Fisiologia para Anestesiologos

Basic Physiology for
Anaesthetists
Downloaded from Cambridge Books Online by IP 216.195.11.197 on Thu Nov 05 03:28:27 GMT 2015.
http://ebooks.cambridge.org/ebook.jsf?bid=CBO9781139226394
Cambridge Books Online © Cambridge University Press, 2015
Basic Physiology for
Anaesthetists
David Chambers BMBCh MChem DPhil

MRCP FRCA PGDipMedEd
Specialty Registrar, Salford Royal NHS Foundation Trust, North West School of Anaesthesia,
Manchester, UK
Christopher Huang BMBCh PhD DM

DSc FSB
Professor of Cell Physiology and Fellow and Director of Medical Studies, Murray Edwards College,
University of Cambridge, UK
Gareth Matthews MA PhD MSB

Translational Medicine and Therapeutics Research Fellow, School of Clinical Medicine and Fellow in
Medical Physiology, Murray Edwards College, University of Cambridge, UK
University Printing House, Cambridge CB2 8BS, United Kingdom
Cambridge University Press is part of the University of Cambridge.

It furthers the University’s mission by disseminating knowledge in the pursuit of
education, learning and research at the highest international levels of excellence.
www.cambridge.org
Information on this title: www.cambridge.org/9781107637825
© Cambridge University Press 2015
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published 2015
Printed in the United Kingdom by Clays, St Ives plc
A catalogue record for this publication is available from the British Library
Library of Congress Cataloging-in-Publication Data
Chambers, David, 1979- author.
Basic physiology for anaesthetists / David Chambers, Christopher Huang,
Gareth Matthews.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-107-63782-5 (Hardback)
I. Huang, Christopher L.-H., author. II. Matthews, Gareth, 1987– author.
III. Title.
[DNLM: 1. Physiological Phenomena. 2. Anesthesiology–methods.
QT 104]
RD82
617.90 6–dc23 2014010869
ISBN 978-1-107-63782-5 Hardback
Additional resources for this publication at www.cambridge.org/
9781107637825
Cambridge University Press has no responsibility for the persistence or
accuracy of URLs for external or third-party internet websites referred
to in this publication, and does not guarantee that any content on such
websites is, or will remain, accurate or appropriate.
..................................................................................................
Every effort has been made in preparing this book 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 book. Readers are strongly advised to
pay careful attention to information provided by the manufacturer of any
drugs or equipment that they plan to use.
Contents
Foreword ix
Preface xi
Abbreviations xii
24. Ventilatory failure 104

Section 1 – The basics
25. Anaesthesia and the lung 107
1. General organization of the body 1
2. Cell components and function 5
Section 3 – Cardiovascular physiology
3. Genetics 8
26. Cardiac anatomy and function 111
4. The cell membrane 13
27. Cardiac cycle 117
5. Enzymes 18
28. Cardiac output and its measurement 120
29. Starling’s law and cardiac
Section 2 – Respiratory physiology dysfunction 130
6. Lung anatomy and function 21 30. Pressure–volume loops 135
7. Oxygen transport 28 31. Systemic circulation 141
8. Carbon dioxide transport 36 32. Arterial system 144
9. Alveolar diffusion 40 33. Arterial pressure waveforms 150
10. Ventilation and dead space 45 34. Capillaries and endothelium 153
11. Static lung volumes 50 35. Venous system 158
12. Spirometry 56 36. Venous pressure waveforms 161
13. Hypoxia and shunts 64 37. Lymphatics 164
14. Ventilation–perfusion relationships 69 38. Cardiovascular reflexes 166
15. West zones 72 39. Valsalva manoeuvre 171
16. Oxygen delivery and demand 74 40. Exercise physiology 174
17. Alveolar gas equation 77
18. Oxygen cascade 80 Section 4 – Neurophysiology
19. Lung compliance 82 41. Neuronal structure and function 183
20. Work of breathing 88 42. The brain 186
21. Control of ventilation 92 43. Cerebrospinal fluid 191
22. Pulmonary circulation 96 44. Blood–brain barrier 194
23. Oxygen toxicity 102 45. Cerebral blood flow 197
vii
Contents
46. Intracranial pressure and head injury 201 Section 7 – Blood and immune system
47. The spinal cord 207 67. Haemostasis 337
48. Resting membrane potential 217 68. Transfusion 345
49. Nerve action potential and 69. Anaemia and polycythaemia 351
propagation 221
70. Immune system 355
50. Synapses and the neuromuscular
junction 228 71. Plasma constituents 366
51. Skeletal muscle 236

52. Muscle spindles and Golgi tendon Section 8 – Energy balance
organs 243 72. Metabolism 369
53. Smooth muscle 247 73. Starvation 381
54. Cardiac muscle 250 74. Stress response 384
55. The electrocardiogram 261
56. Autonomic nervous system 265 Section 9 – Endocrine physiology
57. Pain physiology 269 75. Hypothalamus and pituitary 387
76. Thyroid, parathyroid and adrenal 392
Section 5 – Gastrointestinal tract
58. Saliva, oesophagus and swallowing 275 Section 10 – Developmental physiology
59. Stomach and vomiting 279 77. Maternal physiology during pregnancy 401
60. Gastrointestinal digestion and 78. Fetal physiology 408
absorption 286
79. Paediatric physiology 416
61. Liver anatomy and blood supply 292
80. Physiology of ageing 420
62. Liver function 297
Section 11 – Environmental physiology

Section 6 – Kidney and body fluids
81. Altitude 425
63. Renal function, anatomy and
blood flow 305 82. Diving 429
64. Renal filtration and reabsorption 311 83. Temperature regulation 431
65. Renal regulation of water and electrolyte

balance 316
66. Acid–base physiology 328 Index 434
viii
Foreword
The authors of this comprehensive physiology text- This book is an enjoyable and thought-provoking
book have brought together their backgrounds in clini- read, and brings together the crucial importance of
cal practice and scientific research to produce a work understanding the principles of physiology which are
in which the importance of an in-depth knowledge of as relevant to the practising clinician as they are to the
physiology is translated into clinically relevant appli- scientist.
cations. The central relationship between the clinical
practice of anaesthesia and the science of physiology is Dr Deborah M Nolan MB ChB FRCA
illustrated with precision throughout the volume, and Consultant Anaesthetist,
the practical question and answer format provides a University Hospital of South Manchester
clear foundation for examination revision. Vice-President of the Royal College of Anaesthetists
ix
http://dx.doi.org/10.1017/CBO9781139226394.001
Preface
An academically sound knowledge of both normal senior anaesthetists engaged in education and training,
and abnormal physiology is essential for day-to-day physician assistants in anaesthesia, operating depart-
anaesthetic practice, and consequently for postgradu- ment practitioners and anaesthetic nurses.
ate specialist examinations. We believe the strength of this book lies in our
This project was initiated by one of us (DC) mixed clinical and scientific backgrounds, through
following his recent experience of the United King- which we have produced a readable and up-to-date
dom Fellowship of the Royal College of Anaesthetists account of basic physiology, and provided links
examinations. He experienced difficulty locating text- to anaesthetic and critical care practice. We hope
books that would build upon a basic undergraduate to bridge the gap between the elementary physi-
understanding of physiology. Many of the anaesthesia- ology learnt at medical school and advanced
related physiology books he encountered assumed anaesthesia-related texts. By presenting the material
too much prior knowledge and seemed unrelated to in a question and answer format, we aimed to
everyday anaesthetic practice. emphasize strategic points, and give the reader a
He was joined by a Professor in Physiology (CH) glimpse of how each topic might be assessed in an
and a Translational Medicine and Therapeutics oral postgraduate examination. Our numerous illus-
Research Fellow (GM) at Cambridge University, both trations seek to simplify and clearly demonstrate key
actively engaged in teaching undergraduate and post- points in a manner easy to replicate in an examin-
graduate physiology, and in physiological research. ation setting.
This book has been written primarily for anaes-
thetists in the early years of their training, and speci- David Chambers
fically for those facing postgraduate examinations. Christopher Huang
In addition, the account should provide a useful Gareth Matthews
summary of physiology for critical care trainees, Manchester and Cambridge.
xi
Abbreviations
ACE angiotensin-converting enzyme ETT endotracheal tube

ACh acetylcholine FAD flavin adenine dinucleotide
AChE acetylcholinesterase FEV1 forced expiratory volume in 1 s
AChR acetylcholine receptor FiO2 fraction of inspired oxygen
ADH antidiuretic hormone FRC functional residual capacity
ADP adenosine diphosphate FVC forced vital capacity
AF atrial fibrillation GBS Guillain–Barré syndrome
AGE alveolar gas equation GFR glomerular filtration rate
ARDS acute respiratory distress syndrome GI gastrointestinal
ARP absolute refractory period Hb haemoglobin
ATP adenosine triphosphate HbA adult haemoglobin
AMP adenosine monophosphate HbF fetal haemoglobin
ANS autonomic nervous system HPV hypoxic pulmonary vasoconstriction
ANP atrial natriuretic peptide HR heart rate
APTT activated partial thromboplastin time ICF intracellular fluid
AV atrioventricular ICP intracranial pressure
BBB blood–brain barrier IVC inferior vena cava
BMR basal metabolic rate LMA laryngeal mask airway
BNP brain natriuretic peptide LOH loop of Henle
BSA body surface area LOS lower oesophageal sphincter
CA carbonic anhydrase LV left ventricle
CaO2 arterial oxygen content LVEDP left ventricular end-diastolic pressure
CBF cerebral blood flow MAC minimum alveolar concentration
CC closing capacity MAO monoamine oxidase
CCK cholecystokinin MAP mean arterial pressure
CI cardiac index MET metabolic equivalent of a task
CMR cerebral metabolic rate MetHb methaemoglobin
CNS central nervous system MG myasthenia gravis
CO cardiac output MPAP mean pulmonary artery pressure
CoA coenzyme A MW molecular weight
COHb carboxyhaemoglobin N2O nitrous oxide
COPD chronic obstructive pulmonary disease NAD+ nicotinamide adenine dinucleotide
CPET cardiopulmonary exercise test NMJ neuromuscular junction
CPP cerebral perfusion pressure OER oxygen extraction ratio
CSF cerebrospinal fluid PAC pulmonary artery catheter
CvO2 venous oxygen content PaO2 arterial tension of oxygen
CVP central venous pressure PaCO2 arterial tension of carbon dioxide
CVR cerebral vascular resistance PB barometric pressure
DBP diastolic blood pressure PCT proximal convoluted tubule
DCT distal convoluted tubule PCWP pulmonary capillary wedge pressure
DNA deoxyribonucleic acid PE pulmonary embolism
ECF extracellular fluid PEEP positive end-expiratory pressure
ECG electrocardiogram PEEPe extrinsic PEEP
EDV end-diastolic volume PEEPi intrinsic PEEP
EEG electroencephalogram PEFR peak expiratory flow rate
EF ejection fraction PNS peripheral nervous system
EPO erythropoietin PPP pentose phosphate pathway
ER endoplasmic reticulum PRV polycythaemia rubra vera
ESV end-systolic volume PT prothrombin time
xii
Abbreviations
PTH parathyroid hormone SBP systolic blood pressure

PVR pulmonary vascular resistance SR sarcoplasmic reticulum
RAA renal–angiotensin–aldosterone SV stroke volume
RAP right atrial pressure SVC superior vena cava
RBC red blood cell SVR systemic vascular resistance
RBF renal blood flow SVV stroke volume variation
RMP resting membrane potential TF tissue factor
RNA ribonucleic acid TLC total lung capacity
RR respiratory rate TOE trans-oesophageal echocardiography
RRP relative refractory period V̇ /Q̇ ventilation–perfusion
RSI rapid sequence induction V̇ A alveolar ventilation
RV residual volume VC vital capacity
RVEDV right ventricular end-diastolic volume V̇ E minute ventilation
RVF right ventricular failure VT tidal volume
SA sinoatrial vWF von Willebrand factor
SaO2 arterial haemoglobin oxygen saturation
xiii
Section 1 The basics
Chapter
General organization of the body
1
Physiology is the study of the functions of the body,
its organs and the cells of which they are composed. It
How do organs differ from body
is often said that physiology concerns itself with systems?
maintaining the status quo or ‘homeostasis’ of bodily The organs of the body are functionally organized
processes. However, even normal physiology is not into 11 physiological ‘systems’:
constant, changing with development (childhood, Respiratory system, comprising the lungs and
pregnancy and ageing) and environmental stresses airways.
(altitude, diving and exercise). Many diseases and Cardiovascular system, comprising the heart and
their systemic effects are caused by a breakdown of the blood vessels. The blood vessels are
homeostasis. subclassified into arteries, arterioles, capillaries,
Anaesthetists are required to adeptly manipulate venules and veins. The circulatory system is
this complex physiology to facilitate surgical and crit- partitioned into systemic and pulmonary circuits.
ical care management. Therefore, before getting Nervous system, which comprises both neurons
started on the areas of physiology which are perhaps (cells which electrically signal) and glial cells
of greater interest, it is worth revising some of the (supporting cells). It can be further subclassified
basics – the next five chapters have been whittled in several ways:
down to the absolute essentials.
– Anatomically, the nervous system is divided
into the central nervous system (CNS) consisting
How do the body’s organs develop? of the brain and spinal cord, and the peripheral
The body is composed of some 100 trillion cells. All nervous system (PNS) consisting of peripheral
life begins from a single totipotent embryonic cell, nerves, ganglia and sensory receptors which
which is capable of differentiating into any cell type. connect the limbs and organs to the brain.
This embryonic cell divides many times and, by the – The PNS is functionally classified into an
end of the second week, gives rise to the three germ afferent limb conveying sensory impulses to
cell layers: the brain and an efferent limb conveying motor
impulses from the brain.
Ectoderm, from which the nervous system and
epidermis develop. – The somatic nervous system refers to the
parts of the nervous system under conscious
Mesoderm, which gives rise to connective tissue,
blood cells, bone and marrow, cartilage, fat and control.
muscle. – The autonomic nervous system (ANS) regulates
the functions of the viscera. It is divided into
Endoderm, which gives rise to the liver, pancreas
and bladder, as well as the epithelial lining of the sympathetic and parasympathetic nervous
lungs and gastrointestinal (GI) tract. systems.
– The enteric nervous system is a semi-
Each organ is composed of many different tissues, all autonomous system of nerves which controls
working together to perform a particular function. the digestive system.
For example, the heart is composed of cardiac muscle, Muscular system, comprising the three different
Purkinje fibres and blood vessels, working together to types of muscle: skeletal muscle, cardiac muscle
propel blood through the vasculature. and smooth muscle.
1
Section 1: The basics
Skeletal system, the framework of the body What is homeostasis?

comprising bone, ligaments and cartilage.
Single-celled organisms (for example, the amoeba) are
Integumentary system, which is essentially entirely dependent on the external environment
the skin and its appendages: hairs, nails,
for their survival. An amoeba gains its nutrients
sebaceous glands and sweat glands. Skin is an
directly from, and eliminates its waste products directly
important barrier preventing invasion by
into, the external environment. The external environ-
microorganisms and loss of water (H2O) from
ment also influences the cell’s temperature and pH,
the body. It is also involved in thermoregulation
along with its osmotic and ionic gradients. Small
and sensation.
fluctuations in the external environment may alter
Digestive system, involving the whole of the GI intracellular processes sufficiently to cause cell death.
tract from mouth to anus, and a number of Humans are multicellular organisms – the vast
accessory organs: salivary glands, liver, pancreas majority of our cells do not have any contact with
and gallbladder. the external environment. Instead, the body bathes its
Urinary system, which comprises the cells in extracellular fluid (ECF). The composition of
organs involved in the production and ECF bears a striking resemblance to seawater, where
excretion of urine: kidneys, ureters, bladder distant evolutionary ancestors of humans would have
and urethra. lived. Homeostasis is the regulation of the internal
Reproductive system, by which new life is environment of the body, to maintain a stable and
produced and nurtured. Many different organs are relatively constant environment for the cells:
involved, including: ovaries, testes, uterus and
Nutrients – cells need a constant supply of
mammary glands.
nutrients and oxygen (O2) to generate energy for
Endocrine system: endocrine cells, whose metabolic processes. In particular, plasma glucose
function is to produce hormones, are concentration is tightly controlled, and many
grouped together in glands located around physiological mechanisms are involved in
the body. Hormones are chemical maintaining an adequate partial pressure of O2.
signalling molecules carried in the blood
Carbon dioxide (CO2) and waste products – as
which regulate the function of the other,
cells produce energy, in the form of adenosine
often distant cells.
triphosphate (ATP), they generate waste
Immune system, which is involved in tissue repair products (for example, H+ and urea) and CO2.
and the protection of the body from Accumulation of these waste products may hinder
microorganism invasion and cancer. The immune cellular processes; they must be transported away.
system is composed of the lymphoid organs (bone
pH – all proteins, including enzymes and ion
marrow, spleen, lymph nodes and thymus), as well
channels, work efficiently only within a narrow
as discrete collections of lymphoid tissue within
range of pH.
other organs (for example, Peyer’s patches are
Electrolytes and water – intracellular water is
collections of lymphoid tissue within the small
tightly controlled; cells do not function correctly
intestine). The immune system is commonly
when they are swollen or shrunken. The
subclassified into:
movement of sodium (Na+) controls
– The innate immune system, which produces a the movement of water: extracellular Na+
rapid but non-specific response to concentration is therefore tightly controlled.
microorganism invasion. The extracellular concentrations of other
– The adaptive immune system, which produces electrolytes (for example, the ions of potassium
a slower, but highly specific response to (K+), calcium (Ca2+) and magnesium (Mg2+))
microorganism invasion. are important in the generation and
propagation of action potentials, and are
The body systems do not act in isolation; for example, therefore also tightly regulated.
arterial blood pressure is the end result of interactions Temperature – all proteins work best within a
between the cardiovascular, urinary, nervous and narrow temperature range; thermoregulation
endocrine systems. is therefore essential.
2
Chapter 1: General organization of the body
(a) Negative-feedback loop (b) Negative-feedback loop for PaCO2
– Increased alveolar
ventilation
Physiological variable PaCO2 = 6.2 kPa
decreases PaCO2
Sensor PaCO2 sensed by central

chemoreceptors in the medulla
Control centre
Respiratory centre in medulla
checks measured PaCO2 against set
point – realizes it is a little high, and
signals to the respiratory muscles
Effector
Respiratory muscles increase

tidal volume and respiratory rate:
alveolar ventilation increases
Figure 1.1 (a) Generic negative-feedback loop; (b) negative-feedback loop for PaCO2.
Homeostasis is a dynamic phenomenon: usually, Extrinsic homeostatic mechanisms occur at a

physiological mechanisms continually make minor distant site, involving one of the two major
adjustments to the ECF, keeping its composition and regulatory systems: the nervous system and the
temperature constant. Sometimes following a major endocrine system. The advantage of extrinsic
disturbance, large physiological changes are required. homeostasis is that it allows the coordinated
regulation of many organs.
The vast majority of homeostatic mechanisms
How does the body exert control over its employed by both the nervous and endocrine systems
physiological systems? rely on negative-feedback loops (Figure 1.1). Negative
Homeostatic control mechanisms may be intrinsic feedback involves the measurement of a physiological
(local) or extrinsic (systemic) to the organ: variable that is then compared with a ‘set point’ and,
Intrinsic homeostatic mechanisms occur within if the two are different, adjustments are made to
the organ itself, through autocrine (in which a correct the variable. Negative-feedback loops require:
cell secretes a chemical messenger that acts on Sensors, which detect a change in the variable.
that same cell) or paracrine (in which the For example, an increase in the arterial partial
chemical messenger acts on neighbouring pressure of CO2 (PaCO2) is sensed by the central
cells) signalling. For example, exercising chemoreceptors in the medulla oblongata.
muscle rapidly consumes O2, causing the O2 A control centre, which receives signals from the
tension within the muscle to fall. The waste sensors, integrates them and issues a response to
products of this metabolism (K+, adenosine the effectors. In the case of CO2, the control
monophosphate (AMP) and H+) cause centre is the respiratory centre in the medulla
vasodilatation of the blood vessels supplying oblongata.
the muscle, increasing blood flow and Effectors. A physiological system (or systems) is
therefore O2 delivery. activated to bring the physiological variable back
3
(a) Positive-feedback loop (b) Positive-feedback loop for oxytocin during labour
Stronger uterine
+ contractions push
Triggering event baby’s head Baby’s head pushes on
against cervix cervix, causing it to stretch
Sensor Nerve impulses from cervix

relayed to the brain
Control centre Brain stimulates pituitary

gland to release oxytocin
Effector
Uterine contractions
augmented by increased
oxytocin concentration
Figure 1.2 (a) Generic positive-feedback loop; (b) positive-feedback loop for oxytocin during labour.
to the set point. In the case of CO2, the stretching triggers the release of more oxytocin,
effectors are the muscles of respiration: by which further augments uterine contractions.
increasing alveolar ventilation, PaCO2 returns to This cycle continues until the baby is born and the
the ‘set point’. cervix is no longer stretched.
Depolarization phase of the action potential.
Voltage-gated Na+ channels are opened by
depolarization, which permits Na+ to enter the
What is positive feedback? cell, which in turn causes depolarization, opening
In physiological terms, positive feedback is a means of more channels. This results in rapid membrane
amplifying a signal: a small increase in a physiological depolarization.
variable triggers a greater and greater increase in
Excitation–contraction coupling in the heart.
that variable (Figure 1.2). Because the body is primar- During systole, the intracellular movement of
ily concerned with homeostasis, negative-feedback Ca2+ triggers the mass release of Ca2+ from the
loops are encountered much more frequently than sarcoplasmic reticulum (SR – an intracellular Ca2+
positive-feedback loops, but there are some important store). This rapidly increases the intracellular Ca2+
physiological examples of positive feedback. concentration, facilitating the binding of myosin
Haemostasis. Following damage to a blood vessel, to actin filaments.
exposure of a small amount of subendothelium
triggers a cascade of events, resulting in the In certain disease states, positive feedback may be
mass production of thrombin. uncontrolled. A classic example is decompensated
Uterine contractions in labour. The hormone haemorrhage: a fall in arterial blood pressure reduces
oxytocin causes uterine contractions during organ blood flow, resulting in tissue hypoxia. In
labour. As a result of the contractions, the baby’s response, vascular beds vasodilate, resulting in a further
head descends, stretching the cervix. Cervical reduction in blood pressure. Death rapidly ensues.
4
Chapter
Cell components and function
2
The cell nucleus is usually a spherical structure
Describe the basic layout of a cell situated in the middle of the cytoplasm. It comprises:
Whilst each cell has specialist functions, there are
many structural features common to all (Figure 2.1). The nuclear envelope, a double-layered
Each cell has three main parts: membrane that separates the nucleus from the
cytoplasm. The membrane contains holes called
The cell membrane, a thin barrier which separates ‘nuclear pores’ that allow the regulated passage of
the interior of the cell from the ECF. Structurally, selected molecules from the cytoplasm to the
the cell membrane is a phospholipid bilayer, a nucleoplasm.
hydrophobic barrier that prevents the passage of
The nucleoplasm, a gel-like substance (the
hydrophilic substances. The most important
nuclear equivalent of the cytoplasm) that
function of the cell membrane is regulation
surrounds the DNA.
of the passage of substances between the ECF
The nucleolus, a densely staining area of the
and the intracellular fluid (ICF). Small, gaseous
nucleus in which RNA is synthesized. Nucleoli
and lipophilic molecules may pass through
are more plentiful in cells which synthesize large
unregulated (see Chapter 4).
amounts of protein.
The nucleus, which is the site of the cell’s genetic
material. The nucleus is the site of messenger The DNA contained within each nucleus contains
ribonucleic acid (mRNA) expression and the individual’s ‘genetic code’, the blueprint from
thus coordinates the activities of the cell which all body proteins are synthesized (see
(see Chapter 3). Chapter 3).
The cytoplasm, the portion of the cell interior that
is not occupied by the nucleus. The cytoplasm
contains the cytosol (a gel-like substance), the What are the organelles? Describe the
cytoskeleton (a protein scaffold that gives the cell
shape and support) and a number of organelles major ones
(small discrete structures that each carry out a Organelles (literally ‘little organ’) are permanent, spe-
specific function). cialized components of the cell, usually enclosed
within their own phospholipid bilayer membrane.
An organelle is to a cell what an organ is to the body –
that is, a functional unit within a cell. Organelles
Describe the composition of the found in the majority of cells are:
cell nucleus Mitochondria, sometimes referred to as the
The cell nucleus contains the majority of the cell’s gene- ‘cellular power plants’, as they generate energy
tic material, deoxyribonucleic acid (DNA). The nucleus in the form of ATP through aerobic metabolism.
is the control centre of the cell, regulating the functions Mitochondria are ellipsoid in shape and are larger
of the organelles through gene expression. Almost all of and more numerous in highly metabolically active
the body’s cells contain a single nucleus. The exceptions cells; for example, red muscle. Unusually,
are mature red blood cells (RBCs), which are anuclear, mitochondria contain both an outer and an inner
skeletal muscle cells, which are multinuclear, and fused membrane, which creates two compartments,
macrophages, which form multinucleated giant cells. each with a specific function:
5
Mitochondrion
Outer membrane
Inner mitochondrial matrix

Cell membrane
Rough endoplasmic reticulum Smooth endoplasmic reticulum

Inner membrane
Ribosome
Christae Inter-membrane space
Nucleus
Nuclear envelope
Nuclear pore
Nucleoplasm
Nucleolus
Golgi apparatus
Lysosome Secretory vesicles
Figure 2.1 Layout of a typical cell.
– Outer mitochondrial membrane. This is a The matrix contains a large range of enzymes.
phospholipid bilayer that encloses the Many important metabolic processes take
mitochondria, separating it from the place within the matrix, such as the citric
cytoplasm. It contains large holes called acid cycle, fatty acid metabolism and the
porins. Molecules less than 5 kDa (such as urea cycle.
pyruvate, amino acids, short-chain fatty acids)
can freely diffuse across the membrane As all cells need to generate ATP to survive, mito-
through these pores. Longer chain fatty acids chondria are found in all the cells of the body (with
require the carnitine shuttle (see Chapter 72) the exception of RBCs, which gain their ATP from
to cross the membrane. glycolysis alone).
– Intermembrane space, the space between Endoplasmic reticulum (ER), the protein and
the outer membrane and the inner membrane. lipid-synthesizing apparatus of the cell. The ER is
As part of aerobic metabolism (see an extensive network (hence the name) of vesicles
Chapter 72), H+ ions are pumped into the and tubules that occupies much of the cytosol.
intermembrane space by the protein There are two types of ER, which are connected to
complexes of the electron transport chain. The each other:
resulting electrochemical gradient is used to – Rough ER, the site of protein synthesis.
synthesize ATP. The ‘rough’ or granular appearance is due to
– Inner mitochondrial membrane, the site of the the presence of ‘ribosomes’, the sites where
electron transport chain. Membrane-bound amino acids are assembled together in sequence
proteins participate in redox reactions, to form new protein. Protein synthesis is
resulting in the synthesis of ATP. completed by folding the new protein into
– Inner mitochondrial matrix, the area bounded its ‘conformation’, or three-dimensional
by the inner mitochondrial membrane. arrangement. Rough ER is especially prominent
6
Chapter 2: Cell components and function
in cells that produce a large amount of protein; glycosylation and phosphorylation

for example, antibody-producing plasma cells. respectively). These modified proteins are
– Smooth ER, the site of steroid and lipid then sorted and packaged into labelled vesicles
synthesis. Smooth ER appears ‘smooth’ (a sphere for transport). The vesicles are
because it lacks ribosomes. Smooth ER is transported to other parts of the cell, or to the
especially prevalent in cells with a role in cell membrane for secretion (a process called
steroid hormone synthesis; for example, the exocytosis).
cells of the adrenal cortex. In muscle cells, the Lysosomes are found in all cells but are
smooth ER is known as the SR, an intracellular particularly common in phagocytic cells
store of Ca2+ that releases Ca2+ following (macrophages and neutrophils). These organelles
muscle cell-membrane depolarization. contain powerful digestive enzymes, acid and free
Golgi apparatus, responsible for the modification radical species, that play a role in cell
and packaging of proteins in preparation for housekeeping (degrading old, malfunctioning or
their secretion. The Golgi apparatus is a series obsolete proteins), programmed cell death
of tubules stacked alongside the ER. The Golgi (apoptosis) and the destruction of phagocytosed
apparatus can be thought of as the cell’s ‘post microorganisms.
office’: it receives proteins, packs them into
envelopes, sorts them by destination and
dispatches them. When the Golgi apparatus Further reading
receives a protein from the ER, it is modified B. Alberts, D. Bray, K. Hopkin et al. Essential Cell Biology,
through the addition of carbohydrate or 3rd edition. Garland Publishing, 2009.
phosphate groups (processes known as
7
Chapter
Genetics
3
Genetics has revolutionized medicine. The human Nucleobases, four different ‘bases’ whose
genome project has resulted in a clarification of sequence determines the genetic code:
the code of every human gene. However, their func- – guanine (G)
tional significance, the physiology, remains poorly – adenine (A)
understood.
– thymine (T)
– cytosine (C).
What is a ‘chromosome’? The nucleobases are often subclassified based on
An individual’s genetic code is packed into the their chemical structure: A and G are purines,
nucleus of each cell, contained in a condensed whilst T and C are pyrimidines.
structure called ‘chromatin’. When the cell is pre-
paring to divide, chromatin organizes itself into The double helical arrangement of DNA has a
thread-like structures called ‘chromosomes’; each number of features:
chromosome is essentially a single piece of coiled Antiparallel DNA chains. The two strands of
DNA. In total, each cell contains 46 chromo- DNA run in antiparallel directions.
somes (23 pairs), with the exception of the gamete Matching bases. The two strands of DNA
cells (sperm and egg) which contain only 23 interlock rather like a jigsaw: a piece with
chromosomes. a tab cannot fit alongside another piece with a
There are two main types of chromosome: tab – nucleotide A does will not fit alongside
Autosomes, of which there are 22 pairs. another nucleotide A. The matching pairs
Allosomes (sex chromosomes), of which there (called complementary base pairs) are:
is only one pair, XX or XY. – C matches G
– A matches T.
Both types of chromosomes carry DNA, but only the
allosomes are responsible for determining an individ- Therefore, for the two DNA strands to fit together,
ual’s sex. the entire sequence of nucleotides of one DNA
strand must match the entire sequence of
nucleotides of the other strand.
What is DNA? Hydrogen bonding. The two strands of DNA are
DNA is a polymer of four nucleotides in sequence, held together by ‘hydrogen bonds’ (a particularly
bound to a complementary DNA strand and folded strong type of van der Waals interaction) between
into a double helix (Figure 3.1). The DNA strand the matching bases.
can be thought of as having two parts:
A sugar–phosphate backbone, made of What is RNA? How does it differ
alternating sugar (deoxyribose) and phosphate
groups. The sugars involved in the DNA from DNA?
backbone are pentose carbohydrates, which are The amino acid sequence of a protein is encoded
produced by the pentose phosphate pathway by the DNA sequence in the cell nucleus. But when
(PPP; see Chapter 72). the cell needs to synthesize a protein, the code is
8
Chapter 3: Genetics
5ⴕ end Double helix structure

Sugar–phosphate
Nucleobases backbone 5ⴕ end
P
3ⴕ end
3ⴕ end
P
G C
P
Pentose sugar
Hydrogen bonds
P
A T
P
P
C G
P
P
T A
P
3ⴕ end
Antiparallel strands P
3ⴕ end 5ⴕ end
5ⴕ end
Figure 3.1 Basic structure of DNA.
anchored in the nucleus, and the protein- RNA sugar groups have a hydroxyl group that
manufacturing apparatus (the ER and Golgi appar- DNA sugars lack (hence ‘deoxy’-ribonucleic acid).
atus – see Chapter 2) is located within the cytoplasm. RNA contains the nucleobase uracil (U) in place
RNA overcomes this problem: RNA is produced as a of thymine (T).
copy of the DNA genetic code in the nucleus and RNA usually exists as a single strand: there is
exported to the cytoplasm, where it is used to synthe- no antiparallel strand with which to form a
size protein. double helix.
In some ways, RNA is very similar to DNA. RNA
has a backbone of alternating sugar and phosphate There are three types of RNA:
groups attached to a sequence of nucleobases. How- Messenger RNA (mRNA). In the nucleus,
ever, RNA differs from DNA in a number of ways: mRNA is synthesized as a copy of a specific
9
section of DNA – this process is called

‘transcription’. mRNA then leaves the GTG (which encodes valine). The substitution of
a polar amino acid (glutamic acid) for a non-polar
nucleus and travels to the ribosomes of
amino acid (valine) causes aggregation of Hb,
the rough ER, the protein-producing factory
and thus a shape change of the erythrocyte,
of the cell. under conditions of low O2 tension.
Transfer RNA (tRNA). In the cytoplasm, the Cystic fibrosis results from mutations in the
20 different types of tRNA gather the 20 different cystic fibrosis transmembrane conductance
amino acids and ‘transfer’ them to the ribosome, regulator (CFTR) gene, which encodes a
ready for protein synthesis. transmembrane chloride (Cl ) channel. The
Ribosomal RNA (rRNA). Within the ribosome, abnormal CFTR gene is characterized by reduced
rRNA aligns tRNA units (with the respective membrane Cl permeability. The clinical result
amino acids attached) in their correct positions is thickened secretions that prevent effective
clearance by ciliated epithelium, resulting in
along the mRNA sequence. The amino acids
blockages of small airways (causing pneumonia),
are joined together, and a complete protein pancreatic ducts (which obstructs flow of
is released. digestive enzymes) and vas deferens (leading
to incomplete development and infertility).
There are over 1000 different point mutations
What is a ‘codon’? described in the CFTR gene. The most common is
A codon is a small piece of mRNA (a triplet of nucleo- the ΔF508 mutation, where there is a deletion
sides) that encodes an individual amino acid. For of three nucleotides (i.e. an entire codon,
example, GCA represents the amino acid alanine. which encodes phenylalanine, F) at the
tRNA also uses codons; as tRNA must bind to mRNA, 508th position.
the codons are the ‘jigsaw match’ of the mRNA Huntingdon’s disease is a neurodegenerative
disorder caused by the insertion of repeated
codons (called anticodons). For example, CGU is the
segments of DNA. The codon for the amino acid
complementary anticodon tRNA sequence to GCA. glutamine (CAG) is repeated multiple times
CGU tRNA therefore binds alanine. within the Huntingdon gene on chromosome 4.
This is known as a trinucleoside repeat disorder.
Clinical relevance: gene mutations
Errors may occur during DNA replication or repair.
This abnormal DNA is then used for protein synthesis:
transcribed mRNA incorporating the error is exported
to the ribosome and translated into an abnormal
What are the modes of Mendelian
protein. Common types of error are: inheritance? Give some examples
Point mutations, where a single nucleoside is Almost all human cells are diploid, as they contain
incorrectly copied in the DNA sequence.
46 chromosomes (23 pairs). Gamete cells (sperm or
Deletions, where one or more nucleosides are
egg) are haploid, as they contain 23 single chromo-
accidentally removed from the DNA sequence.
Insertions, where another short sequence of somes. When the gametes fuse, their chromosomes
DNA is accidentally inserted within the DNA pair to form a new human with 23 pairs of chromo-
sequence. somes. During the formation of the gametes (a pro-
cess known as meiosis), separation of pairs of
Deletions and insertions are far worse than point chromosomes into single chromosomes is a random
mutations as ‘frame shift’ may occur, with the ensu- process. Each person can therefore theoretically pro-
ing DNA encoding a significantly altered protein. duce 223 genetically different gametes, and each
The resulting abnormal proteins have clinical couple can theoretically produce 246 genetically
consequences, for example:
different children!
Sickle cell disease results from a point mutation
A ‘trait’ is a feature (phenotype) of a person
in the DNA code for the β-chain of haemoglobin
(Hb) on chromosome 11. Instead of the codon for encoded by a gene. A trait may be a physical appear-
the sixth amino acid of the DNA sequence read- ance (for example, eye colour), or may be non-visible
ing GAG (which encodes glutamic acid), it reads (for example, a gene encoding a plasma protein). Each
unique type of gene is called an allele (for example,
10
Chapter 3: Genetics
(a) Autosomal dominant (b) Autosomal recessive (c) X-linked recessive
Affected Unaffected ‘Carrier’ ‘Carrier’ Unaffected ‘Carrier’

father mother father mother father mother
A a a a A a A a X Y X X
A a A a a a a a A A A a a A a a X X X X X Y X Y
Affected Affected Unaffected Unaffected Unaffected ‘Carrier’ ‘Carrier’ Affected Unaffected ‘Carrier’ Unaffected Affected
child child child child child child child child girl girl boy boy
50% chance 25% 25% 25% 25%

50% chance 25% chance 50% chance 25% chance
chance chance chance chance
Figure 3.2 Mendelian inheritance patterns: (a) autosomal dominant; (b) autosomal recessive; (c) X-linked recessive.
there are blue-eye alleles and brown-eye alleles). genotype aa (referred to as homozygous).
Every individual has at least two alleles encoding each The parents of a child with an autosomal
trait, one from each parent. It is the interaction recessive disease usually do not have the
between alleles that determines whether an individ- disease themselves: they are carriers (or
ual displays the phenotype (has a particular trait). heterozygotes) with the genotype Aa. A child
‘Dominant’ alleles (denoted by capital letters) mask of two heterozygous parents (genotype Aa)
the effects of ‘recessive’ alleles (denoted by lower case has a 50% chance of having genotype Aa
letters). (a carrier), a 25% chance of genotype AA
Common Mendelian inheritance patterns of dis- (being disease-free) and a 25% chance of
ease are: having genotype aa (i.e. homozygous, having
Autosomal dominant. For an individual the autosomal recessive disease) (Figure 3.2b).
to have an autosomal dominant disease, Examples of autosomal recessive diseases are
one of their parents must also have sickle cell disease, Wilson’s disease and cystic
the disease. A child of two parents, fibrosis.
one with an autosomal dominant disease X-linked recessive. These diseases are
(genotype Aa, where the bold A is the carried on the X chromosome. They
affected allele) and one without (genotype aa), usually only affect males (XY), because females
has a 50% chance of inheriting the (XX) are protected by a normal allele on the
disease (genotype Aa) and a 50% other X chromosome. Of the offspring of
chance of being disease free (genotype aa) female carriers (XX), 25% are female
(Figure 3.2a). Examples of autosomal carriers (XX), 25% are disease-free
dominant diseases are hypertrophic females (XX), 25% are disease-free males
cardiomyopathy, polycystic kidney (XY) and 25% are males with the disease (XY)
disease and myotonic dystrophy. (Figure 3.2c). Examples of X-linked
Autosomal recessive. In an autosomal recessive diseases are haemophilia A,
recessive disease, the phenotype is only seen Duchenne muscular dystrophy and red–green
when both alleles are recessive; that is, colour blindness.
11
Most inherited characteristics do not obey the Further reading

simple monogenetic Mendelian rules. For example,
R. Landau, L. A. Bollag, J. C. Kraft. Pharmacogenetics and
diseases such as diabetes and ischaemic heart disease anaesthesia: the value of genetic profiling. Anaesthesia
may certainly run in families, but the heritability 2012; 67(2): 165–79.
is much more complex, often being polygenetic and A. Gardner, T. Davies. Human Genetics, 2nd edition. Scion
involving environmental as well as genetic factors. Publishing Ltd, 2009.
12
Chapter
The cell membrane
4
The cell membrane separates the intracellular con-
tents from the extracellular environment, and then
Which other structures are found within
controls the passage of substances into the cell. This the cell membrane?
allows the cell to regulate, amongst other things, A number of important structures are found in and
intracellular ion concentrations, water balance and around the cell membrane:
pH. The integrity of the cell membrane is of crucial Transmembrane proteins. As suggested by the
importance to cell function and survival. name, these proteins span the membrane
phospholipid bilayer. Importantly, the fluidity of
the cell membrane allows these transmembrane
What is the structure of the cell proteins to float around, rather like icebergs on a
membrane? sea of lipid.
The cell membrane is composed of two layers of Peripheral proteins. These proteins are mounted
phospholipid, sandwiched together to form a ‘phos- on the surface of the cell membrane, commonly
pholipid bilayer’ (Figure 4.1). Important features of the inner surface, but do not span the cell
this structure are: membrane. Cell adhesion molecules, which
anchor cells together, are examples of outer
Phospholipid is composed of a polar hydrophilic
membrane peripheral proteins. Inner membrane
phosphate ‘head’ to which water is attracted, and a
peripheral proteins are often bound to the
non-polar hydrophobic fatty acid ‘tail’ from which
cytoskeleton by proteins such as ankyrin,
water is repelled.
maintaining the shape of the cell.
The phospholipid bilayer is arranged so that the
polar groups face outwards, and the non-polar Glycoproteins and glycolipids. The outer surface
of the cell membrane is littered with short
groups are interiorized within the bilayer structure.
carbohydrate chains, attached to either protein
The outer surface of the phospholipid bilayer is in
(when they are referred to as ‘glycoproteins’) or
contact with the ECF, and the inner surface of the
lipid (referred to as ‘glycolipids’). The
bilayer is in contact with the ICF.
carbohydrates act as ‘labels’, allowing the cell to be
The non-polar groups form a hydrophobic core, identified by other cells, including the cells of the
preventing free passage of water across the cell
immune system.
membrane. This is extremely important. The cell
Cholesterol. This helps strengthen the
membrane prevents simple diffusion of
phospholipid bilayer and further decreases its
hydrophilic substances, enabling different
permeability to water.
concentrations of solutes to exist inside and
outside the cell.
The phospholipid bilayer is a two-dimensional What are the functions of
liquid rather than a solid structure; the individual
phospholipids are free to move around within transmembrane proteins?
their own half of the bilayer. The fluidity of the The hydrophobic core of the phospholipid bilayer
cell membrane allows cells to change their shape; prevents simple diffusion of hydrophilic substances.
for example, RBCs may flex to squeeze through Instead, transmembrane proteins allow controlled
the small capillaries of the pulmonary circulation. transfer of solutes and water across the cell membrane.
13
EXTRACELLULAR SIDE
Glycoprotein
Hydrophilic outer membrane
Hydrophobic core
Hydrophilic inner membrane
Cholesterol
Peripheral protein
INTRACELLULAR SIDE
Transmembrane protein
Figure 4.1 The phospholipid bilayer.
The cell can therefore regulate intracellular solute By what means are substances
concentrations by controlling the number, permeabil-
ity and transport activity of its transmembrane transported across the cell membrane?
proteins. There are many different types of transmem- The behaviour of substances crossing the cell mem-
brane protein – the important classes are: brane is broadly divided into two categories:
Ion channels, water-filled pores in the Lipophilic substances (for example, O2, CO2 and
cell membrane that allow specific ions steroid hormones) are not impeded by the
to pass through the cell membrane, hydrophobic core of the phospholipid bilayer
along their concentration gradient. and are able to cross the cell membrane
Carriers, which transport specific substances (Figure 4.2). Small lipophilic substances diffuse
through the cell membrane. through the cell membrane in accordance with
Pumps (ATPases), which use energy (in the their concentration or pressure gradients:
form of ATP) to transport ions across the cell molecules diffuse from areas of high concentration
membrane, usually against their concentration (or partial pressure) to areas of low concentration
gradients. (or partial pressure) (see Chapter 9).
Receptors, to which extracellular Hydrophilic substances (for example, electrolytes
ligands bind, initiating an intracellular and glucose) are prevented from passing
reaction (usually) through a second messenger through the hydrophobic core of the phospholipid
system. bilayer. Instead, they traverse the cell membrane
Enzymes, which may catalyse intracellular by passing through channels or by combining
or extracellular reactions. with carriers.
14
Chapter 4: The cell membrane
EXTRACELLULAR FLUID
O2 Na+ Glucose 2K+ Na+ Glucose Na+
3Na+
ATP ADP + Pi K+
Simple diffusion Passive diffusion: Passive diffusion: Primary active transport: Secondary active transport: Secondary active transport:
+ +
ion channel facilitated diffusion Na /K -ATPase co-transport counter-transport
INTRACELLULAR FLUID
Figure 4.2 Means of transport across the cell membrane.
Hydrophilic substances can be transported across the its concentration gradient, but when the
cell membrane by passive or active means (Figure 4.2): channel is closed the membrane becomes
impermeable.
Passive transport. Some transmembrane proteins
act as water-filled channels through which ▪ Ligand-gated channels, where the binding
hydrophilic molecules can diffuse along their of a small molecule (ligand) causes the ion
concentration gradients. These protein channels channel to open or close. For example,
are highly specific for a particular substance. acetylcholine (ACh) binds to the nicotinic
There are two types of passive transport – ion ACh receptor (a ligand-gated cation
channels and facilitated diffusion: channel) of the neuromuscular
junction (NMJ), thereby opening its
– Ion channels are pores in the cell membrane integral cation channel.
that are highly specific to a particular ion. For ▪ Mechanically gated channels, which have
example, a sodium channel is exactly the right pores that respond to mechanical stimuli,
size and charge to allow Na+ to pass through, such as stretch. For example, mechanically
but will not allow a K+ ion to pass.1 Ion gated Ca2+ channels open following
channels may be classified as: distension of arteriolar smooth muscle –
this is the basis of the myogenic response
▪ Leak channels, which are always open,
allowing continuous movement of the (see Chapters 32 and 53).
specific ion along its concentration gradient. – Facilitated diffusion. A carrier protein binds a
▪ Voltage-gated channels, which open by specific substrate before undergoing a number
changing shape in response to an electrical of conformation changes to move the substrate
stimulus, typically a depolarization of the from one side of the cell membrane to the
cell membrane (see Chapter 49).2 When other. Once the substrate has passed through
the ion channel is open, the specific ion the cell membrane, it is released from the
diffuses through the cell membrane along carrier protein. The substance passes down its
concentration gradient, facilitated by the
1
It is easy to understand why a larger ion may not fit carrier protein (Figure 4.3). Facilitated
through an ion channel designed for a small ion, but the diffusion is much faster than simple diffusion,
reverse is also true: a small ion does not fit through a but is limited by the amount of carrier protein
channel designed for a larger ion. The reason for this is
related to the number of water molecules that surround
2
the ion (the hydration sphere): a smaller ion has a larger In contrast, the inward rectifying K+ channels of the
hydration sphere, which cannot pass through the wrong- cardiac action potential open when the cell membrane
sized ion channel. repolarizes (see Chapter 54).
15
EXTRACELLULAR FLUID
Substance undergoing
facilitated diffusion
Conformational Conformational
change change
Carrier protein
INTRACELLULAR FLUID
Figure 4.3 Facilitated diffusion.
in the cell membrane. The most important intracellularly and can only move
example of facilitated diffusion is glucose K+ extracellularly.
transport into the cell through the glucose – Secondary active transport, a combination
transporter (GLUT). An example of passive of primary active transport and facilitated
counter-transport is the Cl /bicarbonate diffusion. Substances are transported
(HCO3 )-antiporter in the renal tubule, where alongside Na+, driven by the low intracellular
Cl and HCO3 are simultaneously concentration of Na+, which in turn is
transported in opposite directions, down their generated by the Na+/K+-ATPase pump. So
respective concentration gradients. whilst the transporter is not directly involved
Active transport. Energy from ATP, is used to in hydrolysing ATP, it relies on primary active
move substances across the cell membrane. Active transport, which consumes ATP. Secondary
transport is further subclassified as: active transport may be:
– Primary active transport. Here, ATP is
▪ Co-transport (or ‘symport’) where both
hydrolysed by the carrier protein itself, as it ions move in the same direction; for
moves ions from one side of the cell membrane example, the absorption of glucose
to the other. An example of primary with Na+ in the renal tubules through
active transport is the plasma membrane the sodium–glucose linked transporter
Ca2+-ATPase, which pumps Ca2+ out of the cell, (SGLT-2).3
keeping the intracellular Ca2+ concentration
▪ Counter-transport (or ‘antiport’), where
very low. An important example of a more
each ion is transported in opposite
complicated system of primary active
directions; for example, the Na+/K+-
transport is the Na+/K+-ATPase pump, which
antiporter in the principal cells of the
uses one molecule of ATP to transport three Na+
renal collecting ducts.
ions from the ICF to the ECF, whilst
simultaneously transporting two K+ ions
3
from the ECF to the ICF. Unlike passive SGLT-2 transports glucose, along with Na+, across the
transport, whose direction of diffusion depends apical membrane of the proximal convoluted tubule
(PCT) by secondary active transport, which consumes
on the relative concentrations of the ATP. Glucose then diffuses along its concentration
substance on either side of the cell membrane, gradient across the basolateral membrane of the tubular
active transport is usually unidirectional. cell by facilitated diffusion (through GLUT-2), which
The Na+/K+-ATPase can only move Na+ does not require ATP.
16
Chapter 4: The cell membrane
Macromolecule Figure 4.4 Mechanism of endocytosis.
Phospholipid bilayer
Pit forms
Cell membrane
encloses macromolecule
Vesicle forms
Are there any other means by which breast milk immunoglobulin A (IgA)
macromolecules through the cell membrane of
substances are transported across the the neonate’s gut.
cell membrane? – Receptor-mediated endocytosis, in which the
An alternative method of transporting substances substance binds to a receptor located on the
across the cell membrane is through vesicular extracellular side of the cell membrane. The
transport: receptor–substance complex then undergoes
endocytosis, transporting the substance across
Endocytosis. This is an energy-consuming process
the cell membrane. Examples of substances
whereby large extracellular substances are
transported by receptor-mediated endocytosis
enveloped within a short section of cell
include iron and cholesterol.
membrane, forming a vesicle. The vesicle carries
Exocytosis, the reverse process of endocytosis.
the substances, together with a small quantity of
Exocytosis is an energy-consuming process in
ECF, into the cytoplasm. Endocytosis is
which substances are transported across the cell
subclassified, depending on the type of substance
membrane from the ICF to the ECF within a
transported:
vesicle. Once the vesicle has reached the
– Phagocytosis is the intracellular transport of extracellular side of the cell membrane, it merges
particulate matter by endocytosis – microbes with the phospholipid bilayer, releasing its
(bacteria, viruses), cells and other debris. contents into the ECF. Exocytosis is an important
Phagocytosis is used by neutrophils and mechanism by which neurotransmitters and
macrophages; these cells engulf and kill hormones are released.
microbes (see Chapter 70). Transcytosis, in which a substance undergoes
– Pinocytosis is the intracellular transport of endocytosis on one side of the cell, is transported
macromolecules by endocytosis. An important across the cell interior and is released on the far
example of pinocytosis is the transport of side of the cell through exocytosis.
17
Chapter
Enzymes
5
Enzymes are biological catalysts whose function is for the chemical reaction, which dramatically
to increase the rate of metabolic reactions. increases the rate of reaction. The three-dimensional
shape of the active site is of crucial importance.
If the shape of the active site is altered (for example
What is a catalyst? by increased temperature or pH), the function of
A catalyst is a substance that increases the rate of the enzyme may be impaired and the chemical
a chemical reaction without being itself chemically reaction slowed.
altered. As the catalyst is not consumed in the As an example, the reaction between CO2 and
reaction, it can be involved in repeated chemical water giving carbonic acid (H2CO3) is very slow:
reactions – only small amounts are required.
CO2 + H2O ! H2CO3
What are the main features However, addition of the enzyme carbonic anhy-
drase (CA), which contains a zinc atom at its active
of an enzyme? site, to the mixture of CO2 and water increases the
Enzymes are complex three-dimensional proteins, speed of the reaction considerably. First, water binds
which have three important features: to the zinc atom, then a neighbouring histidine resi-
Catalysis. Enzymes act as catalysts for biological due removes an H+ ion from the water, leaving the
reactions. highly active OH ion attached to zinc (Figure 5.1).
Specificity. Their complex three-dimensional Finally, there is a pocket within the active site that
structure results in a highly specific binding site, fits the CO2 molecule perfectly: with CO2 and OH in
the active site, for the reacting molecules or close proximity, the chemical reaction takes place
substrates. The active site can even distinguish quickly. Once CO2 and water have reacted, the
between different stereoisomers of the same resulting H2CO3 diffuses out of the enzyme, leaving
molecule. it unchanged chemically; that is, the enzyme acts
Regulation. Many of the reactions in biochemical as a catalyst.
pathways (for example, the glycolytic pathway) The same enzyme can also catalyse the reverse
are very slow in the absence of enzymes. reaction. This is indeed the case for CA, which
Therefore, the rate of a biochemical pathway catalyses
can be controlled by regulating the activity H2CO3 ! H2O + CO2
of the enzymes along its path, particularly the
enzyme controlling the rate-limiting step, Carbonated drinks degas quite slowly when their
which in the case of glycolysis is container is opened, but degas very quickly on contact
phosphofructokinase. with saliva, which contains CA. This gives the sensa-
tion of carbonated drinks being ‘fizzy’ on the tongue.
The overall direction of the reaction obeys Le
How does an enzyme work? Chatelier’s principle: if a chemical equilibrium experi-
Enzymes work by binding substrates in a particular ences a change in concentration or partial pressure,
orientation, bringing them into the optimal position the equilibrium shifts to counteract this change, and
to react together. This lowers the activation energy a new equilibrium is reached.
18
Chapter 5: Enzymes
Zinc ion at the active site

Folded protein
Carbonic
anhydrase O
CO2
C
Zn2+ Zn2+
O
O H O–
His His+
H H H
CO2 binding site
Histidine residue
C
Zn2+ Zn2+
O–
O
O H
H2CO3
His His+
H H
H
H2O
Enzyme emerges from reaction unchanged
Figure 5.1 Catalysis of reaction between water and CO2 by CA.
What types of enzyme are there? What is meant by the terms ‘cofactor’
Enzymes are classified by the type of biological reac- and ‘coenzyme’?
tion they catalyse:
Some enzymes consist purely of protein and
oxidoreductases, which catalyse oxidation and catalyse biological reactions by themselves. Other
reduction (redox) reactions; enzymes require non-protein molecules (called
transferases, which transfer functional groups cofactors) to aid their enzymatic activity. Cofactors
(for example, a kinase transfers a phosphate can be:
group) from one molecule to another;
hydrolases, which catalyse hydrolysis reactions; Inorganic. Many enzymes contain metal ions at
their active site; for example:
lyases, which cleave bonds by means other than
hydrolysis and oxidation; – CA contains Zn2+, as discussed above;
isomerases, which allow a molecule to – the cytochrome P450 group of enzymes all
interconvert between its isomers; contain Fe2+;
ligases, which use energy (derived from ATP – vitamin B12 contains Co2+;
hydrolysis) to join two molecules together with – superoxide dismutase contains Cu2+;
covalent bonds. – hexokinase contains Mg2+.
19
Organic. When the cofactor is organic, it is called

a ‘coenzyme’. Examples are: antidepressants, with significant implications for
the anaesthetist: indirect-acting sympathomimetics
– Coenzyme A (CoA), a coenzyme used to may precipitate a potentially fatal hypertensive
transfer acyl groups by a variety of enzymes; crisis, whilst direct-acting sympathomimetics
for example, acetyl-CoA carboxylase. can be used at a reduced dose.
– Nicotinamide adenine dinucleotide (NAD+), Pseudocholinesterase (also known as plasma
a coenzyme that accepts a hydride (H ) ion. cholinesterase and butyrylcholinesterase).
NAD+ is utilized, for example, in conjunction This is a plasma enzyme that metabolizes
suxamethonium and mivacurium. Patients
with the enzyme alcohol dehydrogenase.
who lack this enzyme, or who have reduced
enzyme activity, experience prolonged muscular
Clinical relevance: enzymes and the anaesthetist paralysis following a dose of suxamethonium
Enzymes are very important in anaesthetic practice. or mivacurium – a condition known as
Many of the drugs we use have their effects termi- ‘suxamethonium apnoea’.
nated by enzymatic activity. Some drugs work by Acetylcholinesterase (AChE). This is an
inhibiting enzymes. And some diseases are the result enzyme found in the synaptic cleft of the NMJ. It
of reduced enzymatic activity. Examples include the hydrolyses the neurotransmitter ACh, terminating
following. neurotransmission. Neostigmine, a reversible AChE
Cytochrome P450. This superfamily of enzymes is inhibitor, is used to increase the concentration
responsible for the metabolism of most anaesthetic of ACh in the synaptic cleft. Increased ACh
drugs. Notable exceptions include atracurium competitively displaces non-depolarizing muscle
(degrades mainly by Hofmann elimination), relaxants from their receptors.
catecholamines, suxamethonium, mivacurium Non-specific tissue and plasma esterases.
and remifentanil (see below). These are responsible for the rapid hydrolysis of
Monoamine oxidase (MAO). Monoamine remifentanil, an ultra-short-acting opioid. This
catecholamines (adrenaline, dopamine, means that accumulation does not occur, and the
noradrenaline) are metabolized by this context-sensitive half-time remains at 4 min,
mitochondrial enzyme. MAO inhibitors are even after prolonged infusion.
20
Section 2 Respiratory physiology
Chapter
Lung anatomy and function
6
means that potentially harmful gases
What are the functions of the lung? can be sensed by rapid short
The functions of the lung can be classified as respira- inspiration (i.e. sniffing) before being
tory and non-respiratory: inhaled into the lungs.
Respiratory functions are those of gas exchange:
Larynx:
– movement of gases between the atmosphere
– During inhalation the vocal cords are in
and the alveoli;
an abducted position, to reduce resistance
– passage of O2 from the alveoli to the
to inward gas flow.
pulmonary capillaries;
– In exhalation the cords adduct slightly,
– passage of CO2 from the pulmonary
increasing the resistance to gas flow, which
capillaries to the alveoli;
results in a positive end-expiratory pressure
– synthesis of surfactant. (PEEP) of 3–4 cmH2O. This ‘physiological’
Non-respiratory functions are: PEEP is important for vocalization and
– acid–base balance; coughing, and also maintains positive pressure
– immunological and lung defence; in the small airways and alveoli during
– vascular; expiration, thus preventing alveolar collapse
– metabolic and endocrine. and maintaining functional residual
capacity (FRC).
Describe the functional anatomy

of the respiratory system Clinical relevance: positive end-expiratory pressure
The respiratory system can be divided into the upper When a patient is intubated, the vocal cords are
airway, larynx and tracheobronchial tree. The no longer able to adduct during exhalation, leading
tracheobronchial tree can be subdivided into the con- to a loss of physiological PEEP. This can result in
ducting and respiratory zones. Important aspects of atelectasis and ventilation–perfusion (V̇ /Q̇ ) mismatch.
the anatomy are: It is common practice to apply extrinsic PEEP
(PEEPe) at physiological levels (3–5 cmH2O) to
Upper airway: maintain FRC and prevent atelectasis following
– Nasal hairs filter any large inhaled particles. intubation.
– The mucosa of the nasal cavity is highly However, PEEP increases intrathoracic pressure,
vascular, which promotes humidification which increases venous pressure, thereby reducing
venous return. There are a small number of situations
of inhaled air. The superior, middle and
where not applying PEEPe may be advantageous –
inferior nasal turbinates direct the
situations where raised venous pressure may have
inspired air over the warm, moist clinical consequences. For example:
mucosa, increasing the surface area for
Raised intracranial pressure (ICP) – increased
humidification.
intrathoracic pressure may hinder venous
– Olfactory receptors are located in the drainage from the cerebral venous sinuses,
posterior nasal cavity. The proximal leading to an increase in ICP.
location of the olfactory receptors
21
Section 2: Respiratory physiology
Airway generation Figure 6.1 Generations of the

tracheobronchial tree.
0 Trachea
1 Main bronchi
2 Lobar bronchi Cartilaginous airways
3–4 Segmental bronchi Conducting zone
5–11 Subsegmental bronchi
12–15 Bronchioles Non-cartilaginous airways
16 Terminal bronchioles
17–19 Respiratory bronchioles
20–22 Alveolar ducts Respiratory zone
23 Alveolar sacs
are responsible for conducting air from the

Tonsillectomy – raised venous pressure may
increase bleeding at the tonsillar bed, obstructing
larynx to the respiratory zone, whilst the
the surgeon’s view of the operative field. respiratory zone is responsible for gas exchange.
– For a 70 kg man, the volume of the conducting
airways, known as the anatomical dead space,
is approximately 150 mL. The volume of
Clinical relevance: humidification the respiratory zone at rest is approximately
Endotracheal and tracheostomy tubes bypass the 3000 mL.
upper airway, so the normal warming and humidifi- Conducting zone. The airways of the
cation of inspired air cannot occur. Inhaling cold, dry conducting zone do not participate in gas
gases results in increased mucus viscosity, which
exchange; their function is to allow the
impairs the mucociliary escalator. This causes:
transfer of air between the atmosphere and
accumulation of mucus in lower airways;
an increased risk of pulmonary infection;
the respiratory zone:
microatelectasis. – The upper airways are lined by ciliated
Artificial humidification and warming of inspired pseudostratified columnar epithelium. Goblet
gases is commonly achieved using a heat and mois- cells are scattered between the epithelial cells.
ture exchanger for surgical procedures, or a hot The goblet cells secrete a mucus layer that
water bath humidifier in the intensive care unit. covers the epithelial cells and traps inhaled
foreign bodies or microorganisms. The cilia
beat in time, propelling mucus towards the
Tracheobronchial tree: oropharynx where it is either swallowed or
– The tracheobronchial tree consists of a series expectorated. This system is known as the
of airways that divide, becoming progressively mucociliary escalator; its function is to protect
narrower with each division. In total, there are the lungs from microorganisms
23 divisions1 or generations between the and particulate matter, and to prevent mucus
trachea and the alveoli (Figure 6.1). As the accumulation in the lower airways.
generations progress, the total cross-sectional – The trachea starts at the lower border of the
area increases exponentially (Figure 6.2). cricoid cartilage (C6 vertebral level) and
– The tracheobronchial tree is subdivided into bifurcates at the carina (T4/5 level). The
the conducting zone (airway generations 0–16) anterior and lateral walls of the trachea are
and the respiratory zone (generations 17–23). reinforced with ‘C’-shaped cartilaginous rings.
As the names suggest, the conducting airways The posterior gap of the cartilaginous rings is
bridged by the trachealis muscle. At times of
1
In fact, some studies claim that there are up to 28 airway extreme inspiratory effort with associated high
generations in humans, but 23 generations is commonly negative airway pressure, these cartilaginous
quoted. rings prevent tracheal collapse.
22
Chapter 6: Lung anatomy and function
Figure 6.2 Increasing cross-sectional

area with airway generation.
500
Total cross–sectional area (cm2)
400
300
Conducting zone Respiratory zone

200
100
0
0 5 10 15 16 20 23
Airway generation
Terminal bronchioles
– The trachea divides into the right and left main

bronchi. The right main bronchus is shorter, Left-sided double-lumen ETTs (DLETTs) are often
favoured over right-sided tubes for one-lung ventila-
wider and more vertical than the left. Inhaled
tion, even for some right-sided thoracic surgery. This
foreign bodies and endotracheal tubes (ETTs)
is because incorrect positioning of a right-sided
are therefore more likely to enter the right DLETT risks occlusion of the right upper lobe bron-
main bronchus than the left. chus by the ETT cuff. Right-sided DLETTs are available
– The right lung has three lobes (upper, middle and have a hole positioned for ventilation of the right
and lower), and the left has two lobes (upper upper lobe. However, there are anatomical variations
and lower). The lingula (Latin for ‘little tongue’) in the position of the right upper lobe bronchus; the
is a part of the left upper lobe, and is considered position of the DLETT and the right upper lobe bron-
to be a remnant of the left middle lobe which chus should therefore be checked using fibre-optic
has been lost through evolution. There are bronchoscopy.
10 bronchopulmonary segments on the right
(three upper lobe, two middle lobe, five lower – Segmental and subsegmental bronchi are lined
lobe), and nine bronchopulmonary segments by respiratory epithelium surrounded by a
on the left (five upper lobe, four lower lobe). layer of smooth muscle. Irregularly shaped
Clinical relevance: double-lumen cartilaginous plates prevent airway collapse.
endotracheal tubes – The bronchioles are the first airway generation
The right upper lobe bronchus originates from the that does not contain cartilage. They have a
right main bronchus only 2 cm distal to the carina. In layer of smooth muscle that contracts
contrast, the left main bronchus bifurcates 5 cm from (bronchoconstriction) and relaxes
the carina. (bronchodilatation) to modulate gas flow:
23
▪ Bronchodilatation results from Type II pneumocytes. These cover the remaining

sympathetic nervous system activity, 10% of the alveolar surface. They are specialized
for example during exercise: this secretory cells that coat the alveolar surface with
reduces resistance to gas flow, allowing pulmonary surfactant.
greater ventilation during periods of O2 Alveolar macrophages. Derived from
demand. Drugs that induce monocytes, alveolar macrophages are
bronchodilatation include β2-agonists and found within the alveolar septa and the lung
anticholinergics. interstitium. They phagocytose any particles
▪ Bronchoconstriction is precipitated by the that escape the conducting zone’s mucociliary
parasympathetic nervous system, escalator.
histamine, cold air, noxious chemicals and
other factors. At rest, the reduction in gas
flow velocity causes particulate material
What is the alveolar–capillary barrier?
to settle in the mucus, which is then The barrier between the alveolus and the pulmonary
transported away from the respiratory capillary is extremely thin, which facilitates efficient
zone by the cilia. gas exchange (see Chapter 9); in some places it is as
thin as 200 nm. There are three layers:
– The terminal bronchioles occur at the 16th type I pneumocytes of the alveolar wall;
airway generation, the last airway generation extracellular matrix;
of the conducting zone. pulmonary capillary endothelium.
Respiratory zone. Airway generations subsequent
to the terminal bronchioles are no longer purely Despite being very thin, the alveolar–capillary bar-
conducting – the respiratory bronchioles and rier is very strong owing to type IV collagen within
alveolar ducts are responsible for 10% of gas the extracellular matrix. The barrier is permeable to
exchange, with the alveoli responsible for small gas molecules such as O2, CO2, carbon mon-
the other 90%: oxide, nitrous oxide (N2O) and volatile anaesthetics.
– Respiratory bronchioles are predominantly The functions of the alveolar–capillary barrier are:
conducting, with interspersed alveoli that to allow efficient gas exchange;
participate in gas exchange. These further to prevent gas bubbles entering the circulation;
divide into alveolar ducts, alveolar sacs and to prevent blood from entering the alveolus;
alveoli. to limit the transudation of water.
– The alveoli form the final airway generation
of the tracheobronchial tree. The human How does the lung inflate and deflate
lungs contain approximately 300 million
alveoli, resulting in an enormous surface during tidal breathing?
area for gas exchange of 70 m2. Each The principal muscles involved in ventilation are the
alveolus is surrounded by a capillary diaphragm and the intercostal muscles:
network derived from the pulmonary Inspiration. The diaphragm is the main
circulation. respiratory muscle during normal quiet breathing;
the external intercostal muscles assist during deep
inspiration.
Which cell types are found in the Expiration. During quiet tidal breathing, the
alveolus? elastic recoil of the lungs produces passive
expiration. The internal intercostal muscles are
The wall of the alveolus is extremely thin, comprising
active during forced expiration.
three main cell types:
Type I pneumocytes. These are specialized Accessory muscle groups are used when additional
epithelial cells that are extremely thin, allowing inspiratory (sternocleidomastoid and scalene
efficient gas exchange. They account for around muscles) or expiratory (abdominal muscles) effort is
90% of the alveolar surface area. required.
24
The forces acting on the lung at rest are:2 ▪ The alveoli pressure PA becomes
Intrapleural pressure Ppl. There are two layers subatmospheric, resulting in air entry.
of pleura that encase the lungs: visceral and ▪ The elastic fibres of the lung are stretched.
parietal. The inner visceral pleura coats each of Pel increases until end-inspiration, where
the lungs, whilst the outer parietal pleura is Pel is again equal to Ppl. PA is now equal to
attached to the chest wall. The space atmospheric pressure again, and gas flow
between the visceral and parietal pleurae ceases (Figure 6.3c).
(the intrapleural space) contains a few
– The volume of air inspired per breath depends
millilitres of pleural fluid whose role is to
on the lung compliance (volume per unit
minimize friction between the pleurae.
pressure change; see Chapter 19). For example,
The pressure in the intrapleural space is
a decrease in intrapleural pressure of 3 cmH2O
normally negative (around 5 cmH2O at rest)
may generate a 500 mL tidal volume VT in
due to the chest wall’s tendency to spring
normal lungs, but much less in a patient with
outwards.
acute respiratory distress syndrome (ARDS).
Inward elastic recoil Pel. The stretched elastic
During tidal expiration (Figure 6.3d):
fibres of the lung parenchyma exert an inward
force, tending to collapse the lung inwards. – The inspiratory muscles relax.
– The rib cage and the diaphragm passively
At rest, when the lung is at FRC, Ppl and Pel are equal return to their resting positions and the
and opposite (Figure 6.3a). The pressure in the alveoli volume of the thoracic cavity decreases.
equals atmospheric pressure, and airflow ceases.
During tidal inspiration (Figure 6.3b): Because the thoracic cage is airtight:
– Diaphragmatic contraction increases the – Decreasing thoracic cage volume causes Ppl to
vertical dimension of the lungs. The fall back to 5 cmH2O.
diaphragm descends 1–2 cm during quiet tidal – The stretched lung elastic fibres passively
breathing, but can descend as much as 10 cm return lung volume to FRC.
during maximal inspiration. – As lung volume decreases, the alveolar volume
– Contraction of the external intercostal muscles falls, resulting in an increase in alveolar
increases the anterior–posterior diameter of pressure. PA exceeds PB and air is expelled
the thoracic cage; this is the so-called ‘bucket from the lungs.
handle’ mechanism. – Air continues to flow out of the lungs until PA
again equals PB at end-expiration.
Arguably the most important aspect of lung
mechanics is the air-tight nature of the thoracic cage:
– When inspiratory muscle contraction Clinical relevance: pneumothorax
increases the volume of the thoracic cavity, Ppl The resting intrapleural pressure is 5 cmH2O. If a
falls from the resting value of 5 cmH2O to communication is made between the atmosphere
8 cmH2O (as is typically generated during and the pleural space (for example, as a result of
tidal breathing). penetrating trauma), the negative intrapleural pres-
– Ppl exceeds the inward elastic recoil of the sure draws in air, resulting in a pneumothorax. As Ppl
lung, and the lung expands. is now equal to PB, the lung succumbs to its inward
elastic recoil and collapses.
– As the alveolar volume increases:
2
Note: this account is simplified. The more complicated
What are the non-respiratory functions
account includes transpulmonary pressure, the difference of the lung?
in pressure between the inside (i.e. alveolar) and the
The non-respiratory functions of the lung are:
outside (i.e. intrapleural) of the lungs. Transpulmonary
pressure determines whether the lung has a tendency to Immunological and lung defence. The lung has
inflate or deflate. an enormous 70 m2 of alveolar surface area to
25
PB= 0
No air flow
PA = PB Outward spring force
of the chest wall
Pel = +5
Thoracic cage
Alveolar space
Intrapleural space
Ppl = –5
(a) At rest (end-expiration)
Air flow
Air flow
External intercostal External intercostal

PA > PB muscles contract PA < PB
muscles relax
Pel = +5 Pel = +5
Ppl = –5 Ppl = –8
Diaphragm relaxes
Diaphragmatic contraction
(d) Passive expiration
(b) Early inspiration
No air flow
PA = PB
Pel = +8
PB = atmospheric pressure (cmH2O) Ppl = –8
PA = alveolar pressure (cmH2O)
Pel = inward elastic recoil (cmH2O) (c) End inspiration
Ppl = intrapleural pressure (cmH2O)
Figure 6.3 Forces acting on the lung: (a) at rest; (b) early inspiration; (c) end-inspiration; (d) during expiration.
26
defend against microorganisms. This compares – Inactivation of noradrenaline, serotonin,

with a skin surface area of 2 m2 and an intestinal prostaglandins, bradykinin (see below) and
surface area of 300 m2. Lung defence mechanisms ACh. Adrenaline, antidiuretic hormone
include: (ADH) and angiotensin II pass through the
– filtering inspired air; lungs unaltered.
– the mucociliary escalator; – Conversion of angiotensin I to angiotensin II
– alveolar macrophages; by angiotensin-converting enzyme (ACE).
ACE is also one of three enzymes responsible
– secretion of IgA.
for the metabolism of bradykinin. Inhibition
The upper airway reflexes of coughing and of ACE with ACE-inhibitors leads to excess
sneezing also play key roles in lung defence. bradykinin, which can cause an intractable
Vascular. The pulmonary circulation is discussed cough and has been implicated in ACE-
in greater detail in Chapter 22. Key points are: inhibitor-induced angioedema.
– The pulmonary circulation is a low-pressure, – Synthesis of surfactant, nitric oxide (NO) and
low-resistance circulation in series with the heparins.
systemic circulation. – Synthesis, storage and release of pro-
– Close to 100% of the cardiac output (CO) inflammatory mediators: histamine,
flows through the pulmonary circulation. ecosanoids, endothelin, platelet aggregating
– The pulmonary capillaries filter debris from factor and adenosine.
the blood; for example, blood clots and gas A number of anaesthetic drugs undergo
bubbles. In the absence of this filtering significant uptake and first-pass metabolism in the
mechanism, systemic embolization may occur. lungs, including lignocaine (lidocaine), fentanyl
For this reason, patients on cardiopulmonary and noradrenaline.
bypass must have their blood filtered before it
is returned to the systemic arterial circulation.
– The pulmonary circulation contains around
Further reading
A. R. Wilkes. Heat and moisture exchangers and breathing
500 mL of blood, which acts as a blood system filters: their use in anaesthesia and intensive care.
reservoir for the left ventricle (LV). Part 1 – history, principles and efficiency. Anaesthesia
– Low-pressure baroreceptors in the right side of 2011; 66(1): 31–9.
the heart and in the great veins play a role in W. Mitzner. Airway smooth muscle: the appendix of
long-term blood volume regulation. the lung. Am J Respir Crit Care Med 2004; 169(7):
Metabolic and endocrine. As nearly the entire CO 787–90.
passes through the lungs, they are ideally suited M. Wild, K. Alagesan. PEEP and CPAP.
for metabolic and endocrine processes, most Contin Educ Anaesth Crit Care Pain 2001; 1(3):
notably: 89–92.
27
Chapter
Oxygen transport
7
wrong to think that dissolved O2 is unimportant.
How is oxygen transported in the blood? The O2 tension of blood is determined from the
O2 is carried within the circulation from the lungs amount of O2 dissolved in plasma – the PO2 within
to the tissues in two forms: an RBC is low because all the O2 is bound to Hb.
Bound to Hb, accounting for 98% of O2 carried Fick’s law of diffusion states that diffusion occurs
by the blood. Each gram of fully saturated Hb can along a pressure gradient, so O2 diffuses to the
bind 1.34 mL of O2 (this is called Hüfner’s tissues from the dissolved portion in the plasma,
constant). not from Hb itself. O2 then dissociates from Hb
Dissolved in plasma, accounting for 2% of O2 as plasma PO2 falls, replenishing the O2 dissolved
carried by the blood. The volume of O2 dissolved in the plasma.
in blood is proportional to the partial pressure of
O2 (this is Henry’s law).
How do the body’s oxygen stores
The total volume of O2 carried by the blood is the compare with its consumption of
sum of the two:
oxygen?
Key equation: oxygen content equation Very little O2 is stored in the body, which means
O2 content per 100 mL of blood ¼ ð1:34 that periods of apnoea can rapidly lead to hypoxia.
×½Hb×Sa O2 =100%Þ+0:023×PO2 In addition to O2 in the lungs (within the FRC),
O2 is stored in the blood (dissolved in plasma
where 1.34 mL/g is Hüfner’s constant at 37 °C and bound to Hb) and in the muscles (bound to
for typical adult blood, [Hb] is the Hb concentration myoglobin).
(g/dL), SaO2 is the percentage Hb O2 saturation,
As described above, approximately 20 mL of O2 is
0.023 is the solubility coefficient for O2 in
carried in each 100 mL of arterial blood, and 15 mL of
water (mL O2/(dL kPa)) and PO2 is the blood O2
tension (kPa). O2 per 100 mL of venous blood. At sea level, a 70 kg
For typical arterial blood ([Hb] ¼ 15 g/dL, SaO2 ¼ man has approximately
97% and PO2 ¼ 13.0 kPa): 5 L of blood, containing approximately 850 mL
of O2;
O2 content per 100 mL arterial blood ðC a O2 Þ ¼
ð1:34×15×0:97Þ+0:023×13 ¼ 19:50+0:30 ¼ 19:8 mL
a further 250 mL of O2 bound to myoglobin;
450 mL of O2 in the lungs, when breathing air.
whereas venous blood (Hb O2 saturation of 75%,
PO2 ¼ 5.3 kPa) contains This gives a total of 1550 mL of O2.
An adult’s resting O2 consumption is approxi-
O2 content per 100 mL venous blood ðC v O2 Þ ¼
mately 250 mL per minute, which means that apnoea
ð1:34×15×0:75Þ+0:023×5:3 ¼ 15:08+0:12 ¼ 15:2 mL
can occur for only a few minutes before the onset of
significant cellular hypoxia. Hypoxic damage occurs
even more quickly when there is reduced O2-carrying
The above worked example demonstrates that capacity (for example, anaemia or carbon monoxide
Hb is a much more efficient means of O2 carriage poisoning) or an increased rate of O2 consumption
than O2 dissolved in plasma. However, it would be (for example, in children).
28
Chapter 7: Oxygen transport
Clinical relevance: minimal flow anaesthesia in the bone marrow during erythropoiesis. By the
time blast cells have become reticulocytes, the final
Low flow and minimal flow anaesthesia are anaes-
thetic re-breathing techniques used to reduce the cell stage of erythropoiesis, their nuclear DNA has
cost and environmental impact of general anaesthe- been lost. Reticulocytes instead have a network of
sia. Fresh gas flow rates are set below alveolar ribosomal RNA (hence the name: reticular, meaning
ventilation, and the exhaled gases are reused once net-like). Reticulocytes normally make up 1% of
CO2 has been removed. Either low (<1000 mL/min) circulating RBCs, but this proportion may be
or minimal (<500 mL/min) fresh gas flow rates are increased if erythropoiesis in the bone marrow is
used. The other requirements for this technique are highly active; for example, in haemolytic anaemia
a closed (or semi-closed) anaesthetic circuit (usually or following haemorrhage.
a circle system), a CO2 absorber, an out-of-circle As the RBC cytoplasm does not contain mito-
vaporizer and a gas analyser.
chondria, aerobic metabolism is not possible. RBCs
When using low fresh gas flows, the anaesthetist
must ensure that the gases absorbed by the patient
are unique, as they constitute the only cell type that
(i.e. O2 and volatile anaesthetic agents) are replaced. is entirely dependent on glucose and the glycolytic
The resting adult O2 consumption is 250 mL/min; pathway (see Chapter 72) to provide energy for
therefore, the minimum required O2 delivery rate metabolic processes – even the brain can adapt
is 250 mL/min. However, most anaesthetists would to use ketone bodies in times of starvation.
deliver a slightly greater rate of O2 than this (300–500
mL/min) to ensure that the mixture is never hypoxic.
What is haemoglobin?
Hb is a large iron-containing protein contained
Describe the structure of red blood cells within RBCs. The most common form of adult Hb
RBCs are small, flexible biconcave discs (diameter 6–8 is HbA, accounting for over 95% of the circulating
µm) that are able to deform enough to squeeze Hb in the adult. It has a quaternary structure
through the smallest of capillaries (around 3 µm in comprising four polypeptide globin subunits (two α
diameter). The cell membrane exterior has a number chains and two β chains) in an approximately tetra-
of antigens that are important in blood transfusion hedral arrangement. The four globin chains are
medicine: the ABO blood group system is composed held together with weak electrostatic forces. Each
of cell-surface carbohydrate-based antigens, while globin chain has its own haem group, an iron-
the Rhesus blood group system is formed by trans- containing porphyrin ring with iron in the ferrous
membrane proteins (see Chapter 68). state (Fe2+). O2 molecules are reversibly bound to
RBCs are unique as they have no nucleus and each haem group through a weak coordinate bond
their cytoplasm has no mitochondria – effectively, to the Fe2+ ion. In total, four O2 molecules can
RBCs can be considered to be ‘bags of Hb’. The be bound to each Hb molecule, one for each haem
RBC nucleus is lost in the latter stages of maturation group (Figure 7.1).
‘Tense’ conformation ‘Relaxed’ conformation Figure 7.1 The reversible binding of O2

to Hb (2,3-DPG: 2,3-diphosphoglycerate).
b O2 O2
a 4 x O2 2,3-DPG
a b
Fe
Fe Fe Fe
PG
D
3-
2,
Fe Fe
Fe
Fe a b a
b 4 x O2 O2
2,3-DPG O2
Oxyhaemoglobin
Deoxyhaemoglobin
29
Figure 7.2 The oxyhaemoglobin

Arterial dissociation curve.
100
80
Venous
75
60
SaO2 (%)
P50
50
40
20
0
0 3.5 5 5.3 10 13.3 15 20
Oxygen tension (kPa)
What is cooperative binding? Once the fourth O2 has bound, Hb is said to be

in the relaxed conformation.
Hb is essentially either fully saturated with O2 (oxy-
haemoglobin) or fully desaturated (deoxyhaemoglobin) Cooperative binding is responsible for the sigmoid
due to cooperativity. shape of the oxyhaemoglobin dissociation curve
Cooperative binding is the increase in O2 affinity (Figure 7.2).
of Hb with each successive O2 binding:
The first O2 molecule is difficult to bind – strong What is the oxyhaemoglobin
electrostatic charges must be overcome to achieve
the required conformational changes in the Hb
dissociation curve?
molecule. This conformation is referred to as the The oxyhaemoglobin dissociation curve describes the
tense conformation, where the β-chains are relationship between SaO2 and blood O2 tension
far apart. (Figure 7.2). As discussed above, the cooperative
binding of Hb is responsible for the curve’s sigmoid
Once the first O2 has bound, the conformation
shape, which has important clinical consequences:
of Hb changes and the β-chains come closer
together. The actual molecular mechanism of The upper portion of the curve is flat. At this
cooperative binding is still a subject of debate. point, even if PaO2 falls a little, SaO2 hardly
It has been suggested that binding O2 to Fe2+ changes. However, when PaO2 is already
simultaneously displaces a histidine residue, pathologically low (for example, in patients with
resulting in a conformation change. The result respiratory disease) and near to the steep part
of the new conformation is the second O2 of the curve, a further fall in PaO2 results in
having a higher binding affinity, thus requiring a large decrease in SaO2.
less energy to bind. The steep part of the curve is very important
Once the second O2 molecule has bound, in the peripheral tissues, where PO2 is low:
the third is easier to bind, and so on. In fact, the the steep fall in SaO2 means a large quantity
fourth O2 molecule binds 300 times more easily of O2 is offloaded for only a small decrease
than the first. in PO2.
30
Figure 7.3 Displacement of the P50 of

100 the oxyhaemoglobin dissociation curve.
Rightward shift:
80 • PCO2
• ¯ pH
• 2,3-DPG
• temperature
SaO2 (%)
60 • HbS
• Exercise
50
Leftward shift:
40 • PCO2
• ¯ pH
• 2,3-DPG
• temperature
20 • MetHb
• COHb
• HbF
0
0 3.5 5 10 13.3
The position of the oxyhaemoglobin dissociation breakdown of glucose to pyruvate (in a process
curve is described by the P50 value – the PO2 at which called glycolysis – see Chapter 72), which is then
50% of Hb is bound to O2. When the position of converted to lactate. One of the intermediates of
the curve moves to the right, the affinity of O2 for the glycolytic pathway is converted to 2,3-DPG
Hb is reduced – O2 is more easily offloaded (that is, in a side pathway. This is thought to be
for a given PO2, SaO2 is lower). Rightward shift is controlled by an O2-sensitive enzyme in the
caused by: glycolytic pathway, likely phosphofructokinase.
increased PCO2; The greater the extent of anaerobic
acidosis; metabolism, the greater the 2,3-DPG
increased 2,3-diphosphoglycerate (2,3-DPG) concentration. 2,3-DPG binds specifically to the
concentration. β-chains of deoxyhaemoglobin, stabilizing this
configuration (Figure 7.1), thus reducing the O2
exercise;
binding affinity of Hb. This mechanism means
increased temperature;
that additional O2 is offloaded to cells undergoing
the presence of HbS in sickle cell disease.
anaerobic metabolism.
(Mnemonic: CADETS – CO2, acidosis, DPG, exercise, O2 loading in the lungs. When blood reaches
temperature, sickle cell disease.) the lungs, CO2 is excreted and the pH normalizes.
This rightward shift of the curve is an important The P50 of the oxyhaemoglobin dissociation curve
physiological mechanism: then returns to its central position. The binding
The Bohr effect. Metabolically active tissues affinity of O2 therefore increases: dissolved O2
produce CO2, heat and H+ ions. When blood binds to Hb, which in turn lowers the blood O2
arrives at these capillaries, the oxyhaemoglobin tension, facilitating O2 diffusion across the
dissociation curve is shifted to the right, alveolar–capillary barrier.
offloading O2 where it is most needed. This
The oxyhaemoglobin dissociation curve is shifted
phenomenon is called the ‘Bohr effect’ or
to the left by the following:
Bohr shift.
Anaerobic metabolism. When cellular PO2 falls the reverse of the above – that is, low PCO2,
below a threshold value, anaerobic metabolism alkalosis, reduced 2,3-DPG levels, hypothermia;
predominates. Energy is produced through the carboxyhaemoglobin (COHb);
31
methaemoglobin (MetHb); – HbF is the normal variant during fetal life

fetal Hb (HbF). and is composed of two α and two γ globin
subunits (α2γ2). HbF has a higher affinity
Leftward shift of the oxyhaemoglobin dissociation for O2 than HbA, and may therefore displace
curve results in an increase in O2 binding affinity. O2 across the placenta from maternal blood
This is an important physiological mechanism in fetal (see Chapter 78). HbF is produced up to
life. HbF must be able to extract O2 from maternal 3 months of age, when γ globin synthesis
oxyhaemoglobin – HbF must therefore have a higher switches to the adult β globin; by 6 months
O2 binding affinity than maternal Hb. This is of age, all HbF should have been replaced by
achieved by two mechanisms: normal adult variants. However, HbF can
HbF causes a leftward shift in the persist in conditions where β-globin synthesis
oxyhaemoglobin dissociation curve, increasing is impaired; for example, beta-thalassaemia.
O2 binding affinity. Pathological:
While 2,3-DPG is present in fetal RBCs, it – HbS. Found in people with sickle cell disease,
cannot bind to HbF: 2,3-DPG is only bound HbS has an abnormal β-globin subunit: a
by β-globin chains, not the fetal γ-chain. This point mutation, where glutamate has been
mechanism further increases the binding affinity replaced by valine at the 6th position.
of HbF for O2.
– MetHb. Methaemoglobinaemia is where the
Clinical relevance: blood transfusion
ferrous iron (Fe2+) within the Hb molecule is
oxidized to ferric iron (Fe3+). Fe3+ cannot bind
Erythrocyte 2,3-DPG concentration rapidly decreases
O2, so MetHb cannot participate in O2 transport.
in stored blood, and is effectively zero after 1–2
weeks’ storage. Low 2,3-DPG concentration shifts – COHb. This is formed when Hb binds inhaled
the oxyhaemoglobin dissociation curve to the left, carbon monoxide molecules.
increasing O2 binding. When stored blood is trans- – CyanoHb. Cyanohaemoglobin is formed when
fused, it takes up to 24 h for erythrocyte 2,3-DPG Hb is exposed to cyanide ions.
concentration to return to normal.
The increased O2 binding affinity means that
transfused blood is not as effective at offloading O2 How does the single point mutation
as native blood. In the anaemic patient facing cause clinical disease in sickle cell
major surgery, it may be advantageous to transfuse
blood 24 h prior to surgery rather than intraopera- disease?
tively, to gain the full benefit of the transfusion. Sickle cell disease is a genetic disease, inherited in an
In contrast, cell-salvaged blood maintains almost all autosomal recessive pattern. Symptomatic clinical
of its 2,3-DPG; O2 binding affinity and O2 offloading disease is only seen in homozygous patients; that is,
are unaffected. where both β-globin chains have amino acid point
mutations. These patients are referred to as having
‘sickle cell disease’, as opposed to heterozygous
What other forms of haemoglobin patients who have ‘sickle cell trait’.
are there? Substitution of a single amino acid has a signifi-
cant impact on how the Hb molecule behaves: under
Types of Hb may be classified as physiological or
hypoxic conditions, Hb molecules aggregate, distort-
pathological.
ing the RBC into a sickle shape. Unfortunately, the O2
Physiological: tension of normal venous blood can be sufficiently
– HbA, which, as discussed above, is the most low to cause sickling, especially within the sluggish
common form, has two α and two β globin flow of the spleen. As the RBCs move from arterial
subunits (α2β2). to venous O2 tensions and back to arterial, repeated
– HbA2, the other normal adult variant of aggregation and de-aggregation results in reduced
Hb, accounts for around 2–3% of total RBC membrane elasticity. Heterozygotic patients
Hb. It has two α and two δ globin are normally asymptomatic, and the trait confers a
subunits (α2δ2). disease resistance to malaria.
32
Clinical disease occurs through two main

mechanisms: Intraoperative management:
– Avoidance of known sickling precipitants:
Vascular occlusion. The reduced elasticity of the hypoxia, acidosis, hypothermia and
sickled cells means that they are less able to hypotension.
deform as they pass through narrow capillaries, – Tourniquets are traditionally avoided, but are
resulting in increased blood viscosity, venous occasionally used if the benefits outweigh
thrombosis and ischaemia. Capillary and venous the risk of precipitating sickling.
occlusion threaten whole organ infarction, – Regional anaesthesia has many advantages
resulting in ischaemic pain and organ over general anaesthesia, but neuraxial
dysfunction. In childhood, vascular occlusion blockade risks hypotension.
commonly causes splenic infarction – patients are
Postoperative management:
subsequently susceptible to encapsulated bacterial – Patients should be managed in a high-
infection; for example, meningococcal dependency unit, given supplemental O2 and
septicaemia. Vaso-occlusive crises are managed kept warm and well hydrated.
by hydration, analgesia and blood exchange – Analgesia can be challenging, as sickle cell
transfusion. patients are rarely opiate naive.
Reduced red cell survival. Normally, RBCs
survive in the circulation for 100–120 days.
In contrast, RBCs in sickle cell disease survive What is the clinical significance of
for a mere 10–20 days due to chronic haemolysis,
resulting in an Hb concentration of 7–11 g/dL
methaemoglobin?
with a reticulocytosis. Sickle cell patients are Normally, MetHb makes up less than 1% of the total
susceptible to aplastic crises; for example, Hb concentration. The low level of MetHb is main-
parvovirus B19 infection briefly stops tained by two mechanisms:
erythropoiesis by destroying RBC precursors, Glutathione/nicotinamide adenine dinucleotide
preventing RBC production for 2–3 days. phosphate (NADPH) system. Oxidizing agents
In normal patients, this is clinically unimportant, within the RBC are reduced by glutathione
but the short RBC life span in sickle cell disease before they are able to oxidize the haem Fe2+
means that the brief cessation of bone marrow to Fe3+. The PPP (see Chapter 72) is
production can lead to a profound anaemia. integral to this process, as it supplies
NADPH to return glutathione back to its
Clinical relevance: anaesthesia for patients with reduced form.
sickle cell disease MetHb reductase/nicotinamide adenine
The principles of management are: dinucleotide (NADH) system. Any MetHb
Identifying undiagnosed sickle cell disease. formed has its Fe3+ ion reduced back to Fe2+
Sickle cell status may not be known by the by a protective reduction system involving the
patient: all patients of at-risk ethnic backgrounds
enzyme MetHb reductase and NADH.
should be tested. Formal screening test is by Hb
electrophoresis, but in an emergency the rapid Methaemoglobinaemia occurs as a result of:
‘sickledex test’ can be used (but it cannot distin-
guish sickle cell trait from sickle cell disease). Oxidizing agents overwhelming the glutathione
Preoperative optimization: system. Implicated drugs include sulphonamide
– Identification and optimization of end-organ antibiotics, NO and the amide local anaesthetic
dysfunction: abnormal physiology; for prilocaine (used in Bier’s block, or as a constituent
example, hypoxia, acidosis, hypothermia of the topical local anaesthetic EMLA™).
or hypotension should be addressed.
Failure of the protective reduction system, for
– Exchange transfusion is sometimes under-
example as a result of glucose-6-phosphate
taken before major elective surgery, but there
is rarely sufficient time before emergency dehydrogenase (G6PD) deficiency, in
surgery. which a genetic defect of the PPP leads to a
deficiency of reduced glutathione.
33
The clinical problems arising from methaemoglobi- Despite their reduced O2-carrying capacity, patients
naemia are twofold: with high COHb concentration do not appear cya-
MetHb cannot bind O2. This results in a reduced nosed. Cyanosis is only clinically evident when there
O2-carrying capacity; that is, a ‘functional is at least 5 g/dL of deoxyhaemoglobin, and any Hb
anaemia’. that has not bound to carbon monoxide is usually
Altered O2 binding affinity. The presence of fully saturated with O2. Rarely, patients have a
MetHb changes the O2 binding affinity of the cherry-red discoloration of the skin and mucous
remaining normal Hb molecules. The membranes.
oxyhaemoglobin dissociation curve shifts to
the left, resulting in less O2 being off-loaded What are the mechanisms of cyanide
to the tissues.
toxicity?
Of further clinical significance: pulse oximeters ‘mis- The toxicity of cyanide is the result of two
read’ MetHb, displaying values of 85% irrespective of mechanisms:
the MetHb concentration. Accurate MetHb concen-
Reduced O2-carrying capacity. In contrast to
tration can be measured using a CO-oximeter. Treat-
carbon monoxide, cyanide binds irreversibly to
ment of methaemoglobinaemia is with supplemental
the O2-binding site of the Hb Fe2+ ion, resulting
O2 for mild cases, and with methylene blue for severe
in a functional anaemia.
cases.
Inhibition of the electron transport chain.
The main toxic effect of cyanide is inhibition
of cytochrome c oxidase (Complex IV) of
How does carbon monoxide poisoning the mitochondrial electron transport chain
affect oxygen carriage? (see Chapter 72).
Carbon monoxide is a very similar molecule to O2, Thus, in cyanide poisoning, not only is there a
and can therefore reversibly bind to the Hb Fe2+ ion reduced O2-carrying capacity, but the mitochondria
in a similar way to O2. However, the Hb binding are unable to make use of the O2 that reaches them.
affinity of carbon monoxide is 250 times greater One of the clinical signs of cyanide poisoning is the
than that of O2. In the presence of carbon monoxide, bright red colour of venous blood, where the blood
Hb preferentially forms COHb rather than oxy- has passed through the tissue capillary network with-
haemoglobin, resulting in a reduced O2-carrying cap- out offloading O2. In other words, mixed venous Hb
acity. Like methaemoglobinaemia, tissue hypoxia is O2 saturation is raised, with a lactic acidosis resulting
exacerbated by a leftward shift of the oxyhaemoglobin from anaerobic metabolism.
dissociation curve, reducing the offloading of O2
to the tissues.
Normally, the proportion of COHb in the blood is Clinical relevance: cyanide poisoning
<2%. Owing to the high binding affinity of carbon Although cyanide poisoning is a popular mode of
monoxide, a patient exposed to low levels of carbon death in fiction books (in part due to the lethal dose
being only 1 mg/kg), cyanide toxicity is relatively
monoxide can still have a significant plasma COHb
rare. Cyanide toxicity occasionally occurs in the
concentration – in heavy smokers, COHb can be as
industrial setting and following administration of
high as 9%. Even higher COHb concentration may sodium nitroprusside, but most commonly occurs
occur with faulty gas appliances, house fires and following inhalation of smoke from burning nylon
following suicidal inhalation of car fumes. Unsurpris- materials in house fires.
ingly, higher COHb concentration results in more In addition to the usual supportive measures,
significant clinical features: there are three specific treatments for cyanide
a COHb concentration of 15–20% causes mild toxicity:
symptoms – headache and confusion. Conversion of Hb (Fe2+) to MetHb (Fe3+) by
treatment with a nitrite (for example, amyl
at higher concentrations – weakness, dizziness, nitrite). Instead of binding to cytochrome c
nausea and vomiting. oxidase, cyanide preferentially binds to MetHb,
at COHb >60% – convulsions, coma and death.
34
Figure 7.4 Oxymyoglobin and

100 oxyhaemoglobin dissociation curves.
Myoglobin
80
Haemoglobin
SaO2 (%)
60
50
40
20
0
0 3.5 5 10 13.3
Owing to its single globin chain, myoglobin is

forming cyanmethaemoglobin. Cyanmethaemo-
globin can then be converted to Hb using unable to exhibit the cooperative binding of Hb. The
sodium thiosulphate. oxymyoglobin dissociation curve is a hyperbolic
Chelation of cyanide, for example with dicobalt shape, positioned well to the left of the oxyhaemo-
edetate. globin dissociation curve (Figure 7.4). The P50 value
Conversion of cyanide to thiocyanate by sodium of myoglobin is much lower than Hb, to allow trans-
thiosulphate. Thiocyanate is water soluble, and is fer of O2 from oxyhaemoglobin to myoglobin.
excreted in the urine.
Further reading
M. Wilson, P. Forsyth, J. Whiteside. Haemoglobinopathy
and sickle cell disease. Contin Educ Anaesth Crit Care
What about myoglobin: what is its Pain 2010; 10(1): 24–8.
structure and oxygen-binding profile? T. F. Cummings. The treatment of cyanide poisoning.
Like Hb, myoglobin is a large O2-binding iron-con- Occup Med 2004; 54: 82–5.
taining protein, but it contains only one globin chain A. D. Pitkin, N. J. H. Davies. Hyperbaric oxygen therapy.
and one haem group. The role of myoglobin is O2 Contin Educ Anaesth Crit Care Pain 2001; 1(5): 150–6.
storage; therefore, it is located in skeletal muscle, M. Hawkins, J. Harrison, P. Charters. Severe carbon
where O2 demand is high. Myoglobin Fe2+ pigments monoxide poisoning: outcome after hyperbaric oxygen
are responsible for the red colour of red meats. therapy. Br J Anaesth 2000; 84(5): 584–6.
35
Chapter
Carbon dioxide transport
8
CO2 + HbNH2 ! HbNHCOOH – this
How does carbon dioxide production is carbaminohaemoglobin
and storage compare with that of
Deoxyhaemoglobin forms carbamino compounds
oxygen? more readily than oxyhaemoglobin (see Haldane
CO2 is produced in the tissues as a by-product effect below).
of aerobic metabolism. One of the important roles As bicarbonate. The enzyme CA catalyses the
of the circulation is to transport CO2 from the tissues reaction between CO2 and water to form H2CO3:
to the lungs, where it is eliminated.
CO2 + H2O Ð H2CO3
A typical adult produces CO2 at a basal rate of 200
mL/min (at standard temperature and pressure), The cytoplasm of RBCs contains ample CA,
slightly lower than basal O2 consumption (250 mL/ whereas CA is absent in plasma. The reaction
min). During vigorous exercise, CO2 production can between CO2 and water can therefore only occur
rise as high as 4000 mL/min. within the RBC. Almost all the H2CO3 then
As discussed in Chapter 7, the body contains only dissociates into HCO3 and a proton (H+):
1.5 L of O2. In contrast, an estimated 120 L of CO2
is stored throughout the body in various forms. H2 CO3 Ð Hþ þ HCO3
CO2, water and HCO3 are able to traverse
the RBC membrane, whilst H+ cannot.
How is carbon dioxide transported As the reaction between CO2 and water is
in the circulation? an equilibrium reaction, it would cease if the
CO2 is transported in the circulation in three forms: H+ or HCO3 formed were allowed to build
Dissolved in plasma. Like O2, the volume of up within the RBC. This problem is prevented
CO2 dissolved in the plasma is proportional by two processes:
to the partial pressure of CO2 above it – Chloride shift. As HCO3 can cross
(Henry’s law). Dissolved CO2 makes a much the RBC membrane, it diffuses out of the
greater overall contribution to total CO2 cell along its electrochemical concentration
carriage than dissolved O2 does to O2 gradient. While the HCO3 ions
carriage, because the solubility diffuse out, chloride ions diffuse into the
coefficient of CO2 is 20 times greater RBC to maintain electrical neutrality
than that of O2. (mediated by a specific transmembrane
Bound to Hb and other proteins as carbamino Cl /HCO3 exchanger), thereby allowing
compounds. Not to be confused with COHb more HCO3 to diffuse out of the RBC.
(carbon monoxide bound to Hb), This is called the chloride shift or the
carbaminohaemoglobin is a compound Hamburger effect (Figure 8.1). The
formed when CO2 reacts with a terminal accumulation of HCO3 in the blood acts
amine group within the Hb molecule. as a buffer to pH changes.
The amine groups involved are the side – Binding of H+ to histidine residues. As H+
chains of arginine and lysine within the cannot cross the cell membrane of the RBC,
globin chains: it instead binds to histidine side chains of the
36
Chapter 8: Carbon dioxide transport
+
H binds to histidine side chains
Figure 8.1 Chloride shift.
DeoxyHb
CO2
CO2 CA H+
+ H2CO3 +
- - -
H2O HCO HCO3 Cl diffuses into the RBC as
3
-
- HCO3 diffuses out, maintaining
- Cl
Cl electrical neutrality
RBC
cytoplasm - -
Cl /HCO exchanger
3
Plasma
Hb molecule, thereby reducing the metabolically active tissues. According to

intracellular concentration of H+. the Haldane effect, the newly formed
Deoxyhaemoglobin is able to bind H+ ions deoxyhaemoglobin is better at binding H+
better than oxyhaemoglobin is (see the and carrying CO2 than oxyhaemoglobin is.
Haldane effect below). The metabolic waste products are therefore
efficiently transported away from the
By keeping the levels of HCO3 and H+ in tissues to the lungs.
the RBC low, the reaction between CO2
In the lungs, PO2 is high. As O2 molecules bind
and water can proceed; CO2 continues to deoxyhaemoglobin, its ability to bind H+ and
to be converted to HCO3 for transport CO2 decreases (reverse of the Haldane effect).
and storage. In consequence:
– There is a release of H+. The H+ ions
combine with HCO3 to form H2CO3.
What is the Haldane effect? How is it Catalysis by CA results in the liberation
of CO2.
related to the Bohr effect? – There is a release of CO2 directly from
The Haldane effect is the observation that deoxyhae- carbaminohaemoglobin.
moglobin is a more effective net carrier of CO2 than
oxyhaemoglobin is. As discussed above, this is for As the liberated CO2 diffuses into the alveoli and
two reasons: away from the blood, the Hb O2 binding affinity
deoxyhaemoglobin more readily forms carbamino increases, facilitating the loading of O2 onto Hb
compounds; (reverse of the Bohr effect).
+
deoxyhaemoglobin is a better H acceptor
than oxyhaemoglobin is, allowing increased What proportion of carbon dioxide is in
HCO3 formation.
each transport form?
The Bohr effect describes the finding that increased In both arterial and venous blood the CO2 is primar-
CO2 tension or reduced pH shifts the P50 of Hb to ily transported as HCO3 .
higher PO2 values (i.e. shifts the oxyhaemoglobin Dissolved CO2 makes a much larger contribution
dissociation curve to the right), thereby resulting in to CO2 carriage than dissolved O2 does to O2
Hb having an apparently lower O2 binding affinity carriage. Despite this, dissolved CO2 remains
(see Chapter 7). The Haldane and Bohr effects are the smallest proportion of the three CO2
important physiological mechanisms in both the per- transport forms.
ipheral tissues and in the lungs with regard to gas Venous blood has a higher CO2 content than
exchange and acid–base balance: arterial blood, and also has a higher concentration
+
Metabolically active tissues produce H and CO2. of deoxyhaemoglobin. As discussed above,
Through the Bohr effect and its effect on P50, deoxyhaemoglobin more readily forms carbamino
additional O2 is offloaded to the most compounds than oxyhaemoglobin does
37
Table 8.1 Approximate proportions of CO2 transport forms.
Dissolved Carbamino compounds Bicarbonate

Arterial blood 5% 5% 90%
Additional CO2 in venous blood 10% 30% 60%
(a) (b)
Deoxyhaemoglobin
80 80
CO2 content (mL CO2/100 mL blood)
CO2 content (mL CO2/100 mL blood)

Oxyhaemoglobin
mino
Carba
60 Oxyhaemoglobin 60
40 40
The increased CO2 carriage by Bicarbonate
deoxyhaemoglobin is the Haldane effect
20 20
Dissolved
0 0
0 5 10 15 0 5 10 15
Partial pressure of CO2 (kPa) Partial pressure of CO2 (kPa)
Figure 8.2 (a) The CO2 dissociation curve; (b) proportions of CO2 transport forms (arterial blood shown).
(the Haldane effect). The additional CO2 content of 52 mL/100 mL blood). The two CO2
carried in venous blood has a six times higher dissociation curves are, of course, diagrammatic
concentration of carbaminohaemoglobin representations of the Haldane effect: deoxygenated
than arterial blood does (Table 8.1). blood (the upper curve) carries more CO2 than
oxygenated blood (the lower curve).
The proportions of the different transport forms Important features of the CO2 dissociation
of CO2 can be represented graphically in the CO2 curve are:
dissociation curve (Figure 8.2). At physiological PCO2, the CO2 dissociation curve
is essentially linear.
As PCO2 increases, CO2 content continues to
What is the carbon dioxide dissociation increase due to an increase in the fraction of CO2
curve? dissolved in the plasma. In contrast, because the
The CO2 dissociation curve describes the relationship O2 solubility coefficient is much less than that
between the partial pressure of CO2 (PCO2) and the of CO2, O2 content increases much more slowly
blood CO2 content (note the difference from the with increased PO2 once the oxyhaemoglobin
oxyhaemoglobin dissociation curve, which relates dissociation curve has reached a plateau
PO2 and SaO2). (see Chapter 7).
The CO2 dissociation curve is often drawn as two
curves: arterial and venous (Figure 8.2a). The typical Clinical relevance: apnoea
partial pressure of CO2 in arterial blood is 5.3 kPa
In total, the circulation and lungs contain approxi-
(resulting in a CO2 content of 48 mL/100 mL blood), mately 2.5 L of CO2 and 1550 mL of O2 (see
whilst in mixed venous blood it is 6.1 kPa (CO2
38
Chapter 8: Carbon dioxide transport
Chapter 7). If a healthy patient stops breathing the period of apnoea, the quantity of stored O2
(for example, on induction of general anaesthesia), increases to over 3 L – even after 5 min of apnoea,
basal processes will continue: 250 mL/min of O2 will SaO2 will remain at 100%. Basal metabolic processes
be consumed and 200 mL/min of CO2 will be will continue, and after 5 min the PaCO2 will
produced. Therefore: approach 10 kPa, resulting in a respiratory acidosis.
PCO2 will increase by 0.4–0.8 kPa/min.
PO2 will fall. The rate of fall is complicated,
involving factors such as Hb concentration,
volume of FRC and total blood volume. Further reading
Typically, SaO2 falls to 70% (PO2 5.0 kPa) after I. Caulder, A. Pearce. Physiology of apnoea and hypoxia. In:
2 min. Core topics in Airway Management, 2nd edition.
Cambridge University Press, 2011.
However, if the patient breathes O2 for sufficient
time to completely de-nitrogenate their FRC prior to G. J. Arthurs, M. Sudhakar. Carbon dioxide transport.
Contin Educ Anaesth Crit Care Pain 2005; 5(6): 207–10.
39
Chapter
Alveolar diffusion
9
Which factors affect the rate of diffusion How is the lung alveolus designed
across a semi-permeable membrane? for efficient gas diffusion?
The diffusion of molecules across a semi-permeable Two aspects of lung anatomy are responsible for
membrane is governed by five factors: efficient gas exchange:
Fick’s law. The rate of diffusion of a substance A large surface area for diffusion. The lungs
across a membrane is directly proportional to the contain around 300 million alveoli, which
concentration gradient (or partial pressure provide a massive 70 m2 surface area for gas
gradient for gases). exchange.
Graham’s law. The rate of diffusion of a A thin alveolar–capillary barrier. The alveolar–
substance across a membrane is inversely capillary barrier is extremely thin, as little as
proportional to the square root of its molecular 200 nm in some places.
weight (MW).
It takes an average of 0.75 s for an RBC to pass
Surface area. The rate of diffusion is directly
proportional to the surface area of the through a pulmonary capillary at rest, so the
membrane. time available for diffusion is limited. However,
the lung is so efficient that O2 diffusion is usually
Membrane thickness. The rate of diffusion is
complete within 0.25 s: at rest there is normally
inversely proportional to the thickness of the
a threefold safety factor for diffusion. The high
membrane.
degree of safety for O2 diffusion means that hypox-
Solubility. The rate of diffusion of a substance aemia is less likely to be due to a diffusion defect,
is directly proportional to its solubility.
when compared with other factors such as V̇ /Q̇
Combining all these factors: mismatch.
Key equation: rate of alveolar diffusion

How does diffusion of oxygen and
surface area × concentration gradient × solubility
Rate of diffusion / pffiffiffiffiffiffiffiffi
thickness × MW carbon dioxide compare in the lungs?
As discussed above, the rate of diffusion is affected
by two factors specific to the substance diffusing:
Of the five factors: MW and solubility. Despite O2 and CO2 having simi-
two factors relate to the diffusion barrier: surface lar MWs (32 Da and 44 Da respectively), the rate of
area and thickness; diffusion of CO2 is 20 times higher than that of O2
two factors are inherent properties of the owing to the much higher solubility coefficient of
substance diffusing: solubility and MW. CO2. Therefore, in clinical situations where there is a
diffusion defect (for example, in pulmonary fibrosis),
So, for a given clinical situation, the only factor that O2 diffusion is more likely to be limited than CO2
can be altered is the concentration gradient; for diffusion, resulting in type 1 respiratory failure. Thus,
example, by increasing the inspired fraction FiO2 in clinically significant hypercapnoea is never caused
the case of O2. by impaired diffusion.
40
Chapter 9: Alveolar diffusion
Figure 9.1 Diffusion of O2, N2O and

carbon monoxide across the alveolar–
Maximum
Pulmonary capillary partial pressure (kPa) capillary barrier at rest.
N 2O
O2
Equilibration of alveolar
and capillary O2 by 0.25 s
Carbon monoxide
Mixed venous
PO2 0
0 0.25 0.5 0.75
Time RBC spends in pulmonary capillary (s)
Start of capillary End of capillary
How does the diffusion of oxygen alveolar–capillary barrier: an equilibrium is never

reached between alveolar and plasma PCO. The trans-
compare with other gases? fer of carbon monoxide is thus said to be ‘diffusion
Comparing the diffusion of O2 with other gases is limited’ because transfer of carbon monoxide is
complicated. As O2 diffuses into the blood, most is limited by the rate of diffusion rather than
bound to Hb but some is dissolved in the plasma (see the amount of blood available (Figure 9.1). For this
Chapter 7). It is the O2 dissolved in the plasma that reason, carbon monoxide is used for testing diffusing
determines its partial pressure PO2. At rest, an RBC capacity (see later).
takes 0.75 s to traverse a pulmonary capillary. As the The transfer of N2O and the volatile anaesthetics
RBC traverses the pulmonary capillary, diffusion of across the alveolar–capillary barrier is different.
O2 into the plasma increases its PO2, which in turn Unlike O2 and carbon monoxide, they do not bind
reduces the pressure gradient across the alveolar– to Hb. Because these gases are relatively insoluble and
capillary barrier. An equilibrium is reached between can only be carried in plasma in a dissolved form, an
the alveolar and plasma PO2 after 0.25 s, after which equilibrium is rapidly reached between the alveolus
diffusion ceases (Figure 9.1). and the plasma, well before the RBC has traversed
The inspired gases relevant to anaesthesia are the pulmonary capillary (Figure 9.1). N2O reaches
N2O, volatile anaesthetics and carbon monoxide. equilibrium the most rapidly, within 0.075 s. N2O is
These are all small molecules with low MWs. Carbon therefore said to be ‘perfusion limited’ because
monoxide and N2O are both considerably more water more N2O would diffuse from the alveolus if there
soluble than O2. were additional blood available. The volatile anaes-
Carbon monoxide binds to Hb with an affinity thetics behave in a similar manner, but equilibrium
250 times that of O2. Because carbon monoxide binds is reached slightly later than N2O.
so strongly to Hb, virtually no carbon monoxide is There are a number of points of interest in
dissolved in the plasma – consequently, the plasma Figure 9.1:
partial pressure of carbon monoxide (PCO) is very The carbon monoxide and N2O partial
low. Even when the RBC has traversed the entire pressure lines start from zero at the outset of
length of the pulmonary capillary, there is still capillary transit, because these gases are not
a substantial partial pressure difference across the normally present in venous blood. In contrast,
41
Figure 9.2 The effect of a thickened

Mild reduction in PO2 alveolar–capillary barrier and exercise on
14
O2 diffusion.
12
10
Pulmonary capillary PO2 (kPa)
8
Equilibrium not reached by
the end of capillary transit
6
Significant
4 hypoxaemia
2
Extreme exercise At rest
0
0 0.25 0.5 0.75
venous blood already contains O2, so this pulmonary capillary, resulting in hypoxaemia
curve does not start from the origin. (Figure 9.2).
The N2O curve reaches a plateau Exercise. CO increases during exercise, which
(i.e. equilibrium between plasma and reduces the length of time that an RBC spends
alveolar partial pressures) earlier than the O2 in the pulmonary capillary. Extreme exercise
curve, and the carbon monoxide curve never can reduce RBC transit time to as little as 0.25 s.
reaches a plateau. In patients with a normal alveolar–capillary
barrier, alveolar and plasma PO2 only
just reach equilibrium during the
Is the transfer of oxygen perfusion- or available pulmonary capillary transit time
(Figure 9.2). In patients with disease of
diffusion-limited? the alveolar–capillary barrier, any exercise-
Under normal conditions (as exist in Figure 9.1), the induced reduction in RBC transit time results
transfer of O2 across the alveolar–capillary barrier is in hypoxaemia.
perfusion limited. Like N2O, an equilibrium is Altitude. At high altitude, the lower barometric
reached between the alveolar and capillary PO2 before pressure PB causes a reduction in alveolar PO2
the RBC has traversed the pulmonary capillary. How- (see Chapters 17 and 81). This results in the
ever, there are a number of circumstances where the transfer of O2 becoming diffusion limited at
transfer of O2 may become diffusion limited: a lower threshold (Figure 9.3). The patient
Disease of the alveolar–capillary barrier. In with mild lung disease in Figure 9.2, where
pulmonary fibrosis there is thickening of the alveolar and plasma PO2 just reach equilibrium
alveolar–capillary barrier, which decreases at rest at sea level, will develop impaired O2
the rate of diffusion. Equilibrium between diffusion at altitude. Even with normal lungs,
alveolar and capillary PO2 is not achieved by severe exercise can result in diffusion limitation
the time the RBC reaches the end of the and hypoxaemia.
42
Chapter 9: Alveolar diffusion
Figure 9.3 The effect of altitude on O2

diffusion.
14
12
Reduced alveolar
Pulmonary capillary PO2 (kPa)
10 pressure at altitude
Normal diffusion
8
Hypoxaemia on exercise
with normal diffusion Hypoxaemia even at rest
6 with impaired diffusion
2
Extreme exercise At rest
0
0 0.25 0.5 0.75
interstitial lung diseases (chronic), or

pulmonary oedema (acutely).
What is meant by ‘lung diffusion Reduced surface area for gas exchange. For
example, emphysema, pulmonary embolus and
capacity’? following pneumonectomy or lobectomy.
The diffusion capacity of the lung for carbon monox-
ide (abbreviated DLCO, or alternatively called In patients with a pneumonectomy or lobectomy, a
‘transfer factor’ or ‘TLCO’) is a measurement of the correction (called the transfer coefficient KCO) is
lungs’ ability to transfer gases. It is one of the meas- made to account for the loss of alveolar volume, so
urements taken during pulmonary function testing. that the diffusion capacity of the remaining alveoli
As discussed above, carbon monoxide is a can be assessed.
diffusion-limited gas. The test involves a single vital An increased diffusion capacity is less common,
capacity breath of 0.3% carbon monoxide, which is but can be found with:
held for 10 s and then exhaled. The inspired and exercise, following recruitment and distension
expired PCO are measured – the difference is the of pulmonary capillaries;
amount of carbon monoxide that has diffused across pulmonary haemorrhage;
the alveolar–capillary barrier and bound to Hb. The asthma, but DLCO may also be normal;
diffusion capacity is usually corrected for the patient’s obesity.
Hb concentration, but is also affected by altitude, age
and sex.
The diffusion capacity is used to diagnose disease
Clinical relevance: lung resection
of the alveolar–capillary barrier. Diffusion capacity is
Pneumonectomy is associated with mortality rates of
reduced as a result of:
up to 8% (lobectomy mortality is around 2%). As part
Thickened alveolar–capillary barrier. For of the preoperative assessment, it is important to be
example, pulmonary fibrosis and other
43
able to predict a patient’s postoperative lung func- barrier can be offset by increasing FiO2, thus
tion. Patients being considered for lung resection increasing the O2 pressure gradient. For example,
routinely undergo pulmonary function tests (PFTs). portable supplemental O2 is used to overcome
Postoperative pulmonary function is estimated exercise-induced hypoxaemia in patients with
using a calculation based on the measured preopera- pulmonary fibrosis.
tive forced expiratory volume in 1 s (FEV1) and DLCO, Surface area/thickness of alveolar–capillary
and comparing these with predicted values. By con- membrane. In the specific case of acute
sidering both the mechanical abilities of the lung and pulmonary oedema, raised pulmonary venous
chest wall (FEV1) and a gross measure of the alveolar/ pressure results in fluid extravasation into the
capillary function (DLCO), patients can be categor- alveoli and pulmonary interstitium. The alveolar–
ized as being at low or high risk of death and post- capillary barrier is thickened and the area
operative pulmonary complications. More recently, available for gas exchange is reduced, both of
cardiopulmonary exercise testing (CPET) has been which reduce the rate of diffusion. In addition to
incorporated in some centres to further quantify the increasing the FiO2, PEEP can be applied, which:
operative morbidity and mortality. – recruits collapsed alveoli, thus increasing the
surface area for diffusion;
– increases alveolar pressure to redistribute
alveolar oedema, thus reducing the thickness
of the alveolar–capillary barrier.
Clinical relevance: management of a patient with
diffusion impairment
As discussed above, the consequence of impaired
alveolar diffusion is hypoxaemia. When managing a
patient with a diffusion defect, the prevention and Further reading
management of hypoxaemia is the anaesthetist’s G. Gould, A. Pearce. Assessment of suitability for lung
main concern. resection. Contin Educ Anaesth Crit Care Pain 2006;
Of the five factors that govern the rate of diffu- 6(3): 97–100.
sion, solubility and MW of O2 are fixed, but the
H. Ranu, M. Wilde, B. Madden. Pulmonary function tests.
anaesthetist has a degree of control over the other
Ulster Med J 2011; 80(2): 84–90.
three factors:
Pressure gradient. The reduction in the rate of P. Agostoni, M. Bussotti, G. Cattadori et al. Gas diffusion
diffusion due to a thickened alveolar–capillary and alveolar–capillary unit in chronic heart failure. Eur
Heart J 2006; 27(21): 2538–43.
44
Chapter
Ventilation and dead space
10
a third of the normal VT (7 mL/kg). V Anat may be
In the lungs, what is meant by the term altered by a number of factors:
D
‘dead space’? Size of patient – V Anat

D increases as the size
The air inspired during a normal breath VT is divided of the lungs increases.
into: Lung volume: at high lung volumes, radial
alveolar volume VA, the volume of air which traction on the airway walls increases airway
reaches perfused alveoli, and diameter, thus increasing V Anat
D .
dead space VD, the volume of inspired air that Posture: lung volume decreases in the supine
plays no part in gas exchange; that is, the air position, which reduces airway diameter and
remaining in either the conducting airways or therefore reduces V Anat
D .
non-perfused alveoli. Bronchoconstriction reduces airway diameter:
V Anat
D therefore decreases.
Mathematically:
Bronchodilatation increases airway diameter:
VT ¼ VA + VD
V Anat
D therefore increases.
What are the different types

What about alveolar dead space? How is
of dead space?
Dead space is classified as ‘anatomical’, ‘alveolar’ or
it measured, and which factors affect it?
‘physiological’: Alveolar dead space cannot be measured directly.
Phys
As V D ¼ V Anat Alv
D +V D , the alveolar dead space can
Anatomical dead space V Anat D is the volume of the Phys Phys
be calculated if V D and V Anat D are known. V D is
first 16 generations of the tracheobronchial tree,
measured using the Bohr equation (see p. 49), and
which form the conducting airways (see Chapter 6).
V Alv
D is measured using Fowler’s method. In normal
Alveolar dead space V Alv D is the total volume of lungs, V Alv
D is negligible as alveolar ventilation and
the ventilated alveoli that are unable to take part in
perfusion are well matched. However, V Alv D may
gas exchange due to impaired perfusion (i.e. due
increase as a result of:
to V̇ /Q̇ mismatch; see Chapter 14).
Physiological
Phys
dead space V D is the total dead Upright posture. Owing to the effect of gravity,
space; that is, the sum of anatomical and alveolar blood only just perfuses the lung apices (i.e. West
dead space: zone 2 – see Chapter 15). The apical alveoli are
well ventilated but not adequately perfused, which
VD
Phys
¼ V Anat Alv
D +V D :
increases V Alv
D .
Low pulmonary artery pressure – for example,
Which factors affect anatomical dead as a result of reduced right ventricular CO – leads
to insufficient perfusion of the lung apices. In
space? How is anatomical dead space common with upright posture, this results in a
measured? high V̇ /Q̇ ratio and thus an increase in V Alv
D .
Anatomical dead space is measured using Fowler’s PEEP and positive pressure ventilation both
method (see p. 48). Typical V Anat
D is 150 mL for a increase alveolar pressure. In the lung apices, the
70 kg man; that is, approximately 2 mL/kg, or around increase in alveolar pressure causes compression
45
of the pulmonary capillaries, reducing alveolar How are alveolar ventilation and
perfusion. This is West zone 1 (see Chapter 15).
In addition, the increase in intrathoracic pressure arterial carbon dioxide tension related?
reduces venous return to the right ventricle, As V_ A increases, there is an increased exchange of
which in turn reduces pulmonary artery pressure. alveolar gas with atmospheric air. Therefore:
Both effects increase V Alv
D . As atmospheric air contains negligible CO2,
Pulmonary embolism (PE). Obstruction of a alveolar CO2 tension (PACO2) falls.
pulmonary artery by an embolus, whether The lower PACO2 facilitates diffusion of CO2
arising from thrombus, gas, fat or amniotic across the alveolar–capillary barrier, leading to a
fluid, results in the downstream alveoli fall in arterial CO2 tension (PaCO2).
being ventilated but not perfused, thus
increasing V Alv In consequence, there is an inverse mathematical
D .
Chronic obstructive pulmonary disease (COPD). relationship between PaCO2 and V_ A (Figure 10.1):
Destruction of alveolar septa results in enlarged
Key equation: PaCO2 equation
air spaces. The surface area available for gas
exchange is therefore reduced. Much of the air V_ CO2
entering the enlarged airspaces cannot Pa CO2 ¼ K
V_ A
participate in gas exchange, which results in
an increase in V Alv where V_ CO2 is the rate of CO2 production through
D .
metabolism; K is a correction factor for the dissimilar
units of V_ CO2 (mL/min), V_ A (L/min) and PaCO2. If
What is dead-space ventilation? How PaCO2 is measured in kilopascals, K ¼ 0.115.
does it differ from minute ventilation?1

Ventilation is the movement of air in and out of the The PaCO2 equation indicates three important
lungs. There are many key definitions and formulae principles:
related to ventilation: For a given metabolic rate, doubling V_ A will halve
Minute ventilation V_ E is the volume of air PaCO2.
inspired per minute, written mathematically as If metabolic rate increases without a
compensatory increase in V_ A , hypercapnoea
V_ E ¼ V T × RR will result. This is exemplified by the
where RR is the respiratory rate (breaths per minute). increasing end-tidal CO2 concentration
observed in ventilated patients with malignant
Alveolar ventilation V_ A is the proportion of
hyperpyrexia.
V_ E that takes part in gas exchange, written
mathematically as Alveolar ventilation is the key factor that
determines PaCO2. V_ E does not take into
V_ A ¼ V A ×RR account dead-space ventilation.
¼ ðV T V D Þ×RR
Dead-space ventilation V_ D is the proportion of
Clinical relevance: hyperventilation
V_ E that cannot take part in gas exchange. It can be
written mathematically as Consider two different patients with normal lungs:
Patient 1: breathing with VT of 500 mL and RR
V_ D ¼ V D ×RR of 15 breaths per minute, resulting in V_ E of
¼ ðV T V A Þ×RR 7500 mL.
Patient 2: breathing with VT of 250 mL and RR
of 30 breaths per minute, resulting in V_ E of
Overall: V_ E ¼ V_ A +V_ D 7500 mL.
Would you expect both patients to have equal

1
Note: V represents volume in millilitres, whilst V̇ PaCO2?
represents volume per unit time.
46
Chapter 10: Ventilation and dead space
Figure 10.1 Inverse relationship

between V_ A and PaCO2.
10
8
PaCO2 (kPa)
.
Doubling VA results in
6
a halving of PaCO2
5
2.5
2
0
0 2 4 6 8 10 12 14
.
Alveolar ventilation, VA (L/min)
The answer is ‘no’. Assuming both patients have a Later, alveolar gas is exhaled. As this gas has
V Anat
D of approximately 150 mL: undergone gas exchange, it contains CO2 and
For patient 1, VA ¼ 500 mL 150 mL ¼ 350 mL water vapour, and has a lower PO2.
At end-expiration, the entire volume of the
) V_ A ¼ 350 mL × 15 breaths per minute snorkel contains alveolar gas.
¼ 5250 mL:
When the patient comes to take their next breath,
the alveolar gas within the snorkel is inspired before
For patient 2, VA ¼ 250 mL 150 mL ¼ 100 mL any ‘fresh’ gas from the atmosphere – this is known
as ‘re-breathing’. The problem with re-breathing is
) V_ A ¼ 100 mL × 30 breaths per minute
that the used alveolar gas has a lower PO2 and a
¼ 3000 mL:
higher PCO2 than atmospheric air, risking hypox-
As patient 1 has a higher V_ A than patient 2, Patient aemia and hypercapnoea. The higher the mechanical
1’s PaCO2 will be lower. dead space (i.e. the volume of the snorkel), the
greater the re-breathing that occurs. If the mechan-
ical dead space exceeds VT, the patient will solely
inspire ‘used’ gases and become progressively more
hypoxaemic.
Clinical relevance: anaesthesia and dead space
As mechanical dead space is inevitable, anaes-
In addition to alveolar and anatomical dead space, thetic circuits have various designs to prevent re-
there is a third type of dead space associated with breathing. For example:
anaesthesia: that of the equipment. Mechanical dead The Bain circuit (Mapleson D) requires a high
space is the part of the anaesthetic breathing system fresh gas flow for spontaneous ventilation – used
that contains exhaled gases at the end of expiration. gases are flushed along the tubing during the
Whether it is a Bain circuit, a circle system or merely a expiratory pause.
Hudson mask, all airway devices inevitably increase The circle system is designed to allow
a patient’s mechanical dead space. re-breathing of gases – CO2 is absorbed
Imagine a patient breathing through a snorkel. (for example, by soda lime) and O2 is replenished.
When the patient exhales:
The first gas exhaled is the anatomical dead Some re-breathing is inevitable as a result of the
space, which has not undergone gas exchange. volume of airway devices and tubing between
47
Figure 10.2 Fowler’s method for

measuring V Anat
D and CC.
1 2 3 4
Nitrogen concentration (%)
40
B
A
0
0 Anatomical dead space Closing capacity
Expired volume (L)
analyser, which measures the

the patient and the anaesthetic circuit. Because
of the additional V_ D , V_ E must increase if V_ A is to stay
concentration of expired N2.
the same. This is particularly important in paediatric The result is a plot of expired N2 against
anaesthesia, where mechanical dead space may volume of expired gas. This graph has four
represent a significant proportion of V Phys D . For this
phases (Figure 10.2):
reason, mechanical dead space should be minimized; – Phase 1: gas from the anatomical dead space
for example, by cutting ETTs, by reducing the length
is expired – it contains only O2; no N2 is
of catheter mounts and by minimizing the use
present.
of angle pieces.
– Phase 2: a mixture of dead-space gas and
alveolar gas is expired. The midpoint of this
curve (where area A equals area B) is taken as
What is Fowler’s method for the being V Anat
D .
measurement of anatomical dead – Phase 3: expired N2 concentration reaches a
plateau. All the gas expired is now alveolar
space? gas. Note that the plateau has a slight
Fowler’s method is a single-breath nitrogen (N2) upwards slope.
washout, used to calculate V Anat
D and closing capacity – Phase 4: there is a sudden increase in N2
(CC; see Chapter 11): concentration at the CC, the lung volume at
The patient starts by breathing tidal volumes of which the smallest airways in the dependent
room air. parts of the lung begin to collapse during
At the end of a normal tidal expiration (i.e. FRC), expiration. The basal alveoli are more compliant
the patient takes a vital capacity breath of 100% than the apical alveoli: during inspiration, the
O2. basal alveolar volume increases more than apical
The patient then expires slowly into a alveolar volume. Therefore, during the O2
mouthpiece to maximal expiration (i.e. residual breath, most of the inspired O2 enters the basal
volume (RV)). alveoli. At the start of expiration, the process
The mouthpiece is attached to a reverses: the basal alveoli empty first. When
spirometer, which measures the the lower airways close, the N2-rich gas from
volume of expired air. Also attached apical alveoli is exhaled, resulting in the sudden
to the mouthpiece is a rapid N2 increase in expired N2 concentration.
48
Chapter 10: Ventilation and dead space
What is the Bohr method for the which essentially says that all expired CO2 comes
from either the alveolus or dead space.
measurement of physiological dead Dead-space CO2 content should be zero; that is,
space? FD ¼ 0.
Phys
The Bohr method is used to calculate V D . The Bohr
) V TFE ¼ V AFA
equation calculates the ratio of physiological dead
space to tidal volume, VD/VT. The ‘normal’ value is
0.2–0.35 during tidal breathing. Substituting in VA ¼ VT VD:
VTFE ¼ (VT VD)FA
Key equation: the Bohr equation2
Multiplying out the brackets:
V D Pa CO2 PET CO2 VTFE ¼ VTFA VDFA
¼
VT Pa CO2 Rearranging:
where PaCO2 is the arterial tension of CO2 and PETCO2
VDFA ¼ VT(FA FE)
is the end-tidal tension of CO2. Rearranging:
So, to measure VD/VT, an arterial blood gas must be V D FA FE
taken at the same time as end-tidal CO2 is measured. ¼
VT FA
Because partial pressures are proportional to
The Bohr equation can be derived using simple math- concentrations:
ematics. It is based on the principle that all CO2
comes from alveolar gas, and thus from alveoli that V D PA CO2 PE CO2
¼
are both ventilated and perfused, and none comes VT P A CO2
from the dead space. This is the Bohr equation.
We know that VT ¼ VA + VD. For ease of measurement, PACO2 ≈ PaCO2 and
Rearranging: VA ¼ VT VD. PECO2 ≈ PETCO2, which gives the ‘simplified’ Bohr
If we define equation in the box above.
– FA as the fractional concentration of alveolar
CO2,
– FE as fractional concentration of expired CO2,
Further reading
G. Tusman, F. S. Sipmann, S. H. Bohm. Rationale of dead
– FD as the fractional concentration of space measurement by volumetric capnography. Anesth
dead-space CO2, Analg 2012; 114(4): 866–74.
then VT ¼ VA + VD can be written as J. M. Raurich, M. Vilar, A. Colomar, et al.
Prognostic value of the pulmonary dead-space
V T F E ¼ V A F A +V D F D ,
fraction during the early and intermediate phases
of acute respiratory distress syndrome. Resp Care 2010;
55(3): 282–7.
2
Note: this is a usable, simplified version of the Bohr
equation.
49
Chapter
Static lung volumes
11
– Expiratory reserve volume ERV ¼ 1500 mL.
What is the difference between a lung ERV is the volume of additional air that
volume and a lung capacity? can be expired following normal tidal
A lung volume is measured directly, by a spirometer exhalation.
(Figure 11.1) or by a gas dilution technique (see p. 52). – Residual volume RV ¼ 1500 mL. RV is the
A lung capacity is the sum of two or more lung volume of air that remains in the lungs
volumes; it is therefore a derived value. There are four following maximum expiration.
lung volumes and four lung capacities (values given Four capacities:
are typical for a 70 kg man when standing):
– Functional residual capacity
Four volumes: FRC ¼ RV + ERV ¼ 3000 mL.
– Tidal volume VT ¼ 500 mL. VT is the volume – Vital capacity VC ¼ ERV + VT + IRV ¼
of air inspired per breath during normal quiet 4500 mL.
breathing. – Inspiratory capacity IC ¼ VT + IRV ¼
– Inspiratory reserve volume IRV ¼ 2500 mL. 3000 mL.
IRV is the volume of additional air that can be – Total lung capacity TLC ¼ RV + ERV + VT +
inspired over and above VT. IRV ¼ 6000 mL.
4 volumes 4 capacities Figure 11.1 Spirometry trace with

lung volumes and capacities.
6
5 IRV IC VC TLC
2500 mL 3000 mL 4500 mL 6000 mL
4
Lung volume (L)
VT 500 mL
3
ERV
2 1500 mL
1 RV FRC
1500 mL 3000 mL
0
0 5 10 15 20 25 30 35
Time (s)
50
Chapter 11: Static lung volumes
Clinical relevance: tidal volume in mechanically Prevention of alveolar collapse. If FRC did
ventilated patients not exist (i.e. expiration to RV) alveoli would
Normal VT is typically around 500 mL for a 70 kg collapse. Atelectasis would result in V̇ /Q̇ mismatch
adult, or 7 mL/kg. In mechanically ventilated patients, and hypoxaemia. Re-expansion of atelectatic
ventilator-associated lung injury can occur as a alveoli with every tidal breath would significantly
result of: increase the work of breathing.
Volutrauma – diffuse alveolar damage caused by Optimal lung compliance. Conveniently, lung
overdistension of the lung. Traditionally, tidal compliance is at its lowest at FRC. Pulmonary
volumes of 12 mL/kg were delivered to mechan- vascular resistance (PVR) is also at its lowest
ically ventilated patients. This high-volume ven-
(see Chapter 22).
tilation strategy is now thought to cause
volutrauma and lung damage. Most intensive FRC is of crucial importance to anaesthetists:
care units have adopted a low VT ventilation
strategy (6 mL/kg), as it has been shown to Apnoea. FRC not only buffers swings in PAO2
reduce mortality in patients with ARDS. during tidal breathing, but also crucially
Barotrauma – damage to the lung as a result acts as an O2 reservoir at times of apnoea; for
of high airway pressure. Strategies to prevent example, at induction of general anaesthesia.
barotrauma include maintenance of peak airway Small airway closure. If FRC falls below a
pressure Ppeak below 35 cmH2O, or plateau certain volume (the CC), small airways
airway pressure Pplat below 30 cmH2O. close, resulting in V̇ /Q̇ mismatch and hypoxaemia.
If a patient has particularly poor lung compliance (for
example, ARDS), ventilation using lung-protective par-
ameters (VT ¼ 6 mL/kg and Pplat ≤ 30 cmH2O) may not Which factors affect functional residual
achieve sufficient V_ T to maintain normocapnoea. In capacity?
this situation, it is preferable to practice ‘permissive
FRC is not fixed; its volume is affected by surgical,
hypercapnoea’ rather than increase VT or inspiratory
anaesthetic and patient factors:
pressure, which may risk volutrauma or barotrauma,
resulting in further lung damage. This is referred to as FRC is reduced by:
a lung protective ventilation strategy. – Position. FRC falls by 1000 mL just by lying
supine.
– Raised intra-abdominal pressure; for example,
What is the importance of the obesity, pregnancy, acute abdomen,
functional residual capacity? laparoscopic surgery.
FRC is the starting point of tidal breathing. At end- – Anaesthesia, irrespective of whether
expiration, the inspiratory and expiratory muscles are ventilation is spontaneous or controlled.
relaxed – the inward elastic force of the lung paren- The cause is not known, but is thought to be
chyma is exactly equal and opposite to the force with related to decreased thoracic cage muscle tone
which the chest wall springs outwards (see Chapter 6, and loss of physiological PEEP.
Figure 6.3). – Decreasing age; that is, neonates, infants and
FRC is physiologically important for three young children.
reasons: – Lung disease; for example, pulmonary fibrosis,
pulmonary oedema, atelectasis, ARDS.
O2 buffer. The air within the FRC acts as an O2
buffer during normal breathing. O2 continuously FRC is increased by:
diffuses from the alveoli to the pulmonary – PEEP, which is commonly used to maintain
capillaries. If FRC did not exist, there would be FRC intraoperatively, especially in paediatric
fewer aerated alveoli and therefore less O2 in the anaesthesia and following intubation (where
lungs – alveolar partial pressure of O2 PAO2 would physiological PEEP has been lost – see Chapter 6).
decrease during expiration. Pulmonary capillary – Emphysema. Lung elastic tissue is destroyed,
blood would be intermittently oxygenated, only resulting in reduced inward elastic recoil.
being fully oxygenated during inspiration. The balance between the forces of inward
51
elastic recoil and outward springing of the Can all lung volumes and capacities
thoracic cage is found at a higher volume,
resulting in patients having a ‘barrel chest’. be measured with a spirometer?
– Increasing age. The elderly have a reduced All lung volumes, with the exception of RV, can be
quantity of lung elastic tissue: FRC increases in measured with a spirometer. By definition, RV is the
a similar manner to emphysema. volume of gas that remains in the lungs at the end of
– Asthma, caused by air trapping and high maximal expiration; therefore, it cannot be directly
intrinsic PEEP. measured. In consequence, any capacities that include
RV also cannot be directly measured by spirometry;
that is, TLC and FRC.
Clinical relevance: pre-oxygenation for general Instead, FRC can be calculated by one of the
anaesthesia following three methods:
A normal adult lying supine (i.e. with an FRC of Gas dilution.
about 2000 mL) with a typical O2 consumption Body plethysmography.
(250 mL/min) will exhaust the O2 within their lungs
Multiple-breath N2 washout.
in just over 1 min. Critical hypoxaemia occurs even
more rapidly in patients with reduced FRC or an
increased rate of O2 consumption.
Pre-oxygenation involves the patient breathing
How is functional residual capacity
100% O2 for a period of time (traditionally 3 min) calculated using gas dilution?
prior to induction of anaesthesia. Over time, N2 mol- The gas dilution method involves a patient breathing
ecules within the FRC are replaced by O2 molecules.
helium (He), an inert gas, through a spirometer. As
If the same supine patient as above had an FRC full of
O2, their lungs would contain 1800 mL of O2 (slightly
He does not diffuse across the alveolar–capillary bar-
less than a full FRC of 2000 mL, as the alveoli also rier, any drop in He concentration can be attributed
contain CO2). The increased O2 reservoir would allow to distribution in the lung rather than absorption into
the anaesthetist 8 min to secure the airway before the body (Figure 11.2):
onset of hypoxaemia. At the end of tidal expiration, a spirometer
For every five molecules of O2 consumed, four containing a known concentration of He is
molecules of CO2 are produced, corresponding to the opened to the patient.
normal respiratory quotient of 0.8 (see Chapter 17).
The patient then breathes in and out through
Therefore, during periods of apnoea, the total volume
of the lungs decreases. If 100% O2 is applied to a patent
the spirometer for sufficient time to allow
airway, some additional O2 is drawn into the lungs as He to equilibrate between the lungs and the
O2 is consumed, further prolonging the time before spirometer.
onset of hypoxaemia. This is the principle behind pass- The new concentration of He in the spirometer
ing O2 into the lungs via a suction catheter as part is then measured. From this, the FRC is
of the ‘apnoea test’ during brainstem death testing. calculated.
Figure 11.2 Gas dilution method for

Helium C2
calculation of FRC.
C1
V1 FRC
Before shutter opens After equilibration
52
Mathematically: patent. For example, air-trapping can occur in COPD:

Before equilibration not all of the alveolar air is in direct communication
with the mouth. Inspired He cannot access these
– The initial amount of He is calculated from the
closed-off alveoli, so these alveoli will not be included
equation:
in the calculation of FRC.
Number of moles ¼ Concentration (M) ×
volume (L) How is functional residual capacity
– The volume of the spirometer is V1 and the calculated using body
initial concentration in the spirometer is C1, so plethysmography?
the amount of He before connection to the
In contrast to the gas dilution method, body plethys-
patient is equal to C1V1.
mography takes into account all gas within the lung,
After equilibration including any gas trapped behind closed airways.
– The total volume is now the initial spirometer The body plethysmograph (the ‘body box’) is a large
volume V1 plus the volume in the lungs (FRC). airtight box in which the patient sits. The patient
– The concentration of He measured in the breathes in and out through a mouthpiece that has a
spirometer is lower (C2). shutter and a pressure transducer. There is also a pres-
– He cannot diffuse across the alveolar–capillary sure transducer in the wall of the box (Figure 11.3).
barrier, so the amount of He before equilibration The physical principle behind this method is
equals the amount of He after equilibration: Boyle’s law, which states that, ‘at a constant tempera-
ture, the volume of a fixed mass of gas is inversely
C1V1 ¼ C2(V1 + FRC) proportional to its absolute pressure’. Mathematically,
C1 C2
) FRC ¼ V 1 Boyle’s law states
C2
Pressure (P) × Volume (V) ¼ a constant
If the same spirometer is opened to the patient after
a full inspiration (i.e. at TLC), the TLC can be calcu- The body plethysmograph calculates FRC as follows:
lated instead of FRC. At the end of normal expiration, the mouthpiece
The gas dilution method may underestimate lung shutter closes.
volumes. It is reliant on He equilibrating with all the The patient tries to inhale against the closed
air in the lungs, which it can only do if all airways are mouthpiece. Respiratory effort increases the
Mouthpiece Mouthpiece
pressure pressure
P3 P4
Box volume V1 Box volume

V1- DV
FRC FRC + DV
Box pressure Box pressure
Diaphragmatic contraction
P1 P2
(a) Before mouthpiece shutter closes (b) Mouthpiece shutter closes, patient tries to inspire
Figure 11.3 The body plethysmograph.
53
Inspiratory limb Figure 11.4 The multiple-breath N2

