Physics, Pharmacology and Physiology for Anaesthetists

Key concepts for the FRCA

Physics, Pharmacology and
Physiology for Anaesthetists
Key concepts for the FRCA

Matthew E. Cross MB ChB MRCP FRCA

Specialist Registrar in Anaesthetics, Queen Alexandra Hospital, Portsmouth, UK

Emma V. E. Plunkett MBBS MA MRCP FRCA

Specialist Registrar in Anaesthetics, St Mary’s Hospital, London, UK

Foreword by
Tom E. Peck MBBS BSc FRCA
Consultant Anaesthetist, Royal Hampshire County Hospital, Winchester, UK
CAMBRIDGE UNIVERSITY PRESS
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© M. Cross and E. Plunkett 2008

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Every effort has been made in preparing this publication to provide accurate and up-to-
date information which is in accord with accepted standards and practice at the time of
publication. Although case histories are drawn from actual cases, every effort has been
made to disguise the identities of the individuals involved. Nevertheless, the authors,
editors and publishers can make no warranties that the information contained herein is
totally free from error, not least because clinical standards are constantly changing through
research and regulation. The authors, editors and publishers therefore disclaim all liability
for direct or consequential damages resulting from the use of material contained in this
publication. Readers are strongly advised to pay careful attention to information provided
by the manufacturer of any drugs or equipment that they plan to use.
To Anna and Harvey for putting up with it all
and for Dad
MC

For all my family

but especially for Adrian
EP
 Contents

Acknowledgements page x
Preface xi
Foreword
Tom E. Peck xiii

Introduction 1

Section 1 Mathematical principles

*
5
Mathematical relationships 5
Exponential relationships and logarithms 7
Physical measurement and calibration 14
The SI units 18

Section 2 Physical principles

*
21
Simple mechanics 21
The gas laws 24
Laminar flow 26
Turbulent flow 27
Bernoulli, Venturi and Coanda 28
Heat and temperature 30
Humidity 33
Latent heat 35
Isotherms 37
Solubility and diffusion 38
Osmosis and colligative properties 40
Resistors and resistance 42
Capacitors and capacitance 43
Inductors and inductance 46
Defibrillators 48
Resonance and damping 50
Pulse oximetry 54
Capnography 57
Absorption of carbon dioxide 62
Cardiac output measurement 64
The Doppler effect 68
Neuromuscular blockade monitoring 69
viii Contents

Surgical diathermy 74
Cleaning, disinfection and sterilization 76

Section 3 Pharmacological principles

*
78
The Meyer–Overton hypothesis 78
The concentration and second gas effects 80
Isomerism 82
Enzyme kinetics 85
Drug interactions 88
Adverse drug reactions 89

Section 4 Pharmacodynamics
*
91
Drug–receptor interaction 91
Affinity, efficacy and potency 93
Agonism and antagonism 97
Hysteresis 103

Section 5 Pharmacokinetics
*
104
Bioavailability 104
Volume of distribution 105
Clearance 107
Compartmental models 109
Context-sensitive half time 113

Section 6 Respiratory physiology

*
115
Lung volumes 115
Spirometry 117
Flow–volume loops 119
The alveolar gas equation 123
The shunt equation 124
Pulmonary vascular resistance 126
Ventilation/perfusion mismatch 127
Dead space 128
Fowler’s method 129
The Bohr equation 130
Oxygen delivery and transport 132
The oxyhaemoglobin dissociation curve 134
Carriage of carbon dioxide 136
Work of breathing 138
Control and effects of ventilation 139
Compliance and resistance 142
 Contents ix

Section 7 Cardiovascular physiology

*
144
Cardiac action potentials 144
The cardiac cycle 146
Pressure and flow calculations 149
Central venous pressure 151
Pulmonary arterial wedge pressure 153
The Frank–Starling relationship 155
Venous return and capillary dynamics 157
Ventricular pressure–volume relationship 162
Systemic and pulmonary vascular resistance 167
The Valsalva manoeuvre 169
Control of heart rate 171

Section 8 Renal physiology

*
173
Acid–base balance 173
Glomerular filtration rate 176
Autoregulation and renal vascular resistance 177
The loop of Henle 179
Glucose handling 181
Sodium handling 182
Potassium handling 183

Section 9 Neurophysiology
*
184
Action potentials 184
Muscle structure and function 188
Muscle reflexes 191
The Monro–Kelly doctrine 193
Intracranial pressure relationships 194
Formation and circulation of cerebrospinal fluid 197
Pain 198

Section 10 Statistical principles

*
200
Data types 200
Indices of central tendency and variability 202
Types of distribution 206
Methods of data analysis 208
Error and outcome prediction 217
Clinical trials 219
Evidence-based medicine 220

Appendix 222
Index 236
 Acknowledgements

We are grateful to the following individuals for their invaluable help in bringing
this book to publication
Dr Tom Peck MBBS BSc FRCA
Anaesthetics Department, Royal Hampshire County Hospital, Winchester, UK
Dr David Smith DM FRCA
Shackleton Department of Anaesthetics, Southampton General Hospital,
Southampton, UK
Dr Tom Pierce MRCP FRCA
Shackleton Department of Anaesthetics, Southampton General Hospital,
Southampton, UK
Dr Mark du Boulay BSc FRCA
Anaesthetics Department, Royal Hampshire County Hospital, Winchester, UK
Dr Roger Sharpe BSc FRCA
Anaesthetics Department, Northwick Park Hospital, London, UK
In addition we are grateful for permission to reprint the illustrations on pages 183
and 184 from International Thomson Publishing Services Ltd.
Cheriton House, North Way, Andover, UK
 Preface

The examinations in anaesthesia are much feared and respected. Although fair,
they do require a grasp of many subjects which the candidate may not have been
familiar with for some time. This is particularly true with regards to the basic
science components.
This book does not aim to be an all-inclusive text, rather a companion to other
books you will already have in your collection. It aims to allow you to have an
additional reference point when revising some of these difficult topics. It will
enable you to quickly and easily bring to hand the key illustrations, definitions or
derivations that are fundamental to the understanding of a particular subject. In
addition to succinct and accurate definitions of key phrases, important equations
are derived step by step to aid understanding and there are more than 180
diagrams with explanations throughout the book.
You should certainly find a well-trusted textbook of anaesthesia if you wish to
delve deeper into the subject matter, but we hope to be able to give you the
knowledge and reasoning to tackle basic science MCQs and, more crucially, to
buy you those first few lines of confident response when faced with a tricky basic
science viva.
Good luck in the examinations, by the time you read this the end is already in
sight!
 Foreword

Many things are currently in a state of flux within the world of medical education
and training, and the way in which candidates approach examinations is no
exception. Gone are the days when large weighty works are the first port of call
from which to start the learning experience. Trainees know that there are more
efficient ways to get their heads around the concepts that are required in order to
make sense of the facts.
It is said that a picture says a thousand words and this extends to diagrams as
well. However, diagrams can be a double-edged sword for trainees unless they are
accompanied by the relevant level of detail. Failure to label the axis, or to get the
scale so wrong that the curve becomes contradictory is at best confusing.
This book will give back the edge to the examination candidate if they digest its
contents. It is crammed full of precise, clear and well-labelled diagrams. In
addition, the explanations are well structured and leave the reader with a clear
understanding of the main point of the diagram and any additional information
where required. It is also crammed full of definitions and derivations that are very
accessible.
It has been pitched at those studying for the primary FRCA examination and I
have no doubt that they will find it a useful resource. Due to its size, it is never
going to have the last word, but it is not trying to achieve that. I am sure that it will
also be a useful resource for those preparing for the final FRCA and also for those
preparing teaching material for these groups.
Doctors Cross and Plunkett are to be congratulated on preparing such a clear
and useful book – I shall be recommending it to others.

Dr Tom E. Peck MBBS BSc FRCA

Consultant Anaesthetist, Royal Hampshire County Hospital, Winchester, UK
 Introduction

This book is aimed primarily at providing a reference point for the common
graphs, definitions and equations that are part of the FRCA syllabus. In certain
situations, for example the viva sections of the examinations, a clear structure to
your answer will help you to appear more confident and ordered in your response.
To enable you to do this, you should have a list of rules to hand which you can
apply to any situation.

Graphs
Any graph should be constructed in a logical fashion. Often it is the best-known
curves that candidates draw most poorly in their rush to put the relationship
down on paper. The oxyhaemoglobin dissociation curve is a good example. In
the rush to prove what they know about the subject as a whole, candidates
often supply a poorly thought out sigmoid-type curve that passes through none
of the traditional reference points when considered in more detail. Such an
approach will not impress the examiner, despite a sound knowledge of the
topic as a whole. Remembering the following order may help you to get off to a
better start.

Size
It is important to draw a large diagram to avoid getting it cluttered. There will
always be plenty of paper supplied so don’t be afraid to use it all. It will make the
examiner’s job that much easier as well as yours.

Axes
Draw straight, perpendicular axes and label them with the name of the variable
and its units before doing anything else. If common values are known for the
particular variable then mark on a sensible range, for example 0–300 mmHg
for blood pressure. Remember that logarithmic scales do not extend to zero as
zero is an impossible result of a logarithmic function. In addition, if there are
important reference points they should be marked both on the axis and where
two variables intersect on the plot area, for example 75% saturation corres-
ponding to 5.3 kPa for the venous point on the oxyhaemoglobin dissociation
curve. Do all of this before considering a curve and do not be afraid to talk out
loud as you do so – it avoids uncomfortable silences, focuses your thoughts and
shows logic.
2 Introduction

Beginning of a curve
Consider where a curve actually starts on the graph you are drawing. Does it
begin at the origin or does it cross the y axis at some other point? If so, is there
a specific value at which it crosses the y axis and why is that the case? Some
curves do not come into contact with either axis, for example exponentials
and some physiological autoregulation curves. If this is the case, then you should
demonstrate this fact and be ready to explain why it is so. Consider what
happens to the slope of a curve at its extremes. It is not uncommon for a
curve to flatten out at high or low values, and you should indicate this if it is
the case.

Middle section
The middle section of a curve may cross some important points as previously
marked on the graph. Make sure that the curve does, in fact, cross these points
rather than just come close to them or you lose the purpose of marking them on in
the first place. Always try to think what the relationship between the two variables
is. Is it a straight line, an exponential or otherwise and is your curve representing
this accurately?

End of a curve
If the end of a curve crosses one of the axes then draw this on as accurately as
possible. If it does not reach an axis then say so and consider what the curve will
look like at this extreme.

Other points
Avoid the temptation to overly annotate your graphs but do mark on any
important points or regions, for example segments representing zero and first-
order kinetics on the Michaelis–Menten graph.

Definitions
When giving a definition, the aim is to accurately describe the principle in
question in as few a words as possible. The neatness with which your definition
appears will affect how well considered your answer as a whole comes across.
Definitions may or may not include units.

Definitions containing units

Always think about what units, if any, are associated with the item you are trying
to describe. For example, you know that the units for clearance are ml.min1 and
so your definition must include a statement about both volume (ml) and time
 Introduction 3

(min). When you are clear about what you are describing, it should be presented
as succinctly as possible in a format such as
‘x’ is the volume of plasma . . .
‘y’ is the pressure found when . . .
‘z’ is the time taken for . . .
Clearance (ml.min1) is the volume (ml) of plasma from which a drug is
completely removed per unit time (min)
Pressure (N.m2) describes the result of a force (N) being applied over a given
area (m2).

You can always finish your definition by offering the units to the examiner if you
are sure of them.

Definitions without units

If there are no units involved, think about what process you are being asked to
define. It may be a ratio, an effect, a phenomenon, etc.
Reynold’s number is a dimensionless number . . .
The blood:gas partition coefficient is the ratio of . . .
The second gas effect is the phenomenon by which . . .

Conditions
Think about any conditions that must apply. Are the measurements taken at
standard temperature and pressure (STP) or at the prevailing temperature and
pressure?
The triple point of water is the temperature at which all three phases are in
equilibrium at 611.73 Pa. It occurs at 0.01 8C.

There is no need to mention a condition if it does not affect the calculation. For
example, there is no need to mention ambient pressure when defining saturated
vapour pressure (SVP) as only temperature will alter the SVP of a volatile.
Those definitions with clearly associated units will need to be given in a clear
and specific way; those without units can often be ‘padded’ a little if you are not
entirely sure.

Equations
Most equations need only be learned well enough to understand the components
which make up the formula such as in

V ¼ IR

where V is voltage, I is current and R is resistance.

4 Introduction

There are, however, some equations that deserve a greater understanding of their
derivation. These include,
The Bohr equation
The Shunt equation
The Henderson–Hasselbach equation

These equations are fully derived in this book with step by step explanations of the
mathematics involved. It is unlikely that the result of your examination will hinge
on whether or not you can successfully derive these equations from first princi-
ples, but a knowledge of how to do it will make things clearer in your own mind.
If you are asked to derive an equation, remember four things.
1. Don’t panic!
2. Write the end equation down first so that the examiners know you
know it.
3. State the first principles, for example the Bohr equation considers a
single tidal exhalation comprising both dead space and alveolar gas.
4. Attempt to derive the equation.

If you find yourself going blank or taking a wrong turn midway through then do
not be afraid to tell the examiners that you cannot remember and would they
mind moving on. No one will mark you down for this as you have already
supplied them with the equation and the viva will move on in a different direction.
 Section 1 * Mathematical principles

Mathematical relationships

Mathematical relationships tend not to be tested as stand-alone topics but an

understanding of them will enable you to answer other topics with more authority.

Linear relationships

y¼x

Draw and label the axes as shown. Plot the line so that it passes through the
origin (the point at which both x and y are zero) and the value of y is equal to
the value of x at every point. The slope when drawn correctly should be at 458
if the scales on both axes are the same.

y ¼ ax þ b

b Slope = a

This line should cross the y axis at a value of b because when x is 0, y must be
0 þ b. The slope of the graph is given by the multiplier a. For example, when the
equation states that y = 2x, then y will be 4 when x is 2, and 8 when x is 4, etc. The
slope of the line will, therefore, be twice as steep as that of the line given by y = 1x.
6 Section 1  Mathematical principles
Hyperbolic relationships (y = k/x)

This curve describes any inverse relationship. The commonest value for the
constant, k, in anaesthetics is 1, which gives rise to a curve known as a
rectangular hyperbola. The line never crosses the x or the y axis and is
described as asymptotic to them (see definition below). Boyle’s law is a good
example (volume = 1/pressure). This curve looks very similar to an exponen-
tial decline but they are entirely different in mathematical terms so be sure
about which one you are describing.

Asymptote
A curve that continually approaches a given line but does not meet it at any
distance.

Parabolic relationships (y = kx2)

k=2 k=1
y

These curves describe the relationship y = x2 and so there can be no negative

value for y. The value for ‘k’ alters the slope of the curve, as ‘a’ does for the
equation y = ax þ b. The curve crosses the y axis at zero unless the equation is
written y = kx2 þ b, in which case it crosses at the value of ‘b’.
 Exponential relationships and logarithms

Exponential
A condition where the rate of change of a variable at any point in time is
proportional to the value of the variable at that time.
or
A function whereby the x variable becomes the exponent of the equation
y = ex.

We are normally used to x being represented in equations as the base unit (i.e.
y = x2). In the exponential function, it becomes the exponent (y = ex), which
conveys some very particular properties.

Euler’s number
Represents the numerical value 2.71828 and is the base of natural logarithms.
Represented by the symbol ‘e’.

Logarithms
The power (x) to which a base must be raised in order to produce the number
given as for the equation x = logbase(number).

The base can be any number, common numbers are 10, 2 and e (2.71828).
Log10(100) is, therefore, the power to which 10 must be raised to produce the
number 100; for 102 = 100, therefore, the answer is x = 2. Log10 is usually written
as log whereas loge is usually written ln.

Rules of logarithms
Multiplication becomes addition

logðxyÞ ¼ logðxÞþlogðyÞ

Division becomes subtraction

logðx=yÞ ¼ logðxÞlogðyÞ

Reciprocal becomes negative

logð1=xÞ ¼ logðxÞ
8 Section 1  Mathematical principles
Power becomes multiplication

logðxn Þ ¼ n: logðxÞ

Any log of its own base is one

log10 ð10Þ ¼ 1 and lnðeÞ ¼ 1

Any log of 1 is zero because n0 always equals 1

log10 ð1Þ ¼ 0 and lnð1Þ ¼ 0

Basic positive exponential (y = ex)

The curve is asymptotic to the x axis. At negative values of x, the slope is shallow
but the gradient increases sharply when x is positive. The curve intercepts the
y axis at 1 because any number to the power 0 (as in e0) equals 1. Most
importantly, the value of y at any point equals the slope of the graph at that
point.

Clinical tear away positive exponential (y = a.ekt)

a
Time (t )

The curve crosses y axis at value of a. It tends towards infinity as value of t

increases. This is clearly not a sustainable physiological process but could be seen
in the early stages of bacterial replication where y equals number of bacteria.
 Exponential relationships and logarithms 9

Basic negative exponential (y = ax)

The x axis is again an asymptote and the line crosses the y axis at 1. This time
the curve climbs to infinity as x becomes more negative. This is because x is
now becoming more positive. The curve is simply a mirror image, around the
y axis, of the positive exponential curve seen above.

Physiological negative exponential (y = a.ekt)

Time (t )

The curve crosses the y axis at a value of a. It declines exponentially as t increases.

The line is asymptotic to the x axis. This curve is seen in physiological processes
such as drug elimination and lung volume during passive expiration.

Physiological build-up negative exponential (y = a  b.ekt)

Asymptote
a

Time (t )
10 Section 1  Mathematical principles
The curve passes through the origin and has an asymptote that crosses the y
axis at a value of a. Although y increases with time, the curve is actually a
negative exponential. This is because the rate of increase in y is decreasing
exponentially as t increases. This curve may be seen clinically as a wash-in
curve or that of lung volume during positive pressure ventilation using
pressure-controlled ventilation.

Half life
The time taken for the value of an exponential function to decrease by half is
the half life and is represented by the symbol t1/2
or
the time equivalent of 0.693t t = time constant

An exponential process is said to be complete after five half lives. At this point,
96.875% of the process has occurred.

Graphical representation of half life

Percentage of initial

100
value (y )

50

25

t½ t½
Time (t )

This curve needs to be drawn accurately in order to demonstrate the principle.

After drawing and labelling the axes, mark the key values on the y axis as
shown. Your curve must pass through each value at an equal time interval on
the x axis. To ensure this, plot equal time periods on the x axis as shown, before
drawing the curve. Join the points with a smooth curve that is asymptotic to
the x axis. This will enable you to describe the nature of an exponential decline
accurately as well as to demonstrate easily the meaning of half life.
 Exponential relationships and logarithms 11

Time constant
The time it would have taken for a negative exponential process to complete,
were the initial rate of change to be maintained throughout. Given the symbol t.
or
The time taken for the value of an exponential to fall to 37% of its previous value.
or
The time taken for the value of an exponential function change by a factor
of e1.
or
The reciprocal of the rate constant.

An exponential process is said to be complete after three time constants. At this

point 94.9% of the process has occurred.

Graphical representation of the time constant

100
Percentage of initial
value (y )

50
37

τ
Time (t )

This curve should be a graphical representation of the first and second

definitions of the time constant as given above. After drawing and labelling
the axes, mark the key points on the y axis as shown. Draw a straight line falling
from 100 to baseline at a time interval of your choosing. Label this time
interval . Mark a point on the graph where a vertical line from this point
crosses 37% on the y axis. Finally draw the curve starting as a tangent to your
original straight line and falling away smoothly as shown. Make sure it passes
through the 37% point accurately. A well-drawn curve will demonstrate the
time constant principle clearly.
12 Section 1  Mathematical principles
Rate constant
The reciprocal of the time constant. Given the symbol k.
or
A marker of the rate of change of an exponential process.

The rate constant acts as a modifier to the exponent as in the equation y = ekt (e.g.
in a savings account, k would be the interest rate; as k increases, more money is
earned in the same period of time and the exponential curve is steeper).

Graphical representation of k (y = ekt)

k=2
k=1

t2 t1

Time (t )

k = 1 Draw a standard exponential tear-away curve. To move from y = et to

y = et þ 1 takes time t1.
k = 2 This curve should be twice as steep as the first as ‘k’ acts as a 2
multiplier to the exponent ‘t’. As ‘k’ has doubled, for the same change in y
the time taken has halved and this can be shown as t2 where t2 is half the
value of t1. The values t1 and t2 are also the time constants for the equation
because they are, by definition, the reciprocal of the rate constant.

Transforming to a straight line graph

Start with the general equation as follows

y ¼ ekt

take natural logarithms of both sides

ln y ¼ lnðekt Þ

power functions become multipliers when taking logs, giving

ln y ¼ kt: lnðeÞ

the natural log of e is 1, giving

ln y ¼ kt:1 or ln y ¼ kt
 Exponential relationships and logarithms 13

You may be expected to perform this simple transformation, or at least to describe

the maths behind it, as it demonstrates how logarithmic transformation can make
the interpretation of exponential curves much easier by allowing them to be
plotted as straight lines ln y ¼ kt:

100 k=2 k=1

In(y) 10 τ τ

Time (t )

k = 1 Draw a curve passing through the origin and rising as a straight line at
approximately 458.
k = 2 Draw a curve passing through the origin and rising twice as steeply as
the k = 1 line. The time constant is half that for the k = 1 line.
 Physical measurement and calibration

This topic tests your understanding of the ways in which a measurement device
may not accurately reflect the actual physiological situation.

Accuracy
The ability of a measurement device to match the actual value of the quantity
being measured.

Precision
The reproducibility of repeated measurements and a measure of their likely
spread.

In the analogy of firing arrows at a target, the accuracy would represent how close
the arrow was to the bullseye, whereas the precision would be a measure of how
tightly packed together a cluster of arrows were once they had all been fired.

Drift
A fixed deviation from the true value at all points in the measured range.

Hysteresis
The phenomenon by which a measurement varies from the input value by
different degrees depending on whether the input variable is increasing or
decreasing in magnitude at that moment in time.

Non-linearity
The absence of a true linear relationship between the input value and the
measured value.

Zeroing and calibration

Zeroing a display removes any fixed drift and allows the accuracy of the measuring
system to be improved. If all points are offset by ‘þ x’, zeroing simply subtracts ‘x’
from all the display values to bring them back to the input value. Calibration is
used to check for linearity over a given range by taking known set points and
checking that they all display a measured value that lies on the ideal straight line.
The more points that fit the line, the more certain one can be that the line is indeed
 Physical measurement and calibration 15

straight. One point calibration reveals nothing about linearity, two point calibra-
tion is better but the line may not necessarily be straight outside your two
calibration points (even a circle will cross the straight line at two points). Three
point calibration is ideal as, if all three points are on a straight line, the likelihood
that the relationship is linear over the whole range is high.

Accurate and precise measurement

Measured value
(y)

Input value
(x )

Draw a straight line passing through the origin so that every input value is
exactly matched by the measured value. In mathematical terms it is the same as
the curve for y ¼ x.

Accurate imprecise measurement

Measured value
(y)

Input value
(x )

Draw the line of perfect fit as described above. Each point on the graph is
plotted so that it lies away from this line (imprecision) but so that the line of
best fit matches the perfect line (accuracy).
16 Section 1  Mathematical principles
Precise inaccurate measurement

Measured value
(y)

Input value
(x )

Draw the line of perfect fit (dotted line) as described above. Next plot a series
of measured values that lie on a parallel (solid) line. Each point lies exactly on a
line and so is precise. However, the separation of the measured value from the
actual input value means that the line is inaccurate.

Drift
Measured value
(y)

Input value
(x )

The technique is the same as for drawing the graph above. Demonstrate that
the readings can be made accurate by the process of zeroing – altering each
measured value by a set amount in order to bring the line back to its ideal
position. The term ‘drift’ implies that accuracy is lost over time whereas an
inaccurate implies that the error is fixed.
 Physical measurement and calibration 17

Hysteresis

Measured value
(y)

Input value
(x )

The curves should show that the measured value will be different depending
on whether the input value is increasing (bottom curve) or decreasing (top
curve). Often seen clinically with lung pressure–volume curves.

Non-linearity
Measured value

B
(y)

Input value
(x )

The curve can be any non-linear shape to demonstrate the effect. The curve
helps to explain the importance and limitations of calibration. Points A and B
represent a calibration range of input values between which linearity is likely.
The curve demonstrates how linearity cannot be assured outside this range.
The DINAMAP monitor behaves in a similar way. It tends to overestimate at
low blood pressure (BP) and underestimate at high BP while retaining accu-
racy between the calibration limits.
 The SI units

There are seven basic SI (Système International) units from which all other units
can be derived. These seven are assumed to be independent of each other and have
various specific definitions that you should know for the examination. The
acronym is SMMACKK.

The base SI units

Unit Symbol Measure of Definition

second s Time The duration of a given number

of oscillations of the caesium-133
atom
metre m Distance The length of the path travelled by light in
vacuum during a certain fraction of a
second
mole mol Amount The amount of substance which
contains as many elementary particles
as there are atoms in 0.012 kg of
carbon-12
ampere A Current The current in two parallel conductors
of infinite length and placed 1 metre
apart in vacuum, which would
produce between them a force of
2  10 7 N.m 1
candela cd Luminous intensity Luminous intensity, in a given direction,
of a source that emits monochromatic
light at a specific frequency
kilogram kg Mass The mass of the international
prototype of the kilogram held in
Sèvres, France
kelvin K Temperature 1/273.16 of the thermodynamic
temperature of the triple point of
water

From these seven base SI units, many others are derived. For example,
speed can be denoted as distance per unit time (m.s 1) and acceleration as
speed change per unit time (m.s 2). Some common derived units are given
below.
 The SI units 19

Derived SI units

Measure of Definition Units

Area Square metre m2

Volume Cubic metre m3
Speed Metre per second m.s 1
Velocity Metre per second in a given direction m.s 1
Acceleration Metre per second squared m.s 2
Wave number Reciprocal metre m 1
Current density Ampere per square metre A.m2
3
Concentration Mole per cubic metre mol.m

These derived units may have special symbols of their own to simplify them. For
instance, it is easier to use the symbol O than m2.kg.s 3.A 2.

Derived SI units with special symbols

Measure of Name Symbol Units

Frequency hertz Hz s 1
2
Force newton N kg.m.s
Pressure pascal Pa N.m 2
Energy/work joule J N.m
Power watt W J.s 1
Electrical charge coulomb C A.s
Potential difference volt V W/A
Capacitance farad F C/V
Resistance ohm O V/A

Some everyday units are recognized by the system although they themselves are
not true SI units. Examples include the litre (10 3 m3), the minute (60 s), and the
bar (105 Pa). One litre is the volume occupied by 1 kg of water but was redefined
in the 1960s as being equal to 1000 cm3.

Prefixes to the SI units

In reality, many of the SI units are of the wrong order of magnitude to be useful. For
example, a pascal is a tiny amount of force (imagine 1 newton – about 100 g – acting
on an area of 1 m2 and you get the idea). We, therefore, often use kilopascals (kPa)
to make the numbers more manageable. The word kilo- is one of a series of prefixes
that are used to denote a change in the order of magnitude of a unit. The following
prefixes are used to produce multiples or submultiples of all SI units.
20 Section 1
Mathematical principles
Prefixes

Prefix 10n Symbol Decimal equivalent

yotta 1024 Y 1 000 000 000 000 000 000 000 000
zetta 1021 Z 1 000 000 000 000 000 000 000
exa 1018 E 1 000 000 000 000 000 000
peta 1015 P 1 000 000 000 000 000
tera 1012 T 1 000 000 000 000
giga 109 G 1 000 000 000
mega 106 M 1 000 000
kilo 103 k 1000
hecto 102 h 100
deca 101 da 10
100 1
deci 10 1 d 0.1
centi 10 2 c 0.01
milli 10 3 m 0.001
micro 10 6 m 0.000 001
nano 10 9 n 0.000 000 001
pico 10 12 p 0.000 000 000 001
femto 10 15 f 0.000 000 000 000 001
atto 10 18 a 0.000 000 000 000 000 001
zepto 10 21 z 0.000 000 000 000 000 000 001
yocto 10 24 y 0.000 000 000 000 000 000 000 001

Interestingly, 10100 is known as a googol, which was the basis for the name of the
internet search engine Google after a misspelling occurred.
 Section 2 * Physical principles

Simple mechanics

Although there is much more to mechanics as a topic, an understanding of some

of its simple components (force, pressure, work and power) is all that will be
tested in the examination.

Force
Force is that influence which tends to change the state of motion of an object
(newtons, N).
or

F ¼ ma

where F is force, m is mass and a is acceleration.

Newton
That force which will give a mass of one kilogram an acceleration of one metre
per second per second
or

N ¼ kg:m:s2

When we talk about weight, we are really discussing the force that we sense when
holding a mass which is subject to acceleration by gravity. The earth’s gravita-
tional field will accelerate an object at 9.81 m.s2 and is, therefore, equal to 9.81 N.
If we hold a 1 kg mass in our hands we sense a 1 kg weight, which is actually 9.81 N:

F ¼ ma
F ¼ 1 kg  9:81 m:s2
F ¼ 9:81 N

Therefore, 1 N is 9.81 times less force than this, which is equal to a mass of 102 g
(1000/9.81). Putting it another way, a mass of 1 kg will not weigh 1 kg on the
moon as the acceleration owing to gravity is only one-sixth of that on the earth.
The 1 kg mass will weigh only 163 g.
22 Section 2  Physical principles
Pressure
Pressure is force applied over a unit area (pascals, P)

P ¼ F=A

P is pressure, F is force and A is area.

Pascal
One pascal is equal to a force of one newton applied over an area of one
square metre (N.m2).

The pascal is a tiny amount when you realize that 1 N is equal to 102 g weight. For
this reason kilopascals (kPa) are used as standard.

Energy
The capacity to do work (joules, J).

Work
Work is the result of a force acting upon an object to cause its displacement in
the direction of the force applied (joules, J).
or

J ¼ FD

J is work, F is force and D is distance travelled in the direction of the force.

Joule
The work done when a force of one newton moves one metre in the direction
of the force is one joule.

More physiologically, it can be shown that work is given by pressure  volume.

This enables indices such as work of breathing to be calculated simply by studying
the pressure–volume curve.

P ¼ F=A or F ¼ PA

and
V ¼ DA or D ¼ V=A

so
J ¼ FD

becomes
J ¼ ðPAÞ:ðV=AÞ
 Simple mechanics 23

or
J ¼ PV

where P is pressure, F is force, A is area, V is volume, D is distance and J is work.

Power
The rate at which work is done (watts, W).
or

W ¼ J=s

where W is watts (power), J is joules (work) and s is seconds (time).

Watt
The power expended when one joule of energy is consumed in one second is
one watt.

The power required to sustain physiological processes can be calculated by

using the above equation. If a pressure–volume loop for a respiratory cycle is
plotted, the work of breathing may be found. If the respiratory rate is now
measured then the power may be calculated. The power required for respiration
is only approximately 700–1000 mW, compared with approximately 80 W needed
at basal metabolic rate.
 The gas laws

Boyle’s law
At a constant temperature, the volume of a fixed amount of a perfect gas varies
inversely with its pressure.

PV ¼ K or V / 1=P

Charles’ law
At a constant pressure, the volume of a fixed amount of a perfect gas varies in
proportion to its absolute temperature.

V=T ¼ K or V / T

Gay–Lussac’s law (The third gas law)

At a constant volume, the pressure of a fixed amount of a perfect gas varies in
proportion to its absolute temperature.

P=T ¼ K or P / T

Remember that water Boyle’s at a constant temperature and that Prince Charles is
under constant pressure to be king.

Perfect gas
A gas that completely obeys all three gas laws.
or
A gas that contains molecules of infinitely small size, which, therefore, occupy
no volume themselves, and which have no force of attraction between them.

It is important to realize that this is a theoretical concept and no such gas actually
exists. Hydrogen comes the closest to being a perfect gas as it has the lowest
molecular weight. In practice, most commonly used anaesthetic gases obey the gas
laws reasonably well.

Avogadro’s hypothesis
Equal volumes of gases at the same temperature and pressure contain equal
numbers of molecules.
 The gas laws 25

The universal gas equation

The universal gas equation combines the three gas laws within a single equation
If PV ¼ K1, P/T ¼ K2 and V/T ¼ K3, then all can be combined to give

PV=T ¼ K

For 1 mole of a gas, K is named the universal gas constant and given the
symbol R.

PV=T ¼ R

for n moles of gas

PV=T ¼ nR

so

PV ¼ nRT

The equation may be used in anaesthetics when calculating the contents of an

oxygen cylinder. The cylinder is at a constant (room) temperature and has a fixed
internal volume. As R is a constant in itself, the only variables now become P and n
so that
P/n

Therefore, the pressure gauge can be used as a measure of the amount of oxygen
left in the cylinder. The reason we cannot use a nitrous oxide cylinder pressure
gauge in the same way is that these cylinders contain both vapour and liquid and
so the gas laws do not apply.
 Laminar flow

Laminar flow describes the situation when any fluid (either gas or liquid) passes
smoothly and steadily along a given path, this is is described by the Hagen–Poiseuille
equation.

Hagen–Poiseuille equation

ppr 4
Flow ¼
8l

where p is pressure drop along the tube (p1  p2), r is radius of tube, l is length
of tube and  is viscosity of fluid.

The most important aspect of the equation is that flow is proportional to the
4th power of the radius. If the radius doubles, the flow through the tube will
increase by 16 times (24).
Note that some texts describe the equation as

ppd 4
Flow ¼
128l

where d is the diameter of tube.

This form uses the diameter rather than the radius of the tube. As the diameter
is twice the radius, the value of d4 is 16 times (24) that of r4. Therefore, the
constant (8) on the bottom of the equation must also be multiplied 16 times to
ensure the equation remains balanced (8  16 ¼ 128).
Viewed from the side as it is passing through a tube, the leading edge of
a column of fluid undergoing laminar flow appears parabolic. The fluid flowing
in the centre of this column moves at twice the average speed of the fluid column
as a whole. The fluid flowing near the edge of the tube approaches zero velocity.
This phenomenon is particular to laminar flow and gives rise to this particular
shape of flow.
 Turbulent flow

Turbulent flow describes the situation in which fluid flows unpredictably with
multiple eddy currents and is not parallel to the sides of the tube through which it
is flowing.
As flow is, by definition, unpredictable, there is no single equation that defines
the rate of turbulent flow as there is with laminar flow. However, there is a
number that can be calculated in order to identify whether fluid flow is likely to
be laminar or turbulent and this is called Reynold’s number (Re).

