ and VO is maintained even in the
2 marginally higher than the 68–77% range of SvO2 . 86
face of 29
a decreasing DO . 2 −1 −1 Section 2: diffusive oxygen transport by
However, at a critical DO (DO crit) of ∼4 ml kg min in hu-
2 2 gu
mans, the O2ER is maximal (O2ER 0.6–0.8) and VO is said to 2 Diffusion est
become on
‘supply dependent’. If DO continues to decrease further below the
2
Within the lung, oxygen diffuses from the alveoli into the pul- 20
DO crit, or if VO increases for a given DO crit, tissue hypoxia Ju
ensues
2 2 2 ne
with resultant anaerobic respiration and lactate production sec- DO increases, it does not match the increase in V O required by 20
21
2 2

ondary to an imbalance between ATP supply and demand ( produ- exercise. In critical illness, however, especially sepsis, VO may
2

cing a type A hyperlactataemia).21 While this theoretical

framework underpins our understanding of oxygen physiology
in the shocked patient, the empirical evidence supporting these
phenomena is limited and the concepts remain controversial. It
is also important to highlight that even if global oxygen consump-
tion appears to be supply independent, it does not rule out patho-
logical oxygen supply dependency at a regional or local level,
which may only manifest clinically at a later stage.22
Figure 2 illustrates the theoretical biphasic relationship be-
tween oxygen consumption and oxygen delivery. The solid line
‘ABC’ depicts what is seen in health, the broken line ‘DEF’ in
crit-
ical illness. Points B and E depict DO crit in health and critical
2

illness, respectively. In health, V O is ‘supply independent’ be-

2

tween B and C (D O is above DO crit) and ‘supply dependent’ be-

2 2

tween A and B. O2ER is known to increase during exercise,

peaking at maximal exercise at 0.8. This is because although
monary capillaries, driven by the gradient between the partial
pressure of oxygen in the alveolar space and that in the
deoxyge- nated pulmonary capillary blood. In the tissues,
oxygen diffuses down a gradient between oxygenated blood in
the systemic capil- laries and the oxygen-consuming cells.
Diffusion can be described by either a phenomenological
ap- proach using Fick’s laws or an atomistic approach applying
the principle known as the random walk of the diffusing
particles
(another example of which is Brownian motion).

Fick’s laws of diffusion1–4

Adolf Fick (1829–1901) derived two laws of diffusion in 1855. His
first law states that at steady state, particles move from an
area of high concentration to an area of low concentration, the
rate of which is proportional to the difference in their
concentrations (i.e. it relates flux to concentration gradient).
Thus:

@C
J D @x ¼
—
 Do
wn
loa
de
d
fro
m
htt
ps:
//a
ca
de
mi
c.o
up
Fig 3 A diagram illustrating the importance of diffusion distance from capillary to cell and local oxygen tension in determining diffusive oxygen flow rate. Taken from .co
Leach and Treacher14 with kind permission from BMJ Publishing Group Ltd. m/
bja
ed/
art
icl
e/1
6/
10
/3
41
/2
28
86
29
by
gu
est
on
20
Ju
ne
20
21

Fig 4 A participant undergoing CPET. Reproduced with permission.

where J is the diffusion flux [(amount of substance) area−1

Fick’s second law describes how diffusion causes the concen-
time−1], D the diffusion coefficient or diffusivity of the
tration gradient to change with respect to time:
diffusing species (length2 time−1), C the concentration
(amount of substance volume −1), and x the position (diffusion
@C @2C
length). ¼D 2
@t @x
where C is the concentration (amount of substance volume−1), t
content, at a tissue level diffusion distance and partial pressure
the time, D is diffusion constant or diffusivity of the diffusing
gradients will have the greatest effect in altering the diffusive
species (length2 time−1), and x the position (length).
oxygen flux. This is shown in Figure 3.
Therefore, adapting Fick’s first law to human physiology, it
can be shown that the rate of diffusion (rate of flux) for a gas
across a capillary wall is: Section 3: clinical applications of oxygen
transport
Flux ¼ DAðC1 — C2Þ Whole-body oxygen transport and utilization can be estimated
T
using two principle approaches:
Sol
D pffi ffiffiffiffi ffiffiffiffiffi • Estimation of oxygen mass transport, through separate
M W
meas- urement of cardiac output and the elements of oxygen
where D is the diffusion constant (or capillary permeability) for content. In combination with the latter approach, additional
a specific gas at a specified temperature, combining the factors measure-
that affect diffusion of a substance such as molecular size, ment of mixed venous oxygen content allows calculation of Do
charge, and lipid solubility, A the capillary surface area, C1 − C2 oxygen extraction and therefore oxygen consumption. wn
loa
the concentration gradient (or difference in partial pressures) of • Evaluation of oxygen consumption through measurement of de
the gas across the membrane (flow is from C1 to C2), T the steady state, or dynamically changing, oxygen uptake using d
capil- lary wall thickness, Sol the gas solubility, and MW the expired gas analysis to measure gas flows and fro
molecular weight. concentrations [cardiopulmonary exercise testing (CPET), m
Thus, although the global oxygen delivery (oxygen flux) may metabolic cart]. htt
be manipulated through changes in cardiac output and oxygen ps:
It is worth noting that expired gas analysis, although less inva- //a
sive, is more direct in its measurement of cellular oxygen
ca
de
consumption.
mi
c.o
up
.co
m/
bja
ed/
art
icl
e/1
6/
10
/3
41
/2
28
86
29
by
gu
est
on
20
Ju
ne
20
21