O2 washout method.
Expiratory limb
Expired
gases
collected
N2 analyser
anterior–posterior diameter of the thoracic cage, same as the decrease in body box volume; that
increasing lung volume. The gas remaining in the is, ΔV, which has already been calculated above.
lungs expands. – Therefore, according to Boyle’s law:
As lung volume increases, the volume within the P3 × FRC ¼ P4 (FRC + ΔV)
body plethysmograph decreases by an equal amount.
All values except FRC are known, so FRC can be
The body box is airtight, so a decreased volume
within the box must result in an increased calculated:
pressure (according to Boyle’s law, as PV ¼ P3 × FRC ¼ P4 × FRC + P4ΔV
constant). This increase in pressure is measured ) FRCðP 3 P 4 Þ ¼ P4 ΔV
by the pressure transducer in the wall of the box. P4 ΔV
First, the change in volume within the box is ) FRC ¼
P3 P4
calculated:
In reality, all these calculations are made by computer.
– Before closure of the mouthpiece shutter, the
box pressure P1 and the box volume V1 are
measured. How is functional residual capacity
– After inspiration against a closed mouthpiece, calculated using the multiple-breath
box pressure P2 is measured.
– ΔV is the change in volume in the box after nitrogen washout method?1
inspiration: Normally, N2 makes up 79% of dry inspired air. The
multiple-breath N2 washout technique involves a spir-
P1V1 ¼ P2(V1 - ΔV) according to Boyle’s law
ometer circuit with an N2 analyser on the expiratory
As P1, P2 and V1 are measured, ΔV can be limb (Figure 11.4).
calculated. Like the gas dilution method, the N2 washout
Then the lungs are considered: method underestimates lung volume when there is
– Before closure of the mouthpiece shutter, the gas-trapping. The procedure is carried out as follows:
mouthpiece pressure P3 is measured. The Initially, the patient breathes room air.
mouthpiece shutter closes at the end of tidal
expiration, so the initial lung volume is the FRC. 1
Note: this method is different from the single-breath N2
– After inspiration, the mouthpiece pressure P4 is washout known as Fowler’s method, used to calculate
measured. The increase in lung volume is the anatomical dead space and CC.
54
At the end of tidal expiration (i.e. FRC), the This can increase the work of breathing signifi-
inspired gas is switched from air to 100% O2. cantly, and is one of the factors that predisposes
From the next exhalation, all expired gases pass both the elderly and the very young to respiratory
through the N2 analyser and are collected. failure.
As the patient breathes in and out, N2 in the lungs
is replaced by O2. Clinical relevance: emergency anaesthesia,
The test finishes when the expired N2 functional residual capacity and closing capacity
concentration is less than 1%, when all N2 in the Consider a 65-year-old patient with an acute abdo-
lungs has been exchanged for O2. men lying supine, awaiting a rapid sequence induc-
The total volume of expired N2 is calculated tion (RSI) for an emergency laparotomy.
from the total volume of expired gas multiplied FRC is significantly reduced: the patient is lying
by the concentration of N2 within the supine with an acute abdomen.
collected gas. CC is increased: CC ordinarily exceeds FRC at
The FRC can then be calculated using the age 65.
equation Small airway closure during tidal breathing results
in V̇ /Q̇ mismatch, even before any co-morbidities
½N2 f
FRC ¼ total expired N2 volume× are taken into account (for example, COPD or
½N2 i obesity).
Prior to RSI, the patient should have 100% O2
where [N2]f is the final fractional N2 concentration
administered for at least 3 min. Pre-oxygenation
of expired gas and [N2]i is the initial fractional N2
and induction of general anaesthesia could take
concentration of expired gas. place with the patient sitting at 45° to maximize
FRC. Rapid and profound hypoxaemia can be
expected if pre-oxygenation is insufficient.
What is the closing capacity?
The lungs are affected by gravity. When the subject is
upright, the lung parenchyma is more stretched at the How is closing capacity measured?
apices and more compressed in the bases. One conse-
CC is measured using Fowler’s method (single-breath
quence of basal lung parenchymal compression is that
N2 washout method) – see Chapter 10.
the basal airways have a reduced radius; these airways
are the first to be compressed during active expir-
ation, resulting in a V̇ /Q̇ mismatch. The lung volume Further reading
at which this occurs is called the CC. Being a capacity, B. Kilpatrick, P. Slinger. Lung protective strategies
CC is the sum of two volumes: RV and closing in anaesthesia. Br J Anaesth 2010; 105(Suppl. 1):
i108–16.
volume.
In young healthy adults, airway closure is not usu- C. R. O’Donnell, A. A. Bankier, L. Stiebellehner, et al.
ally a problem because CC is well below FRC. If CC Comparison of plethysmograhic and helium dilution
lung volumes: which is best for COPD? Chest 2010;
were to exceed FRC, airway closure would occur during 137(5): 1108–15.
normal tidal breathing, resulting in V̇ /Q̇ mismatch and
hypoxaemia. CC may exceed FRC because either: R. Sirian, J. Wills. Physiology of apnoea and the benefits of
pre-oxygenation. Contin Educ Anaesth Crit Care Pain
FRC is lower than normal, for one of the 2009; 9(4): 105–8.
reasons discussed above. For example, CC
The Acute Respiratory Distress Syndrome Network.
exceeds FRC in neonates because of their Ventilation with lower tidal volumes as compared to
reduced FRC. traditional tidal volumes for acute lung injury and
CC is increased – CC increases with age, acute respiratory distress syndrome. N Engl J Med 2000;
encroaching on FRC at age 45 when supine, and 342(18): 1301–8.
age 60 when standing. C. J. L. Newth, P. Enright, R. L. Johnson. Multiple-breath
nitrogen washout techniques: including measurements
Airway closure during tidal expiration also means with patients on ventilators. Eur Respir J 1997; 10(9):
that airways must be reopened during inspiration. 2174–85.
55
Chapter
Spirometry
12
What are the clinical uses of Dynamic spirometry. Lung measurements that
depend on the rate (i.e. volume per unit time) at
pulmonary function tests? which air flows in and out of the lungs are called
What equipment is needed? ‘dynamic’. Dynamic PFTs include:
PFTs are used to quantify an individual patient’s – FEV1.
respiratory physiology. A battery of tests and man- – Forced vital capacity (FVC).
oeuvres are performed to measure the performance of – Peak expiratory flow rate (PEFR).
the different lung components: – Expiratory flow–volume curve.
Large and small airways. – Flow–volume loops.
Alveoli. Special tests such as diffusion capacity (which
Pulmonary vasculature. gives a measure of alveolar diffusion – see
Respiratory muscles. Chapter 9), gas dilution and N2 washout
(used to calculate FRC – see Chapter 11).
The clinical uses of PFTs are:
Diagnosis of respiratory disease.
Grading the severity of respiratory disease, and to How are forced expiratory volume in 1 s,
guide its pharmacological management. forced vital capacity and peak
Estimation of surgical risk, in particular of
thoracic surgery.
expiratory flow rate measured?
A spirometer is used for performing PFTs. There are
How is forced spirometry used clinically?
Forced spirometry is a simple bedside test. From full
many types of spirometer, classified as:
inspiration, the patient breathes out as hard and as
Volume-sensing; for example, the vitalograph, rapidly as possible into the spirometer, to full expir-
based on a bellows mechanism. ation, resulting in the expiratory volume–time graph
Flow-sensing; for example, the (Figure 12.1).
pneumotachograph, which is much more Two parameters are measured: FEV1 and FVC.
portable. FEV1 and FVC are compared with their ‘predicted’
values, based on normal patients matched for age,
Which variables are measured using gender, height and ethnic origin. One parameter is
calculated: FEV1/FVC ratio – an FEV1/FVC ratio less
spirometry? than 0.7 is considered abnormal. Use of this ratio
Spirometers are used to take many different lung identifies a relative difference between FEV1 and
measurements, broadly classified as: FVC: a patient with low FVC will also have a low
Static lung volumes. The patient breathes in and FEV1 simply as there is less gas to be expelled, rather
out of a spirometer, first with tidal volume breaths than necessarily being due to an obstructive pathology.
and then with vital capacity breaths. As discussed PEFR can also be calculated from the forced spiro-
in Chapter 11, all static lung volumes and metry trace: flow is volume per unit time, so the
capacities can be measured, with the exception of gradient of the spirometry curve represents flow.
RV, FRC and TLC. The ‘peak’ flow is therefore the initial gradient of the
56
Chapter 12: Spirometry
Figure 12.1 Normal forced expiratory

volume–time graph.
6
FVC
5
FEV1 FEV1 / FVC = 0.8

Expired volume (L)
1
Initial gradient = PEFR
0
0 1 2 3 4 5 6
Time (s)
forced volume–time curve (Figure 12.1). However, Restrictive lung diseases (for example, lung
PEFR is more commonly measured by a separate fibrosis, kyphoscoliosis, respiratory muscular
device: the peak flow meter. weakness) are characterized by (Figure 12.2b):
Forced spirometry is particularly useful for the – FEV1 <80% predicted.
diagnosis of obstructive and restrictive lung diseases: – FVC <80% predicted.
Obstructive airways diseases (asthma and COPD) – FEV1/FVC ratio >0.7; that is, ‘normal’ or even
can be diagnosed by comparing forced spirometry ‘high’, the latter due to increased FEV1 from
measurements with predicted values (Figure decreased pulmonary compliance.
12.2a). Diagnostic criteria are:
– FEV1 <80% predicted.
Clinical relevance: Guillain–Barré syndrome
– FEV1/FVC ratio <0.7.
Guillain–Barré syndrome (GBS) refers to a collection of
Severity of disease can be assessed using the FEV1: acute polyneuropathies, characterized by motor, sens-
ory and autonomic dysfunction. The most common
– Mild disease, FEV1 50–79% predicted.
variant of GBS is acute inflammatory demyelinating
– Moderate disease, FEV1 30–49% predicted. polyneuropathy, which is caused by autoimmune
– Severe disease, FEV1 <30% predicted. attack of the myelin-producing Schwann cells that
surround the peripheral nerve axon. This variant has
PEFR can also be used for the diagnosis of obstructive the classic presentation of ascending motor paralysis.
airways disease (a diurnal variation of >20% is sug- Around 25% of patients with GBS will require
gestive of asthma), but is more commonly used to respiratory support due to respiratory muscle weak-
compare a patient’s baseline respiratory function with ness or failure to clear secretions with a secondary
that during an exacerbation. pneumonia. Invasive ventilation is preferred over
Differentiation between asthma and COPD is non-invasive ventilation as it enables secretions to
based on the history, and on the reversibility of airway be cleared.
It is important to be able to identify patients in
obstruction. Forced spirometry is performed before and
need of respiratory support before respiratory failure
15 min after administration of a bronchodilator – an occurs. Clinical features such as bulbar weakness and
improvement in FEV1 of 400 mL is said to correspond poor cough suggest a need for intubation. In
to significant airway reversibility, suggesting asthma.
57
(a) Figure 12.2 Forced expiratory volume–

time graphs: (a) obstructive airways
FEV1 / FVC ratio significantly reduced disease; (b) restrictive lung disease.
Normal lungs
5
Expired volume (L)
1
Initial gradient (i.e. PEFR) reduced
0
0 1 2 3 4 5 6 7
Time (s)
(b)
FEV1 / FVC ratio increased

Normal lungs
5
Expired volume (L)
Restrictive lung disease

3
0
0 1 2 3 4 5 6 7
Time (s)
addition, there are a number of well-recognized cri-

Normal expiratory flow–volume curve
teria for intubation, many based on spirometry. Most (Figure 12.3a). There is an initial rapid rise
commonly, serial FVC is measured (at least every 6 h in expiratory flow, reaching a maximum at
initially) and intubation considered if FVC falls below the PEFR. This part of the curve is
20 mL/kg, or if FVC falls by >30% from baseline. effort-dependent. This is followed by a steady,
uniform decline in flow rate until all air is
expired – this part of the curve is effort-
independent, as it is limited by dynamic airway
What is an expiratory flow–volume compression.
curve? What is it used for clinically? Obstructive airways disease (Figure 12.3b).
Expiratory flow can be measured by forced spirome- Small airway obstruction increases the
try. When plotted against expired volume, this results resistance to gas flow, reducing the expiratory
in an expiratory flow–volume curve (Figure 12.3). flow rate:
The expiratory flow–volume curve can give add- – In the effort-dependent part of the curve,
itional diagnostic information: PEFR is reduced.
58
(a) (b) Reduced PEFR

PEFR 8 8 Normal
Obstructive airways
disease
Expiratory flow (L/s)

6 6
‘Effort independent’
4 ‘Effort 4 Concave
dependent’
2 2
RV Increased RV due
TLC to air trapping
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Vital capacity, VC Expired volume (L) Expired volume (L)
(c) (d)
8 Normal 8 Normal
Expiratory flow (L/s) Reduced PEFR

6 6
Significantly reduced PEFR

Restrictive lung
disease
4 Severe obstructive 4
airways disease
RV is relatively
Severe concavity TLC is reduced preserved
2 2
Increased RV:
air trapping
0 0
0 1 2 3 4 5 0 1 2 3 4 5
Expired volume (L) Expired volume (L)
Figure 12.3 Expiratory flow–volume curve: (a) normal; (b) mild obstructive airways disease; (c) severe obstructive airways disease;
(d) restrictive lung disease.
– The effort-independent part has a – The effort-independent part of the curve

characteristic change from linear to concave, remains linear as there is no dynamic airway
with the concavity related to the severity of compression.
disease (Figure 12.3c).
The other major difference in obstructive airways Can you explain the shape of the
disease is the presence of air trapping at full expir-
ation, represented graphically by increased RV
forced expiratory flow–volume curve?
(Figure 12.3b). Air-trapping increases with disease The shape of the forced expiratory flow–volume curve
severity (Figure 12.3c). can be explained by considering the airway radius at
different lung volumes (Figure 12.4):1
Restrictive lung disease (Figure 12.3d):
– The expiratory flow–volume curve has a
characteristic reduction in TLC. 1
Explaining the shape of the forced expiratory flow–time
– In the effort-dependent part of the curve,
curve is actually a little more complex, and is best
PEFR may be reduced: respiratory muscle described by the equal pressure point hypothesis. This
weakness reduces the maximal expiratory hypothesis is based on the physiological changes to
effort that can be generated. transairway pressure, and the compressibility of the airways.
59
No air flow Air flow Reduced air flow Figure 12.4 Schematic to illustrate the
mechanism of dynamic airway
compression.
PA Early As expiration
expiration continues,
lung volume
0 Ppl +40 reduces +40
-10 +30 +30
(a) End-inspiration (b) Initial rapid airflow (c) Dynamic airways

compression
At the start of forced expiration, lung volume is trace should be followed clockwise; that is, forced
high: expiration from TLC to RV, followed by inspiration
– At high lung volume (Figure 12.4a) the lung at maximal effort back to TLC (Figure 12.5a). The
parenchyma is generally more stretched, and tidal volume flow–volume loop is also shown
the radius of the airways is at its greatest. (Figure 12.5a). Note that the end-expiratory point of
According to the Hagan–Poiseuille equation tidal breathing on the x-axis is FRC.
(see Chapter 20), airways of greater radius Clinically, flow–volume loops are especially useful
allow a much greater rate of gas flow. when there is diagnostic uncertainty about the ana-
– On forced expiration, the expiratory muscles tomical location of airway obstruction, as additional
generate a high intrapleural pressure Ppl. information can be gained from the inspiratory por-
This in turn generates a high alveolar pressure tion of the flow–volume loop. For example, a patient
(Figure 12.4b). Expiratory flow rate is initially may present with wheeze and a history inconsistent
‘effort dependent’ – the greater the positive Ppl with asthma or COPD.
generated by the expiratory muscles, the Obstructive airways disease (Figure 12.5b and c).
greater the PEFR and FEV1. As described above, the expiratory portion of the
As forced expiration continues, lung volume loop has a reduced PEFR, a concave rather than
decreases: linear appearance of the effort-independent part
– The lung parenchyma becomes less stretched of the curve, and may have an increased RV due
and the radius of the airways decreases. to air-trapping. Inspiration is relatively unaffected
by small airways obstruction.
– Ppl remains high.
– The smallest airways without any cartilaginous Restrictive lung disease (Figure 12.5d). As
described above, the expiratory flow–volume
support become squashed by the high
curve has a reduced PEFR, a normal appearance of
intrapleural pressure. This is called dynamic
the effort-independent portion of the curve, and
airway compression (Figure 12.4c).
a significantly reduced VC. Depending on the
– Resistance to gas flow increases, leading to a
severity of disease, the TLC is substantially lower
reduced expiratory flow.
whilst the RV is proportionally less reduced.
– Expiratory flow is now said to be effort
This is shown graphically as a rightward shifted
independent. Expiratory flow is instead
loop, with a substantially reduced FRC.
dependent on lung volume, reducing linearly
Fixed upper airway obstruction; for example,
as lung volume approaches RV (Figure 12.3a).
tracheal stenosis or foreign body (Figure 12.6a).
‘Fixed’ refers to airway narrowing that is
unchanged throughout the respiratory cycle.
What is the difference between a flow– Lung volumes are unchanged, but there is a
volume curve and a flow–volume loop? reduction in both peak expiratory and inspiratory
A flow–volume loop has an inspiratory flow–volume flows, resulting in a characteristic flattening of
curve in addition to the expiratory flow–volume both the inspiratory and expiratory flow–volume
curve, thus completing a loop. The spirometry curves. Additional respiratory effort cannot
60
(a) (b)
8 8
Minor concavity
Tidal breathing
Flow rate (L/s)
Flow rate (L/s)

4 4
Expiration
0 Volume (L) 0 Volume (L)

TLC FRC RV TLC RV
Inspiration
-4 -4
(c) (d)
8 8
RV reduced (shifted to right
compared to ‘normal’ loop)
Flow rate (L/s)
Flow rate (L/s)

4 Extreme concavity 4
Air trapping
0 Volume (L) 0 Volume (L)

TLC RV TLC RV
-4 -4
FRC reduced
Figure 12.5 Flow–volume loops: (a) normal; (b) mild small airways obstructive disease; (c) severe small airways obstructive disease;
(d) restrictive lung disease.
overcome this obstruction – it is said ‘Intrathoracic’ refers to airway obstruction at or

to be effort independent. below the sixth tracheal ring. Once the
Variable extrathoracic airway obstruction; for airways enter the thoracic cage, they become
example, vocal cord palsy (Figure 12.6b). subject to intrathoracic pressure. During
‘Extrathoracic’ refers to a level above the sixth inspiration, Ppl (and therefore intrathoracic
tracheal ring and ‘variable’ refers to airway pressure) is negative – radial traction pulls the
obstruction that is free to move with the changes airways apart. An obstructed airway is ‘opened
in airway pressure throughout the respiratory up’, so that inspiratory flow is unaffected.
cycle. Again, lung volumes are unchanged. During However, in forced expiration, positive Ppl results
inspiration, the subatmospheric airway pressure in dynamic airway compression, compounded by
Paw in the trachea ‘pulls’ the obstructing lesion the obstructing lesion. Expiratory flow is limited
inwards, reducing the inspiratory flow, and thus and effort independent, resulting in a flattening
leading to flattening of the inspiratory flow– of the expiratory flow–volume curve.
volume curve. During expiration, positive Paw
‘pushes’ the obstructing lesion outwards – the
expiratory flow is therefore unaffected. This Clinical relevance: lung resection and spirometry
makes sense if you consider a patient with partial Spirometry is a key investigation in the preoperative
laryngospasm following extubation (i.e. a variable work-up for patients undergoing lung resection.
extrathoracic airway obstruction) – the patient has Simple forced spirometry can predict patient suitabil-
ity for lung resection:
great difficulty with inspiration but not with
FEV1 >2.0 L indicates suitability for
expiration. pneumonectomy.
Variable intrathoracic airway obstruction; for FEV1 >1.5 L indicates suitability for lobectomy.
example, by a tumour (Figure 12.6c).
61
(a)
4
Flow rate (L/s)
0 Volume (L)
TLC RV
Inspiration Expiration
-4
(b)
8
Flow rate (L/s)
0 Volume (L)
TLC RV
-4 Paw < PB Paw > PB
(c)
8
Flow rate (L/s)
0 Volume (L)
TLC RV
Paw > Ppl Paw < Ppl

-4
Figure 12.6 Flow–volume loops: (a) fixed upper airway obstruction; (b) variable extrathoracic airway obstruction; (c) variable intrathoracic
airway obstruction (PB: atmospheric pressure).
62
When a patient’s FEV1 is less than these gross Further reading

thresholds, further spirometric measurements are D. Portch, B. McCormick. Pulmonary function tests and
taken; for example: assessment for lung resection. Update Anaesth 2009;
Predicted postoperative FEV1 (ppoFEV1): a 25(1): 13–21.
patient with a ppoFEV1 <30% of the predicted D. Hayes, S. S. Kraman. The physiologic basis
FEV1 is more likely to require postoperative ven- of spirometry. Respir Care 2009; 54(12):
tilation and has a high risk of mortality. 1717–26.
Predicted postoperative transfer factor
K. J. C. Richards, A. T. Cohen. Guillain–Barré
(ppoTLCO) estimates postoperative diffusion
syndrome. Contin Educ Anaesth Crit Care Pain 2003;
capacity. ppoTLCO <40% of the predicted value 3(2): 46–9.
is associated with increased morbidity and
mortality.
63
Chapter
Hypoxia and shunts
13
What is meant by the term ‘hypoxia’? What are the causes of hypoxaemic
Hypoxia refers specifically to the situation in which hypoxia?
tissues are unable to undergo aerobic metabolism. Hypoxaemia can be classified according to aetiology:
This can result from either a failure of O2 delivery
or a failure of O2 utilization. The following conditions hypoventilation
must be fulfilled for cells to utilize O2 for aerobic diffusion limitation
metabolism: shunt
Adequate arterial O2 tension (PaO2) – blood V̇ /Q̇ mismatch.
leaving the lungs must be adequately oxygenated.
Adequate O2-carrying capacity – blood must How does hypoventilation cause
have an adequate Hb concentration. hypoxaemia?
Adequate CO and arterial flow ensures that the Hypoxaemia resulting from hypoventilation is
O2 carried by Hb reaches the tissues.
described in detail in Chapter 17. In brief:
Adequate mitochondrial function – the cells
must be able to use O2 effectively for aerobic V_ A and PaCO2 are inversely related (see
Chapter 10); hypoventilation therefore leads to
metabolism.
high PaCO2.
Hypoxia is therefore classified in terms of failure of According to the alveolar gas equation
one or more of the processes above: (AGE; see Chapter 17), PAO2 decreases:
the O2 partial pressure gradient across the
Hypoxaemic hypoxia – caused by low PaO2.
When PaO2 falls below 8 kPa, there is a steep fall alveolar–capillary barrier is reduced, leading
in the saturation of Hb (see Figure 7.2), which to low PaO2.
reduces O2-carrying capacity.
Anaemic hypoxia – PaO2 is normal but O2- Is diffusion limitation an important
carrying capacity is reduced. This is exemplified cause of hypoxaemia?
by severe anaemia and carbon monoxide
Alveolar diffusion is discussed in detail in Chapter 9,
poisoning (see Chapter 7).
but in summary:
Stagnant hypoxia – PaO2 and Hb concentration
are normal, but circulatory failure means that Diffusion limitation is rarely a cause of
tissue O2 delivery is reduced. This is exemplified hypoxaemia.
by cardiogenic shock and acute limb ischaemia PAO2 and pulmonary capillary O2 tension have
following an arterial embolus. normally reached equilibrium before the RBC has
Cytotoxic hypoxia – PaO2, O2-carrying capacity travelled a third of the way along the pulmonary
and O2 delivery are normal, but the capillary.
mitochondria fail to utilize O2 effectively. This is Diffusion limitation can cause hypoxaemia when:
exemplified by severe sepsis and cyanide – The alveolar–capillary barrier is thickened, as
poisoning. occurs in pulmonary fibrosis.
64
Chapter 13: Hypoxia and shunts
– Inspired O2 tension is low, as occurs at high through a VSD in a left-to-right direction.

altitude. However, if there were an increase in right
– Exercising, in the presence of mild ventricular pressure (exemplified by the
disturbances of either of the above. presence of a pulmonary stenosis associated
with the tetralogy of Fallot), blood flow may
What is meant by the term ‘shunt’? change to a right-to-left direction, resulting
Shunting is said to occur when blood passes from the in a pathological shunt.
right side to the left side of the heart, without taking – Through large communicating vessels,
part in gas exchange. Deoxygenated venous blood exemplified by a direct communication
consequently passes directly into the arterial system between the pulmonary artery and either the
and mixes with arterial blood, decreasing PaO2. pulmonary vein (pulmonary arteriovenous
A shunt can either be physiological or pathological: malformation, AVM) or the aorta (patent
ductus arteriosus, PDA). In common with a
Physiological shunt, subclassified as anatomical
and functional: VSD, the direction of blood flow depends on
the pressure in each vessel:
– Anatomical shunt – deoxygenated blood
enters the left side of the heart for anatomical ▪ A pulmonary AVM has right-to-left blood
reasons: flow, and therefore pathological shunt,
because pulmonary arterial pressure is
▪ Bronchial circulation. Most of the venous greater than pulmonary venous pressure.
blood from the large airways drains Pulmonary AVMs are classified as
directly into the pulmonary veins, congenital or acquired. The latter is
returning to the left side of the heart. exemplified by the multiple pulmonary
▪ Thebesian veins. A small amount of AVMs that occur in hepatic cirrhosis,
coronary venous blood drains directly into resulting in hepatopulmonary syndrome.
the four chambers of the heart via the ▪ A PDA usually has left-to-right blood flow
Thebesian veins. The blood that drains into because aortic pressure is normally higher
the left atrium and the LV contributes to than pulmonary arterial pressure.
the anatomical shunt. However, the direction of blood flow may
– Functional shunt – pulmonary proportion of change if pulmonary arterial hypertension
the CO passes through alveolar capillaries develops, as can occur with hypoxic
which have insufficient V_ A to fully pulmonary vasoconstriction (HPV) in a
oxygenate all of their blood; that is, a local neonate, resulting in pathological shunt.
V̇ /Q̇ mismatch. – Intra-pulmonary shunts. These constitute by
The normal physiological shunt fraction is 2–5%, far the commonest cause of pathological
approximately half of which is due to anatomical shunts. Shunting occurs when alveoli are
shunt and half due to functional shunt. perfused but are unable to participate in gas
Physiological shunt can be thought of as being exchange. This may occur when alveoli are
analogous to physiological dead space: completely filled with fluid (as occurs, for
physiological dead space is the sum of anatomical example, in pulmonary oedema or
dead space (analogous to anatomical shunt) and pneumonia) or as a result of a proximal airway
alveolar dead space (analogous to occlusion (for example, with bronchial
functional shunt). obstruction or one-lung ventilation).
Pathological shunt, classified on the basis of its
location:
– Intra-cardiac; for example as the result of a
What is the difference between shunt
ventricular septal defect (VSD). Normally, the and ventilation–perfusion mismatch?
pressure in the LV is higher than that in the Ideally, ventilation and perfusion in the lung are
right ventricle. Accordingly, blood flows matched. Ventilation (V̇ , L/min) in a particular
65
area of the lung is then approximately the same as What happens to arterial carbon
that area’s perfusion (Q̇ , L/min), giving a V̇ /Q̇ ratio
of one. dioxide tension in the presence of
V̇ /Q̇ mismatch occurs when there is either: a shunt?
Ventilation with relatively less perfusion, giving PaCO2 is related to:
a V̇ /Q̇ ratio >1. Pulmonary capillary blood
The rate of production of CO2, which is
traverses ventilated alveoli; gas exchange takes
determined by the metabolic rate.
place, resulting in a normal PaO2. However, as
The rate of elimination of CO2, which
there is a relative excess of ventilation, some of
depends on V_ A .
this ventilation is wasted, which increases alveolar
dead space. In the presence of a shunt, blood bypasses the
Perfusion with relatively less ventilation, giving a alveolar–capillary barrier. CO2 cannot diffuse out
V̇ /Q̇ ratio <1. Some of the pulmonary capillary of the shunted blood, so PaCO2 might be expected
blood traverses alveoli that are not being to increase. However, the respiratory centre responds
ventilated. Gas exchange cannot take place to any increase in PaCO2 by increasing V_ A (see Chap-
at these alveoli, so overall PaO2 is reduced. ter 21). Therefore, in the presence of a shunt, PaCO2
A pure intra-pulmonary shunt can be usually remains in the normal range but V_ A increases.
thought of as a regional V̇ /Q̇ ratio of zero.
For example, in the case of one-lung ventilation,
the affected lung is no longer ventilated but
What is the shunt equation?
is still perfused. Consequently, the V̇ /Q̇ ratio The shunt equation is used to calculate the proportion
of the affected lung is zero. All pulmonary of the CO that is shunted from the venous to the
arterial blood entering the affected lung is arterial system.
returned to the pulmonary veins without
Key equation: the shunt equation
further oxygenation.
The shunt equation is in the form of a ratio, the shunt
The important difference between shunt and V̇ /Q̇ fraction:
mismatch concerns the response to O2 Q_ S C c O2 C a O2
administration: ¼
Q_ T C c O2 C v O2
Hypoxaemia due to a pathological shunt responds
where Q_ S (L/min) is the flow of blood through the
poorly to the administration of supplemental O2.
shunt, Q_ T (L/min) is the total flow of blood (i.e. CO),
This is because, by definition, shunted blood C c O2 (mL O2/100 mL blood) is the O2 content of end-
bypasses aerated alveoli and so is never able to capillary blood, C a O2 (mL O2/100 mL blood) is the O2
take part in gas exchange. PaO2 does improve content of arterial blood and C v O2 (mL O2/100 mL
a little with supplemental O2 administration, due blood) is the O2 content of mixed venous blood.
to the small amount of additional dissolved O2
in the blood.
In contrast, hypoxaemia due to mild V̇ /Q̇ The proportion of CO involved in a shunt can therefore
mismatch does respond to O2 administration. be calculated if the O2 contents of arterial, mixed venous
Increasing FiO2 increases PAO2, according to the and end-capillary blood are known (Figure 13.1).
AGE. In underventilated alveoli, this re-establishes Using the O2 content equation (see Chapter 7):
an adequate O2 partial pressure gradient for C a O2 ¼ ½Hb×1:34×Sa O2 +ðP a O2 ×0:023Þ.
diffusion, and PaO2 increases. Ca O2 can therefore be calculated from peripheral
Hypoxaemia due to a large V̇ /Q̇ mismatch (where arterial blood gas analysis.
the V̇ /Q̇ ratio approaches zero) responds poorly to Cv O2 ¼ ½Hb×1:34×Sv O2 +ðP v O2 ×0:023Þ, where
O2 administration, behaving more like a right-to- SvO2 is the Hb O2 saturation of venous blood,
left shunt. Therefore, the difference between a and PvO2 is the venous O2 tension. Cv O2 can
severe V̇ /Q̇ mismatch and a shunt is largely therefore be calculated by sampling blood from a
academic: clinically, neither responds to O2 central line (for mixed venous blood, this should
therapy. strictly be from a pulmonary artery catheter (PAC)).
66
Chapter 13: Hypoxia and shunts
Figure 13.1 Schematic representing

a shunt.
Alveolus
Blood to ventilated alveoli
Pulmonary artery Pulmonary vein

S
-Q
T
Q
QT QT
QS
Shunt – cannot take part in gas exchange
End-capillary blood cannot be measured directly. Substituting these values into the shunt equation:
Instead, Cc O2 can be estimated: as end-capillary
blood has just left the alveolus, it is assumed to have Q_ S 20:4 20:2
¼ ×100 ¼ 4% shunt
an Hb O2 saturation of 100%, with pulmonary Q_ T 20:4 15:2
capillary O2 tension equal to PAO2. Therefore, which is fairly typical for healthy lungs.
Cc O2 ¼ ½Hb×1:34×100%+ðP A O2 ×0:023Þ. PAO2
can be calculated from the AGE using PaCO2
(see Chapter 17). How is the shunt equation derived?
Overall, the shunt fraction can be calculated using The shunt equation is not too difficult to derive.
arterial and central venous blood gas analysis, First, consider pulmonary blood flow:
together with Hb concentration.
For example, in a ‘normal’ patient: [Hb] is 15 g/ – According to Figure 13.1, the
dL, PaO2 is 13.0 kPa with an SaO2 of 99%, PvO2 is total pulmonary blood flow is Q_ T
5.3 kPa with venous Hb saturation of 75%, and PaCO2 and the blood flow to unventilated
is 5.3 kPa. Atmospheric pressure is 101 kPa, the alveoli is Q_ S
saturated vapour pressure of water is 6.3 kPa and – Therefore, the blood flow to ventilated alveoli
the respiratory quotient R ¼ 0.8. Therefore: is Q_ T Q_ S .
Ca O2 ¼ 15×1:34×0:99+13:0×0:023 Next, consider the volume of O2:
¼ 20:2 mL=100 mL blood – The volume of O2 in the pulmonary vein must
equal the volume of O2 in the ventilated
Cv O2 ¼ 15×1:34×0:75+5:3×0:023
capillaries plus volume of O2 in shunt
¼ 15:2mL=100mL blood capillaries.
Using the AGE: – The same statement written mathematically is
Pa CO2 Q_ T Ca O2 ¼ ðQ_ T Q_ S ÞCc O2 þ Q_ S Cv O2
PA O2 ¼ F i O2 ðPB P SVP water Þ
R
Multiplying out the brackets gives
5:3
PA O2 ¼ 0:21×ð101 6:3Þ ¼ 13:3 kPa
0:8 Q_ T Ca O2 ¼ Q_ T Cc O2 Q_ S Cc O2 +Q_ S Cv O2
Therefore:
Rearranging gives
Cc O2 ¼ 15×1:34×100%+13:3×0:023
¼ 20:4 mL=100 mL blood Q_ S Cc O2 Q_ S Cv O2 ¼ Q_ T Cc O2 Q_ T Ca O2
67
Figure 13.2 The effect of FiO2 on PaO2

0% shunt at different shunt fractions.
10%
60
50
40
Arterial PO2 (kPa)
20%
Breathing
30 room air
20 30%
40%
10
50%
0
0 20 40 60 80 100
Inspired fraction of O2 (%)
Or the alveolar–capillary barrier. In turn, the increased rate

Q_ S ðCc O2 Cv O2 Þ ¼ Q_ T ðCc O2 C a O2 Þ of O2 diffusion leads to an increase in PaO2.
As discussed above: blood that bypasses the
ventilated alveoli is not exposed to any extra O2
This leads to the shunt equation: administered to the patient. As the shunt fraction
Q_ S Cc O2 C a O2 increases, more and more blood bypasses the venti-
¼ lated alveoli – the higher FiO2 has less and less impact
Q_ T Cc O2 C v O2
on PaO2 (Figure 13.2).
What is the effect of administering

oxygen at different shunt fractions? Further reading
According to the AGE (see Chapter 17), O2 adminis- J. R. Gossage, G. Kanj. Pulmonary arteriovenous
malformations. A state of the art review. Am J Respir Crit
tration (i.e. an increase in FiO2) leads to an increase Care Med 1998; 158(2): 643–61.
in PAO2, which increases the O2 pressure gradient across
68
Chapter
Ventilation–perfusion relationships
14
becomes greater than that of the anterior
How does gravity affect blood lung. Similarly, in the lateral position, the
flow to the lungs? dependent lung (the lowermost) has a greater
The heart is positioned at the vertical centre of the perfusion than the non-dependent lung
lungs – the lung apices are situated above the level of (the uppermost).
the heart, and the lung bases are below. Lung perfu-
sion1 increases linearly from the top to the bottom
of the lungs (Figure 14.1, lung perfusion line). What is the effect of gravity on alveolar
The difference in perfusion at the top and bottom ventilation?
of the lung can be explained by the effect of gravity The effect of gravity on V_ A is discussed in detail in
on pulmonary capillary pressure. The difference in Chapter 19. In summary:
pulmonary capillary pressure between the lung apex
The weight of the lung parenchyma results in
and base is equivalent to the hydrostatic pressure
intrapleural pressure being more negative at the
exerted by a column of blood. The distance from
apex than the base. At FRC, the apical alveoli
apex to base is 30 cm, so the pressure difference
are nearly fully inflated whereas the basal alveoli
is 30 cmH2O (equivalent to 22 mmHg). The pulmo-
are hardly inflated at all.
nary circulation is a low-pressure system: mean
pulmonary artery pressure (MPAP) is typically just At FRC, the basal alveoli have a greater
compliance (i.e. a greater increase in volume per
15 mmHg. A pressure difference of 22 mmHg
unit pressure applied) than the apical alveoli, as
between the top and the bottom of the lungs is
they are less distended by the weight of the lung
therefore very significant (this is discussed further
parenchyma.
in Chapter 15).
The regional differences in lung perfusion are During inspiration, intrapleural pressure
altered by: becomes more negative, which causes the
volume of the basal alveoli to increase more
Exercise. When CO increases, MPAP than the apical alveoli. V_ A therefore increases
also increases. The difference in capillary
from apex to base (Figure 14.1, alveolar
hydrostatic pressure between the lung
ventilation line).
apex and base therefore becomes less
significant; blood is distributed more evenly
throughout the lung. What is meant by the term ‘ventilation–
Body position. When a patient is supine,
the vertical difference between the apex
perfusion ratio’?
and base is abolished. Instead, the anterior For ideal gas exchange, the ventilation and perfu-
lung becomes vertically higher than the sion to each alveolus should be matched: exactly
posterior lung. For the same reasons as the right amount of V_ A to fully oxygenate all
above, perfusion of the posterior lung the passing blood; that is, a ventilation–perfusion
ratio V̇ /Q̇ ¼ 1. Too little ventilation would lead to
partial oxygenation of blood, whereas too much
1
Pulmonary blood flow is referred to as the ‘perfusion’, ventilation is unnecessarily wasteful of respiratory
termed Q̇ . effort. However, normal lung perfusion is 5 L/min,
69
Figure 14.1 Perfusion, ventilation and

0.15 the V̇ /Q̇ relationship.
L/min % of lung volume
Ventilation–perfusion ratio
0.1
2
0.05 1
V/Q ratio
0 0
6 5 4 3 2 1
Bottom of lungs Anterior rib number Top of lungs
(i.e. normal CO) and V_ A is 4 L/min.2 The normal Problems with lung ventilation, resulting
V̇ /Q̇ ratio is therefore 0.8. in low V̇ /Q̇ ratio.
Whilst the global V̇ /Q̇ ratio in healthy lungs is 0.8, This is the most common cause of
there is considerable regional variation. Owing to the hypoxaemia. Causes include:
effects of gravity, both ventilation and perfusion are – upper airway obstruction
increased in the lung bases compared with the apices. – foreign body aspiration
However, gravity has a greater effect on perfusion
– pneumonia
than on ventilation, as represented by the steeper
– pneumothorax
gradient of the lung perfusion line in Figure 14.1.
The V̇ /Q̇ ratio therefore increases from the bottom – atelectasis
to the top of the lungs: – ARDS
– emphysema
In the bases, the V̇ /Q̇ ratio is approximately 0.6.
As perfusion is greater than ventilation, blood – one-lung ventilation
may leave the pulmonary capillaries without being – normal ageing
fully oxygenated, resulting in a right-to-left shunt. – increased CC associated with obesity.
A greater amount of O2 is extracted from the Problems with lung perfusion, resulting in
alveoli, resulting in a low alveolar O2 tension high V̇ /Q̇ ratio.
PAO2. Causes include:
In the apices, V̇ /Q̇ > 3. As ventilation is – PE
proportionally greater than perfusion, blood – reduced right ventricular stroke volume (SV),
leaving the apical pulmonary capillaries is fully due to hypovolaemia, right ventricular
oxygenated. However, as only a small volume infarction or pericardial tamponade.
of blood passes by the apical alveoli, little gas
exchange takes place: PAO2 is high and PACO2
is low. How might you manage hypoxaemia
associated with V̇ /Q̇ mismatch?
What are the causes of abnormal V̇ /Q̇ The commonest cause of hypoxaemia (defined as a
PaO2 < 8 kPa) is V̇ /Q̇ mismatch with a low V̇ /Q̇ ratio.
ratio? The mainstay of treatment is:
There are many pathological causes of V̇ /Q̇ mis- O2 administration. Hypoxaemia associated with
match. These are broadly grouped into: low V̇ /Q̇ ratio is responsive to O2 therapy. As
discussed earlier, poorly ventilated alveoli with
2
Note: V_ E is around 5 L/min, but approximately a fifth is normal perfusion have low PAO2. By
dead-space ventilation (see Chapter 10). administering a higher fraction of inspired O2
70
Chapter 14: Ventilation–perfusion relationships
FiO2, PAO2 is increased. The O2 partial pressure

gradient across the alveolar–capillary barrier is All three factors lead to a low V̇ /Q̇ ratio, resulting
in hypoxaemia.
increased, and blood leaving the pulmonary
capillaries becomes better oxygenated.
Reversing the cause of the V̇ /Q̇ mismatch. For
example, using antibiotics for pneumonia, or Is gravity the only factor influencing V̇ /Q̇
PEEP for atelectasis. matching?
The gravitational model of lung ventilation and
Clinical relevance: hypoxaemia with pulmonary perfusion described above has been used to explain
embolism
whole-lung V̇ /Q̇ matching for nearly 50 years. How-
Why do patients with PE become hypoxaemic?
ever, the model cannot explain certain differences
At first glance this seems a facile question, but if
in V̇ /Q̇ matching discovered more recently. For
you consider the V̇ /Q̇ relationship associated with
PE, it becomes intriguing. example, it has been shown that different areas of
PE results in obstruction (by a blood clot, gas, the lung at the same vertical height can have a differ-
fat or amniotic fluid) of one or more major ent V̇ /Q̇ ratio. In addition, even under zero gravity
branches of the pulmonary arterial tree. Down- the lung has been shown to have a non-uniform V̇ /Q̇
stream of the arterial obstruction the V̇ /Q̇ ratio is relationship.
high, as alveolar ventilation continues as normal During embryonic development, the airways and
whilst alveolar perfusion ceases. Since the affected blood vessels develop together. The branching of
alveoli are ventilated but no longer perfused, PAO2 the vessels and airways is quite asymmetric, but
increases and PACO2 decreases. However, all the because the airways and blood vessel branch at
blood leaving the pulmonary capillaries should
the same points the diameters of the vessels and
still be fully oxygenated. Therefore, one would
airways are well matched. This leads to similarities
expect a patient with PE to have an increased V_ E
(due to the increased alveolar dead space), but a in ventilation and perfusion at the alveolar level,
normal PaO2. which contributes to V̇ /Q̇ matching.
Clinically, patients with PE become hypoxaemic. In addition, the lung has a physiological mechan-
The mechanism for this has been a topic of some ism, HPV, which directs blood away from poorly
controversy for many years. The most accepted ventilated alveoli (see Chapter 22). In a region of
explanation is: the lung with relatively less ventilation, PAO2 is low.
Embolus settles in a branch of the pulmonary In response, pulmonary arteriolar vasoconstriction
arterial tree, causing mechanical obstruction, reduces perfusion to this region, thus normalizing
stopping blood flow to the downstream pul- the V̇ /Q̇ ratio. Blood is instead redirected to well-
monary capillaries. This causes a high V̇ /Q̇ ratio
ventilated regions, which accommodate the increased
and increased alveolar dead space, as
volume through the recruitment and distension of
discussed above.
J-receptors in the alveolar walls are activated
pulmonary capillaries, which again normalizes the
by pulmonary emboli, causing a feeling V̇ /Q̇ ratio.
of breathlessness and stimulating an
increase in V_ E . This explains the low PaCO2 Further reading
found in patients with PE.
I. Galvin, G. B. Drummond, M. Nirmalan. Distribution of
In addition to mechanical obstruction, the
blood flow and ventilation in the lung: gravity is not
embolus causes local release of inflammatory
the only factor. Br J Anaesth 2007; 98(4): 420–8.
mediators, causing:
– bronchoconstriction of small airways; R. P. Mahajan. Acute lung injury: options to improve
– alveolar–capillary barrier damage, oxygenation. Contin Educ Anaesth Crit Care Pain 2005;
leading to pulmonary oedema; 5(2): 52–5.
– reduced pulmonary surfactant production, G. Stratmann, G. A. Gregory. Neurogenic and humoral
leading to atelectasis. vasoconstriction in acute pulmonary thromboembolism.
Anesth Analg 2003; 97(2): 341–54.
71
Chapter
West zones
15
lower: alveolar pressure exceeds venous pressure,
What are the West zones of the lung? causing compression of the venous end of the
In the upright position, ventilation and perfusion pulmonary capillary. Capillary blood flow is
both increase from the top to the bottom of the lung. therefore dependent on the arterial–alveolar
This has traditionally been attributed to the effect pressure difference. Systolic pulmonary arterial
of gravity (the so-called gravitational model), but it pressure is greater than alveolar pressure, but
is now thought that structural similarities between diastolic pulmonary arterial pressure is not –
the pulmonary arteries and bronchioles contribute blood therefore only flows through the pulmonary
(see Chapter 14). capillary during systole. The intermittent nature
J. B. West built on the gravitational model of ven- of blood flow causes a mismatch between alveolar
tilation and perfusion. He recognized that, in addition ventilation and perfusion. Thus, the V̇ /Q̇ ratio is
to the effects of gravity, capillary blood flow to the higher than zone 1, with an increased alveolar
alveolus is dependent on the pressure of the gas dead space and, consequently, wasted ventilation.
within the alveolus. This is particularly important West zone 2 is how normal lungs behave between
in anaesthesia, as positive pressure ventilation signi- the apex and the hilum.
ficantly alters alveolar pressure. West divided the
In West zone 1, PA > Pa > Pv. Alveolar pressure
upright lung into three vertical zones, numbered 1
exceeds systolic pulmonary arterial pressure.
(at the apex) to 3 (at the base). The arterial, venous
The pulmonary capillary is completely
and alveolar pressures differ in each zone, which has
compressed by the alveolus, with alveolar
implications for the V̇ /Q̇ ratio.
perfusion ceasing. The apical alveoli are still
ventilated – V̇ /Q̇ ratio is therefore high, with a
How do the changes in arterial, venous high alveolar dead space. West zone 1 does not
exist in normal lungs.
and alveolar pressures affect alveolar
perfusion?
The variation in alveolar perfusion in the three West When does West zone 1 become
zones (Figure 15.1) is most easily explained by
starting from West zone 3, in the base of the lung: clinically significant?
In West zone 3, Pa > Pv > PA (a: arterial; v: In a healthy non-anaesthetized person, alveolar pres-
venous; A: alveolar). Both arterial and venous sure is approximately equal to atmospheric pressure,
pressures are greater than alveolar pressure, with small pressure variations due to inspiration and
due to the effects of gravity on blood flow. expiration (0±2 cmH2O). The situation of West zone 1,
Capillary blood flows continuously throughout where alveolar pressure exceeds systolic pulmonary
the cardiac cycle – flow is dependent on the arterial pressure, therefore does not normally occur.
arterial–venous pressure difference. West zone 3 is However, West zone 1 can occur when:
how normal healthy lungs behave below the level Pulmonary arterial pressure is abnormally low;
of the hilum. for example, haemorrhagic shock. Normal
In West zone 2, Pa > PA > Pv. Zone 2 is vertically alveolar pressure may therefore exceed pulmonary
higher than zone 3, so the venous pressure is arterial pressure.
72
Chapter 15: West zones
Arteries Capillaries Veins
West zone 1 does not
Vertical height
Pa Pv normally occur
PA West zone 1:
PA > Pa > Pv
Intermittent blood flow

Pa Pv
PA
West zone 2:
Pa > PA > Pv
QT Pa Pv QT
West zone 3:
PA Pa > Pv > PA
Continuous blood flow
Blood flow
Figure 15.1 West zones of the lung.
Alveolar pressure is abnormally high; for

example, during positive pressure ventilation, For accurate measurement of PCWP, the PAC must
wedge in a pulmonary artery within West zone 3.
or high intrinsic PEEP (PEEPi) associated with
It is essential that the PAC is in communication
acute severe asthma. with an uninterrupted static column of blood between
the pulmonary artery and the left atrium. As discussed
When West zone 1 does occur, the increase in above, this can only occur in West zone 3 where
alveolar dead space means that ventilation is wasted. capillary blood flow is continuous.
In the case of acute severe asthma, the increased Because the majority of pulmonary blood flow is
ventilatory effort required may precipitate respiratory to West zone 3, the tip of the flow-directed PAC is
failure. likely to position itself correctly. A clinical method of
checking the position of the PAC is to increase PEEP
Clinical relevance: pulmonary artery catheters by 10 cmH2O – if the PCWP increases by more than
25%, it is likely that the tip is not in West zone 3.
One of the key measurements obtained from the
PAC is the pulmonary capillary wedge pressure
(PCWP). When inflated, the balloon-tipped end of
the PAC is ‘floated’ through the right ventricle and Further reading
into the pulmonary arterial tree, until it wedges in a I. Galvin, G. B. Drummond, M. Nirmalan. Distribution
branch of the pulmonary artery. of blood flow and ventilation in the lung: gravity is not
the only factor. Br J Anaesth 2007; 98(4): 420–8.
73
Chapter
Oxygen delivery and demand
16
What is meant by the term ‘global What is meant by the term global
oxygen consumption’? oxygen delivery?
Global O2 consumption V_ O2 (mL/min) is the volume _ 2 (mL/min) is the amount
Global O2 delivery DO
of O2 that is consumed by the body per minute. of O2 delivered to the tissues from the lungs per
During aerobic metabolism, V_ O2 is closely minute. DO_ 2 can be calculated using the O2 flux
matched to the body’s metabolic rate. Resting V_ O2 equation:
for a 70 kg man is typically 250 mL/min (at sea level
and standard temperature). During exercise, V_ O2 Key equation: oxygen flux equation
increases as the body consumes additional O2 to
_ 2 ¼ CO×C a O2 ×10
DO
power muscle contraction. As exercise intensity
increases, V_ O2 increases, but there comes a point where DO_ 2 (mL/min) is the global O2 delivery; 10 is
where V_ O2 is limited by the rate of O2 delivery to a unit conversion factor.
the tissues, which is likely due to the number of
muscle capillaries. When this happens, the muscles
switch from aerobic metabolism, where O2 is con- What is a typical resting global
sumed, to anaerobic metabolism, where energy is
obtained from glycolysis. The O2 consumption at this
oxygen delivery?
transition point is termed V_ O2 max . Using the O2 flux equation with typical values for a
Global V_ O2 can be calculated using the reverse resting patient breathing room air (CO ¼ 5 L/min,
Fick principle: [Hb] ¼ 15 g/dL, SaO2 ¼ 98%, PaO2 ¼ 13 kPa), first
the CaO2 is calculated:
Key equation: reverse Fick principle
C a O2 ¼ ð1:34×½Hb×Sa O2 =100%Þ+0:023×Pa O2
V_ O2 ¼ CO×ðC a O2 C v O2 Þ×10
Therefore:
where CO (L/min) is the cardiac output, CaO2 is the
O2 content of arterial blood (ml/100 mL of blood), C a O2 ¼ ð1:34×15×98=100Þ+0:023×13
CvO2 is the O2 content of venous blood (ml/100 mL ¼ 20:0 mL=100 mL blood
of blood), 10 is a unit conversion factor, and _ 2 is calculated:
Then DO
C a O2 ¼ ð1:34×½Hb×Sa O2 =100%Þ+0:023×Pa O2
_ 2 ¼ CO×C a O2 ×10
DO
(see Chapter 7), where [Hb] (g/dL) is the Hb
concentration. Therefore:
_ 2 ¼ 5×20:0×10
DO
The equation above essentially states that the V_ O2 is ¼ 1000 mL=min
the same as the O2 ‘taken out of the arterial blood’, as
reflected in the difference in arterial and venous O2 Clinical relevance: anaemia
contents. CO and CvO2 can be measured with the aid What happens to DO _ 2 if a patient is anaemic? If the
of a PAC (as CvO2 should really be measured using patient described above became anaemic, with an
mixed venous blood), and CaO2 can be measured Hb concentration of, say, 8 g/dL:
by peripheral arterial blood gas analysis.
74
Chapter 16: Oxygen delivery and demand
C a O2 ¼ ð1:34×8×98=100Þ+0:023×13 An OER of 0.2–0.3 corresponds to a mixed venous

¼ 10:8 mL=100 ml blood Hb O2 saturation of 70–80%.
_ 2 ¼ 5×10:8×10
) DO
¼ 540 mL=min
As DO_ 2 falls (for example, as a result of hypotension)
This corresponds to a fall in DO_ 2 to nearly half the _
or V O2 rises (for example, as a result of exercise or
normal value. sepsis), the tissues must extract more O2 from the
However, there is a flaw in the calculation above.
passing blood if they are to continue to undergo
The CO of an anaemic patient is not the normal
aerobic metabolism. There is also a considerable
value of 5 L/min. Anaemia causes a compensatory
increase in CO in order that DO_ 2 is maintained. The difference in the normal OER between different
increased CO is in part a result of the reduced viscos- organs. For example:
ity of anaemic blood. The carotid bodies have high DO _ 2 but low V_ O2 ,
resulting in a low OER.
The heart has a high OER (approximately 0.6),
_ 2 and V_ O2 related?
How are DO which makes it very susceptible to ischaemia
_ 2 (typical value 1000
At rest in a normal patient, DO following a reduction in coronary artery perfusion
mL/min) is much higher than V_ O2 (typical value 250 pressure.
mL/min). Thus, the tissues are said to have an
O2 extraction ratio (OER) of 25%.
Is there a point where oxygen delivery
Key equation: oxygen extraction ratio becomes inadequate?
At rest, the tissues will continue to extract O2 for
V_ O2 aerobic metabolism from the passing capillary blood
OER ¼
_ 2
DO at a rate of 250 mL/min, until a critical value of DO_ 2
_
is reached (Figure 16.1a). This critical DO2 is referred
Normal OER is 0.2–0.3; that is, only 20–30% of
delivered O2 is consumed by the tissues, the to as the ‘anaerobic threshold’.
rest being returned to the lungs in the venous blood. Before the anaerobic threshold is reached, V_ O2 is
said to be ‘supply independent’. Once DO _ 2 falls below
(a) Normal O2 supply and demand (b) Critical illness O2 supply and demand
400 400
Oxygen consumption, VO2 (mL/min)
Oxygen consumption, VO2 (mL/min)
300 300
Supply independent
Normal
250 250
200 200
100 100
Normal O2
Critical DO2 = anabolic threshold
extraction
0 0
0 200 400 600 0 200 400 600
Oxygen delivery, DO2 (mL/min) Oxygen delivery, DO2 (mL/min)
Figure 16.1 O2 supply and demand: (a) normal situation; (b) critical illness.
75
this critical value, V_ O2 rapidly decreases and the

tissues are forced to gain their energy by anaerobic Mechanical ventilation and muscle paralysis,
which abolish the work of breathing.
means – V_ O2 is now said to be ‘supply dependent’.
Preoperative starvation, which reduces O2
consumption in the gut.
Clinical relevance: critical illness and oxygen
delivery The inflammatory response following major surgery
In the critically ill patient, O2 supply and demand is increases resting V_ O2 by 50% – this increase is then
more complicated. sustained over many days. It is important to know
Additional factors may significantly increase V_ O2 : preoperatively that a patient has sufficient cardiopul-
Inflammation, sepsis and pyrexia. monary reserve to meet the required postoperative
Administration of adrenergic drugs. increase in DO_ 2 . A number of preoperative tests of
Weaning from the ventilator. cardiopulmonary function are available – recently,
Interventions such as physiotherapy. cardiopulmonary exercise testing (CPET) has
Conditions such as burns, trauma and seizures. attracted much interest.
_ 2 CPET measures a number of parameters, includ-
There is an altered relationship between V_ O2 and DO
ing V_ O2 and the rate of CO2 production, V_ CO2 .
in patients with severe sepsis or ARDS. V_ O2 becomes
_ 2 One of the main outcomes of CPET testing is the
supply dependent at a much higher DO
anaerobic threshold, a measure of physiological
(Figure 16.1b) – the normal biphasic relationship
_ 2 is no longer observed. It is fitness incorporating the heart, lungs and circula-
between V_ O2 and DO
tion. As the exercise intensity during the test
not clear whether this effect is the result of critical _ 2 – anaerobic
_ 2 being much higher than normal in critical increases, V_ O2 starts to exceed DO
DO
metabolism commences, which produces lactic acid.
illness, or whether the tissues are less able to extract
The lactic acid is buffered in the circulation by
O2 from the blood.
HCO3 , releasing CO2. Graphically, the anaerobic
Early goal-directed therapy involves the invasive
threshold is determined as the point at which the
monitoring and aggressive haemodynamic manage-
rate of CO2 production exceeds the rate of O2 con-
ment of patients at risk of organ failure. Many of the
_ 2; sumption. Low anabolic threshold (i.e. occurring
haemodynamic targets involve optimization of DO
early in the CPET test) predicts postoperative
for example, aiming for a mixed venous O2 satur-
complications.
ation of 70–80%. Early trials demonstrated a reduc-
tion in morbidity and mortality when patients with
septic shock received protocol-based resuscitation.
However, the recently published PROCESS trial Further reading
found no difference between protocol-based resus- R. P. Dellinger, M. M. Levy, A. Rhodes, et al. Surviving
citation and ‘usual care’ (see Further reading). Sepsis Campaign: international guidelines for the
management of severe sepsis and septic shock: 2012. Crit
Care Med 2013; 41(2): 580–637.
J. G. Hopker, S. A. Jobson, J. J. Pandit. Controversies
Clinical relevance: anaesthesia, oxygen in the physiological basis of the ‘anaerobic
consumption and oxygen delivery threshold’ and their implications for clinical
cardiopulmonary exercise testing. Anaesthesia 2011;
In the perioperative period, V_ O2 is frequently higher
66(2): 111–23.
than the ‘resting’ value of 250 mL/min. A number of
factors are implicated: C. M. Lilly. The PROCESS trial – a new era in sepsis
Surgery. management. N Engl J Med 2014; 370(18): 1683–93.
Pain and anxiety. N. Agnew. Preoperative cardiopulmonary exercise
Inflammation, sepsis and pyrexia. testing. Contin Educ Anaesth Crit Care Pain 2010; 10(2):
Postoperative shivering. 33–7.
S. A. McLellan, T. S. Walsh. Oxygen delivery and
Under general anaesthesia, some of this increase in
haemoglobin. Contin Educ Anaesth Crit Care Pain 2004;
V_ O2 is offset due to:
4(4): 123–6.
Sedatives/hypnotics, which reduce cerebral
metabolic rate (CMR), a major component of the E. Rivers, B. Nguyen, S. Havstad, et al. Early goal-directed
resting V_ O2 . therapy in the treatment of severe sepsis and septic
shock. N Engl J Med 2001; 345(19): 1368–77.
76
Chapter
Alveolar gas equation
17
According to the AGE, as the elevation above sea
Can you measure the partial pressure level increases, the fall in PB results in a lower
of oxygen in the alveolus? PAO2, and thus a reduced rate of O2 diffusion
The partial pressure gradient of O2 between the alveo- across the alveolar–capillary barrier.
lus and the pulmonary capillaries is one of the key Alveolar ventilation. As PaCO2 is inversely
factors that determine the rate of O2 diffusion across proportional to V_ A (see Chapter 10):
the alveolar–capillary barrier (see Chapter 9). Unfor- – Hyperventilation. An increase in V_ A results
tunately, it is not possible to directly measure the in a decrease in PaCO2. According to the
PAO2. Instead, PAO2 can be estimated using the AGE. AGE: PAO2 will increase, thus increasing the
rate of O2 diffusion across the alveolar–
What is the alveolar gas equation? capillary barrier.
– Hypoventilation. A decrease in V_ A results in
The AGE1 allows PAO2 to be estimated from variables
an increase in PaCO2. According to the AGE:
that are easily measured.
PAO2 will decrease, thus reducing the rate of
Key equation: alveolar gas equation O2 diffusion across the alveolar–capillary
barrier.
Pa CO2
PA O2 ¼ F i O2 ðPB PSVP water Þ
R
where FiO2 for dry air is 20.93%; PB at sea level is What is the respiratory quotient? Why
101.325 kPa. Inspired air becomes fully saturated
with water vapour by the time it reaches the carina.
does it differ for different dietary
PSVP water is the saturated vapour pressure of water, substrates?
which at body temperature is 6.3 kPa. PaCO2 is mea- The respiratory quotient R is the ratio of CO2
sured in kilopascals. R is the respiratory quotient,
production and O2 consumption:
usually taken as 0.8.
volume of CO2 produced
R¼
volume of O2 consumed
The AGE tells us that PAO2 is essentially dependent
on three variables: R differs between the three dietary metabolic
The inspired fraction of O2. According to the substrates: fat, protein and carbohydrate. R can be
AGE, increasing FiO2 will result in a greater PAO2, calculated for each substrate using the chemical
thus increasing the pressure gradient across the formula of the overall aerobic metabolism reaction.
alveolar–capillary barrier; the rate of O2 diffusion For example, consider glucose:
will increase (Fick’s law – see Chapter 9). C6H12O6 + 6O2 ! 6CO2 + 6H2O
Barometric pressure. PB decreases exponentially
with ascent to altitude (see Chapter 81). Therefore, as six molecules of CO2 are produced
for every six molecules of O2 consumed, R = 1.0 for
a purely carbohydrate-based diet. Likewise:
1
The derivation of the AGE is beyond the scope of this R = 0.7 for a purely fat-based diet.
book; see Further reading for full details. R = 0.9 for a purely protein-based diet.
77
The respiratory quotient is usually taken as 0.8, the

figure for a balanced Western diet. In normal lungs, PAO2 and pulmonary capillary O2
tension are approximately equal because there is
sufficient time for the O2 partial pressures on either
Using the alveolar gas equation, side of the alveolar–capillary barrier to equilibrate
before the RBCs have traversed the capillary (see Chap-
calculate the alveolar oxygen tension ter 9). But the arterial O2 tension PaO2 is always lower
than PAO2. Even in normal lungs with perfect V̇ /Q̇
for a typical patient breathing room matching, there is always an anatomical shunt as
air at sea level a result of the bronchial and Thebesian veins (see
A typical patient has a PaCO2 of 5.3 kPa, and a normal Chapter 13), resulting in a small A–a gradient:
diet, i.e. R = 0.8. The values for FiO2, PB and PSVP water In a healthy young adult, a normal A–a gradient
are given above. is considered to be <1.5 kPa.
Substituting these values into the AGE: A–a gradient increases with age, due to a
worsening of V̇ /Q̇ matching in the ageing lung.
P a CO2
P A O2 ¼ F i O2 ðP B P SVP water Þ The A–a gradient is an index used clinically to
R
diagnose the cause of hypoxaemia. Increased A–a
Therefore: gradient is seen in:
5:3 V̇ /Q̇ mismatch, by far the most common cause
P A O2 ¼ 20:93%×ð101:325 6:3Þ of an increased A–a gradient; for example,
0:8
pneumonia, ARDS, atelectasis.
P A O2 ¼ 13:3 kPa
Right-to-left shunt; for example, pulmonary
AVM, intra-cardiac shunt.
Severe diffusion impairment; for example,
Clinical relevance: hypoventilation end-stage pulmonary fibrosis.
A known intravenous drug user is admitted uncon- Normal A–a gradient is seen with:
scious after an opioid overdose. His Hb saturations Hypoxic mixtures; for example, a faulty
are only 91%, and arterial blood gas analysis shows a anaesthetic machine.
PaCO2 of 9 kPa – explain this. Alveolar hypoventilation; for example,
Acute opiate overdose depresses the respiratory airway obstruction, neuromuscular disease,
centre in the medulla, resulting in decreased V_ A , with drug-induced respiratory depression.
a consequent rise in PaCO2. Using the AGE for a
patient breathing room air with a PaCO2 of 9 kPa:
PA O2 ¼ F i O2 ðPB PSVP water Þ

Pa CO2
R
How is the alveolar gas equation
PA O2 ¼ 20:93%×ð101:325 6:3Þ
9 relevant to the physiological
0:8
PAO2 = 8.6 kPa, equivalent to an SaO2 of approxi-
adaptation to altitude?
mately 91%. At altitude, the proportion of O2 in the air is the same
In hypoventilation, the A–a gradient (PAO2 PaO2) is as at sea level (i.e. FiO2 remains the same), but PB is
normal because the lungs are normal with little V̇ /Q̇ reduced. For example, PB is 65 kPa at the Tibetan
mismatch or shunt (see below). Plateau (one of the highest places to live in the world).
Hyperventilation is an important physiological mech-
anism that increases PAO2. If a person did not hyper-
ventilate at altitude (i.e. PaCO2 remained at 5.3 kPa),
PAO2 would be calculated by the AGE as
Clinical relevance: alveolar–arterial (A–a) gradient
Pa CO2
The A–a gradient is the difference between the PA O2 ¼ F i O2 ðPB PSVP water Þ
R
calculated alveolar PAO2 (using the AGE) and the
5:3
measured arterial PaO2 (using arterial blood gas PA O2 ¼ 20:93%ð65 6:3Þ
0:8
analysis).
PA O2 ¼ 5:7 kPa
78
Chapter 17: Alveolar gas equation
Figure 17.1 The relationship between

PAO2 and minute ventilation.
FiO2 0.4
20
FiO2 0.3
FiO2 0.21
15
PAO2 (kPa)
13.3
10
0
0 5 10 15
Minute ventilation (L/min)
Physiological shunt in the lungs would result in (see Chapter 10 and Figure 10.1) means that,
an even lower PaO2; that is, significant hypoxaemia. beyond a modest increase in V_ A (around 10 L/min),
However, if a person were to hyperventilate and a large increase in V_ A is required to achieve a small
PaCO2 decreased to, say, 3.0 kPa, then decrease in PaCO2. Therefore, as V_ A increases, PAO2
3:0 reaches a plateau. As demonstrated in Figure 17.1, O2
PA O2 ¼ 20:93%ð65 6:3Þ administration will increase PAO2 (and therefore
0:8
PaO2) substantially more than hyperventilation.
PA O2 ¼ 8:5 kPa
Hyperventilation therefore increases PAO2 sufficiently Further reading
to allow human existence at altitude, albeit with a S. Cruickshank, N. Hirschauer. The alveolar gas
chronic respiratory alkalosis. equation. Contin Educ Anaesth Crit Care Pain 2004;
However, there is a limit to the extent to which 4(1): 24–7.
hyperventilation can increase PAO2 (Figure 17.1). A. B. Lumb. Nunn’s Applied Respiratory Physiology, 7th
The hyperbolic relationship between V_ A and PaCO2 edition. Churchill Livingstone, 2010.
79
Chapter
Oxygen cascade
18
P a CO2
The O2 cascade concept draws together areas of PA O2 ¼ F i O2 ðP B PSVP water Þ
respiratory physiology covered in other chapters. In R
an examination setting, it allows the examiner to PAO2 can be calculated using the typical values:
assess your knowledge of more than one topic within PA CO2 ¼ 5:3 kPa and R ¼ 0.8:
a single question. 5:3
PA O2 ¼ 20:93%×ð101:325 6:3Þ
0:8
What is the oxygen cascade? ) P A O2 ¼ 13:3 kPa
Aerobic metabolism is the body’s most efficient Arterial blood. There is a ‘step’ reduction in PO2
method of energy production. O2 tension PO2 between the alveolus and the systemic arteries.
is high in the atmosphere (21.2 kPa) and low This A–a gradient is the result of three factors:
in the mitochondria (<5 kPa). The O2 cascade
– Diffusion across the alveolar–capillary barrier.
refers to the stepwise reduction in PO2 as O2
Normally there is sufficient time for O2 to
passes from the environment to the tissues
diffuse across the alveolar–capillary barrier;
(Figure 18.1).
that is, for PAO2 and pulmonary capillary PO2
to equilibrate at 13.3 kPa. Transfer of O2 is
Explain each of the steps in the oxygen then said to be perfusion limited (see
Chapter 9). However, in lungs with a
cascade thickened alveolar–capillary barrier or a
The steps along the O2 cascade are: decreased alveolar surface area, O2 may
Atmosphere. PB at sea level is 101.325 kPa, and become diffusion limited; pulmonary capillary
FiO2 of dry air is 20.93%. Atmospheric PO2 is PO2 then becomes a step lower than PAO2.
calculated as follows: – Shunts. There is normally a small anatomical
PO2 ¼ P B ×F i O2 right-to-left shunt arising from the bronchial
circulation and the Thebesian veins
) PO2 ¼ 101:325×20:93% ¼ 21:2 kPa
(see Chapter 13).
Trachea. By the time inspired air reaches the – V̇ /Q̇ mismatch. Any area of lung with relatively
carina it has become fully saturated with more perfusion than ventilation results in a
water vapour. Water has a saturated vapour functional right-to-left shunt, causing a further
pressure PSVP water of 6.3 kPa at 37 °C. The PO2 reduction in PaO2 (see Chapter 14). The
of humidified air at the carina is calculated normal physiological shunt fraction (the sum
as follows: of anatomical and functional shunt) is 2–5%,
PO2 ¼ ðP B P SVP water ÞF i O2 which corresponds to a fall in PaO2 to 13.0 kPa.
Tissue capillaries. As O2 is taken up by the tissues,
) PO2 ¼ ð101:325 6:3Þ×20:93% ¼ 19:9 kPa
the PO2 falls progressively from the arterial end to
Alveolus. PAO2 is mainly dependent on FiO2, the venous end of the capillary. However, not all
PB and V_ A , as described by the AGE (see the arteriolar blood flows through the capillaries:
Chapter 17): pre-capillary sphincters control how much blood
80
Chapter 18: Oxygen cascade
Figure 18.1 The O2 cascade.
21.2 Humidification
20
19.9 Alveolar gas equation
15 Diffusion
PO2 (kPa)
13.3 Physiological shunt
13.0
Pulmonary capillary
10
Mitochondria
6.3
Atmosphere
5
Alveolus
Trachea
Artery
Vein
1.0
0
Location
flows into each capillary network. The

remaining blood bypasses the capillaries and of ATP production. This critical threshold is called
the Pasteur point.
flows directly into the venules via arteriovenous
For mitochondrial PO2 to be adequate, capillary
anastomoses.
blood PO2 must be high enough for O2 to diffuse
Mitochondria. The mitochondrial PO2 is very readily from the blood to the tissues. Well-
much lower than that of arterial blood, and is oxygenated capillary blood is dependent on all the
related to the metabolic activity of the tissues. preceding steps of the O2 cascade. Anaerobic metab-
For example, in exercising skeletal muscle, O2 olism can occur if any of the ‘steps’ of the cascade
utilization is high and so the mitochondrial PO2 are greater than normal. For example:
is very low. Therefore, there is a large O2 partial High altitude reduces atmospheric PO2, the
pressure gradient between the capillary blood starting point of the cascade. All subsequent
and the mitochondria, increasing the rate of O2 steps will then have a lower PO2 than at sea level.
diffusion. In addition, metabolites (for example, Hypoventilation increases PaCO2, which in turn
reduces PAO2 (see Chapter 17).
H+ and CO2) cause arteriolar vasodilatation,
Pneumonia causes a V̇ /Q̇ mismatch, resulting in a
increasing local blood flow and hence O2 delivery. lower PaO2.
Clinical relevance: the Pasteur point and anaerobic
metabolism
If the mitochondrial PO2 falls below a critical point Further reading
(between 0.15 and 0.3 kPa) there is insufficient O2 C. C. W. Hsia, A. Schmidt, M. Lambertz, et al. Evolution of
tension for aerobic metabolism. Anaerobic metabol- air breathing: oxygen homeostasis and the transitions
ism then takes over as the dominant mechanism from water to land and sky. Compr Physiol 2013; 3(2):
849–915.
81
Chapter
Lung compliance
19
What is lung compliance? Therefore, at FRC, a VT of 500 mL is achieved
with a transpulmonary pressure of just
Compliance is a measure of the distensibility of the 2.5 cmH2O.
lungs. Compliance is defined as the change in lung
volume produced by a unit change in transpulmonary
pressure: What is respiratory compliance? How
Compliance ¼
ΔVolume does it differ from lung compliance?
ΔTranspulmonary pressure Respiratory compliance refers to the compliance of
the whole lung–chest unit. It is made up of two
Graphically, lung compliance is represented by
components:
the gradient of the pressure–volume curve. Math-
ematically, lung compliance is the inverse of lung Lung compliance.
elastance, which provides a measure of the elastic Thoracic cage compliance.
recoil force obtained by a given quantity of lung
distension.
Essentially, compliance is the property that deter- Key equation: respiratory compliance
mines the volume by which the lungs expand when Respiratory, lung and thoracic cage compliances are
pressure is applied to them: either negative pressure mathematically related:
(as in spontaneous ventilation) or positive pressure 1 1 1
¼ +
(as in intermittent positive pressure ventilation). For a RC LC TCC
spontaneously breathing patient: where RC is respiratory compliance, LC is lung com-
When compliance is high, the respiratory muscles pliance and TCC is thoracic cage compliance. Typical
only need to generate a small transpulmonary values for both lung and thoracic cage compliance
pressure to expand the lungs during tidal are 200 mL/cmH2O. Therefore, a typical value for
inspiration. respiratory compliance is 100 mL/cmH2O.
When compliance is low, a high
transpulmonary pressure is required to
expand the lung to the same VT – the Which factors affect lung and thoracic
respiratory muscles must therefore work harder cage compliance?
during inspiration and respiratory failure
Thoracic cage compliance is affected by diseases
may ensue.
causing chest wall deformity or rigidity; for
Normal tidal breathing starts from the FRC, the rest example, kyphoscoliosis and ankylosing spondylitis
point where inward elastic recoil is equal and opposite respectively.
to the force tending to spring the thoracic cage out- Lung compliance is broadly affected by two
wards. Conveniently, the lungs are at their most factors:
compliant at FRC, which means that the work of The elastic recoil of the lung connective
breathing at rest is minimal: tissue.
For a typical patient at FRC, compliance is 200 The surface tension at the air–fluid interface
mL/cmH2O. in the alveoli.
82
Chapter 19: Lung compliance
Outline some clinical situations in which How does surfactant increase lung
respiratory compliance is increased or compliance?
decreased Surface tension is caused by forces of attraction
between water molecules. The inner surface of the
Respiratory compliance may be affected by both
alveolus has a thin layer of fluid whose surface tension
physiological and pathological factors.
exerts an inward force. Opposing this inward force of
Causes of increased respiratory compliance surface tension is the alveolar transmural pressure. As
include: alveoli are approximately spherical, they obey
– Emphysema, in which there is destruction of Laplace’s law.
lung elastic tissue.
Key equation: Laplace’s law
– Advancing age, in which there is
degeneration of lung elastic tissue, similar For a sphere with only one surface,
to mild emphysema. 2T
P¼
Causes of decreased respiratory compliance r
include: where P is the transmural pressure, T is the surface
– Posture – the lung is generally less compliant tension and r is the radius.
when supine.
– Pregnancy – lung compliance is relatively Surface tension poses a number of problems:
unaffected, but thoracic cage compliance is
reduced in late pregnancy. An alveolus has reduced compliance when
its radius is low. In expiration, the alveolus
– Fluid within the alveoli or lung interstitium –
becomes smaller; that is, its radius
exemplified by pneumonia and
decreases. According to Laplace’s law,
pulmonary oedema (both cardiogenic and
if surface tension is constant, a larger
non-cardiogenic). Owing to the effects of
transmural pressure will be required to
surface tension, fluid-filled alveoli
reinflate the alveolus.
require a much higher transmural
pressure to expand than aerated alveoli Smaller alveoli empty into bigger alveoli. When
do. Consequently, compliance is significantly two connected alveoli are of different sizes,
reduced. the alveolus with the smaller radius will
require a higher transmural pressure to
– Atelectasis – collapsed alveoli (i.e. alveoli
remain inflated than the larger alveolus
with small radius) require a much higher
will. As airway pressure is uniform
transmural pressure than larger alveoli do to
throughout the lung, the smaller alveolus
overcome surface tension forces (see Laplace’s
would collapse, emptying its air into the
law below).
bigger alveolus.
– Pulmonary hypertension, in which
Transudation of interstitial fluid. The inward
the pulmonary capillaries are engorged with
force of surface tension tends to suck fluid from
blood – this hinders alveolar enlargement,
the interstitium into the alveolus. This process is
thus decreasing lung compliance.
called ‘transudation’.
– Pulmonary fibrosis – the lung interstitium
becomes stiff and less easily distensible. These three problems are dealt with through
– Extremes of lung volume – at high lung the presence of pulmonary surfactant. Surfactant is
volume, compliance is reduced because the produced by the type II pneumocytes in the alveolar
elastic fibres are stretched to their limit. At low wall. It is a mixture of phospholipids, of which
lung volume, lung compliance is reduced as a dipalmitoylphosphatyldicholine (DPPC) is the most
result of atelectasis. important, and proteins, particularly the surfactant
– Obesity – thoracic cage compliance is reduced apolipoproteins (SP-A, SP-B, SP-C). Surfactant
due to the increased weight of the chest wall has three main roles, through its action in reducing
opposing thoracic expansion. surface tension:
83
A general decrease in alveolar surface tension.

Surfactant increases global lung compliance, thus time allows, or by instilling artificial surfactant into
the neonate’s lungs.
reducing the work required to expand the lung.
A similar clinical picture is also seen in near-
Stabilization of small alveoli. Surfactant is an drowning: pulmonary surfactant is washed away,
especially elegant solution to the problem of resulting in lungs of low compliance, with areas of
surface tension: it further reduces alveolar surface atelectasis and areas of pulmonary oedema.
tension as the radius of the alveolus decreases.
By varying the surface tension, small alveoli have
a reduced tendency to collapse. What is the difference between static
Prevention of fluid transudation. As the surface
tension forces are generally reduced by surfactant, and dynamic compliance?
less interstitial fluid is sucked into the alveolus. As indicated above, lung compliance is represented by
the gradient of the pressure–volume curve. However,
the gradient of the pressure–volume curve depends
What is the mechanism of this variation on which technique is used for measuring pressure
and volume. Static compliance and dynamic compli-
in surface tension? ance refer to this dependence on how the pressure and
The phospholipids within pulmonary surfactant are volume are measured.
hydrophobic at one end and hydrophilic at the other. Static compliance is determined when pressure
They therefore align over the surface of the liquid on and volume measurements are taken at steady state;
the interior of the alveolus. The intermolecular repul- that is, when there is no gas flow:
sive forces between aligned DPPC molecules act to The patient inspires in 500 mL increments.
oppose the intermolecular attractive forces between In between increments there is a pause – gas flow
water molecules, and so surface tension is reduced. stops and intrapleural pressure is measured using
As the radius of the alveolus is reduced, the DPPC an oesophageal balloon catheter.
molecules are forced closer together, thus increasing
The results are plotted on a pressure–volume
the intermolecular repulsive forces and so further graph (Figure 19.1). Note: the resultant sigmoid-
reducing surface tension. shaped curve represents the combined thoracic
cage and lung compliance.
Clinical relevance: infant respiratory distress
syndrome
In utero, pulmonary surfactant is synthesized from The lung does not expand linearly with increasingly
about 24 weeks’ gestation, stimulated by maternal negative intrapleural pressure. Some key points to
corticosteroid release. However, full lung maturation make about the static compliance curve are:
is not complete until about 35 weeks’ gestation. At low intrapleural pressure, lung volume is low –
Infant respiratory distress syndrome (IRDS), otherwise the pressure–volume curve is flat, so lung
known as hyaline membrane disease, is the condition
compliance is low.
that arises when premature neonates are born with
lungs containing insufficient surfactant. It is the In the normal range of intrapleural pressure
leading cause of death in premature neonates. ( 5 to 10 cmH2O), the pressure–volume
As discussed above, surfactant reduces lung curve is at its steepest; that is, a small change in
compliance, stabilizes small alveoli and prevents transpulmonary pressure results in a large change
fluid transudation. Therefore, in the absence of sur- in lung volume. The lung is therefore at its most
factant, the lungs have low compliance and alveoli compliant at FRC during normal tidal breathing,
become collapsed and fluid filled. Accordingly, IRDS resulting in a low work during tidal inspiration.
is characterized by respiratory distress resulting
At high intrapleural pressure, the pressure–volume
from an increased work of breathing due to poorly
curve flattens out again. Alveoli are already well
compliant lungs, with areas of atelectasis and
inflated and near to their elastic limit – a large
areas of pulmonary oedema. Treatment is either by
administering steroids to the mother before birth to decrease in intrapleural pressure is required
stimulate production of endogenous surfactant, if for a small increase in lung volume; that is,
compliance is low.
84
TLC Gradient = compliance

Expiration
VT
Lung volume (L)
Expiration
Lung volume (L)

FRC
Inspiration Inspiration
RV
FRC
+5 0 –5 –10 –15 –20 –4 –5 –6 –7 –8
Intrapleural pressure (cmH2O) Intrapleural pressure (cmH2O)
Figure 19.1 Static compliance curve. TLC: total lung capacity; VT: tidal volume; FRC: functional residual capacity; RV: residual capacity.
Dynamic compliance is calculated when continuous gas flow is increased. The flow of air through the
pressure and volume measurements are taken through- conducting airways is most rapid, and therefore most
out the respiratory cycle; that is, there is no pause turbulent, at the beginning of inspiration and expir-
between measurements. There are two points in the ation. Consequently, airway resistance is at its greatest
respiratory cycle where gas flow ceases: end-inspiration and compliance at its lowest (and accordingly the
and end-expiration. If these two points are plotted on a pressure–volume curve is at its flattest) at the begin-
pressure–volume graph with a straight line joining ning of inspiration and expiration. Similarly, if the
them, the gradient (i.e. the dynamic compliance) is RR increases but the VT remains the same, inspiration
less than that of the static pressure–volume curve. must occur within a shorter time period. As the
The dynamic compliance is always lower than the static velocity of gas flow increases, airway resistance
compliance. This reduction is due to airway resistance. increases and dynamic compliance falls. Conditions
In fact, the difference between static and dynamic that increase airway resistance (for example, acute
compliance can be used as an indirect measure of the asthma) further decrease the dynamic compliance
flow resistive properties of the airways. (Figure 19.2b).
Static hysteresis is illustrated in Figure 19.1.
Unlike dynamic compliance, static compliance
What is hysteresis? contains no airway resistance element because gas
Hysteresis is the phenomenon whereby a measure- flow ceases during the pauses between measurements.
ment differs depending on whether the value meas- Despite this, the inspiratory and expiratory curves
ured is rising or falling. still display hysteresis; that is, follow different paths.
When lung volume is plotted against intrapleural Static hysteresis is attributed to the viscous resistance
pressure for both inspiration and expiration, the two of the pulmonary surfactant and of the lung paren-
curves follow different courses: a pressure–volume chyma itself.
loop is formed. This loop effect is hysteresis – it is
the result of viscous resistance to changes in lung
volume. The area of the loop represents the amount How does the static compliance curve
of energy expended as heat in overcoming the resist- help to explain regional differences in
ive forces. The phenomenon of hysteresis occurs
when both static and dynamic compliance are lung ventilation?
measured. The lung parenchyma is not uniformly distributed
Dynamic hysteresis is illustrated in Figure 19.2a. from top to bottom. Gravity acts on the lung paren-
The airway resistance increases when the velocity of chyma, resulting in intrapleural pressure being more
85
(a) 10 breaths per minute (b) Acute asthma, 30 breaths per minute
VT Lower dynamic compliance (reduced gradient)

VT
Gradient = dynamic compliance
Wider pressure–
Lung volume (L)
Lung volume (L)

volume loop
High compliance
(steep gradient)
Low compliance (shallow gradient)

FRC FRC
–4 –5 –6 –7 –8 –4 –5 –6 –7 –8 –9
Figure 19.2 Dynamic hysteresis: (a) respiratory rate of 10 bpm; (b) acute asthma with a respiratory rate of 30 bpm.
Volume (L) Figure 19.3 Effect of gravity and

compliance on regional ventilation
Inspiratory curve following a normal tidal inspiration
(3 cmH2O change in intrapleural
pressure).
Change in lung
volume at the
apex
Apex
Change in lung
volume at the
base
Base
+5 0 –3 –6 –10 –13 –15 –20

Intrapleural pressure (cmH2O)
negative at the apex (typically 10 cmH2O), and less Thus, the lung apex is sometimes said to be ‘more
negative at the base (typically 3 cmH2O). Consider aerated’ than the base.
the effect of this regional variation in intrapleural During normal inspiration. During tidal
pressures on static lung compliance (Figure 19.3): breathing, the inspiratory muscles decrease
At the end of tidal expiration (i.e. FRC), intrapleural pressure by 3 cmH2O throughout the
intrapleural pressure is 10 cmH2O at the apex pleural cavity: apical intrapleural pressure
and 3 cmH2O at the base. Therefore, at FRC, the decreases to 13 cmH2O and basal intrapleural
apical alveoli are at near-maximum inflation, pressure decreases to 6 cmH2O. The change in
whereas the basal alveoli are barely inflated at all. pressure results in a much greater volume change
86
at the lung base than at the apex. That is, the lung
base is more compliant (has a steeper pressure– In healthy lungs the lower inflection point of the
static compliance curve is at around 5 cmH2O; that
volume curve gradient) than the apex. Because of
is, approximately the same as the physiological PEEP
the greater increase in volume of the basal alveoli,
generated by the larynx (see Chapter 6). In contrast,
the lung base is said to be better ventilated than diseases that significantly reduce lung compliance
the apex. (for example, ARDS) have a significantly altered
pressure–volume curve. If PEEP is applied to a pres-
Gravity also has an effect on pulmonary blood distri- sure just above the lower inflection point, tidal
bution: the lung base is better perfused than the apex. breathing is shifted to a more compliant part of the
As ventilation and perfusion both increase from top pressure–volume curve and work of breathing is
reduced.
to bottom of the lung, they are said to be matched
In practice this is difficult. Measuring static com-
(see Chapter 14).
pliance in a patient with ARDS (i.e. increasing lung
volume in 500 mL increments with pauses in
Clinical relevance: optimum positive between to allow gas flow to cease and intrapleural
end-expiratory pressure
pressure to be measured) is likely to lead to life-
The static compliance curve (Figure 19.1) can be used threatening hypoxaemia. As discussed above, using
in the intensive care unit to determine the optimum dynamic compliance as a measure of the lower
level of extrinsic PEEP: inflection point is not ideal. In practice, PEEP is
To minimize the work of breathing, tidal increased using clinical judgement, with the intensi-
ventilation should take place on the vist aiming to identify a point where tidal volumes
most compliant (steepest) part of the of 6 mL/kg can be achieved using ‘safe’ peak and
pressure–volume curve. The point of plateau airway pressures.
end-expiration should therefore be above
the lower inflection point.
The point of end-inspiration should be below
the upper inflection point, to avoid lung Further reading
hyperinflation. M. Wild, K. Alagesan. PEEP and CPAP. Contin Educ
Anaesth Crit Care Pain 2001; 1(3): 89–92.
87
Chapter
Work of breathing
20
– Pulmonary fibrosis, which reduces the compliance
What is meant by the term work of of the lung parenchyma.
breathing? – IRDS, in which there is insufficient pulmonary
The work of breathing is the energy consumed by the surfactant, leading to increased alveolar surface
respiratory muscles throughout the respiratory cycle. tension.
Mathematically for a single breath: Resistive work is the work done against friction –
Work (J) ¼ Pressure (Pa) × Volume (L) the energy used is ‘wasted’, as it is dissipated as
heat (and sound). The resistive work of breathing
However, the work of breathing usually refers to the is the work done to overcome:
rate of work rather than the work for a single respira-
tory cycle. It should really be called the power of – Tissue resistance. As the tissues move against
breathing in watts (joules/second). each other during lung inflation and deflation,
Quiet tidal breathing is usually very efficient, frictional forces cause an increase in tissue
requiring relatively little work. The energy required resistance. Tissue resistance usually accounts
for tidal breathing is usually less than 2% of basal for around 10% of the total resistive work.
metabolic rate (BMR). Lung pathology can increase Tissue resistive work is increased by any
the work of breathing substantially, with the potential condition that increases the amount of
for respiratory muscle fatigue and respiratory failure. interstitial lung tissue; for example, pulmonary
fibrosis.
Whatare thetwomain componentsthat – Airway resistance. Gas molecules are
subject to frictional forces when they interact
comprise the work of breathing? with each other, and with the walls of the
The work of breathing is composed of elastic work airways.
and resistive work. In normal lungs, elastic work is
responsible for most (approximately 65%) of the What factors affect airway resistance?
overall work of breathing: The resistance to gas flow is affected by two main
Elastic work is the work done on inspiration to factors: the rate of gas flow and the airway radius.
overcome the elastic forces of the: Rate of gas flow. Turbulent gas flow results in a
– Chest wall (outward). much higher airway resistance than laminar gas
– Lung parenchyma (inward). flow does. During normal tidal breathing, gas
– Alveolar surface tension (inward). flow is usually only turbulent in the trachea, but
may become turbulent in the larger bronchi
The work done against elastic forces is not all wasted. during peak inspiratory flow. If the velocity of
Some is stored as potential energy rather than being gas flow increases (for example, with increasing
dissipated as heat. The stored potential energy is then RR), gas flow becomes turbulent in the
used in expiration (see below). Elastic work is larger bronchi for a greater portion of the
increased by diseases that affect the three factors respiratory cycle, increasing airway resistance.
above; for example: The point at which gas flow changes from
– Obesity, which opposes outward chest wall elastic laminar to turbulent is estimated using the
recoil. Reynolds number.
88
Chapter 20: Work of breathing
Key equation: Reynolds number flow. Heliox, a mixture of He and O2, is

sometimes used in the management of upper
vρd
Reynolds number ¼ airway obstruction: the lower density of heliox
η
reduces Reynolds number, thereby reducing
where v is velocity of gas flow, ρ is the density of gas, turbulent flow.
d is the airway diameter and η is the viscosity of gas. – Deep-sea diving. The barometric pressure of
A Reynolds number of >2000 predicts an 80% air, and therefore its density, increases with
chance of turbulent flow. increasing underwater depth. Because of the
increased air density, Reynolds number
Airway radius. According to the Hagan– predicts turbulent flow at lower gas velocity.
Poiseuille equation, resistance to gas flow is As a result, gas flow becomes turbulent in the
proportional to r4 (r is the radius). Therefore, bronchi even during normal tidal breathing,
small reductions in airway radius can have a large increasing the airway resistance. Again, a
impact on the resistance to flow. mixture of He and O2 is used by divers; the
lower density promotes laminar gas flow,
thereby reducing the work of breathing.
Key equation: Hagen–Poiseuille equation for a tube Factors that reduce airway radius.
_
8Qηl – Bronchoconstriction, as occurs physiologically
ΔP ¼
πr 4 during parasympathetic nervous system
where ΔP is the pressure drop along the tube, Q̇ is activation or pathologically in asthma and
flow, η is the viscosity of the fluid, l is tube length and COPD. The radius of the small airways is
r is the radius. reduced, which increases airway resistance.
Darcy’s law1 states: – Low lung volume. Airway radius increases
_
ΔP ¼ QR during inspiration as a result of radial traction
of the lung parenchyma. Likewise, airway
If ΔP is pressure difference and Q̇ is flow, then the radius decreases during expiration, which
resistance to flow R = 8ηl/πr4.
results in increased airway resistance. This
partially explains why patients with asthma
On the basis of the Hagan–Poiseuille equation, one and COPD have more difficulty with
would expect airway resistance to be highest in the expiration than inspiration.
terminal bronchioles, as these airways have the smallest – Dynamic airway compression. During forced
radius. However, the terminal bronchioles are arranged expiration, the respiratory muscles generate a
in parallel, with a total cross-sectional area much larger positive intrapleural pressure which causes
than that of the more proximal airways. Overall, the compression of airways which lack
main site of airway resistance is between the lobar cartilagenous support, particularly the
bronchi and the subsegmental bronchi. bronchioles, further reducing their airway
Based on the discussion above, airway resistance is radius and thus increasing airway resistance.
increased by: In COPD there is destruction of supportive
Factors that result in turbulent flow. elastic tissue with the lung parenchyma, which
reduces radial traction on the airways, making
– High RR: gas velocity increases, resulting
these patients particularly susceptible to
in turbulent flow in the large bronchi.
dynamic airway compression.
– Upper airway obstruction, as exemplified by
laryngeal oedema or the presence of a foreign
body. The increased velocity of gas flow How can work of breathing be described
around the obstruction results in turbulent
graphically?
As mentioned above, work ¼ pressure × volume.
1
Darcy’s law of flow is analogous to Ohm’s law of Therefore, the work of breathing can be represented
electricity: potential difference ¼ current × resistance. as an area on the pressure–volume graph (Figure 20.1).
89
(a) Inspiration (b) Expiration
VT VT
Inspiration if lungs
were ‘perfect’
Lung volume (L)
Lung volume (L)

X X
(normal lungs) (normal lungs)
Y Z
Expiration if lungs
were ‘perfect’
FRC FRC
–4 –5 –6 –7 –8 –4 –5 –6 –7 –8
Figure 20.1 Pressure–volume curves: (a) normal tidal inspiration; (b) normal tidal expiration.
Pressure–volume loops exhibit hysteresis: the How does this graph change for patients
inspiratory and expiratory curves follow different paths
(see Chapter 19). The area (i.e. pressure × volume) with restrictive or obstructive lung
between the two curves represents the energy expended disease?
in overcoming the resistive forces; that is, the overall In restrictive lung disease, the lung compliance is
work done that is dissipated as heat: reduced. A higher (more negative) intrapleural pres-
During tidal inspiration (Figure 20.1a). sure is required to achieve a VT of 500 mL. The work
– The black dotted diagonal line represents of inspiration is greater, as there is an increase in
inspiration for idealized lungs in which elastic work. Airway resistance is unchanged, so the
resistive forces are absent. In reality, this is not resistive work is the same as in normal lungs. Expir-
the case: the deviation of the black solid line ation remains passive, as the resistive work still lies
from the black dotted line shows how much within the area of potential energy (Figure 20.2a).
resistance there is to lung inflation. In obstructive lung disease, the problem is an
– The triangular area X is the elastic work done, increase in airway resistance. Both inspiratory and
which is stored as potential energy. expiratory work must increase to overcome the add-
– The remaining area Y is the resistive work itional airway resistance. Graphically, this is repre-
done, which is dissipated as heat. sented by a wider pressure–volume loop. If the
During tidal expiration (Figure 20.1b). resistance to gas flow is severe enough, the expiratory
work will exceed the stored potential energy, shown
– The black dotted diagonal line again represents graphically as the expiratory curve bulging to the left.
expiration in the absence of resistive forces. If compliance is also increased (as in COPD), expir-
– The triangular area X is the potential energy ation is no longer passive, requiring active effort by
stored from inspiration that can now be used the expiratory muscles; the shaded area Z is then the
during expiration. active expiratory work of breathing (Figure 20.2b).
– The area Z is the resistive work done during
expiration. Clinical relevance: anaesthesia and airway
– So long as area Z is within area X, the stored resistance
potential energy is sufficient to overcome the General anaesthesia inevitably results in increased
resistive forces of expiration, resulting in resistance to gas flow:
passive expiration. Low lung volume. Loss of respiratory muscle
– At the end of expiration, any potential energy tone, the supine position and loss of physio-
logical PEEP result in low lung volume, and thus
not used for expiration is wasted, as it is
increased airway resistance.
dissipated as heat.
90
Chapter 20: Work of breathing
(a) Restrictive lung disease (b) Obstructive lung disease

Reduced gradient = reduced lung compliance
Normal lungs
VT VT
Active
Normal lungs expiration
Lung volume (L)
Lung volume (L)

Z
Restrictive lung disease

Obstructive lung disease
FRC FRC
–4 –5 –6 –7 –8 –9 –10 –4 –5 –6 –7 –8
Figure 20.2 Pressure–volume loops: (a) restrictive lung disease; (b) obstructive lung disease.
Pharyngeal resistance. In some unintubated Fortunately, airway resistance can be reduced by:
patients, relaxation of the pharyngeal muscles The volatile anaesthetics in current use, which
may result in partial or complete upper are all potent bronchodilators: the radius of the
airway obstruction, increasing the resistance to small airways increases, thus offsetting some of
airflow. the effects of general anaesthesia on lung volume.
Airway devices. To fit within the trachea, Application of extrinsic PEEP, which increases
ETTs necessarily have a smaller radius. lung volume: radial traction increases airway
According to the Hagen–Poiseuille equation, radius, thus reducing airway resistance.
reduced radius significantly increases airway Laryngeal mask airway (LMA). In patients sus-
resistance. ETT radius is especially important for ceptible to pharyngeal collapse, the LMA stents
small children, who are often not permitted to open pharyngeal tissues, thus reducing the
breathe spontaneously when intubated due to resistance to gas flow.
the substantially increased work of breathing.
It is also why critically ill patients should be If a patient is to breathe spontaneously under general
intubated with as wide an ETT as possible, so that anaesthesia, the airway resistance must be minim-
airway resistance is as low as possible for ized as much as possible. LMAs are well designed
weaning. for spontaneous ventilation: they have wide tubing
Anaesthetic circuits. These inevitably cause to minimize resistance to gas flow.
an increase in airway resistance, ranging from
negligible to significant. Corrugated tubing,
angle-pieces and high gas flow rates promote
turbulent flow, whilst heat and moisture
Further reading
A. Carter, S. J. Fletcher, R. Tuffin. The effect of inner
exchangers and adjustable pressure-limiting
tube placement on resistance and work of breathing
valves further increase resistance to
through tracheostomy tubes: a bench test. Anaesthesia
gas flow. 2013; 68(3): 276–82.
Increased inspiratory gas flow. Airway devices
and anaesthetic circuits increase mechanical S. Farrow, C. Farrow, N. Soni. Size matters: choosing the
dead space. To maintain V_ A , V_ E must increase: right tracheal tube. Anaesthesia 2012; 67(8): 815–22.
inspiratory gas flow increases, resulting in an S. H. Loring, M. Garcia-Jacques, A. Malhotra. Pulmonary
increase in turbulent flow. characteristics in COPD and mechanics of increased
work of breathing. J Appl Physiol 2009; 107(1): 309–14.
91
Chapter
Control of ventilation
21
Which anatomical sites are involved The pneumotaxic centre in the upper pons
modifies DRG impulses to reduce the depth of
in the control of ventilation? inspiration, acting to modulate the respiratory
Ventilation is controlled by means of neuronal feed- pattern. The pneumotaxic centre can also increase
back loops. All feedback loops involve sensors, effect- the RR.
ors and a control centre. For ventilation, these are:
Older theories of ventilatory control suggest a model
Sensors – the central and peripheral of reciprocal inhibition between the DRG and VRG,
chemoreceptors.
where the activation of one area results in the inhib-
Control centre – the respiratory nuclei in the ition of another. This is no longer thought to be
brainstem. the case as no evidence exists for the widespread
Effectors – the muscles of respiration. inhibitory action between these centres. The actual
mechanism is complex and remains poorly
understood.
How does the respiratory centre
control ventilation? What are the inputs to the
The respiratory centre has four main anatomical
areas, each with a different function. respiratory centre?
The dorsal respiratory group (DRG) of neurons The major inputs to the respiratory centre are the
in the medulla contains mostly inspiratory peripheral chemoreceptors, central chemoreceptors,
neurons. The DRG primarily controls the mechanoreceptors and bronchial irritant receptors.
diaphragm, and thus is responsible for normal Peripheral chemoreceptors. These are located
tidal inspiration. in the:
The ventral respiratory group (VRG) of neurons – Carotid bodies at the bifurcation of the carotid
contains both inspiratory and expiratory neurons. artery. Their afferent nervous impulses are
The VRG controls the intercostal muscles; its carried by the glossopharyngeal nerve. The
function is to initiate forced expiration and to carotid bodies are the most important of the
increase the force of inspiration. Additionally, the peripheral chemoreceptors.
VRG contains the pre-Bötzinger complex, a – Aortic bodies on the aortic arch. Their afferent
cluster of neurons thought to be the respiratory nervous impulses are carried by the vagus
pacemaker.1 Ablation of this area abolishes nerve.
respiratory drive.
The apneustic centre in the lower pons modifies The peripheral chemoreceptors have a very high
DRG neurons to prevent overexpansion of the blood flow in relation to their weight. They are
lungs. Ablation of this area results in apneusis: stimulated by:
pathologically long, deep breaths. – Low arterial O2 tension (PaO2). The aortic
and carotid bodies are the only chemoreceptors
1
These neurons express hyperpolarization-activated cyclic in the body that respond to hypoxaemia.
nucleotide-gated channels, the same channels as the Note: the peripheral chemoreceptors are
pacemaker cells of the sinoatrial node. stimulated by low arterial O2 tension not low
92
Chapter 21: Control of ventilation
O2 content – anaemia and carbon monoxide – Respiratory acidosis stimulates the central
poisoning do not stimulate the chemoreceptors. chemoreceptors more than metabolic acidosis:
– High arterial CO2 tension (PaCO2). Both aortic CO2 can diffuse across the BBB whereas H+
and carotid bodies are stimulated by ions cannot. However, in profound metabolic
hypercapnoea. The peripheral chemoreceptors acidosis, as exemplified by diabetic ketoacidosis,
are only responsible for 20% of the body’s ventilation is stimulated via the carotid bodies.
response to hypercapnoea, with the central – The cerebral vasodilatation that accompanies
chemoreceptors responsible for the remainder. hypercapnoea enhances the central
However, the peripheral chemoreceptors chemoreceptor mechanism by increasing the
respond the most rapidly, within the order of blood flow to the medulla.
1–3 s. – If hypercapnoea becomes chronic, as occurs
– Acidaemia (pH <7.35). Only the carotid bodies in a subset of COPD patients, the increase in
are stimulated by acidaemia. V_ E ventilation cannot be sustained and returns
– Hypotension. Reduced perfusion of the carotid to near normal. The mechanism behind this is
and aortic bodies increases their neuronal as follows: HCO3 ions are actively secreted
output. This is why an increased RR is seen into the CSF to buffer the change in pH.
during the development of septic shock, even CSF pH returns to normal and the central
when there is no impairment of gas exchange. chemoreceptors are no longer stimulated:
Central chemoreceptors. These are located on the the activity of the respiratory centre is reduced.
ventral surface of the medulla close to, but The kidneys also reabsorb more HCO3 ,
separate from, the VRG neurons. In contrast to which normalizes arterial pH, thus reducing
the peripheral chemoreceptors, central the stimulation of the respiratory centre by
chemoreceptors are solely stimulated by a fall in the carotid bodies. These compensatory
cerebrospinal fluid (CSF) pH. However, because mechanisms result in a loss of sensitivity to
H+ and HCO3 ions cannot cross the blood–brain CO2, causing these patients to rely on
barrier (BBB), changes in plasma pH do not hypoxaemic drive alone. Care must be taken
directly affect ventilation. Instead, the course of when administering O2 to COPD patients with
events is as follows: chronic hypercapnoea, as there is a theoretical
risk that these patients will stop breathing.
– CO2 freely diffuses from the blood into the – Unlike the peripheral chemoreceptors, the
CSF, and then from the CSF into the ECF central chemoreceptors are not stimulated by
surrounding the central chemoreceptors. hypoxaemia. In fact, in the absence of the
– The reaction between CO2 and water (catalysed peripheral chemoreceptors, hypoxaemia
by CA) results in the formation of H2CO3. depresses the respiratory centre.
H2CO3 then dissociates into H+ and HCO3 .
– H+ diffuses into the chemoreceptor tissue, The inputs of the peripheral and central
stimulating the chemoreceptors to activate the chemoreceptors are synergistic. For example,
respiratory centre. The pH of the if hypoxaemia is sensed by the peripheral
chemoreceptor ECF therefore provides an chemoreceptors and hypercapnoea by the
indirect measure of arterial PaCO2. central chemoreceptors, the resulting ventilatory
– Therefore, as PaCO2 increases, the central response is greater than the sum of the two effects.
chemoreceptors are stimulated and V_ E Mechanoreceptors. The contribution that
increases. mechanoreceptors make to the stimulation of
ventilation is controversial.2 Mechanoreceptors
There are a few important points to make that possibly affect the respiratory centre are:
about the central chemoreceptors:
– The CSF protein concentration is much lower 2
It was thought that a number of mechanoreceptors
than plasma, and thus minimal buffering of contributed to the control of ventilation. This has been
CO2 occurs. This makes the CSF more called into question, as denervated transplanted lungs
sensitive to small changes in PCO2 than plasma. have been shown to exhibit a normal ventilatory response.
93
– Lung stretch receptors, located in bronchial – Limbic system. Extreme emotional states
smooth muscle. Overinflation of the lung stimulate the respiratory centre, resulting in
stimulates these stretch receptors, whose hyperventilation.
impulses are conveyed to the apneustic centre – Cerebral cortex. All the other inputs to the
by the vagus nerve, causing a reduction in the respiratory centre can be overridden by
depth of inspiration. This is called the Hering– voluntary thought. However, one cannot
Breuer reflex. breath-hold indefinitely; after a short period of
– Muscle spindles. The ventilatory response to apnoea, chemoreceptor stimulation by
exercise is thought to be initiated by muscle hypoxaemia or hypercapnoea overrides
spindle activity. voluntary control, known as the
Other factors. The respiratory centre also receives ‘break-point’.
other inputs from the PNS and CNS:
– Juxtacapillary receptors (J-receptors). These
are non-myelinated C-fibres in the alveolar
Summarize the ventilatory response
walls. Activation causes an increase in to hypoxaemia
ventilation, a feeling of dyspnoea, bradycardia When PaO2 falls below 8 kPa, the peripheral
and hypotension. It is thought that J-receptors chemoreceptors rapidly stimulate the respiratory
are stimulated by pulmonary oedema and centre, which significantly increases V_ E (Figure 21.1).
pulmonary emboli. This ventilatory response is further augmented in
– Irritant receptors. Located in the airway the presence of hypercapnoea. However, severe pro-
epithelium, these cause bronchoconstriction longed hypoxaemia has a depressive effect on the
and stimulate ventilation in the presence of respiratory centre, causing apnoea.
noxious gases.
– Pain receptors. Activation of pain receptors
stimulates ventilation. Summarize the ventilatory response
– Thalamus. An increase in core body to hypercapnoea
temperature stimulates ventilation. The respiratory centre is stimulated by:
Figure 21.1 Ventilatory response to

hypoxaemia.
20
Enhanced ventilatory
15
response to hypoxaemia
Hypercapnoea (PaCO2= 8 kPa)

10
Normocapnoea (PaCO2= 5.3 kPa)

5
Dramatic increase
in ventilation at
PaO2= 8 kPa
0
0 5 8 10 15 20
PaO2 (kPa)
94
Chapter 21: Control of ventilation
Figure 21.2 Ventilatory response to

Normal ventilatory response Respiratory depression hypercapnoea.
30 at high PaCO2
Linear response
20 between 5 and 10 kPa
Blunted ventilatory response:

10 rightward shift of the curve with
anaesthetic agents and opioids
0
0 5 10 15
PaCO2 (kPa)
High PaCO2, which activates both peripheral

chemoreceptors. Opioids have no effect on the response of the
peripheral or central chemoreceptors to hypox-
Low arterial pH, which activates the carotid aemia or hypercapnoea. In contrast, opioids have
bodies. a significant depressant effect on the medullary
High CSF PCO2, leading to low central respiratory centre. Thus, the ventilatory response
chemoreceptor ECF pH, which activates the to hypoxaemia and hypercapnoea is blunted,
central chemoreceptors. with the CO2 response curve shifted to the right
(Figure 21.2).
The response of ventilation to CO2 is linear within The respiratory stimulant doxapram acts at the
normal clinical limits (PaCO2 5–10 kPa), but experi- peripheral chemoreceptors, but the mechanism
ments in animals have shown that V_ E reduces with involved is unclear.
profound hypercapnoea (Figure 21.2).
Clinical relevance: drugs and control of ventilation Further reading

All anaesthetic agents have a depressant effect on H. V. Forster, C. A. Smith. Contributions of central
both the respiratory centre and the peripheral and peripheral chemoreceptors to the ventilatory
chemoreceptors, leading to reduced ventilatory response to CO2/H+. J Appl Physiol 2010; 108(4):
response to both hypercapnoea and hypoxaemia. 989–94.
Graphically, anaesthetic agents shift the CO2
K. T. S. Pattinson. Opioids and the control of respiration.
response curve to the right (Figure 21.2).
Br J Anaesth 2008; 100(6): 747–58.
95
Chapter
Pulmonary circulation
22
What are the unique features of the despite the loss of the bronchial artery, the bron-
chial circulation had been considered to be un-
pulmonary circulation? necessary. However, a subset of lung transplant
Many features of the pulmonary circulation are patients develop an ischaemic bronchiolitis obli-
very different to those of the systemic circulation. terans, thought to be due to loss of the bronchial
The pulmonary circulation is a low-pressure, low- circulation. There is currently a trend towards direct
resistance circulation: a blood flow of 5 L/min bronchial artery revascularization to overcome this
problem.
(i.e. 100% of CO) is achieved with a driving pres-
sure (i.e. MPAP) of only 15 mmHg.
The anatomy of the pulmonary circulation is not
entirely straightforward. Why is the pressure within the
As may be expected, there are two pulmonary pulmonary circulation low?
arteries: one for each lung. In contrast, there are at Unlike the systemic circulation, the pulmonary circu-
least four pulmonary veins: two arising from lation does not need to direct blood flow from one
each lung. region to another, with the exception of the property
Initially, the arteries, veins and bronchi run in of HPV (see later). Therefore, pulmonary arterial
close proximity to each other, dividing at the same pressure only needs to be high enough to propel
points. In the periphery of the lung, the vessels blood to the lung apices.
separate: the veins pass between lung lobules The pulmonary capillaries are unique – they are
whilst the arteries and bronchi travel together to almost entirely surrounded by alveolar gas. They
the centre of the lobules. are also very fragile with little connective tissue, and
The pulmonary capillaries are fragile and very are therefore prone to distension or collapse. Transu-
narrow (diameter 7–10 µm), just wide enough for dation of fluid from the pulmonary capillary to the
RBCs to squeeze through. alveolus (i.e. pulmonary oedema) is dependent in part1
The conducting airways of the lung also have on the transmural pressure, given by the difference
their own blood supply, called the bronchial in pressures between the capillary and the alveolus. As
circulation. Some of the deoxygenated alveolar pressure is very low, having a low-pressure
blood is carried away by the pulmonary pulmonary capillary is essential if pulmonary oedema
veins, where it mixes with oxygenated blood is to be avoided.
and enters the systemic circulation. This is
one of the causes of anatomical shunt
(see Chapter 13). How do the pulmonary and systemic
vascular resistances compare?
Clinical relevance: lung transplantation and the The pulmonary circulation is a low resistance circula-
bronchial circulation
tion. PVR can be calculated as follows:
Historically, during lung transplant surgery, despite
the fact that the bronchial arteries normally
receive 3–5% of CO, the donor bronchial artery was
1
not re-anastomosed. Because most grafts survived Pulmonary surfactant also contributes to the prevention
of fluid transudation.
96
Chapter 22: Pulmonary circulation
Key equation: Darcy’s law MAP

mean right atrial pressure
SVR ¼ 80 ×
This is akin to Ohm’s law in an electrical circuit: CO
100 2
Potential difference ¼ current × resistance, V ¼ IR ) SVR ¼ 80 × ¼ 1568 dyn s cm 5
5
Similarly, for the vascular system:
Pressure difference across vascular system ¼ total Likewise, calculating PVR with typical values
flow × vascular resistance (MPAP ¼ 15 mmHg, PCWP ¼ 5 mmHg, CO ¼ 5
pressure difference L/min):
) vascular resistance ¼
total flow
MPAP PCWP
Therefore: PVR ¼ 80 ×
CO
MPAP PCWP 15 5 5
PVR ¼ 80 × ) PVR ¼ 80 × ¼ 160 dyn s cm
CO 5
Similarly: PVR is approximately one-tenth of SVR. Note that all
MAP mean right atrial pressure values required to calculate SVR and PVR (with the
SVR ≈ 80 × exception of MAP) can be measured with a PAC.
CO
where MPAP (mmHg) is the mean pulmonary artery
pressure, PCWP (mmHg) is the pulmonary capillary
wedge pressure, MAP (mmHg) is the mean arterial
Which factors affect pulmonary vascular
pressure (MAP), SVR (dyn s cm 5) is the systemic resistance?
vascular resistance (SVR), PVR (dyn s cm 5) is the PVR is affected by three main factors:
pulmonary vascular resistance, CO (L/min) is the car-
diac output and 80 is a constant related to unit
Pulmonary artery pressure. Increased MPAP
conversion. results in a significant reduction in PVR
(Figure 22.1). This is the result of two
mechanisms:
Calculating SVR using typical values (MAP ¼ 100 – Recruitment, where collapsed pulmonary
mmHg, mean right atrial pressure is 2 mmHg and capillaries are reopened. This is the most
CO ¼ 5 L/min): important mechanism at low MPAP.
Figure 22.1 Relationship between PVR
and MPAP.
200
Pulmonary vascular resistance (dyn s cm–5)
160
150
100
50
0
10 15 20 25 30
Mean pulmonary arterial pressure (mmHg)
97
– Distension, where open pulmonary capillaries – At high lung volume, PVR increases primarily
are further distended. This is the most as a result of resistance to blood flow within
important mechanism at high MPAP. the alveolar capillaries; these capillaries are
stretched and distorted, which significantly
During exercise, despite a large increase in CO, increases their resistance to flow. The extra-
MPAP only rises moderately due to the recruit- alveolar vessels contribute little resistance to
ment and distension of pulmonary capillaries and blood flow as lung volume increases; the
the corresponding fall in PVR. However, there is a radius of the vessels increases by radial
limit to recruitment and distension of the pulmon- traction, thereby reducing resistance to
ary capillaries. In racehorses, this limit is reached blood flow.
at moderate exercise – severe exercise can lead to – At low lung volumes, PVR is high primarily as a
very high MPAP and pulmonary haemorrhage can result of resistance to flow within the extra-
result. Fortunately, this is not common in humans. alveolar vessels; these vessels are very narrow
Lung volumes. Functionally, there are two types and offer high resistance to flow.
of pulmonary blood vessels: HPV. The response of the pulmonary circulation
– Alveolar capillaries, which have little to hypoxia is unique. In the systemic circulation,
connective tissue and are compressed when tissue hypoxia causes vasodilatation of
subjected to raised alveolar pressure. neighbouring blood vessels, so that local perfusion
– Extra-alveolar vessels, which are not exposed to is matched to local metabolism. In contrast, the
alveolar pressure and can be pulled open by radial pulmonary vessels vasoconstrict in response to
traction of the surrounding lung parenchyma. low alveolar O2 tension (PAO2 < 8 kPa). This is a
useful physiological mechanism: vasoconstriction
The changes in the shape of alveolar and extra- of the pulmonary arterioles adjacent to hypoxic
alveolar vessels account for the changes in PVR at alveoli increases local vascular resistance, thus
different lung volumes (Figure 22.2): redirecting blood flow to better ventilated areas
– At FRC, PVR is at its lowest. This is a useful piece of the lung. While the pulmonary arterioles are
of design: tidal breathing takes place around the main site of vasoconstriction, venoconstriction
FRC and PVR is therefore low for the majority of small pulmonary venules also contributes to
of the time, reducing right ventricular workload. HPV (albeit to a lesser degree). The response
Figure 22.2 Relationship between PVR

and lung volume.
Total pulmonary
Pulmonary vascular resistance (dyn s cm–5)
vascular resistance
Alveolar vessels
Extra-alveolar vessels
RV FRC TLC
Lung volume (L)
98
of HPV to low PAO2 is rapid, occurring within High altitude. Low PB results in alveolar
seconds; pulmonary lobar blood flow can halve hypoxia throughout the lungs. The result is
within minutes. When alveolar hypoxia is generalized pulmonary vasoconstriction and
prolonged, there is a second phase of slow, venoconstriction; pulmonary venoconstriction
sustained pulmonary vasoconstriction. is implicated in the development of high-altitude
The exact mechanism for HPV is not fully pulmonary oedema (see Chapter 81).
established: Upper lobe diversion in cardiogenic pulmonary
– The main determinant of HPV is low alveolar oedema. In left ventricular failure (LVF), left
PO2, but low mixed venous PO2 contributes ventricular end-diastolic pressure (LVEDP) and
around a fifth of the response. pulmonary venous pressure are raised. Owing
– HPV continues to operate in denervated lungs to the effect of gravity, pulmonary venous
(i.e. following lung transplantation), so is not pressure is greater at the lung bases than the
extrinsically (neurally) mediated. apices; the greater pressure results in transudation
– The factors thought most likely to mediate of fluid across the alveolar–capillary barrier
HPV are: (i.e. pulmonary oedema). The basal alveoli
become hypoxic: HPV diverts blood to the
▪ NO, a potent pulmonary arteriolar better ventilated apices.
vasodilator that is synthesized in the
pulmonary endothelium when PAO2 is Whilst HPV is primarily the result of alveolar hyp-
>9.3 kPa. Alveolar hypoxia decreases the oxia, some pulmonary vasoconstriction occurs in
amount of NO produced, resulting in response to arterial hypoxaemia. Some patients with
arteriolar vasoconstriction. arterial hypoxaemia secondary to chronic lung disease
▪ O2-sensitive potassium channels, which are (for example, pulmonary fibrosis and COPD) develop
stimulated by alveolar hypoxia, leading to a pulmonary arterial hypertension, which is thought
depolarization of the arteriolar membrane to be due to widespread HPV. The resulting pulmon-
potential. Ca2+ channels are opened, ary hypertension can lead to right ventricular failure
resulting in arteriolar vasoconstriction. (RVF), known as cor pulmonale.
HPV is modified by various factors. It is enhan-
ced by:
Give some examples of hypoxic acidosis
pulmonary vasoconstriction in hypercapnoea.
clinical practice HPV is reduced by:
HPV plays a key role in a number of physiological
alkalosis
and pathological situations:
hypocapnoea
The fetal circulation. In utero, the fetal lungs
vasodilators – nitrates, sodium nitroprusside, NO
have yet to expand: PAO2 is zero, and HPV
bronchodilators
causes widespread pulmonary vasoconstriction.
The resulting high PVR means that only 10% of volatile anaesthetic agents.
the fetal CO passes through the fetal lungs, with
blood instead being redirected through the
ductus arteriosus. At the first breath, O2 enters Clinical relevance: hypoxic pulmonary
the alveoli; PVR decreases dramatically, vasoconstriction and the anaesthetist
resulting in an increase in pulmonary By diverting blood away from hypoxic alveoli, HPV
blood flow. reduces V̇ /Q̇ mismatch. Therefore, if HPV is inhibited,
V̇ /Q̇ mismatch and hypoxaemia may result.
Pneumonia. HPV increases the PVR of the HPV is inhibited by volatile anaesthetics. In a
arterioles in the vicinity of hypoxic alveoli, which patient with pneumonia, intraoperative inhibition
directs blood to better ventilated alveoli, thereby of HPV by volatile anaesthetic agents may cause a
reducing V̇ /Q̇ mismatch.
99
significant shunt, resulting in hypoxaemia. Fortunately, In this eventuality, continuous positive airways
significant inhibition of HPV only occurs with the pressure can be applied to the non-dependent
commonly used volatile anaesthetics above 1 MAC lung at the same pressure as PEEP is applied
(minimum alveolar concentration). N2O has little to the dependent lung (for example, 5 cmH2O).
effect on HPV and intravenous agents have no effect. This increases the PVR of the non-dependent
HPV is important in one-lung anaesthesia. With- lung, diverting blood back to the dependent
out HPV, one-lung ventilation would result in a lung. The only problem with this strategy
significant V̇ /Q̇ mismatch. HPV redirects blood from is that the volume of the non-dependent
the unventilated lung to the ventilated lung, lung increases, which may hinder the surgeon
minimizing hypoxaemia. (but arguably less than returning to two-lung
ventilation!).
Bizarrely, patients with ‘normal’ lungs (i.e. good pre-

Clinical relevance: positive end-expiratory operative spirometry) are more likely to develop hyp-
pressure, pulmonary vascular resistance and oxaemia with one-lung ventilation than patients with
one-lung ventilation poorer lung function; for example, those with COPD.
PEEP and positive-pressure ventilation both increase The reason for this paradox is not proven with any
alveolar pressure, leading to compression of alveolar certainty, but it is likely that gas trapping in patients
capillaries, and therefore higher PVR. This can be an with COPD causes intrinsic PEEP, which increases the
issue in one-lung ventilation: volume of the dependent lung, reducing atelectasis
In the lateral position, the weight of the medias- and improving V̇ /Q̇ matching.
tinum and non-dependent (upper) lung tends to
reduce the volume of the ventilated dependent
(lower) lung. Atelectasis is more common at low
lung volumes, leading to V̇ /Q̇ mismatch and
Describe the changes in pressure
hypoxaemia. waveform seen when ‘floating’ a
To counteract this, many anaesthetists apply
PEEP to the dependent lung to prevent atelecta-
balloon-tipped pulmonary artery
sis. However, if too much PEEP is applied, the PVR catheter
of the dependent lung can increase – blood is The flow-directed balloon-tipped PAC (also known as
diverted to the non-dependent lung, which the Swan–Ganz catheter) has many uses:
increases V̇ /Q̇ mismatch and worsens
hypoxaemia. Diagnostic; for example, pulmonary hypertension
and ARDS.
Figure 22.3 Characteristic pressure

(a) (b) (c) (d) waveforms as a pulmonary artery catheter
is advanced (RA: right atrium; RV: right
25
ventricle; PA: pulmonary artery).
20
Pressure (mmHg)
15 PCWP
10
0
RA RV PA Branch of
Location of catheter tip pulmonary artery
100
Measurement of haemodynamic parameters; for Once the PAC has been inserted as far as the right
example, CO and mixed venous O2 saturation. ventricle (Figure 22.3b) (about 20 cm), the balloon
Therapeutic; for example, aspiration of air emboli. is inflated. The tip of the PAC is guided by the flow
of blood through the pulmonary valve and into a
Despite its wide applicability in critical illness, the use pulmonary artery (Figure 22.3c), until it wedges in a
of the Swan–Ganz catheter has declined in recent branch of the pulmonary artery (Figure 22.3d), giving
years: in the general adult intensive care population, the PCWP.
using a PAC has not been shown to reduce mortality.
In addition, the PAC is associated with several serious
complications:
Further reading
K. Nowak, M. Kamler, M. Bock, et al. Bronchial artery
line infection revascularization affects graft recovery after lung
cardiac arrhythmias transplantation. Am J Respir Crit Care Med 2002; 165(2):
pulmonary infarction 216–20.
pulmonary artery rupture. J. Eastwood, R. Mahajan. One-lung anaesthesia. Contin
Educ Anaesth Crit Care Pain 2002; 2(3): 83–7.
The PAC has a length of 150 cm and is usually R. Naeije, S. Brimioulle. Physiology in medicine:
inserted through a sheath in the right internal jugular importance of hypoxic pulmonary vasoconstriction in
vein. The pressure at the tip of the PAC is transduced maintaining arterial oxygenation during acute
and used to identify the tip’s location (Figure 22.3). respiratory failure. Crit Care 2001; 5(2): 67–71.
101
Chapter
Oxygen toxicity
23
and hydroxyl free radicals (OH•): these are collect-
What is oxygen toxicity? ively known as reactive oxygen species (ROS). ROS
Breathing O2 at high partial pressure can have harm- are also generated when cells are exposed to ionizing
ful effects on the body. Many organ systems can be radiation. O2 toxicity is thought to be due to the
affected by O2 toxicity, but the most common are: harmful effects of ROS on nucleic acids, fatty acids,
The CNS, causing seizures and unconsciousness amino acids and sulphydryl-containing enzymes.
when breathing hyperbaric O2, which is of
obvious importance for divers. CNS toxicity is
known as the Paul Bert effect. Is there a natural antioxidant system in
The lungs, causing bronchopulmonary dysplasia the body?
in premature neonates, whilst older children and Antioxidants can be either exogenous or endogenous.
adults develop absorption atelectasis and ARDS. Exogenous antioxidants are obtained from the diet,
Lung toxicity is known as the Lorraine Smith and include ascorbic acid (vitamin C). The body
effect. has many endogenous antioxidant systems to protect
The retina, leading to retrolental fibroplasia against oxidative stress. The most important are
in neonates, also known as the retinopathy of the glutathione, catalase and superoxide dismutase
prematurity. systems. However, at times of oxidative stress, these
systems are overwhelmed by ROS, leading to cell
What is the mechanism of oxygen damage.
toxicity? Does the body make any use of reactive

Toxicity is due to the unique structure of the O2
molecule. The O2 molecule is made up of two oxygen oxygen species?
atoms, each with an unpaired electron in its outer Despite their potential toxicity, ROS are also essential
shell. It is these unpaired electrons that give O2 its to the normal function of the body:
property of paramagnetism. Molecules containing Neutrophils and macrophages kill phagocytosed
unpaired electrons, or free radicals, are usually highly bacteria by synthesizing and secreting ROS into
reactive. Fortunately, the unpaired electrons of the O2 the phagosome. The consumption of O2 during
molecule are fairly unreactive, requiring metal ions this process is called the respiratory burst.
(such as those found in metalloproteins) to help Thyroid follicular cells synthesize H2O2, which is
the O2 molecule accept electrons. This is of particular used to oxidize iodine anions (I ) to iodine (I2)
importance in the electron transport chain, where elec- (see Chapter 76).
trons are transferred to O2 molecules, mediated by the
copper-containing cytochrome c oxidase (Complex IV),
to form water molecules. How much oxygen is harmful?
The reduction of O2 to 2H2O requires four elec- Inspired O2 below 50 kPa (an inspired fraction of O2
trons: O2 molecules accept one electron at a time, FiO2 of 50% at atmospheric pressure) is considered
passing through a number of oxidation states along to be safe. The risk of O2 toxicity increases as
the way. Known intermediate molecules are the the inspired partial pressure of O2 increases and the
superoxide anion (O2• ), hydrogen peroxide (H2O2) duration of exposure increases.
102
Chapter 23: Oxygen toxicity
Divers are particularly susceptible to CNS toxicity, who have received bleomycin who subsequently require
due to the breathing of gases at hyperbaric pressures, supplemental O2 (for example, owing to pneumonia
and due to the consequences of losing consciousness or general anaesthesia) appear to be at increased risk
underwater. To minimize the risk of O2 toxicity, divers of a rapidly developing life-threatening pulmonary
calculate their maximum O2 exposure times based on fibrosis. Because of this, patients who have been
the depth of the dive and the total time underwater. treated with bleomycin carry an alert card – O2
administration should be avoided if possible, and
Clinical relevance: intensive care and oxygenation if O2 is absolutely necessary, it should be titrated to
Studies have shown evidence of a reduction in pul- an SaO2 of 88–92%.
monary function in healthy volunteers following 24 h The connection between bleomycin and O2-
of exposure to 100% O2, whilst at 48 h some evi- induced lung injury is controversial, and the mechan-
dence of early ARDS has been shown. However, there ism of the bleomycin-induced lung toxicity is not
is a significant variability in the length of exposure completely resolved. However, it is known that bleo-
and FiO2 required to develop toxicity between
mycin acts by chelating iron. The bleomycin–iron
patients.
Most intensive care guidelines recommend keep- complex reacts with O2, resulting in ROS (superoxide
ing the FiO2 below 50% where possible. If higher FiO2 and hydroxide) which cleave DNA. It is certainly
is required, the time that the patient is exposed possible that administration of O2 results in an excess
should be minimized. However, in the hypoxaemic of ROS, which overwhelm the body’s protective
patient, high inspired concentrations of O2 should mechanisms.
never be withheld for fear of O2 toxicity.
Further reading
N. Allan, C. Siller, A. Breen. Anaesthetic implications
of chemotherapy. Contin Educ Anaesth Crit Care Pain
What is the connection between 2012; 12(2): 52–6.
bleomycin and oxygen toxicity? R. Taneja, R. S. Vaughan. Oxygen. Contin Educ Anaesth
Bleomycin is a chemotherapy drug used in the treatment Crit Care Pain 2001; 1(4): 104–7.
of Hodgkin’s lymphoma and testicular carcinoma. The I. Fridovich. Oxygen toxicity: a radical explanation. J Exp
most serious side effect of bleomycin is pulmonary Biol 1998; 201(8): 1203–9.
fibrosis, which usually occurs within the first 6 months D. D. Mathes. Bleomycin and hyperoxia exposure in the
of treatment. Of concern to anaesthetists is that patients operating room. Anesth Analg 1995; 81(3): 624–9.
103
Chapter
Ventilatory failure
24
The term ventilation can be confusing. As discussed
What is meant by the term ‘respiratory in Chapter 10, ventilation may refer to:
failure’? Minute ventilation V_ E , the total gas inspired per
Respiratory failure occurs when the respiratory minute:
system fails in one or both of its main functions;
namely, the oxygenation of blood and the elimi- V_ E ¼ V T × RR
nation of CO2. Respiratory failure is categorized Dead-space ventilation V_ D , the volume of gas
as ‘type 1’ and ‘type 2’ on the basis of blood gas per minute that is inspired, but does not take part
analysis: in gas exchange:
Type 1 respiratory failure is defined as a
PaO2 < 8.0 kPa with a normal or low PaCO2. V_ D ¼ dead space ðV D Þ × RR
Type 2 respiratory failure is defined as a PaCO2 Alveolar ventilation V_ A , the volume of gas per
> 6.0 kPa. Type 2 respiratory failure is also minute that reaches perfused alveoli and
frequently accompanied by hypoxaemia. participates in gas exchange:
V_ A ¼ ðV T V D Þ × RR
What is the difference between Importantly, V_A facilitates the diffusion of
oxygenation and ventilation? CO2 from the pulmonary capillaries to the alveoli:
The respiratory system can be considered as two V_A (and not V_ E ) is inversely proportional to
parts: a gas-exchange system and a ‘bellows’. PaCO2 (see Chapter 10). Failure of alveolar
ventilation leads to increased PaCO2; that is,
The gas-exchange system is made up of:
type 2 respiratory failure.
– alveolar–capillary units
– pulmonary circulation.
Which pathophysiological processes
The gas-exchange system is responsible for
oxygenation; deficiency leads to hypoxaemia and cause type 2 respiratory failure?
type 1 respiratory failure. Type 2 respiratory failure is defined as PaCO2 >
The bellows system is made up of: 6 kPa. Normally, ventilation is controlled by a
negative-feedback mechanism:
– chest wall and pleura
– respiratory muscles A rise in PaCO2 stimulates the respiratory centre
– airways in the medulla oblongata via the peripheral and
central chemoreceptors (see Chapter 21).
– nerves
– respiratory centre. The respiratory centre sends excitatory impulses
to the respiratory muscles to increase the rate and
The bellows system is responsible for depth of inspiration.
ventilation: moving air from the atmosphere V_ E and V_ A both increase.
to the alveoli on inspiration, and from the Owing to the inverse relationship between PaCO2
alveoli to the atmosphere on expiration. and V_ A , PaCO2 decreases.
104
Chapter 24: Ventilatory failure
In health, this system is very sensitive: PaCO2 is decreases, resulting in hypercapnoea (i.e. type 2
kept within tight limits. If PaCO2 rises above 6 kPa, respiratory failure). In addition, the small inspira-
V_ A must be inadequate – one of the components of tory volumes cause microatelectasis, which decreases
ventilation must be malfunctioning: lung compliance and further increases the work of
Failure of the respiratory centre to respond breathing. This situation can be worsened if there is
appropriately. This may be due to: an associated pneumonia or aspiration due to poor
cough and secretion clearance, leading to a V_ =Q_
– Respiratory centre depression by opioids or
mismatch, which causes hypoxaemia in addition to
general anaesthesia.
hypercapnoea.
– Reflex desensitization of the respiratory centre
to high PaCO2, to prevent respiratory muscle
fatigue (for example, patients with COPD who
develop chronic hypercapnoea – see below). Describe how patients with stable
A problem with chest wall movement. This chronic obstructive pulmonary disease
could be: develop chronic hypercapnoea
– Mechanical; for example, flail chest. COPD is characterized by small airway obstruction
– Neuropathic; for example, GBS. and destruction of lung elastic tissue, leading to
– Muscular; for example, myopathies. chest hyperinflation. Hyperinflation has adverse
Respiratory muscle fatigue. Fatigue occurs when consequences:
the respiratory muscles cannot synthesize Diaphragmatic flattening, which puts the
sufficient ATP to meet the demands of muscle diaphragm at a mechanical disadvantage. During
contraction. High inspiratory work of breathing, inspiration, the diaphragm must contract with a
as might result from increased airway resistance in greater force to generate the same negative
an exacerbation of COPD, can cause inspiratory intrapleural pressure as a normal patient.
muscles fatigue: the muscles can no longer Increased anterior–posterior diameter of the
generate an intrapleural pressure sufficient to thoracic cage, which results in an increased
maintain V_ A , despite an intact respiratory drive fibre length of the intercostal muscles. The
and chest wall. sarcomere overlap is no longer ideal, so
Very rarely, a high PaCO2 may be the result of a intercostal muscle contraction requires more
hypermetabolic process; for example, malignant energy to generate the same chest wall
hyperpyrexia. movement as a normal patient.
Patients with chronic stable COPD therefore have
Describe how a patient with myasthenia increased inspiratory work of breathing compared
with normal patients.
gravis may develop respiratory failure A subset of COPD patients develops chronic
Myasthenia gravis (MG) is an autoimmune disease hypercapnoea. The mechanism behind this is not
resulting in the destruction of post-synaptic nicotinic entirely clear. What is known is that:
ACh receptors at the NMJ (see Chapter 50). Clinic- most patients with chronic hypercapnoea can
ally, this results in weakness of voluntary muscle with bring their PaCO2 back down to normal levels
characteristic fatigability. The muscles groups most through voluntary hyperventilation;
commonly affected are ocular, facial, bulbar and these patients start to develop respiratory muscle
limb. Respiratory muscles are usually only mildly fatigue after a few minutes of voluntary
affected. hyperventilation.
During a myasthenic crisis, the respiratory
muscles may become profoundly weak. The inspira- It is likely, therefore, that these patients’ respiratory
tory muscles become too weak to maintain normal centres have ‘chosen’ to hypoventilate, rather than
VT and breathing becomes shallow and rapid. ventilating to achieve a normal PaCO2 and risking
Shallow breathing is particularly ineffective as dead respiratory muscle fatigue. This is known as reflex
space makes up a higher proportion of V_ E : V_ A desensitization of the respiratory centre.
105
Clinical relevance: exacerbation of chronic

PEEPe is applied to offset PEEPi and dynamic
obstructive pulmonary disease
hyperinflation, thereby reducing the work
An exacerbation of COPD is defined as an acute of inspiration;
change in a COPD patient’s dyspnoea, cough and/ pressure support helps to overcome the
or sputum that is beyond normal day-to-day vari- increased inspiratory airway resistance, restoring
ations. Exacerbations are commonly infective in VT to normal.
origin, but also have a number of other causes,
including atmospheric pollution. The use of non-invasive ventilation in the man-
During COPD exacerbations, there is a significant agement of COPD exacerbations has been shown to
increase in the resistive and elastic work of breathing. reduce the need for invasive ventilation. Intensive
During expiration, dynamic airway obstruction results care complications are reduced, as are the length of
in PEEPi, which must then be overcome on the intensive care and hospital stay.
next inspiration, causing further inspiratory work. As
discussed above, patients with COPD, especially
those who have chronic hypercapnoea, are very Further reading
susceptible to respiratory muscle fatigue. Owing to S. Mehta. Neuromuscular disease causing acute respiratory
the high inspiratory work during exacerbations, failure. Respir Care 2006; 51(9): 1016–23.
the metabolic demand of the respiratory muscles C. Roussos, A. Koutsoukou. Respiratory failure. Eur Respir J
cannot be met – V_A decreases and PaCO2 rises. 2003; 22(Suppl. 47): 3s–14s.
Decreased V_A and high inspiratory workload may
be overcome by respiratory support – either invasive M. Thavasothy, N. Hirsch. Myasthenia gravis. Contin Educ
or non-invasive ventilation. Non-invasive ventilation Anaesth Crit Care Pain 2002; 2(3): 88–90.
acts in two ways: M. J. Garfield. Non-invasive ventilation. Contin Educ
106
Chapter
Anaesthesia and the lung
25
Other drugs commonly used in anaesthesia with
What effects do anaesthetic drugs have effects on the respiratory system are:
on the respiratory system? Opioids, causing:
Many of the drugs used by anaesthetists have effects
– Depression of the respiratory centre, resulting
on the medullary respiratory centre, the peripheral
in a reduced RR and blunting of the
chemoreceptors and the airways. Their effects are
ventilatory response to hypercapnoea.
most easily classified by drug class:
– Antitussive action, depressing the cough reflex.
Volatile anaesthetic agents. The inhalational – Histamine release (with morphine), which may
agents have dose-dependent effects on the
precipitate bronchospasm in susceptible
respiratory system:
patients.
– An increase in RR, but with reduced VT. – Rarely, chest wall rigidity (wooden chest
– Blunted ventilatory response to hypercapnoea, syndrome) following the rapid intravenous
the extent of which varies between volatile injection of strong opioids, which can interfere
agents: enflurane > desflurane > isoflurane > with ventilation.
sevoflurane > halothane. The exceptions are Benzodiazepines cause depression of the
N2O (which has no effect), and ether (which respiratory centre, resulting in a decrease in RR
may increase V_ E ). and blunting of the ventilatory response to
Intravenous anaesthetic agents. hypercapnoea.
– Initial respiratory stimulation. Following Depolarizing and non-depolarizing muscle
induction of general anaesthesia, there is a relaxants. The most obvious effect of the muscle
brief period of respiratory stimulation relaxants on the respiratory system is respiratory
producing increased VT and RR. muscle paralysis necessitating mechanical
– Subsequent respiratory depression. Respiratory ventilation. Adequate reversal of neuromuscular
stimulation is followed by abrupt respiratory blockade is required to prevent postoperative
centre depression. VT falls and apnoea may respiratory failure. Other respiratory effects
occur, especially if using propofol. specific to particular agents are:
– Depression of protective airway reflexes. This is – atracurium may cause histamine release,
used to the anaesthetist’s advantage: depression resulting in bronchospasm;
of laryngeal reflexes allows the insertion of – suxamethonium and mivacurium may cause
an LMA. prolonged respiratory muscle weakness in
– Specific to certain drugs: patients with reduced levels of plasma
cholinesterase (suxamethonium apnoea).
▪ propofol is thought to abolish the
peripheral chemoreceptor response to Non-steroidal anti-inflammatory drugs
hypoxaemia; (NSAIDs) may precipitate bronchospasm in
▪ ketamine differs from the other intravenous susceptible asthmatics.
agents – in addition to its cardiovascular Local anaesthetics used in neuraxial blockade.
stability, ketamine preserves airway reflexes During spinal anaesthesia, intrathecal local
and spontaneous ventilation. anaesthetic may rise high enough to cause
107
weakness of the intercostal muscles. This Lung volumes. At induction of general

occurs most commonly in obstetric anaesthesia, anaesthesia, FRC (the essential store of O2
where sensory levels of T2 to T4 are typical. during apnoea) is inevitably reduced due to:
The diaphragm is unaffected (as it is supplied
by nerve roots C3–5), unless the level of block – The supine position.
is exceptionally high. – The relaxation of the chest wall muscles
associated with general anaesthesia.
– Co-morbidities; for example, acute abdomen,
How are the lungs affected by general obesity.
anaesthesia? – Patient population; for example, paediatric and
obstetric patients.
There are many physiological changes during induc-
tion and maintenance of anaesthesia. Those affecting Anaesthesia reduces FRC below CC in
the respiratory system are: otherwise healthy middle-aged patients, leading
Airway devices. to hypoxaemia.
– Laryngospasm and bronchospasm. To maximize FRC at induction of anaesthesia,
Manipulation of the airway (by laryngoscopy, and therefore to maximize the volume of O2
intubation or insertion of an LMA) can in the lungs, it may help if the patient is in
precipitate laryngospasm or bronchospasm. a semi-recumbent position. Despite adequate
Bronchospasm is more common in patients pre-oxygenation, some patients are particularly
who already have reactive airways (asthmatics, prone to hypoxaemia on induction of anaesthesia;
smokers), whilst laryngospasm is more for example, the obese. Intraoperatively, the
common in children, particularly with lithotomy and Trendelenburg (head down)
inhalational inductions (as propofol is a useful positions further reduce FRC by increasing
depressant of laryngeal reflexes). the pressure of the abdominal contents on the
– Humidification. ETTs and LMAs both diaphragm.
bypass the upper airway. The typical functions Low lung volumes also cause a reduction
of the upper airway (humidification, filtration in airway radius (which increases resistance to gas
and warming of inspired gases) are usually flow, leading to an increased work of breathing)
performed instead by a heat and moisture and an increase in PVR.
exchanger. Inadequate warming and Atelectasis has three causes: absorption of gases
humidification may result in dry, tenacious behind closed airways, alveolar compression and
secretions, leading to mucous plugging. loss of pulmonary surfactant. The first two are
– Loss of physiological PEEP. ETTs also bypass the common during general anaesthesia:
larynx: the 3–5 cmH2O of physiological PEEP – Absorption atelectasis. When breathing room
is lost, predisposing the patient to atelectasis. air, very little N2 diffuses across the alveolar–
– Increased work of breathing. The extent to capillary barrier: N2 remains in the alveoli,
which airway devices increase the resistance to ‘splinting’ them open. During anaesthesia, the
gas flow depends on their internal radius, as combination of diffusible gases (O2 and N2O)
determined by the Hagen–Poiseuille equation. and small airway closure (due to CC
The larger radius of the LMA makes it suitable encroaching on the reduced FRC) means that
for spontaneous ventilation. The narrower all the alveolar contents may diffuse into the
radius of the ETT increases the work of blood, leading to atelectasis.
breathing. This is of particular importance in – Compression atelectasis. Under general
small children (very small ETT radius) and anaesthesia, a combination of reduced
intensive care patients in the weaning phase. diaphragmatic tone and compression from the
– Increased dead space. All airway devices abdominal contents causes basal atelectasis.
increase mechanical dead space: V_ E must This is exacerbated by the loss of physiological
increase (sometimes significantly) if V_ A is to PEEP and increased abdominal pressure
be maintained. (for example, due to pneumoperitoneum).
108
Chapter 25: Anaesthesia and the lung
V̇ /Q̇ relationships. V̇ /Q̇ mismatch results from: Postoperative shivering sometimes occurs at
– Low lung volume, causing closure of small emergence from anaesthesia. Shivering
airways (due to CC encroaching on FRC). increases metabolic demand at a time when the
– Increased tendency for atelectasis. respiratory centre’s response to hypercapnoea
and hypoxaemia is blunted by the residual
– Positive pressure ventilation, which alters
effects of anaesthetic agents and opioids.
intrathoracic pressure, reducing right
Respiratory failure (either type 1 or type 2)
ventricular preload and changing pulmonary
may occur.
capillary dynamics; West zone 1 occurs in the
lung apex (see Chapter 15). Where neuromuscular blockade has been used,
inadequate reversal may cause respiratory muscle
– Impairment of HPV by volatile anaesthetic
weakness in the immediate postoperative period.
agents.
Muscular weakness may be exacerbated by
The hypoxaemia resulting from V̇ /Q̇ mismatch electrolyte disturbances (hypokalaemia or
can usually be managed simply by increasing hypocalcaemia) resulting from fluid shift
FiO2 and adding PEEPe to reduce atelectasis between body compartments and increased
and increase lung volume. mineralocorticoid activity as part of the
stress response.
How does general anaesthesia affect One of the aims of anaesthetic management is
to minimize the disturbance in postoperative lung
postoperative respiratory function? function. The approach is multifactorial, taking into
Postoperative pulmonary complications are common, account many of the factors discussed above:
accounting for around 25% of deaths within the first Preoperative assessment. Risk stratification of
6 days following surgery. Common postoperative patients based on type of surgery and presence of
complications include: any underlying lung disease.
atelectasis Regional versus general anaesthesia. Depending
bronchospasm on the type of surgery, the use of regional
pneumonia anaesthesia avoids many of the adverse effects of
pulmonary oedema general anaesthesia on the lungs.
pneumothorax Laparoscopic surgery. For abdominal
ventilatory failure. procedures, laparoscopic surgery reduces
postoperative pain and improves postoperative
Whilst underlying lung and cardiac disease may pre- oxygenation when compared with open
dispose patients to postoperative pulmonary compli- procedures. However, there is currently
cations, surgical and anaesthetic techniques also insufficient evidence to determine whether
contribute: laparoscopic surgery reduces postoperative
Upper abdominal and thoracic surgery carry the pulmonary complications.
highest risk of postoperative pulmonary Normothermia. Intraoperative temperature
complications. Reduced FRC, basal atelectasis and management minimizes the risk of postoperative
V̇ /Q̇ mismatch are inevitable and often persist shivering.
for many days. V̇ /Q̇ mismatch causes Adequate reversal of neuromuscular blockade.
hypoxaemia, whilst atelectasis and reduced lung Reversal of neuromuscular blockade is important
volume both contribute to an increased work of for adequate postoperative respiratory muscle
breathing. function. Long-acting neuromuscular blocking
Inadequate analgesia following laparotomy, agents (for example, pancuronium) are more
sternotomy and thoracotomy results likely to lead to postoperative respiratory failure
in an inadequate cough and limited than short- and intermediate-acting agents.
inspiration. This exacerbates atelectasis and Neuromuscular monitoring may be of
predisposes the patient to secretion retention use in determining adequate reversal of
and pneumonia. neuromuscular block.
109
Adequate pain relief. This is especially important Further reading

in upper abdominal and thoracic surgery where a V. A. Lawrence, J. E. Cornell, G. W. Smetana. Strategies to
regional anaesthetic technique is commonly used; reduce postoperative pulmonary complications after
for example, a continuous infusion of local noncardiothoracic surgery: systematic review for the
anaesthetic via a thoracic epidural or paravertebral American College of Physicians. Ann Intern Med 2006;
catheter. 144(8): 596–608.
Postoperative breathing exercises. Lung G. Hedenstierna. Airway closure, atelectasis and gas
expansion exercises have been shown to reduce exchange during anaesthesia. Minerva Anestesiol 2002;
postoperative pulmonary complications following 68(5): 332–6.
abdominal and thoracic surgery. G. H. Mills. Respiratory physiology and anaesthesia. Contin
Educ Anaesth Crit Care Pain 2001; 1(2): 35–9.
110
Section 3 Cardiovascular physiology
Chapter
Cardiac anatomy and function
26
What are the functions of the heart? The endocardium, a layer of epithelial cells that
line the inner surface of the heart. The
The mechanical function of the heart is to eject blood endocardium is in contact with blood and is
into the vascular system: continuous with the endothelial layer of the blood
The right side of the heart generates flow around vessels.
the pulmonary circulation, moving deoxygenated
venous blood from the heart to the lungs. The heart can be divided into right and left sides,
The left side of the heart generates pressure in the each consisting of an atrium and a ventricle. The two
arterial circulation, moving oxygenated blood sides of the heart are separated by the interatrial and
from the heart to the other organs of the body. interventricular septae.
Flow can then be regulated according to tissue The right atrium receives deoxygenated blood
demand. from the superior and inferior venae cavae. When
the right atrium contracts, blood passes through
Technically, the heart does not operate as a true the tricuspid valve (a trileaflet valve) and into
‘pump’ as it does not suck from the venous system: the right ventricle.
negative pressure would cause these compliant vessels The right ventricle has a complex shape.
to collapse. However, the term ‘pump’ is Viewed in the transverse plane it is shaped
commonly used. as a crescent, whilst it is triangular in the
The heart is also an endocrine organ with a role in longitudinal plane. Because of this complex
the regulation of plasma volume. Stretch receptors in shape, the structure of the right ventricle
the cardiac atria and ventricles sense increases is difficult to model mathematically. It is
in plasma volume, secreting atrial natriuretic peptide therefore difficult to estimate right
(ANP) and brain natriuretic peptide (BNP) in ventricular volume by echocardiography.
response. Both ANP and BNP act on the kidney to When the right ventricle contracts,
produce a natriuresis, which restores plasma volume blood is driven through the pulmonary
to normal. valve (a trileaflet valve) and into the
pulmonary artery.
The left atrium. Oxygenated blood returns
Describe the structure of the heart from the lungs through four (normal
The heart is located in the thorax, enclosed within a variation from three to five) pulmonary
fibrous sac called the pericardium. The pericardium veins and enters the left atrium. When
forms attachments to surrounding structures that the left atrium contracts, blood passes
hold the heart in place. into the LV through the mitral valve
The heart is made up of three tissue layers: (a bileaflet valve)
The epicardium, the outer connective tissue layer. The LV has a circular transverse section and a
A small amount of pericardial fluid separates the conical longitudinal section, amenable to
epicardium from the pericardium, which helps accurate echocardiographic estimates of its
reduce frictional forces as the heart moves. volume. When the LV contracts, blood is
The myocardium, the middle layer, which is forced through the aortic valve (a trileaflet valve)
composed of cardiac muscle. and into the aorta.
111
Section 3: Cardiovascular physiology
What is meant by the term ‘functional artery travels a short distance in the left
atrioventricular (AV) groove (less than 2.5 cm)
syncytium’? before bifurcating into:
The myocardium is arranged in networks of striated – The left interventricular artery (left anterior
cardiac muscle cells joined together by intercalated descending artery). As the names suggest, this
discs. Intercalated discs contain three different types artery descends in the anterior interventricular
of cell–cell interaction: groove, giving off septal and diagonal
Gap junction complexes permit the direct passage branches. The left interventricular artery
of intracellular ions and larger molecules from supplies most of the LV; specifically:
one cell to another. This allows direct electrical
spread of action potentials from cell to cell ▪ the anterolateral myocardium
without the need for neurotransmission. ▪ the apex
Fascia adherens anchor the actin filaments within ▪ the interventricular septum.
the sarcomere to the cell membrane. The left interventricular artery often forms an
Macular adherens (also known as desmosomes) anastomosis with the posterior interventricular artery
anchor cardiac cells to one another. after passing over the apex.
Cardiac muscle is therefore electrically, chemically – The left circumflex artery. This artery
and mechanically coupled together as a ‘functional continues in the left AV groove, giving off one
syncytium’.1 or more ‘obtuse marginal’ branches. Normally,
the terminal end of the left circumflex artery
meets the right coronary artery in the AV
Describe the coronary circulation groove, where the two arteries form an
Whilst a large volume of blood passes through the anastomosis. The left circumflex artery
cardiac chambers, the ventricular wall is too thick for supplies:
effective diffusion of O2 to occur; only the endocardium
is nourished directly. The bulk of the cardiac muscle ▪ the posterolateral LV;
is perfused by the coronary circulation. Coronary arter- ▪ the sinoatrial (SA) node in 40% of
ies are ‘end arteries’ – they represent the only source individuals.
of blood for the downstream myocardium, with few
The right coronary artery originates from the
anastomoses. Consequently, acute obstruction of a anterior aortic sinus, just above the right cusp of
coronary artery causes myocardial ischaemia. the aortic valve. It travels along the right AV
The coronary circulation is divided into right and groove, before dividing into:
left sides, which both originate at the aortic root
(Figure 26.1). The aortic root has three dilatations – the SA branch, which is present in 60% of
just above the aortic valve, known as the aortic sinuses individuals and supplies the SA node;
(or sinuses of Valsalva). These sinuses produce eddy – the right marginal artery, which travels down
currents, which tend to keep the valve cusps away the right margin of the heart towards the
from the aortic walls, and facilitate smooth valve apex and supplies the right ventricle; it is
closure. This is important, as the left and right coron- the right-sided equivalent of the left
ary arteries originate from the left posterior and interventricular artery.
anterior coronary sinus respectively, and the eddy The right coronary artery continues in the AV groove
currents prevent their occlusion. until it reaches the posterior interventricular groove.
In the majority of individuals the right coronary artery
The left coronary artery (left main stem) arises
then divides into:
from the left posterior aortic sinus, just above the
left cusp of the aortic valve. The left coronary
– the posterior interventricular artery
(posterior descending artery), which
1
A (true) syncytium is a multinucleate cell; for example, a supplies the posterior part of the septum
skeletal myocyte. and the AV node.
112
Chapter 26: Cardiac anatomy and function
Figure 26.1 The (simplified) coronary

arterial and venous circulations.
Left coronary artery
Oblique vein
Coronary sinus Great cardiac vein
Right coronary artery Left circumflex artery
Small cardiac vein Left interventricular

artery
Right marginal branch
Posterior interventricular artery Middle cardiac vein
The right coronary continues in the AV – the small cardiac vein, which runs alongside
groove, where it forms an anastomosis with the the right coronary artery in the posterior AV
left circumflex artery. groove;
– the oblique vein, which traverses the back of
The coronary circulation has a number of recog-
the left atrium.
nized variants, the most common of which is called
The anterior cardiac veins are small veins that
‘left dominance’. In around 15% of the population,
arise on the anterior surface of the right ventricle
the posterior interventricular artery is not a branch of
and drain into the right atrium.
the right coronary artery, but is instead a branch
of the left circumflex artery. The Thebesian veins, the smallest of the cardiac
veins, drain directly into the four chambers of the
heart. The Thebesian veins are predominantly
Describe the venous drainage found in the right atrium and ventricle. Note: the
of the heart few Thebesian veins that drain into the left side of
the heart pass deoxygenated blood directly into
There are three different systems through which
the stream of fully oxygenated blood returning
venous blood is drained from the myocardium:
from the lungs, and thus contribute to
The coronary sinus. Venous blood from the LV physiological shunt (see Chapter 13).
(which accounts for around 85% of venous blood)
is collected by the cardiac veins, which coalesce to
Clinical relevance: electrocardiogram changes with
form the coronary sinus. The sinus opens into the myocardial ischaemia
right atrium, between the inferior vena cava (IVC)
The electrocardiogram (ECG) is a key investigation
and the tricuspid valve. The cardiac veins lie in the
in the diagnosis of acute myocardial ischaemia and
grooves between atria and ventricles. Thus, they infarction. Both the depolarization (Q-wave) and
follow the same paths as the coronary arteries repolarization (ST segment and T-wave) of ischaemic
(Figure 26.1). They are: myocardium may be abnormal, resulting in charac-
– the great cardiac vein, which runs alongside teristic changes to the ECG. These ECG changes are
the left interventricular artery in the anterior dependent on the extent and location of ischaemic
myocardium. By correlating Einthoven’s triangle (see
interventricular groove;
Chapter 55) with the anatomical location of injured
– the middle cardiac vein, which myocardium and its arteries, the angiographic
runs alongside the posterior appearance and certain complications may be pre-
interventricular artery in the posterior dicted. As a rough guide:
interventricular groove;
113
Extent of myocardial ischaemia: ejection fraction (EF) is <35%, and where there is a
– Subendocardial ischaemia/infarction is conduction defect (characterized by a widened QRS
associated with ST segment depression. complex) resulting in asynchronous contraction of
– Subepicardial or transmural infarction is the left and right ventricles. A CRT device improves
associated with ST segment elevation. atrial and ventricular synchrony through the use of
Location of ischaemia: three pacemaker wires: atrial, right ventricular and
– Inferior wall ischaemia affects leads II, III and left ventricular.
aVF. This inferior portion of the heart is sup- Like standard pacemakers, the CRT leads are usu-
plied by the right coronary artery and the ally inserted through the subclavian vein, which
posterior interventricular artery. As the right poses a question – how does the left ventricular wire
coronary artery frequently supplies the SA reach the left ventricular myocardium?
node, occlusion may result in hypotension and Atrial and right ventricular wires are passed
bradycardia. through the subclavian vein and superior vena
– Lateral wall ischaemia affects leads I, II, V5 and cava (SVC), into the right atrium and right
V6. This area of the heart is supplied by ventricle.
the circumflex artery. Infarction results in The left ventricular wire is also advanced into the
left ventricular dysfunction. right atrium, where it is passed into the coronary
– Septal ischaemia affects leads V1 and V2, sinus and along the great cardiac vein until it
corresponding to occlusion of a septal branch reaches the left ventricular myocardium.
of the left interventricular artery. As the inter-
ventricular septum is the site of the bundle of
His, infarction may cause bundle branch block.
– Apical ischaemia affects leads V3 and V4, cor- Is blood flow to the myocardium
responding to occlusion of a terminal portion
of the left interventricular artery, or (in right
continuous or intermittent?
dominant circulations) the posterior interven- The heart is constantly beating, so has a high O2
tricular artery. requirement even in an inactive subject:
– Anterior wall ischaemia may affect up to eight The resting heart receives 250 mL/min of blood,
leads: I, aVL, V1, V2, V3, V4, V5 and V6. This 5% of the CO. Coronary blood flow may
part of the myocardium is supplied by the left increase up to fivefold during strenuous exercise.
interventricular artery: complete occlusion will
Myocardial O2 extraction is greater in the heart
result in ischaemia of a considerable portion of
(around 70% at rest) than any other organ; in
the LV, and is therefore associated with severe
left ventricular dysfunction.
contrast, resting skeletal muscle O2 extraction is
– Posterior wall ischaemia is difficult to diagnose. only 25%.
Posterior wall infarction causes ST segment
This requirement for high blood flow and efficient
depression in leads V1, V2, V3 and V4, and
results in left ventricular dysfunction. The
O2 extraction makes the heart very susceptible to
posterior wall is supplied by the circumflex ischaemia.
artery and the posterior interventricular artery. The coronary arteries run along the epicardial
surface, and their arterioles penetrate into the myo-
cardium at an approximate right angle. During
systole, the pressure within the contracting muscle
of the LV exceeds coronary arterial pressure; the
Clinical relevance: cardiac resynchronization intramuscular arterioles are compressed, preventing
therapy blood flow to the myocardium. During diastole,
Some patients with severe heart failure have conduc- the heart relaxes and its pressure falls; blood flow
tion defects that disrupt the timing of right and left to the myocardium resumes (Figure 26.2). Blood
ventricular contraction. Ventricular dyssynchrony flow to the LV is therefore intermittent. The pressure
results in a reduced SV and delayed ventricular
generated within the right ventricle is much less than
relaxation.
Cardiac resynchronization therapy (CRT) is indi-
that of the LV; the right ventricular myocardium
cated in heart failure patients in sinus rhythm where is therefore perfused throughout the cardiac cycle
(Figure 26.2).
114
Chapter 26: Cardiac anatomy and function
Figure 26.2 Coronary blood flow.