Reynold’s number

vd
Re ¼


where Re is Reynold’s number,  is density of fluid, v is velocity of fluid, d is

diameter of tube and  is viscosity of fluid.

If one were to calculate the units of all the variables in this equation, you would
find that they all cancel each other out. As such, Reynold’s number is dimension-
less (it has no units) and it is simply taken that
when Re < 2000 flow is likely to be laminar and when Re > 2000 flow is likely to
be turbulent.
Given what we now know about laminar and turbulent flow, the main points to
remember are that
viscosity is the important property for laminar flow
density is the important property for turbulent flow
Reynold’s number of 2000 delineates laminar from turbulent flow.
 Bernoulli, Venturi and Coanda

The Bernoulli principle

An increase in the flow velocity of an ideal fluid will be accompanied by a
simultaneous reduction in its pressure.

The Venturi effect

The effect by which the introduction of a constriction to fluid flow within a tube
causes the velocity of the fluid to increase and, therefore, the pressure of the
fluid to fall.

These definitions are both based on the law of conservation of energy (also known
as the ‘first law of thermodynamics’).

The law of conservation of energy

Energy cannot be created or destroyed but can only change from one form to
another.

Put simply, this means that the total energy contained within the fluid
system must always be constant. Therefore, as the kinetic energy (velocity)
of the fluid increases, the potential energy (pressure) must reduce by an
equal amount in order to ensure that the total energy content remains the
same.
The increase in velocity seen as part of the Venturi effect simply demonstrates
that a given number of fluid particles have to move faster through a narrower
section of tube in order to keep the total flow the same. This means an increase in
velocity and, as predicted, a reduction in pressure. The resultant drop in pressure
can be used to entrain gases or liquids, which allows for applications such as
nebulizers and Venturi masks.

The Coanda effect

The tendency of a stream of fluid flowing in proximity to a convex surface to
follow the line of the surface rather than its original course.

The effect is thought to occur because a moving column of fluid entrains

molecules lying close to the curved surface, creating a relatively low pressure,
 Bernoulli, Venturi and Coanda 29

contact point. As the pressure further away from the curved surface is rela-
tively higher, the column of fluid is preferentially ‘pushed’ towards the surface
rather than continuing its straight course. The effect means that fluid will
preferentially flow down one limb of a Y-junction rather than being equally
distributed.
 Heat and temperature

Heat
The form of energy that passes between two samples owing to the difference
in their temperatures.

Temperature
The property of matter which determines whether heat energy will flow to or
from another object of a different temperature.

Heat energy will flow from an object of a high temperature to an object of a lower
temperature. An object with a high temperature does not necessarily contain
more heat energy than one with a lower temperature as the temperature change
per unit of heat energy supplied will depend upon the specific heat capacity of the
object in question.

Triple point
The temperature at which all three phases of water – solid, liquid and gas – are
in equilibrium at 611.73 Pa. It occurs at 0.01 8C.

Kelvin
One kelvin is equal to 1/273.16 of the thermodynamic triple point
of water. A change in temperature of 1 K is equal in magnitude to that
of 1 8C.

Kelvin must be used when performing calculations with temperature. For exam-
ple, the volume of gas at 20 8C is not double that at 10 8C: 10 8C is 283.15 K so the
temperature must rise to 566.30 K (293.15 8C) before the volume of gas will
double.

Celsius/centigrade
Celsius (formerly called the degree centigrade) is a common measure of
temperature in which a change of 1 8C is equal in magnitude to a change of
1 K. To convert absolute temperatures given in degrees celsius to kelvin, you
must add 273.15. For example 20 8C ¼ 293.15 K.
 Heat and temperature 31

Resistance wire
The underlying principle of this method of measuring temperature is that the
resistance of a thin piece of metal increases as the temperature increases. This makes
an extremely sensitive thermometer yet it is fragile and has a slow response time.

Draw a curve that does not pass through the origin. Over commonly measured
ranges, the relationship is essentially linear. The slope of the graph is very slightly
positive and a Wheatstone bridge needs to be used to increase sensitivity.

Thermistor
A thermistor can be made cheaply and relies on the fact that the resistance of
certain semiconductor metals falls as temperature increases. Thermistors are fast
responding but suffer from calibration error and deteriorate over time.

Draw a smooth curve that falls as temperature increases. The curve will never
cross the x axis. Although non-linear, this can be overcome by mathematical
manipulation.
32 Section 2  Physical principles
The Seebeck effect
At the junction of two dissimilar metals, a voltage will be produced, the
magnitude of which will be in proportion to the temperature difference
between two such junctions.

Thermocouple
The thermocouple utilizes the Seebeck effect. Copper and constantan are the two
metals most commonly used and produce an essentially linear curve of voltage
against temperature. One of the junctions must either be kept at a constant
temperature or have its temperature measured separately (by using a sensitive
thermistor) so that the temperature at the sensing junction can be calculated
according to the potential produced. Each metal can be made into fine wires that
come into contact at their ends so that a very small device can be made.

This curve passes through the origin because if there is no temperature

difference between the junctions there is no potential generated. It rises as a
near linear curve over the range of commonly measured values. The output
voltage is small (0.04–0.06 mV. 8C1) and so signal amplification is often
needed.
 Humidity

The term humidity refers to the amount of water vapour present in the atmo-
sphere and is subdivided into two types:

Absolute humidity
3
The total mass of water vapour present in the air per unit volume (kg.m
or g.m 3).

Relative humidity
The ratio of the amount of water vapour in the air compared with the amount
that would be present at the same temperature if the air was fully saturated.
(RH, %)
or
The ratio of the vapour pressure of water in the air compared with the satu-
rated vapour pressure of water at that temperature (%).

Dew point
The temperature at which the relative humidity of the air exceeds 100% and
water condenses out of the vapour phase to form liquid (dew).

Hygrometer
An instrument used for measuring the humidity of a gas.

Hygroscopic material
One that attracts moisture from the atmosphere.

The main location of hygroscopic mediums is inside heat and moisture exchange
(HME) filters.
34 Section 2
Physical principles
Humidity graph
The humidity graph is attempting to demonstrate how a fixed amount of water
vapour in the atmosphere will lead to a variable relative humidity depending on
the prevailing temperature. It also highlights the importance of the
upper airways in a room fully humidifying by the addition of 27 g.m 3 of
water vapour. You will be expected to know the absolute humidity of air at
body temperature.

100 100% relative humidity

80
Absolute humidity (g.m–3)

60
50% relative humidity
44 g.m–3
40

20
17 g.m–3

0
0 10 20 30 40 50
Temperature (°C)

100% RH After drawing and labelling the axes, plot the key y values as
shown. The 100% line crosses the y axis at 8 g.m 3 and rises as a parabola
crossing the points shown. These points must be accurate.
50% RH This curve crosses each point on the x axis at a y value half that of
the 100% RH line. Air at 50% RH cannot contain 44 g.m 3 water until over
50 8C. The graph demonstrates that a fixed quantity of water vapour can
result in varying RH depending on the temperature concerned.
 Latent heat

Not all heat energy results in a temperature change. In order for a material
to change phase (solid, liquid, gas) some energy must be supplied to it to
enable its component atoms to alter their arrangement. This is the concept of
latent heat.

Latent heat
The heat energy that is required for a material to undergo a change of phase (J).

Specific latent heat of fusion

The amount of heat required, at a specified temperature, to convert a unit mass
of solid to liquid without temperature change (J.kg 1).

Specific latent heat of vaporization

The amount of heat energy required, at a specified temperature, to convert a
unit mass of liquid into the vapour without temperature change (J.kg 1).

Note that these same amounts of energy will be released into the surroundings
when the change of phase is in the reverse direction.

Heat capacity
The heat energy required to raise the temperature of a given object by one
degree (J.K 1 or J.8C 1).

Specific heat capacity

The heat energy required to raise the temperature of one kilogram of a sub-
stance by one degree (J.kg 1.K 1 or J.kg 1.8C 1).
36 Section 2
Physical principles
Specific heat capacity is a different concept to latent heat as it relates to an actual
temperature change.
There is an important graph associated with the concept of latent heat. It is
described as a heating curve and shows the temperature of a substance in relation
to time. A constant amount of heat is being supplied per unit time and the main
objective is to demonstrate the plateaus where phase change is occurring. At these
points, the substance does not change its temperature despite continuing to
absorb heat energy from the surroundings.

Heating curve for water

The curve crosses the y axis at a negative value of your choosing. Between the
plateaus, the slope is approximately linear. The plateaus are crucial as they are
the visual representation of the definition of latent heat. The first plateau is
at 0 8C and is short in duration as only 334 kJ.kg 1 is absorbed in this time
(specific latent heat of fusion). The next plateau is at 100 8C and is longer in
duration as 2260 kJ.kg 1 is absorbed (specific latent heat of vaporization).
 Isotherms

An isotherm is a line of constant temperature and it forms part of a diagram that

shows the relationship between temperature, pressure and volume. The graph is
gas specific and usually relates to nitrous oxide. Three lines are chosen to illustrate
the volume–pressure relationship above, at and below the critical temperature.

Nitrous oxide isotherm

Liquid and vapour Draw this outline on the diagram first in order that your
other lines will pass through it at the correct points.
20 8C From right to left, the line curves up initially and then becomes
horizontal as it crosses the ‘liquid/vapour’ curve. Once all vapour has
been liquidized, the line climbs almost vertically as liquid is incompressible,
leading to a rapid increase in pressure for a small decrease in volume.
36.5 8C The critical temperature line. This climbs from right to left as a
rectangular hyperbola with a small flattened section at its midpoint. This is
where a small amount of gas is liquidized. It climbs rapidly after this section
as before.
40 8C A true rectangular hyperbola representing Boyle’s law. The pressure
doubles as the volume halves. As it is above the critical temperature, it is a
gas and obeys the gas laws.
 Solubility and diffusion

Henry’s law
The amount of gas dissolved in a liquid is directly proportional to the partial
pressure of the gas in equilibrium with the liquid.

Graham’s law
The rate of diffusion of a gas is inversely proportional to the square root of its
molecular weight.
p
Rate / 1= MW

Fick’s law of diffusion

The rate of diffusion of a gas across a membrane is proportional to the
membrane area (A) and the concentration gradient (C1 – C2) across the
membrane and inversely proportional to its thickness (D).

A½C1  C2 
Rate of diffusion /
D

Blood : gas solubility coefficient

The ratio of the amount of substance present in equal volume phases of blood
and gas in a closed system at equilibrium and at standard temperature and
pressure.

Oil : gas solubility coefficient

The ratio of the amount of substance present in equal volume phases of oil
and gas in a closed system at equilibrium and at standard temperature and
pressure.

Bunsen solubility coefficient

The volume of gas, corrected to standard temperature and pressure,
that dissolves in one unit volume of liquid at the temperature con-
cerned where the partial pressure of the gas above the liquid is one
atmosphere.
 Solubility and diffusion 39

Ostwald solubility coefficient

The volume of gas that dissolves in one unit volume of liquid at the tempera-
ture concerned.

The Ostwald solubility coefficient is, therefore, independent of the partial

pressure.
 Osmosis and colligative properties

Osmole
One osmole is an amount of particles equal to Avogadro’s number
(6.02  1023).

Osmolarity
The amount of osmotically active particles present per litre of solution
(mmol.l 1).

Osmolality
The amount of osmotically active particles present per kilogram of solvent
(mmol.kg 1).

Osmotic pressure
The pressure exerted within a sealed system of solution in response to the
presence of osmotically active particles on one side of a semipermeable
membrane (kPa).

One osmole of solute exerts a pressure of 101.325 kPa when dissolved in 22.4 L of
solvent at 0 8C.

Colligative properties
Those properties of a solution which vary according to the osmolarity of the
solution. These are:

depression of freezing point. The freezing point of a solution is depressed by

1.86 8C per osmole of solute per kilogram of solvent
reduction of vapour pressure
elevation of boiling point
increase in osmotic pressure.

Raoult’s law
The depression of freezing point or reduction of the vapour pressure of a
solvent is proportional to the molar concentration of the solute.
 Osmosis and colligative properties 41

Osmometer
An osmometer is a device used for measuring the osmolality of a solution.
Solution is placed in the apparatus, which cools it rapidly to 0 8C and then
supercools it more slowly to 7 8C. This cooling is achieved by the Peltier effect
(absorption of heat at the junction of two dissimilar metals as a voltage is applied),
which is the reverse of the Seebeck effect. The solution remains a liquid until a
mechanical stimulus is applied, which initiates freezing. This is a peculiar pro-
perty of the supercooling process. The latent heat of fusion is released during the
phase change from liquid to solid so warming the solution until its natural
freezing point is attained.

Graph

20
Temperature (°C)

Time (s)
0 60

–7
–10 Freezing point

–20 Mechanical pulse

Plot a smooth curve falling rapidly from room temperature to 0 8C. After this
the curve flattens out until the temperature reaches 7 8C. Cooling is then
stopped and a mechanical stirrer induces a pulse. The curve rises quickly to
achieve a plateau temperature (freezing point).
 Resistors and resistance

Electrical resistance is a broad term given to the opposition of flow of current

within an electrical circuit. However, when considering components such as
capacitors or inductors, or when speaking about resistance to alternating current
(AC) flow, certain other terminology is used.

Resistance
The opposition to flow of direct current (ohms,
).

Reactance
The opposition to flow of alternating current (ohms,
).

Impedance
The total of the resistive and reactive components of opposition to electrical
flow (ohms,
).

All three of these terms have units of ohms as they are all measures of some form
of resistance to electrical flow. The reactance of an inductor is high and comes
specifically from the back electromotive force (EMF; p. 46) that is generated
within the coil. It is, therefore, difficult for AC to pass. The reactance of a capacitor
is relatively low but its resistance can be high; therefore, direct current (DC) does
not pass easily. Reactance does not usually exist by itself as each component in a
circuit will generate some resistance to electrical flow. The choice of terms to
define total resistance in a circuit is, therefore, resistance or impedance.

Ohm’s law
The strength of an electric current varies directly with the electromotive force
(voltage) and inversely with the resistance.

I ¼ V=R
or
V ¼ IR

where V is voltage, I is current and R is resistance.

The equation can be used to calculate any of the above values when the other
two are known. When R is calculated, it may represent resistance or impe-
dance depending on the type of circuit being used (AC/DC).
 Capacitors and capacitance

Capacitor
A device that stores electrical charge.

A capacitor consists of two conducting plates separated by a non-conducting

material called the dielectric.

Capacitance
The ability of a capacitor to store electrical charge (farads, F).

Farad
A capacitor with a capacitance of one farad will store one coulomb of charge
when one volt is applied to it.

F ¼ C=V

where F is farad (capacitance), C is coulomb (charge) and V is volt (potential

difference).

One farad is a large value and most capacitors will measure in micro- or picofarads

Principle of capacitors
Electrical current is the flow of electrons. When electrons flow onto a plate of a
capacitor it becomes negatively charged and this charge tends to drive electrons
off the adjacent plate through repulsive forces. When the first plate becomes full of
electrons, no further flow of current can occur and so current flow in the circuit
ceases. The rate of decay of current is exponential. Current can only continue to
flow if the polarity is reversed so that electrons are now attracted to the positive
plate and flow off the negative plate.
The important point is that capacitors will, therefore, allow the flow of AC in
preference to DC. Because there is less time for current to decay in a high-
frequency AC circuit before the polarity reverses, the mean current flow is greater.
The acronym CLiFF may help to remind you that capacitors act as low-frequency
filters in that they tend to oppose the flow of low frequency or DC.
Graphs show how capacitors alter current flow within a circuit. The points to
demonstrate are that DC decays rapidly to zero and that the mean current flow is
less in a low-frequency AC circuit than in a high-frequency one.
44 Section 2  Physical principles
Capacitor in DC circuit

Charge (C )

Current (I )

Time (t )

These curves would occur when current and charge were measured in a circuit
containing a capacitor at the moment when the switch was closed to allow the
flow of DC. Current undergoes an exponential decline, demonstrating that the
majority of current flow occurs through a capacitor when the current is
rapidly changing. The reverse is true of charge that undergoes exponential
build up.

Capacitor in low-frequency AC circuit

Mean
positive
Current (I )

current

Mean
negative
current

Time (t )

Base this curve on the previous diagram and imagine a slowly cycling AC
waveform in the circuit. When current flow is positive, the capacitor acts as it
did in the DC circuit. When the current flow reverses polarity the capacitor
generates a curve that is inverted in relation to the first. The mean current flow
is low as current dies away exponentially when passing through the capacitor.
 Capacitors and capacitance 45

Capacitor in high-frequency AC circuit

Mean
positive
current

Current (l )

Mean
negative
current
Time (t )

When the current in a circuit is alternating rapidly, there is less time for
exponential decay to occur before the polarity changes. This diagram should
demonstrate that the mean positive and negative current flows are greater in a
high-frequency AC circuit.
 Inductors and inductance

Inductor
An inductor is an electrical component that opposes changes in current flow by
the generation of an electromotive force.

An inductor consists of a coil of wire, which may or may not have a core of
ferromagnetic metal inside it. A metal core will increase its inductance.

Inductance
Inductance is the measure of the ability to generate a resistive electromotive
force under the influence of changing current (henry, H).

Henry
One henry is the inductance when one ampere flowing in the coil generates a
magnetic field strength of one weber.

H ¼ Wb=A

where H is henry (inductance), Wb is weber (magnetic field strength) and A is

ampere (current).

Electromotive force (EMF)

An analogous term to voltage when considering electrical circuits and compo-
nents (volts, E).

Principle of inductors
A current flowing through any conductor will generate a magnetic field around
the conductor. If any conductor is moved through a magnetic field, a current will
be generated within it. As current flow through an inductor coil changes, it
generates a changing magnetic field around the coil. This changing magnetic
field, in turn, induces a force that acts to oppose the original current flow. This
opposing force is known as the back EMF.
In contrast to a capacitor, an inductor will allow the passage of DC and low-
frequency AC much more freely than high-frequency AC. This is because the
amount of back EMF generated is proportional to the rate of change of the current
 Inductors and inductance 47

through the inductor. It, therefore, acts as a high-frequency filter in that it tends to
oppose the flow of high-frequency current through it.

Graphs
A graph of current flow versus time aims to show how an inductor affects current
flow in a circuit. It is difficult to draw a graph for an AC circuit, so a DC example is
often used. The key point is to demonstrate that the back EMF is always greatest
when there is greatest change in current flow and so the amount of current
successfully passing through the inductor at these points in time is minimal.
Current (I )

Back EMF

Time (t )

Current Draw a build-up exponential curve (solid line) to show how cur-
rent flows when an inductor is connected to a DC source. On connection,
the rate of change of current is great and so a high back EMF is produced.
What would have been an instantaneous ‘jump’ in current is blunted by
this effect. As the back EMF dies down, a steady state current flow is
reached.
Back EMF Draw an exponential decay curve (dotted) to show how back EMF
is highest when rate of change of current flow is highest. This explains how
inductors are used to filter out rapidly alternating current in clinical use.
 Defibrillators

Defibrillator circuit
You may be asked to draw a defibrillator circuit diagram in the examination in
order to demonstrate the principles of capacitors and inductors.

Charging

When charging the defibrillator, the switch is positioned so that the 5000 V
DC current flows only around the upper half of the circuit. It, therefore, causes
a charge to build up on the capacitor plates.

Discharging
 Defibrillators 49

When discharging, the upper and lower switches are both closed so that the
stored charge from the capacitor is now delivered to the patient. The inductor
acts to modify the current waveform delivered as described below.

Defibrillator discharge
The inductor is used in a defibrillation circuit to modify the discharge waveform
of the device so as to prolong the effective delivery of current to the myocardium.

Unmodified waveform
Current (I )

Time (t )

The unmodified curve shows exponential decay of current over time. This is
the waveform that would result if there were no inductors in the circuit.

Modified waveform
Current (I )

Time (t )

The modified waveform should show that the waveform is prolonged in

duration after passing through the inductor and that it adopts a smoother
profile.
 Resonance and damping

Both resonance and damping can cause some confusion and the explanations of
the underlying physics can become muddled in a viva situation. Although the
deeper mathematics of the topic are complex, a basic understanding of the
underlying principles is all the examiners will want to see.

Resonance
The condition in which an object or system is subjected to an oscillating force
having a frequency close to its own natural frequency.

Natural frequency
The frequency of oscillation that an object or system will adopt freely when set
in motion or supplied with energy (hertz, Hz).

We have all felt resonance when we hear the sound of a lorry’s engine begin to
make the window pane vibrate. The natural frequency of the window is having
energy supplied to it by the sound waves emanating from the lorry. The principle
is best represented diagrammatically.

The curve shows the amplitude of oscillation of an object or system as the

frequency of the input oscillation is steadily increased. Start by drawing a
normal sine wave whose wavelength decreases as the input frequency
increases. Demonstrate a particular frequency at which the amplitude rises
to a peak. By no means does this have to occur at a high frequency; it depends
on what the natural frequency of the system is. Label the peak amplitude
frequency as the resonant frequency. Make sure that, after the peak, the
amplitude dies away again towards the baseline.
 Resonance and damping 51

This subject is most commonly discussed in the context of invasive arterial

pressure monitoring.

Damping
A decrease in the amplitude of an oscillation as a result of energy loss from a
system owing to frictional or other resistive forces.

A degree of damping is desirable and necessary for accurate measurement, but too
much damping is problematic. The terminology should be considered in the context
of a measuring system that is attempting to respond to an instantaneous change in
the measured value. This is akin to the situation in which you suddenly stop flushing
an arterial line while watching the arterial trace on the theatre monitor.

Damping coefficient
A value between 0 (no damping) and 1 (critical damping) which quantifies the
level of damping present in a system.

Zero damping
A theoretical situation in which the system oscillates in response to a step
change in the input value and the amplitude of the oscillations does not
diminish with time; the damping coefficient is 0.

The step change in input value from positive down to baseline initiates a
change in the output reading. The system is un-damped because the output
value continues to oscillate around the baseline after the input value has
changed. The amplitude of these oscillations would remain constant, as
shown, if no energy was lost to the surroundings. This situation is, therefore,
theoretical as energy is inevitably lost, even in optimal conditions such as a
vacuum.
52 Section 2
Physical principles
Under-damped
The system is unable to prevent oscillations in response to a step change in the
input value. The damping coefficient is 0–0.3.

The step change in input value from positive to baseline initiates a change in
the output reading. The system is under-damped because the output value
continues to oscillate around the baseline for some time after the input value
has changed. It does eventually settle at the new value, showing that at least
some damping is occurring.

Over-damped
The system response is overly blunted in response to a step change in the input
value, leading to inaccuracy. The damping coefficient is > 1.

This time the curve falls extremely slowly towards the new value. Given enough
time, it will reach the baseline with no overshoot but clearly this type of response is
unsuitable for measurement of a rapidly changing variable such as blood pressure.
 Resonance and damping 53

Critical damping
That degree of damping which allows the most rapid attainment of a new
input value combined with no overshoot in the measured response. The
damping coefficient is 1.

The response is still blunted but any faster response would involve overshoot
of the baseline. Critical damping is still too much for a rapidly responding
measurement device.

Optimal damping
The most suitable combination of rapid response to change in the input value
with minimal overshoot. The damping coefficient is 0.64.

Draw this curve so that the response is fairly rapid with no more than two
oscillations around the baseline before attaining the new value. This is the level
of damping that is desirable in modern measuring systems.
 Pulse oximetry

There are a number of equations and definitions associated with the principles
behind the working of the pulse oximeter.

Beer’s law
The absorbance of light passing through a medium is proportional to the
concentration of the medium.
Absorbance

Slope = β L

Concentration (C )

Draw a line that passes through the origin and which rises steadily as C increases.
The slope of the line is dependent upon the molar extinction coefficient (),
which is a measure of how avidly the medium absorbs light, and by the path
length (L). Note that if emergent light (I) is plotted on the y axis instead of
absorbance, the curve should be drawn as an exponential decline.

Lambert’s law
The absorbance of light passing through a medium is proportional to the path
length.
Absorbance

Slope = β c

Path length (L)

 Pulse oximetry 55

The line is identical to that above except that in this instance the slope is
determined by both  and the concentration (C) of the medium. Again, if
emergent light (I) is plotted on the y axis instead of absorbance, the curve
should be plotted as an exponential decline.

Both laws are often presented together to give the following equation, known as
the Beer–Lambert law, which is a negative exponential equation of the form
y ¼ a.ekt

I ¼ I0 :eðLCÞ

or taking logarithms

logðI0 =IÞ ¼ LC

where I is emergent light, I0 is incident light, L is path length, C is concentration

and b is the molar extinction coefficient.

The relation log(I0/I) is known as the absorbance.

In the pulse oximeter, the concentration and molar extinction coefficient are
constant. The only variable becomes the path length, which alters as arterial blood
expands the vessels in a pulsatile fashion.

Haemoglobin absorption spectra

The pulse oximeter is a non-invasive device used to monitor the percentage
saturation of haemoglobin (Hb) with oxygen (SpO2). The underlying physical
principle that allows this calculation to take place is that infrared light is absorbed
to different degrees by the oxy and deoxy forms of Hb.
Two different wavelengths of light, one at 660 nm (red) and one at 940 nm
(infrared), are shone intermittently through the finger to a sensor. As the
vessels in the finger expand and contract with the pulse, they alter the amount
of light that is absorbed at each wavelength according to the Beer–Lambert law.
The pulsatile vessels, therefore, cause two waveforms to be produced by the
sensor.
If there is an excess of deoxy-Hb present, more red than infrared light will be
absorbed and the amplitude of the ‘red’ waveform will be smaller. Conversely, if
there is an excess of oxy-Hb, the amplitude of the ‘infrared’ waveform will be
smaller. It is the ratios of these amplitudes that allows the microprocessor to give
an estimate of the SpO2 by comparing the values with those from tables stored in
its memory.
In order to calculate the amount of oxy-Hb or deoxy-Hb present from the
amount of light absorbance, the absorbance spectra for these compounds must be
known.
56 Section 2  Physical principles
Haemoglobin absorption spectra

Red Infrared

Isobestic point

Absorbance Oxy-Hb
Deoxy-Hb

660 805 940

500 600 700 800 900 1000
Wavelength (nm)

Oxy-Hb Crosses the y axis near the deoxy-Hb line but falls steeply around
600 nm to a trough around 660 nm. It then rises as a smooth curve through
the isobestic point where it flattens out. This curve must be oxy-Hb as the
absorbance of red light is so low that most of it is able to pass through to the
viewer, which is why oxygenated blood appears red.
Deoxy-Hb Starts near the oxy-Hb line and falls as a relatively smooth curve
passing through the isobestic point only. Compared with oxy-Hb, it
absorbs a vast amount of red light and so appears ‘blue’ to the observer.
 Capnography

You will be expected to be familiar with capnography. The points to understand

are the shape and meaning of different capnograph traces and the nature of the
reaction taking place within the CO2 absorption canister.

Capnometer
The capnometer measures the partial pressure of CO2 in a gas and displays the
result in numerical form.

Capnograph
A capnograph measures the partial pressure of CO2 in a gas and displays the
result in graphical form.

A capnometer alone is unhelpful in clinical practice and most modern

machines present both a graphical and numerical representation of CO2 partial
pressure.

Normal capnograph

5
Pco2 (kPa)

0
0 1 2 3 4 5
Time (s)

Assume a respiratory rate of 12 min 1. From zero baseline, the curve initially
rises slowly owing to the exhalation of dead space gas. Subsequently, it rises
steeply during expiration to a normal value and reaches a near horizontal
plateau after approximately 3 s. The value just prior to inspiration is the end-
tidal CO2 (PETCO2) . Inspiration causes a near vertical decline in the curve to
baseline and lasts around 2 s.
58 Section 2
Physical principles
Rebreathing

Pco2 (kPa)

0
0 1 2 3 4 5
Time (s)

The main difference when compared rebreathing with the normal trace is that
the baseline is not zero. Consequently the PETCO2 may rise. If the patient is
spontaneously breathing, the respiratory rate may increase as they attempt to
compensate for the higher PETCO2.

Inadequate paralysis

5
Pco2 (kPa)

0
0 1 2 3 4 5
Time (s)

The bulk of the curve appears identical to the normal curve. However, during
the plateau phase, a large cleft is seen as the patient makes a transient
respiratory effort and draws fresh gas over the sensor.
 Capnography 59

Cardiac oscillations

Pco2 (kPa)

0
0 1 2 3 4 5
Time (s)

Usually seen when the respiratory rate is slow. The curve starts as normal
but the expiratory pause is prolonged owing to the slow rate. Fresh gas
within the circuit is able to pass over the sensor causing the PCO2 to fall.
During this time, the mechanical pulsations induced by the heart force
small quantities of alveolar gas out of the lungs and over the sensor, causing
transient spikes. Inspiration in the above example does not occur until
point A.

Hyperventilation

5
Pco2 (kPa)

0
0 2 4 6 8
Time (s)

In this example, the respiratory rate has increased so that each respiratory
cycle only takes 3 s. As a consequence the PETCO2 has fallen to approx
2.5 kPa.
60 Section 2
Physical principles
Malignant hyperpyrexia

10

Pco2 (kPa)
5

0
0 5 10 15 20
Time (s)

Rarely seen. The PETCO2 rises rapidly such that there may be a noticeable
increase from breath to breath. The excess CO2 is generated from the increased
skeletal muscle activity and metabolic rate, which is a feature of the condition.

Acute loss of cardiac output

5
Pco2 (kPa)

0
0 2 4 6 8 10 12
Time (s)

The PETCO2 falls rapidly over the course of a few breaths. With hyperventila-
tion, the fall would be slower. Any condition that acutely reduces cardiac
output may be the cause, including cardiac arrest, pulmonary embolism or
acute rhythm disturbances. If the PCO2 falls instantly to zero, then the cause is
disconnection, auto-calibration or equipment error.

Breathing system disconnection

5
Pco2 (kPa)

0
0 3 6 9 12 15 18
Time (s)
 Capnography 61

Following a normal trace, there is the absence of any further rise in PCO2. You
should ensure that your x axis is long enough to demonstrate that this is not
simply a result of a slow respiratory rate.

Obstructive disease

5
Pco2 (kPa)

0
0 1 2 3 4 5
Time (s)

Instead of the normal sharp upstroke, the curve should be drawn slurred. This
occurs because lung units tend to empty slowly in obstructive airways disease.
In addition, the PETCO2 may be raised as a feature of the underlying disease.

Hypoventilation

10
Pco2 (kPa)

0
0 3 6 9 12
Time (s)

The respiratory rate is reduced such that each complete respiratory cycle takes
longer. This is usually a result of a prolonged expiratory phase, so it is the
plateau that you should demonstrate to be extended. The PETCO2 will be raised
as a consequence.
 Absorption of carbon dioxide

Carbon dioxide is absorbed in most anaesthetic breathing systems by means of a

canister that contains a specific absorbing medium. This is often soda lime but
may also be baralime in some hospitals.
Soda lime:
4% sodium hydroxide NaOH
15% bound water H2O
81% calcium hydroxide Ca(OH)2
Baralime:
20% barium hydroxide octahydrate Ba(OH)2.8H2O
80% calcium hydroxide Ca(OH)2

Mesh size
The smaller the granules, the larger the surface area for CO2 absorption. However,
if the granules are too small then there will be too little space between them and
the resistance to gas flow through the canister will be too high. As a compromise, a
4/8 mesh describes the situation where each granule should be able to pass
through a sieve with four openings per inch but not through one with eight
openings per inch.

Chemical reaction
You may be asked to describe the chemical reaction that occurs when CO2 is
absorbed within the canister. The most commonly cited reaction is that between
soda lime and CO2:

CO2 þ H2O ! H2CO3

2NaOH þ H2CO3 ! Na2CO3 þ 2H2O þ heat
Na2CO3 þ Ca(OH)2 ! CaCO3 þ 2NaOH þ heat

Heat is produced at two stages and water at one. This can be seen and felt in
clinical practice. Note that NaOH is reformed in the final stage and so acts only as
a catalyst for the reaction. The compound that is actually consumed in both
baralime and soda lime is Ca(OH)2.
 Absorption of carbon dioxide 63

Colour indicators

Compound Colour change

Ethyl violet White to purple

Clayton yellow Pink to cream
Titan yellow Pink to cream
Mimosa Z Red to white
Phenolphthalein Red to white
 Cardiac output measurement

The Fick principle

The total uptake or release of a substance by an organ is equal to the product
of the blood flow to the organ and the arterio-venous concentration difference
of the substance.

This observation is used to calculate cardiac output by using a suitable marker

substance such as oxygen, heat or dye and the following equation:

V̇o2 ¼ CO ðCao2  C v̄o2 Þ

so

CO ¼ V̇o2 =ðCao2  C v̄o2 Þ

where V̇O2 is the oxygen uptake, CO is cardiac output, CaO2 is arterial O2

content and C v̄O2 is mixed venous O2 content.

Thermodilution and dye dilution

A marker substance is injected into a central vein. A peripheral arterial line is used
to measure the amount of the substance in the arterial system. A graph of
concentration versus time is produced and patented algorithms based on the
Stewart–Hamilton equation (below) are used to calculate the cardiac output.
When dye dilution is used, the graph of concentration versus time may show a
second peak as dye recirculates to the measuring device. This is known as a
recirculation hump and does not occur when thermodilution methods are used.

Stewart–Hamilton equation
If the mass of marker is known and its concentration is measured, the volume
into which it was given can be calculated as

V ¼ M=C

If concentration is measured over time, flow can be calculated as

Flow ¼ M=ðC:DtÞ

where M is mass, V is volume and C is concentration. A special form of the

equation used with thermodilution is
 Cardiac output measurement 65

V inj ðTb  Tt Þ:K

Flow ¼
Tblood ðtÞt

where the numerator represents the ‘mass’ of cold and the denominator
represents the change in blood temperature over time; K represents computer
constants.