Fig 5 An example of a CPET nine-panel plot (data from authors’ laboratory). Panels 1–3 are in the first row, 4–6 in the second row, and 5–9 in the third row. Panel 1 plots VCO 2

vs VO2 and illustrates the V-slope (linear regression analysis) method to determine (ventilatory) AT: at the AT, the gradient of the VO2/VCO2 relationship increases above
1. The AT can also be ascertained by evaluating: the ventilatory equivalents for oxygen and carbon dioxide in panel 4; end-tidal oxygen tension in panel 7; and
ventilatory equivalents against workload in panel 9. The vertical red line denotes the AT. VO2, oxygen consumption; VCO2, carbon dioxide elimination; IC, inspiratory
capacity; VE, minute ventilation; VE/VO2, ventilatory equivalent for oxygen (i.e. the ratio of minute ventilation to oxygen consumption); VE/VCO2, ventilatory equivalent
for carbon dioxide; PE O2 , partial pressure of end-tidal oxygen; PEC0 O2 , partial pressure of end-tidal carbon dioxide; RER, respiratory exchange ratio; HR, heart rate;
0

O2pulse, oxygen pulse (the amount of oxygen consumed per heart beat, VO2/HR; can also be used to estimate cardiac stroke volume); Vt, tidal volume; Load, exercise
workload.
Cardiopulmonary exercise testing23,24
In addition to its use in the physiological assessment of elite ath-
letes, CPET has been developed as a tool to assess a patient ’s pre-
operative functional capacity, that is, their ability to do external
physical work, before major surgery. Also determining VO , a 2peak
respiratory and cardiovascular systems combine to facilitate
the movement of oxygen from where it enters the circulation in
the pulmonary capillary to where it is ultimately utilized in
mito- chondria within cells is fundamental for anaesthetists.

subject’s (ventilatory) anaerobic threshold (AT) may be calcu- Declaration of interest