SYSTOLE DIASTOLE
120
Aortic pressure (mmHg)
Dicrotic notch
110
Aorta
100
90
80
Greater coronary blood

200 flow during diastole
150 Left coronary

Coronary blood flow (mL/100 g/min)
100
50 Sharp fall in coronary blood flow

during isovolumetric contraction
Greater coronary blood

30 flow during systole
20 Right coronary
10
0
0 0.25 0.5 0.75 1.0
Time (s)
Which other factors influence coronary – An increase in cardiac work, as occurs

in exercise, leads to a reduction in
blood flow? myocardial cytosolic ATP and an increase
A number of factors are involved in the regulation in AMP.
of coronary blood flow: – Adenosine is released from the
O2 demand. As indicated above, the O2 extraction myocardial cells.
ratio is higher in the heart than in any other – In response, adenosine triggers
organ. Any increase in O2 demand requires a vasodilatation of the coronary arterioles, thus
corresponding increase in coronary blood flow. increasing coronary blood flow.
Coronary blood flow is therefore tightly coupled – Other possible vasodilatory mediators are K+,
to O2 demand. One possible mechanism for this is: CO2, H+ and NO.
115
Autoregulation. In common with blood flow to

the brain and kidneys, coronary blood flow is Nitrates (for example, glyceryl trinitrate) cause
vasodilatation of the coronary arteries in
autoregulated. The coronary arterioles vasoconstrict
common with their effects on other arterial beds.
and vasodilate to maintain a constant coronary The consequent venodilatation and peripheral
blood flow in the face of varying coronary perfusion vasodilatation reduce cardiac preload and
pressure,2 between 60 and 180 mmHg. At a afterload respectively. Myocardial O2 demand
coronary perfusion pressure of 60 mmHg, the falls, and therefore overall coronary blood flow
coronary arterioles are then maximally vasodilated is reduced.
and any further reduction in coronary perfusion β-blockers (for example, bisoprolol) reduce HR,
pressure results in a fall in coronary blood flow. which prolongs the diastolic time. Blood flow to
Heart rate (HR). An increase in HR encroaches the LV therefore increases. In addition, β-blockers
on the diastolic time more than the systolic time, inhibit catecholamine-induced increases in
myocardial contractility, as occurs with exercise,
resulting in a decrease in left coronary blood flow.
which limits any increase in O2 demand.
Right coronary blood flow is relatively unaffected. Ca2+ channel blockers (for example, nifedipine)

Patency of coronary vessels: cause coronary arteriolar vasodilatation, which
– The presence of atheroma in the walls of the increases coronary blood flow, and peripheral
coronary arteries makes them unable to vasodilatation, which decreases afterload
vasodilate in response to increased O2 and therefore decreases myocardial O2 demand.
K+ channel openers (for example, nicorandil)
demand. Downstream myocardium then
increase K+ efflux from arteriolar smooth
receives insufficient O2 to meet its demand,
muscle cells. This hyperpolarizes the smooth
resulting in myocardial ischaemia. muscle cells, reducing their cytosolic Ca2+
– Acute obstruction of the coronary arteries by concentration, which causes smooth muscle
thrombosis, embolus or vasospasm can cause relaxation. The resultant coronary arteriolar
myocardial ischaemia even without an vasodilatation leads to an increase in coronary
increase in O2 demand. blood flow. Nicorandil dilates both normal
and stenotic segments of coronary artery.
Chronic atheroma results in downstream Antiplatelet agents (for example, aspirin and
ischaemic preconditioning in the tissues, allowing clopidogrel) prevent an occlusive thrombus
larger degrees of stenosis than acute occlusion. forming within the coronary arteries.
Autonomic control. The ANS has only a minor
direct effect on coronary blood flow:
– Parasympathetic activity has a weak Further reading
vasodilatory effect on the coronary arterioles. P. Barash, S. Akhtar. Coronary stents: factors contributing
– Sympathetic activity causes an increase in CBF. to perioperative major adverse cardiovascular events. Br
J Anaesth 2010; 105(Suppl. 1): u3–15.
But this is mainly the result of increased O2
demand secondary to an increase in inotropy B. M. Biccard, R. N. Rodseth. The pathophysiology of peri-
and HR. operative myocardial infarction. Anaesthesia 2010; 65(7):
733–41.
T. Ramanathan, H. Skinner. Coronary blood flow. Contin
Clinical relevance: drugs and coronary blood flow Educ Anaesth Crit Care Pain 2005; 5(2): 61–4.
Drugs influence coronary blood flow through a N. Herring, D. J. Paterson. ECG diagnosis of acute
number of mechanisms: ischaemia and infarction: past, present and future.
Q J Med 2006; 99(4): 219–30.
2
Coronary perfusion pressure ¼ aortic blood pressure
LVEDP.
116
Chapter
Cardiac cycle
27
AV valves into the ventricles. At rest, this atrial
What is the cardiac cycle? ‘kick’ accounts for only 10% of ventricular
The cardiac cycle refers to the complete sequence of filling: 90% of the blood flows into the
events that occur in the heart, from the beginning of ventricle passively. However, during exercise,
one heart beat to the beginning of the next. when diastole is shortened, atrial contraction
The cardiac cycle consists of two phases: contributes up to 40% of ventricular filling.
The diastolic phase, during which the ventricles – The pressure generated during atrial
fill with blood. Diastole consists of four stages: contraction is transmitted along the venae
– isovolumetric relaxation cavae and pulmonary veins as they have no
– rapid ventricular filling valves: atrial contraction is represented by
– slow ventricular filling the a wave on the atrial pressure waveform
– atrial contraction. (Figure 27.1).
The systolic phase, during which the ventricles – The volume of blood within the ventricle at the
contract and eject blood into the aorta and end of atrial contraction is the end-diastolic
pulmonary artery. Systole consists of two stages: volume (EDV).
Isovolumetric contraction. The action potential
– isovolumetric contraction
continues through the AV node and is conducted
– ejection.
throughout the ventricles by the His–Purkinje
system, represented on the ECG by the QRS
Describe the events making up the complex. Initially, ventricular contraction causes
a rapid rise in intraventricular pressure:
cardiac cycle
– Once intraventricular pressure exceeds atrial
Traditionally, the cardiac cycle is described from late
pressure, the AV valves close, resulting in the
diastole, when the atria and ventricles are relaxed and
first heart sound, S1. The mitral valve normally
the AV valves are open:
closes slightly earlier than the tricuspid valve,
Slow ventricular filling. The pressure within the resulting in a ‘split’ S1.
atria is slightly higher than intraventricular – There is a period of time between the closure
pressure. The AV valves are therefore open, of the AV valves and the opening of the aortic
allowing blood to flow slowly from atrium to and pulmonary valves (semilunar valves)
ventricle. during which ventricular pressure rises
Atrial contraction. without a change in ventricular volume – this
– The pacemaker cells of the SA node is isovolumetric contraction.
spontaneously depolarize, generating an action – During isovolumetric contraction, the
potential (see Chapter 54). The resulting increased right ventricular pressure causes the
electrical impulse is rapidly conducted tricuspid valve to bulge into the right atrium.
throughout the atria, triggering atrial This corresponds to the c wave on the atrial
contraction. pressure waveform. Similarly, increased left
– As a result of atrial contraction, much of the ventricular pressure causes the mitral valve to
remaining atrial blood is ejected through the bulge into the left atrium.
117
Isovolumetric contraction Isovolumetric relaxation Figure 27.1 The cardiac cycle. Note: left
atrial pressure is shown.
DIASTOLE SYSTOLE DIASTOLE
Dicrotic notch
120 Aortic valve
opens
Aortic
press
100 ure
Aortic valve
closes
Pressure (mmHg)
80
Gradient
reflects
60 Mitral valve contractility
closes Mitral valve
opens
40 a wave c wave
x descent
20 v wave y descent Left atrial
pressure
Left ventricular
0 pressure
P QRS T P
ECG
Heart sounds
S1 S2
0 0.25 0.5 0.75 1.0
Time (s)
Ejection. Once ventricular pressure exceeds the – The volume of blood within the ventricle
pressure in the aorta and pulmonary artery, the following valve closure is the end-systolic
semilunar valves open and blood is ejected from volume (ESV).
the ventricles. Isovolumetric relaxation. Following the closure
– Right ventricular contraction pulls the of the semilunar valves, it takes a short time for
tricuspid valve downwards. As the length of the ventricles to relax and their pressure to fall
the right atrium increases, its pressure falls to below that of the atria. Throughout late systole
zero and it is rapidly filled with blood. This is and isovolumetric relaxation, atrial pressure
the origin of the x descent on the atrial slowly rises due to venous return from the
pressure waveform. lungs and venae cavae. This corresponds to
– Initially, the flow of blood through the the v wave of the atrial pressure waveform
semilunar valves is rapid; but as the ventricular (Figure 27.1).
myocytes start to repolarize, the force of Rapid ventricular filling. Once atrial pressure
contraction wanes. exceeds ventricular pressure, the AV valves open.
– As time goes on, the ventricular pressure falls Blood flows down its pressure gradient from the
below that of the aorta and pulmonary artery; atria to the ventricles. During the early part of
the semilunar valves close, resulting in the diastole, the ventricles are still undergoing
second heart sound, S2. The aortic valve relaxation and intraventricular pressure continues
usually closes slightly earlier than the to decrease – blood therefore flows rapidly into
pulmonary valve. Inspiration can accentuate the ventricles. The fall in atrial pressure is
this difference, particularly in young people, represented by the y descent of the atrial pressure
resulting in a ‘physiological split S2’. waveform (Figure 27.1).
– Aortic valve closure is represented on the Ventricular filling is normally silent, but an
aortic pressure curve (Figure 27.1) by the increased volume of atrial blood (for example,
dicrotic notch, a positive deflection caused by in mitral regurgitation) flowing into a poorly
the elastic recoil of the aortic valve and the aorta. compliant LV (as occurs, for example, following
118
Chapter 27: Cardiac cycle
a myocardial infarction or in dilated

cardiomyopathy) results in reverberation of the At rest (HR ¼ 75), a single cardiac cycle lasts for
0.8 s: the typical duration of systole is 0.3 s and
ventricular wall and a third heart sound, S3.
diastole is 0.5 s. The LV fills during diastole, when
its pressure is low and the mitral valve is open.
A young athlete at maximal exercise may
What is stroke volume?
have an HR of 200; each cardiac cycle lasts just
SV is the volume of blood ejected from the LV per 0.3 s: systole lasts 0.15 s and diastole 0.15 s.
heart beat. The volume of blood in the LV prior to Such a short diastolic time limits ventricular
contraction is the left ventricular end-diastolic filling.
volume (LVEDV), and the volume of blood
Therefore, the relationship between HR, SV and CO is
remaining in the LV after contraction is the left ven-
more complex than it first seems:
tricular end-systolic volume (LVESV). Therefore:
When HR is high, diastolic filling time decreases,
and thus SV decreases, leading to a fall in CO.
Key equation: stroke volume
Likewise, when HR falls below 40 beats per
SV ¼ LVEDV LVESV minute (bpm), CO still decreases despite a
moderate increase in SV (to 80–90 mL, due
Typical values for a 70 kg man are: to the increased diastolic filling time).
LVEDV of 120 mL. A (sinus) HR between 50 and 150 bpm is optimal
LVESV of 50 mL. in most patients.
So, SV ¼ 70 mL. The heart undergoes changes with age:
Reduced compliance of the aorta results in an
increase in afterload. In response, the LV under-
The ‘normal range’ for SV is 55–100 mL, though this goes hypertrophy, which reduces its compliance.
depends on the size of the patient. LV relaxation is less efficient in diastole, again
EF is also commonly used. EF is the proportion of leading to a decrease in its compliance.
blood ejected from the LV per heart beat: Fibrosis of atrial pacemaker cells predisposes to
atrial fibrillation (AF).
Key equation: ejection fraction
As a result of the changes in LV compliance, the rate
SV of ventricular filling during the rapid filling stage is
EF ¼ reduced. The maximum HR achieved during exercise
LVEDV
therefore decreases with age:
As typical values are SV ¼ 70 mL and LVEDV ¼ 120
HRmax ¼ 208 (0.7 × age)
mL:
Therefore, HRmax is 194 at age 20, whilst HRmax falls
70
EF ¼ ×100 to 152 at age 80.
120 Atrial contraction becomes ever more important
¼ 58%
to ventricular filling with advancing age, contributing
The ‘normal range’ for EF is 55–70%. up to 40% of LVEDV. The onset of AF, in which there
is an absence of atrial contraction, may therefore lead
to a significant fall in CO.
Clinical relevance: cardiac output, ageing and

tachycardia
CO ¼ HR × SV (see Chapter 28). Therefore, it seems
Further reading
logical that as HR increases so does CO. However: M. D. Cheitlin. Cardiovascular physiology – changes with
aging. Am J Geriatr Cardiol 2003; 12(1): 9–13.
119
Chapter
Cardiac output and its measurement
28
– PCWP provides an indication of
Which factors affect the cardiac left ventricular preload, as it affects
output? LVEDV.
The CO is the volume of blood ejected by the left or Myocardial contractility is the intrinsic ability
right ventricle per minute. of cardiac myocytes to generate mechanical
CO is dependent on two factors: HR and SV. power at a given preload and afterload.
Factors that increase myocardial contractility are
Key equation: cardiac output said to exert a positive inotropic effect, whilst
CO ¼ SV × HR factors which decrease contractility exert a
negative inotropic effect. Contractility is
At rest, the typical SV is 70 mL, and HR is 75 bpm.
difficult to measure directly, but an index of
Typical resting CO is therefore 70×75 ¼ 5:25
L=min, but CO may increase fivefold during maximal
myocardial contractility is provided by the
exercise.1 rate of change of pressure (i.e. the gradient)
during the isovolumetric contraction phase
of the cardiac cycle (see Chapter 27 and
In turn, SV is determined by three factors: preload, Figure 27.1).
myocardial contractility and afterload.
Afterload is the stress developed in the
Preload is defined as the intraluminal pressure left ventricular wall during ejection, and
that stretches the right- or left ventricle to its end- reflects the force opposing the shortening of
diastolic dimensions. Preload is therefore related cardiac myocytes. As afterload increases, both
to the diastolic length of the cardiac myocyte. the rate and extent of sarcomere shortening
According to Starling’s law, the force of cardiac decrease, resulting in a reduction in SV.
myocyte contraction depends on the preceding Like preload, afterload is not easily measured
diastolic length of the ventricular fibres (see in vivo, and is assessed through surrogate
Chapter 29): increased preload produces an markers:
increased SV.
– MAP and SVR reflect left ventricular afterload.
In practice, preload is very difficult to
– PVR reflects right ventricular afterload.
measure. It is impossible to measure sarcomere
length in vivo, so surrogate measurements are
used: LVEDV (measured by echocardiography),
or more commonly LVEDP.2 Similarly: How does the body regulate
– Central venous pressure (CVP) provides an cardiac output?
indication of right ventricular preload, as it
CO is not static; it varies depending on the changing
affects right ventricular end-diastolic
requirements of the body. For example:
volume (RVEDV).
Age. Taking into account their proportionately
1 greater body surface area (BSA, m2), children have
In elite athletes, peak CO may be as high as 40 L/min.
2
Note: the relationship between EDV and EDP depends a greater CO than adults.
on ventricular compliance, which may vary between Exercise. CO may increase up to fivefold in
patients. normal individuals.
120
Chapter 28: Cardiac output and its measurement
Pregnancy is associated with an increase in resting left ventricular preloads is the venous return to the
CO of up to 50% at term. right ventricle; that is, RVEDV. Venous return
Eating is associated with an increase in CO of depends on a number of factors, which are
around 25%. discussed in detail in Chapter 35.
Myocardial contractility is affected by four
As discussed above, the main factors that influence factors:
CO are HR, preload, myocardial contractility and
afterload. The regulation of these four factors is com- – The sympathetic nervous system. Release of
plex, as changes in each rarely occur in isolation. noradrenaline from cardiac sympathetic
However, HR may undergo a threefold increase (for neurons (and to a lesser extent circulating
example, from 60 bpm to 180 bpm), whereas SV may noradrenaline and adrenaline) increases
only increase by around 50% (for example, from myocardial contractility through its action
70 mL to 105 mL). Under normal circumstances, the on β1-adrenoceptors.
major factor that influences CO is therefore HR. – Tachycardia. Intrinsic myocardial contractility
is increased when the HR is high. This is
HR is set by SA node pacemaker activity, which is
known as the ‘Bowditch effect’.
in turn modulated by the ANS:
– Drugs with positively inotropic effects
– A denervated heart has a basal HR of around include dobutamine, isoprenaline,
100–120 bpm. glucagon, enoximone and digoxin. Drugs
– At rest, the parasympathetic nervous system with negatively inotropic effects include
(via the vagus nerve) is tonically active in the β-blockers, Ca2+ channel blockers and
heart (note: this is an exception – elsewhere the anaesthetic agents.
sympathetic nervous system is tonically – Disease states may reduce myocardial
active). ACh is continually released from contractility, such as sepsis, myocarditis,
parasympathetic nerve terminals, reducing the ischaemic heart disease, electrolyte and acid–
resting HR to 60–70 bpm through its effect at base disturbance.
muscarinic M2 receptors.
Positive inotropy increases myocardial O2
– At the onset of exercise, parasympathetic tone
demand. As myocardial contractility increases,
is withdrawn, which increases HR.
there may come a point where O2 delivery
Noradrenaline is released from sympathetic
becomes insufficient, resulting in myocardial
nerve terminals and adrenaline is released from
ischaemia. This is especially so in patients with
the adrenal medulla, both of which increase
coronary artery disease, where atherosclerosis
HR through activation of β1-adrenoceptors.
limits coronary blood flow. Ischaemic myocardium
CO decreases with bradycardia and increases cannot contract as effectively, and SV decreases.
with tachycardia. However, tachycardia is not Afterload, which is governed by SVR. As
always beneficial: discussed above, an increase in afterload results
in a reduction in SV. As less blood is ejected from
– Up to around 140 bpm, CO increases. the heart per beat, there is a greater volume of
– Above 150 bpm, the diastolic time becomes blood remaining in the ventricle at end-systole,
very short (~0.15 s). As ventricular filling can and therefore (following the ventricular filling
only occur during diastole, SV falls with a phase) a greater LVEDV. According to Starling’s
consequent reduction in CO (see Chapter 27). law, a greater LVEDV produces a greater SV.
– When HR is rapid, as may occur with Overall, following a sudden increase in afterload,
ventricular tachycardia, the fall in CO may be SV transiently decreases before gradually
sufficient to cause myocardial ischemia, thus returning to normal.
further reducing myocardial contractility; a In addition, an increase in afterload causes an intrinsic
vicious cycle ensues. increase in inotropy. This ‘Anrep effect’ ensures that
Preload. Starling’s law ensures that the CO of the increases in afterload cause smaller reductions in SV
right and left ventricles is exactly matched. than would be predicted from the Frank–Starling
Therefore, the main determinant of both right and mechanism alone.
121
What is the Bowditch effect? How is mean arterial blood pressure

The Bowditch effect (also known as the ‘Treppe effect’ related to cardiac output?
or the ‘staircase effect’) is an intrinsic autoregulatory
MAP describes the average arterial pressure during a
phenomenon in which tachycardia leads to increased
single cardiac cycle. Pressure and flow are related by
myocardial contractility. The mechanism for this is
Darcy’s law:
thought to be:
Pressure ¼ flow × resistance
As HR increases, the time period for each In the case of MAP and CO:
cardiac cycle falls, with the diastolic
interval shortened more than the systolic Key equation: determinants of mean arterial
interval. pressure3
2+
At high HR, there is increased systolic Ca influx MAP ≈ CO × SVR
2+
through the L-type Ca channels.
+
In addition, the diastolic Na efflux due to the
+ + In turn, SVR is dependent on the radius of the
Na /K -ATPase cannot keep pace with the systolic
influx of Na+. arterioles, and (to a much lesser extent) the blood
+ 2+
The Na /Ca exchanger is normally viscosity.
responsible for the low intracellular Ca2+ Therefore, at a given CO:
concentration. However, with tachycardia, MAP is increased by:
the increase in cytosolic Ca2+ and Na+ – Vasoconstriction, as might take place following
concentrations leads to an accumulation catecholamine release.
of intracellular Ca2+, with a consequent – Increased blood viscosity, as occurs in patients
positive inotropic effect. This is also seen with with polycythaemia rubra vera (PRV), who are
digoxin therapy, where the Na+/K+-ATPase is consequently often hypertensive.
blocked.
MAP is decreased by:
– Vasodilatation, as occurs in septic shock or
following general anaesthesia.
What is the cardiac index? – Decreased blood viscosity.
The typical resting CO in a 70 kg adult is said to
be 5–6 L/min, but varies with body size. Cardiac Clinical relevance: aortic stenosis
index (CI) is a means of standardizing CO based Aortic stenosis is a degenerative disease of the aortic
on BSA. valve. Lifetime incidence is estimated at 1%. The
most common cause of aortic stenosis is repeated
Key equation: cardiac index mechanical stress causing fibrosis and calcification of
a previously normal trileaflet aortic valve, usually
CO presenting over the age of 70. Patients with a con-
CI ¼
BSA genital bicuspid aortic valve tend to develop aortic
Normal resting CI is 3–3.5 L/(min m2). stenosis at a younger age.
The normal aortic valve area is 2.6–3.5 cm2. As the
area of the aortic valve decreases over time, there is
Likewise, SV can be standardized based on BSA, an initial compensatory hypertrophy of the LV: sys-
resulting in the SV index (SVI): tolic function is maintained, preserving SV and there-
fore CO. However, this pathological left ventricular
Key equation: stroke volume index hypertrophy has adverse effects:
SV
SVI ¼
BSA
Normal resting SVI is 33–47 mL/m2 per beat. 3
If right atrial pressure (RAP) is assumed to be much
smaller than MAP.
122
usually limits their use to critical care and theatre

A decrease in left ventricular compliance,
which impairs ventricular relaxation and areas. Methods of CO measurement in clinical use
diastolic filling. Atrial contraction becomes can be classified as:
ever more important in left ventricular
Invasive, involving a PAC, central line or
filling, contributing up to 40% of LVEDV.
arterial line.
The development of AF may have devastating
consequences in patients with aortic stenosis, Minimally invasive, utilizing ultrasound
and occurs more frequently due to increased techniques and the proximity of the oesophagus to
atrial stretch. the heart and great vessels.
Increased myocardial O2 demand. As the Non-invasive, encompassing a variety of
aortic valve becomes increasingly stenotic, techniques, including trans-thoracic
a greater left ventricular pressure is required Doppler echocardiography, trans-thoracic
to maintain SV. Therefore, left ventricular electrical bioimpedance and magnetic
O2 demand increases. At the same time, the resonance imaging.
increase in left ventricular mass and higher left
ventricular pressure reduces coronary blood
flow. The mismatch between myocardial
O2 delivery and demand is why patients Describe the invasive methods of
with severe aortic stenosis develop angina,
despite often having normal coronary arteries.
cardiac output measurement
Invasive methods may be divided into methods based
Patients with severe aortic stenosis (below 1.0 cm2) on the Fick principle and methods using pulse con-
effectively have a fixed CO. In consequence: tour analysis:
Exertional syncope. Exercise causes a decrease
Methods based on the Fick principle. The Fick
in SVR, which is normally compensated for
by an increase in CO, to maintain MAP. In
principle states that ‘the uptake or excretion of a
severe aortic stenosis, the required increase in substance by an organ is equal to the difference
CO cannot be met; MAP falls, leading to a between the amount of substance entering the organ
decrease in cerebral blood flow (CBF) and and the amount of substance leaving the organ’.
thus syncope. Therefore:
Central neuraxial blockade. The decrease in
SVR caused by sympathetic nervous system Key equation: Fick principle
blockade cannot be met by an increase
in CO, resulting in a devastating reduction Blood flow to an organ
in MAP. Rate of uptake or excretion of substance
¼
Arterio venous concentration difference
or
Classify the methods of measuring
M
cardiac output Q¼
A V
CO is a measure of overall cardiovascular blood flow, where Q is the blood flow to the organ per minute,
and is therefore considered one of the most important M is the number of moles of substance added or
cardiovascular parameters. In 1928, Adolf Jarisch removed from the blood per minute, A is the arterial
wrote: ‘It is a source of regret that measurement of concentration of substance and V is the venous con-
flow is so much more difficult than measurement of centration of substance.
pressure. This has led to an undue interest in the
blood pressure manometer. Most organs, however,
require flow rather than pressure.’ This statement The Fick principle can be applied in a number
remains equally true today. of ways to determine CO:
Since 1928, many methods of CO measurement – Using O2 as the substance, known as the ‘direct
have been developed; all have limitations and sources Fick method’. As the entire CO passes through
of error. The invasive nature of most techniques the lungs (i.e. pulmonary blood flow equals CO),
123
(a) (b)
Log10 (concentration)
Concentration
Area under the curve

Recirculation
Primary passage
0 5 10 15 20 0 5 10 15 20
Time (s) Time (s)
Figure 28.1 Indicator dye technique: (a) concentration–time graph; (b) logarithmic transformation.
and the lungs add O2 to the blood, the Fick minute, the volume of O2 remaining in the
principle can be applied to determine the CO: spirometer allows the calculation of the O2
uptake into the lungs.
Key equation: Fick principle applied to O2 For example, using typical resting
values (CaO2 ¼ 0.2 mL O2 per mL blood,
V_ O2 CvO2 ¼ 0.15 mL O2 per mL blood and
CO ðL=minÞ ¼
C a O2 C v O2 V_ O2 ¼ 250 mL=min):
where V_ O2 (mL/min) is the rate of O2 uptake, CaO2
V_ O2
(mL O2/h blood) is the arterial O2 content and CvO2 CO ¼
(mL O2/h blood) is the mixed venous O2 content. Ca O2 Cv O2
250
¼ ¼ 5000 mL=min
0:2 0:15
▪ CaO2 can be determined by
peripheral arterial blood gas analysis
Measurement of CO by this method is
(see Chapter 7).
cumbersome, and is clearly not practical in the
▪ CvO2 can be determined by analysing a clinical setting. For this reason, other methods
mixed venous sample from a PAC.4 Some
based on the Fick principle were developed.
PACs are modified with a fibre-optic
– Dye dilution method. A known amount of
bundle incorporated in the catheter to
indicator dye is injected directly into the
continuously measure mixed venous Hb
pulmonary artery (a PAC is therefore
O2 saturation SvO2.
required) and its concentration is
▪ _ O2 over 1 min can be determined by
V
continuously sampled at a peripheral arterial
asking the patient to breathe from a
line. Indocyanine green was traditionally used
spirometer containing a known volume of
as the indicator dye, as it had low toxicity and
100% O2 and a CO2 absorber. After a
a short half-life. An alternative indictor is
lithium, which can be measured using a
4
Note: the ‘true’ mixed venous sample taken from the tip lithium-sensitive electrode incorporated into
of a PAC includes blood from the superior and inferior an arterial catheter. The change in indicator
venae cavae, and the coronary sinus. Blood samples taken concentration over time is recorded as a graph
from the tip of a central line are often used as surrogates
of the ‘true’ mixed venous blood sample, introducing a
(Figure 28.1a). CO can then be calculated from
source of error: the blood sampled mainly originates the integral of this curve (i.e. the area under the
from the upper body (via SVC) and may not accurately curve) and the amount of indicator substance
reflect venous blood from the lower body and heart. using a modification of the Fick equation:
124
(a) (b)
Time (s)
Log10 (temperature change)

0 5 10 15 20
0
Temperature change (oC)
Area under the curve
–0.5
–1.0 0 5 10 15 20
Time (s)
Figure 28.2 Thermodilution method: (a) temperature–time curve; (b) logarithmic transformation.
Key equation: the Stewart–Hamilton equation ▪ 10–15 mL of cold saline is injected through
the most proximal lumen of the PAC
amount of indicator (located in the right atrium).
CO ¼ Ð ∞
concentration of indicator dt ▪ The change in pulmonary arterial blood
0 temperature is measured by the thermistor,
Or simplified as resulting in a temperature–time graph
(Figure 28.2a).
amount of indicator
CO ¼ ▪ CO is calculated using a modification of
area under concentration -- time graph
the Stewart–Hamilton equation:
Key equation: modified Stewart–Hamilton equation

One of the main drawbacks of the dye
dilution method is ‘recirculation’ of the indicator VðT B T I ÞK 1 K 2
CO ¼ Ð∞
dye. Indicator that passes through the circulation 0 T B ðtÞ dt
for a second time causes a second peak in the where V is the volume of injectate, TB is the initial
concentration–time graph (Figure 28.1a), which blood temperature, TI is the initial injectate tempera-
makes accurate measurement of the area under ture, K1 is the density
Ð∞ constant, K2 is the computation
the graph difficult. This drawback is partially constant and 0 T B ðtÞdt is the area under the blood
overcome by using a logarithmic transformation temperature–time curve.
of concentration (which in practice is done by
using logarithmic paper). Using this logarithmic
transformation, the area under the first The thermodilution method became the
curve is easier to measure (Figure 28.1b). ‘gold standard’5 against which other methods
– Thermodilution method. Following the of CO assessment are compared. The
introduction of a balloon-tipped, flow-directed thermodilution method became popular, as:
PAC with a thermistor located near its tip by ▪ Blood sampling is not required.
Swan and Ganz in 1970, the thermodilution ▪ There is no second recirculation peak in the
method became the most frequently adopted temperature–time graph, the main source of
method of determining CO. The technique is inaccuracies with the dye dilution method.
as follows:
▪ Inflating the balloon at the tip of the PAC 5
The direct Fick method described above is often
allows it to be ‘floated’ through the right considered the physiological ‘gold standard’, and was
atrium and right ventricle to the originally used to validate the thermodilution method,
pulmonary artery. but cannot be used practically in critical care patients.
125
Figure 28.3 Pulse contour analysis.

Beat-to-beat interval
Systolic Diastolic Pulse

phase phase time
120
Pressure (mmHg)
100
Area under the curve (AUC)
80
Cardiac output µ AUC x HR
60
0 1 2
Time (s)
▪ It can be used accurately in the presence of SV varies throughout the respiratory cycle, as a
intra-aortic balloon pumps and arrhythmias. result of changes in venous return to the heart
▪ Inaccuracies (such as variation in the speed with changes in intrathoracic pressure. SVV is a
of injection of the cold saline) could be measure of the difference between the maximum
reduced by performing three or four SV and the minimum SV within a respiratory
measurements and averaging the results. cycle, and is used as a measure of ‘fluid
responsiveness’. The CO of a patient with an SVV
However, the use of the PAC is associated
15% is likely to increase with fluid resuscitation,
with a number of serious complications:
whereas a patient with an SVV <10% is unlikely
arrhythmias, infection, tricuspid and
to respond to additional fluid.
pulmonary valve damage, and pulmonary
The commercially available pulse contour
artery rupture. In 2005, a study investigating
analysis systems can be classified as calibrated
the use of PACs in the management of
or non-calibrated. An overview is provided
intensive care patients (the PAC-Man study)
below.
found no clear evidence of benefit or harm.
Since then, the worldwide use of the PAC – Calibrated systems: PiCCO and LiDCO.
has significantly reduced, as intensivists move ▪ PiCCO (pulse contour cardiac output) uses
towards other (arguably less accurate) methods a standard central line and a thermistor-
of CO estimation, or alternatively abandon tipped arterial line, sited at the femoral,
CO monitoring entirely (see Further reading). brachial or axillary artery. CO is estimated
Pulse contour analysis. As discussed in by analysis of the arterial pressure
Chapter 33, the morphology of the arterial waveform. The PiCCO system is calibrated
pressure waveform is related to SV and SVR. using a transpulmonary thermodilution
A continuous estimate of CO is produced by method, in which cold saline is injected
means of a computer-based algorithm. The into the central line and the resulting blood
commercially available pulse contour analysis temperature change detected at the arterial
systems each use their own patented algorithm for line. This introduces an element of error
estimating CO (Figure 28.3). In addition to CO, a when compared with the thermodilution
number of other variables are measured or method using a PAC, as heat is dissipated
derived, including: as the cold injectate passes through
– HR the lungs.
– SV ▪ LiDCO (lithium dilution cardiac output)
– CI requires only a standard arterial line. The
– SV variation (SVV). arterial pressure waveform is analysed in a
126
similar way to PiCCO.6 The LiDCO system – aortic regurgitation

is calibrated by a lithium dilution method, – an intra-aortic balloon pump.
whereby lithium chloride is injected into a
peripheral or central vein and the fall in its
arterial concentration measured by a Describe the minimally invasive
lithium electrode sampling the arterial line. methods of cardiac output estimation
Recalibration should be performed every The proximity of the heart and great vessels to the
8 h, or whenever major haemodynamic oesophagus allows the use of ultrasound-based tech-
changes occur. The use of lithium avoids the niques to estimate CO. Two methods are commonly
error introduced by heat dissipation when used in clinical practice:
thermodilution is used for calibration.
However, the LiDCO cannot be calibrated Oesophageal Doppler (CardioQ). A small
ultrasound transducer mounted on the tip of
in patients who take therapeutic lithium
a flexible probe is inserted through the nose
(for example, bipolar disorder), and
or mouth into the oesophagus. The tip of the
frequent calibration (and therefore repeated
probe is adjusted so that it lies immediately
doses of lithium) results in inaccuracies. In
alongside the descending thoracic aorta. The
addition, muscle relaxants may cross-react
ultrasound beam is orientated at an angle of 45°
with the lithium electrode.
to the aortic blood flow, where it reflects off the
– Uncalibrated systems: FloTrac/Vigileo and
passing RBCs. As the RBCs are in motion, the
LiDCOrapid.
ultrasound beam is reflected at a different
▪ FloTrac/Vigileo: this system uses a frequency – this is the Doppler principle.
specialized pressure sensor (FloTrac) Using the Doppler equation, the velocity of
attached to a standard arterial line. blood flow within the descending thoracic
The pressure transducer is connected to aorta can be calculated:
a Vigileo monitor, where the arterial
pressure waveform is analysed. The Key equation: the Doppler equation
FloTrac/Vigileo algorithm is not externally
calibrated; instead, it uses an estimate of Fdc
V¼
aortic vascular compliance based on 2F 0 cos θ
population demographics and the patient’s where V is the velocity of blood in the descending
age, height, gender and weight. thoracic aorta, F0 is the transmitted ultrasound fre-
▪ LiDCOrapid: this system is based on the quency, Fd is the change in frequency (Doppler shift)
same pulse power analysis algorithm as of the reflected ultrasound, θ is the angle between
the LiDCO system. However, like the the ultrasound beam and the bloodstream (45°) and
c is the velocity of ultrasound in tissue (1540 m/s).
FloTrac/Vigileo system, LiDCOrapid is
uncalibrated, using nomograms based on
demographic data. Blood flow in the descending thoracic aorta is
In general, pulse contour analysis shows good determined by multiplying the measured blood
correlation with PAC thermodilution methods. velocity by the cross-sectional area of the
However, a number of situations may make pulse descending thoracic aorta, which is estimated
contour analysis inaccurate: from a nomogram (using the patient’s height and
weight) based on cadaveric studies.7 CO is
– an over- or under-damped arterial line trace calculated from aortic blood flow, on the basis that
– cardiac arrhythmias 70% of SV passes through the descending thoracic
aorta with the remainder flowing to the
6 upper body.
There is a subtle difference in the analysis of the arterial
pressure waveform using LiDCO – the algorithm is based
7
on ‘pulse power analysis’ rather than ‘pulse contour Newer machines use M-mode ultrasound to measure the
analysis’. diameter of the aorta.
127
Peak velocity Figure 28.4 Oesophageal Doppler

waveform.
Velocity (cm/s)
Area under curve (known as velocity–

time integral, VTI) = stroke distance
0 1 2 Time (s)
Flow time
Cycle time
In addition to SV, HR and CO, a number of However, there are a number of disadvantages:
other cardiovascular parameters are derived from – Oesophageal Doppler probes are poorly
the oesophageal Doppler waveform (Figure 28.4), tolerated in awake patients.
including:
– Movement of the probe may lead to a
– Stroke distance (SD), the area under the poor trace.
velocity–time curve. SD is the distance in – Surgical diathermy interferes with the trace.
centimetres that a column of blood moves – The estimates of aorta cross-section and the
along the aorta with each heart beat. division of SV may be inaccurate.
– Peak velocity (PV), the highest blood velocity – The use of oesophageal Doppler probes is
recorded during systole. PV is an indicator of contraindicated in patients with pharyngo-
left ventricular contractility. The normal range oesophageal pathology; for example,
of PV alters with age: 90–120 cm/s for a oesophageal varices.
20-year-old, decreasing to 50–80 cm/s for a
Trans-oesophageal echocardiography (TOE).
70-year-old.
The use of TOE is fast becoming standard
– Flow time corrected (FTc), the duration of in cardiothoracic anaesthesia and cardiac
blood flow when corrected for HR, which intensive care. Manipulation of a large
reflects left ventricular preload. Normal FTc is multiplane ultrasound transducer in the
330–360 ms. A low FTc suggests hypovolaemia oesophagus of an anaesthetized patient allows
or increased afterload, whilst a high FTc detailed two-dimensional views of the heart
suggests vasodilatation. and great vessels.
Oesophageal Doppler offers a number of advan- CO may be calculated in two ways using TOE:
tages over other methods: – Calculation from estimated volumes. The
– There is no requirement for arterial or central conical shape of the LV allows its EDV and
lines (though these are often already present in ESV to be estimated with reasonable accuracy,
a patient for whom CO monitoring is being by measuring the longitudinal and transverse
considered). diameters in systole and diastole. The
– Oesophageal tone helps to keep the probe in difference between EDV and ESV is SV, which
position, though repositioning is when multiplied by HR gives CO.
intermittently required. – Calculation using Doppler. Blood flow is
– No calibration is required. measured across the left ventricular outflow
– It provides a continuous cardiovascular tract using the Doppler principle and the
measurements. measured cross-sectional area.
128
In addition to CO, SV and HR, TOE gives useful wall motion abnormalities. However, the bulk and
information on the mechanical function of the expense of the equipment, and the extensive training
heart, identifying valve dysfunction and regional required, currently limit the widespread use TOE.
Further reading oesophageal Doppler monitoring.

Anaesthesia 2011; 66(12):
S. Jhanji, J. Dawson, R. M. Pearse.
Cardiac output monitoring: basic
K. E. Drummond, E. Murphy. 1081–7. science and clinical application.
Minimally invasive cardiac Anaesthesia 2008; 63: 172–81.
output monitors. Contin Educ C. G. Morris, R. M. Pearse. Pro–con
Anaesth Crit Care Pain 2012; 12(1): debate: we should not measure J. Brown, N. J. Morgan-Hughes. Aortic
5–10. cardiac output in critical care. stenosis and non-cardiac surgery.
J Inten Care Soc 2009; 10(1): Contin Educ Anaesth Crit Care Pain
S. Ghosh, B. Arthur, A. A. Klein. NICE 8–12. 2005; 5(1): 1–4.
guidance on CardioQTM
129
Chapter
Starling’s law and cardiac dysfunction
29
What is Starling’s law of the heart? At 3.6 μm there is no overlap between actin and
myosin myofilaments; the active tension
The Frank–Starling law (also known as Starling’s law developed is zero (Figure 29.2d).
of the heart) states that the strength of ventricular
contraction is dependent on the length of the resting At a given sarcomere length, the contractility of
fibres. In other words, when all other factors are kept cardiac muscle exceeds that of skeletal muscle. It is
constant, an increase in left ventricular preload causes now known that in addition to the length–tension
SV to increase, without the need for extrinsic neural relationship, a ‘length-independent’ mechanism is in
or humoral regulatory mechanisms. As left ventricu- operation. This may be a consequence of a different,
lar preload (i.e. LVEDV) is difficult to measure, Ca2+-sensitive troponin C isoform in cardiac muscle,
LVEDP is often used as its surrogate marker. The which is not present in skeletal muscle. As an increase
relationship between SV and LVEDP is nonlinear in preload stretches the cardiac sarcomere, the sensi-
(Figure 29.1). tivity of troponin C for Ca2+ ions increases, which
The mechanism of Starling’s law remains incom- increases the rate of actin–myosin crossbridge
pletely understood. It has been attributed to the cycling; that is, contractility is increased.
degree of overlap of the actin and myosin myofila- The most important consequence of the Frank–
ments in diastole, which in turn determines the extent Starling mechanism is the matching of SV between
of crossbridge formation on activation. This is known the right and left sides of the heart. An increase in
as the length–tension relationship: venous return to the right ventricle increases its
The maximal force of contraction occurs when the SV, resulting in a greater pulmonary blood flow,
sarcomere is stretched to around 2.2 μm. This a greater LVEDV and hence a greater left ventri-
length corresponds to an optimal point where the cular SV. If the LV ejected just 1 mL of blood less
number of actin and myosin crossbridges formed than the right ventricle per cycle, after an hour the
is high (Figure 29.2b) but there is no overlapping pulmonary circulation would contain over 3 L of
of the thin filaments. In a normal heart, this additional blood.
optimal sarcomere length corresponds to an
LVEDP of approximately 10–12 mmHg.
What is cardiac failure?
When the sarcomere is shorter than 2.2 μm (i.e.
Cardiac failure (or heart failure) is said to occur
EDV is decreased, and the sarcomere is less
when the heart is unable to provide sufficient CO to
stretched), overlapping of thin filaments reduces
meet the demands of the tissues. Heart failure may
the tension that may be generated (Figure 29.2a):
either be:
– contractile energy is lost due to work against
High-output heart failure: CO is normal but the
friction;
tissue O2 demand is high; for example,
– the sarcomere becomes distorted. thyrotoxicosis and pregnancy.
When the sarcomere is stretched beyond 2.2 μm, Low-output heart failure: the tissue’s O2 demand
fewer actin–myosin crossbridges are formed; the is normal, but the CO is insufficient to meet it.
force of contraction is thus reduced (Figure 29.2c).
This situation does not occur in the normal heart, In low-output failure, the right or left ventricles may
but may occur in ventricular failure. be affected, resulting in RVF or LVF respectively.
130
Chapter 29: Starling’s law and cardiac dysfunction
Figure 29.1 The Frank–Starling curve.

Normal operating range
Positive inotropy
100
Normal
Stroke volume (mL)
75
Negative inotropy
50
25
0
0 5 10 15 20
Left ventricular end-diastolic pressure (mmHg)
(b)
100
(a) (a) (c)
Tension (% of maximum)
75
(b)
50
(c)
25 Normal range of
sarcomere length
(d)
(d)
0
1.0 1.5 2.0 2.5 3.0 3.5
Thick (myosin-containing) filament Thin (actin-containing) filament Sarcomere length (mm)
Figure 29.2 Tension developed at different cardiac sarcomere lengths.
In addition, progressive pump failure of the LV may following myocardial infarction and scar
lead to RVF – this is known as congestive cardiac formation. The reduction in SV leads to an
failure. Heart failure may be classified as follows. increased LVEDV, and in turn the size of the
heart is increased; this pathological dilatation
Systolic heart failure, in which the pump function of the heart is known as cardiomegaly.
of the heart is impaired; that is, EF is reduced – Chronically raised afterload; for example,
to below 45% (Figure 29.3). Systolic heart systemic hypertension or aortic stenosis.
failure occurs when the strength of myocardial Chronically increased afterload causes a
contraction is inadequate, due to: compensatory left ventricular concentric
– Dysfunction of myocytes, as a result of hypertrophy. Over time, further increases
ischaemia (coronary artery disease), in afterload exceed the heart’s ability to
inflammation (myocarditis), congenital compensate by hypertrophy. SV falls and
disease (Duchenne muscle dystrophy), or LVEDV increases.
131
Figure 29.3 Reduced contractility in

systolic heart failure.
100
Normal SV of 70 mL
Normal ventricle
75
Stroke volume (mL)
Reduced SV
Failing ventricle
50
25
Normal LVEDV of 120 mL
0
0 20 40 60 80 100 120 140 160 180 200
Left ventricular end-diastolic volume (mL)
Whatever the cause, the heart must then expend heart failure. Annual mortality in diastolic heart
more energy to achieve a normal SV. This increases failure is 8% – less than that of systolic heart failure.
myocardial O2 demand, thus reducing cardiac Again, these patients suffer significant morbidity.
reserve – a vicious positive feedback ensues during
periods of increased demand (for example, during What is compensated heart failure?
exercise), where increased myocardial O2 demand
Compensated heart failure refers to the situation in
in the face of low output exacerbates the failure.
which ventricular function is impaired, but CO is still
At 20%, the annual mortality of patients with
normal as a result of two compensatory mechanisms
systolic heart failure is higher than many cancers;
(Figure 29.4):
patients also suffer considerable morbidity.
Sympathetic stimulation. This causes both an
Diastolic heart failure, in which ventricular
increase in myocardial contractility and an
compliance is reduced, either as a result of
increase in HR, thereby maintaining CO despite
impaired ventricular relaxation (for example,
the reduced SV. Over time, the heart becomes less
ischaemic heart disease, restrictive
responsive to this sympathetic nervous system
cardiomyopathy) or as a result of pathological
activity, as β-receptors are downregulated.
ventricular hypertrophy (for example,
hypertension, hypertrophic obstructive An expansion in blood volume. A reduction in
cardiomyopathy, aortic stenosis). Reduced CO results in a fall in renal blood flow (RBF). The
ventricular compliance leads to impaired kidneys respond by increasing plasma volume
ventricular filling and thus reduced SV. Because through the renin–angiotensin–aldosterone
atrial contraction makes a significant contribution (RAA) axis; the increase in blood volume results
to ventricular filling in these patients, a fourth in an increase in left ventricular preload. An
heart sound may be heard. The development increase in LVEDV results in an increase in SV,
of AF significantly reduces ventricular filling; according to Starling’s law. This is offset to some
a high atrial rate results in reduced diastolic filling extent through the production of ANP and BNP
time, thus reducing LVEDV further. Rate control by the heart, resulting in a natriuresis.
using β-blockers or Ca2+-channel antagonists
helps prevent this. As the disease progresses, the heart reaches a point
where, despite compensatory mechanisms, it can no
Diastolic heart failure is recognized as being increas- longer eject a normal SV. CO then falls, resulting
ingly common, and often coexists with systolic in a situation termed ‘decompensated heart failure’.
132
Chapter 29: Starling’s law and cardiac dysfunction
Sympathetic stimulation increases contractility Figure 29.4 Compensated heart failure.
100
Slightly reduced SV, but
compensated for by increased HR
Normal ventricle
Stroke volume (mL)
75
Failing ventricle with sympathetic compensation
Failing ventricle without sympathetic compensation

50
25
Slightly increased LVEDV, but not as much as
would be needed without sympathetic stimulation
0
0 20 40 60 80 100 120 140 160 180 200
Left ventricular end-diastolic volume (mL)
Figure 29.5 The Frank–Starling curve in

decompensated heart failure.
100
The sarcomeres are overstretched – further

Stroke volume (mL)
75
increases in LVEDV result in reduced SV
50
25
Decompensated heart failure
0
0 20 40 60 80 100 120 140 160 180 200
Left ventricular end- diastolic volume (mL)
The cardiac sarcomeres are stretched beyond their produce a lower pressure than a ventricle of smaller
optimal length and the tension generated during radius. This again increases the myocardial work
contraction is reduced (Figure 29.2). Beyond the required to generate the same pressure.
optimum sarcomere length, increases in preload only
serves to further decrease SV, represented by the
Frank–Starling curve in Figure 29.5. Additionally, What are the clinical consequences
when the heart has a large ventricular radius, it is at of decompensated heart failure?
a mechanical disadvantage due to Laplace’s law: Decompensated heart failure has many effects, classi-
fied into forward heart failure and backward heart
Key equation: Laplace’s law
failure:
For a sphere with only one surface:
Forward heart failure. The heart is unable to
2T pump sufficient blood to meet the metabolic
P¼
r demands of the body. Consequences of left
where P is the transmural pressure, T is the surface ventricular forward heart failure include:
tension and r is the radius. – Renal failure. Reduced RBF causes kidney
dysfunction and activation of the RAA axis.
Therefore, for the same active tension generated in This has the effect of further expanding plasma
the ventricular wall, an LV of greater radius will volume, exacerbating backward heart failure.
133
– Exercise. The LV cannot meet the increased O2 to the heart. As the LV is unable to increase
demand associated with exercise, resulting in its output any further, the effect of this
fatigue. As heart failure worsens, the onset of increase in blood volume is further pulmonary
fatigue occurs after minimal exercise, and oedema. This leads to paroxysmal nocturnal
then at rest. This is reflected in the New York dyspnoea.
Heart Association classification of heart
– Increased RAP results in an increase in CVP:
failure.
the Starling filtration forces favour fluid
– Coronary circulation. Acute left ventricular extravasation, initially in the dependent
dysfunction may lead to cardiogenic shock: areas, resulting in ankle and sacral oedema.
reduced CO causes a fall in coronary blood More advanced RVF results in ascites and
flow. In turn, myocardial ischaemia reduces hepatomegaly, which may be associated with
myocardial contractility, reducing CO further liver dysfunction (for example, coagulopathy).
and leading to a vicious cycle.
Backward heart failure. The increase in LVEDV
results in an abnormally high atrial pressure: Further reading
– Increased left atrial pressure causes an increase H. Fukuta, W. C. Little. The cardiac cycle and the
in interstitial pressure in the pulmonary physiological basis of left ventricular contraction,
circulation. As left atrial pressure increases, ejection, relaxation and filling. Heart Fail Clin 2008; 4
the balance of Starling filtration forces (see (1): 1–11.
Chapter 34) favours fluid extravasation in the R. Pirracchio, B. Cholley, S. De Hert, et al. Diastolic heart
lung bases, resulting in pulmonary oedema failure in anaesthesia and critical care. Br J Anaesth 2007;
and dyspnoea. Chronically increased 98(6): 707–21.
pulmonary venous pressure increases right L. Groban, J. Butterworth. Perioperative management of
ventricular afterload, which may cause RVF. chronic heart failure. Anesth Analg 2006; 103(3): 557–75.
When the patient is supine (for example, L. Mandinov, F. R. Eberli, C. Seiler, et al. Diastolic heart
overnight), redistribution of blood from failure. Cardiovasc Res 2000; 45(4):
the legs further increases the venous return 813–25.
134
Chapter
Pressure–volume loops
30
Describe the left ventricular Isovolumetric relaxation, a vertical line
representing the fall in intraventricular
pressure–volume loop pressure without a change in ventricular
The left ventricular pressure–volume loop provides a volume.
useful representation of left ventricular performance Diastolic ventricular filling, in which the
through the cardiac cycle (Figure 30.1; see also ventricle fills with blood ready for the next
Figure 27.1). contraction.
In a normal LV, the pressure–volume loop is
approximately rectangular and can be divided into
four phases:
How does the pressure–volume loop
Isovolumetric contraction, a vertical line
representing the increase in intraventricular change when preload is increased?
pressure without a change in ventricular volume. Preload can be thought of as the volume of blood within
Ventricular ejection, in which the SV is ejected the ventricle prior to contraction (see Chapter 28). For
into the aorta. the LV, it is the LVEDV. According to Starling’s law, an
Figure 30.1 Pressure–volume loop of

the normal LV.
140 Aortic valve
Vent
closes ricula
r eje
ction
120
Systolic BP
Left ventricular pressure (mmHg)
Aortic valve opens

100
Diastolic BP
80
Isovolumetric
Isovolumetric
relaxation
contraction
60
40
Mitral valve Mitral valve closes

opens
20
Diastolic filling
End-diastolic volume
0
0 20 40 60 80 100 120 140 160
Left ventricular end- Left ventricular volume (mL)
diastolic pressure Stroke volume
End-systolic volume
135
Systolic and diastolic BP increase slightly Figure 30.2 Effect of increased preload
on the pressure–volume loop (EDPVR:
140
end-diastolic pressure–volume
relationship).
120
100
80
60
40 LVEDP
increased EDPVR
20
Higher end-diastolic
volume
0
0 20 40 60 80 100 120 140 160 180 200
Left ventricular volume (mL)
Stroke volume increased
increase in preload results in a greater diastolic stretch As a reduced volume of blood is ejected from the
of the contractile myocardial fibres (see Chapter 29). LV, LVESV is increased.
The stretched sarcomeres contract more forcefully, thus In turn, the addition of the venous return leads to
increasing SV (Figure 30.2). an increase in LVEDV.
Figure 30.2 illustrates a number of important According to Starling’s law, an increase in LVEDV
features: causes an increase in myocardial contractility.
The width of the pressure–volume loop, which Thus, SV increases, returning LVEDV to near
represents SV, is increased due to the increase in normal.
LVEDV. The LVESV increases slightly due to an
Overall, the increase in LVESV is greater than that of
increase in afterload (aortic pressure) caused by
LVEDV. SV is slightly decreased, and the left ven-
the greater CO.
tricular pressure–volume loop looks taller and thinner
The EDPVR line reflects the passive diastolic (Figure 30.3).
compliance of the LV. Beyond a certain preload,
LVEDP increases sharply reflecting the nonlinear
compliance of the left ventricular wall. This is due How does an increase in myocardial
to the elastic proteins and connective tissue within
the myocardium reaching their elastic limit.
contractility alter the pressure–volume
loop?
Myocardial contractility may be altered extrinsically
How does the pressure–volume loop by the ANS, circulating hormones or positively ino-
change when afterload is increased? tropic drugs. It is therefore independent of preload
Afterload is the stress developed in the left ventricular and afterload. Graphically, increased contractility
wall during ejection, and reflects the force opposing (positive inotropy) increases the gradient of the
the shortening of cardiac myocytes. As afterload ESPVR line (Figure 30.4).
increases – for example, due to an increase in diastolic The increased strength of myocardial contraction
aortic pressure – both the rate and extent of sarcomere ejects additional blood, resulting in a lower LVESV.
shortening decrease, resulting in a reduction in SV: Following the addition of venous return, LVEDV is
136
Chapter 30: Pressure–volume loops
ESPVR Figure 30.3 Effect of increased

afterload on the pressure–volume loop
(ESPVR: end-systolic pressure–volume
relationship).
160
Increased systolic
140 and diastolic BP
Increased afterload
120
100
80
60
40
EDPVR
20
0
0 20 40 60 80 100 120 140 160 180 200
Stroke volume Left ventricular volume (mL)
reduced
reduced. As positive inotropy decreases LVESV more heat energy during diastole; that is, the energy
than LVEDV, overall SV is increased. expended is potential energy. The area enclosed
within the ESPVR, the EDPVR and the
isovolumetric relaxation lines represents the
How is the left ventricular pressure– internal work.
volume loop related to cardiac work?
The mechanical work of the heart can be divided into: The total work done – that is, the sum of external
External work (or stroke work), the kinetic and internal work – is known as the pressure–volume
energy expended when blood is ejected under area (PVA). PVA correlates surprisingly well with the
pressure from the ventricle. The area enclosed by myocardial O2 consumption for the heart. Note:
the ventricular pressure–volume loop (i.e. whilst mechanical work accounts for most of the
pressure times volume) represents the external heart’s energy expenditure, basal metabolism accounts
work done during a single cardiac cycle for a small percentage, resulting in a small discrepancy
(Figure 30.5). between PVA and myocardial O2 consumption.
Internal work, the energy expended during Looking back at this chapter’s previous figures, it
isovolumetric contraction. It is sometimes known can be seen that:
as ‘pressure-work’. As contractile protein Increased preload leads to increased external work
shortening does not occur, the energy expended (Figure 30.2); thus myocardial O2 demand is
during isovolumetric contraction is converted to higher.
137
ESPVR Figure 30.4 Effect of increased

contractility on the pressure–
volume loop.
160
Increased contractility
140
120
100
80
60
40 LVEDV is
slightly lower
LVESV is lower
20
0
0 20 40 60 80 100 120 140 160
Stroke volume Left ventricular volume (mL)
is increased
Increased afterload may not increase external ventricle must overcome a much lower afterload,
work significantly, but does increase internal work as PVR and thus pulmonary artery pressure
(Figure 30.3); thus, myocardial O2 demand are low.
increases. Despite pumping the same volume of blood
Increased myocardial contractility may not (i.e. the SV), the area enclosed by the right
increase internal work, but does increase external ventricular pressure–volume loop (i.e. the stroke
work (Figure 30.4). Overall, myocardial O2 work) is only 20–25% that of the left
consumption is increased. ventricular loop.
Ejection of blood from the right ventricle begins
How does the pressure–volume loop of early in systole: right ventricular volume starts to
the right ventricle compare with that of fall shortly after right ventricular pressure
increases.
the left? In the right ventricle, stroke work makes up a
The right ventricular pressure–volume loop has a greater proportion of the total work than the LV
characteristic triangular shape (Figure 30.6). Some does. The right ventricle is therefore more
important points regarding Figure 30.6 are: susceptible to failure in the presence of pulmonary
The pressure developed within the right ventricle hypertension than the LV is in the presence of
is significantly lower than that of the LV; the right systemic hypertension.
138
Chapter 30: Pressure–volume loops
Figure 30.5 External and internal work

expended during the cardiac cycle.
ESPVR
140
Area =
120 internal work
100
Area = external work
80
60
40 EDPVR
20
0
0 20 40 60 80 100 120 140 160 180 200
Figure 30.6 Right ventricular pressure–

volume loop.
Ejection
30
Right ventricular pressure (mmHg)
25
20
Ventricular Ventricular
relaxation contraction
15
10
5
Diastolic filling
0
0 20 40 60 80 100 120 140 160
Right ventricular volume (mL)
failure results in a reduction in myocardial contract-

How does the left ventricular pressure– ility (reduced gradient of the ESPVR line) and an
volume loop change in heart failure? increase in LVEDV. A sub-normal SV is ejected from
As discussed in Chapter 29, LVF is classified as sys- the LV, resulting in a higher than normal LVESV
tolic, diastolic or mixed. Left ventricular systolic (Figure 30.7).
139
Reduced Figure 30.7 Left ventricular systolic

contractility ESPVR failure.
140
120
100
80
60
EDPVR
40
20 Increased EDV
0
0 20 40 60 80 100 120 140 160 180 200
Stroke volume
reduced
ESPVR unchanged Figure 30.8 Left ventricular diastolic

failure.
140
120
100
80
Increased LVEDP, reduced LVEDV
60 EDPVR
Reduced left
ventricular compliance
40
20
0
0 20 40 60 80 100 120 140 160 180 200
Stroke volume
reduced
Left ventricular diastolic failure is due to reduced Further reading

left ventricular compliance. The EDPVR line follows a
R. E. Klabunde. Cardiovascular Physiology Concepts, 2nd
different course, but the contractility of the LV (the edition. Lippincott Williams & Wilkins, 2011.
ESPVR line) is unchanged. Overall, SV is reduced
(Figure 30.8).
140
Chapter
Systemic circulation
31
The cardiovascular system distributes blood around The arterial system, consisting of arteries and
the body. It is divided into the pulmonary circulation arterioles.
and the systemic circulation. The systemic circulation Capillaries.
is a ‘pressure-constant, flow-variable’ system. The venous system, consisting of venules
and veins.
What are the functions of the
Only 15% of circulating blood volume is found within
circulation? the arterial system. Most of the circulating blood,
Functions include: 65%, is found within the venous system due to its
Transport of O2 from the lungs to the tissues. greater compliance. The veins thus act as an import-
Transport of CO2 from the tissues to the lungs. ant reservoir for blood, with venous tone responsible
Transport of metabolic waste products from the for maintaining venous return to the right atrium.
tissues to the liver and kidneys for excretion. The remainder of the circulating volume is found
Distribution of nutrients from the sites of within the pulmonary circulation (10%), the cardiac
absorption (gut) or production (liver) to the tissues. chambers (5%) and the capillaries (5%).
Distribution of body water and electrolytes
between intracellular, interstitial and intravascular
body compartments. What are the main differences between
Transport of immunologically active substances the systemic and pulmonary
(antibodies, leucocytes, complement).
Transport of hormones from their site of circulations?
production (for example, the parathyroid gland) The primary function of the pulmonary circulation
to their target site (for example, the kidney). is the transport of blood from the right ventricle
Production of hormones (for example, ANP). to the lungs, for participation in gas exchange (see
Assisting in thermoregulation by redistributing Chapter 22). The right ventricle, therefore, acts as a
blood flow between the core organs and the skin. flow generator around a low-resistance pulmonary
circulation. This is in contrast to the role of the
The transport and distributive properties of the cir- systemic circulation, where the LV generates pressure
culation are utilized by anaesthetists to distribute a in the arterial system. This pressure is then used as
range of substances: drugs, fluids, nutrition and heat. the energy gradient to perfuse tissues (create flow)
according to the demand. The transport of blood
What are the constituent parts of the from the LV to the rest of the body is thus determined
by local tissue metabolism, or by stereotyped
systemic circulation? responses (for example, an increase in sympathetic
The systemic circulation is composed of: outflow). The main differences between the two
A ‘pump’, the LV, that drives blood through the circulations stem from this pressure difference
vessels. (Table 31.1).
141
Table 31.1 Differences between the systemic and pulmonary circulations.
Systemic circulation Pulmonary circulation

Arteries
Typical pressure (systolic/diastolic) 140/80 mmHg 25/8 mmHg
Typical mean pressure 100 mmHg 15 mmHg
Vessel wall Thick walled, elastic Thin walled, distensible
Resting vasoconstrictor tone Highly constricted at rest No vasoconstrictor tone at rest
Arterioles
Vessel wall Thick walls, small lumen, muscular Thin walls, large lumen
Vessel resistance High resistance, typical SVR Low resistance, typical PVR
1600 dyn s cm 5 160 dyn s cm 5
Response to hypoxia Vasodilatation Vasoconstriction
Capillaries
Wall thickness Thin, to allow exchange of O2, CO2 and Extremely thin, to allow efficient gas
nutrients exchange
Blood flow Owing to high resistance in arterioles, Low resistance in arteries and
flow is continuous arterioles means blood flow is still
pulsatile at the capillaries
Distensibility/compressibility Little change in radius, as little change Compressible with increased alveolar
in external/internal pressures pressure; distensible with increased
pulmonary venous pressure
Veins
Typical mean pressure 2 mmHg 5 mmHg
Venous reservoir High venous capacitance, holding Only holds around 500 mL of blood
>1000 mL which can be released back which can be released back into the
into the circulation if required circulation if required
What happens to blood velocity as For a typical adult, aortic cross-sectional area is
4 cm2, whilst the mean blood velocity in the aorta
blood passes through the systemic is 20 cm/s. Therefore, typical aortic blood flow is
circulation? 80 cm3/s (i.e. 80 mL/s). At an HR of 60 bpm, there
There is an important relationship between blood is one cardiac cycle per second; that is, SV is 80 mL.
velocity, flow and cross-sectional area: As blood passes along the arterial system, large
arteries branch into many small arteries, small arter-
Key equations: blood velocity and flow ies branch into many arterioles, and so on. The cross-
section of each individual blood vessel decreases as its
Q_ radius decreases. However, the overall cross-sectional
V¼
A area A summed over all the vessels at a given level of
where V (cm/s) is the blood velocity (the distance bifurcation increases dramatically. The total blood
travelled per unit time), Q̇ (mL/s) is the blood flow flow Q̇ remains the same (i.e. CO of 80 mL/s); so, as
(the volume of blood passing a point per unit time) _
V ¼ Q=A, if Q̇ remains constant and A is signifi-
and A (cm2) is the cross-sectional area of the cantly higher, then the velocity of blood flow must
vessel. be significantly reduced (Figure 31.1).
142
Chapter 31: Systemic circulation
20 cm/s Figure 31.1 Changes in velocity and

4000 cm2 20 cross-sectional area across the systemic
circulation.
1000
Cross-sectional area (cm2)
15
Mean velocity (cm/s)

12 cm/s
100
10
10 7 cm2 5
4 cm2
0.2 mm/s
1 0
Aorta Arteries Arterioles Capillaries Venules Veins Vena cavae
Type of vessel
The capillaries account for a combined cross- lower half of the body combine to form the IVC, and
sectional area of around 4000 cm2 (Figure 31.1). Total those from the upper half of the body form the SVC.
blood flow is the same, so the velocity of blood flow The blood flow entering the right atrium is approxi-
through the capillaries is mately equal to CO, allowing for some fluid being
filtered into the interstitial space and carried away by
Q_ 80 the lymphatics. The cross-sectional area of the venae
V¼ ¼ ¼ 0:2 mm=s
A 4000 cavae is 7 cm2, so the velocity of blood flow rises to
that is, slow enough to allow capillary–tissue exchange. 12 cm/s (Figure 31.1).
As blood is moved from the capillaries to the
venules and then to the veins, the cross-sectional area Further reading
of each individual vessel increases, but the total cross- W. R. Levick. An Introduction to Cardiovascular Physiology,
sectional area decreases. Eventually, all veins in the 5th edition. London, Taylor & Francis Ltd, 2009.
143
Chapter
Arterial system
32
The arterial system is the high-pressure component of and recoil in diastole, thereby maintaining the
the systemic circulation. The arterial system divides diastolic pressure. The expansion and recoil of the
from the aorta into large arteries, smaller arteries and elastic arteries acts to dampen the pulsatile arterial
finally arterioles before joining the capillary networks. blood flow.
Arteries normally carry fully oxygenated blood to the Muscular arteries: medium-sized arteries, which
capillaries. The two exceptions are the pulmonary follow on from the large elastic arteries and, in
arteries and the umbilical arteries in the fetus. turn, divide into the smaller ‘resistance’ arterioles.
Muscular arteries supply individual organs;
examples include the renal and coronary arteries.
Describe the cross-section of an artery Their tunica media are composed primarily of
A thick muscular wall surrounds the normally circu- smooth muscle, whose diameter is tonically
lar arterial lumen. The arterial wall is made up of controlled by the sympathetic nervous system:
three layers:
– Increased sympathetic activity results in
Tunica externa (formerly known as the tunica smooth muscle contraction (vasoconstriction),
adventitia), the outermost layer, made up of loose which narrows the vessel lumen and reduces
connective tissue, such as collagen fibres. blood flow.
Tunica media, a thick layer of circumferential – Reduced sympathetic activity permits
smooth muscle and elastic tissue. vasodilatation, which increases the lumen
Tunica intima, the innermost layer, comprising a diameter and increases blood flow.
single layer of endothelial cells. Some larger vessels
There is little or no parasympathetic
also have a subendothelium, made up of
innervation of the arterioles, although the walls
connective tissue and basement membrane.
do contain muscarinic ACh receptors, perhaps
Larger arteries have their own blood supply: the vasa for some local, paracrine effects.
vasorum, a network of small blood vessels that supply
the outer layers of the arterial wall.
What is the mathematical relationship
between vessel radius and resistance
Are there different types of artery? to blood flow?
Arteries are subclassified into two types:
Laminar flow of an incompressible, Newtonian fluid
Elastic arteries: the more proximal, larger arteries; in a rigid tube with a circular cross-section is nor-
that is, the aorta and its immediate branches. mally governed by the Hagen–Poiseuille equation:
Their role is the conduction of blood. The
relatively large radius of these arteries results in Key equation: Hagen–Poiseuille equation
their resistance to blood flow being low. Elastic
_
8Qηl
arteries have more elastic tissue than muscular ΔP ¼
tissue in their tunica media, allowing them to πr 4
withstand the high pressure generated by the heart where ΔP is the pressure drop along the tube, Q̇ is
during systole. The arteries expand in systole, flow, η is viscosity, l is tube length and r is radius.
accommodating the blood ejected from the heart,
144
Chapter 32: Arterial system
reduced haematocrit increases blood flow; a

The equation can also be rearranged to give
haematocrit of around 0.3 is considered to be
4
ΔPπr the optimal balance between blood flow and
Q_ ¼
8ηl O2-carrying capacity.
Darcy’s law states that pressure equals flow times – Temperature. Viscosity increases as
resistance; so, if ΔP is pressure and Q̇ is flow, then temperature decreases. This is relevant in
the resistance to flow is 8ηl/πr4. intensive care: patients who are cooled
following cardiac arrest have an increased
blood viscosity; thus, blood flow is decreased
According to the Hagen–Poiseuille equation, the at a time when flow may already be low due to
most important factor affecting flow is the tube coexisting cardiogenic shock.
radius, owing to its fourth power. For example, – Fahraeus–Lindqvist effect. At vessel diameters
doubling the radius produces a 16-fold increased below 300 μm (i.e. arterioles), RBCs tend to
flow. However, the Hagen–Poiseuille equation pro- stream towards the centre of the vessel, leaving
vides only an approximation of blood flow, because: the plasma at the vessel walls. As plasma has a
The pressure drop along the vessel is not lower viscosity than whole blood, the resistance
continuous – it has a pulsatile component. to blood flow is reduced. This Fahraeus–
Blood does not behave like a Newtonian Lindqvist effect opposes the tendency for
fluid – instead, it varies with: resistance to increase as the vessel radius
– Flow rate. At low blood flow, there is increased decreases, especially in arterioles and capillaries.
interaction between RBCs: they aggregate into Vessels are not uniform rigid tubes
rouleau, thereby increasing blood viscosity, – Vessels are non-uniform. They may have
and thus resistance to flow is greater. At branches, turn corners or be narrowed due
normal flow rates, aggregation is prevented by to atherosclerotic plaques or external
negatively charged sialic acid residues on the compression.
RBC surface repelling other RBCs. – Vessels are distensible. According to the
– Haematocrit. Interactions between RBCs Hagen–Poiseuille equation, a rigid tube has a
means that high haematocrit is associated with constant resistance: flow is therefore
a greater overall blood viscosity. In anaemia, a proportional to pressure (Figure 32.1).
Figure 32.1 Comparison of distensible

Distensible vessel vessels, rigid tubes and myogenic
Rigid tube response.
Distensible vessel with

some myogenic response
Flow
Autoregulation
Pressure
145
However, large vessels are distensible: an because mechanically gated ion channels in the
increase in pressure causes an increase in vascular wall are opened by stretch, leading to
vessel radius, which reduces resistance and the opening of voltage-gated Ca2+ channels,
thus increases flow. In contrast, if the pressure Ca2+ influx and thus to contraction of
falls near to zero (as may occur in veins), the arteriolar smooth muscle. Likewise, arterioles
vessel tends to collapse, resulting in no flow. vasodilate in response to reduced intraluminal
– Myogenic autoregulation is the intrinsic ability pressure. The overall effect is the maintenance
of an arteriole to maintain a constant blood of a relatively constant blood flow over a range
flow despite changes in intraluminal pressure of intraluminal pressures. Autoregulation is an
(see below) (Figure 32.1). important feature of arterioles in the brain,
heart and kidney, but does not occur in
What are the functions of the the skin.
– Metabolites. The tissues regulate blood flow in
arterioles? proportion to their metabolic rate. When an
The arterioles are the vessels with the smallest radii of organ increases its metabolic activity, the local
the arterial tree, and are therefore the main source of O2 tension falls and the concentration of
resistance to blood flow. Structurally, their tunica metabolites (CO2, H+ ions, lactate) increases.
media is made up of one or two layers of circumferen- The arteriole vasodilates in response to
tial smooth muscle. Vasoconstriction increases the increased metabolite concentration, increasing
vessel’s resistance to blood flow; this is very sensitive blood flow and therefore O2 delivery to the
owing to the fourth power relationship of the radius tissues. This is thought to be the mechanism
in the Hagen–Poiseuille equation. Likewise, vasodila- behind reactive hyperaemia: the large increase
tation reduces the vessel’s resistance to blood flow. in blood flow following temporary cessation of
Compared with arteries, the arterioles lack elastin in organ perfusion (for example, critical limb
their tunica media. Pulsatile blood flow is damped, ischaemia) or following deflation of an arterial
becoming continuous flow by the time the blood tourniquet in limb surgery.
reaches the capillaries. Humoral factors
In addition to conducting blood from small arter- A number of locally and systemically produced
ies to the capillaries, the arterioles have three other chemical substances affect arteriolar smooth
roles: muscle tone, including:
Control of the distribution of blood flow to – Kinins (for example, bradykinin), which cause
different organs by altering organ vascular vasodilatation in the salivary glands, gut
resistance. and skin.
Control of total SVR. – Histamine, released from basophils and mast
Alteration of capillary hydrostatic pressure, cells as part of the inflammatory response. The
effectively controlling bulk flow of water between resulting arteriolar vasodilatation increases
intravascular and interstitial body fluid blood flow to the affected tissues. During
compartments (see Chapter 34). allergic reactions, the systemic release of
histamine is responsible for widespread
Which factors are involved in arteriolar arteriolar vasodilatation.
vasoconstriction and vasodilatation? – NO, previously known as endothelium-derived
relaxing factor (EDRF), released from the
The control of arteriolar smooth muscle is complex,
endothelium in response to shear stress. NO is
influenced by local, humoral and neural factors.
a potent arteriolar vasodilator, increasing
Local factors blood flow to the damaged area. NO also
– Myogenic autoregulation. This is an intrinsic causes venodilatation; this is the mechanism
property of the arteriolar smooth muscle in underlying a technique familiar to all
which the vessel vasoconstricts in response to anaesthetists: tapping the skin overlying a
increased intraluminal pressure. This occurs peripheral vein prior to cannulation.
146
– Serotonin and thromboxane A2 are released like adrenaline, activates arteriolar α1-
from platelets when they are activated; for adrenoceptors, resulting in vasoconstriction.
example, when a blood vessel is cut. Both In contrast to adrenaline, noradrenaline only
chemicals cause arteriolar vasoconstriction, weakly activates β2-adrenoceptors, causing
which reduces the local blood flow, minimal arteriolar vasodilatation. Sympathetic
allowing the clot to form without it being nervous stimulation causes arteriolar
washed away. vasoconstriction in the skin, kidneys and gut,
– Adrenaline activates both α1-adrenoceptors, where α1-adrenoceptors are plentiful, but has
resulting in vasoconstriction, and β2- minimal effect on the arterioles of the brain
adrenoceptors, resulting in vasodilatation. The and heart, which have relatively few α1-
response of arterioles to adrenaline differs adrenoceptors. Sympathetic stimulation
between organs, depending on their relative therefore preferentially directs blood flow to
proportions of α1- and β2-adrenoceptors. In these vital organs.
the gut and skin there is a high concentration – Parasympathetic nervous system.
of arteriolar α1-adrenoceptors: adrenaline Parasympathetic control of arteriolar smooth
causes vasoconstriction, resulting in reduced muscle tone is only found in the penis, where
blood flow. In contrast, heart and skeletal parasympathetic stimulation results in
muscle have high concentrations of β2- vasodilatation and erection.
adrenoceptors, the activation of which causes – Skeletal muscle. Skeletal muscle is unique.
vasodilatation. It possesses a sympathetic cholinergic
– ADH (or arginine vasopressin), which is pathway, which is only activated following
synthesized in the hypothalamus and released the onset or anticipation of exercise, fear,
from the posterior lobe of the pituitary gland anger or pain. ACh is released at post-
in response to low plasma volume and high ganglionic nerve endings instead of
plasma osmolarity. In addition to its anti- noradrenaline, resulting in arteriolar
diuretic effect on the collecting ducts, ADH is vasodilatation and a substantial increase
a potent arteriolar vasoconstrictor. This effect in skeletal muscle blood flow.
is unimportant in health, but is an important
mechanism for maintaining blood pressure in
haemorrhage. Vasopressin is used clinically as How can the combined resistance of all
an arteriolar vasoconstrictor in the intensive
care unit: patients with septic shock have been arterioles be calculated?
shown to have relatively reduced ADH The combined resistance of all arterioles in the arter-
concentrations. ial system is the SVR. This can be calculated by using
– Other hormones. Angiotensin II is a potent Darcy’s law:
arteriolar vasoconstrictor, whilst ANP is an
Key equation: systemic vascular resistance
arteriolar vasodilator that also decreases the
sensitivity of the arterioles to other Darcy’s law states:
vasoconstrictors. Together with ADH, these pressure difference ¼ flow × resistance
hormones are normally concerned with When considering the systemic circulation as a
control of blood volume and total body water. single circuit:
Neural factors ‘Pressure difference’ refers to the difference in
– Sympathetic nervous system. The arterioles pressure between the arterial and venous
have a rich sympathetic nervous supply; the circulations.
basal sympathetic outflow is responsible for Flow is the CO.
Resistance is the SVR.
setting the resting arteriolar smooth muscle
tone. Activation of the sympathetic nervous Therefore:
system results in the release of noradrenaline MAP RAP ¼ CO × SVR
from post-ganglionic neurons, which,
147
Whether SBP, DBP and MAP are directly meas-

Rearranging:
ured or calculated depends on the method used:
MAP RAP
SVR ¼ 80 × Non-invasive blood pressure measurement:
CO
– Cuff and manometer. SBP is pressure
where MAP (mmHg) is the mean arterial pressure,
measured at the onset of the first Korotkoff
RAP (mmHg) is the right atrial pressure, CO (L/min)
sound, whilst DBP is the pressure measured at
is the cardiac output, SVR (dyn s cm 5) is the sys-
temic vascular resistance and 80 is a conversion the fifth Korotkoff sound. MAP is calculated
factor between units. using the equation above.
– Automated oscillometric method (DINAMAP).
SBP is the pressure measured when
Using typical values: MAP ¼ 100 mmHg, RAP ¼ oscillations are first detected by the pressure
2 mmHg and CO ¼ 5 L/min: transducer, whilst MAP is the pressure
MAP RAP measured when oscillations are maximal. DBP
SVR ¼ 80 × is calculated using the formula above. As it is
CO
100 2 5
calculated and not measured, DBP may be
) SVR ¼ 80 × ¼ 1568 dyn s cm inaccurate in tachycardia.
5
Invasive blood pressure measurement: SBP is the
peak and DBP is the trough of the arterial pressure
How are systolic, diastolic and mean waveform (Figure 32.2). MAP is calculated by
blood pressures measured? integrating the area under the arterial pressure
For each cardiac cycle (Figure 32.2): waveform and dividing it by the length of the
cardiac cycle – this calculation is accurate at all HRs.
The peak blood pressure is the systolic blood
pressure (SBP).
The lowest blood pressure is the diastolic blood Which factors determine arterial
pressure (DBP).
MAP is somewhere in-between, and is considered
blood pressure?
to be the most important of the three blood As discussed above:
pressure measurements. Once arterial pulsations MAP RAP ¼ CO × SVR
have been damped, the pressure within the As RAP is usually much smaller than MAP in a
arterioles (i.e. the pressure perfusing the organs) normal adult,1 this can be approximated to
is the MAP. However, MAP is not simply
the average of the systolic and diastolic MAP ≈ CO × SVR
pressures. This is because the systolic portion Therefore, the main determinants of MAP are:
of the cardiac cycle is shorter than the diastolic SVR, which depends on the degree of arteriolar
portion at rest. Usually, diastole is twice the smooth muscle contraction. As discussed above,
length of systole; so: arteriolar smooth muscle tone depends on
2 1 complex interactions between local, humoral and
MAP ¼ DBP+ SBP neural factors.
3 3
CO, which depends on SV and HR. (see Chapter 28):
or
CO ¼ HR × SV
1
MAP ¼ DBP+ PP In turn, SV depends on a complex interaction of:
3
where PP is the pulse pressure, the difference – preload
between SBP and DBP; that is, PP ¼ SBP DBP. – myocardial contractility
The assumption that one-third of the cardiac – afterload.
cycle is systole does not hold true in tachycardia;
calculated values of MAP can therefore be
1
inaccurate. RAP may become significant in RVF.
148
Systole Diastole Figure 32.2 The arterial pressure

120 waveform.
Systolic BP
Pressure (mmHg)
100
Mean BP
80 Diastolic BP
60
0 1 2 3
Time (s)
HR results from the balance of cardio-

acceleratory sympathetic outflow and the cardio- volume, and vasopressors to counteract arteriolar
vasodilatation. Two vasopressors commonly used in
inhibitory parasympathetic outflow.
septic shock are noradrenaline (selective α1-agonist)
and vasopressin.
Cardiogenic shock. When hypotension is
Clinical relevance: manipulation of blood pressure
due to left ventricular dysfunction, positively
In clinical practice, anaesthetists use a variety of inotropic drugs may be used to increase myo-
pharmacological and non-pharmacological methods cardial contractility, thereby increasing MAP; for
to increase or decrease MAP, by manipulating the example, dobutamine (β1-agonist) or adrenaline
five factors described above: preload, myocardial (mainly a β1- and β2-agonist at low/moderate
contractility, afterload, HR and SVR. For example: doses). An intra-aortic balloon pump is
Neuraxial blockade causes a decrease in sometimes used to decrease left ventricular
sympathetic nervous activity below the level of afterload.
the block. This causes arteriolar vasodilatation, Hypotensive anaesthesia. This is a (mainly his-
which decreases SVR and, therefore, decreases torical) technique where controlled hypotension
MAP. Anaesthetists often use vasopressors to is induced in anaesthetized patients to establish a
counteract the decreased SVR, thereby increasing bloodless surgical field, of particular interest in
MAP; for example, phenylephrine (α1-agonist) or middle-ear surgery and neurosurgery. Hypoten-
metaraminol (direct and indirect α1-agonist with sion may be induced by:
some β-effects). – Patient position. The reverse-Trendelenburg
Septic shock causes hypotension through two position reduces venous return, thereby
mechanisms: reducing left ventricular preload.
– Fluid leakage from the intravascular space to – Drugs that cause arteriolar vasodilatation
the interstitial space, which reduces left ven- and reduce SVR; for example, volatile
tricular preload, thereby reducing SV and CO. anaesthetics, glyceryl trinitrate, sodium
– Systemic release of vasodilatory inflammatory nitroprusside.
mediators, which reduce SVR. – Drugs that reduce HR and myocardial con-
tractility; for example, esmolol (β1-antagonist),
Management of hypotension in septic shock is there-
labetalol (mixed α1- and β-antagonist).
fore by fluid resuscitation to restore intravascular
Further reading Experimental and Clinical

Principles. Hodder Arnold, 2011.
with septic shock. New Engl J Med
2008; 358(9): 877–87.
W. W. Nichols, M. F. O’Rourke.
McDonald’s Blood Flow in Arteries, J. A. Russell, K. R. Walley, J. Singer, M. Ward, J. A. Langton. Blood pressure
6th Edition: Theoretical, et al. Vasopressin versus measurement. Contin Educ Anaesth
norepinephrine infusion in patients Crit Care Pain 2007; 7(4): 122–6.
149
Chapter
Arterial pressure waveforms
33
The rate and character of the arterial pulse has been
used for millennia for the diagnosis of a wide range of
What is the arterial pressure wave?
disorders. Perhaps more useful, however, is the direct Ejection of blood into the aorta generates both an
cannulation of an artery, which allows quantitative arterial pressure wave and a blood flow wave. The
information to be extracted. arterial pressure wave is caused by the distension of
the elastic walls of the aorta during systole. The wave
propagates down the arterial tree at a much faster rate
What is the Windkessel effect? (around 4 m/s) than the mean aortic blood velocity
During systole, the LV ejects around 70 mL of blood (20 cm/s). It is the arterial pressure wave that is felt as
into the aorta (the SV). The elastic aortic walls expand the ‘radial pulse’, not the blood flow wave.
to accommodate the SV, moderating the consequent
increase in intra-aortic pressure from a DBP of Describe the arterial pressure waveform
80 mmHg to an SBP of 120 mmHg. The ejected blood
possesses kinetic energy, whilst there is storage of for the aorta
potential energy in the stretched aortic wall. In dia- Starting from end-diastole (Figure 33.1), the pressure
stole, recoil of the aortic wall converts the stored generated by the LV ejects the SV into the aorta. The
potential energy back into kinetic energy. This main- intra-aortic pressure rises to a peak value, the SBP,
tains the onward flow of blood during diastole, and then falls to a trough, the DBP. The smooth
thereby maintaining DBP; this is known as the ‘Wind- decent of the curve is interrupted at the dicrotic
kessel effect’. This effect converts the sinusoidal pres- notch, when the aortic valve closes.
sure wave generated in the heart into a positive and
constant pressure at the tissues, much like converting How does the arterial pressure
AC to DC electricity. With advancing age, there is
degeneration of elastin in the wall of the aorta. The waveform differ at peripheral arteries?
aortic wall becomes less compliant, and its ability to The morphology of the arterial pressure waveform
accommodate SV without a large increase in pressure differs depending on where it is measured
reduces. This accounts for the development of systolic (Figure 33.2). As the site of measurement moves more
hypertension in the elderly. distally:
SBP Systole Diastole Pressure increases as Figure 33.1 The arterial waveform.
blood flows into the aorta
120
Aortic valve closes

Pressure (mmHg)
100 Pressure falls as blood

flows out of the aorta
80
Dicrotic notch
DBP Aortic valve opens

60
0 1 2 3
Time (s)
150
Chapter 33: Arterial pressure waveforms
per upstroke Figure 33.2 Arterial pressure waveform

120 Increasing SBP and stee at different sites.
Pressure (mmHg)
100 MAP
80
Decreasing DBP, dicr
otic notch later and less
sharp
60
Aorta Brachial Radial Femoral Dorsalis pedis

Site of arterial waveform
(a) Characteristic arterial pressure waveforms

Reduced gradient Bifid waveform
of upstroke Steep downstroke
120
Pressure (mmHg)
100
80
Reduced pulse Increased pulse Low dicrotic High dicrotic

pressure pressure notch notch
60
‘Normal’ Aortic stenosis Aortic regurgitation Low SVR High SVR
(b) Respiratory swing with hypovolaemia and positive pressure ventilation

Area 1
120 Area 2
Pressure (mmHg)
100
80
Inspiratory phase Expiratory phase Inspiratory phase
60
0 5 10 15
Time (s)
Figure 33.3 (a) Characteristic changes of the arterial waveform; (b) variation through the respiratory cycle with positive pressure ventilation.
The arterial upstroke is steeper and SBP is The morphology of the dicrotic notch changes:
increased. – The dicrotic notch is positioned further down
DBP is decreased. the pressure curve.
Crucially, MAP is relatively constant wherever it is – Rather than being a sharp interruption in the
measured; this is another reason why MAP is the pressure descent, the dicrotic notch becomes
most important measure of blood pressure. more of a dicrotic wave.
151
The change in shape and position of the dicrotic contractility but often has a pressure wave with a
wave is due to it being caused by reflections of the bisferens appearance.
arterial pressure wave rather than aortic valve SVR. The downstroke of the arterial pressure
closure. waveform gives information about SVR: a steep
downstroke with a low dicrotic notch indicates a
low SVR – the arterial waveform looks thin and
Can any other information be pointed (Figure 33.3a). Likewise, a high dicrotic
gathered from the arterial pressure notch implies a high SVR.
Hypovolaemia. In positive-pressure ventilated
waveform? patients, a ‘respiratory swing’ in the arterial
Although the arterial pressure waveform is often only pressure waveform is an indicator of
used for measuring SBP, DBP, MAP and HR, it has hypovolaemia. There is beat-to-beat variation in
many other clinical uses: the systolic pressure of the waveform, caused by
Myocardial contractility. The slope of the the variation in preload throughout the
waveform upstroke is a reflection of myocardial respiratory cycle (Figure 33.3b).
contractility: an increased upstroke gradient Arterial pulse contour analysis. SV is
suggests a greater pressure generated per unit proportional to the area under the systolic portion
time. However, a reduced upstroke gradient is of the arterial pressure waveform; arterial pulse
sometimes seen in aortic stenosis (Figure 33.3a). contour analysis allows calculation of the CO
In contrast, aortic regurgitation is usually (see Chapter 28). SVV is calculated by dividing the
associated with normal myocardial minimum SV (Area 2) by the maximum SV (Area 1).
Further reading dysfunction. Circ Heart Fail 2010;

3(1): 149–56.
Nephrol Dial Transplant 2010;
25(12): 3815–23.
S. J. Denardo, R. Nandyala, G. L.
Freeman, et al. Pulse wave analysis G. M. London, B. Pannier. Arterial B. Lamia, D. Chemla, C. Richard, et al.
of the aortic pressure waveform in functions: how to interpret Interpretation of arterial pressure
severe left ventricular systolic the complex physiology. wave in shock states. Crit Care 2005;
9(6): 601–6.
152
Chapter
Capillaries and endothelium
34
capillaries. These fenestrations are large enough
What are the roles of the capillaries? (60–80 nm) to allow passage of all but the largest
The capillaries are tiny vessels (measuring 5–10 μm in plasma proteins (i.e. albumin).
diameter) arranged in an interweaving network called
Sinusoidal capillaries, a special type of fenestrated
the capillary bed. Capillaries have two main roles:
capillary found in the bone marrow and lymph
Delivery of nutrients to and removal of nodes. The fenestrations are large enough to allow
metabolites from the tissues. white blood cells and RBCs to pass through (up to
Distribution of body water between intravascular 10 μm). In the liver and spleen, even greater
and interstitial fluid compartments. movement of cells is required – in addition to
large fenestrations, their sinusoidal capillaries also
In contrast to arteries and veins, the capillary wall is
lack tight junctions. These vessels are called
entirely composed of endothelium and is only one cell
‘discontinuous sinusoidal capillaries’.
thick, supported by a basement membrane.
How does capillary–tissue exchange

What are the different types of
occur?
capillary? Capillary exchange involves the matrix properties
There are three main capillary types: of the capillary basement membrane as well as the
Continuous capillaries, the most common class features of the endothelial layer itself. It takes place
of capillary, found in muscle, brain and through three overall mechanisms:
connective tissue. Features include: Simple diffusion.
– A continuous basement membrane. – Gases (for example, O2 and CO2) and small
– Neighbouring cells joined by tight junctions; lipophilic molecules (for example, anaesthetic
endothelial cells are closely associated. agents) are able to diffuse across the
– BBB. In the brain, tight junctions hold the phospholipid bilayer of the endothelial cell.
endothelial cells especially close and are – Small water-soluble molecules traverse the
surrounded by astrocyte foot processes capillary either through pores in the cell
(see Chapter 44). Only the smallest membrane or through gaps between
molecules such as water, O2 and CO2 can endothelial cells.
then freely diffuse from one side of the cell
to the other. The diffusion of larger molecules The rate of diffusion is affected by a number of
(nutrients, metabolites and drugs) across factors; most importantly, the concentration (or
the capillary is dependent on carrier-mediated partial pressure) gradient of the substance across
transport mechanisms. the capillary wall (Fick’s law – see Chapter 9).
Fenestrated capillaries, found in the renal Bulk flow. Water is filtered through the fluid-filled
glomeruli, intestinal mucosa and choroid plexus. pores within (fenestrations) or between (tight
Fenestrated capillaries have large pores within the junctions) endothelial cells. Any dissolved solutes
endothelial cell called fenestrations, which makes (for example, electrolytes) can be dragged along
them much more permeable than continuous with the water. This mechanism is particularly
153
important in the fenestrated renal glomerular

capillaries. Filtration and reabsorption of fluid As capillary walls are normally relatively imper-
meable to proteins, the Starling filtration equation
across the capillary is governed by the balance of
can be simplified as
Starling filtration forces.
Pinocytosis. This is an energy-consuming type of Net fluid filtration across capillary wall
endocytosis where substances in the capillary / (Pc – Pi) – (πc – πi)
lumen are enveloped by the endothelial cell Note: Starling pressures are usually measured in
membrane to form a vesicle. The vesicle is then mmHg.
transported across the endothelial cell and its
contents released into the interstitium. Pinocytosis
makes only a minor contribution to capillary Normally, three values are relatively constant:
exchange. πc is 24 mmHg.
Pi and πi are both low, 2 mmHg and 3 mmHg
respectively.
How do the Starling filtration forces Pc is therefore the main determinant of whether fluid
determine transmembrane fluid flow? is filtered or reabsorbed:
The net fluid filtration across the capillary wall results At the arterial end of the capillary, Pc ¼ 36 mmHg.
from the balance of the four opposing Starling filtra- Net filtration pressure ¼ (36 – 2) – (24 – 3) ¼ 13
tion forces (Figure 34.1). mmHg. Therefore, there is bulk flow out of the
Forces tending to move fluid out of the capillary: capillary; that is, filtration.
At the venous end of the capillary, Pc ¼ 10 mmHg.
– capillary hydrostatic pressure Pc
Net filtration pressure ¼ (10 – 2) – (24 – 3) ¼ 13
– interstitial fluid oncotic pressure πi.
mmHg. Therefore, there is bulk flow into the
Forces tending to move fluid into the capillary: capillary; that is, absorption.
– interstitial fluid hydrostatic pressure Pi
– plasma oncotic pressure πc. As the capillary hydrostatic pressure decreases
from the arteriolar to the venous end of the capillary,
Key equation: the Starling filtration equation the direction of bulk flow changes from net filtration
to net absorption. The Starling filtration forces can
Net fluid filtration across capillary wall
¼ Kf [(Pc – Pi) – σ (πc – πi)]
be demonstrated graphically: Area 1 represents net
filtration, whilst Area 2 represents net absorption
where Kf is the filtration coefficient, a constant (Figure 34.2a). Filtration and absorption are not
related to the permeability of the capillary wall (high exactly matched – overall, there is a daily net filtration
Kf indicates high water-permeability, whilst low Kf
of around 4 L of fluid. This fluid is returned to the
indicates low water-permeability); σ is the reflection
circulation via the lymphatic system.
coefficient, a constant that represents the permeabil-
ity of the capillary to proteins (σ ¼ 1 implies that the The body controls the bulk flow of water through
capillary wall is 100% impermeable). alterations in Pc. Arteriole and venule tone is con-
trolled by the sympathetic nervous system:
Capillary hydrostatic pressure, Pc Figure 34.1 The balance of Starling

Interstitial fluid oncotic pressure, πi filtration forces across a capillary.
BLOOD FLOW BLOOD FLOW
Arteriolar end Venous end
Interstitial fluid hydrostatic pressure, Pi

Plasma oncotic pressure, πc
154
Chapter 34: Capillaries and endothelium
(a) ‘Normal’ situation
Net filtration
40 Net reabsorption
36
Pressure (mmHg)
30
Area 1
24
20 Area 2
10
0
Arteriolar end Middle Venular end
Site in capillary
(b) In the kidney (c) Hypoalbuminaemia
45
40 40
Area 1 36
Pressure (mmHg)
Pressure (mmHg)
30 Area 2 30 Area 1 Area 2
24 24
20 20
10 Increased net filtration 10

Increased net filtration
0 0
Arteriolar end Middle Venular end Arteriolar end Middle Venular end
Site in capillary Site in capillary
(d) Congestive cardiac failure (e) In the lungs
40 40 Increased net reabsorption

36 36
Pressure (mmHg)
Pressure (mmHg)
30 Area 1 Area 2 30
24 24
20 20
Area 2
Increased net filtration
10 10
0 0
Arteriolar end Middle Venular end Arteriolar end Middle Venular end
Site in capillary Site in capillary
Figure 34.2 Graphical representation of Starling filtration forces.
155
Arteriolar vasodilatation and venule

venoconstriction both increase Pc, resulting in net A reduction in the hydrostatic pressure of down-
stream capillaries.
filtration.
Arteriolar vasoconstriction and venule According to the Starling filtration equation, the
venodilatation both reduce Pc, resulting in net reduced capillary hydrostatic pressure results in net
absorption. absorption of fluid from the interstitial space. In an
acute haemorrhage, around 500 mL of fluid can be
The Starling filtration forces can be used to mobilized within 30 min from the interstitial space to
explain a number of physiological and pathological the intravascular space, known as autotransfusion.
situations. This constitutes an important compensatory mechan-
In the kidney: the system of afferent and efferent ism for temporarily increasing the circulating volume.
arterioles produces a high glomerular capillary
hydrostatic pressure, which increases net
filtration – this is how the kidney manages to filter Does blood always flow through all the
180 L of plasma per day (Figure 34.2b). capillary networks?
Additionally, glomerular disease may result in a
At rest, only around a quarter of capillaries are patent.
decrease in the reflection coefficient σ. As a result,
Blood can entirely bypass the capillary networks,
proteins such as albumin enter the filtrate,
passing from arterioles to venules via short shunting
resulting in proteinuria.
vessels called metarterioles.
In critical illness: hypoalbuminaemia reduces
The flow of blood into each capillary network is
plasma oncotic pressure, which increases net
controlled by small pre-capillary sphincters: one or
filtration. Clinically, this results in peripheral
two smooth muscle cells that form a cuff around the
oedema (Figure 34.2c).
arteriolar end of the capillary. When the pre-capillary
In congestive cardiac failure: venous pressure is sphincter constricts, blood is prevented from entering
increased. This increases net filtration, again the capillary network and is diverted elsewhere, either
resulting in peripheral oedema (Figure 34.2d). to other capillaries or along the metarterioles to the
In the lungs: the pulmonary circulation is a low- venules. Pre-capillary sphincter dilatation allows
pressure system – mean capillary hydrostatic blood to flow through the capillary network, deliver-
pressure is only 8 mmHg. The plasma constituents ing O2 and nutrients to the tissues. Like the arterioles
are unchanged, so plasma oncotic pressure (see Chapter 32), the tone of the pre-capillary sphinc-
remains the same (around 24 mmHg). Overall, ter is controlled by neural and local metabolic factors:
there is net fluid absorption, which explains why
At rest, the tissues are only minimally
alveoli are usually fluid free (Figure 34.2e). If
metabolically active. The demand for O2 and
pulmonary venous pressure were to increase, as
nutrients is low and so most of the pre-capillary
occurs in LVF, capillary hydrostatic pressure
sphincters are closed.
would rise. Should pulmonary capillary pressure
increase sufficiently, there would be net filtration In metabolically active tissues, such as exercising
of fluid into the alveolus, resulting in pulmonary muscle, a large proportion of the pre-capillary
oedema. sphincters open in response to neural stimulation,
low O2 tension and high concentrations of
Clinical relevance: haemorrhage metabolites (for example, H+ and CO2). Blood is
permitted to flow through the capillary networks,
Following haemorrhage, the sudden loss of intravas-
cular blood volume risks organ hypoperfusion. The resupplying the tissues with O2 and metabolic
body responds to haemorrhage through a massive substrates.
increase in sympathetic outflow, involving many
reflexes and mechanisms (see Chapter 38). This sym-
pathetic outflow causes arteriolar vasoconstriction, What are the functions of the
which has two effects:
An increase in SVR to maintain MAP, and there-
endothelium?
fore organ perfusion pressure. The endothelium is far from an inert blood vessel
lining. In a typical adult, the endothelium comprises
156
Chapter 34: Capillaries and endothelium
nearly 1 kg of cells. As described above, the endothe- circulation. The thrombomodulin–thrombin

lium acts as a semi-permeable membrane, controlling complex also activates protein C, a potent
the movement of gases, nutrients and metabolites anticoagulant. NO and PGI2 are both
across the capillary wall. In addition, the endothelium inhibitors of platelet aggregation. Heparan
is involved in many other processes, including: sulphate is an endothelial cell membrane-
Synthesis of vasoactive substances, the most bound molecule that activates the plasma
important of which are NO, prostacyclin (PGI2) protein antithrombin III, which in turn
and endothelin (ET); NO and PGI2 are inactivates thrombin and factor Xa.
vasodilators, whilst ET is a potent vasoconstrictor. – Procoagulant properties. Endothelial cells
These vasoactive substances are released in synthesize von Willebrand factor (vWF),
response to local metabolic and mechanical which is released into the plasma where it
stimuli, and play a major role in the control of binds to factor VIII. When blood vessels are
vascular tone. NO is synthesized from l-arginine damaged, vWF acts as an adhesion molecule,
by nitric oxide synthase (NOS) and has a wide binding the exposed collagen (in the vessel
range of functions. It is of particular interest to basement membrane) to platelets, which leads
anaesthetists: to platelet activation.
– Inhaled NO has been used in neonatal and Inflammatory system. Inflammatory cytokines
adult pulmonary hypertension and in ARDS like interleukin 1 and tissue necrosis factor
to reduce PVR through pulmonary arteriolar stimulate the endothelium to express adhesion
vasodilatation. molecules. These adhesion molecules attract
neutrophils and lymphocytes, causing them to roll
– NO is released when a vein is traumatized
along the endothelial surface before migrating
(for example, by tapping it), causing local
across the endothelial cell (see Chapter 70).
venodilatation, which makes veins easier to
cannulate.
– NO donors, such as glyceryl trinitrate, are used Further reading
as anti-anginal drugs. At therapeutic levels, T. E. Woodcock, T. M. Woodcock. Revised Starling
equation and the glycocalyx model of transvascular fluid
NO dilates the capacitance veins, reducing
exchange: an improved paradigm for prescribing
venous return. The resulting decrease in intravenous fluid therapy. Br J Anaesth 2012; 108(3):
preload leads to a reduction in myocardial O2 384–94.
demand, easing the pain of angina. J. R. Levick, C. C. Michel. Microvascular fluid exchange and
Haemostasis. The endothelium normally has the revised Starling principle. Cardiovasc Res 2010, 87
anticoagulant properties, but becomes (2): 198–210.
procoagulant when injured (see Chapter 67): H. F. Galley, N. R. Webster. Physiology of the endothelium.
– Anticoagulant properties. The endothelial cell Br J Anaesth 2004; 93(1): 105–13.
surface receptor thrombomodulin binds C. C. Michel. Fluid exchange in the microcirculation.
thrombin, effectively removing it from the J Physiol 2004, 557(3): 701–2.
157
Chapter
Venous system
35
of blood to flow through the skin, dissipating
Whataretherolesofthevenoussystem? heat to the environment.
The venous system has a number of roles:
Transport of deoxygenated blood from the
capillaries to the right side of the heart, the main How does the structure of a vein differ
role of the venous system. There are a few to an artery?
exceptions to this rule: Arteries have three layers (see Chapter 32):
– The pulmonary veins carry oxygenated blood the tunica externa
from the pulmonary capillaries to the left side the tunica media
of the heart (see Chapter 22). the tunica intima.
– The umbilical vein carries oxygenated blood
from the placenta to the fetus (see Chapter 78). The tunica media is the thickest layer, with a much
– A portal vein is a vein that connects two higher proportion of smooth muscle than elastin.
capillary networks. For example: In contrast, veins:
Have thinner walls and larger lumens than
▪ The hepatic portal vein carries
equivalent-sized arteries.
deoxygenated blood between two capillary
beds: from the gut to the liver (see Have much less smooth muscle and more elastin
Chapter 61). in their tunica media.
Have as their thickest layer the tunica externa,
▪ The long hypophyseal portal veins connect
the capillary networks of the lower containing elastin and collagen.
hypothalamus and the anterior lobe of the Are much more distensible than arteries, and are
pituitary gland (see Chapter 75). often collapsed.
▪ The short hypophyseal portal veins Have valves formed by folds of tunica intima,
connect the capillary networks of the which prevents backflow of blood. Note that there
posterior and anterior lobes of the are no valves in the venae cavae, portal veins or
pituitary gland. cerebral veins.
Storage of blood. The venous system contains

65% of the circulating blood volume.
What is compliance? How does this
Venous return to the heart. The rate at which relate to the venous system?
blood returns to the right atrium determines the Compliance is the change in volume caused by a unit
cardiac preload, and is therefore a major factor change in distending pressure. The venous system is
determining the CO. around 30 times more compliant than the arterial
Thermoregulation. Arteriovenous anastomoses system. This means that the veins can accommodate
are short channels that connect arterioles to large volumes of blood for only a small increase in
venules, bypassing the capillary networks. intraluminal pressure. In fact, the venous system
Arteriovenous anastomoses are plentiful in holds 65% of the circulating blood volume compared
the skin. They are opened when body with only 15% within the arterial system, which is
temperature increases, allowing a large amount under considerably higher pressure.
158
Chapter 35: Venous system
Which factors are involved in The cardiac pump. During ventricular

contraction, the fibrous AV rings are pulled
determiningvenousreturntotheheart? downwards, increasing the volume of the atria.
When standing upright, the majority of the venous Atrial pressure therefore decreases, sometimes to
blood is situated vertically below the level of the heart. below zero, which aids the flow of blood from the
This blood must therefore return to the heart against venae cavae and pulmonary veins, but is limited
the force of gravity. In addition to gravity, venous by venous collapse.
return is hindered by fluctuations in abdominal and The skeletal muscle pump. Rhythmical
thoracic pressures, and disease states such as congest- contraction and relaxation of skeletal muscle,
ive cardiac failure. There are a number of mechan- particularly the calf, propels blood through the
isms involved in venous return: deep veins. Blood is first drawn from the
Valves. One-way valves are positioned every few superficial to deep veins by skeletal muscle
centimetres along the veins – an intact valvular relaxation. Skeletal muscle contraction then
system means that blood can only be propelled compresses the deep veins, which propels blood
forwards. forwards. Valves within the veins ensure
Venous pressure (or more correctly mean unidirectional flow towards the heart. This
systemic filling pressure). As blood fills the venous mechanism increases venous return during
capacitance vessels, the venous pressure increases, exercise.
which increases venous return to the heart. Body position. Standing leads to venous pooling
Venous pressure is increased by filling the veins in the lower limbs. Venous pressure increases in
with a greater blood volume, or by increasing the supine position, leading to an increase in
venous tone through an increase in sympathetic venous return. The Trendelenburg position (head-
nervous activity.1 Similarly, loss of blood volume down tilt) further increases venous return to
(for example, haemorrhage) or loss of sympathetic the heart.
tone (for example, following central neuraxial
blockade) results in a decrease in venous pressure,
and thus a fall in venous return. Clinical relevance: venous return and anaesthesia
The respiratory (or abdominothoracic) pump. Anaesthesia may be responsible for a fall in venous
return:
– In the spontaneously breathing patient,
Positive pressure ventilation increases intra-
negative intrathoracic pressure pulls open the thoracic pressure during inspiration, which
distensible venae cavae by radial traction, reduces venous return, right ventricular preload
reducing their resistance to flow. At the same and CO. Clinically, at induction of general anaes-
time, the increased intra-abdominal pressure thesia patients commonly become hypotensive;
propels blood towards the heart. The end this is partly the result of propofol- or
result is increased venous return on thiopentone-induced arteriolar vasodilatation,
inspiration. During exercise, an increase but also partly the result of positive-pressure
in RR produces a greater respiratory pump ventilation.
effect, increasing venous return. PEEP worsens this situation, increasing intra-
thoracic pressure and further reducing venous
– Positive-pressure ventilation increases
return.
intrathoracic pressure and thus has the
IVC compression. From mid-pregnancy,
opposite effect, reducing venous return. the gravid uterus compresses the IVC when
lying supine, reducing venous return and
thus resulting in hypotension (see Chapter 77).
1
Like arteries, venous smooth muscle is innervated by When awake, pregnant women generally prefer
post-ganglionic sympathetic neurons, which act at any position other than being supine. When
α1-adrenoceptors. Sympathetic stimulation results in anaesthetized, patients obviously cannot alter
venoconstriction, which reduces venous wall compliance. their own position. It is then essential to perform
Owing to the relatively large radius of veins, a lateral tilt, or position the pregnant patient in
venoconstriction causes only a small increase in the the full lateral position to relieve pressure on the
resistance to blood flow.
159
IVC. Lateral tilt is especially important during

At 1 mmHg the vein lumen is often collapsed; the
cardiopulmonary resuscitation of a pregnant resistance to blood flow increases markedly.
patient.
Intraluminal pressure decreases along the venous
system – typical pressures are:
venules 10–15 mmHg
How does the venous pressure affect veins 4–8 mmHg
resistance to blood flow? IVC 0–2 mmHg.
As discussed in Chapter 32, laminar blood flow is
described by the Hagen–Poiseuille equation. Venules, therefore, have a circular lumen, providing
According to this equation: minimal resistance to blood flow. In contrast, a col-
lapsed IVC can significantly increase flow resistance.
8ηl During exercise, the increased sympathetic outflow
Resistance to flow ¼
πr 4 increases the venomotor tone, increasing the intra-
Compared with vessels in the arterial system, veins luminal pressure. This makes the lumen more circu-
and venules have a relatively large radius. As resist- lar and reduces the venous resistance to blood flow.
ance is inversely proportional to the fourth power of As the heart provides a negligible pressure to the
the radius, resistance to blood flow in the venous venous system and the intravascular resistance is
system should therefore be markedly lower. However, low, strangely the greatest contribution to venous
veins do not necessarily have a circular lumen. In fact, resistance is the local pressure gradients generated
the shape of the lumen alters with intraluminal pres- by the skeletal muscle and respiratory pumps. In
sure, and this has an effect on the resistance to blood other words, the action of these mechanisms is to
flow: reduce the effective resistance to venous return
during exercise.
Above 12 mmHg the vein lumen is circular;
resistance to blood flow is relatively low.
At 4 mmHg the vein lumen is elliptical; resistance
Further reading
W. R. Levick. An Introduction to Cardiovascular Physiology,
to blood flow is increased. 5th edition. London, Hodder Arnold, 2010.
160
Chapter
Venous pressure waveforms
36
Describe the key features of the central Third-degree heart block. Electrical impulses
cannot pass through the AV node. As a result,
venous pressure waveform atrial and ventricular contraction occur
The CVP waveform is measured using a central independently. There will be times when the atria
venous catheter positioned just above the right contract at the same time as the ventricles (i.e.
atrium, within the SVC. The normal CVP waveform when the tricuspid valve is closed), resulting in the
is shown in Figure 36.1. occasional larger a wave on the CVP waveform;
Starting from mid-diastole, key features of the this is called a ‘cannon a wave’.
waveform are: Tricuspid regurgitation. During ventricular
The a wave corresponds to the increase in systole, blood is ejected from the right ventricle
pressure when the right atrium contracts, into the right atrium, increasing the CVP. The
occurring just after the P wave on the ECG. CVP waveform has a ‘giant v wave’, a large
The c wave occurs in time with the carotid positive deflection that replaces the c wave, the x
pulsation. In early systole, right ventricular descent and the v wave.
contraction causes the tricuspid valve to bulge into
the right atrium, leading to a small increase
in CVP. What constitutes a normal central
The x descent corresponds to atrial relaxation venous pressure?
and the downward movement of the right The normal mean CVP is said to be 2–8 mmHg, when
atrium during right ventricular contraction. The measured at the level of the right atrium. However,
resultant low CVP leads to rapid right atrial isolated CVP readings should be interpreted with
filling. care. CVP is not purely related to central venous
The v wave corresponds to the continued venous blood volume. It is also affected by venous compli-
return to the right atrium during ventricular ance, the compliance of the right atrium and right
systole; that is, right atrial filling with a closed ventricle, and the intrathoracic pressure.
tricuspid valve. Common causes of raised CVP (>8 mmHg) are:
The y descent corresponds to the decrease transducer below the level of the right atrium;
in CVP after the tricuspid valve opens, when positive-pressure ventilation/PEEP;
blood flows from the right atrium into the congestive cardiac failure;
right ventricle.
isolated RVF (right ventricular infarction, cor
pulmonale);
How can the shape of the central venous hypervolaemia;
pressure waveform help the diagnosis pulmonary embolus;
constrictive pericarditis.
of arrhythmias?
A number of cardiac conditions impact on the CVP Common causes of low CVP (<2 mmHg) are:
waveform: transducer above the level of the right atrium;
AF. The loss of coordinated atrial contraction acute hypovolaemia; for example anaphylaxis,
leads to the absence of a waves. acute haemorrhage.
161
Diastole Systole Diastole Figure 36.1 The CVP waveform.
QRS
T
P
6
a
Pressure (mmHg)
4 c v
x
y
2
0
0 0.5 1
Time (s)
How can central venous pressure readings can be used to assess the response to a
fluid bolus:
be used to guide fluid A transient rise in CVP implies that the right
management? ventricle is on the ascending part of the Starling
Because of its ease of measurement, CVP has histor- curve; further fluid administration may be needed
ically been used to guide fluid management. The to optimize preload.
physiology underlying this is as follows: A sustained rise in CVP implies that the
CVP provides a good approximation of RAP. right ventricle is on the plateau of the Starling
curve, and at maximal preload. When
RAP approximately correlates with right
ventricular end-diastolic pressure (RVEDP) operating at this part of the Starling curve, the
and RVEDV; that is, right ventricular right ventricle is already at a mechanical
preload. disadvantage – any further increase in preload
is likely to precipitate RVF. A further increase
RVEDP approximately correlates with
in CO can only be achieved by increasing
LVEDP and LVEDV; that is, left ventricular
myocardial contractility, increasing HR or
preload.
reducing afterload.
One of the determinants of CO is left ventricular
preload. A clinical deterioration and marked rise in CVP
implies that the right ventricle is on the
CVP therefore reflects left ventricular preload, and
descending part of the Starling curve, with
can be used to optimize CO.
excessive preload overstretching the myocardial
Even in healthy patients, there are just too many fibres, causing RVF.
assumptions and approximations for CVP to pro-
CVP is still commonly used to assess adequate
vide a precise guide to fluid management. LVEDV
venous filling. A target CVP of 8–12 mmHg (12–15
corresponds poorly to CVP, and individual CVP
mmHg in mechanically ventilated patients) is one of
readings are of little use. However, trends of CVP
162
Chapter 36: Venous pressure waveforms
many resuscitation targets in the Surviving Sepsis Further reading

Campaign guidelines. However, many would argue
R. P. Dellinger, M. M. Levy, A. Rhodes, et al. Surviving
that the equally invasive central venous O2 saturation Sepsis Campaign: international guidelines for the
ScvO2 offers a more useful measurement of cardiovas- management of severe sepsis and septic shock: 2012. Crit
cular status than the CVP does. Care Med 2013; 41(2): 580–637.
163
Chapter
Lymphatics
37
Describe the anatomy of the What are the functions of the
lymphatic system lymphatic system?
The lymphatic system is part of the systemic circula- The lymphatic system has three main functions:
tion. Its two main components are the conducting Fluid balance. As blood passes through the
system and lymphoid tissue. capillaries, most of the fluid filtered into the
Key aspects of the conducting system are: interstitial fluid is then reabsorbed back into the
Small lymphatic capillaries drain lymph into capillary (see Chapter 34). Overall, there is slight
larger lymphatic vessels, which converge on the excess of filtration. Each day approximately 4 L of
right lymphatic duct and the thoracic duct. interstitial fluid must consequently be returned
The right lymphatic duct is quite short to the circulation by the lymphatic system – this
(around 1.5 cm). It drains lymph into the fluid is called lymph.
right subclavian vein. Immune. In addition to fluid, the lymph
The thoracic duct (also known as the left capillaries are the only means by which filtered
lymphatic duct) is much larger, and drains into proteins, lymphocytes and other debris
the left brachiocephalic vein. It collects lymph (including cells) can leave the interstitial space.
from the majority of the body (everywhere Lymph passes through lymph nodes before
except the right arm, right chest, and right side passing back into the systemic circulation. The
of the head and neck) and returns it to the lymph nodes are packed full of lymphocytes,
systemic circulation. which detect foreign bodies and pathogens,
Lymphatic vessels are pulled opened as a result of triggering an immune response. Distribution by
radial traction by the surrounding connective the lymphatic system is the most common
tissue. This permits fluid, proteins and even cells method by which carcinomas may metastasize.
to enter. Like veins, lymph flow is promoted by Digestion. Dietary triglycerides are esterified and
skeletal muscle activity and deep inspiration. combined with cholesterol esters, phospholipids
The larger lymph vessels have valves to ensure and apolipoprotein B-48 to form chylomicrons
unidirectional flow. (see Chapter 60). These chylomicrons pass into
lacteals, the lymphatic capillaries of the intestine,
The lymphoid tissue consists of: and combine with lymph to form a fluid called
Primary lymphoid organs – thymus and bone ‘chyle’. Chyle is then conducted through the
marrow. These organs are involved in the lymphatic vessels, until it enters the systemic
production of lymphocytes from progenitor cells. circulation via the thoracic duct.
Secondary lymphoid organs – these include
Clinical relevance: central venous cannulation
lymph nodes and lymphoid follicles within the
Internal jugular and subclavian vein cannulation is a
tonsils, spleen, Peyer’s patches, skin and other
commonly performed procedure in major surgical
mucosa-associated lymphoid tissue. This
and critical care patients. There is a long list of poten-
lymphoid tissue contains mature lymphocytes, tial complications, including infection, air embolus,
and is the site where foreign antigens activate the pneumothorax and arterial puncture.
adaptive immune response (see Chapter 70).
164
Chapter 37: Lymphatics
Left-sided central venous cannulation also and most importantly by cannulating under ultra-
risks damage to the thoracic duct, which is in close sound guidance.
proximity to the junction of the internal jugular
and subclavian veins. Puncture of the thoracic
duct can lead to a chylothorax. Damage to the
thoracic duct can be prevented by using the right- Further reading
sided internal jugular and subclavian veins, using A. Pikwer, J. Akeson, S. Lindgren. Complications associated
a high-neck approach to the internal jugular vein, with peripheral or central routes for central venous
cannulation. Anaesthesia 2012; 67(1): 65–71.
165
Chapter
Cardiovascular reflexes
38
Why is it important to minimize Describe the arterial baroreceptor
fluctuations in blood pressure? reflex
The organs require a fairly constant MAP to ensure The arterial baroreceptor reflex is an extremely import-
adequate perfusion. Some organs (most notably the ant mechanism for minimizing fluctuations in MAP.
brain, heart and kidneys), despite fluctuations in MAP, The arterial baroreceptors are mechanoreceptors that
intrinsically maintain their blood flow better than sense the degree of distension of the walls of the carotid
other organs through autoregulation (see Chapter 32), sinus, a dilatation at the bifurcation of the carotid
but are still affected by significantly reduced or artery, and the aortic arch (of lesser importance):
increased MAP. An increase in MAP distends the wall of the
carotid sinus/aortic arch, which increases
How is mean arterial pressure the frequency of action potentials generated
by the baroreceptor afferent fibres.
kept constant? A decrease in MAP reduces carotid sinus/aortic
Normal activities (including changes in body pos- arch wall distension, which decreases the
ition, exercise and digestion) can potentially result in frequency of action potential generation.
major changes in MAP, as they can cause both vaso-
dilatation or vasoconstriction of vascular beds, and The baroreceptors transmit their action potentials to
can increase or decrease venous return to the heart. the vasomotor centre, located in the medulla oblon-
The cardiovascular system rapidly responds to fluctu- gata, through the glossopharyngeal nerve (carotid
ations in MAP through a series of neural reflexes. sinus baroreceptors) and the vagus nerve (aortic arch
These cardiovascular reflexes may be classified as: baroreceptors). The vasomotor centre is divided into
two functional areas:
Reflexes originating from stimuli within the
cardiovascular system: The vasoconstrictor (pressor/defence) area. This
– The arterial baroreceptor reflex. Changes in area triggers tachycardia, increased myocardial
MAP are detected by mechanoreceptors in the contractility, vaso- and venoconstriction, and
aortic arch and carotid sinus. In response, promotes adrenaline release from the adrenal
sympathetic outflow from the CNS is rapidly medulla through sympathetic efferent neurons.
altered, which in turn modifies HR and SVR, The vasodilator (depressor) area. This area acts
returning MAP to its set point. on the vasoconstrictor centre, decreasing its
– The Bainbridge reflex, in which an increase in sympathetic outflow.
CVP results in an isolated tachycardia. Overall:
– The chemoreceptor reflex, in which activation
An increase in MAP increases the frequency of
of the peripheral chemoreceptors triggers an
action potentials produced by the baroreceptors. In
increase in sympathetic nervous activity, thus
response, the vasodilator area inhibits sympathetic
increasing HR and MAP.
outflow, causing peripheral vasodilatation and a
Reflexes triggered by stimuli external to the decrease in both HR and myocardial
cardiovascular system: for example, pain, contractility, thus returning MAP to normal.
emotion or temperature.
166
Chapter 38: Cardiovascular reflexes
A decrease in MAP reduces the frequency of

action potentials produced by the baroreceptors. peripheral vasoconstriction. The purpose of this
reflex is to increase MAP with the aim of maintaining
In response, the vasoconstrictor area increases
cerebral perfusion pressure (CPP).
sympathetic outflow, causing peripheral The increase in MAP is detected by the carotid
vasoconstriction and an increase in both HR and sinus and aortic arch baroreceptors, which relay
myocardial contractility, thus returning MAP to afferent signals to the vasomotor area, triggering a
normal. decrease in HR.
Some important points to note about this system are:

In addition to short-term changes in HR, What is the Bainbridge reflex?
myocardial contractility and SVR, the Low-pressure mechanoreceptors are located within
baroreceptor reflex also influences plasma volume. the great veins and the walls of the right atrium at its
Following a fall in MAP, the increased junction with the superior and inferior venae cavae, and
sympathetic outflow triggers renin secretion by are activated by increased wall distension. An increase
the kidney, thus increasing plasma volume via the in CVP, therefore, stimulates these low-pressure
RAA axis. Likewise, an increase in MAP decreases mechanoreceptors, increasing their frequency of action
sympathetic outflow, which decreases renin potential generation – these action potentials are then
secretion and thus plasma volume. In clinical relayed to the CNS via the vagus nerve. In response, the
practice, this can be seen in patients with pre- vasomotor centre increases sympathetic outflow to
eclampsia, where persistently raised MAP results the SA node (but not to the cardiac ventricles or periph-
in a relative hypovolaemia. eral vasculature), resulting in an isolated tachycardia.
There are two types of neurons involved in the Physiological manifestations of the Bainbridge
baroreceptor reflex. Large myelinated A fibres are reflex are:
activated at lower pressure, whilst small
Respiratory sinus arrhythmia. This occurs in
unmyelinated C fibres are activated at higher
children and young adults. During inspiration,
pressure. In combination, these neurons provide a
negative intrathoracic pressure leads to a transient
system that is sensitive over a wide range of MAP,
increase in venous return to the right atrium,
from 80 to 150 mmHg.
which activates low-pressure mechanoreceptors.
In patients with chronic hypertension, the As a result, HR increases during inspiration, and
baroreceptors reset their working range and decreases during expiration.
sensitivity.
Uterine autotransfusion. Following delivery,
The compliance of the arterial tree is reduced with sustained uterine contraction returns around
ageing and atherosclerosis. In turn, this affects the 500 mL of uteroplacental blood to the maternal
sensitivity and rapidity of the baroreceptor reflex; circulation. The resulting increase in CVP
postural hypotension (i.e. a failure of the stretches the right atrial wall, resulting in a
baroreceptor reflex to compensate for the postural tachycardia.
changes in MAP) is common in the elderly.
What are the cardiovascular

Clinical relevance: Cushing’s reflex
Cushing’s reflex is a triad of:
consequences of chemoreceptor
hypertension activation?
bradycardia The peripheral chemoreceptors (the carotid and
irregular respiratory pattern
aortic bodies) are activated by low arterial O2
in response to brainstem ischaemia. The mechanism tension PaO2, high PaCO2 and, in the case of the
is as follows.
carotid bodies, low arterial pH (see Chapter 21).
Brainstem ischaemia (for example, due to raised
ICP – see Chapter 46) triggers a massive increase in In addition, the peripheral chemoreceptors are acti-
sympathetic outflow, resulting in widespread vated by severe hypotension (MAP < 60 mmHg).
The action potentials generated by the peripheral
167
chemoreceptors are relayed to the respiratory centre carotid bodies), leading to tachypnoea.
in the medulla and pons. The medullary respiratory Severe hypotension further activates the
centre is located in close proximity to the vasomotor respiratory centre.
centre, to which it is neurally connected; activation – Venoconstriction of the capacitance veins. The
of the peripheral chemoreceptors, therefore, has a compliance of the capacitance veins is reduced,
minor effect on blood pressure regulation. Hypoxia, thereby tending to restore venous return to the
hypercapnoea and acidosis, therefore, trigger an heart despite the reduction in total blood
increase in sympathetic outflow from the vasomotor volume.
centre. The early response. In the minutes and hours
following blood loss, the body attempts to restore
circulating volume through a number of
Outline the physiological changes that mechanisms:
occur following haemorrhage – Transcapillary refill/autotransfusion. Though
The fall in circulating volume that accompanies the body’s capillaries are not innervated
haemorrhage causes a reduction in mean systemic by the sympathetic nervous system, they
filling pressure, and thus venous return to the heart are not immune from its effects. Capillary
falls. The consequent fall in CO results in decreased hydrostatic pressure depends on arteriolar
MAP. Organ perfusion pressure falls, leading to organ and venous pressures (see Chapter 34).
dysfunction. The cardiovascular, nervous and endo- Following the increase in sympathetic
crine systems act to redistribute blood flow to the vital outflow, arteriolar vasoconstriction
organs, namely the brain, the heart and, to a lesser decreases capillary hydrostatic pressure.
extent, the kidneys. The balance of Starling filtration forces
The physiological response to haemorrhage can be is altered – interstitial fluid is reabsorbed
classified as immediate, early and late: into the capillaries. 500 mL of interstitial
The immediate response involves the fluid can be reabsorbed within 30 min
cardiovascular reflexes, which act within seconds by this mechanism.
of the haemorrhage to restore MAP, maintaining – Increased plasma glucose concentration
the perfusion pressure of the vital organs. through sympathetic nervous system-mediated
Haemorrhage is detected by low-pressure glycogenolysis and gluconeogenesis in the
mechanoreceptors in the right atrium, and arterial liver. The raised glucose concentration causes
baroreceptors of the carotid sinus and aortic arch. plasma to have a greater osmotic pressure,
In response, the vasomotor centre increases which acts to draw water from the extracellular
sympathetic outflow,1 resulting in: space. This mechanism approximately
– Tachycardia and increased myocardial matches (or may even exceed) the volume of
contractility. HR increases in proportion to autotransfusion generated by alterations in
the degree of blood loss. hydrostatic pressure.
– Generalized arteriolar vasoconstriction. Blood – Renal conservation of sodium and water. RBF
flow to the kidney, brain and heart initially decreases as a result of arterial hypotension,
falls, but quickly recovers to near normal due which in turn decreases glomerular filtration
to autoregulation. Blood flow to the skin, gut rate (GFR). Thus, a reduced volume of urine
and skeletal muscle dramatically falls; is produced. There are a number of additional
anaerobic metabolism results in lactic acid mechanisms that further reduce fluid loss
production. The resulting fall in arterial pH from the kidney:
stimulates the respiratory centre (through the ▪ The RAA axis is activated by the increase
in sympathetic activity, the reduction in
1 RBF and the reduction in Na+ delivery to
Note: in severe haemorrhage, a massive sympathetic
outflow is triggered by brainstem ischaemia, when the macula densa. The RAA axis acts to
CPP falls below the lower limit of autoregulation reabsorb Na+ and water, predominately
(50 mmHg). in the distal convoluted tubule (DCT).
168
Chapter 38: Cardiovascular reflexes
▪ Decreased venous return to the heart results The mechanism for the paradoxical vasodilata-
in decreased stretch of the atrial and tion remains unclear, although some studies have
ventricular walls. As a result, ANP and BNP implicated endogenous opioids in the patho-
secretion is decreased, which ordinarily physiology. A recent meta-analysis concluded that
promotes Na+ and water excretion. administration of naloxone improves MAP in
▪ ADH is released from the hypothalamus in decompensated shock, but it is unclear whether
response to plasma osmolarity and (to mortality is reduced.
some extent) volume changes. ADH has
three effects in severe haemorrhage: it acts
as a vasopressor, augmenting Clinical relevance: classes of haemorrhagic shock
noradrenaline-mediated arteriolar As discussed above, the physiological response to
vasoconstriction, and also acts at the renal haemorrhagic shock is proportional to the degree
of haemorrhage. Haemorrhagic shock is divided into
collecting ducts, where it increases
four classes:
water reabsorption. Finally, ADH acts at
the hypothalamus to stimulate thirst.
▪ Additional cortisol is released from the Class 1 Class 2 Class 3 Class 4
adrenal gland in response to major
haemorrhage. Cortisol has a minor Blood <15 15–30 30–40 >40
mineralocorticoid role, increasing the loss (%)
reabsorption of Na+ and water at the DCT Blood loss <750 750–1500 1500–2000 >2000
and collecting ducts. Cortisol also (mL, 70 kg
promotes gluconeogenesis. adult)
HR (bpm)
The late response. In the longer term, plasma
<100 >100 >120 >140
volume is restored over the next 2 days by oral SBP Normal Normal Reduced Very low
intake of water and renal reabsorption of (mmHg)
electrolytes. However, because only water and DBP Normal Raised Reduced Very low
electrolytes are returned to normal, blood has a (mmHg)
reduced haematocrit and plasma protein RR <20 20–30 30–40 >35
concentration. The liver rapidly synthesizes (breaths/
albumin, restoring plasma albumin concentration min)
to normal within 4–6 days. Restoration of RBC
Urine 20–30 5–15 Negligible
mass takes much longer: erythropoietin (EPO) is
>30
output
released from the kidney in response to hypoxia, (mL/h)
activating erythropoiesis in the bone marrow. Hb
concentration usually returns to normal within 8 Mental Normal Anxious Confused Drowsy
weeks, if sufficient iron is available. status or
unconscious
Decompensated shock. If blood loss is extensive
(>30%) and rapid without treatment, Class 1 and 2 haemorrhagic shock are referred to
compensatory mechanisms are unable to restore as compensated shock, as blood pressure is main-
MAP and haemorrhage may become tained, whilst Class 3 and 4 haemorrhagic shock
decompensated. This level of blood loss reflects are decompensated, as hypotension has occurred.
the change from stressed (contributes to Decompensated shock is associated with >50%
stretching the vessel wall) to unstressed blood mortality.
volume (simply fills the vessel lumen). Note: ‘pure’ haemorrhagic shock is unusual.
Decompensated shock is characterized by a Haemorrhage usually occurs in conjunction with
paradoxical vasodilatation and decrease in trauma. Following trauma, tissue damage triggers a
tachycardia. This results in myocardial cascade of inflammatory mediators, resulting in the
systemic inflammatory response syndrome (SIRS) and
ischaemia and thus cardiac depression, resulting
organ dysfunction, further increasing mortality.
in a rapid fall in MAP.
169
Further reading R. P. Dutton. Haemostatic resuscitation. Br J Anaesth 2012;

109(Suppl. 1): i39–46.
G. Gutierrez, H. D. Reines, M. E. Wulf-Gutierrez.
Clinical review: haemorrhagic shock. Crit Care 2004; B. Boeuf, V. Poirier, F. Gauvin, et al. Naloxone
8(4): 373–81. for shock. Cochrane Database Syst Rev 2003; (4):
CD004443.
170
Chapter
Valsalva manoeuvre
39
What is the Valsalva manoeuvre? What Phase 1. At the start of the Valsalva
manoeuvre, the increase in intrathoracic
was it originally used for? pressure compresses the pulmonary vessels,
The Valsalva manoeuvre is performed by forced squeezing blood into the left side of the heart.
expiration against a closed glottis. It is attributed to This transiently increases the SV, resulting in a
Antonio Valsalva (1666–1723), who described it as a transient increase in MAP. The baroreceptor
test of Eustachian tube patency, and as a method reflex responds to the rise in MAP by transiently
of expelling pus from the middle ear. reducing HR.
Phase 2. Next, the high intrathoracic
How might a patient perform a Valsalva pressure prevents venous return to the heart.
SV is reduced, which leads to a steady fall in
manoeuvre? MAP. Again, the baroreceptor reflex is
The Valsalva manoeuvre involves increasing triggered: HR increases, which returns MAP
intrathoracic pressure to ~40 cmH2O and holding it to near normal.
for 10 s. The methods of achieving this depend on Phase 3. After 10 s, the first airway pressure
whether the patient is awake or anaesthetized: is released. Venous return fills the empty
Awake. The patient attempts to forcibly intrathoracic vessels. SV decreases, resulting
exhale whilst keeping their mouth and in a further fall in MAP and a further reflex
nose closed. This can be difficult to explain rise in HR.
to a patient – the same effect can be gained Phase 4. As left ventricular preload is restored,
by asking a patient to try to blow the the MAP increases. However, because the
plunger out of a syringe. HR is still high, there is an overshoot in MAP.
Anaesthetized. The adjustable pressure-limiting The baroreceptor reflex rapidly corrects this,
valve of the anaesthetic circuit is closed and causing a reflex bradycardia through vagal
the airway pressure is increased to 40 cmH2O stimulation. Both MAP and HR then return
and held for 10 s. This is really only possible to normal.
for intubated patients; LMA leak above pressures
of 20 cmH2O.
What are the uses of the Valsalva
What are the cardiovascular changes manoeuvre nowadays?
that occur during the Valsalva Obviously, the Valsalva manoeuvre is no longer the
manoeuvre? primary method used to expel pus from the ear.
A sudden generation of a high intrathoracic pressure, Instead, it has found a number of other uses, both
such as that occurring during the Valsalva man- clinical and non-clinical, including:
oeuvre, results in dramatic changes to MAP, CO Termination of a supraventricular tachycardia.
and HR. The Valsalva manoeuvre is divided into four The intense vagal stimulation of Phase 4 slows
phases (Figure 39.1): conduction through the AV node.
171
Phases: 1 2 3 4 Figure 39.1 The Valsalva manoeuvre.
110
Overshoot of BP
MAP (mmHg)
100
90
80
70
HR (beats per minute)
90
Reflex bradycardia
80
70
60
50
0 5 10 15 20 25 30
Time (s)
Intrathoracic pressure
of 40 cmH2O applied Positive airway
pressure released
An aid to diagnosis of a murmur. A Valsalva How is the Valsalva manoeuvre used to

manoeuvre increases the intensity of the
murmur of hypertrophic obstructive test autonomic function?
cardiomyopathy, whilst decreasing the The integrity of the ANS can be tested by demon-
intensity of most other murmurs, strating a normal cardiovascular response to the Val-
including aortic stenosis, the main salva manoeuvre. The baroreceptor reflex is often
differential diagnosis of an ejection abnormal in conditions affecting the ANS, such as
systolic murmur. diabetic autonomic neuropathy and spinal cord
Diving. During descent, a Valsalva injury (Figure 39.2):
manoeuvre helps the diver to open In Phase 2, there is no compensatory reflex
their Eustachian tubes and equalize middle- tachycardia – MAP continues to fall until the
ear pressure with ambient pressure. intrathoracic pressure is released.
However, it is not advisable to do this during In Phase 4, there is no overshoot of MAP and
ascent – there is a risk of opening a patent no compensatory bradycardia.
foramen ovale (PFO). A PFO in
combination with decompression illness
arising from dissolved N2 coming out of
solution, producing gas bubbles in the
venous circulation, may result in an arterial
What other abnormal responses are
gas embolus. there to the Valsalva manoeuvre?
Temporary increase in venous pressure. The A ‘square-wave response’ to the Valsalva manoeuvre
Valsalva manoeuvre is often used to increase is seen in conditions characterized by high venous
venous pressure to check for adequate pressure; for example, congestive cardiac failure and
haemostasis following, for example, a radical constrictive pericarditis (Figure 39.3). These patients
neck dissection. survive with the LV operating on the plateau of
172
Chapter 39: Valsalva manoeuvre
Positive airway Figure 39.2 Autonomic dysfunction

pressure applied Phases: 1 2 3 4 and the Valsalva manoeuvre.
110 Positive airway

pressure released
MAP (mmHg)
100
90
80 No BP overshoot in Phase 4
70
No reflex tachycardia
in Phase 2
90
No reflex bradycardia
80 in Phase 4
70
60
50
0 5 10 15 20 25 30
Time (s)
Positive airway Figure 39.3 Square wave response to

pressure applied Phases: 1 2 3 4 the Valsalva manoeuvre.
110 Positive airway

pressure released
MAP (mmHg)
100
90
80 ‘Square wave response’
70
90
Little change in HR
80
70
60
50
0 5 10 15 20 25 30
Time (s)
the Starling curve, with a chronically raised sympa- Further reading

thetic outflow resulting in near-maximal vaso- and
G. Smith. Management of supraventricular tachycardia
venoconstriction. Performing the Valsalva man- using the Valsalva manoeuvre: a historical review and
oeuvre leads to an elevation of MAP throughout the summary of published evidence. Eur J Emerg Med 2012;
duration of raised intrathoracic pressure, with little 19(6): 346–52.
change in HR and no MAP overshoot in Phase 4.
173
Chapter
Exercise physiology
40
Exercise is a major physiological challenge to the in DBP. In addition, sympathetic nervous
body, affecting all the main body systems. A substan- activity increases HR, but to a lesser extent
tial increase in muscle blood flow must be facilitated than dynamic exercise.
whilst maintaining MAP. The increase in muscle
metabolic rate results in an increase in O2 demand
and a requirement for an increased rate of removal of What types of skeletal muscle fibres
CO2 and other metabolites, including lactic acid and are there?
ketone bodies. In addition, despite an increased rate There are two main types of skeletal muscle fibre:
of carbohydrate metabolism, normoglycaemia must
Type I (slow-twitch or fatigue-resistant) fibres.
be maintained. Finally, exercising muscle generates
This type of muscle fibre derives its metabolic
a large amount of heat, yet core temperature must
energy from the oxidative metabolism of
be controlled.
triglycerides, and is therefore rich in myoglobin
(hence its red appearance), mitochondria and
Whatisthedifference betweendynamic capillaries. Type I fibres are found in groups of
muscles where sustained contraction is required;
and static exercise? for example, the postural muscles. Type I fibres
Exercise involves the activation of skeletal muscle. It contract more slowly but are resistant to fatigue.
may be classified as: Type II (fast-twitch) fibres. There are two types:
Dynamic (or isotonic), where muscles – Type IIa (fast-twitch oxidative) fibres.
rhythmically contract and relax, moving joints – Type IIb (fast-twitch glycolytic) fibres.
(for example, running).
Static (or isometric), where muscles contract Type IIb fibres are more reliant on anaerobic
against a resistance but do not lengthen or shorten metabolism (glycolysis) for ATP generation and
(for example, weight lifting). thus have large glycogen stores; their lack of myo-
globin leads to a white appearance. These fibres
Both types of exercise may involve the same muscles, occur in muscles that require short, rapid, power-
but differ in their effects on muscle blood flow and ful movements, for activities such as sprinting.
metabolism: Because of the limited capacity of anaerobic
During dynamic exercise, there is marked metabolism to generate ATP, type IIb muscle
muscle capillary bed vasodilatation in response fibres are more prone to fatigue. Type IIa fibres
to aerobic metabolic activity. Accordingly, are functionally intermediate between type IIb and
SVR falls. The baroreceptors initiate a type I fibres. They utilize both aerobic and anaer-
tachycardia in response to the consequent obic metabolism using large glycogen stores, con-
reduction in DBP. tract more slowly, but are more resistant to fatigue
During static exercise, the muscle capillaries than type IIb fibres.
are compressed by muscle contraction, Individual muscles contain varying mixtures of
with a resultant increase in anaerobic type I, IIa and IIb fibres, with the proportions of each
metabolism. Vessel compression results in fibre type depending on the muscle’s function. The
an increase in SVR, which causes an increase percentage of each fibre type also differs widely
174
Chapter 40: Exercise physiology
between individuals. Individuals genetically equipped weight of carbohydrate. However, such fat
with a greater proportion of type IIb fibres will be mobilization takes place over a longer time
better sprinters than those who have a higher propor- course than the corresponding carbohydrate
tion of type I fibres, who make better endurance metabolism and, therefore, contributes little in
athletes. the early phases of exercise. Fat metabolism
becomes more important during sustained
exercise, when muscle and liver glycogen stores
Which substrates are used by skeletal become depleted. In marathon running, the
muscle to generate energy for sudden fatigue associated with glycogen store
contraction? depletion is called ‘hitting the wall’.
In common with other cells, skeletal muscle uses ATP
as the direct energy source to power contractions.
However, only a small amount of ATP is stored in
What is muscle fatigue?
the muscles, enough for 1–2 s of muscle contraction. Muscle contraction cannot be sustained indefinitely;
It is therefore essential that ATP can be rapidly regen- muscle fatigue is defined as the decline in the ability
erated. There are a number of means by which the of a muscle to generate a force. Peak muscle tension
muscles do this: and the velocity of contraction may be reduced.
Muscle fatigue is a protective mechanism; it stops
Breakdown of phosphocreatine. This is a high- the muscle from contracting to the point where it
energy molecule that is used to rapidly
runs out of ATP, which would result in ‘rigor mortis’
resynthesize ATP from adenosine diphosphate
or, worse still, apoptosis. The exact mechanism
(ADP). Despite muscles only having sufficient
underlying muscle fatigue is unknown, with a number
phosphocreatine stores for around 7 s of intense
of factors thought to be involved:
exercise, it acts as an important energy buffer that
allows time for the more definitive energy- Increased ADP and phosphate as a result of ATP
generating processes to occur. breakdown, which has been variously suggested to
reduce Ca2+ reuptake into the SR (see Chapter 51)
Glycolysis utilizes either glucose or the muscle
or to trigger the opening of ATP-sensitive K+
glycogen store to generate ATP without the
channels, which reduces muscle membrane
need for O2. Considering the number of steps
excitability.
involved (see Chapter 72), glycolysis results in +
a rapid but relatively inefficient increase in ATP Increased extracellular K . In severe exercise,
+
synthesis: arterial K concentration can rise as high as 8
mmol/L (the exercising heart seems to be
– The maximum glycolysis rate is achieved protected from the effects of hyperkalaemia). The
within a few seconds of the onset of exercise. muscle interstitial K+ concentration rises even
– The glycolytic breakdown of glucose generates higher, up to 12 mmol/L. Hyperkalaemia is
two ATP molecules, whilst that of glycogen thought to contribute to muscle fatigue.
generates three ATP molecules. Accumulation of lactate within the muscle.
Lactic acid is produced as a by-product of glycoly- Intense exercise may inhibit enzymes involved in
sis. In strenuous exercise, lactic acid is not cleared aerobic metabolism.
from the circulation as quickly as it is produced, as Exhaustion of muscle glycogen stores following
the blood supply to the liver is reduced. prolonged exercise.
Oxidative phosphorylation. The most efficient
way to generate ATP. Complete breakdown of
glucose (through glycolysis, the citric acid cycle
What physiological changes occur in
and oxidative phosphorylation by the electron anticipation of exercise?
transport chain) generates 36 ATP molecules. Some physiological changes occur before the onset of
Fat metabolism. Metabolism of fats through exercise. Merely anticipating exercise results in
β-oxidation (see Chapter 72) generates a greater greater sympathetic outflow and parasympathetic
number of ATP molecules than an equivalent nervous system inhibition, causing:
175
In the venous system, venoconstriction, which pre-capillary sphincters, allowing blood to

causes an increase in the venous return to flow through the muscle capillary bed.
the heart. Cardiovascular system. The cardiovascular
In the heart, an increase in HR and myocardial system undergoes significant changes with
contractility, which, in conjunction with the exercise (Figure 40.1):
increased venous return, leads to an increase
in CO. – A large increase in CO. Resting skeletal muscle
blood flow accounts for around 20% of CO
In skeletal muscle, vasodilatation of capillary beds
(1000 mL/min). In normal individuals, CO
through activation of sympathetic cholinergic
may increase fivefold with strenuous exercise
fibres. This is an important mechanism that
to match the metabolic demands of exercising
prevents large increases in blood pressure
muscles, from 5 L/min to 25 L/min. At
following the anticipatory increase in CO.
maximum exercise intensity, skeletal muscle
In the peripheries, vasoconstriction in the gut
blood flow accounts for 80% of CO. The
and skin.
increase in CO is mediated by the sympathetic
The cardiovascular effects vary depending on the nervous system:
anticipated duration and intensity of the exercise.
For example, anticipation of a short sprint results in ▪ Preload is increased as a result of
a greater increase in HR than anticipation of an venoconstriction, the skeletal muscle pump
endurance run. This is because it would be impossible and the respiratory pump (see Chapter 35).
to increase HR to near maximal levels over the short ▪ Afterload is reduced – SVR falls due to
duration of a sprint distance, whereas in a marathon the release of vasodilatory metabolites
there is ample time to instigate the cardiovascular from the muscle.
response. ▪ HR increases in proportion to exercise
intensity, due to a reduction in
parasympathetic nervous activity and an
What are the physiological effects of increase in sympathetic nervous activity in
the heart. However, there is a limit to the
exercise on each body system? value of tachycardia: above a certain rate,
Considering each system in turn: the diastolic filling time is so short that CO
Skeletal muscle. Exercising muscle requires falls (see Chapter 27).
a substantial increase in blood flow to ▪ Myocardial contractility increases, due to
increase the delivery of O2 and metabolic both sympathetic nervous system
substrates, and to remove CO2 and other stimulation of the cardiac myocytes and
waste products. also the Bowditch effect, where tachycardia
– Resting skeletal muscle blood flow is around induces an increase in myocardial
2–4 mL/100 g of muscle/minute. At rest, pre- contractility (see Chapter 28).
capillary sphincters are closed and blood is
diverted from the muscle capillary beds into – Changes in blood pressure. Little change in
large vessels. blood pressure occurs in anticipation and
during early phases of exercise, as the
– In fit, healthy adults undergoing strenuous
increased CO is mitigated by sympathetic
exercise, muscle blood flow increases up to
cholinergic arteriolar vasodilatation in the
50–100 mL/100 g of muscle/minute,
skeletal muscle. SBP increases as cardiac
depending on the type of muscle.
contractility increases.
– This marked increase in blood flow to muscle
is caused by the local action of vasodilatory ▪ In dynamic exercise, DBP remains similar
metabolites (for example, H+, AMP, K+, or may even decrease, due to a reduction in
phosphate). These metabolites are produced the SVR caused by skeletal muscle arteriole
in proportion to O2 consumption; they open vasodilatation. As the SBP increases more
176
Figure 40.1 Cardiovascular changes

ic
s to l with dynamic exercise.
Sy
Blood pressure (mmHg)
180
Increased
pulse
n
Mea pressure
120
Diastolic
60
140
Stroke volume (mL)
100
Fall in SV as diastolic
filling time shortens
60
Heart rate (beats per minute)
200
100
0
Rest Mild Moderate Intense
Intensity of exercise
than the DBP falls, MAP may slowly muscle, the blood flow to other organs is also
increase with increased exercise intensity altered during exercise:
or duration.
▪ Coronary blood flow increases fivefold
▪ In static exercise, the DBP increases as the to meet the increased O2 demand
muscle capillary beds are occluded.
of the myocytes, from a resting value
Therefore, MAP increases rapidly.
of 250 mL/min to 1250 mL/min.
– Changes in regional blood flow. Whilst the ▪ Blood flow to the skin substantially
greatest increase in blood flow is to the skeletal increases to aid heat dissipation.
177
Figure 40.2 Respiratory changes with

exercise.
Mean pulmonary artery pressure
30
(mmHg)
20
10
100
Initial sudden
increase in
ventilation
50
Acidosis stimulates
further increase in
ventilation
0
▪ Splanchnic blood flow falls substantially to exercise intensity up to 20-fold, from a basal
during exercise. level of 5 L/min up to 100 L/min. This
▪ RBF falls, but to a lesser extent than compares with a fivefold increase in CO
splanchnic blood flow, due to a stronger by the cardiovascular system. The
autoregulatory mechanism. respiratory system is thus not usually
▪ CBF does not alter at any exercise intensity. the limiting factor in exercise performance.
The control of ventilation is discussed in
Respiratory system. detail in Chapter 21. In brief:
– A substantial increase in V_ E . In strenuous ▪ At the onset of exercise, there is a
exercise, O2 consumption may increase rapid increase in V_ E : both RR and VT
from a typical basal value of 250 mL/min increase (Figure 40.2). The respiratory
to 5000 mL/min; CO2 production centre is stimulated by two factors:
increases proportionately. In healthy lungs, increased activity of the motor cortex
the respiratory system has a remarkable and afferent signals from limb joint
capacity: V_ E increases in proportion proprioceptors.
178
▪ With continued exercise, V_ E increases Thermoregulation. Skeletal muscle activity is

in proportion to the PaCO2, sensed relatively inefficient: only 20–25% of the chemical
predominantly by the central energy within the metabolic substrates is
chemoreceptors, but also by the converted to mechanical energy, with the rest
peripheral chemoreceptors. As CO2 is a dissipated as heat energy. As discussed in
by-product of skeletal muscle metabolism, Chapter 83, thermoregulation is controlled
V_ E increases in proportion to the intensity through a complex negative-feedback loop
of exercise. involving peripheral and central sensors, whose
▪ With extremely intense exercise, V_ E signals are integrated by the hypothalamus.
increases disproportionately (Figure 40.2). Effectors are:
There comes a point where O2 delivery to – Eccrine sweat glands in the skin – heat is lost as
the exercising muscle is unable to a result of the latent heat of evaporation.
match O2 consumption (the anaerobic – Cutaneous vasodilatation – heat is lost by
threshold), and anaerobic metabolism conduction.
commences. Lactic acid is produced Following the onset of exercise:
as a consequence, which causes a fall in
arterial pH. The lower arterial pH – There is an initial transient fall in core
is sensed by the carotid bodies, temperature of 1 °C as venous return increases
resulting in further stimulation from the limbs.
of the respiratory centre. – As exercise continues, there is net heat
generation. Heat loss mechanisms (sweating
– Increased pulmonary blood flow. As discussed and peripheral vasodilatation) commence.
above, exercise results in a substantial Further heat is lost as a result of the large
increase in CO; pulmonary blood flow increase in V_ E (through the latent heat of
therefore increases to the same degree. evaporation as dry inhaled gases are
If it were not for the pulmonary vasculature humidified), although this mechanism is less
responding by recruitment and distension important in humans than in other animals.
(see Chapter 22), MPAP would increase – In hot, humid climates, heat loss mechanisms
substantially. The mild increase in are impaired. When the environmental
MPAP that actually occurs (Figure 40.2) temperature is greater than body temperature,
is physiologically important, as it diminishes there is no net gradient for heat loss
the effect of gravity within the lung: by conduction; sweating becomes the
the regional V̇ /Q̇ ratio trends towards only heat loss mechanism. In humid
1.0 (0.8 is typical in the resting lung). conditions, evaporation of sweat is impaired.
Gas exchange, therefore, becomes more Thermoregulation thus fails, leading to
efficient with exercise, and physiological increased core temperature. Heat stroke
shunt is reduced. (a core body temperature greater than 40.6 °C)
– PaO2. Despite the high O2 consumption of may result, with a variety of symptoms,
exercising muscle, PaO2 remains normal, including confusion and syncope. Rapid
even during intense exercise. As discussed external cooling is required.
in Chapter 9, transfer of O2 across the
alveolar–capillary barrier is not diffusion
limited in normal lungs at sea level. SaO2 is What is meant by the term V_ O2 max ?
therefore unchanged. However, the position O2 consumption V_ O2 increases linearly with exercise
of the oxyhaemoglobin dissociation curve intensity, but reaches a plateau at V_ O2 max
changes: acidosis and raised temperature (Figure 40.3). V_ O2 max is the maximum capacity of a
shift the P50 to the right (see Chapter 7), person’s body to transport and use O2 during incre-
which aids O2 offloading to the metabolically mental exercise (units: millilitres of O2/kilogram of
active tissues. body weight/minute), and is used as a measure of a
179
Figure 40.3 Effect of exercise intensity