Dye dilution graphs

Concentration

0 5 10 15 20
Time (s)

Draw a curve starting at the origin that reaches its maximum value at around
5 s. The curve then falls to baseline but is interrupted by a recirculation hump
at around 15 s. This is caused by dye passing completely around the vascu-
lature and back to the sensor a second time.
Log10 concentration

AUC

0 5 10 15 20
Time (s)

Demonstrate that the semi-log plot makes the curve more linear during its rise
and fall from baseline. The recirculation hump is still present but is discounted
by measuring the area under the curve (AUC) enclosed by a tangent from the
initial down stroke. This is the AUC that is used in the calculations.
66 Section 2  Physical principles
Thermodilution graphs
The actual graph of temperature versus time for the thermodilution method
would resemble the one below.

Demonstrate that the thermodilution curve has no recirculation hump when

compared with the dye dilution method. Otherwise the line should be drawn
in a similar fashion.

For reasons of clarity, the graph is usually presented with temperature decrease
on the y axis so that the deflection becomes positive.
 Cardiac output measurement 67

Thermodilution graphs

The semi-log transformation again makes the rise and fall of the graph linear.
Note that this time there is no recirculation hump. As the fall on the initial plot
was exponential, so the curve is transformed to a linear fall by plotting it as a
semi-log. The AUC is still used in the calculations of cardiac output.
 The Doppler effect

The Doppler effect is used in practice to visualize directional blood flow on

ultrasound, to estimate cardiac output and in some types of flow meter.

Doppler effect
The phenomenon by which the frequency of transmitted sound is altered as it
is reflected from a moving object. It is represented by the following equation:

DF:c
V¼
2F0 :cos

where V is velocity of object, DF is frequency shift, c is speed of sound in blood,

F0 is frequency of emitted sound and  is the angle between sound and object.

Principle
Sound waves are emitted from the probe (P) at a frequency F0. They are reflected off
moving red blood cells and back towards the probe at a new frequency, FR. The phase
shift can now be determined by FR – F0. The angle of incidence () is shown on the
diagram . If a measurement or estimate of the cross-sectional area of the blood vessel
is known, flow can be derived as area multiplied by velocity (m2.m.s1 ¼ m3.s1).
This is the principle behind oesophageal Doppler cardiac output monitoring.

P
Skin
F0
FR

Area
Velocity (m2)
(m.s–1)

It is also possible to calculate the pressure gradients across heart valves using the
Doppler principle to measure the blood velocity and entering the result into the
Bernoulli equation.

Bernoulli equation

DP ¼ 4v 2

where DP is the pressure gradient and v is the velocity of blood.

 Neuromuscular blockade monitoring

This topic tests your knowledge of the physics and physiology behind the use of
neuromuscular blocking drugs (NMBDs). You will benefit from a clear idea in your
mind about what each type of nerve stimulation pattern is attempting to demonstrate.

Single twitch
A single, supra-maximal stimulus is applied prior to neuromuscular blockade
as a control. The diminution in twitch height and disappearance of the twitch
correlates crudely with depth of neuromuscular block.

Supra-maximal stimulus
An electrical stimulus of sufficient current magnitude to depolarize all nerve
fibres within a given nerve bundle. Commonly quoted as > 60 mA for transcu-
taneous nerve stimulation.

Train of four

0.2 ms
60
Current (mA)

30

0
0 500 1000 1500
Time (ms)

Notice that you are being asked to describe the output waveform of the nerve
stimulator. The axes must, therefore, be time and current as shown. Each
stimulus is a square wave of supra-maximal current delivered for 0.2 ms. The
train of four (TOF) is delivered at 2 Hz so there is one stimulus every 500 ms.
This means that if the TOF starts at time 0, the complete train takes 1500 ms.

Tetanic stimulus
A supra-maximal stimulus applied as a series of square waves of 0.2 ms
duration at a frequency of 50 Hz for a duration of 5 s is tetanic stimulation.
70 Section 2
Physical principles
Depolarizing block train of four

100
5s

Response (%)
1.5 s

50

0
0 5 10 15
Time (s)

Notice now that you are being asked to describe the response to a TOF
stimulus. The axes are, therefore, changed to show time and percentage
response as shown. It is important to realize that each twitch is still being
delivered at the same current even though the response seen may be reduced.
Partial depolarizing neuromuscular block causes an equal decrease in the
percentage response to all four stimuli in the TOF. After a period of tetany
that does not cause 100% response, there is no increase in the height of
subsequent twitches.

Non-depolarizing block train of four

100 5s 1.5 s
Response (%)

50

0
0 5 10 15
Time (s)

Initial TOF should demonstrate each successive twitch decreasing in ampli-

tude: this is fade. The tetanic stimulus should fail to reach 100% response and
should also demonstrate fade. The second TOF should still demonstrate fade
but the twitches as a group should have increased amplitude. This is post-
tetanic potentiation.
 Neuromuscular blockade monitoring 71

Train of four ratio

The ratio of the amplitudes of the fourth to the first twitches of a TOF stimulus is
known as the TOF ratio (TOFR); it is usually given as a percentage T4:T1.

The TOFR is used for assessing suitability for and adequacy of reversal. Three
twitches should be present before a reversal agent is administered and the TOFR
after reversal should be > 90% to ensure adequacy.

Draw four twitches at 0.5 s intervals with each being lesser in amplitude than
its predecessor. In the example, the TOFR is 20% as T4 gives 20% of the
response of T1. Explain that this patient would be suitable for reversal as all
four twitches are present. However, had this trace been elicited after the
administration of a reversal agent, the pattern would represent an inadequate
level of reversal for extubation (TOFR < 90%).

Assessment of receptor site occupancy

Twitches seen Percentage receptor sites blocked

All present < 70

1 twitch lost > 70
2 twitches lost > 80
3 twitches lost > 90
All lost 95–100

Double-burst stimulation
Two bursts of three stimuli at 50 Hz, each burst being separated by 750 ms.

In double-burst stimulation, the ratio of the second to the first twitch is assessed. There
are the same requirements for adequacy of reversal as TOFR ( >90%); however,
having only two visible twitches makes assessment of the ratio easier for the observer.
72 Section 2
Physical principles
No neuromuscular block

750 ms
100

Response (%)
50

0
0 500 1000
Time (m)

Demonstrate two clusters of three stimuli (duration 0.2 ms, frequency 50 Hz)
separated by a 750 ms interval. The heights of both clusters are identical. If
questioned, the current should be greater than 60 mA for the same reasons as
when using the TOF.

Residual neuromuscular block

750 ms
100
Response (%)

70

50

0
0 500 1000
Time (ms)

Demonstrate the two clusters with the same time separation. In the presence of
a neuromuscular blocking agent, the second cluster will have a lesser ampli-
tude than the first (70% is shown).
 Neuromuscular blockade monitoring 73

Post-tetanic count
A post-tetanic count is used predominantly where neuromuscular blockade is so
deep that there are no visible twitches on TOF. The post-tetanic twitch count can
help to estimate the likely time to recovery of the TOF twitches in these situations.
The meaning of the count is drug specific.

Draw a 5 s period of tetany followed by a 3 s pause. Note that the tetanic

stimulus fails to reach 100% response as this test is being used in cases of
profound muscle relaxation. Next draw single standard twitches at a frequency
of 1 Hz: 20 stimuli are given in total. Using atracurium, a single twitch on the
TOF should appear in approximately 4 min if there are four post-tetanic
twitches evident.

Phase 1 and phase 2 block

Phase 1 Phase 2

Cause Single dose of depolarizing Repeated doses of depolarizing

muscle relaxant muscle relaxant
Nature of block Partial depolarizing Partial non-depolarizing
Single twitch Decreased Decreased
T4:T1 > 0.7 < 0.7
1 Hz twitch Sustained Fade
Post-tetanic potentiation No Yes
Effect of anticholinesterases Block augmented Block antagonized
 Surgical diathermy

The principle behind the use of surgical diathermy is that of current density.
When a current is applied over a small area, the current density is high and heating
may occur. If the same current is applied over a suitably large area then the current
density is low and no heating occurs. For unipolar diathermy, the apparatus
utilizes a small surface area at the instrument end and a large area on the
diathermy plate to allow current to flow but to confine heating to the instrument
alone. Bipolar diathermy does not utilize a plate as current flows directly between
two points on the instrument.

Frequency
The safety of diathermy is enhanced by the use of high frequency (1 MHz) current,
as explained by the graph below.

Note that the x axis is logarithmic to allow a wide range of frequencies to be

shown. The y axis is the current threshold at which adverse physiological
events (dysrhythmias etc.) may occur. The highest risk of an adverse event
occurs at current frequencies of around 50 Hz, which is the UK mains fre-
quency. At diathermy frequencies, the threshold for an adverse event is
massively raised.
 Surgical diathermy 75

Cutting diathermy
This type of diathermy is used to cut tissues and is high energy. It differs from
coagulation diathermy by its waveform.
+
Activation

Current flow

–
Time

When activated, the instrument delivers a sustained high-frequency AC wave-

form. Current density is high at the implement and local heating causes tissue
destruction. The sine wave continues until the switch is released.

Coagulation diathermy

+
Activation
Current flow

–
Time

When activated, the instrument delivers bursts of high-frequency AC inter-

rupted by periods of no current flow. Local tissue heating still occurs but is not
sustained and, therefore, causes less destruction than cutting diathermy.
 Cleaning, disinfection and sterilization

Maintaining cleanliness and sterility is involved in everyday practice but, for the
most part, is not under the direct control of anaesthetists. Nevertheless, a famil-
iarity will be expected with the main definitions and methods of achieving
adequate cleanliness.

Cleaning
The process of physically removing foreign material from an object without
necessarily destroying any infective material.

Disinfection
The process of rendering an object free from all pathogenic organisms except
bacterial spores.

Sterilization
The process of rendering an object completely free of all viable infectious
agents including bacterial spores.

Decontamination
The process of removing contaminants such that they are unable to reach a site
in sufficient quantities to initiate an infection or other harmful reaction.

The process of decontamination always starts with cleaning and is followed by

either disinfection or sterilization.
 Cleaning, disinfection and sterilization 77

Methods

Technique Process

Cleaning Manual Washing

Automated Ultrasonic bath
Automated Low-temperature steam
Disinfection Chemical Gluteraldehyde 2%
Chemical Alcohol 60–80%
Chemical Chlorhexidine 0.5–5%
Chemical Hydrogen peroxide
Heat Pasteurization
Sterilization Chemical Ethylene oxide
Chemical Gluteraldehyde 2%
Heat Autoclave
Radiation Gamma irradiation
Other Gas plasma
 Section 3 * Pharmacological principles

The Meyer–Overton hypothesis

The Meyer–Overton hypothesis is the theory of anaesthetic action which

proposes that the potency of an anaesthetic agent is related to its lipid
solubility.

Potency is described by the minimum alveolar concentration (MAC) of an agent

and lipid solubility by the oil:gas solubility coefficient.

Minimum alveolar concentration

The minimum alveolar concentration of an anaesthetic vapour at equilibrium
is the concentration required to prevent movement to a standardized surg-
ical stimulus in 50% of unpremedicated subjects studied at sea level
(1 atmosphere).

The Meyer–Overton hypothesis proposed that once a sufficient number of anaes-

thetic molecules were dissolved in the lipid membranes of cells within the central
nervous system, anaesthesia would result by a mechanism of membrane disrup-
tion. While an interesting observation, there are several exceptions to the rule that
make it insufficient to account fully for the mechanism of anaesthesia.

Meyer–Overton graph of potency versus lipid solubility

100 Nitrous oxide

Xenon
Log10 MAC

10
Desflurane
Sevoflurane Enflurane
1
Isoflurane
Halothane
0.1

1 10 100 1000
Log10 oil:gas partition coefficient
 The Meyer–Overton hypothesis 79

After drawing and labelling the axis (note the slightly different scales), draw a
straight line with a negative gradient as shown. Make sure you can draw in the
position of the commonly used inhalational agents. Note that the line does not
pass directly through the points but is a line of best fit, and also that although
isoflurane and enflurane have near identical oil:gas partition coefficients they
have different MAC values and, therefore, this relationship is not perfect.
 The concentration and second gas effects

The concentration effect

The phenomenon by which the rise in the alveolar partial pressure of
nitrous oxide is disproportionately rapid when it is administered in high
concentrations.

Nitrous oxide (N2O), although relatively insoluble, is 20 times more soluble in the
blood than nitrogen (N2). The outward diffusion of N2O from the alveolus into
the blood is therefore much faster than the inward diffusion of N2 from the blood
into the alveolus. Consequently, the alveolus shrinks in volume and the remaining
N2O is concentrated within it. This smaller volume has a secondary effect of
increasing alveolar ventilation by drawing more gas into the alveolus from the
airways in order to replenish the reduced volume.

Graphical demonstration
The above concept can be described graphically by considering the fractional
concentration of an agent in the alveolar gas (FA) as a percentage of its fractional
concentration in the inhaled gas (FI) over time.

1.0 Nitrous oxide

Desflurane
Sevoflurane
Isoflurane
FA/FI ratio

0.5 Halothane

0
Time (min)

After drawing and labelling the axis draw a series of build-up negative expo-
nential curves with different gradients as shown. The order of the curves is
according to the blood:gas partition coefficients. The more insoluble the
agent, the steeper the curve and the faster the rate of onset. The exceptions
to this are the N2O and desflurane curves, which are the opposite way round.
This is because of the concentration effect when N2O is administered at
 The concentration and second gas effects 81

high flows and is the graphical representation of the word ‘disproportionately’

in the definition. You may be asked what would happen as time progressed
and you should indicate that the lines eventually form a plateau at an FA/FI
ratio of 1.0.

The second gas effect

The phenomenon by which the speed of onset of inhalational anaesthetic
agents is increased when they are administered with N2O as a carrier gas.

This occurs as a result of the concentration effect and so it is always useful to

describe the concentration effect first, even if being questioned directly on the
second gas effect. If there is another gas present in the alveolus, then it too will be
concentrated by the relatively rapid uptake of N2O into the blood.
 Isomerism

Isomerism is a subject which can easily become confusing due to the myriad of
definitions and nomenclature it involves. Remembering a schematic diagram such
as the one below often helps to focus the mind as to where each type of isomer fits.

Isomerism
The phenomenon by which molecules with the same atomic formulae have
different structural arrangements.

Isomers are important because the three-dimensional structure of a drug may

determine its effects.

Structural isomerism
Identical chemical formulae but different order of atomic bonds.

Tautomerism
The dynamic interchange between two different forms of a molecular structure
depending on the environmental conditions.

Stereoisomerism
Identical chemical formulae and bond structure but different three-dimensional
configuration.

Enantiomers
Compounds that have a single chiral centre and form non-superimposable
mirror images of each other.
 Isomerism 83

Diastereoisomers
Compounds containing more than one chiral centre or which are subject
to geometric isomerism and, therefore, have more than just two mirror
image forms.

Geometric isomerism
Two dissimilar groups attached to two atoms that are in turn linked by a double
bond or ring creates geometric isomerism because of the reduced mobility of
the double bond or ring.

Chiral centre
A central atom bound to four dissimilar groups.

Chiral centres encountered in anaesthetics usually have carbon or quaternary

nitrogen as the chiral centre. Any compound which contains more than one chiral
centre is termed a diastereoisomer by definition.

Optical isomerism
Differentiation of compounds by their ability to rotate polarized lights in
different directions.

Dextro- and laevorotatory

Compounds can be labelled according to the direction in which a molecule
of the substance will rotate polarized light. Abbreviated to either d- and l-
or þ and .

D- and L-prefixes
The use of D- and L-prefixes is a nomenclature for orientation of atomic
structure of sugar and amino acid molecules. It is a structural definition and
is not related to the optical properties.
84 Section 3  Pharmacological principles
Rectus and sinister
Molecules at a chiral centre can be labelled according to the direction in which
groups of increasing molecular weight are organized around the centre: rectus
and sinister, abbreviated to R and S, depending on whether the direction of
increment is clockwise or anti-clockwise, respectively.

In the diagram, the chiral centre is shaded and attached to four groups of different
molecular weights. The smallest group (G1) is then orientated away from the
observer and the remaining groups are assessed. If the groups increase in mass in a
clockwise direction as in the figure, the compound is labelled R- and vice versa.

Racemic mixture
A mixture of two different enantiomers in equal proportions.

Enantiopure
A preparation with only a single enantiomer present.
 Enzyme kinetics

Enzyme
A biological catalyst that increases the speed of a chemical reaction without
being consumed in the reaction itself.

The rate of a chemical reaction, therefore, depends on the concentration of the

substrates and the presence of the catalysing enzyme.

First-order reaction
A reaction whose rate depends upon the concentration of the reacting com-
ponents. This is an exponential process.

Zero-order reaction
A reaction whose rate is independent of the concentration of reacting compo-
nents and is, therefore, constant.

A first-order reaction may become zero order when the enzyme system is saturated.

The Michaelis–Menten equation

Michaelis–Menten equation predicts the rate of a biological reaction according
to the concentration of substrate and the specific enzyme characteristics:

Vmax ½S
V¼
Km þ ½S

where V is the velocity of reaction, Vmax is the maximum velocity of reaction, Km

is the Michaelis constant and [S] is the concentration of substrate.

The value of Km is the substrate concentration at which V ¼ ½Vmax and is specific

to the particular reaction in question. It is the equivalent of the ED50 seen in
dose–response curves. This equation has a number of important features.
If [S] is very low, the equation approximates to

Vmax ½S
V
Km

as the þ [S] term becomes negligible. This means that V is proportional to [S] by
a constant of Vmax/Km. In other words the reaction is first order.
86 Section 3  Pharmacological principles
If [S] is very high the equation approximates to

V  Vmax

and the reaction becomes zero order, as V is now independent of [S].

Michaelis–Menten graph

Vmax
Velocity of reaction (V )

½Vmax

0
Km
Substrate concentration [s]

The shape of the curve is an inverted rectangular hyperbola approaching Vmax.

Ensure you mark Km on the curve at the correct point. The portion of the
curve below Km on the x axis is where the reaction follows first-order kinetics,
as shown by a fairly linear rise in the curve with increasing [S]. The portion of
the curve to the far right is where the reaction will follow zero-order kinetics,
as shown by the almost horizontal gradient. The portion in between these two
extremes demonstrates a mixture of properties.

Lineweaver–Burke transformation
To make it easier to measure Km mathematically a Lineweaver–Burke transforma-
tion can be performed by taking reciprocals of both sides of the initial equation.

1 K m þ ½S
¼
V V max ½S

This can be rearranged to give

1 Km 1
¼ þ
V V max ½S V max

or
 Enzyme kinetics 87
 
1 Km 1 1
¼ : þ
V Vmax ½S Vmax

The equation may appear complex but is simply a version of the linear
equation

y ¼ ðaxÞ þ b

where y is 1/V, a is Km/Vmax, x is 1/[S] and b is 1/Vmax.

Lineweaver–Burke graph

1/V

Km/Vmax

1/Vmax

1/Km 0 1/[S]

It may help to write the equation down first to remind yourself which func-
tions go where. The simple point of this diagram is that it linearizes the
Michaelis–Menten graph and so makes calculation of Vmax and Km much
easier as they can be found simply by noting the points where the line crosses
the y and x axes, respectively, and then taking the inverse value.
 Drug interactions

Summation
The actions of two drugs are additive but each has an independent action of
its own.

Potentiation
The action of one drug is amplified by the addition of another, which has no
independent action of its own.

Synergism
The combined action of two drugs is greater than would be expected from a
purely additive effect.

Isobologram
The isobologram shows the amount of drug B that is needed in the face of
increasing amounts of drug A in order that the end effect remains constant.

A, additive Draw the axes as shown and a linear relationship labelled A. This
represents an additive effect of drug A and drug B such that less of drug B is
needed as the dose of drug A is increased.
B, inhibitory Draw an upwardly convex curve labelled B which begins and
terminates at the same points as line A. This represents inhibition because
now, at any given dose of drug A, more of drug B needs to be given to
maintain a constant effect compared with an additive relationship.
C, synergistic Finally draw a downwardly convex curve labelled C. This
represents synergy in that less of drug B is required at any point compared
with what would be seen with an additive relationship.
 Adverse drug reactions

Although not often tested in depth, a knowledge of the terminology used

to describe adverse drug reactions is useful. True anaphylactic and anaphylac-
toid reactions clearly require a more detailed knowledge. The official World
Health Organization (WHO) definition of an adverse drug reaction is lengthy
and unlikely to be tested. A more succinct definition is used in relation to
anaesthesia.

Adverse drug reaction

The occurrence of any drug effect that is not of therapeutic, diagnostic or
prophylactic benefit to the patient.

Types of adverse reactions

The WHO definition encompasses six groups, which need not be memorized but
which are included for completeness.
Group 1 Dose-related reactions
Group 2 Non-dose-related reactions
Group 3 Dose- and time-related reactions
Group 4 Time-related reactions
Group 5 Withdrawal reactions
Group 6 Treatment failure.
The reactions can be more simply defined as one of two types:
Type A
 dose dependent
 common
 extension of known pharmacological effect.

Type B
 dose independent
 uncommon
 symptoms and signs of drug allergy.

The most important type to the anaesthetist is type B, which encompasses both
anaphylactic and anaphylactoid reactions.
90 Section 3
Pharmacological principles
Anaphylactic reaction
A response to a substance to which an individual has been previously sensi-
tized via the formation of a specific IgE antibody. It is characterized by the
release of vasoactive substances and the presence of systemic symptoms.

Anaphylactoid reactions
A response to a substance that is not mediated by a specific IgE antibody but is
characterized by the same release of vasoactive substances and presence of
systemic symptoms as an anaphylactic reaction.
 Section 4 * Pharmacodynamics

Drug–receptor interaction

A basic understanding of the interaction between drugs and receptors underlies

much of what is covered in the examinations.

Ligand
A ligand is a chemical messenger able to bind to a receptor. May be endogen-
ous or exogenous (drugs).

Receptor
A receptor is a component of a cell that interacts selectively with a compound
to initiate the biochemical change or cascade that produces the effects of the
compound:

D þ R $ DR

where D is drug, R is receptor and DR is drug–receptor complex.

It is assumed that the magnitude of the response is proportional to the concen-

tration of DR (i.e. [DR]).

Law of mass action

The rate of a reaction is proportional to the concentration of the reacting
components.

Kf
½D þ ½R $ ½DR
Kb

where Kf is the rate of forward reaction and Kb is the rate of backward reaction.

At equilibrium, the rates of the forward and back reactions will be the same and
the equation can be rearranged

K f ½D½R ¼ K b ½DR
92 Section 4  Pharmacodynamics
The affinity constant
The affinity constant, measured in l/mmol, has the symbol KA where

K A ¼ K f =K b

and it reflects the strength of drug–receptor binding

The dissociation constant

The dissociation constant, measured in mmol/l, has the symbol KD where

KD ¼ Kb =Kf

and it reflects the tendency for the drug–receptor complex to split into its
component drug and receptor.

Often, KD is described differently given that the law of mass action states that, at
equilibrium

K f ½D½R ¼ K b ½DR

or

K b =K f ¼ ½D½R=½DR

so

½D½R
KD ¼
½DR

If a drug has a high affinity, the DR form will be favoured at equilibrium, hence
the value of [D][R] will be small and that of [DR] will be high. Therefore, the
value of KD will be small. The opposite is true for a drug with low affinity, where
the D and R forms will be favoured at equilibrium.
Another way of looking at KD is to see what occurs when a drug occupies exactly
50% of receptors at equilibrium. In this case, the number of free receptors [R]
will equal that of occupied receptors [DR] and so cancel each other out of the
equation above, leaving

K D ¼ ½D

In other words

KD is the molar concentration of a drug at which 50% of its receptors are

occupied at equilibrium (mmol.l1).

Classical receptor theory suggests that the response seen will be proportional to
the percentage of receptors occupied, although this is not always the case.
 Affinity, efficacy and potency

Affinity
A measure of how avidly a drug binds to a receptor.

In the laboratory, affinity can be measured as the concentration of a drug

that occupies 50% of the available receptors, as suggested by the definition
of KD.

100
receptors occupied
Percentage of

50

KD
0
Drug concentration (mmol.l–1)

The curve should be drawn as a rectangular hyperbola passing through the

origin. KD is shown and in this situation is a marker of affinity (see text). In
practice, drug potency is of more interest, which encompasses both affinity
and intrinsic activity. To compare potencies of drugs, the EC50 and ED50
values (see below) are used.

Efficacy (intrinsic activity)

A measure of the magnitude of the effect once the drug is bound.

Potency
A measure of the quantity of the drug needed to produce maximal effect.

Potency is compared using the median effective concentration (EC50) or median

effective dose (ED50), the meanings of which are subtly different.
94 Section 4
Pharmacodynamics
Median effective concentration (EC50)
The concentration of a drug that induces a specified response exactly half way
between baseline and maximum.

This is the measure used in a test where concentration or dose is plotted on the x
axis and the percentage of maximum response is plotted on the y axis. It is a
laboratory result of a test performed under a single set of circumstances or on a
single animal model.

Median effective dose (ED50)

The dose of drug that induces a specified response in 50% of the population to
whom it is administered.

This is the measure of potency used when a drug is administered to a population

of test subjects. This time the 50% figure refers to the percentage of the popula-
tion responding rather that a percentage of maximal response in a particular
individual.
A drug with a lower EC50 or ED50 will have a higher potency, as it suggests that a
lower dose of the drug is needed to produce the desired effect. In practice, the
terms are used interchangeably and, of the two, the ED50 is the most usual
terminology. You are unlikely to get chastised for putting ED50 where the correct
term should technically be EC50.

Dose–response curves

100
maximum response
Percentage of

50

EC50
0
Drug concentration (mg.ml–1)

The curve is identical to the first but the axes are labelled differently with
percentage of maximum response on the y axis. This graph will have been
produced from a functional assay in the laboratory on a single subject and
is concerned with drug potency. Demonstrate that the EC50 is as shown.
 Affinity, efficacy and potency 95

Quantal dose–response curves

100

population responding
Percentage of
50

ED50
0
Dose (mg)

The curve is again identical in shape but this time a population has been
studied and the frequency of response recorded at various drug doses. It is,
therefore, known as a quantal dose–response curve. The marker of potency is
now the ED50 and the y axis should be correctly labelled as shown. This is the
‘typical’ dose–response curve that is tested in the examination.

Log dose–response curve

100
population responding
Percentage of

50

ED50
0
Log10 dose

The curve is sigmoid as the x axis is now logarithmic. Ensure the middle third
of the curve is linear and demonstrate the ED50 as shown. Make this your
reference curve for a full agonist and use it to compare with other drugs as
described below.
96 Section 4
Pharmacodynamics
Median lethal dose (LD50)
The dose of drug that is lethal in 50% of the population to whom it is
administered.

Therapeutic index
The therapeutic index of a drug reflects the balance between its useful effects
and its toxic effects. It is often defined as

LD50 =ED50

100
population responding
Percentage of

50

ED50 LD50
0
ED95
Log10 dose

Both curves are sigmoid as before, The curve on the left represents a normal
dosing regimen aiming to achieve the desired effect. Label the ED50 on it as
before. The curve to the right represents a higher dosing regimen at which
fatalities begin to occur in the test population. The LD50 should be at its
midpoint. The ED95 is also marked on this graph; this is the point at which
95% of the population will have shown the desired response to dosing.
However, note that by this stage some fatalities have already started to occur
and the curves overlap. You can draw the curves more widely separated if you
wish to avoid this but it is useful to demonstrate that a dose that is safe for one
individual in a population may cause serious side effects to another.
 Agonism and antagonism

Agonist
A drug which binds to a specific receptor (affinity) and, once bound, is able to
produce a response (intrinsic activity).

Antagonist
A drug that has significant affinity but no intrinsic activity.

Full agonist
A drug that produces a maximal response once bound to the receptor.

Partial agonist
A drug with significant affinity but submaximal intrinsic activity.

Partial agonist curves

Full agonist
100
population responding
Percentage of

Partial agonist
50

25

ED50
0
Log10 dose

Draw a standard log-dose versus response curve as before and label it ‘full
agonist’. Next draw a second sigmoid curve that does not rise so far on the
y axis. The inability to reach 100% population response automatically makes
this representative of a partial agonist as it lacks efficacy. The next thing to
consider is potency. The ED50 is taken as the point that lies half way between
baseline and the maximum population response. For a full agonist, this is
always half of 100%, but for a partial agonist it is half whatever the maximum
is. In this instance, the maximum population response is 50% and so the ED50
is read at 25%. In this plot, both the agonist and partial agonist are equally
potent as they share the same ED50.
98 Section 4  Pharmacodynamics
Partial agonist curve

Full agonist (A)

100

population responding
Percentage of
Partial Partial
agonist (B) agonist (C)
50

25

0
ED50 ED50 ED50
B A C
Log10 dose

This graph enables you to demonstrate how the partial agonist curves change
with changes in potency. Curve A is the standard sigmoid agonist curve. Curve
B is plotted so that its ED50 is reduced compared with that of A. Drug B is,
therefore, more potent than drug A but less efficacious. Curve C demonstrates
an ED50 that is higher than that of curve A, and so drug C is less potent than
drug A and less efficacious.

Alternative partial agonist curve

H
100
G
maximum response

F
Percentage of

E
50 D
C Efficacy
of partical
B agonist
A
0
Log10 dose partial agonist

Partial agonists can also behave as antagonists, as demonstrated by this graph.

The graph is constructed by starting with a number of different concentrations
(A–H) of full agonist to which a partial agonist is successively added. The
curves are best explained by describing the lines at the two extremes, ‘A’ and
‘H’. Lines B–G demonstrate intermediate effects.
 Agonism and antagonism 99

Line H This line shows a high baseline full agonist concentration and so
begins with 100% maximal response. As an increasing dose of partial agonist
is added, it displaces the full agonist from the receptors until eventually they
are only able to generate the maximal response of the partial agonist (in this
case 50%). The partial agonist has, therefore, behaved as an antagonist by
preventing the maximal response that would have been seen with a full
agonist alone.
Line A This line shows the opposite effect where there is no initial full
agonist present and hence no initial response. As more partial agonist is
added, the response rises to the maximum possible (50%) and so in this
instance the partial agonist has behaved as an agonist by increasing the
response seen.

Competitive antagonist
A compound that competes with endogenous agonists for the same binding
site; it may be reversible or irreversible.

Non-competitive antagonist
A compound that binds at a different site to the natural receptor and produces
a conformational distortion that prevents receptor activation.

Reversible antagonist
A compound whose inhibitory effects may be overcome by increasing the
concentration of an agonist.

Irreversible antagonist
A compound whose inhibitory effects cannot be overcome by increasing the
concentration of an agonist.

Allosteric modulator
An allosteric modulator binds at a site different from the natural receptor and
alters the affinity of the receptor for the ligand, thus increasing or decreasing
the effect of the natural agonist.
100 Section 4  Pharmacodynamics
Reversible competitive antagonist curves

Full agonist
100

population responding
Addition of
competitive
Percentage of

antagonist
50

ED50 ED50
0
Log10 dose

Draw the standard sigmoid curve and label it as a full agonist. Draw a second
identical curve displaced to the right. This represents the new [DR] curve for
an agonist in the presence of a competitive antagonist. The antagonist has
blocked receptor sites; consequently, more agonist must be added to displace
antagonist and achieve the same response. Demonstrate this by marking the
ED50 on the graph and showing that potency of the agonist decreases in the
presence of a competitive antagonist.

Irreversible competitive antagonist curves

Full agonist
100 B
population responding
Percentage of

50 C

0
Log10 dose

The standard curve is displaced to the right initially as some receptor sites
are blocked by the antagonist. Given enough agonist, maximum response
is still possible (line B) at the expense of reduced potency. With higher
levels of antagonist present (line C), the potency and efficacy are both
reduced as too many receptor sites are blocked by the antagonist to enable
maximum response. With the addition of enough antagonist, no response
will be seen.
 Agonism and antagonism 101

Non-competitive antagonist curve

Full agonist
100

population responding
Percentage of With non-competitive
antagonist
50

25

0
Log10 dose

Because a non-competitive antagonist alters the shape of the receptor, the

agonist cannot bind at all. The usual sigmoid curve is displaced down and to
the right in a similar manner to the graph of agonist versus partial agonist
drawn above. Increasing the dose of agonist does not improve response as
receptor sites are no longer available for binding.

Inverse agonist
A compound that, when bound, produces an effect opposite to the endogen-
ous agonist.

100
Agonist
Percentage of maximum response

50

0
Log10 dose

–50

Inverse
agonist
–100

This plot is more theoretical than most. Draw the y axis so that it enables
positive and ‘negative’ response. The upper curve is a standard sigmoid full
agonist curve. The lower curve represents the action of the inverse agonist and
should be plotted as an inverted curve. This is different from the curve of a
pure antagonist, which would simply produce no effect rather than the
opposite effect to a full agonist.
102 Section 4  Pharmacodynamics
Dose ratio
The factor by which the agonist concentration must be increased when in the
presence of a competitive antagonist to produce an equivalent response:

Dose of agonist in presence of inhibitor

Dose ratio ¼
Dose of agonist in absence of inhibitor

Affinity of an antagonist for a receptor: pA2

The pA2 is the negative log10 of the concentration of antagonist that requires a
doubling of the dose of agonist to achieve the same response.

It is a measure of the affinity of the antagonist for the receptor (the equilibrium
dissociation constant). It is used to compare the potency of antagonists in a
similar manner to the use of the ED50 to compare the potency of agonists.
 Hysteresis

Hysteresis is defined on p. 14 but occurs in pharmacology as well as during

physical measurement. The phenomenon occurs because the concentration of a
drug at the intended site of action (the ‘effector site’ or ‘biophase’) often differs
from the plasma concentration at any given time. The reasons for this time lag
include the degree of ionization of the drug, its lipid solubility, prevailing con-
centration gradients and many other factors. All these alter the length of time it
actually takes a drug to reach its intended site of action.
If a drug was to be administered orally, the following graph may be obtained.