lated. The AT is the VO (in ml kg−1 min−1) at which, with
2
M.G.M. is Smiths Medical Professor of Anaesthesia and Critical
increas- ing work, anaerobic metabolism commences. While
Care UCL and a Consultant at UCLH. He is Director of the UCL
this is often presented as being evidence of the demand for
Centre for Anaesthesia and The UCL Discovery Lab and a resident
oxygen outstrip-
PI at the Institute of Spots Exercise and Health. He is a paid
ping supply, it may in fact be more closely related to the
Consultant for Edwards Lifesciences (via UCL Consulting and
recruit- ment of muscle fibres with different patterns of
independently) and Deltex in the USA. He was a National
metabolism.
Clinical Advisor for the Department of Health Enhanced
During CPET, anaerobic metabolism is shown when carbon
Recovery Do
dioxide production (VCO ) outstrips VO , whereas during aerobic Partnership until May 2013; Stock holder and advisory board
2 2
metabolism, VCO increases proportionately with VO (see panel wn
2 2
loa
1 in Fig. 5). A high level of functional capacity ( physical fitness) for Medical Defence Technologies LLC (³Gastrostim² patented); de
is an index of a substantial physiological reserve over and Director Bloomsbury Innovation Group a community interest d
above resting values. This in turn is inferred to provide benefit company owned by UCLH Charity; Co-Inventor of ³QUENCH² fro
in withstanding the physiological challenge of major surgery. ( fluid managementsystem) IPbeing exploited by UCL Business. m
In patients undergoing major surgery, postoperative morbidity His institution has also received charitable donations and grants htt
and mortality are consistently increased in individuals with from Smiths Medical Endowment, Deltex Medical and Fresenius- ps:
lower values of AT and VO kabi. He was also co-author of the GIFTASUP guidelines on peri- //a
. A standard CPET set-up is shown
2peak
ca
in Figure 4 and an example of a nine-panel plot in Figure 5. See affected by multiple factors. However, understanding how our
de
the American Thoracic Society/American College of Chest mi
Physi- cians Joint Statement25 and the American Heart c.o
Association Sci- entific Statement26 on CPET for more in-depth up
reviews. .co
m/
bja
Goal-directed hemodynamic therapy ed/
art
In GDT, blood flow and/or oxygen delivery (DO ) is augmented
2 icl
through the use of supplemental oxygen and fluids (both crystal- e/1
loids and colloids), and in some cases, additional inotropes, vaso- 6/
pressors, and vasodilators are also used to achieve the stated 10
goals. Blood flow measurements are obtained using haemo- /3
41
dynamic monitoring equipment such as the oesophageal
/2
Doppler (Deltex Medical Ltd), LiDCO (LiDCO Ltd), and PiCCO
28
(PUL- SION Medical Systems SE, Germany). A variety of 86
physiological variables have been targeted including DO , cardiac
2
29
index (CI), stroke volume (SV), and indexed systemic vascular by
resistance (SVRI). Originally, measurement of these variables gu
required ther- modilution techniques and a pulmonary artery est
(right heart) cath- eter;27 however, this modality has subsequently on
20
gone out of favour following concerns about its safety.28
Ju
GDT is used perioperatively in anaesthesia and critical care. ne
Theoretically, by improving D O (convection) to the tissues, the
2 20
oxygen concentration gradient between the microcirculation 21
and the cells increases, causing increased oxygen diffusion (or ra-
ther increased diffusive flux). However, although GDT may provide
more oxygen at tissue level, this will not necessarily affect
oxygen utilization (in the absence of supply-dependency). It is
also assumed that capillary surface area and diffusion
coefficient remain constant, which may not hold if tissue fluid
status changes, for example, in the case of the tissue oedema
often seen in critically unwell patients. A more in-depth review
of GDT is beyond the scope of this article; however, see the
clinical re- views by Lobo and de Oliveira,29 Ramsingh and
colleagues,30 and Lees and colleagues, 31 and also the Cochrane
Review by Grocott and colleagues32 for further information.

Conclusion
The convective and diffusive transport of oxygen from the air
into the tissues is clearly complex, with each step in the process
operative fluid management; Editor in Chief of Peri-operative
Medicine; on the Editorial Board of the BJA and Critical Care; a
member of the Improving Surgical Outcomes Group; Expert
advisor to the NICE IV fluids guideline development group; Chair-
man of the Board of The National Institute of Academic Anaes-
thesia; Co-Director Xtreme Everest; Co-Chair Evidence Based
Perioperative Medicine (EBPOM). In the past 20 years he has
also received honoraria and travel expenses from Fresenius-
kabi, BBraun, Baxter, Cheetah, LidCo, AQIX, Hospira and Massi-
mo. He does a small amount of Private Medical Practice.
M.P.G. serves on the Medical Advisory Board of Sphere
Medical Ltd through a consulting contract via the University of
Southamp- ton. He also serves (no renumeration for any of these
roles) as a director of Oxygen Contol Systems Ltd, as a director of
the Blooms- bury Innovation Group (a novel community interest
group using an innovative low-cost open source IP model to drive
innovation and development in medical devices in the areas of
anaesthesia and critical care within the NHS) and is chair of the
board of the Xtreme-Everest Community Interest Company
( jointly owned by University of Southampton and UCL;
maintenance, development and exploitation of the Xtreme
Everest Bioresource). He also leads the Xtreme-Everest Oxygen
Research Consortium which has received unrestricted research
grant funding paid to his institution (UoS/UHS/UCL/UCLH) from
BOC Medical (Linde Group), Ely-Lilly Critical Care, Smiths
Medical, Deltex Medical, London Clinic, Rolex, UCLH Special
Trustees, and the Royal Free Special Trustees. He has also
received honoraria for speaking and/or travel expenses from
Edwards Lifesciences (2009 and 2016), Fresenius-Kabi (2008),
BOC Medical (Linde Group)(2008), Ely-Lilly Critical Care (2008)
and Cortex GmBH (2008 & 2009).
J.-O.C.D. has no conflicts of interest to declare.

MCQs
The associated MCQs (to support CME/CPD activity) can be
accessed at https://access.oxfordjournals.org by subscribers to
BJA Education.

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