50 on O2 consumption.
.
Oxygen consumption (mL/(kg min))
VO2 max
40
30
20
10
0
person’s physical fitness – athletes have much greater V_ O2 max . Additionally, hypoxaemia results in EPO
V_ O2 max than normal individuals. secretion and increased haematocrit.
V_ O2 max is one of the main measurements In patients with cardiovascular disease, exercise
attained by CPET.1 Clinically, V_ O2 max gives a useful capacity may be limited if the heart cannot
measure of cardiopulmonary ‘physiological reserve’, increase CO sufficiently to match the increased
in order to predict how well a patient will cope with demand of the muscles. Additionally, patients who
the additional metabolic demands of surgery. take medication that limits CO (for example,
The determinants of V_ O2 max remain poorly β-blockers) have a correspondingly lower
understood, and some studies suggest that it may even V_ O2 max .
be an artefact of measurement. Exercise limitation is With the exception of severe lung disease,
usually attributed to the cardiovascular system, but is the respiratory system almost never limits exercise
likely multifactorial: capacity. The increase in V_ E usually far exceeds
Factors involved in delivery of O2 to the muscles the increase in CO, and transfer of O2 across
include: the alveolar–capillary barrier is usually not
diffusion limited.
– O2-carrying capacity of the blood; that is,
anaemia reduces V_ O2 max . Clinical relevance: V_ O2 max and surgical risk
– The capillary density of the muscles
Preoperative CPET aims to quantify an individual’s
themselves. This is likely to be the limiting risk of perioperative morbidity and mortality, to aid
factor in normal exercise. decision-making and the planning of postoperative
care (for example, the need for a critical care bed). As
Athletes train at altitude to increase their perform- discussed above, V_ O2 max is one important measure-
ance; the resulting hypoxaemia is a strong inducer ment of CPET (the other important measurement
of vascular endothelial growth factor, which being anaerobic threshold – the point at which O2
induces muscle vascularization and thus increases demand exceeds O2 delivery and anaerobic metab-
olism commences).
V_ O2 max measurements are typically 25–40 mL/
(kg min) for ‘normal’ patients (the highest recorded
1
Strictly, it is peak V_ O2 rather than V_ O2 max that is V_ O2 max was from an elite cyclist: 97.5 mL/(kg min)).
measured in CPET. Peak V_ O2 is the maximum V_ O2 Low measured V_ O2 max has been associated with
achieved within the time period of the CPET test. Many of higher perioperative morbidity and mortality across
the patients referred for CPET never achieve the plateau a number of surgical sub-specialties:
shown in Figure 40.3.
180
O2 deficit – the difference

between ideal and real O2 uptake
40
Oxygen consumption (mL/(kg min))
s e
e rci
30 Ex
Re
Chemical
co
20
ve
ventilatory drive Alactacid phase
ry
EPOC – extra O2 is needed
to restore metabolic stores
Lactacid phase
Increase in neural
10 ventilatory drive
Rest
0
0 1 2 3 4 5 6 7 8 9 10
Time (min)
Figure 40.4 Excess post-exercise O2 consumption.
V_ O2 max <15 mL/(kg min) carries a high risk of What happens to oxygen consumption
postoperative complications;
V_ O2 max <10 mL/(kg min) is associated with very
after a patient stops exercising?
high mortality; conservative management should A person continues to breathe deeply for a period
be considered. of time after exercise has ceased. V_ O2 remains high
during the recovery phase – this is known as the
The metabolic equivalent of a task (MET, excess post-exercise O2 consumption (EPOC) or O2
or metabolic equivalent) is another method of
debt. There are two distinct phases to the EPOC
expressing the energy cost of a particular physical
(Figure 40.4):
activity (see Chapter 72). One MET, the BMR of a
fasted, resting patient, is associated with a V_ O2 The alactacid phase, which is rapid and involves
of 3.5 mL/(kg min). Therefore, METs can be related the:
to V_ O2 :
– replenishment of high-energy phosphocreatine
A patient who is unable to climb one flight of
and ATP stores that were depleted
stairs (an activity of approximately 3 METs,
equivalent to a V_ O2 < 10 mL/(kg min)) has a high in the early phase of exercise;
perioperative mortality risk. – replenishment of O2 to myoglobin;
The ability to climb two flights of stairs without – replenishment of muscle and liver
stopping (an activity of approximately 4 METs, glycogen stores.
equivalent to a V_ O2 of at least 14 mL/(kg min)) is The lactacid phase, which takes much longer
associated with a much lower perioperative and involves the conversion of lactate back
mortality risk. to pyruvate, mostly in the liver.
Climbing five flights of stairs (an activity of
around 8 METs, equivalent to a V_ O2 > 20 mL/(kg
min)) is associated with minimal perioperative In the longer term, high catecholamine levels and
mortality. raised temperature causes a global increase in meta-
bolic rate. Anabolic processes (for example, muscle
181
fibre repair and hypertrophy) may occur over days to In addition, there are changes in:
weeks of repeated exercise. The lungs. Maximum breathing rate increases, the
The time taken to repay the O2 debt depends on volume of the lungs increases and the number of
the duration and intensity of exercise: following a pulmonary capillaries also increases. Altogether,
short walk, V_ O2 may be raised for a few minutes, maximal V_ E may increase by up to 15 L/min
but it may take more than a day to fully recover with training.
metabolically after running a marathon. Skeletal muscle. Hypertrophy occurs as a result of
training (an effect of the resistive work done by
the muscles, rather than aerobic training).
How do elite athletes differ from the Endurance training increases the diameter
‘normal’ population? of type I muscle fibres and encourages the
Unsurprisingly, the main changes that occur with formation of muscle capillaries, increases
physical training are to the cardiovascular system: the density of mitochondria, and the activity of
SV. Physical training causes cardiac hypertrophy,
2 oxidative metabolic enzymes. Exercise carried
which results in up to 40% greater SV. out in repetitive intense episodes increases
HR. Maximum HR does not change, but the the diameter of type IIb muscle fibres and
resting HR of athletes is often lower than the increases the activity of anaerobic metabolic
general population due to increased vagal tone. As enzymes.
the resting SV is increased, resting CO remains Bone mineral density. Weight-bearing exercise
approximately the same. increases bone mineral density. Exercise is a
CO. The increased SV means that the maximal particularly important means of reducing the
CO is increased in athletes. risk of fractures in the elderly.
V_ O2 max may increase by up to 25% with training.
This is thought to be due to an increase in O2 Further reading
delivery as a result of increased muscle D. A. Burton, K. Stokes, G. M. Hall. Physiological effects
vascularization. of exercise. Contin Educ Anaesth Crit Care Pain 2004;
4(6): 185–8.
N. Agnew. Preoperative cardiopulmonary exercise
testing. Contin Educ Anaesth Crit Care Pain 2010;
2 10(2): 33–7.
This is different from pathological cardiac hypertrophy
resulting from, for example, aortic stenosis.
182
Section 4 Neurophysiology
Chapter
Neuronal structure and function
41
What are the functions of the Describe the structure of a neuron
nervous system? The neuron is the functional unit of the nervous
The nervous system is a complex network of special- system. Although neurons vary in their detailed cellu-
lar structure, all include the following components
ized cells, called neurons, which coordinate and con-
(Figure 41.1):
trol the other organ systems.
The nervous system has three basic functions: The cell body, which in common with other cell
types contains cytoplasm, a nucleus and
Sensory input. Sensory receptors detect changes
organelles. The cell body is involved in protein
in the external and internal environments. In
synthesis and the generation of ATP. However, as
response to a stimulus, the sensory receptor
mature neurons lack a centriole, which is
generates an electrical signal, an action potential,
necessary for cell division, neurons cannot
which is then relayed to the brain and spinal cord
undergo mitosis. The cell bodies form the grey
(collectively known as the CNS).
matter in the brain and spinal cord. Groupings of
Integration. Sensory input is received and
cell bodies are termed nuclei in the CNS and
processed by the CNS. Decisions are made on the
ganglia in the PNS.
basis of this sensory integration.
Dendrites are branched projections that receive
Motor output. Neurons relay action potentials
signals from other neurons through synapses, and
from the CNS to the muscles and glands. Motor
propagate them towards the cell body.
output is the only way we can interact with our
external environment; even salivation requires The axon is a long projection originating at the
cell body. Action potentials are generated at the
smooth muscle contraction. Much of the nervous
axon hillock1 and conducted along the axon,
system is therefore dedicated to producing
away from the cell body. The axon may be either
movement.
unmyelinated or myelinated. Myelin is made up
Neurons communicate between themselves and other of multiple layers of electrically insulating lipid
organs through two forms of signalling: and protein, produced by the Schwann cells in the
Neural. An action potential is conducted from the PNS or oligodendrocytes in the CNS. Lipid gives
cell body of a pre-synaptic neuron to its terminus. axons a white colour, and therefore forms the
The signal is then transmitted from the pre- ‘white matter’ of the brain and spinal cord. Myelin
synaptic neuron to a post-synaptic cell (which increases the speed of action potential propagation
may be another neuron, a muscle cell or a gland) (see Chapter 49).
by means of an electrical or chemical synapse. An axon terminal, the distal end of the axon. At
Whilst nerve conduction is relatively rapid (up to the axon terminal, the neuron communicates with
120 m/s in large myelinated nerves), conduction another cell through a synapse. In a motor
across a chemical synapse is slower. neuron, this synapse is the NMJ.
Endocrine. The brain synthesizes and releases
hormones into the circulation, which conveys 1
The axon hillock has the lowest threshold for action
them to the target organ. Endocrine signalling is potential generation in the cell, owing to its high density
therefore much slower than neural signalling. of voltage-gated Na+ channels.
183
Section 4: Neurophysiology
Axon terminal Figure 41.1 Basic structure of a neuron.
Nucleus Node of Ranvier
Myelin sheath
Terminal bouton
Axon hillock
Axon
Cell body
Dendrites
– The spinal cord contains long sensory and

These components can be arranged to give differing motor pathways that convey information
nerve morphologies. The major neuron classes are between the periphery and the CNS, as well as
(Figure 41.2): local integrative networks. Interneurons (for
Unipolar. These neurons have an axon projecting example, Renshaw,2 multipolar and pyramidal
from a cell body. They are not common in cells) provide connections between neurons
humans but may be found in the cochlear. within the CNS.
Bipolar. These neurons have a cell body between The PNS, whose cell types are:
the dendrites and the axon. Bipolar cells are found – Sensory (afferent) neurons, which relay
in the retina and the olfactory neurons. information from the external environment
Pseudounipolar. Some bipolar neurons may look and viscera to the CNS. Most have a
unipolar – the axon is interrupted by the cell body pseudounipolar structure with the cell body on
approximately midway down. Most sensory a process to the side of the axon (Figure 41.2)
neurons are pseudounipolar. located in the dorsal root ganglion.
Multipolar. The dendrites insert directly into the – Motor (efferent) neurons, also known as
cell body without coalescing. The classical example ‘somatic motor neurons’, are under voluntary
of a multipolar neuron is a motor neuron. control. Motor neurons transmit action
Anaxonic. Dendrites and axons are potentials from the CNS to skeletal muscle.
indistinguishable, looking like a large tree of These neurons are typically multipolar; they
insertions into a cell body. Amacrine cells in the receive many inputs through multiple
retina are anaxonic. dendrites, with the resultant action potential
Pyramidal cells. These have a triangular cell body propagated through a single axon
(hence the name), a single axon and a large number (Figure 41.2).
of dendrites – through these dendrites, pyramidal – Enteric neurons form a large network around
cells can integrate many afferent signals. the GI tract. The enteric nervous system is
sometimes referred to as the ‘second brain’, as
it operates with relative independence from
the CNS. The brain can still influence the
How is the nervous system divided? enteric nervous system through the action of
All of the elements of the nervous system work autonomic neurons.
together holistically. However, the nervous system – Autonomic neurons deal with the more
has traditionally been divided into: primitive ‘housekeeping’ functions of the
The CNS, consisting of the brain and spinal cord: viscera, as well as the body’s emergency
– The brain is the site of higher integration
of sensory inputs, motor output, thinking
2
and learning. Renshaw cells are simple inhibitory interneurons.
184
Chapter 41: Neuronal structure and function
Bipolar Pseudounipolar Multipolar Pyramidal cell Figure 41.2 Common types of neuron.
responses. The ANS is involuntary and divided Perineurium. Many nerve fibres are bundled
into two subsystems, the sympathetic and together into groups called fascicles. Each
parasympathetic nervous systems, discussed in fascicle is wrapped in a layer of connective
more detail in Chapter 56. tissue called perineurium, which supports the
fascicles.
What are the component tissue layers Epineurium. This is the thick outer layer of the
peripheral nerve. The epineurium encloses the
of peripheral nerves? multiple fascicles, together with their blood
A peripheral nerve is a bundle of many nerve axons. vessels.
Connective tissue physically separates and electrically
insulates the axons from one another. The result is a For local anaesthetic to exert its effects on the
layered structure, rather like an onion skin, containing: nerve axons, it must therefore diffuse through three
Schwann cells. Myelinated nerve axons are layers: the epineurium, the perineurium and the
surrounded by a layer of myelin, produced by the endoneurium.
Schwann cells. An axon surrounded by a myelin
sheath is often referred to as a nerve fibre. Further reading
Endoneurium. Each nerve fibre is surrounded by E. Pannese. Neurocytology: Fine Structure of Neurons, Nerve
a thin layer of connective tissue called Processes and Neuroglial Cells. Thieme Publishing
endoneurium. Group, 1994.
185
Chapter
The brain
42
Describe the gross anatomy of the brain – Frontal lobe. The majority of the frontal lobe is
The brain performs complex sensory, motor and involved in higher functions: problem solving,
higher functions, coordinating the activity of other reasoning, planning, language generation, and
body systems. It has a high metabolic activity and complex social and sexual behaviour. The
receives a much greater proportion of the resting premotor and primary motor cortex, located
CO (around 15%) than would be predicted based on in the posterior frontal lobe, are involved in
its weight. It can be divided into five regions: the planning and initiation of movement.
– Parietal lobe, the area of the brain involved in
The telencephalon (cerebrum) is the largest
sensory integration. The post-central gyrus, the
part of the human brain, occupying the anterior
most anterior part of the parietal lobe, contains
and middle cranial fossae. It comprises three
the primary somatosensory cortex. The left and
sub-regions:
right parietal lobes have slightly different
– The right and left cerebral hemispheres perform functions. The dominant hemisphere (the left
higher functions of memory, thinking, hemisphere in 97% of the population) is
planning and language, in addition to being concerned with structure and order; for example,
essential for sensory perception and the reading and mathematics involve ordering letters
initiation of voluntary movement. and numbers respectively. The non-dominant
– The basal ganglia, a collection of nuclei hemisphere is concerned with spatial awareness.
located deep within the cerebral hemispheres, – Temporal lobe, which controls hearing,
has classically been regarded as part of the language and memory. The left temporal lobe
extrapyramidal system which coordinates fine contains the primary auditory cortex.
motor control, muscle tone and posture. Wernicke’s area, an area of cortex important in
– The limbic system, a collection of structures receptive language, lies between the temporal
located on either side of the thalamus, is and frontal lobes of the dominant hemisphere.
involved in a number of higher functions, – Occipital lobe, the area of the brain that
including long-term memory, emotion and interprets visual stimuli.
behaviour. The diencephalon, which includes:
The right and left cerebral hemispheres are – The thalamus, which acts as a relay station.
connected by a thick bundle of myelinated nerve Sensory afferent neurons, with the exception
axons called the corpus callosum. The cerebral of the olfactory neurons, synapse in the lateral
cortex, the outer layer of the cerebrum, is made thalamic nuclei before relaying to the cerebral
up of grey matter reflecting the relatively large cortex. The medial structures of the thalamus
number of nerve cell bodies. The deeper layers of have roles in pain perception, awareness and
the cerebrum are composed of white matter, the regulation of sleep.
reflecting the greater proportion of myelinated – The hypothalamus, a specialized area of the brain
nerve axons. The cerebral cortex has a large sur- that regulates autonomic function and links the
face area thrown into numerous folds with ridges nervous system to the endocrine system. The
(gyri) and troughs (sulci). Each cerebral hemi- hypothalamus exerts control over the pituitary
sphere has four lobes: gland, a major endocrine gland (see Chapter 75).
186
Chapter 42: The brain
In addition, the hypothalamus has roles in On each side, afferent and efferent nerve
appetite and satiety, thirst and control of impulses are carried between the cerebellum and
osmolarity, thermoregulation and circadian the brainstem through three nerve bundles:
rhythm. – The superior and middle cerebellar peduncles
– The subthalamus contains the subthalamic connect the cerebellum to the pons.
nucleus, which is thought to be part of the – The inferior cerebellar peduncle connects the
basal ganglia. cerebellum to the medulla.
– The metathalamus contains the lateral The rhombencephalon consists of the following
geniculate nucleus, which relays visual structures:
information from the optic nerve to the
– The pons (‘bridge’) connects the cerebellum
primary visual cortex, and the medial
to the brainstem, and the medulla oblongata
geniculate nucleus, which relays auditory
to the midbrain. The nuclei of cranial nerves V
information to the primary auditory cortex.
to VIII are also located in the pons.
The mesencephalon (midbrain) joins the The pneumotaxic and apneustic centres, nuclei
hindbrain to the cerebral hemispheres. The
which form part of the respiratory centre, are
midbrain contains the cerebral aqueduct of
located at the border between the pons and
Sylvius, which connects the third ventricle to the
medulla.
fourth ventricle (see Chapter 43). The midbrain
– The medulla oblongata connects the brain to
also contains the third (oculomotor) and fourth
the spinal cord. Most descending motor tracts
(trochlear) cranial nerve nuclei and the red nuclei,
of the pyramidal system decussate (cross over
which relay extrapyramidal tracts from the
to the contralateral side) in the medulla, at the
cerebellum and cerebral cortex to the spinal cord.
bulges known as the pyramids. Ascending
The medulla oblongata, pons and midbrain are
sensory tracts of the dorsal column–medial
collectively referred to as the brainstem.
lemniscal pathway also decussate in the
The cerebellum (meaning ‘little brain’) occupies medulla. The medulla contains the nuclei
the posterior cranial fossa. Although it makes up
involved in the physiological functions most
only 10% of the brain’s volume, the cerebellum
essential to life: the respiratory and vasomotor
contains over 50% of the brain’s neurons,
centres, and extrinsic regulation of the heart
reflecting its central role in the refinement of
through the ANS. The medulla controls many
movement. The cerebellum does not initiate
stereotyped reflexes, including the vomiting,
movements (this is the role of the motor cortex).
swallowing, sneezing, gag and cough reflexes.
Instead, it modifies movements to ensure they are
smooth, coordinated and accurate. The An alternative embryological classification divides
cerebellum is also responsible for learning motor the brain into three embryological regions:
movements: it builds a ‘working model’ of the The forebrain (prosencephalon), which develops
environment based on experience. Damage to into the cerebral hemispheres, and the
the cerebellum, therefore, does not result in diencephalon.
paralysis, but in ataxia and poor motor learning. The midbrain (mesencephalon).
The cerebellum is divided into two main parts:
The hindbrain (rhombencephalon), which
– The vermis, the central part, is concerned with develops into the cerebellum, pons and medulla
motor and postural control of the trunk. oblongata.
– The cerebellar hemispheres, located on either
side of the vermis, are concerned with
coordinated motor control of the limbs. What are the meninges?
Damage to the right cerebellar hemisphere The meninges are membranes that cover the brain
causes limb ataxia on the right side (i.e. the and spinal cord, providing protection to the CNS. The
ipsilateral side) and vice versa. This is in contrast meninges consist of three layers:
to damage to the right side of the motor cortex, The dura mater, a thick outer membrane.
which causes a left-sided hemiplegia. The dura consists of an outer periosteal layer
187
and an inner meningeal layer, and has Astrocytes, the most abundant of the neuroglia.
four infoldings: Astrocytes anchor neurons to blood vessels and
– Falx cerebri, which separates the cerebral form the BBB, providing the neurons with a
hemispheres. constant external environment (see Chapter 44).
– Tentorium cerebelli, which separates the Oligodendrocytes, which have an equivalent role
occipital lobes from the cerebellum. to that of Schwann cells in the PNS, coating the
– Falx cerebelli, which lies inferior to the tentorium, nerve axons in myelin, an electrical insulator
separating the cerebellar hemispheres. (see Chapter 49).
– Diaphragma sellae, a circular fold of dura that Ependymal cells, which form the epithelial
envelops the pituitary gland in the sella turcica. lining of the ventricles of the brain, and the central
canal of the spinal cord.
The arachnoid mater, a thin membrane with a
spider-like appearance. Microglia, the specialized macrophages of the CNS.
The pia mater, a very thin and highly vascular
membrane that adheres to the surface of the brain
and spinal cord. Beyond the terminus of the spinal Describe the cerebral arterial
cord, the pia continues as the filum terminale, blood supply
which (along with the dura) tethers the spinal cord The cerebral arterial blood supply is derived from four
to the coccyx. main arteries: the right and left internal carotid arteries
Some features of the meninges are common to (ICAs), and the right and left vertebral arteries. Two-
both the brain and spinal cord: thirds of cerebral blood comes from the ICAs.
The unique feature of the cerebral circulation is
The subdural space is a potential space located the ‘circle of Willis’, an anastomosis of cerebral vessels
between the dura and arachnoid. The two
(Figure 42.1):
meningeal layers may be separated by blood as a
result of a tear in a bridging vein – this is referred Right and left anterior cerebral arteries (ACAs),
to as a subdural haematoma. branches of the ICAs that supply the superior and
medial portions of the cerebral hemispheres.
The subarachnoid space contains CSF, and is
located between the arachnoid and pia. ACom ACA
Other features are unique to the brain or spinal cord:

In the brain, venous blood drains into the dural ICA
venous sinuses (for example, the superior and
inferior sagittal, carvernous, sigmoid and
transverse), which are located between the two MCA
layers of dura mater.
In the spinal cord, the spinal dura mater is PCom
separated from the ligamenta flava and the
periosteum of the vertebral bodies, pedicles and PCA
laminae by the epidural (or extradural) space. The
epidural space contains lymphatics, spinal nerve Basilar
roots, loose connective tissue and the epidural
venous plexus. The epidural space extends from the
sacrococcygeal membrane to the foramen magnum.
Vertebral
What are the neuroglia?

The neurons of the CNS are supported by four types Posterior inferior
cerebellar
of cell, known collectively as the neuroglia. Unlike
neurons, which cannot replicate, neuroglia continue Anterior spinal
to divide throughout life. The neuroglial cell types are: Figure 42.1 The circle of Willis.
188
Chapter 42: The brain
Anterior communicating artery (ACom), a small

artery that connects the left and right ACAs. circulation of the circle of Willis, resulting in a
large cortical infarct. The vessel most commonly
Right and left middle cerebral arteries (MCAs), affected is the MCA. As discussed above, the
which arise from the ICAs and supply the lateral anterior circulation supplies the medial, superior
aspect of the cerebral hemispheres. and lateral portions of the cerebral hemispheres.
Basilar artery, a single artery that arises from the ACI is therefore associated with three categories
amalgamation of the two vertebral arteries. of clinical signs:
Branches of the basilar artery supply the – Contralateral weakness, when the motor cor-
brainstem. tex is affected.
Right and left posterior cerebral arteries (PCAs), – Homonymous hemianopia, when the optic
tract is affected.
which are formed when the basilar artery divides.
– Higher cerebral dysfunction; for example,
The PCAs supply the occipital lobes and the
dysphasia or visuospatial disorder, depending
medial portion of the temporal lobes. on whether the dominant or non-dominant
Right and left posterior communicating arteries parietal lobe is affected.
(PComs), which connect the PCA to the ICA on
either side of the brain. Posterior circulation infarct, PCI. Thrombus
or embolus obstructing blood flow in the
vertebrobasilar circulation results in infarction of
The cerebral vessels supplied by the ICAs (ACAs, the downstream areas of the brain, causing:
ACom and MCAs) are referred to as the anterior – Cerebellar dysfunction – ataxia, nystagmus.
circulation, whilst the cerebral vessels supplied by – Cranial nerve palsies or loss of consciousness,
the vertebral arteries (basilar, PCAs, PComs) are as a result of brainstem involvement.
called the posterior circulation. – Homonymous hemianopia, as a result of
occipital lobe involvement.
Describe the venous drainage of Lacunar infarct, due to occlusion of a small
sub-cortical vessel. The resulting clinical effects (for
the brain example, a motor hemiparesis) are out of propor-
The cerebral venous system can be subdivided into tion to the small size of the infarct. This is because
superficial and deep systems: the infarct affects important structures deep in the
Superficial, comprising the dural venous sinuses: cerebral hemisphere through which motor or
venous channels located between the two layers of sensory nerve axons pass; for example, the lateral
dura mater (see above). Blood from the dural thalamus or the posterior limb of the internal cap-
sule. Lacunar infarcts are not associated with higher
sinuses ultimately drains into the paired internal
cerebral dysfunction, and as such have a much
jugular veins. The venous sinuses are different
better prognosis than ACI or PCI.
from veins elsewhere in the body: they are formed
from dura, they lack valves and they are not Theoretically, the circle of Willis should provide a
collapsible, which in part explains the higher risk collateral circulation if a vessel becomes occluded.
of air embolus during neurosurgery. However, the circle is often anatomically incomplete,
resulting in stroke being the third leading cause of
Deep, consisting of traditional veins that drain
death in the UK.
blood from the deep structures of the brain. These
veins merge to form the vein of Galen, which
drains into the inferior sagittal sinus.
What is an electroencephalogram?
Clinical relevance: stroke
The electroencephalogram (EEG) is a recording of the
The Bamford classification divides ischaemic stroke electrical activity of the brain, measured using 19 scalp
into categories based on the affected cerebral
electrodes. The electrical potential generated by
circulation:
depolarization of a single neuron is far too small to
Anterior circulation infarct, ACI (sub-classified
as total or partial), in which a thrombus or be detected at the scalp. In the heart, the ECG records
embolus obstructs blood flow in the anterior simultaneous depolarization of all the ventricular
myocytes. In a similar way, the EEG records patterns
189
representing the synchronized depolarization of

groups of neurons. However, the complexity of the Bispectral index (BIS) is an attempt to simplify the
highly complex EEG into a simple dimensionless
brain’s electrical activity makes interpretation of
number, to help the anaesthetist assess depth of
the EEG a very difficult task. Electrical activity
anaesthesia and prevent intraoperative awareness.
in the brain is categorized based on its frequency: BIS converts the frontal EEG to a number between 0
δ waves: 0–4 Hz (no brain electrical activity) and 100 (fully awake),
θ waves: 4–8 Hz where 40–60 is considered to be an appropriate level
α waves: 8–13 Hz of anaesthesia for surgery. There are a number of
potential problems with using BIS:
β waves: >13 Hz.
BIS demonstrates a dose–response
In anaesthetic practice, the clinical uses of the relationship with some anaesthetic agents;
EEG are: for example, propofol, inhalational agents and
midazolam. But some agents which have
Diagnosis of epilepsy. Seizure activity results in synergistic effects with anaesthetic agents have
organized, simultaneous activity in neurons, no effect on the BIS number; for example,
which can be identified on the EEG. Non- N2O and opioids.
convulsive status epilepticus is an important In contrast to other anaesthetic agents, ketamine
differential diagnosis in a critical care patient who increases EEG activity, increasing the BIS number.
fails to wake following a sedation hold. Studies assessing the efficacy of BIS are
Diagnosis of encephalopathy. This is characterized contradictory:
by a progressive increase in slow wave activity. – The B-Aware study found that BIS-guided
anaesthesia reduced the risk of awareness
As an adjunct test of brain death. This is not
with recall by 82%.
required to diagnose brain death under UK law, – The B-Unaware trial found that BIS-guided
but is used elsewhere in the world to confirm anaesthesia provided no greater reduction in
brain death. The EEG of a brain-dead patient is intraoperative awareness than using end-tidal
isoelectric, reflecting the lack of electrical activity. volatile concentration.
As a measure of depth of anaesthesia, both in
Despite the controversy, the National Institute for
theatre anaesthetics (see below) and in critical
Clinical Excellence has recently recommended the
care; for example, burst suppression of the EEG in use of BIS in patients considered to be at higher risk
barbiturate coma. of awareness, and in those undergoing total intra-
Somatosensory-evoked potentials (SSEPs). venous anaesthesia.
During spinal surgery, SSEPs are used to reduce the
risk of damage to the spinal cord. SSEP monitoring
involves stimulating a peripheral nerve and
detecting a response in the somatosensory cortex, Further reading
through appropriately placed scalp electrodes. A. Raithatha, G. Pratt, A. Rash. Developments in the
SSEPs are usually combined with motor-evoked management of acute ischaemic stroke: implications
potentials. During spinal surgery, a loss of for anaesthetic and critical care management. Contin Educ
amplitude or increased latency of the SSEP signal
suggests neurological injury. M. S. Avidan, L. Zhang, B. A. Burnside, et al. Anesthesia
awareness and the bispectral index. N Engl J Med 2008;
358(11): 1097–108.
Clinical relevance: monitoring depth of anaesthesia
P. S. Myles, K. Leslie, J. McNeil, et al. Bispectral index
The spontaneous electrical activity of the brain
monitoring to prevent awareness during anaesthesia: the
reduces under general anaesthesia. This reduction
B-Aware randomised controlled trial. Lancet 2004;
can be measured by the EEG. However:
363(9423): 1757–63.
The reduction in electrical activity is nonlinear,
and requires expert interpretation. S. D. Whyte, P. D. Booker. Monitoring depth of anaesthesia
Different anaesthetic agents generate different by EEG. Contin Educ Anaesth Crit Care Pain 2003; 3(4):
EEG patterns. 106–10.
Intraoperative physiological events, such as C. Macchi, R. M. Lova, B. Miniati, et al. The circle of Willis
hypercapnoea and hypotension, affect the EEG. in healthy older persons. J Cardiovasc Surg (Torino)
2002; 43(6): 887–90.
190
Chapter
Cerebrospinal fluid
43
waste products that need to be cleared, but lacks a
What are the functions of lymphatic system. Instead, the recently discovered
cerebrospinal fluid? ‘glymphatic system’ allows CSF to circulate in
CSF is a transcellular fluid located within the ven- paravascular channels, between the blood vessels
tricles and subarachnoid space that bathes the brain and the astrocyte foot processes, where it collects
and spinal cord. CSF has a number of functions: and removes waste products. The name
Buoyancy and cushioning. The adult brain ‘glymphatic’ comes from astrocytes (a type of glial
weighs around 1400 g. However, when suspended cell) performing the role of the lymphatic system
in CSF, the brain has an effective weight of less in the CNS.
than 50 g. Sudden head movement produces
potentially damaging acceleration and
deceleration forces – the lower effective weight of Where is cerebrospinal fluid produced?
the brain reduces its inertia, protecting it from How does cerebrospinal fluid circulate
damage. CSF cushions the brain, protecting it
from damage, especially from the ridged
through the central nervous system?
skull base. CSF is produced by the choroid plexus, located in the
ventricles of the brain: the two lateral ventricles, third
Maintenance of a constant ionic environment.
ventricle and fourth ventricle. CSF is produced by
Neurons are highly sensitive to changes in their
a combination of filtration and active secretion of
external environment; maintaining a constant
substances at a rate of 0.3 mL/min, equivalent to
ionic environment is essential for normal
500 mL/day. The choroid plexus is formed by modi-
neuronal activity.
fied ependymal cells, ciliated cells that line the surface
Buffering changes in ICP. Displacement
of the ventricles of the brain and the central canal
of CSF from the cranium is an important,
of the spinal cord. Ciliary action propels CSF through
but limited, compensatory mechanism that
the ventricles:
occurs following an increase in ICP (see
Chapter 46). From the lateral ventricles, CSF flows through the
two foramina of Monro into the third ventricle,
Control of respiration. As a small lipid-soluble
molecule, CO2 can freely diffuse from the blood to located between the right and left thalamic nuclei.
the CSF. The CSF has a much lower protein CSF travels through the aqueduct of Sylvius,
concentration than plasma and, therefore, has located within the midbrain, to the fourth
a reduced buffering capacity, making the CSF ventricle, located within the pons.
PCO2 very sensitive to changes in blood PCO2. CSF flows into the subarachnoid space from the
The central chemoreceptors detect CSF PCO2, fourth ventricle, via the two lateral foramina of
causing the respiratory centre to make Luschka and the midline foramen of Magendie.1
adjustments in V_ E (see Chapter 21). Most of the CSF flows around the cerebral
Glymphatic system. Outside the CNS, the hemispheres, whilst the remainder flows around
lymphatic system is responsible for removing the spinal cord.
extracellular proteins, excess fluid and some
1
metabolic waste products. The brain also produces Mnemonic: lateral ¼ Luschka, midline ¼ Magendie.
191
Table 43.1 Comparison of CSF and plasma.

What is hydrocephalus?
CSF Plasma Hydrocephalus is the abnormal resistance to the
+
Sodium, Na (mmol/L) 140 140 circulation, or the impaired absorption, of CSF.
The rate of CSF production exceeds the rate at which
Glucose (mmol/L) 4 6
CSF can circulate past the obstruction or the rate of
Chloride, Cl (mmol/L) 120 110 CSF absorption, resulting in a local increase in CSF
Bicarbonate, HCO3 (mmol/L) 24 24 pressure within the ventricles. The increase in CSF
pressure compresses brain parenchymal tissue,
pH 7.32 7.4
resulting in enlargement of the ventricles, known as
Protein (g/L) 0.2–0.4 70 ventriculomegaly. Ongoing compression of brain
3
White blood cells (cells/mm ) 0–5 4000–11 000 parenchyma results in irreversible damage. Hydro-
cephalus may be classified by site of obstruction to
flow of CSF:
No obstruction. Where there is no obstruction to
Overall, the total volume of CSF is 100–150 mL, the circulation or absorption of CSF,
around half of which is located within the ventricular overproduction is the likely pathology. This
system and half located within the rare situation results from a choroid plexus
subarachnoid space. papilloma.
Foramina of Monro. These may be blocked as a
Where is cerebrospinal fluid absorbed? result of compression by a tumour.
Aqueduct of Sylvius. This narrow channel may be
CSF is absorbed by the arachnoid granulations, villi
blocked as a result of congenital stenosis, or
that project from the arachnoid mater to the dural
compression by a tumour.
venous sinuses:
The outlets of the fourth ventricle. These may be
90% of CSF is absorbed by the arachnoid villi of obstructed by subarachnoid haemorrhage, chronic
the sagittal and sigmoid dural sinuses;
meningitis or as a result of the congenital Arnold–
10% of CSF is absorbed through the spinal Chiari malformation type II.
arachnoid villi.
Arachnoid granulations. The absorption of CSF
CSF absorption depends on the pressure difference may be obstructed by blood clots caused by a
between CSF (typically 15 cmH2O) and venous blood subarachnoid haemorrhage.
(typically 8 cmH2O), and the difference between
The management of hydrocephalus is twofold:
plasma (typically 25 mmHg) and CSF oncotic pres-
removal of the obstructing lesion (if this is
sure (effectively 0 mmHg). An increase in CSF pres-
surgically possible), and diversion of CSF flow to
sure (for example, following traumatic brain injury
relieve the pressure on the ventricles by means of
(TBI)) results in an increase in CSF absorption (see
the following.
Chapter 46).
An external ventricular drain (EVD), a
temporary means of draining CSF. An EVD also
How do the constituents of allows CSF to be sampled, CSF pressure to be
measured and the administration of
cerebrospinal fluid differ from those intrathecal drugs.
of plasma? A ventricular shunt, a more permanent device
As discussed above, CSF is produced by a combin- that diverts CSF to the peritoneal cavity or the
ation of filtration and active secretion. Despite their right atrium.
common origin, CSF and plasma have a number of An endoscopic third ventriculostomy, in which
important differences; see Table 43.1. a hole is made in the floor of the third ventricle
Note: CSF contains very little protein or cellular to allow CSF to pass directly into the basal
material, which accounts for its very low oncotic cisterns, thus bypassing an obstruction in the
pressure. aqueduct of Sylvius or fourth ventricle.
192
Chapter 43: Cerebrospinal fluid
Clinical relevance: analysis of cerebrospinal fluid

CSF may be sampled by lumbar puncture, to aid in the subarachnoid haemorrhage
diagnosis of: multiple sclerosis
meningitis metastases.
encephalitis
Importantly, the different types of meningitis may be
distinguished by analysing the constituents of CSF:
Neutrophilic Lymphocytic, normoglycaemic Lymphocytic, hypoglycaemic

picture picture picture
Appearance Yellow, turbid Clear Normal or slightly turbid
White cells Raised neutrophils Raised lymphocytes Raised lymphocytes
Red cells Normal Normal Normal
Protein High or very high Normal or high High or very high
Glucose Very low Normal or low Very low
Potential Bacterial Viral, spirochetes Mycobacterium tuberculosis,
causes Cryptococcus
Further reading
H. L. Rekate. The definition and classification of
hydrocephalus: a personal recommendation to stimulate
debate. Cerebrospinal Fluid Res 2008; 5: 2.
193
Chapter
Blood–brain barrier
44
These three layers form a virtually impenetrable bar-
What are the functions of the rier to lipophobic molecules, comparable to a con-
blood–brain barrier? tinuous capillary.
The BBB is a physiological barrier that prevents the
free movement of substances between the capillaries
and the ECF of the brain. The BBB has several How do substances cross the blood–
functions: brain barrier?
To maintain a constant extracellular environment, Some signalling and nutritional substances must gain
arguably the most important feature. The entry to the brain ECF through a number of
concentration of solutes in blood varies mechanisms:
considerably – neuronal function may be adversely Simple diffusion. Small lipid-soluble molecules
affected if neurons are directly exposed to this can cross the phospholipid bilayers of the BBB by
variation. For example, exercise produces changes simple diffusion, in common with cellular barriers
in plasma pH and K+ concentration that may elsewhere in the body. Examples include O2, CO2,
depress neuronal activity if transmitted to the CNS. ethanol and steroid hormones.
To protect the brain from harmful or neuroactive Active transport. The passage of small ions across
blood-borne substances. the BBB, such as Na+, K+, Mg2+, Ca2+, Cl ,
To prevent the release of CNS neurotransmitters HCO3 and H+, is controlled by active transport.
into the systemic circulation. This means that blood and CSF may differ in pH
and ion concentrations. The high density of
mitochondria in the cerebral capillaries reflects
What are the anatomical layers of the the high metabolic activity of this process.
blood–brain barrier? Facilitated diffusion. Some small molecules are
The BBB comprises three layers: transported across the BBB by facilitated
Capillary endothelial cells, which are joined diffusion, along their concentration gradients:
together by tight junctions, restricting the passage – Glucose is transported by GLUT1 transporters,
of substances to the brain ECF. The capillaries of which do not require ATP.
the BBB also differ from extracerebral capillaries – Water is transported through pores called
in having a high density of mitochondria. aquaporins.
A thick basement membrane, which lies Pinocytosis. Other small molecules (for example,
alongside the endothelial cells. insulin) are thought to cross the BBB by
Astrocyte foot processes. Astrocytes are a type of pinocytosis (see Chapter 4).
supportive glial cell with projections called foot
processes that encircle and are closely applied to
the capillaries. Astrocytes secrete chemicals that Which substances it is important to
reduce the permeability of the capillary
endothelial cells. In contrast, the choroid plexus is exclude from the brain?
not surrounded by astrocytes, and its endothelial Importantly, a number of substances are prevented
cells are therefore highly permeable. from crossing the BBB:
194
Chapter 44: Blood–brain barrier
Catecholamines, such as noradrenaline and

dopamine, as these molecules act as Disruption of the BBB by osmotic means. An
intracarotid injection of mannitol may be used to
neurotransmitters in the CNS. Note: whilst
disrupt the BBB, enhancing the transport of drugs
dopamine cannot cross the BBB, its precursor into the CNS.
l-dihydroxyphenylalanine (l-DOPA) is
transported by facilitated diffusion. Patients The BBB is also weakened by inflammation:
with Parkinson’s disease, in which there is a antibiotics, which do not normally cross the BBB,
dopamine deficiency of the substantia nigra, are may become effective in meningitis.
therefore treated with l-DOPA rather than
dopamine.
Amino acid transport across the BBB Which central nervous system
is tightly regulated. A number of amino structures are located outside the
acids also act as neurotransmitters in
the CNS; for example, glycine and glutamic blood–brain barrier?
acid. The BBB protects the brain from harmful blood-
Ammonia (NH3), a small lipophilic borne substances. However, it is important that the
molecule that is potentially neurotoxic, brain retains a direct connection with the systemic
might be expected to cross the BBB. However, circulation, for two reasons:
it is rapidly metabolized in the astrocytes detection of alterations in composition of
to glutamine and does not normally the blood;
reach the neurons in significant secretion of hormones.
concentrations.
Some structures are characterized by their lack of a
normal BBB: their capillaries are fenestrated, making
Clinical relevance: drug transport across the the BBB ‘leaky’. These structures are located around
blood–brain barrier
the third ventricle, so are often referred to as the circum-
The tight junctions of the BBB not only prevent ventricular organs, and are said to be located outside
endogenous molecules from entering the brain ECF,
the BBB:
but also exogenous molecules. The BBB, therefore,
represents a major obstacle to the delivery of drugs The area postrema, also known as the
to the CNS. Drugs may cross the BBB through a chemoreceptor trigger zone, located in the
variety of mechanisms: posterior medulla oblongata. The presence of
Simple diffusion. Lipid-soluble drugs may noxious substances in the systemic circulation
cross the BBB by simple diffusion. Examples causes the area postrema to send afferent
are propofol, thiopentone, volatile anaesthetics, signals to the vomiting centre, triggering
benzodiazepines and phenytoin. vomiting.
Bypassing the BBB. Drugs may be
administered directly into the CNS; for example,
The hypothalamus, within which hypothalamic
intrathecal methotrexate and intracerebral osmoreceptors monitor the osmolarity of
implantation of polymer-bound chemotherapy systemic blood.
agents. Anterior and posterior lobes of the
Transport by transmembrane carriers. pituitary gland. The leaky BBB allows
As discussed above, L-DOPA is transported secretion of the eight pituitary hormones,
into the CNS through a neutral amino acid six from the anterior lobe and two from the
transporter, where it is then converted to posterior lobe, directly into the systemic
dopamine. circulation.
Increasing the lipophilicity of drugs. The
The pineal gland, which secretes melatonin
increased lipophilicity of diamorphine results in it
crossing the BBB 100 times more easily than its
directly into the systemic circulation.
parent compound morphine. The choroid plexus, which uses plasma from
systemic blood to produce CSF.
195
Whilst the BBB is deficient in the circumventricular Further reading

organs, the blood–CSF barrier remains intact. Hence,
B. K. Lawther, S. Kumar, H. Krovvindi. Blood brain barrier.
substances can leak out of the capillaries and into the Contin Educ Anaesth Crit Care Pain 2011; 11(4): 128–32.
circumventricular organs, but are unable to enter the
R. Daneman. The blood–brain barrier in health and disease.
CSF and access the brain’s neurons. Ann Neurol 2012; 72(5): 648–72.
196
Chapter
Cerebral blood flow
45
What proportion of the cardiac output What is cerebral autoregulation?
is directed to the brain? CBF is remarkably constant, remaining close to
In the adult, CBF is typically 15% of the resting CO 50 mL/100 g/min across a wide range of cerebral
perfusion pressures, from 50 to 150 mmHg
(approximately 750 mL/min). CBF is commonly
(Figure 45.1). This property of the brain is known as
expressed in terms of the weight of brain paren-
autoregulation.
chyma – normal CBF is 50 mL/100 g brain tissue/
Autoregulation is thought to take place through a
min. It is determined by the ratio of the CPP and
myogenic mechanism in which the cerebral arterioles
cerebral vascular resistance (CVR).
vasoconstrict in response to an increase in wall tension,
and vasodilate in response to a decrease in wall tension,
thereby increasing or decreasing CVR (see Chapter 32).
What is cerebral perfusion pressure? Outside the autoregulatory range:
CPP is the net pressure gradient driving blood flow When CPP is greater than 150 mmHg, CBF becomes
through the cerebral circulation. CPP may be defined directly proportional to CPP. The sympathetic
in two ways: nervous system is thought to play a part in limiting
the vasodilatation of the cerebral arterioles.
Key equation: cerebral perfusion pressure When CPP falls below 50 mmHg, CBF falls below
In relation to ICP: the ‘normal’ value of 50 mL/100 g/min, resulting
CPP ¼ MAP – ICP in brain ischaemia.
In relation to CVR: The autoregulation curve (Figure 45.1) is shifted to

the right in patients with chronic hypertension and
CPP ¼ CBF × CVR
to the left in neonates.
Normotension Figure 45.1 Cerebral autoregulation.
100 Chronic hypertension

Range of autoregulation
Cerebral blood flow (mL/100 g/min)
75
50
25
0
0 50 100 150 200
Cerebral perfusion pressure (mmHg)
197
Whathappenstoneuronswhencerebral cerebral arteriolar vasoconstriction, and a

corresponding reduction in CBF. CBF has
blood flow falls below 50 mL/100 g/min? an approximately linear relationship with PaCO2
The brain is more sensitive to even short periods of between 3.5 and 8 kPa (Figure 45.2). Outside
ischaemia than any other organ in the body. For these limits:
example, a reduction in CBF to 30 mL/100 g/min – PaCO2 > 8 kPa: the cerebral arteries are
for just 5 s, as may occur during a vasovagal episode, already maximally vasodilated. Any further
results in loss of consciousness. As CBF decreases, increase in PaCO2 has no effect on CVR
there is a corresponding reduction in cerebral O2 or CBF.
delivery, which leads to cellular ischaemia: – PaCO2 < 3.5 kPa: the cerebral arteries are
CBF < 50 mL/100 g/min results in cellular acidosis. already maximally vasoconstricted. A further
CBF < 40 mL/100 g/min results in impaired reduction in PaCO2 causes no additional
protein synthesis. vasoconstriction, but the resulting alkalosis
CBF < 30 mL/100 g/min results in cellular oedema. may shift the oxyhaemoglobin curve to the
CBF < 20 mL/100 g/min leads to failure of cell left, reducing the offloading of O2 to the brain.
membrane ion pumps, with loss of The resulting brain tissue hypoxia causes
transmembrane electrochemical gradients. cerebral arterial vasodilatation and thus an
CBF < 10 mL/100 g/min results in cellular death. increase in CBF (see below).
O2. This has little effect on the cerebral arterioles
at ‘normal’ PaO2. However, if PaO2 falls below
What is meant by the term 8 kPa a sudden vasodilatation of the cerebral
‘flow–metabolism coupling’? arterioles is triggered, resulting in a significant
increase in CBF (Figure 45.3).
Although the overall CBF remains close to 50 mL/100
g/min, blood is preferentially routed to the most Blood haematocrit. According to the
metabolically active brain regions. For example, CBF Hagen–Poiseuille equation (see Chapter 32), flow
to grey matter is 70 mL/100 g/min, whereas CBF to increases as viscosity decreases. Therefore, a
white matter is only 20 mL/100 g/min. Areas of meta- reduced haematocrit, which causes a decrease in
bolically active brain have higher concentrations of blood viscosity, leads to an increase in CBF.
vasodilatory metabolites (for example, CO2, H+, K+ However, blood of lower haematocrit contains less
and adenosine), thereby increasing local blood flow Hb and can, therefore, deliver less O2 to the
and O2 delivery. brain parenchyma. The optimum balance
between CBF and cerebral O2 delivery is said
to occur at a haematocrit of 0.3.
Which other factors affect global
cerebral blood flow? Clinical relevance: effect of drugs on cerebral
Just as local CBF is closely matched to local CMR, blood flow
total brain CBF is matched to total brain metabolism. A number of anaesthetic drugs have important
An increase in overall CMR, as occurs in status epi- effects on CBF:
lepticus or pyrexia, results in a corresponding Intravenous induction agents
increase in CBF. Likewise, a decrease in CMR, as – Propofol, thiopentone and etomidate all reduce
occurs with general anaesthesia or hypothermia, CMR. Owing to flow–metabolism coupling,
results in a corresponding fall in CBF. these drugs all accordingly reduce CBF.
In addition to locally produced metabolites, cere- – In contrast, ketamine increases CMR and thus
bral vessel tone (and therefore CVR) is affected by a increases CBF.
number of blood constituents: The volatile anaesthetic agents are unique, as
they uncouple CMR and CBF. Whilst they
CO2. An increase in the PaCO2 results in decrease CMR, which would be expected to
cerebral arteriolar vasodilatation. CVR is decrease CBF, they also cause cerebral arteriolar
reduced, resulting in a corresponding increase vasodilatation, which has the effect of increasing
in CBF. Likewise, hypocapnoea results in
198
Chapter 45: Cerebral blood flow
Chronic Figure 45.2 The effect of PaCO2 on CBF.

Normal hypercapnoea
Linear response
100 between 3.5 and 8 kPa
75
‘Normal’ CBF
50
25
0
0 5 10 15
PaCO2 (kPa)
Figure 45.3 The effect of PaO2 on CBF.

100
75
50
25
0
0 5 8 10 15 20
PaO2 (kPa)
CBF. Which of these two effects is predominant – At 1.5 MAC, the reduction in CMR is
depends on the volatile agent and its partial already maximal, and CBF increases due
pressure: to cerebral arteriolar vasodilatation.
– At 0.5 MAC, the effect on CMR exceeds
the vasodilatory effect on the cerebral Halothane has the greatest propensity to induce
vasculature, resulting in a reduction in cerebral arteriolar vasodilatation: the point at
CBF. which CBF increases is at lower MAC than the other
– At 1 MAC, both effects are approximately agents. In contrast, sevoflurane has the lowest pro-
equal; CBF is unchanged. pensity for cerebral arteriolar vasodilatation.
199
needle is directed cranially. Once the tip of the

N2O is a potent cerebral arteriolar vasodilator,
and also increases CMR. As a result of both catheter is within the jugular bulb, blood can be
effects, its use is associated with a significant sampled for O2 tension, Hb O2 saturation and
increase in CBF. lactate. This method estimates the overall
Opioids have no significant effect on either adequacy of CBF on the ipsilateral side of the
CMR or CBF. brain, but does not give any information about
regional blood flow within the brain.
Of note, both opioids and volatile anaesthetics
depress the respiratory centre, thereby reducing V_ E The following are primarily research methods:
in spontaneously breathing patients. The resulting
hypercapnoea increases CBF, and thus ICP may
Kety–Schmidt technique, which applies the Fick
increase in neurosurgical patients. principle using arterial and jugular venous
N2O concentration. Only global CBF can be
measured using this method.
How can cerebral blood flow Radioactive xenon-133. The radioactive decay of
injected radioactive isotope 133Xe can be detected
be measured? by a gamma camera, giving information about
CBF can be measured by a number of methods. The regional CBF.
two methods most commonly encountered in clinical Functional magnetic resonance imaging (fMRI)
practice are: and positron emission tomography (PET) rely on
Transcranial Doppler ultrasonography. This is flow–metabolism coupling to identify areas of
by far the most common clinical method of increased activity in the brain. fMRI analyses the
measuring CBF. An ultrasound probe is placed on brain for areas of O2-rich blood and O2-poor
the temple, and the Doppler principle is used to blood (although its accuracy has been the subject
determine the velocity of blood in the middle of much recent debate), whilst PET utilizes a
cerebral artery. From this, CBF in one half of the radioactive analogue of glucose.
brain can be estimated. Transcranial Doppler is
also used to detect emboli during carotid Further reading
endarterectomy and to diagnose vasospasm M. ter Laan, J. M. C. van Dijk, J. W. J. Elting, et al.
following subarachnoid haemorrhage. Sympathetic regulation of cerebral blood flow in
Jugular bulb catheterization. The jugular bulb is humans: a review. Br J Anaesth 2013; 111(3): 361–7.
a dilatation of the internal jugular vein, just below E. C. Peterson, Z. Wang, G. Britz. Regulation of cerebral
the base of the skull. The jugular bulb can be blood flow. Int J Vasc Med 2011; Article ID 823525.
catheterized by using a Seldinger technique C. Ayata. Spreading depression and neurovascular coupling.
similar to inserting a central line, but instead the Stroke 2013; 44(6 Suppl. 1): S87–9.
200
Chapter
Intracranial pressure and head injury
46
in vivo. However, drift has been shown to be as
What is intracranial pressure? little as 1 mmHg after 5 days’ use. An
How is it measured? intraparenchymal probe only measures the
The ICP is simply the hydrostatic pressure within the pressure of the brain parenchyma in which it is
skull, but reflects the pressure of the CSF and brain located, which may not represent global ICP.
parenchyma. At rest in a normal supine adult, ICP is Subarachnoid probe: now considered relatively
5–15 mmHg; ICP varies throughout the cardiac and obsolete. The subarachnoid probe is easier to
respiratory cycles. Even in a normal brain, coughing, insert and is associated with a low infection rate,
straining and sneezing can transiently increase ICP to but is much less accurate than the first two
as high as 50 mmHg. methods.
Unfortunately, ICP cannot be estimated, only Subdural probe: also considered obsolete.
invasively measured. ICP may be measured by a var- Like the subarachnoid probe, the subdural
iety of devices, each with their advantages and probe is easier to insert and has a lower
disadvantages: infection risk than the first two methods, but is
By an EVD: a catheter inserted into the lateral less accurate and prone to blockage, requiring
ventricle, which is considered the ‘gold standard’ regular flushing.
for measuring ICP. In addition to ICP
measurement, an EVD can be used to remove CSF
for diagnostic and therapeutic purposes (to reduce What is the Monro–Kellie hypothesis?
ICP – see later) and for the administration of The Monro–Kellie hypothesis states that the cranium
intrathecal medication. However, to measure ICP, is a rigid box of fixed volume, which contains:
the EVD must be ‘clamped’; that is, CSF cannot be Brain tissue, 1400 g or approximately 80% of the
simultaneously drained. An EVD may be intracranial volume.
surgically challenging to insert, especially if the CSF, 150 mL or approximately 10% of intracranial
ventricles are small or displaced. Also, EVDs are volume.
frequently complicated by blockage and are Arterial and venous blood, 150 mL or
associated with an infection risk of up to 5%. approximately 10% of intracranial volume.
Intraparenchymal probe: a fibre-optic-tipped
catheter placed within the brain parenchyma An increase in the volume of any of these intracranial
through a small burr hole. An intraparenchymal contents will increase ICP, unless there is also a cor-
probe is much easier to insert than an EVD, and responding reduction in the volume of one or both of
can be used in situations where the ventricles are the other contents.
compressed or displaced. Measurement of ICP For example:
using an intraparenchymal probe is almost as An increase in the volume of brain tissue may be
accurate as an EVD, and infection rates are localized (for example, a brain tumour or abscess)
substantially lower. However, there are concerns or generalized (such as occurs with cerebral
about the accuracy of intraparenchymal catheters oedema).
used for prolonged periods: the catheter is zeroed The volume of CSF may be increased in
at the time of insertion, and cannot be recalibrated hydrocephalus (see Chapter 43).
201
Figure 46.1 Change in ICP with

increasing intracranial volume.
60
Global
50 ischaemia
Intracranial pressure (mmHg)
40
Focal
30 ischaemia
20
s
Compensatory mechanism
10
Point of decompensation
0
Volume of expanding intracranial mass (mL)
The volume of intracranial blood may be Severe intracranial hypertension may result in
increased following haemorrhage (extradural, additional signs, as a result of brain displacement:
subdural or intraparenchymal) or venous sinus – Cranial nerve palsies – most commonly the
thrombosis. abducens (cranial nerve VI).
When one of the intracranial contents increases in – Pupillary dilatation – caused by compression
volume, there is a limited capacity for displacement of of the oculomotor nerve (cranial nerve III).
the other contents: – Cushing’s triad:
Some CSF is displaced from the cranium into the ▪ systemic hypertension
spinal subarachnoid space. Whilst the rate of CSF ▪ bradycardia
production remains approximately the same, CSF ▪ abnormal respiratory pattern.
absorption by the arachnoid villi is increased.
Dural venous sinuses are compressed, displacing
venous blood into the internal jugular vein, thus
reducing the volume of intracranial blood.
Can you explain Cushing’s triad?
As discussed in Chapter 45, CPP is related to ICP:
After these small compensatory changes have
CPP ¼ MAP ICP
occurred, ICP will rise. The only options left are then
potentially disastrous: a reduction in arterial blood According to this equation, an increase in ICP results
volume or displacement of brain parenchyma in a decrease in CPP, unless MAP also increases.
through the foramen magnum (Figure 46.1). Between a CPP of 50 and 150 mmHg, cerebral auto-
Symptoms suggesting raised ICP include: regulation maintains CBF at its normal value of
50 mL/100 g of brain tissue/min (see Chapter 45
– A headache that is worse in the morning and is
and Figure 45.1).
exacerbated by straining and lying flat.
The Cushing response is a late physiological
– Nausea and vomiting.
response to increasing ICP. When CPP falls below 50
Signs of raised ICP include: mmHg, the cerebral arterioles are maximally vasodilated
– A bulging fontanelle in infants and neonates. and cerebral autoregulation fails. CBF falls below the
– Papilloedema. ‘normal’ value of 50 mL/100 g/min, resulting in cellular
– Altered level of consciousness. ischaemia.
202
Chapter 46: Intracranial pressure and head injury
In the event of brainstem ischaemia, the brain has drain from the cranium. As ICP increases, the
an ‘emergency’ hypertensive mechanism: the vaso- dural venous sinuses are compressed,
motor area dramatically increases sympathetic ner- displacing blood into the internal jugular vein,
vous system outflow, triggering an intense systemic thereby reducing the volume of intracranial
arteriolar vasoconstriction that results in systemic venous blood. As discussed in Chapter 42, the
hypertension. The rise in MAP restores perfusion, dural venous sinuses do not have valves.
and hence CBF, to the brainstem. In response to Therefore, venous drainage from the cranium
systemic hypertension, the arterial baroreceptors is entirely dependent on the venous pressure
induce a reflex bradycardia. gradient between the venous sinuses and the
If ICP continues to rise, the brain parenchyma right atrium. Venous drainage is therefore
starts to be displaced downwards. The cerebellar promoted by:
tonsils are pushed through the foramen magnum, a
▪ Keeping the head in a neutral position and
process referred to as ‘tonsillar herniation’ or ‘coning’.
removing neck collars and tight-fitting
The cerebellar tonsils compress the brainstem, caus-
ETT ties, which prevents kinking or
ing the failure of brainstem functions:
occlusion of the internal jugular veins.
Irregular breathing and apnoea through ▪ Nursing the patient in a 30° head-up tilt.
compression of the respiratory centre.
▪ Using minimal PEEP. Positive intrathoracic
Decreased consciousness: Glasgow coma scale pressure reduces the venous pressure
(GCS) of 3–5 is usual.
gradient. Therefore, in ventilated patients,
Hypotension, as the vasomotor centre is PEEP should be reduced to the lowest value
compressed. required to achieve adequate oxygenation.
The Cushing reflex is a desperate attempt to maintain ▪ Using muscle relaxants to prevent
CPP (and therefore CBF) in the face of substantially coughing and straining, both of which
increased ICP. Unless (and often despite) swift action transiently increase intrathoracic pressure.
is taken, brainstem death is inevitable.
– Arterial blood. An adequate volume of
well-oxygenated arterial blood is essential to
meet the metabolic demands of the brain, but
How may intracranial pressure CBF in excess of that required merely serves
be reduced? to increase ICP. Therefore, the aim is to
The Monro–Kellie hypothesis states that an increase provide just sufficient CBF to meet the brain’s
in the volume of one of the three intracranial contents metabolic needs. Two main strategies are
will cause an increase in ICP, unless there is also a employed:
reduction in the volume of one or both of the other
▪ Reducing CMR. Owing to flow–
components. It therefore follows that ICP may be
metabolism coupling, CBF is related to
reduced if the volume of one or more of the intracra-
CMR. Seizure activity substantially
nial contents is reduced:
increases CMR, which in turn increases
Reduction in the volume of CSF by means of an CBF and consequently increases ICP –
EVD. This method can be used to reduce ICP even seizures should be rapidly treated with
when hydrocephalus is not the cause. Even the benzodiazepines and anti-epileptic drugs.
removal of a few millilitres of CSF can result in a CMR may be reduced to sub-normal levels
significant decrease in ICP. through the use of drugs (propofol,
Reduction in the volume of blood: if the cause of thiopentone or benzodiazepines such as
raised ICP is a haematoma, this should be midazolam) or through therapeutic cooling
urgently evacuated. Otherwise, in the context of (CMR is reduced by 7% per 1 °C reduction
raised ICP, intracranial venous and arterial blood in brain temperature). Therapeutic
can be considered as two entirely different entities: cooling has not yet been proven to reduce
– Venous blood. Intracranial venous blood serves mortality, and is not recommended
no useful purpose and should be permitted to unless the patient is pyrexial.
203
▪ Preventing hypoxaemia or hypercapnoea. Patients presenting with mild TBI have a good
As discussed in Chapter 45, hypoxaemia prognosis with a mortality of 0.1%. However,
and hypercapnoea both trigger cerebral patients with moderate and severe TBI have a much
arteriolar vasodilatation, which increases higher mortality, around 10% and 50% respectively.
CBF and consequently increases ICP. In Many survivors are left with severe disability.
situations of raised ICP, PaO2 should be Area of brain injury. Brain injury can be focal
maintained above 10 kPa, and PaCO2 (for example, extradural haematoma, contusions)
between 4.5 and 5.0 kPa. or diffuse (for example, diffuse axonal injury,
hypoxic brain injury), but both types of injury
Reduction in the volume of brain parenchyma:
commonly coexist.
– Severely raised ICP may be temporarily
reduced by decreasing brain ECF volume
through osmotherapy, following intravenous What is the difference between
administration of an osmotic diuretic; for primary and secondary brain injury?
example, mannitol or hypertonic saline. Brain injury may be classified as primary or
– When raised ICP is caused by a brain tumour, secondary:
the volume of surrounding oedema may be
Primary brain injury is damage to the brain
reduced by using dexamethasone, or surgical
during the initial injury caused by mechanical
excision may be considered.
forces: stretching and shearing of neuronal and
– The volume of a cerebral abscess may be
vascular tissue. Neuronal tissue is more
reduced by surgical drainage and by antibiotic
susceptible to damage than blood vessels; this is
therapy.
why diffuse axonal injury frequently accompanies
injuries where there has been vessel disruption; for
How is head injury classified? example, extradural haematoma or traumatic
Head injury is defined as any trauma to the head, subarachnoid haemorrhage.
whether or not brain injury has occurred. Head injury Secondary brain injury refers to the further
may be classified by: cellular damage caused by the pathophysiological
Mechanism of injury, which may be blunt (road consequences of the primary injury. Cells injured
traffic collision or fall) or penetrating (gunshot or in the initial trauma trigger inflammatory
stab wounds). In the military setting, blast injury reactions, resulting in cerebral oedema and an
can also occur. Blunt head injury may be: increase in ICP. Secondary brain injury occurs
– Closed, where the dura mater remains intact. hours to days after the primary injury through a
– Open, where the dura mater is breached, number of different mechanisms:
exposing the brain and CSF to environmental – damage to the BBB
microorganisms. – cerebral oedema
– raised ICP
Penetrating head injury is, by definition, open.
– seizures
Presence of other injuries. Following trauma,
– ischaemia
patients may have an isolated head injury or there
– infection.
may be accompanying traumatic injuries.
Once primary brain injury has occurred, it cannot
Where a head injury results in a TBI, further
be reversed. Prevention of trauma is the best method
classifications can be made:
of reducing primary brain injury: reducing speed
Severity of injury. On arrival to hospital, the severity limits, safer driving strategies, and so on. The impact
of TBI is commonly assessed using the GCS: of trauma on the brain can be reduced by the use of
– Mild TBI corresponds to a GCS score of 13–15. airbags and seatbelts in cars, and of helmets for cyc-
– Moderate TBI corresponds to a GCS score of lists and motorcyclists. Medical and surgical efforts
9–12. are concentrated on preventing secondary brain
– Severe TBI corresponds to a GCS score of 3–8. injury: preserving as many neurons as possible.
204
Chapter 46: Intracranial pressure and head injury
How would you approach the Hypertension can also be detrimental: the
hypertensive response to laryngoscopy can cause
management of a patient with a surge in MAP, exceeding the upper limit of
traumatic brain injury? autoregulation, which causes a surge in CBF and
Patients with TBI frequently present with other, consequently an increase in ICP. Therefore, when
more immediately life-threatening injuries. The broad intubating a patient with suspected TBI, some
principles of initial trauma management are the same means of attenuating the sympathetic response to
whether in the emergency department or the laryngoscopy should be used, such as pretreat-
pre-hospital setting: with a multidisciplinary team ment with a strong opioid.
following an airway–breathing–circulation–disability– Normocapnoea. As discussed in Chapter 45, CBF
exposure (ABCDE) approach, ensuring spinal immo- varies linearly with PaCO2 (see Figure 45.2).
bilization and treating life-threatening injuries first. Hypercapnoea causes cerebral arteriolar
Following the initial resuscitation phase, patients vasodilatation, increasing CBF above 50 mL/100
with suspected TBI will require rapid transfer for g/min, which consequently increases ICP.
brain imaging, the results of which will help guide Hypocapnoea causes cerebral arteriolar
further medical and surgical management. vasoconstriction, reducing CBF to below 50 mL/
100 g/min, inducing cellular ischaemia. In
addition, hypocapnoea causes a respiratory
What are the main principles of medical alkalosis that shifts the oxyhaemoglobin
management in a patient with dissociation curve to the left, reducing O2
traumatic brain injury? unloading to the tissues; as discussed above, low
tissue PO2 results in substantially increased CBF
The medical management of TBI is concerned with
and ICP. The AAGBI recommends maintaining
preventing secondary brain injury and reducing ICP.
PaCO2 between 4.5 and 5.0 kPa following TBI.
It is divided into maintenance of:
Normoglycaemia. Normally, the brain uses
Normoxia. Hypoxaemia (defined as PaO2 < 8 glucose as its sole metabolic substrate. The stress
kPa) is associated with a worse outcome following response to TBI commonly results in
TBI, due to its detrimental effects on CBF and hyperglycaemia, which is associated with a worse
hence ICP. Hypoxaemia may occur for a number overall outcome. Insulin therapy is indicated
of reasons, such as airway obstruction, associated when plasma glucose rises, and is typically
chest injuries and aspiration pneumonitis. In the instituted at a plasma glucose concentration of
initial resuscitation phase, all trauma patients 10 mmol/L.
should have high-flow O2 administered, and
patients with the potential to develop hypoxaemia Hypoglycaemia is rarely the direct result of TBI, but
(for example, those with a low GCS) should be a hypoglycaemic episode in an insulin-dependent
intubated at an early stage. diabetic may have been the cause of the traumatic
Normotension. A fall in CPP below 50 mmHg incident. Hypoglycaemia further exacerbates cellu-
leads to failure of cerebral autoregulation, reduced lar acidosis within the brain; prolonged hypogly-
CBF and cellular ischaemia. Therefore, in the caemia may result in neuronal cell death.
neurointensive care unit, when ICP is being Normothermia. As discussed above, pyrexia
measured, CPP should be kept above 60 mmHg. (defined as core body temperature >37.6 °C)
Unfortunately, trauma patients do not arrive in increases CMR, which leads to an increase in CBF
hospital with ICP monitoring in situ – the and consequently an increase in ICP.
Association of Anaesthetists of Great Britain Hyperthermia should therefore be treated
and Ireland (AAGBI) recommends maintaining promptly using an antipyretic (such as
MAP >80 mmHg. This should be achieved paracetamol) and external cooling devices.
initially using fluid resuscitation, and then Venous drainage. This is promoted by
by using vasopressors. Even a single episode nursing the patient in a 30° head-up tilt, with
in which SBP is <90 mmHg has been shown a neutral head position and ensuring that ETT
to worsen outcome. ties are loose. Minimal PEEP should be used.
205
Further reading L. A. Steiner, P. J. D. Andrews. Monitoring the

injured brain: ICP and CBF. Br J Anaesth 2006; 97(1):
R. T. Protheroe, C. L. Gwinnutt. Early hospital care of 26–38.
severe traumatic brain injury. Anaesthesia 2011; 66(11):
1035–47. K. Pattinson, G. Wynne-Jones, C. H. E. Imray.
Monitoring intracranial pressure, perfusion and
I. K. Moppett. Traumatic brain injury: assessment, metabolism. Contin Educ Anaesth Crit Care Pain 2005;
resuscitation and early management. Br J Anaesth 2007; 5(4): 130–3.
99(1): 18–31.
K. Girling. Management of head injury in the intensive-care
H. B. Lim, M. Smith. Systemic complications after head unit. Contin Educ Anaesth Crit Care Pain 2004; 4(2):
injury: a clinical review. Anaesthesia 2007; 62(5): 474–82. 52–6.
206
Chapter
The spinal cord
47
Describe the anatomy of the spinal cord The cauda equina is the collection of spinal nerves
that continue inferiorly in the spinal canal after
The spinal cord is part of the CNS, located within the the cord has ended, until they reach their
spinal canal of the vertebral column. The spinal cord respective intervertebral foramina.
begins at the foramen magnum, where it is continu-
ous with the medulla oblongata. The spinal cord is
much shorter than the vertebral column, ending at a Describe the cross-sectional anatomy
vertebral level of L1/2 in adults, but at a lower level of
around L3 in neonates. of the spinal cord
Like the brain, the spinal cord is enveloped in In cross-section the spinal cord is approximately oval,
three layers of the meninges: pia, arachnoid and dura with a deep anterior median sulcus and a shallow
mater. CSF surrounds the spinal cord in the subar- posterior median sulcus. The centre of the cord con-
achnoid space, and extends inferiorly within the dural tains an approximately ‘H’-shaped area of grey
sac to approximately S2 level. After the spinal cord matter, surrounded by white matter:
terminates, the pia and dura merge to form the filum The grey matter contains unmyelinated axons and
terminale, which tethers the cord to the coccyx. the cell bodies of interneurons and motor
The spinal cord is divided into 31 segments, each neurons. Located in the centre of the grey matter
emitting a pair of spinal nerves. There are: is the CSF-containing central canal. The points of
Eight cervical segments. Note: there is one more the ‘H’ correspond to the dorsal and ventral
pair of cervical nerves emitted than there are (posterior and anterior) horns. There are also
cervical vertebrae. lateral horns in the thoracic region of the cord,
Twelve thoracic segments. which correspond to pre-ganglionic sympathetic
Five lumbar segments. neurons.
Five sacral segments. The white matter contains columns of myelinated
axons, called tracts. These tracts are organized into:
One coccygeal segment.
– ascending tracts, containing sensory axons;
With the exception of C1 and C2, the spinal nerves – descending tracts, containing motor axons.
exit the spinal canal through the intervertebral
foramina. The most important ascending tracts are shown in
The spinal cord enlarges in two regions: Figure 47.1:
The cervical enlargement at C4–T1, The dorsal (posterior) columns contain axons of
corresponding to the brachial plexus, which nerves concerned with proprioception (position
innervates the upper limbs. sense), vibration and two-point discrimination
The lumbar enlargement at L2–S3, (fine touch).
corresponding to the lumbar plexus, which The anterior and lateral spinothalamic tracts
innervates the lower limbs. carry sensory information about pain,
temperature, crude touch and pressure.
At the terminal end of the spinal cord: The anterior and posterior spinocerebellar tracts
The conus medullaris is the tapered terminal carry proprioceptive information from the
portion of the cord. muscles and joints to the cerebellum.
207
ASCENDING DESCENDING
Dorsal columns Cuneate Gracile

tract tract
Central canal
Posterior
spinocerebellar tract Dorsal (posterior) horn
Lateral corticospinal tract

Anterior
spinocerebellar tract
Lateral horn (present in

thoracic segments only)
Ventral (anterior) horn
Lateral Anterior corticospinal tract

spinothalamic tract
Anterior spinothalamic tract Anterior median sulcus
Figure 47.1 Cross-section of the spinal cord (extrapyramidal tracts not shown).
cervical region – an additional contribution from

The most important descending tracts are radicular arteries is essential. The three spinal arteries
(Figure 47.1): are:
The anterior and lateral corticospinal tracts, also One anterior spinal artery, which arises from
known as the pyramidal tracts, carry the axons branches of the right and left vertebral
of upper motor neurons. In the ventral horn of artery (see Figure 42.1). The anterior spinal
the spinal cord, these axons relay to α-motor artery descends in the anterior median sulcus
neurons (or lower motor neurons) that innervate and supplies the anterior two-thirds of the
muscle. spinal cord, essentially all the structures with
The extrapyramidal tracts: rubrospinal, the exception of the dorsal columns. The
tectospinal, vestibulospinal, olivospinal and anterior spinal artery is replenished along its
reticulospinal tracts. The extrapyramidal neurons length by several radicular arteries, the largest
originate at brainstem nuclei and do not pass of which is called the artery of Adamkiewicz.
through the medullary pyramids. Their primary The location of this vessel is variable, but is
role is in the control of posture and muscle tone. most commonly found on the left between
T8 and L1.
Describe the blood supply to Two posterior spinal arteries, which arise from
the posterior inferior cerebellar arteries (see
the spinal cord Figure 42.1). The posterior spinal arteries are
The spinal cord is supplied by three arteries, derived located just medial to the dorsal roots, and supply
from the posterior circulation of circle of Willis (see the posterior one-third of the cord. Again, the
Chapter 42). However, the blood flow through these posterior spinal arteries are replenished by
vessels is insufficient to perfuse the cord below the radicular arteries.
208
Chapter 47: The spinal cord
Blood from the spinal cord is drained via three the optic nerve and gives the impression of light,
anterior and three posterior spinal veins, located in despite the stimulus being pressure rather than
the pia mater, which anastomose to form a tortuous photons.
venous plexus. Blood from this plexus drains into the First-order neurons transmit action potentials
epidural venous plexus. from sensory receptors to the spinal cord, where
they synapse with second-order neurons. These
Clinical relevance: anterior spinal artery syndrome neurons are pseudounipolar with their cell bodies
The artery of Adamkiewicz most commonly arises located in the dorsal root ganglion, a swelling of
from the left posterior intercostal artery, a branch of the dorsal root just outside the spinal cord.
the aorta. Damage or obstruction of the artery can Second-order neurons conduct action potentials

occur through atherosclerotic disease, aortic dissec-
to the thalamus, where they synapse with third-
tion or surgical clamping during aortic aneurysm
repair. As the anterior spinal artery supplies the
order neurons.
anterior two-thirds of the spinal cord, cessation of Third-order neurons relay action potentials to the
blood flow can have profound consequences (see cerebral cortex via the internal capsule.
Figure 47.4). The primary somatosensory cortex is the area of
Signs and symptoms of anterior spinal artery the cerebral cortex that receives and performs an
syndrome are: initial processing of the sensory information. The
Paraplegia, as a result of involvement of α-motor primary somatosensory cortex is located in the
neurons within the anterior horn of the cord (i.e. post-central gyrus of the parietal lobe. It is
a lower motor neuron deficit at the level of the
organized in a somatotropic way with specific
lesion), and the corticospinal tracts carrying the
areas of cortex dedicated to specific areas of the
axons of upper motor neurons (i.e. an upper
motor neuron deficit below the level of the body, known as the sensory homunculus. Of note:
lesion). the hands and lips make up a major component,
Loss of pain and temperature sensation, due reflecting their tactile importance. Inputs from
to involvement of the spinothalamic tracts. specific sensory modalities end in specific
Autonomic dysfunction involving the bladder columns of cerebral cortical tissue.
or bowel, due to disruption of the sacral para-
sympathetic neurons. There are two major pathways by which sensory
Crucially, proprioception and vibration sensation information ascends in the spinal cord:
remain intact. These sensory modalities are carried The dorsal column–medial lemniscal (DCML)
in the dorsal columns, which are supplied by the pathway carries sensory information about two-
posterior spinal arteries and thus remain unaffected. point discrimination, vibration and
proprioception (Figure 47.2a). The name of the
pathway comes from the two structures through
which the sensory signals pass: the dorsal columns
Describe the main sensory afferent of the spinal cord and the medial lemniscus in the
pathways brainstem:
The somatosensory nervous system consists of: – The first-order neuron is extremely long. It
Sensory receptors, which encode stimuli by enters the dorsal root of the spinal cord and
repetitive firing of action potentials. The different ascends in the dorsal columns on the same side
sensory receptor types are specific to their sensory (ipsilateral). Sensory neurons from the lower
modalities: proprioceptors, nociceptors, body travel in the medial gracile tract and
thermoreceptors and mechanoreceptors relay synapse in the gracile nucleus in the medulla
sensory information concerning limb position, oblongata, whilst sensory neurons from the
tissue damage (potentially causing pain), upper body travel in the lateral cuneate tract
temperature and touch respectively. The and synapse in the cuneate nucleus.
perception of the stimulus is dependent upon the – In the medulla, first-order neurons synapse
neuronal pathway rather than the sensory receptor with second-order neurons, which then cross
itself. For example, pressing on the eye activates over to the contralateral side and ascend to the
209
(a) Dorsal column–medial lemniscuspathway (b) Spinothalamic pathway
Somatosensory
cortex
Third-order
neurons
Thalamus
Medial lemniscal tract
Second-order Third-order
Gracile nucleus
neurons
neurons Cuneate nucleus
Medulla
oblongata
Fibres cross the midline Second-order neurons within

Cuneate tract spinothalamic tract
First-order neuron First-order neuron

from upper limbs from upper limbs
Dorsal root ganglion Second-order fibres cross in
Gracile tract anterior commissure
First-order neuron First-order neuron

from lower limbs from lower limbs
Figure 47.2 The two major sensory pathways: (a) DCML; (b) spinothalamic.
thalamus. After this sensory decussation, the Clinical relevance: dissociated sensory loss
fibres ascend through the brainstem in a tract Dissociated sensory loss is a relatively rare pattern of
called the medial lemniscus. neurological injury characterized by the selective loss
The spinothalamic tract carries sensory of two-point discrimination, vibration-sense and pro-
information about crude touch, pressure, prioception without the loss of pain and tempera-
temperature and pain (Figure 47.2b). In contrast ture, or vice versa. This is due to the different points
to the DCML pathway, the spinothalamic tract of decussation of the DCML and spinothalamic tracts.
Causes of dissociated sensory loss include:
crosses the midline at the level of the spinal cord
Brown-Séquard syndrome, in which a
rather than the medulla:
hemi-section of the spinal cord causes ipsilateral
– The first-order neurons enter the dorsal root motor weakness, ipsilateral loss of two-point
of the spinal cord, and may ascend or descend discrimination, proprioception and vibration
one or two vertebral levels (along Lissauer’s sensation with contralateral loss of pain and
tract) before synapsing with second-order temperature sensation below the level of the
neurons in the dorsal horn. lesion (see Figure 47.4). Hemi-section of the cord
may be the result of trauma (such as a gunshot
– The axons of the second-order neurons
wound), inflammatory disease (for example,
decussate anterior to the central canal of the multiple sclerosis), or by local compression: spinal
spinal cord, in an area called the anterior cord tumour or infection (for example,
commissure, before ascending to the thalamus tuberculosis).
in the contralateral spinothalamic tract.
210
Motor cortex Figure 47.3 The corticospinal tract.
Internal capsule
Upper motor neurons

90% of fibres decussate in the medulla
Lateral corticospinal tract
Anterior corticospinal tract
To skeletal
Most of the remaining 10% of fibres muscles
decussate in the anterior commissure
Lower motor neurons
Syringomyelia, a condition in which the central contralateral side of the body and the trigeminal
canal of the spinal cord expands over time (referred nerve nuclei. Clinically, therefore, lateral medullary
to as a syrinx), destroying surrounding structures. syndrome is characterized by loss of pain and
The axons of the spinothalamic tract that decussate temperature sensation on the contralateral side of
at the anterior commissure are usually the first to the body and the ipsilateral side of the face.
be damaged. The clinical consequence is loss of
pain and temperature sensation at the level of the
syrinx, usually involving the upper limbs, with
preservation of two-point discrimination, Describe the course of the
proprioception and vibration sensation. corticospinal tract
Lateral medullary syndrome, a brainstem stroke
The corticospinal tract, also known as the pyramidal
in which occlusion of the posterior inferior cere-
bellar artery causes infarction of the lateral medulla,
tract, is the most important descending tract as it is
a very important area containing, amongst other the primary route for somatic motor neurons. The
structures,1 the spinothalamic tracts from the corticospinal tract is composed of (Figure 47.3):
The motor cortex, located in the pre-central
gyrus. This area is the brain’s final common
1
Other important structures affected are the vestibular
output, resulting in the initiation of movement.
nuclei (resulting in nystagmus and vertigo), the inferior
cerebellar peduncle (resulting in ataxia), the nucleus dysphagia and hoarseness) and the sympathetic chain
ambiguus (affecting cranial nerves IX and X, resulting in (resulting in an ipsilateral Horner’s syndrome).
211
An upper motor neuron, which originates in the common. A higher level of the cord injury results
motor cortex and descends through the spinal in a greater loss of neurological function.
cord within the corticospinal tract: Stability of vertebral column. The vertebral
– Upper motor neurons travel through the column is anatomically divided into anterior,
posterior limb of the internal capsule. middle and posterior columns. Unstable vertebral
– At the level of the pons, a significant fractures (those potentially involving anything
proportion of upper motor neurons synapse in other than solely the anterior column) require
the pontine nuclei, forming the ventral part of immobilization to prevent further damage to the
the pons. These post-synaptic fibres then travel spinal cord. The high mobility of the cervical spine
posteriorly to reach the cerebellum through makes it especially vulnerable to unstable fractures;
the middle cerebral peduncle. fortunately, the spinal cord has more space within
– At the medullary pyramids, 90% of the the spinal canal at the cervical level than elsewhere.
remaining nerve fibres decussate and descend in Extent of neurological injury. Approximately half
the lateral corticospinal tract of the spinal cord. of spinal cord injuries involve complete transection
– The 10% of nerve fibres that do not decussate of the cord, with an absence of motor and sensory
descend in a separate ipsilateral tract: the neurological function below the level of injury.
anterior corticospinal tract.2 A spinal cord injury is said to be ‘incomplete’ if
some neurological function remains below the
– When they have reached their intended
level of injury; for example, sacral sparing.
vertebral level in the spinal cord, the upper
motor neurons synapse with lower motor
neurons in the ventral horn of the spinal cord. How does the level of a complete
A lower motor neuron, which leaves the CNS to
innervate skeletal muscle. There are two types of spinal cord injury affect the different
lower motor neuron: body systems?
– α-motor neurons leave the anterior horn, The spinal cord is the exclusive relay of sensory,
forming the spinal nerve. The spinal nerve exits motor and autonomic (with the exception of the
the spinal canal via the intervertebral foramen, vagus nerve) information between the CNS and the
becoming a peripheral nerve. Ultimately, the peripheries. The level of spinal cord injury determines
α-motor neuron innervates extrafusal fibres of whether individual organs will remain in communi-
skeletal muscle, causing muscle contraction. cation with the brain:
– γ-motor neurons innervate the intrafusal fibres Respiratory system. Respiratory failure is
of skeletal muscle (the ‘muscle spindles’), common after spinal cord injury; respiratory
which are involved in proprioception (see complications are the most common cause of
Chapter 52). death. The higher the spinal cord lesion, the
greater the impact on ventilation:
– Injury above T8 vertebral level will cause
How can acute spinal cord injury intercostal muscle weakness or paralysis. The
be classified? ‘bucket-handle’ mechanism is abolished, and
diaphragmatic contraction becomes the sole
Spinal cord injury is often devastating – permanent
mechanism of inspiration. The loss of intercostal
neurological injury is common. Spinal cord injury
muscle tone reduces the outward spring of the
can be classified in a number of ways:
chest wall. FRC (the point at which the inward
Level of injury. The majority of injuries occur in elastic recoil of the lung equals the outward
the cervical and thoracic regions of the spinal spring of the chest wall) is therefore reduced.
cord – lumbar cord injuries are much less
– Injury below C5 vertebral level does not
directly affect diaphragmatic contraction (the
2
Most of these upper motor neurons decussate in the phrenic nerve is formed by the C3, C4 and C5
spinal cord (through the anterior commissure) before nerve roots). However, diaphragmatic
synapsing with a lower motor neuron. contraction is indirectly affected as a result of
212
intercostal muscle paralysis: the loss of sympathetic stimulation of HR. SV must

intercostal muscle tone results in paradoxical therefore be maintained by adequate cardiac
movement of the chest wall – it is drawn preload; hypovolaemia is poorly tolerated in
inwards during diaphragmatic contraction. high spinal cord injury.
As a result, VC reduces by up to 50%. PNS. Spinal cord injury results in disruption of
– Injury at C3 vertebral level and above will result the motor, sensory and autonomic fibres:
in paralysis of all respiratory muscles. Patients – Initially, there is flaccid paralysis and loss
have gross ventilatory impairment requiring of reflexes below the level of the spinal cord
immediate ventilatory support. These patients lesion; this is referred to as spinal shock
usually require long-term mechanical (note: neurogenic shock refers to the
ventilation or phrenic nerve stimulation. cardiovascular collapse that accompanies
Spinal cord injury also alters lung mechanics spinal cord injury).
in other ways: – Over the next 3 weeks, spastic paralysis and
brisk reflexes develop.
– Paralysis of the external intercostal muscles and
– Below the level of injury, somatic and visceral
the abdominal muscles results in markedly
sensation is absent.
reduced forced expiratory gas flows. FEV1 is
significantly reduced and cough is severely GI system. Though the enteric nervous system
impaired, leading to impaired clearance of is semi-autonomous, it is still affected by the
respiratory secretions. sudden disruption of sympathetic fibres, resulting
in unopposed parasympathetic input via the
– Impaired inspiration results in basal atelectasis,
vagus nerve:
reduced lung compliance and V̇ /Q̇ mismatch.
– As a consequence of the lower lung volume, – Delayed gastric emptying and paralytic ileus
the production of pulmonary surfactant is are common. Abdominal distension may
reduced. Lung compliance is further decreased, further impair ventilation.
which increases the work of breathing. – In high spinal cord lesions, gastric ulceration
– Rarely, neurogenic pulmonary oedema can is almost inevitable without gastric protection
result from cervical cord injury, though the (for example, an H2 receptor antagonist such
mechanism for this is unclear. as ranitidine). Gastric ulceration is thought
Cardiovascular system. Like the respiratory to be due to the unopposed vagal stimulation
system, the cardiovascular consequences of spinal of gastric acid secretion.
cord injury are more significant with higher – Patients usually become constipated as the
spinal cord lesions. Adverse cardiovascular effects sensations of defecation are lost; regular
result from the interruption of the sympathetic laxatives and bowel care regimes are important
nervous system: to prevent faecal impaction.
– Injury above T6 vertebral level results in Metabolic. Spinal cord injury has several
metabolic consequences:
hypotension, known as neurogenic shock.
Sympathetic nervous outflow to the systemic – Thermoregulation may be impaired due to the
arterioles is interrupted, resulting in arteriolar loss of sympathetic outflow below the level of
vasodilatation. Similarly, venodilatation leads the spinal cord injury:
to venous pooling, which increases the risk of ▪ Arteriolar vasodilatation in the skin may
thromboembolic disease and reduces venous result in heat loss.
return to the heart, further contributing to
▪ Overzealous attempts to warm patients
hypotension.
may cause hyperthermia, as sweating is
– Lesions above T1 vertebral level can result in impaired.
bradycardia; the sympathetic
cardioacceleratory nerves are disconnected – Hyperglycaemia is common following
from the heart, allowing unopposed spinal cord injury as a result of the stress
parasympathetic activity. CO cannot be response; good glycaemic control is needed
increased by the normal mechanism of to prevent exacerbation of ischaemic cord injury.
213
Describe the common patterns of – Patients typically present with severe leg
weakness, with at least partially preserved
incomplete spinal cord injury sensation. ‘Saddle anaesthesia’ (sensory loss
Incomplete spinal cord injury describes a situation in around the anus, buttocks, perineum and
which there is partial damage to the spinal cord: some genitals) is the most common sensory
motor and sensory function remains below the level disturbance. Autonomic disturbance is extremely
of the cord lesion. Important patterns of incomplete common; urinary retention is almost universal.
cord injury are shown in Figure 47.4: – The most common cause of cauda equina
Anterior spinal artery syndrome, which, as syndrome is an acute central intervertebral
described above, results in paraplegia, loss of pain disc herniation: a surgical emergency
and temperature sensation, and autonomic requiring lumbar discectomy. Other causes are
dysfunction below the level of the lesion. metastatic disease, trauma and epidural
Crucially, proprioception and vibration sensation abscess. Of particular interest to the
remain intact. anaesthetist: there is an association between
Central cord syndrome, the most common cauda equina syndrome and the technique of
incomplete spinal cord injury: continuous spinal anaesthesia with fine-bore
– Central cord syndrome results from spinal catheters. It is not clear whether this is
hyperextension of the neck, usually in older due to the hyperbaric 5% lignocaine that was
patients with cervical spondylosis, but used in the technique, or the introduction of
sometimes in younger patients involved in small amounts of neurotoxic chlorhexidine
high-force trauma. cleaning solution into the CSF.
– Signs and symptoms are upper and lower limb
weakness below the level of the lesion, with a
varying degree of sensory loss. Autonomic Describe the initial management of
disturbance is common, especially bladder acute spinal cord injury
dysfunction.
Trauma patients frequently have multiple injuries; for
– Central cord syndrome is now thought to be
example, 25% of patients with a cervical spine injury
due to selective axonal disruption of the lateral
also have a TBI. Unfortunately, nothing can be done to
columns at the level of the injury, with relative
reverse the mechanical aspects of a spinal cord injury;
preservation of grey matter.
for example, an axonal injury due to rotational and
Brown-Séquard syndrome, which, as described shearing forces. The aim of medical management is
above, results in three characteristic clinical the prevention of secondary spinal cord damage. The
features: ipsilateral motor weakness, ipsilateral most common cause of secondary damage is cord
loss of two-point discrimination, proprioception ischaemia resulting from systemic hypoxaemia, or cord
and vibration sensation with contralateral hypoperfusion due to vascular damage, cord oedema or
loss of pain and temperature sensation below systemic hypotension.
the level of the lesion. The anaesthetic management of patients with spinal
Cauda equina syndrome. Although cauda equina injury frequently starts in the resuscitation room of the
syndrome is not strictly speaking a spinal cord emergency department, and increasingly in the pre-
injury, it is sufficiently similar to be included: hospital setting. Patients should be managed following
– In adults, the spinal cord ends at L1/2 vertebral an ABCDE approach (for example, following the ATLS ®
level, where it gives rise to the ‘horse-tail’ of L1 algorithms), treating life-threatening problems first.
to S5 nerve roots: the cauda equina. A lesion at Whenever spinal trauma is suspected, spinal immobil-
or below the level of L2, therefore, compresses ization must be maintained throughout to prevent any
these nerve roots rather than the spinal cord; further mechanical spinal cord injury. The cervical
this is called cauda equina syndrome. spine is immobilized by means of a hard collar,
– The nerve roots carry sensory afferent nerves, sandbags either side of the head and straps holding
parasympathetic nerves and lower motor the patient’s head to a backboard. The thoracic
neurons. and lumbar spine are immobilized simply by the patient
214
Dorsal columns – proprioception and vibration
Corticospinal tract – motor fibres
Normal spinal cord

Lateral horn – sympathetic fibres
Spinothalamic tract – pain

and temperature
Sparing of dorsal columns
Anterior spinal artery syndrome

Loss of all other motor
and sensory function
Some involvement of dorsal columns
Motor fibre involvement
Central cord syndrome

Autonomic fibre involvement
Some sensory sparing
Loss of ipsilateral proprioception

and vibration sense
Loss of ipsilateral motor function

Brown–Séquard syndrome
Loss of contralateral pain and

temperature sensation
Figure 47.4 Characteristic patterns of incomplete spinal cord injury.
lying still on a flat surface. If the patient needs to be Airway. Jaw thrust is the only airway manoeuvre
moved, the spine is kept in alignment by ‘log-rolling’. that does not risk displacing a cervical fracture.
Aspects of anaesthetic management specific to Oxygenation should be maintained – either by
spinal injuries are: high-flow O2 administration in a conscious
215
patient, or by intubation and ventilation in an Circulation. Hypovolaemia should be treated

unconscious patient. If intubation is likely to be promptly with fluids to minimize secondary
required, this should take place at an early stage to ischaemic damage of the spinal cord. In a trauma
prevent hypoxaemia-related secondary cord patient, hypotension is most likely to be the result
damage. A difficult intubation should be of haemorrhage – the search for the site of
anticipated, owing to: bleeding is both clinical and radiological: chest
– sub-optimal positioning of the patient on the and pelvic X-rays, abdominal ultrasound and
spinal board; computed tomography (CT). Bradycardia with
– RSI with cricoid pressure; hypotension may be due to spinal cord injury with
– manual in-line stabilization of the unopposed parasympathetic innervation of the
cervical spine; heart – atropine or glycopyrrolate should be given.
– associated maxillofacial injuries; Disability. A basic neurological assessment should
include an assessment of conscious level using the
– blood and debris in the oral cavity.
GCS or the ‘alert, voice, pain, unresponsive’
Nasal intubation should be avoided owing to (AVPU) scale, pupil size and reactivity, and
the possibility of associated basal skull fractures. tendon reflexes. Patients with a reduced level
Induction of anaesthesia. The high risk of of consciousness will almost inevitably
pulmonary aspiration necessitates RSI. The choice require imaging of their brain in addition to
of intravenous induction agent is a matter of their spine.
personal preference, but in the setting of trauma a Everything else. Plasma glucose and electrolytes
cardio-stable drug (ketamine or etomidate) may should be tested and abnormalities corrected.
be required. The muscle relaxant of choice in the A full secondary survey should be carried out
acute phase of spinal cord injury is when the patient has been stabilized – this
suxamethonium. However, from 24 h after the includes log-rolling the patient to examine the
injury, the use of suxamethonium is spine, flanks and anal motor tone. Care should be
contraindicated: a significant rise in plasma K+ taken to keep the patient warm; hypothermia is
may occur due to the depolarization of the newly common, due to prolonged exposure to the
developed extra-junctional ACh receptors (see environment at the scene of trauma, cold
Chapter 50). If head injury is suspected (which it intravenous fluids and blood, and removal of
is in arguably all major trauma patients), some clothes for clinical examination.
means of obtunding the sympathetic response to
laryngoscopy should be used to avoid a rise in Further reading
ICP; for example, by administering a fast-acting, J. A. Kiernan, R. Rajakumar. Barr’s The Human Nervous
strong opioid. System: An Anatomical Viewpoint, 10th edition.
Breathing. In the acute phase, PaO2 should Lippincott Williams and Wilkins, 2013.
be kept above 10 kPa. Oxygenation may J. H. Martin. Neuroanatomy Text and Atlas, 4th edition.
be impaired by associated chest injuries McGraw-Hill Medical, 2012.
(for example, flail chest, haemothorax), which M. Denton, J. McKinlay. Cervical cord injury and critical
should be dealt with promptly. As discussed care. Contin Educ Anaesth Crit Care Pain 2009; 9(3):
above, the respiratory consequences of cervical 82–6.
spine injury make hypoxaemia particularly J. Šedy, J. Zicha, J. Kuneš, et al. Mechanisms of neurogenic
common; if a conscious patient is unable to pulmonary edema development. Physiol Res 2008; 57:
maintain adequate arterial oxygenation or 499–506.
becomes hypercapnoeic, intubation and P. Veale, J. Lamb. Anaesthesia and acute spinal cord injury.
ventilation are indicated. Contin Educ Anaesth Crit Care Pain 2002; 2(5): 139–43.
216
Chapter
Resting membrane potential
48
The membrane potential of a cell is the electrical bind positively charged ions and repel negatively
voltage of its interior relative to its exterior. At rest, charged ions.
the membrane potential is negative, and is then
described as being polarized. The resting membrane The RMP is influenced by the concentrations and
potential (RMP) takes typical values of 70 mV in membrane permeability of three major ions:
+ +
nerve, 90 mV in skeletal muscle cells, and much K : the intracellular K concentration is normally
lower negative values (around 30 mV) in non- greater (150 mmol/L) than the extracellular K+
excitable cells. The action potential (see Chapter 49) concentration (5 mmol/L). The phospholipid
is a transient change in the membrane potential from bilayer of the cell membrane is impermeable to K+
the RMP to a positive value; the cell membrane is then ions, as they are polar. However, the cell
described as being depolarized. membrane contains open K+ leak channels1 that
permit K+ to pass down its concentration
gradient, from the ICF to the ECF.
How is the membrane potential Na+: the extracellular Na+ concentration is higher
(140 mmol/L) than the intracellular Na+
produced? concentration (20 mmol/L). The resulting
When there are exactly equal numbers of positively electrochemical gradient, therefore, tends to drive
and negatively charged ions on either side of the cell movement of Na+ from ECF to ICF. However,
membrane, the electrical potential across the mem- Na+ ions are polar and, therefore, do not traverse
brane will be zero. Inequalities in the distribution of the cell membrane, and Na+ channels present in
charged ions across the cell membrane result in an the membrane are normally closed at RMP,
electrical potential. For example: leaving the resting cell membrane impermeable to
A negative membrane potential is produced Na+.2
when there are a greater number of positively Cl : membrane permeability varies with cell type:
charged ions on the outside of the cell membrane – In neurons, the cell membrane is relatively
relative to the inside. impermeable to Cl : permeability to Cl is
A positive membrane potential is produced when about 1000 times less than that of K+, and
there are a greater number of positively charged therefore its contribution is often ignored.
ions on the inside of the cell membrane relative to – Muscle contains open membrane Cl
the outside. channels. Cl therefore distributes itself across
The distribution of ions across the cell membrane the cell membrane passively according to its
is due to the combined effects of: electrochemical gradient. At RMP, Cl is
driven out of the cell by the negatively charged
The different ionic compositions of the ICF
and ECF.
The selective permeability of the cell membrane to 1
These are also called two-pore-domain K+ channels.
the different ions. 2
In reality, the resting cell membrane is not completely
Negatively charged intracellular proteins, whose impermeable to Na+, as the K+ leak channels are not
large MW and charge means that they are unable completely specific to K+. Overall, Na+ permeability is
to cross the cell membrane. These proteins tend to about 100 times less than that of K+.
217
cell interior. However, membrane How may the Nernst equation be

depolarization results in a positively charged
cell interior, producing a Cl influx. applied to explain the resting
Therefore, in most cells, Cl movement does membrane potential?
not influence the RMP; rather, the membrane The resting membrane has a significantly higher K+
potential passively influences Cl movement. permeability than Na+ permeability. This permits a
net efflux of positively charged K+ from the cell inter-
ior down its concentration gradient, driving the
What is the Nernst equation? membrane potential towards the Nernst potential
Consider a particular membrane-permeant ion, X: for K+. As K+ ions exit, the cell interior becomes
X will distribute on either side of a cell membrane, increasingly negatively charged, thus generating an
according to its chemical (i.e. concentration) and opposing electrical gradient that limits further K+
electrical gradients across the membrane. efflux.
The movement of X ceases when the net In contrast, there is a considerably lower resting
chemical and electrical gradients of X across membrane permeability to Na+ ions, and so there is
the membrane are zero; that is, at electrochemical little contribution from the transmembrane distribu-
equilibrium. tion of Na+ to the resting potential.
Accordingly, the measured neuronal RMP
The contribution that ion X makes to the RMP
may be calculated using the Nernst equation from ( 70 mV) is close to the calculated Nernst potential
its valency, the concentration difference across the for K+, which reflects the major contribution that
membrane, and the temperature: K+ makes to the RMP due to the high membrane K+
permeability, and the low membrane Na+ and Cl
Key equation: the Nernst equation permeability.
RT ½Xo
EX ¼ ln
zF ½Xi What is the Goldman equation?
As discussed above, the Nernst equation is used to
where EX (mV) is the Nernst potential for a particular
calculate the membrane potential for a single ion,
ion, R is the universal gas constant (8.314 J/(K mol)),
T (K) is the absolute temperature, F is the Faraday
assuming that the cell membrane is completely per-
constant, the electrical charge per mole of electrons meable to that ion. However, the cell membrane has
(96 500 C/mol), z is the valency of the ion, [X]o (mmol/ differing permeability to a number of ions. The RMP
L) is the ion concentration outside the cell and [X]i can be more precisely quantified by considering all
(mmol/L) is the ion concentration inside the cell. the ionic permeabilities and concentrations using the
Goldman–Hodgkin–Katz equation.
For example, the Nernst potential for K+ is calcu- Key equation: the Goldman–Hodgkin–Katz
lated as follows: equation
Assuming a temperature of 37 °C (i.e. 310 K), with RT PK ½K+ o + PNa ½Na+ o + PCl ½Cl i
ICF and ECF K+ concentrations as above: Em ¼
F
ln
PK ½K+ i + PNa ½Na+ i + PCl ½Cl o
RT ½K+ o where Em (mV) is the calculated membrane potential
EK ¼ ln
zF ½K+ i and PX is the permeability of the membrane to ion X.
8:314×310 5 Note:
EK ¼ ln
1×96500 150 If the membrane is permeable only to K+, then
E K ≈ 90 mV PNa and PCl equal zero and the equation reduces
to the Nernst equation for K+.
Similarly: There is no valency term as only monovalent ions
+
The Nernst potential for Na is calculated as are considered.
+50 mV. The concentrations of Cl are shown opposite to
The Nernst potential for Cl is calculated those of K+ and Na+ to account for its negative
as 70 mV. valency.
218
Chapter 48: Resting membrane potential
How does the Na+/K+-ATPase K+.

contribute to the resting membrane – Hyperkalaemia depolarizes the RMP. From the
Nernst equation, an increase in extracellular
potential? K+ concentration from 4.0 to 7.5 mmol/L
The Na+/K+-ATPase causes the efflux of three Na+ changes the Nernst potential for K+ from 90
ions in exchange for the influx of two K+ ions, with to 80 mV. The RMP approaches threshold
the following consequences: potential (the potential at which an action
+ + potential is triggered), making spontaneous
Na and K concentration gradients. The generation of action potentials more likely.
+ +
Na /K -ATPase is responsible for the high In the heart, dangerous arrhythmias such
extracellular relative to intracellular Na+ as ventricular fibrillation (VF) may occur.
concentration, and conversely the high – Hypokalaemia causes the opposite effect:
intracellular relative to extracellular K+ the cell membrane becomes hyperpolarized.
concentration, which ultimately generate It becomes harder to generate and propagate
the RMP. action potentials. Muscular weakness and
The osmotic effect of the high extracellular ECG changes may occur.
concentration of impermeant Na+ balances the Na+. As discussed above, the cell membrane is
osmotic effect of the high intracellular relatively impermeable to Na+ at rest. Therefore,
concentration of negatively charged protein, changes to the Na+ extracellular concentration
thereby ensuring an osmotic balance across the would be expected to make little difference to
cell membrane. the RMP. However, hyponatraemia alters the
+ + distribution of water in the body (see Chapter 65).
Electrogenic effect. Each cycle of Na /K -ATPase
activity results in the net loss of one positive The reduced ECF osmolarity causes cells to
charge from the cell, making the cell interior swell – for example, severe hyponatraemia leads
to cerebral oedema. The additional intracellular
slightly more negative (i.e. hyperpolarization) by
water causes a fall in intracellular K+ concentra-
around 3 to 6 mV, depending on the overall tion, which in turn leads to cell membrane
cell membrane resistance. depolarization towards threshold potential;
spontaneous action potentials are more
Clinical relevance: the effect of electrolyte likely to be generated. This is in part why
disturbances cerebral oedema secondary to hyponatraemia
As discussed above, the RMP depends on the relative is associated with seizure activity.
concentrations of ions on either side of the cell Ca2+. As discussed above, K+ is the major deter-
membrane. Changes in extracellular ionic concentra- minant of the RMP – Ca2+ essentially plays no
tion may therefore alter the RMP (Figure 48.1): role. However, Ca2+ is integral to the normal
Figure 48.1 Changes to RMP and

threshold potential with electrolyte
–10
disturbances.
Membrane potential (mV)
Threshold potential
–30 more negative
–50 Threshold potential
RMP
–70
Depolarization of RMP
Hyperpolarization of RMP
–90
‘Normal’ Hypokalaemia Hyperkalaemia Hypocalcaemia
Electrolyte disturbance
219
function of the cell membrane Na+ channels; binds to the outside of the cell membrane,
hypocalcaemia activates these Na+ channels, attached to glycoproteins. This increases the
bringing the threshold potential nearer to amount of positive charge directly apposed
RMP. The clinical result is spontaneous to the extracellular side of the membrane,
depolarization of neurons; that is, tetany which causes a temporary hyperpolarization of
and parasthesias. the RMP.
Ca2+ may be given for cardioprotection in hyper-

kalaemia, allowing time for the underlying cause
to be dealt with. Administering Ca2+ does not
Further reading
change intracellular Ca2+ concentration signifi- R. D. Keynes, D. J. Aidley, C. L-H. Huang. Nerve and
cantly, as the membrane is impermeable to Ca2+ Muscle, 4th edition. Cambridge, Cambridge University
Press, 2011.
at rest. However, Ca2+ has a membrane-stabilizing
effect due to the ‘surface charge hypothesis’. Ca2+ S. H. Wright. Generation of resting membrane potential.
Adv Physiol Educ 2004; 28: 139–42.
220
Chapter
Nerve action potential and propagation
49
transmembrane voltage-gated Na+ channels;
What is an action potential? Na+ influx then exceeds K+ efflux. This is
An action potential is a transient reversal of the mem- known as the ‘threshold potential’.
brane potential that occurs in excitable cells, includ-
The resulting membrane depolarization results
ing neurons, muscle cells and some endocrine cells
in a further opening of voltage-gated Na+
(Figure 49.1). The action potential is an ‘all or noth-
channels, thus further increasing the membrane
ing’ event: if the triggering stimulus is smaller than a
permeability to Na+ (Figure 49.2). This further
threshold value, the action potential does not occur.
increases the Na+ influx, which in turn produces
But once triggered, the action potential has a well-
further membrane depolarization, resulting in
defined amplitude and duration. Action potentials
the rapid upstroke of the action potential.
allow rapid signalling within excitable cells over rela-
This drives the membrane potential towards
tively long distances.
the Nernst equilibrium potential for Na+
of approximately +50 mV. However,
Describe the events that result in the the action potential never reaches this
theoretical maximum, as two further events
nerve action potential intervene:
Action potentials usually begin at the axon hillock of
– Inactivation of voltage-gated Na+ channels: the
motor neurons, or at sensory receptors in sensory
voltage-gated Na+ channels make a further
afferent neurons. Events proceed as follows
transition from the open state, to a closed
(Figure 49.1):
(refractory) state; membrane Na+ permeability
As discussed in Chapter 48, the neuronal decreases.
RMP of approximately 70 mV is close to the – Delayed activation of voltage-gated K+
Nernst equilibrium potential for K+ of around channels: membrane depolarization slowly
90 mV. opens voltage-gated K+ channels (Figure 49.2).
An initial depolarization of a sensory receptor, Membrane K+ permeability increases, and
synapse or another part of the nerve results in the resulting K+ efflux acts to drive the
Na+ and K+ movements producing a net membrane potential back towards the Nernst
depolarization of the cell membrane: equilibrium potential for K+ of approximately
– If the stimulus is small, the Na+ influx is 90 mV.
exceeded by K+ efflux through K+ leak The membrane potential briefly becomes
channels, primarily responsible for the RMP more negative than the RMP. This
(see Chapter 48). The cell membrane returns after-hyperpolarization occurs because of
to 70 mV. the gradual closure of the voltage-gated K+
– If the stimulus is large enough, depolarizing the channels.
cell membrane to approximately 55 mV,1
there is a significant activation of In summary, the action potential results from a
brief increase in membrane conductance to Na+
1
Threshold potential is dependent on a number of factors, followed by a slower increase in membrane conduct-
but is commonly between 55 and 40 mV. ance to K+ (Figure 49.2).
221
Voltage-gated K+ channels open Figure 49.1 The nerve action potential.
+30
Voltage-gated Na+
+10 channels start to close
tion
Repolarizatio
–10
Depolariza
Voltage-gated K+ channels
Increasing number start to close
–30
of voltage-gated Na+
n
channels open
–55

–70
Hyperpolarization
Sub-threshold stimulus Threshold stimulus
–90
0 1 2 3 4 5 6 7
Time (ms)
Figure 49.2 Changes in the membrane permeability of Na+ and

K+ throughout the action potential.
+30 Na+ Membrane potential
conductance
Relative membrane permeability
+10
100
K+ conductance
–10
10
–30
–50
–55
1
–70
–90 0.1
0 1 2 3 4 5
Time (ms)
How are action potentials propagated in the intracellular surface becoming

positively charged. The action potential
along nerve axons? is limited to a small portion of cell
Electrical depolarization propagates by the formation membrane; neighbouring segments remain
of local circuits (Figure 49.3): quiescent.
The intracellular surface of a resting portion of Ion movement at the edges of the depolarized cell
cell membrane is negatively charged. membrane results in current flow; the
Following an action potential, the portion neighbouring quiescent portions of cell
of cell membrane depolarizes, resulting membrane become depolarized.
222
Chapter 49: Nerve action potential and propagation
+ + + + + + + + + + + + + + + + + + Figure 49.3 Action potential

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ propagation in unmyelinated neurons.
Resting neuronal
cell membrane _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + + + + + + + + + + + + + + + +
ICF negatively charged ECF positively charged
Area undergoing an
action potential _ _
+ + + + + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ +
Action potential is
initiated by stimulus _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
+ +
_ _
+ + + + + + + + + + + + + + + +
Induced local electrical currents

Stimulus
_ _ _ _
+ + + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _ _ _
+ + + +
Action potential
propagation
+ + + + _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _
+ + + + + + + + + + + + + +
_ _ _ _ _ _ _ _
+ + + + + + + + + +
_ _ _ _ _ _ _ _ _ _
+ + + + + + + +
Action potential
propagation _ _ _ _ _ _ _ _ _ _
+ + + + + + + +
_ _ _ _ _ _ _ _
+ + + + + + + + + +
Wave of depolarization
_ _ _ _ _ _ _ _ _ _ _ _
+ + + + + +
_ _ _ _ + + + + + + + + + + + + _ _
Membrane
repolarization _ _ _ _ _ _
begins + + + + + + + + + + + +
_ _ _ _ _ _ _ _ _ _ _ _
+ + + + + +
Wave of repolarization
Current decays exponentially along the length of quiescent cell membrane is sufficient to reach
the nerve axon, with a length constant of a few threshold potential, an action potential is
millimetres.2 Nevertheless, provided the generated.
propagated depolarization in the previously This process of local circuit propagation and action
potential generation is continued until the action
2
Longitudinal current is reduced by a deposition of charge potential reaches its destination (Figure 49.3).
on intervening membrane, as well as its leak across the The velocity of action potential conduction is
membrane into the ECF. affected by several factors:
223
The axon diameter. Just like a copper wire, the is known as saltatory conduction (Figure 49.4).
ICF within a larger nerve axon diameter has a Action potential conduction velocity increases from
smaller resistance to the longitudinal flow of 2 m/s in unmyelinated nerves to up to 120 m/s in
current, thereby permitting a higher conduction myelinated axons.
velocity.
The transmembrane resistance. This determines Clinical relevance: demyelination
how easily current may flow out of the nerve As discussed above, myelination is an extremely
and into the ECF. A higher transmembrane important determinant of nerve conduction velocity.
resistance reduces this loss of current The myelin sheath is especially important in nerves
that require the rapid conduction of action potentials
flow, thereby enhancing conduction.
for their function; for example, motor and sensory
Myelination increases the transmembrane
nerves.
resistance as the myelin sheath is made There are two important diseases in which
of insulating lipids. there is autoimmune destruction of the myelin
The membrane capacitance. The greater sheath: multiple sclerosis (where CNS neurons
the capacitance of the membrane, the demyelinate) and GBS (where demyelination occurs
longer it takes to alter the membrane in the PNS).
polarity, thus slowing action potential A demyelinated neuron is not the same as
propagation. Myelination decreases membrane an unmyelinated neuron. Demyelinated neurons
capacitance. have Na+ channels tightly packed at the nodes
of Ranvier, but do not have adequate numbers
Temperature. Like enzymes, the activity of
of Na+ channels in the newly exposed areas of
ion channels is very dependent on temperature. cell membrane. Therefore, action potentials often
The rate of ion channel opening increases fail to be conducted effectively along demye-
around three- or fourfold with a 10 °C linated axons. In contrast, whilst unmyelinated
increase in temperature. Therefore, the axons conduct action potentials slowly, they are
voltage-gated Na+ channels open more reliably conducted along the entire length of the
rapidly, increasing the velocity of action neuron.
potential propagation. The clinical features of demyelinating disease are
therefore deficiencies in sensation, motor function,
autonomic function or cognition, depending on the
type and location of the nerves involved.
How does myelination alter the nature
of action potential propagation?
Larger diameter nerve axons are coated in a white
lipid-rich insulating material called myelin. The How are nerve fibres functionally
myelin sheath is produced by Schwann cells in classified?
the PNS, and by oligodendrocytes in the CNS. The
Nerves can be classified based on their diameter and
myelin sheath covers the nerve axon except at regu-
conduction velocity:
larly spaced gaps known as nodes of Ranvier. These
exposed regions of membrane are densely populated Type A fibres are myelinated fibres of large
with voltage-gated Na+ channels. diameter (12–20 μm) with a conduction velocity
The electrical impulse propagates across the of 70–120 m/s. Type A fibres are subdivided into
internode (where the axon is covered by the myelin α, β, γ and δ, in order of decreasing nerve
sheath) by local circuit conduction, as in conduction velocity:
Figure 49.3. As discussed above, the myelin sheath – Aα motor fibres supply extrafusal muscle
insulates the nerve axon, preventing loss of current fibres; that is, those involved in skeletal muscle
to the ECF and decreasing the effect of membrane contraction.
capacitance. This ensures that the membrane is – Aβ sensory fibres carry sensory information
depolarized in excess of the threshold potential at from receptors in the skin, joints and muscle.
the adjacent node of Ranvier. The action potential – Aγ motor fibres supply intrafusal muscle
therefore appears to ‘jump’ from node to node; this spindle fibres.
224
Myelin sheath Node of Ranvier Figure 49.4 Saltatory conduction in

myelinated axons.
+ + + + + + + +
_ _ _ _ _ _ _ _
Resting neuronal
cell membrane _ _ _ _ _ _ _ _
+ + + + + + + +
Area undergoing an
action potential _
+ + + + + + +
_ _ _ _ _ _ _
Action potential is +
initiated by stimulus _ _ _ _ _ _ _
+
_
+ + + + + + +
Induced local electrical currents

Stimulus
_ _ _
+ + + + +
_ _ _ _ _
Saltatory + + +
conduction + + _ _ _ _ _
+
_ _ _ + + + + +
_ _ _ _ _ + + +
_ _ _
Saltatory + + + + +
conduction + + + + _ _ _
+
_ _ _ _ _
+ + +
Wave of depolarization
– Aδ sensory fibres relay information from fast

nociceptors and thermoreceptors. The lower pH within the axoplasm means that
Type B fibres are narrow (diameter <3 μm) as soon as the local anaesthetic has crossed the
myelinated fibres. Their conduction velocity is cell membrane it is protonated (becomes
correspondingly lower, at 4–30 m/s. The pre- ionized) and therefore cannot diffuse back into
ganglionic neurons of the ANS are type B fibres. the ECF.
The ionized local anaesthetic blocks the
Type C fibres have narrow (diameter 0.4–1.2 μm)
voltage-gated Na+ channels by binding to the
unmyelinated axons with a correspondingly slow inner surface of the ion channels when they are
conduction velocity (0.5–4 m/s). Post-ganglionic in their refractory state.
neurons of the ANS and slow pain fibres are type In other words, local anaesthetics indefinitely
C fibres. prolong the absolute refractory period (ARP);
further action potentials are prevented.
Clinical relevance: local anaesthetics Some nerves are more sensitive to local anaes-
Local anaesthetics act by blocking fast voltage-gated thetics than others. In general:
Na+ channels, thereby preventing further action poten- Small nerve fibres are more sensitive to local
tials being propagated. The mechanism of action is: anaesthetics than large nerve fibres are.
Local anaesthetics are weak bases. Myelinated fibres are more sensitive to local
Only unionized local anaesthetic can diffuse anaesthetics than equivalent-diameter
across the phospholipid bilayer of the neuronal unmyelinated fibres are. This is probably
cell membrane. owing to myelinated fibres having only small
225
Figure 49.5 Absolute and relative

ARP RRP refractory periods.
+30
+10
–10
–30
–50
–55
–70
–90
0 1 2 3 4 5
Time (ms)
(ARP), or only with application of a stimulus of

areas of cell membrane exposed (nodes of
Ranvier), in which the Na+ channels are densely increased size (relative refractory period (RRP)):
packed. The ARP starts from the moment the
voltage-gated Na+ channels open, and
The overall clinical effect is:
continues until repolarization is one-third
Intermediate-sized myelinated fibres are the
complete (a period of around 1 ms). The basis
easiest to block; for example, Aδ (which relay fast
nociceptive signals) and B fibres (pre-ganglionic of the ARP is:
autonomic fibres). – Shortly after the voltage-gated Na+ channels
Larger Aα, Aβ and Aγ fibres (which relay touch, have opened, they become refractory.
pressure and proprioception) are the next easiest – The Na+ channels remain in their
to block. refractory state, and are incapable of
Unmyelinated C fibres are the most resistant to
reopening until the membrane regains its
local anaesthetics.
negative potential.
The RRP continues for 2–3 ms after the ARP
has ended. The mechanism behind the RRP is as
What is meant by the term follows:
‘refractory period’? – During the repolarization phase, both the K+
The refractory period describes the time following an leak channels and voltage-gated K+ channels
action potential when a further action potential either are open. The membrane K+ permeability is
cannot be triggered whatever the size of the stimulus therefore at its highest.
226
– During this period the threshold potential is Limiting the frequency of action potentials. The
higher, as a greater stimulus is required to refractory period limits the number of action
counteract the increased K+ efflux. potentials that can be generated in a given time
period.
The refractory period is important for two
reasons:
Further reading
To ensure unidirectional propagation of R. D. Keynes, D. J. Aidley, C. L-H. Huang. Nerve and
action potentials. When a segment of a cell Muscle, 4th edition. Cambridge, Cambridge University
membrane depolarizes, the trailing region of cell Press, 2011.
membrane is in its refractory state, whilst the A. Scholz. Mechanisms of (local) anaesthetics on voltage-
leading segment of cell membrane is in its gated sodium and other ion channels. Br J Anaesth 2002;
resting state. 89(1): 52–61.
227
Chapter
Synapses and the neuromuscular junction
50
What is a synapse? It must be released from the pre-synaptic
membrane in sufficient quantity to trigger an
A synapse is the functional point of contact between effect at the post-synaptic membrane.
two excitable cells, across which a signal can be trans-
When given exogenously (i.e. as a drug) it must
mitted. There are two types of synapse:
mimic the physiological effect.
Chemical synapse, in which the signal is relayed There must be a mechanism for removing it from
by means of a chemical messenger called a the synapse.
neurotransmitter. Arrival of an action potential
triggers neurotransmitter release into the Neurotransmitters may be classified as:
synaptic cleft, a narrow (20–50 nm) gap between Small molecules, of which there are three main

the pre- and post-synaptic membranes, which classes:
excites or inhibits the post-synaptic cell. An
example of a chemical synapse is the NMJ: the – Amines – ACh, histamine, serotonin (5-HT),
terminal bouton of an α-motor neuron forms a catecholamines (noradrenaline, adrenaline,
synapse with the motor end plate of a skeletal dopamine).
muscle cell. Chemical synapses are unidirectional: – Amino acids – γ-amino butyric acid (GABA),
the signal can only be transmitted from pre- to glycine, glutamate.
post-synaptic cell. – Purines – ATP, adenosine.
Electrical synapse, in which the pre- and post- Large molecules; over 50 neuroactive peptides are
synaptic cells are joined by gap junctions that known, including:
allow electric current to pass; an action potential – Opioids – β-endorphin, enkephalins.
in the pre-synaptic cell induces a local current in – Tachykinins – substance P, neurokinins.
the post-synaptic cell, which triggers an action – Secretins.
potential. Signals are transferred from neuron to – Somatostatins.
target cell much faster when the cells are
connected by an electrical synapse than by a Most neurotransmitters exert excitatory effects
chemical synapse. This is exemplified by cardiac on the target cell, which may result in the triggering
muscle, where gap junctions are essential for the of an action potential (if the target cell is a nerve or
rapid conduction of action potentials (see muscle) or secretion (if the target cell is a gland).
Chapter 54). Electrical synapses are bidirectional: The most prevalent excitatory neurotransmitter is
the signal can be transmitted from pre- to post- glutamate, present in over 90% of synapses in the
synaptic cell, or vice versa. brain. Some neurotransmitters are inhibitory, causing
either hyperpolarization or increased Cl conduct-
ance at the post-synaptic membrane, thereby redu-
What are neurotransmitters? cing the likelihood of an action potential being
A neurotransmitter is a substance released by a generated. GABA, the second most prevalent neuro-
neuron at a synapse, which then affects the post- transmitter in the brain, is the major inhibitory
synaptic cell. There are four classical requirements neurotransmitter. Glycine is an inhibitory neuro-
for a substance to be a neurotransmitter: transmitter particularly widespread in the spinal cord
It must be synthesized or stored within a neuron. and brainstem.
228
Chapter 50: Synapses and the neuromuscular junction
Occasionally, neurotransmitters have an excita- Ionotropic signalling may produce either an excitatory
tory effect at one synapse, whilst having an inhibitory (EPSP) or inhibitory (IPSP) post-synaptic potential,
effect at another. For example, ACh is an excitatory depending on the flow of ions at the post-synaptic
neurotransmitter at the nicotinic receptors of the ion channel:
NMJ, whilst producing an inhibitory response at the In an EPSP, binding of neurotransmitter at the
muscarinic M2 receptors of the heart. post-synaptic membrane opens non-specific
cation channels.
How are neurotransmitters released – Na+ and K+ diffuse along their
electrochemical gradients: Na+ flows into the
into the synaptic cleft? post-synaptic cell from the synaptic cleft,
Neurotransmitters are stored in packets called vesicles whilst K+ diffuses out of the cell. Overall,
which are docked at the active zone of the pre-synaptic Na+ influx is greater than K+ efflux; the net
membrane. When the action potential propagates down intracellular movement of positively charged
the axon and into the terminal bouton (Figure 50.1a), ions causes a depolarization of the post-
a well-defined sequence of events occurs: synaptic membrane, the EPSP.
2+
Increase in pre-synaptic Ca concentration. – There is usually an excess of post-synaptic ion
Depolarization results in the opening of voltage- channels; the size of the EPSP is therefore
gated Ca2+ channels (N-type). Ca2+ diffuses down dependent on the number of neurotransmitter
its electrochemical gradient from the ECF to the vesicles released.
neuron interior (Figure 50.1b).
▪ The spontaneous exocytosis of a single
Exocytosis. Periodically, vesicles in the active zone vesicle of neurotransmitter results in a
spontaneously fuse with the pre-synaptic membrane, small 0.5 mV depolarization. This
releasing their neurotransmitter contents into the depolarization is not large enough to reach
synaptic cleft. Following an action potential, axonal threshold potential, and the EPSP will fade
Ca2+ binds to a vesicular membrane protein called back to the RMP.
synaptotagmin which, in conjunction with proteins
▪ Following an action potential, a large
known as SNAREs, triggers 50–100 vesicles to number of neurotransmitters are released
undergo exocytosis. Thus, a very large number of into the synaptic cleft. The depolarizing
neurotransmitter molecules are released into the effect of each vesicle’s contents at the post-
synaptic cleft following an action potential. synaptic membrane is additive; to exceed
Diffusion across the synaptic cleft. The threshold potential and generate an action
neurotransmitters diffuse down their potential at the post-synaptic cell, many
concentration gradient, travelling the short vesicles must be released simultaneously
distance to the post-synaptic membrane. (Figure 50.2a).
Binding to post-synaptic receptors.
Neurotransmitters that reach the post-synaptic In an IPSP, the post-synaptic membrane contains
membrane bind to specific receptors, resulting in either ligand-gated K+ or Cl channels.
excitation or inhibition of the membrane – K+-mediated IPSPs: binding of
(Figure 50.1c). neurotransmitter opens specific K+ channels.
K+ ions diffuse along their electrochemical
gradient, from the post-synaptic cell to the
synaptic cleft. The efflux of positively charged
What are ionotropic receptors? ions hyperpolarizes the cell membrane,
At the post-synaptic membrane, neurotransmitters making it more difficult to reach threshold
encounter two types of receptor: potential (Figure 50.2b).
Ionotropic receptors are ligand-gated post-synaptic – Cl -mediated IPSP: binding of
ion channels. neurotransmitter opens Cl channels. The
Metabotropic receptors exert their effects through resulting intracellular movement of Cl ions
chemical second messengers. usually makes little difference to the
229
(a) Action potential Figure 50.1 The mechanism of a

chemical synapse.
Terminal bouton
Closed voltage- Vesicles containing

gated Ca2+ channel neurotransmitter
...
... .. ... Post-synaptic membrane
.. ..
... ...
.. ..
Synaptic cleft
Pre-synaptic membrane
Chemically gated ion
channel (closed)
(b)
Voltage-gated Ca2+
channels open
...
..
Ca2+ Ca2+ Ca2+ Ca2+ Vesicles fuse with post-
... ... synaptic membrane
.. ..
. .
.. .
. . . . .
Neurotransmitters
released
(c)
...
..
... ...
.. ..
. . . .
.
. . . . . .
Open ion channel
post-synaptic membrane potential, as the

Nernst potential of Cl ( 70 mV) is Clinical relevance: mechanism of action of general
anaesthetics
approximately the same voltage as the RMP.
However, to reach threshold, an excitatory Despite general anaesthetics having been adminis-
tered since 1846, their exact mechanism of action
signal must trigger sufficient Na+ influx to
remains a matter of debate. The most likely explan-
exceed the combined effects of Cl influx and ation is a receptor theory, whereby general anaes-
K+ efflux, making it much more difficult to thetics interact with two main transmembrane
depolarize the cell membrane; this is known as proteins in the CNS:
the ‘chloride clamp’.
230
(a) Excitatory post-synaptic potential Figure 50.2 Excitatory and inhibitory

post-synaptic potentials.
+30
Post-synaptic potential (mV)
+10
–10 Multiple vesicles of

neurotransmitter
When the EPSP exceeds threshold,
released simultaneously
–30 an action potential is triggered
EPSP
–55
–70
Neurotransmitter release at synapse

–90
0 5 10 15 20 25 30
Time (ms)
(b) Inhibitory post-synaptic potential
+30
Post-synaptic potential (mV)
+10
–10
–30
Neurotransmitter release at synapse

–55
–70
IPSP: membrane potential is further from the threshold
potential, inhibiting action potential generation
–90
0 5 10 15 20 25 30
Time (ms)
The GABAA receptor utilizes the inhibitory distant to the GABA binding site, and act by
neurotransmitter GABA. The receptor has five increasing the conductance of Cl . The exact
subunits arranged around a Cl channel. binding site and why their effects differ from
A number of drugs act at this receptor: those of the benzodiazepines are not yet
– Benzodiazepines – a subset of GABAA recep- known.
tors bind benzodiazepines in addition to The N-methyl-D-aspartate (NMDA) receptor is
GABA. The benzodiazepine binding site is a tetrameric receptor, which utilizes the
located at a different site to that of GABA, excitatory neurotransmitter glutamate. A number
between the α- and γ-subunits. Following the of anaesthetic agents are thought to act by
binding of a benzodiazepine, the GABAA antagonizing this excitatory receptor, thus
receptor changes its conformation, which reducing neurotransmission:
increases its affinity for GABA. – Ketamine binds at a site distant to the
– Propofol, thiopentone and etomidate – all these glutamate binding site. A conformation change
drugs act, at least in part, at the GABAA recep- occurs in the NMDA receptor that prevents
tor. Like the benzodiazepines, all bind at a site the subsequent binding of glutamate.
231
– N2O, Xe – both are also thought to exert their What is the neuromuscular junction?
anaesthetic effects through antagonism of The NMJ is the chemical synapse between an α-motor
the NMDA receptor. neuron and a muscle cell. The transmission of motor
action potentials, or indeed their prevention, is of
obvious importance to anaesthetists. The NMJ exem-
What are metabotropic receptors? plifies many of the features of synapses discussed
Some synapses are metabotropic rather than ionotro- above, but its importance makes it worth reiterating
pic. Binding of a neurotransmitter causes a metabo- the key features.
tropic receptor to change its conformation, but unlike The α-motor neuron originates in the ventral horn
ionotropic receptors the conformation change does of the spinal cord. Its axon is myelinated, as the
not directly result in ion channel opening. Instead, conduction of motor action potentials needs to be
metabotropic receptors are indirectly linked to mem- rapid. Before the axon reaches the NMJ, it branches
brane ion channels through intermediate chemical to innervate several muscle cells. A motor unit con-
messengers, usually involving a G protein. An sists of an α-motor neuron and the muscle cells that it
important example of a metabotropic synapse is the innervates.
muscarinic (M2) ACh receptor of the pacemaker cells The NMJ itself consists of (Figure 50.3):
in the heart (see Chapter 54). The terminal boutons of the nerve axon, within
which are located vesicles containing the
neurotransmitter ACh.
How is neurotransmission terminated? The synaptic cleft, across which ACh must
Once released, neurotransmitters are rapidly removed diffuse.
from the synaptic cleft. This prevents repetitive and The motor end plate (post-synaptic membrane),
unwanted stimulation of the post-synaptic cell. There which is folded into peaks and troughs; the peaks
are three possible mechanisms by which this takes are densely packed with ACh receptors (AChRs),
place: whilst the troughs contain the enzyme AChE.
Diffusion. Neurotransmitters may diffuse out of There are estimated to be in excess of 1 000 000
the synaptic cleft along their concentration AChRs at each motor end plate.
gradients. This is a minor and relatively slow
mechanism.
Before the action potential arrives, the NMJ must
Degradation. Specific enzymes within the be ready for neurotransmission to occur:
synaptic cleft may inactivate the
neurotransmitters. An important example is the ACh synthesis. In the axoplasm of the nerve
hydrolysis of ACh by AChE into acetic acid and terminal, ACh is synthesized from choline and
choline. acetyl CoA, a reaction catalysed by the enzyme
choline-O-acetyltransferase. Choline originates
Neuronal reuptake. Neurotransmitters may be
from the diet or by hepatic synthesis, whilst acetyl
actively transported back into the pre-synaptic
CoA is produced in the axon mitochondria.
membrane. Instead of synthesizing large amounts
of new neurotransmitter, the pre-synaptic nerve ACh storage. Once synthesized, ACh is packaged
recycles the neurotransmitter molecules, storing into vesicles. Each vesicle contains around
them in vesicles ready for release. This occurs with 5000 ACh molecules, known as a ‘quantum’.
catecholamine neurotransmitters such as There are functionally three types of vesicle:
noradrenaline and dopamine, which are – Vesicles in the active zone (1% of the vesicles) –
metabolically expensive to produce. In clinical these vesicles are ‘docked’ at the pre-synaptic
practice, the action of neurotransmitters may be membrane, ready for immediate release.
prolonged through the use of reuptake inhibitors. – Vesicles in the reserve pool (around 80% of
Examples include selective serotonin reuptake vesicles) – these vesicles move forward to replace
inhibitors (SSRIs), which prevent the reuptake of the vesicles in the active zone as they are used.
serotonin in the CNS, and cocaine, which blocks – Vesicles in the stationary store (around 20%) –
the reuptake of dopamine in the CNS. these vesicles cannot release their ACh.
232
Action potential
Myelin sheath
Stationary store of vesicles

Closed voltage-
gated Ca2+channel
Vesicles in active zone, Reserve pool of vesicles

ready for immediate release
ACh receptors opposite

to the active zone
Extra-junctional ACh receptors
Acetylcholinesterase in the
troughs and within the synapse
Pre-synaptic ACh receptors
Motor end plate, folded into peaks and troughs

Figure 50.3 The NMJ.
Neurotransmission occurs as follows: – The AChR is composed of five subunits:

ACh release. When an action potential reaches the two α, one β, one δ and one ε subunit.
terminal bouton, it causes voltage-gated Ca2+ The subunits are arranged in a cylinder,
channels to open: forming a central ion channel.
– To open the ion channel, two ACh molecules
– Ca2+ ions diffuse from the ECF to the nerve
must bind to the two α subunits. Na+ and K+
axoplasm.
may then diffuse along their electrochemical
– An increase in intracellular Ca2+ concentration gradients; the net influx of cations depolarizes
triggers the vesicles of the active zone to fuse the post-synaptic membrane. The AChR ion
with the pre-synaptic membrane, releasing channel stays open for a very brief period,
their contents by exocytosis. Typically, 50–100 around 1 ms.
vesicles release >250 000 ACh molecules into
– Following an action potential, a significant excess
the synaptic cleft.
of ACh molecules is released; the resulting post-
The ACh receptor is a nicotinic receptor, a synaptic depolarization (the end-plate potential)
ligand-gated non-specific cation channel. It has easily exceeds threshold potential, thereby
some important features: triggering an action potential in the muscle cell.
– AChRs are densely packed into the peaks of the This safety margin is clinically important:
post-synaptic membrane, directly opposite to 70–80% of AChRs must be blocked by muscle
the active zone of the pre-synaptic membrane. relaxants to prevent neurotransmission.
233
Termination of neurotransmission. ACh is

rapidly removed from the synaptic cleft, mainly by by AChE. The AChR remains open for a pro-
longed period, and the muscle membrane
degradation:
remains depolarized. The muscle action
– ACh is rapidly hydrolysed by the enzyme potential can only fire once: the fast voltage-
AChE to choline and acetic acid. These gated Na+ channels which open during cell
breakdown products are actively transported membrane depolarization become inacti-
into the pre-synaptic membrane for the vated and cannot return to their resting state
resynthesis of ACh. until the cell membrane repolarizes, which
cannot happen until suxamethonium diffuses
– AChE is mainly found in the junctional folds
away from the AChR. Clinically, depolarizing
of the synaptic cleft.
block is characterized by muscle fascicula-
– The structure of AChE is of pharmacological tions followed by flaccid paralysis.
importance. The active site of the enzyme has – Non-depolarizing muscle relaxants:
two binding sites: anionic and esteratic. aminosteroids and benzylisoquinoliniums.
Anticholinesterases, drugs that inhibit the These drugs compete with ACh for its binding
AChE enzyme, reversibly or irreversibly bind site at the AChR. Non-depolarizing muscle
to these binding sites. relaxants have no intrinsic activity at the AChR –
they merely antagonize ACh. Insufficient ACh
reaches the AChRs to trigger an action potential
Clinical relevance: drugs acting at the in the muscle cell. Clinically, non-depolarizing
neuromuscular junction muscle relaxants cause flaccid paralysis without
Neurotransmission at the NMJ may be blocked by a any initial muscle contraction.
number of means, not just the muscle relaxants
(though these are the only clinically practical drugs):
Inhibition of ACh synthesis: hemicholinium
blocks the uptake of choline in the nerve axon,
Where else are acetylcholine
preventing ACh synthesis. receptors found?
Inhibition of vesicle exocytosis may occur In addition to the post-synaptic membrane, AChRs
through two mechanisms:
are found:
– Mg2+ and aminoglycosides block the pre-
synaptic voltage-gated Ca2+ channels. With- At the pre-synaptic membrane. Following ACh
out Ca2+ influx, vesicles cannot release their exocytosis, some ACh binds to pre-synaptic AChRs,
contents into the synaptic cleft. This is why which allows Na+ ions to enter the terminal bouton.
patients receiving prolonged Mg2+ infusions This triggers the mobilization of vesicles from the
(for example, in pre-eclampsia) are at risk of reserve pool to the active zone, ready for release.
muscle weakness. Outside the NMJ, where they are known as extra-
– Botulinium toxin degrades a protein called
junctional AChRs. In health, only a small number
SNAP-25 that is required for vesicle docking
of AChRs are present on areas of the muscle cell
at the pre-synaptic membrane. If vesicles
cannot dock, ACh cannot be released into the membrane outside the motor end plate. However,
synaptic cleft. following denervation, extra-junctional AChRs
Blockage of the AChR. There are, of course, two proliferate over the entire muscle cell membrane,
classes of drug which act at the AChR: with significant implications for the anaesthetist
– Depolarizing muscle relaxants; for example, (see Clinical relevance box below).
suxamethonium. Chemically, suxamethonium
is two ACh molecules joined end-to-end. The Clinical relevance: myasthenia gravis
spacing between the ACh components is MG is an autoimmune condition characterized by
exactly right for both to bind to the two α- fatigable weakness, in which immunoglobulin
subunits of the AChR. Because it acts like ACh, G (IgG) autoantibodies are directed at the nicotinic
suxamethonium opens the AChR cation AChR of the NMJ:
channel, causing depolarization of the post- Autoantibody attack of AChRs results in inflam-
synaptic membrane. In contrast to ACh, mation that not only reduces the number of
however, suxamethonium is not hydrolysed AChRs, but also flattens the folds of the post-
234
synaptic membrane, widening the distribution of number of AChRs activated, the K+ efflux is sig-
AChRs and AChE. nificantly greater.
The overall effect is a reduction in the number of Once open, extra-junctional AChRs remain open
ACh–AChR interactions, which reduces the size of for up to 10 ms, much longer than their junc-
end-plate potential and decreases the likelihood tional counterparts.
of an action potential being triggered in the
muscle cell, leading to weakness. The combination of these two effects has the poten-
There is also autoimmune destruction of pre- tial for a life-threatening increase in plasma K+
synaptic AChRs. Therefore, in MG, when action concentration.
potentials are repeatedly fired, fewer vesicles are Following acute denervation, extra-junctional
moved from the reserve pool to the active zone. AChRs take a little time to develop – clinically signifi-
Consequently, as fewer vesicles are available for cant hyperkalaemia is a risk from 24 h post-injury.
release, fewer molecules of ACh are released into Therefore, suxamethonium can safely be adminis-
the synaptic cleft. This is the basis of the fatig- tered for up to 24 h following the insult. After around
ability associated with MG. 100 days, the risk of hyperkalaemia is thought to
reduce sufficiently to permit the cautious use of sux-
Note: 10% of patients with MG are sero-negative; amethonium. In chronic denervation, suxametho-
that is, do not raise autoantibodies against the nico- nium has an unpredictable response, depending on
tinic AChR. Instead, they generate autoantibodies the numbers of extra-junctional AChRs formed.
against another protein at the post-synaptic mem-
brane: MuSK. This causes inflammation at the motor
end plate, with the same clinical effects.
Further reading
R. Khirwadkar, J. M. Hunter. Neuromuscular physiology
and pharmacology: an update. Contin Educ Anaesth Crit
Care Pain 2012; 12(5): 237–44.
Clinical relevance: denervation hypersensitivity
Extra-junctional AChRs are structurally different to P. L. Chau. New insights into the molecular mechanisms of
those at the motor end plate: they also have five general anaesthetics. Br J Pharm 2010;
161(2): 288–307.
subunits, but the adult ε subunit is replaced by the
fetal γ subunit. Classic examples of acute denervation M. J. Fagerlund, L. I. Eriksson. Current concepts in
include burns and acute spinal cord injury. However, neuromuscular transmission. Br J Anaesth 2009; 103(1):
chronic denervation also leads to proliferation of 108–14.
extra-junctional AChRs; for example, motor neuron A. Srivastava, J. M. Hunter. Reversal of neuromuscular
disease and some peripheral neuropathies (for block. Br J Anaesth 2009; 103(1): 115–29.
example, Charcot–Marie–Tooth). C. J. Weir. The molecular mechanisms of general
Extra-junctional AChRs are not just of academic anaesthesia: dissecting the GABAA receptor. Contin Educ
interest. Following administration of the depolarizing Anaesth Crit Care Pain 2006; 6(2): 49–53.
muscle relaxant suxamethonium, a potentially fatal
J. M. King, J. M. Hunter. Physiology of the neuromuscular
hyperkalaemia can occur. This is due to:
junction. Contin Educ Anaesth Crit Care Pain 2002;
Suxamethonium binding to both junctional and 2(5): 129–33.
extra-junctional AChRs, opening their non-
specific cation channels. Owing to the sheer M. Thavasothy, N. Hirsch. Myasthena gravis. Contin Educ
235
Chapter
Skeletal muscle
51
Myocytes have a number of unusual anatomical
What are the functions of skeletal features:
muscle? Size. A mammalian muscle fibre may span the
The primary function of skeletal muscle is locomo- entire length of the muscle, and have a diameter of
tion: contraction of muscle reduces the distance up 50 μm.
between its sites of origin and insertion, thereby pro- Nuclei. Myocytes are multinucleate.
ducing movement. Skeletal muscle has a number of Striations. Skeletal and cardiac muscle, but not
additional roles: smooth muscle, have a striped or ‘striated’
Maintenance of posture and joint stability: this is appearance due to regularly repeating sarcomeres
achieved through tonic contraction of multiple (see below).
synergistic and opposing muscle groups.
Support of soft tissues: the muscles of the Myocytes have a number of specialized cellular fea-
abdominal wall and pelvic floor support and tures in addition to the usual complement of Golgi
protect their underlying viscera. apparatus, mitochondria and ribosomes:
Sphincteric function in the GI and urinary The SR is a modified ER that acts as an
tracts: skeletal muscle provides voluntary control intracellular store of Ca2+, which can rapidly
over swallowing, defecation and micturition. release and sequester Ca2+.
Heat production: this occurs through alterations in The transverse (T)-tubules are invaginations of
background muscle metabolic rate and shivering the muscle surface membrane, or sarcolemma,
(repeated muscle contraction and relaxation). capable of relaying action potentials deep into the
myocyte interior.
Myofibrils, the contractile apparatus of the cell,
Describe the macroscopic and are arranged in parallel with one another spanning
the entire length of the myocyte. Because
microscopic anatomy of skeletal muscle myofibrils are anchored to the sarcolemma at
Skeletal muscles are made up of many muscle fibres either end of the myocyte, the whole myocyte
(myocytes), which are served by blood vessels and shortens when they contract.
nerves, and supported by a number of connective Myofilaments – within the myofibrils are bundles
tissue layers: of myofilaments, containing the contractile
Endomysium, the thin layer of connective tissue proteins actin and myosin.
surrounding each myocyte. Glycogen stores, which release glucose to provide
Perimysium – bundles of around 100 myocytes energy for muscle contraction.
surrounded by perimysium are called fascicles.
Epimysium, the thick layer of connective tissue
that encases the entire muscle.
What is a sarcomere?
A sarcomere is the functional unit of skeletal
At each end of the muscle, the layers of connective muscle. It contains interdigitating thick, myosin-
tissue (endomysium, perimysium and epimysium) containing, and thin, actin-containing, filaments
merge to form a tendon or an aponeurosis, which (Figure 51.1a). These are arranged in a regular,
usually connects the muscle to bone. repeating overlapping pattern, giving an alternating
236
Chapter 51: Skeletal muscle
(a) Sarcomere
½ I band A band ½ I band
Z disc
Thin filament H band

Myosin head
Thick filament
(b) Myofibril
A band I band A band
Z Z Z
Cut end allows actin and

myosin filaments to be seen
H band H band
Sarcomere
Figure 51.1 Structure of (a) the sarcomere and (b) the myofibril.
237
(a) Thick filament

Two myosin heads Figure 51.2 Structure of (a) the thick
per myosin protein filament and (b) the thin filament.
Actin binding site
Myosin tails
ATP binding site
(b) Thin filament Ca2+ binding site Z disc
Myosin binding Troponin C

site blocked by Troponin
Troponin I
complex
Myosin binding site tropomyosin
Troponin T
Tropomyosin
Actin protein (note: for clarity, only a single strand of actin is shown instead of a double strand)
sequence of dark and light bands, resulting in a Describe the key structural features of
striated appearance. Key features of the sarcomere
are: the thick and thin filaments
Z disc, located at either end of the sarcomere, Key features are:
bisecting the I band. Thick filament. Each thick filament contains
Thick and thin filaments. The thin filaments myosin, a large protein that has two globular
are joined at one end to the Z disc. The ‘heads’ and a long ‘tail’. The myosin heads
thick filaments are at the centre of the have distinct binding sites for actin and ATP
sarcomere, interdigitating with thin (Figure 51.2a). Each thick filament is surrounded
filaments. by six thin filaments, in an approximately
I (isotropic) or light band, containing the portion hexagonal arrangement
of the thin filament that does not overlap with Thin filament. Each thin filament is composed of
the thick filament. three proteins: the contractile protein actin, and
A (anisotropic) or dark band, the entire length the regulatory proteins tropomyosin and troponin
of the thick filament, including regions that (Figure 51.2b):
overlap the thin filament. – Actin is a globular protein that forms
H (heller) band, the part of the A band that chains that are twisted together in double
contains only myosin. strands. Each thin filament contains
around 300–400 actin molecules, with
Each mammalian sarcomere, therefore, contains regularly spaced myosin binding sites along
one A band and two half I bands (Figure 51.1b). its length.
238
– Tropomyosin is a fibrous protein chain that The ryanodine receptor (RyR). The DHPR is in
lies in the groove between the two strands of physical contact with the cytoplasmic portion of
actin. Tropomyosin covers the myosin binding another important Ca2+ channel, the RyR. The
site, preventing crossbridges forming between RyR also contains an intramembrane portion
actin and myosin. embedded within the SR membrane. Following a
– Troponin. This protein complex is located at conformation change in the DHPR, these physical
regularly spaced intervals along the connections cause the RyR to open and release
tropomyosin protein chain. The troponin Ca2+ from the SR, where Ca2+ is present at high
complex is made up of three subunits, each concentration, to the sarcoplasm, where Ca2+
with its own role: concentration is low.2
2+
Release of Ca from the SR increases the
▪ Troponin T binds the troponin complex
intracellular Ca2+ concentration by a factor
to tropomyosin (hence ‘T’).
of 2000.
▪ Troponin I has an uncertain role. 2+
Ca binds to troponin C, causing a
▪ Troponin C contains the Ca2+ binding site
conformational change of the whole troponin–
(hence ‘C’ for Ca2+). Binding of Ca2+ to
tropomyosin complex. The myosin binding site is
troponin C causes tropomyosin to roll
uncovered, which allows actin–myosin
deeper into the actin groove, which
interaction.
uncovers the myosin binding site, allowing
crossbridges to form between actin and Clinical relevance: malignant hyperthermia
myosin.
Malignant hyperthermia (MH) is an inherited disorder
of skeletal muscle that may produce a potentially
fatal combination of hypermetabolism (with a conse-
quent hyperthermia), muscle rigidity and rhabdo-
What is meant by ‘excitation– myolysis. MH is a condition especially feared by
anaesthetists, as the only universally accepted trig-
contraction coupling’? gering agents are the halogenated volatile
Excitation–contraction coupling refers to the pro- anaesthetics and suxamethonium.
cesses linking depolarization of the muscle cell It is now known that the genetic defect in MH is a
RyR mutation. Once triggered, the abnormal RyR
membrane to the initiation of myocyte contraction.
allows uncontrolled Ca2+ release from the SR. Clinic-
In common with neurons, the sarcolemma has
ally, this results in tetanic muscle contraction, which
excitable properties: consumes ATP and generates heat. Prolonged
The myocyte RMP is typically 90 mV (see muscle tetany may result in rhabdomyolysis. Mean-
Chapter 48). while, the SR has increased activity, sequestering
The sarcolemma has the capacity to fire action cytosolic Ca2+ through its Ca2+-ATPase, which exacer-
potentials (see Chapter 49): synaptic activity at bates this ATP consumption. The resulting
the motor end plate causes depolarization of the
sarcolemma, triggering an action potential
that propagates along the myocyte surface
membrane. 1
A very small quantity of Ca2+ passes through the DHPR,
but this Ca2+ influx is of insufficient quantity and has a
Excitation–contraction coupling occurs as follows: time course that is too slow to trigger muscle contraction;
The T-tubules transmit the action potential therefore, its function remains unclear. Some studies
deep into the myocyte interior, and close to the suggest it may be important in controlling gene
sarcoplasmic reticular Ca2+ store. expression within the muscle fibre (so-called ‘excitation–
transcription coupling’).
The dihydropyridine receptor (DHPR) senses 2
Note: the mechanism of excitation–contraction coupling
the depolarization of a T-tubule. The DHPR is a is different in cardiac muscle. Here, Ca2+ enters the
modified subtype of voltage-gated L-type Ca2+ cardiac myocyte during the plateau phase of the action
channel; depolarization causes a conformation potential, triggering Ca2+-induced Ca2+ release at the SR
change but allows little Ca2+ to pass.1 (see Chapter 54).
239
Figure 51.3 Sliding filament theory.