Plasma
Concentration (C )

E2

C
Effector site

E1
t1 t2
Time (t )

Plasma After drawing and labelling the axes, plot the concentration versus
time curve for an orally administered drug. Label this curve ‘plasma’ to
show how the concentration rises and falls with time following an oral dose.
Effector site Now draw a second, similar curve to the right of the first. This
shows the concentration of the drug at its site of action. The degree of
displacement to the right of the first curve is determined by the factors
mentioned above.
Key points When both curves are drawn, mark a fixed concentration point
on the y axis and label it C. Demonstrate that the plasma concentration
curve crosses this value twice, at times t1 and t2. At time t1 the concentration
in the plasma is rising and at t2 it is falling. The crucial point now that
enables you to define hysteresis is to demonstrate that the effector site
concentration is different at these two times depending on whether the
plasma concentration is rising (giving concentration E1) or falling (giving
concentration E2).
 Section 5 * Pharmacokinetics

Bioavailability

Bioavailability is defined as the fraction of drug that reaches the circulation

compared with the same dose given intravenously (i.v.) (%).
or
The ratio of the area under the stated concentration–time curve (AUC) divided
by the area under the i.v. concentration–time curve.
Concentration (mg.ml–1)

i.v.

Oral

Time (min)

Intravenous After drawing and labelling the axes, plot an exponential

decline curve to show how concentration changes with time following the
i.v. administration of a drug. Note that the graph assumes a single com-
partment (see below). Although the concentration at time zero is not
possible to measure, it is still conventional to plot the curve crossing the
y axis. If you are asked how to calculate this initial concentration, it requires
you to perform a semi-log transformation on the curve and to extrapolate
the resultant straight line back to the y axis.
Oral Draw a second curve that shows the concentration of the same drug
changing with time following its oral administration. The second curve
does not have to be contained entirely within the i.v. curve although this is
often the case in practice.

Extraction ratio
Fraction of total drug removed from the blood by an organ in each pass
through that organ.
 Volume of distribution

Volume of distribution
The theoretical volume into which a drug distributes following its administra-
tion (ml)

Dose
VD ¼
C0

where VD is the volume of distribution and C0 is the concentration at time 0.

It is not possible to measure C0 since mixing is not instantaneous; therefore, a

semi-logarithmic plot is drawn and extrapolated back to the y axis in order to
calculate this concentration.

C0
Concentration (ln)

Time (t )

After drawing and labelling the axes as shown, plot a straight line (solid) which
does not cross the y axis. This will be the curve which is found in the real world
situation. To calculate C0 the line must be extrapolated back (dotted) to the y
axis and the concentration read at that point.
106 Section 5  Pharmacokinetics
Using a simple one-compartment model, the loading dose and the infusion rate
required to maintain a constant plasma concentration can be calculated as
follows.
LD ¼ VD :C

where LD is the loading dose and C is the required plasma concentration.

and

Rinf ¼ C:Cl

where Rinf is the infusion rate required and Cl is the clearance.

 Clearance

Clearance
The volume of plasma from which a drug is removed per unit time (ml.min1).

It is important to remember that clearance refers to the amount of plasma

concerned as opposed to the amount of a drug. Try to remember the units of
ml.min1, which, in turn, should help you to remember the definition:
Dose
Cl ¼
AUC
where AUC is the area under concentration–time curve
or

Cl ¼ Q:ER

where Q is the flow rate and ER is the extraction ratio.

Clearance gives a value for the amount of plasma cleared of a drug. The mechan-
ism of this clearance can involve elimination, excretion or both.

Elimination
Removal of drug from the plasma. This may be via distribution, metabolism or
excretion.
Relim ¼ Concentration  Clearance
or
Relim ¼ V D  K elim
Relim is the rate of elimination and Kelim is the rate constant of elimination.

First-order elimination
A situation where the rate of drug elimination at any time depends upon the
concentration of the drug present at that time.

This is an exponential process and a constant proportion of drug is eliminated in a

given time.

Zero-order elimination
A situation where the rate of drug elimination is independent of the concen-
tration of drug and is, therefore, constant.
108 Section 5  Pharmacokinetics
This time a constant amount of drug is eliminated in a given time rather than a
constant proportion. First-order elimination may become zero order when the
elimination system (often a metabolic pathway) is saturated.

Excretion
The removal of drug from the body.
 Compartmental models

The concept of compartmental modelling allows predictions of drug behaviour to

be made from mathematical models of the body that are more accurate than the
assumption of the body being a simple container.

Compartment
One or more components of a mathematical model that aim to replicate the
drug-handling characteristics of a proportion of the body.

Models may contain any number of compartments but single-compartment mod-

els are generally inaccurate for studying pharmacokinetics. A three-compartment
model allows fairly accurate modelling with only limited complexity.

Catenary
A form of multicompartmental modelling in which all compartments are
linked in a linear chain with each compartment connecting only to its immedi-
ate neighbour.

Mamillary
A form of multicompartmental modelling in which there is a central compart-
ment to which a stated number of peripheral compartments are connected.

Mamillary models are the most commonly used and are described below.

One-compartment model

Drug administered
K01

VD C1

K10

Drug eliminated

The terminology for the so-called ‘central’ compartment is C1. There are various
rate constants that should be included in the diagram: K01 is the rate constant
for a drug moving from the outside of the body (compartment 0) to the central
compartment (compartment 1); K10 is the rate constant of elimination from C1
to C0. Single-compartment models do not occur physiologically.
110 Section 5  Pharmacokinetics
Two-compartment model

Drug administered

K01

K12
C1 C2
K21
K10

Drug eliminated

A second (peripheral) compartment can now be added, which may mathemati-

cally represent the less vascular tissues of the body. All the rate constants that were
in the previous model still apply but in addition you must indicate that there are
additional constants relating to this new compartment. The terminology is the
same; K12 represents drug distribution from C1 to C2 and K21 represents drug
redistribution back into C1. Demonstrate in your diagram that elimination
occurs only from C1 no matter how many other compartments are present.

A semi-log plot of drug concentration versus time will no longer be linear as the drug
has two possible paths to move along, each with their own associated rate constants.

C0
A
Concentration (ln)

Phase 1

B b
Phase 2
a

Time (t )

To show the concentration time curve for two compartments, first draw and
label the axes as on p. 106. Instead of being linear, a bi-exponential curve
should be drawn. Phase 1 equates to distribution of drug from C1 to C2
whereas phase 2 represents drug elimination from C1. A tangent (b) to phase 2
intercepts the y axis at B. Subtracting line b from the initial curve gives line a,
which intercepts the y axis at A and is a tangent to phase 1. The values of A and
B sum to give C0. Because the scale is logarithmic on the y axis, B is small in
comparison with A and, therefore, C0 and A are close.
 Compartmental models 111

Formula for two-compartment model

Ct ¼ A:et þ B:et

where Ct is the concentration at time t, A is the y intercept of line a,  is the

slope of line a, B is the y intercept of line b and  is the slope of line b.

The value of Ct can, therefore, be found simply by adding the values of exponen-
tial declines a and b at any given time. The terms  and  are the rate constants for
these processes.

Three-compartment model

Drug administered
K01
Slow equilibration Rapid equilibration
K13 K12
C3 C1 C2
K31 K21
K10

Drug eliminated

A third compartment can now be added that mathematically represents the

least vascular tissues of the body. All the rate constants that were in the
previous model still apply but in addition you must indicate that there are
additional constants relating to this new compartment. The terminology is the
same. Demonstrate in your diagram that elimination occurs only from C1 no
matter how many other compartments are present. Most anaesthetic drugs are
accurately modelled in this way. Remember that the compartments are not
representing precise physiological regions of the body. Instead they are
designed to model areas of the body that share similar properties in terms of
rates of equilibration with the central compartment. Your diagram should
show, however, that one of the peripheral compartments models slowly
equilibrating tissues while the other models tissues that are equilibrating
more rapidly.
112 Section 5  Pharmacokinetics
Concentration versus time

C0
A

Loge concentration Phase 1

a

C Phase 2

b Phase 3
B

Time (min )

Draw and label the axes as before. This time draw a tri-exponential decline.
Draw a tangent to phase 3 (line b) as before giving a y intercept at B. Next draw a
tangent to phase 2 (line c) that would occur if line b were subtracted from the
original tri-exponential decline. Show that this line intercepts the y axis at C.
Finally draw a tangent to phase 1 (line a), which would occur if lines b and c
were subtracted from the original tri-exponential decline. Show that this inter-
cepts the y axis at A. As before, A þ B þ C should equal C0. Line a represents
distribution to rapidly equilibrating tissues and line c represents distribution to
slowly equilibrating tissues. Line b always represents elimination from the body.

Formula for three-compartment model

Ct ¼ A:et þ B:et þ C:et

where C is the y intercept of line c and g is the slope of line c.

The equation is compiled in the same way as that for a two-compartment model:
B.et continues to represent the terminal elimination phase and the term C.et
is added to represent slowly equilibrating compartments.
Three-compartment models show how drug first enters a central (first) com-
partment, is then distributed rapidly to a second and slowly to a third whilst being
eliminated only from the first. Distribution to, and redistribution from, the
peripheral compartments occurs continuously according to prevailing concen-
tration gradients. These peripheral compartments may act as reservoirs keeping
the central compartment full even as elimination is occurring from it. The ratio of
the rate constants to and from the central compartment will, therefore, affect the
length of time taken to eliminate a drug fully.
 Context-sensitive half time

The use of compartmental models leads onto the subject of context-sensitive half
time (CSHT).

Context-sensitive half time

The time taken for the plasma concentration of a drug to fall by half after the
cessation of an infusion designed to maintain a steady plasma concentration
(time).

Although there is not a recognized definition for the term ‘context’, it is used to
identify the fact that the half time will usually alter in the setting of varying
durations of drug infusion.

300 Fentanyl
CSHT (min)

200

100 Thiopental

b Alfentanil
Propofol
0 Remifentanil
0 1 2 3 4 5 6 7 8
Duration of infusion (h)

Draw and label the axes as shown. In terms of accuracy, it is often easiest to draw in
the curves from the drugs with the shortest CSHT first before plotting the others.
Remifentanil This is the exceptional drug in anaesthetic practice in that it is
context insensitive. Draw a straight line starting from the origin and
becoming near horizontal after the CSHT reaches 5 min. This demonstrates
that the half time is not dependent on the length of infusion as clearance by
plasma esterases is so rapid.
Propofol Starting at the origin, draw a smooth curve rising steadily towards
a CSHT of around 40 min after 8 h of infusion. Propofol is not context
insensitive as its CSHT continues to rise; however it remains short even
after prolonged infusions.
Alfentanil The curve rises from the origin until reaching a CSHT of 50 min
at around 2 h of infusion. Thereafter the curve becomes horizontal. This
demonstrates that alfentanil is also context insensitive for infusion dura-
tions of 2 h or longer.
114 Section 5
Pharmacokinetics
Thiopental The curve begins at the origin but rises more steeply than the
others so that the CSHT is 50 min after only 30 min infusion duration. The
curve should be drawn like a slightly slurred build-up exponential reaching
a CSHT of 150 min after 8 h of infusion. As the CSHT continues to rise,
thiopental does not become context insensitive.
Fentanyl The most complex curve begins at the origin and is sigmoid in
shape. It should cross the alfentanil line at 2 h duration and rise to a CSHT
of 250 min after 6 h of infusion. Again, as the CSHT continues to rise,
fentanyl does not become context insensitive.

It is important to realize that the CSHT does not predict the time to patient
awakening but simply the time until the plasma concentration of a drug has fallen
by half. The patient may need the plasma concentration to fall by 75% in order to
awaken, and the time taken for this or any other percentage fall to occur is known
as a decrement time.

Decrement time
The time taken for the plasma concentration of a drug to fall to the specified
percentage of its former value after the cessation of an infusion designed to
maintain a steady plasma concentration (time).

The CSHT is, therefore, a form of decrement time when the ‘specified percentage’
is 50%. When using propofol infusions, the decrement time is commonly quoted
as the time taken to reach a plasma level of 1.2 mg.ml 1, as this is the level at which
wake up is thought likely to occur in the absence of any other sedative agents.
 Section 6 * Respiratory physiology

Lung volumes

Most lung volumes can be measured with a spirometer except total lung capacity
(TLC), functional residual capacity (FRC) and residual volume (RV). The FRC
can be measured by helium dilution or body plethysmography.

Tidal volume (TV)

The volume of gas which is inhaled or exhaled during the course of a normal
resting breath. Also represented by the symbol VT (ml).

Residual volume (RV)

The volume of gas that remains in the lungs after a maximal forced
expiration (ml).

Inspiratory reserve volume (IRV)

The volume of gas that can be further inhaled after the end of a normal tidal
inhalation (ml).

Expiratory reserve volume (ERV)

The volume of gas that can be further exhaled after the end of a normal tidal
exhalation (ml).

Capacity
The sum of one of more lung volumes.

Vital capacity (VC)

The volume of gas inhaled when a maximal expiration is followed immediately
by a maximal inspiration. The sum of the ERV, IRV and TV (ml).

Functional residual capacity (FRC)

The volume of gas that remains in the lungs after a normal tidal expiration. It is
the sum of the ERV and the RV (ml).
116 Section 6
Respiratory physiology
You may be asked for the definitions above, and to explain them clearly it is often
useful to refer to a diagram. You will be expected to be familiar with a diagram of
normal respiratory volumes against time, and to be able to explain its main
components.

Lung volumes

As the FRC is around 3000 ml, the TV should be drawn as an undulating line
with its baseline at 3000 ml rising to 3500 ml on inspiration. Consider, and be
prepared to explain, how the curve would shift in pathological situations. For
example, in asthmatics the FRC may increase while the IRV decreases as a
consequence of gas trapping.

Closing volume
The volume of gas remaining in the lung when the small airways start to
close (ml).

It is calculated by measuring the nitrogen concentration in expired gas after a

single breath of 100% oxygen. The nitrogen wash-out test is the same method
used to measure anatomical dead space. Closing volume increases with age and
reaches the standing FRC at 70 years and the supine FRC at 40 years.
 Spirometry

Simple spirometry using a Vitalograph or similar produces a well-defined curve

that can aid in the interpretation of various lung diseases.

Normal spirometry

Draw and label the axes as shown. Next draw a horizontal line at the level of
the forced vital capacity (FVC; 4500 ml) to act as a target point for where the
curve must end. Normal physiology allows for 75% of the FVC to be forcibly
expired in 1 s (FEV1) . The normal FEV1 should, therefore, be 3375 ml. Mark
this volume at a time of 1 s. Construct the curve by drawing a smooth arc
passing through the FEV1 point and coming into alignment with the FVC line
at the other end.
118 Section 6
Respiratory physiology
Obstructive pattern

On the same axes, draw a horizontal line at a lower FVC to act as a target end
point. Obstructive airway diseases limit the volume of gas that can be forcibly
expired in 1 s and, therefore, the FEV1/FVC ratio will be lower. In the graph
above, the ratio is 33% giving a FEV1 of 1000 ml for a FVC of 3000 ml.
Construct the curve in the same way as before.

Restrictive pattern

On the same axes, draw a horizontal line at a lower FVC than normal to act as a
target end point. Restrictive lung disease curtails the FVC but generally does
not affect early expiration. For this reason, the FEV1/FVC ratio is normal or
high. In the graph above, the ratio is 85%, giving a FEV1 of 3000 ml for a FVC
of 3500 ml. Construct the curve in the same way as before.
 Flow–volume loops

You should be able to draw the following loops as examples of various respiratory
system pathologies.

Normal loop

A
8
Expiration

4
Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8 Inspiration

Draw and label the axes as shown; the x axis need not display numerical values
but a note should be made of the TLC and RV. Note that the highest volume
(TLC) is on the left of the x axis. The units on the y axis are litres per second as
opposed to litres per minute. Positive deflection occurs during expiration and
negative deflection during inspiration. The patient takes a VC breath before
starting the test with a forced expiration. The loop is drawn in a clockwise
direction starting from TLC. The normal loop (A) rises rapidly to a flow rate of
8–10 l.s 1 at the start of forced expiration. The flow rate then decreases steadily
as expiration continues in a left to right direction so that a relatively straight
curve is produced with a slight concavity at its centre. An important point to
demonstrate is the phenomenon of dynamic compression of the airways. The
curve traced by the normal loop represents the maximum possible flow rate at
each lung volume. Even if patients ‘holds back’ their maximal effort by expiring
slowly at first (B), they will be unable to cross this maximal flow line. This is
because the airways are compressed by a rise in intrathoracic pressure, thus
limiting flow. The more effort that is put into expiration, the more these airways
are compressed and so total flow remains the same. The inspiratory limb has a
much squarer shape to it and a maximum flow of 4–6 l.s 1 is usually achieved.
Inspiration occurs from RV to TLC in a right to left direction as shown.
120 Section 6
Respiratory physiology
Obstructive disease

Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8

Obstructive disease reduces peak expiratory flow rate (PEFR) and increases
RV via gas trapping. The TLC may also be higher although this is difficult to
demonstrate without values on the x axis. The important point to demonstrate
is reduced flow rates during all of expiration, with increased concavity of the
expiratory limb owing to airway obstruction. The inspiratory limb is less
affected and can be drawn as for the normal curve but with slightly lower
flow rates.

Restrictive disease

4
Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8

In contrast to obstructive disease, restrictive disease markedly reduces TLC

while preserving RV. The PEFR is generally reduced. Demonstrate these points
by drawing a curve that is similar in shape to the normal curve but in which the
flow rates are reduced. In addition, the left-hand side of the curve is shifted to
the right, demonstrating a fall in TLC.
 Flow–volume loops 121

Variable intrathoracic obstruction

Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8

An intrathoracic obstruction is more likely to allow gas flow during inspiration

as the negative intrathoracic pressure generated helps to pull the airways open.
As such, the inspiratory limb of the curve may be near normal. In contrast, the
positive pressure generated during forced expiration serves only to exacerbate
the obstruction, and as such the expiratory limb appears similar to that seen in
obstructive disease. Both TLC and RV are generally unaffected.

Variable extrathoracic obstruction

4
Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8

An extrathoracic obstruction is more likely to allow gas flow during expiration

as the positive pressure generated during this phase acts to force the airway
open. As such, the expiratory limb may be near normal. In contrast, the
negative pressure generated in the airway during inspiration serves to collapse
the airway further and the inspiratory limb will show markedly reduced flow
rates at all volumes while retaining its square shape. Both TLC and RV are
generally unaffected.
122 Section 6
Respiratory physiology
Fixed large airway obstruction

Flow rate (l.s–1)

TLC RV
0
Volume

–4

–8

This curve is seen where a large airway has a fixed orifice through which gas is
able to flow, such as may be seen in patients with tracheal stenosis. The peak
inspiratory and expiratory flow rates are, therefore, dependent on the di-
ameter of the orifice rather than effort. The curves should be drawn almost
symmetrical as above, with both limbs demonstrating markedly reduced flow.
The TLC and RV are generally unaffected.
 The alveolar gas equation

The alveolar gas equation is used to estimate the PAO2 of a ‘perfect’ alveolus with
varying fractions of inspired oxygen and it states that

PAO2 ¼ ½F IO2 ðP ATM  P H2 OÞ  ðP ACO2 =RÞ

where PAO2 is the alveolar O2 partial pressure, PACO2 is the alveolar CO2 partial
pressure, PATM is the atmospheric pressure, FIO2 is the fraction of inspired air,
PH2O is the standard vapour pressure (SVP) of water at 37 8C and R is the
respiratory quotient.

Note that the SVP of water in the airways is subtracted from the atmospheric
pressure before multiplying by the FIO2. This is because the fractional concentra-
tion of O2 only applies to the portion of inhaled mixture that is dry gas.
The PACO2 is assumed to be in equilibrium with arterial CO2 tension (PaCO2)
and this number will either be given or will be assumed to be within the normal
range.
The value of R varies according to which energy substrates make up the
predominant part of the diet. With a normal diet, it is assumed to have a value
of 0.8; pure carbohydrate metabolism gives a value of 1.0.
Therefore, under normal conditions:

PAO2 ¼ ½0:21  ð101:3  6:3Þ  ð5:3=0:8Þ

¼ ð0:21  95Þ  6:6
¼ 19:95  6:6
¼ 13:35 kPa

Note that there is no difference between the ideal alveolar value and the normal
arterial PaO2 of 13.3 kPa. In practice a difference of up to 2 kPa is allowable owing
to ventilation–perfusion (V̇/Q̇) mismatch and shunt.
 The shunt equation

The purpose of the shunt equation is to give a ratio of shunt blood flow to total
blood flow. The normal ratio is 0.3. Under abnormal conditions, the ratio will
tend to increase and so markedly reduce the PaO2.

Shunt
Those areas of the lung that are perfused but not ventilated:

Q̇S ðCc0 O2  CaO2 Þ

¼
Q̇T ðCc0 O2  CvO2 Þ

where Q̇T is total blood flow, Q̇S is shunted blood flow, Cc0 O2 is end-capillary
blood content, CvO2 is shunt blood O2 content and CaO2 is arterial blood O2
content.

Principle of the shunt equation

Start with the theoretical lungs shown above and remember that blood entering
the systemic circulation has a component that is shunted past the pulmonary
circulation (Q̇S) and another component that passes through it (Q̇T – Q̇S).

Cc′O2
C vO2
CaO2

QT – QS

QS
QT QT

Now consider the blood flow generated in a single beat. The O2 delivered in this
volume of blood is equal to (Q̇T.CaO2). This must be made up of shunted blood
(Q̇S.CvO2) and capillary blood ([Q̇T – Q̇S].Cc0 O2).

Q̇T:CaO2 ¼ ðQ̇S:CvO2 Þ þ ½ðQ̇T  Q̇SÞ:Cc0 O2 

 The shunt equation 125

Derivation
Q̇T:CaO2 ¼ ðQ̇S:CvO2 Þ þ ½ðQ̇T  Q̇SÞ:Cc0 O2 

Rearrange the brackets to give

Q̇T:CaO2 ¼ ðQ̇S:CvO2 Þ þ ðQ̇T:Cc0 O2 Þ  ðQ̇S:Cc0 O2 Þ

Q̇S needs to be moved to the left, aiming for Q̇S/Q̇T in the final equation.

ðQ̇T:CaO2 Þ þ ðQ̇S:Cc0 O2 Þ ¼ ðQ̇S:CvO2 Þ þ ðQ̇T:Cc0 O2 Þ

then

ðQ̇S:Cc0 O2 Þ ¼ ðQ̇S:CvO2 Þ þ ðQ̇T:Cc0 O2 Þ  ðQ̇T:CaO2 Þ

then

ðQ̇S:Cc0 O2 Þ  ðQ̇S:CvO2 Þ ¼ ðQ̇T:Cc0 O2 Þ  ðQ̇T:CaO2 Þ

Then simplify the brackets

Q̇SðCc0 O2  CvO2 Þ ¼ Q̇TðCc0 O2  CaO2 Þ

To get Q̇S/Q̇T on the left, both sides must be divided by Q̇T. At the same time,
the term (Cc’O2 – Cv O2) can be moved from left to right by also dividing both
sides by (Cc’O2 – Cv O2).

Q̇S ðCc0 O2  CaO2 Þ

¼
Q̇T ðCc0 O2  CvO2 Þ

The O2 content of the mixed venous (shunt) and arterial blood can be calculated
from the relevant samples by using the equations below, which are explained later
in the section.

C v O2 ¼ ð1:34 ½Hb SatsÞ þ ð0:0225 : PaO2 Þ

or

CaO2 ¼ ð1:34 ½Hb SatsÞ þ ð0:0225 : PaO2 Þ

The value for Cc0 O2 cannot be calculated in this way very easily as a sample is
technically difficult to take without a catheter in the pulmonary vein. It is, there-
fore, assumed to be in equilibrium with the PAO2, which, in turn, is given by the
alveolar gas equation.
 Pulmonary vascular resistance

Pulmonary vascular resistance (PVR) is given by:

ðMPAP  LAPÞ
PVR ¼  80
CO
where MPAP is mean pulmonary artery pressure, LAP is left atrial pressure and
CO is cardiac output.

The units for PVR are dyne.s1.cm5 and 80 is used as a conversion factor to
account for the different units used within the equation

Factors affecting PVR

Increased by Decreased by

Increased PaCO2 Decreased PaCO2

Decreased pH Increased pH
Decreased PaO2 Increased PaO2
Adrenaline (epinephrine) Isoprenaline
Noradrenaline (norepinephrine) Acetylcholine
Thromboxane A2 Prostacyclin (prostaglandin I2)
Angiotensin II Nitric oxide (NO)
Serotonin (5-hydroxytryptamine) Increased peak airway pressure
Histamine Increased pulmonary venous pressure
High or low lung volume Volatile anaesthetic agents

Lung volume versus PVR graph

The point to demonstrate is that resistance is lowest around the FRC. The
curve rises at low lung volumes as there is direct compression of the vessels. At
high lung volumes, the vessels are overstretched, which alters the flow
dynamics and increases resistance further. The curve will be moved up or
down by those other factors (above) which increase or decrease PVR.
 Ventilation/perfusion mismatch

The V̇/Q̇ term describes the imbalance between ventilation (V̇) and perfusion (Q̇)
in different areas of the lung. Given that alveolar ventilation is 4.5 l.min1 and
pulmonary arterial blood flow is 5.0 l.min1, the overall V̇/Q̇ ratio is 0.9. Both
ventilation and perfusion increase from top to bottom of the lung, but perfusion
by much more than ventilation.

Ventilation/perfusion graph

. .
V/Q
6 Perfusion 3
Flow (l.min–1)

V/Q ratio
2

. .
Ventilation
5

4 0
Bottom Top
Region of lung

The graph can be drawn with either one or two y axes. The example above has
two, flow and V̇/Q̇ ratio, and gives a slightly more complete picture. The x axis
should be arranged from the bottom to the top regions of lung in a left to right
direction as shown. Both ventilation and perfusion decrease linearly from
bottom to top. Perfusion starts at a higher flow but decreases more rapidly
than ventilation so that the lines cross approximately one third of the way
down the lung. At this point the V̇/Q̇ ratio must be equal to 1. Using this point
and a maximum V̇/Q̇ ratio of around 3, draw a smooth curve passing through
both of these as it rises from left to right. The graph demonstrates that higher
lung regions tend towards being ventilated but not perfused (dead space,
V̇/Q̇  1) and lower regions tend towards being perfused but not ventilated
(shunt, V̇/Q̇  0).
 Dead space

Dead space is an important concept in anaesthesia. As dead space increases, a

smaller proportion of the inhaled gas mixture takes part in gas exchange.

Dead space
The volume of the airways in which no gas exchange occurs. It can be either
anatomical or alveolar (ml).

Anatomical dead space

The volume of the conducting airways that does not contain any respiratory
epithelium. This stretches from the nasal cavity to the generation 16 terminal
bronchioles (ml).

The anatomical dead space can be measured by Fowler’s method.

Alveolar dead space

The volume of those alveoli that are ventilated but not perfused, and so cannot
take part in gas exchange (ml).

Physiological dead space

The sum of the anatomical and alveolar dead space (ml).

The physiological dead space can be calculated using the Bohr equation.
 Fowler’s method

Fowler’s method principle

The patient takes a single vital capacity breath of O2 and exhales through a N2
analyser. Dead space gas, which is pure O2, passes the analyser first, followed by a
mixture of dead space and alveolar gas. When pure alveolar gas passes the
analyser, a plateau is reached. At closing capacity, small airways begin to close,
leading to preferential exhalation from the larger-diameter upper airways. These
airways contain more N2 as they are less well ventilated, so the initial concentra-
tion of N2 within them was not diluted with O2 during the O2 breath.

Fowler’s method graph

Phase 1 Pure dead space gas so no value on the y axis.

Phase 2 A mixture of dead space gas and alveolar gas. The curve rises steeply
to a plateau. Demonstrate a vertical line that intercepts this curve such that
area A equals area B. The anatomical dead space is taken as the volume
expired at this point.
Phase 3 Plateau as alveolar gas with a steady N2 content is exhaled. Note the
curve is not completely horizontal during this stage.
Phase 4 Draw a final upstroke. This occurs at the closing volume. Note that
the volume on the x axis at this point is not the value for the closing volume
itself but rather the volume exhaled so far in the test. The closing volume
represents the volume remaining within the lung at this point.
 The Bohr equation

The purpose of the Bohr equation is to give a ratio of physiological dead space
volume to tidal volume. Dead space volume is normally around 30% of tidal
volume and so the normal ratio is quoted as 0.3. Under abnormal conditions, the
ratio will tend to increase and so make ventilation inefficient.
The equation is:

V D=V T ¼ ðPaCO2  PECO2 Þ=PaCO2

where VD is the physiological dead space volume, VT is the tidal volume, and
PECO2 is the partial pressure of CO2 in expired air.

Principle of the Bohr equation

Start with the theoretical lungs shown in the figure and remember that each VT
has a component that is dead space (VD) and a remainder that must take part in
gas exchange at the alveolus (VT – VD). This is the alveolar volume.
FI
FE
VD

VT
VT–VD
FA

The fractional CO2 concentrations are FI for inhaled, FE for exhaled and FA for
alveolar CO2.
Now consider a single tidal exhalation. The CO2 in this breath is equal to FE. VT.
This must be made up of alveolar gas (FA [VT – VD]) and dead space gas (FI.VD).

Derivation
F E:V T ¼ ðF I:V DÞ þ ðF A½V T  V DÞ

But FI ¼ 0 so the term (FI.VD) can be ignored

F E:V T ¼ F AðV T  V DÞ

Rearrange the brackets to give

F E:V T ¼ ðF A:V TÞ  ðF A:V DÞ

 The Bohr equation 131

The term VD needs to be moved to the left, aiming for VD/VT in the final
equation. Start by adding (FA.VD) to both sides and subtracting (FE.VT) from
both sides to give

ðF E:V TÞ þ ðF A:V DÞ ¼ F A:V T

or

F A:V D ¼ ðF A:V TÞ  ðF E:V TÞ

Then simplify the brackets

F A:V D ¼ V TðF A  F EÞ

To get VD/VT on the left, both sides must be divided by VT. At the same time, the
term FA can be moved from left to right by also dividing both sides by FA

V D=V T ¼ ðF A  F EÞ=F A

Since the concentration of a gas is proportional to its partial pressure (Dalton’s

law) FA and FE can be substituted for some more familiar units

F A ¼ P ACO2

F E ¼ P ECO2

Giving the Bohr equation as

V D=V T ¼ ðPACO2  PECO2 Þ=P ACO2

As arterial CO2 tension is practically identical to alveolar CO2 partial pressure, it

can be used as a surrogate measurement. This is desirable as measuring arterial
CO2 tension involves only a simple blood gas analysis. The term PACO2, therefore,
becomes PaCO2 and so the equation is often written as

V D=V T ¼ ðPaco2  P Eco2 Þ=Paco2

Some forms of the equation have the modifier þ[R] added to the end as a
correction for high inspired CO2.
 Oxygen delivery and transport

Oxygen cascade
Oxygen flux is a term used to describe delivery of O2 to the tissues. An under-
standing of how the PO2 changes according to the location in the body is, there-
fore, useful when considering how the mitochondrial O2 supply is achieved. It can
be represented by the O2 cascade.

25
Humidification
Alveolar gas equation
20 Diffusion
Shunt
P O2 (kPa)

15

10

0
Air

Alveolus

Capillary

Artery

Mitochondria

Vein
Trachea

Stage Process Notes and equations

Air – PO2 ¼ F IO2 :PATM

Trachea Humidification PO2 ¼ F IO2 ðPATM  PH2 OÞ
Alveolus Ventilation PAO2 ¼ ½F IO2 ðPATM  PH2 OÞ  ðPACO2 =RÞ
Capillary Diffusion Diffusion barrier negligible for O2
Artery Shunt, V̇/Q̇ A–a gradient usually < 2 kPa
mismatch
Mitochondria – Low PO2 of around 1.5 kPa is usual
Veins – Normal Pv̄O2 ¼ 6.3 kPa
 Oxygen delivery and transport 133

The delivery of any substance to an organ can be calculated if the concentration of

the substance and the flow rate are measured.
DO2 ¼ CO:CaO2 :10

where DO2 is delivery of O2, CO is cardiac output and CaO2 is arterial O2

content.

The multiplier 10 is used because CaO2 is measured in ml.dl1 whereas CO is

measured in l.min1. The O2 content of the blood is calculated using a specific
equation that depends mainly on haemoglobin concentration, [Hb] and satura-
tion (Sats).
CaO2 ¼ ð1:34½HbSatsÞ þ ð0:0225:PaO2 Þ

if PaO2 is measured in kilopascals

or

CaO2 ¼ ð1:34½HbSatsÞ þ ð0:003:PaO2 Þ

if PaO2 is measured in millimetres of mercury.

The number 1.34 is known as Hüffner’s constant. It describes the volume of O2

(ml) that can combine with each 1 g Hb. In vitro, its value is 1.39 but this becomes
1.34 in vivo because abnormal forms of Hb such as carboxyhaemoglobin and
methaemoglobin are less able to carry O2.

Supply and demand

300
Supply independent
VO2 (ml.min–1)

200

100
.

Supply
dependent
0
0 200 400 600
DO2 (ml.min–1)

This curve demonstrates the relationship between oxygen delivery (DO2) and
oxygen consumption (V̇O2). The latter is normally around 200 ml.min1 and
you should demonstrate that it is not affected until delivery falls to below
approximately 300 ml.min1, which is known as critical DO2. When O2 deliv-
ery is less than this, consumption becomes supply dependent. Above the
critical value, it is termed supply independent.
 The oxyhaemoglobin dissociation curve

The oxyhaemoglobin (oxy-Hb) dissociation curve is core knowledge for the

examination and in clinical practice. You will be expected to have a very clear
understanding and to be able to construct a very precise graph.

P50
The partial pressure of O2 in the blood at which haemoglobin is 50%
saturated (kPa).

The oxyhaemoglobin dissociation curve

Arterial
100

Venous
75
Saturation (%)

P50
50

25

0 3.5 5.3 13.3

0 5 10 15 20 25
PaO2 (kPa)

Draw and label the axes as shown; O2 content can also be used on the y axis
with a range of 0–21 ml.100 ml 1. Your graph should accurately demonstrate
three key points. The arterial point is plotted at 100% saturation and 13.3 kPa.
The venous point is plotted at 75% saturation and 5.3 kPa. The P50 is plotted at
50% saturation (definition) and 3.5 kPa. Only when these three point are
plotted should you draw in a smooth sigmoid curve that passes through all
three. The curve is sigmoid because of the cooperative binding exhibited by
Hb. In the deoxygenated state (deoxy-Hb), the Hb molecule is described as
‘tense’ and it is difficult for the first molecule of O2 to bind. As O2 binds to Hb
the molecule relaxes (a conformational change occurs) and it become pro-
gressively easier for further molecules to bind. If asked to compare your curve
with that of a different O2 carrier such as myoglobin, draw a hyperbolic curve
to the left of the original line. Myoglobin can only carry one O2 molecule and
so the curve does not have a sigmoid shape.
 The oxyhaemoglobin dissociation curve 135

Factors affecting the curve

It is the change in position of the P50 that determines whether the curve has shifted
to the left or to the right. You will be expected to be familiar with a number of
factors that alter the position of the P50.