(a) When myosin binds ATP, its affinity for actin is low:
Myosin binding sites
Actin filament
Myosin tail
ATP ATP ATP
Myosin head
Z disc
(b) ATP is hydrolysed, energizing the myosin head and allowing crossbridges to form:
ADP ADP ADP

Pi Pi Pi
(c) The myosin head flexes and ADP dissociates – this is the ‘power stroke’:
Leftward movement
(d) ATP binds, reducing the affinity of myosin for actin – the crossbridges are broken:
ATP ATP ATP
How does skeletal muscle contract?

hypermetabolic state increases total O2 consumption
Exposure of the myosin binding site on the actin
and CO2 production, and generates a metabolic
filament permits the process of crossbridge cycling,
acidosis.
In addition to supportive measures, the only spe- which in turn generates mechanical force:
cific treatment for MH is dantrolene, which is thought The myosin heads bind ATP (Figure 51.3a). The
to bind to the RyR, inhibiting further Ca2+ release. ATP molecule is hydrolysed to ADP and
Untreated, the mortality for MH is very high, in the inorganic phosphate (Pi), and the released bond
order of 80%. However, the introduction of dantro- energy transferred to the myosin head. Energized
lene together with a greater awareness of the condi- myosin heads are now able to bind to their
tion has led to a much lower mortality of 2–3%.
240
2+
neighbouring actin molecules, forming Muscle relaxation: Ca is sequestered in the SR
crossbridges (Figure 51.3b). by the SERCA.
The energized myosin head flexes on its actin
binding site, and the action of this on the After death, muscle ATP stores are rapidly
myosin tail gives rise to the ‘power stroke’ that depleted. There is no longer sufficient ATP to power
moves the actin filament closer to the centre the SERCA. Ca2+ therefore remains bound to tropo-
of the sarcomere (Figure 51.3c). In this process, nin C, and thus actin–myosin crossbridges cannot
ADP and Pi dissociate from the energized detach, resulting in a high skeletal muscle tone known
myosin head. as rigor mortis.
A fresh ATP molecule binds to the myosin head.
The myosin–ATP complex has a low affinity for What is the motor unit?
its binding site on the actin filament, and The motor unit consists of a single α-motor neuron,
dissociates from it (Figure 51.3d). ATP is then its axon and the many muscle cells that it innervates.
hydrolysed to ADP, and the whole process repeats. A single action potential in an α-motor neuron results
in the contraction of all the myocytes within the
During contraction, the movement of the actin motor unit. Motor units have some key features:
filament results in the following changes: Each motor unit innervates only one myocyte
The Z lines move closer together – the overall type; for example, type I muscle fibres (see
width of the sarcomere decreases. Chapter 40).
The width of the I band decreases, as thin Groups of motor units often work together to
filaments overlap thick filaments to a greater coordinate the contraction of a single muscle. The
extent. force of contraction within a muscle is controlled
There is no change in the width of the A band, as by the number of motor units activated.
thick filaments do not shorten. The number of muscle fibres within each motor
unit varies considerably between muscles:
This movement of the thick and thin filaments rela- – Large powerful muscles, like the quadriceps
tive to each other was first suggested by the sliding femoris, perform gross movements. The
filament theory. quadriceps, therefore, contains >1000
Actin–myosin crossbridge cycling continues until myocytes per motor unit.
the intracellular Ca2+ concentration decreases. This – Some muscles require fine control, and thus
occurs when Ca2+ is re-sequestered into the SR by have proportionally more motor units which
means of the SR/ER Ca2+-ATPase (SERCA). As sar- contain fewer myocytes. The extraocular
coplasmic Ca2+ concentration decreases: muscles have as few as 10 myocytes per
2+
Ca dissociates from troponin C. motor unit.
Troponin T and tropomyosin return to their
resting configurations. Tropomyosin covers the How is the force of muscle contraction
myosin binding sites: crossbridges can no longer
form between actin and myosin. The muscle determined?
relaxes and the sarcomere returns to its original Three main factors determine muscle tension:
length. Recruitment of motor units. The force of
contraction of a whole muscle depends on the
Overall, ATP therefore has three crucial roles in number of contracting myocytes. Initially, the
skeletal muscle contraction: smallest motor units are recruited; larger motor
Energizing the myosin head: the hydrolysis of units are additionally recruited as greater muscle
ATP energizes the myosin head, providing the tension is required.
energy for the power stroke. Frequency of action potentials. The duration of
Detachment of crossbridges: following the power the refractory period in nerve and skeletal muscle
stroke, binding of ATP causes dissociation of the is shorter than the time course of both the
myosin head from the actin filament. relaxation of muscle tension and Ca2+ uptake into
241
the SR. Delivery of action potentials at a high

frequency, therefore, results in a progressive Myotonic dystrophy, an autosomal dominant
disorder characterized by an abnormal Na+ or Cl
accumulation of Ca2+ in the cytoplasm, and thus
channel in the muscle sarcolemma. The myocytes
an increased and sustained muscle tension, or
exist in an abnormal hyperexcitable state, result-
tetanus. ing in repetitive action potentials and sustained
Initial muscle length. The tension generated muscle contraction. Patients have a number of
within a single muscle fibre is related to the clinical features, including myotonia (abnormally
number of actin–myosin crossbridges formed (see prolonged muscle contraction after voluntary
Chapter 29 and Figure 29.2): relaxation), muscle wasting, cardiomyopathy and
cardiac conduction defects.
– At the optimal sarcomere length, the myosin
Myotonia congenita, an autosomal dominant
heads have the greatest possible overlap with disorder characterized by an abnormal sarco-
actin filaments. lemma Cl channel. Like myotonic dystrophy,
– Excessive sarcomere stretch can completely the myocytes become hyperexcitable, leading
remove actin–myosin overlap; no crossbridges to myotonia. However, the two conditions differ:
can then form. myotonia congenita is not associated with gen-
– Excessive sarcomere shortening results in eralized muscle weakness, but may cause pala-
filament collisions, leading to an increase in topharyngeal dysfunction, leading to dysphagia.
frictional forces and distortion of the Critical illness myopathy, which may coexist
with critical illness neuropathy (axonal degener-
sarcomere, which precludes further
ation of motor and sensory nerves associated
contraction.
with multiorgan failure and severe sepsis). Critical
Normally, the sarcomeres within skeletal muscles illness myopathy usually presents with diffuse
weakness and failure to wean. The condition is
are arranged near to their optimal length, so the
poorly understood; factors implicated in its
initial muscle length usually contributes little to
development are the administration of cortico-
muscle tension. steroids, non-depolarizing neuromuscular block-
ing agents and aminoglycosides.
Clinical relevance: disorders of skeletal muscle

Skeletal muscle disorder is a broad term encompass-
ing dystrophies, myotonias, myopathies and meta-
Further reading
bolic disorders. The most common are: R. D. Keynes, D. J. Aidley, C. L-H. Huang. Nerve and
Duchenne’s muscular dystrophy (DMD), an Muscle, 4th edition. Cambridge, Cambridge University
Press, 2011.
X-linked recessive disorder that causes a defi-
ciency of dystrophin, a protein that anchors actin C. L.-H. Huang, T. H. Pedersen, J. A. Fraser. Reciprocal
to the sarcolemma. Clinically, patients present dihydropyridine and ryanodine receptor interactions in
between the ages of 3 and 5 with proximal skeletal muscle activation. J Muscle Res Cell Motil 2011;
muscle weakness. The sarcomeres are 32(3): 171–202.
inadequately tethered to the cell membrane S. Marsh, N. Ross, A. Pittard. Neuromuscular disorders
and become replaced by fibrous tissue, which and anaesthesia. Part 1: generic anaesthetic management.
clinically results in pseudohypertrophy. DMD is Contin Educ Anaesth Crit Care Pain 2011; 11(4):
usually fatal by late adolescence from respiratory 115–8.
or cardiac failure. S. Marsh, A. Pittard. Neuromuscular disorders and
Becker’s muscular dystrophy (BMD), also an anaesthesia. Part 2: specific neuromuscular disorders.
X-linked recessive disorder affecting the dystro- Contin Educ Anaesth Crit Care Pain 2011; 11(4): 119–23.
phin protein. In BMD, the amount of dystrophin P. J. Hasall, P. M. Hopkins. Malignant hyperthermia. Contin
protein is reduced and structurally abnormal. Educ Anaesth Crit Care Pain 2003; 3(1): 5–9.
Clinically, BMD is less severe than DMD, present-
ing in adolescence, with death in the fourth or C. F. Louis, E. M. Balog, B. R. Fruen. Malignant
fifth decade. hyperthermia: an inherited disorder of skeletal muscle
Ca2+ regulation. Biosci Rep 2001; 21(2): 155–68.
242
Chapter
Muscle spindles and Golgi tendon organs
52
Electrical activity in type Ia fibres reflects
What is proprioception? changes in both static intrafusal fibre length
Proprioception refers to the detection of stimuli relat- and rate of such change.
ing to body position in space and postural equilib-
– Type II afferent neurons receive inputs from
rium. Mechanoreceptors within muscle, joints and
nuclear chain fibres only. Type II neurons
tendons relay sensory information about joint pos-
relay information only about the static
ition, movement, vibration and pressure to the CNS.
intrafusal fibre length.
The major sensory receptors involved include:
Efferent nerve supply: γ-motor neurons innervate
Muscle spindles, which detect changes in muscle the contractile outer portions of the intrafusal
length. fibres. Each γ-motor neuron innervates a number
Golgi tendon organs, which detect muscle of muscle spindles.
tension.
Voluntary contraction involves the simultaneous
activation of both α- and γ-motor neurons. Contrac-
What is a muscle spindle? tion of the outer portions of the intrafusal fibres
The muscle spindle is an encapsulated structure con- prevents slackening of the spindle, despite the
taining between 3 and 12 specialized intracapsular shortening of the extrafusal fibres. The sensitivity of
muscle fibres, known as intrafusal fibres. Intrafusal the muscle spindles is therefore maintained despite
fibres are arranged in parallel with contractile extra- skeletal muscle shortening and variations in its load.
fusal fibres; stretch of the extrafusal fibres, therefore,
alters the intrafusal fibre length. An intrafusal fibre
consists of a central non-contractile elastic portion
What is a Golgi tendon organ?
with outer contractile ends. Golgi tendon organs are stretch receptors located at
There are two morphologically distinct types of the junction between skeletal muscle and tendon.
intracapsular muscle fibre (Figure 52.1): Golgi tendon organs are arranged in series rather than
in parallel with the extrafusal muscle fibres, and there-
Nuclear bag fibres, in which the nuclei are
fore sense muscle tension. Each Golgi tendon organ is
collected in a central dilated portion of the fibre.
innervated by a single type Ib afferent neuron. They
Nuclear chain fibres, in which the nuclei are
have no motor innervation.
distributed along the fibre without a dilatation.
What is a reflex arc?

A reflex is an automatic, predictable response to a
How are muscle spindles innervated? stimulus that is generally not under voluntary control.
Muscle spindles have their own dedicated afferent and The most simple reflexes involve a sensory receptor,
efferent nerve supply (Figure 52.1): an afferent neuron, one or more synapses, an efferent
Afferent nerve supply: sensory afferent neurons neuron and an effector organ.
wind around the central portion of the intrafusal Reflex arcs may be classified by their number of
fibres. There are two types: synapses:
– Type Ia afferent neurons receive inputs from Monosynaptic reflex arcs. The classical example
both nuclear bag and nuclear chain fibres. is the knee-jerk (see below).
243
Muscle spindle capsule
γ-motor neuron
Type Ia afferent neuron
Type II afferent neuron
Nuclear chain fibre Nuclear bag fibre

Figure 52.1 Basic layout of the muscle spindle.
Polysynaptic reflex arcs. For example, the known as the knee-jerk or patellar reflex. The knee-
withdrawal reflex: when a limb touches a hot jerk is classically regarded as a monosynaptic reflex1
object, the whole limb moves away through the involving (Figure 52.2):
coordinated contraction and relaxation of many Sensory receptors – muscle spindles of the
muscle groups. quadriceps muscle. When the patellar tendon is
struck, the quadriceps muscle is stretched along
Reflex arcs may also be classified by the origin of
with its embedded muscle spindles.
the sensory signal:
An afferent neuron – type Ia afferent neurons
From a peripheral sensory afferent neuron – for from the muscle spindles relay information about
example, the knee-jerk. the degree of muscle stretch to the ventral horn of
From the ANS – for example, the baroreceptor the spinal cord through the dorsal root.
reflex.
A synapse – in the ventral horn of the spinal
From a cranial nerve – for example, the gag reflex. cord, the afferent neuron synapses directly with an
Describe the knee-jerk reflex 1

Note: although classical descriptions refer to the knee-jerk
Striking the patellar tendon with a tendon hammer as a monosynaptic reflex, there is also a relaxation of the
results in a predictable response: contraction of the antagonistic hamstring muscles through a polysynaptic
quadriceps muscle and extension of the knee – this is mechanism.
244
Chapter 52: Muscle spindles and Golgi tendon organs
Figure 52.2 The knee-jerk reflex.

Dorsal root ganglion
Type Ia afferent +
_
n sor
te
Ex
or
ex
Fl
Inhibitory interneuron
Muscle spindle
Tap patellar tendon
α-motor neuron. This synapse is excitatory – The knee-jerk reflex is lost following repeated
(utilizing glutamate as the neurotransmitter). rapid strikes of the patellar tendon.
An efferent neuron – the α-motor neuron leaves – The Jendrassik manoeuvre, where the patient
the ventral horn in a spinal nerve and travels to clenches their teeth or pulls their interlocked
the quadriceps muscle, where it innervates hands apart, results in an increased level of
several muscle fibres. γ-motor neuron firing, thereby increasing the
An effector organ – the quadriceps muscle background stretch in the spindle, which
contracts in response to α-motor neuron results in an accentuation of the knee-jerk
activity. reflex.
As the knee-jerk is a monosynaptic pathway, the

latency period between muscle spindle activation
and quadriceps contraction is relatively short. How is muscle tone controlled?
However, other processes contribute to the knee- Muscle tone reflects a continuous, basal level of
jerk reflex: muscle contraction. Muscle tone is controlled by des-
The type Ia afferent neurons branch within the cending extrapyramidal supraspinal neurons, which
spinal cord, synapsing through interneurons with innervate the γ-motor neurons of the muscle spindles.
α-motor neurons of antagonistic muscles, which γ-motor neuron activation leads to:
in this case would oppose knee flexion; for Shortening of the contractile ends of the intrafusal
example, the hamstrings. This synapse is fibres, which in turn stretches the central non-
inhibitory, utilizing glycine as neurotransmitter. contractile portion of the fibre, increasing the level of
Inhibition of antagonistic muscles allows the action potentials firing in the type Ia afferent fibres.
quadriceps muscle to contract unopposed Type Ia afferent activity in turn activates α-motor
(Figure 52.2). neurons through the monosynaptic reflex arc,
Additionally, descending inputs from the brain causing contraction of the extrafusal fibres,
may modulate the intensity of reflexes: thereby increasing the tone of the skeletal muscle.
245
Clinical relevance: spinal shock

known as muscle spasticity. The exact mechanism
As discussed above, muscle tone is primarily behind the increase in γ-motor neuron activity is
determined by extrapyramidal supraspinal neurons. not known.
In acute spinal cord injury, these supraspinal
pathways are interrupted. The γ-motor neurons
become inactive and the muscles become hypotonic
or flaccid, which is termed spinal shock. Further reading
After around 2 weeks, the activity in the U. Proske, S. C. Gandevia. The proprioceptive senses: their
γ-motor neurons becomes excessive, which results roles in signaling body shape, body position and
in increased muscle tone. This hypertonicity is movement, and muscle force. Physiol Rev 2012; 92(4):
1651–97.
246
Chapter
Smooth muscle
53
Where is smooth muscle found Multi-unit smooth muscle is found in the large
elastic arteries, the trachea and the iris. These
in the body? smooth muscle cells are not connected by gap
Smooth muscle is a type of involuntary muscle, junctions. A single autonomic nerve branches to
innervated by the ANS. In contrast to skeletal and innervate many smooth muscle cells, in a similar
cardiac muscle, smooth muscle is non-striated. way to the motor unit in skeletal muscle.
Smooth muscle is found within the walls of hollow
organs and tubes. The following are important
examples: How do smooth muscle cells differ from
The uterus is primarily composed of smooth skeletal muscle cells?
muscle. Uterine smooth muscle has an obvious Smooth muscle and skeletal muscle have a number
function during labour. Smooth muscle of anatomical and functional differences:
contraction is also essential in the immediate
Size: skeletal muscle cells are large, cylindrical
post-partum period; uterine atony is a common cells that span the entire length of the
cause of post-partum haemorrhage. muscle. Smooth muscle cells are much smaller,
The arteries contain layers of vascular smooth spindle-shaped cells that are arranged in sheets.
muscle within their tunica media. Contraction of
Nuclei: skeletal muscle cells are multi-nucleate,
vascular smooth muscle reduces the vessel radius, whilst smooth muscle cells have only one nucleus.
increasing its resistance to blood flow.
Sarcomeres: like skeletal muscle, the primary
The respiratory tract, where bronchiolar smooth function of smooth muscle is contraction. In both
muscle contraction results in skeletal and smooth muscle, actin and myosin
bronchoconstriction. are the main contractile proteins: actin is arranged
The GI tract – coordinated contraction of in thin filaments and myosin in thick filaments.
longitudinal and circular smooth muscle However, in smooth muscle, the thick and
(segmentation and peristalsis) in the intestinal thin filaments are not organized into sarcomeres –
wall mixes and propels the luminal contents smooth muscle is therefore not striated.
along the gut.
Troponin complex: whilst tropomyosin is present
in both smooth and skeletal muscle, troponin is
There are two types of smooth muscle: absent in smooth muscle.
T-tubules: the tube-like invaginations of the
what are they? skeletal muscle sarcolemma are absent in smooth
Smooth muscle is classified into two types: muscle. Instead, smooth muscle has shallower,
Single-unit smooth muscle is found in the viscera rudimentary invaginations known as caveolae,
and the blood vessels (except the large elastic which increase the surface area to volume ratio
arteries) as sheets of smooth muscle cells forming of the muscle cell.
2+
syncytial units. The ANS innervates a single cell The SR: an intracellular store of Ca . Despite
within the sheet, with action potentials rapidly the important role of the SR in skeletal muscle
propagated to neighbouring cells through gap excitation–contraction coupling (see Chapter 51),
junctions, leading to synchronous contraction. the SR is poorly developed in smooth muscle.
247
Describe the how smooth muscle junctions, but are not relayed directly to the
cell interior. Caveolae increase the surface area
is excited to volume ratio, which facilitates Ca2+ entry.
Smooth muscle cells receive both excitatory and 2+
Ca : like skeletal muscle, an increase in
inhibitory signals: excitatory signals depolarize whilst intracellular Ca2+ concentration triggers
inhibitory signals hyperpolarize the smooth muscle muscle contraction. But smooth muscle cells
cell membrane. If the net effect of these signals is lack T-tubules and have an absent or poorly
depolarization to threshold potential, contraction developed SR. Smooth muscle cells have various
occurs. Like skeletal muscle, multi-unit smooth mechanisms to increase Ca2+ influx:
muscle can only be stimulated by nerve impulses.
– voltage-gated Ca2+ channels
However, single-unit smooth muscle cells may be
stimulated in a number of ways: – ligand-gated Ca2+ channels
– stretch-responsive Ca2+ channels.
Autonomic neuronal input. Single-unit smooth
muscle is often innervated by two neurons: Smooth muscle cells with a functional SR augment
sympathetic (releasing noradrenaline as the the increase in sarcoplasmic Ca2+ by releasing
neurotransmitter) and parasympathetic (releasing further Ca2+.
ACh). These two autonomic inputs are usually Calmodulin: as discussed above, the thin
antagonistic: one tends to excite whilst the other filaments of smooth muscle do not contain
tends to inhibit the smooth muscle cell. troponin. Instead, calmodulin regulates smooth
Hormones and other circulating molecules. muscle contraction. When the sarcoplasmic Ca2+
Smooth muscle cells may be excited or inhibited concentration rises, Ca2+ binds to calmodulin.
by circulating molecules, including O2, CO2, NO, The resulting Ca2+–calmodulin complex then
adrenaline, noradrenaline, histamine, activates smooth muscle contraction through
prostaglandins and serotonin. three pathways:
Stretch of the smooth muscle sheets triggers
smooth muscle contraction. In the arterial system, – Myosin light-chain kinase (MLCK). The
this is referred to as the ‘myogenic response’, sarcoplasmic enzyme MLCK is activated
responsible for the autoregulation of blood flow by the Ca2+–calmodulin complex. MLCK
(see Chapter 32). In the GI tract, peristalsis is phosphorylates the myosin light-chains,
triggered when the luminal contents stretch the allowing myosin to form crossbridges with
smooth muscle of the gut wall. actin filaments.
Pacemaker activity. Like the heart, the GI tract – Caldesmon. In skeletal muscle, the troponin
contains pacemaker cells (the interstitial cells of complex positions tropomyosin over the
Cajal) whose cell membrane spontaneously myosin binding site, preventing actin–myosin
depolarizes, triggering an action potential. The interaction. Troponin is absent in smooth
spontaneous oscillation in the pacemaker cell muscle – this role is instead played by a
membrane potential is called the ‘slow wave’. The protein called caldesmon. The Ca2+–
frequency of slow waves differs throughout the calmodulin complex causes a conformational
GI tract. For example, around 12 action potentials change in caldesmon that leads to
are generated per minute in the duodenum, tropomyosin movement, unblocking the
compared with only three per minute in the colon. myosin binding site and permitting
actomyosin crossbridge cycling.
– Calponin. This protein inhibits the ATPase
Describe how excitation–contraction activity of the myosin head. It may be activated
either by the Ca2+–calmodulin complex or
coupling occurs in smooth muscle directly by Ca2+.
Smooth muscle excitation–contraction coupling
differs from skeletal muscle in several respects: There are thus more points of regulation in smooth
Lack of T-tubules: action potentials are muscle contraction than in skeletal muscle
propagated rapidly between cells through gap contraction.
248
Chapter 53: Smooth muscle
How does smooth muscle contract? How is smooth muscle adapted

The mechanism of contraction is similar to that for its function?
of skeletal muscle (Chapter 51), involving ATP
Compared with skeletal muscle, smooth muscle must
binding to the myosin head, ATP hydrolysis, the
be energy efficient and often needs to maintain ten-
‘power stroke’, the release of ADP and inorganic
sion for long durations. This is achieved in two ways:
phosphate followed by binding of a new ATP
molecule. Slow contraction consumes less energy, as the
The rate of smooth muscle contraction is much power of contraction is equal to the force
slower than that of skeletal muscle: multiplied by the velocity.
Latch bridge formation. If myosin is
Smooth muscle action potentials are typically
dephosphorylated whilst still attached to actin, the
slower and more prolonged than those of skeletal
crossbridge remains in place. This is known as
muscle: smooth muscle sarcoplasmic
latch bridge formation. The tension in smooth
Ca2+ concentration increases and decreases slowly.
muscle, therefore, remains high without further
Enzymatic phosphorylation is required before consumption of ATP.
myosin can bind to actin.
Crossbridge cycling is also much slower than that Smooth muscle is therefore well suited to contract for
of skeletal muscle. sustained periods of time, whilst using ATP economically.
Smooth muscle also relaxes much more slowly than Further reading
skeletal muscle, due to slower Ca2+ removal from the R. D. Keynes, D. J. Aidley, C. L-H. Huang. Nerve and
sarcoplasm in the absence of an efficient SR. Overall, Muscle, 4th edition. Cambridge, Cambridge University
contraction occurs up to 10 times slower and lasts Press, 2011.
up to 30 times longer in smooth muscle, but the K. M. Sanders. Regulation of smooth muscle excitation and
muscle tension generated is equal to that of skeletal contraction. Neurogastroneterol Motil 2008; 20(Suppl. 1):
muscle. 39–53.
249
Chapter
Cardiac muscle
54
Describe the structural features of What is the resting membrane potential
cardiac muscle in cardiac muscle cells?
The primary function of the heart is ejection of blood Like the neuronal RMP discussed in Chapter 48,
into the vascular system. However, not all cardiac the cardiac myocyte RMP is due to:
myocytes are contractile: A large difference between intracellular and
Atrial and ventricular myocardial cells, which extracellular K+ and Na+ ion concentrations.
perform mechanical work, are capable of both The resting cell membrane having a higher
contraction and conduction of excitation. permeability to K+ than to Na+.
Pacemaker and conducting cells are excitable but – In neurons, K+ permeability is predominantly
non-contractile: due to membrane K+ leak channels (two-
– Pacemaker cells, found in the SA and AV pore-domain K+ channels), which are
nodes, generate spontaneous cardiac action constitutively open.
potentials. – In cardiac myocytes, K+ permeability is due to the
– Conducting cells, known as Purkinje fibres, presence of inward rectifying K+ channels (Kir
spread the cardiac action potentials around channels), which are open at negative membrane
the ventricles. potentials, but close with depolarization.
+
K diffuses down its electrochemical gradient,
Cardiac myocytes share a number of structural resulting in the cell interior becoming negatively
features with skeletal muscle: charged with respect to the cell exterior.
A striated appearance, owing to organized
rows of thick and thin filaments within The RMP varies depending on the cardiac region:
the sarcoplasm. SA node, approximately 50 mV, but unstable;
A sarcotubular system – ventricular atrial myocyte, 70 mV;
myocytes have both T-tubules and SR, Purkinje fibre, 90 mV;
although they are often less developed ventricular myocyte, 90 mV.
than in skeletal muscle.
However, cardiac myocytes also share a number of How do cardiac and nerve action
similarities with smooth muscle: potentials differ?
Involuntary control. Like smooth muscle, the There are a number of important differences between
ANS and endocrine axes modulate the function nerve and cardiac action potentials:
of cardiac myocytes. RMP. As discussed above, the RMP of cardiac
Cells connected by gap junctions. These myocytes varies with cardiac region. Ventricular
low-resistance electrical connections allow myocytes and Purkinje fibres have an RMP that
the rapid conduction of action potentials is more negative ( 90 mV) than the neuronal
throughout the myocardium. Thus, the RMP ( 70 mV).
cardiac myocytes contract as a single unit, Duration. The nerve action potential is very short
or functional syncytium. (1–2 ms), whilst the cardiac action potential has
250
Chapter 54: Cardiac muscle
Voltage-gated Na+ channels close

Fast voltage-gated K+ channels transiently open
L-type Ca2+ channels open

+30 Fast voltage-gated K+ channels close
+20 Slow delayed rectifier K+ channels open
1
+10
2 L-type Ca2+ channels close
–10 Rapid delayed rectifier K+ channels open
–30 0
Fast voltage-gated Na+ channels open 3
Kir channels close
–50
Kir channels reopen
Threshold potential
–65
–70
Resting membrane potential 4

4
–90
–110
0 100 200 300 400
Time (ms)
Figure 54.1 The phases of the cardiac action potential.
a much longer duration, depending on Threshold potential is reached by the

myocardial cell type (200–400 ms in depolarizing action of local currents conducted
ventricular myocytes and Purkinje fibres). through gap junctions from neighbouring
Shape. Morphologically, the nerve action myocytes.
potential is a single spike, whilst the cardiac action – Stimuli that exceed threshold potential
potential varies from having a triangular trigger the opening of fast voltage-gated Na+
waveform (atrial muscle) to having a long channels, thereby increasing membrane Na+
plateau phase (ventricular myocytes and permeability.
Purkinje fibres). – The resultant increased Na+ influx
2+ 2+
The role of Ca . In cardiac cells, Ca influx causes a further membrane depolarization,
prolongs the duration of the action potential, which triggers further opening of voltage-gated
resulting in the characteristic plateau phase of Na+ channels; a positive feedback loop is created.
ventricular myocytes. Ca2+ plays no role in the – The end result is rapid depolarization to
nerve action potential. approximately +20 mV.
Phase 1, early rapid repolarization. Following
the membrane depolarization of phase 0:
Outline the phases of the cardiac
– Voltage-gated Na+ channels inactivate,
action potential resulting in a rapid decrease in the membrane
The cardiac action potential has five phases Na+ permeability.
(Figure 54.1): – Fast voltage-gated K+ channels transiently
Phase 0, rapid depolarization. The threshold open, resulting in a transient outward K+
potential for cardiac myocytes is around 65 mV. current Ito. (Figure 54.2).
251
Figure 54.2 Changes in membrane

Membrane potential 100 permeability to ions during the cardiac
+30 action potential.
Relative membrane permeability

+10
Na+
–10 Ca2+ K+ 10
–30
–50
1
–70
–90
0.1
–110
0 100 200 300 400
Time (ms)
The overall effect is a brief phase of repolarization. Phase 4, electrical diastole. During this phase, the
Phase 2, plateau. Membrane depolarization membrane is maintained at RMP due to K+ efflux
is maintained for a prolonged period through Kir channels. There is also a correction
(around 200 ms) through a balance of of the small net fluxes of Na+, K+ and Ca2+ that
inward and outward currents: took place during the action potential through
– Inward current: voltage-gated L-type Ca2+ Na+/K+-ATPase and Na+/Ca2+-exchanger activity.
channels slowly open following In summary (Figure 54.2):
membrane depolarization. Ca2+ ions flow Phase 0 – a brief, rapid increase in
down their concentration gradient from Na+ conductance results in rapid depolarization.
the ECF, where the ionized Ca2+ concentration +
Phase 1 – K conductance increases transiently.
is around 1.2 mmol/L, to the ICF, which has a +
Phase 2 – the increase in Ca conductance results in
considerably lower ionized Ca2+ 2+
an inward Ca current, which opposes the tendency
concentration (around 500 nmol/L). of the outward K+ current to restore the membrane
– Outward current: as discussed above, Kir potential, resulting in the action potential plateau.
channels are predominantly responsible for 2+
Phase 3 – a decrease in Ca conductance and a
generating the RMP, but close following +
progressive increase in K conductance results
membrane depolarization. At the same time, in membrane repolarization.
membrane depolarization causes slow delayed 2+ + +
Phase 4 – Ca , Na and K conductance have
rectifier K+ channels to open. returned to resting levels with K+ conductance
Overall, there is a net inward current that exceeding Ca2+ and Na+ conductance, resulting in
maintains the plateau. the RMP.
Phase 3, repolarization. A gradual inactivation of At an HR of 75 bpm, the ventricular action potential
voltage-gated Ca2+ channels reduces the inward lasts for around 250 ms:
Ca2+ current. Additional outward K+ currents1
Phases 0 and 1 have a total duration of 1–2 ms,
return the membrane to its RMP (Figure 54.2). similar to that of the nerve action potential.
1
Rapid and slow delayed rectifier K+ channels produce
outward K+ current, IKr and IKs respectively. As the cell Kir channels reopen, which further increases membrane
membrane develops an increasingly negative potential, K+ permeability and thus K+ efflux.
252
Phase 2 lasts for around 200 ms, and corresponds the fast voltage-gated Na+ channels
to the ST segment of the ECG. become inactivated. Inactivated Na+
Phase 3 takes around 50 ms, and corresponds channels cannot return to their resting
to the T wave of the ECG. state until membrane repolarization has
occurred. The prolonged plateau phase of
The duration of the action potential decreases with the cardiac action potential means that the
increasing HR: at a rate of 200 bpm, the action poten- ARP is 200 ms, considerably longer than
tial lasts for only 150 ms. that of the nerve action potential. The long
ARP of cardiac muscle means that further
What are the refractory periods of the action potentials cannot be triggered until
muscle contraction is nearly complete
cardiac action potential? (Figure 54.4). A short ARP could potentially lead
In common with the nerve action potential (Chap- to tetany of the cardiac muscle, which would be
ter 49), the cardiac action potential has two refractory incompatible with diastolic filling.
periods (Figure 54.3): The RRP, when a further action potential can
The ARP, where a further action potential cannot be initiated, but it requires a greater stimulus
be initiated, no matter how large a stimulus is than normal.
applied. Following membrane depolarization,
Clinical relevance: antiarrhythmic drugs

The Singh–Vaughan Williams classification categorizes antiarrhythmic drugs into four classes on the basis of their
ionic mechanism. Later, class V was added to include antiarrhythmic drugs with mechanisms dissimilar to the other
four classes. However, few antiarrhythmic drugs are specific to one class. For example, flecainide (class IC) also
blocks K+ channels, amiodarone (class III) also blocks Na+ and Ca2+ channels, and sotalol (class III) is also a β-blocker.
It is also important to note that relatively few drugs are effective in the treatment of VF; cardioversion is therefore
indicated.
Class Mechanism Examples Use Physiological effect

+
I Na channel # membrane excitability and conduction
blockers velocity
A Intermediate Quinidine, AF, SVT " APD and ERP
kinetics procainamide
B Fast kinetics Lignocaine Digoxin toxicity # APD and ERP
(VF)
C Slow kinetics Flecainide AF, SVT Normal APD
II β-blockers Propranolol VT, AF, SVT # Sympathetic drive and AVN conduction
+
III K channel Amiodarone, sotalol VT, AF, SVT, (VF) " APD and ERP
blockers
IV Ca2+ channel Verapamil AF, SVT # AVN conduction without affecting
blockers sympathetic drive
V Other Adenosine, digoxin, SVT # AVN conduction
MgSO4 AF # AVN conduction and HR
Tdp, AF # Ca2+ influx and EADs
VT: ventricular tachycardia; AF: atrial fibrillation; SVT: supraventricular tachycardia; VF: ventricular fibrillation;
Tdp: torsades de pointes (polymorphic VT); AVN: AV node; APD: action potential duration; ERP: effective refractory
period; EADs: early afterdepolarizations.
253
Figure 54.3 The absolute and relative

refractory periods of the cardiac action
Absolute refractory period Relative
+30 potential.
refractory
+20 1 period
+10 2
–10
–30 0
3
–50
–70
4 4
–90
–110
0 100 200 300 400
Time (ms)
Action potential Figure 54.4 Relationship between the

Muscle contraction cardiac action potential and the
+30 contractile response of cardiac muscle.
80
Percentage of maximum tension (%)
+20
+10
–10 60
–30
40
–50
–70
20
–90
–110 0
0 100 200 300 400
Time (ms)
Where are action potentials generated The SA node, located at the junction
between the SVC and right atrium.
in the heart? The SA node generates action potentials
Pacemaker cells are specialized cardiac myocytes at a higher frequency than the other
whose spontaneous activity results in the regular gen- pacemaker cells, and therefore normally
eration of action potentials. The rate at which action sets the HR.
potentials are produced by the pacemaker cells deter- The AV node, located between the atrial septum
mines the frequency of cardiac contraction. Several and tricuspid valve, just above the opening of the
sites within the heart may act as pacemakers: coronary sinus.
254
HCN and Ca2+ channels close Figure 54.5 The pacemaker action
Voltage-gated K+ channels open potential.
+20
e
Re p
0
trok
HCN channels open 0
olar
Ups
izat
–20 T-type Ca2+
ion
channels open
Threshold potential
–40
tial’ ial’
en ent
4 pot L-type Ca2+ 4 pot
–60 ker ker
c e ma channels open
ce ma
`Pa `P a
–80
0 100 200 300 400 500
Time (ms)
The bundle of His, located within the Following an action potential, membrane
interventricular septum. hyperpolarization opens HCN channels, allowing
The Purkinje fibres, a specialized network of Na+ and K+ to diffuse along their electrochemical
cardiac myocytes that conduct electrical gradients. Overall, Na+ influx slightly exceeds K+
impulses to the ventricles. efflux, resulting in a slow depolarization of
the cell membrane from its initial voltage of
60 mV.
What is meant by the term ‘pacemaker When the membrane potential reaches
approximately 50 mV, T-type (transient) Ca2+
potential’? channels open in the pacemaker cell membrane
The pacemaker potential refers to the spontaneous resulting in inward Ca2+ current from ECF,
decay of the membrane potential of a pacemaker cell, where Ca2+ concentration of ionized Ca2+ is
from a membrane potential of approximately 60 mV approximately 1.2 mmol/L, to the ICF,
(in the SA node) to threshold potential (approximately where the Ca2+ concentration is ~500 nmol/L.
40 mV in the SA node), thereby initiating an action The influx of Ca2+ ions enhances membrane
potential. The rate at which the pacemaker potential to depolarization.
decays to threshold determines the HR; this property of The action of both is to cause a spontaneous
the pacemaker potential is called automaticity. migration of the membrane potential to the
Historically, the pacemaker potential was called threshold potential of 40 mV.
the ‘funny’ current If. It is now known that the slow
depolarization of the membrane potential is due to
the intracellular movement of Na+ ions exceeding the
extracellular movement of K+ ions (see below). How are action potentials conducted
through the heart?
An efficient conducting system is essential to ensure
Describe the action of the pacemaker the synchronous contraction of the ventricular myo-
currents cytes. Action potentials generated in the SA node are
The action potential in pacemaker cells relayed as follows:
(Figure 54.5) includes contributions from The internodal pathways. Action potentials
hyperpolarization-activated cyclic nucleotide- are relayed from the SA node to the AV
gated (HCN) channels. These channels are node through three specific internodal
permeable to both Na+ and K+. pathways:
255
– Anterior, the Bachmann pathway, which release, rather than as a result of a physical connection
also relays action potentials to the left between the T-tubule, the RyR and the DHPR.
atrium via the Bachmann bundle. The process of excitation–contraction coupling in
– Middle, the Wenckebach pathway. cardiac muscle is as follows:
– Posterior, the Thorel pathway. Ventricular and atrial myocytes differ in the
The AV node is the only means of transmitting anatomy of their cell membranes:
action potentials between the atria and the – Ventricular myocytes have T-tubules, which
ventricles; elsewhere, the junction between the contain L-type Ca2+ channels (that is, DHPRs).
chambers is insulated by the annulus fibrosus.2 The The T-tubules conduct action potentials deep
AV node delays transmission of the action potential into the myocyte interior.
between atria and ventricles, allowing the atria – The atrial myocyte cell membrane contains
time to contract. AV nodal delay is a major L-type Ca2+ channels. The surface area of
component of the PR interval of the ECG. the cell membrane is increased by small
The bundle of His. Shortly after leaving the AV invaginations called caveolae.
node, the bundle of His divides into the right and In both cell types, membrane depolarization
left bundle branches. The left bundle branch causes L-type Ca2+ channels to open. Ca2+ diffuses
divides again into the left anterior and left through the open Ca2+ channels from the ECF to
posterior fascicles. the sarcoplasm.
The Purkinje fibres. The branches of the Like skeletal muscle, the SR of cardiac muscle
bundle of His divide to form the Purkinje contain RyRs. Ca2+ influx opens the RyR, causing
fibres, which rapidly conduct action the SR to release Ca2+. This process is known as
potentials throughout the right and left Ca2+-induced Ca2+ release.
ventricles, thereby synchronizing ventricular
activation. The Purkinje fibres terminate just Therefore, excitation–contraction coupling in cardiac
below the endocardium; thereafter, action muscle involves both DHPRs and RyRs, but unlike in
potential conduction is performed by the skeletal muscle there is no physical connection
cardiac myocytes themselves. between the two.
The cardiac myocytes have both mechanical
and electrical connections. The myocytes are
connected end to end by intercalated discs, which How does cardiac muscle contract?
allow them to contract as a single unit or functional Cardiac muscle contraction starts shortly after
syncytium. Adjacent to the intercalated discs are depolarization, and continues until about 50 ms after
gap junctions, which allow the action potential repolarization is complete; that is, contraction has a
to pass from one myocyte to the next. duration of around 300 ms (Figure 54.4). Once Ca2+
has been released from the SR, activation of cross-
bridge cycling follows a similar ATP-dependent
Describe the process of excitation– mechanism to that of skeletal muscle (see
contraction coupling in a cardiac Chapter 51):
myocyte 2+
Binding of sarcoplasmic Ca to troponin
Excitation–contraction coupling in cardiac muscle C causes tropomyosin to roll deeper into the
is slightly different to that of skeletal muscle (see groove between actin filaments.
Chapter 51). In cardiac muscle, intracellular Ca2+ con- This conformation change leads to the
centration is increased through Ca2+-induced Ca2+ uncovering of myosin binding sites on the
actin filament, allowing myosin to form
crossbridges with actin.
2
The existence of congenital accessory conduction The myosin head pulls the actin filament towards
pathways between the atria and ventricles (collectively
the centre of the sarcomere in the power stroke.
known as the ‘bundle of Kent’) can result in action
potential conduction bypassing the AV node, with Crossbridge cycling continues until the
arrhythmic consequences referred to as the Wolff– cytoplasmic Ca2+ concentration decreases during
Parkinson–White syndrome. repolarization.
256
How is cardiac contraction terminated? – Negative chronotropy (decreased HR). The

intrinsic rate of the SA node is 90–120 bpm.
Crossbridge cycling is terminated by actively remov-
At rest, there is continuous parasympathetic
ing Ca2+ from the cell. As the sarcoplasmic concen-
nervous discharge at the SA node, known as
tration of Ca2+ decreases, Ca2+ dissociates from
vagal tone, which decreases the resting HR to
troponin C. Tropomyosin re-covers the actin binding
60–80 bpm. The mechanism behind this is:
site; myosin can no longer bind to actin, and relax-
ation occurs. ▪ ACh is released by the pre-synaptic neuron
In diastole, the intracellular Ca2+ concentration is (parasympathetic post-ganglionic neuron),
extremely low (around 0.1 μmol/L). This is achieved and binds to an inhibitory G protein-
through three mechanisms: coupled receptor on the post-synaptic
2+
The plasma membrane Ca -ATPase pump membrane.
(PMCA), which uses energy (from ATP ▪ The associated G protein becomes
hydrolysis) to actively remove Ca2+ ions from the activated, triggering the division of
cell (i.e. primary active transport). its Gαi and Gβγ subunits.
+ 2+
The Na /Ca -exchanger (NCX), which removes ▪ The Gαi subunit inhibits the intracellular
2+
one Ca ion from the cell in exchange for the enzyme adenylate cyclase, which leads to a
influx of three Na+ ions. The efflux of Ca2+ occurs decrease in the intracellular concentration
against its concentration gradient and is driven of cyclic AMP (cAMP). HCN channels, as
by the low intracellular concentration of Na+, the name suggests, are activated by cyclic
itself maintained by the Na+/K+-ATPase pump nucleotides. Therefore, decreased cAMP
(i.e. secondary active transport). leads to decreased Na+ influx, and thus a
2+
Sarcoplasmic/ER Ca -ATPase pump (SERCA), reduction in If, resulting in a reduced HR
which uses energy (from ATP hydrolysis) to (Figure 54.6a).
sequester Ca2+ in the SR. ▪ The Gβγ subunit activates G protein-
coupled inwardly rectifying K+ channels.
Diastolic relaxation is therefore an ATP-dependent
The resulting additional K+ efflux causes
process, as ATP is required to actively remove Ca2+
membrane hyperpolarization
from the sarcoplasm by either primary or secondary
(Figure 54.6a) that counteracts the
active transport, or by sequestration in the SR.
pacemaker current, thereby decreasing HR.
– Decreased conduction velocity through the AV

How does the autonomic nervous node. AV nodal delay is increased. Sometimes,
marked parasympathetic nervous activity may
system influence the heart? prevent transmission of electrical impulses
The HCN channels give the heart the property of through the AV node altogether. If this occurs,
automaticity: action potentials can be generated the pacemaker cells within the bundle of His
independently of the nervous system. However, the and Purkinje system generate action potentials
ANS and endocrine axes can modulate both the rate at the much slower rate of 15–40 bpm – this is
(chronotropic effects) and force (inotropic effects) referred to as a ventricular escape rhythm.
of contraction: The sympathetic nervous system. The heart is
Parasympathetic nervous system. The right innervated by post-ganglionic sympathetic fibres
vagus nerve supplies the SA node, whilst the from the upper thoracic sympathetic chain
left vagus nerve supplies the AV node. Atrial (mainly T1–T3). Increased sympathetic
muscle is also innervated by parasympathetic nervous system activity causes release of
neurons, but ventricular muscle is not (and is noradrenaline at sympathetic nerve endings
therefore unaffected). Parasympathetic nervous and release of adrenaline from the adrenal
system activity, therefore, affects HR and medulla. Both noradrenaline and adrenaline
conduction, but has little effect on the force of act at the cardiac β1 adrenergic receptor, a
contraction: G protein-coupled receptor whose activation
257
increases the intracellular concentrations of cAMP

and protein kinase A, resulting in: – Depressive phase. This is followed by blockade
of Na+ channels in excitatory interneurons,
– Positive chronotropy – in the SA node, resulting in global CNS depression: coma,
cAMP opens HCN channels, which respiratory depression.
increases Na+ influx, thereby increasing Cardiac toxicity. In addition to Na+ channels,
the gradient of the pacemaker potential local anaesthetics block K+ and Ca2+ channels in
(Figure 54.6b). Threshold potential the heart. Initial signs of cardiotoxicity are those
is reached more quickly, which increases of direct myocardial depression and bradycardia;
higher plasma concentration may lead to refrac-
the HR.
tory VF. Important points to note are:
– Positive inotropy (increased myocardial – Ion channels are stereospecific – one enantiomer
contractility) – in the cardiac myocytes, of local anaesthetic has much greater toxicity
protein kinase A phosphorylates L-type Ca2+ than the other enantiomer. For example,
channels, which increases Ca2+ influx during levobupivacaine, the pure S-enantiomer of
the plateau phase. Intracellular Ca2+ bupivacaine, has a lower cardiac and CNS
concentration rises, which increases the toxicity than racemic bupivacaine.
strength of contraction. – Bupivacaine is particularly cardiotoxic when
– Shorter action potential duration – protein compared with other local anaesthetics. In
addition, signs of cardiac toxicity may occur
kinase A increases the opening of
before CNS toxicity; that is, there is potentially
delayed rectifier K+ channels that open during no ‘warning’ before the onset of cardiovascu-
phase 3 of the cardiac action potential, lar collapse. This marked cardiotoxicity is
shortening the repolarization time. thought to be due to the high affinity of
– Increased rate of transmission through the bupivacaine for Na+ channels in the heart, and
AV node – the opposite effect of due to the fact that bupivacaine also binds Ca2+
parasympathetic activity. channels, inhibiting Ca2+ release from the SR.
In addition to supportive management, a specific

treatment of local anaesthetic toxicity is administra-
Clinical relevance: local anaesthetic toxicity tion of Intralipid®. Intralipid is thought to act as a
‘lipid sink’, drawing the lipophilic bupivacaine out of
The potential for toxicity when using local anaesthet-
the plasma and away from cardiac ion channels
ics has been known for more than 100 years. It is
(though this mechanism has recently been disputed –
hardly surprising:
see Further reading).
Local anaesthetics are extremely effective at
blocking the fast voltage-gated Na+ channels of
peripheral nerves.
+
The same fast voltage-gated Na channels are
also found in CNS neurons and cardiac myocytes.
Clinical relevance: heart transplant
Clinical signs and symptoms of local anaesthetic A transplanted donor heart is denervated – it has
toxicity fall into three categories: neither sympathetic nor parasympathetic innerv-
Immunological. Local anaesthetics can cause ation. In the resting state, this is relatively well toler-
allergy, especially ester-based local anaesthetics ated owing to automaticity and intrinsic regulation
whose metabolite para-aminobenzoic acid is via Starlings law. However, there are a number of
especially allergenic. Allergy may be local physiological consequences:
(urticaria) or systemic (anaphylaxis). Loss of resting vagal tone, resulting in a resting
CNS toxicity. High plasma concentrations of HR of around 100 bpm.
local anaesthetic may result in CNS toxicity, Loss of cardiovascular reflexes – the usual car-
which occurs in two phases: diovascular responses to, for example, laryngo-
– Excitatory phase. Initially, blockade of Na+ scopy and peritoneal traction are lost. The fall in
channels in inhibitory interneurons causes SVR caused by anaesthetic drugs is poorly toler-
excitatory phenomena: tinnitus, circumoral ated, with the potential for dramatic hypotension
parasthesias, seizures. if cardiac preload is not maintained.
258
(a) Parasympathetic stimulation – HR decreases
Baseline action potential Action potential following parasympathetic activity
+20
0
–20
–40
–60
Hyperpolarization of
membrane potential
–80
0 0.5 1.0 1.5 2.0 2.5 3.0
Time (s)
(b) Sympathetic stimulation – HR increases
Baseline action potential Action potential following sympathetic activity
+20
0
–20
–40
–60
Increased gradient of pacemaker potential

–80
0 0.5 1.0 1.5 2.0 2.5 3.0
Time (s)
Figure 54.6 The effects of (a) parasympathetic and (b) sympathetic nervous system activity on the pacemaker action potential.
Blunted cardiovascular response to exercise – to respond to the circulating catecholamines

the HR gradually increases with exercise, followed released from the adrenal medulla. There may also
by a gradual decrease with rest (the normal be a contribution from the Bainbridge reflex.
response involves rapid changes in HR – see
Chapter 40). This is because β1 adrenergic Heart transplant also has pharmacological implica-
receptors on the transplanted heart are still able tions, including:
259
M. E. Stone, B. Salter, A. Fischer. Perioperative

Atropine and glycopyrrolate have no
management of patients with cardiac implantable
effect – these drugs are competitive electronic devices. Br J Anaesth 2011; 107(Suppl. 1):
antagonists of the muscarinic M2 ACh i16–26.
receptor. The transplanted heart has no
parasympathetic innervation, and therefore R. D. Keynes, D. J. Aidley, C. L-H. Huang. Nerve and
no ACh to antagonize. Instead, isoprenaline Muscle, 4th edition. Cambridge, Cambridge University
Press, 2011.
may be used to increase HR in the
transplanted heart. AAGBI Safety Guideline. Management of Severe Local
Adrenaline and noradrenaline have an Anaesthetic Toxicity, Association of Anaesthetists of
increased effect – sympathetic Great Britain and Ireland, 2010; www.aagbi.org/sites/
denervation causes upregulation of β1 adrenergic default/files/la_toxicity_2010_0.pdf.
receptors. Therefore, the transplanted heart J. Pinnell, S. Turner, S. Howell. Cardiac muscle physiology.
has an exaggerated response to these Contin Educ Anaesth Crit Care Pain 2007; 7(3): 85–8.
catecholamines. J. M. Dippenaar. Local anaesthetic toxicity. S Afr J Anaesth
Analges 2007; 13(3): 23–8.
S. Rohr. Role of gap junctions in the propagation of the
Further reading cardiac action potential. Cardiovasc Res 2004; 62(2):
E. Litonius, P. Tarkkila, P. J. Neuvonen, et al. Effect of 309–22.
intravenous lipid emulsion on bupivacaine plasma N. J. Morgan-Hughes, G. Hood. Anaesthesia for a patient
concentration in humans. Anaesthesia 2012; 67(6): with a cardiac transplant. Contin Educ Anaesth Crit Care
600–5. Pain 2002; 2(3): 74–8.
260
Chapter
The electrocardiogram
55
The ECG represents a summation of electrical activity PR interval ST segment T wave
in the heart, derived from electrode recordings on the
body surface (i.e. extracellular). Although a detailed
description of ECG analysis for detecting cardiac
pathology is beyond the scope of this book, this chap-
ter provides a simplified outline of the electrical basis
of the normal ECG.
Describe the normal electrocardiogram

The normal ECG, as recorded using lead II, is shown
in Figure 55.1. HR may be calculated from the ECG
most simply by dividing 300 by the number of large
squares between adjacent QRS complexes. For
example, if there are five large squares between adja- P wave
cent QRS complexes, the HR is 60 bpm (note: this QT interval
shortcut is only valid for regular heart rhythms). QRS complex
The P wave represents atrial depolarization. The Figure 55.1 The normal ECG.
smaller muscle mass of the atria compared with
the ventricles results in the P wave having a
smaller amplitude than the QRS complex. The nodal block is characterized by a prolonged PR
duration of the P wave is normally <100 ms, or interval, whilst the δ-wave of Wolff–Parkinson–
<2.5 ‘small squares’.1 P waves are absent in AF, White syndrome characteristically shortens the
where there is uncoordinated atrial PR interval.
depolarization. In mitral stenosis, left atrial The QRS complex represents ventricular
hypertrophy results in a larger, and sometimes depolarization and its propagation. The normal
bifid, P wave. QRS complex is <0.12 s; that is, three small
The PR interval is the time between the onset of squares. A widened QRS complex may occur in a
atrial and ventricular depolarization, which bundle branch block: a conduction defect in
represents AV nodal delay. It is conventionally either the right or left bundle branches.
measured as time from the beginning of the Pathological Q waves may result from a
P wave to the beginning of the Q wave rather than pulmonary embolus, which classically gives an
the R wave. The normal PR interval is 0.12–0.2 s; S1Q3T3 pattern, or a previous myocardial
that is, three to five small squares. First-degree AV infarction. Pathological Q waves have a duration
>40 ms (one small square), or an amplitude
1 25% of the subsequent R wave.
At the standard UK ECG recording speed of 25 mm/s,
each 1 mm ‘small square’ represents 0.04 s. One large The ST segment is the isoelectric segment
square contains five small squares, and thus represents that follows the QRS complex. The ST segment
0.2 s. The voltage is calibrated so that +1 mV is corresponds to the plateau phase of the cardiac
represented by a positive deflection of 10 mm. action potential. Myocardial ischaemia or
261
infarction may cause the ST segment to become cross-section, thus facilitating the use of the
depressed or elevated respectively. 12-lead ECG as a diagnostic tool.
The T wave represents the wave of ventricular
repolarization. Repolarization of cardiac myocytes
is not nearly as rapid as depolarization; the T wave
Explain the waveform of the
is therefore wider than the QRS complex. Inverted QRS complex
T waves may be caused by ventricular ischaemia. The wave of cardiac depolarization (Figure 55.2):
The QT interval is the time from the onset of starts from the SA node;
ventricular depolarization to the completion of spreads through the atria to the AV node;
ventricular repolarization. The QT interval,
in the interventricular septum, as the wave of
therefore, represents the duration of the cardiac depolarization propagates towards the apex,
action potential. As discussed in Chapter 54, the cardiac myocytes depolarize from left to right;
duration of the cardiac action potential shortens
finally, the wave of depolarization spreads from
with increasing HR. The QT interval is therefore
the apex to the base of the ventricles.
routinely ‘corrected’ (QTc) for HR using an
algorithm, the most popular of which is Bazett’s
The active electrode (lead II is shown in Figure 55.2)
formula (QT interval divided it by the square root
measures the change in potential as ventricular myo-
of the R–R interval, the time between consecutive
cytes depolarize. Positive and negative deflections
R waves). Normal QTc is <0.44 s; that is, 11 small
indicate net electrical current flow towards and away
squares. A prolonged QTc interval is associated
from the electrode respectively:
with a propensity to ventricular tachyarrhythmias.
Septal depolarization produces a small negative
deflection known as a Q wave (Figure 55.2a).
What is meant by an As the remaining ventricular muscle begins to
electrocardiogram lead? depolarize, net current flows towards the
The potential difference between pairs of electrodes in electrode, resulting in a large positive deflection
different body areas is referred to as a lead. Each lead known as the R wave (Figure 55.2b).
views electrical activity in the heart from a different The wave of depolarization then flows towards the
angle. A standard 12-lead ECG consists of: bases of the ventricles, away from the electrode
(Figure 55.2c) returning the electrical potential
The limb leads (I, II and III) use electrodes on the
to zero.
right arm, left arm and left leg:
Finally, the base of the LV depolarizes
– Lead I records the potential difference between (Figure 55.2d), resulting in a small negative
right and left arm electrodes. deflection known as the S wave.
– Lead II records potential difference between
right arm and left leg electrodes.
– Lead III records potential difference between What is the cardiac axis?
left arm and left leg electrodes. The leads that view the heart in the coronal plane
The augmented limb leads (aVF, aVR and aVL) (the six limb leads and augmented limb leads) can be
are derived from the same three electrodes, but used to determine the cardiac axis: the net direction
offer additional angles to those provided by leads I, (or vector) of the depolarization wave (Figure 55.3).
II and III. For example, aVF records the potential Owing to the large mass of ventricular excitable
difference between the left leg electrode and the tissue, the net direction of depolarization normally
average of the right arm and left arm electrodes. runs diagonally from the SA node to the apex, giving
The six chest or precordial leads (V1–V6) a typical cardiac axis of around 45°. A normal cardiac
measure the potential difference between chest axis is considered to be between 30° and +90°.
leads and a voltage given by the average of the An axis more negative than 30°, termed left axis
three limb leads. Whereas the limb leads and deviation, may result from left ventricular
augmented limb leads view the heart in the hypertrophy, or the leftward displacement of the
coronal plane, the chest leads view the heart in heart during pregnancy.
262
Chapter 55: The electrocardiogram
(a) Path viewed by electrode (b)
Lead II recording Lead II recording

AV node
Q wave R wave
Lead II electrode
Depolarization of Depolarization
septum from left to right towards the electrode
(c) (d)
Lead II recording Lead II recording
S wave
Depolarization away
from the electrode
Figure 55.2 The path of ventricular depolarization (atrial depolarization not shown).
An axis greater than +90°, termed right axis

deviation, may result from right ventricular
hypertrophy.
The cardiac axis of an ECG can be estimated from the
aVR –150o –30o aVL QRS complexes of leads I, II, III, aVF and aVL:
Identify the isoelectric lead, the one in which the
QRS has equal positive and negative deflections.
0o lead I The cardiac axis is 90° (i.e. at right angles) to
this lead.
For example if lead II (which represents a vector
of +60°) is the isoelectric lead, the cardiac axis is at
90° to lead II. The cardiac axis is therefore either 30°
lead III +120o +60o lead II
or +150°. Referring to the deflection in aVL
+90o aVL (which represents a vector of 30°) will confirm the
Figure 55.3 Vectors of the ECG leads. cardiac axis:
263
If the QRS complex of lead aVL has a Further reading

predominantly positive deflection, the cardiac F. Kusumoto. ECG Interpretation: From
axis is 30° and therefore just within the Pathophysiology to Clinical Application. Springer,
normal range. 2009.
If the QRS complex of lead aVL has a
predominantly negative deflection, the cardiac
axis is +150°; that is, extreme right axis deviation.
264
Chapter
Autonomic nervous system
56
of these neurons, the location of their synapses (gan-
What is the autonomic nervous system? glia) and the neurotransmitter utilized (Figure 56.1).
The ANS is the portion of the nervous system respon-
sible for regulating the functions of the body’s viscera, Sympathetic nervous system:
including HR, blood pressure, digestion, micturition, – Sympathetic pre-ganglionic neurons originate
defecation, sweating and sexual function. from the lateral horn of the spinal cord
between T1 and L2/3, the so-called
thoracolumbar outflow of the ANS.
Describe the two divisions of the – Pre-ganglionic nerves emerge from the spinal
autonomic nervous system cord with the spinal nerves in white rami
The ANS is subdivided into two separate nervous communicantes,1 but quickly separate to form
systems: sympathetic and parasympathetic, which either paravertebral or prevertebral ganglia. The
usually have antagonistic effects. Most viscera are paravertebral ganglia form the sympathetic
innervated by both divisions of the ANS. chain; important named prevertebral ganglia are
The function of the sympathetic nervous system is the coeliac, the superior mesenteric and the
often summarized by fight, flight or fright. Its role is inferior mesenteric (Figure 56.1).
concerned with preparing the body for stressful situ- – The sympathetic chain is often divided into
ations: increasing CO (by increasing HR, SV and four parts:
myocardial contractility), vasoconstriction, mobiliz-
▪ Cervical, which supplies the head and neck.
ing glucose stores and pupillary dilatation.
The function of the parasympathetic nervous ▪ Thoracic: the upper thoracic sympathetic
system is often summarized by rest and digest. It chain (T1–T5) supplies the heart, lungs
carries out the basic functions required for life, and aorta, whilst the lower thoracic
including decreasing HR, salivation, stimulating peri- sympathetic chain (T6–12) supplies the
stalsis in the gut, urination and pupillary constriction. foregut and midgut viscera.
▪ Lumbar (or abdominal), which supplies
the hindgut viscera.
Name some of the effects of ▪ Sacral (or pelvic), which supplies the
sympathetic and parasympathetic pelvic viscera.
nervous system activity on the viscera – In the ganglia, pre-ganglionic neurons synapse
The effects of sympathetic and parasympathetic activ- with post-ganglionic neurons. The
ity on the viscera are perhaps best described in a table; neurotransmitter at this synapse is ACh, which acts
see Table 56.1. upon nicotinic post-synaptic membrane receptors.
– Post-ganglionic neurons leave the ganglia
through grey rami communicantes2 and travel
Describe the anatomy of the autonomic
nervous system in more detail 1
Referred to as ‘white’ because there are more myelinated
Irrespective of the ANS subdivision, action potentials fibres than unmyelinated. Pre-ganglionic fibres are type
reach the viscera through two neurons: pre- B neurons.
ganglionic and post-ganglionic. The sympathetic and 2
Referred to as ‘grey’ because they are unmyelinated. Post-
parasympathetic nervous systems differ in the length ganglionic fibres are type C neurons.
265
Table 56.1 Comparison of sympathetic and parasympathetic effects on viscera.
Organ Sympathetic nervous stimulation Parasympathetic nervous stimulation

Heart Increased HR, increased contractility Reduced HR3
Lung Bronchodilatation Bronchoconstriction
Increased mucus production
Pupils Pupillary dilatation Pupillary constriction
Salivary glands Inhibition of salivation Stimulation of salivation
Arterioles Vasoconstriction No effect4
Sweat glands Activates sweating No effect
Adrenal gland Release of adrenaline and noradrenaline No effect
GI tract Inhibits peristalsis Stimulates peristalsis
Bladder Relaxes bladder Contracts bladder
Penis Ejaculation Erection
Pre-ganglionic neurotransmitter = ACh PARASYMPATHETIC SYMPATHETIC Pre-ganglionic neurotransmitter = ACh

Post-ganglionic neurotransmitter = ACh Post-ganglionic neurotransmitter = noradrenaline
III
Eye
VII
Lacrimal, submandibular
and sublingual glands Eye and salivary gland
IX
Parotid gland
X
Heart, lungs and upper
abdominal viscera
Heart and lungs
T1
T4
T5 Adrenal medulla
Coeliac ganglion
Foregut and
midgut viscera
T12 Superior mesenteric ganglion

L1
Hindgut, bladder
and genitalia
L3
Inferior mesenteric ganglion
Lower abdominal viscera, S2
bladder and genitalia
S4
Sympathetic chain
Long pre-ganglionic neurons Long post-ganglionic neurons

Short post-ganglionic neurons Short pre-ganglionic neurons
Figure 56.1 Layout of the ANS.
3 4
The ventricular muscle of the heart receives very little The arterioles have insignificant parasympathetic
parasympathetic innervation (see Chapter 54). innervation, aside from in the penis.
266
Chapter 56: Autonomic nervous system
within peripheral nerves to synapse with their

target organ. The neurotransmitter at this under fluoroscopic guidance. Lumbar sympath-
ectomy is used in the diagnosis and manage-
synapse is noradrenaline, which acts upon
ment of sympathetically mediated pain of the
post-ganglionic adrenergic receptors.
lower limbs.
There are three major exceptions to the system In addition, there is increasing evidence of the
outlined above: importance of sympathetic blockade in the manage-
– The adrenal medulla is directly innervated by ment of acute pain, and in reducing the risk of
pre-ganglionic neurons, with ACh as the developing chronic pain. In clinical practice, this is
neurotransmitter. This is because the adrenal usually achieved by using spinal, epidural or
paravertebral blocks.
gland is effectively a modified sympathetic
ganglion that releases its neurotransmitter
directly into the blood.
– The sweat glands are innervated by
Parasympathetic nervous system:
sympathetic cholinergic neurons, which
release ACh but act through muscarinic – Parasympathetic neurons are carried with
receptors. cranial nerves III, VII, IX and X, and with
– Metarterioles in skeletal muscle beds are also spinal nerves S2–4. This forms the so-called
innervated by sympathetic cholinergic fibres. craniosacral outflow of the ANS.
These metarterioles cause functional arterio- – The axons of the pre-ganglionic neurons are
venous shunting, thus preventing increases in often long. They synapse in ganglia close to
MAP at the onset of exercise. their target organs. The post-ganglionic
neurons are therefore relatively short.
– The cranial parasympathetic nerves supply
Clinical relevance: sympathetic blockade viscera in the upper half of the body, up to the
The sympathetic nervous system has long been
junction of the midgut and hindgut (just
implicated in the development of chronic neuro- before the splenic flexure of the transverse
pathic, vascular and visceral pain. The sympathetic colon). The sacral parasympathetic outflow
chain may be pharmacologically blocked, either tem- supplies the viscera of the lower half of
porarily with local anaesthetic or semi-permanently the body.
with phenol or alcohol, for the diagnosis or treatment – In the ganglia, pre-ganglionic neurons release
of sympathetically mediated pain. ACh, which acts upon post-synaptic nicotinic
Stellate ganglion blockade. The stellate gan- receptors.
glion is a fusion of the inferior cervical sympa-
– At the target organ, the post-ganglionic
thetic ganglion with the first thoracic ganglion
located at C7. Stellate ganglion blockade may be
neuron releases ACh, which acts upon post-
used to treat sympathetically mediated pain of synaptic muscarinic receptors.
the upper limbs (for example, Raynaud’s
These features are summarized in Table 56.2.
syndrome), complex regional pain syndrome
(CRPS), and for the treatment of hyperhydrosis.
Coeliac plexus blockade. The coeliac plexus is
located at either side of the L1 vertebral body,
and provides the sympathetic supply to most of
Outline the types of acetylcholine
the abdominal viscera. Pain associated with receptor
pancreatic carcinoma and chronic pancreatitis As suggested above, there are two types of ACh
may be treated by semi-permanent blockade receptor:
of the coeliac plexus using phenol under
fluoroscopic guidance. Nicotinic ACh receptors are directly linked to
Lumbar sympathectomy. The lumbar portion of an ion channel; that is, are ionotropic. Nicotinic
the sympathetic chain may be blocked through ACh receptors are found in the post-synaptic
an injection anterolateral to the L3 vertebral body membrane of the NMJ, within autonomic
ganglia and within the brain. The receptor is
267
Table 56.2 Comparison of sympathetic and parasympathetic

nervous system anatomy. What are the subtypes of adrenergic
Feature Division of ANS
receptors?
Adrenergic receptors, or adrenoceptors, are
Sympathetic Parasympathetic G protein-coupled receptors whose ligands are cat-
Location of pre- Lateral horn of Brainstem, lateral echolamines. Adrenoceptors are therefore metabotro-
ganglionic spinal segments grey areas of pic, exerting their effects through intracellular second
neuron cell T1–L3 spinal segments messenger systems. There are four main subtypes:
bodies S2–4 α1 adrenoceptors are Gq-coupled receptors found
Length of pre- Short Long in arteriolar smooth muscle and the urethral
ganglionic sphincter. The vasoconstrictors noradrenaline,
neuron metaraminol and phenylephrine are all α1
Location of post- Sympathetic Ganglia close to adrenoceptor agonists. Doxazosin and tamsulosin
ganglionic cell chain and the target organ are examples of selective α1 adrenoceptor
bodies prevertebral antagonists, used to treat hypertension and benign
ganglion prostatic hypertrophy.
Pre-ganglionic ACh, nicotinic ACh, nicotinic α2 adrenoceptors are pre-synaptic Gi-coupled
neurotransmitter, receptor receptor receptors found in the pancreas, arterioles and
post-ganglionic CNS. Both noradrenaline and adrenaline activate
receptor α2 adrenoceptors, resulting in vasodilatation,
Length of post- Long Short inhibition of insulin release from the pancreas,
ganglionic sedation and analgesia. Clonidine, an α2 agonist, is
neuron used as a sedative and analgesic.
Post-ganglionic Noradrenaline, ACh, muscarinic β1 adrenoceptors are Gs-coupled receptors found
neurotransmitter, adrenergic receptor in the heart and kidney. Activation by adrenaline
target organ receptor and noradrenaline results in positive chronotropy
receptor (exceptions and inotropy, and renin secretion. Bisoprolol,
described in text) a β1 adrenoceptor antagonist, is used to reduce
myocardial contractility and HR in ischaemic
heart disease.
referred to as nicotinic because, in addition to β2 adrenoceptors are also Gs-coupled receptors,
ACh, nicotine acts as an agonist. Nicotinic ACh found in the smooth muscle of the bronchioles
receptors in the NMJ (fetal: α2βγδ; adult: α2βεδ) and uterus. β2 adrenoceptors are predominantly
and autonomic ganglia (α2β3) have different activated by adrenaline, resulting in
subunit configurations and are thus acted upon by bronchodilatation and uterine relaxation.
different drugs. Salbutamol, a β2 agonist, is used as a
Muscarinic ACh receptors are G protein-coupled bronchodilator in acute asthma, and as a tocolytic
receptors and act through an intracellular second in premature labour.
messenger system; that is, are metabotropic. The
fungal alkaloid muscarine also acts on these
receptors. There are five subtypes of muscarinic Further reading
receptors: M. H. Andreae, D. A. Andreae. Regional anaesthesia to
prevent chronic pain after surgery: a Cochrane
– M1 receptors are commonly found in secretory systematic review and meta-analysis. Br J Anaesth 2013;
glands (for example, the salivary glands) and 111(5): 711–20.
the CNS. J. G. McDonnell, O. Finnerty, J. G. Laffey. Stellate ganglion
– M2 receptors are found in the heart. blockade for analgesia following upper limb surgery.
– M3 receptors are found in smooth muscle of Anaesthesia 2011; 66(7): 611–4.
the bronchioles and arterioles. R. Menon, A. Swanepoel. Sympathetic blocks. Contin Educ
– M4 and M5 receptors are found in the CNS. Anaesth Crit Care Pain 2010; 10(3): 88–92.
268
Chapter
Pain physiology
57
What is the definition of pain? What is a nociceptor?
Pain is defined as an unpleasant sensory and emo- A nociceptor is a free, unmyelinated nerve ending
tional experience associated with actual or potential capable of generating action potentials in response
tissue damage. to a variety of stimuli that are generated by cellular
damage. For example:
+
K is released from damaged cells.
How does pain differ from Histamine is released from mast cells near to the
site of tissue damage.
nociception? Bradykinin is increased at the site of injury, as a
Nociception is the process by which noxious signals result of inflammation.
are encoded as action potentials and transmitted from Leukotrienes and prostaglandins are synthesized
the peripheries to the CNS. Pain results from the in response to cellular damage as part of the
brain’s interpretation of these nociceptive signals, inflammatory process.
resulting in the perception of an unpleasant sensory Serotonin is released by platelets in response to
and emotional experience. vascular injury.
How is pain classified? What nerve fibre types carry pain

Traditionally, pain has been classified as either acute sensation?
or chronic. Acute pain is defined as pain of <12 There are two types of nociceptor fibre, classified by
weeks’ duration, and chronic pain as pain of >12 fibre structure (see Chapter 49):
weeks’ duration. This arbitrary distinction has been Type Aδ fibres carry impulses produced in
replaced, and chronic pain is now defined as pain that response to mechanical and thermal stimuli.
extends beyond the expected period of healing These neurons have myelinated axons of large
following tissue injury. diameter, and have a relatively high conduction
Pain may be arbitrarily classified as nociceptive, velocity of around 20 m/s. As a consequence of the
caused by stimulation of nociceptors, or neuropathic, higher conduction velocity, nociceptive impulses
caused by damage to the neurons themselves. Noci- carried by type Aδ fibres produce the first
ceptive pain may be classified as: sensation of pain, often perceived as being sharp
Superficial or cutaneous pain, due to skin and well localized in character.
damage and characterized by sharp, well- Type C fibres carry impulses produced in
localized pain. response to thermal, mechanical and chemical
Deep pain, a dull aching and poorly localized pain stimuli. These neurons have unmyelinated axons
arising from structures such as muscles, tendons of small diameter, which results in a relatively low
and ligaments. action potential conduction velocity (0.5–4 m/s).
Visceral pain, a dull, diffuse and poorly localized Firing of their associated nociceptors produces a
pain arising from the viscera; for example, spasm sensation of dull, poorly localized pain that often
or overdistension of a hollow viscus. follows the early sharp pain mediated by Aδ fibres.
269
What are the pathways by which pain through the brainstem to the thalamus, where
they synapse with third-order neurons.
signals are relayed to the brain? The third-order neurons relay action potentials to
As discussed in Chapter 47, the afferent neurons that the somatosensory cortex.
relay nociceptive impulses from the peripheries travel
in the spinothalamic tract:
A first-order neuron (C or Aδ fibre) relays action How is pain modulated?
potentials from a nociceptor to the substantia It has long been known that the pain associated with
gelatinosa (Rexed lamina II) or nucleus proprius an injury may not always correlate with the severity of
(Rexed laminae III, IV and V) in the dorsal horn that injury. For example, soldiers with severe battle
of the spinal cord. Here, the first-order neuron wounds may experience little or no pain. Clearly, the
synapses with a second-order interneuron, with traumatic amputation of a limb will result in acti-
substance P as the neurotransmitter. vation of peripheral nociceptors. This suggests an
The second-order interneuron decussates in the existence of mechanisms by which nociceptive signals
anterior commissure, before ascending the length received by the brain are modulated. Three mechan-
of the spinal cord in the spinothalamic tract. The isms contribute to pain modulation:
second-order neuron synapses on a third-order Segmental inhibition. It is well known that
neurons in the thalamus. rubbing an injured area, or the external
The third-order neuron relays nociceptive action application of heat or ice, reduces the sensation of
potentials to the somatosensory cortex. pain. This led to the gate theory of pain control
(1965). At the time, it was thought that only
Sensation from the face is relayed to the brain
C fibres carried pain, whereas Aδ fibres carried
through the trigeminal pathway:
touch, pressure and vibration sensory modalities.
A first-order neuron (C or Aδ fibre) relays action The gate control theory hypothesized that both
potentials from the face to the trigeminal nucleus. type C and Aδ fibres converge on the same
Most of this sensory information is relayed to the second-order neuron, and that greater activity of
brain through the trigeminal nerve, but a small the Aδ fibres reduced the transmission of pain
number of sensory afferent neurons from the through C fibres (Figure 57.1).
oropharynx and ear travel in the facial,
Gate theory has now largely been disproved by the
glossopharyngeal and vagus nerves. Irrespective of
subsequent identification of interneurons
the cranial nerve, all sensory afferent fibres
dedicated to carrying nociceptive impulses from
synapse on second-order neurons in the
Aδ fibres alone. This does not exclude alternative
trigeminal nucleus, the equivalent of the dorsal
mechanisms for segmental inhibition that may
horn of the spinal cord. Again, substance P is
explain phenomena, such as transcutaneous
thought to be the neurotransmitter at this synapse.
electrical nerve stimulation, in which electrical
The trigeminal nucleus (also known as the stimulation of Aδ fibres using skin electrodes
Gasserian ganglion) is large, extending from the reduces pain intensity in some patients.
medulla to the midbrain. Three parts of the
Endogenous opioid system. Opioid receptors are
trigeminal nucleus receive different sensory located throughout the CNS, but especially in the
modalities: periaqueductal grey matter, the ventral medulla
– The spinal trigeminal nucleus receives pain and and the spinal cord. Opioid receptors are
temperature information. G protein-coupled receptors of three classes: μ, κ
– The main trigeminal nucleus receives touch and δ. When endogenous opioids (enkephalins,
and proprioception information from the face endorphins and dynorphin) bind to opioid
and mouth. receptors, there is reduced transmission of
– The mesencephalic trigeminal nucleus receives nociceptive impulses along the second-order
proprioceptive information from the jaw. neurons; that is, activation of opioid receptors
Like the spinothalamic pathway, the second-order inhibits pain transmission. Opioid receptors
neurons immediately decussate and ascend achieve this by either:
270
Chapter 57: Pain physiologyPain physiology
Ad fibre carrying mechanoreceptor impulses
To the dorsal columns
+
C fibre carrying nociceptive impulses
–
–
+
+
To the spinothalamic tract
Figure 57.1 Gate theory of pain control.
– opening K+ channels on the post-synaptic What is referred pain?

membrane, thus hyperpolarizing the second-
Referred pain is said to occur where the brain per-
order neuronal membrane;
ceives the pain originating from an area other than
– inhibiting Ca2+ influx into the pre-synaptic
the site of the painful stimulus.
terminal, thus reducing neurotransmitter
The viscera are innervated solely by type C fibres,
release (substance P).
which travel to the substantia gelatinosa in the dorsal
Descending inhibition. Neurons from the horn of the spinal cord. Here, they converge on the
periaqueductal grey matter project to the same second-order neurons as the first-order neurons
dorsal horn of the spinal cord via the raphe from cutaneous nociceptors. The brain may therefore
nuclei in the brainstem, where they influence perceive visceral pain as originating from cutaneous
the activity of ascending second-order nociceptors. For example:
nociceptive neurons (Figure 57.2). By Ischaemic myocardial pain is classically referred
inhibiting neurotransmission at the synapse to the left arm and neck.
between the first- and second-order Pancreatic pain is often referred to the back.
nociceptive neurons, the perception of pain is Pain associated with appendicitis may be referred
reduced. Serotonin and noradrenaline are to the umbilicus.
thought to be the main neurotransmitters
Diaphragmatic pain may be referred to the
of the descending inhibition pathway, which shoulder tip.
in part explains the analgesic properties
of SSRIs and tricyclic antidepressant
(TCA) drugs. The analgesic effects of
Define hyperalgesia and allodynia.
clonidine, an α2 adrenergic How do they occur?
agonist, are thought to Hyperalgesia is defined as increased pain from a
occur through augmentation of activity in the stimulus that normally provokes pain. Hyperalgesia
descending inhibitory pathway. is of two types:
271
Figure 57.2 Descending inhibition.
Third-order neuron Periaqueductal grey matter
Raphe magnus nucleus

in the medulla
Inhibitory synapse
Second-order neuron
First-order neuron from

peripheral nociceptor
Primary hyperalgesia occurs in damaged tissues. pain. Whilst hyperalgesia can be thought of as a
For example, areas of sunburnt skin have a greater protective mechanism, preventing an area of
sensitivity to pain than normal areas of skin. damaged tissue becoming further damaged, allodynia
Primary hyperalgesia is due to release of serves no useful purpose. Allodynia is often a
substance P, bradykinin and histamine at the site feature of neuropathic pain; for example, trigeminal
of tissue damage which sensitize the nociceptors, neuralgia.
decreasing their threshold potential for the The physiological mechanism behind the develop-
generation of action potentials. ment of allodynia is far from clear. One possible
Secondary hyperalgesia occurs in the tissues mechanism involves reorganization of the circuitry
surrounding the areas of tissue damage. of the spinal cord, so that the interneurons serving
Secondary hyperalgesia is thought to result from nociceptors are exchanged with the interneurons
the increased release of substances (for example, transmitting mechanoreceptor impulses.
substance P, calcitonin-gene-related peptide and
glutamate) by activated second-order
interneurons, which sensitize neighbouring What is neuropathic pain?
second-order interneurons. Because neurons in Neuropathic pain is pain caused by a lesion or disease
the brain and spinal cord are somatotropically of the somatosensory nervous system. Neuropathic
organized, these neighbouring neurons pain may originate from either the PNS or the CNS.
correspond to the tissue surrounding the site of For example:
tissue damage.
the PNS may be damaged by diabetes, infections
Allodynia is defined as pain due to a stimulus such as herpes zoster, or invasion by cancer;
that does not normally provoke pain; for example, central neuropathic pain may result from multiple
light touch or a cold breeze may be perceived as sclerosis or spinal cord injury.
272
Chapter 57: Pain physiologyPain physiology
Neuropathic pain differs from nociceptive pain. chronic sympathetic nervous system dysfunction
Whilst nociceptive pain is usually sharp or aching, following tissue trauma, resulting in the CRPS.
neuropathic pain may be an episodic pain, like an Patients with CRPS develop chronic abnormalities at
electric shock, or a burning pain. Abnormal sensa- the site of injury:
tions are common; for example, paraesthesias and Vasomotor changes – the affected limb may be
allodynia. hotter or colder than the other limb.
Neuropathic pain may result from a number of Sudomotor changes – reduced sweating.
mechanisms; for example: Reduced hair or nail growth.
In diabetic neuropathy, ischaemia of a myelinated Osteoporosis of the underlying bone.
nerve fibre causes demyelination. The newly Neuropathic pain – hyperalgesia and allodynia are
exposed axon fires ectopic action potentials, which common.
are perceived as a shooting or burning pain.
Transected nerve axons attempt to regrow, with The significance of the sympathetic nervous system in
the aid of nerve growth factor released from the the development of acute pain is a matter of debate
supporting Schwann cells. However, axon (see Chapter 56).
regrowth may be disorganized: sprouting nerve
endings may spontaneously generate action
potentials or may have altered threshold Further reading
potentials. E. Albrecht, K. R. Kirkham, S. S. Liu, et al. Perioperative
intravenous administration of magnesium sulphate and
postoperative pain: a meta-analysis. Anaesthesia 2013;
How is the sympathetic nervous system 68(1): 79–90.
involved in the development of pain? J. Sandkühler. Models and mechanisms of hyperalgesia and
Trauma to the tissues not only damages somatic allodynia. Physiol Rev 2009; 89(2): 707–58.
nerves, but also sympathetic nerves. For reasons as R. D’Mello, A. H. Dickenson. Spinal cord mechanisms of
yet unknown, a small number of patients develop pain. Br J Anaesth 2008; 101(1): 8–16.
273
Section 5 Gastrointestinal tract
Chapter
Saliva, oesophagus and swallowing
58
– Haptocorrin is a protein that binds to vitamin
What are the functions of saliva? B12, protecting it from the low-pH
A volume of 500–1000 mL of saliva is secreted by the environment of the stomach.
parotid, submandibular and sublingual glands per
Neutralization of acid: the HCO3 -containing
day, in response to the thought, smell, taste and
saliva dilutes and neutralizes gastric acid when
presence of food in the mouth or stomach. Saliva is
the contents of the stomach either:
98% water, with the remaining 2% made up of:
– Reflux into the oesophagus.
Electrolytes. Saliva is hypotonic – it has a lower
Na+ concentration but a higher K+ concentration – Enter the oral cavity during vomiting. There is
than plasma. Resting salivary pH is 7.0, but when a large increase in salivation immediately
HCO3 secretion is increased, the pH rises to 8.0. before vomiting, which protects tooth enamel
against acid erosion.
Proteins and enzymes, including mucin,
haptocorrin, α-amylase and lingual lipase. Antibacterial effects: despite the many
bactericidal constituents of saliva, there is little
Bactericidal substances, including thiocyanate,
evidence of any significant bacteriostatic action in
lysozyme, lactoferrin and IgA.
humans.
Unsurprisingly, the functions of saliva are reflected by
its constituents:
How is saliva produced?
Lubrication of food: saliva protects the
Salivary glands are composed of acinar cells and
pharyngeal and oesophageal mucosa from damage
ducts surrounded by contractile myoepithelial cells.
during swallowing. Mucin is primarily responsible
Production of saliva occurs in two phases:
for the lubrication properties of saliva.
Digestion: The acinar cells produce the primary secretion by
the active transport of electrolytes, followed by the
– α-Amylase is an enzyme identical to pancreatic passive movement of H2O. The primary secretion
amylase, which catalyses the breakdown of is approximately isotonic: Na+, Cl and HCO3
carbohydrate polymers. It works optimally at concentrations approximately resemble those of
pH 7, the pH of saliva, and manages to cleave plasma.
up to 75% of starch before becoming
The duct cells modify the primary secretion to
denatured by the acidic environment of the give a secondary secretion. Na+ and Cl are
stomach. Mixing of saliva with food during reabsorbed, whereas K+ and HCO3 are secreted.
chewing results in a longer period of action, as Reabsorption takes place at a greater rate than
amylase in the centre of the food bolus is secretion – saliva, therefore, becomes more
protected from the acidic environment of the hypertonic as it progresses through the duct.
stomach.
– Lingual lipase commences the digestion of The rate of saliva production affects its composition.
dietary triglyceride. It is particularly important At higher rates, saliva is rich in Na+ and HCO3 ,
in neonates, whose pancreatic lipase is whilst at lower rates it has a greater proportion of
immature and not particularly effective at K+ and Cl . Aldosterone increases Na+ reabsorption
digesting milk fats. and K+ secretion, similar to its effect in the kidney.
275
Section 5: Gastrointestinal tract
How are the salivary glands innervated? – Closure of the nasopharynx by the soft palate.
– Protection of the laryngeal inlet by adduction of
The basic secretory unit of the salivary gland is the
the vocal cords (lateral cricoarytenoid, oblique
acinus. The acini of the parotid, submandibular and
and transverse arytenoid muscles) followed by
sublingual glands have both:
adduction of the aryepiglottic folds
Parasympathetic innervation – stimulation (aryepiglottic muscles). All these laryngeal
produces vasodilatation of blood vessels supplying muscles are supplied by the recurrent
the acini and myoepithelial cell contraction, laryngeal nerve.
resulting in the secretion of a mainly serous, – Elevation of the hyoid (by the digastric and
electrolyte-rich saliva. stylohyoid muscles), which moves the larynx
Sympathetic innervation – stimulation produces superiorly and anteriorly. In addition, the
vasoconstriction of blood vessels supplying the epiglottis moves downwards to direct the food
acini and myoepithelial cell contraction. This bolus towards the posterior pharynx and away
results in a brief increase in the secretion of from the larynx.
mainly mucous saliva that is rich in amylase,
followed by a period of decreased saliva The food bolus is propelled towards the oesopha-
production. gus by successive contractions of the superior and
middle pharyngeal constrictor muscles. The infer-
Serous saliva is mainly produced by the parotid and
ior pharyngeal constrictor muscle (cricopharyn-
submandibular glands, while the sublingual gland
geus), which is normally closed, relaxes to allow
produces mainly mucous saliva.
the food bolus to pass. Cricopharyngeus is also
The origin of the parasympathetic fibres differs
known as the upper oesophageal sphincter.
between the salivary glands:
During the pharyngeal phase of swallowing, the
The parotid gland is supplied by the larynx is involuntarily closed by the true and false
glossopharyngeal nerve (cranial nerve IX); pre- vocal cords and covered by the epiglottis, only
ganglionic fibres synapse at the otic ganglion. reopening once the food bolus has passed. It is there-
The submandibular and sublingual glands are fore impossible to breathe during the pharyngeal
supplied by the facial nerve (cranial nerve VII); phase; the respiratory centre in the medulla coordin-
pre-ganglionic fibres synapse at the ates a 1–2 s period of apnoea during swallowing.
submandibular ganglion, whilst post-ganglionic
The oesophageal phase, which is also involuntary.
fibres travel in the lingual nerve.
– Once the food bolus has entered the
oesophagus, the upper oesophageal sphincter
What are the phases of swallowing? closes and the lower oesophageal sphincter
Swallowing is a complex process involving the coord- (LOS) partially relaxes.
ination of a number of muscles, both voluntary and – The food bolus is then propelled along the
involuntary. Swallowing involves passing a food bolus oesophagus by peristalsis. There are two types
from the oral cavity to the oesophagus via the phar- of peristaltic waves propagated by the enteric
ynx, with closure of larynx to prevent pulmonary nervous system:
aspiration. The swallowing reflex is controlled by the
▪ A primary peristaltic wave is initiated by
swallowing centre in the medulla oblongata. Swallow- the medullary swallowing centre during
ing is divided into three phases: swallowing, and continues from the
The oral phase, the only voluntary phase of beginning of the oesophagus to the LOS
swallowing. A food bolus is pushed against the regardless of the location of the food bolus.
hard palate by the tongue. Sensory information ▪ Secondary peristaltic waves are initiated by
from the hard palate is fed back to the medulla via the food bolus stretching the
the glossopharyngeal nerve, which triggers the oesophageal wall.
initiation of the involuntary phases of swallowing.
The pharyngeal phase, which is under – By the time the peristaltic wave reaches the
involuntary control. The medulla coordinates: LOS it has fully relaxed to allow the food bolus
276
Chapter 58: Saliva, oesophagus and swallowing
to pass. The smooth muscle of the LOS then contraction assists the oesophageal
contracts to prevent gastric contents refluxing smooth muscle contraction.
into the oesophagus. The oesophagus follows an acute angle at the
– The speed at which the food bolus moves point where it passes through the diaphragm,
along the oesophagus is much slower (3 cm/s) which further reduces the reflux of gastric
than along the pharynx (30 cm/s). contents into the oesophagus.
While the upper oesophageal sphincter
(cricopharyngeus) has a high resting pressure
Clinical relevance: aspiration pneumonia (up to 100 mmHg), the LOS has a much lower
Aspiration pneumonia occurs when foreign materials resting pressure. ‘Barrier pressure’ is defined as
(usually vomit, food, fluids, oral or nasal secretions) the difference between the LOS pressure
enter the tracheobronchial tree, causing infection (normally 20–30 mmHg) and intragastric pressure
and inflammation in the lungs. Aspiration pneumo- (normally 5–10 mmHg). Barrier pressure is
nia has many causes, including: reduced by:
Decreased conscious level, causing depression
of the cough reflex. Examples include alcohol – Swallowing. When a peristaltic wave reaches
intoxication, drug overdose and general the LOS, the smooth muscle relaxes to allow
anaesthesia. the food bolus to pass.
Disorders of the oesophagus; for example, – Pregnancy. LOS tone is reduced by
gastro-oesophageal reflux, oesophageal stricture progesterone. In addition, the gravid uterus
and tracheoesophageal fistula. increases intra-abdominal pressure, further
Problems with swallowing. These can be: reducing barrier pressure.
– Generalized weakness of pharyngeal muscles;
for example, MG, motor neurone disease, – Hiatus hernia. Barrier pressure is reduced
GBS and critical illness polyneuropathy. through two mechanisms:
– Damage to the swallowing centre or its neural
▪ The LOS is no longer anatomically aligned
connections; for example, multiple sclerosis
with its diaphragmatic opening, so the
and stroke.
diaphragm can no longer assist
oesophageal smooth muscle contraction.
▪ The acute angle taken by the oesophagus as
Describe the functional anatomy it passes through the diaphragm is lost.
of the oesophagus
– Drugs. Many drugs reduce LOS tone; for
The oesophagus is a muscular tube that transmits
example, alcohol, volatile anaesthetics,
food from the pharynx to the stomach. It has some
propofol, thiopentone, opioids, atropine and
important features:
glycopyrrolate. Important drugs that increase
The upper third of the oesophagus has LOS tone are metoclopramide,
skeletal (striated) muscle, whereas the lower suxamethonium and anticholinesterases
two-thirds has smooth muscle. Despite the (for example, neostigmine and edrophonium).
two different muscle types, peristalsis It is worth noting that the non-depolarizing
occurs smoothly along the length of the muscle relaxants have no significant effect on
oesophagus. LOS tone.
Normal oesophageal mucosa is stratified
squamous epithelium. In Barrett’s oesophagus, Clinical relevance: gastro-oesophageal reflux
chronic gastro-oesophageal reflux causes normal disease
mucosa to be replaced with columnar epithelium Gastro-oesophageal reflux disease occurs when
(similar to gastric/duodenal mucosa). gastric acid enters the oesophagus. This causes
damage to the mucosa, resulting in retrosternal pain.
The LOS is formed by the tonic contraction
Gastro-oesophageal reflux disease is caused by:
of smooth muscle in the distal 2–4 cm of
Raised abdominal pressure – obesity, gravid
the oesophagus, just as it passes through uterus, acute abdomen.
the diaphragmatic hiatus. Diaphragmatic
277
Reduced LOS barrier pressure – see above. – an H2-receptor antagonist (for example,
Anatomical changes to the LOS – hiatus hernia. ranitidine);
– a non-particulate antacid (for example,
Mendelson’s syndrome is a pneumonitis caused sodium citrate).
by pulmonary aspiration of gastric contents associ- The use of a RSI with cricoid pressure.
ated with general anaesthesia. Aspiration of >25 mL Induction of anaesthesia in the semi-recumbent
of gastric fluid of pH <2.5 is said to be sufficient to position.
cause a severe pneumonitis. Prevention of aspiration
in high-risk patients is multifactorial:
Preoperative starvation.
A freely draining nasogastric tube for patients
Further reading
with intestinal obstruction, aspirated before D. M. Jolliffe. Practical gastric physiology. Contin Educ
induction of anaesthesia. Anaesth Crit Care Pain 2009; 9(6): 173–7.
Neutralization of gastric acid through pre- H. J. Skinner, N. M. Bedforth, K. J. Girling, et al. Effect of
medication with: cricoid pressure on gastro-oesophageal reflux in awake
subjects. Anaesthesia 1999; 54(8): 798–808.
278
Chapter
Stomach and vomiting
59
stomach. The proenzyme pepsinogen is secreted
What are the functions of the stomach? into the stomach lumen by chief cells, where
The stomach has a range of functions: it is converted to pepsin by the acidic
Temporary storage of large meals – releasing environment. The chief cells are triggered to
ingested food slowly into the small intestine. secrete pepsinogen by:
Secretion of digestive enzymes – for example, – Gastrin.
gastrin.
– Parasympathetic nervous activity, through the
Mixing – vigorous contraction of gastric smooth vagus nerve.
muscle helps mix and liquefy ingested food.
Gastrin. This peptide hormone is secreted by
Secretion of gastric acid – in part to defend G cells in the stomach in response to:
against ingested microorganisms.
Secretion of intrinsic factor (IF) – which aids the – Parasympathetic nervous activity, through the
absorption of vitamin B12. vagus nerve.
Endocrine – secreting hormones to control gastric – Distension of the stomach.
emptying. – The presence of partially digested proteins in
the stomach.
Which substances are secreted by Gastrin has three main roles:

the stomach? – Stimulation of parietal cells to secrete HCl, both
directly and through stimulation of histamine
A total of 2 L of gastric fluid is produced by the
release by the ECL cells.
stomach per day. There are five important substances
– Stimulation of chief cells to secrete pepsinogen.
secreted by the stomach:
– Stimulation of gastric motility.
Hydrochloric acid (HCl). The parietal cells secrete
HCl to concentrations of up to 150 mmol/L Gastrin secretion is controlled by negative
(equivalent of a pH of 0.8). HCl secretion is feedback: high acid concentration releases
promoted by three stimuli: somatostatin from δ cells, which inhibits further
– Histamine, which stimulates H2 receptors – the release of gastrin from G cells.
most important stimulus for gastric acid IF – a glycopeptide secreted by parietal cells.
secretion. IF has an important role in vitamin B12
– Parasympathetic stimulation through the absorption:
vagus nerve. ACh acts as the neurotransmitter – Vitamin B12 is released from ingested animal
at muscarinic M3 receptors. proteins as they are broken down in the
– Gastrin, the least important direct stimulus of stomach.
the parietal cells. However, gastrin has an – In the low-pH environment of the stomach, IF
important indirect effect, as it triggers has a low binding affinity for vitamin B12, so
histamine release from neighbouring very little is bound. Released vitamin B12 is
enterochromaffin-like (ECL) cells. instead bound by haptocorrin, a vitamin B12
Pepsinogen. Pepsin is an important peptidase that binding protein. This protects the acid-
starts the process of protein breakdown in the sensitive structure of vitamin B12.
279
Blood Catalysed by Parietal cell Stomach lumen

carbonic anhydrase
CO2 diffuses
into parietal cell H+/K+-ATPase - the ‘proton pump’
CO2
Basolateral Na+/K+-ATPase
H2O
K+ K+
K+
Na+ Na+
H2CO3
BasolateralCl−/HCO3− ATPase
K+
ACh and gastrin K+
stimulate HCO3− HCO3− + H+ H+ HCl
histamine release
Cl− Cl− Cl−
ACh M3
Ca2+
Gastrin G Cl−
ECL cell Histamine H2 cAMP

Secondary messengers
SS
Stimulatory receptors
Inhibitory somatostatin receptor
Figure 59.1 The parietal cell and secretion of gastric acid.
– In the duodenum, vitamin B12 is re-released as How do the parietal cells secrete
haptocorrin is digested by trypsin. In contrast,
IF is resistant to trypsin. gastric acid?
– In the higher pH environment of the The parietal cells are triangular-shaped epithelial cells
duodenum, IF avidly binds vitamin B12. of the gastric mucosa (Figure 59.1). Key features are:
– In the terminal ileum, IF receptors allow Their close proximity to ECL cells.
absorption of the IF–vitamin B12 complex. An extensive network of secretory canaliculi.
The H+/K+-ATPase pump.
In pernicious anaemia, autoimmune destruction
of parietal cells leads to an IF deficiency. Three stimulatory receptors: histamine H2, ACh
and gastrin.
Vitamin B12, therefore, cannot be absorbed,
resulting in a megaloblastic anaemia. One inhibitory receptor: somatostatin.
Mucus. Mucous cells secrete an HCO3 -rich CA within the cell cytoplasm.
mucus that covers the gastric mucosa. It has two The main stimulus for the secretion of gastric
main roles: acid is histamine, synthesized and stored by
– Protection of the gastric mucosa from the neighbouring ECL cells that release histamine in
highly acidic contents of the stomach lumen. response to gastrin or parasympathetic stimuli.
– Lubrication of the stomach wall, protecting Histamine acts by increasing cAMP concentration
it from frictional damage due to vigorous within the parietal cell. Gastrin and ACh also dir-
peristalsis and mixing of partially digested ectly stimulate the parietal cell, but to a lesser extent
food. than histamine.
280
Chapter 59: Stomach and vomiting
The mechanism for gastric acid secretion is:

Gastric acid inhibitors. These drugs prevent
CO2 diffuses into the parietal cell from the blood. gastric acid being secreted. They therefore take
CO2 reacts with water to give H2CO3, in a reaction longer to act than antacids but have a much
catalysed by CA. longer duration of action. They target some of
+
H2CO3 dissociates into H and HCO3 . These the steps in the synthesis of gastric acid
ions then go their separate ways: discussed above:
– Histamine H2 receptor antagonists (for
– In the apical membrane: the H+/K+-ATPase
example, ranitidine) block the action of hista-
actively pumps H+ into the secretory canaliculi mine on the parietal cell, thus decreasing the
in exchange for K+. The H+/K+-ATPase is production of gastric acid. Some gastric acid
known as the proton pump. is still secreted due to the direct effects of
– In the basolateral membrane: HCO3 is gastrin and ACh on the parietal cell.
exchanged for Cl . HCO3 enters the blood, – Proton-pump inhibitors (PPIs); for example,
where it causes a measurable increase in blood omeprazole. PPIs act by irreversibly inhibiting
pH whenever gastric acid secretion is the H+/K+-ATPase (the proton pump), the final
stimulated; this is referred to as the alkaline common pathway of gastric acid secretion.
tide. They are more effective than H2 receptor
antagonists at increasing gastric pH, but
Cl diffuses down its concentration gradient longer term use carries a greater risk of
through a Cl channel to the secretory canaliculi. Clostridium difficile infection, osteoporosis,
+
K also diffuses down its electrochemical gradient, vitamin B12 deficiency and iron-deficiency
back into the secretory canaliculi through a K+ anaemia.
channel.
The overall effect is HCl secretion into the stomach

lumen, and NaHCO3 secretion into the bloodstream.
What are the phases of gastric
Clinical relevance: neutralization of gastric acid secretion?
Neutralization of gastric acid is a key part of the There are three phases of gastric secretion:
management of gastro-oesophageal reflux disease
and gastric and duodenal ulcers. Gastric acid can also Cephalic phase. Around 30% of the total gastric
be neutralized prior to induction of general anaes- acid secreted per meal is produced in response to
thesia in patients at risk of aspiration pneumonia; for the anticipation, smell and sight of food. Vagus
example, acute abdomen and pregnancy. nerve activity results in the secretion of HCl,
The neutralization of gastric acid can achieved by: gastrin and pepsinogen.
Antacids. These alkaline drugs react directly with Gastric phase. Gastric distension triggers gastrin
HCl in the gastric fluid. Gastric acid is rapidly release from G cells, which in turn stimulates
neutralized, resulting in prompt resolution of pepsinogen release from the chief cells, histamine
symptoms. Antacids include: release from the ECL cells and HCl secretion by
– Particulate antacids – for example, aluminium
the parietal cells. Sixty per cent of gastric acid is
hydroxide, magnesium hydroxide and calcium
carbonate. Particulate antacids are so-called
secreted during the gastric phase.
because the aluminium, magnesium and cal- Intestinal phase. Once the acidic chyme enters
cium salts produced are non-absorbable, the duodenum, secretin is released from the
resulting in particulate matter. The import- duodenal mucosa. Secretin reduces the acidity
ance of this is that, despite a higher pH, pul- of the chyme by:
monary aspiration of the salts of particulate
– Stimulating pancreatic ductal cells to secrete
antacids still cause pulmonary damage.
HCO3 , thus increasing the pH of chyme (see
– Non-particulate antacids – for example,
sodium citrate, commonly used immediately Chapter 60).
prior to caesarean section because of its – Inhibiting gastrin release from G cells, which in
speed of action and non-particulate nature. turn reduces the amount of acid produced by
the parietal cells.
281
How is gastric emptying controlled? above, secretin promotes pancreatic HCO3

secretion and inhibits gastrin secretion. As gastrin
It is important that the stomach is gradually emptied
is responsible for stimulating gastric motility,
into the duodenum. Following gastric surgery, a con-
reduced gastrin concentration slows gastric
dition called ‘gastric dumping syndrome’ may occur
emptying.
in which rapid gastric emptying leads to chyme pass-
Fat. Cholecystokinin (CCK) is secreted by the
ing into the small intestine largely undigested. This
duodenal mucosa in response to the presence of
causes:
duodenal lipid. CCK increases the tone of the
Duodenal distension, Large amounts of pylorus, thereby reducing gastric emptying, which
hyperosmolar chyme enter the duodenum, allows the small intestine more time to digest the
causing the osmotic movement of water from the lipids that have already passed from the stomach.
ECF to the duodenal lumen. The rapid increase in
Hyperosmolarity. Hyperosmolar chyme passing
duodenal volume causes cramping pains, nausea into the duodenum inhibits gastric emptying
and bloating. This is called ‘early’ dumping through a complex enteric nervous system reflex.
syndrome, because it occurs soon after ingestion
of a meal. In addition, there are a number of other factors that
Hypoglycaemia. Rapid absorption of a large inhibit gastric emptying:
amount of carbohydrate triggers the β cells of the sympathetic nervous system activity;
islets of Langerhans in the pancreas to secrete pain;
large amounts of insulin. Plasma glucose is rapidly drugs (for example, opioids);
taken up by the cells; plasma insulin concentration
diseases such as diabetic autonomic neuropathy,
takes longer to fall back to normal, resulting in acute abdomen and ileus.
hypoglycaemia. This is referred to as late dumping
syndrome, as it occurs 1–3 h after a meal.
The rate of gastric emptying into the duodenum

How long does gastric emptying take?
As discussed above, gastric emptying depends on
depends on:
whether gastric contents are solid or liquid:
The consistency of the chyme. Liquids pass
through the stomach much faster than solids. The Solids. After consuming a typical meal, there is a
20–30 min period where there is minimal gastric
pyloric sphincter constricts when solids come
emptying. This lag period allows time for mixing
close, preventing them from leaving the stomach
of food with gastric secretions, and for pepsin to
until they are essentially liquefied.
start the breakdown of proteins. After 30 min the
The volume of chyme. Increased gastric volume
rate of gastric emptying is approximately linear,
promotes gastric emptying.
resulting in a steady decrease in gastric volume
The content of the chyme. Protein enters the (Figure 59.2).
small intestine the most rapidly, followed by
Liquids. Unlike solids, clear liquids empty from
carbohydrate. High-fat meals are associated with
the stomach exponentially and without a lag phase
the slowest gastric emptying.
(Figure 59.2). However, if the fluid is
The rate of gastric emptying is primarily controlled hyperosmolar, acidic or contains fats, the rate of
by the duodenum – chyme passes through the pyl- gastric emptying will be slower and may mirror
orus and into the small bowel at an optimal rate for the non-exponential pattern of solid food.
digestion and absorption of food. The four main
duodenal factors that slow the rate of gastric empty-
ing are: Clinical relevance: preoperative fasting
The aim of preoperative fasting is to reduce the
Duodenal distension. This results in a reflex
volume and acidity of gastric fluid, thereby reducing
inhibition of the enteric nervous system, reducing
the risk of pulmonary aspiration. However, there is
gastric emptying. increasing evidence of the harms of excessive starva-
Acid. Low duodenal pH triggers the release of tion periods, including:
secretin from the duodenal mucosa. As discussed
282
Figure 59.2 Gastric emptying of solids

100 and liquids.
Percentage of stomach contents (%)
75
50
So
lid
me
al
25
Liquid meal
0
0 0.5 1 1.5 2 2.5 3
Time after consumption (hours)
abdominal sensation, though nausea commonly

patient discomfort;
dehydration; occurs without vomiting.

electrolyte disturbance; Vomiting is coordinated by the vomiting centre,
increased incidence of postoperative nausea and an anatomically ill-defined area in the medulla oblon-
vomiting (PONV); gata. The vomiting centre is in close contact with (but
glycaemic disturbance in patients with diabetes; not part of) three important structures:
potentially, increased body muscle catabolism The respiratory centre.
following major surgery.
The nucleus tractus solitarius, which receives
As discussed above, the rate of gastric emptying is afferent information from various cranial nerves.
very different for solids and liquids. The risk of pul- The chemoreceptor trigger zone (CTZ), located
monary aspiration is related to the volume of gastric on the floor of the fourth ventricle of the medulla
contents: at a given time after ingestion, gastric in the ‘area postrema’.
volume is considerably less for liquids than solids.
Therefore, liquids can be ingested much nearer to Crucially, the CTZ receives blood directly from the
the time of general anaesthesia than solids can. systemic circulation; it is located outside the
There has been much debate over the last few BBB, which provides a faster vomiting response to
decades regarding guidelines for perioperative emetic stimuli. This is convenient, as antiemetic drugs
fasting. The latest European evidence-based recom- do not have to cross the BBB to reach their target
mendations for perioperative fasting are: receptors.
6 h for solids; Many inputs to the vomiting centre can trigger
4 h for breastfeeding infants (formula milk counts
nausea and vomiting:
as ‘solid food’);
2 h for clear fluids, which include: The CTZ, which has many stimulatory receptors:
– carbohydrate drinks – dopamine, D2
– tea or coffee with milk (up to one-fifth of the – serotonin, 5-HT3
total volume).
– ACh
– opioid
– substance P (NK-1).
What is vomiting? Where is vomiting Cranial nerve VIII, which carries afferent
controlled? information from the vestibular system and
Vomiting is the involuntary, forceful, rapid expulsion involves muscarinic and histamine H1 receptors.
of gastric contents through the mouth. Vomiting is This input to the vomiting centre is implicated in
usually preceded by nausea, an unpleasant upper travel sickness.
283
Cranial nerve IX, which carries afferent Ejection phase. Consisting of:
information from the pharynx. This input is – Continuation of glottic closure.
involved in the gag reflex. – Contraction of the pylorus, which pushes
The enteric nervous system and cranial nerve X, gastric contents into the body and fundus of
which carries afferent information from the GI the stomach.
system. GI mucosal cells stimulate the vomiting – Relaxation of the LOS and the oesophagus.
centre through activation of serotonin 5-HT3
– Sudden dramatic increase in intra-abdominal
receptors in response to distension, infection (for
pressure, resulting from contraction of
example, gastroenteritis), chemotherapy and
abdominal muscles and descent of the
radiotherapy.
diaphragm. This pushes the gastric contents
Higher centres (for example, the limbic system) completely out of the stomach and into the
can also initiate vomiting in response to anxiety oesophagus.
and extreme emotional states.
– The soft palate occludes the nasopharynx, and
In response to emetic stimuli, the vomiting centre reverse peristalsis in the oesophagus rapidly
coordinates the parasympathetic nervous system, the expels its contents upwards, out of the mouth.
sympathetic nervous system and motor neurons
to produce a characteristic series of events that
results in the expulsion of gastric contents through Clinical relevance: antiemetic drugs
the mouth. The aetiology of PONV is multifactorial, with anaes-
thetic, surgical and patient risk factors:
Anaesthetic factors: use of volatile anaesthetics
Describe the sequence of events and/or N2O, intraoperative or postoperative opi-
involved in vomiting oids, and high-dose anticholinesterases.
Surgical factors: longer duration of surgery,
Vomiting is a highly organized series of events, middle-ear surgery, laparoscopic surgery,
divided into three phases: neurosurgery.
Pre-ejection phase. Consisting of: Patient factors: female, child, history of PONV,
history of motion sickness, non-smoker.
– Nausea.
– Decreased gastric motility. Strategies in anaesthesia to reduce PONV include:
– Reverse peristalsis of the small intestine, which Avoidance of emetic drugs: avoidance of
pushes proximal small bowel contents back opioids/use of short-acting opioids only, avoidance
into the stomach. of volatile anaesthetics through the use of regional
anaesthesia, or total intravenous anaesthesia.
– Secretion of HCO3 -rich saliva mediated by the
Intravenous fluid therapy: to replace fluid
parasympathetic nervous system. losses resulting from preoperative fasting.
– Sweating and tachycardia, mediated by the Use of antiemetic drugs.
sympathetic nervous system.
Retching phase. Consisting of: Antiemetic drugs target the receptors of the CTZ,
the vestibular apparatus and the GI tract. For example:
– Deep inspiration followed by closure of the Domperidone (a butyrophenone) antagonizes
glottis, which protects the trachea from dopamine D2 receptors in the CTZ.
aspiration of gastric contents. Hyoscine is an antagonist of the muscarinic ACh
– Rhythmic contraction of the intercostal receptor in the vestibular apparatus, and is used
muscles, diaphragm and abdominal muscles as an antiemetic in motion sickness.
against a closed glottis. The alkaline contents Cyclizine is an antagonist of the histamine H1
of the proximal small intestine are vigorously receptor in the vestibular apparatus, and is also
commonly used in motion sickness.
mixed with stomach contents, thereby
Ondansetron is a serotonin 5-HT3 receptor
increasing the pH of gastric fluid. The antagonist, and has a wide spectrum of uses as
increased intrathoracic pressure compresses an antiemetic as it blocks 5-HT3 receptors in the
the oesophagus, preventing reflux of stomach CTZ and the GI tract.
contents.
284
Further reading K. Clark, L. T. Lam, S. Gibson, et al. The effect of ranitidine

versus proton pump inhibitors on gastric secretions: a
I. Smith, P. Kranke, I. Murat, et al. Perioperative fasting in meta-analysis of randomised control trials. Anaesthesia
adults and children: guidelines from the European 2009; 64(6): 652–7.
Society of Anaesthesiology. Eur J Anaesthesiol 2011;
28(8): 556–69.
285
Chapter
Gastrointestinal digestion and absorption
60
nervous system, lies between the muscle layers,
Which gastrointestinal organs are where it coordinates smooth muscle contraction.
involved in digestion? The submucosa contains nerve cells making up
The GI tract is a tube that extends from mouth to Meissner’s plexus (a secondary enteric nervous
anus, approximately 9 m in length. It consists of the system plexus), blood vessels, lymphatic vessels
mouth, oesophagus, stomach, small intestine and and elastic connective tissue.
large intestine. In addition, there are a number of The mucosa, the innermost layer, is divided into
accessory organs of digestion: (from outermost to innermost):
The teeth and tongue are involved in the initial – Muscularis mucosae, a layer of smooth muscle
mixing of food with saliva. provides continuous agitation of the mucosa,
The salivary glands, liver, gallbladder and increasing contact with the luminal contents
pancreas secrete substances involved in the and preventing their adherence.
chemical and enzymatic breakdown – Lamina propria, which contains blood
of food. vessels and collections of immune cells.
In the ileum, the immune cells are organized
into lymphoid nodules called Peyer’s
How is the small intestine anatomically patches.
and histologically arranged? – Epithelium – the absorptive cells of the
The small intestine is divided into three parts: intestine are called enterocytes.
duodenum
Although the length of the small intestine is only 7 m,
jejunum
the absorptive surface area of the small intestine is
ileum.
enormous: over 250 m2. The absorptive surface area is
Most dietary nutrients are absorbed in the jejunum, increased as a result of:
but some are absorbed at other sites: Valvulae conniventes, mucosal folds that project
Vitamin B12 and bile salts are absorbed in the into the lumen of the small intestine.
terminal ileum. Villi, tiny finger-like projections of the intestinal
Iron is absorbed in the duodenum. wall. In between the intestinal villi are goblet cells,
Dietary fat and water are absorbed throughout the which secrete mucous, and intestinal crypts, which
small intestine. secrete the brush border enzymes and contain
stem cells.
The small intestine is made up of four layers: Microvilli, microscopic projections on top of the
The adventitia, the outermost layer, is composed villi. The fuzzy microscopic appearance of the
of loose connective tissue. microvilli superimposed on the intestinal villi
The muscularis externa consists of an outer gives rise to the name brush border.
layer of longitudinal smooth muscle and an inner
layer of circular smooth muscle. Peristalsis results Each villus has three vessels:
from coordinated contraction of the smooth A single arteriole. This gives rise to a capillary
muscle. The myenteric plexus, part of the enteric network at the tip of the villus.
286
Chapter 60: Gastrointestinal digestion and absorption
A single venule. The capillary network drains into sodium–glucose linked transporter, SGLT1)
a single venule, which returns blood to the liver requires a low enterocyte intracellular Na+
through the portal vein. concentration, generated as a result of
A single lacteal. Each villus also has a single basolateral Na+/K+-ATPase pump activity.
lymphatic capillary called a lacteal, which – Fructose is absorbed by facilitated diffusion,
transports absorbed dietary fats as chylomicrons not by Na+ co-transport.
to the thoracic duct. – Pentose sugars are absorbed by simple
diffusion.
What are the three main classes Within the enterocyte. Once absorbed into the
enterocyte, glucose and galactose travel down their
of dietary nutrients? concentration gradients. They pass through the
The three main dietary nutrients are carbohydrates, basolateral membrane and into the capillary by
amino acids and fats. Each is broken down and facilitated diffusion (via the transmembrane
absorbed very differently. glucose transporter, GLUT-2). As
monosaccharides are osmotically active, their
absorption across the enterocyte also results in the
How are carbohydrates digested absorption of water.
and absorbed?
Dietary carbohydrate polymers (for example, starch) Clinical relevance: oral rehydration therapy
must be broken down into their constituent mono- Worldwide, diarrhoea is the second commonest
saccharides before they can be absorbed: cause of death in children under 5 years old. It is, of
course, the complications of dehydration rather than
In the mouth. Digestion of carbohydrate begins in diarrhoea that are to blame for this high mortality.
the mouth, where salivary amylase breaks down Oral rehydration therapy (ORT) is an effective
complex carbohydrates into smaller carbohydrate method of rehydration in diarrhoeal illness, reducing
polymers and monosaccharides. the need for intravenous fluid therapy in cases of
In the duodenum. Pancreatic amylase continues moderate and severe dehydration. Oral rehydration
the breakdown of complex carbohydrates. solution is essentially just water, salt (sodium chlor-
At the brush border. Specific brush border ide) and glucose. ORT exploits the intestinal Na+–
enzymes (for example, sucrase, maltase and glucose co-transport system to facilitate the absorp-
tion of water:
lactase) hydrolyse the smaller carbohydrate
Both Na+ and glucose are osmotically active, and
polymers into their constituent monosaccharides.
their absorption into the enterocyte is accom-
For example, sucrase hydrolyses the disaccharide panied by a significant amount of water.
sucrose into glucose and fructose. The brush Because Na+ is also absorbed with oral rehydra-
border enzymes are integral membrane proteins, tion solutions, some of the Na+ lost from the GI
attached to the villi. Individuals with brush border tract is replaced.
enzyme deficiencies cannot digest certain
However, ORT does not contain potassium, so hypo-
carbohydrates. For example, lactose intolerance is
kalaemia can occur following prolonged diarrhoea
caused by brush border lactase enzyme deficiency.
and oral replacement.
Some carbohydrates, such as cellulose, pass
through the GI tract unchanged, as humans do
not have the brush border enzymes necessary for
hydrolysis.
How are proteins digested
At the enterocyte. Once carbohydrate has been and absorbed?
broken down, the resulting monosaccharides Ingested proteins must be broken down into single
(glucose, fructose, galactose, pentose sugars) can amino acids, dipeptides and tripeptides before they
be absorbed by the enterocytes: can be absorbed:
– Glucose and galactose can only be absorbed In the stomach, protein digestion begins. The
by secondary active transport through an Na+ proenzyme pepsinogen is released by chief cells in
co-transporter. This co-transporter (called the the stomach. The low-pH environment then
287
converts pepsinogen into pepsin. Pepsin cleaves of lipid droplets. This is why bile salts are required
the peptide bonds of dietary protein, resulting in to divide large droplets into small ones, increasing
shorter polypeptides. the surface area upon which pancreatic lipase acts.
In the duodenum, protein digestion continues. Micelle formation. The free fatty acids and
The two most important peptidases are trypsin monoglycerides released from triglyceride
and chymotrypsin, both of pancreatic origin. combine with bile salts, forming micelles
Polypeptides are progressively cleaved by these consisting of small balls of mixed lipids and
powerful peptidases, resulting in dipeptides and bile salts.
tripeptides (but not single amino acids). At the enterocyte. When a micelle makes contact
At the brush border, peptidases cleave dipeptides with an enterocyte, the lipid contained within it is
and tripeptides into single amino acids. Again, absorbed by simple diffusion. The bile salts
these brush border enzymes are integral remain in the gut lumen and are absorbed in the
membrane proteins, attached to the villi. terminal ileum, where they return to the liver and
At the enterocyte, single amino acids are are recycled.
absorbed in a similar way to glucose, through Within the enterocyte. Monoglycerides and fatty
Na+-linked co-transport. There are different co- acids travel to the ER where they are recombined
transporters for neutral, basic and acidic amino to form triglyceride. The triglyceride is packaged
acids. Short peptides (two or three amino acids in together with cholesterol, phospholipid and a
length) are also absorbed by secondary active cellular label called apolipoprotein to form lipid
transport using an H+-linked co-transport system. balls called chylomicrons. The chylomicrons are
Inside the enterocyte, these short peptides are released from the enterocytes into lacteals, the
broken down into single amino acids, which then lymphatic capillaries that service each villus.
exit the enterocyte by facilitated diffusion across Chylomicrons flow through the lymphatic system
the basolateral membrane. Amino acids are until they are released into systemic circulation at
osmotically active: as they are transported from the thoracic duct.
the gut to the capillary, water molecules are also
absorbed. Clinical relevance: lipase inhibitors
The weight-reduction drug Orlistat is a lingual and
pancreatic lipase inhibitor. It prevents dietary trigly-
ceride being hydrolysed into free fatty acids and
How are lipids digested and absorbed? monoglyceride. Dietary triglyceride, therefore, remains
Most dietary lipid is triglyceride (a glycerol backbone undigested and is excreted in the faeces, resulting in
with three fatty acid residues attached), with smaller steatorrhoea. Similarly, steatorrhoea is the main pre-
amounts of phospholipid, cholesterol and fat-soluble senting symptom in pancreatic insufficiency.
vitamins. In common with carbohydrates and proteins,
triglyceride must first be broken down into its con-
stituent parts before absorption can take place. What are the functions of the pancreas?
Emulsification in the duodenum. Lipids are The pancreas has both endocrine and exocrine func-
insoluble in water. Triglyceride, therefore, tends to tions. Most of the pancreatic tissue is dedicated to the
aggregate in large droplets when exposed to the secretion of pancreatic fluid. Despite only occupying
aqueous environment of the GI tract. In a process 1–2% of pancreatic mass, the islets of Langerhans are
called emulsification, bile acids (secreted by the the sole producers of glucagon (α cells), insulin
liver, stored in and then released from the (β cells) and pancreatic polypeptide (PP cells), and
gallbladder) coat the lipid droplets, dividing them one of the main sites of somatostatin secretion (δ cells).
into smaller and smaller droplets.
Enzymatic breakdown of triglyceride. How are pancreatic secretions involved
Pancreatic lipase acts to hydrolyse each
triglyceride molecule into two free fatty acid in digestion?
molecules and 2-monoglyceride. However, A total of 1.5 L of pancreatic juice is produced per
pancreatic lipase can only act on the surface day, which drains into the duodenum through the
288
pancreatic duct. The main cell types of the exocrine

pancreas are: into the interstitium where it digests retroperitoneal
fat – the retroperitoneal haemorrhagic necrosis that
Acinar cells, which produce digestive enzymes. results is the cause of Grey–Turner’s sign (discolor-
Ductal cells, which secrete HCO3 and water. ation of the flanks) and Cullen’s sign (periumbilical
discoloration).
Acinar cells produce four main enzymes and
proenzymes:
Trypsinogen and chymotrypsinogen. On The inorganic portion of pancreatic juice is
entering the duodenum, the proenzyme produced by the ductal cells. HCO3 is an essential
trypsinogen is cleaved by the duodenal enzyme component of pancreatic juice: it neutralizes the gas-
enterokinase, resulting in trypsin, a powerful tric acid that enters the duodenum. Without secretion
peptidase. Trypsin then cleaves both of HCO3 , many of the pancreatic enzymes would
chymotrypsinogen and trypsinogen, resulting in become denatured by the acidic environment. HCO3
chymotrypsin and more trypsin. The process of synthesis utilizes the enzyme CA in a similar manner
trypsin catalysing the formation of more trypsin is to gastric acid secretion (Figure 60.1):
called autocatalysis, which, once initiated, results CO2 diffuses into the ductal cells from the blood.
in an exponential increase in peptidase activity, CO2 combines with water to form H2CO3,
and therefore needs to be kept in check catalysed by CA.
(see box below). +
H2CO3 dissociates into H and HCO3 . These
Pancreatic α-amylase. This catalyses the two ions then go their separate ways:
hydrolysis of large polysaccharides to smaller
– HCO3– ions diffuse down their concentration
carbohydrate polymers; for example, starch to
gradient into the lumen of the pancreatic duct,
maltose. It has no activity against the
crossing the luminal membrane by exchange
polysaccharide cellulose.
with Cl ions. The Cl ions can then return to
Pancreatic lipase. This catalyses the hydrolysis the lumen of the pancreatic duct through a
of dietary triglyceride to free fatty acid and
separate Cl channel, CFTR. It is this Cl
2-monoglyceride.
channel whose function is abnormal in cystic
fibrosis.
Clinical relevance: acute pancreatitis
– H+ is expelled from the ductal cell across the
Acute pancreatitis is inflammation of the pancreas,
basolateral membrane into the capillary by
resulting in a wide spectrum of disease from a mild
self-limiting illness to a fulminant illness with multi- exchange with Na+. As with many cellular
organ dysfunction. There are many causes of acute processes, the exchange of H+ and Na+ is
pancreatitis, the most common of which are alcohol driven by the low intracellular concentration
and gallstones. of Na+ generated by the Na+/K+-
Whatever the precipitant, the problem is inappro- ATPase pump.
priate activation of proenzymes within the pancreas. HCO3 is osmotically active, and so its movement
Trypsinogen is activated to produce trypsin, which into the pancreatic duct is accompanied by water.
then undergoes autocatalysis to produce more tryp-
sin. Trypsin also activates other pancreatic proen-
zymes; for example, prophospholipase A2 and How are pancreatic secretions
proelastase. One of the hallmarks of severe acute
pancreatitis is haemorrhagic necrosis of the pancreas:
controlled?
Phospholipase A2 digests pancreatic cell mem- Between meals, there is very little secretion of pancre-
brane phospholipids, causing necrosis. atic fluid. However, when food enters the stomach,
Elastase digests blood vessel walls, causing and especially when chyme enters the duodenum,
haemorrhage. secretion of pancreatic fluid is strongly stimulated.
Secretion of pancreatic fluid has both neural and
As pancreatic cells are digested, inflammatory medi-
humoral control mechanisms:
ators (most notably TNF-α and IL-1) are released,
causing a severe SIRS. Pancreatic lipase is released Neural. The pancreas is innervated by the vagus
nerve; when activated during the cephalic phase of
289
Interstitium Pancreatic ductal cell Pancreatic duct lumen
Catalysed by
carbonic anhydrase
CO2
H2O
CO2 diffuses
into ductal cell HCO3−/Cl− exchanger
H2CO3
Na+/H+ exchanger End result: bicarbonate
secretion
H+ H+ + HCO3− HCO3−
Cl− Cl−
Na+ Na+
Affected in cystic fibrosis

K+ K+
H2O H2O
Basolateral
Na+/K+-ATPase
Water diffuses, following
osmotically active HCO3−
Figure 60.1 HCO3 synthesis in the pancreatic ductal cells.
digestion (anticipation of a meal), there is a small How does intestinal motility differ in
increase in pancreatic acinar cell activity.
Gastrin. This hormone is secreted by the G cells of the fed and fasted states?
the stomach in response to gastric distension. As In the fed state, the contractions of the small intestine
well as stimulating gastric acid secretion by the are designed to:
parietal cells of the stomach, gastrin also Promote mixing of chyme with digestive enzymes
stimulates pancreatic acinar cells to secrete and bile salts.
digestive enzymes in preparation for the arrival of Propel chyme along the small intestine to the large
carbohydrates, proteins and fats. This is a feed- intestine.
forward control system.
CCK. This hormone is secreted by the duodenal The two types of contractions of the small intestine
mucosal cells in response to fat- or protein-rich reflect these two functions:
chyme entering the duodenum. As well as Segmental contractions. Contraction of the
increasing the production of bile in the liver, circular smooth muscle in neighbouring segments
stimulating contraction of the gallbladder and compartmentalizes a section of bowel. This is
slowing gastric emptying, CCK stimulates the followed by continuous contraction and relaxation
pancreatic acinar cells to secrete digestive enzymes. of the longitudinal muscle, which results in the
This is a negative-feedback control system. mixing of chyme with digestive enzymes rather
Secretin. This hormone is secreted by the than its propulsion along the GI tract. Segmental
duodenal mucosa in response to the presence of contractions also bring chyme in contact with the
acid-containing chyme in the duodenum. As well brush border, promoting nutrient absorption.
as slowing gastric emptying, secretin stimulates Propulsive contractions. Highly coordinated
the duct cells of the pancreas to secrete HCO3 to contraction of the circular muscle behind the food
neutralize the chyme. bolus and longitudinal smooth muscle results in
290
propulsion of chyme along the GI tract. Each autonomously, with inputs from the sympathetic
peristaltic wave lasts only a few seconds, travelling and parasympathetic nervous systems:
at only a few centimetres per second. – The sympathetic nervous system, through
In the fasted state, there are infrequent, irregular synapses in the prevertebral ganglia, causes
contractions of the small intestine. Every 90 min there inhibition of the enteric nervous system,
is a period of intense coordinated intestinal contrac- reducing intestinal motility and GI secretions.
tion, spreading from the duodenum to the ileocaecal In addition, blood flow to the gut is reduced by
valve; this is known as the migrating motor complex splanchnic vasoconstriction.
(MMC). It takes about 90 min for the contraction to – The parasympathetic nervous system, through
sweep along the length of the small intestine, moving the vagus nerve, causes an increase in intestinal
undigested chyme towards the colon. motility and stimulates GI secretions; the
parasympathetic nervous system is thus often
referred to as the ‘rest and digest’ system.
How is intestinal motility controlled? The endocrine system. Whilst a number of
Like nerve cells, the smooth muscle cells of the small hormones are involved in the modification of
intestine have a negative RMP ( 40 to 70 mV). gastric motility (for example, CCK and secretin),
Contraction of smooth muscle occurs when the mem- the endocrine control of intestinal motility is less
brane potential exceeds threshold potential; opening well understood.
of voltage-gated channels permits a sudden influx of
– Motilin is a hormone released from the
Na+ and Ca2+, which depolarizes the cell membrane
duodenal mucosa every 90 min during fasting,
and stimulates contraction.
and is responsible for stimulating the MMC.
Normally, the smooth muscle cell membrane
The stimulus for the release of motilin is
potential fluctuates 20–30 times per minute, in a
unknown. Erythromycin is a motilin agonist,
pattern called slow waves. The fluctuations in cell
which is why it is used as a pro-kinetic in the
membrane potential are insufficient to exceed thresh-
intensive care unit.
old potential by themselves. Instead, they help to
– Vasoactive intestinal peptide (VIP) has multiple
coordinate depolarizations and contractions of the
effects on the GI tract. In the small intestine it
GI tract. The presence of a food bolus stretches the
increases secretion of water and electrolytes
intestinal walls and triggers the release of neurotrans-
and stimulates intestinal motility. This is why
mitters, which cause a small depolarization of the cell
VIP overproduction due to a VIPoma usually
membrane. The threshold potential is exceeded when
presents with watery diarrhoea.
the next slow wave occurs, resulting in a spike poten-
tial: smooth muscle contraction is triggered.
Small intestinal motility is influenced by inputs
Further reading
L. G. Collis, D. J. Chambers, B. Carr.
from both the nervous and endocrine systems: Hypertriglyceridaemia-induced acute pancreatitis: is
The enteric nervous system. This extensive plasmapheresis really indicated? J Intensive Care Soc
nervous system controls the GI tract. It consists of 2014; 15(1): 66–9.
efferent and afferent neurons, converging on two L. R. Johnson. Gastrointestinal Physiology: Mosby Physiology
types of ganglion: the myenteric (Auerbach’s) Monograph Series, 7th edition. Mosby, 2006.
plexus and the submucosal (Meissner’s) plexus. K. Barrett. Gastrointestinal Physiology, 2nd edition. Lange,
The enteric nervous system operates semi- 2006.
291
Chapter
Liver anatomy and blood supply
61
autoregulation fails and blood flow becomes
Describe the blood supply to the liver pressure dependent.
The liver is the largest solid organ in the body (the
skin is overall the largest organ), and receives a large In contrast, the portal vein has very little smooth
volume of blood. At rest, the liver receives around muscle, so it cannot regulate blood flow in the
25% of the CO (approximately 1500 mL/min). Unlike same way. Instead, blood flow is proportional to
other organs, the liver receives a dual blood supply: the pressure gradient in the portal vein.
The right and left hepatic arteries, branches of the The two different sources of hepatic blood
coeliac artery, contribute approximately one-third have a semi-reciprocal relationship, referred to as
of the blood supply to the liver (500 mL/min). the hepatic arterial buffer response. If portal vein
blood flow falls, the hepatic arteries maintain
– Blood from the hepatic arteries is fully overall liver blood flow through a vasodilatation
oxygenated (SaO2 of 98–100%). response, involving adenosine as the chemical
– Whilst the hepatic arteries only supply one- mediator. However, if hepatic arterial blood flow
third of the blood to the liver, they supply falls, the portal vein cannot compensate (this is
nearly half of its O2. why the relationship is semi-reciprocal).
The portal vein accounts for the remainder of the Extrinsic mechanisms. The hepatic vessels are
blood supply to the liver (1000 mL/min). The term innervated by the sympathetic nervous system:
portal refers to a vein that connects two capillary
– In the hepatic artery, increased sympathetic
systems. Blood in the portal vein flows between the
activity causes vasoconstriction.
capillary networks of the abdominal organs
(intestines, stomach, spleen and pancreas) and the – Perhaps more important is the effect of
liver. Because the blood has already passed through sympathetic nervous activity on the portal vein,
the abdominal organs, its SaO2 saturation is lower: portal venules and hepatic veins. Around
500 mL of blood is stored within these
– In the fasting state, portal blood has an SaO2 capacitance vessels. Sympathetic stimulation
saturation of approximately 85%. increases the tone of the vessels, resulting in
– In the fed state, portal blood has an SaO2 around 250 mL of blood being returned to the
saturation of approximately 70%. circulation. Together with the splanchnic
capacitance vessels, around 1000 mL of blood
can be mobilized at times of physiological stress.
How is hepatic blood flow regulated?
Because of its dual blood supply, regulation of hepatic
blood flow is more complicated than that of other How does the respiratory cycle affect
organs. Hepatic blood flow is regulated by intrinsic hepatic venous blood flow?
and extrinsic mechanisms: During spontaneous breathing, hepatic venous blood
Intrinsic mechanisms. In common with other flow is increased during inspiration as a result of
arterial systems, hepatic arterial blood flow negative intrathoracic pressure. During expiration,
remains relatively constant despite changes in the opposite occurs.
arterial pressure as a result of autoregulation In contrast, positive pressure ventilation causes a
(see Chapter 32). Below a MAP of 60 mmHg, decrease in hepatic venous blood flow as a result of
292
Chapter 61: Liver anatomy and blood supply
positive intrathoracic pressure. Likewise, PEEP – The point where the portal vein, common bile
increases intrathoracic pressure, which results in a duct and hepatic artery enter the liver is
reduced hepatic venous blood flow. known as the hilum or porta hepatis.
– An imaginary line between the gallbladder
Clinical relevance: intraoperative liver blood flow fossa and IVC (called ‘Cantlie’s line’) separates
Intraoperatively, liver blood flow is altered by both the functional right and left halves of the liver
anaesthetic and surgical factors: (this is not the falciform ligament). The vessels
Anaesthetic factors: of the porta hepatis divide into right and left
– Positive pressure ventilation and PEEP – as
branches at this point.
discussed above.
– Drugs – volatile agents and vasopressors From a surgical perspective, the Couinaud classi-
reduce hepatic arterial blood flow. fication is much more useful: any given lobe can
– Minute ventilation – hypocapnoea continue its normal function when neighbouring
reduces portal vein blood flow whilst lobes are resected.
hypercapnoea increases flow through the
portal vein.
– Regional anaesthesia – neuraxial blockade Describe the microscopic anatomy
reduces hepatic blood flow to a similar extent of the liver
as general anaesthesia.
Like the macroscopic anatomy, the liver micro-
Surgical factors: Intraoperative retraction and
packing of the liver reduces hepatic blood flow architecture can be considered in terms of either a
significantly more than any of the above anaes- classical histological or a functional description:
thetic factors. Histological approach. The liver is composed of
tens of thousands of lobules (Figure 61.1). These
are hexagon-shaped arrangements with a branch
Describe the macroscopic anatomy of the hepatic vein at the centre:
of the liver – Radiating out from the central vein are
Liver anatomy is described in terms of either its columns of hepatocytes and hepatic sinusoids.
morphological anatomy or its functional anatomy: – At each of the six corners of the lobule is a
hepatic triad: a portal venule, hepatic arteriole
Morphological anatomy. Based on the external
and a bile duct.
appearance of the liver:
– The liver is divided into the right anatomical However, this classical model was derived from
lobe (much larger) and the left anatomical lobe studies of pig livers; human liver micro-architecture
by the falciform ligament. is more disorganized, with a large amount of
– When viewed from beneath, two extra small connective tissue and fewer well-defined lobules.
lobes can be seen between the right and left Functional approach. Current thinking considers
lobes. These are the caudate (posterior) and the functional unit of the liver to be the acinus.
quadrate (inferior) lobes. The elliptical acinus has a terminal branch of the
hepatic vein at either end, with two portal triads at
This morphological anatomy is not particularly useful
the midpoint of the flattened sides (Figure 61.2).
when it comes to hepatobiliary surgery.
Blood flows from the portal triad towards the
Functional anatomy. The Couinaud classification terminal vein. The further a hepatocyte is
divides the liver into eight functionally positioned from the portal triad, the lower the O2
independent lobes: tension. Each acinus is therefore said to have three
– Each of the eight lobes has its own blood zones of oxygenation – zones 1, 2 and 3:
supply derived from branches of the hepatic – Zone 1 is the area of the acinus closest to the
artery and portal vein, along with its own two portal triads, and is therefore the best
hepatic venous drainage and biliary drainage. oxygenated. The most energy-consuming
– The segments are numbered 1 to 8 in a clockwise processes (for example, gluconeogenesis and
direction, starting from the caudate lobe. β-oxidation of fatty acids) occur in zone 1.
293
Portal triad Figure 61.1 The hepatic lobule.
Central vein
Hepatic lobule
Zones of oxygenation Figure 61.2 The hepatic acinus.
3 2 1 2 3
Acinus
– Zone 2 is an intermediate area where there are other non-parenchymal cells: sinusoidal,
hepatocytes carry out processes characteristic peri-sinusoidal and biliary epithelial cells.
of both zone 1 and zone 3. Hepatocytes are highly specialized cells that are
– Zone 3 is the area of the acinus closest to the arranged in columns, making up about 80% of the
terminal vein, and is therefore the area of lowest volume of the liver. They perform a wide range of
O2 tension. The hepatocytes of zone 3 carry out metabolic, synthetic and exocrine functions (see
the least energy-consuming processes; for Chapter 62).
example, glycolysis and drug metabolism.
Within the column of hepatocytes are small
channels called bile canaliculi (Figure 61.3). The
What are the different cell types within hepatocytes secrete bile into the canaliculi. Bile
the liver? flows from canaliculi to bile ductules, and then to
The liver has two main cell types: hepatocytes (60% by bile ducts. Bile ducts merge and exit the liver as the
mass) and Kuppfer cells (10% by mass). In addition, common hepatic duct. On either side of the
294
Chapter 61: Liver anatomy and blood supply
Figure 61.3 Hepatocytes, canaliculi and

Portal venule sinusoids.
Hepatic arteriole
Kuppfer cell
Bile Bile Hepatocyte
Bile canaliculus
Hepatic sinusoid
Peri-sinusoidal space
Hepatic venule
hepatocyte columns are blood-filled spaces called

Clinical relevance: centrilobular necrosis
hepatic sinusoids. Oxygenated blood flows from
Centrilobular necrosis (zone 3 of the acinus) is a
the hepatic arteriole and portal venule towards a
common histological finding in severe liver disease,
branch of the hepatic vein. The sinusoidal due to:
epithelial cells have very large fenestrations and Hypoxic injury. Owing to their distance from the
lack gap junctions, making them highly permeable portal triad, the hepatocytes of zone 3 are the
(see Chapter 34). Substances within the blood most susceptible to hypoxic injury. Centrilobular
(nutrients, drugs, toxins, etc.) are filtered through necrosis is often found on liver biopsy of patients
the sinusoidal epithelial cells to the peri-sinusoidal with severe sepsis complicated by hepatic
space, where they come into contact with the dysfunction.
hepatocytes (Figure 61.3). Drug metabolism. Zone 3 is the main site
of drug metabolism; toxic metabolites
Kuppfer cells are specialized macrophages that line
produced by the cytochrome P450 enzyme
the walls of the hepatic sinusoids (Figure 61.3). system may cause damage to local hepatocytes.
Their role is to destroy bacteria or other foreign Zone 3 is the site of accumulation of the toxic
material contained within the venous blood flowing paracetamol metabolite NAPQI in paracetamol
from the GI tract. They also remove worn-out overdose.
RBCs and leucocytes from the circulation.
295
Halothane hepatitis exemplifies both of the above. 50%. The mechanism is thought to be auto-
Following halothane exposure, a patient can develop immune: trifluoroacetyl metabolites bind to
two types of hepatocyte injury: hepatocyte proteins in zone 3, forming a hapten
Type I halothane hepatitis is characterized by a complex that activates the immune system.
mild transient postoperative rise in serum liver Antibodies are produced that target these
enzymes. Halothane is metabolized in zones hepatocyte–metabolite complexes, resulting in
2 and 3 by cytochrome P450, usually through an massive centrilobular necrosis and fulminant liver
oxidative pathway resulting in the metabolite failure.
trifluoroacetic acid. A small amount of metabol-
ism occurs through a reductive pathway; this is
favoured by the relatively hypoxic environment
of zone 3. This reductive pathway generates free Further reading
radicals, which damage hepatocytes. J. A. Hinson, D. W. Roberts, L. P. James.
Type II halothane hepatitis is a rare complica- Mechanisms of acetaminophen-induced liver
tion of halothane anaesthesia with a mortality of necrosis. Handb Exp Pharmacol 2010; 196:
369–405.
296
Chapter
Liver function
62
The liver acts as the body’s chemical plant, synthesiz- Carbohydrate metabolism. Many metabolic
ing and eliminating a huge number of molecules for a processes occur in the liver in order to maintain a
variety of purposes. A healthy liver has some import- normal plasma glucose concentration:
ant features: – Glycolysis. Like all other cells, the liver
A huge physiological reserve. Even if 80% of liver produces energy by transforming glucose into
is removed, it can continue to carry out all of its pyruvate.
physiological functions. – Glycogenesis. Following a meal, plasma glucose
Regeneration. In contrast to the other organs, concentration rises, which causes insulin to be
following resection of up to three-quarters of the released from the pancreas. In the liver, insulin
liver, active mitosis can regenerate a normal liver stimulates the polymerization of excess glucose
mass. This amazing ability of the liver has been into its storage form, glycogen. Up to 100 g of
used in transplantation medicine: living donor glucose can be stored in this way.
transplantation involves transplanting four – Glycogenolysis. When plasma glucose
segments of the right lobe (50–60% of the liver concentration falls between meals, insulin
mass) from a live donor to a recipient. In the secretion is reduced and glucagon is released
donor, the remaining liver regenerates to full from the pancreas. In response to glucagon
size within 6–8 weeks; in the recipient, secretion, the liver releases glucose by breaking
regeneration takes a little longer. Eventually, both down its glycogen store.
donor and recipient have fully functioning, – Gluconeogenesis. When plasma glucose
normal-sized livers. concentration is low, glucagon also simulates
the liver to synthesize glucose from non-
carbohydrate precursors (for example, amino
Classify the functions of the liver acids, lactate and glycerol).
The functions of the liver are varied, and can be
Fat metabolism. Lipid is the body’s most efficient
broadly classified as:
method of energy storage. The liver is involved in
metabolic lipid metabolism in a number of ways:
exocrine
– Lipid breakdown. Energy is extracted from free
endocrine fatty acids as they are metabolized in a process
immunological called ‘β-oxidation’ within the hepatocyte
synthetic mitochondria.
hepatic clearance of drugs – Lipid synthesis. The liver synthesizes
a number of additional miscellaneous triglyceride from excess glucose. Cholesterol is
functions. also synthesized in the liver. Cholesterol is
used as a structural component of cell
membranes, and as a precursor for steroid
What are the metabolic functions hormone and bile salt synthesis.
of the liver? – Lipid processing. Apolipoproteins are
The liver has a vast array of metabolic functions (see synthesized in the liver. These are involved in
Chapter 72), the most important of which are: the packaging of cholesterol and triglyceride as
297
low-density lipoprotein (LDL), very low – The micelles then make contact with
density lipoprotein (VLDL) and high-density enterocytes, which absorb the lipid contents.
lipoprotein (HDL). The fat-soluble vitamins (vitamins A, D, E
Protein metabolism: and K) are also absorbed by this micelle-
– Deamination. Individual amino acids have mediated mechanism.
their amino groups removed by the liver. The The bile salts are left behind in the gut lumen, and
resulting carbon skeleton (a keto acid) can be absorbed at the terminal ileum. The bile salts
used for energy in the citric acid cycle (see travel back to the liver through the portal vein,
Chapter 72), transformed into another amino where they are reused.
acid or used as a substrate for gluconeogenesis.
Bile is the main route of excretion of bilirubin
– Urea formation. The other product of metabolites, also known as bile pigment. The
deamination is NH3. This is detoxified in the metabolism of bilirubin is complex (Figure 62.1):
liver through conversion to urea or glutamine.
– Amino acid synthesis. Keto acids can be – RBCs are taken up by the spleen when they get
transformed into non-essential amino acids by old or damaged.
transamination, taking an amino group from – In the spleen, Hb is broken down (1) and its
one amino acid and transferring it to a keto useful components recycled: the globin chain
acid, forming a new amino acid. Essential is broken down into its constituent amino
amino acids are only found in the diet. acids, and the Fe2+ ion is bound to transferrin
– Protein synthesis. The liver synthesizes most and transported to the bone marrow for use in
plasma proteins, with the exception of erythropoiesis (see Chapter 69). However, the
immunoglobulins and some hormones body cannot make further use of the
(see below). porphyrin ring.
– Within the macrophages of the spleen, the
porphyrin ring is oxidized to biliverdin and
What are the exocrine functions then reduced to bilirubin (2).
of the liver? – This unconjugated bilirubin is not water
soluble, so is bound to albumin and transported
The liver is an important exocrine organ as it secretes
to the liver for further processing (3).
bile:
– In the liver, the hepatocytes take up bilirubin
Around 1000 mL of bile is produced by the and conjugate it to glucuronic acid, making it
hepatocytes per day. This is then concentrated to a water soluble (4). The enzyme responsible for
fifth of its volume within the gallbladder. this process is glucuronosyltransferase.
The main constituents of bile are water, – This conjugated bilirubin is excreted with the
electrolytes, bile salts, bile pigment, cholesterol bile into the small intestine (5). Almost all of
and phospholipids. the conjugated bilirubin in the small intestine
Bile acids are produced through the oxidation of ends up being reabsorbed (6), transported to
cholesterol. Bile salts, the Na+ and K+ salts of bile the liver in the portal vein and re-secreted into
acids, have an essential role in the emulsification the small intestine; this is known as
of dietary lipid: ‘enterohepatic circulation’. However, some
– Bile salts are amphipathic: they are conjugated bilirubin inevitably passes into the
hydrophobic at one end and hydrophilic at large intestine.
the other. – In the large intestine, conjugated bilirubin is
– Bile salts surround the dietary lipid, breaking converted into urobilinogen by colonic
up large fat droplets into a suspension of small bacteria (7). Urobilinogen has two fates: it may
fat droplets. be oxidized further to urobilin and stercobilin
– Formation of these micelles is essential; (8) and excreted with faeces (stercobilin gives
without them, pancreatic lipase is unable to act faeces its brown colour). Alternatively,
on the dietary lipid in their core. urobilinogen may be reabsorbed by the gut (9)
298
Chapter 62: Liver function
Globin Fe2+
SYSTEMIC CIRCULATION (1) Hb breakdown
(3) (Unconjugated) bilirubin transported in the blood by albumin

Porphyrin ring
(10) Urobilinogen not taken up by the liver reaches the systemic circulation
Biliverdin
(2) Bilirubin
LIVER
SPLEEN
Unconjugated bilirubin Urobilinogen
(4)
Conjugated bilirubin
Urobilinogen
BILIARY SYSTEM
KIDNEY
(5)
Urobilinogen
excreted into intestine
via biliary system
(11) Urobilinogen
excreted in urine
(6) (9)
Conjugated bacteria Further
Conjugated bilirubin Urobilinogen Urobilin + stercobilin Faeces
bilirubin oxidation
(7)
(8)
SMALL INTESTINE LARGE INTESTINE
Figure 62.1 Bilirubin metabolism and excretion.
and transported via the portal vein to the liver

(i.e. enterohepatic circulation). Hepatic uptake unconjugated bilirubin is filtered by the glom-
erulus, so urinary dipstick is negative for bilirubin.
of urobilinogen is incomplete, so some reaches
the systemic circulation (10) and is excreted by Although anatomically within the liver, condi-
the kidney (11), giving urine its yellow colour. tions involving the failure of bilirubin conjugation
are often included with the ‘pre-hepatic’ causes
Clinical relevance: jaundice of jaundice; for example, neonatal jaundice
Jaundice (plasma bilirubin concentration of >30 (as a result of immature glucuronosyltransferase
μmol/L) may be caused by excessive RBC breakdown, enzyme) and Gilbert’s syndrome (a common
or a failure of any of the excretory mechanisms genetic disorder where there is reduced activity
described above: of the glucuronosyltransferase enzyme). As the
Pre-hepatic jaundice – increased bilirubin as a problem is conjugation of bilirubin, the plasma
result of increased RBC breakdown; for example, concentration of unconjugated bilirubin is high.
haemolytic anaemia due to blood transfusion, Post-hepatic jaundice – failure of excretion of
sickle cell crisis or malaria. The large amount of conjugated bilirubin in the bile; for example, as a
bilirubin produced far exceeds the liver’s capacity result of a gallstone obstructing the common bile
to conjugate – jaundice is therefore the result of duct. When the normal route of bilirubin excre-
a high plasma concentration of unconjugated tion is blocked, conjugated bilirubin instead
bilirubin. Because it is water insoluble, no enters the systemic circulation resulting in a high
299
and must travel through the liver before reaching

plasma concentration of conjugated bilirubin. As
conjugated bilirubin is water soluble, it is freely the systemic circulation. These microorganisms
filtered at the glomerulus and excreted in the are phagocytosed by the Kuppfer cells, specialized
urine; dipstick is therefore positive for bilirubin. macrophages that line the sinusoids (see
As conjugated bilirubin does not enter the small Chapter 61).
intestine, urobilinogen and stercobilin are never Initiation of inflammation. Like other
formed; faeces is therefore pale in colour. macrophages, Kuppfer cells can initiate an
Hepatocellular jaundice – hepatocyte necrosis inflammatory response by the secretion of pro-
and disruption of the biliary tree lead to a inflammatory cytokines.
reduced ability to conjugate and excrete biliru-
Protein synthesis. In addition, the liver is a key
bin. Causes include cirrhosis, acute viral hepatitis
and paracetamol toxicity. Whether conjugated or
part of the innate immune system, synthesizing
unconjugated bilirubin predominates depends the complement proteins and C-reactive protein.
on the relative degrees of hepatocyte dysfunc-
tion compared with biliary duct disruption.
Which substances are synthesized
by the liver?
The liver is such an important synthetic organ that it
What are the endocrine functions would be much quicker to list the substances not
synthesized by the liver! In addition to the substances
of the liver? already described above, the liver synthesizes:
The liver has an array of endocrine roles, extending
Haemostatic substances. Clotting factors
beyond the secretion of hormones: I (fibrinogen), II (prothrombin), V, VII, IX, X, XI,
Secretion of hormones – including antithrombin III, protein C and protein
angiotensinogen, thrombopoietin, hepcidin S. Clotting factors II, VII, IX and X, protein C and
(see Chapter 69) and insulin-like growth factor 1 protein S are referred to as the vitamin-K-
(IGF-1). dependent clotting factors because vitamin K is
Synthesis of hormone binding proteins – for required as a cofactor in their synthesis, which
example, thyroxine-binding globulin and sex involves vitamin-K-catalysed γ-carboxylation.
hormone-binding globulin. Plasma transport proteins. For example:
Activation of hormones – thyroxine (T4) is – Albumin (see Chapter 71).
converted into either the activated thyroid
– α-globulins – for example, haptoglobin binds
hormone triiodothyronine (T3), or inactivated
free Hb released from RBCs as a result of
(to reverse T3) (see Chapter 76). Vitamin
haemolysis; ceruloplasmin transports copper;
D undergoes the initial part of its activation in the
thyroxine-binding globulin transports
liver (the 25-hydroxylation of cholecalciferol).
thyroxine.
Inactivation of hormones – the liver inactivates
– β-globulins – for example, transferrin binds
many hormones, including aldosterone, ADH and
iron in its ferric form (Fe3+); sex hormone-
oestrogen. Insulin is worth a special mention: up
binding globulin binds androgens and
to half the insulin released by the pancreas into the
oestrogen.
portal vein is inactivated by the liver before it
– α1-acid glycoprotein – transports basic and
passes into the systemic circulation.
neutrally charged drugs.
What are the immunological functions Of note is that immunoglobulins, the most
important subgroup of the γ-globulins, are not
of the liver? synthesized in the liver. They are made by plasma
The liver is an extremely important immunological cells (see Chapter 70).
organ, with a number of roles: Serine protease inhibitors. α1-Antitrypsin is
Phagocytosis. Ingested bacteria, viruses and synthesized in the liver. It protects the body’s
parasites in the GI tract pass into the portal vein tissues from the damaging enzymes released by
300
activated inflammatory cells; for example,

neutrophil elastase. The importance of – Patients fall into two categories of acetylation:
fast and slow. Drugs that are metabolized by
α1-antitrypsin is seen when it is genetically
acetylation (for example, isoniazid) have very
deficient – the tissues of the lungs and liver are
different half-lives depending on whether the
attacked by neutrophil elastase: patient has fast or slow acetylation status.
– In the lung, chronic destruction of elastic – Alcohol metabolism involves two phase
tissue results in COPD, even in the absence of 1 oxidation reactions; the enzymes involved
cigarette smoking. are alcohol dehydrogenase and acetaldehyde
– In the liver, chronic inflammation results in dehydrogenase. Fifty per cent of patients of
Chinese origin lack an effective acetaldehyde
cirrhosis.
dehydrogenase enzyme, resulting in an
increased incidence of acute alcohol intoxi-
How does the liver metabolize drugs? cation and alcohol-flush reaction, due to slow
Drug metabolism is divided into three phases: ethanol metabolism and increased plasma
acetaldehyde concentration respectively.
Phase 1: modification. The hepatocytes use their
Interaction of enzymes with other drugs.
cytochrome P450 enzyme system to make the
Certain drugs increase (induce) or decrease
drug more polar (and therefore more
(inhibit) the activity of the cytochrome P450
hydrophilic). The main chemical reactions enzyme system:
involved are oxidation, reduction and hydrolysis. – Drugs that induce hepatic enzymes –
The resulting metabolites may be physiologically phenytoin, carbamazepine, barbiturates (not-
active, in some cases more active than the parent ably phenobarbitone), rifampicin, alcohol
drug. If the metabolites are sufficiently (chronic abuse), smoking (induces the
water soluble they can be excreted at this point. enzyme CYP 1A2, involved in the metabolism
If not, they progress to undergo phase 2 of drugs such as olanzapine and
reactions. aminophylline). Mnemonic: PC BRAS.
– Drugs that inhibit hepatic enzymes –
Phase 2: conjugation. The drug, or the product of
omeprazole, allopurinol, disulfiram,
a phase 1 reaction, is attached to a polar molecule
erythromycin, valproate, isoniazid, cimetidine,
such as glucuronic acid, acetate or sulphate. The ethanol (acute alcohol binge), sulphona-
process is called glucuronidation, acetylation and mides. Mnemonic: OA DEVICES.
sulphation respectively. The consequence of
For example:
conjugation is the production of water-soluble – The oral contraceptive pill is metabolized
metabolites of the drug ready for excretion in bile more quickly by patients taking enzyme
or urine. inducers, leading to a risk of pregnancy.
Phase 3: excretion. This recently discovered phase – Ciclosporin metabolism may be slowed,
involves ATP-dependent excretion of drug potentially leading to toxicity in patients who
metabolites into the bile. are given enzyme inhibitors, such as a course
of the pro-kinetic erythromycin in intensive
Clinical relevance: factors affecting drug care.
metabolism
There is considerable inter-patient variability in the
rate of drug metabolism, for a variety of reasons: Does the liver have any other
Genetic differences in phase 1 and phase 2 reac-
tions; for example: physiological roles?
– Codeine is a prodrug that is metabolized to In addition to the many functions described above,
morphine by the enzyme CYP 2D6 in the liver. the liver has a number of other functions:
Approximately 6% of Caucasians have an Storage. As well as storing glycogen, the liver is
inactive or dysfunctional CYP 2D6 enzyme;
the main site of iron, copper and fat-soluble
these patients do not gain any analgesic
vitamin storage.
effects from codeine (but often still have the
side-effects of nausea and constipation). Haematological. In the first trimester, the fetal
liver is the main site of erythropoiesis. In addition,
301
old or damaged RBCs are removed from the venous pressure were to rise, venous drainage
circulation by the liver’s Kuppfer cells (though the of the spleen would become impaired and the
spleen carries out the majority of this role). spleen engorged – over time, splenomegaly
Blood reservoir. As discussed in Chapter 61, the occurs. An increased number of platelets and
liver can release up to 250 mL of venous blood erythrocytes are removed from the circulation,
into the systemic circulation in response to resulting in thrombocytopaenia and anaemia
sympathetic stimulation. respectively.
– Portocaval anastomoses – high portal venous
pressure opens collateral vessels between the
What physiological changes occur portal and systemic circulations. These vessels
become dilated and engorged, leading to
in cirrhosis? oesophageal varices, rectal varices and caput
There are many causes of chronic liver failure, includ- medusae. These engorged veins, especially
ing viral hepatitis, alcohol, steatohepatitis, metabolic oesophageal varices, are liable to mechanical
diseases (for example, Wilson’s disease, haemochro- damage that may result in a potentially
matosis), biliary disease (primary biliary cirrhosis, catastrophic haemorrhage. Nitrogen-
primary sclerosing cholangitis) and autoimmune containing molecules from the portal blood
hepatitis. Whatever the cause, chronic inflammation are able to pass directly into the systemic
and scarring of the liver results in cirrhosis – a disor- circulation without first traversing the liver,
ganized mixture of hepatocyte fibrosis and regener- increasing the risk of hepatic encephalopathy.
ation. Cirrhosis results in the following.
Alteration of liver function, leading to: What are liver function tests?
– Disturbed carbohydrate metabolism, resulting Liver function tests (LFTs) are laboratory tests that
in hyper- or hypoglycaemia. help to diagnose and monitor liver disease or damage.
– Decreased protein synthesis, resulting in However, because of the large physiological reserve of
clotting abnormalities and hypoalbuminaemia, the liver, LFTs may remain normal until a significant
which predisposes to oedema and alters the reduction in liver function has occurred. LFTs can
protein binding of drugs. divided into:
– Altered drug metabolism, which may be Tests of liver synthetic function: albumin and
considerably slower. prothrombin time (PT).
– Inadequate clearance of NH3, leading to – Albumin has a plasma half life of 30 days.
hepatic encephalopathy (see below). Hypoalbuminaemia may be a useful measure
Alteration of liver anatomy, resulting in of liver function in chronic liver disease.
increased resistance to blood flow as fibrosis However, the long half-life of albumin,
disrupts and obstructs the sinusoids. The portal capillary leakage and protein catabolism make
vein is usually a low-pressure system, but in serum albumin a poor marker of liver
cirrhosis the increased resistance to blood flow synthetic function in acute liver disease.
increases portal vein pressure. Normal portal vein – PT is a test of the extrinsic pathway of
pressure is 5–10 mmHg – portal hypertension is coagulation (see Chapter 67). PT depends on
defined as a pressure >12 mmHg. Portal clotting factors II, V, VII and X, and
hypertension results in: fibrinogen. The liver is responsible for the
– Ascites – high venous hydrostatic pressure synthesis of all of these factors. The half-life of
leads to net fluid filtration into the peritoneal these clotting factors is <24 h; that is,
cavity. Ascites poses an especially high considerably shorter than albumin. Therefore,
infection risk, as the fluid is relatively stagnant PT acts as an effective measure of liver
and patients with cirrhosis are relatively synthetic function in acute liver dysfunction.
immunosuppressed. Tests of hepatic clearance: bilirubin (discussed
– Splenomegaly – venous blood from the spleen above) and NH3. Normally, NH3 is converted to
drains into the portal vein. Therefore, if portal urea by the liver. In severe liver dysfunction,
302
serum NH3 concentration rises. NH3 is implicated – ALT is present in the cytosol of hepatocytes.
in hepatic encephalopathy; as it is a small Therefore generalized hepatocellular injury
uncharged molecule, osmotically active NH3 is results in an increase in serum ALT. For
able to cross the BBB, leading to cerebral oedema example, ALT rises as a result of centrilobular
and encephalopathy. However, serum NH3 does necrosis in paracetamol overdose.
not correlate particularly well with the clinical
severity of hepatic encephalopathy. Clinical relevance: King’s College criteria for liver
transplantation
Serum hepatic enzyme tests: alkaline phosphatase
(ALP), γ-glutamyl transpeptidase (γ-GT) and Paracetamol overdose is relatively common, and liver
alanine aminotransferase (ALT). These tests are transplantation subjects the patient to a lifetime of
used to aid the exact diagnosis of hepatic immunosuppression. Following a paracetamol over-
dose, it is important to be able to predict which
dysfunction.
patients are likely to deteriorate and require a life-
– ALP is an enzyme concentrated in the biliary saving liver transplant. LFTs play a part in this predic-
canalicular membrane of the hepatocyte. tion. The King’s College criteria identify patients at
Disease of the biliary system causes release of risk of poor outcome following paracetamol over-
ALP into the systemic circulation. Very high dose. Liver transplantation is considered if either:
(greater than three times normal) ALP arterial pH is <7.3
suggests biliary obstruction, either intrahepatic or all three of PT >100 s (equivalent to an inter-
national normalized ratio (INR) of >6.5), serum
or extrahepatic. Of note, ALP occasionally
creatinine of >300 μmol/L, and hepatic enceph-
originates from sources other than the liver: alopathy grade III or IV.
kidney, bone and placenta.
– γ-GT is also raised in biliary obstruction; this
is because γ-GT is found in hepatocytes
surrounding the biliary canaliculi. In fact,
Further reading
A. Kortgen, P. Recknagel, M. Bauer. How to assess
γ-GT is found in similar tissues to ALP, except
liver function? Curr Opin Crit Care 2010; 16(2):
it is only present in low concentrations in 136–41.
bone. This may be diagnostically useful,
B. P. Sweeney, J. Bromilow. Liver enzyme induction and
distinguishing between bone and liver as the inhibition: implications for anaesthesia. Anaesthesia
origin of a high ALP. γ-GT is often elevated by 2006; 61(2): 159–77.
alcohol ingestion: a disproportionally raised
J. K. Limdi, G. M. Hyde. Evaluation of abnormal
γ-GT compared with ALP or ALT suggests liver function tests. Postgrad Med J 2003; 79(932):
alcohol abuse. 307–12.
303
Section 6 Kidney and body fluids
Chapter
Renal function, anatomy and blood flow
63
The blood supply to the kidneys is carried by the renal
What are the functions of the kidney? arteries, paired arteries that arise directly from the
The kidney has an array of functions that can be aorta. The right renal artery is longer, as the aorta is
classified and subclassified as: positioned slightly to the left of the midline. Some-
Homeostasis of blood composition, including: times there are also additional accessory arteries.
– Regulation of plasma volume and electrolyte Venous drainage of the kidneys is through the renal
concentration. veins, which drain directly into the IVC. The left renal
– Control of plasma osmolarity. vein is longer than the right owing to the position of
– Removal of waste products and drugs or their the IVC to the right of the midline.
metabolites.
– Gluconeogenesis – the kidney is a major Describe the histology of the kidney
gluconeogenic organ.
The functional unit of the kidney is the nephron
– Control of the metabolic aspects of acid–base (Figure 63.1), of which there are around 1 000 000
balance. per kidney. A nephron consists of:
Endocrine roles:
The glomerulus, a network of capillaries located
– EPO synthesis, which in turn controls RBC in the renal cortex that receive blood from the
production. afferent arteriole (see below). The layers of the
– Activation of vitamin D to 1,25- glomerulus control filtration:
dihydroxycholecalciferol.
– The glomerular capillary endothelium has
– Secretion of renin, the first hormone of the fenestrations large enough to allow free
RAA axis. filtration of fluid, solutes and proteins, but not
RBCs or albumin. Filtered fluid is collected in
Describe the anatomy of the kidney the surrounding Bowman’s capsule.
The kidneys are solid ‘bean-shaped’ retroperitoneal – The basement membrane is a relatively thick
organs located at vertebral levels T12 to L3. From layer of type IV collagen, laminins and
inside to outside, the kidney is surrounded by the heparan sulphate.
renal capsule, perirenal fat, renal fascia and pararenal – Podocytes are cells with negatively charged
fascia. At the midpoint of the concave medial border foot-like processes that control the passage of
of each kidney is the hilum, the point of entry of the certain substances into Bowman’s capsule.
nerves, vessels and lymphatics. In cross-section, the – Mesangial cells are also found in the
kidney contains: glomerulus, in between the capillary loops.
These are unusual cells: they are of smooth
An outer renal cortex.
muscle origin and their contraction plays a
An inner renal medulla, interrupted by renal
part in the regulation of filtration. Yet they
columns (extensions of the cortex) that penetrate
also have roles in structural support and
deep into the renal medulla.
phagocytosis.
Towards the hilum, minor calyces coalesce to
form major calyces, which merge to form the The fluid collected in Bowman’s capsule passes along
renal pelvis, and finally the ureter. a series of tubes, starting with:
305
Section 6: Kidney and body fluids
Afferent arteriole
Juxtaglomerular apparatus
Glomerular capillaries
Mesangial cell Distal convoluted tubule
Bowman’s capsule
Proximal
convoluted tubule
RENAL CORTEX
RENAL MEDULLA
Efferent arteriole
Collecting duct
Thin descending limb

of loop of Henle
Thick ascending limb

of loop of Henle
Thin ascending limb

of loop of Henle
Urine excretion
Figure 63.1 Structure of a nephron.
The PCT – a twisting tubule within the renal The collecting duct – the DCT becomes the
cortex where the majority of the filtered products collecting duct, before forming a minor calyx.
are reabsorbed. The collecting duct is an important site of
The loop of Henle (LOH) – the PCT straightens water reabsorption.
and then enters the medulla to become the thin
descending limb. This undergoes a hairpin bend The arterial blood supply of the nephron is unique:
to continue as the thin and then the thick The renal arterial tree divides as usual to
ascending limb of the LOH. The main role of the give afferent arterioles, which in turn divide to
LOH is to generate a longitudinal osmotic give rise to the glomerular capillaries. These
gradient in the renal medulla, which allows capillaries then unite to form efferent
controlled water reabsorption from the arterioles.
collecting ducts. By varying the relative resistances of the afferent
The DCT – the thick ascending limb of the LOH and efferent arterioles, glomerular capillary
returns to the renal cortex to form the DCT, the hydrostatic pressure, which is the main driving
site of regulated reabsorption. force for glomerular filtration, can be modified.
306
Chapter 63: Renal function, anatomy and blood flow
Glomerular filtration is therefore controllable (see time for reabsorption processes to occur in the
Chapter 64). tubules, resulting in a pressure diuresis.
The vasa recta are an additional set of arterioles Too low a flow results in ischaemia, particularly of
that arise from the efferent arterioles, whose role the relatively poorly vascularized medulla and
is to supply blood to the renal medulla. The vasa metabolically active PCTs, as well as a build-up of
recta also have an unusual feature: they descend toxic metabolites in the blood due to reduced
with the ascending limb of the LOH and ascend filtration.
with the descending limb, providing a
countercurrent flow of blood. This countercurrent For this reason, RBF is kept constant over a range of
arrangement is required to generate the high normal perfusion pressures (MAP 75–165 mmHg)
solute concentration gradients of the renal (Figure 63.2). This phenomenon is called renal auto-
medulla (see Chapter 65). regulation (see Chapter 32).
It is important to note that this anatomy results in What is the mechanism of renal
a well-vascularized renal cortex, but a relatively poor
blood supply to the renal medulla. This latter feature autoregulation?
prevents washout of solutes from the medullary inter- Both RBF and GFR are controlled through alterations
stitium, which are required for water reabsorption. in afferent and efferent arteriolar tone:
Constriction of either the afferent or efferent
What is the juxtaglomerular apparatus? arteriole increases the overall renal vascular
resistance, which reduces RBF.
The DCT folds back to lie anatomically very close to
its corresponding glomerulus. At this point are Constriction of the afferent arteriole reduces
located a group of specialized cells that form the glomerular capillary hydrostatic pressure, and
juxtaglomerular apparatus, consisting of three thus reduces GFR.
components: Constriction of the efferent arteriole increases
glomerular capillary hydrostatic pressure by
Granular cells, located within the wall of the
causing a build-up of blood in the glomerulus,
afferent arteriole, whose role is renin secretion.
which in turn increases GFR.
Macula densa cells, located at the junction of the
DCT and the thick ascending limb of the LOH. Therefore, separate control of these vessels allows
Macula densa cells sense tubular Na+ and Cl RBF and GFR to be determined independently.
concentration. The biological mechanism for autoregulation
Extra-glomerular mesangial cells. in the kidney is not completely elucidated. It is
divided into myogenic and tubuloglomerular feed-
The juxtaglomerular apparatus regulates RBF and the back mechanisms:
GFR (see p. 308).
Myogenic mechanism:
– When perfusion pressure increases, the afferent
How is renal blood flow regulated? arterioles are stretched. The arteriole responds
Despite only making up 1% of total body weight, the by contracting its smooth muscle, which
kidneys receive approximately 20% of the CO (1000 reduces the vessel diameter: vascular resistance
mL/min). Unlike tissues such as skeletal muscle, the increases, which keeps blood flow constant.1
kidneys receive far more blood than is required for – When perfusion pressure decreases, the afferent
their metabolic activity, reflecting their function arteriole responds by relaxing its smooth
of blood filtration. There is a greater proportion of muscle: vascular resistance is reduced, which
blood flow to the glomerulus (500 mL/100 g of tissue/ keeps blood flow constant.
min) than the medulla (outer medulla: 100 mL/100
g/min; inner medulla: 20 mL/100 g/min). 1
Stretching of the arteriolar smooth muscle opens
RBF must be tightly controlled:
mechanically gated non-specific cation channels, which
Too high a flow results in end-organ damage due cause depolarization of the arteriolar membrane, leading
to high pressure. In addition, there is insufficient to smooth muscle contraction.
307
Figure 63.2 Renal autoregulation.

Range of autoregulation
200
Glomerular filtration rate (mL/min)
150
125
100
50
0
0 50 75 100 150 165 200
Mean arterial pressure (mmHg)
Tubuloglomerular feedback: This mechanism is – The secondary messenger acts at adenosine A1

more complex. The juxtaglomerular apparatus receptors located within the juxtaglomerular
monitors the fluid flow through the DCT and apparatus, resulting in a reduction in RBF
adjusts glomerular filtration accordingly: and GFR:
– An increase in renal perfusion pressure leads ▪ Afferent arterioles vasoconstrict, which
to increased pressure within the glomerular increases renal vascular resistance, thereby
capillaries, and therefore increased glomerular reducing RBF.
filtration. This in turn increases the rate of ▪ Glomerular mesangial cells contract, which
delivery of Na+ and Cl ions to the reduces the surface area for filtration,
macula densa. thereby reducing GFR.
– The macula densa senses the Na+ and Cl ▪ Granular cells are inhibited from secreting
concentrations through its own Na+/K+/2Cl renin (see below).
co-transporter. The intracellular movement of
Na+, K+ and Cl ions is coupled with the The response to a decrease in renal perfusion
osmotic movement of H2O into the macula pressure is the opposite: the afferent arteriole
densa cell, causing cellular swelling in vasodilates, the mesangial cells relax and renin
proportion to the GFR. secretion is increased.
– An adenosine-based secondary messenger is
released in proportion to the degree of cell
swelling.2 How does the renin–angiotensin–
aldosterone axis regulate renal blood
2
It is not clear whether the secondary messenger is ATP, flow?
ADP or AMP. One potential mechanism is that, in order Renin is released from the granular cells of the juxta-
to reduce cell swelling, the activity of the basolateral Na+/ glomerular apparatus in response to:
K+-ATPase must be increased to remove Na+. This in
turn reduces the amount of intracellular ATP and
Decreased tubular flow, sensed by the macula
increases ADP and AMP, which then leak from the cell. densa as discussed above.
308
Chapter 63: Renal function, anatomy and blood flow
Low afferent arteriolar pressure, which directly How are eicosanoids involved in the
stimulates the release of renin. Granular cells
effectively act as ‘intra-renal baroreceptors’. regulation of renal blood flow?
Sympathetic nervous system stimulation, In situations where the concentrations of the circulat-
through β1 adrenoceptors. ing vasopressors noradrenaline and angiotensin II are
persistently high, including haemorrhage and sepsis,
Renin, a proteolytic enzyme, does not itself affect prolonged afferent and efferent arteriolar vasoconstric-
the vasculature. Renin cleaves the plasma protein tion causes a significant reduction in RBF. In response,
angiotensinogen (produced by the liver) into angio- the vasodilatory prostaglandins (PGE2 and PGI2),
tensin I, which is then converted into angiotensin II which oppose the effects of the circulating vasocon-
by ACE. The renin-mediated proteolysis of angioten- strictors, are produced locally within the kidney in an
sinogen forms the rate-determining, regulatory, step attempt to increase RBF and GFR. Patients who take
in this sequence. Angiotensin II increases systemic NSAIDs are less able to utilize this safety mechanism:
blood pressure, and therefore renal perfusion pres- NSAIDs inhibit the cyclo-oxygenase (COX) enzyme
sure, through a number of mechanisms: that is required for prostaglandin synthesis.
In the kidney, angiotensin II causes
vasoconstriction of both afferent and efferent Clinical relevance: pathophysiology of acute
arterioles, but has a greater effect on the efferent kidney injury
arterioles owing to their smaller basal diameter. Acute kidney injury (AKI) is defined as a rapid (<48 h)
The end result is an increase in systemic blood reduction in kidney function, as determined by a rise
pressure due to the increased vascular resistance in serum creatinine or a reduction in urine output.
of the renal arterioles, but with a relatively The causes of AKI may be classified as:
preserved glomerular capillary hydrostatic Pre-renal, in which severe hypovolaemia and
hypotension compromise RBF. As a consequence
pressure, and therefore GFR.3
of the reduction in glomerular capillary hydro-
In the systemic vasculature, angiotensin II is a static pressure, GFR falls. It is important to note
potent veno- and vasoconstrictor, thereby that pre-renal AKI is potentially reversible, as
increasing the systemic blood pressure. glomerular and tubular function remain intact.
In the adrenal gland, angiotensin II triggers Intrinsic renal, in which ischaemic, cytotoxic
the release of aldosterone from the zona or inflammatory insults cause structural damage
glomerulosa in the adrenal cortex. Aldosterone to the glomerulus or tubules. In contrast to
acts at the DCT and collecting duct of the pre-renal failure, this structural damage means
kidney, promoting the reabsorption of Na+ that intrinsic renal failure is not immediately
reversible once the causative factors have been
and water, thus expanding plasma volume
removed. The main causes of intrinsic renal AKI
(see Chapter 65).
may be classified according to anatomical
In the brain, angiotensin II acts on: location:
– The hypothalamus, where it increases the – Acute tubular necrosis (ATN), the most
sensation of thirst and triggers the release of common cause of intrinsic renal disease.
ADH from the posterior lobe of the pituitary The high metabolic activity and relatively
gland. ADH increases water reabsorption at poor blood supply make tubules particularly
susceptible to ischaemia. Prolonged renal
the collecting duct.
hypoperfusion results in tubular cell death.
– The sympathetic nervous system, where it ATN may also be caused by tubular toxins
directly increases noradrenaline release at such as myoglobin (due to rhabdomyolysis)
sympathetic neurons, resulting in arteriolar and aminoglycosides.
vasoconstriction. – Glomerular inflammation (glomerulonephritis)
centred on:
▪ The podocytes, known as minimal change
disease.
3
However, very high angiotensin II levels cause glomerular ▪ The basement membrane, as occurs in
mesangial cells to contract, reducing the glomerular Goodpasture’s disease.
filtration area, which leads to a significant fall in GFR.
309
Volume of urine excreted per unit time×½Xurine

▪ The mesangial cells; for example, IgA Clearance ¼
½Xplasma
nephropathy, in which IgA deposits in the
mesangial cells. Therefore, for PAH:
▪ The glomerular capillaries, following
antigen–antibody complex deposition in Volumeurine ×½PAHurine
systemic lupus erythematosus and
RPF ¼
½PAHplasma
rheumatoid arthritis.
– Acute interstitial nephritis, a hypersensitivity This method gives renal plasma flow, not renal blood
reaction to drugs such as NSAIDs, penicillins flow. RBF can be calculated using the haematocrit:
and allopurinol.
Post-renal, in which there is obstruction to the RPF
flow of urine. Raised tubular pressure decreases RBF ¼
1 haematocrit
glomerular filtration pressure, resulting in
decreased GFR.
RBF can be measured even more accurately by can-
nulating the renal artery and renal vein, sampling
the PAH concentration in each and applying the Fick
How can renal blood flow be principle. However, this is far too invasive to be used
measured? routinely. In either case, using PAH always underesti-
Measurement of RBF requires a substance that is both mates RBF as only 90% of the RBF supplies the
freely filtered and actively secreted into the tubule, so glomerulus – the remainder supplies the renal paren-
that all the substance entering the renal arteries passes chyma, so cannot be secreted into the tubules.
into the urine, with none in the venous outflow.
A substance that approaches these criteria is para- Further reading
amino hippuric acid (PAH). PAH is a small enough M. A. Ferguson, S. S. Walkar. Established and emerging
molecule (194 Da) to be freely filtered, and is later markers of kidney function. Clin Chem 2012; 58(4):
secreted into the tubules through the organic anion 680–9.
transporter (OAT1). Renal plasma flow (RPF) is then K. Karkouti. Transfusion and risk of acute kidney injury in
calculated by the clearance of PAH: cardiac surgery. Br J Anaesth 2012; 109(Suppl. 1):
i29–38.
PAH amount entering the kidney ¼ PAH amount appearing in urine
E. M. Moore, R. Bellomo, A. D. Nichol. The meaning of
Therefore: acute kidney injury and its relevance to intensive care
and anaesthesia. Anaesth Intensive Care 2012; 40(6):
RPF ¼ Clearance of PAH 929–48.
The clearance of a substance X is the volume of J. Mårtensson, C.-R. Martling, M. Bell. Novel biomarkers of
plasma completely cleared of X by the kidneys per acute kidney injury and failure: clinical applicability. Br
unit time (see Chapter 64), calculated as J Anaesth 2012; 109(6): 843–50.
310
Chapter
Renal filtration and reabsorption
64
– Plasma proteins are retained. When negatively
How does filtration occur in the kidney? charged plasma proteins approach the
The basic filtration unit of the kidney is the renal glomerular fenestrations, they are repelled by
corpuscle, consisting of a glomerulus surrounded by the negative charges of the glomerular
a Bowman’s capsule. The high glomerular capillary basement membrane and podocyte foot
hydrostatic pressure forces a fraction of the plasma processes.
(i.e. water and solutes) through the capillary wall and
– Small anions are filtered. Small anions do not
into the Bowman’s space. This filtration barrier is
come into close enough contact with the
composed of three layers:
glomerular membrane proteins to be repelled.
Glomerular capillary endothelium, a specialized In fact, a build-up of negatively charged
endothelium with large fenestrations. plasma proteins in the glomerular capillary
Glomerular basement membrane, a layer of results in a small additional repulsive force
supportive basal lamina. that drives anions through the fenestrations
Podocytes, the epithelial cells of Bowman’s and into Bowman’s space.
capsule. These cells have foot-like projections that
wrap around glomerular capillary endothelial A final determinant of whether a particle is filtered
cells, leaving slit-like openings between them. is the extent of its binding to plasma proteins: acidic
compounds bind to albumin, whilst basic compounds
It is important that filtration permits the passage of bind to α-1-glycoprotein. The extent of protein bind-
water and solutes but that the capillary retains blood ing is an important determinant in the clearance of
cells and proteins. This selectivity results from: many drugs.
The effective pore size of the glomerular
capillaries. This is determined by the size of the
capillary wall fenestrations and the spacing
What happens to the filtrate in
between podocyte foot processes: the renal tubules?
– Particles below 7 kDa are freely filtered into the Filtration results in a tubular fluid that contains not
Bowman’s space. only metabolic waste products but also useful solutes
– Particles above 70 kDa – for example, such as electrolytes, glucose and amino acids. The
immunoglobulins (around 150 kDa) – cannot nephron reabsorbs essential components.
pass between through the pores. Most of the reabsorption occurs in the PCT. Here,
– Between 7 and 70 kDa, partial filtration occurs. 67% of Na+, K+, Cl and water, 85% of HCO3 and
(in normal subjects) 100% of glucose and amino acids
Albumin (67 kDa) is just small enough to fit are reabsorbed. Reabsorption takes place through
through the pores, but filtration is prevented due to its active or passive processes:
negative charge (see below). Hb is a 69.8 kDa protein, Active reabsorption. The reabsorption of most
just small enough to be filtered. Hb must therefore substances is active (i.e. requires energy),
be sequestered within RBCs to prevent filtration. accounting for the high metabolic activity of the
Particle charge. Most plasma proteins are kidney. In the basolateral membrane of the
negatively charged, as their pKa is less than tubular cells, Na+/K+-ATPase ion pumps actively
physiological pH. As a result: extrude Na+ ions from the tubular cells into the
311
peritubular capillaries, in exchange for K+. The

resulting low intracellular Na+ concentration is changes, this accounts for the increased incidence of
glycosuria in pregnancy.
used to drive:
– Co-transporters – for example, the sodium–
glucose linked transporter (SGLT2) How else may substances be
responsible for glucose reabsorption.
– Counter-transporters – for example, the renally excreted?
Na+/H+ counter-transporter, which is involved The PCT also actively secretes waste products into the
in acid excretion. tubular filtrate. Secretion is an active, energy-
Passive reabsorption. Water is reabsorbed consuming process, in which substances are trans-
passively: the balance of Starling forces favours ported from the peritubular capillaries to the PCT.
bulk reabsorption of water (see Chapter 34). It allows more effective excretion of waste products
Some of the dissolved electrolytes and small than filtration alone. Of clinical importance, many
molecules such as urea are passively reabsorbed drugs are cleared from the blood with the aid of active
with water. secretion through two different carriers:
The organic anion transporter, which secretes a
Clinical relevance: hyperglycaemia number endogenous and exogenous anionic
substances; for example, uric acid, penicillin,
The reabsorption capacity of the co-transporters in
the PCT is limited. In the case of glucose, the SGLT2 probenecid and aspirin. Because the same
transporters have a maximum reabsorption capacity transporter is used for all substances and has a
Tmax of approximately 300 mg/min. Tmax is reached limited capacity for secretion, the presence of one
when filtrate glucose concentration is around substance affects the clearance of another. For
12 mmol/L. example, probenecid is secreted by the anion
This is relevant in diabetes mellitus: when plasma transporter in preference to penicillin; co-
glucose concentration exceeds the ability of the administration therefore reduces the clearance of
kidney to reabsorb, glucose will appear in the urine penicillin. This pharmacological interaction was
(Figure 64.1). exploited during World War II, when penicillin
GFR increases in pregnancy (see Chapter 77). As a
supplies were limited.
result, there is an increased filtration of glucose into
the renal tubules: Tmax is exceeded at a lower plasma The organic cation transporter, which secretes a
glucose concentration. Along with hormonal number of important cationic substances; for
example, creatinine, catecholamines and morphine.
Glucose excreted Figure 64.1 Reabsorption of glucose in

the PCT.
500
400
Glucose transport (mg/min)
300 Glucose reabsorbed
200
Tmax
100
0
0 10 20 30
Plasma glucose (mmol/L)
312
Chapter 64: Renal filtration and reabsorption
What is meant by the term ‘clearance’? πi and πo are the oncotic pressures inside and outside
The clearance of a given solute quantifies the capacity the glomerular capillary respectively.
of the kidney to eliminate that solute from the blood, NB: in a normal glomerulus, the reflection coeffi-
whether through filtration, reabsorption or secretion. cient σ approaches one as proteins are almost per-
fectly excluded and is therefore ignored (see
Key definition: renal clearance Chapter 34).
Clearance (mL/min) is the volume of plasma com-
pletely cleared of a substance by the kidneys per unit
time. The glomerular filtration coefficient Kf reflects
the ease with which fluid leaves the glomerular
capillaries under the forces acting across the
The concept develops from a simple conservation glomerular filtration barrier. It depends on
condition, in which pore size, which is essentially constant, and
Amount (i.e. moles) of X cleared from plasma ¼ surface area of the glomerular capillaries, which
Amount of X in urine can be altered a little through contraction and
relaxation of the glomerular mesangial cells
As moles ¼ volume × concentration: (see Chapter 63).
Volume of plasma filtered × [X]plasma The balance of Starling filtration forces
¼ Volume of urine excreted × [X]urine across the filtration barrier (see Chapter 34).
which rearranges to The attainment of high volumes of filtrate
requires a high driving hydrostatic pressure.
Volume of plasma filtered Glomerular capillary hydrostatic pressure is
Volume of urine excreted × ½Xurine much higher than that of capillaries elsewhere
¼ in the body. This is due to the unique
½Xplasma
arrangement of the afferent and efferent
Therefore: arterioles on either side of the glomerular
capillary (see Chapter 63).
Key equation: clearance
Clearance
A typical value of Pi is 48 mmHg, whilst Po is
10 mmHg. This gives a driving hydrostatic pressure
Volume of urine excreted per unit time × ½Xurine
¼ across the glomerular capillary of 38 mmHg.
½Xplasma
Oncotic pressure is a measure of the number of
osmotically active particles within a compartment.
πi is the result of the osmotic properties of plasma
What is glomerular filtration rate? proteins and is typically 25 mmHg. In contrast, as
How is it related to the Starling essentially no protein is filtered, πo is zero.
forces? Overall:
GFR is the volume of fluid passing into the tubules GFR ¼ K f ½ðPi Po Þ ðπ i π o Þ
per unit time. The typical GFR of a healthy adult is ) GFR ¼ K f ½ð48 10Þ ð25 0Þ
125 mL/min. This means 180 L of fluid is filtered by ) GFR ¼ K f ×13 mmHg
the glomerulus per day. GFR is determined by the
balance of Starling forces: That is, there is a net driving pressure of 13 mmHg
that forces fluid from the glomerular capillaries to the
Key equation: Starling filtration equation applied Bowman’s space, and then on to the renal tubules.
to the kidney This driving pressure may be altered by changes in
the glomerular hydrostatic pressure (for example,
GFR ¼ K f ½ðPi Po Þ ðπ i π o Þ
decompensated systemic hypotension) or by
where Pi and Po are the hydrostatic pressures inside changes to blood oncotic pressure (for example,
and outside the glomerular capillary respectively, and hypoalbuminaemia).
313
How is clearance used in the patients, in those with advanced renal failure
the error becomes proportionally much
measurement of glomerular larger: filtration reduces with the disease
filtration rate? progression but secretory mechanisms are
GFR is an indicator of kidney function and is used left intact.
clinically to assess the degree of renal failure. If a – In clinical practice, it is not practical to collect
substance X is freely filtered at the glomerulus and 24 h urine samples to perform a formal
not secreted or reabsorbed later in the tubule, then the creatinine clearance calculation. However, by
rate at which the substance appears in the urine must measuring plasma creatinine alone, GFR may
equal the rate of its filtration. GFR can therefore be fall by as much as 50% (from 180 to 90 L/day)
indirectly measured using the clearance formula without being detected.
above:
Many researchers have tried to identify an alter-
Rate of urine excretion × ½Xurine native biomarker with which to estimate GFR. Urea
GFR ¼ has previously been used, but is produced at an even
½Xplasma
more variable rate than creatinine, being dependent
Ideally, the substance used for GFR calculation is one on dietary protein, catabolism and hormonal status.
that is produced endogenously at a constant rate, Urea is also reabsorbed in large quantities in the PCT
freely filtered at the glomerulus and not reabsorbed and collecting ducts, making it a very inaccurate
or secreted in the tubules. A number of substances measure of GFR. Cystatin C is a small endogenous
have been used for the estimation of GFR: molecule that is freely filtered at the glomerulus, and
Inulin (not to be confused with insulin) is a then reabsorbed and almost totally metabolized by the
small exogenous polysaccharide that is tubular cells. In the future, a combination of creati-
freely filtered at the glomerulus, and not nine and cystatin C may prove to be the best estimate
reabsorbed or secreted later along the tubule. of GFR.
Measurement of inulin clearance represents the
‘gold standard’ in GFR calculation, but is Clinical relevance: renal replacement therapy
relatively invasive (requiring a continuous Renal failure may occur acutely or insidiously – there
infusion of inulin), and is really only used in are a multitude of causes, and the pathogenesis is
research where very accurate measurements of complex. The end result is a loss of the essential
GFR are required. functions of the kidney, most notably failure of:
Clearance of toxic substances, leading to
Creatinine is an endogenous molecule produced
uraemia.
during skeletal muscle metabolism. Its clearance
Electrolyte homeostasis, leading to life-
can be accurately measured using blood and 24 h threatening hyperkalaemia.
urine samples. However, creatinine clearance is Water excretion, leading to fluid overload.
only an estimate of GFR: Acid excretion, leading to acidaemia.
– The rate of creatinine production is dependent Management of renal failure involves artificially per-
on skeletal muscle mass. This in turn is forming the key functions of the kidney. Methods of
influenced by age, sex and race, amongst other renal replacement therapy (RRT) are:
factors. Numerous algorithms exist to try to Peritoneal dialysis. Hyperosmolar dialysate
compensate for these factors; for example, the solution is infused into the peritoneal cavity.
Cockcroft–Gault formula compensates for age, ‘Filtration’ is achieved by using the peritoneum as
sex and weight. a semi-permeable membrane. Water is
– Creatinine is actively secreted into the PCT, reabsorbed by making use of the osmolar
accounting for 10–20% of excreted gradient across the peritoneum. Diffusion
along concentration gradients across the
creatinine. This results in a slight
peritoneum allows clearance of toxic
overestimation of creatinine clearance, substances and correction of electrolyte
and therefore an overestimation of GFR. abnormalities.
Whilst this error is tolerable in normal
314
Chapter 64: Renal filtration and reabsorption
Intermittent haemodialysis and continuous What is meant by the term

haemofiltration. Whilst conceptually simple,
these methods are inherently complex,
‘filtration fraction’?
involving extracorporeal circuits and an artificial The filtration fraction is the fraction of the plasma
semipermeable membrane. ‘Filtration’ occurs that is filtered by the glomerulus.
within an artificial ‘kidney’, a cellulose or For example, the kidney receives a blood at a rate of
synthetic semipermeable membrane. Like the 1000 mL/min. Assuming a haematocrit of 0.4, glom-
native kidney, this membrane selectively ‘sieves’ erular plasma flow is approximately 600 mL/min. We
the blood, allowing small molecules (H2O, know that a healthy adult’s GFR is 125 mL/min. There-
electrolytes and waste products) to pass through fore, the filtration fraction is (125/600) × 100 ≈ 20%.
but retaining cells and large proteins in the
blood. Depending on the type of RRT, simple
diffusion, convection or a combination of the two
Further reading
D. C. Eaton, J.D. C.Eaton, J. Pooler. Vander’s Renal
may be utilized. Reabsorption is achieved by
Physiology, 8th edition. McGraw-Hill Medical, 2013.
returning electrolyte-rich, pH-balanced fluid to
the blood. G. Choi, C. D. Gomersall, Q. Tian, et al. Principles of
Renal transplant. The best method of replacing antibacterial dosing in continuous renal replacement
the function of a failed native kidney is by therapy. Crit Care Med 2009; 37(7): 2268–82.
replacing it for another kidney. Artificial RRT can N. A. Hall, A. J. Fox. Renal replacement therapies in critical
never be as effective as the real thing! care. Contin Educ Anaesth Crit Care Pain 2006; 6(5):
197–202.
315
Chapter
Renal regulation of water
65 and electrolyte balance
cannot cross the capillary endothelium; for

How is water distributed in the body? example, radio-labelled albumin.
Water is the most abundant component of the human
Calculation of ECF volume requires an indicator
body. On average, 60% of the body is composed of
that is able to cross the capillary endothelium but
water (this figure varies with sex, body habitus and
cannot gain access to the ICF by crossing the cells’
age). Body water is distributed between the two major
phospholipid bilayer. An example of such an
body compartments: intracellular and extracellular.
indicator is thiosulphate.
For the average 70 kg man:
Calculation of total body water requires an
Total body water is 42 L (60% of 70 kg, where 1 kg indicator that can distribute across all body fluid
of water has a volume of 1 L). compartments. The indicator must be able to
Approximately two-thirds of body water is ICF; cross both the capillary endothelium and the cells’
that is, 28 L. phospholipid bilayer. Deuterated water (2H2O) is
Approximately one-third of body water is ECF; often used.
that is, 14 L. Of the ECF: The volumes of the ICF and interstitial fluid
– Approximately one-fifth is intravascular fluid; compartments cannot be directly measured.
that is, plasma volume is around 3 L. Instead, interstitial fluid volume can be calculated
– A smaller proportion (around 1 L) is from the difference between ECF and plasma
transcellular fluid; for example, CSF, occular volumes. Likewise, ICF volume can be calculated
fluid, synovial fluid. from the difference of total body water and
– The remainder is interstitial fluid (around ECF volume.
10 L), the fluid that occupies the spaces
between cells. It is within this fluid that
capillaries and cells exchange nutrients and
How is plasma volume regulated?
waste products. The maintenance of intravascular volume is a prob-
lem familiar to anaesthetists:
Too low a blood volume results in reduced venous
How is the volume of water within return, reduced cardiac preload and, therefore,
different body compartments reduced CO, systemic hypotension and organ
measured? ischaemia.
Too high a blood volume is also potentially
Body fluid compartments are measured using an
harmful: excessive preload stretches cardiac
indicator-dilution method. A known amount of an
myocytes, which may precipitate LVF, and
indicator substance is administered, allowed to equili-
induces hypertension, which damages organs such
brate across the body compartment of interest, and its
as the kidneys, heart and retina.
concentration measured. The key to this method is an
understanding of the barriers between body compart- The body cannot control the volume of ECF by
ments and selection of the correct indicator: moving water directly: there are no water pumps in
Calculation of plasma volume requires an the body. Na+ is the major cation of the ECF; together
indicator that, once infused into the circulation, with its conjugate anion, Na+ accounts for over 90% of
316
Chapter 65: Renal regulation of water and electrolyte balance
the body’s osmotic activity. ECF volume is therefore What is osmolality? How does it differ
regulated by controlling the movement of Na+,
and thus water. Extracellular Na+ concentration is a from osmolarity?
balance of: Osmolality is a measure of the number of dissolved
+
Na intake – dietary or intravenous. osmotically active particles per unit mass of a solu-
+
Extra-renal Na loss – for example, sweating, faeces. tion. The problem with using osmolarity results from
+
Renal Na excretion. changes in volume of solvent (water) with changes in
temperature, and with the introduction of solute. As
The kidney is essentially responsible for plasma Na+ solvent mass does not vary with temperature, osmol-
regulation, as it can significantly vary its Na+ excre- ality is independent of temperature and the weight of
tion. The kidney, therefore, regulates plasma volume, the solute. Osmolality is measured in the laboratory
and thus ECF volume: by a method based on the depression of the freezing
+
Net Na loss ¼ ECF volume reduction. point of the solution.
+
Net Na gain ¼ ECF volume expansion.
Key definition: osmolality
Osmolality is defined as the number of osmoles per
What is osmolarity? How does it differ kilogram of solvent.
from molarity?
Osmolarity is a measure of the number of dissolved Osmolarity and osmolality are often used inter-
osmotically active particles per unit volume of a changeably, as numerically they are similar in normal
solution. patients. However, in certain situations, an osmolar
gap exists – a difference between the measured osmol-
Key definitions: osmolarity and molarity
ality and the calculated osmolarity:
Osmolarity is defined as the number of osmoles per
litre of solution, where osmoles denotes the number Key equation: osmolar gap
of moles of particles that are able to exert an osmotic
Osmolar gap ¼ osmolality osmolarity
pressure.
In contrast, molarity is the number of moles of
solute dissolved per litre of solution; that is, the
An osmolar gap indicates the presence of additional
concentration.
unmeasured osmotically active particles in the plasma
that are not included in the estimation of osmolarity.
For example, 1 mol of sodium chloride dissolved in Clinically important causes of a high osmolar gap
water completely dissociates into Na+ and Cl ions; that include alcohol intoxication, hypertriglyceridaemia,
is, 2 Osmol of osmotically active particles. In compari- methanol and ethylene glycol poisoning.
son, 1 mol of glucose dissolves in water but cannot
dissociate into ions, so contributes only 1 Osmol.
Plasma osmolarity can be estimated at the bedside Why is it so important that plasma
by summing the concentrations of the most common osmolarity is regulated?
osmolytes: Osmolarity must be tightly regulated, as it alters the
fluid tonicity; tonicity refers to the response of intra-
Key equation: estimated plasma osmolarity
cellular water to the osmolarity of the surrounding
Plasma osmolarity ¼ 2[Na+]+ 2[K+]+[glucose]+[urea] ECF:
where [X] (mmol/L) is the concentration of substance X. If the ECF is isotonic, the cells stay the
same size.
If the ECF is hypertonic, the cells shrink due to the
In this estimate, the concentrations of Na+ and K+ are extracellular movement of water by osmosis.
doubled to account for their conjugate anions (which If the ECF is hypotonic, the cells swell due
may not be routinely measured in the laboratory; for to the intracellular movement of water
example, sulphate). by osmosis.
317
Clinical relevance: hypotonicity response to an increase in plasma osmolarity,

the hypothalamus signals the posterior lobe of
Infusion of sterile water into a peripheral vein acutely
lowers the osmolarity of venous blood. The circulat- the pituitary to secrete ADH into the systemic
ing RBCs find themselves surrounded by hypotonic circulation. ADH acts at the collecting ducts of
solution. Water moves into the RBCs, causing them to the kidney, increasing the reabsorption of free
swell. An RBC can only accommodate a limited water and thus reducing plasma osmolarity.
amount of extra water before haemolysis occurs.
For this reason, infusions of 5% dextrose are used in Similarly, if plasma osmolarity were to fall, the hypo-
place of sterile water: thalamus reduces the sensation of thirst and inhibits
5% dextrose is approximately isotonic (osmolarity the secretion of ADH, thereby increasing the amount
of 278 mOsmol/L compared with plasma osmo- of water excreted by the kidney.
larity of 285–295 mOsmol/L). ADH has an additional role: peripheral vasocon-
Once the glucose is metabolized, it is as if free striction. Normally, circulating ADH has a negligible
water has been infused, but without the acute influence on arteriolar tone. In situations of hypovo-
drop in osmolarity. laemic shock (for example, haemorrhage) the poster-
Severe hyponatraemia is usually accompanied by a ior lobe of the pituitary gland secretes large amounts
fall in plasma osmolarity, which results in generalized of ADH. At high concentrations, ADH is a powerful
cell swelling. This is particularly dangerous in the peripheral vasoconstrictor and plays an important
brain, which is confined within the rigid structure of role in maintaining systemic blood pressure.
the skull. Cerebral oedema may result in symptoms
of raised ICP, seizures, altered consciousness and
brainstem herniation. What is the mechanism by which
anti-diuretic hormone acts at the
How is plasma osmolarity controlled kidney?
ADH regulates the water permeability of the collect-
in the body? ing ducts in the kidney (Figure 65.1):
Plasma osmolarity is controlled by means of a
Normally, the luminal wall of the collecting ducts
feedback loop. Like all feedback loops in the body,
is impermeable to water. Therefore, any renal
there are:
filtrate that passes through the DCT and into the
Sensors. Osmoreceptors are located in the collecting duct is destined for excretion as urine.
organum vasculosum of the lamina terminalis The basolateral wall (facing away from the lumen)
(OVLT) and subfornical organ (SFO) within the is constitutively permeable to water owing to the
hypothalamus. presence of water channels known as aquaporins
Control centre. The hypothalamus interprets the (in this case, aquaporin 3 and 4). Control of
response from the osmoreceptors. Osmoreceptors water reabsorption, therefore, takes place at the
are extremely sensitive: they can detect as little as a luminal membrane.
1% change in plasma osmolarity. The normal set ADH binds to V2 receptors in the collecting ducts,
point of plasma osmolarity is 285–295 mOsmol/L. which, through a cAMP second messenger system,
Effectors. The hypothalamus responds to a rise in results in aquaporin 2 being inserted in the
plasma osmolarity in two ways: luminal walls of the collecting ducts.
– Stimulating thirst – oral water intake is This makes the collecting ducts permeable to water,
increased. which flows along an osmotic gradient, from an
– Reducing water excretion by the kidney – the area of low osmolarity (the filtrate) to an area of
paraventricular (PVN) and supraoptic (SON) high osmolarity (the renal medulla). A reduced
nucleus of the hypothalamus synthesizes ADH volume of water is therefore excreted in the urine.
(also known as (arginine) vasopressin), a nine- The key to this process is the extremely high
amino acid peptide. ADH is transported to the osmolarity of the renal medulla, generated by the
posterior lobe of the pituitary gland through LOH, its countercurrent mechanism and urea
nerve axons, where it is stored in granules. In cycling.
318
Figure 65.1 H2O reabsorption at the

ADH absent ADH present collecting ducts.
Distal convoluted tubule
Collecting duct
Aquaporin 2
RENAL CORTEX
RENAL MEDULLA
H2O H22O
H O H 2O
Area of high osmolarity
H2 O H2O H 2O
H2 O H 2O H 2O
H2O H 2O H 2O
Dilute urine Concentrated urine
How is the high osmolarity of the renal limb of the LOH is therefore roughly the same as
plasma osmolarity; that is, 300 mOsmol/L (1).
medulla generated? When the filtrate reaches the thick ascending limb
As discussed in Chapter 63, the LOH is located in the of the LOH, the Na+/K+/2Cl co-transporter
renal medulla, where it connects the PCT to the DCT. moves Na+, K+ and Cl from the filtrate to the
It is composed of three functional parts: medullary interstitium (2). As the ascending limbs
The thin descending limb, which is permeable to are impermeable to water:
water but relatively impermeable to ions and urea.
– the filtrate entering the DCT becomes
The thin ascending limb, which is permeable to hypo-osmolar;
ions and urea, but impermeable to water,
– the renal medulla interstitium becomes
potentially leading to a separation of ion and
hyper-osmolar.
water movement.
Filtrate entering the descending limb of the LOH
The thick ascending limb, which is also
now passes by the hyper-osmolar medullary
impermeable to water but additionally moves ions
interstitium. Because the walls of the descending
via secondary active transport involving luminal
limb are water permeable, water moves down its
Na+/K+/2Cl co-transporters powered by the
osmotic gradient into the medullary interstitium.
basolateral Na+/K+-ATPase.
As water leaves, the remaining filtrate becomes
Figure 65.2 summarizes alterations in the renal fil- more concentrated; that is, the osmolarity
trate as it passes along the LOH: increases (3).
In the PCT, water is reabsorbed in conjunction Filtrate moves along the LOH, until it reaches the
with ions, amino acids and glucose. The thin ascending limb (4). Here, ions move out of
osmolarity of the fluid entering the descending the tubule into the interstitium down a
319
PCT DCT
(1) (2) (3)
300 300 300 300 400 200 350 350 200

Na+ H2O
300 300 300 300 400 200 350 350 200
K+ H2O
300 300 300 300 400 200 350 350 200
Cl− H2O
300 300 300 300 400 200 350 350 200
Na+ H2O
300 300 300 300 400 K+ 200 350 350 200
H2O
300 300 300 300 400 Cl− 200 350 H2O 350 200
PCT DCT
(4) (5) (6)
300 350 200 300 350 125 300 300 100

Na+
300 350 200 300 375 150 400 400 200
K+
350 350 200 350 400 175 600 600 300
Cl−
350 350 200 350 425 Na+ 200 800 800 400
350 350 350 350 450 K+ 250 1000 1000 600
350 350 350 350 450 Cl− 250 1200 1200 1000
1200 1200
1200
Figure 65.2 Generation of the medullary osmolar gradient.
concentration gradient. Ions continue to move As the vasa recta descend in the medulla, the
into the interstitium in the thick ascending limb, electrolyte content and osmolarity of their blood
but by secondary active transport (5). equilibrates with that of the surrounding
This countercurrent multiplier mechanism results interstitium: ions diffuse into the vessel and
in a medullary interstitial osmolar gradient, with water diffuses out.
the tip of the LOH having the highest osmolarity As the vasa recta ascend, their contents equilibrate
(1200 mOsmol/L) (6). with the surrounding interstitium: water diffuses
into the vessel and solutes diffuse out.
As the LOH is highly metabolically active, it Blood flows sufficiently slowly in the vasa recta to
requires a good blood supply. However, if blood allow near-complete equilibration between the blood
vessels were to simply pass through the renal medulla, and the medullary interstitium. The osmolarity of
they would carry solutes away, washing away the the blood leaving the vasa recta is near normal
osmotic gradient (Figure 65.3a). To avoid this prob- (around 320 mOsmol/L). Therefore, the interstitial
lem, the LOH has a specialized blood supply. The vasa medullary osmolar gradient is minimally disturbed.
recta, arteriolar branches of the efferent arterioles,
follow the LOH deep into the medulla, descending Clinical relevance: clinical disorders of osmolarity
with the ascending limb of the LOH, turning a hairpin The hypothalamus is crucial to the regulation of
bend and ascending with the descending limb to form plasma osmolarity through its roles in sensing
a ‘countercurrent’ flow of blood. The hairpin design of plasma osmolarity and triggering the secretion of
the vasa recta is important in the maintenance of the ADH. The hypothalamus may malfunction; for
medullary osmolar gradient (Figure 65.3b):
320
(a) If blood vessels simply passed through the (b) ‘Hairpin loop’ arrangement of the vasa recta
loop of Henle
No ‘washout’ of
osmotic gradient
‘Hypothetical’
blood vessel
300
100
300 300
300
100 100
400 200 400 200

600
600
300
600 300 600 300
800 400 800 400
600
1000
1000
1000 600 1000 600
1200 1000 1200 1000

1200
1200
1200 1200 1200 1200
1200
1200
1200
‘Wash-out’ of osmolarity gradient

Figure 65.3 Schematic illustrating how the vasa recta avoids disturbing the medullary osmolar gradient.
example, following a head injury. Two important mechanism: the collecting ducts fail to respond
clinical syndromes are: to circulating ADH.
Central diabetes insipidus (DI), in which the Syndrome of inappropriate ADH secretion.
posterior lobe of the pituitary gland fails to Circulating ADH is in excess of that required to
secrete adequate ADH. Without ADH, maintain normal plasma osmolarity. Excess ADH
water cannot be reabsorbed at the collecting may be secreted by the posterior lobe of the pitu-
ducts. Clinically, DI is characterized by the itary gland or by an ectopic source; for example, a
production of large amounts of excessively small cell lung carcinoma. Excessive ADH secretion
dilute urine and signs of hypovolaemia. results in additional water reabsorption at the
Biochemically, excessive water excretion leads collecting duct. The clinical features are those of
to hypernatraemia, high plasma osmolarity hyponatraemia (headache, nausea, confusion,
and an inappropriately low urine osmolarity. seizures, coma), sometimes associated with
Note: nephrogenic DI, which may be caused fluid overload. Biochemically, in addition to
by lithium therapy, has identical clinical hyponatraemia and low plasma osmolarity, urine
and biochemical features, but a different osmolarity is inappropriately high.
321
Describe how urea is handled and How does the kidney regulate
involved in generating the medullary Na+ excretion?
osmolar gradient As discussed in Chapter 64, the kidney filters 180 L of
Na+-containing plasma per day, significantly more
Urea is produced by the liver as the end-product of
than the total volume of body water. Typical urine
nitrogen metabolism. It is freely filtered at the glom-
erulus and then reabsorbed along the tubule. The output is in the region of 1.5 L/day. Clearly most of
the Na+, and therefore water, is reabsorbed by the
result is that around 40% of the filtered urea is cleared
kidney.
into the urine. The remaining urea contributes to the
Na+ excretion is controlled in two ways:
high osmolarity of the medullary interstitium along
with the countercurrent reabsorption of Na+ ions in Changes in GFR. When plasma volume is high,
the LOH. In fact, urea provides around half of the GFR is increased. More Na+ is then filtered at the
osmolarity of the medullary interstitium. The process glomerulus and delivered to the nephron,
is as follows. resulting in more Na+ being excreted in the
urine. Perhaps more importantly, when plasma
In the PCT, the reabsorption of water (coupled to
volume is low, Na+ is conserved through a
Na+ reabsorption) results in reabsorption of urea
reduced GFR.
due to solvent drag. The concentration of urea +
within tubule is increased as water is reabsorbed: Changes in Na reabsorption. This is the main
urea is additionally reabsorbed by diffusion. mechanism in operation during euvolaemia. Na+
Approximately 50% of the filtered urea is is reabsorbed in two phases in the kidney
reabsorbed in the PCT. (Figure 65.4):
In the LOH, the concentration of urea is higher in – Bulk reabsorption in the PCT and LOH.
the renal medullary interstitium than the tubular Around 60% of filtered Na+ is reabsorbed in
fluid. Urea diffuses into the tubular fluid through the PCT, driven by the basolateral Na+/K+-
facilitated diffusion.1 Approximately 60% of the ATPase pump. This ion pump keeps the Na+
filtered urea is secreted by the thin and thick concentration within the tubular cells low. Na+
ascending limbs of the LOH, leading to 110% of is reabsorbed from the tubular lumen by a
the filtered urea being present in the DCT. variety of means: passive diffusion, co-
In the inner medullary collecting duct, urea is transport with molecules such as glucose,
reabsorbed by facilitated diffusion2 from the counter-transport with H+ (see Chapter 66).
collecting duct, where urea concentration is high, Approximately 30% of filtered Na+ is
to the renal medullary interstitium, where urea reabsorbed in the LOH through the Na+/K+/
concentration is lower. Two-thirds of the filtered 2Cl co-transporter (see above).
urea is reabsorbed from the inner medullary – Reabsorption in the DCT and collecting duct.
collecting duct, with the remaining third being Around 90% of the filtered Na+ has been
excreted under normal circumstances. reabsorbed by the time the filtrate reaches the
DCT. The intracellular Na+ concentration in
As well as increasing aquaporin expression, ADH the DCT and collecting duct cells is kept low as
increases the expression of UT-A1 (but not UT-A3) a result of the basolateral Na+/K+-ATPase. Na+
in the inner medullary collecting duct. This permits transfer across the tubular cell luminal
increased urea reabsorption, which facilitates the membrane is controlled by aldosterone,
reabsorption of water. through three mechanisms:
+
▪ In the DCT, 5% of filtered Na is
+
reabsorbed through an Na /Cl co-
1
In the thin descending limb, the urea transporter is transporter in the luminal membrane.
UT-A2. The urea transporter in the thin ascending limb is Aldosterone controls the number of
unclear.
2
The urea transporter UT-A1 is present on the luminal transmembrane co-transporters.
membrane, and UT-A3 is present on the basolateral ▪ In the late DCT and collecting duct,
membrane. aldosterone acts on two different cell types.
322
5% Na + reabsorbed in DCT
Site of action of
thiazide diuretics
Na+ filtered
~1–2% Na+ reabsorbed

in collecting duct
Na+
HCO3− Na+ Cl− Principal cells
Na+
Site of action of
K+
carbonic anhydrase
inhibitors Site of action of
K+-sparing diuretics
60% Na + reabsorbed in PCT
Na+ Na+
K+ H+
2Cl−
Intercalated cells
Site of action of
30% Na +
loop diuretics
reabsorbed
in LOH
Na+ excretion variable, less than

20 mmol /L in severe
hypovolaemia
Figure 65.4 Na+ handling by the kidney and the effect of diuretics.
Principal cells reabsorb Na+ and secrete K+, atrial stretch receptors. Secretion of ANP and BNP is
whilst intercalated cells reabsorb Na+ and reduced. Afferent nervous impulses relay information
secrete H+. The combined effect of to the medulla oblongata and hypothalamus. In turn,
aldosterone on these cells is the thirst is stimulated and three ‘hypovolaemia hor-
reabsorption of Na+ and water in exchange mones’ are released: noradrenaline, ADH and renin.
for the secretion of K+ and H+. Noradrenaline causes both afferent and efferent
arterioles to vasoconstrict, reducing RBF and
therefore GFR. Na+ excretion is consequently
Summarize the physiological response reduced.
to low plasma volume ADH increases the permeability of the collecting
Low-pressure mechanoreceptors monitor the degree duct to water, allowing the renal medullary osmotic
of stretch within the cardiac atria and pulmonary gradient to be used for the reabsorption of water.
vessels. Hypovolaemia results in reduced venous Renin is released in response to both sympathetic
return, and therefore reduced stimulation of the right stimulation by the medulla oblongata and the
323
reduced Na+ content of the tubular filtrate, as

detected by the juxtaglomerular apparatus. Renin is disrupted. Loop diuretics are therefore
extremely effective, known as high-ceiling
leads to the production of both angiotensin II and
diuretics.
aldosterone (see Chapter 64):
Thiazide diuretics (for example, bendroflume-
– Angiotensin II acts at the PCT, where it thiazide). Thiazides act by blocking the Na+/Cl
increases Na+ reabsorption, and at the afferent co-transporter in the early DCT.
and efferent arterioles, where it causes Potassium-sparing diuretics (for example, spir-
vasoconstriction, thus reducing GFR. onolactone and amiloride). Spironolactone blocks
– Aldosterone acts on the DCT and collecting aldosterone receptors in the DCT and collecting
duct. It therefore exerts biochemical effects
ducts, where it increases the reabsorption of
opposite to those of aldosterone in the form of
Na+ and water and the secretion of K+ and H+. increased Na+ excretion and reduced H+ and K+
In combination, these mechanisms result in the excretion; hence the term potassium-sparing.
Amiloride blocks Na+ channels in the DCT and
conservation of fluid through reductions in renal
collecting duct. The biochemical effects of
Na+ excretion. The maximum possible concentration amiloride are therefore similar to those of
of urine is 1200 mOsmol/L; that is, the osmolarity at spironolactone.
the inner renal medulla. The kidney must still excrete
osmotically active waste products, accounting for
around 600 mOsmol/day. Therefore, the minimum
daily urine output is
Anti-diuretic hormone is involved in the
600 mOsmol
1200 mOsmol=L
¼ 500 mL regulation of both osmolarity and
Around 500 mL/day of fluid is lost through sweating,
plasma volume. Which takes priority?
faeces and respiration; these are termed ‘insensible For absolute control of the volume and consistency of
losses’. Therefore, to maintain euvolaemia, a min- the plasma, osmolarity and volume should be regu-
imum daily intake of 1000 mL water is required. lated independently. However, the two regulatory
mechanisms overlap:
Clinical relevance: diuretics Even small changes in plasma osmolarity may be
A diuretic is a drug that increases the production of catastrophic owing to brain cell swelling in the
urine. Different classes of diuretics act at different closed compartment of the cranium. In contrast,
sites within the kidney (Figure 65.4). Commonly used small changes in plasma volume are relatively well
classes of diuretic include the following. tolerated owing to the high compliance of the
Osmotic diuretics (for example, mannitol) are venous circulation, which acts as a blood
osmotically active agents freely filtered at the reservoir.
glomerulus and not reabsorbed by the tubules.
The increased osmolarity of the filtrate results in The osmoreceptors in the hypothalamus are
less water being reabsorbed, which increases the therefore sensitive to changes in osmolarity as
volume of urine produced. small as 2–3%, whereas volume and baroreceptors
CA inhibitors (for example, acetazolamide). CA is require a 7–10% change in blood volume to
an enzyme located in the PCT. It is required for trigger a response.
HCO3 reabsorption (see Chapter 66). Inhibition Therefore, it is the osmolarity that is first
of CA increases HCO3 excretion through conserved even if this disturbs the plasma volume;
the urine. for example, intravenous infusion of hypertonic
Loop diuretics (for example, furosemide and saline results in the secretion of ADH, which acts
bumetanide), which inhibit the Na+/K+/2Cl
to conserve water to correct plasma osmolarity,
co-transporter in the thick ascending limb of
despite an increase in volume.
the LOH. Not only are Na+, K+ and Cl not
reabsorbed, but the countercurrent mechanism With larger volume losses (>7%), volume
that generates the medullary osmolarity gradient regulation takes priority owing to the potential for
tissue ischaemia.
324
Summarize the physiological response its mechanisms take time. Instead, rapid changes in
plasma K+ concentration are achieved by the move-
to high plasma volume ment of K+ between the ICF and ECF.
The stretch receptors of the cardiac atria and pulmon- +
K intake. A typical Western diet contains
ary vessels respond to hypervolaemia by reducing 70 mmol of K+ per day (10 times more than is
their afferent output to the medulla oblongata. This required), nearly all of which is absorbed in the
reduces the release of the three hypovolaemia hor- gut. One might, therefore, expect a surge in
mones. As a result, a greater amount of Na+ and plasma K+ concentration following a meal. This is
water is excreted in the urine. An expansion in plasma avoided through an important effect of insulin
volume causes a relative dilution of plasma proteins – (released in response to ingested glucose), which
plasma oncotic pressure is reduced. This changes stimulates the activity of the basolateral Na+/K+-
Starling’s forces at the glomerular capillary, favouring ATPase, thus increasing cellular K+ uptake, which
an increase in filtration fraction. keeps plasma K+ concentration constant.
In addition, ANP and BNP are released from the Movement between intra- and extracellular
cardiac atria and ventricles respectively, in response to spaces, through a number of mechanisms:
stretch. ANP and BNP have a number of effects on
the kidney, all of which increase Na+ excretion: – Insulin promotes intracellular movement of
K+ by increasing the activity of the Na+/K+-
Afferent arteriolar vasodilatation with efferent ATPase, as discussed above.
arteriolar vasoconstriction. This increases
– Sympathetic stimulation. α adrenoceptor
glomerular capillary hydrostatic pressure, thus
activation triggers K+ release from cells. This
increasing GFR and Na+ excretion.
mechanism is important in exercising muscle:
Relaxation of the glomerular mesangial cells, local hyperkalaemia stimulates glycogenolysis
which increases the surface area for filtration, thus and vasodilatation. β2 adrenoceptor activation
increasing GFR and Na+ excretion. causes intracellular uptake of K+. This is, in
+
Blockage of Na channels in the DCT and part, why hypokalaemia is commonly
collecting ducts, which directly inhibits Na+ associated with the acute stress response.
reabsorption. – Extracellular pH. In metabolic acidosis, much
Inhibition of both renin secretion by the granular of the additional H+ is buffered intracellularly.
cells and aldosterone secretion by the adrenal Intracellular acidosis impairs the basolateral
glands. Na+/K+-ATPase, leading to extracellular leak
of K+ ions, and thus hyperkalaemia (see
How is plasma potassium concentration Chapter 66). In metabolic alkalosis, the
regulated? opposite occurs.
+ +
K excretion by the kidney (Figure 65.5). K is
K+ is predominantly an intracellular ion:
+
freely filtered at the glomerulus. Almost all of the
98% of total body K is found in the ICF, where filtered K+ is reabsorbed in the PCT (through
+
typical K concentration is 150 mmol/L. As the diffusion) and LOH (through the Na+/K+/2Cl co-
major intracellular ion, K+ is responsible for transporter), irrespective of whether body K+ is high
intracellular osmotic pressure. or low. Instead, plasma K+ is regulated through K+
+
2% of total body K is found in the ECF, where secretion in the DCT and collecting ducts:
+
normal K concentration is 3.5–5.5 mmol/L.
– When plasma K+ concentration is low, the
+
Maintaining the large K concentration difference kidney tries to conserve as much K+ as
between the ICF and ECF is very important, as it is possible. Additional K+ is reabsorbed in the
responsible for the RMP (see Chapter 48). DCT, probably through the H+/K+-ATPase. In
Plasma K+ concentration is a balance between K+ total, up to 99% of K+ is reabsorbed.
intake, movement of K+ between the intra- and extra- – When plasma K+ concentration is high, the
cellular spaces, and K+ excretion. The kidney is adrenal cortex is directly stimulated to secrete
responsible for overall regulation of K+ balance, but aldosterone. As discussed above, aldosterone
325
Normal / high K+: 10–50% K+ secreted

Low K+: ~2–3% K+ reabsorbed
K+ filtered
Normal / high K+: 5–30% K+ secreted
Low K+: ~5–7% K+ reabsorbed
60% K+ reabsorbed
30% K+
reabsorbed
Low K+: ~1% K+ excreted

Normal / high K+ : up to 80% of filtered K+ excreted
Figure 65.5 Renal K+ handling in states of high and low total body K+.
acts at the DCT and collecting ducts, where it

reabsorbs Na+ and water, whilst secreting K+ but can also be caused by drugs (for example,
spironolactone and suxamethonium), Addison’s
and H+.
disease and cellular breakdown (haemolysis and
rhabdomyolysis).
Clinical relevance: management of hyperkalaemia The clinical management of hyperkalaemia
Significant hyperkalaemia (plasma K+ concentration involves, in part, intracellular movement of plasma
>6 mmol/L) affects cells’ RMP; membrane depolar- K+ through manipulation of the mechanisms
ization may cause life-threatening cardiac arrhyth- described above:
2+
mias such as VF. Classical ECG changes include tall, Ca (for example, 10 mL of 10% calcium chloride
tented, T-waves and, later, widened QRS com- solution) is given for cardioprotection; it stabilizes
plexes. Hyperkalaemia is frequently the result of the RMP as Ca2+ ions bind to the outer surface of
acute renal failure or severe metabolic acidosis, the membrane. This creates a local high density
326
of positive charge, leading to a relatively more low dietary intake, diarrhoea, alkalosis and Conn’s
negative intracellular voltage (see Chapter 48). syndrome, an aldosterone-secreting tumour. As
An insulin/dextrose infusion reduces plasma K+ anaesthetists, we tend to become involved with
concentration by increasing cellular K+ uptake. severe hypokalaemia either because patients have
Salbutamol promotes intracellular movement of developed severe weakness or because they need
K+ through its β2-agonist activity. central venous replacement of K+.
A sodium bicarbonate infusion may be useful K+ may be replaced enterally or intravenously;
in the context of hyperkalaemia and metabolic rapid replacement by the intravenous route risks
acidosis: by increasing the pH of ECF, seques- ventricular tachyarrhythmias. A safe rate of periph-
tered intracellular H+ moves back into the ECF eral venous K+ replacement is 10 mmol/h, whilst
as K+ moves intracellularly. central venous K+ may be administered at up to
The latter three management options merely 20 mmol/h, with appropriate monitoring. It is worth
move K+ between body compartments; they do not mentioning that half of patients with significant
hypokalaemia also have significant hypomagnesae-
alter total body K+. In the longer term, K+ may need
to be removed from the body. This can be achieved mia (the mechanisms of loss of both cations are
using calcium resonium (an ion-exchange resin), or similar). Hypokalaemia is often resistant to treatment
in the presence of hypomagnesaemia, as Mg2+ is
by renal replacement therapy: haemodialysis or
haemofiltration. required for the Na+/K+-ATPase to function normally.
Therefore, both electrolyte disturbances require
treatment.
Clinical relevance: hypokalaemia Further reading

Like hyperkalaemia, significant hypokalaemia B. Taylor, D. J. Chambers, N. Patel, et al. Hypokalaemia: the
(K+ <3 mmol/L) alters the RMP: hyperpolarization dangers of a sweet tooth. J Intensive Care Soc 2012; 13(4):
makes the membrane more difficult to depolarize. 342–5.
Patients with hypokalaemia may therefore develop M. Doherty, D. J. Buggy. Intraoperative fluids: how much is
muscular weakness and myalgia; severe hypokalae- too much? Br J Anaesth 2012; 109(1): 69–79.
mia may cause flaccid paralysis and respiratory fail-
K. M. Ho, B. M. Power. Benefits and risks of furosemide in
ure. The classical ECG changes of hypokalaemia
acute kidney injury. Anaesthesia 2010; 65(3): 283–93.
are flattened or inverted T-waves, increased PR inter-
val, U-waves and ST-segment depression. The differ- M. A. Glasby, C. L.-H. Huang, eds. Applied Physiology for
ential diagnosis of hypokalaemia is wide, including Surgery and Critical Care. Butterworth-Heinneman,
1995.
327
Chapter
Acid–base physiology
66
What is an acid? Key equation: pH
The word acid is derived from the Latin acidus,
pH ¼ log10[H+]
meaning sour. Early chemists defined an acid as a
where log10 is the logarithm (base 10) and [H+] is the
chemical substance whose aqueous solution tastes
molar concentration of H+ ions.
sour, changes the colour of litmus paper to red, and
Note: pH is dimensionless; that is, it has no units.
reacts with certain metals to produce the flammable
gas hydrogen. Likewise, a base is a chemical substance
whose aqueous solution tastes bitter, changes the Because the pH scale is logarithmic, a small change in
colour of litmus paper to blue, and reacts with acids pH represents a much larger change in [H+]:
to produce a salt. ‘Normal’ body pH of 7.4 is equivalent to an H
+
concentration of 40 nmol/L.
What are the Brønsted–Lowry Acidaemia is defined as an arterial pH below 7.35.
Alkalaemia is defined as an arterial pH above 7.45.
definitions of an acid and base? A small reduction in pH from 7.4 to 7.0 represents
Brønsted and Lowry independently recognized that more than a doubling of H+ concentration, from
acid–base reactions in aqueous solution involve the 40 to 100 nmol/L.
transfer of a H+ from one molecule to another:
An acid is defined as a proton donor.
A base is defined as a proton acceptor.
What is pKa?
Acids may be classified as being either strong or weak:
The generic reaction between an acid and base is: A strong acid is one that completely dissociates in
HA + B Ð BH+ + A solution.
where HA is a Brønsted–Lowry acid (as it donates A weak acid is one that only partially dissociates in
solution.
H+), B is a Brønsted–Lowry base (as it accepts H+),
BH+ is referred to as the conjugate acid and A is pKa is a measure of the strength of an acid, normally
referred to as the conjugate base. used to characterize weak acids. Consider the
For example, consider the equilibrium between following equation:
H2CO3 and water:
k1
+ HA Ð H+ +A
H2 CO3 +H2 O Ð HCO3 +H3 O k2
where k1 is the rate constant for the forward reaction

H2CO3 is the Brønsted–Lowry acid, water is the
and k2 is the rate constant for the backward reaction.
Brønsted–Lowry base, HCO3 is the conjugate base
When the rate of the forward reaction equals the
and H3O+ is the conjugate acid.
rate of the backward reaction, the reaction is said to
be at equilibrium. The equilibrium constant Ka can be
What is pH? written as:
pH is a measure of the acidity of an aqueous solution. k1 ½H+ ½A
Ka ¼
pH depends on the concentration of H+ ions: k2
¼
½HA
328
Chapter 66: Acid–base physiology
pKa is the negative logarithm of this dissociation Applying the Henderson–Hasselbalch equation to the
constant Ka: HCO3 /H2CO3 buffer system:
½HCO3
Key equation: pKa pH ¼ pK a +log10
½H2 CO3
pKa ¼ log10 Ka
As the pKa of the HCO3 /H2CO3 equilibrium is 6.1
and [H2CO3] can be related to the solubility and
From the equilibrium equation above, it can be seen
partial pressure of CO2 PaCO2, this equation can be
that:
rewritten as
A high Ka represents greater dissociation of HA
into H+ and A , and therefore a greater pH ¼ 6:1+log10
½HCO3
concentration of free H+. A low pKa therefore 0:23 ×Pa CO2
corresponds to increased acidity. where 0.23 is a solubility factor. PaCO2 is measured in
A low Ka represents less dissociation of HA, kilopascals.
resulting in a lower concentration of free H+. Normal plasma pH can therefore be predicted by
A high pKa therefore corresponds to reduced inserting the ‘normal’ plasma values of
acidity. [HCO3 ] ¼ 24 mmol/L and PaCO2 ¼ 5.3 kPa:
Like pH, pKa is a logarithmic scale. Therefore, a small 24
pH ¼ 6:1+log10 ¼ 7:4
reduction in pKa represents a much larger increase in 0:23×5:3
acidity.
The acidity of a substance can be related to pH in How are disorders of acid–base
a more formal way. Rearranging the above equation:
balance classified?
½HA
½H+ ¼ K a Acid–base disturbance is traditionally classified by pH
½A
disturbance – that is, acidosis or alkalosis – and by
As pH ¼ log10[H+]: aetiology, whether it is of respiratory or metabolic
origin. Acids of respiratory origin, namely CO2, are
½HA
pH ¼ log10 K a known as volatile acids, as they may escape as a gas.
½A
Acids that are non-volatile (for example, lactic acid) are
Multiplying out the brackets: known as fixed acids as they may not escape the system.
½HA
The four classes of acid–base disorders are:
pH ¼ log10 K a log10 Respiratory acidosis, in which decreased V_ A
½A
results in pH <7.35 and PaCO2 >6.0.
And as pKa ¼ log10 Ka: Hypoventilation may be due to:
– Depression of the respiratory centre; for
Key equation: the Henderson–Hasselbalch
equation example, due to opioids or obesity
hypoventilation syndrome.
½A – Nerve or muscle disorders, such as GBS and MG.
pH ¼ pK a +log10
½HA – Chest wall disease; for example, flail chest.
Or: – Airway disease, such as asthma and COPD.
– Lung parenchymal disease; for example, ARDS.
½Conjugate base
pH ¼ pK a +log10
½Acid Of particular relevance to anaesthesia,
hypercapnoeic acidosis may also occur due to:
The most important physiological buffering system is – Insufficient mechanical ventilation, which may of
that of CO2, H2CO3 and HCO3 , which follows the course be intentional; for example, permissive
reaction hypercapnoea in patients with ARDS.
– Increased CO2 production in malignant
CO2 + H2O Ð H2CO3 Ð H+ + HCO3 hyperpyrexia.
329
– Exogenous CO2 intake; for example, What is the base excess?

re-breathing CO2-containing exhaled gases or
Acid–base imbalance is often of mixed aetiology. One
insufflation of CO2 in laparoscopic surgery.
of the failings of the Henderson–Hasselbalch method
If a respiratory acidosis persists for a period of is that, when an acidosis or alkalosis is of mixed
days, the kidneys increase HCO3 reabsorption; metabolic and respiratory origin, it is difficult to
this is termed metabolic compensation. Raised quantify each component.
plasma HCO3 concentration (>26 mmol/L) may The base excess (BE) is defined as the amount of
be seen in patients with COPD, ARDS and obesity acid or base that must be added to titrate the blood
hypoventilation syndrome. sample to pH 7.40, when PaCO2 has been corrected to
Metabolic acidosis, in which there is an increase 5.3 kPa and the temperature of blood is 37 °C.
in fixed acid, which may be endogenous (for Therefore:
example, lactic acid) or exogenous (for example, Blood that is already at pH 7.40 and which has a
salicylate). As the increased fixed acid is buffered PaCO2 of 5.3 kPa will have a BE of zero.
by HCO3 , metabolic acidosis is characterized by In metabolic acidosis, BE will be negative.
low plasma HCO3 concentration (<22 mmol/L) In metabolic alkalosis, BE will be positive.
and pH <7.35. Identification of the cause of Normal BE is considered to be 2 to +2 mEq/L.
metabolic acidosis may be aided by the anion gap
(see below). The respiratory system responds to a Base excess is useful when identifying the cause of a
metabolic acidosis by rapidly increasing V_ A , metabolic acidosis. For example, a patient with pneu-
thereby reducing PaCO2; this is referred to as monia has the following blood gas results: pH 7.2,
respiratory compensation. BE 8 mEq/L and lactate 3 mmol/L. A BE of 8 mEq/L
Respiratory alkalosis, in which hyperventilation represents a significant metabolic acidosis. As lactate
results in hypocapnoea (PaCO2 <4.7 kPa) and is only 3 mmol/L, there must be another source of
alkalosis (pH >7.45). Increased V_ A may be the acid present to account for the remaining 5 mEq/L.
result of: Given the history, this may be the result of acute
kidney injury with failed excretion of fixed acids.
– Central causes; for example, head injury, pain,
anxiety, progesterone (in pregnancy) and
drugs (such as salicylate overdose). What is the anion gap?
– Hypoxaemia, in which afferent signals from The anion gap is the apparent difference between the
peripheral chemoreceptors stimulate the total concentration of measured cations and the total
respiratory centre. This may occur, for concentration of measured anions. In practice, only
example, at high altitude. the most common cations and anions are measured
– Activation of lung J receptors, as occurs in PE by the blood gas machine, giving the formula
and pulmonary oedema.
– Excessive mechanical ventilation. Key equation: anion gap
Metabolic alkalosis, the least common of the
Anion gap ¼ sum of cation concentrations
main acid–base disorders, in which plasma
sum of anion concentrations
HCO3 exceeds 26 mmol/L in the absence of a
¼ ð½Na+ +½K+ Þ ð½Cl +½HCO3 Þ
primary respiratory acidosis. The more common
causes of metabolic alkalosis are:
– Gain of exogenous alkali; for example, an The normal anion gap is 10–20 mEq/L, which repre-
infusion of sodium bicarbonate, and massive sents unmeasured anions such as sulphates, phosphates
transfusion, where citrate is metabolized to and plasma proteins. The anion gap is used clinically to
HCO3 . identify the cause of a metabolic acidosis. A raised
– Loss of endogenous acid; for example, from the anion gap metabolic acidosis may be the result of:
stomach through severe vomiting or Increased endogenous anions; for example:
nasogastric drainage, or from the kidney – Lactic acid, produced during anaerobic
through the use of diuretics. metabolism.
330
– Fixed acids, which accumulate in acute kidney ▪ Hb. The histidine side chains of Hb
injury. act as a buffer by binding H+ ions.
– Ketoacids, whose production is increased by Deoxyhaemoglobin is better able to bind
diabetic ketoacidosis. H+ than oxyhaemoglobin (see the Haldane
Increased exogenous anions; for example: effect, Chapter 8).
– Salicylate. – Intracellular buffers:
– Ethanol.
– Methanol. ▪ The phosphate buffer system (H2PO4 /
HPO42 ). The concentration of phosphate
– Ethylene glycol.
is very low in ECF, making it an
A normal anion-gap metabolic acidosis, which unimportant buffer. Phosphate is,
occurs much less commonly, may be caused by however, an important buffer of both ICF
chronic gastrointestinal HCO3 loss or renal tubular and urine, as the phosphate concentration
acidosis. is higher.
Albumin is the major unmeasured anion. Hypoal- ▪ Proteins. Amino acid side chains can
buminaemia, common in critically ill patients, is buffer both acids (amine side chains) and
therefore associated with a reduced anion gap. It is alkalis (carboxyl side chains). Whilst
important to note that a metabolic acidosis may be plasma proteins play only a minor role in
missed in a hypoalbuminaemic critical care patient, as buffering, intracellular proteins are present
the anion gap may be normal. at higher concentrations, making them
important intracellular buffers.
How is body pH regulated? Respiratory regulation. The respiratory system
pH homeostasis is very important, as the effects of responds within minutes to correct pH
acidaemia and alkalaemia on the body are potentially disturbances. The PaCO2 is inversely related to V_ A
very serious. Body pH is normally1 maintained (see Chapter 10). In turn, pH is related to PaCO2.
between 7.35 and 7.45 through three mechanisms. Therefore:
As acidosis is much more frequently encountered – An increase in V_ A results in an increase in
than alkalosis, these mechanisms are primarily con- blood pH.
cerned with limiting the harmful effects of acidosis: – A reduction in V_ A results in a decrease in
Buffering. A buffer is a substance that responds blood pH.
rapidly to oppose the change in pH when an acid
The respiratory centre responds rapidly to a
or base is added to the plasma, according to Le
pH disturbance, increasing or decreasing V_ A
Chatelier’s principle. Buffers are salts of weak
in response to acidaemia or alkalaemia
acids or bases, and work by releasing or absorbing
respectively:
H+ in response to addition of stronger base or acid
respectively. Buffer systems can be classified as: – Metabolic acidosis is sensed by the carotid
bodies (see Chapter 21), which stimulate
– Extracellular buffers:
the respiratory centre; V_ A increases in
▪ The H2CO3/HCO3 buffer system is the proportion to the degree of acidosis. The
most important extracellular buffer owing increase in V_ A is predominantly due to an
to the abundance of HCO3 in plasma, and increase in VT with little increase in RR; this
the fact that CO2 (in equilibrium with breathing pattern is called ‘Kussmaul
H2CO3) may be eliminated by the lungs breathing’ and is commonly seen in diabetic
(see below). The pKa of the H2CO3/HCO3 ketoacidosis.
system is 6.1; therefore, at pH 7.4, HCO3 – Hypercapnoea is sensed by both the peripheral
is a good buffer of acids but not alkalis. and central chemoreceptors (see Chapter 21),
which stimulate an increase in V_ A .
1
In pregnancy, a mild physiological alkalosis is expected Hypercapnoea is a potent stimulus: the
(see Chapter 77). combined effects of acidosis and hypercapnoea
331
generate a twofold greater increase in V_ A than generated by the basolateral Na+/K+-

acidosis alone. ATPase.
– Alkalaemia reduces stimulation of the carotid ▪ As CO2 is lipid soluble, it diffuses along its
bodies, and thus causes a limited reduction in concentration gradient, across the apical
V_ A . membrane of the tubule and into the PCT
Renal regulation. The kidneys correct pH cell (3).
disturbances over a period of days, through three ▪ In the PCT cell, the reverse reaction occurs:
mechanisms: CA catalyses the reaction between CO2 and
– Excretion of fixed acids; for example, water, producing H+ and HCO3 (4). H+ is
phosphoric, sulphuric and keto acids. Renal secreted back into the tubular lumen
filtration and excretion constitutes the only through the Na+/H+-antiporter, and HCO3
means of excreting fixed acids. moves into the blood through a sodium–
– Controlled reabsorption of filtered HCO3 . bicarbonate co-transporter (5). Overall,
HCO3 is freely filtered at the glomerulus. HCO3 is reabsorbed from the renal filtrate.
Around 80% of filtered HCO3 is reabsorbed In the DCT and collecting ducts, the type
in the PCT, irrespective of changes in plasma A intercalated cells and principal cells control
pH. The mechanism of reabsorption is as the reabsorption of the remaining tubular
follows (Figure 66.1): HCO3 . The mechanism for HCO3
▪ HCO3 cannot directly cross the apical reabsorption is similar to the PCT, relying on
membrane of the tubules. H+ secretion into the tubular lumen. Under
+ normal conditions, nearly all the filtered
▪ Instead, H is secreted into the tubular
lumen (1), where it combines with HCO3 , HCO3 is reabsorbed. Alkalaemia leads to less
resulting in CO2 (2). This reaction is HCO3 being reabsorbed; more HCO3
catalysed by the brush border enzyme CA. appears in the urine, resulting in a higher
H+ is secreted into the PCT lumen by urinary pH.
secondary active transport, using an – Ammoniagenesis. In response to acidosis, the
Na+/H+-antiporter and the Na+ gradient liver shifts from turning ammonium (NH4+)
HCO3− cannot cross apical membrane Figure 66.1 Mechanism of HCO3

Filtered HCO3− reabsorption in the PCT.
Na+/H+-countertransporter Basolateral
Na+/K+-ATPase
Na+ Na+ Na+ Na+

HCO3−
H+ K+ K+
(1) H+ HCO3 −
(4)
H2CO3
HCO3− (5)
H2CO3
CA
Na+ Na+
CA
H2O + CO2 CO2 Bicarbonate reabsorption via
(2) (3) H2O bicarbonate–Na+ cotransporter
Tubular lumen PCT cell Extracellular fluid
CO2 diffuses across the cell membrane
332
ions and HCO3 into urea, to producing membrane hyperpolarization makes action
glutamine. Glutamine travels in the blood to potential generation more difficult.
the cells of the PCT, where NH4+ and HCO3
are reproduced. NH4+ is secreted into the The clinical effects of acid–base disturbance can
tubular lumen in exchange for Na+ (again, the be considered system by system:
process is driven by the basolateral Na+/K+- Cardiovascular system. It is difficult to separate
ATPase), and HCO3 is moved into the blood the effects of acidosis from the effects of
in exchange for Cl . This generation of hypercapnoea on the heart and vasculature. In
HCO3 is beneficial in the correction of the general:
acidosis, but kidney must now excrete the – Sympathetic response. Hypercapnoea
NH4+: stimulates catecholaminergic release from the
adrenal medulla.
▪ In the thick ascending limb of the LOH,
NH4+ is reabsorbed via the Na+/K+/2Cl – Effect on cardiac output. Acidosis causes direct
transporter (NH4+ passes through the myocardial depression, manifesting as a
K+ site). decrease in SV. However, in mild acidosis,
+ these effects are offset by catecholaminergic
▪ In the medullary interstitium, NH4 loses
+
an H to become NH3. release from the adrenal medulla. Below pH
7.0, the negative inotropy associated with
▪ The membrane of the medullary collecting
acidosis outweighs the positively inotropic
duct is permeable to NH3; therefore, NH3
effects of adrenaline. In addition,
diffuses into the collecting duct.
+ parasympathetic outflow increases, which
▪ In continued acidosis, H ions are present in counteracts the effects of catecholamines on
high concentration within the tubular fluid
HR, resulting in bradycardia. As a result of
and thus bind to NH3 to reform NH4+. The
these two effects, cardiac output falls.
collecting duct membrane is impermeable to
– Cardiac arrhythmias, including ventricular
NH4+, and thus it is excreted.
ectopic beats and AF, are common in acidosis,
Overall, one H+ ion is excreted into the whether metabolic or respiratory in origin.
renal filtrate per molecule of glutamine This is a consequence of increased circulating
metabolized. The capacity of this system to adrenaline and electrolyte disturbance
excrete H+ is very high, even when the tubular (see below).
filtrate is already very acidic. – Vascular tone. The effects of acidosis and
hypercapnoea on the vasculature is complex:
whilst acidosis per se causes arteriolar
What are the main systemic vasoconstriction, hypercapnoea causes many
vascular beds to vasodilate; for example, in
consequences of acid–base skin (thus accounting for the bounding pulse
disturbance? found in hypercapnoeic patients) and the
At a molecular level, pH affects: cerebral arterioles.
Enzyme function – outside a narrow range of pH, Alkalosis increases myocardial contractility by
enzymes may become denatured and their increasing the responsiveness of the myocardium
function impaired. to circulating catecholamines; therefore,
The ionization of molecules – this may alter their myocardial O2 demand increases. However,
ability to cross cell membranes, or affect their alkalosis also reduces myocardial O2 delivery,
shape and function. through vasoconstriction of the coronary
RMP – a pH disturbance may alter the circulation and by shifting the oxyhaemoglobin
permeability of neuronal membrane ion channels, dissociation curve to the left, thus impairing
which in turn affects the RMP. Membrane offloading of O2 to the myocardium.
depolarization towards threshold potential makes Respiratory system. As discussed above, the main
spontaneous action potentials more likely, whilst effect of acidosis on the respiratory system is an
333
increase in V_ A . The respiratory centre in the (spontaneous depolarization of motor neurons)

medulla oblongata is stimulated by the carotid may therefore occur.
+
bodies in response to decreased plasma pH, and CNS. Whilst H cannot cross the BBB owing to its
by the central chemoreceptors in response to charge, the high lipid solubility of CO2 allows it to
hypercapnoea (see Chapter 21). diffuse into the brain. As discussed in Chapter 45,
hypercapnoea causes vasodilatation of the cerebral
Additional effects of acid–base disturbance on the vasculature. CBF is therefore directly proportional
respiratory system are: to PaCO2, between the limits of 3.5 and 8.0 kPa:
– The oxyhaemoglobin dissociation curve is
– Below 3.5 kPa, the cerebral arterioles are
shifted to the right by acidosis and to the left
maximally vasoconstricted. Further reductions
by alkalosis (see Chapter 7).
in PaCO2 have no effect on the cerebral
– Airway resistance. The effect of acidosis on vasculature, but the alkalosis-induced leftward
airway calibre is complex. Hypercapnoea shift of the oxyhaemoglobin dissociation curve
causes bronchodilatation through a direct may cause tissue hypoxia, leading to a
effect of CO2 on the bronchial smooth muscle. subsequent increase in CBF.
But hypercapnoea also triggers an increase in
– Above 8.0 kPa, the cerebral arterioles are
parasympathetic outflow to the bronchi,
maximally vasodilated. Further increases in
indirectly causing bronchoconstriction. In
PaCO2 cause no further increase in CBF.
otherwise healthy hypercapnoeic patients,
indirect bronchoconstriction outweighs direct As CO2 can freely diffuse into the CSF, the pH of
bronchodilatation, resulting in an increase in CSF reflects PaCO2, which in turn affects neuronal
airway resistance, and consequently an function. Patients with respiratory acidosis may
increase in the work of breathing. therefore experience headaches (due to the
Electrolyte changes. Acidosis is commonly increased CBF), confusion and impaired
associated with hyperkalaemia, which may consciousness, extensor plantar responses and
precipitate cardiac arrhythmias. Plasma K+ asterixis (CO2 flapping tremor).
increases by 0.6 mmol/L for every 0.1 unit Respiratory alkalosis may precipitate epilepsy.
decrease in plasma pH. It was previously thought Hypocapnoea induces an alkalosis within the
that H+ underwent intracellular buffering through CNS. In a similar way to the peripheral nerves, the
exchange with intracellular K+, but it is now RMP of the brain’s neurons becomes more
thought that acidosis impairs the Na+/K+-ATPase, unstable, which results in neuronal excitation and
resulting in extracellular K+ leak. Despite the high spontaneous depolarization.
plasma K+ concentration, total body K+ stores are Bones. Chronic metabolic acidosis leads to bone
frequently depleted. Thus, the treatment of decalcification, as bone phosphate is mobilized to
acidosis may result in hypokalaemia if K+ is not buffer H+ ions. In chronic renal failure, this
simultaneously replaced. contributes to the development of renal
osteodystrophy.
Plasma calcium occurs in two forms: biologically
active ionized Ca2+ and protein-bound unionized
Ca2+ (see Chapter 76). In acidosis, H+ ions How does pH change with temperature?
compete for the same binding sites as Ca2+ on Consider the dissociation equilibrium of pure water:
albumin, displacing Ca2+ and thus increasing the
fraction of ionized Ca2+. Conversely, alkalosis H2O Ð H+ + OH
reduces the fraction of ionized Ca2+. As ionized The pH of pure water is temperature dependent: a
Ca2+ is the biologically active form, alkalosis decrease in temperature shifts the equilibrium to the
results in an effective hypocalcaemia. left, thus reducing the concentration of free H+, which
Hypocalcaemia increases the Na+ permeability of consequently increases the pH of water.
the neuronal cell membrane, making the RMP Likewise, the pH of blood is temperature depend-
more unstable. Paraesthesias (spontaneous ent. Blood pH increases by 0.015 for every 1 °C
depolarization of sensory receptors) and tetany decrease in temperature. In addition, as temperature
334
decreases, the blood solubility of CO2 increases, and What is the Stewart approach to
therefore PaCO2 falls.
Arterial blood gas analysers operate at 37 °C. As long acid–base physiology?
as the patient’s temperature is near to 37 °C, the pH The traditional Henderson–Hasselbalch approach
measured by blood gas analysis will roughly correlate outlined above is well established, and can easily be
with the patient’s actual blood pH. However, in a applied to most clinical situations. However, the trad-
hypothermic patient, the pH measured at 37 °C may itional approach often fails to explain the complex
be significantly lower than the patient’s actual blood pH, acid–base abnormalities that occur in critical care
and the measured PaCO2 will be higher than the actual patients.
PaCO2. The pH and PaCO2 can be mathematically cor- The Stewart approach was developed in the 1980s.
rected to determine their actual values at the patient’s Though academically sound, the new acid–base
temperature. For example, a patient whose temperature theory was often considered too complex for routine
is 27 °C may have blood gas analysis (measured at 37 °C) clinical use. The Stewart approach has recently seen a
demonstrating normal pH and PaCO2; that is 7.4 and resurgence of interest amongst intensive care phys-
5.3 kPa respectively. However, when mathematically icians since the publication of simplified versions of
corrected to 27 °C, these values are significantly differ- Stewart theory, most notably by Story et al. in 2004
ent: pH is 7.55 and PaCO2 is 3.3 kPa. (see Further reading). A full explanation is beyond the
scope of this book, but a brief account is given below.
Clinical relevance: hypothermic cardiopulmonary There are three independent variables when con-
bypass sidering acid–base balance:
Clinically, the temperature dependence of pH is
PaCO2, which is determined by the balance of
important in the context of hypothermic cardiopul-
CO2 production through cellular metabolic
monary bypass, when the patient’s PaCO2 and thus
pH are controlled by the perfusionist:
processes, and CO2 elimination by alveolar
The pH-stat method involves adding CO2 to ventilation.
+ +
blood in the bypass circuit, in order that the Strong ions, electrolytes such as Na , K and Cl ,
patient’s pH and PaCO2 are maintained at nom- which are always fully dissociated from their
inally normal values, when corrected to the counterions. In plasma, strong cations outnumber
patient’s body temperature. It has been sug- strong anions – the difference is called the strong
gested that this practice counteracts the leftward ion difference (SID).
shift in the oxyhaemoglobin dissociation curve Weak acids, which are only partially dissociated
that occurs with hypothermia, thereby improving
in solution. Weak acids are mainly plasma
O2 delivery. However, increased PaCO2 causes
proteins, of which albumin is the major
cerebral vasodilatation, which in turn increases
CBF and abolishes cerebral autoregulation. This contingent.
increase in CBF may possibly increase the
embolic load, thus increasing the risk of post- Key equations: Stewart–Fencl–Story approach
operative cognitive dysfunction and stroke. The simplified Stewart model involves two equations:
The alpha-stat method involves permitting the
alkaline drift that occurs with hypothermia, BDENaCl ¼ ½Na+ ½Cl 38 ð1Þ
instead targeting nominally normal pH and where BDENaCl (mEq/L) is the base deficit excess for
PaCO2 when measured at 37 °C, and accepting Na+/Cl /free water.
that the patient’s actual blood pH will be >7.45.
This method is thought to maintain cerebral BDEAlb ¼ 0:25×ð42 ½albuminÞ ð2Þ
autoregulation and electrochemical neutrality at where BDEAlb (mEq/L) is the base deficit excess for
a cellular level, thus maintaining the function of albumin (in units of grams per litre).
cellular enzymes.
Despite many studies, it remains unclear whether

pH-stat or alpha-stat is the better technique in The BDENaCl is the Stewart equivalent of base excess
hypothermic cardiopulmonary bypass and deep in Henderson–Hasselbalch theory:
hypothermic circulatory arrest. BDENaCl >0 implies alkalaemia.
BDENaCl <0 implies acidaemia.
335
The greater the BDENaCl, the greater the extent of the

acid–base disturbance. This approach demonstrates a hyperchloraemic
metabolic acidosis and an alkalosis due to severe
As albumin is negatively charged, hypoalbuminae-
hypoalbuminaemia.
mia causes a metabolic alkalosis, the extent of which
is quantified by BDEAlb.
These simple equations agree with the original
complex Stewart equations surprisingly well. Cru- Further reading
cially, the Stewart model can be used to explain the K. A. A. Aziz, A. Meduoye. Is pH-stat or alpha-stat the best
technique to follow in patients undergoing deep
complex acid–base disturbances that occur in critical
hypothermic circulatory arrest? Interact Cardiovasc
care. Thorac Surg 2010; 10(2): 271–82.
A. Badr, P. Nightingale. An alternative approach to acid-
Clinical example: complex acid–base disturbance in base abnormalities in critically ill patients. Contin Educ
a critical care patient
A patient is admitted to intensive care following a
D. A. Story, H. Morimatsu, R. Bellomo. Strong ions, weak
laparotomy for bowel perforation. Over the next day,
acids and base excess: a simplified Stewart–Fencl
the patient developed severe sepsis. Several days of approach to clinical acid–base disorders. Br J Anaesth
mechanical ventilation later, arterial blood gas analy- 2004; 92(1): 54–60.
sis demonstrated: pH 7.45, PaO2 12.1 kPa, PaCO2
5.0 kPa, HCO3 26 mmol/L, Na+ 147 mmol/L, Cl J. M. Handy, N. Soni. Physiological effects of
115 mmol/L, albumin 12 g/L. hyperchloraemia and acidosis. Br J Anaesth 2008; 101(2):
141–50.
Using the Henderson–Hasselbalch approach, one
might think there was no acid–base abnormality: the C. G. Morris, J. Low. Metabolic acidosis in the critically ill:
pH and HCO3 are just within the normal range. Part 1. Classification and pathophysiology. Anaesthesia
However, using the Stewart–Fencl–Story approach: 2008; 63(3): 294–301.
BDENaCl ¼ 147 115 38 ¼ 6 mEq/L. C. G. Morris, J. Low. Metabolic acidosis in the critically ill:
BDEAlb ¼ 0.25 × (42 12) ¼ 7.5 mEq/L. Part 2. Causes and treatment. Anaesthesia 2008; 63(4):
396–411.
336
Section 7 Blood and immune system
Chapter
Haemostasis
67
diphosphatase which degrades ADP, an essential
What is haemostasis? compound for platelet activation.
Haemostasis is a collective term for the mechanisms
Anticoagulant effects result from two endothelial
that stop blood loss. Macroscopically, the most obvi-
membrane-bound proteins:
ous haemostatic mechanism is the conversion of
liquid blood to a solid gel – a process called coagula- – Heparan sulphate, which has a similar
tion. The process of clot formation is known as structure to heparin, activates the plasma
thrombosis. protein antithrombin III, which in turn
Haemostasis can be life-saving: when blood vessels inactivates thrombin (also known as factor IIa)
have been damaged, it is important that haemostasis and factor Xa.
occurs rapidly to prevent excessive blood loss. How- – Thrombomodulin has two roles: it directly
ever, it is equally important that the haemostatic binds thrombin, effectively removing
response is controlled and localized to the area of thrombin from the circulation. The thrombin–
vessel damage. Widespread coagulation could prevent thrombomodulin complex also activates
blood flow completely, damage RBCs (microangio- protein C. Together with a cofactor (protein S),
pathic haemolytic anaemia) or lead to paradoxical activated protein C is a potent anticoagulant,
bleeding due to depletion of clotting factors (dissem- inactivating factor Va and VIIIa.
inated intravascular coagulation (DIC)). Therefore, Fibrinolytic effects – endothelial cells also secrete
the mechanisms that promote and inhibit haemo- the enzyme tissue plasminogen activator (t-PA).
stasis are finely balanced. This potent enzyme cleaves the proenzyme
The three main components involved in haemo- plasminogen to form plasmin. Plasmin degrades
stasis are: fibrin clots from the endothelial cell surface in a
Platelets process called fibrinolysis (see p. 343).
Endothelium
Coagulation proteins. Outline the steps involved in
All three must be intact for haemostasis to be effective. haemostasis
Clot formation has three key steps:
How does the vascular endothelium Vasoconstriction
prevent haemostasis? Platelet aggregation
Coagulation.
The endothelium is extremely important in the bal-
ance between haemostasis and anti-haemostasis. Its When a vessel is disrupted, platelets must aggregate
normal function is to prevent haemostasis and pro- and plug the hole. To prevent the platelet plug being
mote blood flow, but when damaged it rapidly initi- washed away as it is being formed, the vessel first
ates a haemostatic response. The endothelium vasoconstricts, resulting in decreased blood flow –
prevents haemostasis by: this also has the effect of minimizing blood loss. The
Inhibition of platelet adhesion through the plasma coagulation proteins then trigger a fibrin
secretion of NO and prostacyclin (PGI2). The mesh to form around the platelet plug, resulting in a
endothelium also produces the enzyme adenosine stable clot.
337
Section 7: Blood and immune system
How is haemostasis initiated? The key steps of platelet aggregation are:

When a vessel is damaged, plasma becomes exposed Serotonin and thromboxane A2 are potent
to a number of substances: vasoconstrictors that reduce blood flow at the
site of injury.
Von Willebrand factor (vWF). Endothelial
Platelets are attracted to the site of injury. Initially,
cells are the main site of synthesis and storage of
platelets are activated by, and bind to,
vWF. Normally, a limited amount of vWF is
sub-endothelial collagen (via vWF); the exposed
secreted into the vessel lumen where it binds to
collagen becomes coated in a layer of platelets.
factor VIII, protecting the clotting factor from
The next cohort of platelets cannot make contact
degradation. A damaged vessel releases a large
with collagen. Instead, they are activated by the
amount of vWF from its endothelial cells; vWF
ADP molecules released from the first cohort of
then binds platelets to sub-endothelial
platelets. Binding of ADP causes the platelets to
collagen fibres.
change shape and release more chemicals from
Collagen fibres. Vessel damage exposes sub- storage granules.
endothelial collagen fibres. Platelets bind to
Activated platelets exhibit a glycoprotein IIb/IIIa
collagen (through a bridging vWF molecule) and
receptor on their surface. Fibrinogen and vWF
become activated. Activated platelets release a
‘glue’ platelets together through this receptor
number of stored molecules that attract other
(Figure 67.1). More and more platelets become
platelets to the site of vessel injury.
activated and bind to the site of injury, forming a
Tissue factor (TF) is expressed by sub-endothelial soft platelet plug.
cells, such as smooth muscle cells, but not
The soft platelet plug formed is often not enough
normally by endothelial cells, unless they become
to achieve haemostasis – the plug must be
damaged. TF activates plasma coagulation
reinforced to make a strong clot. Conveniently,
proteins (through the extrinsic pathway),
the strands of fibrinogen that are interwoven in
culminating in the production of thrombin.
the soft platelet plug are converted to fibrin
(a strong insoluble protein) by thrombin, the
Describe the steps involved in end-point of the coagulation cascade.
platelet activation and
aggregation Describe the steps of the coagulation
Platelets are disc-shaped (hence the name) anuclear
cell fragments. They have a short life span in the
cascade
circulation, typically of 7 days. As discussed above, The coagulation cascade is a complex biochemical
blood vessel damage exposes TF, collagen and vWF. pathway involving a number of plasma proteins, cul-
Passing platelets are activated by collagen and vWF, minating in the formation of thrombin. The coagula-
and also by thrombin itself, produced by TF- tion cascade is an example of a biological amplification
activation of the coagulation cascade. When platelets system: starting from a small number of activated
are activated, they change shape from disc-like to molecules, the sequential activation of circulating
stellate, and release a number of molecules from stor- coagulation proteins results in a magnified response.
age granules (Figure 67.1): Classically, the coagulation cascade is initiated by
one of two distinct pathways: intrinsic and extrinsic
Serotonin (5-HT)
(Figure 67.2). The two pathways converge on a final
Thromboxane A2
common pathway, resulting in thrombin formation.
ADP These classical pathways explain the mechanism of
Platelet activating factor (PAF) coagulation in vitro and reflect the laboratory clotting
vWF screen. However, there are a number of flaws with
Fibrinogen the classical model that have recently led to the
Thrombin development of a new cell-based coagulation model,
2+
Ca ions thought to better reflect the mechanism of in vivo
Platelet-derived growth factor (PDGF). coagulation.
338
Chapter 67: Haemostasis
Figure 67.1 Platelet activation and

Platelet activation aggregation.
Collagen in
basement
membrane
vWF
vWF vWF vWF
PDGF
Damaged endothelium Ca2+
Thrombin
Activated
Circulating platelet platelet
Fibrinogen
5-HT
Vasoconstrictors – reduce
blood flow to damaged
Thromboxane A2 vWF
capillary
ADP PAF
Platelet aggregation
vWF
Platelet binds to injury site through
collagen and vWF via Gp Ia/IIa receptors
ADP
ADP receptor – ADP binding
ADP
required for platelet activation
vWF
Platelets are bound together vWF

by vWF and fibrinogen Fib
Gp IIb/IIIa receptor binds

fibrinogen and vWF ADP
Clinical relevance: antiplatelet drugs

thromboxane A2 and endothelial cells from pro-
Antiplatelet drugs are commonly prescribed for ducing PGI2. However, as platelets contain no
patients at risk of arterial thrombosis; for example, nucleus, COX remains inhibited for the entirety of
myocardial infarction. Antiplatelet drugs act through their life span (approximately 7 days). Conversely,
different mechanisms, each targeting a different endothelial cells may produce new COX within
part of the platelet activation and aggregation hours. The result is a net increase in platelet
mechanism: inhibition.
COX inhibitors; for example, aspirin. Thrombox- ADP receptor antagonists; for example, clopi-
ane A2 is a potent platelet activator and vaso- dogrel. This class of drug specifically blocks the
constrictor produced from platelet membrane platelet ADP receptor, which prevents further
phospholipid, a process that is catalysed by the platelet activation and inhibits the expression of
enzyme COX. At the same time, endothelial cells the glycoprotein IIb/IIIa complex, thus inhibiting
produce PGI2, a platelet inhibitor also catalysed platelet aggregation.
by COX. The balance between thromboxane A2 Glycoprotein IIb/IIIa inhibitors; for example,
and PGI2 determines whether a clot is formed. abciximab. Platelet aggregation is inhibited
Aspirin is a non-specific, irreversible inhibitor of by preventing platelets from binding to
COX, preventing platelets from producing fibrinogen.
339
Tested by activated partial Figure 67.2 The classical coagulation

thromboplastin time (APTT) cascade. Roman numerals represent
Tested by prothrombin unactivated clotting factors; ‘a’ denotes
Intrinsic pathway time (PT)
activated clotting factors; PF3: platelet
Surface contact factor 3.
XII XIIa Extrinsic pathway
XI XIa TF
IX IXa VIIa VII

VIIIa
TF
Ca2+
PF3
X Xa X
Va Antithrombin III deactivates
Activated protein C (with protein S)
Ca2+ Xa and thrombin
deactivates Va and VIIIa
PF3
Thrombomodulin–thrombin Prothrombin (II) Thrombin (IIa)

complex activates protein C
Thrombomodulin binds and
inactivates thrombin Fibrinogen (I) Fibrinogen (Ia)
Tested by the XIIIa

thrombin time (TT)
Final common pathway Cross-linked fibrin clot
factor X at the start of the final common pathway

Phosphodiesterase inhibitors; for example,
dipyridamole, which acts through a number of
(Figure 67.2). Whilst the intrinsic pathway is now
possible mechanisms. One mechanism is the thought to have only a minor haemostatic role in
inhibition of the platelet phosphodiesterase vivo, an understanding remains important for the
enzyme, whose usual role is to break down cAMP. interpretation of laboratory coagulation studies
Increased platelet cAMP inhibits ADP release, and the diagnosis of specific clotting factor
resulting in impaired platelet aggregation and deficiencies.
reduced thromboxane A2 synthesis. Final common pathway. Along with a number of
co-factors (factor V, Ca2+ and PF3), factor Xa
(produced by either the intrinsic or extrinsic
Key features are:
pathway) converts prothrombin (factor II) to
Extrinsic pathway. The extrinsic pathway is thrombin (factor IIa). Thrombin then acts on the
socalled because it is activated by TF, which is fibrinogen mesh within the platelet plug,
not normally found within the lumen of intact hydrolysing the soluble fibrinogen to produce
blood vessels. Blood vessel disruption exposes insoluble fibrin strands. In addition, thrombin has
circulating clotting factors to sub-endothelial TF: other key roles:
any factor VII passing the site of injury is
activated to factor VIIa. Factor VIIa activates – Activation of factor XIII. Factor XIIIa forms
factor X, the clotting factor at the start of the final covalent crossbridges between fibrin strands in
common pathway (Figure 67.2). the platelet plug, forming a stable clot.
– Generation of a positive feedback loop.
Intrinsic pathway. The intrinsic pathway is
so called because it was recognized that initiation of Thrombin activates factors V and VIII, which
coagulation did not always require TF, especially in feed into the coagulation cascade to produce
vitro: plasma can clot without the addition of any more thrombin.
extrinsic material. It has since been found that the – Activation of protein C. Thrombin forms a
intrinsic pathway is activated by contact with complex with thrombomodulin (an
negatively charged substances such as endothelial cell membrane protein). The
sub-endothelial collagen in vivo, or glass in vitro. plasma glycoprotein protein C is activated by
The intrinsic pathway involves a number of the thrombin–thrombomodulin complex,
clotting factors, culminating in the activation of producing activated protein C. Activated
340
protein C is an important inhibitor of (Figure 67.3). Of particular interest, several of the

coagulation, as it deactivates factors Va proteins traditionally included in the intrinsic path-
and VIIIa. way (for example, factor XII and prekallikrein) have
been shown to make little in vivo contribution to
coagulation, and are not included in the cell-based
Clinical relevance: haemophilia and von
Willebrand disease
coagulation model:
Haemophilia A is an X-linked autosomal recessive Initiation phase. Coagulation is triggered by
disease, which results in a deficiency of factor VIII. vessel damage, which exposes plasma to TF. The
Following vessel injury, a soft platelet plug forms but initiation phase of coagulation takes place on a
fibrin cannot be produced to reinforce the platelet TF-bearing endothelial cell. Any nearby factors
plug. As a consequence, patients with haemophilia V and VII become activated. These activated
bleed for a much longer time than patients with factors go on to activate other nearby clotting
normal coagulation. Bleeds into joints may cause factors. This culminates in the formation of a
permanent disability, and intracerebral bleeds are small amount of thrombin. In addition, passing
frequently fatal. platelets are activated by TF and vWF, and by the
Management is either prophylactic or by treat-
small amount of thrombin that has been formed.
ment of bleeding episodes when they occur: infu-
sions of human or recombinant factor VIII are used in Amplification phase. The amplification phase
severe haemophilia. Alternatively, patients with mild involves the further activation of clotting factors
haemophilia may use desmopressin (DDAVP, a syn- and platelets in preparation for the large-scale
thetic form of ADH) to boost the body’s own produc- generation of thrombin.
tion of factor VIII. Propagation phase. The propagation phase
Von Willebrand disease is the most common her- occurs on the surface of an activated platelet,
editary coagulation disorder: patients have either loaded with activated clotting factors. With all its
deficient or defective vWF. vWF normally has two co-factors in place, the activated platelet can
roles:
catalyse the formation of large amounts of
Forming a bridge between platelets and sub-
thrombin.
endothelial collagen.
Binding to clotting factor VIII, thus protecting it
from degradation. The cell-based coagulation model has thrombin at
its centre. Thrombin is involved in its own generation
Therefore, if vWF is reduced or ineffective, both for- and regulation through feedback loops, as well as the
mation of the platelet plug and coagulation are conversion of fibrinogen to a cross-linked fibrin
affected. Von Willebrand disease has a wide disease
polymer.
spectrum, but fortunately most cases are mild –
patients present with nosebleeds, easy bruising and
bleeding following dental extraction. What are the main laboratory tests
Treatment for mild bleeding is usually unneces-
sary. Like haemophilia A, DDAVP can be used to of clotting?
boost the body’s own factor VIII and vWF production, The main laboratory tests of clotting are:
and is commonly used prior to surgery or dental PT, a test of the extrinsic pathway. The test
extraction. In severe bleeding, a factor VIII concen-
involves adding TF to a sample of plasma and
trate rich in vWF can be given intravenously.
measuring the time of clot formation. The INR is
the ratio of a patient’s PT compared with the
average PT of a control sample. PT mainly
What is the cell-based model of assesses clotting factor VII of the extrinsic
coagulation? pathway, along with clotting factors II, X and
Whilst the classical coagulation cascade accurately fibrinogen of the final common pathway. PT is
reflects in vitro laboratory coagulation tests, it does prolonged by:
not adequately explain in vivo haemostasis. The cell- – Decreased hepatic synthesis of the vitamin-K-
based model of coagulation is thought to better dependent clotting factors: II, VII, IX and X.
represent the in vivo mechanism of coagulation This may be the result of warfarin therapy
341
Figure 67.3 Cell-based coagulation model.