Change in position of the P50

100
Saturation (%)

75

50

25

0
0 5 10 15 20 25
PaO2 (kPa)

Left shift (increased affinity for O2) Right shift (decreased affinity for O2)

Decreased PaCO2 Increased PaCO2

Alkalosis Acidosis
Decreased temperature Increased temperature
Decreased DPG Increased DPG
Fetal haemoglobin Pregnancy
Carbon monoxide Altitude a
Methaemoglobin Haemoglobin S

DPG, 2,3-diphosphoglycerate.
a
High altitude can also cause a left shift of the P50 where PaO2 is critically low.

The effect of pH on the affinity of Hb for O2 is described as the Bohr effect.

The Bohr effect

The situation whereby the affinity of haemoglobin for oxygen is reduced by a
reduction in pH and increased by an increase in pH.

A decrease in pH results in a rightward shift of the curve and decreases the affinity
of Hb for O2. This tends to occur peripherally and allows the offloading of O2 to
the tissues. Conversely, in the lungs, the pH rises as CO2 is offloaded and, there-
fore, O2 affinity is increased to encourage uptake.
 Carriage of carbon dioxide

Carbon dioxide is 20 times more soluble in blood than O2 and is carried in three
different forms.

Arterial(%) Venous(%)

Dissolved 5 10
Bicarbonate 90 60
Carbamino compounds 5 30

The following reaction occurs in erythrocytes in the tissues and explains how CO2
is carried as HCO3

CO2 þ H2 O $ H2 CO3 $ Hþ þ HCO3

The reverse reaction occurs in the pulmonary capillaries.

The Haldane effect

The phenomenon by which deoxygenated haemoglobin is able to carry more
CO2 than oxygenated haemoglobin.

This occurs because deoxy-Hb forms carbamino-complexes with CO2 more read-
ily than oxy-Hb. Secondly, deoxy-Hb is a better buffer of Hþ than oxy-Hb and
this increases the amount of HCO3 formed. Once formed, HCO3 diffuses out
of the erythrocyte. To maintain electrical neutrality Cl moves in. This is known
as the Cl shift or the Hamburger effect.

The Hamburger effect (chloride shift)

The transport of chloride ions into the cell as a result of outwards diffusion of
bicarbonate in order to maintain electrical neutrality.
 Carriage of carbon dioxide 137

Dissociation of carbon dioxide versus oxygen

80 CO2

Content (ml.100 ml–1)

60

40

O2
20

0
0 5 10 15
Gas arterial partial pressure (kPa)

Carbon dioxide dissociation curves

80 Deoxygenated
Content (ml.100 ml–1)

Oxygenated
60

40 Carried as
bicarbonate
20

Dissloved
0
0 5 10 15
PaCO2 (kPa)

Dissolved The curve passes though the origin, rising as a shallow straight
line as PaCO2 rises.
Oxygenated The curve does not extend below 2 kPa as this lies outside the
physiological range. It rises steeply at first before levelling off at approxi-
mately 60 ml.100 ml1.
Deoxygenated It is important to plot this line. At any PaCO2, the CO2
content will be higher than that of oxy-Hb. This is a graphical representa-
tion of the Haldane effect. As a result, the curve is plotted slightly above that
of oxy-Hb. Be sure to point this relationship out to the examiner.
Other The amount of CO2 lying between the dissolved line and the upper
lines is that carried as HCO3. The graph also demonstrates, therefore, that
a greater percentage is carried as HCO3 in venous blood (area between
deoxygenated and dissolved) than in arterial blood (area between oxyge-
nated and dissolved).
 Work of breathing

Work of breathing
In normal circumstances, the work done on expiration utilizes energy stored within
the elastic tissues on inspiration. Expiration is, therefore, said to be passive unless
the energy required to overcome airway resistance exceeds that which is stored.

Work of breathing graph

The purpose of the graph is to demonstrate the effect of airway and tissue
resistance on the pressure–volume relationship within the chest.

D
500 C
Increased
above FRC (ml)

400 work
Lung volume

300 B
B‘
200

100 Increased
work
A
0
0 –0.5 –1 –1.5
Pressure (kPa)

Draw and label the axes as shown. Remember the curve should only start to
rise from 0.5 kPa on the x axis as the intrapleural pressure within the lung
remains negative at tidal volumes. If there were no resistance to breathing,
each tidal breath would increase its volume along the theoretical line AC and
back again on expiration along the line CA.
Inspiration The line ABC is the physiological line traced on inspiration. The
area ACDA represents work to overcome elastic tissues resistance. The
extra area enclosed by ABCA represents the work done in overcoming
viscous resistance and friction on inspiration. If this resistance increases,
the curve bows to the right as shown.
Expiration The line CB0 A is the physiological line traced on expiration. The
area enclosed by CB0 AC is the work done on expiration against airway
resistance. As this area is enclosed within the area ACDA, the energy
required can be supplied from the stored energy in the elastic tissues. If
this resistance increases, the curve bows to the left, as shown. The difference
in area between ACB0 A and ACDA represents the energy lost as heat.
 Control and effects of ventilation

You may be asked to draw the curves related to the control of ventilation or to the
response of PACO2/PAO2 to changes in ventilation. It is important to be very clear
about what question is being asked. The axes can be labelled in very similar ways
but the curves are very different. There is no harm in asking for clarification in a
viva setting before embarking on a description that may not be what the examiner
is asking for.

Control of ventilation
Minute ventilation versus alveolar oxygen partial pressure
Minute ventilation (l.min–1)

20

PACO2 = 10 kPa
10

PACO2 = 5 kPa

0
0 10 20 30
PAO2 (kPa)

At PACO2 of 5 kPa The line should demonstrate that, under normal condi-
tions, the minute volume (MV) remains relatively constant around 6 l.min 1
until the PAO2 falls below 8 kPa. Show that the rise in MV following this is
extremely steep. This illustrates the hypoxic drive, which is so often talked
about in the setting of COPD.
At PACO2 of 10 kPa This line is plotted above and to the right of the first and
demonstrates the effect of a coexisting hypercarbia on hypoxic ventilatory
drive.
140 Section 6
Respiratory physiology
Minute ventilation versus alveolar carbon dioxide partial pressure

Normal Raised

Minute ventilation (l.min–1)

30 response threshold

20
Reduced
sensitivity
10

0
0 5 10 15
PACO2 (kPa)

Normal Draw and label the axes as shown. Plot a normal PACO2 (5 kPa) at a
normal MV (6 l.min 1). If the PACO2 is doubled, the MV increases four-fold
in a linear fashion. Therefore, join the two points with a straight line. Above
10–11 kPa, the line should fall away, representing depression of respiration
with very high PACO2. At the lower end of the line, the curve also flattens out
and does not reach zero on either axis.
Raised threshold Plot a second parallel curve to the right of the first. This
represents the resetting of the respiratory centre such that a higher PACO2 is
required at any stage in order to achieve the same MV. This is seen with
opiates.
Reduced sensitivity Plot a third curve with a shallower gradient. This repre-
sents decreased sensitivity such that a greater increment in PACO2 is required
in order to achieve the same increment in MV. Also seen with opiates.

The following graphs deal with the effect that changes in ventilation have on the
PACO2 or PAO2, respectively. Make sure that you are clear about the differences
between these graphs and the ones shown above.
 Control and effects of ventilation 141

Alveolar carbon dioxide partial pressure versus minute ventilation

10

PACO2 (kPa) 5

0
0 5 10 15 20 25
Minute ventilation (l.min–1)

Draw and label the axes as shown. This graph demonstrates the effect that
ventilation has on PAco2 rather than the control of ventilatory drive by CO2
itself. As MV doubles, so the PACO2 halves. The curve is, therefore, a rectan-
gular hyperbola. Begin by plotting a normal PACO2 (5 kPa) at a normal MV
(6 l.min 1). Draw one or two more points at which MV has doubled (or
quadrupled) and PACO2 has halved (or quartered). Finish by drawing a smooth
curve through all the points you have drawn.

Alveolar oxygen partial pressure versus minute ventilation

FIO2 0.4
20 FIO2 0.3
FIO2 0.21
PAO2 (kPa)

10

0
0 5 10 15 20 25
Minute ventilation (l.min–1)

Draw and label the axes as shown. This graph demonstrates the effect of
ventilation on PAO2. Start by marking a point at a normal MV of 6 l.min 1
and a normal PAO2 of 13.3 kPa. Draw a hyperbolic curve passing through this
point just before flattening out. It should not pass through the origin as this is
unphysiological. The curve illustrates how large increases in MV have little
effect on PAO2. The only reliable way to increase the PAO2 is to increase the FIO2,
which is demonstrated by drawing additional parallel curves as shown.
 Compliance and resistance

Compliance
The volume change per unit change in pressure (ml.cmH2O1 or l.kPa1).

Lung compliance
When adding compliances, it is their reciprocals that are added (as with capaci-
tance) so that:

1=CTOTAL ¼ ð1=CCHEST Þ þ ð1=CLUNG Þ

where CCHEST is chest compliance (1.5–2.0 l.kPa1 or 150–200 ml.cmH2O1),

CLUNG is lung compliance (1.5–2 l.kPa1 or 150–200 ml.cmH2O1) and CTOTAL
is total compliance (7.5–10.0 l.kPa1 or 75–100 ml.cmH2O1).

Static compliance
The compliance of the lung measured when all gas flow has ceased
(ml.cmH2O1 or l.kPa1).

Dynamic compliance
The compliance of the lung measured during the respiratory cycle when gas
flow is still ongoing (ml.cmH2O1 or l.kPa1)

Static compliance is usually higher than dynamic compliance because there is

time for volume and pressure equilibration between the lungs and the measuring
system. The measured volume tends to increase and the measured pressure tends
to decrease, both of which act to increase compliance. Compliance is often plotted
on a pressure–volume graph.

Resistance
The pressure change per unit change in volume (cmH2O.ml1 or kPa.l1).

Lung resistance
When adding resistances, they are added as normal integers (as with electrical
resistance)

Total resistance ¼ Chest wall resistance þ lung resistance

 Compliance and resistance 143

Whole lung pressure–volume loop

TLC Expiration A

Lung volume
Lung
FRC Inspiration B

RV

0 –1 –2 –3
Pressure (kPa)

This graph can be used to explain a number of different aspects of compliance.

The axes as shown are for spontaneous ventilation as the pressure is negative. The
curve for compliance during mechanical ventilation looks the same but the
x axis should be labelled with positive pressures. The largest curve should
be drawn first to represent a vital capacity breath.
Inspiration The inspiratory line is sigmoid and, therefore, initially flat as
negative pressure is needed before a volume change will take place. The mid
segment is steepest around FRC and the end segment is again flat as the
lungs are maximally distended and so poorly compliant in the face of
further pressure change.
Expiration The expiratory limb is a smooth curve. At high lung volumes, the
compliance is again low and the curve flat. The steep part of the curve is
around FRC as pressure returns to baseline.
Tidal breath To demonstrate the compliance of the lung during tidal
ventilation, draw the dotted curve. This curve is similar in shape to the
first but the volume change is smaller. It should start from, and end at, the
FRC by definition.
Regional differences You can also demonstrate that alveoli at the top of the
lung lie towards the top of the compliance curve, as shown by line A. They
are already distended by traction on the lung from below and so are less
compliant for a given pressure change than those lower down. Alveoli at the
bottom of the lung lie towards the bottom of the curve, as shown by line B.
For a given pressure change they are able to distend more and so their
compliance is greater. With mechanical ventilation, both points move
down the curve, resulting in the upper alveoli becoming more compliant.
 Section 7 * Cardiovascular physiology

Cardiac action potentials

General definitions relating to action potentials are given in Section 9. This

section deals specifically with action potentials within the cardiac pacemaker
cells and conducting system.

Pacemaker action potential

20
Membrane potential (mV)

0
0 3
Sympathetic
stimulation 4
–40
Parasympathetic
stimulation

–80
0 100 200 300 400
Time (ms)

Phase 0 Spontaneous ‘baseline drift’ results in the threshold potential being

achieved at  40 mV. Slow L-type Ca2þ channels are responsible for further
depolarization so you should ensure that you demonstrate a relatively
slurred upstroke owing to slow Ca2þ influx.
Phase 3 Repolarization occurs as Ca2þ channels close and Kþ channels
open. Efflux of Kþ from within the cell repolarizes the cell fairly rapidly
compared with Ca2þ-dependent depolarization.
Phase 4 Hyperpolarization occurs before Kþ efflux has completely stopped
and is followed by a gradual drift towards threshold (pacemaker) potential.
This is reflects a Naþ leak, T-type Ca2þ channels and a Naþ/Ca2þ pump,
which all encourage cations to enter the cell. The slope of your line during
phase 4 is altered by sympathetic (increased gradient) and parasympathetic
(decreased gradient) nervous system activity.
 Cardiac action potentials 145

Cardiac conduction system action potential

30
1

Membrane potential (mV)

2
0
ARP RRP

3
0

4
–90
–100
0 100 200 300 400 500
Time (ms)

Phase 0 Rapid depolarization occurs after threshold potential is reached

owing to fast Naþ influx. The gradient of this line should be almost vertical
as shown.
Phase 1 Repolarization begins to occur as Naþ channels close and Kþ
channels open. Phase 1 is short in duration and does not cause repolariza-
tion below 0 mV.
Phase 2 A plateau occurs owing to the opening of L-type Ca2þ channels,
which offset the action of Kþ channels and maintain depolarization.
During this phase, no further depolarization is possible. This is an impor-
tant point to demonstrate and explains why tetany is not possible in cardiac
muscle. This time period is the absolute refractory period (ARP). The
plateau should not be drawn completely horizontal as repolarization is
slowed by Ca2þ channels but not halted altogether.
Phase 3 The L-type Ca2þ channels close and Kþ efflux now causes repolar-
ization as seen before. The relative refractory period (RRP) occurs during
phases 3 and 4.
Phase 4 The Naþ/Kþ pump restores the ionic gradients by pumping 3Naþ
out of the cell in exchange for 2Kþ. The overall effect is, therefore, the slow
loss of positive ionic charge from within the cell.
 The cardiac cycle

The key point of the cardiac cycle diagram is to be able to use it to explain the flow
of blood through the left side of the heart and into the aorta. An appreciation of
the timing of the various components is, therefore, essential if you are to draw an
accurate diagram with which you hope to explain the principle.

Cardiac cycle diagram

Systole
120 IVC IVR

100
Pressure (mmHg)

80 B C Aorta
60

40

20 A D CVP
0 LV
Heart sounds
S1 S2
ECG

0 0.25 0.5
Time (s)
Timing reference curves

Electrocardiography It may be easiest to begin with an ECG trace. Make

sure that the trace is drawn widely enough so that all the other curves can be
plotted without appearing too cramped. The ECG need only be a stylized
representation but is key in pinning down the timing of all the other curves.
Heart sounds Sound S1 occurs at the beginning of systole as the mitral and
tricuspid valves close; S2 occurs at the beginning of diastole as the aortic
and pulmonary valves close. These points should be in line with the
beginning of electrical depolarization (QRS) and the end of repolarization
(T), respectively, on the ECG trace. The duration of S1 matches the dura-
tion of isovolumic contraction (IVC) and that of S2 matches that of
isovolumic relaxation (IVR). Mark the vertical lines on the plot to demon-
strate this fact.
 The cardiac cycle 147

Systole
120 IVC IVR

100

Pressure (mmHg)
80 B C Aorta
60

40

20 A D CVP
0 LV
Heart sounds
S1 S2
ECG

0 0.25 0.5
Time (s)

Pressure curves

Central venous pressure (CVP) The usual CVP trace should be drawn on at
a pressure of 5–10 mmHg. The ‘c’ wave occurs during IVC owing to bulging
of the closed tricuspid as the ventricle begins to contract. The ‘y’ descent
occurs immediately following IVR as the tricuspid valve opens and allows
free flow of blood into the near empty ventricle.
Left Ventricle (LV) A simple inverted ‘U’ curve is drawn that has its baseline
between 0 and 5 mmHg and its peak at 120 mmHg. During diastole, its
pressure must be less than that of the CVP to enable forward flow. It only
increases above CVP during systole. The curve between points A and B
demonstrates why the initial contraction is isovolumic. The LV pressure is
greater than CVP so the mitral valve must be closed, but it is less than aortic
pressure so the aortic valve must also be closed. The same is true of the
curve between points C and D with regards to IVR.
Aorta A familiar arterial pressure trace. Its systolic component follows the
LV trace between points B and C at a slightly lower pressure to enable
forward flow. During IVR, closure of the aortic valve and bulging of the
sinus of Valsalva produce the dicrotic notch, after which the pressure falls
to its diastolic value.
148 Section 7
Cardiovascular physiology
Important timing points

A Start of IVC. Electrical depolarization causes contraction and the LV

pressure rises above CVP. Mitral valve closes (S1).
B End of IVC. The LV pressure rises above aortic pressure. Aortic valve
opens and blood flows into the circulation.
C Start of IVR. The LV pressure falls below aortic pressure and the aortic
valve closes (S2).
D End of IVR. The LV pressure falls below CVP and the mitral valve opens.
Ventricular filling.

The cardiac cycle diagram is sometimes plotted with the addition of a curve to
show ventricular volume throughout the cycle. Although it is a simple curve, it
can reveal a lot of information.

Left ventricular volume curve

This trace shows the volume of the left ventricle throughout the cycle. The
important point is the atrial kick seen at point a. Loss of this kick in atrial
fibrillation and other conditions can adversely affect cardiac function through
impaired LV filling. The maximal volume occurs at the end of diastolic filling
and is labelled the left ventricular end-diastolic volume (LVEDV). In the same
way, the minimum volume is the left ventricular end-systolic volume
(LVESV). The difference between these two values must, therefore, be the
stroke volume (SV), which is usually 70 ml as demonstrated above. The
ejection fraction (EF) is the SV as a percentage of the LVEDV and is around
60% in the diagram above.
 Pressure and flow calculations

Mean arterial pressure

SBP þ ð2 DBPÞ
MAP ¼
3
or
MAP ¼ DBP þ ðPP=3Þ

MAP is mean arterial pressure, SBP is systolic blood pressure, DBP is diastolic
blood pressure and PP is pulse pressure.

Draw and label the axes as shown. Draw a sensible looking arterial waveform
between values of 120 and 80 mmHg. The numerical MAP given by the above
equations is 93 mmHg, so mark your MAP line somewhere around this value.
The point of the graph is to demonstrate that the MAP is the line which makes
area A equal to area B

Coronary perfusion pressure

The maximum pressure of the blood perfusing the coronary arteries (mmHg).
or
The pressure difference between the aortic diastolic pressure and the LVEDP
(mmHg).
So
CPP ¼ ADP  LVEDP
CPP is coronary perfusion pressure and ADP is aortic diastolic pressure.

Coronary blood flow

Coronary blood flow reflects the balance between pressure and resistance
CPP
CBF ¼
CVR
150 Section 7  Cardiovascular physiology
CBF is coronary blood flow, CPP is coronary perfusion pressure and CVR is
coronary vascular resistance.

Coronary perfusion pressure is measured during diastole as the pressure

gradient between ADP and LVEDP is greatest during this time. This means that
CBF is also greatest during diastole, especially in those vessels supplying the high-
pressure left ventricle. The trace below represents the flow within such vessels.

IVC Systole Diastole

Coronary blood flow Aortic pressure
120
(mmHg)

100

80
(ml.min–1.100 g–1)

200

100

0
0 0.5 1.0
Time (s)

Draw and label two sets of axes so that you can show waveforms for both aortic
pressure and coronary blood flow. Start by marking on the zones for systole
and diastole as shown. Remember from the cardiac cycle that systole actually
begins with isovolumic contraction of the ventricle. Mark this line on both
graphs. Next plot an aortic pressure waveform remembering that the pressure
does not rise during IVC as the aortic valve is closed at this point. A dicrotic
notch occurs at the start of diastole and the cycle repeats. The CBF is approxi-
mately 100 ml.min1 .100 g1 at the end of diastole but rapidly falls to zero
during IVC owing to direct compression of the coronary vessels and a huge
rise in intraventricular pressure. During systole, CBF rises above its previous
level as the aortic pressure is higher and the ventricular wall tension is slightly
reduced. The shape of your curve at this point should roughly follow that of
the aortic pressure waveform during systole. The key point to demonstrate is
that it is not until diastole occurs that perfusion rises substantially. During
diastole, ventricular wall tension is low and so the coronaries are not directly
compressed. In addition, intraventricular pressure is low and aortic pressure is
high in the early stages and so the perfusion pressure is maximized. As the
right ventricle (RV) is a low-pressure/tension ventricle compared with the left,
CBF continues throughout systole and diastole without falling to zero. Right
CBF ranges between 5 and 15 ml.min1. 100 g1. The general shape of the
trace is otherwise similar to that of the left.
 Central venous pressure

The central venous pressure is the hydrostatic pressure generated by the blood
in the great veins. It can be used as a surrogate of right atrial pressure (mmHg).

The CVP waveform should be very familiar to you. You will be expected to be able
to draw and label the trace below and discuss how the waveform may change with
different pathologies.

Central venous pressure waveform

The a wave This is caused by atrial contraction and is, therefore, seen
before the carotid pulsation. It is absent in atrial fibrillation and abnor-
mally large if the atrium is hypertrophied, for example with tricuspid
stenosis. ‘Cannon’ waves caused by atrial contraction against a closed
tricuspid valve would also occur at this point. If such waves are regular
they reflect a nodal rhythm, and if irregular they are caused by complete
heart block.
The c wave This results from the bulging of the tricuspid valve into the right
atrium during ventricular contraction.
The v wave This results from atrial filling against a closed tricuspid valve.
Giant v waves are caused by tricuspid incompetence and these mask the ‘x’
descent.
152 Section 7
Cardiovascular physiology
The x descent The fall at x is caused by downward movement of the heart
during ventricular systole and relaxation of the atrium.
The y descent The fall at y is caused by passive ventricular filling after
opening of the tricuspid valve.
 Pulmonary arterial wedge pressure

The pulmonary artery wedge pressure (PAWP) is an indirect estimate of left atrial
pressure. A catheter passes through the right side of the heart into the pulmonary
vessels and measures changing pressures. After the catheter has been inserted, a
balloon at its tip is inflated, which helps it to float through the heart chambers. It is
possible to measure all the right heart pressures and the pulmonary artery occlusion
pressure (PAOP). The PAOP should ideally be measured with the catheter tip in
west zone 3 of the lung. This is where the pulmonary artery pressure is greater than
both the alveolar pressure and pulmonary venous pressure, ensuring a continuous
column of blood to the left atrium throughout the respiratory cycle. The PAOP may
be used as a surrogate of the left atrial pressure and, therefore, LVEDP. However,
pathological conditions may easily upset this relationship.

Pulmonary arterial wedge pressure waveform

Right atrium (RA) The pressure waveform is identical to the CVP. The
normal pressure is 0–5 mmHg.
Right ventricle (RV) The RV pressure waveform should oscillate between
0–5 mmHg and 20–25 mmHg.
Pulmonary atery (PA) As the catheter moves into the PA, the diastolic
pressure will increase owing to the presence of the pulmonary valve.
Normal PA systolic pressure is the same as the RV systolic pressure but
the diastolic pressure rises to 10–15 mmHg.
154 Section 7
Cardiovascular physiology
PAOP This must be lower than the PA diastolic pressure to ensure forward
flow. It is drawn as an undulating waveform similar to the CVP trace. The
normal value is 6–12 mmHg. The values vary with the respiratory cycle and
are read at the end of expiration. In spontaneously ventilating patients, this
will be the highest reading and in mechanically ventilated patients, it will be
the lowest. The PAOP is found at an insertion length of around 45 cm.
 The Frank–Starling relationship

Before considering the relationship itself, it may be useful to recap on a few of the
salient definitions.

Cardiac output

CO ¼ SV  HR

where CO is cardiac output, SV is stroke volume and HR is heart rate.

Stroke volume
The volume of blood ejected from the left ventricle with every contraction (ml).

Stroke volume is itself dependent on the prevailing preload, afterload and

contractility.

Preload
The initial length of the cardiac muscle fibre before contraction begins.

This can be equated to the end-diastolic volume and is described by the

Frank–Starling mechanism. Clinically it is equated to the CVP when studying
the RV or the PAOP when studying the LV.

Afterload
The tension which needs to be generated in cardiac muscle fibres before
shortening will occur.

Although not truly analogous, afterload is often clinically equated to the systemic
vascular resistance (SVR).

Contractility
The intrinsic ability of cardiac muscle fibres to do work with a given preload and
afterload.

Preload and afterload are extrinsic factors that influence contractility whereas
intrinsic factors include autonomic nervous system activity and catecholamine
effects.
156 Section 7  Cardiovascular physiology
Frank–Starling law
The strength of cardiac contraction is dependent upon the initial fibre length.

Inotropy

Cardiac output (I.min–1)

Normal

Failure

LVEDP (mmHg)

Normal The LVEDP may be used as a measure of preload or ‘initial fibre

length’. Cardiac output increases as LVEDP increases until a maximum is
reached. This is because there is an optimal degree of overlap of the muscle
filaments and increasing the fibre length increases the effective overlap and,
therefore, contraction.
Inotropy Draw this curve above and to the left of the ‘normal’ curve. This
positioning demonstrates that, for any given LVEDP, the resultant cardiac
output is greater.
Failure Draw this curve below and to the right of the ‘normal’ curve.
Highlight the fall in cardiac output at high LVEDP by drawing a curve
that falls back towards baseline at these values. This occurs when cardiac
muscle fibres are overstretched. The curve demonstrates that, at any given
LVEDP, the cardiac output is less and the maximum cardiac output is
reduced, and that the cardiac output can be adversely affected by rises in
LVEDP which would be beneficial in the normal heart.
Changes in inotropy will move the curve up or down as described above.
Changes in volume status will move the status of an individual heart along
the curve it is on.
 Venous return and capillary dynamics

Venous return
Venous return will depend on pressure relations:

ðMSFP  RAPÞ
VR ¼ 80
Rven

where VR is venous return, MSFP is mean systemic filling pressure, RAP is right
atrial pressure and Rven is venous resistance.

The MSFP is the weighted average of the pressures in all parts of the systemic
circulation.

10
Cardiac output (I.min–1)

Reduced
resistance

MSFP = RAP
Increased
resistance
0
–5 0 5 10
Right atrial pressure (mmHg)

Draw and label the axes as shown. Venous return depends on a pressure
gradient being in place along the vessel. Consider the situation where the
pressure in the RA is was equal to the MSFP. No pressure gradient exists and so
no flow will occur. Venous return must, therefore, be zero. This would
normally occur at a RAP of approximately 7 mmHg. As RAP falls, flow
increases, so draw your middle (normal) line back towards the y axis in a
linear fashion. At approximately 4 mmHg, the extrathoracic veins tend to
collapse and so a plateau of venous return is reached, which you should
demonstrate. Lowering the resistance in the venous system increases the
venous return and, therefore, the cardiac output. This can be shown by
drawing a line with a steeper gradient. The opposite is also true and can
similarly be demonstrated on the graph. Changes in MSFP will shift the
intercept of the line with the x axis.
158 Section 7  Cardiovascular physiology
Changes to the venous return curve
The slope and the intercept of the VR curve on the x axis can be altered as
described above. Although it is unlikely that your questioning will proceed this
far, it may be useful to have an example of how this may be relevant clinically.

Increased filling

Cardiac
10 function curve
Cardiac output (I.min–1)

MSFP = RAP

0
–5 0 5 10
Right atrial pressure (mmHg)

Construct a normal VR curve as before. Superimpose a cardiac function curve

(similar to the Starling curve) so that the lines intercept at a cardiac output of
5 l.min1 and a RAP of 0 mmHg. This is the normal intercept and gives the
input pressure (RAP) and output flow (CO) for a normal ventricle. If MSFP is
now increased by filling, the VR curve moves to the right so that RAP ¼ MSFP
at 10 mmHg. The intercept on the cardiac function curve has now changed.
The values are unimportant but you should demonstrate that the CO and RAP
have both increased for this ventricle by virtue of filling.

Altered venous resistance

Cardiac
10
function curve
Cardiac output (I.min–1)

Reduced
resistance
5

MSFP = RAP

0
–5 0 5 10
Right atrial pressure (mmHg)
 Venous return and capillary dynamics 159

Construct your normal curves as before. This time the patient’s systemic
resistance has been lowered by a factor such as anaemia (reduced viscosity)
or drug administration (vessel dilatation). Assuming that the MSFP remains
the same, which may require fluid administration to counteract vessel dilata-
tion, the CO and RAP for this ventricle will increase. Demonstrate that
changes in resistance alter the slope of your line rather than the ‘pivot point’
on the x axis.

Capillary dynamics
As well as his experiments on the heart, Starling proposed a physiological expla-
nation for fluid movement across the capillaries. It depends on the understanding
of four key terms.

Capillary hydrostatic pressure

The pressure exerted on the capillary by a column of whole blood within it
(Pc ; mmHg).

Interstitial hydrostatic pressure

The pressure exerted on the capillary by the fluid which surrounds it in the
interstitial space (Pi ; mmHg).

Capillary oncotic pressure

The pressure that would be required to prevent the movement of water across
a semipermeable membrane owing to the osmotic effect of large plasma
proteins. (pc ; mmHg).

Interstitial osmotic pressure

The pressure that would be required to prevent the movement of water across
a semipermeable membrane owing to the osmotic effect of interstitial fluid
particles (pi; mmHg).

Fluid movement
The ratios of these four pressures alter at different areas of the capillary network so
that net fluid movement into or out of the capillary can also change as shown below.
160 Section 7  Cardiovascular physiology
Net filtration pressure ¼ Outward forces  Inward forces
¼ K½ðPc þ pi Þ  ðPi þ pc Þ

where K is the capillary filtration coefficient and reflects capillary permeability.

Arteriolar end of capillary

πi Pi
2 mmHg 2 mmHg

Net
Pc πc 10 mmHg
33 mmHg 23 mmHg outwards

Outwards Inwards
35 mmHg 25 mmHg

Centre region of capillary

πi Pi
2 mmHg 2 mmHg

No net
Pc πc fluid
23 mmHg 23 mmHg movement

Outwards Inwards
25 mmHg 25 mmHg

Venular end of capillary

πi Pi
2 mmHg 2 mmHg

Net
Pc πc 10 mmHg
13 mmHg 23 mmHg inwards

Outwards Inwards
15 mmHg 25 mmHg

The precise numbers you choose to use are not as important as the concept that,
under normal circumstances, the net filtration and absorptive forces are the
same. Anything which alters these component pressures such as venous con-
gestion (Pc increased) or dehydration loss (pc increased) will, in turn, shift the
 Venous return and capillary dynamics 161

balance towards filtration or absorption, respectively. You should have some

examples ready to discuss.
The above information may also be demonstrated on a graph, which can help to
explain how changes in vascular tone can alter the amount of fluid filtered or
reabsorbed.

40
Pressure (mmHg)

30 b
Area A
πc
20 a Area B

10 Pc

0
Arteriolar Middle Venular
Capillary segment

Draw and label the axes and mark a horizontal line at a pressure of 23 mmHg
to represent the constant pc. Next draw a line sloping downwards from left to
right from 35 mmHg to 15 mmHg to represent the falling capillary hydrostatic
pressure (Pc). Area A represents the fluid filtered out of the capillary on the
arteriolar side and area B represents that which is reabsorbed on the venous
side. Normally these two areas are equal and there is no net loss or gain of
fluid.
Arrow a This represents a fall in pc; area A, therefore, becomes much larger
than area B, indicating overall net filtration of fluid out of the vasculature.
This may be caused by hypoalbuminaemia and give rise to oedema.
Arrow b This represents an increased Pc. If only the arteriolar pressure rises,
the gradient of the line will increase, whereas if the venous pressure rises in
tandem the line will undergo a parallel shift. The net result is again filtra-
tion. This occurs clinically in vasodilatation. The opposite scenario is seen
in shock, where the arterial pressure at the capillaries drops. This results in
net reabsorption of fluid into the capillaries and is one of the compensatory
mechanisms to blood loss.
Other features An increase in venous pressure owing to venous congestion
will increase venous hydrostatic pressure. If the pressure on the arterial side
of the capillaries is unchanged, this moves the venous end of the hydrostatic
pressure line upwards and the gradient of the line decreases. This increases
area A and decreases area B, again leading to net filtration.
 Ventricular pressure–volume relationship

Graphs of ventricular (systolic) pressure versus volume are very useful tools and can
be used to demonstrate a number of principles related to cardiovascular physiology.

End-systolic pressure–volume relationship

The line plotted on a pressure–volume graph that describes the relationship
between filling status and systolic pressure for an individual ventricle (ESPVR).

End-diastolic pressure–volume relationship

The line plotted on a pressure–volume graph that describes the relationship
between filling status and diastolic pressure for an individual ventricle (EDPVR).

A–F This straight line represents the ESPVR. If a ventricle is taken and filled
to volume ‘a’, it will generate pressure ‘A’ at the end of systole. When filled
to volume ‘b’ it will generate pressure ‘B’ and so on. Each ventricle will have
a curve specific to its overall function but a standard example is shown
below. Changes in contractility can alter the gradient of the line.
a–f This curve represents the EDPVR. When the ventricle is filled to volume
‘a’ it will, by definition, have an end-diastolic pressure ‘a’. When filled to
volume ‘b’ it will have a pressure ‘b’ and so on. The line offers some
information about diastolic function and is altered by changes in compli-
ance, distensibility and relaxation of the ventricle.
 Ventricular pressure–volume relationship 163

Pressure–volume relationship

After drawing and labelling the axes as shown, plot sample ESPVR and EDPVR
curves (dotted). It is easiest to draw the curve in an anti-clockwise direction
starting from a point on the EDPVR that represents the EDV. A normal value
for EDV may be 120 ml. The initial upstroke is vertical as this is a period of
isovolumic contraction during early systole. The aortic valve opens (AVO)
when ventricular pressure exceeds aortic diastolic pressure (80 mmHg).
Ejection then occurs and the ventricular blood volume decreases as the
pressure continues to rise towards systolic (120 mmHg) before tailing off.
The curve should cross the ESPVR line at a point after peak systolic pressure
has been attained. The volume ejected during this period of systole is the SV
and is usually in the region of 70 ml. During early diastole, there is an initial
period of isovolumic relaxation, which is demonstrated as another vertical
line. When the ventricular pressure falls below the atrial pressure, the mitral
valve opens (MVO) and blood flows into the ventricle so expanding its volume
prior to the next contraction. The area contained within this loop represents
the external work of the ventricle (work ¼ pressure  volume).