Initiation Exposed tissue factor
Endothelial damage
TF TF TF TF
TF X
VII VIIa Va V
IX
Xa
IXa
Prothrombin (II) Thrombin (IIa)
Amplification
VIII
Thrombin (IIa) Va
Va
VIIIa
Circulating Activated
platelet platelet
Xa
Also activated by
TF and vWF
IXa
X
Propagation
Prothrombin (II)
Va
VIIIa
Activated
platelet
Xa Fibrinogen (I)
IXa
Thrombin (IIa)
Fibrin (Ia)
XIII XIIIa
Cross-linked fibrin clot
342
(vitamin K antagonism), vitamin K deficiency A sample of whole blood is added to a slowly

(for example, fat malabsorption) or liver rotating cuvette – the low-shear environment mimics
disease. sluggish venous flow. A plastic pin attached to a
– DIC, due to the consumption of clotting torsion wire is lowered into the cuvette. As the blood
factors. clots, fibrin strands form between the cuvette and the
Activated partial thromboplastin time (APTT), a pin and the torsion of the wire changes. The speed
test of the intrinsic pathway. The test involves and strength of clot formation are calculated from the
adding phospholipid and an activator (for change in torsion of the wire, resulting in a cigar-
example, silica) to a plasma sample and measuring shaped graph.
the time taken to clot. APTT mainly assesses Gross abnormalities of haemostasis can be quickly
clotting factors VIII, IX, XI and XII of the assessed from the shape of the thromboelastogram, or
intrinsic pathway, and clotting factors II, X and a more detailed analysis of haemostasis can be made
fibrinogen of the common pathway. APTT is by analysing various parameters.
prolonged by:
– Unfractionated heparin therapy, through What is the fibrinolysis pathway?
activation of antithrombin III (which Fibrinolysis is a physiological mechanism in which
inactivates factors Xa and thrombin). Low the fibrin within blood clots is slowly dissolved. It is a
MW heparins are too small to activate normal part of wound healing, and is an important
antithrombin III effectively, instead mechanism to keep small vessels patent. The fibrino-
inactivating factor Xa directly. APTT is then lysis pathway is shown in Figure 67.4.
usually not prolonged. Key points are:
– Haemophilia (factor VIII deficiency),
Plasminogen is a β-globulin, a proenzyme
Christmas disease (factor IX deficiency) and synthesized by the liver.
von Willebrand disease (vWF deficiency).
Plasminogen becomes interwoven into the fibrin
– DIC, due to the consumption of clotting clot as it is formed.
factors.
Plasminogen is converted to plasmin, a serum
In addition, there are other less commonly used protease. The main physiological activator of
tests that may be indicated in certain circumstances: plasminogen is t-PA, expressed by the endothelial
cells: it helps to keep the endothelial cell surface
Thrombin time (TT), a test of the final common
pathway. Thrombin is added to plasma and the free of fibrin deposits, and therefore small vessels
clotting time measured. TT tests the interaction patent.
between thrombin and fibrinogen, and is Fibrin is cleaved by plasmin, producing fibrin
prolonged in fibrinogen deficiency; for example, degradation products (FDPs). One of these
due to DIC. FDPs is called the d-dimer, a cleavage product
of cross-linked fibrin. D-dimer concentration is
Bleeding time. A standard incision is made and
time to stop bleeding is measured; that is, the time a laboratory test commonly used to aid the
it takes for an effective platelet plug to form. diagnosis of venous thromboembolic disease
Bleeding time is therefore a test of platelet (for example, PE).
function. This test is rarely performed, as it does Fibrinolysis is a much slower process than
not help to predict surgical bleeding. coagulation. The time lag between clot formation
and clot dissolution allows healing to take place.
What is thromboelastography? The fibrinolysis pathway can be manipulated as
Thromboelastography is a near-patient method of required:
testing the whole haemostatic process. It assesses Thrombolysis. In life-threatening thrombosis (for
platelet function, coagulation and fibrinolysis in a example, ST-elevation myocardial infarction,
single test. Not only is thromboelastography quicker acute ischaemic stroke, massive PE), thrombolytic
to perform than laboratory-based tests, it is thought drugs are used to dissolve the thrombus. These
to better represent in vivo haemostasis. drugs (for example, alteplase, streptokinase,
343
Process enhanced by tPA released Conversion inhibited by antifibrinolytics:

from damaged blood vessels (for example, tranexamic acid)
Plasminogen
D-dimer is a laboratory measurement

of fibrin degradation products
Recombinant tPA (e.g. alteplase) Plasmin
also promotes plasmin production
– this is ‘thrombolysis’
Cross-linked fibrin Fibrin degradation products
Figure 67.4 Fibrinolysis.
urokinase) all promote the conversion of Further reading

plasminogen to plasmin, thus increasing
E. Ortmann, M. W. Besser, A. A. Klein. Antifibrinolytic
fibrinolysis. agents in current anaesthetic practice. Br J Anaesth 2013;
Inhibition of fibrinolysis. Antifibrinolytic drugs 111(4): 549–63.
(for example, tranexamic acid) inhibit the A. N. G. Curry, J. M. T. Pierce. Conventional and near-
activation of plasminogen. It may be patient tests of coagulation. Contin Educ Anaesth Crit
advantageous to inhibit fibrinolysis (for example, Care Pain 2007; 7(2): 45–50.
following haemorrhage), thus promoting B. T. Colvin. Physiology of haemostasis. Vox Sanguinis 2004;
haemostasis. Tranexamic acid is commonly used 87(Suppl. 1): S43–6.
in trauma, cardiac surgery and for the treatment M. Hoffman. Remodelling the blood coagulation cascade.
of menorrhagia. J Thromb Thrombolysis 2003; 16(1–2): 17–20.
344
Chapter
Transfusion
68
What are red blood cell antigens? What is the Rhesus system?
As discussed in Chapter 7, RBCs can be thought of as The Rhesus blood group is the second most important
‘bags of Hb’. However, the composition of the ‘bag’ in transfusion medicine. It is named after the Rhesus
itself differs between patients. The RBCs have surface monkey, the animal whose blood was used in the
antigens that act as markers, identifying the RBC to discovery of the Rhesus system. There are 50 different
the immune system. RBC surface antigens may be Rhesus antigens discovered to date, of which the most
polypeptides, polysaccharides and glycoproteins. important are: D, C, c, E and e. By far the most
Which specific antigens are expressed is determined important Rhesus antigen is D – this is the antigen
genetically. There are at least 30 different RBC antigen that is present when patients are referred to as being
systems, the most important of which are: Rhesus positive, Rh factor positive or RhD positive.
The ABO blood group system. The RhD antigen is a large (30 kDa) cell mem-
The Rhesus blood group system. brane protein, thought to be a subunit of an NH3
transport protein. As with other blood group systems,
Minor blood group systems include Kell, MNS, Lewis, the presence or absence of the RhD antigen on a
P and Duffy. patient’s RBCs is genetically determined – around
85% of the UK population are RhD positive.
Describe the ABO system
As well as being the first RBC antigen system dis- Why does the immune system develop
covered, the ABO blood system remains the most
important for blood transfusion. The ABO blood antibodies to red blood cell antigens?
groups are carbohydrate-based antigens. All patients’ The immune system develops antibodies to fragments
RBCs have a disaccharide ‘core’ antigen, called the of foreign material presented by antigen-presenting
H antigen. Patients then fall into one of four blood cells (see Chapter 70). Patients may develop anti-
groups: bodies to non-self RBC antigens for two reasons:
Group O. These patients’ RBCs only express the Exposure to foreign RBCs; for example, following
H antigen; ‘O’ signifies that no other sugars a blood transfusion or placental abruption.
are added. Exposure to environmental antigens (food,
Group A. An additional carbohydrate group bacteria, etc.) that happen to have a chemical
(N-acetylgalactosamine) is bound to the structure similar to that of a non-self RBC antigen
H antigen, making a trisaccharide: the A antigen. results in the production of antibodies which also
Group B. A different carbohydrate group cross-react with non-self RBCs.
(d-galactose) is bound to the H antigen, making a
The two main blood groups exemplify this:
different trisaccharide: the B antigen.
Group AB. These patients’ RBCs express both ABO blood group system. At birth, antibodies to
A and B antigens. non-self ABO antigens are not present: they
appear in the plasma from around 6 months of
In the UK, the most common blood groups are age. Antibody development is thought to be an
O (44%) and A (42%). Group B makes up 10%, while immune response to environmental antigens that
group AB is found in only 4% of patients. have a similar chemical structure to the ABO
345
antigens. As a result, antibodies are raised to non-

self antigens: and at delivery, in an attempt to prevent maternal
sensitization to RhD. The parenteral anti-RhD IgG
– Blood group O: develop anti-A and anti-B binds any fetal RBCs which pass into the maternal
antibodies. circulation.
– Blood group A: develop anti-B antibodies only.
– Blood group B: develop anti-A antibodies only.
– Blood group AB: do not develop anti-A or anti- What is meant by the terms ‘allogenic’
B antibodies.
The anti-A and anti-B antibodies produced
and ‘autologous’ blood transfusion?
Allogenic blood transfusion is where donor blood,
are immunoglobulin M (IgM). This is
usually packed RBCs, is given intravenously to a recipi-
important as IgM is unable to cross the
ent. In contrast, autologous blood transfusion is where
placenta – if it could, every fetus of a different
blood is taken from a patient and re-infused back to
ABO blood group to the mother would have
the same patient when required (for example, intra-
its RBCs attacked by the maternal immune
operative cell salvage, preoperative autologous blood
system.
donation, acute normovolaemic haemodilution).
Rhesus blood group system. In contrast to the
ABO blood group system, the 15% of the
population who are genetically RhD antigen What is meant by the term ‘haemolytic
negative do not naturally develop RhD antibodies.
Anti-RhD antibodies are only acquired on transfusion reaction’?
exposure to foreign RBCs carrying the RhD Early allogenic blood transfusions were fraught with
antigen. Clinically, this may occur due to: complications: many patients died after receiving
– Incompatible blood transfusion. Transfusion of incompatible blood. It was not until the ABO blood
RhD-positive blood into an RhD-negative group system was discovered that the reasons for
patient will trigger anti-RhD antibody these deaths became clear.
production. A haemolytic transfusion reaction will occur if the
recipient’s plasma contains antibodies that are react-
– Fetal-maternal haemorrhage. If the blood of an
ive against the donor’s RBC antigens. The recipient’s
RhD-positive fetus and RhD-negative mother
antibodies coat the donor RBCs: the antibody–
mix (for example, following childbirth,
antigen complex activates complement, leading to
abortion, trauma or placental abruption), the
haemolysis of donor RBCs. Haemolytic transfusion
maternal immune system will be exposed to
reactions are of two types:
RhD antigen and will develop anti-RhD
antibodies. Immediate haemolytic transfusion reaction.
Unfortunately, RhD antibodies are usually ABO incompatibility causes rapid intravascular
IgG, and are therefore able to cross the placenta. haemolysis, the severity depending on the
antibody titre. Urticaria, flushing, chest pain,
Clinical relevance: Rhesus disease dyspnoea, jaundice, tachycardia, shock,
haemoglobinuria and DIC may occur.
Rhesus disease affects RhD-negative mothers with
RhD-positive offspring. When an RhD-negative
Transfusion of RhD-incompatible blood tends to
mother is exposed to RhD-positive fetal blood (for result in extravascular haemolysis, which is
example, following trauma), her immune system pro- usually less severe than intravascular haemolysis.
duces anti-RhD IgG. Maternal anti-RhD IgG is then Delayed haemolytic transfusion reaction. Minor
able to cross the placenta and attack the RBCs of a RhD antigens and the minor blood group systems
RhD-positive fetus, either for the same or a subse- may cause a delayed haemolytic transfusion
quent pregnancy. The fetus develops a severe reaction, occurring 7–21 days following
anaemia in utero and, if the fetus survives to birth, transfusion. Delayed transfusion reactions are
Rhesus disease (haemolytic disease of the newborn). difficult to prevent. Following a prior exposure to
RhD-negative mothers are given anti-RhD
a blood antigen, patients develop a low titre of
immunoglobulin once or twice during pregnancy
antibody – too low for laboratory detection. When
346
Chapter 68: Transfusion
incompatible blood is transfused, a secondary and donor antigens. If donor RBCs clump
immune response occurs: it takes time for new together, the blood is incompatible.
IgG antibodies to be produced, leading to a delay Minor cross-match. The recipient’s RBCs are
before haemolysis is evident. mixed with the donor’s plasma. Minor cross-
match is no longer routinely performed because
RBCs are now transfused as packed cells, and
What is meant by the terms ‘universal thus contain an insignificant amount of donor
donor’ and ‘universal recipient’? plasma.
There are two groups of patients of particular import-
ance in transfusion medicine – the universal donor How are blood products stored?
and the universal recipient:
The three main blood products are packed RBCs,
The universal donor is a blood group O RhD- fresh frozen plasma (FFP) and platelets:
negative patient. This is because:
Packed RBCs. Donated whole blood is spun in a
– Group O RBCs only express the core H centrifuge and the plasma removed. The RBCs are
antigen, so are safe for donation to recipients resuspended in the minimum amount of fluid,
with anti-A or anti-B antibodies. resulting in a haematocrit of >75%. Citrate,
– RhD-negative RBCs are safe to transfuse in adenine and glucose are added and the mixture
recipients with anti-RhD antibodies. stored at 4° C, resulting in a shelf-life of 42 days.
During storage:
In an emergency situation, where there is insufficient
time to establish the blood type of the recipient – Some RBCs become spherical, reducing their
(for example, trauma, ruptured aortic aneurysm, life span.
obstetric haemorrhage), it is considered safe to – K+ concentration rises to 30 mmol/L by 28
transfuse with O negative blood. However, there days’ storage.
may still be minor blood group antigen–antibody – ATP and 2,3-DPG levels fall. Following
incompatibility reactions; a full cross-match is transfusion it takes 24 h for 2,3-DPG
required to ensure blood is fully compatible. concentrations to return to normal.
The universal recipient is more of academic than Transfused blood, therefore, has a higher
clinical interest. Blood group AB RhD-positive O2-binding affinity than native blood, and
patients can receive donor blood irrespective of its thus O2 offloading to the tissues is impaired
ABO and Rh status: (see Chapter 7). Whether this is clinically
significant is a matter of debate.
– Their plasma has neither anti-A nor anti-B
FFP. As the name suggests, the plasma removed
antibodies, because their RBCs contain both
from whole blood during the process of producing
antigens.
packed RBCs is cooled to 30 °C within 8 h of
– Similarly, their plasma does not contain anti-
donation. FFP has a shelf-life of 1 year. FFP is
RhD antibodies, because their RBCs express
used to replace coagulation factors, and should be
the RhD antigen.
blood type-matched to ensure compatibility.
It is important to note that the minor blood group Other FFP-derived blood products are:
antigens are not necessarily compatible; a cross- – Cryoprecipitate: FFP is frozen to 70 °C, then
match is still required. thawed and centrifuged, and the precipitate
collected. Cryoprecipitate is rich in factors
VIII, XIII, fibrinogen and vWF, and is used in
What is a ‘cross-match’? clotting factor deficiencies and
Cross-match is a compatibility test between donor hypofibrinogenaemia.
and recipient blood. There are two types: – Freeze-dried factor VIII concentrate, which also
Major cross-match. The recipient’s serum is contains a small amount of fibrinogen, is used
mixed with donor RBCs – this is a test of to replace factor VIII in patients with
compatibility between the recipient’s antibodies haemophilia A.
347
– Freeze-dried factor IX concentrate, which within the donor blood attack the recipient’s
also contains a small amount of factors II, VII tissues. Non-immune TRALI is thought to be
and X, is used to replace factor IX in due to neutrophil activation following release
patients with factor IX deficiency of reactive lipid products from the donor
(Christmas disease). RBC membranes. Whatever the mechanism,
Platelet concentrate. Platelets are either pooled TRALI causes a spectrum of lung disease
from the whole blood of multiple donors, or indistinguishable from ARDS.
collected from one donor by a process called – Graft-versus-host disease. In
apheresis. Platelet concentrates are ultraviolet immunocompromised patients,
irradiated to reduce the risk of transmission of T-lymphocytes within the donor blood launch
infectious diseases. Platelets are stored at room an immune response against the recipient’s
temperature as they quickly become non- tissues. Following the introduction of
functional at 4 °C, and so only have a short shelf- universal leucodepletion, this has become a
life (5 days). Platelets can be transfused without rare but very serious complication of blood
cross-match, but the platelet count rises more if transfusion.
they are ABO type-specific. Non-immunological complications. These are
divided into infective and non-infective:
What are the other serious – Septicaemia. Bacterial contamination of blood
products can lead to septicaemia. Platelets are
complications of blood transfusion? at a particular risk because they are stored at
Complications of transfusion range from mild to fatal room temperature, which allows bacteria to
reactions. Transfusion complications can be classified replicate.
as immunological and non-immunological: – Infectious disease transmission; for example,
Immunological complications. In addition to hepatitis B, hepatitis C, HIV, cytomegalovirus,
immediate and delayed haemolytic transfusion malaria, prion disease. Donors are screened for
reaction, the immune system is responsible for blood-borne infectious diseases, both by
other transfusion complications: questionnaire and serology. Rarely, disease
– Non-haemolytic febrile reactions. Recipient transmission may occur in the early stages of
antibodies react with antigens on the small an infection when the donor is infectious but
number of donor leucocytes contained within has not developed antibodies: serological
donor blood. The antibody–antigen complex screening tests are therefore negative. No
activates complement and cytokines are serological tests for prion disease exist;
released. Febrile reactions were previously screening is based on questionnaire alone, but
common, but febrile reactions have become the risk of transmission has been reduced
much more rare since the introduction of following leucodepletion.
universal leucodepletion. Febrile reactions are – Volume overload. Rapid transfusion can
usually mild, but it is important to note that lead to LVF in susceptible patients. The
fever is also an early symptom of the life- resulting dyspnoea may be confused with
threatening immediate haemolytic transfusion TRALI.
reaction. – Iron overload. The body does not have a
– Allergic reactions. Foreign protein in the donor disposal mechanism for excess iron; only
blood cross-reacts with recipient IgE. Allergic the absorption of iron is regulated.
reactions are usually mild, causing urticaria Haemosiderosis (iron overload) can occur
and pruritis. in patients who require frequent blood
– Transfusion-related acute lung injury (TRALI), transfusions; for example, those with
the most common cause of death following thalassaemia or sickle cell disease. Excess
blood transfusion. TRALI is thought to occur iron deposits in the liver, heart and
through both immune and non-immune endocrine organs, resulting in organ
mechanisms. In immune TRALI, antibodies damage.
348
Chapter 68: Transfusion
What is cell salvage? volume in a 24 h period, or transfusion of more than

half a patient’s circulating volume in a 4 h period
Cell salvage is a method of autologous blood transfu-
(note: there are many other similar definitions in
sion: a patient’s own blood is collected, processed,
circulation).
stored and retransfused. It is an important method
Massive transfusion carries all the risks of a single-
of reducing the requirement for allogenic transfusion,
unit transfusion outlined above, but also has add-
with all its associated risks. Cell salvage is usually
itional risks:
performed intraoperatively, where spilt blood is col-
lected from the surgical field. This blood is then Hypothermia. Transfusion of multiple units of
processed and returned to the patient. The steps refrigerated packed cells leads to a fall in core
involved in the processing of blood depend on the body temperature through conduction.
particular cell salvage equipment – for example, RBCs Hypothermia is associated with coagulopathy,
may be centrifuged, washed and resuspended in cardiac arrhythmias, and reduced tissue
saline. Cell salvage has some obvious advantages, oxygenation (as the oxyhaemoglobin dissociation
but also has some disadvantages: curve is shifted to the left), and a worse overall
outcome. The risk of hypothermia can be reduced
Advantages by warming all transfused blood and fluids, as well
– Cell salvage is more cost effective than as active warming of the patient; for example, by
autologous transfusion. using a forced-air warmer.
– It does not have the infective and immune Dilutional coagulopathy. Multiple transfusions of
risks of autologous transfusion. packed RBCs along with crystalloid
– Cell salvage is accepted by some Jehovah’s administration leads to dilution of plasma
Witnesses. constituents. Of particular importance are clotting
Disadvantages factors and platelets, because haemostasis will
– Electrolyte abnormalities may occur, become impossible, leading to further
particularly in massive transfusion. haemorrhage and a requirement for more blood
– Clotting factors are lost when blood is products. Aggressive and pre-emptive
processed; a dilutional coagulopathy replacement of clotting factors and platelets with
may occur. FFP, cryoprecipitate and platelet concentrate is
required.
– In obstetric haemorrhage, there is a risk of
precipitating an amniotic fluid embolus, as Hypocalcaemia. Packed cells contain only a small
amniotic fluid mixed with the salvaged RBCs amount of the anticoagulant citrate; FFP and
may not be completely removed by the platelet concentrate contain much higher citrate
washing process, and subsequently reinfused. concentrations. The role of citrate is the chelation
However, cell salvage is now considered safe, if of Ca2+, preventing the coagulation of stored
used in combination with a leucocyte blood products. In massive transfusion, there is
depletion filter. sufficient intravascular citrate to cause a severe
hypocalcaemia. Without Ca2+ replacement, this
– In cancer surgery, there is a risk that malignant
can lead to hypotension and ECG changes
cells suctioned along with spilt blood from the
(bradycardia, flat ST segments, prolonged QT
surgical site may not be completely removed
interval). Hypocalcaemia should be treated with
by the washing process and be reinfused.
10 mL of 10% calcium chloride.
Again, a number of studies have shown that
the use of a leucocyte depletion filter reduces Hyperkalaemia. As discussed above, when RBCs
this risk significantly. are stored, K+ seeps out of the erythrocytes. When
blood is transfused, K+ tends to diffuse back into
the RBCs, but this process is hindered if the
What is massive transfusion? What patient is acidotic or hypothermic, leading to
additional complications occur? hyperkalaemia.
Massive transfusion is the transfusion of a greater Acidosis. A unit of packed RBCs has a lower pH
volume of stored blood than a patient’s circulating (around 6.8) than plasma, mainly as a result of
349
lactate accumulation due to the anaerobic Human blood can only be stored for 30 days and
metabolism of erythrocytes during storage. must be refrigerated. Blood substitutes have a
Massive transfusion may therefore worsen much greater shelf life and can be stored at
acidosis, though the additional lactate is usually ambient temperature, which makes them an
rapidly cleared by the liver. attractive prospect in military trauma medicine.
Alternative O2-carrying solutions are likely to be
acceptable to Jehovah’s Witnesses.
Is there any alternative to using blood
for oxygen carriage? Further reading
There are a number of alternative O2-carrying solu- J. P. Cata, H. Wang, V. Gottumukkala, et al. Inflammatory
response, immunosuppression, and cancer recurrence
tions (blood substitutes) currently undergoing clinical
after perioperative blood transfusions. Br J Anaesth 2013;
trials, which can be classified as: 110(5): 690–701.
Hb-based O2 carriers. Pure Hb from RBCs S. J. Mercer, N. T. Tarmey, T. Woolley, et al. Haemorrhage
cannot be used, as it causes renal tubular damage. and coagulopathy in the Defence Medical Services.
Instead, Hb must be cross-linked, polymerized or Anaesthesia 2013; 68(Suppl. 1): 49–60.
encapsulated. A. Ashworth, A. A. Klein. Cell salvage as part of a blood
Perfluorocarbon-based O2 carriers. These man- conservation strategy in anaesthesia. Br J Anaesth 2010;
made chemicals are able to dissolve significant 105(4): 401–16.
quantities of gases, including O2 and CO2. P. M. Ness, M. M. Cushing. Oxygen therapeutics: pursuit of
However, perfluorocarbons are hydrophobic and an alternative to the donor red blood cell. Arch Pathol
therefore must be prepared as an emulsion to mix Lab Med 2007; 131(5): 734–41.
with blood. They do not have the same complex M. J. Maxwell, M. J. A. Wilson. Complications of blood
dissociation kinetics as Hb. transfusion. Contin Educ Anaesth Crit Care Pain 2006; 6
(6): 225–9.
There are some potential advantages to using blood C. Madjdpour, D. R. Spahn. Allogeneic red blood cell
substitutes over human blood: transfusions: efficacy, risks, alternatives and indications.
Blood transfusion is expensive, and associated Br J Anaesth 2005; 95(1): 33–42.
with a number of immune and non-immune D. R. Spahn, R. Rossaint. Coagulopathy and blood component
complications (see above). transfusion in trauma. Br J Anaesth 2005; 95(2): 130–9.
350
Chapter
Anaemia and polycythaemia
69
erythropoiesis by stimulating the differentiation
What steps are involved in red blood of BFU-E and CFU-E progenitor cells. A negative-
cell production? feedback loop is therefore created: hypoxaemia
Erythropoiesis, the production of RBCs, occurs stimulates EPO production, which increases RBC
within the bone marrow. Erythrocytes differentiate production, which increases O2-carrying capacity,
through several cell types during their development: counteracting the initial hypoxaemia.
The starting point is the common pluripotent
haemopoietic stem cell. This stem cell
differentiates into myeloid progenitor stem cells Why do patients become anaemic?
dedicated to erythropoiesis, first called burst- Anaemia is defined as an Hb concentration below the
forming unit erythroid (BFU-E) cells before expected value, when gender, pregnancy and altitude
becoming colony-forming unit erythroid have been taken into account. The World Health
(CFU-E) cells. Organization defines anaemia as Hb <130 g/L in
CFU-E cells then pass through a series of men and Hb <120 g/L in non-pregnant women.
erythroblast phases in the bone marrow. Anaemia is further subclassified as:
Erythroblasts require both vitamin B12 and folate mild anaemia – Hb 110–129 g/L for men, Hb
for their DNA synthesis. 110–119 g/L for women;
Erythroblasts synthesize Hb from the early moderate anaemia – Hb 80–109 g/L;
stages of their maturation. Globin chains are severe anaemia – Hb 65–79 g/L;
produced in the cytoplasm, whilst the haem life-threatening anaemia – Hb <65 g/L.
moiety, which requires iron, is synthesized in the
mitochondria. Anaemia occurs when RBC loss exceeds RBC produc-
The penultimate cell type is the reticulocyte. By tion. There are many causes of anaemia, which may
this stage of maturation the cell has lost its be classified as follows.
nucleus. However, Hb continues to be synthesized Insufficient RBC production. Examples include:
by the residual ribosomal RNA within the – Iron-deficiency anaemia. Deficient haem
cytoplasm. synthesis results in a reduced number of
1–2 days following their release into the microcytic and hypochromic RBCs.
circulation, reticulocytes lose their RNA – Folic acid and vitamin B12 deficiency. RBCs
(and therefore their ability to synthesize Hb), and produced are megaloblastic.
become mature erythrocytes.
– End-stage renal disease. Insufficient EPO is
Erythropoiesis is controlled by the hormone EPO. produced by the kidneys.
EPO is a glycoprotein secreted mainly by the kidney – Anaemia of chronic disease. This is now
in response to hypoxaemia.1 EPO increases thought to result from cytokine-mediated
(especially IL-6) hepatic synthesis of a
protein hormone called hepcidin. Hepcidin
1
Note that around 10% of the EPO originates from the blunts the response of the erythropoietic
liver; this EPO is especially important in end-stage renal progenitor cells to EPO and reduces the GI
failure. absorption of iron (see later).
351
RBC haemolysis. RBCs are haemolysed either Those with pre-existing coronary artery disease or
intravascularly or (more commonly) peripheral arterial disease may experience angina
extravascularly within the spleen. Examples or claudication respectively; high-output heart
include: failure may develop.
– Inherited abnormalities of RBCs; for example,
hereditary spherocytosis. Abnormally shaped How is iron handled in the body?
RBCs are taken out of circulation by the Iron is an extremely important element in all living
spleen, reducing their life span. organisms. In humans, iron is primarily involved in:
– Inherited abnormalities of Hb; for example, O2 transport and storage – Hb and myoglobin.
sickle cell disease. The spleen haemolyses
Catalysis of biological reactions – the
sickle-shaped cells, significantly reducing the cytochrome class of enzymes, catalase and
average RBC life span. peroxidase all have iron atoms at their active site.
– RBC enzyme deficiencies; for example, G6PD
deficiency causes some Hb in the ferrous state Total body iron is typically 3–5 g. The majority of
(Fe2+) to be oxidized to the ferric state (Fe3+), iron in the body is found within Hb (60–70%), with a
forming MetHb (see Chapter 7). RBCs further 5–10% incorporated within myoglobin and
containing MetHb are haemolysed by the spleen. iron-containing enzymes. The rest (20–30%) is found
– Transfusion reactions; transfusion of in the liver, where it is stored as ferritin and its
ABO-incompatible blood leads to an degradation product haemosiderin. Key features of
antibody-mediated intravascular haemolysis iron absorption are:
reaction (see Chapter 68). A typical Western diet contains 15 mg of iron per
– Autoimmune haemolytic anaemia; RBCs are day, but usually only 1–2 mg of this is absorbed.
haemolysed by autoimmune attack. However, iron absorption can double in
– Mechanical trauma to RBCs; for example, pregnancy and iron deficiency.
cardiopulmonary bypass results in traumatic There are two forms of dietary iron, both of which
haemolysis. are absorbed in the duodenum:
Bleeding. This may be acute (for example, post- – Haem groups can be directly absorbed by the
partum haemorrhage) or chronic (for example, enterocytes through a haem transport protein.
colonic carcinoma, menstruation). In critical care Once inside the enterocytes, iron is released.
patients, repeated arterial blood sampling is a – Dietary iron salts are found in both oxidation
major contributor to anaemia. states – ferrous (Fe2+) and ferric (Fe3+).
Enterocytes can only absorb iron in the ferrous
What are the adverse consequences state; this is why iron supplements are ferrous
rather than ferric (for example, ferrous
of anaemia? fumerate). Fe3+ salts precipitate when the
In itself, mild anaemia has few consequences. How- environmental pH is greater than pH 3 (i.e. the
ever, the disease underlying the anaemia may be very duodenum) and therefore cannot be absorbed.
significant; for example, colonic carcinoma. There-
The low-pH environment of chyme entering the
fore, it is important to investigate and establish the duodenum facilitates the enzymatic reduction of iron
cause of anaemia where possible. from Fe3+ to Fe2+, thus allowing duodenal absorption.
Patients with acute blood loss exhibit the signs of Drugs that reduce the acidity of the stomach (for
hypovolaemia: tachycardia, hypotension and oliguria. example, PPIs) significantly decrease duodenal
Patients with chronic anaemia develop signs and ferrous iron, leading to iron deficiency.
symptoms dependent on its severity:
Those with mild anaemia may develop general Fe2+ absorbed by the enterocyte has two possible
malaise and dyspnoea on exertion. fates:
In severe anaemia, reduced O2-carrying capacity Storage as ferritin within the enterocyte. After a
necessitates an increase in CO; patients may few days, the GI cells slough, leading to loss of this
experience palpitations. absorbed iron.
352
Chapter 69: Anaemia and polycythaemia
2+
Transport across the basolateral membrane. Fe how hepatocytes regulate hepcidin production, and
passes through an iron channel in the basolateral what goes wrong in haemochromatosis, is not yet
membrane called a ‘ferroportin’. Once within established.
the plasma, Fe2+ is oxidized to Fe3+ and bound to
the plasma transport protein transferrin.
Transferrin transports Fe3+ within the circulation
What is polycythaemia?
to where it is needed; for example, the bone Polycythaemia is a persistently increased ratio of RBCs
marrow. Excess iron is stored by the intracellular to plasma (i.e. haematocrit) – above 0.51 in men and
protein ferritin. 0.48 in women. Polycythaemia is classified as:
Primary polycythaemia, where an abnormality in
Conservation of iron within the body is extremely the bone marrow results in the inappropriate
important: iron absorption is as little as 1 mg/day, yet production of an increased number of RBCs. For
erythropoiesis requires 20 mg of iron per day. At the example, PRV is a myeloproliferative condition in
end of the erythrocyte life span, iron is liberated from which the bone marrow undergoes excessive
Hb and carried by transferrin to the bone marrow, erythropoiesis.
where it is recycled. Secondary polycythaemia, where increased
erythropoiesis is due to increased EPO secretion.
EPO is usually secreted in response to chronic
How does the body control iron hypoxaemia (for example, high altitude, chronic
homeostasis? respiratory disease, congenital heart disease,
Iron homeostasis is tightly regulated. Unusually, the obesity hypoventilation syndrome), but is
body does not have a mechanism for iron excretion, occasionally due to an EPO-secreting tumour.
so control of the body’s iron content is solely through
Patients with primary polycythaemia are at greatly
regulation of iron absorption. This is why iron over-
increased risk of thrombosis, both arterial and
load can be a major problem in patients requiring
venous. This is due to:
regular blood transfusions.
When body iron stores are low, more iron is Hyperviscosity. Increased haematocrit results in
transported across the enterocyte basolateral mem- increased blood viscosity, which, according to the
brane. Conversely, when iron stores are plentiful, iron Hagen–Poiseuille equation, increases resistance to
absorption is inhibited. Traditionally, it was thought blood flow. The resultant reduction in venous
that the GI mucosal cells somehow inherently regu- blood flow predisposes to venous thrombosis.
lated iron absorption; this is ‘mucosal block theory’. Hypercoagulability. The coagulation cascade is
Recently, our understanding of the iron absorption abnormal in patients with PRV – they are at
mechanism has progressed: it is regulated by a liver greater risk of thrombotic disease, even when their
protein hormone called hepcidin. Hepcidin binds to haematocrit is normalized by venesection.
and inhibits ferroportin, the enterocyte basolateral Thrombocytosis. Some patients with PRV also
membrane iron channel: have excessive platelet production, increasing their
2+
When hepcidin levels are high, Fe cannot be risk of arterial thrombosis.
transported out of the enterocyte. Iron is therefore Patients with secondary polycythaemia also have
stored within the enterocyte’s cytoplasmic ferritin increased blood viscosity, but seem not to have an
before being excreted from the body as the increased risk of thrombosis. Therefore, in primary
mucosal cell sloughs. polycythaemia, the abnormalities of coagulation and
2+
When hepcidin levels are low, Fe is allowed to platelet count are probably responsible for the greater
pass into the circulation through the enterocyte thrombosis risk.
basolateral ferroportin channels.
Clinical relevance: anaesthesia for patients with
Hepcidin deficiency is implicated in hereditary polycythaemia rubra vera
haemochromatosis, a genetic condition of iron Patients with primary polycythaemia are at increased
overload: hepcidin levels are inappropriately low, risk of perioperative arterial and venous thromboses,
resulting in an excess of total body iron. Exactly
353
including stroke, pulmonary embolus, myocardial potential for abnormal coagulation and platelet func-
infarction, and hepatic and portal venous thrombosis. tion means that neuraxial blockade is relatively
Paradoxically, these patients are also at greater risk contraindicated.
of haemorrhage as platelet function is often
abnormal.
The management of patients with PRV differs for
elective and emergency surgery. Before elective sur- Further reading
gery, patients’ Hb concentration should be reduced A. Shander, M. Javidroozi, S. Ozawa, et al. What is really
to ‘normal’ levels, by phlebotomy or drugs such as dangerous: anaemia or transfusion? Br J Anaesth 2011;
hydroxyurea. Prior to urgent surgery, Hb concentra- 107(Suppl. 1): i47–59.
tion can be normalized by venepuncture: replacing G. Papanikolaou, K. Pantopoulos. Iron metabolism and
whole blood with the same volume of crystalloid. The toxicity. Toxicol Appl Pharmacol 2005; 202(2): 199–211.
354
Chapter
Immune system
70
Immunology is vast and complex, for which this Lysozyme secretion in saliva and tears
chapter provides a very simplified account. causes bacterial cell wall lysis. Transferrin
secretion in mucosa creates a low-iron
environment, thus inhibiting bacterial
What is an antigen? How does it differ replication.
from a hapten and an allergen? ▪ Inflammation.
An antigen is a substance that stimulates the immune ▪ Complement system.
system, resulting in an immune response. Antigens are ▪ Cellular components – neutrophils,
either proteins or polysaccharides. The immune system macrophages, natural killer (NK) cells,
produces antibodies that specifically bind to the antigen. mast cells, basophils and eosinophils.
A hapten is a small molecule that may also stimu- ▪ Acute-phase proteins; for example,
late the immune system, but only when attached to a C-reactive protein, α1-antitrypsin.
larger carrier protein. The immune system produces
Adaptive immune system. Key features are:
antibodies to the hapten–carrier complex; these anti-
bodies can also bind to the hapten (when not attached – Slower response, but specific to the invading
to a carrier protein). microorganism. The adaptive immune
An allergen is an environmental antigen that pro- response is slower than the innate immune
duces a vigorous immune response, even though the system, but has the advantage of ‘memory’ –
allergen is usually harmless. a much quicker response occurs if the same
microorganism invades for a second time.
– Involvement of both cellular and humoral
What are the differences between the elements:
innate and adaptive immune systems? ▪ Cytotoxic T cells are responsible for cell-
The role of the immune system is to defend the body mediated immunity – defence against
against microorganisms, abnormal host cells, toxins intracellular pathogens and abnormal
and other foreign material. The two main parts of the host cells.
immune system are the innate and adaptive immune ▪ B cells and T helper cells are responsible
systems. for antibody-mediated (humoral)
Innate immune system. Key features are: immunity – defence against pathogens
– Immediate line of defence. within body fluids.
– Rapid but non-specific response to a potential
threat. No previous exposure to an invading Which cells are involved in the innate
microorganism is required. immune response?
– Composed of several parts: The innate immune response involves different types
▪ Anatomical/physiochemical, including of white blood cells (leucocytes):
skin, mucociliary escalator of the Neutrophils account for 60% of all leucocytes.
respiratory tract, low gastric pH, peristalsis They are involved in the phagocytosis
and biliary secretions of the GI tract. (engulfing and ingestion) of bacteria and fungi.
355
A neutrophil can phagocytose around 5–20 and not fully understood. A simplified sequence of
bacteria before it dies. events is:
Monocytes migrate from blood into tissues, where Recognition of tissue damage. The two most
they become macrophages. Macrophages common causes of tissue damage are trauma and
phagocytose microorganisms and cellular debris. infection. The body recognizes these threats in
A macrophage may phagocytose up to different ways:
100 bacteria before it dies. – Trauma. Mechanical damage causes blood
Eosinophils are involved in the killing of vessel disruption and local mast cell
multicellular microorganisms; for example, degranulation. Blood vessel disruption
helminths and parasites. Eosinophils (along with activates platelets and the coagulation cascade
mast cells) are also important in the pathogenesis (see Chapter 67), whilst mast cells release
of allergic reactions and asthma (serum eosinophil histamine and other inflammatory mediators.
count increases in both conditions). – Infection. Tissue macrophages recognize the
Basophils are the least common of the leucocytes. presence of microorganisms. In addition to
Basophils seem to act like circulating mast cells: phagocytosing the microorganisms,
they have granules that contain inflammatory macrophages release pro-inflammatory
mediators, including histamine and heparin. cytokines (IL-1, IL-6, TNF-α) that trigger local
Basophils are involved in allergic reactions and mast cells to degranulate, releasing more pro-
defence against parasites. inflammatory cytokines.
NK cells are classed as lymphocytes, but in Local inflammatory response. Irrespective of the
contrast to the other lymphocytes (B and T cells), mechanism of initiation, inflammation follows a
NK cells are non-specific in their immune stereotypical series of events:
function. NK cells are extremely important: they
destroy tumour cells, and cells infected with – Local arterioles vasodilate in response to
viruses. They are also thought to be involved in histamine. This increases blood flow to the
the suppression of a pregnant mother’s immune area of injury, thus delivering the necessary
system to prevent immune attack of the fetus. quantities of leucocytes and plasma proteins.
– Post-capillary venules increase their
permeability. These venules already have very
What is inflammation? thin walls with little muscle or connective
Inflammation is a non-specific response triggered by tissue. The vessels swell in response to pro-
either microorganism invasion or tissue injury. First inflammatory cytokines, mainly TNF-α and
described over 2000 years ago, the symptoms of histamine, allowing gaps to develop between
inflammation are redness, heat, swelling and pain. endothelial cells. Large volumes of plasma,
Inflammation is characterized by the following including large molecules such as complement,
processes: coagulation proteins and, later on in the
Vasodilatation, which increases blood flow to the inflammatory process, antibodies, pass into
site of injury/infection, thus explaining the the interstitial space. Complement acts in two
redness and heat associated with inflammation. main ways (see below): by triggering further
Increased vascular permeability, which allows degranulation of mast cells, and through
plasma proteins to leak from the vessels to the site of opsonization (coating) of microorganisms to
injury/infection. The leak of plasma from the facilitate their phagocytosis.
intravascular space to the interstitial space accounts – Recruitment of cellular components. The
for the oedema associated with inflammation. increased permeability of the post-capillary
Migration of phagocytes, which kill invading venules is not in itself a sufficient signal to
microorganisms and remove debris in preparation induce leucocytes to migrate into the interstitial
for tissue healing. space. Capillaries’ endothelial cells need a way
of signalling to passing leucocytes, informing
Inflammation can be initiated by a number of them of a pathogen threat. In response to
insults. The mechanisms of initiation are complex inflammatory mediators, endothelial cells
356
Chapter 70: Immune system
express cell surface adhesion molecules that

slow down circulating neutrophils and Pyrexia >38 °C (or <36 °C).
HR >90 bpm.
macrophages, allowing them to pass between
RR >20 breaths per minute.
the endothelial cells, a process known as
White cell count >12 × 109/L or <4 × 109/L.
‘transmigration’. The leucocytes are then guided
towards the site of injury/infection by attractant The same stereotyped processes that usually only
molecules called chemotactic molecules. occur local to the site of tissue damage now spread
Systemic inflammatory response. Pro- to the whole body, resulting in:
inflammatory cytokines are usually concentrated Generalized vasodilatation and leaky
post-capillary venules. This leads to systemic
at the site of injury/infection. However, in severe
hypotension and intravascular fluid depletion
inflammation, or in cases where a microorganism respectively.
escapes from the site of invasion, pro- Neutrophil migration into organs distant to the
inflammatory cytokines are released into the site of infection/injury.
systemic circulation, causing: A pro-coagulant state, resulting in microvascular
– Fever, which augments phagocytosis and thrombosis.
impairs bacterial multiplication. Myocardial depression, probably due to
delayed Ca2+ uptake and release by the SR.
– Release of neutrophils from the bone marrow.
Mitochondrial dysfunction, resulting in a failure
– Release of acute-phase proteins from the liver – of oxidative phosphorylation.
plasma C-reactive protein concentration
correlates with the degree of inflammation. As many of these complications result in reduced O2
delivery to the tissues, it is no surprise that patients
with SIRS may go on to develop multiple organ
What are eicosanoids and kinins? How dysfunction. Organ dysfunction is usually a combin-
ation of macro- and microvascular ischaemia. The
are these involved in inflammation? lung is the most common organ to malfunction in
Eicosanoids are a family of signalling molecules response to systemic inflammation – this is termed
whose main role is that of a pro-inflammatory ARDS. Note: SIRS is most commonly triggered by
cytokine. Eicosanoids are all derived from severe infection (especially Gram-negative infection),
arachidonic acid, and are subclassified into but is also triggered by non-infective aetiology; for
prostaglandins, prostacyclins, thromboxanes and example, acute pancreatitis and severe trauma.
leucotrienes. One of the enzymes involved in the
synthesis of prostaglandins, prostacyclins and
thromboxanes is COX. The COX-1 and COX-2 What are the roles of complement?
enzymes are important targets for the clinical The complement system is a collection of 25 plasma
management of inflammation. proteins. Although it is considered part of the innate
Kinins are poorly understood. During acute immune system, the complement system also contrib-
inflammation, bradykinin is produced through utes to the adaptive immune system, as it ‘comple-
cleavage of inactive precursors. Like histamine, ments’ the activity of antibodies. The complement
bradykinin causes arteriolar vasodilatation and system may be activated in two ways:
increases the permeability of post-capillary Coming into contact with a particular type of
venules. Bradykinin is also implicated in the bacterial cell wall – this is called the alternative
sensitization of peripheral pain fibres. pathway.
Exposure to an antibody–antigen complex – this
Clinical relevance: systemic inflammatory response is called the classical pathway.
syndrome
Following severe tissue damage or infection, inflam- Once activated, complement has a number of roles:
mation can spiral out of control when pro- Bacterial cell lysis. Many activated complement
inflammatory cytokines are released into the systemic
proteins come together to form a ‘membrane
circulation. SIRS is the result of this cytokine storm,
attack complex’. This complex kills bacteria by
defined by two or more of the following signs:
punching holes in their cell membranes.
357
water diffuses along its osmotic gradient through Like T cells, immature B cells are tested for
these holes, causing the bacteria to swell and burst. reactivity against self-antigens in the bone marrow
Opsonization. Fragments of complement protein before being released into the circulation. Any B cell
coat the microorganisms, and then act as binding receptor (BCR, which is actually a cell-surface-bound
sites for neutrophils and macrophages, making antibody molecule) that reacts strongly with self-
phagocytosis more efficient. antigens is prevented from maturing further and is
Chemotaxis. After leucocytes migrate into the eliminated through apoptosis. All the remaining
tissues from the circulation, bits of complement B cells complete their maturation in the bone marrow
act as homing beacons, guiding leucocytes before being released into the circulation. Once in the
towards the site of infection. circulation, they are taken up by lymphoid tissue
Triggering local mast cells to degranulate, where they are stored.
releasing vasoactive mediators such as histamine,
thus augmenting inflammation. What are antibodies? How are
they produced?
What is lymphoid tissue? How is the An antibody (also known as immunoglobulin, Ig) is a
‘Y’-shaped protein produced by the adaptive immune
thymus involved in lymphocyte system. Antibodies are produced in response to patho-
maturation? gen invasion and are specific to the invading
Lymphoid tissue is a collective term for tissues that: pathogen; that is, they bind to specific parts of the
Produce lymphocytes – bone marrow. pathogen. The functions of antibodies are:
Process lymphocytes – thymus. Opsonization. Antibodies label pathogens,
Store lymphocytes – lymph nodes, spleen, tonsils, making them easier for leucocytes to identify. The
appendix, gut-associated lymphoid tissue (Peyer’s Fc region forming the tail of the antibody points
patches). away from the pathogen (see below), and acts as a
binding site for leucocytes, thus facilitating
The bone marrow produces naive B and T lympho- phagocytosis.
cytes from common lymphoid progenitor stem cells. Agglutination. Antibodies all have more than one
B cells mature in the bone marrow, whilst T cells leave binding site. Binding more than one pathogen
the bone marrow and migrate to the thymus, where causes pathogens to clump together, making them
they mature. bigger targets for leucocytes.
The importance of the thymus is obvious when it Inactivation of the pathogen. The antigenic part
is absent: DiGeorge syndrome is a genetic disorder of the microorganism may be important to its
that results in a midline congenital defect, which function; binding of an antibody may render the
usually includes thymic aplasia. Children born with- microorganism harmless. Alternatively, the
out a thymus suffer from severe immunodeficiency. antibody may bind a toxin produced by the
The thymus is very important in T cell matur- pathogen, making it innocuous.
ation, as its epithelial cells are able to synthesize and Activation of complement. As discussed above,
express all the proteins found elsewhere in the body. when antibodies bind to an antigen (for example, a
Each T cell has a receptor (the T cell receptor, TCR) microorganism), the complement cascade is
whose protein sequence is essentially generated at activated through the classical pathway.
random. Each TCR is therefore able to bind a differ- Complement aids phagocytosis through chemotaxis
ent antigen. In the thymus, the T cells undergo pro- and opsonization, promotes inflammation through
cessing; any T cell that interacts strongly with a host mast cell degranulation and directly attacks the
protein is eliminated through apoptosis. This process pathogen by forming a membrane attack complex.
results in the death of almost all the immature T cells
(around 98%). Despite only 2% of immature When a pathogen invades, the adaptive immune
T cells surviving to full maturation, there are still an system responds in a well-defined series of steps
estimated 100 million different T cells, each with a (Figure 70.1). These result in the mass production
unique TCR. of a highly specific antibody:
358
AT THE SITE OF INFECTION = bacterium antigen
Presentation of a fragment of bacterium
Phagocytosis Antigen processing APC

APC APC
APCs travels
Antigen-presenting cell
= bacterium to lymph node
IN THE LYMPH NODE

B B B B B
Immature B cells
APC APC APCs drift through the lymph

node, looking for B and T cells
whose receptors bind the antigen
APC
APC
B Th
Immature T helper cells

Th Th Th Th Th
Clonal
Clonal expansion
expansion
Th (activated T h cell
required)
Activated T helper cell
Th Memory T helper cell

Th Th
B + mT h
B
B Th
B Th
CIRCULATION Antibodies
Differentiation into P
plasma cells and P Production of
memory B cells P antibodies
P
Activated B cell P Travel to site
of infection
+
AT THE SITE OF
Plasma cell INFECTION
mB
Memory B cell
Antigen binding
Figure 70.1 The steps involved in antibody production.
359
Macrophages and dendritic cells (similar to astonishing: each plasma cell can produce
macrophages) are collectively known as antigen- 2000 antibody molecules per second. They are
presenting cells (APCs). so committed to antibody synthesis that they
When APCs phagocytose pathogens, they take do so to the detriment of protein synthesis for
small parts of the microorganism (antigens) and normal cellular function, and thus only survive
express them on their cell surface. The antigens for around a week.
are displayed on the cell membrane by a large – Memory cells are dormant plasma cells, ready
protein called major histocompatibility complex to be reactivated if the same pathogen were to
(MHC) class II. The APCs then travel from the invade again.
site of infection to nearby lymphoid tissue, often a
lymph node. What is the difference between
The lymph nodes contain a huge number of B cells
and T helper cells, each with uniquely different the primary and secondary
BCRs and TCRs. The APCs wander through the immune response?
lymph node, presenting their cell surface antigen The steps outlined above are termed the primary
to every B and T helper cell that passes. Eventually, immune response. The whole process from pathogen
the APCs find B and T helper cells whose receptors invasion to antibody production takes around 5 days.
are an exact match for the APC antigen. The main Ig produced by the plasma cells is IgM, with
Antibodies are produced as a result of the some IgG produced later. Most of the plasma cells
interaction of B and T helper cells with APCs and T helper cells die within the next 5 days, after the
(Figure 70.1): pathogen has been destroyed.
– T helper cells become activated when their TCR If the same pathogen were to invade again, the
matches the APC antigen. Activated T helper immune response is much faster and more vigorous;
cells become blast cells that undergo rapid this is the secondary immune response. APCs trans-
proliferation, resulting in a clone of identical port antigen to the lymph nodes as before, but this
T helper cells, all with TCRs specific to the time memory T helper cells and memory B cells,
same antigen. A small proportion of activated formed during the clonal expansions of the primary
T helper cells become memory T helper cells – immune response, are activated. These memory cells
these cells lie dormant, ready to be rapidly are primed to divide rapidly and can produce anti-
reactivated if the same pathogen invades again. bodies within hours of infection. In contrast to the
T helper cells are also called CD4+ T cells, as it primary immune response, IgG is the main Ig pro-
is the T cell CD4+ receptor that interacts with duced by the secondary immune response, with IgM
the APC MHC class II molecule. making up the minority. The secondary immune
– B cells are also activated when their membrane response is so rapid that pathogens can be killed
surface Ig (the BCR) binds to a matching APC before they make the host ill – this is called active
antigen, but this activation process (usually) immunity, where a person is immune from a particu-
requires help from the corresponding T helper lar infection as a result of a previous exposure.
cell. This is effectively a safety mechanism built
into the design of the immune system – in What is the difference between active
order for a B cell to become activated, the APC
antigen must make two exact matches, one and passive immunization?
with a T helper cell and one with a B cell. Immunization is the process whereby a person is
Activated B cells then rapidly divide to made immune or resistant to an infectious disease:
produce a clone of daughter cells, all with Active immunization. An inactive portion of a
identical membrane-bound Ig. The daughter virus or bacterium is given to the patient, usually
B cells differentiate into either plasma cells through injection (vaccination). The patient’s
(the majority) or memory cells. immune system produces antibodies to the antigen,
– Plasma cells are antibody production factories. during which memory B and T helper cells are
The rate of antibody production is produced. If the individual were subsequently
360
exposed to the active pathogen, a rapid secondary What is cell-mediated immunity?

immune response occurs, making the pathogen
effectively harmless. Active immunization requires How are T cells involved?
the patient to be immunocompetent; that is, able to Some pathogens, particularly some viruses, parasites,
mount an immune response to the vaccine. yeasts and certain bacteria (for example, Mycobacter-
Passive immunity. Pre-formed antibodies are ium tuberculosis), hide in the body’s own cells, where
given to a patient. Two important uses of passive they grow, manipulate the cells’ protein synthesis and
immunization are: replicate.
All of the body’s cells are programmed to take
– Physiological. Antibodies (IgG) are transferred samples of intracellular protein, process them and
across the placenta from mother to fetus, to display them on the cell membrane. These small por-
protect the fetus from pathogens at a time tions of intracellular proteins are displayed on the cell
when its immune system is immature and membrane MHC class I molecules. When the host cell
unable to mount an immune response. After is infected, this intracellular protein sampling con-
birth, antibodies (IgA) are also transferred to tinues; foreign protein is amongst the protein dis-
the infant through breast milk. played on the cell membrane. Cytotoxic T cells patrol
– Clinical. Recombinant antibodies can be given the body, checking that none of the body’s cells display
parenterally to a patient to neutralize a foreign material. Cytotoxic T cells are also known as
pathogen or toxin. Examples include varicella CD8+ T cells, as it is the T cell CD8+ receptor that
zoster Ig, which is given to at-risk pregnant interacts with the MHC class I molecule. As discussed
patients to prevent fetal infection, and tetanus above, during their development, cytotoxic T cells were
Ig, which is given to neutralize the tetanus only allowed to leave the thymus if their TCR did not
toxin in severe tetanus infection. bind to any proteins normally found in host cells.
Tc
Virus-infected
host cell Patrolling Tc cell’s TCR
matches the viral antigen
Tc
Viral antigen presented

on surface of host cell
= virus
Cytotoxic T cell
Dead host cell
triggers apoptosis
containing virus
Tc
Clonal
Tc Tc expansion
Tc +
Tc
Tc
Activated cytotoxic T cell

Tc cells travel in the circulation Macrophage
looking for other infected host cells
Phagocytosis
Figure 70.2 Cell-mediated immunity.
361
Therefore, any host cell that displays a protein that display abnormal proteins on their cell membranes.
binds to the cytotoxic T cell’s receptor is likely to be Cytotoxic T cells are involved in inducing the apop-
infected. When this happens, the cytotoxic T cell tosis of these abnormal host cells.
becomes activated (Figure 70.2): It was previously thought that the antibody
The cytotoxic T cell induces apoptosis in the host response played no role in cell-mediated immunity;
cell. The pathogen remains within the cell as it however, recent studies have demonstrated this to be
undergoes apoptosis. Tissue macrophages then incorrect. IgG binds to a virus or bacterium, which then
ingest the dead host cell, killing the intracellular infects a cell with the IgG still bound. Inside the cell,
pathogen. the Fc component of the IgG is directed to the protea-
The cytotoxic T cell rapidly divides, producing a some by a protein called TRIM21, where the pathogen-
large number of clone daughter cells, each with an IgG complex is degraded. This process is known as
identical TCR. These daughter cells travel in the intracellular antibody-mediated degradation.
circulation, looking for other infected cells.
What is the basic structure of
This is known as cell-mediated immunity, an
immune response that does not involve antibodies
immunoglobulin? What are the
or complement. Importantly, it is not just intracellu- different types?
lar infections that result in foreign protein being An antibody is a large ‘Y’-shaped protein consisting of
displayed on the cell membrane. Malignant cells also two identical heavy chains and two identical light
STRUCTURE OF IMMUNOGLOBULIN: Figure 70.3 Structure and types of
immunoglobulin.
Two antigen binding sites
(also known as ‘Fab’)
Grey = variable part
‘Light’ chain White = constant part

Disulphide bridges
‘Heavy’ chain
Binding site for complement and
phagocytes (also known as ‘Fc’)
TYPES OF IMMUNOGLOBULIN:
IgG IgA
IgE IgM IgD
362
chains, linked by disulphide bridges (Figure 70.3). Primary immunodeficiency, due to a defect of
Antibodies have two regions: immune system development. Various parts of the
The variable region, Fab – the area that immune system may be dysfunctional:
recognizes and binds antigen. Every antibody has – T cell dysfunction – for example, DiGeorge
a different Fab. syndrome, in which thymic aplasia results in
The constant region, Fc – the area that binds to failure of T cell maturation, as described above.
other parts of the immune system; for example, – Combined B and T cell dysfunction – for
phagocytes and complement. Each different type example, severe combined immunodeficiency.
of Ig (i.e. IgG, IgM, etc.) has an identical Fc. – B cell dysfunction – for example, X-linked
agammaglobulinaemia, in which genetically
There are five types of Ig – all types of Ig contain defective B cells fail to synthesize antibodies.
the same basic ‘Y’ structure, but some aggregate into – Complement deficiency – in which the absence
polymers: of single complement proteins leads to
IgM is the largest Ig, consisting of an aggregate of infection or an autoimmune disease.
five ‘Y’ Ig subunits. This is the first type of antibody Secondary immunodeficiency. Causes include:
produced in the primary immune response, and – Iatrogenic – most commonly due to steroids,
is particularly good at binding large antigens. chemotherapy agents, radiotherapy and
IgG is most abundant Ig. IgG is composed of a specific immunosuppressive drugs to prevent
single ‘Y’ Ig, and is the only Ig that can cross the transplant rejection.
placenta. – Ageing and malnutrition – which is associated
IgA is a dimer of ‘Y’ Ig. It is found in the mucosa with a general reduction in immune function.
(respiratory tract, gut, etc.), saliva, tears and – Specific diseases – cancer (especially those
breast milk. affecting the immune cells; for example,
IgE is a monomer Ig found on the surface of leukaemia and myeloma) and acquired
mast cells. When an antigen binds to IgE, the mast immunodeficiency syndrome (AIDS).
cell is triggered to degranulate. This is the
mechanism of type 1 hypersensitivity (see
below). IgE is normally present in the plasma in What is hypersensitivity? What types
low concentration, but this may be increased
with atopy (for example, in asthma),
are there?
parasitic infections and hypersensitivity Hypersensitivity is an exaggerated or inappropriate
reactions. immune response that causes discomfort, tissue
IgD is a monomer Ig, usually attached alongside damage or even death. Hypersensitivity is classified as:
IgM to the cell membrane of naive B cells (cells Type I or immediate hypersensitivity. This
not yet activated by antigen). The physiological occurs in asthma, allergic rhinitis (hay fever) and
purpose of IgD is a bit of a mystery – IgD the feared anaphylaxis. This is an allergic reaction
disappears once the B cell is activated, when it that occurs following re-exposure to an allergen.
becomes entirely covered with IgM. On first exposure to the allergen, T helper and
B cells interact as usual, producing IgE specific to
the allergen. IgE travels in the circulation and
How can immunodeficiency coats the surface of mast cells. On subsequent
be classified? exposure, the allergen binds to the specific IgE on
Immunodeficiency is a disorder in which the immune mast cells, causing rapid degranulation and release
system is impaired or absent. The complications of of inflammatory mediators: histamine,
immunodeficiency depend on which component leukotrienes and prostaglandins. The clinical
of the immune system is affected, but generally effects depend on the location of the mast cells
include opportunistic infection and an increased inci- and the route of entry of the allergen:
dence of certain malignancies. Immunodeficiency – Asthma – inhaled allergens bind to mast cell
may be classified as: IgE within the bronchial smooth muscle,
363
causing degranulation. Release of histamine antibody production. The resulting antibody–

and leukotrienes triggers bronchospasm. antigen complexes deposit in the lungs,
– Allergic rhinitis – allergens (for example, grass causing inflammation.
pollen) bind to mast cell IgE in the mucosa of Type IV or delayed-type hypersensitivity. Some
the nasopharynx. Mast cell degranulation allergens trigger a type of hypersensitivity that
releases histamine, causing itchy eyes and involves T cells, not antibodies. The response is
inflammation of nasal mucosa with an much slower, taking 2–3 days to develop. T helper
increased secretion of mucus. cells recognize an antigen presented by an APC.
– Anaphylaxis – allergens that reach the systemic The activated T helper cells divide and secrete
circulation cause widespread mast cell cytokines, initiating inflammation. Cell damage is
degranulation, resulting in a potentially life- caused by the macrophages that become activated
threatening vasodilatation, bronchospasm and in response to these cytokines. Examples include:
fluid extravasation. Anaphylaxis is especially – Tuberculosis, the classic delayed-type
severe when the allergen is injected directly hypersensitivity. Activated macrophages fuse
into the circulation, which is why it occurs to form giant cells around the tuberculosis
most commonly in association with antigen, the centre of which may become
anaesthesia. necrotic – this is known as a caseating
Type II or cytotoxic hypersensitivity. Antibodies granuloma. The importance of T helper cells
produced by the immune system bind to antigens is seen when they are absent: patients with
on the surface of the body’s own cells. The AIDS are very susceptible to intracellular
antibody–antigen complex triggers complement, pathogens such as M. tuberculosis.
which initiates inflammation and facilitates – Contact dermatitis, where contact with certain
phagocytosis by macrophages. Examples of type II allergens (for example, nickel) causes a delayed
hypersensitivity reactions include: skin reaction.
– Idiopathic thrombocytopaenic purpura. IgG
antibodies coat platelets and their precursor
Clinical relevance: immune consequences of
megakaryocytes, resulting in phagocytosis by
anaesthesia and surgery
splenic and hepatic macrophages. The result is
The immune system is affected in the perioperative
a very low platelet count.
period in a number of ways:
– Goodpasture’s disease. IgG binds to type IV Disruption of physicochemical barriers,
collagen in the basement membrane of the allowing easier access for pathogens. The most
renal glomerulus and pulmonary alveolus, obvious route of pathogen entry is the site of
causing acute kidney injury and pulmonary surgery, where the skin or mucosa has been
haemorrhage respectively. breached. In addition, endotracheal intubation
Type III hypersensitivity or immune complex and breathing dry air inhibits ciliary function in
disease. Sometimes when antibodies (usually IgG) the tracheobronchial tree, predisposing to
bind antigens, there are insufficient antibody– pneumonia.
antigen complexes to activate complement, Exposure to allergens. The incidence of
anaphylaxis during general anaesthesia is
particularly when the amount of antibody is small.
estimated at between 1/10 000 and 1/20 000
The antibody–antigen complexes float around in anaesthetics; 10% of cases are fatal. The most
the circulation and get lodged in small blood common precipitants of anaphylaxis in the
vessels, joints and glomeruli, where they cause perioperative period are:
inflammation. Examples include: – Muscle relaxants, accounting for around 60%
– Systemic lupus erythematosus, in which anti- of cases.
nuclear antibodies complex with nuclear – Antibiotics (most notably penicillin),
accounting for 15% of cases. Recently, a
antigens, causing skin, glomerulus and joint
number of cases of anaphylaxis due to
inflammation. chlorhexidine-impregnated central lines
– Farmer’s lung, a hypersensitivity pneumonitis have been reported.
in which inhaled mould spores trigger
364
– Latex, accounting for 15%. TRIM may sometimes be useful; for

– More rarely, colloids, amide local anaesthetics example, improved graft survival has been
(esters have a very low incidence of allergy), demonstrated when patients undergoing
induction agents. kidney transplantation had a preoperative
Depression of the immune system. Various blood transfusion. In cancer surgery, there is a
parts of the immune system may be suppressed theoretical risk that blood transfusion may
in the perioperative period: increase the incidence of cancer
– The stress response to surgery depresses recurrence.
lymphocyte function and phagocytosis. – Perioperative hypothermia depresses both
– Anaesthetic agents: volatile anaesthetics have innate and adaptive immune systems, which
been implicated in the reduced phagocytic may reduce survival in cancer surgery.
activity of neutrophils. Propofol and
thiopentone both impair neutrophil and
macrophage phagocytosis.
– Opioids impair macrophage, neutrophil and Further reading
NK cell function, lymphocyte proliferation and Á. Heaney, D. J. Buggy. Can anaesthetic and analgesic
cytokine release. NK cells are particularly techniques affect cancer recurrence or metastasis?
important in cancer surgery, as they kill the Br J Anaesth 2012; 109(Suppl. 1): i17–28.
stray tumour cells that evade the surgeon. S. Gando. Microvascular thrombosis and multiple organ
Recently, there have been a number of dysfunction syndrome. Crit Care Med 2010; 38
studies (with mixed results) investigating (Suppl. 2): S35–42.
whether the use of regional anaesthesia (for G. L. Snyder, S. Greenburg. Effect of anaesthetic technique
example, using paravertebral blocks instead and other perioperative factors on cancer recurrence.
of systemic opioids in breast surgery) Br J Anaesth 2010; 105(2): 106–15.
prevents cancer recurrence.
A. D. Axon, J. M. Hunter. Anaphylaxis and anaesthesia –
– Transfusion-related immunomodulation (TRIM),
all clear now? Br J Anaesth 2004; 93(4): 501–4.
where allogenic blood transfusion causes a
temporary depression of the immune system. C. Snowden, E. Kirkman. The pathogenesis of sepsis.
365
Chapter
Plasma constituents
71
– α1-acid glycoprotein transports basic and
What are the components of blood? neutrally-charged drugs.
Constituents of blood can be classified as:
Enzyme inhibitors; for example, α1-antitrypsin is
Plasma (55%), consisting of: a protease inhibitor.
–Water Coagulation and anticoagulation; for example,
–Electrolytes fibrinogen, protein C and antithrombin III.
–Dissolved gases (O2, CO2) Endocrine; for example, ADH and angiotensin II.
–Plasma proteins Immunological; for example, IgG and IgM.
–Other dissolved substances, including Mixed function; for example, albumin has major
hormones, glucose, amino acids, coagulation roles in both transport and colloid oncotic
proteins, lactic acid and urea. pressure.
Cellular components (45%), consisting of:
– Erythrocytes What are the functions of albumin?
– Leucocytes
Albumin has many roles:
– Platelets.
Colloid oncotic pressure. Albumin is responsible
for around 80% of the intravascular oncotic
Classify the different plasma proteins pressure. The development of peripheral oedema
The plasma contains over 500 different proteins. The mainly depends on the oncotic gradient between
total plasma protein concentration is 60–85 g/dL. the intravascular and interstitial spaces (see
Plasma proteins are traditionally classified into: Chapter 34). At a MW of 67 kDa, albumin is
Albumin, making up 60% of plasma proteins. normally too large to pass between the capillary
Globulins, 35% of total plasma protein, fenestrations. However, if the capillaries become
subclassified as α-, β- and γ-globulins. leaky, two patients with the same serum albumin
Fibrinogen, making up 4% of total plasma may have very different degrees of peripheral
protein. oedema. Thus:
– A malnourished elderly patient with a serum
Most plasma proteins, with the major exception of
albumin of 20 g/dL and normal capillaries will
γ-globulin, are synthesized in the liver. The most
have minimal peripheral oedema.
important type of γ-globulin is Ig, which is produced
by plasma cells. – A patient with severe sepsis, a serum albumin
Alternatively, plasma proteins can be classified of 20 g/dL and leaky capillaries will have
according to function: significant peripheral oedema.
Transport of endogenous substances and drugs.
Transport proteins; for example:
Albumin has a number of organic and inorganic
– transferrin transports iron; binding sites through which it transports a variety
– ceruloplasmin transports copper; of substances: unconjugated bilirubin, bile salts,
– lipoproteins transport lipids; electrolytes and free fatty acids. Albumin also
– thyroxine-binding globulin transports the binds and transports some important drugs:
thyroid hormone thyroxine; warfarin, digoxin, NSAIDs and thiopentone.
366
Chapter 71: Plasma constituents
This is clinically important, as many of these In hypoalbuminaemia, the anion gap is therefore
drugs compete with each other for the same reduced. Albumin also contributes to acid–base
binding site, leading to an increased fraction balance: hypoalbuminaemia results in a mild
of free drug and potentially toxic effects. Thus, metabolic alkalosis. This is why albumin
if a patient who already takes warfarin is given concentration is included in the Stewart method
an NSAID, some warfarin will be displaced from of acid–base analysis (see Chapter 66).
2+
albumin, thus increasing the unbound fraction: Plasma Ca handling. The negative charge of
PT and INR will increase. albumin also sequesters Ca2+ ions in the plasma,
Free radical scavenging. Sulphydryl reducing the amount of free Ca2+.
groups within albumin act as free radical
scavengers. Further reading
Acid–base balance. Albumin is negatively C. A. Burtis, E. R. Ashwood, D. E. Bruns. Tietz Textbook
charged, contributing significantly to the anion of Clinical Chemistry and Molecular Diagnostics,
gap – the unmeasured anions within the plasma. 5th edition. Saunders, 2012.
367
Section 8 Energy balance
Chapter
Metabolism
72
Metabolism refers to the whole range of biochemical The citric acid cycle, in which acetyl-CoA and
reactions that occur within living organisms. Metab- other metabolites are broken down through a series
olism broadly encompasses anabolism, the building of redox reactions within the inner mitochondrial
up of larger molecules from smaller ones, and catab- matrix. The resulting NADH, FADH2 and H+ are
olism, their breaking down into smaller entities with then processed by the electron transport chain.
the extraction of energy. The electron transport chain, located within the
inner mitochondrial matrix, is the final step of
aerobic metabolism. NADH and FADH2 transfer
What is meant by the term ‘cellular electrons to O2, releasing energy that is used to
respiration’? pump H+ across the inner mitochondrial
Cellular respiration is the series of catabolic processes membrane. The resulting electrochemical gradient
by which carbohydrates, fats and proteins are broken is used to generate ATP.
down to yield ATP through a series of redox reactions,
ultimately using O2 as the oxidizing agent. As O2 is
too reactive to be used directly, this process employs a Describe the important steps of the
series of intermediate electron carriers, including glycolytic pathway
NAD+ and flavin adenine dinucleotide (FAD). Glycolysis (also called the Embden–Meyerhof path-
way) is the metabolic pathway through which glucose
How are carbohydrates, fats is converted into pyruvate, with the generation of two
ATP and two NADH molecules (Figure 72.1).
and proteins metabolized to adenosine Key features of the glycolysis pathway are:
triphosphate? Glycolysis occurs in the cytoplasm.
Details of the metabolic processes involved are com- The first step is the phosphorylation of glucose,
plex, but an overview remains useful for clinical prac- resulting in glucose-6-phosphate – the ‘active’ form
tice. Catabolism involves a number of processes: of glucose. One ATP molecule is used up in this
Glycolysis, the process by which glucose is process. This reaction is catalysed by the enzymes
converted to pyruvate, which then enters the citric glucokinase (in the liver) or hexokinase (in the
acid cycle. Glycolysis takes place in the cytoplasm other tissues).1 Phosphorylation of glucose means
and can occur in either aerobic or anaerobic that the cytoplasmic concentration of glucose is
conditions. always low, so a concentration gradient for glucose
Lipolysis, the process by which free fatty acids are diffusion from the plasma is always maintained.
oxidized to acetyl-CoA, which then enters the Glucose-6-phosphate (a six-carbon molecule)
citric acid cycle. is broken down to two molecules of pyruvate
Protein catabolism, a process of oxidative (a three-carbon molecule) through a series of
deamination in which amino acids have their seven intermediates. During this process, a further
amino groups removed to form keto acids. The
keto acids may then enter the citric acid cycle, or 1
Glucose-6-phosphate is also obtained from the
be converted to glucose or fatty acids. The amino breakdown of the storage molecule glycogen by the
groups are converted to urea by the urea cycle. enzyme glycogen phosphorylase (see p. 376).
369
Section 8: Energy balance
Catalysed by glucokinase (liver) Glucose Glucose-6-phosphate = ‘activated glucose’ Figure 72.1 The glycolytic pathway
or hexokinase (other tissues)
ATP (simplified).
ADP
Glucose-6-phosphate Pentose phosphate pathway
ATP
6-carbon molecules ADP
3-carbon molecules
2 x Glyceraldehyde 3-phosphate NAD+ regenerated by exchange of
NAD+ electrons across the mitochondrial
NADH + H+ wall under aerobic conditions
2 x 1,3-bisphosphoglycerate 2,3-diphosphoglycerate (2,3-DPG)

4 x ADP
4 x ATP
Anaerobic conditions
2 x pyruvate 2 x lactate
Aerobic 2 x NADH 2 x NAD+

conditions
Citric acid cycle in mitochondria
molecule of ATP is consumed, and then four Lactate has a number of fates:
molecules of ATP are produced.
▪ If PO2 is restored, it can be oxidized
The overall glycolysis reaction is back to pyruvate and enter the citric
C6H12O6 + NAD+ + 2ADP + 2Pi !2C3H4O3 acid cycle.
+ 2H+ + 2ATP + 2H2O + 2NADH ▪ Lactate can leave the cell cytoplasm and
travel in the circulation to the liver, where
It is important to note that O2 is not consumed it can either oxidized back to pyruvate or
and CO2 is not produced. Glycolysis can converted to glucose through a process
therefore occur under both aerobic or anaerobic called gluconeogenesis. This is known as
conditions. the Cori cycle.
+
NAD is required for glycolysis. This is where
▪ In organisms without a liver (for example,
aerobic and anaerobic conditions differ: yeast), lactate is converted to ethanol to
– Under aerobic conditions: NADH produced regenerate NAD+, a process called
during glycolysis exchanges electrons with fermentation.
NAD+ or FAD across the mitochondrial wall,
which regenerates NAD+, thus allowing An important intermediate in the glycolytic
pathway is 1,3-bisphosphoglycerate (1,3-BPG).
glycolysis to continue. Pyruvate then passes
1,3-BPG isomerizes to 2,3-DPG, a molecule that
into the mitochondrion, where it enters the
binds strongly to deoxyhaemoglobin. In times of
citric acid cycle.
low PO2 the rate of glycolysis becomes increased,
– Under anaerobic conditions: the electron
as the enzyme phosphofructokinase involved in
transport chain is not active, so there are no
glycolysis is O2 sensitive. This results in increased
NAD+ or FAD molecules within the
2,3-DPG levels, which aids the offloading of O2
mitochondrion with which to exchange
from Hb (see Chapter 7).
electrons. Glycolysis can only continue if
NAD+ is regenerated through a different Clinical relevance: lactic acidosis
reaction: the production of lactic acid.
Lactic acidosis usually results from either regionally
Pyruvate is reduced to lactate by NADH in a or globally reduced O2 delivery; for example, limb
reaction catalysed by the enzyme lactate ischaemia, mesenteric ischaemia, cardiac arrest,
dehydrogenase. This regenerates NAD+ in severe shock (septic, cardiogenic, etc.). However, it
order that glycolysis can continue: is important to remember that lactic acidosis may
occur for other reasons, including:
Pyruvate + NADH ! Lactate + NAD+
370
Chapter 72: Metabolism
Pyruvate (3 carbon)
CoA-SH + NAD+
CO2 + NADH + H+
Acetyl CoA (2 carbon)
CoA-SH
6 carbon
4 carbon Citrate 6 carbon
NAD+
Oxaloacetate Isocitrate
NADH NADH
NAD+
CO2
4 carbon Malate a-Ketoglutarate 5 carbon
Carbon number decreases

CoA-SH NAD+ as CO2 is expelled
NADH
Fumarate Succinyl-CoA
CO2
4 carbon 4 carbon
Succinate
4 carbon
FADH2 ADP
FAD+ ATP +
CoA-SH
Figure 72.2 The citric acid cycle (simplified).
Reduced clearance of plasma lactate. This may Rarely, administration of sodium bicarbonate may be
occur in hepatic or renal dysfunction. Metformin indicated if there is cardiovascular compromise as a
(a biguanide) reduces hepatic gluconeogenesis. result of profound acidosis, or severe hyperkalaemia
As lactate is used by the liver as a substrate for accompanying the acidosis.
gluconeogenesis, metformin reduces hepatic
lactate uptake, thus exacerbating a lactic acidosis.
Cytotoxic hypoxia. The electron transport chain What are the important steps of the
can be poisoned by substances such as cyanide.
Cells are then no longer able to utilize O2 for citric acid cycle?
aerobic respiration and are reliant on glycolysis The citric acid cycle (also known as the Kreb’s cycle
for ATP production. and the tricarboxylic acid cycle) takes place in the
inner mitochondrial matrix. It involves a complex
Treatment of lactic acidosis is focused on diagnosis
and correction of the underlying cause; this may
cycle of metabolic intermediates, producing CO2,
involve surgery or organ support (O2 administration, ATP and electron donors (NADH and FADH2) that
fluid or inotropic support, haemofiltration, etc.). are then utilized in the electron transport chain
(Figure 72.2). Whilst O2 is not consumed in the citric
371
acid cycle, the cycle nevertheless ceases to operate Describe the key steps of the electron
under anaerobic conditions corresponding to a mito-
chondrial PO2 <0.4 kPa. This is because the electron transport chain
transport chain, which is dependent upon O2, is The electron transport chain is the final step of carbo-
needed to regenerate NAD+ and FAD for use in the hydrate, fat and protein catabolism. The electron
citric acid cycle. transport chain consists of five protein complexes
The main substance consumed by the citric acid on the inner surface of the inner mitochondrial
cycle is acetyl-CoA. Acetyl-CoA is a two-carbon mol- membrane, which use the electron donors NADH
ecule (the acetyl part) attached to a carrier (CoA, derived and FADH2 to produce ATP (Figure 72.3).
from vitamin B). Acetyl-CoA is produced either from Key features of the electron transport chain are:
pyruvate, according to the reaction Electrons are transferred from NADH to Complex
I and from FADH2 to Complex II.
Pyruvate (3) + CoA-SH + NAD+ ! Acetyl-
CoA (2) + CO2 + NADH Co-enzyme Q (also called ubiquinone, UQ) is
involved in facilitating electron transfer from
(numbers in parentheses refer to number of carbon Complexes I and II to Complex III.
atoms in the molecule) or Cytochrome c is involved in electron transfer
β-oxidation of fatty acids – see below. between Complexes III and IV.
Complex IV (also called cytochrome c oxidase)
However, other substances (for example, keto acids
transfers the collected electrons to O2, forming
formed from the deamination of amino acids) can
water. Complex IV is the part of the electron
enter the citric acid cycle at different points.
transport chain that is affected by cyanide
The citric acid cycle is a complex system of eight
poisoning: cyanide binds to the Complex IV haem
molecular intermediates, enzymes and co-enzymes.
group, preventing it from binding O2.
Key features of the citric acid cycle are:
As electrons are transferred along the electron
Acetyl-CoA (2) reacts with oxaloacetate (4) to transport chain, and as electrons are combined
form citrate (6). Citrate is considered the starting with O2, the energy released is used to pump H+
point of the cycle (hence the name), and is from the inner mitochondrial matrix to the inter-
traditionally drawn at the 12 o’clock position. membrane space. This generates an
Citrate (6) (through an intermediate) electrochemical gradient between the inter-
decarboxylates to give α-ketoglutarate (5), NADH membrane space and the inner mitochondrial
and CO2. matrix.
α-Ketoglutarate (5) decarboxylates when it The final stage in the electron transport chain is
reacts with CoA to give succinyl-CoA (4), NADH ATP synthesis. Complex V (also known as ATP
and CO2. synthase) is a pore in the inner mitochondrial
The four-carbon succinyl-CoA undergoes a series matrix through which the inter-membrane H+
of reactions and isomerizations, passing through a ions pass, generating ATP in the process. This
number of intermediate states before regenerating final step of the electron transport chain is known
oxaloacetate (4). No CO2 is produced during these as oxidative phosphorylation.
changes – the carbon number of the molecules
is unchanged. However, the process does produce Oxidative phosphorylation is usually coupled; that is,
a molecule each of ATP, NADH and FADH2. H+ movement across the inner mitochondrial mem-
brane is used to generate ATP. In brown adipose tissue,
The NADH, FADH2 and H+ produced in the citric
acid cycle are used in the electron transport chain pores can be opened that allow H+ ions to travel down
to produce ATP. their electrochemical gradient from the inter-
membrane space to the inner mitochondrial matrix
The overall reaction for each acetyl group entering
without passing through Complex V. This is called
the citric acid cycle is:
uncoupling, where oxidation and phosphorylation are
Acetyl-CoA + 3NAD+ + FAD + ADP + Pi no longer strictly matched. The energy released during
+ 2H2O ! CoA-SH + 3NADH H+ movement generates heat instead of ATP. This is an
+ FADH2 + 3H+ + ATP + 2CO2 important mechanism for thermogenesis in neonates.
372
Electrons transferred by co-enzyme Q Electrons transferred by cytochrome C

Outer mitochondrial membrane
Inner mitochondrial H+ H+ H+
membrane
Q Cyt c
I III IV
NADH NAD+ ½O2 H2O

H+
H+ H+
H+ gradient
H+
ADP + Pi
Citric acid
cycle H+ V H+
ATP H+
H+
FADH2 FAD+ H+ ½ O2 H2O
II Q ATP synthase
III IV
Cyt c
Intermembrane space
H+ H+
Figure 72.3 The electron transport chain (simplified).
Overall at the electron transport chain: Aerobic metabolism ¼ 36 × ATP:

NADH generates three ATP molecules. – Through glycolysis, one glucose molecule
FADH2 generates one ATP molecule. results in 2 × ATP, 2 × pyruvate and
2 × NADH.
– As each pyruvate is converted to acetyl-CoA,
How much adenosine triphosphate is one NADH molecule is generated.
generated from a molecule of glucose – In the citric acid cycle, each acetyl-CoA
during aerobic and anaerobic generates 3 × NADH, 1 × FADH2 and
1 × ATP.
metabolism? – Overall, one molecule of glucose thus
Anaerobic metabolism ¼ 2 × ATP: produces: 4 × ATP, 10 × NADH and
– Metabolism of glucose involves glycolysis only. 2 × FADH2.
– Two molecules of ATP are generated. – In the electron transport chain, each NADH
– Two molecules of NADH are also generated, produces 3 × ATP and each FADH2 produces
but cannot be utilized under anaerobic 1 × ATP. In total, one molecule of glucose
conditions. produces 36 × ATP.
373
How are fats metabolized? for its ATP. In times of starvation the brain can
Fats are a useful source of energy as they have a high adapt to using ketone bodies as its energy
energy value – they produce more than twice the source. During prolonged starvation, up to 70%
amount of ATP than equivalent masses of carbohy- of the brain’s metabolic demands can be pro-
drate or protein. vided by ketone bodies.
Free fatty acids are catabolized by the cells in a RBCs do not have mitochondria, so are entirely
process called β-oxidation. β-oxidation takes place in dependent on glycolysis for their metabolism and are
the mitochondrial matrix and involves removing suc- unable to utilize ketone bodies.
cessive two-carbon units from the fatty acid, each
event producing one molecule of acetyl-CoA
(Figure 72.4). Acetyl-CoA then enters the citric acid How are proteins catabolized?
cycle, as described above.
Proteins are the basic building blocks of the body’s
Key features of fat catabolism are:
structures; the body therefore treats them differently
Free fatty acids are stored as triglyceride: three to the other energy sources. Proteins are only used
fatty acids esterified with glycerol. When needed, for energy production if amino acids are plentiful, or
triglycerides are hydrolysed by lipases to in times of starvation. Protein catabolism is an ineffi-
regenerate free fatty acids and glycerol. Glycerol cient process: 1.75 g of protein is required to produce
can also be metabolized: in the liver, glycerol is the same energy as 1 g of carbohydrate.
transformed into glucose through a process called Proteins are first broken down into their constitu-
gluconeogenesis. The newly formed glucose enters ent amino acids. To be of any use, amino acids must
the circulation, where it is taken up by cells and first have their amino groups removed, through
used to produce ATP. oxidative deamination or transamination:
Short- and medium-chain fatty acids are small Oxidative deamination. This takes place in the
enough to directly enter the mitochondria. Long- liver and is catalysed by deaminase enzymes. The
chain fatty acids have to be bound to a carrier, amino group is removed, producing a keto acid
the carnitine shuttle, in order to cross the and NH3. The keto acid enters the citric acid cycle
mitochondrial membrane. where it may be used for energy, transformed into
glucose (gluconeogenesis) or used to synthesize
Clinical relevance: ketone bodies another amino acid or a fatty acid. NH3 is a toxic
When carbohydrates are scarce (as occurs during substance; it is converted to non-toxic urea
starvation) or unable to enter the cell (as occurs in through a process called the urea cycle (or
diabetic ketoacidosis), fat metabolism becomes the ornithine cycle). Conversion of NH3 to urea is an
main source of energy. β-oxidation results in a high energy-consuming process, requiring three ATP
mitochondrial acetyl-CoA concentration. When molecules per urea molecule formed. Unlike other
acetyl-CoA concentration is high, ketone bodies
amino acids, glutamate can also be deaminated in
(acetone, acetoacetic acid and β-hydroxybutyric acid)
are spontaneously formed by condensation of two
the kidney and its NH3 immediately excreted into
molecules of acetyl-CoA. Ketone bodies are a normal the urine. This is important as it means NH3 can
finding during starvation, but are pathological in be excreted without the need for the energy-
diabetic ketoacidosis. consuming urea cycle.
Ketone bodies can be utilized by the liver, heart Transamination. The amino group of an amino
and brain: acid is transferred, through catalysis by
The liver converts ketone bodies back into acetyl- aminotransferases, to a keto acid or another
CoA, which then enter the citric acid cycle. amino acid, to form a new amino acid. There are
The heart usually favours fatty acids as its main nine essential amino acids: phenylalanine, valine,
energy source, but can also use ketone bodies in
threonine, tryptophan, isoleucine, methionine,
times of starvation.
leucine, lysine and histidine. These amino acids
The brain does not normally metabolize fatty
acids; it is usually entirely dependent on glucose cannot be synthesized by transamination and
must be supplied from the diet.
374
Adipose tissue
O
O
R OH HO CH2
R O CH2 O
O
Lipolysis
OH + CH
O CH R HO
R O
O
CH2 R OH HO CH2
R O
Triglyceride Free fatty acids Glycerol
R = hydrocarbon chain
To the tissues (via the circulation, bound to albumin) To the liver (via the circulation, bound to albumin)
Cell cytoplasm
Long-chain fatty acids are ‘activated’ by co-
Free fatty acid
enzyme A before being helped across the
R = short / R = long chain inner mitochondrial membrane by carnitine
medium chain
CoA
Mitochondrion
CoA
Shorter chain fatty acids Fatty acyl CoA Fatty acyl carnitine
Specific
cross without help
carnitine carnitine
transporters
Carnitine is recycled carnitine
Free fatty acid Fatty acyl CoA Fatty acyl carnitine

CoA CoA O
β-oxidation 5x
H3C SCoA
β-oxidation of e.g. 12-carbon fatty acid:
β-oxidation
Removed as acetyl-CoA
β-carbon
O FAD, NAD+, CoA O O
CH2 +
H3C-(CH2)8 CH2 SCoA H3C SCoA H3C-(CH2)8 SCoA
FADH2, NADH
α-carbon
6 x acetyl-CoA Citric acid cycle Converted

Overall: 12-carbon fatty acid 7 x NADH into approx
Electron transport chain 100 ATPs
7 x FADH2
Figure 72.4 β-oxidation (simplified).
375
How are carbohydrates, fats glycogen in a process called glycogenesis.

Glucose-6-phosphate, the active form of glucose,
and proteins stored in the body? is joined together in chains. This process is
Humans eat sporadically, with gaps in between meals. catalysed by the enzyme glycogen synthase:
At the same time, constant ATP production is required increased insulin concentration upregulates this
to maintain cellular processes. Therefore, the storage enzyme’s activity (Figure 72.5).
and gradual release of nutrients is of great importance: When plasma glucose levels fall, the liver
Glycogen. Carbohydrates are stored as glycogen, a glycogen store liberates glucose, thus returning the
polymer of glucose analogous to the plant glucose plasma glucose concentration to normal. This
storage molecule starch. Glycogen is found in the process is called glycogenolysis and is stimulated
liver and muscles: by the hormones glucagon and adrenaline.
Growth hormone (GH) causes glycogenolysis in
– The liver contains approximately 100 g of
skeletal muscle.
glycogen, which can be released as glucose into
the circulation for use by other organs. Liver Triglyceride. The body’s main energy storage
form is triglyceride, mainly found within adipose
glycogen is only sufficient to maintain plasma
cells. Triglycerides are either absorbed from the
glucose concentration for around 24 h, after
diet or synthesized from carbohydrate or protein
which gluconeogenesis becomes the dominant
precursors:
mechanism (see below).
– The muscle glycogen store contains around – Dietary triglyceride is packaged by enterocytes
200 g of glucose, but its glucose cannot be into chylomicrons (see Chapter 60).
released back into the circulation. Muscle Chylomicrons circulate in the plasma,
glycogen can only be used for metabolic offloading exogenous triglycerides to the
processes within the muscle. tissues. Any excess triglyceride is taken up by
adipose tissue for storage.
Following a carbohydrate-based meal, the – Hepatocytes synthesize triglyceride in an
hormone insulin facilitates the production of anabolic process called lipogenesis. After a
Enhanced by insulin
Glycogenesis
ATP ADP Phosphoglucomutase Glycogen synthetase

Glucose Glucose-6-phosphate Glucose-1-phosphate Glycogen
Phosphoglucomutase Glycogen phosphorylase
Glycogenolysis
Enhanced by adrenaline and glucagon
Fates of glucose-6-phosphate regenerated by glycogenolysis:
Glycolysis pathway
Glucose-6-phosphate
Pentose phosphate pathway
Glucose-6-phosphatase
Glucose This step only occurs in the liver; muscles lack glucose-6-
phosphatase so cannot release glucose into the bloodstream
Release into bloodstream
Figure 72.5 Glycogenesis and glycogenolysis (simplified).
376
meal, insulin levels are high. Once the liver To produce pentose sugars for nucleic acid
glycogen store is full, any excess carbohydrates synthesis.
or amino acids are converted to fatty acids To produce NADPH for intracellular reduction
and glycerol, which are esterified to give reactions (i.e. the reverse of oxidation).
triglyceride. This newly formed triglyceride is
packaged as VLDL in the liver. VLDL is Key features are:
released into the circulation, where it distributes The PPP starts with the active form of glucose,
endogenous triglyceride to the tissues. glucose-6-phosphate.
Protein. Although protein is primarily a structural Whether glucose-6-phosphate proceeds along the
material, the muscles provide a store of amino glycolytic pathway or the PPP depends on the
acids that can be catabolized at times of starvation. activity of the enzyme that catalyses the first step
of the PPP: G6PD. G6PD is controlled by the
cellular concentration of NADP+, becoming more
What is gluconeogenesis? active if NADP+ levels are high.
Gluconeogenesis, as the name suggests, is an energy- The PPP accounts for approximately 60% of the
consuming anabolic process in which glucose is syn- NADPH required by the cells, which is used to
thesized from non-carbohydrate precursors. Gluco- reduce glutathione. Glutathione is an antioxidant
neogenesis mainly occurs in the liver, with a minor used to prevent cellular damage from ROS (see
contribution by the kidney. It is one of two mechan- Chapter 23). It is also important in RBCs, where it
isms that prevent plasma glucose concentration from helps maintain Hb in its ferrous (Fe2+) state.
falling too low, the other being glycogenolysis. It may Patients with G6PD deficiency cannot utilize the
seem odd that the liver synthesizes glucose by an PPP, which leads to a loss of reducing power,
energy-consuming process so that the newly formed predisposing the patient to MetHb (Fe3+)
glucose can be catabolized by other tissues. However, formation (see Chapter 7).
some tissues are predominantly (brain) or entirely
(RBCs) dependent on glucose as their source of
energy. Summarize the effects of insulin
Gluconeogenesis is another complex metabolic and glucagon
pathway. Its key features are: Resting plasma glucose concentration is usually
Molecules used as substrates for gluconeogenesis tightly controlled – it is maintained between 3.5 and
include lactate, pyruvate, glycerol, amino acids 5.5 mmol/L by the balance of two hormones:
and all the intermediates of the citric acid cycle. Insulin, which acts to reduce plasma glucose
The gluconeogenesis pathway is a separate concentration.
biochemical pathway – it is not simply the reverse Glucagon, which acts to increase plasma glucose
of glycolysis. concentration.
Gluconeogenesis starts from oxaloacetate, a four-
carbon intermediate of the citric acid cycle. Insulin is the body’s main anabolic hormone. Insulin
Gluconeogenesis is controlled by the hormone is a peptide hormone produced in the β cells of the
glucagon, released when plasma glucose islets of Langerhans in the pancreas:
concentration is low (see below). Proinsulin. This is an insulin precursor,
The biguanide metformin works by inhibiting consisting of an A and B chain joined together by
gluconeogenesis. two disulphide bridges and a C-peptide.
Insulin. This is formed when the C-peptide of
proinsulin is cleaved by endopeptidases. Insulin
What is the pentose phosphate and free C-peptide are packaged together in
pathway? vesicles, awaiting a physiological trigger for release.
The PPP (also called the hexose monophosphate Exocytosis. The primary trigger for insulin
shunt) is an anabolic carbohydrate pathway with vesicles to undergo exocytosis is an increase in
two functions: plasma glucose concentration:
377
– The facilitated diffusion of glucose (through a Inhibition of endogenous glucose production.

GLUT-2 transmembrane channel) into the Insulin inhibits the breakdown of stored
β-islet cells increases with plasma glucose substrates (i.e. lipolysis and glycogenolysis) and
concentration. gluconeogenesis.
– This increases the metabolic activity of the cell,
causing the formation of a greater amount Insulin also promotes the cellular uptake of amino
of ATP. acids and K+:
– On the β-islet cell membrane, ATP-gated K+ Increased amino acid uptake promotes protein
channels (KATP) are closed by high ATP levels. synthesis.
+
– This results in reduced K+ flux, and therefore The physiological role of increased K uptake is a
membrane depolarization. feedforward response to prevent hyperkalaemia
– Depolarization triggers the opening of voltage- following a meal – the presence of increased
gated Ca2+ channels. glucose suggests feeding and the likelihood of
– Ca2+ influx then triggers insulin containing increased K+. The mechanism can be manipulated
vesicle exocytosis (akin to the presynaptic in hyperkalaemic patients: plasma K+
membrane). concentration can be reduced through the use of
an insulin and dextrose infusion.
Plasma insulin secretion occurs in two phases.
Initially, a rise in plasma glucose concentration
stimulates a rapid increase in plasma insulin Clinical relevance: diabetic ketoacidosis
concentration as vesicles empty their contents In type 1 diabetes, there is an absolute lack of
filled with pre-formed insulin. When all the endogenous insulin due to autoimmune attack
vesicles have emptied, the β-islet cells release of the β-islets of Langerhans. Patients are treated
insulin as it is synthesized. with exogenous insulin.
The sympathetic nervous system inhibits the When exogenous insulin is insufficient (for
example, due to an acute illness, or patient non-
release of insulin from the β-islet cells by direct
compliance with treatment), plasma glucose concen-
innervation, through α2 adrenoceptor action.
tration increases due to:
However adrenaline, released in response to Reduced glucose uptake into cells.
sympathetic nervous activity at the adrenal Increased hepatic glycogenolysis.
medulla, causes an increase in insulin secretion Increased gluconeogenesis.
through β2 adrenoceptor activation. This is
important during exercise: muscles require insulin In addition, low insulin plasma concentration results
in lipolysis and β-oxidation. As discussed above,
for glucose uptake through the GLUT-4 glucose
when the acetyl-CoA concentration in the liver is
transporter (see below).
high, ketone bodies are synthesized. Hyperglycaemia
Insulin has three main physiological effects: and ketone body formation result in adverse effects:
Osmotic diuresis. Hyperglycaemia results in an
Facilitation of glucose uptake. The cell membrane osmotic diuresis, which can cause significant
glucose transporter GLUT-4 requires insulin to hypovolaemia and renal electrolyte loss. In par-
facilitate cellular glucose uptake. GLUT-4 ticular, significant hypokalaemia may occur.
transporters are present in adipose tissue, skeletal Acidosis. Synthesis of ketone bodies may result
muscle and the heart. Note: the cells of the brain in significant acidaemia. The respiratory centre is
and liver have GLUT-1 and GLUT-2 glucose stimulated by the carotid bodies, resulting in an
transporters respectively, which are not insulin increased VT, known as ‘Kussmaul respiration’.
dependent. In addition, acidosis may be exacerbated by lactic
acid production in significantly hypovolaemic
Storage of metabolic substrates. Increased plasma
patients.
insulin concentration promotes substrate storage:
– Hepatic glycogenesis. The paradox in diabetic ketoacidosis is that, despite
high plasma glucose concentration, most of the
– Fatty acid synthesis in the liver.
body’s cells are deficient in glucose as the insulin-
– Increased esterification of fatty acids (to make dependent glucose transporter GLUT-4 is inactive.
triglyceride) in adipose tissue.
378
Glucagon is a peptide hormone produced by the α Pregnancy and lactation – BMR increases by
cells of the islets of Langerhans. Unlike the β-islet 20% in pregnancy, as a consequence of fetal
cells, α-islet cells have no glucose sensing apparatus, and placental metabolism as well as the growth
and therefore: of the uterus and breasts. In the post-natal
Secretion of glucagon is stimulated by period, the metabolic processes involved in
hypoglycaemia, which does not directly stimulate the production of breast milk cause an increased
glucagon release from the α-islet cells, but instead BMR; breastfeeding is promoted as a means
stimulates glucagon release through a of post-natal weight loss.
hypoglycaemia-induced increase in ANS activity. High and low environmental temperature –
In addition, glucagon is secreted in response to an pyrexia causes an increase in BMR.
increase in circulating adrenaline. A recent meal – BMR is raised for the
Glucagon release is inhibited by: 6 h following a large meal, mostly due to
– Insulin. oxidative deamination of amino acids in
the liver.
– Somatostatin.
– Increased plasma free fatty acid and ketone Children – BMR is increased in children owing to
the metabolic needs of growth and
body concentrations.
thermoregulation; neonates have a BMR
Glucagon acts to increase plasma glucose concentra- approximately twice that of adults (see
tion by: Chapter 79).
Promoting gluconeogenesis. BMR is reduced by:
Promoting glycogenolysis.
Hypothyroidism.
Inhibiting glycolysis in the liver – intermediates
Starvation. BMR is reduced to preserve body fat
of the glycolysis pathway are instead used as
and protein stores.
substrates for gluconeogenesis.
Advancing age. BMR declines by approximately
Glucagon is especially important during starvation. 2% per decade.
Maintenance of a normal plasma glucose concentra-
It was previously thought that BMR was lower in
tion is important, as the brain is very dependent on
females than males. However, taking lean body mass
glucose for its metabolism (see Chapter 73).
into account, there is no BMR difference between the
sexes.
What is meant by the term ‘basal Clinical relevance: the metabolic equivalent
metabolic rate’? The metabolic equivalent of a task (MET, or metabolic
BMR is the amount of energy a patient consumes per equivalent) is a method of expressing the energy
unit time in a state of mental and physical rest in a cost of a particular physical activity. Exercise is
comfortable environment, 12 h after a meal. BMR is graded against multiples of BMR:
corrected for age and surface area. Normal BMR for 1 MET equals in a state of rest, awake, fasted for
an adult is approximately 200 kJ/(m2 h), or 40 kcal/ >12 h.
(m2 h). 3 MET equals walking at moderate pace on
the flat.
BMR is not an easy quantity to measure. It may be
4 MET equals climbing two flights of stairs with-
calculated by: out stopping.
Measuring the heat produced by a subject. 8 MET equals jogging.
Measuring the O2 consumption of a subject. >10 MET equals strenuous exercise.
The body’s metabolic rate is increased by: METs can be used in the preoperative anaesthetic
assessment to grade physiological reserve. A func-
Exercise.
tional capacity of less than 4 MET represents poor
Raised catecholamine levels, including stress. physiological fitness, and is associated with a higher
Hyperthyroidism – thyroid hormones play a risk of postoperative cardiac events.
major role in the basal control of metabolic rate.
379
Further reading and perioperative cardiac management for

non-cardiac surgery. Eur Heart J 2009; 30(22):
D. Voet, J. G. Voet. Biochemistry, 4th edition. John Wiley & 2769–812.
Sons, 2011.
F. C. Luft. Lactic acidosis – update for critical care
Taskforce for the European Society of Cardiology. clinicians. J Am Soc Nephrol 2001; 12(Suppl.): S15–9.
Guidelines for pre-operative cardiac risk assessment
380
Chapter
Starvation
73
This process leads to high acetyl-CoA
Describe the changes that occur concentration within the mitochondria,
during starvation resulting in the formation of ketone
Starvation is defined as the failure to ingest or absorb bodies.
sufficient dietary calories to sustain normal body Over the next few days
function, resulting in behavioural, physical and meta- – Gluconeogenesis increases – the substrates for
bolic changes. gluconeogenesis are glycerol, lactate and
During starvation, the body must survive partially amino acids.
or totally on endogenous stores. As starvation pro-
– Plasma insulin concentration becomes
gresses, the balance of the hormones insulin and
very low, which increases ketone body
glucagon alters: insulin concentration decreases to
synthesis.
very low levels, whilst glucagon concentration
Over the next few weeks
increases. This, in turn, is responsible for the major
metabolic changes that occur during starvation. – Gluconeogenesis gradually declines as tissues
adapt to metabolize ketone bodies. Plasma
ketone concentration rises as high as 7 mmol/L.
Describe the biochemical changes – BMR decreases.
of starvation The brain still requires 100–120 g of glucose per
During periods of starvation, the body’s main con- day, and gluconeogenesis is the only means of supply-
cern is maintaining plasma glucose concentration; ing this demand. Whilst glycerol released during lipo-
some tissues, particularly the brain and RBCs, are lysis remains the main substrate for gluconeogenesis,
dependent on glucose for their metabolism. amino acids are increasingly used; high glucagon
During the first 24–48 h, a reduction in plasma concentration stimulates the release of amino acids
glucose concentration causes a fall in plasma from skeletal muscle.
insulin concentration, and a rise in glucagon
concentration:
– Glycogenolysis in the liver is promoted by What other changes occur during
glucagon, releasing glucose into the starvation?
circulation. The liver glycogen store is Along with biochemical changes, starvation induces
exhausted after 48 h. behavioural changes:
– Lipolysis is promoted by high glucagon Initially, energy is conserved through a
concentration and low insulin reduction in unnecessary movement.
concentration, resulting in the liberation of
In severe starvation, all but life-saving
free fatty acids and glycerol from stored movement ceases.
triglyceride.
– β-oxidation of fatty acids is promoted by There are also some additional physiological changes:
low plasma insulin concentration. Most of the activity of the sympathetic nervous system is
the energy produced in the early stages reduced in severe starvation, leading to difficulty with
of starvation comes from β-oxidation. temperature and blood pressure control.
381
What is the usual mode of death Hypophosphataemia.

Hypokalaemia.
in starvation? Hypomagnesaemia.
Total fat stores vary between patients, but a typical Increased ECF.
70 kg man has enough triglyceride to survive around
40–60 days of starvation. After triglyceride stores During starvation, plasma insulin concentration falls
have been exhausted, the amino acids within skeletal to very low levels. When feeding is re-established and
muscle are liberated and used for gluconeogenesis. plasma glucose concentration rises, there is a massive
However, once half the muscle mass has been catabo- increase in insulin secretion by the pancreatic β-islet
lized, there is insufficient respiratory muscle cells. The high insulin concentration promotes cellu-
remaining to adequately clear respiratory secretions, lar glucose, Mg2+, phosphate and K+ uptake, causing
and pneumonia ensues. the plasma concentrations of these substances to
fall dramatically. In addition, there is excessive Na+
Clinical relevance: enhanced recovery and water retention (the mechanism for which is
unknown) which may precipitate LVF. Reintroduction
Traditionally in major surgery, to protect against
aspiration pneumonia on induction of anaesthesia, of carbohydrate increases the respiratory quotient:
patients are starved preoperatively for at least 6 h the respiratory system, already potentially weak from
and often significantly longer. The metabolic conse- respiratory muscle catabolism, must increase V_ A to
quences of major surgery are complex (see Chap- compensate for the increased production of CO2
ter 74), including insulin resistance, hyperglycaemia when carbohydrates are metabolized.
and protein catabolism, all of which worsen outcome. Management of refeeding syndrome is by slow
The enhanced recovery programme is a struc- institution of feeding with aggressive correction of
tured approach to managing the perioperative electrolytes.
period in patients undergoing major surgery. Factors
such as neuraxial blockade and early mobilization are Clinical relevance: anorexia nervosa
incorporated into a protocol-based perioperative
Anorexia nervosa is a psychiatric disorder character-
care bundle, which has been shown to reduce the
ized by strict, psychologically driven weight loss
length of hospital stay and postoperative complica-
through dietary restriction, excessive exercise and
tions. One of the factors included in the enhanced
purging (self-induced vomiting and laxative use).
recovery bundle is preoperative carbohydrate
Anorexia has significant physiological sequelae with
loading. Allowing patients to drink carbohydrate-
implications for anaesthesia:
based drinks up to 2 h preoperatively is associated
Respiratory. Purging may result in a metabolic
with less insulin resistance and a reduced loss of
alkalosis. The respiratory centre may partially
muscle mass, without increasing the risk of aspir-
compensate through bradypnoea.
ation. Glucose is said to have a protein-sparing
Cardiovascular. Anorexic patients are typically
effect, thought to be due to the effects of insulin
hypotensive and bradycardic, as a result of
preventing protein catabolism.
decreased sympathetic outflow. The baseline
ECG may demonstrate abnormalities as a result of
electrolyte disturbances; perioperative arrhyth-
What is refeeding syndrome? mias are common. Myocardial contractility may
Refeeding syndrome is the severe metabolic disturb- be impaired; excessive fluid administration may
ance that can occur following reinstitution of nutri- precipitate overt cardiac failure.
tion to patients who have been starved or severely Gastrointestinal. Repeated vomiting results in
salivary gland hyperplasia, dental caries,
malnourished. It was first reported amongst survivors
oesophageal strictures and Mallory–Weiss tears.
of Japanese concentration camps in World War II. Gastric emptying times are prolonged; all anor-
Patients at risk of refeeding syndrome include exic patients should be considered to have a ‘full
those who have been starved for 5 days or longer; stomach’, warranting RSI. Refeeding syndrome is
refeeding syndrome may therefore be encountered almost universal.
in emergency surgical and critical care patients. Renal. Significant electrolyte disturbances (espe-
The onset of refeeding syndrome is usually within a cially K+, Mg2+, Ca2+, Cl ) may occur in those who
few days of reinstitution of food, causing:
382
Chapter 73: Starvation
abuse diuretics and laxatives. Glomerular filtra- clearance may be reduced due to reduced
tion is often impaired. BMR and renal function. Hypokalaemia and
Thermoregulation. Decreased subcutaneous fat hypocalcaemia may prolong the duration
and an inadequate shivering mechanism predis- of neuromuscular blockade.
pose anorexic patients to perioperative hypo-
thermia. In addition to the usual warming
methods, the ambient theatre temperature may
need to be increased. Further reading
Positioning. The lack of subcutaneous fat pre- C. Jones, S. A. Badger, R. Hannon. The role of carbohydrate
disposes anorexic patients to peripheral nerve drinks in pre-operative nutrition for elective colorectal
injuries – careful positioning and padding are surgery. Ann R Coll Surg Engl 2011; 93(7): 504–7.
required. A. M. Denner, S. A. Townley. Anorexia nervosa:
Pharmacological. A decrease in plasma protein perioperative implications. Contin Educ Anaesth Crit
concentration results in a greater fraction of Care Pain 2009; 9(2): 61–4.
unbound drug – doses need to be adjusted for M. D. Kraft, I. F. Btaiche, G. S. Sacks. Review of the re-
this, and the patient’s weight. In addition, drug feeding syndrome. Nutr Clin Pract 2005; 20(6): 625–33.
383
Chapter
Stress response
74
Once activated:
What is the stress response?
The stress response is a complex neuroendocrine The hypothalamus increases sympathetic
response to physiological stress. The most commonly nervous outflow, resulting in
encountered stressors are trauma, burns, surgery and – Systemic release of adrenaline from the adrenal
critical illness; the magnitude of the neuroendocrine medulla.
response is directly related to the magnitude of the – Systemic release of noradrenaline from post-
stressor. The acute phase of the stress response is ganglionic sympathetic nerve terminals;
referred to as the ‘fight or flight’ response. However, increased sympathetic nervous activity results
the stress response is not confined to this acute phase: in some spill-over of noradrenaline into the
the body responds to physiological stress over a systemic circulation.
longer time period. – Renin release by the kidney, which increases
In addition to its metabolic effects, the stress aldosterone secretion from the adrenal cortex
response leads to activation of the immunological (through the production and action of
and haematological systems. The stress response angiotensin II).
may once have been a useful survival strategy. How- – Glucagon release from the α cells of the islets of
ever, modern medicine considers many of the physio- Langerhans.
logical changes that accompany the stress response to – A reduction in insulin secretion from the β cells
be detrimental, as they may adversely affect surgical of the islets of Langerhans:
outcomes and extend hospital stay.
▪ Noradrenaline released at β-islet cell
How is the stress response initiated? sympathetic nerve endings inhibits insulin
secretion through its action at α
What are its effects on the adrenoceptors.
endocrine system? ▪ Adrenaline, released into the circulation by
The hypothalamus coordinates the stress response the adrenal medulla, stimulates insulin
through the secretion of pituitary hormones and the secretion by the β-islet cells through its
activation of the sympathetic nervous system. It is action at β2 adrenoceptors.
stimulated to do so through two mechanisms: In the stress response (in contrast to exercise –
Relay of autonomic and sensory afferent nervous see Chapter 72), the dominant effect is that of
impulses from the area of injury to the the α adrenoceptors: insulin secretion is reduced,
hypothalamus. and thus plasma glucose concentration rises.
Local activation of inflammation in the area of The hypothalamus signals the pituitary
injury with cytokine release, complement to release
activation, leucocyte attraction, platelet activation – Adrenocorticotropic hormone (ACTH), which
and initiation of the coagulation cascade. stimulates cortisol release from the adrenal
Cytokines such as interleukin 6, interferons and cortex. Cortisol is known as the ‘stress
tumour necrosis factor spill over into the systemic hormone’, owing to the multitude of effects it
circulation, triggering the hypothalamus to mediates in response to physiological stress.
activate the stress response.
384
Chapter 74: Stress response
The mineralocorticoid effects of aldosterone What are the adverse consequences

and cortisol result in excess Na+ and
water reabsorption. Cortisol usually regulates of the stress response?
its own release through a negative-feedback The stress response has many adverse consequences:
loop (see Chapter 76). In the stress Cardiovascular. Increased levels of
response, this negative-feedback mechanism catecholamines and angiotensin II result in
fails: serum cortisol concentration rises. peripheral vasoconstriction, hypertension and
– GH. tachycardia, all of which increase myocardial
– ADH. Increased ADH results in reabsorption work, with the potential to precipitate myocardial
of water at the renal collecting duct. ischaemia in susceptible patients.
Hyperglycaemia. Raised plasma glucose is
The secretion of the other pituitary hormones is
associated with poor wound healing and wound
not altered by the stress response.
infection. In critical illness, hyperglycaemia is
associated with increased mortality, increased risk
What are the metabolic effects of nosocomial infection, requirement for renal
replacement therapy and critical illness
of the hormonal changes? polyneuropathy. The plasma glucose
The stress response has effects on all the major meta- concentration at which insulin therapy should
bolic substrates: be started is controversial: tight glucose control
Carbohydrate. Hyperglycaemia occurs in (for example, plasma glucose 4.4–6.1 mmol/L) has
proportion to the severity of trauma, due to: been shown to reduce these adverse
complications, but it carries an increased risk of
– Low insulin concentration.
iatrogenic hypoglycaemia.
– High glucagon concentration.
Protein catabolism. Negative nitrogen balance is
– The anti-insulin effects of catecholamines,
a major consequence of the stress response. Loss
cortisol and, to a lesser extent, GH.
of skeletal muscle mass can be significant (up to
Protein. Protein metabolism has two phases: 0.5 kg/day) following major surgery. Generalized
– Initially, protein anabolism is inhibited. loss of skeletal muscle makes patients feel weak
– After 12–14 h, skeletal muscle is catabolized – and contributes to postoperative immobility, thus
amino acids are required for use as substrates increasing venous thromboembolism risk. Loss of
for gluconeogenesis and for the synthesis of respiratory muscle predisposes patients to
acute-phase proteins. postoperative respiratory failure. In the severely
malnourished, cardiac muscle mass may be lost,
The extent of protein catabolism is proportional
predisposing to arrhythmias. Unfortunately, no
to the severity of the trauma. This is referred to as
strategy has ever successfully prevented stress-
negative nitrogen balance, where the amount of
related protein catabolism. However, protein
nitrogen excreted from the body is greater than
catabolism does appear to be reduced by
that ingested. The hormones involved are:
preoperative carbohydrate loading and
– Cortisol, which promotes protein breakdown perioperative low-dose glucose infusion.
and gluconeogenesis. Electrolyte disturbance. A consequence of
– GH, which has greater anabolic than catabolic increased mineralocorticoid activity (due to
effects on body protein, and thus may limit aldosterone and cortisol) is increased Na+ and
skeletal muscle breakdown. water reabsorption and increased K+ excretion.
Fat. Lipolysis and ketogenesis are promoted by: Hypokalaemia is very common in hospitalized
– High glucagon concentration. patients, particularly after major surgery and in
– Low insulin concentration. critical illness. Hypokalaemia may result in muscle
– Increased catecholamine concentration. weakness, arrhythmias and ileus.
– Increased cortisol concentration. Fluid overload. Excess ADH and
– Increased GH concentration. mineralocorticoid activity, along with intravenous
385
fluid administration, can result in fluid overload, pain, reduces thromboembolic risk (especially in
precipitating LVF in susceptible patients, and lower limb surgery) and reduces postoperative
contributing to wound breakdown and ileus.
anastomotic leak. Systemic opioids. Opioids are well known to
Thromboembolism. The stress response produces suppress the hypothalamic–pituitary–adrenal axis.
a pro-coagulant state, increasing the risk of deep High-dose fentanyl has been shown to abolish the
vein thrombosis and PE. stress response to abdominal and pelvic surgery,
Immunological. Cortisol, released as part of the but increases the need for postoperative
stress response, has significant effects on T cells. ventilation.
Cortisol stimulates the division of CD8+ cytotoxic General anaesthetic agents. Etomidate is an
T cells, which in turn suppresses the division of inhibitor of 11-β-hydroxylase in the adrenal
CD4+ T helper cells. Overall, the effect on cortex: an induction dose of etomidate reduces
T helper cells results in the body being more aldosterone and cortisol synthesis for up to 8 h
susceptible to invading pathogens. Cortisol also (see Chapter 76). Other general anaesthetic agents
decreases inflammation by decreasing capillary appear to have minimal influence over the stress
permeability, prostaglandin synthesis (through response.
inhibition of the enzyme phospholipase), cytokine Intraoperative warming. Maintaining
release and leucocyte migration. normothermia intraoperatively has been shown to
reduce the magnitude of the stress response.
How may anaesthetists reduce the Surgical technique. Surgeons also have a role to
play in reducing the stress response to surgery.
stress response to surgery? Laparoscopic and other minimally invasive
Looking through the list of adverse consequences surgical techniques are associated with reduced
of the stress response, it is likely to be advantageous cytokine release than the equivalent open
if the stress response to surgery could be reduced or procedures.
eliminated completely. As discussed above, the stress
response is initiated by afferent sensory and auto-
nomic neural input to the hypothalamus, and by Further reading
cytokine release. Methods to reduce the stress F. Fant, E. Tina, D. Sandblom, et al. Thoracic epidural
analgesia inhibits the neuro-hormonal but not the acute
response include:
inflammatory stress response after radical retropubic
Epidural and spinal anaesthesia. This is the most prostatectomy. Br J Anaesth 2013; 110(5): 747–57.
studied and most successful method of reducing M. Mikura, I. Yamaoka, M. Doi, et al. Glucose infusion
the stress response. Preoperative neuraxial suppresses surgery-induced muscle protein breakdown
blockade prevents initiation of the stress response by inhibiting ubiquitin-proteasome pathway in rats.
by afferent neural input, but does not influence Anaesthesiology 2009; 110(1): 81–8.
cytokine release. Lumbar epidurals are more D. Burton, G. Nicholson, G. Hall. Endocrine and
effective than thoracic epidurals at attenuating the metabolic response to surgery. Contin Educ Anaesth Crit
stress response, as the lumbar autonomic nerves Care Pain 2004; 4(5): 144–7.
are less reliably blocked by thoracic epidurals. J. P. Desborough. The stress response to trauma and
Neuraxial blockade also improves postoperative surgery. Br J Anaesth 2000; 85(1): 109–17.
386
Section 9 Endocrine physiology
Chapter
Hypothalamus and pituitary
75
into the circulation; neither is stored. The high
What is a hormone? lipid solubility of steroid hormones allows them to
A hormone is a substance released by a cell, gland or diffuse across target cell membranes, where they
organ in one part of the body that exerts its effects on exert their effects by binding to cytosolic
tissues elsewhere in the body. receptors. The steroid hormone–receptor complex
then travels to the cell nucleus, where it influences
gene transcription. The eicosanoids have a wide
What types of hormone exist? range of functions in the body, and their
Hormones are classified on the basis of their chemical mechanisms of action are complex.
structure: Monoamine derivatives; that is, hormones
Peptide hormones, the most common type, may derived from a single amino acid. For example:
be subclassified as:
– Catecholamines are synthesized from
– Short peptide chains; for example, thyrotropin- phenylalanine or tyrosine.
releasing hormone (TRH), ADH, ACTH and – Serotonin is derived from tryptophan.
insulin. – Thyroxine is derived from tyrosine.
– Longer protein chains; for example, GH and
prolactin (PRL). The monoamine-derived hormones behave very
– Glycopeptides – a protein chain with differently:
carbohydrate groups attached; for example, – Catecholamines and serotonin are stored in
lutenizing hormone (LH), follicle-stimulating granules prior to release, whilst thyroxine
hormone (FSH) and thyroid-stimulating is incorporated within thyroglobulin (see
hormone (TSH). Chapter 76).
– Catecholamines and serotonin exert their
In general, peptide hormones are stored in
effects at the target tissue through cell
granules and are released into the circulation by
membrane receptors, whilst thyroxine binds to
exocytosis. Once they reach their target tissue,
receptors at the cell nucleus.
peptide hormones exert their effects by binding to
cell surface receptors.
Lipid- and phospholipid-derived hormones, of What are the functions of the
which there are two main subtypes:
– Steroid hormones; for example, aldosterone,
hypothalamus?
The hypothalamus is located below the thalamus,
testosterone, oestrogen and cortisol.
making up the ventral part of the diencephalon.
– Eicosanoids; for example, prostaglandins,
Though relatively small, the hypothalamus exerts con-
thromboxanes and leukotrienes.
trol over a large number of body functions, acting as the
The steroid hormones are all derived from link between brain, ANS and endocrine system.
cholesterol, whilst the eicosanoids are derived The functions of the hypothalamus may be classified as:
from the phospholipid bilayer of cell membranes. Autonomic. The hypothalamus receives inputs
Both types of lipid-derived hormone are from the limbic system and relays them to the
synthesized as required and immediately released medulla oblongata. Thus, emotional stress
387
Section 9: Endocrine physiology
(for example, fear) triggers a sympathetic nervous by the pituitary stalk. The pituitary is almost entirely
system response. covered superiorly by a fold of dura mater called the
Thermoregulation. The hypothalamus integrates diaphragma sella; a gap allows the pituitary stalk to
signals from peripheral and central pass through.
(hypothalamic) thermoreceptors, and controls the The pituitary gland lies close to some key
balance of activities of the two hypothalamic structures:
centres: the heat loss centre and the heat gain Superiorly, the pituitary stalk, optic chiasm and
centre (see Chapter 83). third ventricle.
Regulation of hunger. Food intake is controlled Laterally, the cavernous sinus, which contains
through the relative activities of the hypothalamic cranial nerves III, IV, VI, V1 and V2, and the ICA.
feeding and satiety centres. These centres are
influenced by hypothalamic glucose concentration, The pituitary gland itself comprises two main lobes,
GI hormones (CCK and glucagon) and leptin anterior (larger) and posterior, which are separated
(a hormone released from adipose tissue). by a small pars intermedia. These lobes have different
Regulation of body water. As discussed in embryological origins:
Chapter 65, the hypothalamus regulates body The anterior lobe, or adenohypophysis, develops
water through two mechanisms: from a depression of oral ectoderm in the
– The thirst centre controls water intake. embryo’s pharynx, known as Rathke’s pouch.
– Osmoreceptors control renal water excretion, The posterior lobe, or neurohypophysis, develops
in conjunction with ADH secretion by the from a downgrowth of neural ectoderm from the
pituitary gland. hypothalamus. The posterior lobe never separates
from the hypothalamus; the downgrowth persists
Control of sleep–wake cycles. Stimulation of the
as the pituitary stalk.
anterior hypothalamus leads to sleep, whilst
stimulation of the posterior hypothalamus causes The pars intermedia is a very thin layer of cells
wakefulness. Circadian rhythms are thought to located between the anterior and posterior lobes,
originate in the hypothalamus. which also develops from Rathke’s pouch. It is
often considered to be part of the anterior lobe
Control of pituitary function. The hypothalamus
and is not well developed in humans.
exerts control over the pituitary gland through
two mechanisms:
– The anterior lobe is controlled by the secretion Describe the blood supply to the
of hypothalamic hormones into the long pituitary gland
portal vein. The blood supply to the pituitary gland is complex.
– The posterior lobe is controlled by direct neural
The anterior lobe receives blood from:
connections from the hypothalamus.
Behaviour. The hypothalamus contains – The superior hypophyseal artery, a branch of
‘punishment’ and ‘reward’ centres, which the ICA.
moderate behaviour. – The long portal veins, which supply the
Regulation of sexual function. The hypothalamus anterior lobe with the majority of its
controls the pulsatile release of gonadotropins, blood. A portal vein connects two capillary
and the surge of gonadotropins that leads to networks. The long portal veins connect the
ovulation. capillary network of the lower hypothalamus
and pituitary stalk to the capillary network
of the anterior lobe. Thus, hormones released
Describe the anatomy of the by the neurosecretory cells of the
pituitary gland hypothalamus are delivered directly to the
The pituitary gland is a pea-sized gland located in the anterior lobe.
sella turcica, a depression in the sphenoid bone at – The short portal veins, which transport some
the base of the skull. The pituitary is situated directly capillary blood from the posterior lobe to the
below the hypothalamus, to which it is connected capillary networks of the anterior lobe.
388
Chapter 75: Hypothalamus and pituitary
– – Figure 75.1 Feedback loops and the

Hypothalamus hypothalamic–pituitary axis.
Hypothalamic hormone
–
Anterior lobe
Short-loop feedback
Anterior lobe hormone
Peripheral endocrine gland

Long-loop feedback
Peripheral gland hormone
Target tissue
The posterior lobe receives blood from the Short-loop feedback – hormones secreted by the
inferior hypophyseal artery, a branch of the ICA. anterior lobe inhibit the release of their respective
hypothalamic hormones.
Venous blood from both anterior and posterior lobes
Long-loop feedback – the peripheral
drains into the cavernous sinuses. endocrine glands secrete hormones in response
to anterior lobe hormones (for example,
Which hormones does the cortisol is secreted by the adrenal cortex in
hypothalamus secrete? response to ACTH). The resulting peripheral
hormones then inhibit further secretion
The hypothalamus secretes six hormones into the
of both pituitary and hypothalamic
long portal vein, which exert control over the anterior
hormones.
lobe of the pituitary gland:
TRH, which stimulates the release of TSH.
Gonadotropin-releasing hormone (GnRH), which Which hormones are secreted by the
causes the release of FSH and LH. anterior lobe?
Corticotropin-releasing hormone (CRH), which The anterior lobe secretes six hormones, classified as:
triggers the secretion of ACTH.
Directly acting hormones – PRL and GH.
Growth-hormone-releasing hormone (GHRH),
These hormones exert their effects through
which stimulates the release of GH.
PRL and GH receptors at their target tissues
Somatostatin, which inhibits GH release and also (note: the effects of GH are also mediated
moderately inhibits TSH release.
by insulin-like growth factor 1, IGF-1 –
Dopamine, which inhibits the release of PRL. see p. 390).
Stimulating hormones – TSH, FSH, LH and
What is meant by the term ACTH. These hormones act at their respective
‘hypothalamic–pituitary axis’? endocrine glands, stimulating them to release
thyroid hormones, oestrogen, testosterone and
The hypothalamic–pituitary axis refers to the set of
cortisol respectively. Their endocrine axes are
complex endocrine interactions between the hypo-
named
thalamus, the anterior lobe of the pituitary gland
and the target organ. Hormone secretion by the hypo- – the hypothalamic–pituitary–thyroid axis;
thalamus and anterior lobe is controlled by two – the hypothalamic–pituitary–gonadal axis;
negative-feedback loops (Figure 75.1): – the hypothalamic–pituitary–adrenal axis.
389
Taking each anterior lobe hormone in turn: hypothalamic secretion of somatostatin.

TSH is a glycoprotein hormone that acts on the In addition, GH secretion is part of a negative-
thyroid gland, promoting the synthesis and release feedback loop, in which IGF-1 inhibits pituitary
of the biologically active thyroid hormone T3 and secretion of GH. Overall, plasma GH
its precursor T4. TSH release is promoted by concentration is usually very low, but is increased
hypothalamic TRH release, and inhibited by at times of physiological stress, hypoglycaemia
negative feedback from circulating T3. and exercise.
LH is a glycoprotein hormone. In females, a rapid PRL is a protein hormone that has an important
increase in LH stimulates ovulation; following role in lactation, where it promotes breast
ovulation, LH promotes the development of the development during pregnancy and induces milk
corpus luteum. In males, LH stimulates the production following delivery. Regulation of PRL
synthesis and secretion of testosterone by release is different from that of the other anterior
Leydig cells. lobe hormones: there is no hypothalamic
FSH is also a glycoprotein hormone. In females, stimulating hormone. Instead, the hypothalamus
FSH promotes oestrogen synthesis and the controls PRL secretion through tonic dopamine
development of ovarian follicles. In males, FSH release, which in turn inhibits pituitary PRL
aids sperm maturation. FSH and LH are release. In the context of breastfeeding,
collectively known as gonadotropins. FSH and LH PRL secretion is stimulated by suckling. PRL
secretion is promoted by the pulsatile release of concentration also rises following sexual
hypothalamic GnRH, and inhibited by negative intercourse, and as part of the stress response; PRL
feedback from circulating testosterone or concentration is raised following an epileptic
oestrogen. seizure.
ACTH is a small peptide hormone that exerts its In addition, the pars intermedia secretes a seventh
effects on the adrenal gland. In response to ACTH, hormone: α-MSH. Increased α-MSH secretion by
cortisol is released from the zona fasiculata. ACTH the pars intermedia is responsible for the skin pig-
release is promoted by CRH release from the mentation of pregnancy.
hypothalamus, and inhibited by feedback from
circulating cortisol. Of interest, ACTH is degraded
over time to produce α-melanocyte-stimulating Which hormones are released by the
hormone (α-MSH), which accounts for the
pigmentation of skin that occurs in Addison’s
posterior lobe?
disease when ACTH levels are high. The posterior lobe of the pituitary gland releases two
hormones: ADH and oxytocin. It is important to note
GH is a protein hormone that has anabolic effects
that these hormones are not synthesized in the poster-
on tissues throughout the body. GH has two types
ior lobe. Instead, the two hormones are synthesized in
of effect:
the hypothalamus, packaged into tiny vesicles and
– Direct effects. GH stimulates lipolysis through transported to the posterior lobe through nerve axons,
its action on adipose cell GH receptors, thus and stored in granules within the nerve terminals.
increasing the concentration of circulating Following an action potential from the hypothalamus,
fatty acids. the storage granules are released into the systemic
– Indirect effects. The majority of GH effects are circulation.
mediated through IGF-1, a hormone secreted The two posterior lobe hormones are:
by the liver in response to circulating GH.
ADH, a small peptide hormone with two main
IGF-1 promotes cell growth and development. physiological effects.
GH is released from the pituitary gland in a – Antidiuretic effects: ADH acts in the kidney
pulsatile fashion, particularly at night. Regulation where it causes the insertion of
of pituitary GH secretion is complex: GH water channels (aquaporins) and urea
secretion is promoted by the release of transporters (UT-A1) into the cell membrane
hypothalamic GHRH, but inhibited by of collecting duct cells, thus increasing
390
Chapter 75: Hypothalamus and pituitary
water reabsorption (see Chapter 65). ADH is

primarily secreted in response to increased to become apparent at a smaller size owing to
the clinical effects of hormone hypersecretion.
plasma osmolarity. Again, there is a negative-
For example, PRL hypersecretion causes
feedback loop, in that ADH secretion increases
galactorrhoea.
water reabsorption by the kidney. This Hormone hyposecretion. Larger pituitary
decreases plasma osmolarity, which in turn tumours tend to be non-secreting. These large
decreases ADH secretion. tumours encroach on the surrounding normal
– Vasoconstriction, hence the alternative pituitary cells with the potential to cause hypo-
name for ADH: vasopressin. At normal thyroidism, adrenocortical insufficiency or
concentrations, ADH seems to contribute infertility.
little to the resting tone of arterioles. In high Mass effect. Larger pituitary tumours compress
concentrations, ADH acts as a powerful important structures surrounding the pituitary
gland: the optic chiasm (which classically results
vasoconstrictor. In hypovolaemic shock, the
in a bitemporal hemianopia), cranial nerves
dramatic increase in ADH secretion is an
(which result in cranial nerve palsy) and the third
important compensatory mechanism for ventricle (which may cause an obstructive
restoring systemic blood pressure. hydrocephalus).
Incidental finding. Many pituitary adenomas
ADH is also secreted in times of physiological
are now identified when the brain undergoes
stress; ADH secretion is inhibited by alcohol, CT or magnetic resonance imaging for another
leading to a diuresis. reason.
Oxytocin, a small peptide hormone that is
structurally very similar to ADH. The best-known Patients with pituitary adenomas may present
effects of oxytocin are: the anaesthetist with a number of problems:
Nature of surgery. Pituitary debulking surgery is
– Contraction of uterine smooth muscle during commonly carried out via the trans-sphenoidal
labour. Oxytocin is released by the posterior route, which has implications for the anaesthetist,
lobe in response to stretching of the cervix by such as shared airway and the requirements of
the fetal head. minimal haemodynamic instability and a smooth
– The let-down reflex in lactation. Oxytocin is extubation.
secreted in response to suckling, where it Comorbidities. Cushing’s disease results from an
stimulates contraction of myoepithelial cells in ACTH-secreting adenoma. It is associated with
hypertension and diabetes mellitus. Acromegaly
the mammary glands, which squeeze newly
(a GH-secreting adenoma) is also associated with
produced milk into the duct system.
hypertension and diabetes, as well as cardiomy-
– Psychological. Oxytocin is involved in pair opathy and sleep apnoea.
bonding, particularly between mother and Implications for the airway. A combination of
child following birth. Studies suggest it is also macrognathia, macroglossia and upper airway
important for generating trust between adults, soft tissue expansion can potentially make acro-
and it has therefore earned the nickname megalic patients difficult to intubate.
‘cuddle hormone’.
Further reading
Clinical relevance: pituitary adenoma R. Menon, P. G. Murphy, A. M. Lindley. Anaesthesia and
Tumours of the anterior lobe of the pituitary gland pituitary disease. Contin Educ Anaesth Crit Care Pain
are usually benign. However, they still have signifi- 2011; 11(4): 133–7.
cant clinical consequences, presenting in four ways: M. Lim, D. Williams, N. Maartens. Anaesthesia for
Hormone hypersecretion. Functional pituitary pituitary surgery. J Clin Neurosci 2006; 13(4):
tumours (i.e. those which secrete hormones) tend 413–8.
391
Section 9 Endocrine physiology
Chapter
Thyroid, parathyroid and adrenal
76
The thyroid gland Metabolism. T3 affects the activity of a wide
range of metabolic processes; for example,
Which hormones are synthesized by lipolysis and gluconeogenesis. Hyperthyroidism
results in an increase in BMR, and an increased
the thyroid gland? availability of metabolic substrates, such as
The thyroid gland is located in the anterior neck free fatty acids and glucose. In hypothyroidism,
and consists of two lobes connected by an isthmus. the opposite occurs.
It secretes two hormones:
Growth and development. Hypothyroidism in
T3, the strongly biologically active thyroid childhood causes growth retardation. T3 is
hormone. T3 comprises only 10% of the hormones especially important in the development of the
released by the thyroid gland. In the circulation, CNS, where it stimulates neuronal myelination
T3 is very highly protein-bound (99.7%), mainly and nerve axon growth.
to albumin, and has a short half-life (24 h). Only Respiratory system. In hyperthyroidism, O2
the unbound fraction of T3 is able to diffuse into consumption and CO2 production are increased
the tissues to exert its effects. due to the increase in BMR. In turn, V_ E increases.
T4, a weakly biologically active hormone, is Cardiovascular system. In hyperthyroidism, T3
the main hormone synthesized by the thyroid increases the number of β-adrenergic receptors in
gland (90%). T4 is also very highly protein the heart. The result is an increase in HR and
bound, but mainly to a specific carrier protein: myocardial contractility, leading to an increase
thyroxine-binding globulin. At 7 days, the half-life in CO.
of T4 is much longer than that of T3. Around
CNS. T3 has an important effect on mood: in
half of the weakly active T4 is converted to hypothyroidism, depression and psychosis may
the active form, T3, in the peripheral tissues. occur, whilst hyperthyroidism is associated with
The other half is converted to an inactive anxiety.
hormone called reverse T3 (rT3). Bound T3 and
Musculoskeletal system. In hyperthyroidism, T3
T4 provide a large reservoir of thyroid hormone,
induces protein catabolism which predominantly
which delays the onset of symptoms in
affects proximal muscles, resulting in proximal
hypothyroidism.
myopathy.
What are the physiological effects

of triiodothyronine? How are triiodothyronine and thyroxine
T3 is able to diffuse across cell membranes to reach
synthesized?
the cell nucleus, where it regulates gene transcription. The thyroid gland is made up of multiple follicles:
T3 therefore has physiological effects on most tissue spheres of follicular cells surrounding a core of thyro-
types in the body, with the exception of spleen and the globulin, a large protein containing many tyrosine resi-
thyroid gland itself. The main physiological effects of dues. T3 and T4 are synthesized as follows (Figure 76.1).
T3 are perhaps best illustrated when T3 concentration Iodide (I ) uptake. I is actively transported
is either abnormally high or low, as occurs in hyper- from the circulation to the follicular cells through
thyroidism and hypothyroidism respectively: a Na+/I co-transporter. As a result of this the
392
Chapter 76: Thyroid, parathyroid and adrenal
Na+/I− -cotransporter
I− oxidation by thyroid peroxidase:
promoted by TSH
Na+ Na+
I− I− I− I2
H2O2
Thyroglobulin Thyroglobulin
T3 + T4 T3 + T4
T3 T3 DIT MIT
Thyroglobulin Thyroglobulin Thyroglobulin
T4 T4 DIT DIT
Oxidative coupling:
Capillary Thyroid follicular cell Follicular lumen promoted by TSH
Endocytosis:
promoted by TSH
Figure 76.1 Mechanism of thyroid hormone synthesis.
secondary active transport, 25% of the body’s I thyroglobulin protein.1 It is estimated that the thyroid
is stored within the thyroid. The uptake of I gland contains a sufficient store of T3 and T4 to meet
is stimulated by TSH. I diffuses through the the body’s requirements for 1–3 months. In response
follicular cell, and into the follicular lumen. to TSH, droplets of thyroglobulin are endocytosed
I oxidation. As I is relatively inert, it must be by the follicular cells. Within the follicular cell, T3
oxidized to the more reactive iodine (I2) by and T4 are separated from thyroglobulin and released
thyroid peroxidase using H2O2, a reaction that is into the circulation.
promoted by TSH.
I2 reaction with tyrosine. Once synthesized, I2 How is the plasma concentration of thyroid
reacts with the tyrosine residues of the
surrounding thyroglobulin protein. Tyrosine may hormones regulated?
be iodinated at one or two positions, resulting in TSH has multiple roles in both the synthesis and
mono-iodotyrosine (MIT) or di-iodotyrosine release of thyroid hormones. TSH is released by the
(DIT) respectively. anterior lobe of the pituitary gland in response to
Oxidative coupling. Two of the iodinated tyrosine hypothalamic secretion of TRH (see Chapter 75).
molecules are then coupled together. If two DIT In turn, TRH release is controlled through a
molecules join, the resulting compound is T4; if negative-feedback loop: T3, the biologically active thy-
MIT is coupled to DIT, the result is T3. This roid hormone, inhibits the release of TRH at the
oxidative coupling of tyrosine residues is hypothalamus. T3 is highly protein bound; only the
promoted by TSH. unbound fraction is able to inhibit the hypothalamus.
The end result of this process is small T3 and 1

This is why thyroglobulin is often called a colloid; that is,
T4 molecules dispersed throughout the large a substance dispersed within another substance.
393
Disturbances in the hypothalamic–pituitary– Radioiodine. As discussed above, I is actively

thyroid axis usually result from thyroid gland concentrated in the thyroid gland. Likewise,
dysfunction: radioactive iodine (131I) is also actively taken up
Hypothyroidism most commonly results from by the thyroid gland, where the β-radiation
Hashimoto’s thyroiditis, an autoimmune disease emitted causes damage and necrosis of thyroid
of the thyroid gland in which antibodies are tissue.
directed against thyroid peroxidase or Surgery. Total thyroidectomy is a permanent
thyroglobulin. The result is a reduction in T3 and solution to hyperthyroidism, but carries
T4 secretion. In response, the hypothalamus and additional risks: recurrent laryngeal nerve
anterior lobe of the pituitary gland increase their injury, parathyroid gland damage and
secretion of TRH and TSH respectively; a high postoperative haematoma, which may cause
measured TSH normally implies hypothyroidism. airway obstruction.
Hyperthyroidism is most commonly due to
All the above options (usually) render the patient
Graves’ disease, an autoimmune condition that
hypothyroid: T4 replacement is therefore required.
results in increased synthesis and secretion of T3
None of the above options have any effect on Graves’
and T4. The hypothalamus and anterior lobe of
eye disease. As it is mediated by autoantibodies,
the pituitary gland respond by decreasing their
severe Graves’ eye disease may be treated with corti-
secretion of TRH and TSH. A low measured TSH
costeroids or by surgical debulking.
normally implies hyperthyroidism.
Clinical relevance: anaesthesia for thyroid surgery
What is Graves’ disease? There are many indications for thyroid surgery:
thyroid malignancy, hyperthyroidism and goitre with
Graves’ disease is an autoimmune disease: autoanti- associated complications; for example, tracheal
bodies stimulate TSH receptors in the thyroid gland, compression. Anaesthesia for thyroid surgery may be
causing excessive synthesis and release of T3 and T4. particularly challenging owing to the proximity of the
The clinical effects of Graves’ disease can be divided thyroid gland to the trachea.
into: Prior to thyroid surgery, the patient should be
Those due to hyperthyroidism. Symptoms rendered euthyroid by one of the medical methods
include palpitations, heat intolerance, weight loss above. In addition to the usual clinical assessments of
the airway, a CT scan of the neck may be used to
despite increased appetite, fine tremor, diarrhoea
assess size and position of any goitre. It is also
and excessive sweating. Clinical signs include sinus important to identify compression or invasion of
tachycardia, AF, lid lag and a smooth diffusely the structures surrounding the thyroid gland: the
enlarged thyroid gland (a ‘goitre’). trachea (resulting in stridor), SVC (obstruction), sym-
Those caused by the autoantibodies. Graves’ eye pathetic chain (Horner’s syndrome) and recurrent
disease is caused by the same TSH receptor laryngeal nerve (hoarse voice).
autoantibodies that also target fibroblasts in the Induction of anaesthesia may require a gaseous
extraocular muscles. The resulting inflammation or awake fibre-optic technique if the trachea is com-
causes exophthalmos (upper lid retraction), pressed or the anatomy significantly distorted. Occa-
proptosis (bulging eyes) and conjunctivitis. sionally, the only airway option is a tracheostomy
performed under local anaesthesia. Intraoperative
electrophysiological testing of the recurrent laryn-
What are the management options in geal nerve may preclude the use of muscle relaxants
following induction – a remifentanil infusion is there-
Graves’ disease? fore commonly used.
There are three treatment options in hyperthyroidism: A number of serious postoperative complications
may occur:
Anti-thyroid drugs. Carbimazole and
Haemorrhage, which can cause tracheal com-
propylthiouracil mainly act by inhibiting the pression and rapid airway obstruction. Any sus-
thyroid peroxidase-catalysed oxidation of I to I2. picion of developing airway obstruction warrants
Without I2, the iodination of tyrosine an urgent surgical review and removal of the
cannot occur.
394
filled with neurotransmitter into the synaptic

surgical clips – a clip remover should be kept at
the patient’s bedside. cleft (see Chapter 50).
2+
Recurrent laryngeal nerve palsy, which may Excitation–contraction coupling – Ca influx
be due to surgical retraction or transection, and into skeletal, cardiac or smooth muscle is essential
may be unilateral or bilateral. Bilateral recurrent for the binding of myosin to actin (see
laryngeal nerve palsy results in complete Chapters 51, 53 and 54).
adduction of the vocal cords, and therefore 2+
Cell signalling – Ca is an important second
complete airway obstruction. Immediate messenger. For example, G proteins that act via
re-intubation is required, and a tracheostomy inositol triphosphate use Ca2+ as the intracellular
may be necessary.
messenger.
Severe hypocalcaemia – the parathyroid glands
may be inadvertently damaged or excised during
thyroid surgery, resulting in hypocalcaemia. The
signs and symptoms of hypocalcaemia are dis-
What proportion of body calcium is located
cussed below. Of note: severe hypocalcaemia in the plasma?
may result in laryngospasm. The proportion of body Ca2+ located in the plasma is
Tracheomalacia, characterized by flaccid trach-
actually very low:
eal cartilage which collapses on inspiration, 2+
resulting in airway obstruction. Patients who The mass of Ca in an adult is approximately
have long-standing or very large goitres are at 1 kg.
2+
much greater risk of tracheomalacia. Prior to Almost all Ca is located in bone (99%). This
2+
extubation, it is useful to deflate the ETT cuff to Ca cannot be rapidly mobilized. The remaining
check for air leak. 1% is located in teeth and soft tissues.
Only 0.1% of body Ca2+ is located in the ECF, and
only a third of this is located in the plasma.
Regulation of calcium homeostasis
The normal range of plasma Ca2+ is 2.2–2.6 mmol/L.
What are the physiological functions Only around 45% of plasma Ca2+ is in the biologically
of calcium? active ionized form. The remaining 55% is either
Ca2+ has numerous biological roles, the most import- protein bound or associated with various anions, such
ant of which are: as HCO3 , citrate and phosphate. It is important to
Structural – calcium phosphate gives bone its note that whilst the total amount of plasma Ca2+ falls
rigidity. when albumin is low, the ionized portion of Ca2+
2+
Haemostasis – Ca is an essential cofactor in the remains the same. Plasma Ca2+ can be mathematically
coagulation cascade. Blood samples are prevented corrected for hypoalbuminaemia,2 or alternatively
from clotting through the addition of EDTA or ionized Ca2+ can be measured by arterial blood gas
citrate, which irreversibly binds Ca2+ (see analysis. The normal range for ionized Ca2+ is
Chapter 68). 1.1–1.4 mmol/L.
2+
RMP – extracellular Ca concentration affects the
+
cell membrane Na permeability, which in turn How is plasma calcium concentration
affects the RMP of excitable cells. Hypocalcaemia
acts to depolarize the cell membrane towards the regulated?
threshold potential. Thus, nerves may undergo Plasma ionized Ca2+ concentration is tightly regulated
spontaneous depolarization, resulting in tetany between 1.1 and 1.4 mmol/L. Logically, plasma Ca2+
(see Chapter 49). Clinical signs of hypocalcaemia concentration may be altered by:
include Trosseau’s sign (carpal spasm following
inflation of a blood pressure cuff) and Chvostek’s 2
Corrected Ca2+ ¼ measured Ca2+ + 0.02 × (40 serum
sign (inducing facial spasm when tapping over the
albumin), where Ca2+ is measured in millimoles per litre
zygoma). and albumin in grams per litre. Therefore, each 1 g/L
2+
Neurotransmitter release – Ca influx into the decrease in serum albumin decreases plasma Ca2+ by
terminal bouton triggers the exocytosis of vesicles 0.02 mmol/L.
395
Figure 76.2 Vitamin D metabolism.

7-dehydrocholesterol
SKIN UVB radiation
Cholecalciferol Diet
LIVER 25-hydroxylase
Calcidol
Rate-determining step: upregulated by PTH
KIDNEY 1-a-hydroxylase
Calcitriol
Bone effects Intestinal effects

Renal effects
an increase or decrease in intestinal absorption Vitamin D, a steroid hormone. Vitamin D must

of dietary Ca2+; go through a series of modifications before it can
an increase or decrease in renal excretion of exert its effects (Figure 76.2).
Ca2+ salts; – In the skin: cholecalciferol (vitamin D3) is
2+
movement of Ca between body compartments. synthesized through the effects of sunlight on
7-dehydrocholesterol in the skin.
Three hormones are involved in Ca2+ homeo-
Cholecalciferol also originates in the diet;
stasis. Parathyroid hormone (PTH) and vitamin
vitamin D is not a vitamin in the strictest
D act to increase plasma Ca2+ concentration, whilst
sense: individuals who have adequate exposure
calcitonin acts to decrease plasma Ca2+ concentration:
to sunlight do not require dietary
PTH is a protein hormone secreted by the supplementation.
parathyroid glands. There are usually four – In the liver: vitamin D3 is 25-hydroxylated by
parathyroid glands, located on the posterior the enzyme 25-hydroxylase, resulting in
surface of the thyroid gland. Secretion of PTH is calcidiol (25-hydroxy vitamin D3).
triggered by a fall in plasma ionized Ca2+ – In the kidney: calcidiol is 1-α-hydroxylated to
concentration. PTH acts at: give calcitriol (1,25-dihydroxy vitamin D3),
– The kidney. Here, it increases Ca2+ the biologically active form of vitamin D. The
reabsorption and decreases phosphate enzyme that catalyses this process is 1-α-
reabsorption. hydroxylase, which is upregulated by PTH.
– Bone. Here, it increases the activity of
Vitamin D increases plasma Ca2+ concentration
osteoclast cells (the cells that resorb bone),
through its actions on:
releasing stored Ca2+.
– The intestine. This is an indirect effect: PTH – The intestine, where the absorption of dietary
upregulates the renal enzyme 1-α-hydroxylase, Ca2+ and phosphate is increased.
which is responsible for activating vitamin – The kidney, where Ca2+ and phosphate
D (see below). Vitamin D increases the reabsorption is increased.
intestinal absorption of dietary Ca2+ and In addition, vitamin D acts on the bone, where it
phosphate. increases bone calcification.
396
It is important to note that under normal decrease in intestinal Ca2+ absorption and
circumstances, the rate-determining step in renal Ca2+ reabsorption.
the synthesis of calcitriol is 1-α-hydroxylation.
PTH controls the activity of the enzyme
involved in this step; PTH, therefore, Clinical relevance: kidney and liver dysfunction
directly controls the plasma concentration of As discussed above, 25-hydroxylation of vitamin D
calcitriol. occurs in the liver, and 1-α-hydroxylation occurs in
Calcitonin is a peptide hormone secreted by the the kidney.
parafollicular C cells of the thyroid gland. In chronic kidney disease (CKD), 1-α-
Calcitonin has a minor role in Ca2+ hydroxylation of calcidiol is impaired – activated vita-
min D cannot be synthesized. Without vitamin D,
homeostasis, only being secreted when plasma
renal excretion of Ca2+ exceeds intestinal absorption,
Ca2+ rises above 2.4 mmol/L. Calcitonin
resulting in hypocalcaemia. PTH secretion increases
decreases plasma Ca2+ concentration through its as the parathyroid glands attempt to normalize
actions on: plasma ionized Ca2+ concentration. This is referred
– The intestine, where it decreases the to as secondary hyperparathyroidism. PTH causes
absorption of dietary Ca2+ and phosphate. extensive demineralization of the bones as Ca2+ is
– The kidney, where it decreases the redistributed to the ECF, resulting in renal osteody-
strophy. Patients with CKD are treated with calcitriol
reabsorption of Ca2+ and phosphate, and
(i.e. activated vitamin D), thereby bypassing the renal
decreases the activity of the enzyme 1-α- 1-α-hydroxylation mechanism.
hydroxylase, thereby decreasing the effects of The aetiology of bone disease in cirrhosis
vitamin D. patients is more complex than in CKD; for example,
– Bone, where osteoclast activity is alcoholism is associated with a dietary Ca2+ defi-
decreased, thereby decreasing bone resorption. ciency, and haemochromatosis is complicated by
gonadal failure, which is associated with
Other hormones such as gonadal steroids osteoporosis. Severe liver dysfunction may also cause
(increase bone density), glucocorticoids (decrease impaired 25-hydoxylation of cholecalciferol: acti-
bone density) and GH (increase bone density) also vated vitamin D levels are low, which contributes to
affect Ca2+ homeostasis. bone disease.
In summary:
2+
Low plasma ionized Ca concentration:
– Is sensed by the parathyroid glands, which
The adrenal glands
increase PTH secretion. Describe the anatomy of the adrenal glands
– In turn, the rate of vitamin D activation The adrenal glands are triangular organs closely
increases. related to the superior poles of the kidneys at the level
– The combined effects of vitamin D and of the T12 vertebral body. Each adrenal gland is
PTH increase intestinal absorption and surrounded by a protective fat pad and renal fascia.
renal reabsorption of Ca2+. The effect on The adrenal gland consists of two distinct parts that
bone is negligible, as the increase in differ in their embryological origins:
bone resorption by PTH is cancelled
The (outer) adrenal cortex makes up 70% of the
out by the bone calcification effect of adrenal glands’ weight. The adrenal cortex is
vitamin D. derived from mesoderm, and is composed of
2+
High plasma ionized Ca concentration: three layers:3
– Is sensed by the parathyroid glands, which – Zona glomerulosa, the outermost layer, is the
decrease PTH secretion, which in turn main site of aldosterone production.
decreases the rate of activation of vitamin D.
– In addition, the parafollicular C cells release 3
A mnemonic for remembering the order of these layers is:
calcitonin.
GFR – glomerulosa, fasiculata, reticularis. A mnemonic
– The combined effect of reduced PTH, reduced for remembering the hormones secreted by each layer is:
vitamin D and increased calcitonin results in a ACTH – aldosterone, cortisol, ‘testosterone’ hormones.
397
– Zona fasiculata, the middle layer, is the main Plasma acidosis directly stimulates aldosterone
site of glucocorticoid synthesis. release, which in turn promotes renal H+
– Zona reticularis, the inner layer, produces secretion.
androgens. The main androgens produced ACTH, whose main role is stimulating the release
are dehydroepiandrosterone and of cortisol (see p. 399), plays a minor role in
androstenedione, weak androgens that are aldosterone secretion.
converted to testosterone by the peripheral
tissues.
The (inner) adrenal medulla is innervated What are the functions of cortisol?
by T5–T9 pre-ganglionic sympathetic Cortisol is a steroid hormone secreted mainly by the
neurons; the adrenal medulla can be zona fasiculata. It is the main glucocorticoid of the
considered a modified sympathetic ganglion. body; corticosterone, which has a closely related
Sympathetic nervous system activity chemical structure, has a minor role. Cortisol is
stimulates the chromaffin cells to release important in the physiological response to stress and
granules containing adrenaline has actions throughout the body, the most important
(approximately 80%) and noradrenaline of which are:
(approximately 20%). Metabolic. The metabolic effects of cortisol are
essentially the opposite to those of insulin:
Discuss the physiology of aldosterone – Mobilization of amino acids from skeletal
muscle for use as substrates for
Aldosterone is a steroid hormone produced by the
gluconeogenesis.
zona glomerulosa. It accounts for 95% of the miner-
– Stimulation of lipolysis, which releases free
alocorticoid activity in the body, with cortisol con-
fatty acids and glycerol. Glycerol is used
tributing much of the remainder. It therefore
as a substrate for gluconeogenesis.
promotes Na+ and water reabsorption, along with
K+ and acid (H+) excretion. Aldosterone, therefore, – Peripheral glucose utilization is decreased, thus
plays an important role in the regulation of blood increasing plasma glucose concentration.
volume, and consequently blood pressure. – Stimulation of gluconeogenesis, which further
There are four main triggers to aldosterone increases plasma glucose concentration.
secretion: Cardiovascular. Cortisol is essential for normal
cardiovascular function. Cortisol increases the
Angiotensin II is the most important factor
sensitivity of the vasculature to the effects of
in aldosterone release. The RAA axis is a
catecholamines – without cortisol, widespread
complex feedback loop, which helps regulate
vasodilatation occurs. The mineralocorticoid
blood volume:
effects of cortisol result in an increase in plasma
– Renin is released in response to reductions in volume.
RBF (there are some additional triggers of
renin release – see Chapter 63). In chronic excess (for example, in Cushing’s disease),
– Renin converts angiotensinogen to cortisol has additional effects:
angiotensin I. Osteoporosis.
– Angiotensin I is converted to angiotensin II by Anti-inflammatory and immunosuppressive
ACE in the lungs. effects.
– Angiotensin II stimulates aldosterone release, Effects on the CNS; for example, psychosis and
amongst other effects. memory loss.
– Aldosterone increases plasma volume, thereby Peptic ulceration.
restoring RBF.
Hyperkalaemia directly stimulates aldosterone
secretion from the adrenal cortex. How is cortisol secretion regulated?
Similarly, hypokalaemia decreases aldosterone Cortisol secretion is controlled by a negative-feedback
secretion. loop involving the hypothalamus and pituitary gland:
398
Tyrosine
Rate-determining step
Tyrosine hydroxylase
L-DOPA
DOPA decarboxylase
Dopamine
Dopamine β-hydroxylase
COMT
Noradrenaline Normetanephrine MAO
This step can only take place PNMT Vanillylmandelic acid

in the adrenal medulla
COMT
Adrenaline Metanephrine MAO
Figure 76.3 Catecholaminergic synthetic pathway.
CRH is released by the hypothalamus. Normally,

CRH is released in a diurnal pattern, with peak Etomidate, therefore, suppresses cortisol synthesis,
which at a times of physiological stress (for example,
release in the early morning. CRH release is
the perioperative period and severe sepsis) has the
increased under conditions of physiological stress; potential for adrenocortical insufficiency.
for example, pain, infection and following surgery. Despite the theoretical risk of adrenocortical sup-
ACTH is released from the anterior lobe of the pression, a single dose of etomidate for the RSI of a
pituitary gland in response to CRH. critically ill patient has not been shown to increase
Cortisol is released from the zona fasiculata in mortality.
response to ACTH. Ninety per cent of plasma
cortisol is bound to cortisol binding protein and
albumin. Only 10% of plasma cortisol is unbound How are catecholamines synthesized
and therefore biologically active. in the adrenal medulla?
The unbound fraction of cortisol inhibits CRH
Structurally, catecholamines consist of catechol
release from the hypothalamus and ACTH release
(a benzene ring with two hydroxyl groups) with an
from the anterior lobe of the pituitary gland.
amine side-chain. Catecholamines are derived from
the amino acid tyrosine (Figure 76.3):
Clinical relevance: etomidate Tyrosine is acquired from the diet, or through the
Etomidate is an intravenous anaesthetic induction hydroxylation of phenylalanine in the liver.
agent with a reputation for cardiovascular stability. Tyrosine taken up into the cytoplasm of
However, the use of etomidate has diminished since chromaffin cells, where it is converted to l-DOPA.
a study demonstrated an increased mortality when a This is the rate-determining step of catecholamine
continuous infusion of etomidate was used for the synthesis.
sedation of critically ill trauma patients. l-DOPA is converted into dopamine.
The synthesis of steroid hormones is complex,
Dopamine is converted into noradrenaline.
involving many intermediate compounds. The final
step in the biosynthesis of cortisol is hydroxylation of Noradrenaline is converted into adrenaline by the
11-deoxycortisol by the enzyme 11-β-hydroxylase. enzyme phenylethanolamine N-methyl transferase
This enzyme is reversibly inhibited by etomidate. (PNMT). This enzyme is only present in the
chromaffin cells of the adrenal medulla.
399
Therefore, whilst noradrenaline may be concentration. Free fatty acids are liberated from
synthesized elsewhere (for example, sympathetic adipose tissue, and amino acids released from
nerve terminals), adrenaline can only be skeletal muscle.
synthesized within the adrenal medulla. Heart. Adrenaline has positive chronotropic and
Noradrenaline and adrenaline are then packaged positive inotropic effects on the heart, increasing
into granules, which also contain ATP, HR and myocardial contractility respectively,
chromogranin A and opioid peptides such as met- through stimulation of β1 adrenergic receptors.
enkephalin. Vasculature. Adrenaline causes peripheral
vasoconstriction, except in skeletal muscle
capillary beds, where it causes vasodilatation.
How is catecholamine secretion controlled? Lungs. Adrenaline relaxes bronchial smooth
muscle through β2 adrenergic receptors, resulting
Whilst the hormones of the adrenal cortex are con-
in bronchodilatation.
trolled by negative-feedback loops, the catechol-
amines of the adrenal medulla are secreted in Noradrenaline causes peripheral vasoconstriction
response to sympathetic nervous system activity; through the activation of α1 adrenoceptors, with
there is no negative-feedback control of catechol- baroreceptor-mediated reflex bradycardia. Noradren-
amine secretion. aline promotes gluconeogenesis and lipolysis. In add-
Secretion of catecholamines takes place as follows: ition, noradrenaline plays an important role in the
In response to various stimuli (exercise, trauma, normal functioning of the CNS.
pain, hypovolaemia, hypoglycaemia, hypothermia
and anxiety), action potentials are generated in the How are catecholamines metabolized?
pre-ganglionic sympathetic nerves that terminate The plasma half-life of catecholamines is very short:
on the chromaffin cells of the adrenal medulla. both noradrenaline and adrenaline have plasma
Like other pre-ganglionic sympathetic neurons half-lives of around 2 min. Noradrenaline and
(see Chapter 56), ACh is released from the adrenaline are both sequentially metabolized by
terminal bouton. catechol-O-methyltransferase (COMT) and MAO,
ACh activates nicotinic receptors on the two enzymes distributed widely throughout the body.
chromaffin cell membrane, increasing cell Metanephrine is an intermediate in this process, with
membrane Na+ and K+ permeability, which vanillylmandelic acid (VMA) produced after both
results in net depolarization. enzymes have exerted their effects. Phaeochromocy-
Membrane depolarization opens voltage-gated toma, a tumour of chromaffin cells associated with
Ca2+ channels; the influx of Ca2+ into the excessive secretion of catecholamines, may be diag-
chromaffin cells triggers exocytosis of the nosed through raised urinary VMA or metanephrine
catecholamine-containing granules, releasing concentrations.
adrenaline and noradrenaline into the circulation.
It is important to note that catecholamine release
Further reading
D. S. Ross. Radioiodine therapy for hyperthyroidism.
from the adrenal medulla does not take place in N Engl J Med 2011; 364(6): 542–50.
isolation – it is part of a wider sympathetic nervous
S. Malhotra and V. Sodhi. Anaesthesia for thyroid and
response that includes extensive noradrenaline release parathyroid surgery. Contin Educ Anaesth Crit Care Pain
at sympathetic nerve terminals. 2007; 7(2): 55–8.
M. Davies, J. Hardman. Anaesthesia and adrenocortical
What are the physiological effects disease. Contin Educ Anaesth Crit Care Pain 2005; 5(4):
122–6.
of adrenaline and noradrenaline? M. J. Berridge, P. Lipp, M. D. Bootman. The versatility
The most important physiological effects of adrena- and universality of calcium signalling. Nat Rev Mol Cell
line are: Biol 2000; 1(1): 11–21.
Metabolic. Adrenaline stimulates glycogenolysis, I. M. Aguilera, R. S. Vaughan. Calcium and the
which in turn increases plasma glucose anaesthetist. Anaesthesia 2000; 55(8): 779–90.
400
Section 10 Developmental physiology
Chapter
Maternal physiology during pregnancy
77
luteum. β-hCG concentration then falls
How does endocrine function alter and the corpus luteum degenerates.
during pregnancy?
β-hCG is also thought to be involved in
It comes as no surprise that there are major endocrine
suppressing the maternal immune response,
changes during pregnancy. These endocrine changes
protecting the placenta and embryo from
are the driving force for many of the other physio-
immune destruction.
logical and anatomical changes associated with
pregnancy. Human placental lactogen (hPL), a polypeptide
hormone whose structure is similar to that
The main hormones involved are:
of GH. Like β-hCG, hPL is secreted by the
β-Human chorionic gonadotropin (β-hCG), syncytiotrophoblast cells of the placenta.
a glycoprotein hormone with a structure similar Throughout pregnancy, hPL concentration
to that of LH, FSH and TSH. It is secreted by the increases in proportion to fetal and placental
placenta shortly after implantation of the embryo, growth, peaking near term. Its function is to
and can be detected in the maternal circulation ensure adequate provision of nutrients for
from the second week of pregnancy. β-hCG levels the growing fetus through manipulation of
rise rapidly, doubling every 2 days until a peak maternal metabolism:
is reached at 10 weeks’ gestation. Its main role is
– Increased maternal lipolysis increases the
to prolong the life of the corpus luteum:
availability of free fatty acids.
– In the second half of the menstrual cycle, the – Decreased maternal peripheral insulin
corpus luteum secretes progesterone and a sensitivity results in decreased peripheral
small amount of oestrogen. utilization of glucose and thus increased
– After 14 days, in the absence of an implanted maternal plasma glucose concentration. It is
embryo, progesterone secretion stops and the important that the fetus has access to ample
corpus luteum degenerates into the corpus glucose, as this is its primary source of energy.
albicans. The decline in progesterone triggers hPL is implicated in the development of
sloughing of the uterine lining (the gestational diabetes.
endometrium). – Stimulation of breast growth and development.
– If an embryo implants in the endometrium As the name suggests, hPL mimics the action
(or fallopian tube, in the case of an ectopic of PRL; whilst it has a much weaker effect
pregnancy), the syncytiotrophoblast cells than PRL, the high concentration of hPL is
of the newly formed placenta produce thought to be partly responsible for breast
ever-increasing amounts of β-hCG, which development during pregnancy.
stimulates the corpus luteum to continue Progesterone, a steroid hormone often
secreting progesterone. This prevents referred to as the ‘pregnancy hormone’,
sloughing of the endometrium, which would reflecting its many important roles.
cause miscarriage. Progesterone is secreted by the corpus luteum
– After 10 weeks’ gestation, the placenta in early pregnancy, and by the placenta in
slowly takes over oestrogen and the second and third trimesters. The main
progesterone synthesis from the corpus functions of progesterone are:
401
Section 10: Developmental physiology
– Preparing the endometrium for implantation Prolactin. Oestrogen stimulates a dramatic

and promoting growth of the endometrium increase in the pituitary secretion of prolactin,
following implantation. whose role is the preparation of the breasts for
– Uterine muscle relaxation, suppressing lactation. The pituitary gland doubles in size to
myometrial contractions and preventing accommodate the number of extra lactotrophs
miscarriage. required. Because of the increased metabolic
– Formation of a cervical mucus plug, thus demands of the enlarged pituitary gland, it
protecting the developing fetus from becomes vulnerable to ischaemia. Pituitary
ascending infection. infarction can occur if the patient suffers
– Development of milk glands in preparation prolonged hypotension, as may result from post-
for lactation. partum haemorrhage – this is known as
Sheehan’s syndrome.
In addition, progesterone is responsible for many 2+
PTH. Ca is transferred across the placenta to
of the other physiological changes associated with meet the requirements of the growing fetus. As
pregnancy, discussed in more detail below. maternal absorption of dietary Ca2+ cannot meet
Oestrogen. Three oestrogens are synthesized by this placental loss, one might expect maternal
the placenta: oestradiol, oestrone and oestriol. ionized Ca2+ concentration to fall. However, the
Each oestrogen comes from a different precursor, maternal parathyroid glands sense the fall in
and the amount of each oestrogen produced is plasma Ca2+ and respond by increasing secretion
proportional to the amount of each precursor of PTH. PTH increases plasma Ca2+ concentration
delivered to the placenta. The main oestrogen by increasing bone resorption, renal tubular Ca2+
produced in pregnancy is oestriol, whose main reabsorption and activation of vitamin D. Of
role is to increase uteroplacental blood flow clinical significance, pregnant patients at high
(in contrast, oestradiol dominates the menstrual thromboembolic risk, such as those with
cycle). Importantly, oestriol is produced from a prosthetic heart valves, may be treated with low
fetal adrenal precursor called MW heparin (LMWH). LMWH has the
dehydroepiandrosterone sulphate. Consequently, undesirable effect of worsening the PTH-related
uteroplacental blood flow is under the control of reduction in bone mineral density, potentially
the growing fetus. Other roles of oestrogens leading to osteopenia.
include:
– Stimulation of uterine growth. Which other physiological changes of
– Sensitization of the myometrium to oxytocin
in preparation for labour.
pregnancy are of interest to
anaesthetists?
In addition, oestriol is responsible for the This is best answered using a system-by-system
increased risk of thromboembolic disease approach:
associated with pregnancy.
Respiratory system. Changes to the respiratory
Other pregnancy-related endocrine changes system begin as early as 4 weeks’ gestation, but the
include: most significant changes occur from 20 weeks’
Thyroid hormones. In pregnancy, oestriol gestation:
stimulates the liver to synthesize additional – Airway. Pregnancy-related capillary
thyroxine-binding globulin. Therefore, one might engorgement causes oedema of the
expect unbound T3 and T4 concentrations to oropharyngeal mucosa and larynx. In pre-
decrease. However, TRH secretion increases as a eclampsia, the change in capillary dynamics
result of the negative-feedback loop, which can significantly worsen airway oedema, with
increases TSH secretion by the pituitary. Increased distortion of airway anatomy.
TSH stimulates the thyroid to secrete additional – Minute ventilation. From early pregnancy,
T3 and T4, bringing the free fractions of thyroid progesterone stimulates the respiratory centre
hormones back to normal. in the medulla:
402
Chapter 77: Maternal physiology during pregnancy
▪ V_ E increases by 50% at term. This is is further increased during labour

primarily due to an increase in VT (40% due to uterine contractions.
increase); RR only increases by around – Respiratory compliance. Lung compliance is
10%. V_ E increases further in labour due unaffected by pregnancy, but thoracic wall
to pain. compliance is reduced by 20%. This is another
▪ There is a small increase in anatomical consequence of the upward displacement of
dead space due to bronchodilatation; that the diaphragm.
is, progesterone-induced smooth muscle
relaxation.
▪ Despite the increase in CO2 production Clinical relevance: general anaesthesia and
due to fetal metabolism, progesterone- pregnancy
induced maternal hyperventilation causes Beyond 12 weeks’ gestation, the risk of gastro-
a mild reduction in PaCO2 (typically oesophageal reflux increases (see p. 405). The higher
risk of aspiration pneumonia on induction of anaes-
4.3 kPa). This mild respiratory alkalosis
thesia necessitates an RSI and antacids. However,
triggers a compensatory renal HCO3
general anaesthesia in obstetric patients has add-
loss (typical plasma HCO3 concentration itional difficulties:
is 20 mmol/L), which usually corrects The incidence of difficult airway in the obstetric
the pH disturbance. population is around 1 in 250, eight times higher
than the general population. Difficult airway may
This is of clinical significance when be due to:
anaesthetizing a pregnant patient: special – Airway oedema, as discussed above.
attention should be paid to V_ E . One should – Increased mucosal vascularity. Repeated
aim for a PaCO2 of ~4.3 kPa, which represents attempts at laryngoscopy may result in
a normal value for pregnancy. laceration and bleeding. In pre-eclampsia,
coagulopathy only worsens the situation.
▪ The fetus cannot correct a pH disturbance – Weight gain. Large breasts and short neck
by respiratory or renal compensation. make laryngoscopy more challenging.
Therefore, maternal respiratory acidosis – Poorly applied cricoid pressure.
can cause fetal acidosis. The combination of increased O2 consumption
▪ Likewise, maternal alkalosis should be and decreased FRC (the main O2 store) means
avoided: the oxyhaemoglobin dissociation that obstetric patients desaturate quickly.
curve is shifted to the left, reducing O2
As always, preparation is the key to success:
transfer to the fetus with the potential for Good head, neck and shoulder position can be
fetal hypoxia. achieved with standard pillows or with a specially
designed elevation pillow.
– Lung volumes. The gravid uterus causes an Adequate pre-oxygenation over at least 3 min is
upwards displacement of the diaphragm and essential; the time pressure of an emergency
flaring of the lower ribs: the anterior–posterior caesarean section makes it all too easy to cut
diameter of the ribs increases by 2–3 cm. corners here!
Diaphragmatic contraction is not restricted, Most importantly, an experienced assistant with a
but lung volumes are affected: range of ready-prepared airway equipment.
▪ FRC is reduced by 20% when standing.

FRC is reduced by a further 30% in the
supine position. The reduction in FRC is Cardiovascular system. Pregnancy causes major
mainly due to a reduction in RV. changes to cardiovascular physiology, increasing
▪ VC remains unchanged. the demands on the heart considerably.
Myocardial workload is further increased in
– O2 consumption. The O2 requirements of the
labour, with the early post-partum period being
growing fetus result in a 20% increase in O2
particularly high risk. Cardiac disease is now the
consumption at term. O2 consumption
leading indirect cause of death in pregnant
403
patients (CMACE triennium 2006–8 report: ▪ Myocardial contractility is unchanged by

published 2011). The major cardiovascular pregnancy.
changes in pregnancy are:
During labour, CO is increased further
– Blood volume. Total blood volume increases (25–50%) in response to catecholamine
gradually throughout pregnancy, by around secretion. In addition, CO increases by an
40% for a singleton pregnancy and even more additional 20–30% during uterine
for a multiple pregnancy: contractions. Epidural analgesia reduces
the secretion of catecholamines in
▪ Red cell mass increases by 20–30%,
response to pain, which can lessen the
due to an increase in EPO secretion.
impact of labour on the heart. Following
Plasma volume increases by 45% due
delivery, the autotransfusion of 500 mL
to oestrogenic stimulation of the RAA
of uterine blood to the venous system
system. The discrepancy between the
increases cardiac preload, resulting in a
increases in red cell mass and plasma
60–80% increase in CO. This is a moment
volume results in the physiological
of great danger to parturients at risk of
anaemia of pregnancy. Hb concentration
cardiac failure.
falls from a typical pre-pregnancy
– Aortocaval compression. From 20 weeks’
concentration of 150 g/L to around
gestation, the enlarging uterus can compress
120 g/L at term; haematocrit falls to
the IVC and the descending aorta when the
around 0.35.
parturient is supine. This has serious
▪ During labour, each uterine contraction
implications:
squeezes 300–500 mL of blood from the
uterus to the systemic circulation. ▪ Reduced maternal venous return to the
▪ Typical blood loss at delivery is 300 mL heart. Reduced cardiac preload causes a fall
for vaginal delivery and 500 mL for in CO, leading to a feeling of nausea,
caesarean section. The mother is pallor, hypotension or cardiovascular
protected from the impact of this collapse when supine. Symptoms and signs
haemorrhage by ‘autotransfusion’, resolve in the lateral position, where IVC
in which around 500 mL of blood is compression is relieved.
returned to the systemic circulation ▪ Reduced placental blood flow. Blood flow
during uterine involution. to the placenta is not autoregulated;
instead, blood flow is directly proportional
– Cardiac output. The increase in CO starts in to perfusion pressure (see Chapter 78).
early pregnancy, from the fourth week of IVC compression by the gravid uterus
gestation. CO increases by up to 50% by the reduces CO, which impairs placental
third trimester. Factors involved are: perfusion. In addition, compression of the
▪ A reduction in afterload. SVR falls descending aorta further reduces
by 20% due to progesterone-induced uteroplacental blood flow. Impaired
vasodilatation. As a result, SBP placental blood flow may result in
falls by 5% and DBP by 10%. inadequate fetal gas exchange, sometimes
▪ Increased HR. In response to decreased with fatal consequences.
blood pressure, there is a reflex increase in
Most non-anaesthetized parturients are able to
HR of 25% over the course of the
compensate, at least partially, for aortocaval
pregnancy.
compression through two mechanisms:
▪ An increase in preload. Increased
circulating blood volume results in an ▪ Sympathetic outflow increases, which in
increase in cardiac preload. As a result, SV turn increases SVR and HR.
increases by 30%. Much of the increase in ▪ Some blood bypasses the compressed IVC,
SV occurs during the first trimester. returning from the lower limbs to the heart
404
through collateral pathways: the azygos, gastric contents under general anaesthesia. RSI
paravertebral and epidural veins. and non-particulate antacids are indicated for
general anaesthesia in pregnant patients beyond
General anaesthesia and neuraxial blockade
the first trimester; the exact gestational week is
abolish the sympathetic response to
a matter of controversy.
aortocaval compression; severe
Haematological physiology. In addition to the
hypotension or even cardiac arrest may
physiological anaemia of pregnancy described
develop rapidly when the patient is supine.
above, there are other important pregnancy-
It is therefore very important that the
induced haematological changes:
parturient is never supine, and that the uterus
is always displaced from the great vessels. – White cell count (WCC) is elevated in
Aortocaval compression is usually relieved by pregnancy, due to an increase in neutrophils
a lateral tilt (on the operating table or with a and monocytes. The normal range of WCC in
wedge), but relief can only be guaranteed in pregnancy is not universally accepted, but is
the full lateral position. Lateral tilt with a often taken as 6000–16 000/mm3 from the
wedge is especially important to remember 12th gestational week. WCC may increase to as
during cardiopulmonary resuscitation of much as 30 000/mm3 during labour.
pregnant patients. – Platelet count falls gradually throughout
GI system. The changes in GI physiology are of pregnancy; at term, the lower limit of a
particular importance to the anaesthetist. There is normal platelet count is 115 × 109/L. The
a significantly increased risk of gastro- decreased platelet count is due to both
oesophageal reflux in pregnancy due to: haemodilution (a relatively increased plasma
– Decreased LOS tone. Progesterone-induced volume) and shorter platelet lifespan.
smooth muscle relaxation decreases the tone of – Hypercoagulable state. Pregnant patients are at
the LOS, leading to sphincter incompetence. significantly increased risk of venous
– Mechanical changes at the gastro-oesophageal thromboembolism, due to:
junction. The gravid uterus displaces the ▪ An increase in fibrinogen and clotting
stomach and diaphragm upwards, reducing factors VII, X and XII.
the acute angle of the oesophagus as it passes ▪ Decreased fibrinolysis.
through the diaphragm.
– Increased intra-gastric pressure. In the third Renal physiology. Pregnancy induces both
trimester, the gravid uterus increases gastric anatomical and physiological changes to the
pressure. This further reduces the lower kidneys and ureters:
oesophageal barrier pressure.
– Dilatation of the ureters and renal
– Delayed gastric emptying. Gastric emptying is
pelvis, as a result of both mechanical
unaffected by pregnancy. However, in labour
obstruction by the gravid uterus
there is a significant delay in gastric emptying,
and progesterone-induced smooth muscle
which may be further worsened by opioids.
dilatation. These changes make urinary
– Gastric pH. The hormone gastrin is secreted by
tract infection and pyelonephritis more
the placenta from the 15th week of gestation.
common in pregnancy.
Compared with non-pregnant patients, gastric
– Increased GFR. RBF increases by 50%,
volume is increased and gastric pH decreased;
reflecting the increase in CO. GFR is increased
aspiration causes a greater degree of lung
by a similar amount; pregnant patients have
injury.
lower serum creatinine and urea
Gastro-oesophageal reflux commonly causes concentrations.
heartburn in pregnancy, but its main anaesthetic – Uric acid levels. In early pregnancy, increased
implication is an increased risk of Mendelson’s GFR results in a lower uric acid concentration.
syndrome (see Chapter 58), a pneumonitis In the third trimester, uric acid concentration
resulting from pulmonary aspiration of acidic steadily increases above the pre-pregnancy
405
level, due to increased tubular reabsorption The higher epidural pressure is due to
of uric acid. Hyperuricaemia in pregnancy is engorgement of the epidural veins
associated with pre-eclampsia, and has been secondary to mechanical compression of
suggested (controversially) to correlate with its the IVC by the gravid uterus. In the first
severity. stage of labour, epidural pressure increases
– Glycosuria. Tubular reabsorption of to 4–10 cmH2O. Bearing down in the
glucose cannot keep pace with the increase second stage of labour can increase
in GFR. The result is glucose passing into epidural pressure to 60 cmH2O.
the urine, making urinary dipstick testing Epidural vein engorgement means
an unreliable test for diabetes mellitus in accidental venous cannulation is
pregnancy. more common when introducing an
– Proteinuria. In a similar way to glucose, epidural catheter.
tubular protein reabsorption mechanisms – CSF pressure is unchanged from its
are insufficient to match the 50% increase pre-pregnancy value. However, CSF
in GFR. Proteinuria is therefore more pressure undergoes a significant
common in pregnancy; the upper limit increase in the second stage of labour,
of the normal range is generally taken as up to 70 cmH2O.
300 mg of protein in a 24 h urine Hepatic physiology. Hepatic enzymes
collection (compared with 150 mg per (γ-GT, ALT and LDH) are slightly
24 h period in the non-pregnant state). elevated, and some clinical signs usually
Pre-eclampsia causes a pathological increase associated with chronic liver disease
in proteinuria. (for example, palmar erythema, spider naevi)
CNS. The endocrine changes of pregnancy may occur normally in pregnancy. ALP
have a significant effect on the CNS. levels are also increased; ALP originates
The MAC of volatile anaesthetics from both the liver and the placenta.
is reduced by 30–40%. This is thought to Hepatic protein production does not
be due to: keep pace with the increase in plasma
– Progesterone. This is known to have sedative volume, leading to decreased plasma
effects and reduce the MAC of volatile protein concentration. Thus:
anaesthetic agents in both male and female – Albumin concentration decreases
animal models. throughout pregnancy, from around 35 g/L
– β-Endorphins. These are secreted by the to 25 g/L.
placenta throughout pregnancy, but – Plasma cholinesterase concentration falls
especially in labour. Their exact role is by 25%, due both to decreased hepatic
unknown, but β-endorphins are thought synthesis and increased plasma volume.
to be analgesic in labour, contribute to This is of particular interest to anaesthetists,
the reduction in MAC, and possibly as suxamethonium is metabolized by
increase neural sensitivity to local plasma cholinesterase; decreased enzyme
anaesthetics, which partially explains activity leads to prolonged suxamethonium
why lower doses of local anaesthetic action.
are required for regional anaesthesia in Musculoskeletal. Ligaments become
pregnancy. increasingly lax as pregnancy progresses,
due to placental secretion of the
Pregnancy also causes changes to the epidural hormone relaxin. During general
and subarachnoid spaces: anaesthesia it is important to pay
– Epidural pressure is increased to around close attention to positioning to
+1 cmH2O, compared with 1 minimize the risk of postoperative
cmH2O in the non-pregnant state. back and joint problems.
406
Further reading E. Reitman, P. Flood. Anaesthetic considerations for non-

obstetric surgery during pregnancy. Br J Anaesth 2011;
A. T. Dennis, C. B. Solnordal. Acute pulmonary oedema in 107(Suppl. 1): i72–8.
pregnant women. Anaesthesia 2012; 67(6): 646–59.
B. H. Heidemann, J. H. McClure. Changes in maternal
H. Wilkinson. Saving mothers’ lives: reviewing maternal physiology during pregnancy. Contin Educ Anaesth Crit
deaths to make motherhood safer: 2006–2008. Br J Obs Care Pain 2003; 3(3): 65–8.
Gyn 2011; 118(Suppl. S1): 1–203.
407
Chapter
Fetal physiology
78
– Projections called chorionic villi form an
What are the functions of the placenta? extensive network of finger-like chorionic
The placenta has a number of functions: projections into the blood-filled cavities, and
Exchange of nutrients between the fetal and then become vascularized.
maternal circulations. – When the fetal heart becomes active at 5
Endocrine. weeks’ gestation, fetal blood supplies the
Immunological. placenta through the two umbilical
arteries. The umbilical arteries give rise
to chorionic arteries, which branch over
How does the anatomy of the placenta the fetal surface of the placenta until the
relate to these functions? capillaries of the chorionic villi are reached.
Exchange of nutrients. The placenta is an unusual The capillaries of the chorionic villi
organ because it is derived from the tissue converge and return blood to the fetus
of two different organisms: endometrial through a single umbilical vein.
cells (known as decidual cells in pregnancy) The fetal and maternal blood are thus
from the mother and trophoblastic cells from separated only by the fetal endothelium
the fetus. The fetus is entirely reliant on exchange and two (syncytiotrophoblastic and
with the maternal circulation for nutrition cytotrophoblastic) chorionic cell layers.
(supply of O2, glucose, amino acids, etc.) and Nevertheless, there is normally no mixing
excretion (elimination of CO2, urea, creatinine, of maternal and fetal blood. The placenta
uric acid, etc.). Key features of placental grows to match the increasing nutritional
development are: demands of the developing fetus. As a result, at
– The fetal cells form a ball of cells, the term, uterine blood flow has increased 10-fold
blastocyst, which implants within the over its pre-gestational value to 750 mL/min, with
endometrium. placental blood flow accounting for approximately
– The placenta develops from trophoblast cells, 85% of this flow.
derived within the outer cell layer of the Endocrine function. The placenta is an important
blastocyst. endocrine organ during pregnancy, producing
– The trophoblastic cells develop into two layers, both peptide and steroid hormones. Hormone
which together form the chorion. The outer production takes place in syncytiotrophoblast
chorionic layer consists of syncytiotrophoblast cells. The hormones produced are:
cells, whilst the inner layer is made up of – β-hCG
cytotrophoblast cells. – hPL
– The chorion invades the maternal decidua, – oestrogen
releasing enzymes that produce cavities within – progesterone.
the decidua. When the maternal spiral arteries
(which supply the decidua) are invaded, their The roles of these four hormones in pregnancy
blood fills these cavities. is more fully discussed in Chapter 77.
408
Chapter 78: Fetal physiology
Clinical relevance: pre-eclampsia in defence against certain microorganisms;

for example, Listeria monocytogenes.
Pre-eclampsia is a potentially life-threatening com-
plication of pregnancy, characterized by hyperten- The chorion also acts as a barrier to prevent
sion and proteinuria in the third trimester.
bacteria and viruses infecting the fetus. However,
Pre-eclampsia has many associated complications
some bacteria (for example, Listeria) and many
including: eclampsia, HELLP (Haemolysis, Elevated
Liver enzymes and Low Platelet count) syndrome, viruses (including rubella, parvovirus B19 and
liver rupture and cerebral haemorrhage. The exact HIV) manage to cross into the fetal circulation.
pathogenesis of pre-eclampsia is not yet fully estab- The fetal immune system is not fully developed
lished. A possible sequence of events is: until 6 months after birth. In utero, the fetus
There is dysfunction of the spiral arteries that relies on maternal antibodies to fight infections:
constitute the sole blood supply of the placenta. syncytiotrophoblasts have IgG receptors, allowing
It is not clear whether this is due to fetal (for IgG, but not other forms of Ig, to cross the
example, inadequate trophoblast invasion) or placenta by endocytosis.
maternal factors.
The syncytial cells of the chorion, the endocrine
cells of the placenta, produce a number of sub- Clinical relevance: placental antibody transfer
stances in response to hypoxia. These include
The fetus requires maternal IgG as a defence against
cytokines, eicosanoids and the soluble vascular
infections. However, allowing the placental transfer
endothelial growth factor receptor 1. There is also
of IgG also has negative consequences:
an increased rate of apoptosis of
syncytiotrophoblast cells. Haemolytic disease of the newborn. RhD-anti-
These released placental factors cause a systemic gen-negative mothers previously exposed to the
inflammatory response in the mother, resulting in RhD antigen (for example, through blood trans-
endothelial dysfunction. fusion or previous fetomaternal haemorrhage)
produce anti-RhD IgG. When pregnant with an
The only definitive treatment of pre-eclampsia is RhD-positive fetus, maternal anti-RhD IgG crosses
delivery of the placenta; the risks of pre-eclampsia the placenta and attacks fetal RBCs, resulting in
to the mother must be balanced against the early haemolysis.
delivery of the fetus. Transient neonatal myasthenia. MG is an auto-
immune condition in which the immune system
produces IgG against the ACh receptors of the
Immunological function. The fetus is genetically NMJ, causing fatigable muscular weakness (see
distinct from the mother and would accordingly Chapter 50). Placental transfer of these anti-
be expected to provoke a maternal immune bodies causes some neonates to have temporary
response. However, this rarely occurs, and this muscle weakness, resulting in respiratory distress,
immune tolerance is attributed to the placenta: a weak cry and poor feeding.
Congenital heart block. Placental transfer of
– After implantation, trophoblast cells lose many anti-Ro IgG antibodies from mothers with sys-
of their cell surface MHC molecules, making temic lupus erythematosus can cause congenital
them less immunogenic. The trophoblast cells heart block and neonatal lupus erythematosus.
cover themselves in a coat of mucoprotein,
further disguising them from the maternal
immune system. What are the different mechanisms by
– The chorionic cells act as an immunological
barrier, preventing maternal T cells and
which substances cross the placenta?
antibodies from reaching the fetal circulation. Substances may cross the placenta through different
– Progesterone and α-fetoprotein produced by mechanisms:
the yolk sac at implantation act as maternal Simple diffusion of gases, particularly O2 and
immunosuppressive agents, specifically CO2.
damping down cellular immunity. However, Facilitated diffusion. Glucose crosses the placenta
this also decreases the ability of the mother by facilitated transport by the insulin-independent
to launch effective cell-mediated reactions glucose transport proteins GLUT-1 and GLUT-3.
409
Glucose transfer is proportional to maternal

glucose concentration and is increased in diabetic Muscle relaxants are charged molecules, so do
not cross the placenta.
mothers with poor glycaemic control, with a
The intravenous anaesthetic agents thiopentone,
consequent high average fetal plasma glucose
ketamine and propofol are highly lipophilic and
concentration. are readily transferred across the placenta. How-
Active transport. Amino acids are transferred ever, redistribution in the fetus is rapid, so the
across the placenta by Na+-dependent active residual effects are negligible following delivery.
transport. Many amino acids are metabolized in Opioids are lipophilic, so therefore diffuse readily
the placenta. For example, serine is converted to across the placenta. Of particular note is pethid-
glycine, before being released into the fetal ine, which is metabolized by the fetus to norpe-
circulation. thidine. Norpethidine is less lipid soluble than
pethidine, so is less able to diffuse back to the
Transcytosis. IgGs are endocytosed by
maternal circulation. Fetal accumulation occurs,
syncytiotrophoblast cells, transferred across the
risking respiratory depression and poor feeding
placenta in a vesicle and exocytosed into the fetal in the immediate neonatal period.
circulation. Placental transfer of local anaesthetics is greatest
Bulk flow. In a similar way to other capillary for those with lower protein binding (for
systems in the body, water passes between the cells example, lignocaine). Toxic levels in the fetus
of the placenta along its osmotic gradient. Any occur with high maternal local anaesthetic
small molecules dissolved in the water are also plasma concentrations – if the mother has
transported by solvent drag. symptoms and signs of local anaesthetic toxicity,
so will the fetus. In addition, an acidaemic fetus
may also develop local anaesthetic toxicity by a
mechanism called ‘ion trapping’. Low fetal pH
Clinical relevance: placental drug transport causes ionization of any local anaesthetic that
Transfer of drugs across the placenta depends on: crosses the placenta – the local anaesthetic is
Concentration gradient. Rates of diffusion are then unable to diffuse back to the maternal
proportional to concentration gradient. circulation.
Molecular size. Drugs with smaller MWs
(<500 Da) cross the placenta more easily.
Charge. Neutral molecules cross much What are the factors involved in fetal
more readily than charged molecules. The
degree of ionization of a drug may change oxygen delivery?
with pH. Fetal oxygenation is determined by:
Lipid solubility. Highly lipid-soluble drugs
readily diffuse across the lipid-rich placenta. Delivery of O2 to the placenta. Placental O2
Protein binding. Highly protein-bound delivery is a product of placental blood flow
drugs show less diffusion across the and maternal blood O2 content, which in turn
placenta compared with drugs with lower depends on maternal PaO2 and maternal Hb
protein binding. Maternal hypoalbuminaemia concentration.
or acidosis may significantly alter drug Transfer of O2 across the placenta. In addition to
protein binding, and therefore placental drug the large surface area of the placenta, a number of
transfer. factors aid the transfer of O2 from maternal Hb
Any drug given to the mother has the potential (HbA) to HbF:
to reach the fetus. Some drugs (for example, – A large O2 pressure gradient across the
thalidomide) have serious adverse effects on the placenta. The PaO2 of intervillous blood is
growing fetus, whilst others (for example, around 6.7 kPa, compared with the fetal
amoxicillin) are considered safe. Of interest to the
umbilical arterial PaO2 of 2.7 kPa.
anaesthetist:
Glycopyrrolate (a charged quaternary NH4+ salt)
– HbF has a higher O2-binding affinity than
cannot cross the placenta, whilst atropine (an maternal HbA. The HbF oxyhaemoglobin
uncharged tertiary amine) crosses easily. dissociation curve is therefore positioned
to the left of the HbA curve (Figure 78.1).
410
Umbilical vein Figure 78.1 Oxyhaemoglobin

dissociation curves for HbA and HbF.
100 Umbilical artery
Fetal blood Maternal blood

80
Haemoglobin O2 saturation (%)
Uterine vein
Uterine artery
60
40
20
0
0 3.5 5 5.3 10 13.3 15 20
This difference is primarily due to 2,3-DPG (around 18 g/dL at birth), which increases
binding: the placenta actively produces the fetal O2-carrying capacity.
2,3-DPG, which binds avidly to β-globin
chains of HbA but cannot bind to the
γ-globin chains of HbF. 2,3-DPG shifts the What is the double Haldane effect?
oxyhaemoglobin dissociation curve of
The Haldane effect is the increased ability of deoxy-
maternal HbA to the right, offloading
haemoglobin to carry CO2 (see Chapter 8). The Hal-
additional O2 to HbF.
dane effect is particularly relevant at the placenta:
– The double Bohr effect. CO2 diffuses down
its concentration gradient from the fetus As O2 is offloaded from maternal
(typical umbilical artery PaCO2 of 6.7 kPa) oxyhaemoglobin, the resulting deoxyhaemoglobin
to the mother (typical intervillous PaCO2 is better able to carry the CO2 transferred across
of 4.9 kPa). the placenta from fetus to mother.
Likewise on the fetal side of the placenta, binding
▪ As fetal PaCO2 decreases, the HbF of O2 facilitates the release of CO2 from HbF.
oxyhaemoglobin dissociation curve shifts
to the left, further increasing HbF O2 Together, these effects are termed the double
binding affinity – this is the Bohr effect Haldane effect.
(see Chapter 7).
▪ As CO2 crosses the placenta, the What happens to fetal oxygenation
intervillous PaCO2 increases.
The HbA oxyhaemoglobin
during labour?
dissociation curve shifts to the As discussed above, the fetus is entirely dependent on
right, offloading even more O2 – this the placenta for its blood supply. The spiral arteries
is the double Bohr effect. directly supply the placenta; these arise from the
radial arteries, which pass through the myometrium.
Fetal O2-carrying capacity. The fetus has a Importantly, uterine blood flow to the placenta is
higher Hb concentration than adults not autoregulated: blood flow is pressure dependent.
411
Consequently, in labour, when myometrial contrac- the body, including the heart and brain, the
tions compress the radial arteries, placental blood organs most in need of fully oxygenated blood.
flow is temporarily reduced, resulting in mild fetal Deoxygenated blood (PO2 of around 2.5 kPa,
hypoxaemia. The fetus can accommodate a degree of equivalent to saturations of 40%) from the SVC,
hypoxaemia without consequence. The severe hypox- the coronary sinus and the remaining blood
aemia that causes fetal distress usually results from from the IVC (the blood returning from
other pathology: the lower limbs) flows through the right
Maternal factors – hypotension; for example as atrium and into the right ventricle. When the
a result of sepsis or aortocaval compression. right ventricle contracts, blood is ejected into
Fetal factors – for example, malpresentation. the pulmonary artery. However, only 10% of
Placental factors – for example, placenta praevia, this blood enters the pulmonary circulation –
placental abruption. PVR is high owing to the effects of HPV
Umbilical cord factors – for example, (see Chapter 22). Instead, the majority
entanglement around the fetus, true knots. of blood flows through the lower resistance
ductus arteriosus to the descending aorta, which
perfuses the lower half of the body. In this way,
How does the fetal circulation differ the least oxygenated blood flows back to the
placenta for re-oxygenation.
from the adult circulation?
The fetal circulation is shown in Figure 78.2. The fetal heart shows many differences from the
The fetal circulation differs from the adult circu- adult heart:
lation in the following respects. The LV pumps half of the venous return to the
The presence of the umbilical vessels. upper half of the body, whilst the right ventricle
Two vascular shunts: the ductus venosus and pumps the remaining blood to the lower half of
ductus arteriosus. the body. Unlike the adult heart, both ventricles
A defect in the atrial septum, the foramen ovale. pump blood into high-pressure systems – the
right and left ventricles of the fetal heart are
As a result, patterns of fetal blood flow differ from therefore of similar size and wall thickness.
those of an adult: The fetal myocardium is immature, with a high
proportion of non-contractile protein. It cannot
Blood in the umbilical vein flowing from the
placenta is oxygenated. The umbilical vein PO2 is increase its wall tension in response to increased
4.0–5.0 kPa, equivalent to Hb O2 saturations of preload, in contrast to the adult heart. The SV is
around 80–90%.1 therefore fixed: CO is dependent on HR
(remember CO ¼ SV × HR). The normal
Of the blood flowing from the placenta, 40%
fetal HR at term is 110–160 bpm.
enters the fetal liver, whilst 60% bypasses the liver
and flows into the IVC through the ductus The fetal HR is under autonomic control:
venosus. – The parasympathetic nervous system is
Blood from the IVC flows into the right atrium. responsible for the normal baseline variability
A flap of tissue called the Eustachian valve directs in HR.
the flow of the freshly oxygenated blood from the – The sympathetic nervous system is responsible
ductus venosus through the foramen ovale and for the accelerations in HR seen with fetal
into the left atrium. From here, blood flows into activity.
the LV and then into the ascending aorta (PaO2 of
around 3.5 kPa, equivalent to saturations of 65%).
The ascending aorta supplies the upper half of Clinical relevance: labour and fetal cardiovascular
reflexes
During labour, fetal HR may be measured by cardio-
1
Note: the HbF oxyhaemoglobin dissociation curve is tocography (CTG). The CTG records the baseline fetal
shifted to the left in relation to HbA, so SaO2 is higher for HR and the response to uterine contractions.
a given O2 tension.
412
90% of blood passes

PO2 3.5 kPa (sats 65%) Aortic arch through the DA, only 10%
passes through the lungs
L PA
DA
PO2 2.5 kPa SVC R PA
(sats 40%)
PV
LA
FO
RA
PA
LV
RV
PO2 3 kPa
(sats 50%)
DV
D
Liver
60% UV = umbilical vein
40% UA = umbilical artery
IVC = inferior vena cava
SVC = superior vena cava
IVC DV = ductus venosus
FO = foramen ovale
DA = ductus arteriosus
RA = right atrium
LA = left atrium
UV RV = right ventricle
LV = left ventricle
PV = pulmonary vein
PO2 4–5 kPa PA = pulmonary artery (L and R
(sats 80–90%) denote left and right)
UA
UA
Placenta
Figure 78.2 Schematic of the fetal circulation.
413
During uterine contractions, maternal spiral arter- What are the physiological changes that
ies are compressed, resulting in a transient fall in
O2 delivery to the placenta. A healthy fetus may
occur at birth?
exhibit an early deceleration on the CTG trace: a Major physiological changes occur at birth. In utero,
parasympathetic-mediated fall in HR shortly after the fetus is dependent on the placenta for gas
the onset of a uterine contraction, due to mild exchange and nutrition. Following birth, the neonate
hypoxaemia or compression of the fetal head. must fend for itself, with its lungs as the newly estab-
A late deceleration is more sinister. In response lished gas-exchange organ and a circulation of adult
to severe fetal hypoxaemia, the peripheral chemo- configuration. Key changes are as follows.
receptors trigger peripheral vasoconstriction to redir-
Respiratory system:
ect blood to vital organs. The resulting hypertension
stimulates the baroreceptor reflex, resulting in a – The newly delivered neonate is bombarded
bradycardia. The deceleration in HR is late relative with tactile, thermal, visual and auditory
to the onset of uterine contractions because of the stimuli.
time taken in this two-step reflex response. – Along with sensory stimulation, the
falling PaO2, rising PaCO2 and falling pH
stimulate both central and peripheral
chemoreceptors, triggering the neonate
What are the important features of the to take its first breath.
fetal respiratory system? – The first breath requires a large amount
Adequate development of the fetal respiratory system of inspiratory work; the lungs are entirely
prior to birth is very important. Neonatal respiratory fluid filled and poorly compliant, though
immaturity is the most common reason for admission some of the fluid is squeezed out of the
to intensive care. The key features of fetal lung lungs as a result of thoracic compression
development are: during labour.
By 16 weeks’ gestation, the basic lung architecture – As O2 enters the alveoli, PVR rapidly falls as
of vessels and airway divisions down to the HPV is reversed, permitting pulmonary
terminal bronchioles is complete. blood flow.
Between 17 and 27 weeks, the smallest airways Cardiovascular system: the circulation changes
develop: the respiratory bronchioles, alveolar from fetal to adult configurations.
ducts and alveoli. – Immediately following birth, the umbilical
Alveolar type II pneumocytes are first seen arteries vasoconstrict in response to
at around 24 weeks. However, they are mechanical stimulation and exposure to cold
initially immature and only produce small air. Delaying the clamping of the umbilical
amounts of pulmonary surfactant. Premature arteries for 40–60 s allows additional venous
neonates are therefore at high risk of IRDS return from the placenta to the fetus. The
(also known as hyaline membrane disease). removal of the low-resistance placenta from
The lack of surfactant results in poorly the arterial and venous circulations results in
compliant, atelectatic lungs. This results in an an increase in SVR and reduction in right
increased work of breathing that may precipitate atrial venous return respectively. Reduced
respiratory failure. From 35 weeks, type II blood flow through the ductus venosus results
pneumocytes are fully functional and secrete in its closure within 1–3 hours.
adequate pulmonary surfactant. The maturation – Following the first breath, PVR decreases
of the fetal lung can be accelerated by and blood flows into the lungs. Left atrial
administration of maternal glucocorticoids blood flow increases; when left atrial pressure
if pre-term delivery is anticipated, reducing exceeds RAP, a flap-like valve closes the
the risk of IRDS. foramen ovale.
Towards term, irregular fetal breathing – Physiological closure of the ductus arteriosus
movements are present. These become more occurs over the next 10 h, through a number
regular and rapid as time goes on. of mechanisms:
414
▪ Following birth, the higher PaO2 stimulates

vasoconstriction of the ductus arteriosus For example, in hypoxaemic neonates (such as
those with IRDS), HPV results in high PVR. RAP
(the mechanism for this is not known).
is increased whilst left atrial pressure is reduced,
There is a higher incidence of failed ductus
resulting in the foramen ovale reopening. Hypox-
arteriosus closure in neonates with aemia also prevents closure of the ductus arteri-
significant hypoxaemia and those born osus. The right-to-left shunting of blood through a
at altitude. patent foramen ovale and the patent ductus arterio-
▪ Vasodilatory prostaglandins are produced sus exacerbates hypoxaemia and acidosis, further
in fetal life by the ductus arteriosus. increasing pulmonary vascular resistance: a vicious
Following birth, prostaglandin production cycle ensues.
is reduced. Treatment aims to reverse hypoxaemia, using
▪ Bradykinin released from the lungs specific therapies like exogenous surfactant (for IRDS)
and general supportive therapies: O2 administration,
following the first breath is also implicated
continuous positive airway pressure and mechanical
in ductus arteriosus closure. ventilation. PVR may be reduced using inhaled NO as
a pulmonary arterial vasodilator.
Clinical relevance: transitional circulation

The physiological changes that follow birth are not
irreversible. In certain circumstances they may be
Further reading
reversed, resulting in a transitional circulation that often S. Guller. Role of the syncytium in placenta-mediated
has disastrous consequences for the neonate. The complications of preeclampsia. Thromb Res 2009;
124(4): 389–92.
main causes for reversion to a transitional circulation
are hypoxia, hypercapnoea, acidosis and hypothermia. P. J. Murphy. The fetal circulation. Contin Educ Anaesth
Crit Care Pain 2005; 5(4): 107–12.
415
Chapter
Paediatric physiology
79
Children are not merely ‘small adults’. The anatom- – A short trachea (as little as 4 cm). This
ical and physiological differences between children increases the risk of accidental endobronchial
and adults have a significant impact on their anaes- intubation. Intubation of the left main
thetic management. bronchus is as likely as the right, as the angle at
Childhood is classified into the following age the carina is similar. This is in contrast to
groups. the situation in the adult, where the left
Neonate: the first 28 days of life (or more bronchus takes a more acute angle than the
precisely, a baby under 44 weeks post- right, making the right bronchus more
conceptual age). susceptible to endobronchial intubation. The
Infant: 28 days to 1 year. ETT should be positioned at least 1 cm above
Child: 1–12 years. the carina, and should be fixed to the maxilla
(otherwise accidental endobronchial
Adolescent: 13–17 years.
intubation may occur with intraoperative head
and jaw movement).
Describe the main anatomical and – The narrowest part of the trachea is the
cricoid ring in pre-pubescent children. The
physiological differences between mucosa here is loosely bound pseudostratified
children and adults ciliated epithelium that, following airway
The differences between children and adults are most trauma, is very prone to developing
evident below the age of 1 year. System by system, key oedema.
features are as follows. Clinical relevance: choice of endotracheal tube
Airway. in children
– Relatively large head with a prominent occiput. In young children, the trachea is very narrow. Even a
Optimal head position is ‘neutral’ rather than small amount of oedema will have a significant
the ‘sniffing the morning air’ position of impact on the radius of the trachea, and therefore
the adult. the resistance to airflow: the Hagen–Poiseuille equa-
tion indicates that resistance to flow is inversely
– Relatively short neck. proportional to the fourth power of the radius
– Large tongue. (see Chapter 20). Pressure on the tracheal mucosa
– Neonates and infants are obligate nasal by a tight-fitting ETT causes oedema, which could
breathers. Nasal obstruction with secretions or lead to airway obstruction following extubation.
nasogastric tubes can significantly impact on This has implications for the type and size of ETT
respiration. This risk diminishes beyond the used:
age of four months. Below the age of 10, an uncuffed ETT is
traditionally used.
– Large ‘U’-shaped epiglottis. A straight-bladed
In children over the age of 2, the approximate
laryngoscope may be required.
ETT size is given by the formula: 4 + age/4.
– A more cephalad larynx. The larynx is at When inserted, the ETT should not feel tight, and
vertebral level C3 in the neonate and C4 there should be an air leak when positive pres-
in the child, compared with C5 or C6 in sure ventilation is applied.
adults.
416
Chapter 79: Paediatric physiology
(partial adduction of the vocal cords during

Uncuffed ETTs have a wider internal diameter
than cuffed ETTs, reducing the airflow resistance expiration and inspiratory muscle tone) are
which permits spontaneous breathing in the abolished.
anaesthetized child. – CC exceeds FRC. The increase in chest wall
compliance and lower lung volumes mean that
More recently, the use of cuffed ETTs in children small airways collapse easily: CC exceeds FRC
has been revisited – newer designs of cuff have been
in neonates, leading to a significant V̇ /Q̇
developed, and there is growing evidence that
cuffed ETTs can be used safely in children.
mismatch.
– The muscles of respiration are easily fatigued. The
work of breathing is higher due to lower lung
Respiratory physiology. Children (especially volumes, excessive chest wall compliance and
neonates and infants) have limited respiratory the inadequacy of the bucket-handle
reserve. mechanism. The diaphragm and intercostal
– High O2 consumption. Arguably the most muscles fatigue easily, due to a lack of type
important feature of paediatric physiology I muscle fibres.
is a high BMR resulting in increased Cardiovascular system. The cardiovascular
O2 consumption in relation to body mass: differences between children and adults are most
a neonate has an O2 consumption double stark in neonates, becoming more adult-like
that of an adult: 6 mL/(kg min) versus with age.
3 mL/(kg min). – CI (i.e. CO corrected for BSA) is increased
– Increased alveolar ventilation. As a result of by 30–60% in neonates. The high CO is
their high BMR, CO2 production in children is required to increase O2-carrying capacity,
increased. PaCO2 remains within the normal in order that the high metabolic demands
range due to increased V_ A . of the neonate are met.
– Increased RR. VT is 6–8 mL/kg; that is, similar – The Frank–Starling response is limited. The
to adults. The increased V_ A is achieved by neonatal myocardium has a lower proportion
increasing RR rather than VT. of contractile proteins. The ventricles generate
– The diaphragm is the main muscle of less tension during contraction and cannot
inspiration. Ribs are soft and aligned increase their tension in response to increased
horizontally; the ‘bucket-handle’ mechanism preload. The end result is a relatively fixed SV;
of the thoracic cage does not occur. VT is CO is largely rate dependent. As a result,
fairly static; high intrapleural pressure results bradycardia is poorly tolerated: a neonatal HR
in intercostal recession rather than lung of <60 bpm is an indication for
expansion, especially in neonates and infants. cardiopulmonary resuscitation.
An acute abdomen or gas insufflation of – HR decreases with age, from a typical value of
the stomach splints the diaphragm, impairing 120 bpm in neonates to 75 bpm in adults.
ventilation. – Sinus arrhythmia, the variation of HR with
– Reduced FRC. Their soft ribs mean that chest breathing which, despite its name, is not
wall compliance is increased in children. The pathological. It is thought to be due to
elastic recoil of the lung is only slightly less suppression of vagal tone on inspiration
than that of an adult. Overall, FRC (the point leading to an increase in HR, and vice versa on
at which inward lung elastic forces match the expiration. It is often seen on the ECG of
outward elastic recoil of the chest wall) is children below teenage years as a sinusoidal
reduced. As FRC is the O2 reservoir of the variation in R–R interval. In adults, sinus
lung, rapid desaturation may occur during arrhythmia may be preserved in athletes who
periods of apnoea; for example, following have a higher vagal tone.
induction of anaesthesia. FRC is further – Blood pressure increases with age, from typical
reduced during general anaesthesia: the systolic values of 70 mmHg in neonates to
physiological mechanisms that maintain FRC 120 mmHg in adults.
417
– ANS reflexes. The parasympathetic nervous rises by 10–20 g/L as fluid loss results in
system and baroreceptor reflexes are mature in haemoconcentration. Over the first 3 months
neonates, but the sympathetic nervous system of life, Hb concentration falls to 100 g/L,
is relatively immature. The neonatal response before it rises slowly to adult levels by puberty.
to stress (for example, hypoxia) is therefore – During fetal life, vitamin K (a fat-soluble
predominantly parasympathetic, resulting in vitamin) barely crosses the placenta. Neonates
bradycardia. Bradycardia associated with are relatively vitamin K deficient, leading to
hypoxia should be initially treated with O2 and impaired hepatic synthesis of clotting factors
ventilation rather than atropine! II, VII, IX and X, with the potential for
CNS. Key features are: bleeding exemplified by haemorrhagic disease
– ICP. Neonates and infants have a large anterior of the newborn. Breast milk is low in vitamin
fontanelle. Raised ICP can be partially K; this is why neonates are routinely given
compensated for by expansion of the prophylactic vitamin K shortly after birth.
fontanelle and separation of the cranial – Blood volume is approximately 90 mL/kg in
sutures; palpation of the fontanelle can be used the neonate and 80 mL/kg at 6 months. By
to assess ICP. 1 year of age, blood volume reaches the adult
– The BBB is immature and incomplete in value of 70 mL/kg.
neonates. Bilirubin and drugs (for example, Hepatic physiology. The neonatal liver has
opioids and barbiturates) cross the BBB more impaired enzymatic function:
easily. This explains the increased sensitivity of – The function of the glucuronosyltransferase,
neonates to respiratory depressants. which catalyses the glucuronidation of
– Spinal cord. The spinal cord ends at the level of bilirubin, is especially poor. Plasma
L3 in neonates and L2/3 at 1 year of age. The unconjugated bilirubin increases and crosses
adult level of L1/2 is reached at around the age the immature BBB, predisposing to
of 8. Incomplete myelination of nerves results kernicterus.
in better penetration of local anaesthetic; doses – Drugs that undergo hepatic metabolism by
may be reduced slightly. The immaturity of the phase 1 and 2 reactions have prolonged action;
sympathetic nervous system means that for example, barbiturates and opioids.
central neuraxial blockade is well tolerated,
with hypotension being uncommon. The liver reaches normal adult function by
Renal physiology. The neonatal kidneys are three months.
immature. Renal function gradually reaches adult Metabolic.
levels by 2 years of age: – Neonatal BMR is double that of an adult
– GFR in infants is around half that of the adult (50 kcal/kg per day versus 25 kcal/kg per day),
(65 mL/min compared with 120 mL/min). resulting in increased O2 consumption and
– Tubular function is immature and CO2 production. This is due to the metabolic
concentrating ability is reduced, especially in demands of growth and thermoregulation.
the first week of life; a dehydrated infant has a Neonatal BMR is higher than fetal BMR; the
limited ability to conserve water. neonate must expend energy to achieve gas
– Pre-term neonates are unable to significantly exchange (up to 25% of BMR), a process that
increase their Na+ excretion if excessive was performed passively by the placenta in
volumes of crystalloid are administered. fetal life.
Haematology. – Neonates are prone to hypoglycaemia due to
their high BMR coupled with both low liver
– At birth, HbF predominates. By 3 months of glycogen stores and immature gluconeogenesis
age, 95% of Hb is adult HbA. enzymes. Neonates should therefore not be
– During fetal life the HbF concentration is high starved excessively prior to surgery, and most
(around 180 g/L) to maximize O2 carriage. In centres would commence an intravenous
the days following birth, Hb concentration glucose infusion.
418
Chapter 79: Paediatric physiology
Thermoregulation. Neonates and infants are Clinical relevance: pharmacokinetic differences

prone to heat loss due to: between children and adults
– A large surface area to body weight ratio. The differences between a child’s and an adult’s
– Minimal insulating subcutaneous tissue. handling of drugs is most pronounced below the
age of 6 months. Important features are:
– Poorly developed shivering and
Increased volume of distribution of water-
vasoconstriction mechanisms.
soluble drugs. Young children have higher
Neonates and infants have an additional proportions of extracellular and total body water.
Water-soluble drugs (for example, suxamethonium)
method of heat production: non-shivering
therefore have a higher volume of distribution,
thermogenesis (see Chapter 72). Under the influ-
and require a higher per kilogram loading dose.
ence of the sympathetic nervous system, brown An exception is the non-depolarizing muscle
adipose tissue oxidizes free fatty acids for heat relaxants. These drugs are also water soluble, but
generation instead of ATP production. This pro- the amount of ACh released at a young child’s
cess is referred to as the uncoupling of oxidative NMJ is reduced; overall, the dose of drug required
phosphorylation. O2 consumption is significantly is about the same.
increased. Reduced body fat. Muscle and fat contribute a
Hypothermia in neonates is associated with smaller proportion of body weight in very young
acidosis, respiratory depression and decreased children; drugs that normally redistribute to fat
CO. Under general anaesthesia, the main mech- (for example, thiopentone) will therefore have
prolonged effects.
anism of heat loss is radiation. In addition to the
Immature renal and hepatic function. This is
usual measures to prevent heat loss (forced-air
relevant in neonates, where drug metabolism
warming blankets, heat and moisture exchangers, and elimination may be impaired, prolonging
etc.), ambient theatre temperature should be drug action.
increased for younger children. Reduced protein binding. As a result of reduced
Fluid compartments. plasma protein concentration, the fraction of
unbound drug may be higher in children than in
– Neonatal total body water is 75% of body
adults. This is particularly important for drugs
weight, compared with 60% in an adult. that are highly protein bound; for example,
Premature neonates have an even higher barbiturates, phenytoin, bupivacaine and
proportion of body water: up to 85%. diazepam.
– ECF is 40% of total body weight in the Inhalational anaesthetics. MAC is the same at
neonate, compared with 20% of total body birth as in adulthood but is 50% higher in infants,
weight in an adult. gradually decreasing throughout childhood to
– When nil-by-mouth, dehydration occurs more reach adult values by adolescence. Gaseous
rapidly in neonates than in adults, owing to: induction and emergence from anaesthesia are
quicker in children; this is due to a relatively
▪ Increased evaporative losses, due to the smaller FRC, a greater CBF and a greater V_ A .
neonate’s high surface area to body
weight ratio.
▪ Increased respiratory loss of Further reading
water vapour, due to higher V_ E . S. Bell, D. Monkhouse. Age-related pharmacology. Anaesth
▪ Impaired ability to concentrate urine. Intensive Care Med 2005; 6(3): 89–92.
419
Chapter
Physiology of ageing
80
What makes surgery and anaesthesia Respiratory system:
– Airway. The elderly are often edentulous,
in older people higher risk? making bag-valve-mask ventilation more
Ageing is not just a process of physical change, but difficult but intubation easier.
also of psychological and social change. Increasing – Upper airway collapse. The upper airway
numbers of elderly people are undergoing elective becomes more prone to collapse, particularly
and emergency surgery, with postoperative compli- at night: partial obstruction (snoring) and
cations more common in the older population. It is arterial hypoxaemia are common. Decreased
important to understand the normal changes that upper airway tone can be problematic during
occur with advancing age so that anaesthetic tech- recovery from anaesthesia, with airway
niques can be modified, and to allow early identifica- obstruction more common.
tion of anaesthetic and surgical complications.
– The thoracic cage. With advancing age:
Whilst the chronological age of a patient is easily
measured (i.e. years), a patient’s functional age is ▪ The thoracic cage becomes more rigid due
both more important and more difficult to measure. to calcification of the coastal cartilages,
The physiological changes that accompany ageing leading to reduced thoracic wall
affect every organ of the body. Ageing is associated compliance.
with a decline in the physiological reserve of organ ▪ Vertebral column deformity leads to
systems. The mechanism of this decline is either loss kyphosis, which adversely affects lung
of cells from an organ, or reduced function of the mechanics.
remaining cells. The decline in organ function often ▪ The diaphragm and intercostal muscles
begins early in adult life, but is often not clinically atrophy. At times of high respiratory
evident until almost all of the organ reserve is lost. workload, this makes the elderly more
Organ failure occurs either when organ function susceptible to respiratory muscle fatigue.
declines to a level that can no longer support life, or
when a disease state requires an increase in organ – Degeneration of the elastic fibres of the alveolar
function that cannot be met due to insufficient reserve. septae, leading to:
Older patients often have chronic diseases that may
impact on the development or progression of an acute ▪ Loss of support for alveoli and small
illness. The polypharmacy that commonly accompan- airways, resulting in airway collapse
ies chronic illness may also influence the medical and in expiration (i.e. an increased CC).
anaesthetic management of an acute illness. This is a major cause of V̇ /Q̇ mismatch
and hypoxaemia in the elderly (see
Describe the physiological and Chapter 14).
anatomical changes of interest to ▪ Increased lung compliance, which partially
offsets the reduced thoracic wall compliance.
anaesthetists Overall, the combined respiratory
The physiological and anatomical changes associated compliance is lower in older patients; that is,
with ageing can be classified according to organ the gradient of the pressure–volume curve is
system: reduced (Figure 80.1).
420
Chapter 80: Physiology of ageing
▪ An increase in RV and FRC (Figure 80.2). hemi-diaphragms, putting them at a

FRC occurs at the point where the inward mechanical disadvantage; the energy
elastic forces match the outward spring of expended during inspiration increases.
the thoracic cage. Reduced lung elastic
recoil means that FRC occurs at increased – A–a gradient increases with age. This is in part
lung volume. The anterior–posterior due to V̇ /Q̇ mismatch associated with
diameter of the lung increases as a increased CC, but is also due to:
consequence of the higher resting lung ▪ Reduced diffusing capacity of the alveoli,
volume. This results in flattening of the due to both reduced alveolar surface area
and increased alveolar–capillary
membrane thickness.
TLC
20 year old
▪ HPV being less active, which further
70 year old exacerbates V̇ /Q̇ mismatch.
Cardiovascular system:
– Arteries stiffen with age, leading to systolic
Lung volume (L)
hypertension. This has two effects:

▪ The walls of the aorta normally distend to
Gradient less steep with ageing
= decreased lung compliance
accommodate the blood ejected from the
LV. With ageing, the LV must generate a
greater pressure to eject the SV into a
RV stiff aorta.
▪ Normally, ejection of blood into the aorta
causes a pressure wave that passes along
+5 0 –5 –10 –15 –20 the aorta and is reflected back towards the
Intrapleural pressure (cmH2O)
heart. The reflected wave reaches the heart
Figure 80.1 The change in lung compliance with age. after ejection of blood is complete, and is
Figure 80.2 The change in lung

volumes with age.
6
TLC
5
CC exceeds FRC when supine at age 45
4 VC
Volume (L)
CC
3 FRC
RV
2
0
20 30 40 50 60 70 80
Age (years)
421
responsible for the bump after the dicrotic – Cardiac valve degeneration. Calcification of the
notch in the arterial waveform. In the aortic valve leading to aortic sclerosis is more
elderly, stiffened arteries cause an increase common in older patients.
in the speed of the pressure wave. The CNS:
reflected wave consequently reaches the – Loss of brain cells. A generalized loss of cells
heart in late systole, which further leads to a reduced brain weight and the
increases the pressure against which the appearance of cerebral atrophy on CT scan.
ventricle must pump. The remaining neurons compensate by
– Left ventricular hypertrophy. As a consequence forming longer dendrites and making more
of the increase in afterload, the LV undergoes connections to other neurons. Loss of
hypertrophy. Ventricular hypertrophy dopaminergic neurons results in Parkinson’s
increases the stiffness of the LV, which impairs disease, whilst loss of cholinergic neurons in
diastolic relaxation (see Chapter 29). This the hypothalamus is implicated in the
diastolic dysfunction worsens with age. The development of dementia. The reduction in
heart becomes progressively more dependent cell number results in a lower cerebral
on atrial contraction for ventricular filling. metabolic O2 demand; CBF is reduced
This is why development of AF can so easily by 10–20% as a result of the lower metabolic
result in LVF in the elderly. demand.
– Veins stiffen with age. Normally, veins act as a – Sensory impairment is common. Deafness is
reservoir of blood to buffer changes in venous very common in older people, and blindness
pressure, maintaining a constant right affects around a third of the elderly
ventricular preload. With increasing age the population.
veins stiffen, reducing their compliance and – Cognitive impairment becomes more common
impairing the buffering mechanism. This is with advancing age, affecting 20% of patients
why the elderly are more likely to become aged over 80 years old.
hypotensive with mild hypovolaemia. Renal physiology:
– Decreased response to β-adrenergic stimulation – Decrease in GFR. Young adults have a
with ageing, causing: significant reserve in renal function. From
the age of 30, there is a progressive loss of
▪ Reduced responsiveness of HR to
glomeruli and reduced renal plasma flow,
catecholamines during exercise, resulting
resulting in a lower creatinine clearance.
in a reduced maximum HR. Resting HR
is unchanged. – Obstructive nephropathy is common in
elderly men.
▪ The baroreceptors are less able to rapidly
reflexly modify HR in response to changes Hepatic physiology:
in blood pressure, predisposing the elderly – Reduced liver size and hepatic blood flow with
to postural hypotension. advancing age. This results in reduced hepatic
drug clearance.
– Cardiac output falls with age at a rate of
– Decreased synthesis of plasma proteins with
approximately 1% per year. This due to reduced
advancing age. Of note, albumin
contractility of the LV, both as a result of the
concentration decreases, and plasma
reduced response to β-adrenergic stimuli and
cholinesterase levels are reduced.
reduced myocyte function with advancing age.
Endocrine system: Diabetes mellitus is
– Conduction system abnormalities. There is an
common in the elderly. There is an increase in
increased tendency to supraventricular
peripheral insulin resistance and impaired insulin
arrhythmias, particularly atrial and ventricular
secretion in response to hyperglycaemia.
ectopic beats, and AF. This is thought
Locomotor and skin:
to be due to fibrosis of the SA node and
a large reduction in the number of – The elderly tend to have reduced subcutaneous
pacemaker cells. tissue, thin skin and fragile veins; achieving
422
Chapter 80: Physiology of ageing
venous access can be difficult. Infusions of What are the causes of ageing?
fluids or drugs can extravasate, especially if
There are a number of theories of ageing. Ageing is
introduced under pressure. Pressure sores are
thought to be:
more common, and additional care must be
taken with patient positioning and padding of caused by cell damage occurring throughout
pressure points. life, or
– There is a generalized loss of muscle mass genetically pre-programmed.
with advancing age, known as sarcopenia; Some of the more well-recognized theories of
6 kg of muscle is lost by age 80. This is ageing are:
thought to be due to loss of motor neurons,
resulting in decreased levels of Ca2+ within Telomere theory. Telomeres are non-coding
structures at the end of chromosomes. During
the sarcoplasm.
replication, DNA polymerase discards the three
– Arthritis and bony deformity are very
most distal base pairs, thus shortening the DNA
common in older people. This may lead
sequence – the presence of a distal telomere
to difficulty with mobility and positioning,
segment therefore protects the coding section of
potentially making regional anaesthesia
DNA from shortening, which would result in the
more difficult. Larger calibre spinal needles
loss of genetic material. With ageing the telomere
may be required to pass through calcified
is degraded and coding genetic information is lost.
ligaments. Fortunately, post-dural
In response to DNA damage, cells undergo
puncture headache is far less common in
apoptosis.
the elderly.
Free radical theory. Reactive O2 species are highly
Thermoregulation is impaired with advancing
reactive free radicals formed normally as part of
age:
metabolism. Free radicals cause oxidative stress,
– The elderly are at risk of hypothermia, which results in ageing of cells.
due to a reduction in heat production: Somatic mutation theory. Cellular division can
BMR decreases by 1% per year, and there result in random mutations, producing inefficient
is a reduction in the peripheral cells. These cells accumulate with age, causing
vasoconstrictor response to cold progressive organ dysfunction.
exposure.
– Older patients are especially at risk of Clinical relevance: pharmacology and ageing
intraoperative hypothermia. Postoperative The physiological changes that occur with age have a
shivering is the normal mechanism to number of pharmacological implications for the
return to normothermia. The elderly may anaesthetist:
lack the muscle bulk to shiver effectively, Altered drug pharmacokinetics.
or may have insufficient cardiopulmonary – Higher peak plasma concentration of drug,
reserve to meet the increased O2 demand due to the lower volume of distribution.
of shivering. Prevention of perioperative – Prolonged terminal half-life of some drugs,
hypothermia in the elderly is crucial. due to sequestration of lipophilic drugs in the
increased body fat, and the reduced hepatic
– The elderly are also at risk of hyperthermia, and renal clearance. Of particular note is
due to impairment of sweating. that the effects of benzodiazepines given
Body compartments: at induction of anaesthesia may persist into
– A reduced blood volume and a higher the postoperative period.
proportion of body fat can lead to changes in Vasopressors. The reduced cardiac response to
the volume of distribution. β-agonists means that mixed α- and β-agonists
– Plasma protein concentration is reduced, (such as ephedrine) become less effective with
resulting in decreased drug protein advancing age. Pure α-agonists (for example,
binding, an increase in free drug phenylephrine) are as effective in the elderly as in
fraction, and thus a higher free drug young people.
concentration.
423
Intravenous induction agents. The altered – Mivacurium and suxamethonium have pro-
pharmacokinetics in the elderly leads to longed effects; these drugs are metabolized
higher free drug plasma concentrations of the through the action of plasma cholinesterases,
intravenous induction agents. The dose of which are reduced in the elderly. The pro-
induction agent therefore needs to be longed action of suxamethonium is clinically
reduced. The reduced CO prolongs the arm–brain insignificant.
circulation time, so intravenous induction – Aminosteroid muscle relaxants may have pro-
drugs must be injected slowly to avoid longed action in the elderly, as their metab-
inadvertent overdose and the associated olism relies on both hepatic metabolism and
hypotension. renal excretion.
Inhalational agents. MAC of inhalational anaes-
thetics is reduced by up to 30% in the elderly.
The duration of inhalational induction may be
prolonged due to the reduced alveolar diffusion Further reading
and increased V̇ /Q̇ mismatch that occur with G. D. K. Matthews, C. L. H. Huang, L. Sun, et al.
advancing age. Translational musculoskeletal science: sarcopenia the
Neuromuscular blockade. The dose of non- next clinical target after osteoporosis? Ann N Y Acad Sci
depolarizing muscle relaxants is unchanged in 2011; 1237: 95–105.
the elderly. The time taken to reach intubating J. F. Karp, J. W. Shega, N. E. Morone, et al. Advances in
conditions is increased, due to reduced CO. The understanding the mechanisms and management of
duration of neuromuscular blockade may be persistent pain in older adults. Br J Anaesth 2008; 101(1):
prolonged in the elderly, depending on the 110–20.
mechanism of drug metabolism: D. Murray, C. Dodds. Perioperative care of the elderly.
– Atracurium has the same duration of action. Contin Educ Anaesth Crit Care Pain 2004; 4(6): 193–6.
Its metabolism is independent of renal and
B. T. Weinert, P. S. Timiras. Theories of aging. J Appl
liver function as atracurium is metabolized by Physiol, 2003; 95(4): 1706–16.
plasma esterases and through Hofmann
elimination. C. Dodds, D. Murray. Pre-operative assessment of the elderly.
424
Section 11 Environmental physiology
Chapter
Altitude
81
High altitude has no consensus definition. It Therefore, PI O2 decreases with increasing
is most commonly defined as corresponding to elevation.
>2500 m above sea level, where most individuals
begin to show physiological adaption. Extreme alti-
tude is defined as >6000 m, above which long-term How is alveolar oxygen tension PAO2
habitation is impossible. An individual acutely affected by altitude?
exposed to altitude >5500 m is liable to lose con- PAO2 is calculated using the AGE (see Chapter 17):
sciousness, whilst in the ‘death zone’ (elevations
>8000 m), an unacclimatized person loses con- Pa CO2
PA O2 ¼ ½F i O2 ×ðP B PSVPwater Þ
sciousness rapidly. R
Mount Everest is 8848 m high and 100 million As the height above sea level increases, PB decreases;
people live at altitudes >2500 m. Humans are able to PAO2 will also therefore decrease. In turn:
adapt their physiology to survive for short periods of As alveolar gas is in equilibrium with the arterial
time at extreme altitude. gas, PaO2 will fall.
A fall in PaO2 results in lower Hb saturation (see
Chapter 7); O2 carriage is reduced.
What are the problems associated O2 delivery becomes insufficient for the tissues to
with high altitude? maintain their normal metabolic processes; that is,
High altitude presents a number of problems to the hypoxaemic hypoxia develops.
body, classified as:
Saturated vapour pressure of water is unchanged by
Reduced PB: during ascent, the PB decreases altitude (6.3 kPa at 37 °C), so has a proportionally
exponentially.
greater effect on PAO2 at higher altitudes, when PB is
Temperature: the environmental temperature reduced.
falls by 1 °C for every 150 m travelled above
sea level.
Reduced relative humidity: this results in
increased evaporative losses from the skin and
How does the body adapt to survive
respiratory tract. at altitude?
Increased solar radiation: due to reduced Survival at altitude depends on a coordinated
cloud cover. response by the respiratory, cardiovascular, haem-
atological and renal systems. No physiological
changes are seen below 2500 m in a healthy adult,
What happens to the inspired oxygen probably because PaO2 is above the threshold for
tension at high altitude? activation of the peripheral chemoreceptors (around
8 kPa).
During ascent, PB decreases exponentially, but FiO2
The acute response to altitude aims to increase
remains the same (21%). The inspired partial pressure
PaO2 by hyperventilation, but is limited by the
of O2 PIO2 is given by Dalton’s law:
resulting respiratory alkalosis. This is followed by
PIO2 ¼ PB × FiO2 the chronic adaptive response, in which a further
425
Section 11: Environmental physiology
increase in ventilation is permitted as the kidney pressure diuresis (an increase in renal
corrects the pH disturbance. System by system: perfusion driven by the increase in
Respiratory system. Important aspects are: sympathetic activity), increased fluid loss
(hyperventilation and reduced relative
– Hyperventilation. The peripheral
humidity) and decreased oral intake (loss of
chemoreceptors (but not the central
appetite). SV falls as a result of the reduction
chemoreceptors) are sensitive to changes in
in preload, but overall CO remains the same,
PaO2 (see Chapter 21). When PaO2 falls below
owing to tachycardia. Over time, SV remains
8 kPa the peripheral chemoreceptors stimulate
low and HR chronically high – the mechanism
the respiratory centre in the medulla, resulting
for this is not known.
in increased V_ A .
– Increased myocardial work. The high
– The consequent fall in PaCO2 leads to an
haematocrit of the blood (up to 0.6 with
increase in PAO2, according to the AGE
chronic acclimatization) increases the viscosity
(see above).
of the blood. The work required to move blood
– ‘Braking effect’. The unwanted consequence of
in the circulation (i.e. the left ventricular work)
hyperventilation is an increase in arterial pH;
is increased.
that is, a respiratory alkalosis. Hypocapnoea is
– HPV. The pulmonary arterioles vasoconstrict
detected by the central chemoreceptors, whilst
in response to low PAO2 (see Chapter 22).
alkalosis is detected by the carotid bodies; both
Normally, HPV is a useful mechanism to
act to limit the increase in V_ A .
optimize V̇ /Q̇ matching when a region of the
▪ It was previously thought that over the lung is hypoxic (for example, due to a lobar
following days the alkalaemia is partially pneumonia). However, the generalized
corrected as a result of increased renal hypoxia that occurs at altitude results in a
HCO3 excretion: the ‘brakes’ are taken potentially harmful global pulmonary
off, allowing a further increase in V_ A . arteriolar vasoconstriction. PVR increases
▪ However, more recent studies show that by 50–300%, resulting in pulmonary
the braking effect is decreased before renal hypertension. The increase in pulmonary
HCO3 excretion begins. This suggests capillary hydrostatic pressure may cause fluid
that a faster central mechanism is involved transudation, known as high-altitude
in acclimatization. This may be due to a pulmonary oedema (HAPE). In addition, the
decrease in CSF HCO3 concentration, sudden onset of pulmonary hypertension may
although the mechanism for this is not precipitate right heart failure in susceptible
completely elucidated. individuals.
Haematological system. The sigmoid shape of the
– Diffusion limitation. Transfer of O2 across the oxyhaemoglobin dissociation curve is important:
alveolar–capillary barrier may become SaO2 remains >90% at elevations of up to 3000 m
diffusion limited at altitude (see Chapter 9), in normal patients. At higher altitudes,
especially in association with exercise (where compensatory mechanisms occur:
the pulmonary capillary transit time is
reduced) and in patients with high-altitude – Leftward shift of the oxyhaemoglobin
pulmonary oedema (interstitial fluid thickens dissociation curve. Hyperventilation-induced
the alveolar–capillary barrier). alkalosis shifts the P50 of the oxyhaemoglobin
dissociation curve to the left. This aids the
Cardiovascular system. Key features are:
loading of scarce O2 onto the Hb molecule in
– Increased HR, as a result of increased the lungs, but prevents offloading of O2 to the
sympathetic outflow triggered by the tissues (see Chapter 7).
peripheral chemoreceptors. – Increased 2,3-DPG. To compensate for the
– Reduced plasma volume. Haematocrit leftward shift of the oxyhaemoglobin
increases due to a 20% reduction in plasma dissociation curve, erythrocytes produce a
volume. This is the combined result of a greater amount of 2,3-DPG. This causes a
426
Chapter 81: Altitude
rightward shift of the curve in order to High-altitude cerebral oedema (HACE) is similar
facilitate O2 offloading from Hb, returning the to AMS, but at the severe end of the disease
P50 to the normal sea-level position within spectrum. The cardinal features of HACE are
a week. headache combined with ataxia or cognitive
– Increased red cell mass. As discussed above, impairment. This is a serious condition, which
haematocrit increases in the first week of may progress to seizures, coma and death. The
ascent due to a reduction in plasma volume. mechanism by which HACE develops is
The kidney responds to chronic hypoxaemia unknown.
within hours of ascent by increasing the HAPE is thought to occur as a result of changes to
secretion of EPO, which stimulates erythrocyte the Starling forces in the alveolus following HPV.
production by the bone marrow. Over time, Early symptoms are exertional dyspnoea and a
red cell mass increases, restoring the blood’s persistent dry cough; patients later develop
O2-carrying capacity to near normal. haemoptysis and orthopnoea. HAPE is the most
– Increased risk of thrombotic events. This is as a serious of the acute high-altitude illnesses,
result of both the increase in haematocrit accounting for the majority of the mortality.
(which increases the viscosity of the blood)
and the activation of platelets due to The only definitive treatment for the acute
hypoxaemia. high-altitude illnesses is descent. Other treatments
buy time:
Thermoregulation. Continuous exposure to a
cold environment causes a number of metabolic Supplemental O2: the fastest way to increase PAO2,
changes: thereby counteracting the most harmful effects of
high altitude.
– Heat conservation. Mechanisms
Hyperbaric chamber: reduces the effective
include peripheral vasoconstriction,
altitude of the patient, simulating descent.
decreased sweating and behavioural
A portable hyperbaric chamber (the Gamow bag)
changes (for example, wearing more
is available.
clothes).
A variety of pharmacological treatments, including:
– Heat generation. Mechanisms include
acetazolamide, dexamethasone and nifedipine.
increasing BMR, shivering and increased
brown fat activity. All the heat-generating
mechanisms increase O2 consumption at a Clinical relevance: anaesthesia at altitude
time of relative hypoxaemia. Whilst it is clearly inadvisable to perform a general
anaesthetic at extreme altitude, many hospitals
worldwide are located at moderate altitude
What is acute high-altitude illness? (2000–3000 m above sea level). In addition to the
physiological changes associated with high altitude
Acute high-altitude illness is a maladaptive physio-
and the risks of hypoxaemia, there are a number of
logical response to altitude, occurring in unacclima- other equipment-related issues for the anaesthetist:
tized people who ascend too quickly. The rate of Vaporizers. Saturated vapour pressure is not
acclimatization has a significant inter-patient variabil- affected by changes in PB. Therefore, the partial
ity: some people acclimatize much more slowly than pressure of a volatile agent within a plenum
others, making them more susceptible to acute high- vaporizer is the same at high altitude as at sea
altitude illness. Three high-altitude syndromes are level. At altitude, the lower atmospheric pressure
classically described: results in a higher concentration of volatile agent
being delivered to the patient than that ‘dialled’
Acute mountain sickness (AMS) is a neurological
(i.e. percentage when calibrated at sea level).
syndrome whose cardinal feature is headache,
However, it is the alveolar partial pressure of the
combined with a number of other non-specific agent that determines its clinical effect, and this
features: nausea, anorexia, dizziness and remains constant. Therefore, an isoflurane
insomnia. Symptoms usually improve after 3–4 vaporizer set at 1% will have the same clinical
days at the same altitude; that is, allowing effect at high altitude as at sea level.
additional time for acclimatization.
427
Flowmeters. Variable-orifice flowmeters are cali- aeromedical transfer of a critically ill patient.
brated at sea level, and underread at high alti- Unchecked, the increased cuff pressure may
tude owing to a reduction in gas density. cause ischaemic injury to the tracheal or pharyn-
However, since it is the number of molecules (for geal mucosa.
example, of O2) and not the volume of gas that
matters clinically, flowmeters can be used as
normal.
Venturi-type O2 masks. At altitude, these deliver
Further reading
a slightly higher percentage of O2 than at J. P. R. Brown, M. P. W. Grocott. Humans at altitude:
physiology and pathophysiology. Contin Educ Anaesth
sea level.
Crit Care Pain 2013; 13(1): 17–22.
Cuff pressures. Pressures within cuffed ETTs or
LMAs may increase significantly with rapid acute K. B. Leissner, F. U. Mahmood. Physiology and
changes in altitude, such as may occur during an pathophysiology at high altitude: considerations for the
anaesthesiologist. J Anesth 2009; 23(4): 543–53.
428
Chapter
Diving
82
You may wonder what a chapter entitled ‘diving’ is to the diving reflex maximizing CBF by intense
doing in a book for anaesthetists – only the few who peripheral vasoconstriction. Children are more
work in coastal areas will ever be required to anaes- likely to survive prolonged immersion than adults,
thetize patients with decompression sickness. How- owing to:
ever, the primitive diving reflex is of clinical interest, – A stronger diving reflex.
and the physiology and physics associated with des- – A greater surface area to body weight ratio,
cent are not infrequently tested in postgraduate resulting in a faster fall in body temperature,
examinations. which reduces CMR and protects against
cerebral ischaemia.
What is the diving reflex?
The diving reflex is a relic of human evolution from Which physiological changes occur
aquatic species. Exposure of the face, specifically the
areas of trigeminal nerve distribution, to ice-cold during head-out immersion?
water triggers a reflex that is designed to allow pro- The physiology of a body immersed in water differs
longed submersion underwater. There are three car- from normal physiology on land in a number of
diopulmonary changes: ways:
Apnoea. Breathing stops, often with a gasp, which Venous pooling in the legs does not occur. The
prevents the lungs filling with water. effect of gravity is opposed by the external
Bradycardia. In humans, the bradycardia is mild hydrostatic pressure of the surrounding water.
(in the region of 10–25%), but in some sea The end result is the mobilization of around
mammals HR falls by up to 90%. 500 mL of blood back into the circulation.
Peripheral vasoconstriction. Blood is diverted In the heart, increased blood volume stretches
away from the peripheries to maximize heart and the atrial and ventricular walls, causing the
brain perfusion. release of ANP and BNP, which produce a
diuresis.
In humans, the diving reflex is strongest in Increased work of breathing. The hydrostatic
neonates and infants – the diving reflex enables pressure of the surrounding water also has
photographs of babies ‘swimming’ underwater to be implications for respiratory mechanics, increasing
taken without the baby drowning! Perhaps more the work of breathing by 60%.
relevant to anaesthetists is that:
The bradycardia is mediated by the vagus nerve.
In addition to reducing the frequency of SA node
What happens to the air in the lungs
impulses, conduction through the AV node is also during a breath-hold dive?
reduced. Immersing a patient’s face in a bowl of Ambient pressure increases underwater; pressure is
ice-cold water can therefore be used to terminate a measured in metres of seawater (msw). In fact, for
supraventricular tachycardia. every 10 m descent, ambient pressure increases by
People have survived prolonged immersion 100 kPa.
(20–30 min) in icy water (for example, falling As a breath-hold diver descends, ambient pressure
through ice on a frozen lake) – this is in part due increases: the volume of air within the lungs decreases
429
(Boyle’s law). With deeper dives, the volume of the consequences in the context of diving. The risk of
lungs may fall below RV, risking negative-pressure O2 toxicity is prevented by limiting the O2
pulmonary oedema. exposure time: divers calculate their maximum
As the breath-hold diver ascends, the air within time underwater, based on the depth of the dive.
the lungs re-expands. However, as metabolic pro-
cesses continue during the course of the dive, alveolar What is decompression sickness?
O2 will have been consumed and CO2 produced.
Decompression sickness is a consequence of
On reaching the water’s surface, the lung volume will
breathing N2 at high partial pressures. N2 is usually
be reduced slightly due to O2 consumption being
poorly soluble in blood, with very little dissolved in
slightly higher than CO2 production (see Chapter 17).
the circulation at sea level. However, SCUBA divers
The fraction of O2 within the lung will be decreased:
breathing compressed air mixtures inhale higher par-
rapid ascent from a deep-water dive therefore results
tial pressures of N2. According to Henry’s law, the
in a rapid fall in the alveolar partial pressure of
amount of N2 dissolved in solution is proportional to
O2, potentially resulting in cerebral hypoxia and
the partial pressure of N2 above the solution. There-
unconsciousness.
fore, additional N2 crosses the alveolar–capillary
membrane into the circulation, where it deposits into
How does breath-hold diving compare the body’s tissues.
with SCUBA diving? The problem comes at ascent:
SCUBA stands for ‘self-contained underwater Slow, staged ascent allows a steady reduction in
breathing apparatus’. Compressed air is delivered at the partial pressure of inspired N2. Allowing
ambient pressure from a tank to the diver via a time for equilibration facilitates N2 removal
demand valve (bear in mind that the ambient pressure from the body’s tissues.
depends on underwater depth). Breathing air at ambi- During rapid ascent, the sudden change in
ent pressure avoids the problem of reduced lung ambient pressure causes N2 to come out
volume experienced by breath-hold divers, but intro- of solution, with N2 bubbles forming in
duces a number of other complications: (amongst other organs):
Increased gas density. As the diver descends, – Joints, causing pain (‘the bends’).
the partial pressure of the inspired air increases. – The pulmonary circulation, causing dyspnoea
The density of the inhaled gases is therefore also (‘the chokes’) and retrosternal pain.
higher. Increased gas density results in an increase – The arterial circulation, resulting in gas
in turbulent gas flow (see Chapter 20), especially embolism.
during inspiration, resulting in an increased work
of breathing. N2 in air can be replaced by the In addition to slow ascent, decompression sickness
lower density He to counteract this problem. can be prevented by breathing O2–He gas mixtures.
Nitrogen narcosis. Very high pressures of N2 can Once symptoms of decompression sickness have
directly affect the CNS, leading to a feeling of developed, the most effective treatment is recompres-
euphoria, incoordination, loss of concentration sion in a hyperbaric chamber. This forces the N2
and eventually coma. Again, N2 can be replaced by bubbles back into solution. This is then followed by
He, which has no effect on CNS function at a slow, controlled decompression.
equivalent pressures.
O2 toxicity. As discussed in Chapter 23, breathing Further reading
O2 at high partial pressures is potentially harmful, A. Brubakk, T. S. Neuman. Bennett and Elliotts’
causing acute lung injury, seizures and loss of Physiology and Medicine of Diving, 5th edition.
consciousness. The latter two have profound Saunders, 2002.
430
Chapter
Temperature regulation
83
How is body temperature regulated? Effector system.
Core body temperature is one of the most tightly – Temperature-losing mechanisms are controlled
controlled physiological parameters. Normal core by the anterior hypothalamus: sweating and
body temperature ranges from 36.5 to 37.5 °C. skin vasodilatation.
Peripheral body temperature, the skin and subcutane- – Temperature-conserving and -generating
ous tissues of the trunk and limbs, is less well con- mechanisms are controlled by the posterior
trolled – the difference between core and peripheral hypothalamus: vasoconstriction, shivering,
temperatures is usually around 2–3 °C, but can be as non-shivering thermogenesis, behavioural
much as 20 °C in extreme circumstances. changes (for example, putting on more clothes
Body temperature is determined by a balance of or turning up the central heating).
heat loss and production:
Whilst BMR cannot be increased to boost heat pro-
Heat loss occurs due to radiation, convection, duction, shivering is extremely effective, producing
evaporation (sweat and respiration), conduction up to a sixfold increase in heat production.
and loss in urine and faeces.
Heat is produced by basal metabolic processes,
exercise, shivering, and non-shivering How does general anaesthesia disturb
thermogenesis (in neonates and infants). the normal thermoregulatory
Temperature is regulated by both feedforward and mechanisms?
negative-feedback loop control. Feedforward control Mild hypothermia (34.0–36.5 °C) is common during
is mediated by the CNS involving interpretation and general anaesthesia – the cause is often multifactorial:
prediction of the external environment. If it is Patients may arrive at theatre cold; for example,
snowing, you are likely to put on a coat before going following a prolonged wait in a cold preoperative
outside. This prevents any temperature change from ward whilst wearing a thin hospital gown.
occurring. The hypothalamic set-point is lowered during
Negative-feedback control contains the usual elem- general anaesthesia. Normally, the hypothalamus
ents for sensing and correcting the internal environment: responds to a core temperature below 36.5 °C with
Temperature sensors. These are a large family of vasoconstriction, and shivering commences at
temperature-gated ion channels known as 36.0 °C. Under general anaesthesia, these
transient receptor potential (TRP) channels. TRP threshold temperatures are lowered by 2–3 °C.
channels responding to warmth include TRPV4, Behavioural changes are (obviously) lost under
TRPV3, TRPV2 and TRPV1. TRPV1 is also general anaesthesia. The patient is no longer able
activated by capsacin, a chemical found in chillis. to put on additional layers of clothes, or increase
TRP channels responding to cold include TRPM8 the environmental temperature with external
and TRPA1. Peripheral and core temperature heating.
sensors send information to the hypothalamus. Muscle paralysis prevents shivering.
A control centre. The hypothalamus analyses the Most anaesthetic drugs cause vasodilatation,
afferent temperature signals, checks them against counteracting the normal vasoconstriction
a set-point and controls the efferent response. response to hypothermia.
431
Figure 83.1 Characteristic pattern of

37 intraoperative hypothermia.
Re
dis
36 trib
uti
on
Core temperature (oC)
35 Linea
r
Plateau
Neuraxial blockade alone
34
General anaesthesia
33
Combined GA / neuraxial blockade

32
0 1 2 3
Time (h)
The reduction in core body temperature associ- – ‘J’ waves may be seen on the ECG; they are
ated with general anaesthesia normally follows a tri- thought to represent an increase in phase 1
phasic pattern (Figure 83.1): repolarization.
Redistribution phase. A decrease in core – HR and blood pressure decrease with the
temperature of 1.5–2.0 °C over 30–45 min. This is severity of hypothermia; severe bradycardia
a consequence of the administration of a (<30 bpm) is very common below 28 °C.
vasodilator (for example, a volatile anaesthetic) in – Arrhythmias are increasingly common. Below
combination with a reduction in the hypothalamic 28 °C, spontaneous VF can occur; more victims
set-point for vasoconstriction. of the sinking of RMS Titanic died from
Linear phase. A more gradual fall of 1 °C over the hypothermia-induced VF than from drowning.
next 2–3 h due to radiation, convection and – The oxyhaemoglobin dissociation curve is
evaporation. The degree of evaporation depends shifted to the left, increasing O2 affinity and
on the type of surgery, being highest in open reducing O2 offloading to the tissues.
abdominal procedures. – Blood viscosity increases, which increases left
Plateau phase. When peripheral vasoconstriction ventricular work.
becomes activated, core temperature reaches a – Myocardial ischaemia or infarction may be
plateau when the rate of heat loss is matched by basal precipitated by the physiological
metabolic heat production. However, in patients who changes above.
have both general anaesthesia and neuraxial CNS.
blockade, peripheral vasoconstriction is ineffective – Confusion and irritability occur with mild
and core temperature continues to decline. hypothermia.
– At a core temperature of 20 °C, the EEG may
be consistent with brain death.
What are the adverse effects of Metabolic.
hypothermia? – BMR reduces by 6% for every 1 °C drop in
In addition to heat-conserving mechanisms such as core temperature.
peripheral vasoconstriction and shivering, hypother- – Hyperglycaemia occurs due to reduced cellular
mia causes a number of other physiological changes: uptake of glucose.
Cardiovascular system. The most serious effects – Enzymatic reactions are slowed, including
of hypothermia occur in the cardiovascular those of drug metabolism; the action of muscle
system: relaxants is prolonged.
432
Chapter 83: Temperature regulation
Renal. Suppression of ADH secretion results in a

‘cold diuresis’. Common measures to prevent intraoperative hypo-
thermia include:
Haematological. Hypothermia has been
Active warming with forced-air warmers and
implicated in platelet and clotting heated mattresses.
dysfunction, but it is likely that these effects Warming of intravenous fluids and blood.
are only minor. Humidification of inspired gases.
Clinical relevance: adverse effects of intraoperative

hypothermia
There are a number of adverse effects associated
Further reading
C. M. Harper, J. C. Andrzejowski, R. Alexander. NICE and
with mild perioperative hypothermia:
warm. Br J Anaesth 2008; 101(3): 293–5.
Myocardial ischaemia, infarction and arrhythmias.
Increased intraoperative blood loss, and S. C. Kettner, C. Sitzwhol, M. Zimpfer, et al. The effect of
increased requirement for transfusion. graded hypothermia (36 °C–32 °C) on haemostasis in
Increased incidence of postoperative wound anaesthetized patients without surgical trauma. Anesth
infection. Analges 2003; 96(6): 1772–6.
Prolonged postoperative recovery and prolonged D. A. Kirkbride, D. J. Buggy. Thermoregulation and mild
hospital stay. perioperative hypothermia. Contin Educ Anaesth Crit
Care Pain 2003; 3(1): 24–8.
433
Index
abciximab, 339 allergic reactions, 356 anaesthetic breathing systems

ABO blood group system, 29, 345 allergic rhinitis, 363–4 mechanical dead space, 47–8
acetylcholine (ACh), 234 allodynia, 272 re-breathing effect, 47–8
acetylcholine receptors (AChRs), allopurinol, 301, 310 anaesthetic drugs
234–5, 267–8 altitude physiology, 42, 78–9, 81, 99, effects on the respiratory system,
acetylcholinesterase (AChE), 20, 232 425–8 107–8
acid alveolar–arterial (A–a) gradient, 78 effects on ventilation control, 95
Brønsted–Lowry definition, 328 alveolar–capillary barrier, 24, 40, 42–3 anaphylaxis, 363–5
definitions, 328 alveolar dead space (V Alv
D ), 45–6 anatomical dead space
strong and weak acids (pKa), 328–9 alveolar diffusion, 40–4, 64–5 Fowler’s method of measurement,
acid–base disorders, 121, 329–30, 336 rate of diffusion equation, 40 48
acid–base physiology, 330–1, 333–6 alveolar gas equation (AGE), 64, 77–9 anatomical shunt, 96
acidaemia, 328 alveolar surface tension, 83–4, 88 anaxonic neurons, 184
acidosis, 329–30 alveolar ventilation, 46–8, 69 angina
acromegaly, 391 alveolar volume (VA), 45 anti-anginal drugs, 157
action potential, 221 alveoli, 24 anion gap, 330–1
acute high-altitude illness, 427 cell types, 24 equation, 330
acute kidney injury (AKI), 309–10 determining the PAO2, 77 anorexia nervosa, 382–3
acute pancreatitis, 289 aminophylline, 301 Anrep effect, 121
acute respiratory distress syndrome amoxicillin, 410 anterior spinal artery syndrome, 209,
(ARDS), 51, 157, 329, 357 anabolism, 369 214
Addison’s disease, 326 anaemia, 351–3 antiarrhythmic drugs, 253–4
adenine (A), 8 global oxygen delivery in an antibiotics, 195, 364
ADP (adenosine diphosphate) anaemic patient, 74–5 antibodies (immunoglobulins),
receptor antagonists, 339 anaemic hypoxia, 64 358–60, 362–3, 409
adrenal glands, 397–400 anaerobic metabolism, 81 antidiuretic hormone (ADH), 149,
adrenaline, 20, 400 anaesthesia 318, 321, 324, 387, 390–1
adrenergic receptors (adrenoceptors), and airway resistance, 90–1 antiemetic drugs, 284
268 and global oxygen consumption, 76 antifibrinolytic drugs, 344
adrenocorticotropic hormone and global oxygen delivery, 76 antigens, 355
(ACTH), 384, 389–90 at altitude, 427–8 anti-platelet drugs, 116, 338–40
aerobic metabolism, 64 effects of hypoxic pulmonary aortic stenosis, 122–3
ageing, 119, 420–4 vasoconstriction (HPV), 99–100 apneustic centre, 92
Acquired immunodeficiency effects on normal thermoregulatory apnoea, 38–9
syndrome (AIDS) patients, 364 mechanisms, 431–2 test for brainstem death, 52
airway devices effects on the immune system, 364–5 arachnoid mater, 188
effects on the respiratory system, emergency anaesthesia, 55 area postrema, 195
108 for thyroid surgery, 394–5 arginine vasopressin. See antidiuretic
airway resistance, 88–9 halothane hepatitis, 295–6 hormone (ADH)
and anaesthesia, 90–1 heat loss during, 431–2 arterial baroreceptor reflex, 166–7
albumin, 366–7 hypercapnoeic acidosis, 329–30 arterial CO2 tension, 46–8, 66
alcohol hypotensive anaesthesia, 149 arterial pressure wave
acute binge, 301 low flow anaesthesia, 29 Windkessel effect, 150
chronic abuse, 301 management in sickle cell disease, arterial pressure waveform, 150–2
metabolism, 301 33 arterial pulse contour analysis, 152
aldosterone, 387, 398 minimal flow anaesthesia, 29 arterial system, 144–9
alkalaemia, 328 See also general anaesthesia. arterioles, 146–8
alkalosis, 330 anaesthetic agents arteriovenous anastomoses, 158
allergens, 355 negative inotropic effects, 121 aspiration pneumonia, 277, 281
434
Index
aspirin, 116, 312, 339 non-invasive measurement, 148 brain anatomy, 186–7
asthma, 89, 329, 356, 363–4 systolic blood pressure (SBP), 148 basal ganglia, 186
astrocytes, 188 See also mean arterial pressure cerebellum, 187
atelectasis, 21 (MAP). cerebral cortex, 186
caused by general anaesthesia, 108 blood substitutes (O2-carrying cerebral hemispheres, 186
ATP (adenosine triphosphate), 5–6, solutions), 350 corpus callosum, 186
369, 373 blood transfusion diencephalon, 186–7
ATPases, 14 allogenic transfusion, 346 embryological classification, 187
atracurium, 424 autologous transfusion, 346, 349 frontal lobe, 186
atropine, 410 blood groups, 29 hypothalamus, 186–7
autonomic nervous system (ANS), blood substitutes (O2-carrying lateral geniculate nucleus, 187
172, 184–5, 265–8 solutions), 350 limbic system, 186
autonomic neurons, 184–5 cell salvage, 349 medial geniculate nucleus, 187
autosomal dominant inheritance, 11 complications of massive medulla oblongata, 187
autosomal recessive inheritance, 11 transfusion, 349–50 meninges, 187–8
autotransfusion, 156 cross-match tests, 347 mesencephalon (midbrain), 187
axons, 183 haemolytic transfusion reaction, metathalamus, 187
346–7 occipital lobe, 186
Bain circuit (Mapleson D), 47 infectious disease transmission, parietal lobe, 186
Bainbridge reflex, 166–7 348 pons, 187
balloon-tipped pulmonary artery iron overload (haemosiderosis), prosencephalon (forebrain), 187
catheter, 100 348 rhombencephalon (hindbrain), 187
See also pulmonary artery catheter massive transfusion, 349–50 subthalamus, 187
Bamford classification of ischaemic O2 binding in transfused blood, 32 telencephalon (cerebrum), 186
stroke, 189 potential complications, 348 temporal lobe, 186
barbiturates, 301 storage of blood products, 347–8 thalamus, 186
barotrauma, 51 universal donor, 347 Wernicke’s area, 186
Barrett’s oesophagus, 277 universal recipient, 347 brain injury
basal ganglia of the brain, 186 blood velocity and flow equation, 142 primary, 204
basal metabolic rate (BMR), 379 body secondary, 204
base compartments, 316 See also traumatic brain injury
Brønsted–Lowry definition, 328 general organization, 1–4 brainstem death testing
definitions, 328 organs, 1 apnoea test, 52
base excess, 330 systems, 1–2 bronchial circulation, 96
basophils, 356 body plethysmography and lung transplant surgery, 96
Bazett’s formula, 262 calculation of FRC, 53–4 Brønsted–Lowry definitions of acid
Becker's muscular dystrophy, 242 Bohr effect, 37 and base, 328
benzodiazepines, 195, 231, 423 Bohr equation, 45, 49 Brown-Séquard syndrome, 210, 214
β-blockers, 116, 121 Bohr method butyrylcholinesterase, 20
bipolar neurons, 184 measurement of physiological dead
bisoprolol, 116 space, 49 calcitonin, 397
bleomycin-induced oxygen toxicity, bone disease calcium (Ca2+) in the body, 219–20,
103 and kidney dysfunction, 397 395–7
bleomycin treatment and liver dysfunction, 397 calcium channel blockers, 116, 121
pulmonary fibrosis related to, 103 bone mineral density calcium resonium, 327
blood constituents, 366 effects of weight-bearing exercise, capillaries, 153–6
blood–brain barrier (BBB), 153, 196 182 capillary–tissue exchange, 153–4
blood haematocrit botulinum toxin, 234 carbamazepine, 301
influence on cerebral blood flow Bowditch effect, 122 carbaminohaemoglobin, 37
(CBF), 198 Boyle’s law, 53–4 carbohydrates
blood oxygen content equation, 28 brain, 184 digestion and absorption, 287
blood pressure cerebral arterial blood supply, carbon dioxide (CO2)
diastolic blood pressure (DBP), 188–9 Bohr effect, 37
148 electroencephalogram (EEG), diffusion rate, 40
in tachycardia, 148 189–90 Haldane effect, 37
invasive measurement method, extrapyramidal system, 186 methods of transport in the
148 stroke, 189 circulation, 36–7
manipulation in clinical practice, venous drainage, 189 physiological effects of apnoea, 38–9
149 ventriculomegaly, 192 production and storage, 36
435
Index
carbon dioxide (CO2) (cont.) influence of heart rate (HR), 121 carriers, 14
proportion in each transport form, influence of myocardial cholesterol, 13
37–8 contractility, 120–1 endocytosis, 17
carbon dioxide (CO2) arterial partial influence of preload, 120–1 enzymes, 14
pressure myocardial ischaemia, 121 exocytosis, 17
effects on cerebral blood flow, regulatory factors, 120–1 functions of transmembrane
198 relationship to mean arterial proteins, 13–14
carbon dioxide (CO2) dissociation pressure (MAP), 122 glycolipids, 13
curve, 38–9 cardiac output (CO) equation, 120 glycoproteins, 13
carbon monoxide cardiac output (CO) measurement ion channels, 14
carboxyhaemoglobin, 32 invasive methods, 123–7 mechanisms of transport across,
diffusion rate, 41–2 methods based on the Fick 14–17
effects on O2-carrying capacity, principle, 123–6 passive transport across, 15–16
34 methods of measurement, 123 peripheral proteins, 13
lung diffusion capacity (DLCO), minimally invasive methods, pumps (ATPases), 14
43 127–9 receptors, 14
carboxyhaemoglobin, 32 pulse contour analysis, 126–7 structure, 13
cardiac action potential cardiac resynchronization therapy transcytosis, 17
action of the pacemaker currents, (CRT), 114 transmembrane proteins, 13
255 cardiac toxicity transport of hydrophilic substances
conduction through the heart, effects of local anaesthetics, 258 across, 14–17
255–6 cardiac work transport of lipophilic substances
differences from nerve action relationship to left ventricular across, 14
potential, 250–1 pressure–volume loop, 137–8 vesicular transport across, 17
pacemaker cells, 254–5 cardiogenic pulmonary oedema, 99 cell nucleus, 5
pacemaker potential, 255 cardiogenic shock, 149 cell salvage for autologous transfusion,
phases, 251–3 cardiopulmonary bypass, 335 349
refractory periods, 253 cardiovascular reflexes cellular respiration, 369
cardiac arrhythmias, 161, 253–4 arterial baroreceptor reflex, 166–7 central cord syndrome, 214
cardiac cycle Bainbridge reflex, 167 central nervous system (CNS), 184
definition, 117 classes of haemorrhagic shock, brain, 184
events, 117–19 169 neuroglia, 188
phases, 117 classification, 166 oxygen toxicity effects, 102
cardiac failure, 130–4, 139–40 consequences of peripheral spinal cord, 184
cardiac index (CI), 122 chemoreceptor activation, central venous cannulation, 164–5
cardiac muscle 167–8 central venous oxygen saturation
contraction mechanism, 256–7 Cushing’s reflex, 167 (ScvO2), 163
excitation–contraction coupling, decompensated shock, 169 central venous pressure (CVP),
256 physiological response to 161–3
function, 130 haemorrhage, 168–9 central venous pressure (CVP)
functional syncytium, 112 cardiovascular system waveform, 161
influence of the autonomic nervous components, 1, 141 centrilobular necrosis of the liver,
system, 257–8 effects of exercise, 176–8 295–6
resting membrane potential (RMP) effects of physical training, 182 cerebellum, 187
in cells, 250 effects of the Valsalva manoeuvre, cerebral arterial blood supply,
structural features, 250 171 188–9
termination of contraction, 257 See also pulmonary circulation; cerebral autoregulation, 197
cardiac output (CO) systemic circulation cerebral blood flow (CBF)
Bowditch effect, 122 catabolism, 369 cerebral autoregulation, 197
calculation from the arterial production of ATP, 369 cerebral perfusion pressure (CPP),
pressure waveform, 152 catalysts, 18 197
cardiac index (CI), 122 catecholamines, 194–5, 312, 387, effects of anaesthetic drugs,
definition, 120 399–400 198–200
effects of ageing, 119 cauda equina syndrome, 214 effects of CO2 arterial partial
effects of aortic stenosis, 122–3 cell pressure, 198
ejection fraction (EF), 119 basic structure, 5 effects of low CBF on neurons,
factors affecting stroke volume organelles, 5–7 197–8
(SV), 120 cell membrane, 5 effects of O2 arterial partial
influence of afterload, 120–1 active transport across, 16 pressure, 198
436
Index
factors affecting global CBF, 198 cor pulmonale, 99 DiGeorge syndrome, 358
flow–metabolism coupling, 198 coronary blood flow, 114–16 digestion
influence of blood haematocrit, 198 coronary circulation, 112–13 role of the lymphatic system, 164
measurement, 197 corpus callosum, 186 digestive system, 2
methods of measurement, 200 corticospinal tract, 211–12 digoxin, 121–2, 366
normal level, 197 corticotropin-releasing hormone dipyridamole, 339–40
proportion of cardiac output (CO), (CRH), 389 dissociated sensory loss, 210–11
197 cortisol, 386–7, 398–9 disulfiram, 301
cerebral blood supply creatinine, 312 diuretics, 324
stroke, 189 critical illness diving
cerebral cortex, 186 causes of peripheral oedema, 156 airway resistance, 89
voluntary control of breathing, 94 complex acid–base disturbance, ambient pressure change during
cerebral hemispheres, 186 336 descent, 429
cerebral perfusion pressure (CPP), 197 global oxygen delivery, 76 breath-hold and SCUBA compared,
cerebrospinal fluid (CSF), 191–2 hyperglycaemia, 385 430
cerebrum (telencephalon), 186 hypoalbuminaemia, 156 decompression sickness, 430
Charcot–Marie–Tooth disease, 235 myopathy, 242 effects on air within lungs on a
chemoreceptors risk associated with etomidate, 399 breath-hold dive, 429–30
central, 93 Cushing’s disease, 391, 398 physiology of a body during
peripheral, 92–3 Cushing’s reflex, 167, 202–3 head-out immersion, 429
choroid plexus, 195 cyanide poisoning, 32, 34–5 risk of oxygen toxicity, 102–3
chromosomes, 8 cyanohaemoglobin, 32 diving reflex, 429
chronic obstructive pulmonary disease cyclizine, 284 DLCO (lung diffusion capacity for
(COPD), 53, 89–90, 93, 99–100, cyclo-oxygenase (COX) inhibitors, 339 carbon monoxide), 43–4
105–6, 329 cystic fibrosis, 10 DNA (deoxyribonucleic acid), 5,
chyle, 164 cytochrome P450 enzymes, 20 8–9
chylomicrons, 164 cytoplasm, 5 dobutamine, 121, 149
chylothorax, 165 cytosine (C), 8 domperidone, 284
ciclosporin, 301 cytotoxic hypoxia, 64 l-DOPA, 194–5, 399
cimetidine, 301 cytotoxic T-cells (CD8+ T-cells), dopamine, 20, 389
circle of Willis, 188–9 361–2 dorsal respiratory group (DRG) of
circle system (anaesthetic breathing neurons, 92
system), 47 Dalton’s law, 425 double-lumen endotracheal tubes
circulatory system, 1 dantrolene, 240 (DLETTs), 23
circumventricular organs, 195–6 Darcy’s law, 97, 122, 145, 147 doxapram, 95
citric acid cycle, 369, 371–2 decompensated heart failure, 133–4 drug metabolism
clopidogrel, 116, 339 decompensated shock, 169 inter-patient variability, 301
closing capacity (CC), 55 demyelinating disease, 224 processes in the liver, 301
clotting dendrites, 183 drugs
laboratory tests, 341–3 denervation hypersensitivity, 235 effects on ventilation control, 95
coagulation deoxyhaemoglobin, 30, 37 transport across the blood–brain
cell-based model, 341 desmopressin (DDAVP), 341 barrier (BBB), 195
coagulation cascade, 338–41 diabetes insipidus, 321 Duchenne’s muscular dystrophy,
cocaine, 232 diabetes mellitus, 312 242
codeine, 301 diabetic autonomic neuropathy, 172 duodenal ulcers, 281
codons, 10 diabetic ketoacidosis, 374, 378 dura mater, 187–8
coenzymes, 19–20 diamorphine, 195
cofactors, 19–20 diarrhoea ectoderm, 1
compensated heart failure, 132–3 oral rehydration therapy (ORT), eicosanoids, 309, 357, 387
complement system, 357–8 287 Einthoven’s triangle, 113
complex regional pain syndrome diastolic blood pressure (DBP), 148 ejection fraction (EF) equation, 119
(CRPS), 273 diencephalon, 186–7 electrocardiogram (ECG), 113–14,
compliance dietary nutrients 117, 261–4
of the venous system, 158–9 carbohydrate digestion and electroencephalogram (EEG),
congestive heart failure, 156 absorption, 287 189–90
Conn’s syndrome, 327 lipid digestion and absorption, 288 electrolytes, 2, 121, 219–20
contact dermatitis, 364 main classes, 287 electron transport chain, 369, 372–3
continuous positive airway pressure protein digestion and absorption, Embden–Meyerhof pathway, 369–70
(CPAP), 100 287–8 endocrine signalling, 183
437
Index
endocrine system dynamic exercise, 174 pre-eclampsia, 408–9

components, 2 effects on bone mineral density, 182 reversion to a transitional
effects of the stress response, 384–5 effects on skeletal muscle, 176 circulation, 415
endoderm, 1 effects on the cardiovascular system, fibrinogen, 366
endoplasmic reticulum (ER), 6–7 176–8 fibrinolysis pathway, 343–4
endothelin (ET), 157 effects on the respiratory system, Fick’s law, 28, 40
endothelium functions, 156–7 178–9 flail chest, 329
anticoagulant properties, 157 effects on thermoregulation, 179 flavin adenine dinucleotide (FAD),
haemostasis, 157 elite athletes, 182 369
inflammatory system, 157 excess post-exercise oxygen flow–metabolism coupling, 198
procoagulant properties, 157 consumption (EPOC), 181–2 flow–volume curve, 60–1
synthesis of vasoactive substances, meaning of V_ O2 max , 179–80 flow–volume loop, 60–1
157 muscle fatigue, 175 fluid balance
endotracheal tubes (ETTs), 91 O2 consumption after exercise, role of the lymphatic system, 164
choice for children, 416–17 181–2 fluid management, 162–3
enoximone, 121 oxygen debt, 181–2 follicle-stimulating hormone (FSH),
enteric nervous system, 184 physiological challenges of exercise, 387, 389–90
enteric neurons, 184 174 forced spirometry, 56–7
enzymes physiological changes in expiratory flow–volume curve, 58–9
catalysis, 18 anticipation of exercise, 175–6 forebrain (prosencephalon), 187
coenzymes, 19–20 skeletal muscle energy sources, 175 Fowler’s method, 45
cofactors, 19–20 skeletal muscle fibre types, 174–5 measurement of anatomical dead
definition, 18 static exercise, 174 space, 48
hydrolases, 19 expiratory flow–volume curve, measurement of closing capacity
importance in anaesthetic practice, 58–60 (CC), 55
20 expiratory reserve volume (ERV), 50 Frank–Starling mechanism, 121, 130
isomerases, 19 extracellular fluid (ECF) volume frontal lobe of the brain, 186
ligases, 19 regulation by the kidneys, 316–17 functional magnetic resonance
lyases, 19 extrapyramidal system, 186 imaging (fMRI)
main features, 18 measurement of CBF, 200
mode of action, 18 factor VIII, 341 functional residual capacity (FRC), 50
oxidoreductases, 19 Fahraeus–Lindqvist effect, 145 calculation using body
regulation of biochemical pathways, farmer’s lung, 364 plethysmography, 53–4
18 fats calculation using gas dilution,
specificity, 18 metabolism, 374 52–3
transferases, 19 fentanyl, 386 calculation using multiple breath
types of, 19 fetal haemoglobin (HbF), 32 nitrogen washout method, 54–5
eosinophils, 356 fetal physiology factors affecting FRC volume, 51–2
ependymal cells, 188 causes of fetal distress, 411–12 importance in emergency
ephedrine, 423 circulation, 99 anaesthesia, 55
epidural anaesthesia, 386 double Haldane effect, 411 importance of, 51
erythromycin, 301 features of the fetal circulation, 412 pre-oxygenation for general
erythropoiesis, 29, 351 features of the fetal respiratory anaesthesia, 52
erythropoietin (EPO), 351 system, 414
esmolol, 149 fetal cardiovascular reflexes during ganglia (PNS), 183
etomidate, 231, 386, 399 labour, 412–14 gas dilution technique, 52–3
excess post-exercise oxygen functions of the placenta, 408 gastric dumping syndrome, 282
consumption (EPOC), 181–2 mechanisms for transfer across the gastric ulcers, 281
excitation–contraction coupling placenta, 409–10 gastrointestinal (GI) tract
cardiac muscle, 256 oxygen delivery, 410–11 organs involved in digestion, 286
skeletal muscle, 239 oxygenation during labour, gastro-oesophageal reflux disease
smooth muscle, 247–8 411–12 (GORD), 277–8, 281
exercise physiological changes at birth, general anaesthesia
effects on RBC transit time, 42 414–15 atelectasis caused by, 108
effects on venous return, 160 placental anatomy related to effects of airway devices, 108
hypoxaemia induced by, 42 function, 408–9 effects on lung volumes, 108
exercise physiology placental antibody transfer, 409 effects on the lungs, 108–9
changes with physical training, placental development, 408–9 postoperative effects on lung
182 placental drug transport, 410 function, 109–10
438
Index
ventilation–perfusion mismatch, fetal haemoglobin (HbF), 32 Henry’s law, 28

109 HbA form, 32 hepatopulmonary syndrome, 65
See also anaesthesia. HbA2 variant, 32 hepcidin, 353
general anaesthetics HbS in sickle cell disease, 32 hexose monophosphate shunt, 377
mechanisms of action, 230–2 methaemoglobin, 32 hindbrain (rhombencephalon), 187
genetic mutations, 10 methaemoglobin clinical His–Purkinje system, 117
genetics significance, 33–4 homeostasis, 2–4
chromosomes, 8 oxyhaemoglobin dissociation curve, homeostatic control mechanisms,
codons, 10 30–2 3–4
Mendelian inheritance patterns, single point mutation in sickle cell hormones, 387
10–12 disease, 32–3 classification, 387
germ cell layers, 1 structure, 29 released by the pituitary gland
Glasgow coma score (GCS), 204 types of, 32 posterior lobe, 390–1
global oxygen consumption, 74 haemophilia, 341 secreted by the hypothalamus,
and anaesthesia, 76 haemorrhage 389
global oxygen delivery physiological responses, 156, secreted by the pituitary gland
anaemic patient, 74–5 168–9 anterior lobe, 389–90
anaerobic threshold, 75–6 haemorrhagic shock, 169 synthesized by the thyroid gland,
and anaesthesia, 76 haemostasis 392
critically ill patient, 76 anti-platelet drugs, 338–40 Hudson mask, 47
definition, 74 cell-based coagulation model, Hüfner’s constant, 28
typical resting global oxygen 341 human genome project, 8
delivery, 74–5 coagulation cascade, 338–41 humidification of inspired gases, 22
globulins, 366 coagulation disorders, 341 Huntingdon's disease, 10
glomerular filtration rate (GFR), components involved, 337 hyaline membrane disease, 414
313–15 definition, 337 hydrocephalus, 192
glucagon, 121, 377–9 fibrinolysis pathway, 343–4 hydrogen peroxide (H2O2), 102
gluconeogenesis, 377 functions of the endothelium, hydrolases, 19
glyceryl trinitrate, 116, 149, 157 157 hydroxyl free radicals (OH•), 102
glycolysis, 369–70 haemostatic response, 337 hyoscine, 284
glycoprotein IIb/IIIa inhibitors, 339 inhibition of fibrinolysis, 344 hyperalgesia, 271–2
glycopyrrolate, 410 initiation, 337–8 hypercapnoea, 94
glymphatic system, 191 laboratory tests of clotting, 341–3 hyperglycaemia, 312
Goldman–Hodgkin–Katz equation, platelet activation and aggregation, hyperkalaemia, 219, 326–7
218 338 hypersensitivity, 363–4
Golgi apparatus, 7 role of the vascular endothelium, hyperthyroidism, 394
Golgi tendon organs, 243 337 hyperventilation, 46–7, 94
gonadotropin-releasing hormone steps in clot formation, 337 hypervolaemia, 324–5
(GnRH), 389 thromboelastography, 343 hypoalbuminaemia, 156
Goodpasture’s disease, 309, 364 thrombolysis, 343–4 hypokalaemia, 219, 327
graft-versus-host disease Hagen–Poiseuille equation, 89, 144–6 hypomagnesaemia, 327
in blood transfusion, 348 Haldane effect, 37–8, 411 hyponatraemia, 219, 318
Graham’s law, 40 halothane hepatitis, 295–6 hypotension, 149
Graves’ disease, 394 haptens, 355 hypotensive anaesthesia, 149
growth hormone (GH), 376, 389–90 head injury hypothalamic–pituitary axis, 389
growth-hormone-releasing hormone classification systems, 204 hypothalamus, 186–7, 195,
(GHRH), 389 heart 387–9
guanine (G), 8 blood flow to the myocardium, hypothermic cardiopulmonary bypass,
Guillain–Barré syndrome, 57–8, 224, 114 335
329 functions, 111 hypothyroidism, 394
influence of the autonomic nervous hypotonicity, 318
haemochromatosis, 353 system, 257–8 hypoventilation, 64, 78, 81
haemoglobin structure, 111 hypovolaemia, 152, 323–4
carboxyhaemoglobin, 32 venous drainage, 113 hypoxaemia, 42, 64–5, 71, 94
cooperative binding of oxygen, heart failure, 130–4, 139–40 hypoxaemic hypoxia, 64
30 heart rate (HR), 261 hypoxia, 64–5
cyanohaemoglobin, 32 heart transplant:, 258–60 hypoxic pulmonary vasoconstriction
effects of carbon monoxide Henderson–Hasselbalch equation, (HPV), 98–100
poisoning, 34 329–30 hysteresis, 85
439
Index
idiopathic thrombocytopaenic signs and symptoms of raised mechanism of ADH action on,
purpura, 364 pressure, 202 318
IgA nephropathy, 310 ways to reduce, 203–4 nephron structure and function,
immune complex disease, 364 ion channels, 14 305–7
immune system ionotropic receptors, 229–30 pathophysiology of acute kidney
active immunity, 360 iron injury (AKI), 309–10
adaptive immune system, 355, control of iron homeostasis, 353 reabsorption from tubular fluid,
358–60 handling in the body, 352–3 311
antibodies (immunoglobulins), iron overload (haemosiderosis) reabsorption limit in
358–60, 362–3 related to blood transfusion, 348 hyperglycaemia, 312
cell-mediated immunity, 361–2 irritant receptors, 94 reglation of renal blood flow, 307
complement system, 357–8 ischaemic heart disease, 121 regulation of extracellular fluid
components, 2 isomerases, 19 volume, 316–17
cytotoxic T-cells (CD8+ T-cells), isoniazid, 301 regulation of Na+ excretion, 322
361–2 isoprenaline, 121 regulation of plasma volume,
definition of allergen, 355 316–17
definition of antigen, 355 jaundice, 299–300 renal autoregulation, 307
definition of hapten, 355 Jehovah’s Witnesses, 349–50 renal autoregulation mechanism,
development of antibodies to RBC Jendrassik manoeuvre, 245 307–8
antigens, 345–6 jugular bulb catheterization, 200 renal clearance definition, 313
effects of anaesthesia and surgery, juxtacapillary receptors (J-receptors), renal clearance equation, 313
364–5 94 renal replacement therapy (RRT),
hypersensitivity, 363–4 314–15
inflammation, 356–7 ketamine, 231, 410 renal transplant, 315
innate immune system, 355 ketone bodies, 374 role in regulation of plasma K+
lymphocytes, 358 Kety–Schmidt technique, 200 concentration, 325–6
lymphoid tissue, 358 kidney Starling forces and the GFR, 313
passive immunization, 361 actions of diuretics, 324 use of clearance in GFR
primary immune response, 358–60 active secretion of waste products, measurement, 314
role of eicosanoids, 357 312 kidney dysfunction
role of kinins, 357 acute interstitial nephritis, 310 and bone disease, 397
role of the lymphatic system, 164 acute tubular necrosis (ATN), kinins, 357
secondary immune response, 360 309 knee-jerk reflex, 244–5
white blood cells (leucocytes) anatomy, 305 Krebs cycle. See citric acid cycle
involved in the immune response, clearance of drugs from the blood,
355–6 312 labetalol, 149
immunodeficiency classification, effects of ADH, 318 lactic acidosis, 370–1
363 effects of Starling filtration forces, Laplace’s law, 83
immunoglobulins (Igs), 362–3, 366 156 laryngeal mask airway (LMA), 91
See also antibodies filtration fraction, 315 larynx, 21
infant respiratory distress syndrome filtration process, 311 lateral geniculate nucleus, 187
(IRDS), 84, 88, 414 functions, 305 lateral medullary syndrome, 211
inflammation, 356–7 generation of high osmolarity in the left ventricular pressure–volume loop,
inspiratory capacity (IC), 50 renal medulla, 319–20 135–40
inspiratory reserve volume (IRV), 50 GFR as indicator of kidney function, ligases, 19
insulin, 377–9, 387 314 limbic system, 94, 186
integumentary system, 2 glomerular filtration rate (GFR), lipase inhibitors, 288
intensive care 313–14 Listeria monocytogenes, 409
risks related to oxygenation, 103 glomerulonephritis, 309–10 liver
internal carotid arteries, 188–9 handling of urea, 322 blood supply, 292
intra-aortic balloon pump, 149 histology, 305–7 centrilobular necrosis, 295–6
intracranial pressure (ICP) influence of eicosanoids on blood halothane hepatitis, 295–6
Cushing’s triad, 202–3 flow, 309 intraoperative liver blood flow,
definition, 201 influence of 293
factors influencing, 201–2 renin–angiotensin–aldosterone living donor transplantation,
methods of measurement, 201 axis on blood flow, 308–9 297
Monro–Kellie hypothesis, 201–2 juxtaglomerular apparatus, 307 macroscopic anatomy, 293
normal range, 201 measurement of renal blood flow, main cell types, 294–5
raised, 21–2 310 microscopic anatomy, 293–4
440
Index
physiological reserve, 297 lung resection, 43–4 lymphoid tissue, 358

regeneration capability, 297 preoperative work using spirometry, lysosomes, 7
regulation of hepatic blood flow, 61–3
292 lung transplantation macrophages, 356
respiratory cycle influence on and the bronchial circulation, 96 malignant hyperthermia, 239–40
venous blood flow, 292–3 lung ventilation mannitol, 195
liver dysfunction regional differences in, 85–7 mast cells, 356, 358, 363–4
and bone disease, 397 static compliance curve, 85–7 mean arterial pressure (MAP), 120,
liver function lung volumes 148
classification of functions, 297 distinction from lung capacities, 50 arterial baroreceptor reflex, 166–7
drug metabolism, 301 effects of general anaesthesia, 108 Bainbridge reflex, 167
endocrine functions, 300 expiratory reserve volume (ERV), classes of haemorrhagic shock, 169
exocrine functions, 298–9 50 classification of cardiovascular
factors affecting drug metabolism, inspiratory reserve volume (IRV), reflexes, 166
301 50 consequences of peripheral
immunological functions, 300 methods of measurement, 52 chemoreceptor activation, 167–8
jaundice, 299–300 residual volume (RV), 50 Cushing’s reflex, 167
liver function tests, 302–3 tidal volume (VT), 50 decompensated shock, 169
metabolic functions, 297–8 tidal volume in mechanically effects of the Valsalva manoeuvre,
physiological changes in cirrhosis, ventilated patients, 51 171
302 lungs importance of minimizing
physiological functions, 301–2 alveolar dead space (V Alv
D ), 45–6 fluctuations, 166
substances synthesized by the liver, alveolar volume (VA), 45 manipulation in clinical practice,
300–1 anatomical dead space (V Anat
D ), 45 149
testing in paracetamol overdose, anatomy, 23 physiological response to
303 atelectasis caused by general haemorrhage, 168–9
liver transplantation criteria, 303 anaesthesia, 108 relationship to cardiac output (CO),
local anaesthetics causes of pulmonary oedema, 156 122
action on nerve axons, 185 components of tidal volume (VT), mean arterial pressure (MAP)
forms of toxicity, 258 45 equation, 122
placental transfer, 410 defence mechanisms, 25–7 mechanical ventilation, 51
response of different types of nerve definition of dead space (VD), 45 mechanoreceptors, 93–4
fibre, 225–6 definition of dead-space ventilation, medial geniculate nucleus, 187
Lorraine Smith effect, 102 46 medulla oblongata, 187
low flow anaesthesia, 29 effects of general anaesthsia, 108–9 area postrema, 195
lung capacities effects of gravity on perfusion, 69 melatonin, 195
closing capacity (CC), 55 effects of physical training, 182 Mendelian inheritance patterns, 10–12
distinction from lung volumes, 50 endocrine functions, 27 Mendelson’s syndrome, 278
functional residual capacity (FRC), immunological functions, 25–7 meninges, 187–8
50–2 inflation and deflation during tidal meningitis, 195
inspiratory capacity (IC), 50 breathing, 24–5 mesencephalon (midbrain), 187
methods of measurement, 52 metabolic functions, 27 mesoderm, 1
total lung capacity (TLC), 50 non-respiratory functions, 21, 25–7 metabolic acidosis, 326, 330
vital capacity (VC), 50 oxygen toxicity effects, 102 metabolic alkalosis, 330
Phys
lung compliance physiological dead space (V D ), 45 metabolic equivalent (MET), 379
component of respiratory pneumothorax, 25 metabolism
compliance, 82 postoperative effects of general aerobic and anaerobic generation of
definition, 82 anaesthesia, 109–10 ATP, 373–4
dynamic compliance, 84–5 pulmonary circulation, 27 ATP generated from a molecule of
effects of surface tension in alveoli, respiratory functions, 21 glucose, 373–4
83–4 types of dead space, 45 basal metabolic rate (BMR), 379
effects of surfactant, 83–4 vascular functions, 27 catabolism of carbohydrates, fats
factors affecting, 82 West zones, 72–3 and proteins to ATP, 369
measurement, 85 luteinizing hormone (LH), 387, cellular respiration, 369
mechanism of pulmonary surfactant 389–90 citric acid cycle, 369, 371–2
action, 84 lyases, 19 definition, 369
static compliance, 84–5 lymph fluid, 164 effects of glucagon, 377–9
lung diffusion capacity for carbon lymphatic system, 164 effects of insulin, 377–9
monoxide (DLCO), 43–4 lymphocytes, 164, 358 electron transport chain, 369, 372–3
441
Index
metabolism (cont.) myocardial ischaemia, 121 neurotransmitters, 228–9

fats, 374 changes in ECG, 113–14 ionotropic receptors, 229–30
gluconeogenesis, 377 myocarditis, 121 metabotropic receptors, 232
glycolysis, 369–70 myoglobin, 35 release at the synaptic cleft, 229
lactic acidosis, 370–1 myotonia congenita, 242 reuptake inhibitors, 232
pentose phosphate pathway (PPP), myotonic dystrophy, 242 termination of neurotransmission,
377 232
production of ketone bodies, 374 Na+ (sodium) in the body, 219, neutrophils, 355–6
protein catabolism, 374 322–3 nicorandil, 116
storage and release of nutrients, Na+/K+-ATPase nicotinamide adenine dinucleotide
374–7 contribution to resting membrane (NAD+), 369
metabotropic receptors, 232 potential, 218–19 nicotinic ACh receptors, 267–8
metaraminol, 149 naloxone, 169 nifedipine, 116
metarterioles, 156 natural killer (NK) cells, 356 nitrate drugs, 116
metastases and the lymphatic system, near-drowning cases nitric oxide (NO), 157
164 loss of pulmonary surfactant, 84 nitric oxide synthase (NOS), 157
metathalamus, 187 negative-feedback loops, 3–4 nitrous oxide (N2O), 41–2, 231–2
metformin, 370–1 neostigmine, 20 nociception
methaemoglobin, 32–4 Nernst equation, 218 distinction from pain, 269
methotrexate, 195 nerve action potential nociceptive pain, 269
microglia, 188 definition, 221 nociceptor nerve fibres, 269
midbrain (mesencephalon), 187 effects of demyelinating disease, 224 nociceptors, 269
minimal flow anaesthesia, 29 effects of myelination on non-steroidal anti-inflammatory drugs
minute ventilation, 46 propagation, 224 (NSAIDs), 309–10, 366–7
mitochondria, 5–6 events leading to, 221 noradrenaline, 20, 149, 400
mivacurium, 20, 424 propagation along nerve axons, nuclei (CNS), 183
molarity, 317 222–4 nucleobases, 8
monoamine oxidase (MAO), 20 refractory period, 226–7 nutrients
monoamine oxidase (MAO) nerve fibres, 185 control in the body, 2
inhibitors, 20 functional classification, 224–5
monocytes, 356 response of different types to local obesity, 88
Monro–Kellie hypothesis, 201–2 anaesthetics, 225–6 obesity hypoventilation syndrome,
morphine, 195, 312 nervous system 329–30
motor (efferent) neurons, 184 central nervous system (CNS), 184 obstructive lung disease, 90
motor units, 241 component systems, 184–5 occipital lobe of the brain, 186
multiple breath nitrogen washout components, 1 oesophageal phase of swallowing,
method, 54–5 functions, 183 276–7
multiple sclerosis, 224 motor output, 183 oesophagus
multipolar neurons, 184 peripheral nerve structure, 185 functional anatomy, 277
muscarinic ACh receptors, 268 peripheral nervous system (PNS), gastro-oesophageal reflux disease
muscle relaxants, 234, 364, 410, 419, 184–5 (GORD), 277–8
424 sensory input, 183 oestrogen, 387
muscle spindles, 243 sensory integration by the CNS, 183 olanzapine, 301
muscle tone, 245–6 signalling systems, 183 oligodendrocytes, 188
muscular system, 1 neural signalling, 183 omeprazole, 281, 301
myasthenia gravis (MG), 105, 234–5, neuraxial blockade, 149 ondansetron, 284
329 neuroglia, 188 one-lung ventilation
Mycobacterium tuberculosis infection, neuromuscular junction (NMJ), 183, and PEEP, 100
364 232–4 opioid drugs, 386, 410
myelin, 183, 188 neurons perioperative effects, 365
myelinated nerve axons, 185 autonomic, 184–5 respiratory depression, 95, 329
effects of demyelinating disease, enteric, 184 oral contraceptive pill, 301
224 morphologic classes, 184 oral phase of swallowing, 276
effects on propagation of nerve motor (efferent), 184 oral rehydration therapy (ORT), 287
action potential, 224 of the CNS, 188 organs
myocardial blood flow, 114 sensory (afferent), 183 components of body systems, 1–2
myocardial contractility signalling systems, 183 development, 1
information from the arterial structure, 183–4 Orlistat, 288
pressure waveform, 152 neuropathic pain, 272–3 osmolality, 317
442
Index
osmolar gap equation, 317 protection against oxidative stress, parasympathetic nervous system,
osmolarity, 317 102 184–5, 265–7
osteoporosis, 397 reactive oxygen species (ROS), 102 parathyroid gland, 397
oxidoreductases, 19 risk for divers, 102–3 parathyroid hormone (PTH), 396
oxygen (O2) oxygen transfer parietal lobe of the brain, 186
cooperative binding to diffusion limitation, 42 Parkinson’s disease, 195
haemoglobin, 30 effects of altitude, 42 Pasteur point, 81
ROS role in normal body functions, perfusion limitation, 42 patellar reflex, 244–5
102 oxygen transport patent ductus arteriosus, 65
oxygen arterial partial pressure blood oxygen content equation, 28 Paul Bert effect, 102
effects on cerebral blood flow, 198 bound to haemoglobin, 28 penicillins, 310, 312, 364
oxygen binding dissolved in plasma, 28 pentose phosphate pathway (PPP),
myoglobin structure and properties, methods of transport in the blood, 377
35 28 perioperative care
oxygen-carrying capacity oxygenation effects of proceures on the immune
effects of carbon monoxide distinction from ventilation, 104 system, 364–5
poisoning, 34 oxygenation function enhanced recovery programme, 382
oxygen-carrying solutions (blood gas-exchange system, 104 methods of reducing the stress
substitutes), 350 oxyhaemoglobin, 30 response, 386
oxygen cascade oxyhaemoglobin dissociation curve, risks associated with polycythaemia,
anaerobic metabolism, 81 30–2 353–4
definition, 80 Bohr effect, 37 perioperative hypothermia, 431–3
effects of high altitude, 81 O2 binding in transfused blood, 32 peripheral chemoreceptors, 167–8
effects of hypoventilation, 81 oxymyoglobin dissociation curve, 35 peripheral nerve structure, 185
effects of pneumomia, 81 oxytocin, 391 peripheral nervous system (PNS),
Pasteur point, 81 184–5
steps along, 80–1 pacemaker cells, 254–5 peripheral oedema, 156
oxygen consumption pacemaker potential, 255 pethidine, 410
after exercise, 181–2 PaCO2 equation, 46 pH
compared with oxygen stores, 28–9 paediatric anatomy and physiology definition, 328
meaning of V_ O2 max , 179–80 choice of ETT for children, 416–17 equation, 328
V_ O2 max and surgical risk, 180–1 classification of age groups, 416 homeostatic mechanisms, 331–3
oxygen debt, 181–2 differences between children and regulation in the body, 2
oxygen diffusion adults, 416–19 relationship to pKa, 329
compared with gases related to pharmacokinetics in children, 419 pH of blood
anaesthesia, 41–2 pain change with temperature, 334–5
compared with other gases, 41 allodynia, 272 in hypothermic cardiopulmonary
rate compared with CO2, 40 classification, 269 bypass, 335
oxygen extraction ratio (OER), 75 complex regional pain syndrome pharmacokinetics
oxygen flux equation, 74 (CRPS), 273 differences between children and
oxygen levels definition, 269 adults, 419
physiological effects of apnoea, 38–9 distinction from nociception, 269 pharmacology
oxygen partial pressure hyperalgesia, 271–2 effects of ageing, 423–4
regulation in the body, 2 modulation mechanisms, 270–1 pharyngeal phase of swallowing, 276
oxygen stores neuropathic pain, 272–3 phenobarbitone, 301
compared with oxygen nociceptive type, 269 phenotype (trait), 10–11
consumption, 28–9 pain signal pathways to the brain, phenylephrine, 149, 423
oxygen toxicity 270 phenytoin, 195, 301
antioxidants, 102 referred pain, 271 phosphodiesterase inhibitors, 339–40
CNS toxicity, 102 role of the sympathetic nervous physiological dead space
effect on the retina, 102 system, 273 Bohr method of measurement, 49
harmful effects on the body, 102 types of nociceptor nerve fibre, physiological fitness assessment
harmful levels of oxygen, 102–3 269 metabolic equivalents (MET), 379
induced by bleomycin, 103 pain management pia mater, 188
Lorraine Smith effect, 102 sympathetic blockade, 267 pineal gland, 195
lung toxicity, 102 pain receptors, 94 pituitary adenoma, 391
mechanism, 102 pancreas, 288–90 pituitary gland, 186, 195
oxygenation in intensive care, 103 paracetamol overdose, 295 anatomy, 388
Paul Bert effect, 102 liver function testing, 303 blood supply, 388–9
443
Index
pituitary gland (cont.) polycythaemia, 353–4 pulmonary fibrosis, 88, 99

hormones released by the posterior pons, 187 related to bleomycin treatment, 103
lobe, 390–1 portal veins, 158 pulmonary function tests (PFTs), 56
hormones secreted by the anterior positive end-expiratory pressure pulmonary hypertension, 157
lobe, 389–90 (PEEP), 21–2, 44, 87 pulmonary oedema, 96, 156
hypothalamic–pituitary axis, 389 extrinsic, 91 pulmonary surfactant, 83–4
pKa, 329 influence on venous return, 159 pulmonary vascular resistance (PVR),
equation, 328–9 one-lung ventilation, 100 96–100
placenta physiological, 90 pyramidal cells, 184
anatomy related to function, 408–9 positive feedback, 4 pyramidal tract, 211–12
development, 408–9 positive pressure ventilation
functions, 408 influence on venous return, 159 ranitidine, 281
mechanisms for transfer across, one-lung ventilation, 100 rapid sequence induction (RSI), 55
409–10 positron emission tomography (PET) reactive oxygen species (ROS), 102
transfer of drugs across, 410 measurement of CBF, 200 red blood cell (RBC) antigens
placental antibody transfer, 409 postoperative nausea and vomiting ABO blood group system, 345
plasma (PONV), 284 antibody development by the
constituent of blood, 366 potassium (K+) in the body, 219, 325–7 immune system, 345–6
hyperkalaemia, 326–7 potassium channel openers, 116 range of antigen systems, 345
hypokalaemia, 327 pregnancy, 379 Rhesus blood group system, 345
mechanisms to regulate potassium alterations in endocrine function, Rhesus disease, 346
(K+) concentration, 325–6 401–2 red blood cells (RBCs)
plasma cholinesterase, 20 challenges of general anaesthesia, cell membrane antigens, 29
plasma glucose concentration 403 erythropoiesis, 351
effects of insulin and glucagon, incidence of glycosuria, 312 stages of erythropoiesis, 29
377–9 physiological changes and steps in production, 351
plasma osmolarity anaesthesia, 402–6 structure and function, 29
clinical disorders of osmolarity, pre-eclampsia, 408–9 refeeding syndrome, 382
320–1 vena cava compression, 159–60 referred pain, 271
definition of osmolarity, 317 preoperative fasting, 282–3 reflex arcs, 243–4
estimated plasma osmolarity pre-oxygenation for general knee-jerk reflex, 244–5
equation, 317 anaesthesia, 52 remifentanil, 20
feedback loop control, 318 probenecid, 312 renal clearance equation, 313
hypotonicity, 318 prolactin (PRL), 387, 389–90 renin–angiotensin–aldosterone axis,
importance of regulation, 317–18 propofol, 195, 231, 365, 410 308–9
interaction with plasma volume proprioception, 243 Renshaw cells, 184
regulation, 324 prosencephalon (forebrain), 187 reproductive system, 2
plasma pH prostacyclin (PGI2), 157 residual volume (RV) of the lungs, 50
Henderson–Hasselbalch equation, protein, 374 respiration
329 digestion and absorption, 287–8 regulatory role of cerebrospinal
plasma proteins proteinuria, 156 fluid, 191
classification, 366 proton-pump inhibitors (PPIs), 281, respiratory acidosis, 329–30
functions of albumin, 366–7 285 respiratory alkalosis, 330
plasma volume pseudocholinesterase, 20 respiratory centre
interaction with plasma osmolarity pseudounipolar neurons, 184 effects of opioid drugs, 95
regulation, 324 pulmonary arteriovenous inputs, 92–4
physiological response to high malformation (AVM), 65 reflex desensitization, 105
volume, 324–5 pulmonary artery catheter (PAC), role in ventilation control, 92
physiological response to low 73, 100 respiratory compliance, 82–3
volume, 323–4 pulmonary circulation respiratory compliance equation, 82
regulation, 316–17 calculation of pulmonary vascular respiratory failure
platelets, 338 resistance (PVR), 96–7 chronic hypercapnoea in stable
anti-platelet drugs, 116, 338–40 comparison with the systemic COPD patients, 105
pneumonectomy, 43–4 circulation, 141 definition, 104
pneumonia, 99 factors affecting PVR, 97–9 exacerbation of COPD, 106
effects on the oxygen cascade, 81 PVR compared with SVR, 96–7 in patient with myasthenia gravis
pneumotachograph, 56 reason for normal low pressure, 96 (MG), 105
pneumotaxic centre, 92 unique features, 96 processes which cause type 2 failure,
pneumothorax, 25 pulmonary embolism (PE), 71 104–5
444
Index
type 1, 104 selective serotonin reuptake inhibitors sodium nitroprusside, 149

type 2, 104 (SSRIs), 232 somatostatin, 389
respiratory quotient (R), 77–8 semi-permeable membranes, 40 spinal anaesthesia, 386
respiratory system, 1 sensory (afferent) neurons, 183 spinal cord, 184
effects of airway devices, 108 sepsis, 121 anatomy, 207
effects of anaesthetic drugs, 107–8 septic shock, 149 anterior spinal artery syndrome,
effects of exercise, 178–9 serotonin, 387 209
oxygenation function (gas shunt equation, 66–8 blood supply, 208–9
exchange), 104 shunts, 65–8 corticospinal tract, 211–12
ventilation function (bellows), 104 sickle cell disease, 10, 348 cross-sectional anatomy, 207–8
respiratory system functional anaesthesia management, 33 dissociated sensory loss, 210–11
anatomy, 21–4 effects of a single point Hb main sensory afferent pathways,
alveoli, 24 mutation, 32–3 209–10
bronchi, 23 HbS abnormal haemoglobin, 32 meninges, 187–8
bronchioles, 23–4 operative management issues, 33 spinal cord injury, 172
conducting zone, 22–4 testing patients for, 33 classification, 212
larynx, 21 sickle cell trait, 32 effects related to level of complete
lungs, 23 testing patients for, 33 injury, 212–13
mucociliary escalator, 22 skeletal muscle initial management of acute spinal
respiratory bronchioles, 24 anatomy, 236 cord injury, 214–16
respiratory zone, 24 differences from smooth muscle, patterns of incomplete spinal cord
trachea, 22–3 247 injury, 214
tracheobronchial tree, 22–4 disorders, 242 spinal shock, 245–6
upper airway, 21 effects of exercise on, 176 spirometers, 56
resting membrane potential (RMP) effects of physical training, 182 spirometry
cardiac muscle cells, 250 energy sources, 175 dynamic spirometry, 56
contribution of Na+/K+-ATPase, excitation–contraction coupling, expiratory flow–volume curve, 58–9
218–19 239 forced spirometry, 56–7
definition, 217 factors which determine muscle lung variables measured, 56
effects of electrolyte disturbances, tension, 241–2 measurement of lung volumes and
219–20 fibre types, 174–5 capacities, 52
Goldman–Hodgkin–Katz equation, functions, 236 preoperative work before lung
218 malignant hyperthermia, 239–40 resection, 61–3
Nernst equation, 218 mechanism of contraction, 240–1 static lung volume measurements,
Nernst equation applied to explain motor units, 241 56
RMP, 218 muscle fatigue, 175 spironolactone, 326
production of, 217–18 sarcomeres, 236–9 stagnant hypoxia, 64
restrictive lung disease, 90 Type I (slow-twitch, fatigue- staircase effect, 122
reticulocytes, 29 resistant) fibres, 174–5 Starling filtration equation, 154
retina Type II (fast-twitch) fibres, 174–5 Starling forces
oxygen toxicity effects, 102 skeletal system, 2 and the glomerular filtration rate
retinopathy of prematurity, 102 skin (GFR), 313
retrolental fibroplasia, 102 integumentary system, 2 and transmembrane fluid flow,
reverse Fick principle, 74 small intestine, 286–7 154–6
Reynolds number, 88–9 intestinal motility, 290–1 Starling’s law of the heart, 120–1, 130
Rhesus blood group system, 29, smoking starvation, 374, 381–3
345 effect on hepatic enzymes, 301 static compliance curve, 85–7
Rhesus disease, 346 smooth muscle static lung volumes
rhombencephalon (hindbrain), 187 adaptation to its function, 249 use of spirometer to measure, 56
rifampicin, 301 contraction mechanism, 248–9 steatorrhoea, 288
right ventricular pressure-volume description, 247 Stewart–Fencl–Story approach to
loop, 138 differences from skeletal muscle, acid–base physiology, 335–6
RNA (ribonucleic acid), 8–10 247 stomach
excitation–contraction coupling, control of gastric emptying, 281–2
salbutamol, 327 247–8 functions, 279
saliva, 275–6 excitatory inputs, 247–8 gastric acid secretion by parietal
salivary glands, 275–6 locations in the body, 247 cells, 280–1
sarcomeres, 236–9 types of, 247 gastric dumping syndrome, 282
Schwann cells, 185 sodium (Na+) in the body, 219, 322–3 neutralization of gastric acid, 281
445
Index
stomach (cont.) systemic vascular resistance (SVR), transcranial Doppler ultrasonography,

phases of gastric secretion, 281 96–7, 120, 147–8, 152 200
preoperative fasting, 282–3 systolic blood pressure (SBP), 148 transferases, 19
substances secreted by, 279–80 transfusion-related acute lung injury
time taken for gastric emptying, 282 tachycardia (TRALI), 348
See also vomiting blood pressure calculation, 148 transfusion-related
stress response, 384–6 Bowditch effect, 122 immunomodulation (TRIM),
stroke effects on cardiac output (CO), 365
Bamford classification, 189 119 traumatic brain injury (TBI), 204–5
stroke volume (SV), 120, 152 telencephalon (cerebrum), 186 Treppe effect, 122
stroke volume (SV) equation, 119 temperature regulation, 2 tricarboxylic acid cycle. See citric acid
stroke volume index (SVI), 122 adverse efects of hypothermia, cycle
subarachnoid space, 188 432–3 tuberculosis, 364
subdural space, 188 adverse effects of intraoperative
subthalamus, 187 hypothermia, 433 unipolar neurons, 184
sulphonamide drugs, 301 effects of anaesthesia on normal urea
superoxide anion (O2• ), 102 mechanisms, 431–2 handling by the kidney, 322
surfactant. See pulmonary surfactant effects of exercise, 179 urinary system, 2
surgical risk mechanisms, 431
and V_ O2 max , 180–1 role of the venous system, 158 valproate, 301
Surviving Sepsis Campaign guidelines, temporal lobe of the brain, 186 Valsalva manoeuvre, 171–3
163 testosterone, 387 varicella zoster, 361
suxamethonium, 20, 234–5, 239, 326, tetanus, 361 vascular endothelium
419, 424 thalamus, 94, 186 role in haemostasis, 337
suxamethonium apnoea, 20 thalassaemia, 348 vasoactive substances
swallowing, 276–7 thalidomide, 410 synthesis in the endothelium, 157
Swan–Ganz catheter, 100 thiopentone, 195, 231, 365–6, 410, vasopressin. See antidiuretic hormone
sympathetic blockade, 267 419 (ADH)
sympathetic nervous system, 184–5, thoracic cage compliance, 82 veins, 158
265–7, 273 thromboelastography, 343 vena cava
synapses thrombolysis, 343–4 compression in pregnancy, 159–60
definition, 228 thrombosis venous cannulation, 164–5
ionotropic receptors, 229–30 risk in polycythaemia, 353 venous pressure
metabotropic receptors, 232 thymine (T), 8 effects on resistance to blood flow,
neurotransmitter reuptake thymus, 358 160
inhibitors, 232 thyroid gland venous pressure waveforms
neurotransmitters, 228–9 anaesthesia for thyroid surgery, features of the CVP waveform,
termination of neurotransmission, 394–5 161
232 Graves’ disease, 394 venous return to the heart, 158–60
types of, 228 hormones synthesized by, 392 venous system, 158–60
See also neuromuscular junction physiological effects of T3 ventilation
(NMJ). (triiodothyronine), 392 alveolar ventilation, 46
synaptic cleft regulation of plasma thyroid definition of dead-space ventilation,
release of neurotransmitters, 229 hormones, 393–4 46
syndrome of inappropriate ADH synthesis of T3 and T4, 392–3 distinction from oxygenation, 104
secretion, 321 thyroid-stimulating hormone (TSH), minute ventilation, 46
syringomyelia, 211 387, 389–90 ventilation control
systemic circulation, 141 thyrotropin-releasing hormone anatomical sites involved, 92
changes in blood flow, 142–3 (TRH), 387 effects of drugs on, 95
comparison with the pulmonary thyroxine, 387 neuronal feedback loops, 92
circulation, 141 tidal volume (VT), 50 respiratory centre inputs, 92–4
constituent parts, 141 in mechanically ventilated patients, role of the respiratory centre,
functions, 141 51 92
See also arterial system; venous TLCO (lung transfer factor for CO), ventilation–perfusion matching,
system. 43 71
systemic inflammatory response tonsillectomy, 22 ventilation–perfusion mismatch, 21,
syndrome (SIRS), 357 total lung capacity (TLC), 50 65–6, 70–1, 109
systemic lupus erythematosus, 310, trait (phenotype), 10–11 ventilation–perfusion ratio, 69–70
364 tranexamic acid, 344 ventilator-associated lung injury, 51
446
Index
ventilatory response volatile anaesthetics, 41–2, 149, 195, measurement within body
to hypercapnoea, 94 239 compartments, 316
to hypoxaemia, 94 voluntary control of breathing, 94 regulation in the body, 2
ventral respiratory group (VRG) of volutrauma, 51 Wernicke’s area, 186
neurons, 92 vomiting, 283–4 West zones of the lung,
ventricular septal defect, 65 von Willebrand disease, 341 72–3
vertebral arteries, 188–9 von Willebrand factor (vWF), 157 Willis, circle of, 188–9
vital capacity (VC), 50 Windkessel effect, 150
vitalograph, 56 warfarin, 366–7 work of breathing, 88–91
vitamin D, 396–7 waste products
V_ O2 max removal from the body, 2 X-linked recessive inheritance,
and surgical risk, 180–1 water 11–12
meaning of, 179–80 distribution in the body, xenon-133 isotope, 200
vocal cords, 21 316 xenon anaesthesia, 231–2
447

Fisiologia para Anestesiologos

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Fisiologia para Anestesiologos

Uploaded by

Copyright:

Available Formats

Basic Physiology for

David Chambers BMBCh MChem DPhil

Christopher Huang BMBCh PhD DM

Gareth Matthews MA PhD MSB

Cambridge University Press is part of the University of Cambridge.

24. Ventilatory failure 104

51. Skeletal muscle 236

Section 11 – Environmental physiology

65. Renal regulation of water and electrolyte

ACE angiotensin-converting enzyme ETT endotracheal tube

PTH parathyroid hormone SBP systolic blood pressure

 Skeletal system, the framework of the body What is homeostasis?

(a) Negative-feedback loop (b) Negative-feedback loop for PaCO2

Sensor PaCO2 sensed by central

Respiratory muscles increase

Homeostasis is a dynamic phenomenon: usually,  Extrinsic homeostatic mechanisms occur at a

Sensor Nerve impulses from cervix

Control centre Brain stimulates pituitary

Inner mitochondrial matrix

Rough endoplasmic reticulum Smooth endoplasmic reticulum

Lysosome Secretory vesicles

Figure 2.1 Layout of a typical cell.

in cells that produce a large amount of protein; glycosylation and phosphorylation

5ⴕ end Double helix structure

section of DNA – this process is called

(a) Autosomal dominant (b) Autosomal recessive (c) X-linked recessive

Affected Unaffected ‘Carrier’ ‘Carrier’ Unaffected ‘Carrier’

50% chance 25% 25% 25% 25%

Most inherited characteristics do not obey the Further reading

Hydrophilic outer membrane

Hydrophilic inner membrane

Figure 4.2 Means of transport across the cell membrane.

Macromolecule Figure 4.4 Mechanism of endocytosis.

Zinc ion at the active site

 Organic. When the cofactor is organic, it is called

Describe the functional anatomy

Airway generation Figure 6.1 Generations of the

are responsible for conducting air from the

Figure 6.2 Increasing cross-sectional

Conducting zone Respiratory zone

– The trachea divides into the right and left main

▪ Bronchodilatation results from  Type II pneumocytes. These cover the remaining

(a) At rest (end-expiration)

External intercostal External intercostal

PB = atmospheric pressure (cmH2O) Ppl = –8

PA = alveolar pressure (cmH2O)

Pel = inward elastic recoil (cmH2O) (c) End inspiration

Ppl = intrapleural pressure (cmH2O)

defend against microorganisms. This compares – Inactivation of noradrenaline, serotonin,

‘Tense’ conformation ‘Relaxed’ conformation Figure 7.1 The reversible binding of O2

Figure 7.2 The oxyhaemoglobin

What is cooperative binding?  Once the fourth O2 has bound, Hb is said to be

Figure 7.3 Displacement of the P50 of

 methaemoglobin (MetHb); – HbF is the normal variant during fetal life

Clinical disease occurs through two main

Figure 7.4 Oxymyoglobin and

Owing to its single globin chain, myoglobin is

Hb molecule, thereby reducing the metabolically active tissues. According to

Table 8.1 Approximate proportions of CO2 transport forms.

Dissolved Carbamino compounds Bicarbonate

CO2 content (mL CO2/100 mL blood)

Key equation: rate of alveolar diffusion

Figure 9.1 Diffusion of O2, N2O and

Skeletal system, the framework of the body What is homeostasis?

Homeostasis is a dynamic phenomenon: usually, Extrinsic homeostatic mechanisms occur at a

Organic. When the cofactor is organic, it is called

▪ Bronchodilatation results from Type II pneumocytes. These cover the remaining

What is cooperative binding? Once the fourth O2 has bound, Hb is said to be

methaemoglobin (MetHb); – HbF is the normal variant during fetal life

‘dead space’? Size of patient – V Anat

Alveolar pressure is abnormally high; for

A general decrease in alveolar surface tension.