Ejection fraction
The percentage of ventricular volume that is ejected from the ventricle during
systolic contraction: (%)
EDV  ESV
EF ¼ 100
EDV
where EF is ejection fraction, EDV is end-diastolic volume, ESV is end-systolic
volume and (EDV – ESV) is stroke volume.
164 Section 7  Cardiovascular physiology
Increased preload
Although an isolated increase in preload is unlikely to occur physiologically, it is
useful to have an idea of how such a situation would affect your curve.

Based on the previous diagram, a pure increase in preload will move the EDV
point to the right by virtue of increased filling during diastole. This will widen
the loop and thus increase the stroke work. As a consequence, the SV is also
increased. Note that the end systolic pressure (ESP) and the ESV remain
unchanged in the diagram above. Under physiological conditions these would
both increase, with the effect of moving the whole curve up and to the right.

Increased afterload
Again, increased afterload is non-physiological but it helps with understanding
during discussion of the topic.
 Ventricular pressure–volume relationship 165

A pure increase in afterload will move the ESPVR line and thus the ESV point
to the right by virtue of reduced emptying during systole. Emptying is
curtailed because the ventricle is now ejecting against an increased resistance.
As such, the ejection phase does not begin until a higher pressure is reached
(here about 100 mmHg) within the ventricle. The effect is to create a tall,
narrow loop with a consequent reduction in SV and similar or slightly reduced
stroke work.

Altered contractility

A pure increase in contractility shifts the ESPVR line up and to the left. The
EDV is unaltered but the ESV is reduced and, therefore, the EF increases. The
loop is wider and so the SV and work are both increased. A reduction in
contractility has the opposite effect.
166 Section 7  Cardiovascular physiology
The failing ventricle
Diastolic function depends upon the compliance, distensibility and relaxation of
the ventricle. All three aspects combine to alter the curve.

Draw and label the axes as shown. Note that the x axis should now contain
higher values for volume as this plot will represent a distended failing ven-
tricle. Plot a sample ESPVR and EDPVR as shown. Start by marking on the
EDV at a higher volume than previously. Demonstrate that this point lies on
the up-sloping segment of the EDPVR, causing a higher diastolic pressure than
in the normal ventricle. Show that the curve is slurred during ventricular
contraction rather than vertical, which suggests that there may be valvular
incompetence. The peak pressure attainable by a failing ventricle may be lower
as shown. The ESV should also be high, as ejection is compromised and the
ventricle distended throughout its cycle. The EF is, therefore, reduced (30% in
the above example) as is the stroke work.
 Systemic and pulmonary vascular resistance

Systemic vascular resistance

The resistance to flow in the systemic circulation against which the left ven-
tricle must contract (dyne.s.cm5).

Dyne
The force that will give a mass of 1 g an acceleration of 1 cm.s2.

The dyne is, therefore, numerically 1/100 000 of a newton and represents a tiny force.

Equation
Systemic blood pressure is a function of vascular resistance and cardiac output:

SBP ¼ CO  SVR

where SBP is systemic blood pressure, CO is cardiac output and SVR is sys-
temic vascular resistance.
This relationship equates to the well-known relationship of Ohm’s law:

V ¼ IR

where SBP is equivalent to V (voltage), CO to I (current) and SVR to R

(resistance).
To find resistance the equation must be rearranged as R ¼ V/I or

ðMAP  CVPÞ
SVR ¼  80
CO
where MAP is mean arterial pressure, CVP is central venous pressure and 80 is
a conversion factor. This can also be expressed as

ðMAP  RAPÞ
SVR ¼  80
CO
where RAP is right atrial pressure.

A conversion factor of 80 is used to convert from the base units in the equation
(mmHg and l.min1) to the commonly used units of the result (dyne.s.cm5).
It is the pressure difference between input (CVP or RAP) and output (MAP) that is
used in these equations rather than simply SBP. The SVR is usually
1000–1500 dyne.s.cm5.
168 Section 7  Cardiovascular physiology
Pulmonary vascular resistance
The resistance to flow in the pulmonary vasculature against which the right
ventricle must contract (dyne.s.cm5):

ðMPAP  LAPÞ
PVR ¼  80
CO
where PVR is pulmonary vascular resistance, MPAP is mean pulmonary artery
pressure and LAP is left atrial pressure.

The relationship for pulmonary vascular resistance is very non-linear owing to the
effect of recruitment and distension of vessels in the pulmonary vascular bed in
response to increased pulmonary blood flow. The PVR is usually around 10 times
lower than the systemic vascular resistance, at 50–150 dyne.s.cm5.
 The Valsalva manoeuvre

The patient is asked to forcibly exhale against a closed glottis for a period of 10 s.
Blood pressure and heart rate are measured. Four phases occur during the man-
oeuvre. Phase 1 begins at the onset and is of short duration. Phase 2 continues until
the end of the manoeuvre. Phase 3 begins as soon as the manoeuvre has finished and
is of short duration. Phase 4 continues until restoration of normal parameters.

Draw and label all three axes. The uppermost trace shows the sustained rise in
intrathoracic pressure during the 10 s of the manoeuvre. Mark the four phases
on as vertical lines covering all three plot areas, so that your diagram can be
drawn accurately.
Curves Draw normal heart rate and BP lines on the remaining two axes.
Note that the BP line is thick so as to represent SBP at its upper border and
DBP at its lower border.
Phase 1 During phase 1, the increased thoracoabdominal pressure transiently
increases venous return, thereby raising BP and reflexly lowering heart rate.
Phase 2 During phase 2, the sustained rise in intrathoracic pressure reduces
venous return VR and so BP falls until a compensatory tachycardia restores it.
Phase 3 The release of pressure in phase 3 creates a large empty venous
reservoir, causing BP to fall. Show that the heart rate remains elevated.
Phase 4 The last phase shows how the raised heart rate then initially leads to
a raised BP as venous return is restored. This is followed by a reflex
bradycardia before both parameters eventually return to normal.
170 Section 7
Cardiovascular physiology
Uses
The Valsalva manoeuvre can be used to assess autonomic function or to terminate
a supraventricular tachycardia.

Abnormal responses
Autonomic neuropathy/quadriplegia
There is an excessive drop in BP during phase 2 with no associated overshoot in
phase 4. There is no bradycardia in phase 4. The response is thought to be caused
by a diminished baroreceptor reflex and so the normal compensatory changes in
heart rate do not occur.

Congestive cardiac failure

There is a square wave response that is characterized by a rise in BP during
phase 2. This may be because the raised venous pressure seen with this condition
enables venous return to be maintained during this phase. As with autonomic
neuropathy, there is no BP overshoot in phase 4 and little change in heart rate.
 Control of heart rate

The resting heart rate of 60–80 bpm results from dominant vagal tone. The
intrinsic rate generated by the sinoatrial (SA) node is 110 bpm. Control of heart
rate is, therefore, through the balance of parasympathetic and sympathetic activity
via the vagus and cardioaccelerator (T1–T5) fibres, respectively.

Parasympathetic control
The pathway of parasympathetic control is shown below and acts via both the SA
node and the atrioventricular (AV) node.

PARASYMPATHETIC

Nucleus ambiguous
of vagus nerve

Right vagus Left vagus

SA AV
node node

Reduced gradient phase 4

Hyperpolarization

Reduced heart rate

172 Section 7
Cardiovascular physiology
Sympathetic control
Sympathetic control is shown below.

Paediatric considerations
In neonates and children the sympathetic system is relatively underdeveloped
while the parasympathetic supply is relatively well formed. Despite a high resting
heart rate in this population, many insults may, therefore, result in profound
bradycardia. The most serious of these insults is hypoxia.

Post-transplant considerations
Following a heart transplant, both sympathetic and parasympathetic innervation
is lost. The resting heart rate is usually higher owing to the loss of parasympathetic
tone. Importantly, indirect acting sympathomimetic agents will have no effect.
For example, ephedrine will be less effective as only its direct actions will alter
heart rate. Atropine and glycopyrrolate will be ineffective and neostigmine may
slow the heart rate and should be used with caution. Direct acting agents such as
adrenaline (epinephrine) and isoprenaline will work and can be used with
caution.
 Section 8 * Renal physiology

Acid–base balance

When considering the topic of acid–base balance, there are two key terms with
which you should be familiar. These are pH and pKa. Calculations of a patient’s
acid–base status will utilize these terms.

pH
The negative logarithm to the base 10 of the Hþ concentration.

Normal hydrogen ion concentration [Hþ] in the blood is 40 nmol.l1, giving a

pH of 7.4. As pH is a logarithmic function, there must be a 10-fold change in [Hþ]
for each unit change in pH.

1000
Hydrogen ion concentration

750
(nmol.l–1)

500

250

0
6.0 7.0 8.0
pH

Draw and label the axes as shown. At a pH of 6, 7 and 8, [Hþ] is 1000, 100 and
10 nmol.l1, respectively. Plot these three points on the graph and join them
with a smooth line to show the exponential relationship between the two
variables.

pKa
The negative logarithm of the dissociation constant.
or
The pH at which 50% of the drug molecules are ionized and 50% un-ionized.
174 Section 8  Renal physiology
The pKa depends upon the molecular structure of the drug and is not related to
whether the drug is an acid or a base.

Henderson–Hasselbach equation
The Henderson–Hasselbach equation allows the ratio of ionized:un-ionized
compound to be found if the pH and pKa are known. Consider carbonic acid
(H2CO3) bicarbonate (HCO3) buffer system

CO2 þ H2 O $ H2 CO3 $ Hþ þ HCO3

Note that, by convention, the dissociation constant is labelled Ka (‘a’ for acid) as
opposed to KD, which is a more generic term. Although confusing, you should be
aware that a difference in terminology exists.
The dissociation constant is given as

½Hþ ½HCO3 
Ka ¼
½H2 CO3 

Taking logarithms gives

½HCO3 
log K a ¼ log ½Hþ  þ log
½H2 CO3 

Subtract log [Hþ] from both sides in order to move it to the left

þ ½HCO3 
log Ka  log ½H  ¼ log
½H2 CO3 

Next do the same with log Ka in order to move it to the right

þ ½HCO3 
log ½H  ¼ log Ka þ log
½H2 CO3 

which can be written as

½HCO3 
pH ¼ pKa þ log
½H2 CO3 

As H2CO3 is not routinely assayed, CO2 may be used in its place. The blood [CO2] is
related to the PaCO2 by a factor of 0.23 mmol.l1. kPa1 or 0.03 mmol.l1.mmHg1.
The generic form of the equation states that, for an acid

½ionized form
pH ¼ pK a þ log
½un-ionized form

and for a base

½un-ionized form
pH ¼ pKa þ log
½ionized form
 Acid–base balance 175

The Davenport diagram

The Davenport diagram shows the relationships between pH, PCO2 and HCO3. It
can be used to explain the compensatory mechanisms that occur in acid–base
balance. At first glance it appears complicated because of the number of lines but
if it is drawn methodically it becomes easier to understand.

Paco2
40 8 kPa Paco
Plasma [HCO3–] (mmol.l–1)

2
C 5.3 kPa
G Paco2
2.6 kPa
30
B
A
20
D
F
10 E

0
7.0 7.2 7.4 7.6 7.8
pH

After drawing and labelling the axes, draw in the two sets of lines. The solid
lines are lines of equal PaCO2 and the dashed lines are the buffer lines. Normal
plasma is represented by point A so make sure this point is accurately plotted.
The shaded area represents the normal pH and points C and E should also lie
in this area. The line BAD is the normal buffer line.
ABC Line AB represents a respiratory acidosis as the PaCO2 has risen from
5.3 to 8 kPa. Compensation is shown by line BC, which demonstrates
retention of HCO3. The rise in HCO3 from 28 to 38 mmol.l1 (y axis)
returns the pH to the normal range.
AFE Line AF represents a metabolic acidosis as the HCO3 has fallen.
Compensation occurs by hyperventilation and the PaCO2 falls as shown
by line FE.
ADE Line AD represents a respiratory alkalosis with the PaCO2 falling to the
2.6 kPa line. Compensation is via loss of HCO3 to normalize pH, as shown
by line DE.
AGC Line AG represents a metabolic alkalosis with a rise in HCO3 to
35 mmol.l1. Compensation occurs by hypoventilation along line GC.
 Glomerular filtration rate

The balance of filtration at the glomerulus and reabsorption and secretion in the
tubules allows the kidneys to maintain homeostasis of extracellular fluid, nutri-
ents and acid–base balance and to excrete drugs and metabolic waste products.

Glomerular filtration rate

The glomerular filtration rate (GFR) measures the rate at which blood is filtered
by the kidneys.

GFR ¼ Kf ðPG  PB  pG Þ

where Kf is glomerular ultrafiltration coefficient, PG is glomerular hydrostatic

pressure, PB is Bowman’s capsule hydrostatic pressure and pG is glomerular
oncotic pressure.
or

GFR ¼ Clearance

Clearance
The volume of plasma that is cleared of the substance per unit time (ml.min1).
Ux V
Cx ¼
Px
where C is clearance, U is urinary concentration, V is urine flow and P is plasma
concentration.

Clearance is measured most accurately using inulin, which is freely filtered and not
secreted, reabsorbed, metabolized or stored, but creatinine is a more practical surrogate.

Renal blood flow

Renal blood flow (RBF) is a function of renal plasma flow and the density of red
blood cells.

RBF ¼ RPF=ð1HaematocritÞ
Where RPF is renal plasma flow.

The RPF can be calculated using the same formula as the clearance formula but using
a substance that is entirely excreted; p-aminohippuric acid is usually used.

RPP
RBF ¼
RVR
where RPP is renal perfusion pressure and RVR is renal vascular resistance.
This last equation follows the general rule of V ¼ I/R.
 Autoregulation and renal vascular
resistance

Autoregulation of blood flow

Autoregulatory
200 range
GFR (ml.min–1)

125
100

80 180
0
0 100 200
Systolic BP (mmHg)

Draw and label the axes as shown. Your line should pass through the origin
and rise as a straight line until it approaches 125 ml.min 1. The flattening of
the curve at this point demonstrates the beginning of the autoregulatory
range. You should show that this range lies between 80 and 180 mmHg. At
SBP values over 180 mmHg, your curve should again rise in proportion to the
BP. Note that the line will eventually flatten out if systolic BP rises further, as a
maximum GFR will be reached.

Renal vascular resistance

The balance of vascular tone between the afferent and efferent arterioles deter-
mines the GFR; therefore, changes in tone can increase or decrease GFR
accordingly.

Afferent arteriole Efferent arteriole Result

Dilatation Constriction Increased GFR

Prostaglandins Angiotensin II
Kinins Sympathetic stimulation
Dopamine Atrial natriuretic peptide
Atrial natriuretic peptide
Nitric oxide
178 Section 8
Renal physiology
Afferent arteriole Efferent arteriole Result

Constriction Dilatation Reduced GFR

Angiotensin II Angiotensin II blockade
Sympathetic stimulation Prostaglandins
Endothelin
Adenosine
Vasopressin
Prostaglandin blockade
 The loop of Henle

The function of the loop of Henle is to enable production of a concentrated urine.

It does this by generating a hypertonic interstitium, which provides a gradient for
water reabsorption from the collecting duct. This, in turn, occurs under the
control of antidiuretic hormone (ADH). There are several important require-
ments without which this mechanism would not work. These include the differ-
ential permeabilities of the two limbs to water and solutes and the presence of a
blood supply that does not dissipate the concentration gradients produced. This is
a simplified description to convey the principles.

Loop of Henle Collecting duct

300
100 300
300 300
Interstitial osmolarity

Ion transport
(mmol.l–1)

600 600 400 600 Water transport

Water retained
1000 1000 800 1000

1400
1400
Urine

Start by drawing a schematic diagram of the tubule as shown above. Use the
numerical values to explain what is happening to urine osmolarity in each
region.
Descending limb Fluid entering is isotonic. Water moves out down a
concentration gradient into the interstitium, concentrating the urine
within the tubules.
Thin ascending limb Fluid entering is hypertonic. The limb is impermeable
to water but ion transport does occur, which causes the urine osmolarity
to fall.
180 Section 8  Renal physiology
Thick ascending limb This limb is also impermeable to water. It contains
ion pumps to pump electrolytes actively into the interstitium. The main
pump is the Naþ/2Cl/Kþ co-transporter. Fluid leaving this limb is, there-
fore, hypotonic and passes into the distal convoluted tubule.
Collecting duct The duct has selective permeability to water, which is
controlled by ADH. In the presence of ADH, water moves into the inter-
stitium down the concentration gradient generated by the loop of Henle.
 Glucose handling

Filtered
Excreted
600

500
Glucose (mg.min–1)

400
Reabsorbed
300

200
TMAX
100

0
0 10 20 30 40 50
Plasma glucose (mmol.l–1)

Filtered After drawing and labelling the axes, draw a line passing through
origin, rising at an angle of approximately 458. This demonstrates that the
amount of glucose filtered by the kidney is directly proportional to the
plasma glucose concentration.
Reabsorbed This line also passes through the origin. It matches the ‘filtered’
line until 11 mmol.l 1 and then starts to flatten out as it approaches
maximal tubular reabsorption (TMAX). Demonstrate that this value is
300 mg.min 1 on the y axis.
Excreted Glucose can only appear in the urine when the two lines drawn so
far begin to separate so that less is reabsorbed than is filtered. This happens
at 11 mmol.l 1 plasma glucose concentration. The line then rises parallel to
the ‘filtered’ line as plasma glucose continues to rise.
 Sodium handling

Sodium concentration graph

Filtered sodium concentration

600

500
(mmol.l–1)

400
ADH
300

200
No
100 ADH

0
PCT DL Thin Thick DCT CD
AL AL
Tubular segment

PCT is proximal convoluted tubule, DL is descending limb of the loop of Henle,

Thin AL is thin ascending limb of the loop of Henle, Thick AL is thick ascending
limb of the loop of Henle, DCT is distal convoluted tubule and CD is collecting
duct. (This figure is reproduced with permission from Fundamental Principles
and Practice of Anaesthesia, P. Hutton, G. Cooper, F. James and J. Butterworth.
Martin-Dunitz 2002 pp. 487, illustration no. 25.16.)

The graph shows how the concentration of Naþ in the filtrate changes as it
passes along the tubule. An important point to demonstrate is how much of an
effect ADH has on the final urinary [Naþ]. Draw and label the axes as shown.
The initial concentration should be just below 200 mmol.l1. The loop of
Henle is the site of the countercurrent exchange mechanism so should result in
a highly concentrated filtrate at its tip, 500–600 mol.l1 is usual. By the end of
the thick ascending limb, you should demonstrate that the urine is now
hypotonic with a low [Naþ] of approximately 100 mmol.l1. The presence
of maximal ADH will act on the distal convoluted tubule and collecting duct
to retain water and deliver a highly concentrated urine with a high [Naþ] of
approximately 600 mmol.l1. Conversely, show that in the absence of ADH
the urinary [Naþ] may be as low as 80–100 mmol.l1.
 Potassium handling

Potassium concentration graph

Filtered potassium concentration

Low
100 flow
80
(mmole–1)

High
60 flow

40

20

0
PCT DL Thin Thick DCT CD
AL AL
Tubular segment

PCT is proximal convoluted tubule, DL is descending limb of the loop of Henle,

Thin AL is thin ascending limb of the loop of Henle, Thick AL is thick ascending
limb of the loop of Henle, DCT is distal convoluted tubule and CD is collecting
duct. (Reproduced with permission from Fundamental Principles and Practice of
Anaesthesia, P. Hutton, G. Cooper, F. James and J. Butterworth. Martin-Dunitz
2002 pp. 488, illustration no. 25.17.)

The graph shows how the filtrate [Kþ] changes as it passes along the tubule.
Draw and label the axes as shown. The curve is easier to remember as it stays
essentially horizontal at a concentration of approximately 5–10 mmol.l1
until the distal convoluted tubule. Potassium is secreted here along electro-
chemical gradients, which makes it unusual. You should demonstrate that at
low urinary flow rates, tubular [Kþ] is higher at approximately 100 mmol.l1
and so less Kþ is excreted as the concentration gradient is reduced. Conversely,
at higher urinary flow rates (as are seen with diuretic usage) the [Kþ] may only
be 70 mmol.l1 and so secretion is enhanced. In this way, Kþ loss from the
body may actually be greater when the [Kþ] of the urine is lower, as total loss
equals urine flow multiplied by concentration.
 Section 9 * Neurophysiology

Action potentials

Resting membrane potential

The potential difference present across the cell membrane when no stimula-
tion is occurring (mV).

The potential depends upon the concentration of charged ions present, the
relative membrane permeability to those ions and the presence of any ionic
pumps that maintain a concentration gradient. The resting membrane potential
is  60 to  90 mV, with the cells being negatively charged inside.

Action potential
The spontaneous depolarization of an excitable cell in response to a stimulus.

Gibbs–Donnan effect
The differential separation of charged ions across a semipermeable
membrane.

The movement of solute across a semipermeable membrane depends upon the

chemical concentration gradient and the electrical gradient. Movement occurs
down the concentration gradient until a significant opposing electrical potential
has developed. This prevents further movement of ions and the Gibbs–Donnan
equilibrium is reached. This is electrochemical equilibrium and the potential
difference across the cell is the equilibrium potential. It can be calculated using
the Nernst equation.

The Nernst equation

RT ½Co 
E¼  ln
zF ½Ci 

where E is the equilibrium potential, R is the universal gas constant, T is

absolute temperature, z is valency and F is Faraday’s constant.
 Action potentials 185

The values for Cl, Naþ and Kþ are  70, þ 60 and  90 mV, respectively.
Note that the equation only gives an equilibrium for individual ions. If more than
one ion is involved in the formation of a membrane potential, a different equation
must be used, as shown below.

Goldman constant field equation

RT ð½Naþ o :PNaþ þ ½Kþ o :PKþ þ ½Cl o :PCl Þ

E¼  ln
F ð½Naþ i :PNaþ þ ½Kþ i :PKþ þ ½Cl i :PCl Þ

where E is membrane potential, R is the universal gas constant, T is absolute

temperature, F is Faraday’s constant, [X]o is the concentration of given ion
outside the cell, [X]i is the concentration of given ion inside cell and PX is the
permeability of given ion.

Action potentials
You will be expected to have an understanding of action potentials in nerves,
cardiac pacemaker cells and cardiac conduction pathways.

Absolute refractory period

The period of time following the initiation of an action potential when no
stimulus will elicit a further response (ms).

It usually lasts until repolarization is one third complete and corresponds to the
increased Naþ conductance that occurs during this time.

Relative refractory period

The period of time following the initiation of an action potential when a larger
than normal stimulus may result in a response (ms).

This is the time from the absolute refractory period until the cell’s membrane
potential is less than the threshold potential. It corresponds to the period of
increased Kþ conductance.

Threshold potential
The membrane potential that must be achieved for an action potential to be
propagated (mV).
186 Section 9  Neurophysiology
Nerve action potential

30

Membrane Potential (mV)

2 3
0

–55
1
–70
4

0 1 2 3 4 5
Time (ms)

Draw and label the axes as shown.

Phase 1 The curve should cross the y axis at approximately 70 mV
and should be shown to rapidly rise towards the threshold potential of
55 mV.
Phase 2 This portion of the curve demonstrates the rapid rise in membrane
potential to a peak of þ 30 mV as voltage-gated Naþ channels allow rapid
Naþ entry into the cell.
Phase 3 This phase shows rapid repolarization as Naþ channels close and Kþ
channels open, allowing Kþ efflux. The slope of the downward curve is
almost as steep as that seen in phase 2.
Phase 4 Show that the membrane potential ‘overshoots’ in a process known
as hyperpolarization as the Naþ/Kþ pump lags behind in restoring the
normal ion balance.

Cardiac action potential

For cardiac action potentials and pacemaker potentials see Section 7.
 Action potentials 187

Types of neurone
You may be asked about different types of nerve fibre and their function. The table
is complicated but remember that the largest fibres conduct at the fastest speeds. If
you can remember some of the approximate values given below it will help to
polish your answer.

Fibre type Function Diameter (mm) Conduction (m.s1)

Aa Proprioception, motor 10–20 100

Ab Touch, pressure 5–10 50
Ag Muscle spindle motor 2–5 25
Ad Pain, temperature, touch 2–5 25
B (autonomic) Preganglionic 3 10
C Pain, temperature 1 1
C (sympathetic) Postganglionic 1 1

Velocity calculations
For myelinated nerves

V /d

where V is the velocity of transmission and d is the diameter of the neurone.

For unmyelinated nerves

p
V/ d
 Muscle structure and function

Neuromuscular junction
You may be questioned on the structure and function of the neuromuscular
junction and could be expected to illustrate your answer with a diagram.
A well-drawn diagram will make your answer clearer.

Nerve terminal
ACh receptor
Vesicle
ACh
AChE

Muscle membrane

The diagram shows the synaptic cleft, which is found at the junction of the
nerve terminal and the muscle membrane.
Vesicle You should demonstrate that there are two stores of acetylcholine
(ACh), one deep in the nerve terminal and one clustered beneath the
surface opposite the ACh receptors in the so-called ‘active zones’. The
deep stores serve as a reserve of ACh while those in the active zones are
required for immediate release of ACh into the synaptic cleft.
ACh receptor These are located on the peaks of the junctional folds of the
muscle membrane as shown. They are also found presynaptically on the
nerve terminal, where, once activated, they promote migration of ACh
vesicles from deep to superficial stores.
Acetylcholinesterase (AChE) This enzyme is found in the troughs of the
junctional folds of the muscle membrane and is responsible for metaboliz-
ing ACh within the synaptic cleft.
 Muscle structure and function 189

Sarcomere
The contractile unit of the myocyte.

You may be asked to draw a diagram of the sarcomere. It is made up of actin and
myosin filaments, as shown below. The thick myosin filaments contain many cross-
bridges, which, when activated, bind to the thin actin filaments. Tropomyosin
molecules (containing troponin) run alongside the actin filaments and play an
important role in excitation–contraction coupling.

The diagram should be drawn carefully so that the actin and myosin filaments
are shown to overlap while ensuring that enough space is left between them to
identify the various lines and bands.
Z line The junction between neighbouring actin filaments that forms the
border between sarcomeres. It has a Z-shaped appearance on the diagram.
M line The ‘middle’ zone of the sarcomere, formed from the junction
between neighbouring myosin filaments. There are no cross-bridges in
this region.
A band This band spans the length of the myosin filament although it is
confusingly given the letter A.
I band This band represents the portion of actin filaments that are not
overlapped by myosin. It comes ‘in between’ the Z line and the A band.
H band This band represents the portion of the myosin filaments that are
not overlapped by actin.
190 Section 9  Neurophysiology
Excitation–contraction coupling
The series of physiological events that link the depolarization of the muscle
membrane to contraction of the muscle fibre.

This is a complicated chain of events that can easily cause confusion in the
examination setting. The list below gives a summary of the salient points.

1. The action potential is conducted into muscle fibre by T-tubules.

2. Depolarization of the T-tubules results in calcium release from the sarcoplas-
mic reticulum.
3. Calcium-induced Ca2þ release increases the amount of intracellular Ca2þ by
positive feedback.
4. Calcium binds to troponin C on tropomyosin, causing a conformational
change that exposes myosin-binding sites on actin.
5. Myosin heads energized at the end of the previous cycle, can now bind to
actin.
6. Binding of myosin to actin triggers pivoting of the myosin head and short-
ening of the sarcomere. This is the powerstroke.
7. High concentrations of Ca2þ now cause Ca2þ channel closure.
8. Calcium is pumped back into the sarcoplasmic reticulum. This requires
adenosine triphosphate (ATP).
9. ATP binds to the myosin cross-bridges, leading to release of the bond between
actin and myosin.
10. The ATP is hydrolysed, energizing the myosin ready for the next contraction.
11. The muscle relaxes.
12. The decreased [Ca2þ] causes tropomyosin to resume its previous configura-
tion, blocking the myosin-binding site.
 Muscle reflexes

There is only one monosynaptic reflex known to exist in humans – the stretch
reflex. For this reason, it is commonly examined and an overview of its compo-
nents and their functions is given below.

The stretch reflex

A monosynaptic reflex responsible for the control of posture.

Ventral root
motor neurone efferent

Skeletal muscle Anterior horn

stretched cell

Dorsal root
muscle spindle afferent

Stretching of the muscle is sensed in the muscle spindle and leads to firing in
muscle spindle afferent. These nerves travel via the dorsal root and synapse in
the anterior horn of the spinal cord directly with the motor neurone to that
muscle. They stimulate firing of the motor neurones, which causes contraction
of the muscle that has just been stretched. The muscle spindle afferent also
synapses with inhibitory interneurons, which inhibit the antagonistic muscles.
This is called reciprocal innervation.

Muscle spindles
Stretch transducers encapsulated in the muscle fibre responsible for main-
tenance of a constant muscle length despite changes in the load.

Muscle spindles are composed of nuclear bag (dynamic) and chain (static) fibres
known as intrafusal fibres and these are innervated by g motor neurones.
Extrafusal fibres make up the muscle bulk and are innervated by a motor
neurones. Stimulation of the muscle spindle leads to increased skeletal muscle
contraction, which opposes the initial stretch and maintains the length of the
fibre. This feedback loop oscillates at 10 Hz, which is the frequency of a physio-
logical tremor.
192 Section 9
Neurophysiology
In the same way that muscle spindles are responsible for the maintenance of
muscle length, Golgi tendon organs are responsible for maintenance of muscle
tension.

Golgi tendon organs

These are found in muscle tendons and monitor the tension in the muscle.
Their function is to limit the tension that is generated in the muscle.

Tension is the force that is being opposed by the muscle and is a different concept
to stretch. The reflex can be summarized as below.

Ventral root
motor neurone efferent

Skeletal muscle Spinal cord

stretched Inhibitory interneurones

Tendon
Golgi tendon organ

Golgi tendon organs are in series with the muscle fibres. They are stimulated
by an increase in tension in the muscle, which may be passive owing to muscle
stretch or active owing to muscle contraction. Stimulation results in increased
firing in afferent nerve fibres, which causes inhibition of the muscle in ques-
tion, increasing muscle stretch and, therefore, regulating muscle tension. The
antagonistic muscle is simultaneously stimulated to contract.

All these muscle reflexes are under the control of descending motor pathways and
are integrated in the spinal cord.
 The Monro–Kelly doctrine

The skull is a rigid container of constant volume. The Monro–Kelly doctrine

states that any increase in the volume of one of its contents must be compen-
sated for by a reduction in volume of another if a rise in intracranial pressure
(ICP) is to be avoided.

This volume of the skull comprises three compartments:

 brain (85%)
 cerebrospinal fluid (CSF) (10%)
 blood (5%).
Compensation for a raised ICP normally occurs in three stages. Initially there is a
reduction in venous blood volume followed by a reduction in CSF volume and
finally arterial blood volume.

Intracranial volume–pressure relationship

60
Global
Intracranial pressure

50 ischaemia

40
(mmHg)

Focal
30 ischaemia

20
Compensation
10

0
Intracranial volume

Draw and label the axes as shown. Note that the x axis is usually drawn without
any numerical markers. Normal intracranial volume is assumed to be at the left
side of the curve and should be in keeping with an ICP of 5–10 mmHg. Draw a
curve similar in shape to a positive tear-away exponential. Demonstrate on your
curve that compensation for a rise in the volume of one intracranial component
maintains the ICP < 20 mmHg. However, when these limited compensatory
mechanisms are exhausted, ICP rises rapidly, causing focal ischaemia (ICP
20–45 mmHg) followed by global ischaemia (ICP > 45 mmHg).
 Intracranial pressure relationships

Autoregulation
The ability of an organ to regulate its blood flow despite changes in its perfu-
sion pressure.

Autoregulation of cerebral blood flow

Autoregulatory
range
100
Normal Chronic
Cerebral blood flow

hypertension
(ml.100 g–1 min–1)

75

50

25

0
0 50 100 150 200
Mean arterial pressure (mmHg)

Draw and label the axes as shown. Mark the two key points on the x axis (50
and 150 mmHg). Between these points, mark a horizontal line at a y value of
50 ml.100g1.min1. Label this segment the ‘autoregulatory range’. Above this
range, cerebral blood flow (CBF) will increase as mean arterial pressure (MAP)
increases. There will, however, be a maximum flow at some MAP where no
further increase is possible. Below 50 mmHg, CBF falls with MAP; however,
the line does not pass through the origin as neither MAP nor flow can be zero
in live patients. Demonstrate the response to chronic hypertension by drawing
an identical curve displaced to the right to show how the autoregulatory range
‘resets’ itself under these conditions.

Cerebral perfusion pressure

CPP ¼ MAP  ðICP þ CVPÞ

where CPP is cerebral perfusion pressure and CVP is central venous pressure.
 Intracranial pressure relationships 195

Often, CVP is left out of this equation as it is normally negligible. In order to

maintain cerebral perfusion when ICP is raised, the MAP must also be elevated.

Effects of PaCO2 on cerebral blood flow

100
Normal
Cerebral blood flow
(ml.100g–1.min–1)

Chronic
hypercapnoea
50

0
0 5 10 15
PaCO2 (kPa)

Draw and label the axes.

Normal Mark a point at the intersection of a normal PaCO2 and cerebral
blood flow as shown. As CBF will approximately double with a doubling of
the PaCO2 extend a line from this point up to a PaCO2 of around 10 kPa. At
the extremes of PaCO2 there arise minimum and maximum flows that
depend on maximal and minimal vasodilatation, respectively. The line
should, therefore, become horizontal as shown at these extremes.
Chronic hypercapnoea The curve is identical but shifted to the right of the
normal curve as buffering acts to reset the autoregulatory range.
196 Section 9  Neurophysiology
Effects of PaO2 on cerebral blood flow

100

Cerebral blood flow

(ml.100g–1.min–1)
50

8
0
0 5 10 15 20
PaO2 (kPa)

Draw and label the axes. Plot a point at a normal PaO2 and CBF as shown.
Draw a horizontal line extending to the right of this point. This demonstrates
that for values >8 kPa on the x axis, CBF remains constant. Below this point,
hypoxia causes cerebral vasodilatation and CBF rises rapidly. At flow rates
>100 ml.100g1.min1, maximal blood flow will be attained and the curve
will tail off. Remember that the vasodilatory effect of hypoxia will override any
other reflexes to ensure maximal oxygenation of the brain tissue.
 Formation and circulation
of cerebrospinal fluid

Formation of cerebrospinal fluid

The choroid plexus in the ventricles of the brain produce CSF at a constant rate of
500 ml.day 1 or 0.35 ml.min 1. The total volume of CSF is around 150 ml in the
average adult. The rate of reabsorption of CSF is proportional to its outflow pressure.

Circulation of cerebrospinal fluid

An understanding of this well-documented circulatory route for CSF will be
expected in the examinations.

Produced by
choroid plexus of
lateral ventricle

Foramen of
Monro

III ventricle

Sylvian
aqueduct

IV ventricle

Foramen of Magendie
(medial)

Foramen of Lushka
(lateral)

Spinal canal

Absorbed by the
arachnoid villi in
venous sinuses
 Pain

Pain is an unpleasant sensory and/or emotional experience associated with

actual or potential tissue damage.

Chronic pain
Pain that persists after removal of the stimulus and beyond the normal recov-
ery period.

Some believe that pain should be present for at least 3 months in order to be
‘chronic’ although most examiners should accept the definition above.

Nociception
The sensation of the noxious stimulus occurring within the brain.

Allodynia
A painful response to a normally painless stimulus.

Hyperalgesia
An exaggerated response to a normally painful stimulus.

Primary hyperalgesia occurs within the zone of injury and is caused by changes at
the injury site itself. Secondary hyperalgesia occurs around the zone of injury and
results from neuroplasticity and remodelling.

Hyperpathia
Pain in response to a stimulus despite sensory impairment.

Plasticity
The ability of the nervous system to adapt or change according to its
environment.

The gate control theory of pain

Melzack and Wall theorized that the transmission of a peripheral painful stimulus
to the CNS occurs via a ‘gate’ at spinal cord level. This gate comprises an
inhibitory interneurone in the substantia gelatinosa that may be either stimulated
or inhibited by different afferent inputs. A simple line diagram can be useful when
explaining the mechanism to avoid confusion.
 Pain 199

Neuronal connections

The Ab fibres are examples of afferents that stimulate inhibitory interneurones (in
the substantia gelatinosa (SG)) and, therefore, prevent nociceptive transmission
to the CNS. The C fibres are examples of afferents that inhibit inhibitory inter-
neurones and, therefore, enhance nociceptive transmission. Note that both types
of fibre stimulate the second-order neurone (28) directly but it is the interneurone
that modifies the transmission.

Pain pathway
The diagram below shows the pathway of pain transmission from the peripheral
nerves to the cerebral cortex. There are three levels of neuronal involvement and
the signals may be modulated at two points during their course to the cerebral
cortex. Descending inhibitory pathways arise in the midbrain and pass to the
dorsal horn as shown. Multiple different neurotransmitters are involved in the
pathway and include gamma-aminobutyric acid (GABA), N-methyl-D-aspartate
(NMDA), noradrenaline and opioids.

Contralateral cortex
Somatosensory area I (post central gyrus)
Somatosensory area II (sylvian fissure)

Sensory relay 3rd order neurone

Thalamus (midbrain) Modulation

Ventral posterior & medial nuclei Descending
collaterals to periaqueductal gray & locus ceruleus pathways originate

Via lateral spinothalamic tract 2nd order neurone

Dorsal horn of spinal cord Modulation

A : laminae I & V Gate control theory
C:laminae II & III (substantia gelatinose)

Via dorsal root ganglion 1st order neurone

Peripheral nerve fibres

A fibres, C fibres
 Section 10 * Statistical principles

Data types

Population
The entire number of individuals of which the sample aims to be
representative.

Sample
A group taken from the wider population. A sample aims to be representative
of the population from which it is taken.

As samples are smaller, they are easier to collect and to analyse statistically.
However, as they do not contain all of the values in the population, they can
misrepresent it. Statistical analysis is often used to decide whether samples of data
come from the same or from different populations. Populations are described by
parameters and samples by statistics.

Categorical (qualitative) data

Nominal
Data that have no numerically significant order, such as blood groups.

Ordinal
Data that have an implicit order of magnitude, such as ASA score.

Numerical (quantitative) data

Discrete
Data that have finite values, such as number of children.

Continuous
Data that can take any numerical value including fractional values. Examples
include weight or height.
 Data types 201

Ratio
Any data series that has zero as its baseline value, for example blood pressure
or the Kelvin temperature scale.

Interval
Any data series that includes zero as a point on a larger scale, for example the
centigrade temperature scale.

There is a hierarchy of usefulness of data, according to how well it can be

statistically manipulated. The accepted order is continuous data > ordinal
data > nominal data.
 Indices of central tendency and variability

Describing data
Once data have been collected, the values will be distributed around a central
point or points. Various terms are used to describe both the measure of central
tendency and the spread of data points around it.

Measures of central tendency

Mean
The average value: the sum of the data values divided by the number of data
points. Denoted by the symbol x̄ when describing a sample mean and  when
describing a population mean.

The mean is always used when describing the normal distribution and, therefore,
it is the most important measure with regards to the examination.

Median
The middle value of a data series, having 50% of the data points above it and
50% below.

If there are an even number of data points, the median value is assumed to be the
average of the middle two values.

Mode
The most frequently occurring value in a set of data points.

The data can be plotted on a graph to demonstrate the distribution of the values.
The individual values are plotted on the x axis with the frequency with which they
occur on the y axis.

Measures of spread
Variance
A measure of the spread of data around a central point. Described by the
following equation.

ðx  xÞ2
Var ¼
n1
 Indices of central tendency and variability 203

Standard deviation
A measure of the spread of data around a central point. Described by the
following equation ( for population, SD for sample):
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ðx  xÞ2
SD ¼
n1

Begin by finding the mean value (x̄) of the distribution and then subtract each
data point from it to find the difference between the values

x  x

Square the results to ensure that all values are positive numbers:

ðx  xÞ2

Sum the results:

ðx  xÞ2

Next divide the result by the number of observations (minus 1 for statistical
reasons) to give the mean spread or variance

ðx  xÞ2
n1

The units for variance are, therefore, squared, which can cause difficulties. If the
observations are measuring time for instance, the variance may be given in
seconds squared (s2), which is meaningless. The square root of the variance is,
therefore, used to return to the original units. This is the SD.
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
ðx  xÞ2
SD ¼
n1

The spread of data is often described by quoting the percentage of the sample or
population that will fall within a certain range. For the normal distribution, 1SD
either side of the mean will contain 68% of all data points, 1.96SD 95%, 2SD
95.7% and 3SD 99.7%.
204 Section 10  Statistical principles
Standard error of the mean
The standard deviation of a group of sample means taken from the same
population (SEM):
p
SEM ¼ = ðn  1Þ

where  is the SD of the population and n is the number in the samples.

In practice, the population SD is unlikely to be known and so the sample SD is

used instead, giving
p
SEM ¼ SD= ðn  1Þ

In the same way as the SD is used as a measure of spread around a mean, the SEM
is used as a measure of the spread of a group of sample means around the true
population mean. It is used to predict how closely the sample mean reflects the
population mean.
As the sample size increases, SEM becomes smaller. For this reason, the SEM is
sometimes quoted in study results rather than the SD in order to make the data
look better.

Degrees of freedom
Statistics frequently involve calculations of the mean of a sample. In order to be
able to calculate a mean, there must be at least two values present. For this reason,
when describing sample size, the term n  1 is often used instead of the actual
number. One of the sample points must be present in order that each of the other
points can be used in the mean calculation. In other words, the size of the freely
chosen sample must always be one less than are actually present.
For large sample sizes, the correction factor makes no difference to the calcula-
tion, but for small sample sizes it can be quite important. It is, therefore, best
always to describe the sample size in this way.

Confidence intervals
The range of values that will contain the true population mean with a stated
percentage confidence. Used in parametric tests.

A 95% confidence interval is 1.96SD and is the most frequently quoted. There is
a 95% certainty that this range of values around the mean will contain the
population mean.
 Indices of central tendency and variability 205

Quartile
Any one of the three values that divide a given range of data into four
equal parts.

In order to tear a piece of paper into four equally wide strips, three tears must be
made. One to tear the original paper in half and the other two to tear those halves
in half again. A quartile is the mathematical equivalent of this to a range of
ordered data. You should realize that the middle quartile (Q2 ) is, in effect, the
median for the range. Similarly, the first quartile (Q1) is effectively the median of
the lower half of the dataset and the third quartile (Q3) the median of the upper
half. In the same way as for the median calculation, a quartile should be repre-
sented as the mean of two data points if it lies between them.

Interquartile range
The range of values that lie between the first and third quartiles and, therefore,
represent 50% of the data points. Used in non-parametric tests.

Calculating quartiles and using the interquartile range is useful in order to negate
the effect of extreme values in a dataset, which tend to create a less stable statistic.
 Types of distribution

The normal distribution

A bell-shaped distribution in which the mean, median and mode all have the
same value, with defined SD distribution as above.

The curve is symmetrical around the mean, which is numerically identical to

the median and mode. The SD should be indicated; 1SD lies approximately
one third of the way between x̄ and the end of the curve.

Positively skewed distribution

The curve is asymmetrical with a longer tail stretching off towards the more
positive values. The mean, median and mode are now separated so that x̄ is
nearest the tail of the curve; the mode is at the peak frequency and the median
is in between the two. This type of distribution can sometimes be made normal
by logarithmic transformation of the data.
 Types of distribution 207

Negatively skewed distribution

The curve is asymmetrical with a longer tail stretching off towards the more
negative values. The mean, median and mode are now separated in the other
direction, with x̄ remaining closest to the tail. This type of distribution can
sometimes be made normal by performing a power transformation (squaring
or cubing the data).

Bimodal distribution

The curve need not be symmetrical nor have two modes of exactly the same
height but the above curve demonstrates the principle well. The low point
between the modes is known as the antimode. This curve could represent the
heights of the population, with one mode for men and one for women.
 Methods of data analysis

When performing a study, the first step is to pose a question. The question is
formulated as a hypothesis that must be proved or disproved. This question is
known as the null hypothesis.

The null hypothesis

The hypothesis states that there is no difference between the sample groups;
that is, they both are from the same population (H0).

The study then examines whether this is true. The amount of data needed to prove
a difference between the samples depends on the size of the difference that is to be
detected. Enough data must be collected to minimize the risk of a false-positive or
false-negative result. This is determined by a power calculation.

Power
The ability of a statistical test to reveal a difference of a certain magnitude (%):

1

where  is the  error (type II error).

Acceptable power is 80–90%, which equates to a  value of 10–20%. In effect, this

means a 10–20% chance of a false-negative result.

The p value
The likelihood of the observed value being a result of chance alone.

Conventionally a p (probability) value of < 0.05 is taken to mean statistical

significance. This means that if p ¼ 0.05 then the observed difference could
occur by chance on 1 in 20 (5%) of occasions. In effect, this means a 5% chance
of a false-positive result.

Number needed to treat

The number of patients that have to be treated to prevent one outcome event
occurring.
 Methods of data analysis 209

Absolute risk reduction

The numerical difference between the risk of an occurrence in the control and
treatment groups.

ðIncidence in treatment groupÞ  ðIncidence in control groupÞ

Relative risk reduction

The ratio of the absolute risk reduction to the control group incidence (%):

ðAbsolute risk reductionÞ

ðControl incidenceÞ

Relative risk
The ratio of the risk of an occurrence in the treatment group to that in the
control group:

ðIncidence in treatment groupÞ

ðIncidence in control groupÞ

If the control incidence is low, this can lead to an overestimation of the treatment
effect.

Odds ratio
Ratio of the odds of outcome in the treatment group to the odds of outcome in
the control group.

Unpaired test
Different patients are studied in each of the intervention groups.

Paired test
The same patient is studied for each intervention, thereby acting as their own
control. Matched patients can also be used.

Student’s t-test
A parametric test for comparison of sample means where

Difference between sample means

t¼
Estimated SE of the difference
210 Section 10  Statistical principles
Once a value for t is obtained, it is read from a table to see if it represents a
statistically significant difference at the level of probability required, for example
p < 0.05.

One-tailed test
A statistical test in which the values that will allow rejection of the null
hypothesis are located only at one end of the distribution curve.

For example, if a study were to investigate the potential of a new antihypertensive

drug, a one-tailed test may be used to look for a decrease but not an increase in BP.

Two-tailed test
A statistical test in which the values that will allow rejection of the null
hypothesis are located at either end of the distribution curve.

A study investigating the effect of a drug on serum Naþ levels could use a two-tailed
test to identify both an increase and a decrease. In general, unless you are sure that a
variable can only move in one direction, it is wise to use a two-tailed test.

Chi-square (c 2) test
Compares the frequency of observed results against the frequency that would
be expected if there were no difference between the groups.

ðO  EÞ2
2 ¼ 
E
where 2 is the chi-square statistic, E is the number of expected occurrences
and O is the number of observed occurrences.

It is best demonstrated by constructing a simple 3  3 table. You may be provided

with a pre-printed table in the examination but be prepared to draw your own.
 Methods of data analysis 211

The numbers in the unshaded portion of the table give you the observed
frequency. The expected percentage of smokers if there were no difference
between the sexes would be 100/180 (55.6%) smokers and 80/180 (44.4%) non-
smokers in each group. To find the actual frequency in each group, this percen-
tage is multiplied by the respective row total.

Column total
E¼  Row total
Grand total

The table now has an expected frequency in parentheses in each cell along with
the observed frequency. The calculation (O  E)2/E is performed for each cell and
the results summed to give the 2 statistic.

Degrees of freedom for c 2

Degrees of freedom for a table are calculated in a similar way to those for
distributions.

DF ¼ ðNo: of rows  1Þ  ðNo: of columns  1Þ

Therefore for a 2  2 table

DF ¼ ð2  1Þ  ð2  1Þ
DF ¼ 1  1
DF ¼ 1

When the 2 statistic has been calculated, it is cross-referenced to a table of values

together with various degrees of freedom. The table will enable the statistician to
see if the groups are statistically different or not.

Fisher’s exact test

This is a variation of the 2 test that is used when the value for E in any cell is 5 or less.
212 Section 10  Statistical principles
Correlation
A representation of the degree of association between two variables.

Importantly, this does not identify a cause and effect relationship but simply an
association.

Correlation coefficient
A numerical description of how closely the points adhere to the best fit straight
line on a correlation plot (r).

The value of r lies between 1. A value of þ1 indicates a perfect positive correla-
tion and a value of 1 a perfect negative correlation. A value of 0 indicates that
there is no correlation between the two variables.

Regression coefficient
A numerical description of the gradient of the line of best fit using linear
regression analysis (b).

The regression coefficient allows prediction of one value from another. However,
it is only useful when the intercept on the y axis is also known, thereby describing
the relationship by fixing the position of the line as for the equation y ¼ bx þ a.

Positive correlation

r = +0.8
Value y

Value x

Draw and label the axes. The x axis is traditionally where the independent
variable is plotted. Draw a line of best fit surrounded by data points. As the line
of best fit has a positive slope, both b and r will be positive. However, r will not
be þ1 as the data points do not lie exactly on the line. In this case r is
approximately þ0.8.
 Methods of data analysis 213

Negative correlation

r = –0.8

Value y

Value x

This plot is drawn in exactly the same way but now with a negative slope to
the line of best fit. Both b and r will now be negative but, again, r will not be 1
as the data points do not lie exactly on the line. In this case r is approximately
0.8.

Exact negative correlation

r = –1.0
Value y

Value x

This plot is drawn in the same way as the negative plot but now the line of best
fit becomes a line of exact fit. Both b and r will now be negative and r will be 1
as the data points lie exactly on the line.
214 Section 10  Statistical principles
No correlation

r=0

Value y

Value x

Draw and label the axes as before but note that on this plot there is no
meaningful line of best fit as the data points are truly random. It is not possible
to give a value for b as a line of best fit cannot be generated but the value of
r is 0.

Bland–Altman plot
The Bland–Altman plot is superior to regression/correlation analysis when used
to compare two methods of measurement. It is the method of choice when
comparing one method to an agreed gold standard.
The true value being measured by the two methods is assumed to be the average
of their readings. This is then plotted against the difference between the two
readings at that point. The level of agreement or disagreement at every value is,
therefore, obtained and a mean and SD can be calculated.

Bias
The extent to which one method varies with respect to another when the two
methods are compared.

The mean difference between methods should ideally be zero. However, if it is felt
that the clinical difference between the methods is not significant, then the mean
difference can simply be added to or subtracted from the results of one method in
order to bring them into line with the gold standard. The amount by which the
mean differs from zero is called the bias.
 Methods of data analysis 215

No agreement

+2SD

Difference (x–y)
Mean

–2SD

Average of x and y

Draw and label the axes as shown. Widely scattered data points as shown
suggest no firm comparison between methods x and y. Demonstrate that
2SD (95% CI) is wide and the distribution of the points appears arbitrary.
Bias can be demonstrated by showing a mean point that does not lie at zero on
the y axis.

Good agreement
Difference (x–y)

+2SD
0 Mean
–2SD

Average of x and y

On the same axes draw a tightly packed group of data points centred around a
mean difference of zero. The 2SD should show a narrow range. This plot
demonstrates good agreement between the methods used.
216 Section 10  Statistical principles
Interpretation
The test does not indicate which method is superior, only the level of agreement
between them. It is entirely possible that a method which shows no agreement
with a current standard is, in fact, superior to it, although other tests would have
to be used to determine its suitability.

Reference table of statistical tests

Type of data Two groups More than two groups

Unpaired Paired Unpaired Paired

Parametric
Continuous Student’s Student’s ANOVA Paired
unpaired paired t-test ANOVA
t-test
Non-parametric
Nominal 2 with Yates’ McNemar’s 2 –
correction test
Ordinal or numerical Mann–Whitney Wilcoxon Kruskal–Wallis Friedman
U test signed rank
test
 Error and outcome prediction

In medicine, we often try to predict an outcome based on the result of a test. There
are various terms used to describe how useful a test is, which may be best under-
stood by reference to a table such as the one below.

Type I error
The occurrence of a positive test result when the actual value is negative (%).

This type of error equates to box B and is variously described as a type I error, a
false-positive error or the  error. A type I error in a study result would lead to the
incorrect rejection of the null hypothesis.

Type II error
The occurrence of a negative test result when the actual value is positive (%).

This type of error equates to box C and is variously described as a type II error, a
false-negative error or the  error. A type II error in a study result would lead to
the incorrect acceptance of the null hypothesis.

Sensitivity
The ability of a test to correctly identify a positive outcome where one
exists (%):

The number correctly identified as positive

Total number that are actually positive

or, in the Figure:

A=ðA þ CÞ
218 Section 10  Statistical principles
Specificity
The ability of a test to correctly identify a negative outcome where one exists
(%):

The number correctly identified as negative

Total number that are actually negative

or

D=ðB þ DÞ

Positive predictive value

The certainty with which a positive test result correctly predicts a positive value
(%):

The number correctly identified as positive

Total number with positive outcome

or

A=ðA þ BÞ

Negative predictive value

The certainty with which a negative test result correctly predicts a negative
value (%):

The number correctly identified as negative

Total number with negative outcome

or

D=ðC þ DÞ
 Clinical trials

Phases of clinical trials

Clinical trials will be preceded by in-vitro and animal studies before progressing
through the stages shown in the table.

Phase Description Numbers

1 Healthy volunteers: pharmacokinetic and pharmacodynamic 20–50

effects
2 More pharmacokinetic and dynamic information: different drug 50–300
doses and frequencies
3 Randomized controlled trials: comparison with current 250–1000 þ
treatments; assessment of frequent side effects
PRODUCT LICENCE
4 Postmarketing surveillance: rare side effects 2000–10 000 þ

Trial design flow sheet

Ethics approval

Trial design
• Formulate null hypothesis
• Set controls and outcomes
• Define subject selection
• Calculate sample size (power calculations)

The trial
• Randomization
• Blinding
• Data collection
• Minimize/prevent bias

Analysis
• Statistical manipulation of data
• Assess clinical significance
 Evidence-based medicine

Evidence-based medicine
The use of current best evidence, clinical expertise and patient values to make
decisions about the care of individual patients.

Levels of evidence
In this era of evidence-based medicine, there needs to be a method of categorizing
the available evidence to indicate how useful it is. The following system is the one
used by the UK National Institute for Health and Clinical Excellence (NICE).
Other organizations that produce guidelines may use slightly different systems
but the hierarchy of usefulness remains the same. The levels of evidence are based
on study design, with some systems, such as this one, subdividing the grades
further depending on the methodological quality of individual studies.

Level Evidence description

1a Systematic review or meta-analysis of one or more randomized controlled trials

(RCT)
1b At least one RCT
2a At least one well-designed, controlled, non-randomized study
2b At least one well-designed quasi-experimental study; for example a cohort study
3 Well-designed non-experimental descriptive studies; for example comparative,
correlation or case–control studies, or case series
4 Expert opinion

Grade of recommendations
Similarly, the strength of any recommendation made on the basis of the evidence
can be categorized. This is an example from NICE.

Grade Recommendation description

A Based directly on level 1 evidence

B Based directly on level 2 evidence or extrapolated from level 1 evidence
C Based directly on level 3 evidence or extrapolated from level 1 or level 2 evidence
D Based directly on level 4 evidence or extrapolated from level 1, level 2 or level 3
evidence
GPP Good practice point based on the view of the Guideline Development Group
 Evidence-based medicine 221

An alternative is to think in terms of ‘do it’ or ‘don’t do it’, based on conclusions

drawn from high-quality evidence or ‘probably do it’ or ‘probably don’t do it’
based on moderate quality evidence. Low-quality evidence leads to uncertainly
and inability to make a recommendation.

Meta-analysis
A statistical technique that combines the results of several independent stu-
dies that address a similar research hypothesis.

Meta-analysis aims to increase the statistical power of the available evidence by

combining the results of smaller trials together using specific statistical methods.
The validity of the meta-analysis will depend on the quality of the evidence on
which it is based and how homogeneous or comparable the samples are.
Combining very heterogeneous study populations can lead to bias.

Forest plot
A graphical representation of the results of a meta-analysis.

Begin by drawing and labelling the axes as shown. Draw a vertical line from 1
on the x axis. This is the line of no effect. The results of the individual trials are
shown as boxes with the size of the box relating to the size of the trial and its
position relating to the result of the trial. The lines are usually the 95%
confidence intervals. The combined result is shown at the bottom of all the
trials as a diamond, the size of which represents the combined numbers from
all the trials. The result can be considered statistically significant if the con-
fidence intervals of the combined result do not cross the line of no effect.
 Appendix

Intravenous induction agents

Thiopental Methohexital Propofol Ketamine Etomidate

Chemical composition Thiobarbiturate Oxybarbiturate 2,6 Diisopropylphenol Phenylcyclidine Imidazole ester

derivative
Dose (mg.kg1) 3–7 1–1.5 1–2 1–2 i.v., 5–10 i.m. 0.3
pKa 7.6 7.9 11.0 7.5 4.0
pH in solution 10.5 11 6–8.5 3.5–5.5 8.1
Volume of distribution (l.kg1) 2.5 2.0 4.0 3.0 3.0
Protein binding (%) 80 60 98 25 75
Racemic [ [ x [ [
Action "duration of GABAA opening, leading Stimulates GABA; Inhibits NMDA and Stimulates GABA
to " Cl current inhibits NMDA opioid  receptors
(stimulates  and )
Metabolism Oxidation Glucuronidation N-Demethylation Plasma and hepatic
Hydroxylation Hydroxylation esterases
Metabolites Active Minimal activity Inactive Active Inactive
Clearance (ml.kg1.min1) 3.5 11 30–60 17 10–20
Elimination rate (telim) (h) 6–15 3–5 5–12 2 1–4
Hypersensitivity Anaphylaxis More common Rashes in 15% Rare
1:20 000 than thiopental
but less severe
Intravenous induction agents: physiological effects

Thiopental Methohexital Propofol Ketamine Etomidate

Blood pressure # # ## " «

Cardiac output # # ## " «
Heart rate " " #! " «
Systemic vascular resistance ## « «

«
«
Respiratory rate # # # " #
Intracranial pressure # # # " «
Intraocular pressure # # # " «
Pain on injection No Yes Yes No Yes
Nausea/vomiting No No No Yes Yes
Miscellaneous Intra-arterial injection # Fit threshold ? Toxic in children " Salivation; Adrenal suppression
! crystallization (metabolic acidosis ‘dissociative
and bradycardia) anaesthesia’
Inhalational anaesthetic agents

Halothane Isoflurane Enflurane Sevoflurane Desflurane Nitrous oxide

Relative molecular mass 197 184.5 184.5 200.1 168 44

(kDa)
Boiling point (8C) 50.2 48.5 56.5 58.5 23.5 88
Saturated vapour pressure 32.3 33.2 23.3 22.7 89.2 5200
at 20 8C (kPa)
Blood:gas 2.4 1.4 1.8 0.7 0.45 0.47
Oil:gas 224 98 98 80 29 1.4
Minimum alveolar 0.75 1.17 1.68 1.8–2.2 6.6 105
concentration
Odour Non-irritant Irritant Non-irritant Non-irritant Pungent Odourless
Metabolized (%) 20 0.2 2 3.5 0.02 0.01
Metabolites Trifluoroacetic Trifluoroacetic Inorganic and Inorganic and Trifluoroacetic acid Nitrogen
acid, Cl, Br acid, F, organic fluorides organic fluorides;
compounds A–E

Xenon: 131 kDa; boiling point 108 8C; blood:gas solubility coefficient 14; oil:gas solubility coefficient 1.9; MAC 71; odourless.
Inhalational agents: physiological effects

Halothane Isoflurane Enflurane Sevoflurane Desflurane Nitrous oxide

Contractility ### # ## # « #
Heart rate ## "" " « " ("" > 1.5 MAC) «
Systemic vascular # ## # # ##
resistance
Blood pressure ## ## ## # ## –
Sensitivity to """ – " – –
catecholamines
Respiratory rate " "" "" "" "" "
Tidal volume # ## ### # ## #
PaCO2 « "" """ " "" «
Bronchodilatation Yes Yes Yes Irritant –
Cerebral blood flow """ " (Yes MAC > 1) " Preserves " "
autoregulation
Cerebral metabolic # # # # # #
O2 rate
Electroencephalography Burst suppression Burst suppression Epileptiform Burst suppression Burst suppression
activity
Uterus Some relaxation Some relaxation Some relaxation Some relaxation Some relaxation
Muscle relaxation Some Significant Significant Significant Significant
Analgesia Some Some Some Some Some
Miscellaneous Hepatotoxicity; Coronary steal?; Hepatotoxic; Renal toxicity Oxidizes cobalt ion
stored in 0.01% maintains renal avoid in renal in vitamin B12
thymol; light blood flow impairment
sensitive

MAC, minimum alveolar concentration.

Opioids a

Morphine Diamorphine Codeine Pethidine Fentanyl Alfentanil Remifentanil

Chemical Diacetylmorphine Methylmorphine Synthetic phenylpiperidines!

composition
pKa 8.0 7.6 8.2 8.7 8.4 6.5 7.1
Relative lipid 1 250 30 600 90 20
solubility
Relative potency 1 2 0.1 0.1 100 10–20 100
Protein binding 35 40 7 60 83 90 70
(%)
Volume of 3.5 5 5.4 4.0 4.0 0.6 0.3
distribution
(l.kg1)
Oral bioavailability 25–30 Low 50 (20–80) 50 33 N/A N/A
(%)
Metabolism Glucuronidation; Ester hydrolysis Glucuronidation; Ester hydrolysis; N-Dealkylation, N-Demethylation Plasma and
N-demethylation to morphine demethylation N-demethylation then tissue
(CYP2D6) hydroxylation esterases
Clearance 16 3.1 23 12 13 6 40
(ml.kg1.min1)
Elimination rate 170 5 (t1/2) 170 210 190 100 10
(min)

a
Opioids are bases.
Local anaesthetics a

Esters (-COO-) Amides (-NHCO-)

Procaine Amethocaine Lidocaine Prilocaine Bupivicaine Ropivicaine Mepivicaine

Relative potency b 1 8 2 2 8 8 2
Onset c Slow Slow Fast Fast Medium Medium Slow
Duration d Short Long Medium Medium Long Long Medium
Maximum dose (mg.kg1) 12 1.5 3 6 2 3.5 5
Toxic plasma level (mg.ml1) >5 >5 >1.5 >4 >5
pKa 8.9 8.5 7.9 7.7 8.1 8.1 7.6
Protein bound (%) 6 75 70 55 95 94 77
Relative lipid solubility 1 200 150 50 1000 300 50
Volume of distribution (l) 92 191 73 59
Metabolism By esterases to para- By hepatic amidases!
aminobenzoic acid
(allergenic)
Clearance (l.min1) 1 2.4 .6 0.82
Elimination rate (min) 100 100 160 120 115

a
Local anaesthetics are weak bases. They have hydrophilic plus hydrophobic components linked by an ester or amide group (hence classification). Local
anaesthetics can act as vasodilators; prilocaine > lignocaine > bupivicaine > ropivicaine.
b
Potency is related to lipid solubility.
c
Speed of onset is related to pKa.
d
Duration of action is related to protein binding.
Non-depolarizing muscle relaxants

Aminosteroids Benzylisoquinoliniums

Vecuronium Rocuronium Pancuronium Atracurium Cis-atracurium Mivacurium Gallamine Tubocurare

Structure Monoquaternary Monoquaternary Bisquaternary 10 stereoisomers 3 stereoisomers Monoquaternary

Dose (mg.kg 1) 0.1 0.6 0.1 0.5 0.2 0.2 2.0 0.5
Onset Medium Rapid Medium Medium Medium Medium Rapid Slow
Duration Medium Medium Long Medium Medium Short Medium Long
Cardiovascular # HR – " HR – – – " HR # BP
effects
Histamine release – – – Mild Rare Mild Rare Common
Protein bound 10 10 20–60 15 15 10 10 30–50
(%)
Volume of 0.2 0.2 0.3 0.15 0.15 0.2–0.3 0.2 0.3
distribution
(l.kg1)
Metabolism (%) 20 a < 5a 30 a 90 b 95 90 0 0
Elimination in 70 60 20 0 0 0 0 30
bile (%)
Elimination in 30 40 80 10 5 5 100 70
urine (%)
Renal failure Prolonged action! – – – Prolonged action!

HR, heart rate; BP, blood pressure.

a
By deacetylation.
b
By Hoffman degradation and ester hydrolysis.
Intravenous fluids: crystalloids

Naþ Kþ Ca2þ Cl HCO3 Osm pH Glucose

(mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1) (g.l1)

0.9% Saline 154 0 0 154 0 300 5 0

5% Dextrose 0 0 0 0 0 280 4 50
10% Dextrose 0 0 0 0 0 560 4 100
4% Dextrose, 0.18% 31 0 0 31 0 255 4.5 40
saline
Hartmann’s solution 131 5 2 111 29 278 6 0
8.4% NaHCO3 1000 0 0 0 1000 2000 8 0
Intravenous fluids: colloids

Composition MW Naþ Kþ Ca2 þ Mg2þ Cl Osm pH

(kDa) (mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1) (mmol.l1)

Gelofusine Succinylated gelatin 30–35 154 0.4 0.4 0.4 125 279 7.4
Haemaccel Polygelines 30–35 145 5.1 6.25 0 145 301 7.3
Hydroxyethyl Esterified amylopectin 450 154 0 0 0 154
starch (HES)
Dextran 70 Polysaccharides in 5% 70 0 0 0 0 0 287 3.5–7
dextrose
HES 4.5% Fractionation of 69 100–160 <2 0 0 100–160 270–300 6.4–7.4
HES 20% plasma 69 50–120 <10 0 0 <40 135–138 6.4–7.4

MW, relative molecular mass.

Vaughan–Williams classification of antiarrhythmic drugs

Class Action Effect on cardiac conduction Examples

I Sodium channel blockade

Ia Prolongs refractory period Quinidine, procainamide, disopyramide
Ib Shortens refractory period Lidocaine, mexilitine, phenytoin
Ic None Flecainide, propafenone
II Beta blockade Slows atrioventricular conduction Propranolol, atenolol, esmolol
III Potassium channel blockade Slows atrioventricular conduction Amiodarone, sotolol
IV Calcium channel blockade Prolongs refractory period Verapamil, diltiazem
Gases: physical properties

Gas Mw (kDa) BP (8C) CT (8C) CP (bar)  

Nitrogen 28 –196 –147 34 17.6 1.165

Oxygen 32 –182 –118 50 20.4 1.331
Carbon dioxide 44 –78.5 31 74 14.7 1.831
Air 29 –195 –149 38 18.2 1.196
Nitrous oxide 44 –88 36.5 72 14.6 1.83
Helium 4 –269 –268 2.3 19.6 0.166

MW, relative molecular mass; BP, boiling point; CT, critical temperature; CP, critical pressure; , viscosity; , density.
 Appendix 233

Body fluid composition

Component a Plasma Interstitial Intracellular

Percentage total body water b 5 15 40

Naþ (mmol.l1) 145 140 10
Kþ (mmol.l1) 4 5 155
Ca2þ (mmol.l1) 3 2 <1
Mg2þ (mmol.l1) 1 2 40
Cl (mmol.l1) 110 112 3
HCO3 (mmol.l1) 26 28 7
Others c (mmol.l1) 7 9 150
Proteins (mmol.l1) 10 – 45

a
The numbers will vary depending on the source but the cations (positively charged ions)
should always equal the anions (negatively charged ions).
b
Water is 60% of total body weight in an adult male.
c
Include sulphates, phosphates and inorganic acids.

Daily nutritional requirements for a 70 kg male

Requirement per kg body weight

Energy
Calories (kcal) 30–40
Food components(g)
Glucose 3–4
Fat 1
Protein 1
Nitrogen 0.2
Fluid (ml) 30–40
Electrolytes (mmol)
Sodium 1–2
Potassium 1
Calcium 18
Magnesium 12
Chloride 1
Phosphate 18
Urinary electrolytes in renal failure: this table is always difficult to recall but try to remember that in intrinsic renal failure the kidney is unable
to concentrate urine effectively and so a poor quality, dilute urine is produced

Pre-renal Renal
1
Urine (mmol.l )
Osmolarity >450 (concentrated) <350 (dilute, poor quality)
Sodium <15 (Naþ retention) >40 (Naþ loss)
Urea >250 (excreting lots) <160 (not excreting much)
Urine: plasma concentrations a
Osmolarity >2 (urine more concentrated) <1.5 (urine less concentrated)
Creatinine >40 <40
Urea >8 <3

a
If the ratio is high, it means that there is relatively more of the substance in the urine.
Types of muscle fibre

Fibre Slow oxidative (type I) Fast oxidative (type IIa) Fast glycolytic (type IIb)

Diameter Small Intermediate Large

Conduction velocity Slow Fast Fast
Twitch Long Short Short
Colour Red Red White
Myoglobin þþþ þþþ þ
Source of ATP Oxidative phosphorylation Oxidative phosphorylation Glycolysis
Glycogen and glycolytic enzymes þ þþ þþþ
Fatiguability þ þþ þþþ
 Index

A band, sarcomeres, 189 agonists, 97–99

absolute humidity, 33, 65 definition, 97
absolute refractory period, 185 full, 97
cardiac conduction system, 145 inverse, 101
absolute risk reduction, 209 partial, 97
acceleration, SI units, 18, 19 alfentanil, 226
accuracy, 14 context-sensitive half time, 113
and imprecision, 15 allodynia, 198
and precision, 15 allosteric modulators, 99
acetylcholine, stores of, 188 alternating current (AC)
acetylcholine receptors, 188 resistance, 42
acetylcholinesterase, 188 alveolar dead space, 128
acid–base balance, 173–175 alveolar gas equation see respiratory physiology
blood values, 173 amethocaine, 227
Davenport diagram, 175 ampere, 18
Henderson–Hasselbach equation see anaesthetic agents
Henderson–Hasselbach equation inhalational see inhalational anaesthetic agents
actin, sarcomeres, 189 local, 227
action potentials, 184–187 see also specific anaesthetics
absolute refractory period, 185 anaphylactic reactions, 90
cardiac see cardiac action potentials anaphylactoid reactions, 90
definition, 184 anatomical dead space, 128
Gibbs–Donnan effect, 184 Fowler’s method, 128
Goldman constant field equation, 185 antagonists, 97, 99–101
Nernst equation, 184–185 competitive, 99
relative refractory period, 185 definition, 97
resting membrane potential, 184 irreversible, 99
threshold potential, 185 non-competitive, 99
adenosine triphosphate, muscle reversible, 99
contraction, 190 antidiuretic hormone
ADH see antidiuretic hormone loop of Henle, 179
adrenaline, heart rate, 172 sodium handling, 182
adverse drug reactions, 89–90 aorta, pressure curves, 147
anaphylactic reactions, 90 area, SI units, 19
anaphylactoid, 90 arterial pressure, mean, 149
definition, 89 asymptotic relationships, 6
types, 89 atracurium, 228
affinity, pharmacodynamics, 93 atropine, heart rate, 172
affinity constant (KA), 92 autonomic neuropathy, Valsalva manoeuvre, 170
afterload autoregulation, intracranial pressure, 194
Frank–Starling relationship, 155 Avogadro’s hypothesis, 24, 58
increased, 164–165 ‘a’ wave, central venous pressure, 151
 Index 237

back electromotive force, inductance capnography, 24, 57–61

graphs, 47 breathing system disconnection, 60–61
baralime, CO2 absorption, 30, 62 capnographs, 57
Beer–Lambert law, 55 capnometers, 57
Beer’s law, pulse oximetry, 22, 54 cardiac oscillations, 59
Bernoulli principle, 28 cardiac output, acute loss, 60
Doppler effect, 68 hyperventilation, 59
bias, 214 hypoventilation, 61
bicarbonate, CO2 carriage, 136 inadequate paralysis, 58
bicarbonate buffers, Henderson–Hasselbach malignant hyperpyrexia, 60
equation, 174 normal, 57
bimodal distribution, 207 obstructive disease, 61
bioavailability see pharmacokinetics rebreathing, 58
Bland–Altman plot, 214 carbamino compounds, CO2 carriage, 136
blood:gas solubility coefficient, 38 carbon dioxide
body fluid composition, 233 blood concentration, 179
Bohr effect, oxyhaemoglobin dissociation carriage of see respiratory physiology
curve, 135 physical properties, 232
Bohr equation, 128, 130–131 carbon dioxide absorption, 62–63
boiling point, elevation of, 40 baralime, 62
Boyle’s law, 24 colour indicators, 63
as hyperbolic relationship, 6 mesh size, 62
isotherms, 37 soda lime, 62
breathing, work of see respiratory physiology cardiac action potentials, 144–145, 186
breathing system disconnection, capnography, cardiac conduction system, 145
60–61 absolute refractory period, 145
Bunsen solubility coefficient, 38 relative refractory period, 145
bupivacaine, 227 pacemaker, 144
cardiac conduction system see cardiac action
calcium channels, muscle contraction, 190 potentials
calibration, 14–17 cardiac cycle, 146–148
definition, 14 diagram, 146
zeroing, 14–15 left ventricular volume curve, 148
candela, definition, 18 pressure curves, 147
capacitance, 43 aorta, 147
inductance versus, 46 central venous pressure, 147
SI units, 19 left ventricle, 147
capacitors, 43 timing points, 148
alternating current cardiac oscillations, capnography, 59
high frequency, 45 cardiac output
low frequency, 44 Frank–Starling relationship, 155
direct current, 44 cardiac output measurement, 31, 64–67
principles, 43 dye dilution, 64
rate of decay, 43 graphs, 65
capacity, lung volumes, 115 Fick principle, 64
capillary dynamics, cardiovascular equation, 64
physiology, 159 thermodilution, 64
capillary hydrostatic pressure, 159 graphs, 66–67
capillary oncotic pressure, 159 Stewart–Hamilton equation, 64–65
238 Index

cardiovascular physiology, 144–172 clinical trials, 219

pressure–flow calculations, 149–150 design flow sheet, 219
coronary blood flow, 149–150 phases, 219
coronary perfusion pressure, 149 closing volume, lung volumes, 116
mean arterial pressure, 149 coagulation, surgical diathermy, 40, 75
systemic vascular resistance, 167 Coanda effect, 28–29, 62–63
pulmonary vascular resistance, 168 codeine, 226
ventricular pressure–volume relationship, collecting duct, loop of Henle, 179–180
162–166 colligative properties, 40, 75
altered contractility, 165 Raoul’s law, 40
ejection fraction, 163 colloids, 231
end-diastolic pressure–volume colour indicators, CO2 absorption, 30, 63
relationship, 162 compartment models, 109–112
end-systolic pressure–volume relationship, catenary, 109
162–166 concentration versus time, 112
failing ventricle, 166 mamillary, 109
increased afterload, 164–165 one-compartment, 109
increased preload, 164 three-compartment, 111
pressure–volume relationship, 163 formula, 112
see also pulmonary arterial two-compartment, 110
wedge pressure formula, 111
categorical (qualitative) data see statistics competitive antagonists, 99
catenary compartment models, 109 compliance see respiratory physiology
CBF see cerebral blood flow concentration, SI units, 19
celsius/centrigrade scale, 30 the concentration effect, 78–79, 80–81
central venous pressure, 151–152 graphs, 80–81
definition, 151 confidence intervals, 204
pressure curves, 147 conservation of energy, 28, 61
traces, 153–154 context-sensitive half time
waveform, 151–152 see pharmacokinetics
cerebral blood flow, 194 continuous data, 200
definition, 194 contractility
PaCO2 effects, 195 Frank–Starling relationship, 155
PaO2 effects, 196 ventricular pressure–volume
cerebral perfusion pressure, 194–195 relationship, 165
cerebrospinal fluid (CSF), 197 coronary blood flow, 149–150
charging graph, defibrillators, 20, 48 coronary perfusion pressure, 149
Charles’ law, 24, 57 correlation, 212
chiral centre, isomerism, 83 correlation coefficient, 212
chi-square (w2) test see statistics coulomb, definition, 19
chloride shift, 136 critical damping, 22, 53
chronic pain, 198 crystalloids, 229–230
cis-atracurium, 228 CSF see cerebrospinal fluid
cleaning current
definition, 40, 76 inductance graphs, 47
methods, 77 SI units, 18
clearance current density, SI units, 19
glomerular filtration rate, 176 cutting, surgical diathermy, 40, 75
pharmacokinetics see pharmacokinetics CVP see central venous pressure
 Index 239

daily nutritional requirements, 233 Doppler effect, 33, 68

damping, 51–53 Bernoulli equation, 35–36, 68
critical damping, 22, 53 equation, 33, 68
damping coefficient, 51–53 principle, 33–34, 68
optimal damping, 22, 53 dose ratio, pharmacodynamics, 102
over-damping, 52 dose–response curves see pharmacodynamics
under-damping, 52 double-burst stimulation see neuromuscular
zero damping, 51 blockade monitoring
data analysis methods see statistics drift, 14, 16
data descriptions, statistics, 202 drug interactions, 88
Davenport diagram, acid–base balance, 175 isobolograms, 88
DC see direct current drug–receptor interactions see
dead space see respiratory physiology pharmacodynamics
decontamination, 42, 76 dye dilution, cardiac output measurement
decrement time, 114 see cardiac output measurement
defibrillators, 48–49 dynamic compliance, 142
charging graph, 48 dyne, 167
circuit diagram, 48
discharging graph, 20, 48–49 EC50, 94
degrees of freedom, 204 ECG see (electrocardiography)
chi-square (w2) test, 211 ED50, 94
deoxy-haemoglobin absorption spectra, 56 efficacy, pharmacodynamics, 93
depolarizing block train of four, 36, 70 ejection fraction, ventricular pressure–volume
depression of freezing point, 40 relationship, 163
derived SI units see SI units; specific units electrical charge, SI units, 19
desflurane, 224 electrical resistance see resistance (electrical)
concentration effect graph, 80 electrocardiography (ECG), 146
physiological effects, 225 electromotive force (EMF), 20, 46
dew point, 33, 68 elimination see pharmacokinetics
dextran 18, 230 enantiomers, 82
dextrorotatory isomerism, 83 enantiopure preparation, 84
dextrose 4%/saline 0.18%, 229 end-diastolic pressure–volume
dextrose 5%, 229 relationship, 162
dextrose 10%, 229 end-systolic pressure (ESP)
diamorphine, 226 ventricular pressure–volume relationship, 164
diastereoisomers, 83 volume relationship, 162–166
diffusion see solubility/diffusion end-systolic volume (ESV), ventricular
direct current (DC) pressure–volume relationship, 164
capacitors, 32, 44 energy
resistance, 42 conservation of, 28, 61
discrete data, 200 SI units, 19
disinfection enflurane, 224
definition, 41, 76 physiological effects, 225
methods, 77 enzyme kinetics, 85–87
dissociation constant (KD), 92 first-order, 85
dissociation curves, CO2, 137 Lineweaver–Burke transformation, 86–87
dissolved CO2, 136 Michaelis–Menten equation, 85–86
distance, SI units, 18 zero-order, 85
distribution, volume of see pharmacokinetics enzymes, 85
240 Index

errors see statistics Fowler’s method, 129

ERV (expiratory reserve volume), 115 anatomical dead space, 128
etomidate, 222 graph, 129
physiological effects, 223 principle, 129
Euler’s number, 7 Frank–Starling relationship, 155–156
evidence-based medicine, 220–221 afterload, 155
definition, 220 cardiac output, 155
grades of recommendations, 220–221 contractility, 155
levels of evidence, 220 graph, 156
meta-analysis, 221 preload, 155
Forest plot, 221 stroke volume, 155
excretion, pharmacokinetics, 108 FRC see functional residual capacity
expiratory reserve volume (ERV), 115 freezing point, depression of, 40
exponential relationships, 7 frequency
basic negative exponential, 9 natural, 20, 50–51
basic positive exponential, 8 SI units, 19
clinical tear away positive exponential, 8 surgical diathermy, 40, 74
Euler’s number, 7 full agonists, 97
half life, 10 functional residual capacity, 115–116
physiological build-up negative exponential, fusion, specific latent heat of, 35, 69
9–10
physiological negative exponential, 9 gallamine, 228
rate constant, 12 gas laws, 24–25, 57–61
transformation to straight line, 12–13 see also specific laws
time constant, 11 gate control theory of pain, 198
extraction ratios, bioavailability, 104 Gay–Lussac’s law (third gas law), 24
Gelofusine, 230
failing ventricle, 166 genetic isomerism, 83
farad, 28, 43 Gibbs–Donnan effect, action potentials, 184
fast glycolytic muscle fibres, 235 glomerular filtration rate see renal physiology
fast oxidative muscle fibres, 235 glucose handling see renal physiology
fentanyl, 226 Goldman constant field equation, 185
context-sensitive half time, 114 Golgi tendon organs, muscle reflexes, 192
Fick principle see cardiac output measurement grades of evidence, 220
Fick’s law, 38 Graham’s law, 38, 71
first-order elimination, 107
first-order enzyme kinetics, 85 Haemaccel, 230
Fisher’s exact test, 211 haemoglobin absorption spectra see pulse
flow–volume loops, 119–122 oximetry
fixed large airway obstruction, 122 Hagen–Poiseulle equation, 26, 42
normal, 119 Haldane effect, 136
obstructive disease, 120 half life see exponential relationships
peak expiratory flow rate, 120 halothane, 224
restrictive disease, 120 physiological effects, 225
variable extrathoracic obstruction, 121 Hamburger effect see chloride shift
variable intrathoracic obstruction, 121 Hartmann’s solution, 229
force, 21, 52 HAS 4.5%, 230
SI units, 19 HAS 20%, 230
Forest plot, meta-analysis, 221 H band, sarcomeres, 189
 Index 241

heart rate, control of, 171–172 inotropy, Frank–Starling relationship, 156

paediatrics, 171–172 inspiratory reserve volume (IRV), 115
parasympathetic, 171 interstitial fluid composition, 233
post-transplant, 172 interstitial hydrostatic pressure, 159
sinoatrial node, 171 interstitial osmotic pressure, 159
sympathetic, 172 intracellular fluid composition, 233
heart sounds, cardiac cycle, 146 intracranial pressure, 194–196
heat, definition, 30, 62 autoregulation, 194
heat capacity, 35, 69 cerebral perfusion pressure, 194–195
helium, physical properties, 232 see also cerebral blood flow
Henderson–Hasselbach equation, iv, 174–175 intravenous fluids
bicarbonate buffers, 174 colloids, 231
Henry, definition, 46 crystalloids, 229–230
Henry’s law, 38, 71 see also specific types
hertz, definition, 19 intravenous induction agents, 222
high-frequency AC capacitors, 37, 45 physiological effects, 223
Hüffner’s constant, oxygen delivery, 133 inverse agonists, 101
humidity, 33–34, 64–65 irreversible antagonists see antagonists
absolute, 33, 65 IRV (inspiratory reserve volume), 115
dew point, 33, 68 isobolograms see drug interactions
hygrometers, 33, 68 isoflurane, 224
hygroscopic material, 33–34, 68 physiological effects, 225
relative, 33, 66–67 isomerism, 82–84
hydroxyethyl/starch, 230 chiral centre, 83
hyperalgesia, 198 definition, 82
hyperbolic relationships, 6 dextrorotatory, 83
hyperpathia, 198 diastereoisomers, 83
hyperventilation, 26, 59 enantiomers, 82
hypoventilation, 28, 61 enantiopure preparation, 84
hysteresis, 14, 17, 103 geometric, 83
laevorotatory, 83
I band, sarcomeres, 189 optical, 83
impedance, resistors/resistance, 40, 42 racemic mixture, 84
imprecision, 15 rectus, 84
inaccuracy, 16 sinister, 84
inductance stereoisomerism, 82
capacitance versus, 46 structural, 82
definition, 20, 46 tautomerism, 82
graphs, 20, 47 D-isomerism, 83
back electromotive force, 47 L-isomerism, 83
current, 47 isotherms, 37, 70
principles, 20, 46–47 nitrous oxide, 37, 71
magnetic fields, 46 isovolumic contraction, cardiac cycle, 146
induction agents, intravenous see intravenous isovolumic relaxation, cardiac cycle, 146
induction agents
inductors, 46 joule, definition, 19, 22–23, 54–55
inhalational anaesthetic agents, 218
physiological effects, 225 KD (dissociation constant), 92
see also specific anaesthetics kelvin, 18, 30, 62
242 Index

ketamine, 222 mathematical relationships, 5–13

physiological effects, 223 asymptotic relationships, 6
kilo, 19, 20, 46 exponential relationships see exponential
kilogram, 18 relationships
hyperbolic relationships, 6
Lambert’s law, pulse oximetry, 54–55 linear relationships, 5
laminar flow, 26, 59 mean
Hagen–Poiseulle equation, 26, 42 definition, 202
latent heat, 35–36, 68 normal distribution, 202
heat capacity, 35, 69 mean arterial pressure, pressure–flow
specific heat capacity, 35–36, 69 calculations, 149
specific latent heat of fusion, 35, 69 mean systemic filling pressure, venous
specific latent heat of vaporization, return, 157
35, 69 measurements, 14–17
water heating curve, 36, 70 accuracy, 14
law of mass action, drug–receptor drift, 14, 16
interactions, 91 hysteresis, 14, 17
LD50 (median lethal dose), 96 non-linearity, 14, 17
ligands, 91 precision, 14
lidocaine, 227 measures of spread, statistics, 202
Lineweaver–Burke transformation, 86–87 median, definition, 202
local anaesthetics, 227 median lethal dose (LD50), 96
see also specific anaesthetics membrane potential, resting, 184
logarithms, 7–8 mepivacaine, 227
rules, 7–8 mesh size, CO2 absorption, 30, 62
division, 7 meta-analysis see evidence-based medicine
multiplication, 7 methohexital, 222, 234
powers, 8 physiological effects, 223
reciprocal, 7 metre, definition, 18
loop of Henle see renal physiology Meyer–Overton hypothesis, 78–79
luminous intensity, SI units, 18 graph, 78–79, 80–81
lung compliance, 142 Michaelis–Menten equation, 85–86
lung resistance, 142–143 Michaelis–Menten graph, 86
lung volumes, 115–116 minimum alveolar concentration (MAC), 78
capacity, 115 minute ventilation
closing volume, 116 PACO2 versus see ventilation control
expiratory reserve volume, 115 PAO2 versus, 139, 141
functional residual capacity, 115–116 mivacurium, 228
graphs, 116 M line, sarcomeres, 189
inspiratory reserve volume, 115 mode, 202
pulmonary vascular resistance versus, 126 modified waveform, defibrillators, 20, 49
residual volume, 115 mole, 18
tidal volume, 115 morphine, 226
vital capacity, 115 Monro–Kelly doctrine see neurophysiology
muscle fibres, 222, 235
MAC (minimum alveolar concentration), 78 muscle reflexes, 191–192
malignant hyperpyrexia, capnography, Golgi tendon organs, 192
27, 60 muscle spindles, 191–192
mass, SI units, 18 stretch reflex, 191
 Index 243

muscle relaxants, non-depolarizing, 228 nitrous oxide, 224

see also specific drugs concentration effect graphs, 80
muscle spindles, 191–192 isotherms, 37, 71
muscle structure, 188–190 physical properties, 232
excitation–contraction coupling, 190 physiological effects, 225
myosin, 190 nociception, definition, 198
sarcoplasmic reticulum, 190 nominal data, 200
troponin C, 190 non-competitive antagonists see antagonists
T tubules, 190 non-depolarizing muscle relaxants, 228
muscle fibres see muscle fibres see also specific drugs
neuromuscular junction, 188 normal distribution, 206
sarcomeres, 189 mean, 202
myelinated nerves, velocity calculations, 187 null hypothesis, 208
myoglobin, oxygen carrying, 134 number needed to treat, 208
myosin, 189–190 numerical (quantitative) data see statistics

natural frequency, 20, 50–51 obstructive disease

negatively skewed distribution, 207 capnography, 28, 61
negative predictive value, 218 obstructive pattern, spirometry, 118
neostigmine, heart rate, 172 odds ratio, 209
Nernst equation, action potentials, 184–185 ohm, 19
neuromuscular blockade monitoring, Ohm’s law, 42
35, 69–73 oil:gas solubility coefficient, 38
depolarizing block train of four, 36, 70 opioids, 226
double-burst stimulation, 38, 71 see also specific opioids
uses, 38, 71 optical isomerism, 83
phase 1 and phase 2 block, 40–41, 73 optimal damping, 22, 53
post-tetanic count, 39, 73 ordinal data, 200
receptor site occupancy assessment, osmolality, 40, 74
38, 71 osmolarity, 40, 74–75
single twitch, 35, 69 osmole, 40, 42
supramaximal stimulus, 35, 69 osmometers, 41, 76
tetanic stimulus, 35–36, 69 osmosis, 40–41, 73
train of four, 69 graphs, 41, 76
non-depolarizing block, 70 osmotic pressure, 40
train of four ratio, 71 Ostwald solubility coefficient, 39, 73
uses, 71 outcome prediction see statistics
neuromuscular junctions see muscle structure oxygen, physical properties, 232
neuronal connections, pain, 199 oxygen cascade, 132–133
neurophysiology, 184–199 oxygen delivery see respiratory physiology
Monro–Kelly doctrine, 193 oxygen flux, 132
intracranial volume vs. pressure, 193 oxyhaemoglobin, absorption spectra, 56
neurone types, 187 oxyhaemoglobin dissociation curve, 134–135
velocity calculations, 187 affecting factors, 135
myelinated nerves, 187 Bohr effect, 135
unmyelinated nerves, 187 P50, 134
neurotransmitters, pain, 199
newton, 19, 21, 52 pA2, pharmacodynamics, 102
nitrogen, physical properties, 232 pacemaker see cardiac action potentials
244 Index

PACO2 pharmacology, 77, 78–90

alveolar gas equation, 123 phase 1 and phase 2 block, neuromuscular
cerebral blood flow, 195 blockade monitoring, 40–41, 73
minute ventilation versus, see ventilation physiological dead space, 128
control pKa, 173–174
pain, 198–199 plasma, composition, 233
chronic, 198 plasticity, definition, 198
gate control theory, 198 positively skewed distribution, 206
neuronal connections, 199 positive predictive value, 218
pathway, 199 post-tetanic count, neuromuscular blockade
pancuronium, 228 monitoring, 73
parasympathetic nerves, heart rate, 171 potassium handling see
pascal, 19, 22, 53 renal physiology
PAWP see pulmonary arterial wedge pressure potency, pharmacodynamics, 93
peak expiratory flow rate (PEFR), obstructive potential difference, SI units, 19
disease, 120 potentiation, drug interactions, 88
Peltier effect, 41 power, 23, 55
perfect gases, 24, 58 statistics, 208
pethidine, 226 precision, 14
pH, 173 preload
pharmacodynamics, 91–103 Frank–Starling relationship, 155
affinity, 93 increased, 164
dose ratio, 102 pressure
dose–response curves, 94 definition, 22, 53
logarithmic, 95 SI units, 19
quantal dose response studies, 95 volume relationship, ventricles, 163
drug–receptor interactions, 91–92 pressure curves see cardiac cycle
affinity constant (KA), 92 prilocaine, 227
dissociation constant (KD), 92 procaine, 227
law of mass action, 91 propofol, 222, 235
EC50, 94 context sensitive half time, 113
ED50, 94 physiology, 223
efficacy, 93 pulmonary arterial wedge pressure (PAWP),
median lethal dose (LD50), 96 153–154
pA2, 102 pulmonary vascular resistance see respiratory
potency, 93 physiology
therapeutic index, 96 pulse oximetry, 54–56
pharmacokinetics, 104–114 Beer’s law, 54
bioavailability, 104 definition, 55
extraction ratios, 104 haemoglobin absorption spectra,
clearance, 107–108 55, 56
context-sensitive half time, 113–114 deoxyhaemoglobin, 56
decrement time, 114 oxyhaemoglobin, 56
elimination, 107 Lambert’s law, 54–55
first-order, 107 p value, 208
zero-order, 107–108
excretion, 108 QRS interval, cardiac cycle, 146
volume of distribution, 105–106 quantal dose–response studies, 95
one compartment model, 106 quartiles, 205
 Index 245

R, alveolar gas equation, 123 resistance (respiratory), 142–143

racemic mixture, isomerism, 84 lung resistance, 142–143
Raoult’s law, 40, 76 whole-lung pressure–volume loop, 143
rate constant see exponential expiration, 143
relationships inspiration, 143
rate of decay, capacitors, 43 regional differences, 143
RBF (renal blood flow), 176 tidal breath, 143
reactance, resistors/resistance, 26, 42 resistance wire, 31, 64–67
rebreathing, capnography, 24, 58 resonance, 20, 50–51
receptors, definition, 91 natural frequency, 20, 50–51
regression coefficient, 212 respiratory physiology, 115–143
relative humidity, 33, 66–67 alveolar gas equation, 123
relative refractory period (RRP), 185 Bohr equation see Bohr equation
cardiac conduction system, 145 carbon dioxide carriage, 136–137
relative risk, 209 dissociation curves, 137
relative risk reduction, 209 Haldane effect, 136
remifentanil, 226 Hamburger effect (Cl shift), 136
context-sensitive half time, 113 oxygen dissociation versus, 137
renal blood flow (RBF), 176 compliance, 142
renal failure, urinary electrolytes, dynamic compliance, 142
222, 234 lung compliance, 142
renal physiology, 173–183 static compliance, 142
autoregulation, 177–178 dead space, 128
glomerular filtration rate, 176 alveolar, 128
clearance, 176 anatomical, 128
renal blood flow, 176 see also Fowler’s method
glucose handling, 181 definition, 128
graph, 181 physiological, 128
loop of Henle, 179–180 oxygen delivery, 132–133
antidiuretic hormone, 179 Hüffner’s constant, 133
potassium handling, 183 oxygen cascade, 132–133
graph, 183 supply and demand, 133
renal vascular resistance, 177–178 see also oxyhaemoglobin dissociation curve
definition, 177–178 pulmonary vascular resistance, 126, 168
sodium handling, 182 affecting factors, 126
antidiuretic hormone, 182 lung volume versus, 126
graph, 182 resistance see resistance (respiratory)
renal vascular resistance see shunt equation see shunt equation
renal physiology spirometry see spirometry
repolarization, cardiac cycle, 146 ventilation control see ventilation control
residual volume (RV), lung ventilation/perfusion (V/ _ mismatch, 127
_ Q)
volumes, 115 graph, 127
resistance (electrical), 42, 76 work of breathing, 138
alternating current, 42 expiration curve, 138
definition, 42 resting membrane potential, 184
direct current, 42 restrictive disease, flow–volume loops, 120
impedance, 40, 42 restrictive pattern, spirometry, 118
reactance, 26, 42 reversible antagonists see antagonists
SI units, 19 Reynold’s number, 27, 43, 60
246 Index

right atrial pressure, PAWP waveform, 153 speed, SI units, 18, 19

right ventricular pressure, PAWP waveform, 153 spirometry, 117–118
rocuronium, 228 normal, 117
ropivacaine, 227 obstructive pattern, 118
RRP see relative refractory period (RRP) restrictive pattern, 118
RV (residual volume), lung volumes, 115 standard deviation, 203
and standard error of the mean, 204
saline 0.9%, 229 static compliance, 142
saline 0.18%/dextrose 4%, 229 statistics, 200–221
sample, 200 bimodal distribution, 207
size, standard error of the mean, 204 categorical (qualitative) data, 200
sarcomeres see muscle structure nominal, 200
second, 18 ordinal, 200
second gas effect, 81 central tendencies and variability, 202–205
Seebeck effect, 32, 41, 64 confidence intervals, 204
sensitivity, 217–218 data descriptions, 202
sevoflurane, 224 degrees of freedom, 204
physiological effects, 225 measures of, 202
shunt, 124 measures of spread, 202
shunt equation, 124–125 quartiles, 205
derivation, 125 standard deviation, 203
principles, 124–125 chi-square (w2) test, 210–211
simple mechanics, 21–23, 51 degrees of freedom, 211
see also specific topics Fisher’s exact test, 211
single twitch, neuromuscular blockade data analysis methods, 208–216
monitoring, 35, 69 absolute risk reduction, 209
sinoatrial node, heart rate, 171 bias, 214
SI units, 18–20 Bland–Altman plot, 214
base units, 18 correlation, 212
derived, 18, 19 correlation coefficient, 212
symbols, 19 interpretation, 216
prefixes, 19–20 negative correlation, 213
see also specific prefixes; specific units null hypothesis, 208
slow oxidative muscle fibres, 235 number needed to treat, 208
soda lime see CO2 absorption odds ratio, 209
sodium bicarbonate 8.4%, 229 positive correlation, 212
sodium handling see renal physiology power, 208
solubility/diffusion, 38–39, 71 p value, 208
blood:gas solubility coefficient, 38 regression coefficient, 212
Bunsen solubility coefficient, 38 relative risk, 209
Fick’s law, 38 relative risk reduction, 209
Graham’s law, 38 statistical tests, 209–216
Henry’s law, 38 see also specific tests
oil:gas solubility coefficient, 38 data types, 200–201
Ostwald solubility coefficient, 39 hierarchy, 201
specific heat capacity, 35–36, 69 distribution types, 206–207
specificity, 218 negatively skewed distribution, 207
specific latent heat of fusion, 35, 69 normal distribution, 206
specific latent heat of vaporization, 35, 69 positively skewed distribution, 206
 Index 247

error/outcome prediction, 217–218 SI units, 18

negative predictive value, 218 thermistors, 31, 64
positive predictive value, 218 thermocouples, 32, 64
sensitivity, 217–218 triple point, 30, 62
specificity, 218 tera, 46
type I errors, 217 tetanic stimulus, neuromuscular blockade
type II errors, 217 monitoring, 35–36, 69
numerical (quantitative) data, 200–201 therapeutic index, pharmacodynamics, 96
continuous, 200 thermistors, 31, 64
discrete, 200 thermocouples, 32, 64
interval, 201 thermodilution see cardiac output
ratio, 201 measurement
population, 200 thiopental, 222, 234
sample, 200 context-sensitive half time, 114
standard error of the mean, 204 physiology, 223
sample size, 204 third gas law (Gay–Lussac’s law), 24, 57
and standard deviation, 204 threshold potential, 185
Student’s t-test, 209–210 tidal volume (TV), 115
one-tailed test, 210 time, SI units, 18
paired test, 209 time constant see exponential relationships
two-tailed test, 210 timing points, cardiac cycle, 148
unpaired test, 209 timing reference curves see cardiac cycle
stereoisomerism, 82 TOF see train of four
sterilization train of four, neuromuscular blockade
definition, 41, 76 monitoring, 69
methods, 77, 78–90 train of four ratio see neuromuscular blockade
Stewart–Hamilton equation, 33–34, 64–65 monitoring
stretch reflex, 191 triple point, temperature, 30, 62
stroke volume, Frank–Starling tropomyosin, sarcomeres, 189
relationship, 155 troponin C, muscle contraction, 190
structural isomerism, 82 T-tubules, muscle contraction, 190
Student’s t-test see statistics tubocurare, 228
summation, drug interactions, 88 turbulent flow, 27, 60
supra-maximal stimulus, neuromuscular Reynold’s number, 27, 43, 60
blockade monitoring, 69 two-compartment models see compartment
surgical diathermy, 40, 74–75 models
coagulation, 40, 75 two-tailed test, Student’s t-test, 210
cutting, 40, 75 type I errors, statistics, 217
frequency, 40, 74 type II errors, statistics, 217
sympathetic nervous system, heart rate, 172
synergisms, drug interactions, 88 underdamping, 21, 52
systemic filling pressure, mean, 157 universal gas equation, 25, 59
systemic vascular resistance (SVR) see unmodified waveform, defibrillators,
cardiovascular physiology 20, 49
unmyelinated nerves, velocity
tautomerism, 82 calculations, 187
temperature, 30, 62 unpaired test, Student’s t-test, 209
resistance wire, 31, 64–67 urinary electrolytes, renal failure,
Seebeck effect, 32, 64 222, 234
248 Index

Valsalva manoeuvre, 169–170 ventilation/perfusion (V/ _ mismatch, 127

_ Q)
abnormal responses, 170 graph, 127
autonomic neuropathy, 170 ventricle
congestive heart failure, 170 failing, 166
quadriplegia, 170 left, pressure curves, 147
uses, 170 ventricular pressure–volume relationship
vaporization, specific latent heat of, 35, 69 see cardiovascular physiology
vapour pressure, reduction of, 40 Venturi effect, 28, 61
variable extrathoracic obstruction, flow–volume velocity, 28, 43
loops, 121 vesicles, neuromuscular junctions, 188
variable intrathoracic obstruction, flow–volume vital capacity (VC), 115
loops, 121 volt, 19
variance, definition, 233 volume, SI units, 19
Vaughan–Williams classification, 231 volume of distribution see pharmacokinetics
vecuronium, 228 _ Q
V/ _ mismatch see ventilation/perfusion
velocity mismatch
SI units, 19
Venturi effect, 28, 43 water heating curve, 36, 70
venous resistance, venous return, 158–159 watt, 19, 23, 56
venous return, 157–161 weight, definition, 21, 43
altered venous resistance, 158–159 whole-lung pressure–volume loop see resistance
curve changes, 158 (respiratory)
increased filling, 158 work
mean systemic filling pressure, 157 definition, 22, 54
ventilation, minute see minute ventilation SI units, 19
ventilation control, 139–141 work of breathing see respiratory
minute ventilation versus PACO2, 140 physiology
raised threshold, 140
reduced sensitivity, 140 zero damping, 21–23, 51
minute ventilation versus PAO2, 139 zero-order elimination, 107–108
PACO2 versus minute ventilation, 141 zero-order enzyme kinetics, 85
PAO2 versus minute ventilation, 141 Z line, sarcomeres, 189